CN1751047A - Triazole compounds useful in therapy - Google Patents

Triazole compounds useful in therapy Download PDF

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Publication number
CN1751047A
CN1751047A CNA2004800047089A CN200480004708A CN1751047A CN 1751047 A CN1751047 A CN 1751047A CN A2004800047089 A CNA2004800047089 A CN A2004800047089A CN 200480004708 A CN200480004708 A CN 200480004708A CN 1751047 A CN1751047 A CN 1751047A
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compound
milliliters
chloro
azepines
tetrahydrochysene
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J·S·布赖恩斯
P·S·约翰逊
T·里克曼斯
A·斯托比
R·J·拉塞尔
C·P·韦曼
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SmithKline Beecham Ltd
Pfizer Inc
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Abstract

A compound of formula (I), or a pharmaceutically acceptable derivative thereof, wherein V represents -(CH2)d(O)e-, -CO-, or -CH(C1-6 alkyl)-; W is -0-, -S(O)a , or -N(R<1>')-R<1> represents H, C 1-6 alkyl, (CH2)bCOR<2>, CO(CH2)bNR<2>R<3>, S02R<2>, (<CH>2 )cOR<2>, (CH2)c,NR<2>R<3>, or (CH2)bhet<1>; het<1> represents a saturated or unsaturated heterocycle of from 3 to 8 atoms containing one or more heteroatoms selected from O, N, or S, optionally substituted with C 1-6 alkyl; X and Y independently represent H, C 1-6 alkyl, halogen, OH, CF3, OCF3, OR<4>; Z represents -(CH2)f(O)g , -CO- or -CH(C 1-6 alkyl)-; Ring A represents a 4-7 membered, saturated N-containing heterocycle, optionally substituted with OH, and in which optionally at least one ring N is substituted with O;Ring B represents phenyl or a 4-7 membered unsaturated N-containing heterocycle, optionally substituted with OH, halogen, CN, CONH2, CF3, OCF3, and in which optionally at least one ring N is substituted with O; R<2> and R<3> independently represent H, C 1-6 alkyl [optionally substituted with OH, halogen,N(C 1.6 alkyl)2, or C 1.6 alkyloxy], C 1.6 alkyloxy, N(C 1-6 alkyl)2, or [C 3-8 cycloalkyl]; or R<2> and R<3>, together with the nitrogen atom to which they are attached independently represent a heterocycle of from 3 to 8 atoms, optionally substituted with C 1-6 alkyl;R4 represents straight or branched C 1-6 alkyl, a and c independently represent 0, 1, or 2; b, e and g independently represent 0 or 1; d and f independently represent 1 or 2;are useful in the treatment of dysmenorrhoea.

Description

The triazole compounds that can be used for treating
Technical field that the present invention belongs to
The present invention relates to the compounds that can be used for treating and the preparation method of these derivatives, can be used for preparing these derivatives intermediate, contain the composition and use thereof of these derivatives.
Prior art
Japanese patent application is described the triazole quinoxaline that can be used as anti-allergic agent and anti-inflammatory agent No. 09328484.Japanese patent application is described the triazole quinoxaline that can be used as allergic agent and anti-inflammatory agent No. 09132576.No. the 06135965th, Japanese patent application is described and be can be used for treating and the triazole quinoxaline of Ammonium Glycyrrhizate, inflammation and PAF relative disease.The Japanese patent application case is described the triazole quinoxaline of useful as drug and agrochemicals intermediate for No. 06128262.
Find that The compounds of this invention has useful pharmaceutical properties.The compounds of this invention can be used for treating aggressive behaviour, Alzheimer, anorexia nervosa, anxiety, anxiety disorder, asthma, arteriosclerosis, autism, cardiovascular diseases (comprises stenocardia, arteriosclerosis, hypertension, cardiac failure, oedema, hypernatremia), cataract, the central nervous system disease, cerebrovascular ischemia, liver cirrhosis, cognitive disorder, hypercortisolism, dysthymia disorders, diabetes, dysmenorrhoea (primary and Secondary cases), vomiting (comprising motion sickness), endometriosis, gastrointestinal tract disease, glaucoma, gynaecopathia, heart trouble, intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), ischemic, ischemic heart disease, lung tumor, dysuria, middle pain, tumour, pnehrotoxicity, non insulin dependent diabetes, fat, obsession, high intraocular pressure, disease (preclampsia) before the eclampsia, premature ejaculation, premature labor (preterm labor), tuberculosis, Raynaud disease, ephrosis, kidney depletion, the sex sexual dysfunction, septic shock, somnopathy, spinal cord injury, thrombosis, genitourinary tract infects or urinary calculus.
Interesting especially person is following disease or disease disease: disease, premature ejaculation, premature labor (preterm labor) and Raynaud disease before anxiety, cardiovascular diseases (comprising stenocardia, arteriosclerosis, hypertension, cardiac failure, oedema, hypernatremia), dysmenorrhoea (primary and Secondary cases), endometriosis, vomiting (comprising motion sickness), intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), middle pain, the eclampsia.
Especially, The compounds of this invention has the Hou Yejiayasu antagonistic activity, can be used for treating dysmenorrhoea difficulty (primary and Secondary cases).
The height demand that can't satisfy is still arranged on the paramenia field, estimate among the menstruation women high to 90% influenced to a certain degree.Can't work or be engaged in other activity up to 42% women because of dysmenorrhoea, estimated result causes the working hours (the cap loss amount of money is up to about 2,000,000,000 dollars) of the annual loss about 600,000,000 of entire United States.
Abdomen dysmenorrhoea is because uterus muscle hyperactivity and uterine blood flow minimizing institute cause.These pathophysiological change result causes stomachache, and stomachache comes to the back and shank to external irradiation.May cause the women to feel to feel sick, have a headache and have a sleepless night.These situations are referred to as dysmenorrhoea, are classified as primary dysmenorrhoea or secondary dysmenorrhea.
When failing to identify any primary dysmenorrhoea that is diagnosed as when causing this kind situation unusually.Account for up to 50% women crowd.And when the potential gynecological diseases, for example when endometriosis, pelvis inflammatory diseases (PID), hysteromyoma or cancer, then will be diagnosed as secondary dysmenorrhea.The patient who is diagnosed as secondary dysmenorrhea only accounts for suffers from dysmenorrhoea women's about 25%.Dysmenorrhoea also may occur in conjunction with excessive menstruation, accounts for gynaecology's outpatient service patient's about 12% that sees a doctor.
Suffer from the primary dysmenorrhoea women at present and be to use non-steroidal anti-inflammatory drugs (NSADI ' s) or oral contraceptive treatment.And the secondary dysmenorrhea case, may need undergos surgery corrects the potential gynecological diseases.
The circulation of blood Hou Yejiayasu concentration of suffering from the dysmenorrhoea women is higher than the Hou Yejiayasu concentration of the healthy women of identical time of menstrual cycle.Pharmacological action in uterus Hou Yejiayasu acceptor inhibition Hou Yejiayasu can prevent dysmenorrhoea.
Summary of the invention
According to the invention provides a kind of formula (I) compound
Figure A20048000470800121
Or its pharmaceutically acceptable derivates, wherein
V represents-(CH 2) d(O) e-,-CO-or-CH (C 1-6Alkyl)-;
W is-O-,-S (O) a-or-N (R 1)-
R 1Expression H, C 1-6Alkyl, (CH 2) bCOR 2, CO (CH 2) bNR 2R 3, SO 2R 2, (CH 2) cOR 2, (CH 2) cNR 2R 3Or (CH 2) bHet 1
Het 1Expression contains the heteroatoms of one or more O of being selected from, N or S and randomly with C 1-6Saturated or the unsaturated heterocycle that contains 3 to 8 atoms that alkyl replaces;
X and Y represent H, C independently 1-6Alkyl, halogen, OH, CF 3, OCF 3, OR 4
Z represents-(CH 2) f(O) g-,-CO-or-CH (C 1-6Alkyl)-;
Ring A represents randomly to replace with OH and wherein choose wantonly the saturated N of the containing heterocycle of 4-7 person that at least one ring N is replaced by O;
Ring B represents phenyl or randomly with OH, halogen, CN, CONH 2, CF 3, OCF 3Replace, and wherein randomly at least one encircles the unsaturated N of the containing heterocycle of 4-7 person that N is replaced by O;
R 2And R 3Represent H, C independently 1-6Alkyl is [optional by OH, halogen, N (C 1-6Alkyl) 2Or C 1-6Alkoxyl group replaces], C 1-6Alkoxyl group, N (C 1-6Alkyl) 2Or [C 3-8Cycloalkyl];
Or R 2And R 3Optional with the common expression of its attached separately nitrogen-atoms by C 1-6The heterocycle that contains 3-8 atom that alkyl replaces;
R 4Expression straight or branched C 1-6Alkyl,
A and c represent 0,1 or 2 separately;
B, e and g represent 0 or 1 separately;
D and f represent 1 or 2 separately.
In the preamble definition, halogen is represented fluorine, chlorine, bromine or iodine.Contain the alkyl (unless special instructions) of required carbonatoms otherwise can be straight or branched.Example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.The cycloalkyl example comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.The alkoxyl group example comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.
Including in the heterocyclic of " heterocycle " definition is pyrryl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl group, oxadiazole base, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indyl, pseudoindoyl, quinolyl, isoquinolyl, benzimidazolyl-, quinazolyl, 2,3-phthalazinyl, benzoxazolyl and quinoxalinyl, and partially or completely saturated version and azetidinyl, pyrrolidyl, piperidyl, piperazinyl, high piperazinyl, oxygen azepine cyclic group in heptan (oxazepanyl) and morpholinyl.
Preferred compound group wherein is suitable for following one or more of compound:
(i) W is NR 1
(ii) R 1Be C 1-6Alkyl, and more preferably methyl, sec.-propyl or normal-butyl;
(iii) R 1Be H;
(iv) R 1Be (CH 2) bHet 1
(v) het 1For pyrrolidyl, piperidyl, morpholinyl, azetidinyl, oxygen azepine cyclic group in heptan, pyrimidyl, pyridyl, thiazolyl or imidazolyl (are chosen wantonly with C 1-6Alkyl replaces)
(vi) R 1Be CO (CH 2) bNR 2R 3
(vii) R 2For morpholinyl or pyrimidyl (optional with C 1-6Alkyl is [optional with OH, halogen, N (C 1-6Alkyl) 2Or C 1-6Alkoxyl group replaces] or NMe 2Replace).
(viii) R 2And R 3The nitrogen attached with it represents that jointly morpholinyl, pyrrolidyl, piperazinyl, azetidinyl, THP trtrahydropyranyl, pyrimidyl or piperidyl are (optional with C 1-6Alkyl replaces)
(ix) V is-(CH 2) d(O) e-;
(x) Z is-(CH 2) f(O) g-;
(xi) d is 1;
(xii) e is 0;
(xiii) f is 1;
(xiv) g is 0;
(xv) X is H;
(xvi) Y is 4 positions (according to formula (I) numbering) at its attached phenylene ring;
(xvii) Y is a halogen, is preferably chlorine;
(xviii) Y is an alkoxyl group, is preferably methoxyl group;
(xix) Y is an alkyl, is preferably methyl;
(xx) Y is CF 3Or OCF 3
(xxi) Z is (CH 2) d(O) e
(xxii) e is 0;
(xxiii) d is 1;
(xxiv) ring A is bonded to ring B by the nitrogen-atoms that encircles A;
(XXV) ring A is piperidyl (optional replaced by OH, and optional at least one N replaces with O);
(xxvi) ring B is that pyridyl is (optional with one or more OH, halogen, CN, CONH of being selected from 2, CF 3, OCF 3Group replace, and optional at least one ring N replaces with O), be preferably the 2-pyridyl;
(xxvii) ring B is that (the selectivity warp is with one or more OH, halogen, CN, CONH of being selected from for pyrimidyl 2, CF 3, OCF 3Group replace, and at least one ring N of selectivity is through replacing with O), be preferably the 2-pyrimidyl;
(xxviii) n is 1;
(xxix) n is 2.
Preferably be according to compound of the present invention:
8-chloro-5-methyl isophthalic acid-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene tri hydrochloride;
8-chloro-5-sec.-propyl-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene tri hydrochloride;
1-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-the ethyl ketone dihydrochloride;
8-chloro-5-methylsulfonyl-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene;
8-chloro-5-methyl isophthalic acid-(1-pyrimidine-2-base-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene;
8-chloro-5-methylsulfonyl-1-(1-pyrimidine-2-base-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene;
13-chloro-8-methyl-3-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-2,4,5,8-four azepines-three ring [9.4.0.0 *2,6 *] 15 carbon-1 (11), 3,5,12, the 14-pentaene;
13-chloro-3-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-8-Evil-2,4,5-three azepines-three ring [9.4.0.0 *2,6 *] 15 carbon-1 (11), 3,5,12, the 14-pentaene;
1-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-2-dimethylamino ethyl ketone;
[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-morpholine-4-base-ketone;
(+) or (-)-8-chloro-5-(4-methyl-morpholine-2-ylmethyl)-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene;
8-chloro-5-pyrimidine-2-base-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene;
8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-sulfonic acid dimethylformamide;
8-chloro-1-(1-pyrimidine-2-base-piperidin-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-sulfonic acid dimethylformamide;
13-chloro-9-methyl-3-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-2,4,5,9-four azepines-three ring [9.4,0.0 *2,6 *] 15 carbon-1 (11), 3,5,12, the 14-pentaene; And
13-chloro-8-methyl-3-(1-pyrimidine-2-base-piperidin-4-yl)-2,4,5,8-four azepines-three ring [9.4.0.0 *2,6 *] 15 carbon-1 (11), 3,5,12, the 14-pentaene.
A kind of formula (I is provided in addition *) compound,
W is O, S or NR 1
R 1Expression H, C 1-6Alkyl ,-(CH 2) a-[C 3-8Cycloalkyl], phenyl, benzyl, pyridyl, pyrimidyl ,-COR 2,-CO 2R 2,-CO-(CH 2) a-NR 2R 3,-SO 2R 2,-(CH 2) b-OR 2,-(CH 2) b-NR 2R 3, or contain the heteroatomic saturated heterocyclic that contains 3 to 8 atoms of one or more O of being selected from, N and S;
X and Y represent H, halogen, OH, CF independently 3, OCF 3, R 4,-(CH 2) d-CONR 4R 5,-(CH 2) d-CN ,-(CH 2) d-SO 2NR 4R 5,-(CH 2) d-NR 4SO 2Me ,-(CH 2) d-COR 4,-(CH 2) d-OCOR 4,-(CH 2) d-NHCOR 4,-(CH 2) d-NR 4COR 5,-(CH 2) d-OR 6Or-(CH 2) d-CO 2R 6
Ring A represents piperidyl, piperazinyl, pyrrolidyl or azetidinyl;
Ring B represents that phenyl, pyridyl or pyrimidyl are (optional with one or more halogen, CN, CONH of independently being selected from 2, CF 3, OCF 3, R 7And-(CH 2) f-OR 8Group replace);
R 2, R 3, R 4, R 5And R 7Represent H, straight or branched C independently 1-6Alkyl ,-(CH 2) c-[C 3-8Cycloalkyl]-, phenyl, benzyl, pyridyl or pyrimidyl;
Or R 2And R 3, or R 4And R 5With heterocycle that contains 3 to 8 atoms of the common expression of its attached separately nitrogen;
R 6And R 8Represent H, straight or branched C separately 1-6Alkyl ,-(CH 2) c-[C 3-8Cycloalkyl]-,-(CH 2) e-NR 4R 5,-(CH 2) e-OR 4, phenyl, benzyl, pyridyl or pyrimidyl;
N=0,1 or 2;
A, c, d and f are selected from 0,1,2 or 3 separately respectively;
B and e are selected from 2 or 3 respectively.
The salt, solvate, mixture, polymorphic form, prodrug, stereoisomers, rotamerism thing, tautomeric form and the isotropic substance version that comprise formula (I) compound according to the pharmaceutically acceptable derivates of formula of the present invention (I) compound.The pharmaceutically acceptable derivates of preferred formula (I) compound comprises salt, solvate, ester class and the amides of formula (I) compound.More preferably the pharmaceutically acceptable derivates of formula (I) compound is salt and solvate.
The pharmacy acceptable salt class of formula (I) compound comprises its acid salt and alkali salt.
Suitably acid salt is by the sour formed acid salt that can form non-toxic salt.Example comprises acetate, aspat, benzoate, benzene sulfonate, bicarbonate/carbonate, hydrosulfate, borate, camsilate, Citrate trianion, EDTA sulfonate, ethane sulfonate, formate, fumarate, Gu Lusaite (gluceptate) salt, gluconate, glucuronate, hexafluorophosphate, sea this hydrochlorate (hibenzate), hydrochloride/muriate, hydrobromate/bromide, hydriodate/iodide, isethionate, D-lactate and L-lactic acid salt, malate, maleic acid salt, malonate, mesylate, Methylsulfate, naphthoate, the 2-naphthalenesulfonate, nicotinate, nitrate, Orotate, oxalate, palmitate, crust nurse hydrochlorate (palmoate), phosphoric acid salt, hydrophosphate, dihydrogen phosphate, husky card phosphoric acid salt, stearate, succinate, vitriol, D-tartrate and L-tartrate, tosylate and trifluoroacetate.Suitable especially salt is the benzene sulfonate derivative of The compounds of this invention.
Suitably alkali salt is the alkali salt that is formed by the alkali that can form non-toxic salt.Example comprises aluminium, spermine acid, this slag suffering (benzathine), calcium, choline, diethylamide, glycol amine, glycine, relies amino acid, magnesium, meglumin, thanomin, potassium, sodium, Trometamol and zinc salt.
Relevant suitably the summary of salt can be with reference to Stahl and Wermuth, medicine salt handbook: character, selection and use, Willie-VCH, Germany, Wei Han (2002).
Convenient solution and suitable predetermined acid or the alkali and prepare via hybrid (I) compound of the salt of the pharmaceutically acceptable property of formula (I) compound.Salt can be collected by precipitation in the solution and by filtering; Or reclaim by the evaporative removal solvent.The degree of ionization of salt is changed to almost unionized by complete ionization.
The compounds of this invention can be without solvation form and solvation form and exist.Term " solvate " is used for describing the molecular complex that comprises The compounds of this invention and one or more pharmaceutically acceptable solvent molecules (for example ethanol) herein." hydrate " speech uses during for water when this solvent.
Include for example mixture, the medicine-host's inclusion mixture of inclusion compound in the scope of the invention, wherein opposite with the aforementioned solvents thing, medicine and host exist with stoichiometry or nonstoichiometry.Also comprise the medicinal composition that contains two or more organic composition and/or inorganic components, can be stoichiometry or nonstoichiometry.The gained mixture can be ionization, partial ionization or unionized as a result.The summary of relevant this kind mixture can be with reference to J Pharm Sci, 64(8), 1269-1288 author Haleblian (in August, 1975).
Hereinafter all address formula (I) compound and pharmaceutically acceptable derivates thereof and comprise and address its esters, solvate and mixture, and the solvate and the mixture of its esters.
The compounds of this invention comprises as formula (I) compound of definition herein, as its polymorph, prodrug and the isomer (comprising optical isomeric compound, rotamerism thing and compounds tautomeric) of hereinafter definition and through isotope-labeled formula (I) compound.
As shown here, the whole polymorphs as formula (I) compound of preamble definition are contained in the present invention.
Scope of the present invention also comprises " prodrug " of so-called formula (I) compound.Therefore, some formulas (I) compound derivatives with few pharmacologically active or parmacodynamics-less activity can be worked as in the administration body or be transformed into during body surface and had required active formula (I) compound, for example hydrolytic rupture and changing.These derivatives are referred to as " prodrug ".The further information of relevant use premedicant can be with reference to " prodrug be as novel delivery system ", the 14th phase, ACS symposial series (T Higuchi and W Stella) and " but biological reversion carrier of medicinal design ", Pa Jiamo (Pergamon) press, 1987 (editor E B Roche, American Pharmaceutical Association).
According to prodrug of the present invention, for example can be via some part [for example described " prodrug design " with well known by persons skilled in the art being referred to as " forerunner's part ", author H Bundgaard (Ai Suoweier (Elsrvier), 1985)] replace the suitable functional group who is present in formula (I) compound and make.
Some prodrug examples according to the present invention comprise:
(i) its Chinese style (I) compound contain the carboxylic-acid functional base (COOH), its ester, for example be with (C 1-C 8) alkyl displacement hydrogen;
(ii) its Chinese style (I) compound contains alcohol functional group (OH) time, its ether for example is with (C 1-C 6) alkyloyloxyethyl methyl displacement hydrogen; And
(iii) its Chinese style (I) compound contains primary amino or secondary amino group functional group (NH 2Or-R ≠ H), its acid amides for example is with (C to NHR herein 1-C 10) alkyloyl replaces one or two hydrogen.
Other displacement group example and other prodrug classification example according to aforementioned example can be with reference to aforementioned reference.
Last some formula (I) compound itself can be used as the prodrug of other formula (I) compound.
Also be included in the meta-bolites of formula (I) compound that in vivo forms within the scope of the present invention.
Formula (I) compound that contains one or more asymmetric c atoms can be two or more stereoisomerses and exist.If formula (I) compound contains thiazolinyl or alkenylene, then how much suitable/anti-(or Z/E) isomers are possible; When compound for example contains ketone group or oximido or during the aromatic series part, tautomerism (" tautomerization ") may appear.Then the simplification compound can have more than one type of isomerization.
In the scope of the invention, include whole stereoisomerses, rotamerism thing and the tautomeric form of formula (I) compound, comprise the compound that has more than a kind of isomerization type, and the mixture of one or more compounds.Also comprise acid salt or alkali salt, counter ion are for example D-lactate or bad amino acid of L-or for example DL-tartrate or the acid of DL-spermine of racemoid of opticity herein.
Suitable/anti-isomer can be by the well-known routine techniques of those skilled in the art for example fractional crystallization and chromatography and purifying.
The technology of the indivedual enantiomers of conventional preparation/separation comprises by suitable optical purity precursor chirality synthesizes, or for example uses chirality HPLC and by the racemate resolution of (racemoid of salt or derivative).
In addition, racemoid (or racemoid precursor) can react with suitable activity of optically active compounds is for example pure; Or when formula (I) compound contains acidity or basic moiety, can with for example tartrate or the reaction of 1-phenyl ethyl amine of acid or alkali.Gained diastereoisomer mixture can separate by chromatography and/or fractional crystallization as a result, diastereoisomer one or the two can utilize the well-known method of those of skill in the art to change into corresponding pure enantiomer.
Chipal compounds of the present invention (and chirality precursor) can use chromatography to be generally HPLC to enrich form with enantiomerism and obtain, chromatography is on asymmetric resin, moving is to be generally heptane or hexane contains 0 to 50% Virahol by hydrocarbon mutually, be generally 2 to 20%, and 0 to 5% alkylamine, be generally 0.1% diethylamide and form.Elutriant concentrates and can obtain to enrich mixture.
The stereoisomers aggregate can separate by those skilled in the art's routine techniques, for example with reference to " stereochemistry of organic compound ", and author E L Eliel (Valleylad Inc., New York, 1994).
The present invention comprises that also the pharmaceutically acceptable isotropic substance of whole formulas (I) compound changes, its one or more atoms are having equal atomicity, replace but have with being seen nucleidic mass of nature or total mass number are different usually the nucleidic mass or the atom of total mass number.
Be fit to include in the isotropic substance example of The compounds of this invention comprise hydrogen isotope as 2H reaches 3H; Carbon isotope as 11C, 13C reaches 14C; Nitrogen isotope as 13N reaches 15N; Oxygen isotope as 15O, 17O reaches 18O; Phosphorus isotope as 32P; Sulfur isotope as 35S; Fluorine isotope as 18F; Iodine isotope as 123I reaches 125I; And chlorine isotope as 36Cl.
Some through isotope-labeled formula (I) compound for example the isotopic compound of binding radioactivity can be used for medicine and/or the research of substrate tissue distribution.The radio isotope tritium that is 3H, and carbon-14 that is 14C is because therefore combination and convenient detection easily be particularly useful for this purpose.
With heavier isotropic substance for example deuterium that is 2H replaces because metabolism claims qualitative higherly, and for example in vivo the transformation period is long or the dosage demand is lower, therefore can obtain certain treatment advantage, is preferred under some situation.
The isotropic substance of use emission positron for example 11C, 18F, 15O reaches 13N replaces, and can be used for checking that the substrate acceptor occupies the positron emission tomography of situation (PET) research.
Normally prepare through isotope-labeled formula (I) compound by those skilled in the art's the routine techniques of knowing, or embodiment and the described similar approach of preparation example by following, using suitably, the isotope-labeled reagent of process substitutes the reagent of the previous un-marked that adopts and prepares.
Embodiment
Pharmaceutically acceptable solvate according to the present invention comprises the solvent that crystallization solvent wherein can isotropic substance replaces, for example D 2O, d 6-acetone and d 6-DMSO.
The method of a kind of manufacturing formula (I) compound also is provided according to the present invention, and this method comprises:
A) formula (II) compound and acid catalyst reaction
Figure A20048000470800211
Wherein encircle A and ring B and V, W, X, Y, Z and n group definition such as preceding;
B) formula (III) compound
Figure A20048000470800212
React with formula (IV) compound
Figure A20048000470800213
Wherein encircle A and ring B and V, W, X, Y, Z and n group definition such as preceding.Z ' expression leavings group is halogen for example;
C) W when compound (I) represents NR 1The time, the formula V compound
React with formula (VI) compound
Figure A20048000470800221
Wherein encircle A and ring B and R 1, V, X, Y, Z and n group definition such as preceding, and Z " expression leavings group halogen for example; Or
D) W when compound (I) represents NR 1The time, the formula V compound
Figure A20048000470800222
React with formula (VII) compound
Figure A20048000470800223
Wherein encircle A and ring B and R 1, V, X, Y, Z and n group definition such as preceding;
E) formula (XIII) compound
Figure A20048000470800224
React with formula (XXIV) compound
Figure A20048000470800225
Wherein encircle A and ring B and V, W, X, Y and Z group definition such as preceding;
F) formula (XIII) compound
React with formula (XXV) compound
Figure A20048000470800232
Wherein encircle A and ring B and V, W, X, Y and Z group definition such as preceding.
Unless in making separate stipulations herein, otherwise:
WSCDI represents 1-(3-dimethylaminopropyl)-3-ethyl first imide hydrochloride;
DCC represents N, N '-dicyclohexyl first imide;
HOAT represents 1-hydroxyl-7-azepine benzotriazole;
HOBT represents the I-hydroxybenzotriazole hydrate;
PyBOP Expression benzotriazole-1-base oxygen base three (pyrrolidino) phosphonium hexafluorophosphate;
PyBrOP Expression bromo-three-pyrrolidino-phosphonium hexafluorophosphate;
HBTU represents O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-phosphofluoric acid urea.
To Shan Shi reagent (Mukaiyama ' s reagent) expression 2-chloro-1-methyl iodate pyridine;
KHMDS represents two (trimethyl silyl) amidation potassium;
The peaceful alkali of the Chinese (H ü nig ' s base) expression N-ethyl diisopropyl amine;
Et 3N represents triethylamine;
NMM represents N-methylmorpholine;
HMDS represents hexamethyldisilazane;
BINAP represents 2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene;
Dba represents dibenzalacetone;
Boc represents tertbutyloxycarbonyl;
CBz represents carbobenzoxy-(Cbz);
P-TSA represents right-toluenesulphonic acids
TBAF represents tetrabutyl ammonium fluoride
MeOH represents methyl alcohol, and EtOH represents ethanol, and EtOAc represents ethyl acetate;
THF represents tetrahydrofuran (THF), and DMSO represents methyl-sulphoxide, reaches DCM and represents methylene dichloride, and DMF represents N, and dinethylformamide, NMP are represented the N-N-methyl-2-2-pyrrolidone N-;
AcOH represents acetate, and TFA represents trifluoroacetic acid;
Me represents methyl, and Et represents ethyl;
Cl represents chlorine; And
OH represents hydroxyl.
The preparation of following response diagram formula (I) compound, unless indication separately in the response diagram, otherwise ring A and ring B and V, W, X, Y and n group definition such as preceding.When W is NR 1The time, (I ') expression (I).
Response diagram 1.1
Step (a): oxadiazole (II) and acid catalyst reaction acquisition formula (I) compound.Normally, the mode of carrying out of reaction, be via starting material and suitable acid catalyst for example p-TSA, trifluoroacetic acid or lewis acid catalyst such as magnesium chloride, for example 50-150 ℃ of 1 to 48 hour time of experience carries out randomly to use solvent such as dimethylbenzene, toluene or tetrahydrofuran (THF) to be heated to the temperature of rising.
Optimum condition is:
Amine (II) and catalyzer p-TSA continue 48 hours in 140 ℃ in dimethylbenzene; Or
Amine (II), trifluoroacetic acid continue 24 hours in 60 ℃ in tetrahydrofuran (THF).
Work as W=NR 1The time, then:
Response diagram 1.2
Z ' is OH or halogen, is generally Cl
The compound that is suitable as compound (VI) is for getting on the market or being that reference is known.
Step (b): amine (V) can be undertaken by standard method with the reaction of compound (VI).
Work as R 1=(CH 2) bCOR 2, CO (CH 2) bNR 2R 3, SO 2R 2The time, coupling normally can be carried out via the use following manner:
(i) acyl group/alkylsulfonyl/muriate (VI)+amine (V) and excess acid acceptor carry out in appropriate solvent; Or
(ii) acid (VI) is chosen wantonly in catalyzer with conventional coupler+amine (V) and is existed down, uses the excess acid acceptor to carry out in appropriate solvent; And
(iii) work as R 1During the expression aryl, aryl halide (VI)+amine (V) is chosen wantonly in catalyzer and is existed down, carries out in appropriate solvent with the excess acid acceptor.
Representative condition is as back:
Acidylate/sulfonylation, Z '=Cl
(i) excessive acyl group/SULPHURYL CHLORIDE (VI) (producing in original position), for example Et of quantity tertiary amine is chosen and crossed to 1 equivalent amine (V) wantonly 3N, the peaceful alkali of the Chinese or NMM in DCM or THF, carry out through 1 to 24 hour without heating.
Optimum condition is:
Amine (V), 1.1-3.0 angelic acid/SULPHURYL CHLORIDE (VI), 1.5-3 equivalent NMM, Et 3N or pyridine carried out in the room temperature experience in DCM in 1-16 hour.
The formation of amido linkage, Z '=OH
(ii) excess acid (VI), WSCDI/DCC and HOBT/HOAT, 1 equivalent amine (V) and excessive NMM, Et 3N, the peaceful alkali of the Chinese carried out through 4 to 48 hours in room temperature in THF, DCM or EtOAc; Or
Excess acid (VI), PYBOP/PyBrOP/ be to Shan Shi reagent/HBTU, 1 equivalent amine (V) and excessive NMM, Et 3N, the peaceful alkali of the Chinese carried out through 4 to 24 hours in room temperature in THF, DCM or EtOAc.
Optimum condition is:
Amine (V), 2 equivalent HBTU, 2 angelic acid (R 1OH) in DCM in room temperature through 18 hours; Or
Amine (V) HOBT, WSCDI, Et 3N in DCM in room temperature through 18 hours.
Arylation (R 1 =aryl, heteroaryl), Z '=halogen atom
(iii) the mode of carrying out of the arylation of compound (V) is to be undertaken by the catalytic mutual coupled reaction of palladium, this reaction is to use suitable alkali (uncle's fourth sodium oxide), the suitable additives of catalytic amount for example 2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene and suitable palladium catalyst are in toluene, in the following experience 1 to 24 hour of elevated temperature, under inert atmosphere, carry out and obtain compound (I ').Compound (I ') can be via amine (V) and compound (VI) prepared in reaction in addition, this reaction be via elevated temperature for example 50 ℃-140 ℃ in appropriate solvent such as DMF, NMP or 1, in the 4-diox, carried out in about 1-48 hour with alkali such as the peaceful alkali heating of salt of wormwood, sodium bicarbonate or the Chinese.
Optimum condition is:
1-2.5 equivalent halogenide (VI), 1-2 equivalent salt of wormwood is in N, in the dinethylformamide in 50-95 ℃ through 4-18 hour; Or
1-2.5 equivalent halogenide (VI), the peaceful alkali of the 2-3 equivalent Chinese in 1, experience 18-48 hour in reflux temperature among 4-diox or the NMP; Or
1 equivalent halogenide (VI), 3.5 equivalent uncle fourth sodium oxides, 0.08 equivalent BINAP, 0.4 equivalent Pd (dba) 2 in toluene in 70 ℃ through 8 hours.
Alkanisation (R 1 =the alkyl that is substituted), Z '=halogen atom is preferablyBr OrCl
The mode of carrying out of the alkanisation of compound (V) be via with suitable alkylating agent R 1Z ' is in suitable tertiary amine (NMM, Et 3The peaceful alkali of the N or the Chinese) or alkali metal base (K 2CO 3, Cs 2CO 3) exist down, in appropriate solvent (MeCN, DMF), carry out in about room temperature.
Optimum condition is:
Amine (V) R 1Z ', the peaceful alkali of the excessive salt of wormwood or the Chinese in DMF in room temperature through 18 hours.
In addition, compound (I ') can prepare via approach shown in the following response diagram 1.3.
Figure A20048000470800271
Response diagram 1.3
The compound that is suitably used as compound (VII) is for getting on the market or being that reference is known.
Step (c): there are reaction down in amine (V) and excessive aldehyde/ketone (VII) and acquisition formula (I ') compound in reductive agent such as triacetyl oxygen sodium borohydride or sodium cyanoborohydride.This kind reaction can followingly be carried out:
Parent material temperature in 20 ℃-80 ℃ in appropriate solvent such as methylene dichloride stirs 1 to 48 hour time, or
Amine (V) and excessive compound (VII) and suitable lewis acid catalyst such as titanium tetrachloride or four different third titanium oxide heated 1-18 hour in appropriate solvent such as ethylene dichloride or ethanol in for example 50 ℃ of-100 ℃ of temperature; Then use suitable reductive agent such as sodium borohydride reduction intermediate imines/imines; Or with suitable catalyzer such as platinum oxide or palladium/hydrocarbon separating.
Optimum condition is:
Amine (V), 1-1.5 equivalent aldehyde/ketone (VII), 1-2.0 equivalent triacetyl oxygen sodium borohydride are chosen wantonly in the acetate existence to descend in room temperature through 2 hour time in methylene dichloride.
When ring B be by nitrogen atom bonding to encircling A, and W is when representing O or S, then:
Response diagram 2.1
The due care base that Prot represents nitrogen is Boc, CBz or carboxylamine propylene ester for example.Use the standard method of nitrogen-protecting group group, for example the described method of textbook (for example " organic synthesis protecting group " author T.W.Green and P.Wutz).Z " expression leavings group halogen for example.
The compound that is suitably used as compound (IV) is commercially available or is that reference is known.
As above step (b) is described carries out for the arylation of compound (III).
Optimum condition is:
1-2.5 equivalent halogenide (IV), 1-2 equivalent salt of wormwood is in N, in the dinethylformamide in 50 ℃ through 4-18 hour; Or
1-2.5 equivalent halogenide (IV), the peaceful alkali of the 2-3 equivalent Chinese in 1, experience 18-48 hour in reflux temperature among 4-diox or the NMP; Or
1 equivalent halogenide (IV), 3.5 equivalent uncle fourth sodium oxides, 0.08 equivalent BINAP, 0.4 equivalent Pd (dba) 2In toluene in 70 ℃ through 8 hours.
Step (d): the protection of sloughing of compound (IX) uses standard method to carry out, and for example is set forth in " organic synthesis protecting group ", author T.W.Greene and P.Wutz.
When Prot was Boc, preferred method was:
Hydrogenchloride in appropriate solvent as 1, in the 4-diox in room temperature through 1-16 hour; Or
The dichloromethane solution 1-2 of trifluoroacetic acid hour.
When Prot was CBz, preferred method was for using suitable palladium catalyst hydrogenolysis in solvent such as ethanol.
When Prot was carboxylamine propylene ester, optimum condition was the sulphur phenylformic acid, suitably palladium catalyst such as Pd 2(Dba) 3With suitable phosphine additive as 1, two (diphenylphosphino) butane of 4-in tetrahydrofuran (THF) through 20 minutes.
When ring B be by the N atomic linkage to encircling A, and expression NR 1The time, then:
Figure A20048000470800301
Response diagram 2.2
The due care base that Prot represents nitrogen is Boc, CBz or carboxylamine propylene ester for example.Use the standard method of nitrogen-protecting group group, for example the described method of textbook (for example " organic synthesis protecting group " author T.W.Green and P.Wutz).
Z ' represents leavings group (being generally Cl or OH).Z " expression halogen atom (being generally Cl).
The compound that is suitably used as compound (IV) is commercially available or is that reference is known.
Compound (IX ") can use abovementioned steps (b) and the described method preparation of step (c) by compound (IX ') usually.
Compound (III ') can use the described method preparation of abovementioned steps (d) by compound (IX ") usually.
Compound (I ') can use the described method preparation of abovementioned steps (b) by acylated compounds (III ') usually.
Be suitably used as compound (II) and (VIII) compound and be reference known or can following response diagram 3.1,3.2 and 3.3 shown in preparation.
Figure A20048000470800302
LG represents leaving group, is generally halogen atom and is preferably chlorine or bromine.
Response diagram 3.1
When ring A and ring B are during via the N atomic linkage, then:
LG represents leaving group, is generally halogen atom and is preferably chlorine or bromine.
Response diagram 3.2
The compound that is suitably used as compound (XI) is that reference is known, maybe can use the standard method preparation: for example phenylformic acid reduction (with reference to following preparation example 7) or benzonitrile reduction (with reference to following preparation example 10) or nitrobenzene reduction (preparation example 57 and 58).
When W represents NR 1The time:
Step (e): compound (X)/(XII) obtains compound (II)/(VIII) with excessive compound (XI) reaction respectively, this reaction is optional to be to carry out under excess base exists, alkali for example is that triethylamine, the peaceful alkali of the Chinese or NMM or salt of wormwood exist down as proton acceptor, choose wantonly in catalyzer (for example sodium iodide) and exist down, in suitable high boiler such as THF, toluene or DMF, in 50 ℃ to 100 ℃ temperature experience reaction in 1 to 48 hour.
Optimum condition is:
2.5 equivalent compound (XI) in THF in 50 ℃ through 48 hours; Or
1.1 equivalent compound (XI), 1.1 equivalent NMM or salt of wormwood, 0.5 equivalent sodium iodide in THF in 50 ℃.
When W represents O or S:
Step (e): compound (X)/(XII) and excessive compound (XI), exist down in alkali such as sodium hydride, hexamethyldisilazane potassium, n-Butyl Lithium or isopropylmagnesium chloride, in appropriate solvent such as THF, toluene or NMP, experience 1 to 24 hour in 0 ℃ to 50 ℃ thermotonus, obtain compound (II)/(VIII) respectively.
Optimum condition is:
1.1-3 equivalent compound (XI) and 1.1-2.5 equivalent sodium hydride in THF in 20 ℃ through 2 hours.
Work as W=NR 1, when reaching Z=CO, then
Figure A20048000470800321
Response diagram 3.3
Step (i): amine (XX) uses amine R via aminated compound (X) 1NH 2In solvent such as ethanol or tetrahydrofuran (THF), prepared in 5-72 hour in 25-75 ℃ of experience.
Optimum condition is:
Compound (X), excessive R 1NH 2In ethanol and THF, experience about 72 hours in room temperature.
Compound (II) can prepare with acid (XXI) via coupling amine (XX) according to before in the described program of step (b).
Being suitably used as compound (X) and (XII) compound is that reference is known, or can prepare shown in response diagram 4.1 and 4.2.
Figure A20048000470800331
Response diagram 4.1
X ' expression OH or halogen atom and preferably represent Cl.LG represents leaving group, is generally halogen atom and is preferably chlorine or bromine
When ring A and B be during by a N atomic linkage then:
Figure A20048000470800332
Response diagram 4.2
X ' expression OH or halogen atom and preferably represent Cl.LG represents leaving group, is generally halogen atom and is preferably chlorine or bromine
Compound (XIV) is for getting on the market or being that reference is known.
Step (f): hydrazides (XIII/XIII ') can be undertaken by standard method with the reaction of compound (XIV).
Coupling can be carried out via the following reaction of use separately:
(i) acyl chlorides (XIV)+hydrazides (XIII/XIII ') and excess acid acceptor are in appropriate solvent; Or
(ii) acid (XIV) and conventional coupler+hydrazides (XIII/XIII ') chosen wantonly in catalyzer and existed down, with the excess acid acceptor in appropriate solvent.
Usual conditions are as back:
(i) chloride of acid (XIV) (producing) in original position, and excessive hydrazides (XIII/XIII '), choose and cross for example Et of quantity tertiary amine wantonly 3N, the peaceful alkali of the Chinese or NMM are in DCM or THF, without adding thermal history 1 to 24 hour; Or
(ii) acid (XIV), WSCDI/DCC and HOBT/HOAT, excessive hydrazides (XIII/XIII ') and excessive NMM, Et 3N, the peaceful alkali of the Chinese experience 4 to 48 hours in room temperature in THF, DCM or EtOAc; Or
(iii) sour (XIV), PYBOP / PyBrOp / to Shan Shi reagent, excessive hydrazides (XIII/XIII ') and excessive NMM, Et 3N, the peaceful alkali of the Chinese experience 4 to 24 hours in room temperature in THF, DCM or EtOAc.
Optimum condition is:
Hydrazides (XIII/XIII '), 1.5 equivalent chloroacetyl chlorides (XIV), 1.5 equivalent NMM in DCM in room temperature 16 hours.
Step (g): the cyclisation of compound (XV/XV ') is to carry out up to 18 hour time in elevated temperature under drying conditions.
Usually for example tripolyphosphate, phosphoryl chloride, trifluoromethane sulphur acid anhydride (triflicanhydride) used 5 minutes to 12 hours in 20 ℃ to 120 ℃ temperature siccative.Randomly, reaction is in alkali such as pyridine and suitably as under methylene dichloride and the acetonitrile existence carries out.Ling Wai ， oxadiazole (XII/X) can be according to people's synthesising communications such as Rigo 16 (13), 1665,1986 method preparation.
Optimum condition is:
Phosphoryl chloride in 100 ℃ 8 hours, or 2.5 equivalent trifluoromethane sulphur acid anhydrides in acetonitrile in 20 ℃ 5 hours.
It is known or can prepare shown in response diagram 5.1 and 5.2 to be suitably used as compound (XIII/XIII ') compound and to be reference.
Response diagram 5.1
When ring A and ring B be during via nitrogen atom bonding then:
Figure A20048000470800361
Response diagram 5.2
Compound (XVI/XVI ') and through the hydrazine of protection for can get on the market or for standard method known, for example by the hydrolysis acquisition of corresponding ester.
Carboxylic acid (XV/XV ') be the hydrazine through protection, prot herein *Be generally Boc, can use preamble explanation to be used for the condition of preparation (XV/XV '), coupling and obtain compound (XVII/XVII '), prot then *Use as preamble step (d) as described in the standard method removal, and obtain (XVIII/XVIII ').
Obtain following response diagram 6.1 and 6.2 of being shown in of alternative route of compound (XIII/XIII ').
Figure A20048000470800362
R is generally C 1-2Alkyl
Response diagram 6.1
When ring A and ring B be during via nitrogen atom bonding then:
R is generally C 1-2Alkyl
Response diagram 6.2
Step (h): ester (XVIII/XVIII ') can obtain hydrazides (XVII/XVII ') with hydrazine in the elevated temperature reaction in appropriate solvent such as methyl alcohol.
Optimum condition is:
3 equivalent hydrazines in methyl alcohol, refluxed 18 hours.
In addition, formula (I) compound can be according to following response diagram 7.0 preparations.
Figure A20048000470800372
R=H or C 1-C 4Alkyl is generally the tertiary butyl, methyl or ethyl
Response diagram 7.0
When R is H,
Formula (XXIII) compound can prepare in the described program of step (b) according to preamble via the intramolecularly coupling of amino acid (XXII).
Preferred compound (XXII) uses 1.4 equivalent HBTU, 4.5 equivalent NMM in DCM in room temperature treatment about 18 hours.
Work as R=C 1-C 4During alkyl:
Formula (XXIII) compound can prepare via the cyclisation of base catalysis amino ester (XXII), normally carries out 1-5 hour in room temperature or below the room temperature.
Usually alkali such as uncle's fourth potassium oxide, sodium ethylate or isopropylmagnesium chloride are used at 20 ℃ or are lower than 20 ℃, and experience is 1-5 hour in appropriate solvent such as tetrahydrofuran (THF) or ethanol.
Preferred compound (XXII) is to use 1.1 equivalent uncle fourth potassium oxides to handle about 2 hours in 20 ℃ in THF.
Step (j): the formation of thioamides
Acid amides (XXIII) uses suitable vulcanizing agent (as Lao Senshi agent (Lawesson ' sreagent), P 4S 10) sulfuration, and randomly exist down in alkali (as yellow soda ash), in appropriate solvent (as THF), carry out to room temperature in 0 ℃.
Optimum condition is:
1 equivalent P 4S 10, 1 equivalent yellow soda ash, 1 equivalent acid amides (XXIII) in THF in 3-25 ℃ through 18-72 hour time.
Step (k): the formation of thioimines hydrochlorate
Thioamides (XXIV) uses highly basic such as uncle's fourth potassium oxide or LDA to handle in appropriate solvent such as THF or ether, and then cancellation obtains thioimides hydrochlorate (XXV) by the negatively charged ion of suitable methyl source (for example methyl-iodide, right-the toluenesulphonic acids methyl esters) formation.
Optimum condition is:
1 equivalent thioamides (XXIV) is with 1 equivalent uncle fourth potassium oxide, and 1 equivalent is right-and the toluenesulphonic acids methyl esters handles in THF.
The formation of triazole:
Step (1):
Thioimines hydrochlorate (XXV) uses hydrazides (XIII) to handle in appropriate solvent, is generally ethanol and handles and acquisition formula (I) compound in elevated temperature, randomly carries out under acid catalysis such as THF, p-TSA existence.
Optimum condition is:
1 equivalent thioimines hydrochlorate (XXV), 1 equivalent hydrazides (XIII) was in alcohol reflux 2 hours.
Step (m):
Thioamides (XXIV) uses hydrazides (XIII) to handle in appropriate solvent, is generally positive fourth-1-alcohol and handles and acquisition formula (I) compound in elevated temperature, randomly carries out under acid catalysis such as THF, p-TSA existence.
Optimum condition is:
1 equivalent thioamides (XXIV) refluxed 18 hours in 1 equivalent hydrazides (XIII) Yu Zhengding-1-alcohol.
It is known for reference to be suitably used as compound (XXII), maybe can use people such as standard method preparation example such as reference C.Apfel, medical chemistry magazine 44 (12), 1847-1852,2001; People such as C.P.Lang, WO 2002008228; F.Ishikawa, medical chemistry magazine 28 (10), 1387-93,1985 or Uskokovic, people's organic chemistry magazines (1965) such as M, 30 (9), 3111-14.
Those skilled in the art synthesize in the process in formula (I) compound apparently, and responsive functional group can need protection and slough protection.So can reach by routine techniques, for example be set forth in " organic synthesis protecting group ", as T W Grneene and P G M Wuts, John Willie father and son company 1991, illustrates with embodiment 42-49 and 55-58.
Some formula (I) compound can use the standard chemical conversion and be transformed into another kind of formula (I) compound.Its example explanation as back:
Amination(for example embodiment 40 and 41)
Work as R 1Contain leaving group for example during chlorine substituent, leaving group can with suitable amine HNR 2R 3In suitable tertiary amine base (Et 3The peaceful alkali of N, NMM or the Chinese) or alkali metal base (salt of wormwood, cesium carbonate) exist down, in appropriate solvent (for example DMF, MeCN), choose wantonly in elevated temperature and carry out.
Preferred chlorine compound is to exist down in DMF in 70 ℃ in excessive salt of wormwood, uses excessive HNR 2R 3Handle.
Reduction(for example embodiment 50-54,64 and 65)
The compound that contains the carbonyl functional group can use suitable reductive agent for example DIBAL or borine, in appropriate solvent such as ether or THF, reduces in room temperature or under the temperature between room temperature and reaction reflux temperature.The preferred amide compound use 10 equivalent borines in THF in reflow treatment, then for excessive hydrochloric acid in reflow treatment.
Reduction amination(for example embodiment 69-81 and 84-90)
Formula (I) compound that contains the reactive nitrogen atom can react according to the described method of step (c) with aldehydes or ketones.Preferred formula (I) amine uses excessive aldehyde/ketone and 2 equivalent Na (OAc) 3BH handles in DCM, randomly reaches 18 hours in room temperature treatment down in excessive triethylamine and acetate existence.
Oxidation(for example working as W=S)
The formula of sulfur atom-containing (I) compound can use suitable oxidizing agent oxidation, oxygenant for example be hydrogen peroxide or-the chlorine peroxybenzoic acid, this oxidation is in appropriate solvent such as trifluoroacetic acid or 1,1,1,3,3, carries out in 0-25 ℃ in 3-hexafluoro-propan-2-ol.
When being oxidized into sulfoxide (W=S (O) 1) time, preferred formula (I) sulfide uses 1-1.2 equivalent 30% aqueous hydrogen peroxide in 1,1,1,3,3, reaches 1 hour in room temperature treatment in 3-hexafluoro-propan-2-ol.
When being oxidized into sulfone (W=S (O) 2) time, preferred formula (I) sulfide use 2-3 equivalent 30% aqueous hydrogen peroxide is handled in trifluoroacetic acid and is reached 1 hour.
(aforementioned sulfoxide (W=S (O) in addition, 1) can be oxidized into sulfone (W=S (O) 2), this oxidation is to use 1-2 equivalent 30% aqueous hydrogen peroxide to reach 1 hour in trifluoroacetic acid to carry out.)
According to the present invention, further provide a kind of formula (II) intermediate:
Figure A20048000470800411
Formula (III) intermediate:
Figure A20048000470800412
Formula (X) intermediate:
Figure A20048000470800413
Formula (XV) intermediate:
Formula (XXIV) intermediate:
Figure A20048000470800421
With
(XXIV)
Formula (XXV) intermediate:
Figure A20048000470800422
Wherein V, W, X, Y, Z, ring A and ring B, LG and n are as defined above.
The compounds of this invention is useful, because The compounds of this invention has pharmacologically active in animal body.Be particularly useful for treating various disease conditions, comprise aggressive behaviour, alzheimer's disease, anorexia nervosa, anxiety, anxiety disorder, asthma, arteriosclerosis, autism, cardiovascular diseases (comprises stenocardia, arteriosclerosis, hypertension, cardiac failure, oedema, hypernatronemia), cataract, the central nervous system disease, cerebrovascular ischemia, liver cirrhosis, cognitive disorder, Cushing syndrome, dysthymia disorders, diabetes, dysmenorrhoea (primary and Secondary cases), vomiting (comprising motion sickness), endometriosis, gastrointestinal tract disease, glaucoma, gynaecopathia, heart trouble, intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), ischemic, ischemic heart disease, lung tumor, dysuria, month middle pain, tumour, pnehrotoxicity, non insulin dependent diabetes, fat, obsession, high intraocular pressure, disease before the eclampsia, premature ejaculation, premature labor (preterm labor), tuberculosis, Raynaud disease, ephrosis, kidney depletion, the sex sexual dysfunction, septic shock, somnopathy, spinal cord injury, thrombosis, genitourinary tract infects or urinary calculus.Interesting especially is dysmenorrhoea (primary or Secondary cases), is more particularly primary dysmenorrhoea.
Therefore, according to a further aspect in the invention, a kind of method for the treatment of dysmenorrhoea is provided, and this method comprises suffering from the The compounds of this invention that following illness patient treats significant quantity: disease, premature ejaculation, premature labor (preterm labor) or Raynaud disease before anxiety, cardiovascular diseases (comprising stenocardia, arteriosclerosis, hypertension, cardiac failure, oedema, hypernatronemia), dysmenorrhoea (primary and Secondary cases), endometriosis, vomiting (comprising motion sickness), intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), middle pain, the eclampsia.Also provide compound to be used as the purposes of medicine, and the The compounds of this invention manufacturing is used for the treatment of the purposes of following disease treatment medication: disease, premature ejaculation, premature labor (preterm labor) or Raynaud disease before anxiety, cardiovascular diseases (comprising stenocardia, arteriosclerosis, hypertension, cardiac failure, oedema, hypernatronemia), dysmenorrhoea (primary and Secondary cases), endometriosis, vomiting (comprising motion sickness), intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), middle pain, the eclampsia are in particular dysmenorrhoea.
The The compounds of this invention of intention hyoscine can be crystallized product or amorphous product administration.For example can be that solid plug, powder or film are done via precipitation for example, crystallization, freeze-drying, spray or method such as evaporate to dryness obtains.Microwave drying or radio-frequency seasoning also can be used for this purpose.
It can be individually dosed, or make up one or more other The compounds of this invention administrations, or make up one or more other medicines (or being its any array configuration) administration.For example The compounds of this invention oral contraceptive administration capable of being combined.In addition, PDE5 inhibitor capable of being combined administration.NO donor also capable of being combined administration.In addition, L-arginine capable of being combined administration, or be the arginic acid salt administration.The compounds of this invention COX inhibitor also capable of being combined uses.
Normally be the prescription administration of making up one or more pharmaceutically acceptable vehicle." vehicle " speech is used for describing The compounds of this invention any composition in addition herein.The selection of vehicle be according to multinomial factor for example specific administration pattern, vehicle to the influence of solubleness and stability, and formulation character decision.
Pharmaceutical composition that is suitable for carrying The compounds of this invention and preparation method thereof it will be apparent to those skilled in the art.These composition and method of making the sames for example can be with reference to " Lei Mingdun pharmaceutical science ", the 19th edition (Mo Ke publishing company, nineteen ninety-five).
Therefore according to a further aspect in the invention, provide a kind of formula of medicine that comprises the pharmaceutically acceptable assistant agent of formula (I) compound, diluent or carrier.
But The compounds of this invention oral administration.Oral administration medicine supplying comprises to be swallowed, so compound enters gi tract; Or be cheek usefulness or sublingual administration, be directly to enter blood flow by these approach dispensing compounds by the oral cavity.
Be fit to that prescription for oral administration medicine supplying comprises solid for mulation such as tablet, contains particulate, capsule, lozenge (lozenge that comprises liquid filling), chewable tablet, multiparticulates and nanoparticle, gel, solid solution, liposome, membrane agent (comprising mucoadhesive), avette ingot, sprays and the liquid preparation of liquid or powder.
Liquid preparation comprises suspension liquor, solution, syrup and elixir.These preparations can be used for soft capsule or hard capsule as weighting agent, comprise carrier such as water, ethanol, polyoxyethylene glycol, propylene glycol, methylcellulose gum or suitable oil usually, and one or more emulsifying agents and/or suspension agent.Liquid preparation also can for example be modulated again by sachet and prepares via solid.
The compounds of this invention also can be used for dissolving and quickly disintegrated formulation fast, for example is set forth in treatment patient's expert opinion, 11(6), 981-986, author Liang and Chen (calendar year 2001).
For Tabules, to decide according to dosage, medicine can account for the 1wt% to 80wt% of formulation, more typically is to account for 5wt% to 60wt%.Except medicine, tablet contains disintegrating agent usually.Hydroxypropylcellulose, starch, pregelatinized Starch and sodiun alginate that the disintegrating agent example comprises Vivastar P 5000, Xylo-Mucine, calcium carboxymethylcellulose, croscarmellose sodium, crosslinked general Velon (crospovidone), polyvinylpyrrolidone, methylcellulose gum, Microcrystalline Cellulose, replaces through low alkyl group.Usually, disintegrating agent is the 1wt% to 25wt% that accounts for formulation, and preferably accounts for 5wt% to 20wt%.
Tackiness agent normally is used for providing cohesion matter to tablet formulation.Suitably tackiness agent comprises Microcrystalline Cellulose, gelatin, carbohydrate, polyoxyethylene glycol, natural gum and synthetic gum, polyvinylpyrrolidone, pregelatinized Starch, hydroxy propyl cellulose and HYDROXY PROPYL METHYLCELLULOSE.Tablet also can contain thinner such as lactose (monohydrate, spray dried monohydrate, anhydride etc.), mannitol, Xylitol, glucose, sucrose, Sorbitol Powder, Microcrystalline Cellulose, starch and two base calcium phosphate dihydrates.
Tablet also can be chosen wantonly and comprise tensio-active agent for example Sodium Lauryl Sulphate BP/USP and Bo Lisuobei (polysorbate) 80, reaches antiseize paste for example silicon-dioxide and talcum.Tensio-active agent will account for the 0.2wt% to 5wt% of tablet when existing, antiseize paste is the 0.2wt% to 1wt% that accounts for tablet.
Tablet also contains lubricant for example Magnesium Stearate, calcium stearate, Zinic stearas, FUMARIC ACID TECH GRADE sodium stearyl, and the mixture of Magnesium Stearate and Sodium Lauryl Sulphate BP/USP usually.Lubricant normally accounts for the 0.25wt% to 10wt% of tablet, and preferably accounts for 0.5wt% to 3wt%.
Other possible composition comprises antioxidant, tinting material, correctives, preservatives and sense of taste covering agent.
The example tablet contains up to about 80% medicine, and about 10wt% is to about 90wt% tackiness agent, and about 0wt% is to about 85wt% thinner, and the extremely about 10wt% disintegrating agent 0 of about 2wt% and about 0.25wt% are to about 10wt% lubricant.
The tablet adulterant can directly compress or make tablet by the roller compression.Tablet adulterant or part adulterant in addition also can be before the film-making through wet granulation, do granulation or fused mass granulating, melt is coalescent or extruding.End formulation comprise one or more layers and can be coated or not coated; Even can pass through packing.
Tablet formulation is discussed at " pharmaceutical dosage form: tablet, the 1st volume ", author H.Lieberman and L.Lachman, Ma Suodeke (Marcel Dekker), New York, New York, 1980 (ISBN 0-8247-6918-X).
The solid for mulation that oral administration medicine supplying is used can be formulated into and is the release that discharges at once and/or process is modified.Modified release formulation comprises and postpones to discharge, continues release, pulsed release, sustained release, target discharges and sequencing discharges.
For the usefulness of the object of the invention, suitably revise release formulation and be set forth in United States Patent (USP) the 6th, 106, No. 864.Other suitable release tech details for example high energy dispersion liquid and osmotic pressure particle and dressing particle can be with reference to people such as Verma, pharmaceutical technology on the line, 25 (2), 1-14 (2001).Using chewing gum to reach sustained release is to be set forth in WO 00/35298.
The compounds of this invention also directly administration go into become a shareholder meat or the administration of blood flow, administration and go into internal organs.The suitable means of using for the enteron aisle external administration comprise in intravenously, intra-arterial, the abdomen, in the sheath, in the Intraventricular, urethra, in the breastbone, encephalic, intramuscular and subcutaneous administration.The device that suitable enteron aisle external administration is used comprises syringe needle (comprising small syringe needle) syringe, needleless injector and infusion techniques.
The outer prescription of enteron aisle is generally the aqueous solution, it contains vehicle such as salt, carbohydrate and buffer reagent (preferably to pH3 to 9), be more suitable for being deployed into aseptic non-aqueous solution but be used for some purposes, or be deployed into dried forms and the suitably for example aseptic apirogen water use of carrier of combination.
For example preparing the convenient use of enteron aisle external preparation standard pharmaceutical technology well known by persons skilled in the art by freeze-drying under aseptic condition reaches.
The solubleness that is used to prepare formula (I) compound of the outer solution of enteron aisle can improve solubleness via suitable processing, suitably processing for example uses high energy to spray dried dispersion liquid (with reference to WO01/47495), and/or use suitable blending technology, for example use solubility enhancing agent.
The enteron aisle external administration can be formulated into to discharging at once and/or modification release with prescription.The modification release formulation comprises and postpones to discharge, continues release, pulsed release, sustained release, target discharges and program discharges.Therefore, adjustable solid, semisolid or the thixotropic fluid of being of The compounds of this invention is and implants the modification release that the bank administration provides active compound.These formulation examples comprise intravascular stent and the PGLA microballoon that is coated with medicine.
But The compounds of this invention also topical in skin or mucous membrane, skin dosage or offer medicine for example through skin.The prescription that the typical case is used for this purpose comprises gelifying agent, hydrogel adhesive, lotion, solution, newborn creme, ointment, spreading pulvis, dressing, whipping agent, membrane agent, transdermal patches, disk agent, implant, foam agent, fiber, bandage and micro emulsion liquor.Also can use liposome.Typical case's supporting agent comprises alcohol, water, Dormant oils, whiteruss, white vaseline, glycerine, polyoxyethylene glycol and propylene glycol.But the blending penetration enhancer, reference drug science magazine for example, 88(10), 955-958, author Finnin and Morgan (in October, 1999).
Other topical administration means comprise by iontophoresis, electric pore-creating, sound penetrates, ultrasound penetrates and micropin or Needleless injection (for example steep De Jiete (Powderject TM), Baeyer Ztel (Bioject TM) etc.) drug administration by injection.
Topical can be formulated into prescription and discharges at once and/or modification release.Modification discharges and comprises that postponing to discharge, continue release, pulsed release, sustained release, target release and program discharges.
But in the The compounds of this invention intranasal or through inhalation, the typical case is dry powder form (the independent dry powder that is from Diskus, or be form of mixtures, for example do fusion, or be the mixing element particle with lactose, mixed phosphatide matter for example, phosphatidylcholine for example), or be aerosol spray form by and suitable propelling agent can be used or not use to pressurizing vessel, pump, sprinker, atomizer (be preferably and use electrohydraulic dynamic to learn the atomizer that produces mist) or atomizer spray, for example 1,1,1,2-Tetrafluoroethane or 1,1,1,2,3,3, the 3-heptafluoro-propane.For interanasal administration, powder can comprise bioadhesive agents for example chitosan or cyclodextrin.
Pressurizing vessel, pump, sprinker, atomizer or spraying gun contain the solution or the suspension of The compounds of this invention, comprise ethanol for example, water-based ethanol or suitably other agent for dispersion, solubilising or increment release of active ingredients, propelling agent and comprise optional tensio-active agent such as Sorbitol Powder trioleate, oleic acid or few lactic acid as solvent.
Before being used for suspension formulation dry powder, the medicament production micronization becomes the size (usually less than 5 microns) that is fit to by the suction conveying.Micronization can utilize any suitable shredding unit to reach, and for example spiral spray grinding, fluidised-bed spray grinding, treatment with supercritical fluid form nanoparticle, high pressure homogenizing or spray and do.
Capsule (for example being made by gelatin or HPMC), vesicle and the cartridge case that is used for sucker or insufflator can be formulated into and contain The compounds of this invention, suitable powder base lactose or starch and the properties-correcting agent powdered mixture of 1-leucine, mannitol or Magnesium Stearate for example for example.Lactose can be lactose hydrous or monohydrate form, is preferably the latter.Other suitable vehicle comprises glucosan, glucose, maltose, Sorbitol Powder, Xylitol, fructose, sucrose and trehalose.
Contain 1 microgram to 20 milligram The compounds of this invention during the each transmission of the suitable solution formula of the atomizer that is used to adopt the electrohydraulic dynamic length of schooling to make mist, the transmission volume is changed to 100 microlitres by 1 microlitre.Representative formula comprises formula (I) compound, propylene glycol, sterilized water, ethanol and sodium-chlor.The solvent that can be used to alternative propylene glycol comprises glycerine and polyoxyethylene glycol.
Suitably correctives for example menthol and left-handed menthol or sweeting agent for example asccharin or soluble saccharin can be added into of the present invention prescription of intention for inhalation/intranasal administration.
Inhalation/intranasal administration for example can use poly-DL-lactic acid-copolymerization oxyacetic acid (PGLA) with prescription and be deployed into and discharge at once and/or modification discharges.The modification release formulation comprises and postpones to discharge, continues release, pulsed release, sustained release, target discharges and program discharges.
But dispensing of The compounds of this invention per rectum or vaginal dosing for example are suppository, hysterophore or enema formulation.Theobroma oil is traditional suppository base, but suitably also can use other surrogate if belong to.
Prescription for rectum/vagina administration can be formulated into release at once and/or modification release.The modification release formulation comprises and postpones to discharge, continues release, pulsed release, sustained release, target discharges and program discharges.
The compounds of this invention also can be directly to eye or ear administration, normally is in waiting to open the drops formulation that pH makes through the micronization suspension in the aseptic salt solution of adjusting or solution.Other is fit to comprise ointment, biodegradable implant (agent of for example absorbable gel sponge, collagen) and non-biodegradable (for example polysiloxane) implant, disk agent, lens and particulate or cryptomere system for example nanoparticle (niosomes) or liposome for the prescription that eye is used or ear is used.Polymkeric substance is for example HYDROXY PROPYL METHYLCELLULOSE, hydroxy ethyl cellulose or methylcellulose gum of cross linked polyacrylate, polyvinyl alcohol, hyaluronic acid, cellulose polymer compound for example, or the mixed polysaccharide polymkeric substance for example gellan gum (gelan gum) can with for example common fusion of Zephiran chloride of preservatives.These prescriptions also can be carried by iontherapy.
Eye is filled a prescription with dispensing with/ear, and adjustable confession discharges at once and/or modification release.The modification release formulation comprises and postpones to discharge, continues release, pulsed release, sustained release, target discharges and program discharges.
The compounds of this invention solubility giant molecule capable of being combined body is cyclodextrin or contain polyethylene glycol polymer and improve its solubleness, dissolution rate, coverage taste, bioavailability and/or stability and be used for aforementioned any dispensing pattern for example.
For example the drug-cyclodextrin mixture is generally used for most of formulation and dosing way.Can use inclusion complexs and not have inclusion complexs.As with the substituting of the direct complexing of medicine, cyclodextrin can be used as supplementary additive, that is as carrier, thinner or solubilizing agent.Be most commonly used to this purpose for alpha-cylodextrin, beta-cyclodextrin and γ-Huan Hujing, its example can be with reference to No. 98/55148, international patent application WO 91/11172, WO 94/02518 and WO.
When wishing administration for example the specified disease or the state of an illness treated in the combination of active compound, the pharmaceutical composition that comprises two or more in scope of the present invention, the wherein at least a The compounds of this invention that contains can be combined into the suitable administration composition simultaneously of external member group form easily.
Therefore test kit of the present invention comprises two or more and separates pharmaceutical compositions, and wherein at least a with good grounds formula of the present invention (I) compound that contains is separately kept the device of these compositions, for example container, divide uncork or Aluminium Foil Package separately.These external member groups for example are used for package troche, capsule etc. for the general bubble born of the same parents cover plate packing of being familiar with.
Test kit of the present invention is particularly suitable for the administration different dosage form, the outer dispensing of for example oral and enteron aisle be provided with various dose at interval administration separate constituent, or for the titration composition that is separated from each other.For auxiliary patient follows the doctor's advice, the external member group comprises the dispensing indication usually and can be provided with so-called memory supplementary unit.
The administration human patient, The compounds of this invention total every day dosage according to the decision of dispensing pattern, normally in about 0.01 scope to about 15 mg/kg body weight.Always every day, dosage can single agent or separately multi-agent administration in the middle of one day.Dosage is to be benchmark with about 65 kilograms to the 70 kilograms average human body weight of body weight.The doctor is convenient to exceed individuality beyond this scope to body weight for example baby and old man determines suitable dosage.
Be used for " processing " herein and " being used for handling " vocabulary and show relief of symptoms, temporary transient or persistence elimination cause, or the appearance of the prevention or the symptom that slows down." processing " speech comprises relief of symptoms, eliminates cause (temporary or persistence) or prevention primary and/or secondary dysmenorrhea related symptoms and obstacle.Processing can be pre-treatment and handles when seizure of disease.
The compounds of this invention can be tested in the screening of hereinafter enumerating:
1.0V 1A Filter in conjunction with calibrating and analyze
1.1 the preparation of film
It is to carry out on cytolemma that the receptors bind calibrating is analyzed, but this cytolemma is stably express mankind V 1AThe Chinese hamster ovary celI preparation of acceptor, (CHO-hV 1A).CHO-hV 1AClone is by MarcThibonnier, internal medicine portion, and the Cleveland, Ohio, medical college of Kai Saxi storage university authorizes agreement and provides.CHO-hV 1AThe cell routine is to be maintained at 37 ℃ in containing 5% carbonic acid gas humid atmosphere in this (Hams) F12 nutritional blend of the DMEM Chinese, replenishes 10% foetal calf serum, 2mM L-glutaminate, 15mM HEPES and 400 mcg/ml G418 in the nutritional blend.For the mass production cell pellets, the CHO-hV that adheres to 1ACell grows to 90-100% and converges in 850 square centimeters of roller bottles, contain this F12 nutritional blend substratum of the DMEM/ Chinese in the roller bottle, is supplemented with 10% foetal calf serum, 2mM L-glutaminate and 15mM HEPES.The CHO-hV that converges 1ACell is with phosphate buffered saline (PBS) (PBS) washing, and results are to ice-cold PBS and in 1,000rpm is centrifugal.Cell pellets is stored in-80 ℃ to use.Cell pellets is in thawing on ice, and in cell membrane preparation damping fluid homogenizing, this damping fluid is by 50mM Tris-HCl, pH7.4,5mM MgCl 2And additional proteinase inhibitor mixed solution (Roche) is formed.Cell homogenizing thing in 4 ℃ in 1, centrifugal 10 minutes of 000rpm shifts out supernatant liquor and is stored on ice.All the other cell pellets are homogenizing and centrifugal as described above.Supernatant liquor is through compiling, in 4 ℃ in 25,000 * g centrifugal 30 minutes.The cell pellets resuspending is in 50mM Tris-HCl, pH7.4,5mM MgCl 2And the freezing damping fluid formed of 20% glycerine, in-80 ℃ be stored to a small amount of five equilibrium use before till.Use not reagent (Bradford reagent) and use BSA to measure protein concn of Bradley as standard substance.
1.2V 1A Filter combination
By saturated protein linear degree of following the trail of in conjunction with research is that every batch of new cytolemma is carried out.Cytolemma concentration is to select to obtain in the straight line portion of curve the concentration of particular combination.Use then various different concns [ 3H]-arginine vasopressin, [ 3H]-AVP (0.05nM-100nM) carries out saturated in conjunction with studying mensuration K dAnd B Max
Test compounds to [ 3H]-AVP is bonded to CHO-hV 1AThe influence of cytolemma ( 3H-AVP; Specific activity 65.5Ci/ mmole; NEN life science company).Compound is solubilized into methyl-sulphoxide, and uses the calibrating analysis buffer to be diluted to the 10%DMSO working concentration, and damping fluid contains 50mMTris-HCl, pH7.4,5mM MgCl 2And 0.05%BSA.25 microlitre compounds and 25 microlitres [ 3H]-(final concentration is the K that records in the cell membrane batch of material to AVP d, or be lower than K d, be generally 0.5nM-0.6nM), be added into polypropylene orifice plate at the bottom of 96 hole circles.Be to add 200 microlitre cytolemma at the beginning of the association reaction, plate was in the gentle jolting of room temperature 60 minutes.Plate is to use Fitow U.S. (Filtermate) cell harvesting machines (Parker (Packard) instrument company) to filter fast via the single screen plate of 96 hole GF/B to finish reaction, and single screen plate is soaked in 0.5% in advance and polyethylene imine basedly prevents that being stained with of peptide is sticking.Strainer is washed 3 times with 1 milliliter of ice-cold wash buffer, and lavation buffer solution contains 50mM Tris-HCl, pH7.4 and 5mM MgCl 2The orifice plate drying also is added into each hole with 50 microlitres little flicker-0 (Parker instrument company).Orifice plate is counted in desktop counter microwell plate scintillometer (Parker instrument company) through sealing.Use d (CH2) 5Tyr (Me) AVP ([β-sulfydryl-β, β-cyclopentamethylene propionyl, the O-Me-Tyr of 1 μ M un-marked 2, Arg 8]-Hou Yejiayasu) (β MCPVP), (sigma (Sigma) company measures non-specific binding (NSB).The radioligand combined with file is to use four parameter logical equation analyses, and minimum value is forced to 0%.Slope is freely to mate, and efficiency curve falls into-0.75 to-1.25.Obtain the specificity combination by deduction average N SB cpm among average total cpm.For test compound, the amount of ligand that is bonded to acceptor is in conjunction with cpm * 100 expressions with % combination=(sample cpm-average N SBcpm)/specificity.To the mapping of test compound concentration, mate S type curve in conjunction with per-cent.Suppress dissociation constant (K i) be to use thousand-Pu Luosuo (Cheng-Prusoff) equation to calculate: K i=IC 50/ (1+[L]/K d) [L] for being present in ligand concentration in the hole herein, and K dAsk the radioligand dissociation constant of (Scatchard) mapping analysis for deriving from the history lid.
2.0V 1A The function calibrating is analyzed: by FLIPR (fluorescent imaging orifice plate reader) (molecular device) Suppress AVP/V 1A -R mediationCa 2+ Move
CHO-hV 1AThe release of calcium uses FLIPR to measure in the cell, can be activated rapid detection calcium afterwards in acceptor.CHO-hV 1AClone is by Marc Thibonnier, internal medicine portion, and the Cleveland, Ohio, medical college of Kai Saxi storage university authorizes agreement and provides.CHO-hV 1AThe cell routine is to be maintained at 37 ℃ in containing 5% carbonic acid gas humid atmosphere in this (Hams) F12 nutritional blend of the DMEM Chinese, replenishes 10% foetal calf serum, 2mM L-glutaminate, 15mM HEPES and 400 mcg/ml G418 in the nutritional blend.Noon before that day is analyzed in calibrating, and cell is inoculated in the aseptic 96 hole orifice plates of black of clear bottom with 20,000 cells/well density, so can measure by making cellular assay and fluorescent at the bottom of the hole.Lavation buffer solution contains Du Bieke (Dulbecco ' s) phosphate buffered saline (PBS) (DPBS) and 2.5mM Pu Luobennixi (probenecid), being written into this dyestuff is by containing 4 μ M Fluo-3-AM (being dissolved in DMSO and Pu Longni acid (pluronicacid)), the cell culture medium of (molecular probe) and 2.5nM Pu Luobennixi form, and dyestuff is to analyze prepared fresh on the same day in calibrating.Compound dissolution is in DMSO, and in the dilution of calibrating analysis buffer, damping fluid is by containing 1%DMSO, the DPBS composition of 0.1%BSA and 2.5mM Pu Luobennixi.Cell in 37 ℃ under the humid atmosphere that contains 5% carbonic acid gas with 100 microlitre load dyestuff/hole co-cultivation.After dyestuff load, cell uses red sharp (Denley) orifice plate washer to wash 3 times in 100 microlitre lavation buffer solutions, and each hole stays 100 microlitre lavation buffer solutions.Fluorescent is to use FLIPR to measure in the born of the same parents.The fluorescent value of reading is with 2 seconds intervals, added 50 microlitre test compounds and obtain after 30 seconds.Obtain 155 2 seconds observed values at interval then again and be used for detecting any compound agonist activity.Add 50 microlitre arginine vasopressins (AVP) then, calibrating analysis volume is 200 microlitres eventually.Amount to 120 seconds to collect further fluorescent value of reading 1 second at interval.Assaying reaction spike fluorescence intensity (FI).As for the pharmacology feature, be by the basic FI of deduction in each fluorescent reaction.Be used for the AVP dose response curve, each reaction is to represent with maximum concentration AVP concentration-response per-cent in these row.For IC 50Measure, each reaction is to represent IC with the percent reaction to AVP 50Value uses thousand-Pu Luosuo equation to convert the K that process is revised to bValue is wherein considered agonist concentration [A], agonist EC 50And slope: K b=IC 50/ (2+[A]/A 50] n) 1/n-1, [A] is AVP concentration herein, A 50EC for the AVP that derives from dose response curve 50, n=AVP dose response curve slope.
The advantage of The compounds of this invention is that The compounds of this invention is comparatively powerful, and acting duration is longer, and broad field of activity is arranged, and is comparatively stable, less side effect or have selectivity, or have than prior art compound useful properties more.
Therefore, the invention provides:
(i) a kind of formula (I) compound or a kind of its pharmaceutically acceptable derivates;
The method of (ii) a kind of preparation formula (I) compound or its pharmaceutically acceptable derivates;
(iii) a kind of formula of medicine comprises formula (I) compound or its pharmaceutically acceptable derivates vehicle, the diluent or carrier together with pharmaceutically acceptable property;
(iv) a kind of formula (I) compound or its pharmaceutically acceptable derivates or its composition are used as medicine;
(v) formula (I) compound or its pharmaceutically acceptable derivates or its composition are used to make the purposes of the following disease medication of treatment: aggressive behaviour, alzheimer's disease, anorexia nervosa, anxiety, anxiety disorder, asthma, arteriosclerosis, autism, cardiovascular diseases (comprises stenocardia, arteriosclerosis, hypertension, cardiac failure, oedema, hypernatremia), cataract, the central nervous system disease, cerebrovascular ischemia, liver cirrhosis, cognitive disorder, Cushing syndrome, dysthymia disorders, diabetes, dysmenorrhoea (primary and Secondary cases), vomiting (comprising motion sickness), endometriosis, gastrointestinal tract disease, glaucoma, gynaecopathia, heart trouble, intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), ischemic, ischemic heart disease, lung tumor, dysuria, middle pain, tumour, pnehrotoxicity, non insulin dependent diabetes, fat, obsession, high intraocular pressure, disease before the eclampsia, premature ejaculation, premature labor (preterm labor), tuberculosis, Raynaud disease, ephrosis, kidney depletion, the sex sexual dysfunction, septic shock, somnopathy, spinal cord injury, thrombus, genitourinary tract infects or urinary calculus;
(vi) (purposes v), this disease or illness are disease before anxiety disorder, cardiovascular diseases (comprising stenocardia, arteriosclerosis, hypertension, cardiac failure, oedema, hypernatronemia), dysmenorrhoea (primary and Secondary cases), endometriosis, vomiting (comprising motion sickness), intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), middle pain, the eclampsia, premature ejaculation, premature labor (preterm labor) or Raynaud disease herein;
(vi) (purposes v), this disease is dysmenorrhoea (primary and a Secondary cases) herein;
(viii) a kind of mammiferous methods of treatment, be to be used for the treatment of aggressive behaviour, alzheimer's disease, anorexia nervosa, anxiety, anxiety disorder, asthma, arteriosclerosis, unsociable and eccentric disease, cardiovascular diseases (comprises stenocardia, arteriosclerosis, hypertension, cardiac failure, oedema, hypernatronemia), cataract, the central nervous system disease, cerebrovascular ischemia, liver cirrhosis, cognitive disorder, Cushing syndrome, dysthymia disorders, diabetes, dysmenorrhoea (primary and Secondary cases), vomiting (comprising motion sickness), endometriosis, gastrointestinal tract disease, glaucoma, gynaecopathia, heart trouble, intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), ischemic, ischemic heart disease, lung tumor, dysuria, middle pain, tumour, pnehrotoxicity, non insulin dependent diabetes, fat, obsession, high intraocular pressure, disease before the eclampsia, premature ejaculation, premature labor (preterm labor), tuberculosis, Raynaud disease, ephrosis, kidney depletion, the sex sexual dysfunction, septic shock, somnopathy, spinal cord injury, thrombus, genitourinary tract infects or urinary calculus, and this method comprises formula (I) compound or its pharmaceutically acceptable derivates or the described Mammals of its combination treatment of using significant quantity;
(ix) as (method viii), this disease or illness are disease before the anxiety disorder, cardiovascular diseases (comprising stenocardia, arteriosclerosis, hypertension, cardiac failure, oedema, hypernatronemia), dysmenorrhoea (primary and Secondary cases), endometriosis, vomiting (comprising motion sickness), intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), middle pain, eclampsia, premature ejaculation, premature labor (preterm labor) or Raynaud disease herein;
(x) as (method viii), this disease or illness are dysmenorrhoea (primary and Secondary cases) herein;
(xi) formula (II), (III), (X), (XV), (XXIV) and intermediate (XXV);
(xii) combination of formula (I) compound and oral contraceptive is used for the treatment of dysmenorrhoea (primary and/or Secondary cases);
(xiii) combination of formula (I) compound and PDE5 inhibitor is used for the treatment of dysmenorrhoea (primary and/or Secondary cases);
(xiv) combination of formula (I) compound and NO donor is used for the treatment of dysmenorrhoea (primary and/or Secondary cases);
(xv) formula (I) compound and the arginic combination of L-are used for the treatment of dysmenorrhoea (primary and/or Secondary cases);
(xvi) combination of formula (I) compound and COX inhibitor is used for the treatment of dysmenorrhoea (primary and/or Secondary cases).
Following preparation example and embodiment illustrate the present invention:
Preparation example 1:3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-carboxylic acid hydrazides
Figure A20048000470800541
3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-carboxylic acid, ethyl ester (1 gram, 4.3 mmoles) (referring to reference Farmaco, 1993,48 (10), 1439) be dissolved in the methyl alcohol (20 milliliters) that contains hydrazine hydrate (620 microlitres, 20 mmoles), reflux 18 hours.Mixture is cooled to room temperature, in decompression evaporation down.Solid that forms and propan-2-ol development obtain title compound, the solid that is white in color (493 milligrams).
APCI MS m/z 221[M+H] +
Preparation example 1b:3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-carboxylic acid, ethyl ester
Figure A20048000470800542
In the stirred solution of salt of wormwood (52.5 grams, 0.379 mole) (60 restrain 0.379 mole) and different piperidine ethyl formate (59.7 grams, 0.379 mole) in the surrounding temperature filler to the 2-bromopyridine, postheating to 120 ℃ experience 24 hours.Mixture is cooled to room temperature, and the propan-2-ol filler is to solution.Reaction mixture reaches cover and is stacked to preparation example 1c after filtration then.
Preparation example 1c:3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-carboxylic acid hydrazides
Hydrazine hydrate (61.4 milliliters, 1.265 moles) adds to 3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-carboxylic acid, ethyl ester (0.253 mole, 5 milliliters/gram) is (referring to reference Farmaco, 1993,48 (10), 1439) propan-2-ol solution, reflux is 18 hours subsequently.Mixture is cooled to room temperature, is cooled to 10 ℃ then, collects product by filtering, the solid that is white in color (44.5 gram).
APCI MS m/z 221[M+H] +
Preparation example 2:1-pyrimidine-2-base-piperidines-4-carboxylic acid hydrazides
Abide by preparation example 1 described program, title compound derives from 1-pyrimidine-2-base-piperidines-4-carboxylic acid, ethyl ester (with reference to Farmaco, 1993,48 (10), 1439), 91% productive rate.
APCI MS m/z 222[M+H] +
Preparation example 3:3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-carboxylic acid N '-(2-chloracetyl)-hydrazides
Figure A20048000470800552
The hydrazides of preparation example 1 (23.6 grams, 0.11 mole) is suspended in methylene dichloride (500 milliliters) and adds 4-methylmorpholine (17.7 milliliters, 0.16 mole).Mixture uses the ice bath cooling and dropwise adds chloroacetyl chloride (12.8 milliliters, 0.16 mole).Reaction is warmed to room temperature and stirred 3 hours.The solid by filtration that generates is separated, and with methylene dichloride and ether washing, and vacuum-drying obtains title compound (20.4 gram).
LCMS：m/z ES+ 297[M+H] +
Preparation example 3b:3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-carboxylic acid N '-(2-chloracetyl)-hydrazides
Figure A20048000470800553
The hydrazides of preparation example 1c (5.0 grams, 23 mmoles) is suspended in methylene dichloride (100 milliliters) and adds 4-methylmorpholine (3.75 milliliters, 34 mmoles).Mixture uses the ice bath cooling and dropwise adds chloroacetyl chloride (1.9 milliliters, 24 mmoles).Reaction is warmed to room temperature and stirred 3 hours.The solid by filtration that generates is separated, and with washed with dichloromethane, and vacuum-drying obtains title compound (2.2 gram).
LCMS：m/z ES+ 297[M+H] +
Preparation example 4:1-pyrimidine-2-base-piperidines-4-carboxylic acid N '-(2-chloro-ethanoyl)-hydrazides
Figure A20048000470800561
Use preparation example 3 described programs, title compound is by the hydrazides of preparation example 2 and chloroacetyl chloride preparation, 96% productive rate.
APCI MS m/z 298[M+H] +
Preparation example 5:4-(the 5-chloromethyl-[and 1,3,4] oxadiazole-2-yls)-3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl
Figure A20048000470800562
The hydrazides of preparation example 3 (20.4 grams, 69 mmoles) was suspended in phosphoryl chloride (150 milliliters) 4 hours in 100 ℃.Mixture is through cooling, in the evaporative removal solvent down that reduces pressure.Resistates is dissolved in ethyl acetate, is added into water.Water layer separates each phase by adding the solid sodium bicarbonate alkalization.Water merges organic layer with dried over mgso and in decompression evaporation down with ethyl acetate extraction (2 times).Isolating material uses the ether development, obtains title compound, is beige solid (15 gram).
1H NMR(400MHz，CD 3OD)：δ1.91(m，2H)，2.19(m，2H)，3.14(m，2H)，3.30(m，1H)，4.29(m，2H)，4.86(s，2H)，6.69(m，1H)，6.89(d，1H)，7.58(m，1H)，8.08(d，1H)
Preparation example 5b:4-(the 5-chloromethyl-[and 1,3,4] oxadiazole-2-yls)-3,4,5,6-tetrahydrochysene-2H-[1,2 '] dipyridyl
Figure A20048000470800571
The hydrazides of preparation example 3 (50.0 grams, 169 mmoles) is suspended in acetonitrile (250 milliliters), uses the ice bath cooling.℃ dropwise add trifluoromethane sulphur acid anhydride (29.9 milliliters, 177 mmoles) in T＜15.Reaction is warmed to room temperature and stirred 16 hours.The ice bath cooling is used in reaction, dropwise adds the solution of sodium bicarbonate (29.8 grams, 354 mmoles) in water (250 milliliters).Add methylene dichloride (250 milliliters), separate each phase.The organic phase that contains product is used for preparation example 14b.
1H NMR(400MHz，CD 3OD)：δ1.91(m，2H)，2.19(m，2H)，3.14(m，2H)，3.30(m，1H)，4.29(m，2H)，4.86(s，2H)，6.69(m，1H)，6.89(d，1H)，7.58(m，1H)，8.08(d，1H)
Preparation example 6:2-[4-(the 5-chloromethyl-[1,3,4] oxadiazole-2-yls)-piperidines-1-yl]-pyrimidine
Figure A20048000470800581
Use preparation example 5 described programs, title compound is the hydrazides preparation by preparation example 4,84% productive rate.
1H NMR(400MHz，CDCl 3)：δ1.91(m，2H)，2.19(m，2H)，3.14(m，3H)，4.65(s，2H)，4.86(m，2H)，6.49(m，1H)，6.89(d，1H)，8.35(d，1H)
APCI MS m/z 280[M+H] +
Preparation example 7:(2-amino-5-methoxyl group-phenyl)-methyl alcohol
Figure A20048000470800582
Tetrahydrofuran (THF) (20 milliliters) solution of 2-amino-5-methoxyl group-phenylformic acid (2.0 grams, 12 mmoles) dropwise is added into the tetrahydrofuran solution of ice-cold 1 volumetric molar concentration lithium aluminium hydride (14.4 milliliters), stirs 2 hours in 5 ℃.Dropwise add water (0.5 milliliter), then add 2 volumetric molar concentration aqueous sodium hydroxide solutions (0.5 milliliter).The gained emulsion is filtered then with dried over mgso as a result, in decompression evaporation down, obtains title compound, is yellow solid (766 milligrams).
APCI MS m/z 154[M+H] +
1H NMR(400MHz，CD 3OD)：δ3.70(s，3H)，4.55(s，2H)，6.65-6.78(m，3H)
Preparation example 8:(2-amino-6-chloro-phenyl)-methyl alcohol
Figure A20048000470800591
Title compound is to abide by preparation example 7 described programs, and by 2-amino-6-chloro-phenylformic acid preparation, 69% productive rate is pale solid.
APCI MS m/z 158[M+H] +
1H NMR(400MHz，CDCl 3)：δ4.85(s，2H)，6.60(d，1H)，6.80(d，1H)，7.00(t，1H)
Preparation example 9:(2-amino-4-chloro-phenyl)-methyl alcohol
Figure A20048000470800592
Title compound is to abide by preparation example 7 described programs, and by 2-amino-4-chloro-phenylformic acid preparation, 48% productive rate is pale solid.
APCI MS m/z 170[MNa] +
1H NMR(400MHz，CD 3OD)：δ4.55(s，2H)，6.60(d，1H)，6.70(d，1H)，7.00(d，1H)
Preparation example 10:2-amino methyl-4-chloro-phenyl amine
Tetrahydrofuran (THF) (100 milliliters) solution of 2-amino-5-chloro-benzonitrile (9.0 gram, 59 mmoles) dropwise is added into the solution of the tetrahydrofuran (THF) of ice-cold 1 mole of lithium aluminium hydride (100 milliliters), and reaction mixture was in stirring at room 18 hours.Dropwise add water (10 milliliters).The gained emulsion is with dried over mgso, and filtration reaches in decompression evaporates the acquisition title compound down, the solid that is white in color (4.56 restrain).
1H NMR(400MHz，CDCl 3)：δ3.85(s，2H)，4.50(s，2H)，6.60(d，1H)，7.05(m，2H)
Preparation example 11: acetate 2-(2-acetylaminohydroxyphenylarsonic acid 5-chloro-phenyl)-ethyl ester
Figure A20048000470800601
Solution (the 0.98M of the Glacial acetic acid of chlorine, 30 milliliters) dropwise be added into N-[2-(2-hydroxyl-ethyl)-phenyl]-ethanamide (5.0 grams, 27.9 mmoles) is (referring to reference biological chemistry 1979,18 (5), the solution of Glacial acetic acid 860) (50 milliliters), mixture was in stirring at room 20 hours.Go down except that Glacial acetic acid in decompression.Gained oil is developed with ether with ether, obtains title compound (3.3 gram) in filtering the back, is the lark solid.
APCI MS m/z 256，[MH] +，278[MNa] +
1H NMR(400MHz，CDCl 3)：δ2.13(s，3H)，2.26(s，3H)，2.87(t，2H)，4.13(t，2H)，7.11(d，1H)，7.23(dd，1H)，8.05(d，1H)，8.27(s，1H).
Preparation example 12:2-(2-amino-5-chloro-phenyl)-ethanol
Figure A20048000470800602
The compound that derives from preparation example 11 is suspended in 2 volumetric molar concentration water-based hydrochloric acid (20 milliliters) and is heated to 100 ℃ goes through 4 hours.Allow solution cool off, use 0.880 water-based ammonia to be adjusted into alkalescence (pH9), and use ethyl acetate (50 milliliters) to distribute.Organic layer water and saturated brine washing are with dried over mgso.Solution evaporates down in decompression after filtration then.Resistates uses methyl alcohol and ammonium hydroxide to pass through chromatography purification as eluent (5: 0.5: 95) in methylene dichloride on silica gel, obtains title compound, is brown oil (0.43 gram).
APCI MS m/z 172，[MH] +
1H NMR(400MHz，CD 3OD)：δ2.64(t，2H)，3.69(t，2H)，6.61(d，1H)，6.87(dd，1H)，6.93(d，1H).
Preparation example 13:2-([5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazole-2-ylmethyl]-amino }-methyl)-phenyl amine
Figure A20048000470800611
The solution of 2-amino methyl-phenyl amine (2.2 gram, 17.9 mmoles) in tetrahydrofuran (THF) (50 milliliters) is added into preparation example 5 oxadiazoles (2.0 grams, 7.18 mmoles) solution of (50 milliliters) in tetrahydrofuran (THF), and mixture heating up to 50 ℃ is gone through 18 hours.Reaction mixture is in decompression evaporation down, and resistates obtains title compound in using methyl alcohol and ammonium hydroxide to make eluent (5: 0.5: 95) by chromatography purification in methylene dichloride on the silica gel, is lark jelly (2.6 gram).
APCI MS m/z 365[MH] +，387[MNa] +
1H NMR(400MHz，CDCl 3)：δ1.94(m，2H)，2.18(m，2H)，3.14(m，3H)，3.88(s，2H)，4.00(s，2H)，4.31(m，2H)，6.60-6.75(m，4H)，7.02(d，1H)，7.12(t，1H)，7.48(t，1H)，8.20(d，1H).
Preparation example 14:4-chloro-2-([5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazole-2-ylmethyl]-amino }-methyl)-phenyl amine
The solution of the amine of preparation example 10 (6.4 grams, 41 mmoles) in tetrahydrofuran (THF) (50 milliliters) is added into the solution of preparation example 5 oxadiazoles (4.56 grams, 16 mmoles) in tetrahydrofuran (THF) (50 milliliters).Mixture heating up to 50 ℃ is gone through 18 hours.Reaction mixture is in down evaporation of decompression, resistates in use on the silica gel methyl alcohol in methylene dichloride as eluent (5: 95) chromatography purification, obtain title compound, the solid that is white in color (4.65 gram).
APCI MS m/z 399[MH] +
1H NMR(400MHz，CDCl 3)：δ1.95(m，2H)，2.20(m，2H)，3.10(m，2H)，3.20(m，1H)，3.80(s，2H)，4.00(s，2H)，4.30(m，2H)，6.60(m，1H)，6.65(t，1H)，6.70(d，1H)，7.00(s，1H)，7.05(d，1H)，7.50(t，1H)，8.20(d，1H)
Preparation example 14b:4-chloro-2-([5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazole-2-ylmethyl]-amino }-methyl)-phenyl amine
Figure A20048000470800621
Acetonitrile/the dichloromethane solution that derives from preparation example 5b De oxadiazole is through distillation, and resistates places acetonitrile, then with sodium bicarbonate (14.9 grams, 177 mmoles) and derive from amine (39.7 grams, the 253 mmoles) reflux 5 hours of preparation example 10.Mixture adds water (250 milliliters) and methylene dichloride (1500 milliliters) through cooling.Separate each phase, organic phase substitutes through distillation and with ethyl acetate.The gained precipitation obtains title compound by filtering separation, is yellow solid (32.8 gram).
APCI MS m/z 280[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.91(m，2H)，2.19(m，2H)，3.14(m，3H)，4.65(s，2H)，4.86(m，2H)，6.49(m，1H)，6.89(d，1H)，8.35(d，1H)
Preparation example 15:4-chloro-2-([5-(1-pyrimidine-2-base-piperidin-4-yl)-[1,3,4] oxadiazole-2-ylmethyl]-amino }-methyl)-phenyl amine
The solution of the amine of preparation example 10 (4.12 gram, 26 mmoles) in tetrahydrofuran (THF) (50 milliliters) is added into preparation example 6 oxadiazoles (2.95 grams, 11 mmoles) solution of (50 milliliters) in tetrahydrofuran (THF).Mixture heating up to 50 ℃ is gone through 18 hours.Reaction mixture is in decompression evaporation down, and resistates uses ethyl acetate as the eluent chromatography purification on silica gel, obtains title compound, is pale solid (2.34 gram).
APCI MS m/z 400[MH] +
1H NMR(400MHz，CDCl 3)：δ1.80(m，2H)，2.20(m，2H)，3.20(m，3H)，3.80(s，2H)，4.00(s，2H)，4.75(m，2H)，6.50(t，1H)，6.60(d，1H)，7.00(d，1H)，7.05(d，1H)，8.35(d，2H).
Preparation example 16:2-[5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazoles-2-ylmethoxy methyl]-phenyl amine
The solution of (2-amino-phenyl)-methyl alcohol (996 milligrams, 8 mmoles) in tetrahydrofuran (THF) (5 milliliters) dropwise is added into the ice-cold suspension of sodium hydride (60% in Dormant oils, 324 milligrams, 8.1 mmoles) in tetrahydrofuran (THF) (5 milliliters), stirs 0.5 hour.The solution of preparation example 5 oxadiazoles (750 milligrams, 2.69 mmoles) in tetrahydrofuran (THF) (5 milliliters) is through dropwise adding, and mixture was in stirring at room 3 hours.Add ethyl acetate (50 milliliters), solution extracts with water (25 milliliters).The aqueous solution washs with ethyl acetate (2 * 20 milliliters).Merge organic layer with dried over mgso and in decompression evaporation down.Resistates on silica gel, use ethyl acetate in the gradient of pentane as eluent (2: 1 to 100: 0), by chromatography purification, obtain title compound (300 milligrams), solid is white in color.
APCI MS m/z 366[MH] +
1H NMR(400MHz，CDCl 3)：δ1.90(m，2H)，2.20(m，2H)，3.10(m，2H)，3.20(m，1H)，4.20(s，2H)，4.35(m，2H)，4.64(s，2H)，4.66(s，2H)，6.65(m，4H)，7.05(d，1H)，7.15(t，1H)，7.50(t，1H)，8.20(d，1H).
Preparation example 17:3-chloro-2-[5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazoles-2-ylmethoxy methyl]-phenyl amine
Figure A20048000470800641
Title compound is to use preparation example 16 described programs, by the alcohol and the preparation of preparation example 5 De oxadiazoles of preparation example 8,55% productive rate.
APCI MS m/z 400[MH] +
1H NMR(400MHz，CDCl 3)：δ1.95(m，2H)，2.20(m，2H)，3.05(m，2H)，3.20(m，1H)，4.30(m，2H)，4.40(s，2H)，4.70(s，2H)，4.90(s，2H)，6.55(d，1H)，6.60(m，1H)，6.70(d，1H)，6.75(d，1H)，7.00(t，1H)，7.15(t，1H)，7.45(t，1H)，8.20(d，1H).
Preparation example 18:5-chloro-2-[5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazoles-2-ylmethoxy methyl]-phenyl amine
Figure A20048000470800642
Title compound is to use preparation example 16 described programs, by the alcohol and the preparation of preparation example 5 De oxadiazoles of preparation example 9,42% productive rate.
APCI MS m/z 400[MH] +，422[MNa] +
1H NMR(400MHz，CDCl 3)：δ1.90(m，2H)，2.20(m，2H)，3.10(m，3H)，4.30(m，4H)，4.60(s，2H)，4.65(s，2H)，6.75(m，4H)，7.00(d，1H)，7.45(t，1H)，8.20(d，1H).
Preparation example 19:4-methoxyl group-2-[5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazoles-2-ylmethoxy methyl]-phenyl amine
Figure A20048000470800651
Title compound is to use preparation example 16 described programs, by the alcohol and the preparation of preparation example 5 De oxadiazoles of preparation example 7,53% productive rate.
APCI MS m/z 396[MH] +，418[MNa] +
1H NMR(400MHz，CDCl 3)：δ1.95(m，2H)，2.20(m，2H)，3.10(m，3H)，3.75(s，3H)，4.60(s，2H)，4.65(s，2H)，6.70(m，5H)，7.45(t，1H)，8.20(d，1H).
Preparation example 20:4-chloro-2-[5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazoles-2-ylmethoxy methyl]-phenyl amine
Figure A20048000470800652
Title compound is to use preparation example 16 described programs, by (2-amino-5-chloro-phenyl)-methyl alcohol and the preparation of preparation example 5 De oxadiazoles, 61% productive rate.
APCI MS m/z 400[MH] +
1H NMR(400MHz，CDCl 3)：δ1.95(m，2H)，2.20(m，2H)，3.10(m，2H)，3.20(m，1H)，4.20(s，2H)，4.35(m，2H)，4.60(S，2H)，4.70(s，2H)，6.60(m，2H)，6.70(d，1H)，7.10(m，2H)，7.45(t，1H)，8.20(d，1H).
Preparation example 21:2-{2-[5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazole-2-ylmethoxy]-ethyl }-phenyl amine
Figure A20048000470800661
Title compound is to use preparation example 16 described programs, by 2-(2-amino-phenyl)-ethanol and the preparation of preparation example 5 De oxadiazoles, 66% productive rate.
APCI MS m/z 380[MH] +
1H NMR(400MHz，CDCl 3)：δ1.95(m，2H)，2.15(m，2H)，2.80(t，2H)，3.10(m，3H)，3.80(m，4H)，4.30(m，2H)，4.65(s，2H)，6.70(m，4H)，7.00(m，2H)，7.50(t，1H)，8.20(d，1H).
Preparation example 22:4-chloro-2-{2-[5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazole-2-ylmethoxy]-ethyl }-phenyl amine
Figure A20048000470800662
Title compound is to use preparation example 16 described programs, by the alcohol and the preparation of preparation example 5 De oxadiazoles of preparation example 12,52% productive rate.
APCI MS m/z 414[MH] +
1H NMR(400MHz，CDCl 3)：δ1.92(m，2H)，2.15(m，2H)，2.77(t，2H)，3.10(m，3H)，3.79(t，2H)，4.28(m，2H)，4.66(s，2H)，6.58(d，1H)，6.62(d，1H)，6.71(d，1H)，6.97(m，2H)，7.49(t，1H)，8.20(d，1H).
Preparation example 23:4-chloro-2-[5-(1-pyrimidine-2-base-piperidin-4-yl)-[1,3,4] oxadiazoles-2-ylmethoxy methyl]-phenyl amine
Figure A20048000470800671
(850 milligrams of (2-amino-5-chloro-phenyl)-methyl alcohol, 5.4 mmole) solution in tetrahydrofuran (THF) (10 milliliters) dropwise is added into sodium hydride (60% in Dormant oils, 215 milligrams, 5.4 mmoles) the ice-cold suspension in tetrahydrofuran (THF) (5 milliliters) stirred 1 hour.The solution of preparation example 6 De oxadiazoles (500 milligrams, 1.79 mmoles) in tetrahydrofuran (THF) (5 milliliters) is through dropwise adding, and mixture was in stirring at room 1 hour.Add methylene dichloride (50 milliliters), solution extracts with water (25 milliliters).The aqueous solution washs with methylene dichloride (2 * 20 milliliters).Merge organic layer with dried over mgso and in decompression evaporation down.Resistates uses ether then to pass through chromatography purification as ethyl acetate as eluent on silica gel, after using the ether development, obtains title compound (320 milligrams), and solid is white in color.
APCI MS m/z 401[MH] +
1H NMR(400MHz，CDCl 3)：δ1.92(m，2H)，2.19(m，2H)，3.24(m，3H)，4.60(s，2H)，4.68(s，2H)，4.75(m，2H)，6.57(m，1H)，6.63(d，1H)，7.08(m，2H)，8.37(d，2H).
Preparation example 24:2-{2-[5-(1-pyrimidine-2-base-piperidin-4-yl)-[1,3,4] oxadiazole-2-ylmethoxy]-ethyl }-phenyl amine
Title compound is to use preparation example 23 described programs, by 2-(2-amino-phenyl)-ethanol and the preparation of preparation example 6 De oxadiazoles, 54% productive rate.
APCI MS m/z 381[MH] +
1H NMR(400MHz，CDCl 3)：δ1.85(m，2H)，2.15(m，2H)，2.88(m，2H)，3.18(m，3H)，1H)，3.80(t，2H)，4.68(s，2H)，4.74(m，2H)，6.51(m，1H)，6.80(m，2H)，7.08(m，2H)，8.37(d，2H).
Preparation example 25:4-[N ' (2-chloro-ethanoyl)-diazanyl carbonyl]-piperidines-1-carboxylic acid tert-butyl ester
Figure A20048000470800681
4-diazanyl carbonyl-piperidines-1-carboxylic acid tert-butyl ester (referring to reference WO 9703986 A119970206) (25 grams, 103 mmoles) is dissolved in methylene dichloride (300 milliliters), adds 4-methylmorpholine (12.5 milliliters, 113 mmoles).Mixture uses the ice bath cooling, dropwise adds chloroacetyl chloride (8.2 milliliters, 103 mmoles).Reaction is warmed to room temperature and stirred 4 hours.Reaction mixture uses sodium bicarbonate aqueous solution to distribute, and with dried over mgso, filters, and filtrate obtains title compound through evaporation, is pale solid (29.6 gram).
APCI MS m/z 318[MH] +
Measured value; C, 48.01; H, 6.91; N, 12.85; C 13H 22N 3O 4Cl 0.3 H 2O calculated value: C, 48.02; H, 7.01; N, 12.92%
Preparation example 26:4-(5-chloromethyl-[1,3,4]-oxadiazoles-2-yl)-piperidines-1-carboxylic acid tert-butyl ester
Figure A20048000470800682
The hydrazides of preparation example 25 (5.0 grams, 15.6 mmoles) is suspended in methylene dichloride (200 milliliters), adds pyridine (6.4 milliliters, 78 mmoles), and mixture is cooled to 10 ℃ subsequently.Dropwise add trifluoacetic anhydride (6.6 milliliters, 39 mmoles) with 15 fens clock times, then in stirring at room 3 hours.Reaction mixture distributes with water (50 milliliters), and organic layer is with dried over mgso.Mixture after filtration, filtrate is in down evaporation of decompression.Resistates obtains title compound in using methyl alcohol to pass through chromatography purification as eluent (2: 98) on the silica gel in methylene dichloride, is pale solid (2.95 gram).
1H NMR(400MHz，CD 3OD)：δ1.45(s，9H)，1.74(m，2H)，2.19(m，2H)，3.04(m，2H)，3.24(m，1H)，4.09(m，2H)，4.85(s，2H)
Preparation example 27:4-[5-(2-amino-5-chloro-benzyloxymethyl)-[1,3,4] oxadiazole-2-yl]-piperidines-1-carboxylic acid tert-butyl ester
Figure A20048000470800691
The solution of (2-amino-5-chloro-phenyl)-methyl alcohol (1 gram, 6.4 mmoles) in tetrahydrofuran (THF) (10 milliliters) dropwise is added into the ice-cooled suspension of sodium hydride (60% in Dormant oils, 215 milligrams, 5.4 mmoles) in tetrahydrofuran (THF) (5 milliliters), stirs 1 hour.The solution of preparation example 26 oxadiazoles (1 gram, 5.3 mmoles) in tetrahydrofuran (THF) (5 milliliters) dropwise is added into wherein, and mixture was in stirring at room 2 hours.Reaction mixture distributes with methylene dichloride (50 milliliters) and sodium hydrogen carbonate solution (25 milliliters).The aqueous solution is with washed with dichloromethane (2 * 20 milliliters).Merge organic layer with dried over mgso and in decompression evaporation down.Resistates uses methyl alcohol to pass through chromatography purification in methylene dichloride (5: 95) as eluent on silica gel, obtains title compound (1.3 gram), is yellow solid.
APCI MS m/z 423[MH] +，323[M-Boc] +
1H NMR(400MHz，CDCl 3)：δ1.47(s，9H)，1.81(m，2H)，2.07(m，2H)，2.96(m，2H)，3.08(m，1H)，4.12(m，2H)，4.23(s，2H)，4.58(s，2H)，4.68(s，2H)，6.62(d，1H)，7.07(s，1H)，7.12(d，1H).
Preparation example 28:4-(8-chloro-4H, 6H-5-Evil-2,3,10b-three azepines-benzo [e] Azulene-1-yl)-piperidines-1-carboxylic acid tert-butyl ester
Toluene-4-sulfonic acid (80 milligrams, 0.46 mmole) is added into the xylene solution of preparation example 27 De oxadiazoles (1.28 grams, 3.0 mmoles), is heated to 140 ℃ of experience 18 hours.Remove dimethylbenzene down in decompression.Resistates distributes with methylene dichloride (100 milliliters) and sodium bicarbonate (25 milliliters).The aqueous solution is with washed with dichloromethane (2 * 20 milliliters).Merge organic layer with dried over mgso and in decompression evaporation down.Resistates obtains title compound (730 milligrams) in using methyl alcohol and ammonium hydroxide in methylene dichloride (5: 0.5: 95) to pass through chromatography purification as eluent on the silica gel, is the lark foams.
APCI MS m/z 405[MH] +，305[M-Boc] +
1H NMR(400MHz，CDCl 3)：δ1.43(s，9H)，1.85(m，2H)，1.96(m，2H)，2.92(m，2H)，3.08(m，1H)，4.18(m，2H)，4.40(s，2H)，4.66(s，2H)，7.36(d，1H)，7.58(m，2H).
Real side value: C, 57.98; H, 6.17; N, 13.40; C 20H 25N 4O 3Cl 0.5 H 2O calculated value: C, 58.04; H, 6.33; N, 13.54%
Preparation example 29:8-chloro-1-piperidin-4-yl-4H, 6H-5-Evil-2,3,10b-three azepines-benzo [e] Azulene
Figure A20048000470800701
The triazole of preparation example 28 (700 milligrams, 1.73 mmoles) is dissolved in 1, and 4-diox (6 milliliters) adds hydrochloric acid (4M in 1,4-diox, 12 milliliters).Reaction mixture was in stirring at room 4 hours.Remove 1, the 4-diox down in decompression.Resistates distributes with methylene dichloride (100 milliliters) and sodium hydrogen carbonate solution (25 milliliters).The aqueous solution is with washed with dichloromethane (2 * 20 milliliters).Merge organic layer with dried over mgso and in decompression evaporation down, obtain title compound (410 milligrams), be the lark foams.
APCI MS m/z 305[MH] +
1H NMR(400MHz，CD 3OD)：δ1.83(m，4H)，2.65(t，2H)，3.09(m，2H)，3.24(m，1H)，4.41(s，2H)，4.58(s，2H)，7.58(m，3H).
Preparation example 30:(2-amino-5-fluoro-phenyl)-methyl alcohol
Title compound is to abide by preparation example 7 described programs, and by 2-amino-5-fluoro-phenylformic acid preparation, 81% productive rate is pale solid.
APCI MS m/z 142[M+H] +
1H NMR(400MHz，CDCl 3)：δ4.60(s，2H)，6.60(dd，1H)，6.77-6.86(m，2H)
Preparation example 31:4-fluoro-2-[5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazoles-2-ylmethoxy methyl]-phenyl amine
Figure A20048000470800711
Title compound is to use preparation example 16 described programs, by the alcohol and the preparation of preparation example 5 De oxadiazoles of preparation example 30,60% productive rate.
APCI MS m/z 384[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.95(dq，2H)，2.18(d，2H)，3.06-3.21(m，3H)，4.33(td，2H)，4.60(s，2H)，4.70(s，2H)，6.58-6.67(m，2H)，6.73(d，1H)，6.80-6.90(m，2H)，7.52(t，1H)，8.19(d，1H).
Preparation example 32:(2-amino-4,5-two fluoro-phenyl)-methyl alcohol
Figure A20048000470800712
Title compound is to abide by preparation example 7 described programs, by 2-amino-4, and the preparation of 5-two fluoro-phenylformic acid, 86% productive rate is yellow solid.
APCI MS m/z 142[M+H-H 2O] +，160[M+H] +
1H NMR(400MHz，CDCl 3)：δ4.10(bs，2H)，4.58(s，2H)，6.48(dd，1H)，6.92(dd，1H)
Preparation example 33:4,5-two fluoro-2-[5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazole-2-ylmethoxy methyl]-phenyl amine
Figure A20048000470800721
Title compound is to use preparation example 16 described programs, by the alcohol and the preparation of preparation example 5 De oxadiazoles of preparation example 32,50% productive rate.
APCI MS m/z 402[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.94(dq，2H)，2.09(bd，1H)，3.09(bt，2H)，3.18(m，1H)，4.20(bs，2H)，4.33(td，2H)，4.54(s，2H)，4.68(s，2H)，6.47(dd，1H)，6.64(t，1H)，6.72(d，1H)6.92(dd，1H)，7.52(t，1H)，8.19，(d，1H)
Preparation example 34:2-amino-5-trifluoromethoxy-phenylformic acid
5-trifluoromethoxy-1H-indoles-2,3-diketone (3.48 grams, 15.0 mmoles) is dissolved in 2N water-based sodium hydroxide (90 milliliters), is cooled to 17 ℃, dropwise adds 30% aqueous hydrogen peroxide solution (2.75 milliliters, 27 mmoles) with 20 fens clock times subsequently.Mixture adds concentrated hydrochloric acid (7 milliliters) subsequently in stirring at room 1 hour.Gained brown precipitation in 50 ℃ of vacuum-dryings 66 hours, obtains title compound (1.83 gram) through leaching, and is brown solid.
APCI MS m/z 220[M-H] +
1H NMR(400MHz，DMSO)：δ6.80(d，1H)7.24(dd，1H)，7.53(d，1H)
Preparation example 35:(2-amino-5-trifluoromethoxy-phenyl)-methyl alcohol
Figure A20048000470800723
Title compound is to abide by preparation example 7 described programs, by the acid preparation of preparation example 34, and 62% productive rate, solid is white in color.
APCI MS m/z 206[M-H] +
1H NMR(400MHz，CDCl 3)：δ4.85(s，2H)，6.67(d，1H)，6.92-7.00(m，2H)
Preparation example 36:2-[5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazoles-2-ylmethoxy methyl]-4-trifluoromethoxy-phenyl amine
Title compound is to use preparation example 16 described programs, by the alcohol and the preparation of preparation example 5 De oxadiazoles of preparation example 35,28% productive rate.
APCI MS m/z 450[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.94(dq，2H)，2.16(bd，1H)，3.09(t，2H)，3.17(m，1H)，4.37(bd，2H)，4.60(s，2H)，4.67(s，2H)，6.60.6.66(m，2H)，6.70(d，1H)，6.95-7.07(m，2H)，7.49(t，1H)8.19，(d，1H)
Preparation example 37:4-methyl-2-[5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazoles-2-ylmethoxy methyl]-phenyl amine
Figure A20048000470800732
Title compound is to use preparation example 16 described programs, by (2-amino-5-methyl-phenyl)-methyl alcohol (with reference to pharmacy archives (1929), 583) and the preparation of preparation example 5 De oxadiazoles, 38% productive rate.
APCI MS m/z 380[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.92(dq，2H)，2.16(bd，2H)，2.19(s，3H)，3.09(t，2H)，3.17(m，1H)，4.37(bd，2H)，4.60(s，2H)，4.67(s，2H)，6.64(m，2H)，6.85(m，3H)，7.58(t，1H)8.09，(d，1H)
Preparation example 38:N-[2-(2-acetylaminohydroxyphenylarsonic acid ethyl)-phenyl]-ethanamide
Figure A20048000470800741
The solution of acetic anhydride (9.6 milliliters, 101 mmoles) in methylene dichloride (50 milliliters) dropwise is added into 2-(2-amino-ethyl)-phenyl amine (with reference to JACS 99, (1977), 5716) and (8.0 grams, 46 mmoles) and the solution of triethylamine (8.4 milliliters, 60 mmoles) in methylene dichloride (200 milliliters).Mixture distributes with water (100 milliliters) subsequently in stirring at room 18 hours.Organic layer is with saturated brine (50 milliliters) washing, with dried over mgso and in decompression evaporation down.Resistates in use on the silica gel methyl alcohol and ammonium hydroxide in methylene dichloride (5: 0.5: 95) as eluent, by chromatography purification, obtain title compound (4.1 gram), be pale solid.
APCI MS m/z 221[M+H] +
1H NMR(400MHz，CDCl 3)：δ2.04(s，3H)，2.33(s，3H)，2.81(t，2H)，3.28(m，2H)，6.19(bs，1H)，7.03(bt，1H)，7.07(d，1H)，7.22(m，1H)，8.11(d，1H)，8.88(bs，1H)
Measured value: C, 65.18; H, 7.27%; N, 12.70%; C 12H 16N 2O 2Calculated value: C, 65.43%; H, 7.32%; N, 12.72%
Preparation example 39:N-[2-(2-acetylaminohydroxyphenylarsonic acid ethyl)-4-chloro-phenyl]-ethanamide
The solution of the Glacial acetic acid of chlorine (1.22M, 29 milliliters) dropwise was added into the solution of Glacial acetic acid (70 milliliters) of the ethanamide (7.78 gram, 35 mmoles) of preparation example 38, in stirring at room 2 hours.Go down except that Glacial acetic acid in decompression.The gained solid uses the mixture development of ethyl acetate and propan-2-ol (7: 3,20 milliliters), obtains title compound (4.83 gram) in filtering the back, is the lark solid.
ESI MS m/z 277[M+Na] +
1H NMR(400MHz，CDCl 3)：δ2.03(s，3H)，2.33(s，3H)，2.79(m，2H)，3.22(m，2H)，6.28(bs，1H)，7.05(s，1H)，7.20(dd，1H)，8.14(d，1H)，9.09(bs，1H)
Preparation example 40:2-(2-amino-ethyl)-4-chloro-phenyl amine dihydrochloride
Figure A20048000470800751
Preparation example 39 compounds (4.83 gram, 19 mmoles) are suspended in 2 volumetric molar concentration water-based hydrochloric acid (50 milliliters), be heated to 100 ℃ 18 hours.Evaporate the acquisition red solid down in decompression, solid uses propan-2-ol (15 milliliters) development, and acquisition title compound after filtering is grey peachiness solid (3.5 gram).
ESI MS m/z 171[M+H] +
1H NMR(400MHz，DMSO-d 6)：δ3.00(t，2H)，3.12(m，2H)，7.38(dd，1H)，7.40(d，1H)，7.46(d，1H)，8.15(bs，3H)
Measured value C, 39.29%; H, 5.45%; N, 11.46%; C 8H 11N 22HCl calculated value: C, 39.45%; H, 5.38%; N, 11.50%
Preparation example 41:4-chloro-2-(2-{[5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazole-2-ylmethyl]-amino }-ethyl)-phenyl amine
Figure A20048000470800752
The amine of preparation example 40 (3.5 grams, 14.4 the solution of tetrahydrofuran (THF) mmole) (50 milliliters) is added into preparation example 5 De oxadiazoles (4.0 grams, 14.4 mmole) and the solution of the tetrahydrofuran (THF) (50 milliliters) of triethylamine (7.0 milliliters, 50 mmoles), be heated to 50 ℃ and go through 4 hours.Reaction mixture is in decompression evaporation down, and resistates uses ethyl acetate as eluent on silica gel, then uses methyl alcohol and ammonium hydroxide in methylene dichloride (5: 0.5: 95) to obtain title compound by chromatography purification, is brown oil (1.35 gram).
APCI MS m/z 413[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.92(dq，2H)，2.15(bdd，2H)，2.68(t，2H)，2.93(t，2H)，3.07(dt，2H)，3.14(m，1H)，4.01(s，2H)，4.31(btd，2H)，6.57(d，1H)，6.62(dd，1H)，6.70(d，1H)，6.95-7.02(m，2H)，7.27(t，1H)，8.19(d，1H)
Preparation example 42: morpholine-2,4-dicarboxylic acid-4-tert-butyl ester 2-ethyl ester
4-phenyl methyl-2-morpholine carboxylic acid, ethyl ester (medical chemistry magazine 1993,36 (6), 683-9), (8.4 grams, 32.4 mmoles), tert-Butyl dicarbonate (8.47 grams, 38.9 mmole), the 1-methyl isophthalic acid, 4-cyclohexadiene (12.37 milliliters, 110 mmoles) and the mixture heating up to 88 of 10% palladium/carbon (900 milligrams) in ethanol (300 milliliters) ℃ are gone through 22 hours.TLC analyzes and shows the still residual starting material that has, and therefore will react cooling, adds the 1-methyl isophthalic acid again, and 4-cyclohexadiene (2.37 milliliters, 21 mmoles) and 10% palladium/carbon (900 milligrams), reaction mixture are again in 88 ℃ of heating 12 hours.Cooled mixture filters through Ya Bosai (Arbocel), and filtrate is in decompression evaporation down.Remaining brown oil is used methylene dichloride in silica gel: the gradient of methyl alcohol (100: 0 to 95: 5) obtains title compound by the column chromatography purifying, is lark oil, 5.97 grams.
1H NMR(400MHz，CDCl 3)：δ1.30(t，3H)，1.43(s，9H)，3.10(m，2H)，3.50-3.70(m，2H)，4.01(m，1H)，4.25(q，2H).
Preparation example 43: morpholine-2, the 4-dicarboxylic acid 4-tert-butyl ester
Figure A20048000470800762
Lithium hydroxide (28 milliliters, 1M in water, 28 mmoles) be added into the solution of the ester that derives from preparation example 42 (2.85 grams, 11 mmoles) in tetrahydrofuran (THF) (30 milliliters), solution was in stirring at room 19 hours.Mixture uses the 2M hcl acidifying to pH3, extracts with methylene dichloride (2 * 70 milliliters) then.Merge organic extract with dried over mgso and in decompression evaporation down, obtain title compound, be yellow solid, 2.36 grams.
1H NMR(400MHz，CDCl 3)：δ1.47(s，9H)，3.03-3.11(m，3H)，3.60(m，1H)，3.77-3.86(m，1H)，4.02(m，1H)，4.15-4.23(m，1H).
Preparation example 44:6-methylene radical-[1,4] oxygen azepine ring-4-in heptan carboxylic acid tert-butyl ester
Figure A20048000470800771
Sodium hydride (992.6 milligrams, 60% in Dormant oils, 24.8 mmoles) is in-2 ℃ of solution that are divided into several parts and are added into the 1-methyl-2-Pyrrolizidine ketone (20 milliliters) of (2-hydroxyl-ethyl)-t-butyl carbamate (2 grams, 12.4 mmoles), and holding temperature is lower than 5 ℃.Mixture stirred 30 minutes then, was cooled to-5 ℃, dropwise added the solution of the 1-Methyl-2-Pyrrolidone (10 milliliters) of 3-chloro-2-chloromethyl-1-propylene (1.44 milliliters, 12.4 mmoles), and holding temperature is lower than 3 ℃.In case add and to finish, allow reaction mixture be warmed to room temperature and stirred again 18 hours.Reaction mixture is with the water dilution and with ether extraction (2 * 50 milliliters).Merge organic extract with dried over mgso, and in decompression evaporation down.Irreducible oil uses ethyl acetate in silica gel: pentane (10: 90) obtains title compound and is clarified oil, 713 milligrams by the tubing string chromatography purification. 1H NMR(400MHz，CDCl 3)：δ1.46(s，9H)，3.51(d，2H)，3.72(d，2H)，4.00-4.20(m，4H)，4.95(s，1H)，5.04(s，1H).
APCI m/z 236[MNa] +
Preparation example 45:6-oxo-[1,4] oxygen azepine ring-4-in heptan carboxylic acid tert-butyl ester
Sodium periodate (1.0 grams, 4.69 mmole) then be (0.15 milliliter of perosmic anhydride, 2.5wt% is in t-butanol solution, 0.014 mmole) be added into (500 milligrams in the alkene that derives from preparation example 44,2.34 the suspension of mmole) De diox (10 milliliters) and water (10 milliliters) reacted on stirring at room 48 hours.Reaction adds salt solution with water (50 milliliters) dilution, and mixture is with ethyl acetate extraction.Merge organic extract with dried over mgso and in decompression evaporation down, obtain title compound, be brown oil, 567 milligrams.
1H NMR(400MHz，CDCl 3)：δ1.47(s，9H)，3.68(m，2H)，3.91(br m，2H)，4.06(br m，2H)，4.11(s，2H).
APCI m/z 233[M+NH 4] +
Preparation example 46:2-(2-methylamino-ethyl)-phenyl amine
Figure A20048000470800781
(WO 9803473, and pg100) (3 gram, 16.65 mmoles) and Raney nickel (500 milligrams) were connected to 60psi and room temperature hydrogenation 2 hours in the mixture of ethanol (50 milliliters) for N-methyl-N-(2-(2-nitrophenyl) ethyl) amine.Mixture filters through C salt, and filtrate obtains title compound in decompression evaporation down, is oil.
APCI MS m/z 152[MH] +
Preparation example 47:2-(1-methylamino-ethyl)-phenyl amine
Acetate (10) is added into methylamine (10 gram) and is cooled to 5 ℃ solution in methylene dichloride (150 milliliters), then adds neighbour-aminoacetophenone (3.5 grams, 25.9 mmoles), solution stirring 10 minutes.Add triacetyl oxygen sodium borohydride (1.5 grams, 38.8 mmoles), reacted on stirring at room 72 hours.Reaction is diluted with water, separates each layer, and organic solution obtains title compound in decompression evaporation down, is yellow oil.
1H NMR(400MHz，CDCl 3)：δ1.44(s，3H)，2.36(s，3H)，4.77-5.08(brs，1H)，6.56-6.78(m，2H)，7.02(m，2H).
Preparation example 48:N-{2-[2-(ethanoyl-methyl-amino)-ethyl]-phenyl }-ethanamide
4-methylmorpholine (4.45 gram, 44 mmoles) and acetic anhydride (4.49 grams, 44 mmoles) be added into derive from preparation example 46 amine (2.2 grams, 14.67 mmoles) in methylene dichloride (50 milliliters) with ice-cooled solution.Add 4-pyrrolidino pyridine (100 milligrams, 0.7 mmole) then, reaction mixture was in stirring at room 2 hours.Reaction mixture is with dilute hydrochloric acid washing (2 times), and sodium carbonate solution washing (2 times) reaches salt water washing (2 times).With dried over mgso and in decompression evaporation down, obtain title compound and be oil.
1H NMR(400MHz，CDCl 3)：δ2.16(s，3H)，2.36(s，3H)，2.80(m，2H)，3.14(s，3H)，3.36(m，2H)，7.01(m，1H)，7.18(m，1H)，7.22(m，1H)，8.22(d，1H)，9.22(s，1H).
APCI m/z 235[MH] +
Preparation example 49:N-(2-[1-(ethanoyl-methyl-amino)-ethyl]-phenyl }-ethanamide
Figure A20048000470800792
Title compound is to abide by similar preparation example 48 described programs, but does not add 4-pyrrolidino pyridine, and amine and acetic anhydride acquisition by preparation example 47 are oil.
1H NMR(400MHz，CDCl 3)：δ1.55(d，3H)，2.16(s，3H)，2.20(s，3H)，2.78(s，3H)，6.02(q，1H)，7.09(m，2H)，7.36(m，2H)，8.25(d，1H)，9.40(brs，1H).
APCI MS m/z 257[MNa] +
Preparation example 50:N-{2-[2-(ethanoyl-methyl-amino)-ethyl]-4-chloro-phenyl }-ethanamide
Figure A20048000470800801
Chlorine (7.3 gram) feeds acetate (102 gram).Part solution (15 gram) be added into preparation example 48 compounds (3.3 grams, 14.1 mmoles) in acetate (50 milliliters) with ice-cold solution, reacted on stirring at room 20 hours.Mixture concentrates down in decompression, and resistates is dissolved in ethyl acetate.This solution is with saturated sodium carbonate and salt water washing.With dried over mgso and in decompression evaporation down, obtain title compound then, be brown solid, 2.7 grams.
1H NMR(400MHz，CDCl 3)：δ2.16(s，3H)，2.30(s，3H)，2.78(m，2H)，3.12(s，3H)，3.30(m，2H)，7.05(s，1H)，7.19(d，1H)，8.20(d，1H)，9.38(s，1H).
APCI MS m/z 291[MNa] +
Preparation example 51:N-{2-[1-(ethanoyl-methyl-amino)-ethyl]-4-chloro-phenyl }-ethanamide
Figure A20048000470800802
Chlorine (1.88 gram) feeds the solution of preparation example 49 compounds (6.4 grams, 26.6 mmoles) in acetate (30 milliliters), reacts on stirring at room 24 hours.Mixture concentrates down in decompression, and resistates is suspended in ethyl acetate.Solution is with sodium hydrogen carbonate solution and salt water washing, subsequently with dried over mgso and in decompression evaporation down.Product obtains title compound by isopropyl ether and recrystallizing methanol, 3.5 grams.
1H NMR(400MHz，CDCl 3)：δ1.60(d，3H)，2.16(s，3H)，2.20(s，3H)，2.79(s，3H)，6.00(q，1H)，7.24(m，1H)，8.25(d，1H)，9.39(s，1H).
APCI MS m/z 291[MH] +
Preparation example 52:4-chloro-2-(2-methylamino-ethyl)-phenyl amine
Preparation example 50 compounds (2.6 gram, 9.68 mmoles) stirred 1 hour in 80 ℃ in the solution of 2N hydrochloric acid (100 milliliters), again in stirring at room 72 hours.TLC analyzes demonstration and still has starting material residual, therefore adds 12N hydrochloric acid (50 milliliters) again, reacts on 90 ℃ and stirs again 3 hours.Cooled mixture makes use 0.88 ammonia alkaliization, then with ethyl acetate extraction (3 times).Merge organic extract with formaldehyde solution (3 times) and salt solution (2 times) washing, with dried over mgso and in decompression evaporation down, obtain title compound subsequently, be oil, 1.29 grams.
1H NMR(400MHz，CDCl 3)：δ2.42(s，3H)，2.65(t，2H)，2.83(t，2H)，6.59(d，1H)，6.99(m，2H).
Preparation example 53:4-chloro-2-(1-methylamino-ethyl)-phenyl amine
The solution of the compound of preparation example 49 (3.40 grams, 12.65 mmoles) in 12N hydrochloric acid (150 milliliters) stirred 24 hours in 100 ℃.Cooled solution is carefully handled with 0.88 ammonia soln, with dichloromethane extraction (3 times).Merge organic extract with dried over mgso and in decompression evaporation down, obtain oil, 2.24 grams.
1H NMR(400MHz，CDCl 3)：δ1.42(d，3H)，2.38(s，3H)，3.76(q，1H)，6.50(d，1H)，6.99(m，2H).
APCI MZ m/z 185[MH] +
Preparation example 54:2-(5-chloro-2-nitro-phenoxy) ethanol
(125 milligrams of sodium hydrides, 60% in the Dormant oils dispersion liquid, 3.13 mmoles) be added into (0.18 milliliter of 4-chloro-2-fluoronitrobenzene (500 milligrams, 2.85 mmoles) and ethylene glycol, 3.13 the mixture in 1-Methyl-2-Pyrrolidone (5 milliliters) mmole) reacts on 80 ℃ and stirred 18 hours.TLC analyzes and shows that starting material is still residual, therefore adds additional quantity sodium hydride (114 milligrams, 60% in the dispersion liquid of Dormant oils, 2.85 mmoles) and ethylene glycol (0.82 milliliter, 14.25 mmoles) again, and reaction was stirred 18 hours in 110 ℃ again.Cooled mixture is allocated in water and methylene dichloride, separates each layer.Organic phase is with dried over mgso and in decompression evaporation down.Resistates uses ethyl acetate on silica gel: pentane (50: 50) by the column chromatography purifying, obtains title compound as eluent, is solid, 290 milligrams.
1H NMR(400MHz，CDCl 3)：δ4.00(t，2H)，4.22(t，2H)，7.04(d，1H)，7.10(s，1H)，7.85(d，1H).
Preparation example 55:3-[(5-chloro-2-nitro-benzyl)-amino]-methyl propionate
4 dust molecular sieve powder (16.9 gram) and lithium hydroxide monohydrate (1.80 grams, 43 mmoles) be in N, and the mixture in the dinethylformamide (100 milliliters) was in stirring at room 20 minutes.Add β-Beta Alanine methyl ester hydrochloride (5.0 grams, 35.8 mmoles), mixture stirred again 45 minutes.(heterocyclic chemistry periodical 1972.9 (1), 119-22) (8.98 grams, 35.8 mmoles) reacted on stirring at room 16 hours to add 2-(brooethyl)-4-chloro-1-oil of mirbane.Mixture after filtration, filtrate, then with salt solution (3 * 150 milliliters) washing and extracts with 2N hydrochloric acid (2 * 75 milliliters) with ethyl acetate (150 milliliters) dilution.Merge the acid extract thing and use the yellow soda ash alkalization, then with ethyl acetate extraction.Merge organic extract with dried over mgso, and evaporation obtains title compound under decompression, 1.29 grams.
1H NMR(400MHz，CDCl 3)：δ2.56(t，2H)，2.90(t，2H)，3.69(s，3H)，4.05(s，2H)，7.38(dd，1H)，7.72(d，1H)，7.94(d，1H).
APCI MS m/z 272[M-H] -
Preparation example 56:3-[(5-chloro-2-nitro-benzyl)-methyl-amino]-methyl propionate
Figure A20048000470800822
Formaldehyde (37% aqueous solution, 1.2 gram, 26 mmoles), then be triacetyl oxygen sodium borohydride (7.7 grams, 36.4 mmole) and formic acid (30% aqueous solution, 3.1 the gram, 104 mmoles) be added into preparation example 55 amine (7.1 the gram, 26 mmoles) in methylene dichloride (70 milliliters), reacted on stirring at room 18 hours.Mixture concentrates down in decompression, and resistates dilutes with ethyl acetate, and solution is with 1N sodium hydroxide and salt water washing.Solution concentrates down in decompression, and crude product uses pentane in silica gel: the gradient of ethyl acetate (100: 0 to 95: 5) by the column chromatography purifying, obtains title compound, 6 grams.
1H NMR(400MHz，CDCl 3)：δ2.20(s，3H)，2.44(t，2H)，2.72(t，2H)，3.64(s，3H)，3.78(s，2H)，7.35(dd，1H)，7.63(s，1H)，7.80(d，1H).
Preparation example 57:2-(2-amino-5-chloro-phenoxy group)-ethanol
Figure A20048000470800831
Preparation example 56 compounds (280 milligrams, 1.29 mmoles) and the mixture of platinum oxide (80 milligrams) in ethanol (25 milliliters) were in room temperature and 60psi hydrogenation 5 hours.Mixture thoroughly washs with additional quantity ethanol after filtration, and filtrate is in decompression evaporation down.Crude product uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5), by the column chromatography purifying, obtain title compound, and be pale solid, 195 milligrams.
1H NMR(400MHz，CDCl 3)：δ3.98(t，2H)，4.16(t，2H)，6.75(d，1H)，6.82(m，2H).
APCI MS m/z 188[MH] +
Preparation example 58:3-[(2-amino-5-chloro-benzyl)-methyl-amino]-methyl propionate
Figure A20048000470800832
Preparation example 56 compounds (6.01 gram, 22.0 mmoles) and the mixture of platinum oxide (500 milligrams) in ethanol (100 milliliters) were in 60psi and room temperature hydrogenation 1 hour.Mixture filters through C salt, and filtrate is in decompression evaporation down.Crude product uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (90: 10: 1) obtains title compound by the column chromatography purifying.
1H NMR(400MHz，CDCl 3)：δ2.16(s，3H)，2.50(t，2H)，2.72(t，2H)，3.44(s，2H)，3.63(s，3H)，4.62(br s，2H)，6.56(d，1H)，6.98(s，1H)，7.01(dd，1H).
Preparation example 59:3-[(2-amino-5-chloro-benzyl)-methyl-amino]-the propionic acid dihydrochloride
The mixture of the ester of preparation example 58 (1.1 gram, 4.3 mmoles) in tetrahydrofuran (THF) (10 milliliters), in water (1.4 milliliters) and the hydrochloric acid Yu diox (4M, 10 milliliters) be in stirring at room 2 hours, and stirred 8 hours in 90 ℃.Cold soln concentrates down in decompression, and resistates and ethyl acetate and methylbenzene azeotropic distillation obtain title compound.
1H NMR(400MHz，DMSOd 6)：δ2.62(s，3H)，2.81(t，2H)，3.30(t，2H)，4.22(s，2H)，6.78(m，1H)，7.18(d，1H)，7.39(s，1H).
APCI MS m/z 243[MH] +
Preparation example 60: methyl-[5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazole-2-ylmethyl]-amine
Methylamine (2.23 milliliters, 33% ethanolic soln, 17.9 mmoles) is added into the solution of the muriate that derives from preparation example 5 (1 gram, 3.59 mmoles) in tetrahydrofuran (THF) (20 milliliters), and solution was in stirring at room 18 hours.Add additional quantity methylamine (10 milliliters, 33% ethanolic soln), reaction was stirred again 72 hours.React on decompression evaporation down, solid is developed with ethyl acetate, and precipitation is removed by filtering.Filtrate concentrates down in decompression, and resistates and methylene dichloride component distillation obtain title compound, are crystalline solid.
1H NMR(400MHz，CDCl 3)：δ1.98(m，2H)，2.17(brd，2H)，2.48(s，3H)，3.18(t，2H)，3.35(m，1H)，3.95(s，2H)，4.58(br d，2H)，6.62(dd，1H)，6.68(d，1H)，7.46(dd，1H)，8.18(d，1H).
APCI m/z 274[MH] +
Preparation example 61:4-chloro-2-{2-[5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazole-2-ylmethoxy]-oxyethyl group }-phenyl amine
Figure A20048000470800851
Sodium hydride (60% in Dormant oils, 45 milligrams, 1.1 mmoles) is added into the ice-cold solution of alcohol (190 milligrams, 1 mmole) in tetrahydrofuran (THF) (10 milliliters) that derives from preparation example 57, solution stirring 30 minutes.Add the solution of muriate (310 milligrams, 1.1 mmoles) in tetrahydrofuran (THF) (6 milliliters) that derives from preparation example 5, reacted on stirring at room 18 hours.Reaction is by adding water (1 milliliter) cancellation, and mixture is allocated in methylene dichloride and saturated sodium bicarbonate aqueous solution then.Separate each layer, organic phase is with dried over mgso, and evaporation under decompression.Resistates uses ethyl acetate in silica gel: the gradient of methyl alcohol (96: 4 to 95: 5), obtain title compound by the column chromatography purifying, and be grey orange oil, 280 milligrams.
1H NMR(400MHz，CDCl 3)：δ1.99(m，2H)，2.20(m，2H)，3.18(m，3H)，2.96(m，2H)，4.18(m，2H)，4.30(m，2H)，4.80(s，2H)，6.60-6.80(m，5H)，7.55(m，1H)，8.20(m，1H).
APCI MS m/z 452[MNa] +
Preparation example 62:2-amino-5-chloro-N-methyl-N-[5-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-[1,3,4] oxadiazole-2-ylmethyl]-benzyl acid amides
Figure A20048000470800852
(314 milligrams of 5-chloro-o-amino benzoic acids, 1.83 mmole), (350 milligrams of 1-(3-dimethylaminopropyl)-3-ethyl first imide hydrochloride, 1.83 mmole) and (0.4 milliliter of N-methylmorpholine, 3.64 mmole) be added into (500 milligrams of amine that derive from preparation example 60,1.83 mmole) solution in methylene dichloride (20 milliliters) reacted on stirring at room 3 hours.Reaction mixture is with 10% citric acid solution, saturated sodium bicarbonate solution and salt water washing, then with dried over mgso and in decompression evaporation down.Merge water with methylene dichloride (2 * 25 milliliters) extraction, the combined dichloromethane extract is in decompression evaporation down.Merge crude product and use ethyl acetate as eluent in silica gel, by the column chromatography purifying, product and methylene dichloride and ether component distillation obtain title compound, the solid that is white in color, 278 milligrams.
1H NMR(400MHz，CDCl 3)：δ1.92(m，2H)，2.16(d，2H)，3.02-3.22(m，6H)，4.32(d，2H)，4.85(br s，2H)，6.63(m，2H)，6.70(d，1H)，7.14(m，2H)，7.50(dd，1H)，8.20(d，1H).
APCI MS m/z 427[MH] +
Preparation example 63:4-chloro-2-(the 2-{ methyl-[5-(1-pyrimidine-2-base-piperidin-4-yl)-[1,3,4] oxadiazole-2-ylmethyl]-amino }-ethyl)-phenyl amine
Figure A20048000470800861
Derive from amine (1.1 grams of preparation example 52,5.96 mmole), derive from muriate (1.51 grams of preparation example 6,5.42 mmole), N-methylmorpholine (0.60 gram, 5.96 mmole) and the mixture of sodium iodide (400 milligrams, 2.66 mmoles) in tetrahydrofuran (THF) (50 milliliters) stirred 18 hours in 50 ℃.React on decompression and concentrate down, resistates is dissolved in ethyl acetate.Solution reaches with the salt water washing with water washing (3 times), and with dried over mgso and in decompression evaporation down, the acquisition title compound is yellow oil, 1.77 grams then.
APCI MS m/z 428[MH] +
Preparation example 64:4-chloro-2-(1-{[4-(4-chloro-phenyl)-5-(1-pyrimidine-2-base-piperidin-4-yl)-4H-[1,2,4] triazole-3-ylmethyl]-methyl-amino }-ethyl)-phenyl amine
Figure A20048000470800871
Derive from the muriate (1.37 gram, 4.92 mmoles) of preparation example 6, derive from the amine (1.0 grams, 5.41 mmoles) of preparation example 53 and the mixture of salt of wormwood (0.75 gram, 5.41 mmoles) in tetrahydrofuran (THF) (50 milliliters) in stirring at room 18 hours.Add sodium iodide (40 milligrams, 2.67 mmoles), stirring reaction is 24 hours again.React on decompression and concentrate down, resistates is dissolved in ethyl acetate, and solution is with the salt water washing.Solution is with dried over mgso and in decompression evaporation down.Crude product uses methylene dichloride in silica gel: methyl alcohol (99: 1) obtains title compound by the column chromatography purifying, is oil, 1.30 grams.
1H NMR(400MHz，CDCl 3)：δ1.45(d，3H)，1.86(m，2H)，2.18(m，2H)，2.35(s，3H)，3.20(m，3H)，3.78(m，2H)，3.88(d，1H)，4.74(m，2H)，6.50(dd，1H)，6.58(d，1H)，7.00(m，2H)，8.32(s，2H).
APCI MS m/z 428[MH] +
Preparation example 65:3-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-carbonyl]-tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20048000470800872
(426 milligrams in I-hydroxybenzotriazole hydrate, 3.16 mmole), 1-(3-dimethylaminopropyl)-3-ethyl first imide hydrochloride is (658 milligrams, 3.42 mmole), triethylamine is (0.91 milliliter, 6.58 mmole) and the 1-tertiary butyl-1,3-tetramethyleneimine dicarboxylic ester (medical chemistry periodical 44; 1; 2001; 94-1004) (900 milligrams, 3.95 mmoles) are added into the suspension of amine (1 gram, 2.63 mmoles) in methylene dichloride (20 milliliters) that derives from embodiment 4, react on stirring at room 3 hours.TLC analyzes and shows the still residual starting material that has, therefore add (355 milligrams in additional quantity I-hydroxybenzotriazole hydrate, 2.63 mmole), 1-(3-dimethylaminopropyl)-3-ethyl first imide hydrochloride is (506 milligrams, 2.63 mmole) and the 1-tertiary butyl-1, (600 milligrams of 3-tetramethyleneimine dicarboxylic esters, 2.63 mmole), reaction was stirred again 18 hours.The mixture branch is dissolved in 2N sodium hydroxide solution and methylene dichloride, separates each layer.Organic solution is in decompression evaporation down, and resistates uses methylene dichloride in silica gel: methyl alcohol (95: 5), obtains title compound and is the canescence foams, 690 milligrams by the column chromatography purifying as eluent.
1H NMR(400MHz，CDCl 3)：δ1.41(s，9H)，1.68-2.30(m，6H)，2.81-3.18(m，3H)，3.20-3.81(m，5H)，3.83-5.36(m，6H)，6.60(dd，1H)，6.66(d，1H)，7.38-7.62(m，4H)，8.18(m，1H).
APCI MS m/z 578[MH] +
Preparation example 66 to 72:
Following general formula compound:
Be by embodiment 4 and suitably acid, prepare in accordance with similar preparation example 65 described programs.
Figure A20048000470800891
A-4-(tertbutyloxycarbonyl) morpholine-3-carboxylic acid (WO 03035077, and embodiment 6, step 1,88 pages) is used as starting acid.
Preparation example 73:3-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-azetidine-1-carboxylic acid tert-butyl ester
Figure A20048000470800901
3-oxo-a word used for translation is stung pyridine-1-carboxylic acid tert-butyl ester, and (JP 2002/255932, the 6th page) (562 milligrams, 3.16 mmole) and triacetyl oxygen sodium borohydride (1.12 the gram, 5.26 mmole) be added into amine (1 gram that derives from embodiment 4,2.63 mmole) suspension in methylene dichloride (50 milliliters) reacted on stirring at room 72 hours.The mixture branch is dissolved in 2N sodium hydroxide solution and methylene dichloride, separates each layer, and organic solution is in decompression evaporation down.Remaining yellow oil uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5) is as eluent, by the tubing string chromatography purification, obtains the title compound foams that are white in color.
1H NMR(400MHz，CDCl 3)：δ1.42(s，9H)，1.60-2.46(m，4H)，2.90-3.00(m，2H)，3.12(m，1H)，3.50(m，2H)，3.79-3.90(m，3H)，3.99-4.60(m，6H)，6.60(m，1H)，6.60(d，1H)，7.28(d，1H)，7.42-7.56(m，2H)，7.58(dd，1H)，8.18(m，1H).
APCI MS m/z 558[MNa] +
Preparation example 74:3-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20048000470800902
Title compound is to abide by preparation example 73 described similar programs, but also adds acetate (3) to reaction, and amine and 3-oxo-tetramethyleneimine-1-carboxylic acid tert-butyl ester acquisition by embodiment 4 are pale solid, 53% productive rate.
1H NMR(400MHz，CDCl 3)：δ1.44(s，9H)，1.50-1.70(m，2H)，1.75-2.55(m，5H)，2.80-3.90(m，11H)，4.20-4.45(m，2H)，6.60(dd，1H)，6.66(d，1H)，7.35(d，1H)，7.41-7.57(m，3H)，8.18(d，1H).
APCI MS m/z 572[MNa] +
Preparation example 75:4-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-piperidines-1-carboxylic acid tert-butyl ester
(628 milligrams of the 4-oxos-piperidine carboxylic acid tert-butyl ester, 3.16 mmole) and triacetyl oxygen sodium borohydride (1.12 the gram, 5.26 mmole) be added into the suspension of amine (1 gram, 2.63 mmoles) in methylene dichloride (50 milliliters) of embodiment 4, reacted on stirring at room 72 hours.TLC analyzes and shows still have starting material residual, therefore adds 4-oxo-piperidine carboxylic acid tert-butyl ester (628 milligrams, 3.16 mmoles) and triacetyl oxygen sodium borohydride (1.12 grams, 5.26 mmoles) again, and reaction was stirred again 5 hours.The mixture branch is dissolved in 2N sodium hydroxide (100 milliliters) and methylene dichloride (100 milliliters), separates each layer.Organic phase with dried over mgso and in decompression evaporation down, obtains title compound with salt solution (100 milliliters) washing, is colourless jelly.
1H NMR(400MHz，CDCl 3)：δ1.42(s，9H)，1.72-2.20(m，8H)，2.40(m，2H)，2.61-2.78(m，1H)，2.92-3.20(m，2H)，3.40-3.60(m，1H)，3.70(m，2H)，3.82(m，2H)，4.04-4.19(m，2H)，4.34(m，2H)，6.60(m，1H)，6.66(d，1H)，7.32(d，1H)，7.42-56(m，3H)，8.18(m，1H).
Preparation example 76:6-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-[1,4] oxygen azepine ring-4-in heptan carboxylic acid
Derive from (286 milligrams of the ketone of preparation example 45,1.33 the solution of methylene dichloride mmole) (5 milliliters), then be (281.5 milligrams of triacetyl oxygen sodium borohydrides, 1.33 mmole) be added into (500 milligrams of the amine of embodiment 4,1.31 the suspension of methylene dichloride mmole) (20 milliliters) reacted on stirring at room 18 hours.TLC analyzes and shows the still residual starting material that has, so adds ketone (250 milligrams, 1.16 mmoles) again, and reaction was stirred again 70 hours.Add saturated sodium bicarbonate solution (15 milliliters), mixture was in stirring at room 30 minutes.Separate each layer, organic phase is with the salt water washing, with dried over mgso and in decompression evaporation down.Remaining brown oil is used methylene dichloride in silica gel: methyl alcohol (95: 5) by the tubing string chromatography purification, obtains title compound, 189 milligrams as eluent.
APCI MS m/z 580[MH] +
Preparation example 77:1-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-2-dimethylamino-ethyl ketone
Figure A20048000470800922
(107 milligrams in I-hydroxybenzotriazole hydrate, 0.79 mmole), 1-(3-dimethylaminopropyl)-3-ethyl first imide hydrochloride is (184 milligrams, 0.86 mmole), triethylamine is (0.23 milliliter, 1.65 mmole) and N, (71.2 milligrams of N-N-methylsarcosines, 0.69 mmole) be added into the suspension of methylene dichloride (10 milliliters) of the amine (250 milligrams, 0.66 mmole) of embodiment 4, reacted on stirring at room 18 hours.The reaction branch is dissolved in 2N sodium hydroxide solution (10 milliliters) and methylene dichloride (10 milliliters), separates each layer, and water extracts with methylene dichloride (10 milliliters) again.Merge organic solution with salt solution (20 milliliters) washing, with dried over mgso and in decompression evaporation down.Remaining jelly uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5) by the tubing string chromatography purification, obtains title compound, the foams that are white in color, 220 milligrams.
1H NMR(400MHz，CDCl 3)：δ1.58-1.88(m，4H)，2.20-2.40(2xs，6H)，2.60-4.60(m，9H)，5.28-5.60(m，2H)，6.60(m，1H)，6.66(d，1H)，7.40(dd，1H)，7.46(m，1H)，7.57(m，1H)，7.60(d，1H)，8.18(m，1H).
APCI MS m/z 466[MH] +
Preparation example 78:8-chloro-5-methyl-3,4,5,6-tetrahydrochysene-1H-benzo [b] [1,5] diazocine ring-2-ketone
Figure A20048000470800931
Derive from compound (1.35 grams of preparation example 59,4.3 mmole), (2.2 milliliters of N-methylmorpholines, 19.3 mmole) and O-benzotriazole-1-base-N, N, N ', the mixture of N '-tetramethyl-urea hexafluorophosphate (2.3 gram, 6 mmoles) in methylene dichloride (100 milliliters) was in stirring at room 18 hours.Reaction is with 1M sodium hydroxide solution washing (3 times), and Yi Shui and salt water washing concentrate down with dried over mgso and in decompression then.Resistates is developed with ethyl acetate, and the gained solid obtains title compound through leaching and drying.Filtrate concentrates down in decompression, and resistates uses methylene dichloride in silica gel: methyl alcohol (100: 0 to 95: 5) obtains extra title compound by the tubing string chromatography purification, and 550 milligrams, the solid that is white in color (total amount).
1H NMR(400MHz，CDCl 3)：δ2.30(m，2H)，2.45(s，3H)，2.98(m，2H)，3.60(s，2H)，7.04(d，1H)，7.25(d，1H)，7.38(s，1H)，7.78(br s，1H).
APCI MS m/z 225[MH] +
Preparation example 79:8-chloro-5-methyl-3,4,5,6-tetrahydrochysene-1H-benzo [b] [1,5] diazocine ring-2-thioketones
Figure A20048000470800932
Yellow soda ash (254 milligrams, 2.4 mmoles) be added into thiophosphoric anhydride (1.07 gram, 2.4 mmoles) in tetrahydrofuran (THF) (5.5 milliliters) in 5 ℃ solution.Solution is cooled to 3 ℃, adds the compound (540 milligrams, 2.4 mmoles) that derives from preparation example 78.Dropwise add water (83 microlitres, 4.6 mmoles), the gained mixture was in stirring at room 18 hours.Reaction is diluted with 0.88 ammonia, with dichloromethane extraction (2 times).Merge organic extract with the salt water washing, with dried over mgso and in decompression evaporation down.Resistates is adsorbed in silica gel, uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (100: 0: 0 to 90: 10: 1) obtains title compound (0.23 gram) by the tubing string chromatography purification.
1H NMR(400MHz，CDCl 3)：δ2.42(s，3H)，2.78(m，2H)，3.12(m，2H)，3.60(s，2H)，7.10(d，1H)，7.33(d，1H)，7.40(s，1H)，9.50(brs，1H).
APCI MS m/z 241[MH] +
Preparation example 80:8-chloro-5-methyl-2-methyl sulfane base-3,4,5, the hot ring of 6-tetrahydrochysene-benzo [b] [1,5] phenodiazine one alkene
Figure A20048000470800941
Uncle's fourth potassium oxide (0.55 milliliter, 1M in tetrahydrofuran (THF), 0.55 mmole) dropwise be added into tetrahydrofuran (THF) (2 milliliters) solution of preparation example 79 compounds (131 milligrams, 0.55 mmole), solution stirring is 30 minutes then.Add toluenesulphonic acids to methyl esters (102.4 milligrams, 0.55 mmole), reacted on stirring at room 3 hours.Mixture concentrates down in decompression, and the resistates branch is dissolved in methylene dichloride and water, separates each layer.Organic phase with dried over mgso and in decompression evaporation down, obtains title compound (152 milligrams) with the salt water washing.
APCI MS m/z 255[MH] +
Preparation example 81:(2-amino-5-chloro-benzylamino)-tert.-butyl acetate
Figure A20048000470800951
Chloro-tert.-butyl acetate (500 milligrams, 3.34 mmoles) is added into the amine (1.04 gram, 6.65 mmoles) of preparation example 10, and in the solution of THF (20 milliliters), reaction mixture is heated to 65 ℃ through 20 hour time.Allow mixture cool off and filtration.Filtrate is in decompression evaporation down, and the gained gummy residue is used eluent ethyl acetate in silica gel, by the tubing string chromatography purification, obtains title compound (726 milligrams), and crystalline solid is white in color.
1H NMR(400MHz，CD 3OD)：δ1.50(s，9H)，3.28(s，2H)，3.67(s，2H)，6.68(d，1H)，7.00(d，1H)，7.02(s，1H).
APCI MS m/z 271[MH] +，293[MNa] +
Preparation example 82:7-chloro-1,3,4,5-tetrahydrochysene-benzo [e] [1,4] diaza -2-ketone
Add uncle's fourth potassium oxide (20.38 grams, 181.6 mmoles) in the ester of preparation example 81 (49.2 grams, 181.7 mmoles) in the solution of degasification in THF (500 milliliters), mixture was in stirring at room 2 hours.Add for the second time uncle's fourth potassium oxide (2.04 grams, 18.2 mmoles), continue to stir 15 minutes, add saturated ammonium chloride solution (150 milliliters) subsequently.The gained mixture extracts with ethyl acetate (4 cubic decimeters).Organic extract drying (sal epsom) and filtration.Filtrate obtains yellow solid in decompression evaporation down, and solid uses pentane (150 milliliters) development twice and filters and obtains title compound, is canescence crystalline solid (31.1 gram).
1H NMR(400MHz，CD 3OD)：δ3.54(s，2H)，3.92(s，2H)，7.02(d，1H)，7.25(d，1H)，7.27(s，1H).
Preparation example 83:7-chloro-4-methyl isophthalic acid, 3,4,5-tetrahydrochysene-benzo [e] [1,4] diaza -2-ketone
Figure A20048000470800953
Formaldehyde (the 37%w/v aqueous solution, 5 milliliters, 60 mmoles) is added into the amine (8.4 grams, 42.7 mmoles) of preparation example 82 in the suspension of methylene dichloride (140 milliliters) and acetate (1 milliliter).Mixture is divided into several parts subsequently and adds triacetyl oxygen sodium borohydrides (14 grams, 64.1 mmoles) in stirring at room 0.25 hour, stirs again 30 minutes.The reaction mixture branch is dissolved in 2N water-based hydrochloric acid (50 milliliters) and methylene dichloride (200 milliliters).Organic layer is abandoned with 2N water-based hydrochloric acid (50 milliliters) extraction for the second time subsequently.Merge the acid layer and be adjusted into alkalescence, cause the lark solid precipitation, through leaching with 2N.Filtrate is added into the solution that the lark solid filter cake is dissolved in methylene dichloride (500 milliliters) with methylene dichloride (2 * 100 milliliters) extracting twice.Combined dichloromethane layer drying (sal epsom) filtered, and filtrate is evaporated down in decompression and obtained yellow solid.The development of use ether obtains title compound, is lark solid (7.1 gram).
1H NMR(400MHz，CDCl 3)：δ2.54(s，3H)，3.42(s，2H)，3.77(s，2H)，6.94(d，1H)，7.24(m，2H)，8.58(s，1H).
APCI MS m/z 211[MH] +，233[MNa] +
Preparation example 84:7-chloro-4-methyl isophthalic acid, 3,4,5-tetrahydrochysene-benzo [e] [1,4] diaza -2-thioketones
Yellow soda ash (1.06 grams, 10 mmoles) is added into thiophosphoric anhydride (4.45 grams, 10 mmoles) in the suspension of tetrahydrofuran (THF) (25 milliliters) in 5 ℃.Solution is cooled to 3 ℃, adds the compound (2.11 grams, 10 mmoles) that derives from preparation example 83.Dropwise add water (1 milliliter), the gained mixture was in stirring at room 18 hours.Reaction reaches with dichloromethane extraction (2 * 200 milliliters) with 0.88 ammonia (50 milliliters) dilution.Merge organic extract with the salt water washing, with dried over mgso and in decompression evaporation down.Resistates uses ethyl acetate as eluent in silica gel, by the tubing string chromatography purification, obtains title compound, is yellow solid (2.11 gram).
1H NMR(400MHz，CDCl 3)：δ2.62(s，3H)，3.61(s，2H)，3.67(s，2H)，7.00(d，1H)，7.34(m，2H)，10.1(s，1H).
APCI MS m/z 227[MH] +
Preparation example 85:(5-chloro-2-nitro-dibenzylsulfide alkyl)-acetate
Figure A20048000470800971
(1.39 milliliters of Thiovanic acids, 20 mmoles) be dissolved in (12 milliliters of 3.3 mol sodium, 40 mmoles), in ice bath, cool off, slowly add 2-brooethyl-4-chloro-1-oil of mirbane (people such as T.J.McCord, heterocyclic chemistry periodical, 1972 subsequently, 119-12) acetone (50 milliliters) solution of (5 grams, 20 mmoles).Gained solution is in stirring at room 20 hours, subsequently with water (50 milliliters) dilution and extract with methylene dichloride (25 milliliters).Water is adjusted into acidity with acetate, with dichloromethane extraction (2 * 25 milliliters).Merge organic phase with the salt water washing, dry (sal epsom) filters and evaporation, obtains title product, is canescence foams (3.65 gram).
1H NMR(400MHz，CDCl 3)：δ3.15(s，2H)，4.20(s，2H)，7.40(d，1H)，7.50(s，1H)，8.00(d，1H)，11.85(brs，1H).
APCI MS m/z 260[MH] +
Preparation example 86:2-chloro-5,9-dihydro-thia-5-azepine-benzocyclohepta alkene-6-ketone
Figure A20048000470800972
In the solution of preparation example 85 nitro-compounds (2.59 grams, 9.9 mmoles) in ethanol (100 milliliters), add platinum oxide (1 gram).Mixture is in room temperature hydrogenation 1 hour under 40psi pressure.Allow reaction mixture cooling, with after Ya Bosai (Arbocel) plunger filter.Filtrate is through evaporation, and resistates suspension is in dimethylbenzene (50 milliliters), and postheating to 150 ℃ is gone through 20 hours.Allow mixture cooling, use the methylene dichloride wash-out in silica gel, then use eluent ethyl acetate, by the tubing string chromatography purification, obtain the lark solid, solid uses the ether development, obtains the title compound solid (850 milligrams) that is white in color.
1H NMR(400MHz，CDCl 3)：δ3.05(s，2H)，3.80(s，2H)，7.00(d，1H)，7.30(dd，1H)，7.35(s，1H)，7.90(s，1H).
APCI MS m/z 212[MH] +
Preparation example 87:2-chloro-5,9-dihydro-8-thiophene-5-a word used for translation-benzocyclohepta alkene-6-ketone
Figure A20048000470800981
Yellow soda ash (394 milligrams, 3.7 mmoles) is added into the suspension of thiophosphoric anhydride (1.65 grams, 3.7 mmoles) in tetrahydrofuran (THF) (20 milliliters) in 5 ℃.Solution is cooled to 3 ℃, adds the compound (750 milligrams, 3.5 mmoles) that derives from preparation example 86.Dropwise add water (4), the gained mixture was in stirring at room 18 hours.Reaction mixture reaches with dichloromethane extraction (2 * 35 milliliters) with 0.88 ammonia (75 milliliters) dilution.The combination organic extract with dried over mgso and in decompression evaporation down, obtains title compound, the solid that is white in color (603 milligrams) with the salt water washing.
1H NMR(400MHz，CDCl 3)：δ3.55(s，2H)，3.85(s，2H)，7.00(dd，1H)，7.35(m，2H)，9.20(brs，1H).
APCI MS m/z 230[MH] +
Preparation example 88:2-amino-5-chloro-N-methyl benzyl acid amides
Figure A20048000470800982
In the solution of tetrahydrofuran (THF) (100 milliliters), dropwise add the 40%w/w methylamine aqueous solution (19.80 grams, 255 mmoles) in 5-chloroisatoic anhydride (10.0 grams, 51 mmoles) in surrounding temperature.Mixture stirred 1 hour in surrounding temperature.Add ethyl acetate (100 milliliters) and water (100 milliliters), separate each phase.Water layer uses ethyl acetate (100 milliliters) to return extraction.The combination organic phase is evaporated down in decompression and is obtained white solid, and solid obtains title compound by toluene (60 milliliters) recrystallization, the solid that is white in color (8.15) gram.
1H NMR(400MHz，CDCl 3)：δ2.86(s，3H)，6.71-6.73(d，1H)，7.11-7.14(m，1H)，7.41(s，1H)
Preparation example 89:(2-amino-5-benzyl chloride base) methylamine
Figure A20048000470800991
, be lower than 15 ℃ in temperature and dropwise add boron trifluoride Anaesthetie Ether hydrochlorate in the suspension in tetrahydrofuran (THF) (200 milliliters) in 2-amino-5-chloro-N-methyl benzyl acid amides (20.08 grams, 109 mmoles) and sodium borohydride (12.37 grams, 327 mmoles).Mixture stirred 1 hour in surrounding temperature, and postheating is gone through 6 hours to refluxing.Reaction mixture cools off in ice-water bath, dropwise adds the solution of the water (530 milliliters) of piperazine (75.08 grams, 872 mmoles).The mixture reflux is 16 hours then.Mixture is cooled to surrounding temperature, adds ethyl acetate (100 milliliters).Separate each phase, water layer returns extraction with ethyl acetate (40 milliliters).The combination organic phase is with water (3 * 80 milliliters) washing, and evaporation obtains orange oil (17.58 grams, 103 mmoles) under decompression.Oil is dissolved in ethyl acetate (175 milliliters) and Phenylsulfonic acid (16.29 grams, 103 mmoles) stirred 2 hours in surrounding temperature.Collect white precipitate acquisition benzene sulfonate (24.12 gram) by filtering.The white solid branch is dissolved in methylene dichloride (240 milliliters) and 2M sodium hydroxide (240 milliliters), separates each phase.Organic phase obtains title compound in decompression evaporation down, is water white oil (10.78 gram).
1H NMR(400MHz，CDCl 3)：δ2.42(s，3H)，3.72(s，2H)，6.55-6.57(d，1H)，7.00-7.04(m，2H)
Preparation example 90:(2-amino-5-benzyl chloride base) methyl { [5-(1-pyridine-2-phenylpiperidines-4-yl)-1,3,4-oxadiazole-2-yl] methyl } amine
Figure A20048000470800992
The amine (2.53 grams, 14.9 mmoles) of preparation example 5b De oxadiazole (2.77 gram, 9.93 mmoles) and preparation example 89 and sodium bicarbonate (0.88 gram, 10.43 mmoles) reflux 5 hours in acetonitrile.Mixture adds water (20 milliliters) and methylene dichloride (20 milliliters) through cooling.Separate each phase, organic phase obtains title compound in decompression evaporation down, is oil (4.8 gram).
1H NMR(400MHz，CDCl 3)；δ1.91-2.01(m，2H)，2.16-2.20(m，2H)，2.33(s，3H)，3.07-3.21(m，3H)，3.57(s，2H)，3.79(s，2H)，4.29-4.33(m，2H)，6.55-6.57(d，1H)，6.62-6.65(m，1H)，6.69-6.71(d，1H)，6.98(m，1H)，7.03-7.05(m，1H)，7.47-7.51(m，1H)，8.19-8.20(m，1H)
Preparation example 91:8-chloro-5-methyl isophthalic acid-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene diphenyl sulfonate
In 8-chloro-5-methyl isophthalic acid-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene (25.3 grams, 64 mmoles) adds Phenylsulfonic acid (20.3 grams, 128 mmoles) in the suspension of methyl alcohol (250 milliliters).Yellow solution is heated to 60 ℃ and goes through 1 hour, allows it be cooled to surrounding temperature then and stirs 16 hours.Mixture cooled off in frozen water 1 hour, with after vacuum filtration obtains the white particulate solid, after 16 hours, obtained title compound (41.3 gram) in 50 ℃ of vacuum-dryings.
1H NMR(400MHz，D 2O)：δ1.62-1.82(m，2H)，2.04-2.20(m，1H)，2.31-2.43(m，1H)，2.98(s，3H)，3.08-3.23(m，1H)，3.30-3.43(m，1H)，3.44-3.54(m，1H)，3.84-4.02(m，2H)，4.02-4.13(m，1H)，4.13-4.27(m，1H)，4.27-4.40(m，1H)，6.81-6.90(m，1H)，7.17-7.19(d，1H)，7.40-7.54(m，6H)，7.62-7.73(m，5H)，7.73-7.82(m，3H)，7.82-7.94(m，1H)；(Found C，55.6；H，5.0；N，11.8％.C 33H 35ClN 6O 6S 2 requires C，55.7；H，5.0；N，11.8％).
Embodiment 1:1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Toluene-4-sulfonic acid (100 milligrams, 0.58 mmole) is added into preparation example 13 De oxadiazole solution (2.45 grams, 6.8 mmoles), is heated to 150 ℃ and goes through 18 hours.Mixture is through cooling, use methyl alcohol and ammonium hydroxide (5: 0.5: 95) in methylene dichloride to pass through chromatography purification in silica gel as eluent, then use methyl alcohol and ammonium hydroxide (10: 1: 90) in ethyl acetate in silica gel, then use methyl alcohol and ammonium hydroxide in methylene dichloride (7: 1: 93) as eluent, pass through chromatography purification, after using the ethyl acetate development, obtain title compound (770 milligrams), be brown solid.
APCI MS m/z 347[MH] +
1H NMR(400MHz，CDCl 3)：δ1.80-2.40(m，4H)，2.95(m，2H)，3.20(m，1H)，3.73(s，2H)，3.88(s，2H)，4.33(m，2H)，6.57(m，1H)，6.68(d，1H)，7.37(d，1H)，7.50(m，4H)，8.17(d，1H)
Embodiment 2:5-methyl isophthalic acid-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Formaldehyde (the 37%w/v aqueous solution, 1 milliliter, 81 mmoles) is added into the amine (100 milligrams, 0.28 mmole) of embodiment 1 in the solution of methylene dichloride (20 milliliters).Mixture adds triacetyl oxygen sodium borohydride (500 milligrams, 2.4 mmoles) subsequently in stirring at room 0.25 hour.Reaction mixture stirred again 0.25 hour.Remove methylene dichloride down in decompression.Resistates is allocated in 2N aqueous sodium hydroxide solution (50 milliliters) and ethyl acetate (50 milliliters).Organic layer is with the saturated brine washing and with dried over mgso, and subsequent filtration reaches evaporated filtrate under decompression, obtains title compound, is lark foams (75 milligrams).
APCI MS m/z 361[MH] +，384[MNa] +
1H NMR(400MHz，CDCl 3)：δ2.08(m，4H)，2.52(s，3H)，3.00(m，2H)，3.21(m，2H)，3.40(s，2H)，3.70(s，2H)，4.36(m，2H)，6.60(m，1H)，6.68(d，1H)，7.40(d，1H)，7.50(m，4H)，8.18(d，1H)
Embodiment 3:1-[1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-ethyl ketone
Acetyl Chloride 98Min. (22 milligrams, 0.29 mmole) was added into the amine (100 milligrams, 0.29 mmole) of embodiment 1 in the ice-cold solution of methylene dichloride (50 milliliters), in stirring at room 2 hours.In the following evaporative removal methylene dichloride of decompression, resistates in silica gel use methyl alcohol and ammonium hydroxide in methylene dichloride (5: 0.5: 95) as eluent, by chromatography purification, obtain title compound and be brown foams (102 milligrams).
APCI MS m/z 389[MH] +，412[MNa] +
1H NMR(400MHz，CDCl 3)：δ1.50-2.28(m，7H，rotamers)，3.01(brs，2H)，3.10(m，1H)，4.00-5.00(m，6H，rotamers)，6.61(m，1H)，6.68(m，1H)，7.50(m，3H)，7.61(m，2H)，8.18(m，1H)
Embodiment 4:8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Figure A20048000470801022
Toluene-4-sulfonic acid (100 milligrams, 0.58 mmole) is added into the solution of preparation example 14 De oxadiazoles (4.65 grams, 12 mmoles), is heated to 140 ℃ and goes through 18 hours.Mixture uses methyl alcohol and oxyammonia in methylene dichloride (5: 0.5: 95) by chromatography purification, to obtain title compound (2.0 gram) as eluent through cooling in silica gel, is pale solid.
APCI MS m/z 381[MH] +，403[MNa] +
1H NMR(400MHz，CDCl 3)：δ1.80-2.20(m，4H)，2.95(m，2H)，3.14(m，1H)，3.68(s，2H)，3.92(s，2H)，4.36(m，2H)，6.60(m，1H)，6.67(d，1H)，7.35(d，1H)，7.50(m，3H)，8.17(d，1H)
Measured value; C, 59.90; H, 5.48; N, 20.50; C 20H 21N 6Cl 0.33 CH 2Cl 2Calculated value; C, 59.72; H, 5.34; N, 20.55%
Embodiment 4b:8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Figure A20048000470801031
Trifluoroacetic acid (2.9 milliliters, 38 mmoles) is added into the tetrahydrofuran solution of preparation example 14b oxadiazole (10 grams, 25 mmoles), is heated to 65-67 ℃ and goes through 6 hours.Reaction mixture is through cooling and be adjusted to pH7 with sodium hydroxide (5M), is atmospherically distilled to ethyl acetate subsequently.
Reaction mixture is adjusted to pH10 with sodium hydroxide (5M) again then, then is cooled to 10 ℃ and goes through 1 hour.Product is adjusted into slurries then once again by filtering separation in water, refilter subsequently.Product is a white solid, and product is through vacuum-drying (7.75 gram).
APCI MS m/z 381[MH] +，403[MNa] +
1H NMR(400MHz，CDCl 3)：δ1.80-2.20(m，4H)，2.95(m，2H)，3.14(m，1H)，3.68(s，2H)，3.92(s，2H)，4.36(m，2H)，6.60(m，1H)，6.67(d，1H)，7.35(d，1H)，7.50(m，3H)，8.17(d，1H)
Measured value; C, 59.90; H, 5.48; N, 20.50; C 20H 21N 6Cl 0.33 CH 2Cl 2Calculated value; C, 59.72; H, 5.34; N, 20.55%
Embodiment 5:8-chloro-5-methyl isophthalic acid-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene tri hydrochloride
Formaldehyde (37%w/v water-based, 0.1 milliliter, 1.2 mmoles) is added into the amine (200 milligrams, 0.53 mmole) of embodiment 4 in the solution of methylene dichloride (5 milliliters).Mixture adds triacetyl oxygen sodium borohydride (500 milligrams, 2.4 mmoles) subsequently in stirring at room 0.25 hour, and reaction mixture stirred again 18 hours.The reaction mixture branch is dissolved in 2N aqueous sodium hydroxide solution (10 milliliters) and methylene dichloride (10 milliliters).Organic layer uses methyl alcohol and methylene dichloride (5: 95) to pass through chromatography purification as eluent in decompression evaporation down in silica gel.Resistates is dissolved in methylene dichloride (2 milliliters), adds hydrochloric acid (1M in ether, 2 milliliters).Evaporative removal solvent under decompression obtains title compound, is brown foams (96 milligrams).
APCI MS m/z 395[MH] +，417[MNa] +
1H NMR(400MHz，CD 3OD)：δ2.00(m，2H)，2.27(m，1H)，2.58(m，1H)，3.11(s，3H)，3.36(m，1H)，3.62(m，2H)，4.21(m，4H)，4.40(m，1H)，4.55(m，1H)，7.00(t，1H)，7.44(d，1H)，7.88(m，2H)，7.92(m，2H)，8.06(t，1H)
Measured value; C, 44.30; H, 5.52; N, 14.65; C 21H 23N 6Cl 0.33 CH 2Cl 2.3HCl.2.5H 2The O calculated value; C, 44.37; H, 5.53; N, 14.53%.
Embodiment 5b:8-chloro-5-methyl isophthalic acid-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Add the hydrazides (78 milligrams, 0.35 mmole) of preparation example 1 in the thioamides (80 milligrams, 0.35 mmole) of preparation example 84 in the solution of fourth-1-alcohol, mixture heating up to 100 ℃ is gone through 20 hours.Reaction mixture is in decompression evaporation down, and resistates uses methylene dichloride in silica gel: methyl alcohol: 0.880 ammonia (90: 10: 1) by the tubing string chromatography purification, obtains title compound as scrub solution, is brown foams (90 milligrams).
1H NMR(400MHz，CDCl 3)：δ2.00(m，4H)，2.45(s，3H)，3.96(t，2H)，3.15(m，1H)，3.36(m，1H)，3.64(m，2H)，4.36(m，2H)，6.58(m，1H)，6.65(d，1H)，7.32(d，1H)，7.46(t，1H)，7.52(m，2H)，8.18(t，1H)
APCI MS m/z 395[MH] +，417[Mna] +
Embodiment 5c:8-chloro-5-methyl isophthalic acid-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene tri hydrochloride
Figure A20048000470801051
The amine (10 grams, 26 mmoles) that acetate (3 milliliters, 52 mmoles) is added into embodiment 4b in the solution of methylene dichloride (100 milliliters), then adds formaldehyde (37%w/v water-based, 3.2 milliliters, 39 mmoles).In container separately, triacetyl oxygen sodium borohydride (6.7 grams, 31 mmoles) is in methylene dichloride furnishing slurries and be cooled to and be lower than 10 ℃.Imide liquor dropwise is added into cold slurries with 15 fens clock times then.Reaction mixture was in stirring at room 0.5 hour, and the reaction mixture branch is dissolved in 2N aqueous sodium hydroxide solution and methylene dichloride subsequently.Organic phase is washed 3 times with the 50% sodium metabisulfite aqueous solution then, then at last with water washing.Dichloromethane solution is distilled into half amount, adds ethyl acetate subsequently, and rerunning is removed residual dichloromethane.Add ethanol, reaction mixture heated again 0.5 hour, was cooled to 10 ℃ subsequently, separated product, and solid is white in color.Solid obtained title compound (7.48 gram) in 16 hours in 50 ℃ of vacuum-dryings.
APCI MS m/z 395[MH] +，417[MNa] +
1H NMR(400MHz，CD 3OD)：δ2.00(m，2H)，2.27(m，1H)，2.58(m，1H)，3.11(s，3H)，3.36(m，1H)，3.62(m，2H)，4.21(m，4H)，4.40(m，1H)，4.55(m，1H)，7.00(t，1H)，7.44(d，1H)，7.88(m，2H)，7.92(m，2H)，8.06(t，1H)
Measured value; C, 44.30; H, 5.52; N, 14.65; C 21H 23N 6Cl 0.33 CH 2Cl 2.3HCl.2.5H 2The O calculated value; C, 44.37; H, 5.53; N, 14.53%.
Embodiment 6:8-chloro-5-sec.-propyl-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene tri hydrochloride
Figure A20048000470801061
Acetone (0.1 milliliter, 1.36 mmoles) is added into the amine (200 milligrams, 0.53 mmole) of embodiment 4 in the solution of methylene dichloride (5 milliliters).Mixture adds triacetyl oxygen sodium borohydride (500 milligrams, 2.4 mmoles) subsequently in stirring at room 0.25 hour, and reaction mixture stirred again 18 hours.The reaction mixture branch is dissolved in 2N aqueous sodium hydroxide solution (10 milliliters) and methylene dichloride (10 milliliters).Organic layer uses methyl alcohol and methylene dichloride (5: 95) to pass through chromatography purification as scrub solution in decompression evaporation down in silica gel.Resistates is dissolved in methylene dichloride (2 milliliters), adds hydrochloric acid (1M in ether, 2 milliliters).Evaporative removal solvent under decompression obtains title compound, is brown foams (161 milligrams).
APCI MS m/z 423[MH] +，445[MNa] +
1H NMR(400MHz，CD 3OD)：δ1.57(m，6H)，2.00(m，2H)，2.24(m，1H)，2.58(m，1H)，3.38(m，1H)，3.58(m，1H)，3.70(m，1H)，3.86(m，1H)，4.23(m，3H)，4.40(m，1H)，4.62(m，1H)，5.00(m，1H)，7.00(m，1H)，7.43(m，1H)，7.80-8.06(m，5H)
Measured value; C, 46.51; H, 5.98; N, 13.96; C 23H 27N 6Cl 0.28 CH 2Cl 2.3HCl.2.5H 2The O calculated value; C, 46.51; H, 5.96; N, 13.98%.
Embodiment 7:8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5-(tetrahydrochysene-pyrans-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Figure A20048000470801071
Tetrahydrochysene-pyrans-4-ketone (68 milligrams, 0.68 mmole) is added into the solution of amine (130 milligrams, 0.34 mmole) in methylene dichloride (5 milliliters) of embodiment 4.Mixture adds triacetyl oxygen sodium borohydride (217 milligrams, 1.0 mmoles) subsequently in stirring at room 0.25 hour, and reaction mixture stirred again 18 hours.Add tetrahydrochysene-pyrans-4-ketone (68 milligrams, 0.68 mmole) and triacetyl oxygen sodium borohydride (217 milligrams, 1.0 mmoles) again, reaction mixture is heated to 40 ℃ and goes through 24 hours.The reaction mixture branch is dissolved in 2N sodium bicarbonate aqueous solution (10 milliliters) and ethyl acetate (50 milliliters).Organic layer is washed 3 times with 2N aqueous sodium hydroxide solution (10 milliliters), with saturated salt washing 1 time, and then with dried over mgso, subsequent filtration and evaporated filtrate under decompression.Resistates uses ethyl acetate and pentane gradient (0% to 30%) to pass through chromatography purification as eluent in silica gel, then use methyl alcohol and dichloromethane gradient (0% to 5%) to pass through chromatography purification as eluent in silica gel, obtain title compound, be brown foams (80 milligrams).
APCI MS m/z 465[MH] +，487[MNa] +
1H NMR(400MHz，CDCl 3)：δ1.57-175(m，4H)，1.75-2.20(m，6H)，2.72(m，1H)，2.98(t，2H)，3.16(m，1H)，3.39(t，2H)，3.40-3.60(m，2H)，3.60-4.10(m，2H)，4.02(d，2H)，4.34(d，2H)，6.61(dd，1H)，6.69(d，1H)，7.33(d，1H)，7.45-7.59(m，3H)，8.17(d，1H).
Embodiment 8:1-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-the ethyl ketone dihydrochloride
The amine (200 milligrams, 0.53 mmole) that Acetyl Chloride 98Min. (0.1 milliliter, 1.4 mmoles) is added into embodiment 4 in methylene dichloride (5 milliliters) with ice-cooled solution, and in stirring at room 20 hours.Evaporative removal methylene dichloride under decompression, resistates uses methyl alcohol to pass through chromatography purification as eluent in methylene dichloride (5: 95) in silica gel.Resistates is dissolved in methylene dichloride (2 milliliters), adds hydrochloric acid (1M in ether, 2 milliliters), in decompression evaporative removal solvent down, obtains title compound and is brown foams (110 milligrams).
ESI MS m/z 423[M+H] +
1H NMR(400MHz，CD 3OD)：δ1.95-2.40(m，7H，rotamers)，3.40-3.55(m，2H)，3.80(m，1H)，4.20-4.90(m，4H，rotamers)，4.82(s，2H)，7.02(t，1H)，7.46(d，1H)，7.80(m，1H)，7.91(t，1H)，7.95-8.00(m，2H)，8.07(t，1H)
Measured value; C, 45.94; H, 5.77; N, 14.35; C 22H 23N 6N 6ClO.2HCl.0.40CH 2Cl 2.3.07H 2The O calculated value; C, 45.98%; H, 5.50%; N, 14.36%.
Embodiment 9:[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-cyclopropyl-ketone dihydrochloride
Figure A20048000470801081
Title compound is to use embodiment 8 described programs, by the amine preparation of cyclopropane carbonyl chlorine and embodiment 4,50% productive rate.
ESI MS m/z 449[M+H] +
1H NMR(400MHz，CD 3OD)：δ0.83-1.00(m，4H)，1.80-2.50(m，4H，rotamers)，3.40-3.60(m，2H)，3.89(bt，1H)，4.20-5.0(m，3H，rotamers)，4.86(s，2H)，7.04(t，1H)，7.26(d，1H)，7.82(bd，1H)，7.90-8.00(m，3H)，8.08(t，1H)
Embodiment 10:1-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl) 4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-2,2-dimethyl-third-1-ketone dihydrochloride
Title compound is to use embodiment 8 described programs, by 2, and the preparation of the amine of 2-dimethyl-propionyl chloride and embodiment 4,54% productive rate.
APCI MS m/z 465[M+H] +
1H NMR(400MHz，CD 3OD)：δ1.40(s，9H)，1.80-2.60(m，4H，rotamers)，3.40-3.60(m，2H)，3.88(bt，1H)，4.10-5.00(m，4H，rotamers)，4.85(s，2H)，7.04(t，1H)，7.47(d，1H)，7.80-7.86(m，2H)，7.94(d，1H)，7.99(d，1H)，8.08(t，1H)
Embodiment 11:8-chloro-5-methane sulfonyl-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Figure A20048000470801092
The amine (200 milliliters, 0.53 mmole) that methane sulfonyl chloride (0.1 milliliter, 1.29 mmoles) is added into embodiment 4 in methylene dichloride (5 milliliters) with ice-cooled solution, and in stirring at room 20 hours.Evaporative removal methylene dichloride under decompression, resistates uses methyl alcohol to pass through chromatography purification as eluent in methylene dichloride (5: 95) in silica gel, obtains title compound, is brown foams (71 milligrams).
APCI MS m/z 459[M+H] +，481[M+Na] +
Found C，52.98％，H，5.05％，N，17.20％；C 21H 23ClN 6O 2S.0.25CH 2Cl 2 requires C，53.15％，H，4.93％，17.50％
Embodiment 12:8-chloro-1-(1-pyrimidine-2-base-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Figure A20048000470801101
Toluene-4-sulfonic acid (5 milligrams, 0.03 mmole) is added into preparation example 15 De oxadiazole solution (2.34 grams, 5.9 mmoles), is heated to 140 ℃ and goes through 18 hours.Mixture uses methyl alcohol and ammonium hydroxide in methylene dichloride (5: 0.5: 95) by chromatography purification, to obtain title compound (1.12 gram) as scrub solution through cooling in silica gel, is pale solid.
ESI MS m/z 382[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.60-2.20(m，4H)，2.95(bt，2H)，3.10(m，1H)，3.63(s，2H)，3.70-4.00(m，2H)，4.75(d，2H)，6.43(t，1H)，7.26(d，1H)，7.40-7.52(m，2H)，8.22(d，2H)
Measured value C, 57.24%, H, 5.31%, N, 24.10%; C 19H 20ClN 7.0.25CH 2Cl 2Calculated value C, 57.36%, H, 5.13%, N, 24.32%
Embodiment 13:8-chloro-5-methyl isophthalic acid-(1-pyrimidine-2-base-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Formaldehyde (the 37%w/v aqueous solution, 0.1 milliliter, 1.2 mmoles) is added into the solution of amine (100 milligrams, 0.26 mmole) in methylene dichloride (5 milliliters) of embodiment 12.Mixture adds triacetyl oxygen sodium borohydride (111 milligrams, 0.53 mmole) subsequently in stirring at room 0.25 hour, and reaction mixture stirred again 18 hours.The mixture branch is dissolved in 2N aqueous sodium hydroxide solution (10 milliliters) and methylene dichloride (10 milliliters).Organic layer uses methanol dichloromethane (5: 95) to pass through chromatography purification as eluent in decompression evaporation down, obtains title compound, is brown foams (66 milligrams).
ESI MS m/z 382[M+Na] +
1H NMR(400MHz，CDCl 3)：δ1.50-2.20(m，4H)，2.45(s，3H)，2.98(bt，2H)，3.10(bt，1H)，3.20-3.90(m，3H)，4.77(s，2H)，6.45(s，1H)，7.32(d，1H)，7.46-7.53(m，2H)，8.26(d，2H)
Measured value C, 59.12%, H, 5.50%, N, 24.00%; C 20H 22ClN 7.0.15CH 2Cl 2Calculated value C, 59.23%, H, 5.66%, N, 23.99%
Embodiment 14:8-chloro-5-sec.-propyl-1-(1-pyrimidine-2-base-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Title compound is to use embodiment 13 described programs, by the amine preparation of acetone and embodiment 12,65% productive rate.
ESI MS m/z 382[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.20(d，6H)，1.60-2.10(m，4H)，2.90-3.07(m，3H)，3.18(t，1H)，3.30-4.00(m，4H)，4.78(d，2H)，6.47(t，1H)，7,29(d，1H)，7.48-7.58(m，2H)，8.30(d，2H)
Measured value C, 60.55%, H, 6.24%, N, 21.73%; C 22H 26ClN 7.0.22CH 2Cl 2Calculated value C, 60.17%, H, 6.03%, N, 22.11%
Embodiment 15:8-chloro-5-methane sulfonyl-1-(1-pyrimidine-2-base-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Figure A20048000470801112
Title compound is to use embodiment 11 described programs, by the amine preparation of embodiment 12,69% productive rate.
APCI MS m/z 460[M+H] +，482[M+Na] +
1H NMR(400MHz，CDCl 3)：δ1.40-2.40(m，6H)，2.95(s，3H)，2.90-4.20(m，5H)，4.40-5.30(m，4H)，6.52(t，1H)，7.40(d，1H)，7.60-7.70(m，2H)，8.32(d，2H)
Embodiment 16:[8-chloro-1-(pyrimidine-2-base-piperidin-4-yl)-4H, 6H-2,3,5, the 10b-tetrazine is [e] Azulene-5-yl also]-cyclopropyl-ketone
Title compound is to use embodiment 3 described programs, and the amine preparation by cyclopropane carbonyl chlorine and embodiment 12 is the canescence foams, 69% productive rate.
APCI MS m/z 472[M+Na] +
1H NMR(400MHz，CDCl 3)：δ0.86(m，2H)，1.04(m，2H)，1.40-2.40(m，6H)，2.70-3.20(m，3H)，4.40-5.80(m，5H)，6.61(t，1H)，7.39(d，1H)，7.52-7.65(m，2H)，8.32(d，2H)
Embodiment 17:1-[8-chloro-1-(pyrimidine-2-base-piperidin-4-yl)-4H, 6H-2,3,5, the 10b-tetrazine is [e] Azulene-5-yl also]-2,2-dimethyl-third-1-ketone
Figure A20048000470801122
Title compound is to use embodiment 3 described programs, by 2, and the preparation of the amine of 2-dimethyl-propionyl chloride and embodiment 12,42% productive rate.
APCI MS m/z 466[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.38(s，9H)，1.40-2.40(m，7H)，2.90-3.10(m，2H)，3.17(m，1H)，4.60-5.00(m，2H)，5.27(s，2H)，6.58(t，1H)，7.35(d，1H)，7.54-7.68(m，2H)，8.29(d，1H)
Embodiment 18:1-[8-chloro-1-(pyrimidine-2-base-piperidin-4-yl)-4H, 6H-2,3,5, the 10b-tetrazine is [e] Azulene-5-yl also]-ethyl ketone
Figure A20048000470801131
Title compound is to use embodiment 3 described programs, by the amine preparation of Acetyl Chloride 98Min. and embodiment 12,37% productive rate.
APCI MS m/z 424[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.40-2.50(m，10H)，2.70-3.30(m，4H)，4.70-4.90(m，2H)，6.52(t，1H)，7.38(d，1H)，7.54-7.64(m，2H)，8.33(d，2H)
Embodiment 19:8-chloro-1-(6 '-trifluoromethyl-3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-5-Evil-2,3,10b-three azepines-benzo [e] Azulene
Figure A20048000470801132
2-chloro-6-trifluoromethyl-pyridine (55 milligrams, 0.30 mmole) and salt of wormwood (41 milligrams, 0.30 mmole) are added into the amine (45 milligrams, 0.15 mmole) of preparation example 29 in N, the solution in the dinethylformamide (2 milliliters).Mixture is in 100 ℃ of heating 18 hours, subsequently in decompression evaporation down.Resistates uses methyl alcohol and ammonium hydroxide in methylene dichloride (5: 0.5: 95) to pass through chromatography purification as eluent in silica gel, obtains title compound (30 milligrams), is the brown foams.
APCI MS m/z 450[M+H] +，472[M+Na] +
1H NMR(400MHz，CD 3OD)：δ1.88-2.06(m，4H)，3.01(bt，2H)，3.40(m，1H)，4.44(bs，2H)，4.51(d，2H)，4.59(s，2H)，6.94(d，1H)，7.02(d，1H)，7.68(t，1H)，7.74-7.78(m，4H).
Embodiment 20:4-(8-chloro-4H, 6H-5-Evil-2,3,10b-three azepines-benzo [e] Azulene-1-yl)-3,4,5,6-tetrahydrochysene-2H[1,2 '] bipyridyl-6 '-formonitrile HCN
Figure A20048000470801141
Title compound is to use embodiment 19 described programs, by the amine preparation of 6-chloro-pyridine-2-formonitrile HCN and preparation example 20,61% productive rate.
APCI MS m/z 407[M+H] +，429[M+Na] +
1H NMR(400MHz，CD 3OD)：δ1.86-2.08(m，4H)，3.03(bt，2H)，3.44(m，1H)，4.46(m，4H)，4.59(s，2H)，7.03(d，1H)，7.11(d，1H)，7.62(dd，1H)，7.72-7.78(，3H)
Measured value C, 61.31%, H, 4.73%, N, 20.38%; C 21H 19ClN 6O.0.25H 2O calculated value C, 61.31%, H, 4.78%, N, 20.43%
Embodiment 21:4-(8-chloro-4H, 6H-5-Evil-2,3,10b-three azepines-benzo [e] Azulene-1-yl)-3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-6 '-methane amide
Powdered sodium hydroxide (46 milligrams, 81 mmoles) is added into embodiment 20 formonitrile HCNs (110 milligrams, 0.27 mmole) solution of (6 milliliters) in 2-methyl-propan-2-ol.Mixture is in 100 ℃ of heating 18 hours, subsequently in decompression evaporation down.Resistates uses methyl alcohol and ammonium hydroxide (5: 0.5: 95) in methylene dichloride to make eluent in silica gel, by chromatography purification, obtains title compound (62 milligrams), is pale solid.
APCI MS m/z 425[M+H] +，447[M+Na] +
1H NMR(400MHz，CD 3OD)：δ1.89-2.07(m，4H)，3.01(bt，2H)，3.42(m，1H)，4.45(s，2H)，4.52(bd，2H)，4.60(s，2H)，7.02(d，1H)，7.38(d，1H)，7.67(dd，1H)，7.72-7.78(m，4H)
Embodiment 22:13-chloro-3-(3-3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-2,4,5,8-four azepines-three ring [9.4.0.0 *2,6 *] 15 carbon-1 (11), 3,5,12, the 14-pentaene
Figure A20048000470801151
Toluene-4-sulfonic acid (50 milligrams, 0.3 mmole) is added into preparation example 41 De oxadiazole solution (1.35 grams, 3.3 mmoles), is heated to 140 ℃ and goes through 2 hours.Mixture uses ethyl acetate through cooling in silica gel, then uses methyl alcohol and ammonium hydroxide in methylene dichloride (5: 0.5: 95) to obtain chromatography purification as eluent, obtains title compound (273 milligrams), is pale solid.
APCI MS m/z 398[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.42(bd，1H)，1.65(dq，1H)，2.05(dt，1H)，2.16(bd，1H)，2.32(dq，1H)，2.63-2.77(m，2H)，2.79-2.94(m，2H)，2.95(m，1H)，3.10(d，1H)，3.46(dt，1H)，4.18(bd，1H)，4.38(bd，1H)，4.41(d，1H)，6.59(dd，1H)，6.65(d，1H)，7.18(d，1H)，7.38-7.42(m，2H)，7.57(t，1H)，8.17(d，1H)
Measured value C, 62.41%, H, 5.98%, N, 20.45%; C 21H 23ClN 6O.0.12CH 2Cl 2Calculated value C, 62.72%, H, 5.78%, N, 20.75%
Embodiment 23:1-[13-chloro-3-(3-3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-2,4,5,8-four azepines-three ring [9.4.0.0 *2,6 *] 15 carbon-1 (11), 3,5,12,14-pentaene-8-yl]-ethyl ketone
Acetic anhydride (35 milliliters, 0.37 mmole) was added into the amine (120 milligrams, 0.30 mmole) of embodiment 22 and triethylamine in the solution of methylene dichloride (5 milliliters), in stirring at room 2 hours.Methylene dichloride is evaporative removal under decompression, and resistates uses methyl alcohol and ammonium hydroxide in methylene dichloride (5: 0.5: 95) by chromatography purification, to obtain title compound, the solid that is white in color (120 milligrams) as eluent in silica gel.
APCI MS m/z 437[M+H] +，459[M+Na] +
1H NMR(400MHz，CDCl 3)：δ1.44(bd，1H)，1.63(m，1H)，2.16(m，2H)，2.10-2.22(m，2H)，2.28(dt，1H)，2.44(s，3H)，2.63-2.80(m，2H)，2.83-3.05(m，3H)，3.66(d，1H)，4.15(bd，1H)，4.41(bd，1H)，4.94(dd，1H)，5.06(d，1H)，6.59(t，1H)，6.63(d，1H)，7.17(d，1H)，7.38-7.50(m，3H)，8.14(d，1H)
Measured value C, 61.92%, H, 5.93%, N, 18.38%; C 21H 23ClN 6O.0.60H 2O calculated value C, 61.70%, H, 5.90%, N, 18.77%
Embodiment 24:13-chloro-8-methyl-3-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-2,4,5,8-four azepines-three ring [9.4.0.0 *2,6 *] 15 carbon-1 (11), 3,5,12, the 14-pentaene
Figure A20048000470801161
Title compound is to use embodiment 2 described programs, by the amine preparation of embodiment 22,78% productive rate.
APCI MS m/z 409[M+H] +，431[M+Na] +
1H NMR(400MHz，CDCl 3)：δ1.41(bd，1H)，1.62(dq，1H)，2.14(bd，1H)，2.23-2.32(m，2H)，2.37(s，3H)，2.55(dd，1H)，2.66-2.78(m，2H)，2，88(m，1H)，2.96(dt，1H)，3.20(d，1H)，3.26(dd，1H)，4.15(d，2H)，4.35(bd，1H)，6.55(dd，1H)，6.62(d，1H)，7.14(d，1H)，7.32-7.39(m，2H)，7.41(t，1H)，8.12(d，1H)
Embodiment 25:3-(1-pyrimidine-2-base-piperidin-4-yl)-8-Evil-2,4,5-three azepines-three ring [9.4.0.0 *2,6 *] 15 carbon-1 (11), 3,5,12, the 14-pentaene
Title compound is to use embodiment 22 described programs, by the preparation of preparation example 24 De oxadiazoles, 50% productive rate.
ESI MS m/z 364[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.48(bd，1H)，1.65(dq，1H)，2.20(bd，1H)，2.31(dq，1H)，2.44(m，1H)，2.83-2.95(m，2H)，3.01(m，1H)，3.11(dt，1H)，3.50(q，1H)，3.92(d，1H)，4.26(m，1H)，4.60(d，1H)，4.92(d，1H)，5.08(d，1H)，6.50(t，1H)，7.24(t，1H)，7.40(t，1H)，7.46(d，1H)，7.53(t，1H)，8.32(d，2H)
Embodiment 26:8-chloro-1-(1-pyrimidine-2-base-piperidin-4-yl)-4H, 6H-5-Evil-2,3,10b-three azepines-benzo [e] Azulene
Figure A20048000470801172
Title compound is to use embodiment 22 described programs, by the preparation of preparation example 23 De oxadiazoles, 70% productive rate.
ESI MS m/z 383[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.92-2.13(m，4H)，3.07(t，2H)，3.12(m，1H)，4.39(s，2H)，4.66(s，2H)，4.82(m，2H)，6.53(t，1H)，7.39(d，1H)，7.57-7.63(m，2H)，8.33(d，2H)
Embodiment 27:13-chloro-3-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-8-Evil-2,4,5-three azepines-three ring [9.4.0.0 *2,6 *] 15 carbon-1 (11), 3,5,12, the 14-pentaene
Figure A20048000470801181
Title compound is to use embodiment 22 described programs, by the preparation of preparation example 22 De oxadiazoles, 40% productive rate.
APCI MS m/z 396[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.44(bd，1H)，1.66(dq，1H)，2.17(bd，1H)，2.36(dq，1H)，2.43(m，1H)，2.72-2.85(m，2H)，2.89-3.03(m，2H)，3.55(t，1H)，3.97(d，1H)，4.14-4.26(m，2H)，4.40(bd，1H)，5.07(d，1H)，6.59(dd，1H)，6.64(d，1H)，7.19(d，1H)，7.38-7.48(m，3H)，8.15(d，1H)
Measured value C, 62.84%, H, 5.54%, N, 17.34%; C 21H 22ClN 5O.0.08CH 2Cl 2Calculated value C, 62.88%, H, 5.55%, N, 17.39%
Embodiment 28:3-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-8-Evil-2,4,5-three azepines-three ring [9.4.0.0 *2,6 *] 15 carbon-1 (11), 3,5,12,14-pentaene dihydrochloride
Title compound is to use embodiment 22 described programs, by the preparation of preparation example 21 De oxadiazoles, 49% productive rate.Dihydrochloride is to use embodiment 8 described program preparations.
APCI MS m/z 362[M+H] +
1H NMR(400MHz，CD 3OD)：δ1.67-1.81(m，2H)，2.32(dq，1H)，2.47-2.57(m，2H)，3.11(dd，1H)，3.25(dt，1H)，3.33(m，2H)，3.45-3.62(m，3H)，4.07-4.16(m，2H)，4.30(m，1H)，4.40(bd，1H)，5.07(d，1H)，7.00(t，1H)，7.40(d，1H)，7.60-7.66(m，2H)，7.69-7.78(m，2H)，7.96(d，1H)，8.06(t，1H).
Embodiment 29:8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-4H, 6H-5-Evil-2,3,10b-three azepines-benzo [e] Azulene
Figure A20048000470801191
Title compound is to use embodiment 22 described programs, by the preparation of preparation example 20 De oxadiazoles, 60% productive rate.
APCI MS m/z 382[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.97(bd，2H)，2.09(m，2H)，2.98(dt，2H)，3.17(m，1H)，4.32-4.40(m，4H)，4.64(s，2H)，6.59(dd，1H)，6.64(d，1H)，7.39(d，1H)，7.45(t，1H)，7.56-7.61(m，2H)，8.17(d，1H).
Measured value C, 60.19%, H, 5.17%, N, 17.31%; C 21H 22ClN 5O.0.27CH 2Cl 2Calculated value C, 60.14%, H, 5.11%, N, 17.30%
Embodiment 30:7-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-4H, 6H-5-Evil-2,3,10b-three azepines-benzo [e] Azulene dihydrochloride
Figure A20048000470801192
Title compound is to use embodiment 22 described programs, by the preparation of preparation example 17 De oxadiazoles, 21% productive rate.Dihydrochloride is to use embodiment 8 described program preparations.
APCI MS m/z 382[M+H] +
1H NMR(400MHz，CD 3OD)：δ2.10(m，2H)，2.30(m，2H)，3.50(bt，2H)，3.74(m，1H)，4.32(m，2H)，4.93(s，2H)，7.00(t，1H)，7.46(d，1H)，7.77-7.95(m，3H)，8.00(dd，1H)，8.09(t，1H).
Embodiment 31:1-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-4H, 6H-5-Evil-2,3,10b-three azepines-benzo [e] Azulene
Title compound is to use embodiment 22 described programs, by the preparation of preparation example 16 De oxadiazoles, 41% productive rate.
APCI MS m/z 348[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.98(bd，2H)，2.12(m，2H)，2.97(t，2H)，3.24(m，1H)，4.35(d，2H)，4.45(s，2H)，4.65(s，2H)，6.59(dd，1H)，6.69(d，1H)，7.38-7.49(m，2H)，7.53-7.65(m，3H)，8.18(d，1H)
Measured value C, 64.55%, H, 5.84%, N, 17.92%; C 20H 21N 5O.0.40CH 2Cl 2.0.08C 8H 10Calculated value C, 64.82%, H, 5.84%, N, 17.96%
Embodiment 32:8-methoxyl group-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-4H, 6H-5-Evil-2,3,10b-three azepines-benzo [e] Azulene dihydrochloride
Figure A20048000470801202
Title compound is to use embodiment 22 described programs, by the preparation of preparation example 19 De oxadiazoles, 68% productive rate.Dihydrochloride is to use embodiment 8 described program preparations
ESI MS m/z 379[M+H] +
1H NMR(400MHz，CD 3OD)：δ2.08(bq，2H)，2.30(bd，2H)，3.49(t，2H)，3.85(m，1H)，3.95(s，3H)，4.32(bd，2H)，4.59(s，2H)，4.68(s，2H)，7.03(t，1H)，7.31-7.35(m，2H)，7.45(d，1H)，7.80，(d，1H)，7.97(d，1H)，8.08(t，1H).
Embodiment 33:8-fluoro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-4H, 6H-5-Evil-2,3,10b-three azepines-benzo [e] Azulene
Figure A20048000470801211
Title compound is to use embodiment 22 described programs, by the preparation of preparation example 31 De oxadiazoles, 62% productive rate.
APCI MS m/z 366[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.90-2.16(m，4H)，2.97(dt，2H)，3.16(m，1H)，4.28-4.40(m，4H)，4.63(s，2H)，6.58(dd，1H)，6.66(d，1H)，7.24-7.35(m，2H)，7.40-7.52(m，2H)，8.15(d，1H)
Measured value C, 64.47%, H, 5.56%, N, 18.50%; C 20H 20FN 5O.0.07CH 2Cl 2.0.07EtOAc calculated value C, 64.74%, H, 5.53%, N, 18.55%
Embodiment 34:8,9-two fluoro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-4H, 6H-5-Evil-2,3,10b-three azepines-benzo [e] Azulene dihydrochloride
Title compound is to use embodiment 22 described programs, by the preparation of preparation example 33 De oxadiazoles, 44% productive rate.Dihydrochloride is to use embodiment 8 described program preparations.
APCI MS m/z 384[M+H] +
1H NMR(400MHz，CD 3OD)：δ2.00-2.13(m，2H)，2.18-2.37(m，2H)，3.52(dt，2H)，4.33(bd，2H)，4.58(s，2H)，4.68(s，2H)，7.02(t，1H)，7.47(d，1H)，7.81(dd，1H)，7.94-8.02(m，2H)，8.06(t，1H)
Measured value C, 49.58%, H, 5.01%, N, 14.25%; C 20H 19F 2N 5O 1.2HCl.0.30CH 2Cl 20.58H 2O calculated value C, 49.53%, H, 4.66%, N, 14.23%
Embodiment 35:9-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-4H, 6H-5-Evil-2,3,10b-three azepines-benzo [e] Azulene dihydrochloride
Figure A20048000470801221
Title compound is to use embodiment 22 described programs, by the preparation of preparation example 18 De oxadiazoles, 54% productive rate.Dihydrochloride is to use embodiment 8 described program preparations.
APCI MS m/z 383[M+H] +
1H NMR(400MHz，CD 3OD)：δ2.10(m，2H)，2.35(m，2H)，3.55(dt，2H)，4.00(bd，1H)，4.35(m，2H)，4.65(s，2H)，4.80(s，2H)，7.02(m，1H)，7.45(m，1H)，7.81(s，2H)，8.00(m，3H)
Embodiment 36:1-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-8-trifluoromethoxy-4H, 6H-Evil-2,3,10b-three azepines-benzo [e] Azulene
Figure A20048000470801222
Title compound is to use embodiment 22 described programs, by the preparation of preparation example 36 De oxadiazoles, 44% productive rate.
APCI MS m/z 432[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.99(m，2H)，2.13(m，2H)，3.00(dt，2H)，3.17(m，1H)，4.37(d，2H)，4.42(s，2H)，4.66(s，2H)，6.60(dd，1H)，6.68(d，1H)，7.40-7.52(m，4H)，8.16(d，1H)
Measured value C, 58.16%, H, 4.77%, N, 15.84%; C 21H 20F 3N 5O 2. calculated value C, 58.47%, H, 4.67%, N, 16.23%
Embodiment 37:8-methyl isophthalic acid-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-4H, 6H-5-Evil-2,3,10b-three azepines-benzo [e] Azulene
Title compound is to use embodiment 22 described programs, by the preparation of preparation example 37 De oxadiazoles, 48% productive rate.
APCI MS m/z 362[M+H] +
1H NMR(400MHz，CDCl 3)：δ1.99(m，4H)，2.43(m，3H)，2.96(dt，2H)，3.41(m，1H)，4.34(d，2H)，4.42(s，2H)，4.66(brs，2H)，6.62(dd，1H)，6.83(d，1H)，7.44-7.60(m，3H)，7.63(d，1H)，8.06(d，1H)
Embodiment 38:1-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-2-dimethylamino-ethyl ketone
(152 milligrams of HBTU, 0.38 mmole) in N, the solution of (1.9 milliliters) is added into (97 milligrams of the amine of embodiment 4 in the N-N,N-DIMETHYLACETAMIDE, 0.26 mmole), triethylamine (1.5 microlitre catalytic amount) and dimethylamino acetate are (36 milligrams, 0.26 mmole) in N, solution in the N-N,N-DIMETHYLACETAMIDE (2.5 milliliters) is heated to 50 ℃ and goes through 2 hours.Mixture is through cooling, and solvent is in decompression evaporation down.The resistates branch is dissolved in methylene dichloride (10 milliliters) and 2M aqueous sodium hydroxide solution (10 milliliters).Organic phase subsequently in decompression evaporation down, uses methyl alcohol and ammonium hydroxide in methylene dichloride (7: 1: 93) to pass through chromatography purification as eluent with dried over mgso, obtains title compound (70 milligrams), is the brown foams.
APCI MS m/z 466[M+H] +
Measured value C, 60.14%, H, 5.93%, N, 20.29%; C 24H 28ClN 7O.2HCl.0.20CH 2Cl 2Calculated value C, 60.18%, H, 5.93%, N, 20.30%
Embodiment 39:2-chloro-1-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-ethyl ketone
Figure A20048000470801241
Triethylamine [1.37 milliliters, 9.81 mmoles] and chloroacetyl chloride (0.35 milliliter, 4.35 mmoles) are added into the solution of amine (1.5 grams, 3.95 mmoles) in methylene dichloride (50 milliliters) of embodiment 4, react on stirring at room 2 hours.TLC analyzes and shows the still residual starting material that has, so add additional quantity chloroacetyl chloride (0.35 milliliter, 4.35 mmoles), reaction was stirred again 1.5 hours.The mixture branch is dissolved in methylene dichloride and 2N sodium hydroxide solution, separates each layer.Water merges organic solution with salt solution (50 milliliters) washing again with dichloromethane extraction, with dried over mgso and in decompression evaporation down.Remaining foams use methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5), by the tubing string chromatography purification, obtain title compound, and be foams, 1.12 grams.
1H NMR(400MHz，CDCl 3)：δ1.30-2.60(m，4H)，2.84-3.20(m，3H)，3.40-4.80(m，8H)，6.62(m，1H)，6.70(m，1H)，7.40(m，1H)，7.50(m，1H)，7.61(m，2H)，8.18(m，1H).
APCI MS m/z 457[MH] +
Microanalysis measured value: C, 55.13; H, 4.81; N, 17.19.C 22H 22Cl 2N 6O; 0.33CH 2Cl 2Calculated value C, 55.26; H, 4.71; N, 17.31%
Embodiment 40:2-azetidine-1-base-1-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-ethyl ketone
Figure A20048000470801251
(227 milligrams in salt of wormwood, 1.65 mmole) and azetidine (0.06 milliliter, 0.82 mmole) be added into derive from embodiment 39 chlorine compound (250 milligrams, 0.55 mole) in N, solution in the dinethylformamide (55 milliliters), reaction mixture stirred 18 hours in 70 ℃.React on decompression and concentrate down, resistates divides water-soluble (10 milliliters) and ethyl acetate (10 milliliters), separates each layer.Water extracts with ethyl acetate (2 * 10 milliliters).Merge organic solution with water (20 milliliters) and salt solution (10 milliliters) washing, then, with dried over mgso and in decompression evaporation down.Crude product uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5) by the tubing string chromatography purification, obtains title compound, the foams that are white in color, 55 milligrams.
1H NMR(400MHz，CDCl 3)：δ1.68-2.30(m，6H)，2.80-3.90(m，11H)，4.10-4.50(m，2H)，5.10-5.55(m，2H)，6.60(dd，1H)，6.66(d，1H)，7.40(dd，1H)，7.45(m，1H)，7.58(m，2H)，8.18(d，1H).
APCI MS m/z 478[MH] +
Microanalysis measured value: C, 60.26; H, 5.83; N, 19.55.C 25H 28ClN 7O; 0.33CH 2Cl 2Calculated value; C, 60.12; H, 5.71; N, 19.38%
Embodiment 41:1-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-2-tetramethyleneimine-1-base-ethyl ketone
Figure A20048000470801252
Title compound is to abide by embodiment 40 described programs, and chlorine compound and tetramethyleneimine acquisition by embodiment 39 are the lark foams.
1H NMR(400MHz，CDCl 3)：δ1.54-2.01(m，8H)，2.05-4.00(m，11H)，4.20-4.45(m，2H)，5.10-5.58(m，2H)，6.60(m，1H)，6.66(d，1H)，7.40(dd，1H)，7.44(m，1H)，7.56-7.74(m，2H)，8.18(d，1H).
APCI MS m/z 492[MH] +
Embodiment 42:[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-tetramethyleneimine-3-base-ketone tri hydrochloride
Spirit of salt Yu diox (2.98 milliliters, solution 4M) is added into amine (690 milligrams, the 1.10 mmoles) solution of (5 milliliters) in methylene dichloride through protection that derives from preparation example 65, and reaction mixture was in stirring at room 1 hour.Mixture obtains title compound, the solid that is white in color (744 milligrams) in decompression evaporation down.
1H NMR(400MHz，CD 3OD)：δ2.00-2.22(m 3H)，2.56(m，1H)，3.38-4.01(m，14H)，4.24-4.41(m，2H)，7.02(m，1H)，7.45(d，1H)，7.80(m，1H)，7.90-8.00(m，2H)，8.00-8.10(m，2H).
APCI MS m/z 478[MH] +
Embodiment 43 to 49:
Following formula formula compound:
Be to abide by embodiment 42 described programs quantitatively by the suitably preparation of the amine through protecting.
Embodiment 50:8-chloro-5-tetramethyleneimine-(2S)-2-ylmethyl-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
The acid amides (398 milligrams, 0.725 mmole) that borine (1M is solution in tetrahydrofuran (THF), 7.25 milliliters, 7.25 mmoles) is added into embodiment 43 suspension of (10 milliliters) in tetrahydrofuran (THF), mixture heating up refluxed 2 hours.Add hydrochloric acid (6M) till no longer include gas evolution, reaction mixture is reflux 3 hours again.Cooled mixture uses the alkalization of 2N sodium hydroxide solution, then with ethyl acetate extraction (2 times).Merge organic extract with the salt water washing, with dried over mgso and in decompression evaporation down.Colourless jelly uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (80: 20: 3) by the tubing string chromatography purification, obtains title compound, the foams that are white in color, 98 milligrams as eluent.
1H NMR(400MHz，CDCl 3)：δ1.39(m，1H)，1.59-2.18(m，7H)，2.58(m，2H)，2.80-3.76(m，10H)，4.23(m，2H)，6.50(dd，1H)，6.58(d，1H)，7.22(d，1H)，7.36-7.58(m，3H)，8.04(d，1H).
APCI MS m/z 464[MH] +
Embodiment 51 to 54:
Following structure general formula:
Be to abide by embodiment 50 described programs, by suitable amides preparation
Figure A20048000470801301
Embodiment 55:5-azetidine-3-base-8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Hydrochloric acid Yu diox (5.6 milliliters, be added into the solution of the amine through protection (1.2 grams, 2.24 mmoles) in methylene dichloride (10 milliliters) of preparation example 73 in 4M), solution was in stirring at room 18 hours.The mixture branch is dissolved in 2N sodium hydroxide solution and methylene dichloride, separates each layer.Water merges organic solution with the salt water washing with dichloromethane extraction (2 times), with dried over mgso and in decompression evaporation down.Remaining yellow solid uses methylene dichloride in silica gel: methyl alcohol: 0.08 ammonia (95: 5: 0.5 to 93: 7: 1) obtains title compound, the foams that are white in color (300 milligrams) by the tubing string chromatography purification.
1H NMR(400MHz，CDCl 3)：δ1.60-2.20(m，4H)，2.82-3.77(m，10H)，4.35(m，4H)，6.60(d，1H)，6.66(d，1H)，7.36(d，1H)，7.42-7.59(m，3H)，8.18(m，1H).
APCI MS m/z 458[MNa] +
Embodiment 56:8-chloro-5-tetramethyleneimine-3-base-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl) 5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Figure A20048000470801303
Hydrochloric acid Yu diox (1.5 milliliters, be added in 4M) preparation example 74 the amine through protection (767 milligrams, the suspension of 1.39 mmole) Yu dioxs (30 milliliters), reaction mixture was in stirring at room 18 hours.TLC analyzes and shows the still residual starting material that has, and (1.5 milliliters, 4M), reaction was stirred again 5 hours therefore to add hydrochloric acid Yu diox again.Mixture is in decompression evaporation down, and resistates uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (90: 10: 1) is by the tubing string chromatography purification.Resistates and ether component distillation obtain title compound, are the brown foams, 404.6 milligrams.
1H NMR(400MHz，CDCl 3)：δ1.57-2.39(m，9H)，2.78-3.57(m，9H)，4.33(m，2H)，6.59(dd，1H)，6.66(d，1H)，7.32(d，1H)，7.44(m，1H)，7.52(m，2H)，8.18(d，1H).
APCI MS m/z 472[MNa] +
Embodiment 57:8-chloro-5-piperidin-4-yl-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene tri hydrochloride
Hydrochloric acid Yu diox (8.44 milliliters, be added into the solution of the amine through protection (1.9 grams, 3.37 mmoles) in methylene dichloride (50 milliliters) of preparation example 75 in 4M), reaction mixture was in stirring at room 18 hours.Mixture obtains title compound in decompression evaporation down, is grey peachiness solid.
1H NMR(400MHz，CD 3OD)：δ1.70-2.35(m，6H)，2.55-2.65(m，2H)，3.03-3.40(m，7H)，3.60-3.96(m，2H)，4.20-5.08(m，4H)，7.01(dd，1H)，7.43(d，1H)，7.90(s，2H)，7.98(dd，1H)，8.04(m，2H).
APCI MS m/z 464[MH] +
Embodiment 58:8-chloro-5-[1,4] oxygen azepine ring-6-in heptan base-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene tri hydrochloride
Hydrochloric acid Yu diox (1 milliliter, 4M) be added into preparation example 76 the amine through protection (180 milligrams, the solution of 0.31 mmole) Yu diox (5 milliliters), reaction mixture was in stirring at room 18 hours.Mixture is in decompression evaporation down, and resistates uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5) passes through the tubing string chromatography purification as eluent.Product is dissolved in methylene dichloride, and solution is that hydrochloric acid (1M) is handled with ether.Solution evaporates down in decompression and obtains title compound.
1H NMR(400MHz，CD 3OD)：δ2.00-2.60(m，4H)，3.36-3.62(m，7H)，3.70-4.00(m，7H)，4.12-4.40(m，4H)，7.01(dd，1H)，7.43(d，1H)，7.78(dd，1H)，7.81(m，1H)，7.90(s，1H)，7.98(d，1H)，8.05(m，1H).
APCI MS m/z 480[MH] +
Embodiment 59:[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-morpholine-4-base-ketone
Figure A20048000470801322
The amine of embodiment 4 (150 milligrams, 0.42 mmole), morpholine carbonyl chlorine (0.15 milliliter, 1.26 mmoles) and the mixture of triethylamine (0.18 milliliter, 1.26 mmoles) in methylene dichloride (10 milliliters) were in stirring at room 18 hours.Reaction mixture is in down evaporation of decompression, and resistates uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5) is by the tubing string chromatography purification, obtains the title compound solid (130 milligrams) that is white in color.
1H NMR(400MHz，CDCl 3)：δ1.56-1.85(m，4H)，2.85-3.38(m，7H)，3.60-3.98(m，6H)，4.22-4.54(m，3H)，4.78-4.97(m，1H)，6.61(dd，1H)，6.68(d，1H)，7.38(d，1H)，7.50(m，1H)，7.58(m，2H)，8.18(m，1H).
APCI MS m/z 516[MNa] +
Embodiment 60 to 63:
Following structure general formula:
Be to abide by embodiment 59 described programs, prepare by the amine of embodiment 4 and suitable acyl chloride.
Figure A20048000470801332
A-separates without the tubing string chromatography
Embodiment 64:{2-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-ethyl }-dimethyl-amine tri hydrochloride
Borine (1M is solution in tetrahydrofuran (THF), 4.3 milliliters, 4.3 mmoles) is added into the suspension of acid amides (398 milligrams, 0.43 mmole) in tetrahydrofuran (THF) (10 milliliters) of embodiment 61, mixture reflux 2 hours.Add hydrochloric acid (6M) till no longer include gas evolution, reaction mixture is reflux 3 hours again.Cooled mixture uses the alkalization of 2N sodium hydroxide solution, then with dichloromethane extraction (3 * 20 milliliters).Merge organic extract with salt solution (20 milliliters) washing, with dried over mgso and in decompression evaporation down.Colourless jelly uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (93: 7: 1) by the tubing string chromatography purification, obtains colourless jelly as eluent.This jelly is that the salt acid treatment obtains title compound (194 milligrams) with ether.
1H NMR(400MHz，CD 3OD)：δ2.00-2.19(m，4H)，3.00(m，6H)，3.18(m，2H)，3.42-4.46(m，11H)，7.00(dd，1H)，7.42(d，1H)，7.79(dd，1H)，7.63(m，2H)，7.97(m，1H)，8.03(m，1H).
APCI MS m/z 452[MH] +
Embodiment 65:8-chloro-5-(2-tetramethyleneimine-1-base-ethyl)-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene tri hydrochloride
Title compound is to abide by embodiment 64 described similar programs, by the acid amides acquisition of embodiment 62,15% productive rate.
1H NMR(400MHz，CD 3OD)：δ2.03-2.23(m，8H)，3.00-3.83(m，13H)，4.00-4.80(m，4H)，7.00(m，1H)，7.43(d，1H)，7.80-8.08(m，5H).
APCI MS m/z 478[MH] +
Embodiment 66:[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-methyl acetate
The amine of embodiment 4 (500 milligrams, 1.31 mmoles), methyl bromoacetate (260 milligrams, 1.70 mmoles) and salt of wormwood (220 milligrams, 1.59 mmoles) is in N, and the mixture in the dinethylformamide (15 milliliters) was in stirring at room 72 hours.Mixture is in decompression evaporation down, and resistates uses methylene dichloride in silica gel: methyl alcohol (93: 7) is made eluent, by the tubing string chromatography purification, obtains title compound.
1H NMR(400MHz，CDCl 3)：δ1.42-2.40(m，4H)，3.00-3.22(m，3H)，3.39-3.98(m，9H)，4.38(m，2H)，6.63(m，1H)，6.74(m，1H)，7.36(d，1H)，7.57(m，3H)，8.18(d，1H).
APCI MS m/z 453[MH] +
Embodiment 67:1-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-3-methoxyl group-third-1-ketone
Figure A20048000470801352
(116 milligrams of 1-(3-dimethylaminopropyl)-3-ethyl first imide hydrochloride, 0.6 mmole), then be (81 milligrams in I-hydroxybenzotriazole hydrate, 0.6 mmole) and triethylamine (84 microlitres, 0.6 mmole) be added into (63 milligrams of 3-methoxypropionic acid, 0.6 the solution in methylene dichloride (10 milliliters) mmole), solution stirring 10 minutes.Add the amine (150 milligrams, 0.4 mmole) of embodiment 4, reacted on stirring at room 5 hours.Reaction is washed with saturated sodium bicarbonate solution, with dried over mgso and in decompression evaporation down.Resistates uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5) obtains title compound, the solid that is white in color, 166 milligrams by the tubing string chromatography purification.
1H NMR(400MHz，CDCl 3)：δ1.57-2.38(m，4H)，2.63-3.03(m，4H)，3.14(m，1H)，3.26(s，3H)，3.78-3.98(m，3H)，4.23-4.43(m，3H)，4.75-4.92(m，1H)，5.44-5.62(m，1H)，6.61(dd，1H)，6.68(d，1H)，7.40(dd，1H)，7.46(m，1H)，7.58(m，2H)，8.18(d，1H).
APCI MS m/z 489[MNa] +
Embodiment 68:1-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-3-dimethylamino-third-1-ketone
Figure A20048000470801361
O-(1H-benzotriazole-1-yl)-N, N, N ', (200 milligrams of N '-tetramethyl-urea hexafluorophosphate, 0.52 mmole) be added into the solution of 3-dimethylamino propionic salt hydrochlorate (80 milligrams, 0.52 mmole) in methylene dichloride (5 milliliters), solution stirring 15 minutes.The amine (100 milligrams, 0.26 mmole) that adds embodiment 4, reaction mixture was in stirring at room 18 hours.The mixture branch is dissolved in methylene dichloride and sodium bicarbonate aqueous solution, separates each layer.Organic phase is with dried over mgso and in decompression evaporation down.Crude product uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (90: 10: 1) obtains title compound, the solid that is white in color (110 milligrams) by the tubing string chromatography purification.
1H NMR(400MHz，CDCl 3)：δ1.60-2.00(m，2H)，2.20(m，3H)，2.38，2.42(2xs，6H)，2.62(m，1H)，2.75-3.00(m，4H)，3.14(m，1H)，3.97-4.80(m，4H)，5.05-5.66(m，2H)，6.60(dd，1H)，6.66(d，1H)，7.40(m，1H)，7.46(m，1H)，7.59(m，2H)，8.18(d，1H).
APCI MS m/z 480[MH] +
Embodiment 69; 8-chloro-5-(1-methyl-tetramethyleneimine-(2S)-the 2-ylmethyl)-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene tri hydrochloride
Figure A20048000470801371
(0.1 milliliter in formaldehyde, the solution of 33wt% in water) and (64 milligrams of triacetyl oxygen sodium borohydrides, 0.30 mmole) be added into the suspension of amine (70 milligrams, 0.15 mmole) in methylene dichloride (5 milliliters) of embodiment 50, reaction mixture was in stirring at room 2 hours.The mixture branch is dissolved in methylene dichloride and 2N sodium hydroxide solution, separates each phase.Organic solution is in decompression evaporation down, and resistates uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (93: 7: 1) is made eluent, by the tubing string chromatography purification.Product is the salt acid treatment with ether, and solution obtains title compound (35 milligrams) in decompression evaporation down.
1H NMR(400MHz，CD 3OD)：δ1.78-2.98(m，9H)，2.96-3.38(m，8H)，3.40-4.38(m，8H)，7.01(dd，1H)，7.43(d，1H)，7.80(m，1H)，7.89(m，2H)，7.98(d，1H)，8.06(dd，1H).
APCI MS m/z 502[MH] +
Embodiment 70 to 72:
Following structure general formula
Be to abide by embodiment 69 described similar programs, by suitable amine and prepared formaldehyde.
Figure A20048000470801381
A-is free alkali and separates
Embodiment 73 and 74:(+) and (-)-8-chloro-5-(4-methyl-morpholine-2-ylmethyl)-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Figure A20048000470801382
(0.1 milliliter in formaldehyde, the solution of 37wt% in water) and (55 milligrams of triacetyl oxygen sodium borohydrides, 0.26 mmole) be added into the suspension of amine (60 milligrams, 0.12 mmole) in methylene dichloride (5 milliliters) of embodiment 54, reaction mixture was in stirring at room 2 hours.The mixture branch is dissolved in methylene dichloride and 2N sodium hydroxide solution, separates each phase.Organic solution is in decompression evaporation down, and resistates uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (93: 7: 1) is made eluent, by the tubing string chromatography purification.Product uses Kai Luosai (Chiralcel) OD250 * 20 millimeters tubing strings and uses methyl alcohol to make eluent then, by the HPLC purifying, obtains the title compound of embodiment 73;
1H NMR(400MHz，CDCl 3)：δ1.60-2.30(m，9H)，2.55-2.81(m，4H)，2.96(m，2H)，3.13(m，1H)，3.38-3.98(m，7H)，4.37(m，2H)，6.60(dd，1H)，6.66(d，1H)，7.32(d，1H)，7.42-7.59(m，3H)，8.18(m，1H).
APCI MS m/z 516[MNa] +
[α] D＝-1.20(c＝0.33，methanol)
And the title compound of embodiment 74.
1H NMR(400MHz，CDCl 3)：δ1.60-2.20(m，6H)，2.30(s，3H)，2.50-2.79(m，4H)，2.96(m，2H)，3.13(m，1H)，3.20-3.79(m，6H)，3.92(m，1H)，4.37(m，2H)，6.60(dd，1H)，6.65(d，1H)，7.32(d，1H)，7.42-7.59(m，3H)，8.18(m，1H).
APCI MS m/z 516[MNa] +
[α] D＝+3.43(c＝0.23，methanol)
Embodiment 75:[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-((2S)-1-methyl-tetramethyleneimine-2-yl)-ketone
(37wt% is in water for formaldehyde, 0.1 milliliter), triethylamine (0.5 milliliter), (135 milligrams of acetate (0.5 milliliter) and triacetyl oxygen sodium borohydrides, 0.63 mmole) be added into (175 milligrams of the amine of embodiment 43,0.32 the suspension of (10 milliliters) in methylene dichloride mmole), reaction mixture was in stirring at room 1 hour.The mixture branch is dissolved in methylene dichloride (50 milliliters) and 2N sodium hydroxide solution (50 milliliters), separates each phase.Organic solution is in decompression evaporation down, and resistates uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5) is made eluent, by the tubing string chromatography purification, obtains title compound, the foams that are white in color (103 milligrams).
1H NMR(400MHz，CDCl 3)：δ1.60-2.04(m，6H)，2.20-2.52(m，5H)，2.84-3.23(m，6H)，3.60-4.46(m，4H)，5.50-5.85(m，2H)，6.60(dd，1H)，6.66(d，1H)，7.38-7.48(m，2H)，7.58-7.63(m，2H)，8.18(m，1H).
APCI MS m/z 492[MH] +
Embodiment 76 to 81:
Following structure general formula:
Be to abide by embodiment 75 described similar programs, by suitable amine and prepared formaldehyde.
Figure A20048000470801421
A-reacted on stirring at room 24 hours
The b-product is that the salt acid treatment obtains tri hydrochloride with ether
Embodiment 82:[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-(tetrahydrochysene-pyrans-4-yl) ketone
O-(1H-benzotriazole-1-yl)-N, N, N ', (243 milligrams of N '-tetramethyl-urea hexafluorophosphate, 0.64 mmole) be added into (82 milligrams of tetrahydrochysene-4-pyrans carboxylic acids (medical chemistry periodical 37 (26), 4549,1994), 0.64 the solution of (10 milliliters) in methylene dichloride mmole), solution stirring 30 minutes.The amine (120 milligrams, 0.32 mmole) that adds embodiment 4, reaction mixture was in stirring at room 18 hours.TLC analyzes and shows the still residual starting material that has, so add additional quantity O-(1H-benzotriazole-1-yl)-N, N, (122 milligrams of N ' N '-tetramethyl-urea hexafluorophosphate, 0.32 mmole) and tetrahydrochysene-4-pyrans carboxylic acid (41 milligrams, 0.32 mmole), reaction mixture stirred again 24 hours.The mixture branch is dissolved in methylene dichloride and saturated sodium bicarbonate aqueous solution, separates each layer.Organic phase is with dried over mgso and in decompression evaporation down.Crude product uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5) is made eluent, by the tubing string chromatography purification, obtains title compound, the solid that is white in color (105 milligrams).
1H NMR(400MHz，CDCl 3)：δ1.58-2.42(m，10H)，2.81(m，1H)，2.98-3.22(m，4H)，3.50(m，2H)，3.97-4.17(m，2H)，4.22-4.50(m，2H)，5.08-5.46(m，1H)，6.60-6.78(m，2H)，7.40(d，1H)，7.50-7.65(m，3H)，8.20(d，1H).
APCI MS m/z 493[MH] +
Embodiment 83:[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-(1-methyl-piperidin-4-yl)-ketone
O-(1H-benzotriazole-1-yl)-N, N, N ', (395 milligrams of N '-tetramethyl-urea hexafluorophosphate, 1.04 mmole) be added into the solution of 1-methyl piperidine-4-carboxylic acid hydrochloride (210 milligrams, 1.04 mmoles) in methylene dichloride (10 milliliters), solution stirring 30 minutes.The amine (200 milligrams, 0.52 mmole) that adds embodiment 4, reaction mixture was in stirring at room 18 hours.Mixture washs with aqueous sodium carbonate, and organic solution is with dried over mgso.Solution is in decompression evaporation down, and crude product uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (90: 10: 1) obtains title compound, the solid that is white in color (195 milligrams) by the tubing string chromatography purification.
APCI MS m/z 506[MH] +
Embodiment 84:8-chloro-5-(1-methyl-azetidine-3-yl)-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Figure A20048000470801441
(37% in water for formaldehyde, 0.1 milliliter), triethylamine (0.5 milliliter), (75 milligrams of acetate (0.5 milliliter) and triacetyl oxygen sodium borohydrides, 0.36 mmole) be added into (77 milligrams of the amine of embodiment 55,0.18 the suspension of (10 milliliters) in methylene dichloride mmole), reaction mixture was in stirring at room 3 hours.The mixture branch is dissolved in methylene dichloride and 2N sodium hydroxide solution, separates each phase.Water layer merges organic solution in decompression evaporation down again with dichloromethane extraction.Resistates uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5) is made eluent, by the tubing string chromatography purification, obtains title compound, the foams that are white in color (72 milligrams).
1H NMR(400MHz，CDCl 3)：δ1.79-2.21(m，4H)，2.40(s，3H)，2.83-3.78(m，12H)，4.34(m，2H)，6.60(dd，1H)，6.66(d，1H)，7.34(d，1H)，7.42-7.58(m，3H)，8.18(d，1H).
APCI MS m/z 450[MH] +
Embodiment 85 to 88:
Following structure general formula:
Be to abide by embodiment 84 described similar programs, by suitable amine and prepared formaldehyde.
Figure A20048000470801452
Embodiment 89:8-chloro-5-(1-methyl-tetramethyleneimine-3-yl)-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Figure A20048000470801462
Formaldehyde (18 microlitres, the 37wt% aqueous solution, 0.22 mmole) and triacetyl oxygen sodium borohydride (47 milligrams, 0.22 mmole) be added into (100 milligrams of the amine of embodiment 56,0.22 the solution in methylene dichloride (5 milliliters) mmole), reaction mixture was in stirring at room 30 minutes.Add saturated sodium bicarbonate aqueous solution (10 milliliters), mixture high degree of agitation 10 minutes is separated each layer.Organic layer is in decompression evaporation down, and resistates uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5) is made eluent, by the tubing string chromatography purification.Product and ether component distillation obtain title compound (60 milligrams).
1H NMR(400MHz，CDCl 3)：δ1.74-2.30(m，8H)，2.34(s，3H)，2.45(s，1H)，2.57(d，1H)，2.66(d，1H)，2.80(t，1H)，2.93(s，2H)，3.12(t，1H)，3.23(t，1H)，3.48(s，2H)，4.33(s，2H)，6.60(t，1H)，6.64(d，1H)，7.32(d，1H)，7.45(t，1H)，7.52(m，2H)，8.15(d，1H).
APCI MS m/z 564[MH] +
Embodiment 90:8-chloro-5-(1-sec.-propyl-tetramethyleneimine-3-yl)-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene tri hydrochloride
Figure A20048000470801471
The amine (100 milligrams, 0.22 mmole) that is added into embodiment 56 solution of (5 milliliters) in methylene dichloride, reaction mixture was in stirring at room 16 hours.Add saturated sodium bicarbonate aqueous solution (10 milliliters), mixture high degree of agitation 10 minutes is separated each layer.Organic layer is in decompression evaporation down, and resistates uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5) is made eluent, by the tubing string chromatography purification.It is the salt acid treatment that product uses ether, obtains title compound.
1H NMR(400MHz，CD 3OD)：δ1.43(d，6H)，1.85-2.70(m，4H)，3.35-4.85(m，17H)，7.02(t，1H)，7.47(d，1H)，7.80-7.92(m，2H)，7.97(d，2H)，8.06(t，1H).
APCI m/z 492[MH] +
Embodiment 91:2-[8-chloro-1-(1-pyrimidine-2-base-piperidin-4-yl)-4H, 6H-2,3,5,10b-
Figure A20048000470801472
N, N-diisopropyl ethyl amine (80 microlitres, 0.62 mmole), then be added into the amine (200 milligrams, 0.52 mmole) of embodiment 12 in N for ethylene chlorhydrin (52 microlitres, 0.78 mmole), the solution of (6 milliliters) in the dinethylformamide, reaction mixture was in stirring at room 18 hours.Mixture concentrates down in decompression, and resistates uses ethyl acetate in silica gel: methyl alcohol: 0.88 ammonia (90: 10: 1) is made eluent, by the tubing string chromatography purification, obtains title compound, is pale solid (120 milligrams).
1H NMR(400MHz，CDCl 3)：δ1.62-2.22(m，3H)，2.62(m，1H)，2.84(m，2H)，3.00(m，2H)，3.18(m，1H)，3.38-3.90(m，6H)，4.80(m，2H)，6.46(m，1H)，7.38(d，1H)，7.58(m，2H)，8.30(s，2H).
APCI MS m/z 426[MH] +
Embodiment 92:8-chloro-5-(2-methoxyl group-ethyl)-1-(1-pyrimidine-2-base-piperidin-4-yl)-5,6-dihydro-4H-2,3,5, the 10b-tetrazine is [e] Azulene also
Figure A20048000470801481
N, N-diisopropyl ethyl amine (80 microlitres, 0.62 mmole), then be (0.2 milliliter of 2-bromo-ethyl-methyl ether, 0.62 mmole) be added into (200 milligrams of the amine of embodiment 12,0.52 mmole) in N, the solution of (6 milliliters) in the dinethylformamide, reaction mixture stirred 18 hours in 80 ℃.Mixture concentrates down in decompression, and resistates uses ethyl acetate in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5) is made eluent, by the tubing string chromatography purification, obtains title compound, is jelly (76 milligrams).
1H NMR(400MHz，CDCl 3)：δ1.84-2.16(m，4H)，2.78-3.20(m，5H)，3.20-4.50(m，9H)，4.80(m，2H)，6.48(dd，1H)，7.32(d，1H)，7.58(m，2H)，8.30(d，2H).
APCI MS m/z 462[MNa] +
Embodiment 93:8-chloro-5-pyrimidine-2-base-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Figure A20048000470801491
The amine of embodiment 4 (200 milligrams, 0.53 mmole), 2-chloropyrimide (66 milligrams, 0.58 mmole) and salt of wormwood (72 milligrams, 0.53 mmole) is in N, and the mixture of (5 milliliters) was in stirring at room 18 hours in the dinethylformamide.TLC analyzes and shows the still residual starting material that has, so add additional quantity 2-chloropyrimide (66 milligrams, 0.58 mmole), reaction was stirred 72 hours in 80 ℃ again.Cooled mixture is in decompression evaporation down, and the resistates branch is dissolved in ethyl acetate and salt solution, separates each layer.Organic layer, evaporates down in decompression with dried over mgso with the ammonium chloride solution washing then with water washing.Remaining yellow oil uses methylene dichloride in silica gel: methyl alcohol (95: 5) is made eluent, by the tubing string chromatography purification, obtains title compound, is yellow oil (117 milligrams).
1H NMR(400MHz，CDCl 3)：δ1.61-2.40(m，4H)，2.82-3.19(m，3H)，3.63-4.48(m，4H)，5.60-5.84(m，2H)，6.60(m，2H)，6.66(d，1H)，7.40(d，1H)，7.43(m，1H)，7.52(m，1H)，7.60(s，1H)，8.16(m，1H)，8.38(d，2H).
APCI m/z 459[MH] +
Embodiment 94:8-chloro-5-pyrimidine-4-base-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
The amine of embodiment 4 (500 milligrams, 1.3 mmoles), the mixture of salt of wormwood (480 milligrams, 3.5 mmoles) and 4-chloropyrimide (300 milligrams, 2.6 mmoles) stirred 18 hours in 95 ℃.Cooled reaction mixture dilutes with ethyl acetate, and solution concentrates down with dried over mgso and in decompression then with salt water washing (5 times).Crude product uses methylene dichloride in silica gel: methyl alcohol (100: 0 to 95: 5) is made eluent, and by the tubing string chromatography purification, product is developed with ether, obtains title compound (80 milligrams).
1H NMR(400MHz，CDCl 3)：δ1.80-2.24(m，4H)，2.97(m，2H)，3.18(m，1H)，3.90-4.43(m，4H)，5.20-5.80(m，2H)，6.56(d，1H)，6.60(m，1H)，6.66(d，1H)，7.42(m，2H)，7.57(d，1H)，7.62(s，1H)，8.18(m，1H)，8.32(d，1H)，8.70(s，1H).
APCI m/z 459[MH] +
Embodiment 95:8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-formaldehyde
The solution of the amine of embodiment 4 (300 milligrams, 0.79 mmole) in formic acid (15 milliliters) stirred 3 hours in 80 ℃.Cooled mixture concentrates down in decompression, and the resistates branch is dissolved in ethyl acetate and sodium hydrogen carbonate solution.Separate each layer, organic phase is evaporated down in decompression and is obtained title compound.
1H NMR(400MHz，CDCl 3)：δ1.60-2.42(m，4H)，2.98-3.24(m，3H)，3.78-4.58(m，5H)，5.43(m，1H)，6.62(m，1H)，6.75(m，1H)，7.40(m，1H)，7.55(m，1H)，7.60(d，1H)，8.18(m，1H)，8.21(d，1H).
APCI m/z 409[MH] +
Embodiment 96:8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-sulfonic acid dimethylformamide
Figure A20048000470801502
Dimethylamino SULPHURYL CHLORIDE (0.12 milliliter, 1.08 mmoles) is added into amine (140 milligrams, 0.36 mmole) and the solution of pyridine (90 microlitres, 1.08 mmoles) in methylene dichloride (8 milliliters) of embodiment 4, and reaction mixture was in stirring at room 18 hours.TLC analysis demonstration is residual starting material, so add additional quantity dimethylamino SULPHURYL CHLORIDE (0.08 milliliter, 0.72 mmole) again, mixture stirred again 24 hours.Mixture washs with saturated sodium bicarbonate aqueous solution, with dried over mgso and in decompression evaporation down.Crude product uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5) is made eluent, by the tubing string chromatography purification, obtains title compound, is lark jelly (120 milligrams).
1H NMR(400MHz，CDCl 3)：δ1.58-1.94(m，2H)，2.10-2.40(m，2H)，2.78-3.02(m，8H)，3.15(m，1H)，3.62-4.00(m，2H)，4.21-4.97(m，4H)，6.60(dd，1H)，6.67(d，1H)，7.39(d，1H)，7.47(dd，1H)，7.59(d，1H)，7.62(s，1H)，8.19(d，1H).
APCI MS m/z 488[MH] +
Embodiment 97:8-chloro-5-pyridine-2-ylmethyl-1-(1-pyrimidine-2-base-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Figure A20048000470801511
(277 milligrams of triacetyl oxygen sodium borohydrides, 1.31 mmole) be added into (250 milligrams of the amine of embodiment 12,0.65 mmole), (105 milligrams of 2-pyridylaldehydes, 0.98 mmole), and the mixture of acetate (3) in methylene dichloride (5 milliliters), being cooled to 5 ℃, reaction mixture was in stirring at room 18 hours then.0.88 ammonia is added into reaction mixture, separates each phase, organic phase is with dried over mgso and in decompression evaporation down.Crude product uses methylene dichloride in silica gel: methyl alcohol (95: 5) is made eluent, by the tubing string chromatography purification, obtains title compound (167 milligrams).
1H NMR(400MHz，CDCl 3)：δ1.78-2.26(m，4H)，3.00，3.18(2xm，4H)，3.35-3.60，3.80-3.98(2xm，5H)，4.80(m，2H)，6.48(dd，1H)，7.22(m，1H)，7.37(d，1H)，7.53(m，3H)，7.75(m，1H)，8.30(s，2H)，8.60(d，1H).
APCI MS m/z 473[MH] +
Embodiment 98 to 99:
Following structure general formula:
Figure A20048000470801521
Be in accordance with embodiment 97 described similar programs and by suitable amine preparation.
Figure A20048000470801522
Embodiment 100:8-chloro-1-(1-pyrimidine-2-base-piperidin-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-sulfonic acid dimethylformamide
Figure A20048000470801531
N, N-diisopropyl ethyl amine (77 microlitres, 0.44 mmole), then be dimethylamino SULPHURYL CHLORIDE (50 microlitres, 0.44 mmole) be added into the ice-cold solution of amine (150 milligrams, 0.4 mmole) in methylene dichloride (10 milliliters) of embodiment 12, reaction mixture was in stirring at room 4 hours.TLC analyze to show the residual starting material that has, so adding additional quantity dimethylamino SULPHURYL CHLORIDE (91 microlitres, 0.8 mmole) and N, N-diisopropyl ethyl amine (140 microlitres, 0.8 mmole), mixture are again in stirring at room 18 hours.Mixture is in decompression evaporation down, and the resistates branch is dissolved in methylene dichloride and sodium bicarbonate aqueous solution, separates each layer, and organic phase is in decompression evaporation down.Crude product uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5) is made eluent, by the tubing string chromatography purification, obtains title compound, is pale solid (135 milligrams).
1H NMR(400MHz，CDCl 3)：δ1.58-1.89(m，2H)，2.16-2.35(m，2H)，2.83-3.19(m，9H)，3.63-3.99(m，2H)，4.59-4.97(m，4H)，6.50(dd，1H)，7.38(d，1H)，7.59(d，1H)，7.63(s，1H)，8.30(d，2H).
APCI MS m/z 489[MH] +
Embodiment 101:8-chloro-5-methyl isophthalic acid-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4,5-dihydro-2,3,5,10b-four azepines-benzo [e] Azulene-6-ketone
Figure A20048000470801532
The amine (250 milligrams, 0.59 mmole) that acetate (2) is added into preparation example 62 solution of (6 milliliters) in toluene, reaction mixture refluxed stirred 3 hours.Cooled mixture uses ethyl acetate in silica gel: methylene dichloride: methyl alcohol (100: 0: 0 to 0: 95: 5) is made eluent, by the tubing string chromatography purification.Product and methylene dichloride (2 * 10 milliliters) and ether (4 * 10 milliliters) component distillation obtain title compound, the foams that are white in color (151 milligrams).
1H NMR(400MHz，DMSOd 6)：δ1.45(m，2H)，1.92(m，2H)，2.74(m，1H)，2.85-3.35(m，5H)，4.10(m，1H)，4.32-4.60(m，3H)，6.51(m，1H)，6.74(d，1H)，7.42(m，1H)，7.61-7.84(m，3H)，8.00(s，1H).
APCI m/z 409[MH] +
Embodiment 102:13-chloro-9-methyl-3-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-2,4,5,9-four azepines-three ring [9.4.0.0 *2,6 *] 15 carbon-1 (11), 3,5,12, the 14-pentaene
The mixture reflux of hydrazides (121 milligrams, 0.55 mmole) in ethanol (2 milliliters) of compound of preparation example 80 (140 milligrams, 0.55 mmole) and preparation example 1 23 hours allows its cooling then.Mixture concentrates down in decompression, and resistates uses methylene dichloride in silica gel: methyl alcohol: the gradient of 0.88 ammonia (100: 0: 0 to 90: 10: 1), and by the tubing string chromatography purification.Product is dissolved in methylene dichloride (6 milliliters), and solution is handled in the isocyanic ester (0.6 gram, 1.5 mmole/grams) of polymkeric substance combination, and mixture stirred 1 hour.Mixture after filtration, filtrate obtains title compound (57 milligrams) in down evaporation of decompression.
1H NMR(400MHz，CDCl 3)：δ1.42(m，1H)，1.63(m，1H)，2.18(m，1H)，2.30(m，2H)，2.42(s，3H)，2.78(m，2H)，2.83-3.05(m，3H)，3.18(m，2H)，3.61(d，1H)，4.18(m，1H)，4.39(m，1H)，6.58(m，1H)，6.62(d，1H)，7.19(d，1H)，7.42(m，2H)，7.52(s，1H)，8.14(m，1H).
APCI MS m/z 409[MH] +
Embodiment 103:13-chloro-8-methyl-3-(1-pyrimidine-2-base-piperidin-4-yl)-2,4,5,8-four azepines-three ring [9.4.0.0 *2,6 *] 15 carbon-1 (11), 3,5,12, the 14-pentaene
Figure A20048000470801551
Trifluoroacetic acid (1.5 milliliters) is added into compound (1.60 grams, 3.72 mmoles) (100 milliliters) solution in toluene of preparation example 63, and mixture stirred 24 hours in 60 ℃.Cooled mixture concentrates down in decompression, and the resistates branch is dissolved in methylene dichloride and sodium hydrogen carbonate solution.Separate each layer, organic phase is with dried over mgso and in decompression evaporation down.Irreducible oil uses methylene dichloride in silica gel: methyl alcohol (95: 5) is made eluent, by the tubing string chromatography purification.Product is suspended in methylene dichloride (100 milliliters), with activated carbon treatment.Mixture after filtration, filtrate is in down evaporation of decompression, resistates uses methylene dichloride in silica gel: methyl alcohol (96: 4) is made eluent, by the tubing string chromatography purification, obtains title compound and is oil (469 milligrams).
1H NMR(400MHz，CDCl 3)：δ1.42(m，1H)，1.62(m，1H)，2.18(m，1H)，2.25(m，2H)，2.42(s，3H)，2.60(m，1H)，2.80(m，2H)，2.93-3.01(m，2H)，3.28(m，2H)，4.20(d，1H)，4.60(m，1H)，4.86(m，1H)，6.45(dd，1H)，7.18(d，1H)，7.40(d，2H)，8.27(d，2H).
APCI MS m/z 410[MH] +
Embodiment 104:8-chloro-5,6-dimethyl-1-(1-pyrimidine-2-base-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene
Trifluoroacetic acid (0.5 milliliter) is added into the solution of compound (0.9 gram, 2.10 mmoles) in toluene (10 milliliters) of preparation example 64, and reaction mixture stirred 18 hours in 100 ℃.Cooled mixture is with sodium hydrogen carbonate solution and salt water washing, then in decompression evaporation down.Resistates uses methylene dichloride in silica gel: methyl alcohol (95: 5) is made eluent, by the tubing string chromatography purification, obtains title compound, the foams that are white in color (530 milligrams).
1H NMR(400MHz，C 2D 2Cl 4，at 373K)：δ1.23(d，3H)，1.82(m，2H)，2.03(m，2H)，2.40(s，3H)，3.01-3.19(m，3H)，3.29(m，1H)，3.49(m，1H)，3.63(m，1H)，4.64(m，1H)，4.78(m，1H)，6.42(m，1H)，7.24(d，1H)，7.50(m，2H)，8.26(d，2H).
APCI MS m/z 432[MNa] +
Embodiment 105:1-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-8-trifluoromethyl-4H, 6H-5-Evil-2,3,10b-three azepines-benzo [e] Azulene
Figure A20048000470801561
(81 milligrams of sodium hydrides, 60% in Dormant oils dispersion liquid, 2.03 mmoles) be added into (350 milligrams of 2-amino-5-trifluoromethyl methyl alcohol (99/05147,60 page of WO), 1.8 the solution in tetrahydrofuran (THF) (20 milliliters) mmole), solution stirred 30 minutes in 0 ℃.The solution of muriate (560 milligrams, 2.0 mmoles) in tetrahydrofuran (THF) (10 milliliters) that dropwise adds preparation example 5 is finished in case add, and reaction mixture was in stirring at room 5 hours.Reaction mixture is with water (2 milliliters) cancellation, and the mixture branch is dissolved in methylene dichloride and sodium hydrogen carbonate solution.Separate each layer, organic phase is with dried over mgso, and evaporation under decompression.Crude product uses methylene dichloride in silica gel: methyl alcohol: 0.88 chlorine (95: 5: 0.5) is made eluent by the tubing string chromatography purification, obtains white solid (560 milligrams).
This solid stirred 18 hours in 140 ℃ in the mixture of dimethylbenzene (20 milliliters) and right-toluenesulphonic acids (40 milligrams).Cooled solution is in decompression evaporation down, and resistates uses ethyl acetate in silica gel: methyl alcohol: 0.88 ammonia (97: 3: 0.3 to 90: 10: 1) is made eluent, by the tubing string chromatography purification, obtains title compound, is lark solid (210 milligrams).
1H NMR(400MHz，MeOD)：δ1.98(m，4H)，2.98(m，2H)，3.41(m，1H)，4.37(m，2H)，4.57(s，2H)，4.61(s，2H)，6.64(m，1H)，6.63(d，1H)，7.58(m，1H)，7.98(d，1H)，8.03(m，3H).
APCI MS m/z 416[MH] +
Embodiment 106:10-chloro-(1-3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-6,7-dihydro-4H-5,8-Er Evil-2,3,10b-three azepines-benzo [a] pentamethylene [c] cyclonoene
Figure A20048000470801571
Compound of preparation example 61 (250 milligrams, 0.58 mmole) and the mixture of right-toluenesulphonic acids (catalytic amount) in dimethylbenzene (75 milliliters) stirred 24 hours in 140 ℃.Cooled mixture concentrates down in decompression, resistates uses methylene dichloride in silica gel: methyl alcohol: 0.88 ammonia (95: 5: 0.5) is made eluent by the tubing string chromatography purification, use ethyl acetate once again: methyl alcohol: 0.88 ammonia (95: 5: 0.5 to 90: 10: 1) is made the eluent purifying, obtain title compound, be canescence foams (42 milligrams).
1H NMR(400MHz，MeOD)：δ1.30(m，2H)，2.04(m，2H)，2.74-2.98(m，3H)，3.70(m，1H)，3.81(m，1H)，4.19(m，3H)，4.37(m，1H)，4.50(m，1H)，4.78(m，1H)，6.62(m，1H)，6.82(d，1H)，7.36(m，1H)，7.48(m，2H)，7.58(m，1H)，8.02(m，1H).
APCI MS m/z 412[MH] +
Embodiment 107:8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-4H, 6H-5-thia-2,3,10b-three azepines-benzo [e] Azulene
The hydrazides (557 milligrams, 2.53 mmoles) that adds preparation example 1 in the solution of thioamides (851 milligrams, 2.53 mmoles) in fourth-1-alcohol (20 milliliters) of preparation example 87, mixture heating up to 100 ℃ is gone through 20 hours.Reaction mixture is in decompression evaporation down, and resistates uses methylene dichloride in silica gel: methyl alcohol (95: 5) is made eluent, by the tubing string chromatography purification, obtains title compound, is canescence foams (825 milligrams).
1H NMR(400MHz，CDCl 3)：δ1.60(m，1H)，1.65(m，1H)，2.20(m，1H)，2.40(m，1H)，2.80(m，1H)，3.00(m，2H)，3.40(d，1H)，3.60(m，2H)，4.00(d，1H)，4.20(d，1H)，4.40(d，1H)，6.60(dd，1H)，6.65(d，1H)，7.25(d，1H)，7.45(m，3H)，8.20(d，1H)
APCI MS m/z 398[MH] +
Embodiment 108:8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-4H, 6H-5-thia-2,3,10b-three azepines-benzo [e] Azulene 5-oxide compound
Figure A20048000470801581
In 1,1,1,3,3, add 30% aqueous hydrogen peroxide solution (0.09 milliliter) in the sulfide (150 milligrams, 0.38 mmole) of embodiment 107 in the solution in 3-hexafluoro-propan-2-ol (5 milliliters).Gained reaction mixture stirring at room 1 hour is divided molten with the water-based S-WAT subsequently.Organic layer is with the salt water washing, and dry (sal epsom) filters and evaporation.The gained resistates uses methylene dichloride in silica gel: methyl alcohol: 0.880 ammonia (95: 5: 0.5) is made eluent, by the tubing string chromatography purification, obtains title compound, is canescence foams (64 milligrams).
1H NMR(400MHz，CDCl 3)：δ1.55(m，1H)，1.75(m，1H)，2.20(m，1H)，2.30(m，1H)，2.82(m，1H)，3.03(m，2H)，3.18(d，1H)3.28(d，1H)，3.90(d，1H)，4.22(m，1H)，4.42(m，1H)，5.02(d，1H)，6.60(dd，1H)，6.65(d，1H)，7.40(d，1H)，7.45(t，1H)，7.60(m，2H)，8.18(d，1H)
APCI MS m/z 436[MH] +
Embodiment 109:8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-4H, 6H-5-thiophene-2,3,10b-three azepines-benzo [e] Azulene 5,5-dioxide
In 1,1, add 30% aqueous hydrogen peroxide solution (0.09 milliliter) in the sulfide (150 milligrams, 0.38 mmole) of embodiment 107 in the 1-trifluoroacetic acid in the solution of (5 milliliters).The gained reaction mixture is in stirring at room 1 hour, subsequently with the sodium bicarbonate aqueous solution dilution, and with ethyl acetate extraction (2 * 50 milliliters).Organic layer is with the salt water washing, and dry (sal epsom) filters and evaporation, obtains title compound, is pale solid (108 milligrams).
1H NMR(400MHz，CDCl 3)：δ1.80(m，1H)，2.20(m，1H)，2.30(m，1H)，2.82(m，1H)，3.03(m，2H)，3.95(d，1H)，4.10(m，2H)，4.25(m，1H)，4.40(m，1H)，4.80(dd，1H)，6.65(m，2H)，7.405(m，2H)，7.70(m，2H)，8.20(d，1H)
APCI MS m/z 452[MH] +
Embodiment 110:
Specific compound is in the screening 1.0 (V of preamble explanation 1AFiltration combination calibrating analysis) the test example is illustrated in following table
The embodiment sequence number Ki(nM)
5 4.66
6 2.37
8 2.47
11 0.68
13 13.86
15 4.71
24 1.00
27 1.25
38 4.63
59 1.32
73&74 6.84&6.02
93 2.33
96 0.24
100 0.77
102 4.16
103 2.02

Claims (29)

1. formula (I) compound or its pharmaceutically acceptable derivative, wherein
Figure A2004800047080002C1
V represents-(CH 2) d(O) e-,-CO-or-CH (C 1-6Alkyl)-;
W is-O-,-S (O) a-or-N (R 1)-
R 1Expression H, C 1-6Alkyl, (CH 2) bCOR 2, CO (CH 2) bNR 2R 3, SO 2R 2, (CH 2) cOR 2, (CH 2) cNR 2R 3Or (CH 2) bHet 1
Het 1Expression contains the heteroatoms of one or more O of being selected from, N or S and optionally through C 1-6Saturated or the unsaturated heterocycle that contains 3 to 8 atoms that alkyl replaces;
X and Y represent H, C respectively 1-6Alkyl, halogen, OH, CF 3, OCF 3, OR 4
Z represents-(CH 2) f(O) g-,-CO-or-CH (C 1-6Alkyl)-;
Ring A represents the saturated N of the containing heterocycle of a 4-7 person, its be optionally through OH replace and wherein at least one ring N optionally replace through O;
Ring B represents phenyl or the unsaturated N of the containing heterocycle of a 4-7 person, and this nitrogen heterocyclic ring is optionally through OH, halogen, CN, CONH 2, CF 3, OCF 3Replace and wherein at least one ring N optionally replace through O;
R 2And R 3Represent H, C respectively 1-6Alkyl is [optionally through OH, halogen, N (C 1-6Alkyl) 2Or C 1-6Alkoxyl group replaces], C 1-6Alkoxyl group, N (C 1-6Alkyl) 2Or [C 3-8Cycloalkyl];
Or R 2And R 3Represent one optionally through C with its attached separately nitrogen-atoms is common 1-6The heterocycle that contains 3-8 atom that alkyl replaces;
R 4Expression straight or branched C 1-6Alkyl,
A and c represent 0,1 or 2 respectively;
B, e and g represent 0 or 1 respectively; And
D and f represent 1 or 2 respectively.
2. compound as claimed in claim 1, wherein W represents NR 1
3. as the compound of claim 1 or 2, R wherein 1Expression H, C 1-6Alkyl ,-(CH 2) bCOR 2Or SO 2R 2
4. as each compound in the claim 1 to 3, wherein R 1Be methyl.
5. as the compound of claim 1 or 2, R wherein 2For morpholinyl or pyrimidyl (optionally through C 1-6[selectivity is through OH, halogen, N (C for alkyl 1-6Alkyl) 2Or C 1-6Alkoxyl group replaces] or NMe 2Replace).
6. each compound in the claim as described above, wherein X is H.
7. each compound in the claim as described above, wherein Y is 4 positions (according to the numbering of formula (I)) that are positioned at its attached phenylene ring.
8. compound as claimed in claim 7, wherein Y is a chlorine.
9. each compound of claim as described above wherein encircles A and is by the nitrogen-atoms among the ring A binding to encircling B.
10. each compound in the claim as described above wherein encircles A and represents piperidyl (optionally replace through OH, and at least one N optionally replacing through O).
11. each compound in the claim as described above wherein encircles B and represents pyridyl or pyrimidyl (selectivity is through OH, halogen, CN, CONH 2, CF 3, OCF 3Replace, and at least one ring N optionally replaces through O).
12., wherein encircle B and represent pyridyl as the compound of claim 11.
13. each compound in the claim as described above, wherein V represents-CH 2-.
14. each compound in the claim as described above, wherein Z represents-CH 2-.
15., wherein work as R as each compound in the claim 1 to 3 2And R 3During heterocycle of the common expression of the nitrogen attached with it, this heterocycle is to be selected from one optionally through C 1-6Piperazinyl, pyrrolidyl, piperidyl, pyrimidyl, THP trtrahydropyranyl or morpholinyl that alkyl replaces.
16. compound as claimed in claim 1, it is selected from:
8-chloro-5-methyl isophthalic acid-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene tri hydrochloride;
8-chloro-5-sec.-propyl-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene tri hydrochloride;
1-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl) 4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-the ethyl ketone dihydrochloride;
8-chloro-5-methane sulfonyl-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene;
8-chloro-5-methyl isophthalic acid-(1-pyrimidine-2-base-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene;
8-chloro-5-methane sulfonyl-1-(1-pyrimidine-2-base-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene;
13-chloro-8-methyl-3-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-2,4,5,8-four azepines-three ring [9.4.0.0*2,6*] 15 carbon-1 (11), 3,5,12,14-pentaene;
13-chloro-3-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-8-Evil-2,4,5-three azepines-three ring [9.4.0.0 *2,6 *] 15 carbon-1 (11), 3,5,12, the 14-pentaene;
1-[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl) 4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-2-dimethylamino-ethyl ketone;
[8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-yl]-morpholine-4-base-ketone;
(+) or (-) 8-chloro-5-(4-methyl-morpholine-2-ylmethyl)-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene;
8-chloro-5-pyrimidine-2-base-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-four azepines-benzo [e] Azulene;
8-chloro-1-(3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-sulfonic acid dimethylformamide;
8-chloro-1-(1-pyrimidine-2-base-piperidin-4-yl)-4H, 6H-2,3,5,10b-four azepines-benzo [e] Azulene-5-sulfonic acid dimethylformamide;
13-chloro-9-methyl-3-(3,4,5,6-tetrahydrochysene-2H-[1,2 ']-bipyridyl-4-yl)-2,4,5,9-four azepines-three ring [9.4.0.0 *2,6 *] 15 carbon-1 (11), 3,5,12, the 14-pentaene; And
13-chloro-8-methyl-3-(1-pyrimidine-2-base-piperidin-4-yl)-2,4,5,8-four azepines-three ring [9.4.0.0 *2,6 *] 15 carbon-1 (11), 3,5,12, the 14-pentaene;
Or its pharmaceutically useful derivative.
17. the purposes as each compound in the claim 1 to 16, it is to be used as medicine.
18. one kind in order to treat the method for following illness: disease, premature ejaculation, premature labor (preterm labor) and RD before anxiety, cardiovascular diseases (comprising stenocardia, arteriosclerosis, hypertension, cardiac failure, oedema, hypernatremia), dysmenorrhoea (primary and Secondary cases), endometriosis, vomiting (comprising motion sickness), intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), month middle pain, the eclampsia; This method comprises to the patient who suffers this class illness uses each compound in the claim 1 to 16 of a treatment significant quantity.
19. as the method for claim 18, wherein this illness is dysmenorrhoea (primary or a Secondary cases).
20. purposes as each compound in the claim 1 to 16, this purposes is to be used to make medicine, and this medicine is to be used for the treatment of anxiety, cardiovascular diseases (comprising stenocardia, arteriosclerosis, hypertension, cardiac failure, oedema, hypernatremia), dysmenorrhoea (primary and Secondary cases), endometriosis, vomiting (comprising motion sickness), intrauterine growth retardation, inflammation (comprising rheumatoid arthritis), month middle pain, the preceding disease of eclampsia, premature ejaculation, premature labor (preterm labor) and RD.
21. as the purposes of claim 20, it is to be used for the treatment of dysmenorrhoea (primary or Secondary cases).
22. a pharmaceutical preparation comprises as each compound in the claim 1 to 16, and pharmaceutically acceptable vehicle, diluent or carrier.
23. one kind suc as formula (II), (III), (X), (XV), (XXIV) with the intermediate (XXV):
Figure A2004800047080005C1
Figure A2004800047080006C1
Wherein W, X, Y, Z, ring A and ring B and n define as claim 1, and LG represents a suitable leaving group.
24. make formula (I) compound of claim 1 or the method for its pharmaceutically acceptable derivative, comprising for one kind: make the reaction of formula (II) compound and acid catalyst,
Figure A2004800047080006C2
Wherein encircle A and ring B and W, X, Y and n group definition such as preceding.
25. make formula (I) compound of claim 1 or the method for its pharmaceutically acceptable derivative, comprising for one kind: make formula (III) compound
Figure A2004800047080006C3
React with formula (IV) compound;
Figure A2004800047080007C1
Wherein encircle A and ring B and W, X, Y and n group definition such as claim 1, and Z ' represents for example halogen of leaving group.
26. make formula (I) compound of claim 1 or the method for its pharmaceutically acceptable derivative for one kind, wherein W represents NR 1, this method comprises:
Make the formula V compound
Figure A2004800047080007C2
React with formula (VI) compound;
Figure A2004800047080007C3
Wherein encircle A and ring B and R 1, X, Y and n group definition such as claim 1, and Z " expression leaving group halogen for example.
27. make formula (I) compound of claim 1 or the method for its pharmaceutically acceptable derivative for one kind, wherein W represents NR 1, this method comprises:
Make the formula V compound
Figure A2004800047080007C4
React with formula (VII) compound;
Wherein encircle A and ring B and R 1, X, Y and n group such as claim 1 definition.
28. make formula (I) compound of claim 1 or the method for its pharmaceutically acceptable derivative, comprise for one kind: make formula (XIII) compound
Figure A2004800047080008C2
React with formula (XXIV) compound;
Wherein encircle A and ring B and V, W, X, Y and Z group such as claim 1 definition.
29. make formula (I) compound of claim 1 or the method for its pharmaceutically acceptable derivative, comprise for one kind: make formula (XIII) compound
React with formula (XXV) compound;
Figure A2004800047080008C5
Wherein encircle A and ring B and V, W, X, Y and Z group such as claim 1 definition.
CNA2004800047089A 2003-02-19 2004-02-09 Triazole compounds useful in therapy Pending CN1751047A (en)

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GB0303852D0 (en) 2003-03-26

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