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CN1190391A - Tricyclic benzazepine vasopressin antagonists - Google Patents

Tricyclic benzazepine vasopressin antagonists Download PDF

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CN1190391A
CN1190391A CN96192568A CN96192568A CN1190391A CN 1190391 A CN1190391 A CN 1190391A CN 96192568 A CN96192568 A CN 96192568A CN 96192568 A CN96192568 A CN 96192568A CN 1190391 A CN1190391 A CN 1190391A
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low alkyl
alkyl groups
alkyl group
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J·D·阿尔布赖特
A·M·文卡特桑
E·G·德罗斯桑托斯
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Wyeth Holdings LLC
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American Cyanamid Co
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Abstract

Tricyclic compound of general formula (I) as defined herein which exhibit antagonist activity at V1 and/or V2 receptors and exhibit in vivo vasopressin antagonist activity, methods for using such compounds in treating diseases characterized by excess renal reabsorption of water, and process for preparing such compounds.

Description

Tricyclic benzazepine vasopressin antagonists
1st, invention field
The present invention relates to the new non-peptide vasopressin antagonists of three rings, the antagonist is used to treat the disease such as disease for congestive heart failure, for superfluous kidney fluid reabsorption, and for increasing the disease of vascular resistence and coronary vasoconstriction for needing to reduce vasopressin levels.
2nd, background of invention
In the response that the increase of the blood plasma osmolarity for being felt by brain osmoreceptor or the hypovolemia for being felt by low pressure volume receptor and arterial baroreceptor and blood pressure are reduced, posterior pituitary release pitressin.The hormone passes through two kinds of clearly defined hypotype (blood vessel Vs1With kidney epithelium V2Receptor) play a role.The anti-diuresis effect of pitressin induction, it is by kidney epithelium V2Receptor regulation, it can help to maintain normal plasma osmolarity, blood volume and blood pressure.
Pitressin is relevant with the increased some congestive heart failures of peripheral resistance, V1Antagonist can reduce systemic vascular resistance, the output of increase heart and the coronary vasoconstriction for preventing pitressin from inducing.Therefore, in the case where pitressin induces total peripheral resistance to increase and change local blood circulation, V1Antagonist can be therapeutic agent, V1Antagonist can reduce blood pressure, that is, the low blood pressure effect induced, therefore, in acology, for treating certain form of hypertension.
V2The blocking of acceptor can be used for the disease that treatment is characterized with the free fluid reabsorption of superfluous kidney.The pitressin (antidiuretic hormone) discharged by hypothalamus adjusts anti-diuresis, and the pitressin is combined with kidney collecting tubule cell-specific receptor.The water particulate that this combination stimulates adenylyl- (adenylyl) ring enzyme (cyclase) and promotes cAMP- to adjust is attached to the chamber surface of these cells, V2Antagonist can exclude the liquid in congestive heart failure, cirrhosis, nephritic syndrome, central lesion, tuberculosis and hyponatremia.
The rise of vasopressin levels generally occurs in the congestive heart failure with morbus cardiacus old man, in congestive heart failure and the elevated patient of vasopressin levels, V2Antagonist can be beneficial to the excretion for promoting free water by the antagonism of antidiuretic hormone.Biochemistry and pharmacological action based on hormone, in acology, the antagonist of pitressin holds promise for treatment and/or preventing hypertension, cardiac muscle can not entirely, coronary disease vasopasm, cardiac ischemia, Renal vascular spasm, cirrhosis, congestive heart failure, nephritic syndrome, encephaledema, cerebrum ischemia, cerebral hemorrhage shock, the hemorrhagic thrombus stagnation of the blood, and water retention abnormality.
Following prior art references describe peptide vasopressin antagonists：M.Manning etal., J.Med.Chem., 35,382 (1992)；M.Manning et al., J.Med.Chem., 35,3895 (1992)；H.Gavras and B.Lammek, US patent 5,070,187 (1991)；M.Manning and W.H.Sawyer, U.S. patent 5,055,448 (1991)；F.E.Ali, US patent 4,766,108 (1988)；R.R.Ruffolo et al., Drug News andPerspective, 4 (4), 217, (May) (1991).P.D.Williams etc. reports strong effective hexapeptide oxytocin antagonist [J.Med.Chem., 35,3905 (1992)], the antagonist is also shown vasopressin antagonist activity faint when being combined with V1 and V2 acceptors.It is not selective antagonist that peptide vasopressin antagonists, which lack many in Orally active, also, these peptides, therefore, and they go back display portion agonist activity.
Non-peptide vasopressin antagonists are disclosed in the near future, Y.Yamamura et al., Science252,579 (1991)；Y.Yamamura et al., Br.J.Pharmacol, 105,787 (1992)；Ogawa et al., (Otsuka Pharm Co., LTD) EP 0514667-A1；EPO 382185-A2；WO 9105549 and U.S.5,258,510；WO 9404525 YamanouchiPharm.Co.Ltd., WO 9420473；WO 9412476；WO 9414796；FujisawaCo.LTD., EP 620216-A1 Ogawa et al, (Otsuka Pharm.Co.) EP 470514A disclose Carbostyril derivative and the pharmaceutical composition containing it, by Merck and Co.；Bock and P.D.Willams, EP 0533242A；M.G.Bock et al., EP 0533244A；J.M.Erb, D.F.Verber, P.D.Williams, EP 0533240A；K.Gilbert et al., EP0533243A. disclose non-peptide oxytocins and vasopressin antagonists.
Premature labor causes the critical mediator in the health and problem of death of baby, mechanism of labor to be peptide hormone oxytocins.According to the pharmacological action of oxytocins, the hormone antagonist is used to prevent early stage (perterm) childbirth (B.E.Evans et al., J.Med.Chem., 35,3919 (1992), J.Med.Chem., 36,3993 (1993) and this paper bibliography).The compounds of this invention is peptide hormone oxytocin antagonist, and for controlling premature labor.
The present invention relates to new tricyclic derivatives, the derivative shows vasopressin antagonistic activity in antagonistic activity, and display body to V1 and/or V2 acceptors, and the compound also shows oxytocin receptor antagonists activity.
Present invention general introduction
The present invention relates to selected from compounds of formula I：
Figure A9619256801391
Formulas I wherein Y represents (CH2)n, O, S, NH, NCOCH3, N- low alkyl groups (C1-C3), CH- low alkyl groups (C1-C3), CHNH- low alkyl groups (C1-C3), CHNH2, CHN [low alkyl group (C1-C3)]2, CHO- low alkyl groups (C1-C3), CHS- low alkyl groups (C1-C3), wherein n is 0-2 integer；A-B is
Figure A9619256801392
Wherein m is 1-2 integer, and condition is when Y is-(CH2)n- and during n=2, m may also indicate that 0 and when n is 0, m may also indicate that 3, and condition is also when Y is-(CH2)nDuring with n=2, M can not also be 2；R1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3；Low alkyl group (C1-C3)；O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：
Figure A9619256801393
Wherein Ar represents to be selected from following groups：
Figure A9619256801394
R4Represent hydrogen, low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3)；R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula parts
Figure A9619256801411
Wherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen, CH3, C2H5, or represent following formula parts：
Figure A9619256801412
-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen, CH3, C2H5；(b) formula part：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),It is 0-3 with p；X represents O, S, NH, NCH3,Or key and R5And R7It is as defined above (c) formula part：Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：
Figure A9619256801423
Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) lower alkoxy ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicals
Figure A9619256801432
R8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or NH low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；W ' expression O, S, NH, N- low alkyl groups (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3) or NSO2Low alkyl group (C1-C3)；R25Selected from following radicals：
Figure A9619256801441
And group Represent：(1) phenyl or by one or two be selected from (C1-C3) low alkyl group, halogen, amino, (C1-C3) lower alkoxy or (C1-C3) low-grade alkyl amino the phenyl that arbitrarily replaces of substituent；(2) containing fragrant (undersaturated) heterocycle of heteroatomic 5- members selected from O, N or S；(3) fragrant (undersaturated) heterocycle of 6- members containing a nitrogen-atoms；(4) fragrant (undersaturated) heterocycle of 5- or 6- member containing two nitrogen-atoms；(5) fragrant (undersaturated) heterocycle of 5- members containing a nitrogen-atoms and an oxygen atom or a sulphur atom；5- or 6- circle heterocycles therein can be by (C1-C3) low alkyl group, formoxyl, following formula group：
Figure A9619256801443
Halogen or (C1-C3) lower alkoxy is optionally substituted.The heterocycle of such as fusion can be by substituted or unsubstituted furans, pyrroles, pyrazoles, thiophene, thiazole , oxazoles, and imidazoles, pyrimidine or pyridine ring are represented.The present invention is described in detail
Defined in formula I in compound group, the compound of some subgroups is preferred extensively.Following compounds wherein R is preferably extensively3Represent group：Wherein Ar is selected from group：Wherein R5, R6And R7It is as defined above.
Particularly preferably following compound wherein R3Represent group：
Figure A9619256801453
Group is selected from Ar：R6Representing NHCOAr ' and Ar ' isWherein R8, R9, R25It is as defined above with W '.
Also following compounds are especially preferably extensively, and Y is-(CH wherein in Formulas I2)n-, and n is 0 or 1；A-B is：And R4, R5, R6, R7, R8, R9And R10It is as defined above；It is 1-2 integer with m.
Most extensive preferred compound of formula I is following compounds：Wherein Y represents-(CH2)n-, and n is 1；A-B is：
Figure A9619256801462
M is 1 or 2, R3Represent group：
Figure A9619256801463
Ar is represented：R6Represent：With Ar ' expression groups：
Figure A9619256801471
Cycloalkyl Ra, RbIt is as defined above with W ', and R8And R9It is preferred that representing the CF at ortho position3, Cl, OCH3, CH3, SCH3Or OCF3Substituent or the dibasic derivative of Ar ' expressions, wherein R8And R9Independently represent Cl, OCH3, CH3And F.
Most extensive preferred compound of formula I is following compounds, and wherein Y represents-(CH2)n-, n is 0 or 1 and group
Figure A9619256801472
Above-mentioned group represents phenyl, substituted-phenyl, thiophene, furans, pyrroles or pyridine ring；A-B is represented：
Figure A9619256801473
When n is 1, m is 1, and m is 2 when n is 0；R3Represent group：Wherein Ar is represented：
Figure A9619256801475
And R6Selected from following radicals：
Figure A9619256801476
Wherein Ar ' is selected from group：
Figure A9619256801481
And Ra, Rb, R1, R2, R4, R5, R6, R7, R8, R9, R25It is as defined above with W '.Most it is particularly preferably following formula: compound：
Figure A9619256801482
Wherein m is integer 1 or 2；R1And R2It is as defined above；R3Represent group：Wherein Ar is selected from following formulas：
Figure A9619256801484
R6Represent：
Figure A9619256801485
Wherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；Wherein Ar ' is selected from following radicals：RaIndependently selected from hydrogen, CH3Or-C2H5；And R5, R7, R8, R9, R10, R25, X and W ' are as defined above.
Following formula: compound is also particularly preferred：
Figure A9619256801492
Wherein m is integer 1 or 2；R1And R2It is as defined above；R3Represent group：Wherein Ar is selected from following formula parts：R6Represent：
Figure A9619256801495
Figure A9619256801501
Wherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；Wherein Ar ' is selected from following radicals：
Figure A9619256801502
RaIndependently selected from hydrogen, CH3Or-C2H5；And R5, R7, R8, R9, R10, R25, X and W ' are as defined above.
The compounds of this invention can be prepared as shown in reaction scheme I, i.e., react obtaining intermediate 5a and 5b by formula 3a and 3b tricyclic derivatives and 6- nitropyridine -3- acyl chlorides 4.Nitro in reduction intermediate 5a and 5b obtains 6- amino -3- PYRIDYLCARBONYL derivatives 6a and 6b.To the reduction of nitro in intermediate 5a and 5b can under catalytic reductive conditions (hydrogen-Pd/C；Pd/C- hydrazines-ethanol) or in electronation (SnCl2- ethanol；Zn- acetic acid；TiCl3) under the conditions of and it is known in the art nitro can be converted under the relevant reducing condition of amino carry out.The condition that nitro is converted to amino is to carry out selection there is compatible basis with other functional groups in molecule.
As shown in reaction scheme 1, formula 6a and 6b compounds and aroyl chloride, heteroaryl acyl chlorides, aryl sulfonyl chloride, diaryl phosphoroso- chlorine, two phenoxy group phosphoroso- chlorine, alkyl (C3-C8) acyl chlorides, alkenyl (C3-C8) acyl chlorides, alkoxy (C3-C8) acyl chlorides, alkenyloxy (C3-C8) acyl chlorides, alkyl (C3-C8) sulfonic acid chloride, alkenyl (C3-C8) sulfonic acid chloride, cycloalkyl acyl chlorides, arylamino formyl chloride or the reaction of heteroaryl amino formyl chloride obtain new the compound 8a and 8b of the present invention.The reaction can be in 0 DEG C -50 DEG C progress in solvent such as chloroform, dichloromethane, dioxanes, tetrahydrofuran, toluene in the presence of tertiary base such as triethylamine, diisopropyl ethanolamine or pyridine.If introducing more than one aroyl, 4-hetaroylpyrazol or aryl sulfonyl etc. in the reaction, it can obtain producing 8a and 8b using the gentle alkali process (NaOH, KOH etc.) being dissolved in low-level chain triacontanol.
Reaction scheme 1
Figure A9619256801511
The (Continued) of reaction scheme 1
The (Continued) of reaction scheme 1
Figure A9619256801531
The (Continued) of reaction scheme 1
Figure A9619256801541
The reaction of formula 6a and 6b tricyclic derivatives and the carbamoyl derivatives of formula 9 or the isocyanate derivates of formula 10 has obtained formula 11a and 11b compound (reaction scheme 2), and formula 11a and 11b compound is wherein R6It is following formula group and RbIt is H, CH3Or C2H5Formulas I vasopressin antagonists and/or oxytocin antagonist.
Figure A9619256801551
React circuit 2
The reaction of formula 3a and 3b tricyclic derivatives and 6- chlorine or 6- fluorine pyridine -3- acyl chlorides 12 obtains intermediate 13a and 13b (reaction scheme 3).
Reaction scheme 3
Figure A9619256801571
As shown in reaction scheme 4, intermediate 13a and 13b and R10X-(14) reaction can obtain derivative 15a and 15b, R10X-(14) R in10As defined above and X represents O, S, NH or NCH3。
Reaction scheme 4
Figure A9619256801581
As shown in reaction scheme 5, wherein Y, A-B, Z, R1, R2And R3It is as defined above and R3(- COAr) aryl represents following formula group：
Figure A9619256801582
And wherein R6The compound of formula I being as defined above can be prepared by following methods：The pyridinyl moieties 16 connected with tricyclic benzazepine unit are synthesized first.
Figure A9619256801583
Obtained pyridinyl moieties 16 can be activated by carrying out coupling reaction with peptide coupling reagent, or preferably be activated by being converted into pyridine -3- acyl chlorides 17.Coupling reaction can be carried out in atent solvent such as chloroform, dichloromethane, tetrahydrofuran, dioxanes, toluene in the presence of tertiary amine such as triethylamine.The reaction can also be carried out in pyridine and related alkyl pyridine.
Reaction scheme 5
Figure A9619256801591
Initiation material 3a and 3b in reaction scheme 1 can root it is documented that method prepare.The derivative of such as intermediate 6,11- dihydro -5H- dibenzo [b, e] azepines and its substitution can be prepared according to following literature methods：L.H.Werner, et al., J.Med.Chem., 8,74-80 (1965)；A.W.H.Wardrop et al., J.Chem.Soc., Perkins Trans I, 1279-1285 (1976).
5,11- dihydro-dibenzos [b, the e] azepines -6- ketone of substitution can be prepared according to following literature methods：J.Schmutz et al., Helv.Chim.Acta., 48,336 (1965)；And lithium aluminium hydride reduction can be used, monoborane, known reagent that amidocarbonylation can be reduced to methylene of borane-dimethylsulfide and (other) is reduced to 6,11- dihydro -5H- dibenzo [b, e] azepines of substitution.Intermediate 10,11- dihydro-dibenzos [b, f] [Isosorbide-5-Nitrae] thia azepines can prepare-for example refer to K.Brewster et al., J.Chem.Soc.Perkins Trans I, 1286 (1976) according to literature method.To dibenzo [b, f] [Isosorbide-5-Nitrae] oxazepin [A.W.H.Wardrop et al., J.Chem.Soc.PerkinsTrans I, 1279 (1976)] and dibenzo [b, f] [Isosorbide-5-Nitrae] oxazepin -11 (10H) -one and dibenzo [b, f] [1,4] thia azepines -11 (10H) -one-J.Schmutz et al., Helv.Chim.Acta., 48,336 (1965)；Reduction, can be carried out using lithium aluminium hydride reduction in atent solvent Ru dioxane.Three rings 6 of formula 30,7- dihydro -5H- dibenzo [b, d] azepine intermediates can be prepared according to following literature methods：T, Ohta et a1., Tetrahedron Lett., 26,5811 (1985)；Wiesner et al., J.Amer.Chem.Soc., 77,675 (1955)；Or its derivative can be prepared by the Coupling step shown in reaction scheme 7.Nitro also in the compound of original structure 31, then cyclization obtains lactams 32, is reduced three ring azepines of the formula of obtaining 33.
5,11- dihydro -6H- pyridos [3,2-c] [1] benzazepines can prepare-J.Firl et al., Liebigs Ann.Chem.469, (1989) according to literature method.11H- pyridos [2,3-b] [1,4] benzodiazepine  -6 (5H) ketone is by J.F.F. Liegeois et al., J.Med.Chem.36, reported 2107 (1993), and these derivatives can be reduced to 11H- pyridos [2,3-b] [Isosorbide-5-Nitrae] benzodiazepine .Three ring Isosorbide-5-Nitraes, simultaneously-[4,3-c] [1] benzodiazepine  and its 3- chlorine derivatives report-G.Palazzino, et al.J.Heterocyclic Chem., 26,71 (1989) to 5,10- tetrahydro-pyrazoles in the following references.As shown in reaction scheme 6,4,10- dihydro -5H- thienos [3,2-c] [1] benzazepines 21a and 9,10- dihydro -4H- thienos [2,3-c] [1] benzazepines 21b can be coupled by tributyl tin derivative 19 and 20 with 2- nitrobenzyls bromide in the presence of tetrakis (triphenyl phasphine) palladium (0) to be obtained.
Then with obtaining three ring azepines 25 with the coupling of intermediate 24, nitro reduction is obtained into 6- amino Nicotinoyl derivatives 26.Then as shown in reaction scheme 7, derivative 26 is made to obtain product 27 and 27a with suitable acyl chloride reaction.
The synthesis of the ring azepines 30 and 33 of intermediate three is also illustrated in reaction scheme 7.Tricyclic lactam derivatives 29 and 32 can prepare then corresponding aminoderivative cyclization by reducing the nitro of intermediate 28 and 31.Using lithium aluminium hydride reduction (LAH) or the available three ring azepines 30 and 33 of monoborane reduction tricyclic lactam intermediate 29 and 32.
Reaction scheme 6
Figure A9619256801611
Reaction scheme 7
The (Continued) of reaction scheme 7
The (Continued) of reaction scheme 7
The (Continued) of reaction scheme 7
Figure A9619256801661
For synthesizing selective vasopressin antagonists of the invention, (Formulas I, wherein Y are-CH2- and m be the route of synthesis of three ring intermediates 42 1) as shown in reaction scheme 8.When with alkyl lithium reagents such as tert-butyl lithium s-butyl lithium or n-BuLi reaction, suitable 1- nitros -2- chlorine or 1- nitro -2- bromines heterocycle 35 obtains intermediate 37 by Halogen atom exchange, makes its anhydride reaction with formula 38.R12The non-nucleophilic dialkylamine of expression tert-butylpiperidin, sec-butyl piperidines, n-butylpiperidine, 2,6- lupetidines or (having) steric hindrance.Using hydrogen and suitable catalyst or electronation (Zn- acetic acid, TiCl3Deng) reduction nitro product 39 obtain amino intermediate 40.The reaction routine that cyclization obtains cyclic lactam 41 is carried out in dimethylbenzene or atent solvent under 100 DEG C of -200 DEG C of heating.It is easy to go back the cyclic lactam of original structure 41 using monoborane/tetrahydrofuran, borane-dimethylsulfide/tetrahydrofuran, lithium aluminium hydride reduction/suitable solvent such as dioxane, obtains tricyclic compound 42.
Or the derivative 38b for being as defined above phenyl lithium derivative 37b and wherein Z reacts, wherein phenyl lithium derivative 37b is to be prepared by the lithiation or 2- chlorine or 2- bromines of protected benzaldehyde derivative by the lithiation of protection benzaldehyde derivative.Derivative 38b is prepared by standard method, the ring closure reaction (reaction scheme 8) of these methods such as 1- amino -2- carboxyls heteroaromatic ring compounds or 1- amino -2- benzoic acid derivatives and acetic anhydride.
Reaction scheme 8
Figure A9619256801671
Or, as shown in reaction scheme 9, the tricyclic derivatives of some structures 42 can obtain tricyclic lactam 44 by the coupling of " palladium " type or " copper " induction coupling reaction of halo derivatives 43, and the carbonyl of reduction lactams obtains intermediate 42.The activation copper or " palladium " type reaction reagent being coupled using inducible aryl, are made the coupling of halide derivative 45 produce cyclization and obtain lactams 46.Derivative 47 is obtained using monoborane reduction lactams 46.The Ullmann cross couplings of halogenated heterocyclic and 2- bromo nitrobenzenes and pass through low price palladium such as [Pd (PPh3)4] and PdCl2(PPh3)2The related cross coupling of progress is known synthetic method；N.Shimizu et al., Tetrahedron Lett.34,3421 (1993) and bibliography therein；N.M.Ali et al., Tetrahedron, 37,8117 (1992) and bibliography therein；J.Stavenuiter et al., Heterocycles, 26 2711 (1987) and bibliography therein.
Tetrahydrochysene -1H-1- benzazepines -5- ketone 51 and tetrahydrochysene -1H-1- benzazepines -2,5- diketone 52 can be used for synthetic intermediate tricyclic heterocyclic structure 53 and 54 (reaction scheme 10).Tetrahydro benzo azepines -5- ketone 51 and 52 can be configured to hydroxyl methene derivant or be reacted with Vilsmeier reagents or DMF dimethyl-acetal, obtain dimethylamino methylene derivatives.Heterocycle is formed by the reaction with hydrazine, N- methyl hydrazines, hydroxylamine or carbonamidine from a- hydroxy methylenes ketone and respectively obtains pyrroles, N- methylpyrazole , oxazoles or pyrimidine, these are the standard methods that document is recorded.With reference to Vilsmeier formylation reactions-Tetrahedron, 49,4015-4034 (1993) and bibliography therein and cyclization-J.Heterocyclic Chem., 29,1214 (1992) and bibliography therein.
Substitution and unsubstituted tetrahydro benzo azepines -2- ketone are known compounds, and they can prepare [J.Chem.Soc.456 (1937) by the reaction of a- tetralones and sodium azide in acid condition；Tetrahedron 49,1807 (1993) (Schmidt reaction).Reduction tetrahydrochysene -1H- benzazepines -2- ketone obtains tetrahydrochysene -1H- benzazepines 48, is acylated and obtains compound 49.It is a known method for oxidation that the N- acyl group tetrahydrochysene -1H- benzazepines of oxidation-type 49, which obtains 5- ketone derivatives,；R.L.Augustine and W.G.Pierson, J.Org.Chem., 34,1070 (1969).
3,4- dihydro -1H-1- benzazepines -2,5- diketone (52：R15=H) synthesis and 3,4- dihydros -1H-1- benzazepines -2,5- diketone and DMF dimethyl-acetal are to 4- [(dimethylamino) methylene] -3, the conversion reaction of 4- dihydro -1H-1- benzazepines -2,5- diketone has been reported：[W.-Y.-Chen and N.W.Gilman, J.HeterocyclicChem., 20,663 (1983)].Bibliography above describes the synthesis of 2- methyl -5,7- dihydro-pyrimidin simultaneously [5,4-d] [1] benzazepines -6 (6H) -one, can be reduced and remove the carbonyl of lactams and obtain the tricyclic derivatives of structure 54, wherein Z represents pyrimidine ring.
Reaction scheme 10
Figure A9619256801711
The (Continued) of reaction scheme 10
Figure A9619256801721
Reaction scheme 11
Figure A9619256801731
The (Continued) of reaction scheme 11
Figure A9619256801741
R3Partly the aryl in-COAr is the preparation of the compound of following formula group as shown in reaction scheme 11：
Figure A9619256801751
The tricyclic derivatives and the reaction of substituted or unsubstituted 4- nitrobenzoyl chlorides 55 for making 3a and 3b obtain derivative 56a and 56b.Nitryl group in reductive derivative 56a and 56b obtains 4- amino benzoyl intermediate 57a and 57b, it is obtained product 59a and 59b with the acyl chloride reaction shown in formula 58.
R3Partly the aryl in-COAr is that preparing for the compound of following formula group is as described below：Even if three ring azepines 3a and 3b obtain product 61a and 61b with the chlorobenzoyl chloride reaction (reaction scheme 12) shown in structural formula 60.In a similar fashion, heterocycle acyl chlorides 62,63 or 64 and three ring azepines 3a and 3b reaction can obtain product 65a and 65b, and aryl is as shown in reaction scheme 13 here.
Reaction scheme 12
Reaction scheme 13
Figure A9619256801771
Reference implementation example 16,11- dihydro -5H- dibenzo [b, e] azepines
Flow back 48.52g (0.20mol) -2 '-carboxylic acid of 2- aminobenzophenones and 500m1 refluxing xylenes 67 hours, is cooled to room temperature and filters.Solid is washed with dimethylbenzene and obtains 43.3g (97.8%) 5H- dibenzo [b, e] azepines -6,11- diketone, is light brown crystals, mp245-248 DEG C.The tetrahydrofuran solution of 12ml (0.12mol) 10M borane-dimethyl sulfides is added into the 25ml tetrahydrofuran solutions of 4.46g (0.020mol) aforesaid compound, add other 10ml tetrahydrofurans and stir mixture and stay overnight, be then refluxed for 4 hours (solid dissolving).Cooling solution is simultaneously added dropwise to 15ml methanol, vacuum concentrated mixture, adds 50ml 2N sodium hydroxides and the mixture 2 hours of flowing back.Filter solid is crossed, is washed with water, is air-dried and is extracted with dichloromethane.Dry (sodium sulphate) extract and remove solvent and obtain 3.25g (83%) crystal, mp117-122 DEG C.Reference implementation example chloro- 5H- dibenzo [b, e] azepines -6, the 11- diketone of 22-
Chlorine is passed through 1.0g (450mmol) 5H- dibenzo [b, e] azepines -6,11- diketone with the mixture (being partial suspended liquid) of 50ml glacial acetic acids, making mixture temperature be raised to 38 DEG C.Stand, white solid is settled out when solution temperature is reduced.Filtering mixture obtains 0.40g solids (ratio of initiation material and product is 1: 8), stands filtrate and obtains 0.10g products, is crystal, mp289-293 DEG C.Reference implementation example 310,11- dihydro-N-N- dimethyl dibenzo [b, f] [Isosorbide-5-Nitrae] oxazepin -2- sulfonamide
To 5.88g10,11- dihydro-N-N- dimethyl -11- oxo dibenzo [b, f] [Isosorbide-5-Nitrae] oxazepin -2- sulfonamide 5ml tetrahydrofuran solutions in add 20ml (volume) mole (concentration) borane-dimethylsulfide tetrahydrofuran solution.Mixture obtained by stirring, which is stayed overnight, to be then refluxed for 2 hours, and the mixture obtained by cooling is used 10ml methanol dilutions, then concentrated, and adds methanol and concentrates mixture.20ml 2N sodium hydroxides and the mixture 2 hours of flowing back are added into mixture.With the mixture obtained by dichloromethane is extracted, dried extract (magnesium sulfate) is simultaneously filtered, and filtrate is washed thin plate by hydrous magnesium silicate thin plate and with dichloromethane, and concentration filtrate obtains 4.8g crystal, mp99-102 DEG C.3.96g crystal, mp109-110 DEG C are obtained with Di Iso Propyl Ether-recrystallize with dichloromethane.Mass spectrum (FAB) 305 (M+H), C15H16N2O3S theory analysis value：C, 59.2；H, 5.3；N, 9.2；S, 10.6C, 57.6；H, 5.2；N, 8.9；SS, 10.1 reference implementations example chloro- 5, the 6- dihydrophenanthridines of 42-
The chlorination gas 10 minutes into heat (70 DEG C) solution of the 120ml acetic acid of (the 5H)-phenanthridones of 2.62g (17mmol) 6, solution is cooled to room temperature and filter mixture, crystal obtained by filtering obtains 1.35g crystal, mp310-318 DEG C.
The tetrahydrofuran solution of 12ml 10M borane-dimethyl sulfides is added into the 25ml tetrahydrofuran solutions of aforesaid compound (1.57g), the mixture obtained by backflow 18 hours cools down and adds 15ml methanol.Vacuum concentrated mixture, adds 50ml 2N sodium hydroxides, and backflow mixture 2 hours crosses filter solid, is washed with water, is air-dried and obtains product, be white solid.Reference implementation example chloro- 5H- dibenzo [b, e] azepines -6, the 11- diketone of 59-
Heated over steam bath 11.15g 5H- dibenzo [b, e] azepines -6,11- diketone and 600ml glacial acetic acids mixture until solid dissolving, chlorine is passed through in solution until solid is generated by the chlorination gas into solution (70 DEG C).Mixture is cooled to room temperature and be filtrated to get 7.3g products, mp290-295 DEG C.Reference implementation example 69- chloro-6,11-dihydro -5H- dibenzo [b, e] azepines
In argon gas atmosphere, the tetrahydrofuran solution of 8.5ml 10M borane-dimethyl sulfides is added into the mixture of chloro- 5H- dibenzo [b, e] azepines -6, the 11- diketone of 7.28g9- and 25ml tetrahydrofurans.Mixture is stirred at room temperature 18 hours, adds 30ml tetrahydrofurans and the mixture 3 hours (solid dissolving) that flows back.Solution is cooled to room temperature and be added dropwise to 25ml methanol, volatile matter is removed in vacuum.100ml 2N sodium hydroxides are added into residue, mixture refluxed overnight is simultaneously filtered, extract solid with dichloromethane and use 2N citric acids, water washing extract is dried (sodium sulphate).Remove solvent and obtain 4.2g solids, developed with ethylacetate-hexane (1: 2) and obtain crystal, mp137-141 DEG C.Reference implementation example 710,11- dihydro-dibenzos [b, f] [Isosorbide-5-Nitrae] thia azepines
To 3.3g10, the tetrahydrofuran solution of 4.0ml 10M borane-dimethyl sulfide is added in the 25ml tetrahydrofuran solutions of 11- dihydro -11- oxos dibenzo [b, f] [Isosorbide-5-Nitrae] thia azepines, mixture is stirred at room temperature 18 hours, adds 50ml absolute methanols and remove solvent.Add other 30ml methanol and obtain white crystal with solvent is removed.By silica gel chromatography sample, with hexane-chloroform-ethyl acetate (2: 1: 1) as solvent, white crystal, mp145-148 DEG C are obtained.
Method as described in reference implementation example 7 can prepare following compounds：Reference implementation example 84- methyl isophthalic acids 0, 11- dihydro-dibenzos [b, f] [1, 4] thia azepines reference implementation example 94- chloro- 10, 11- dihydro-dibenzos [b, f] [1, 4] thia azepines reference implementation example 102- methyl isophthalic acids 0, 1 1- dihydro-dibenzos [b, f] [1, 4] thia azepines reference implementation example 112- chloro- 10, 11- dihydro-dibenzos [b, f] [1, 4] thia azepines reference implementation example 122- methoxyl groups -10, 11- dihydro-dibenzos [b, f] [1, 4] thia azepines reference implementation example 138- chloro- 10, 11- dihydro-dibenzos [b, f] [1, 4] thia azepines reference implementation example 144, 8- bis- chloro- 10, 11- dihydro-dibenzos [b, f] [1, 4] the thia azepines reference implementation example chloro- 4- methyl isophthalic acids 0 of 158-, 11- dihydro-dibenzos [b, f] [1, 4] thia azepines reference implementation example 168- methoxyl groups -10, 11- dihydro-dibenzos [b, f] [1, 4] the thia azepines reference implementation example chloro- 4- methyl isophthalic acids 0 of 177-, 11- dihydro-dibenzos [b, f] [1, 4] thia azepines
Method as described in reference implementation example 3 can prepare following compounds：Reference implementation example 182- chloro- 10, 11- dihydro-dibenzos [b, f] [1, 4] oxazepin reference implementation example 192- methyl isophthalic acids 0, 11- dihydro-dibenzos [b, f] [1, 4] oxazepin reference implementation example 204- chloro- 10, 11- dihydro-dibenzos [b, f] [1, 4] oxazepin reference implementation example 213- methyl isophthalic acids 0, 11- dihydro-dibenzos [b, f] [1, 4] oxazepin reference implementation example 227- chloro- 10, 11- dihydro-dibenzos [b, f] [1, 4] oxazepin reference implementation example 238- chloro- 10, 11- dihydro-dibenzos [b, f] [1, 4] oxazepin reference implementation example 242, 4- bis- chloro- 10, 11- dihydro-dibenzos [b, f] [1, 4] oxazepin reference implementation example 254, 8- bis- chloro- 10, 11- dihydro-dibenzos [b, f] [1, 4] the oxazepin reference implementation example chloro- 8- methyl isophthalic acids 0 of 264-, 11- dihydro-dibenzos [b, f] [1, 4] oxazepin reference implementation example 274- methyl -7- chloro- 10, 11- dihydro-dibenzos [b, f] [1, 4] the oxazepin reference implementation example chloro- 4- methyl isophthalic acids 0 of 281-, 11- dihydro-dibenzos [b, f] [1, 4] oxazepin reference implementation example 292- fluoro- 10, 11- dihydro-dibenzos [b, f] [1, 4] oxazepin reference implementation example 30N- (2- iodophenyls) -2- iodobenzene yl acetamides
The 75ml thionyl chloride solutions of backflow 13.32g (0.05mol) 2- iodobenzene guanidine-acetic acids 2 hours, are removed in vacuum volatile matter.Add toluene (3 times) and solvent is removed in vacuum after each addition and obtain 2- iodophenyl chloroacetic chlorides, be gum.11g (0.05mol) 2- Iodoanilines and diisopropylethylamine (0.10mol) are added into 100ml toluene-dichloromethane (1: 1) mixture of aforesaid compound (0.05mol).Mixture is stirred at room temperature and stays overnight and remove solvent, dichloromethane neutralization 1NHCl is dissolved the residue in, saturated sodium bicarbonate solution, the solution obtained by salt water washing is dried (sodium sulphate).Remove solvent and obtain 16.0g light brown crystallines, mp160-163 DEG C with methanol-diethyl ether recrystallization residue.The iodo- N- of embodiment 312- (2- iodophenyls) phenyl ethylamine
The tetrahydrofuran solution of 3.75ml 2.0M borane-dimethyl sulfides is added into 30ml tetrahydrofurans-dichloromethane (1: 1) suspension of 1.39g (3mmol) 2- iodo- N- (2- iodophenyls)-phenyl-acetamides, the solution that gained is stirred at room temperature is then refluxed for 16 hours for 1 hour.Cooling mixture is simultaneously slowly added dropwise into water until gas stops producing.Volatile matter is removed in vacuum and moist residue is adjusted to alkalescence with 2N sodium hydroxides.With ether (50ml) extraction mixture and with salt water washing extract, dry (sodium sulphate).Funnel plate is washed by hydrous magnesium silicate thin plate filtering solution and with ether, filtrate is evaporated.1.20g white solids are obtained with isooctane wash residual solid.White crystal is recrystallized to give with diethyl ether/hexane.Embodiment 32N- (4- nitro benzoyls-N- (2- iodophenyls) -2- iodobenzene ethamine
0.41g triethylamines and 0.57g4- nitrobenzoyl chlorides are added into the 4ml tetrahydrofuran solutions of the iodo- N- of 0.90g 2- (2- iodophenyls) phenyl ethylamine, mixture 2 hours is stirred at room temperature and solvent is removed in vacuum.Dissolve the residue in ethyl acetate-dichloromethane (5: 1), use 1N HCl, saturated sodium bicarbonate, salt solution wash solution and drying (sodium sulphate).By hydrous magnesium silicate thin plate filtering solution, evaporate filtrate and obtain 1.10g products with diethyl ether and hexane development residual solids, be white solid.Embodiment 333,4- dihydro -1H-1- benzazepines -2,5- diketone
49.54g (0.30mol) 2 '-nitro-acetophenones and 47.02g (0.50mol) diglycolic acid (hydration) are added into the solution of 225ml glacial acetic acids and the 8.5ml concentrated sulfuric acids.Mixture is heated at 100 DEG C 16 hours, is cooled down mixture and is inclined onto trash ice.Mixture is filtered after ice dissolving and solid is washed with cold water, drying solid is simultaneously recrystallized to give 20.1g3- (2- nitro benzoyls) acrylic acid with dichloromethane/hexane, is white crystal, mp153-158 DEG C.The 80ml ethanol solutions and 1.6g palladiums/charcoal 20 hours of aforesaid compound (9.0g) are hydrogenated under 30 pound/square inch Hydrogen Vapor Pressures in Paar hydrogenator, mixture is filtered by diatomite and solvent is removed.By silica gel chromatography residue (7.0g), 4.0g3- (2- amino benzoyls) propionic acid is afforded using hexane-ethylacetate (1: 1), is orange solids, mp103-107 DEG C.It is stirred at room temperature the 0.50g samples of aforesaid compound, the 20ml dichloromethane solutions of 0.36ml triethylamines and 0.43ml diethoxy phosphinyl cyanides 5 days.Solvent is removed, ethyl acetate, 2N citric acids, 1M sodium acid carbonates, salt solution and drying (sodium sulphate) is added.Remove solvent and by silica gel chromatography residue, with ethylacetate-hexane (1: 1) as solvent, obtain 0.190g light brown crystallines, mp168-170 DEG C.Reference implementation example 344- [(dimethylamino) methylene] -3,4- dihydro -1H-1- benzazepines -2,5- diketone
0.250g (1.43mmol) 3,4- dihydros -1H-1- benzazepines -2,5- diketone and 5.5ml (4.93g are heated at 90 DEG C, 41.5mmol) DMF, the mixture of dimethyl-acetal 1.5 hours, mixture is cooled down, is diluted and filtered with diethyl ether.Solid is fully washed with diethyl ether and 0.26g brown crystals, mp203-205 DEG C are dried to obtain.Reference implementation example 352- methyl -6,7- dihydro -5H- pyrimidos [5,4-d] [1] benzazepines
In argon gas atmosphere, 0.176g (3.26mmol) sodium methoxides are added into the 15ml methanol solutions of 0.308g (3.26mmol) B amidine hydrochloric acid salt and mixture are stirred 15 minutes.0.50g (2.17mmol) 4- [(dimethylamino) methylene] -1,2,3,4- tetrahydrochysene -5H-1- benzazepines -2,5- diketone is added into the mixture of gained and mixture is stirred at room temperature and is stayed overnight.With 3ml methanol dilutions mixture (containing thick precipitation), cool down and filter, the filtrate was concentrated to dryness.Residue and initial solid are merged and chloroform is added.Mixture is washed with water, handles organic layer with activated carbon, is then filtered by hydrous magnesium silicate thin plate, evaporation filtrate obtains 0.41g crystal, mp257-258 DEG C.
The lithium hydride dioxane solutions of heating aforesaid compound and 5 equivalents obtain product in 24 hours, are solid.Reference implementation example 365,6- dihydro pyridos [2,3-b] [Isosorbide-5-Nitrae] Benzothiazepine
To 11.67g2- thiobenzoates 32ml ethanol and 11ml aqueous mixtures solution in, 12.72g solid sodium bicarbonates are added portionwise.After the completion of addition, stir mixture 15 minutes and the chloro- 3- nitropyridines of 10.0g2- are added portionwise.Then backflow mixture 2 hours, cooling is concentrated in vacuo.The aqueous solution of residual is diluted with 15ml water, is acidified with 2N hydrochloric acid and uses 250ml ethyl acetate to extract twice.It is concentrated in vacuo extract and obtains yellow solid residue.Dissolved the residue in by steam bath heating in a small amount of ethyl acetate, cool down solutions overnight and be filtrated to get 2.5g initiation materials.Filtrate is concentrated, cools down and is filtrated to get 12.5g2- (3- nitro -2- pyridylthios) benzoic acid, be yellow solid.45psi hydrogen is depressed in Paar hydrogenator, stirs the aforesaid compound (5.0g) in 60ml ethanol and 0.75gPd/C18 hours.Mixture is filtered by diatomite and filter cake is washed with 200ml dichloromethane, the filtrate merged is evaporated in vacuo and obtains solid.With ethanol developing solid and it is filtrated to get 3.6g yellow solids.With the Pd/C (0.50g) being dissolved in 50ml ethanol and 30ml acetic acid in hydrogenated solids (3.0g) 18 hours once again under 45psi, mixture is filtered by diatomite and filter cake is washed with methanol.It is concentrated in vacuo the filtrate merged and obtains 1.6g solids.Again with 0.80gPd/C in the 25mlN that this solid is reduced under 45psi Hydrogen Vapor Pressures, dinethylformamide solution obtains 0.57g solids.2- (3- amino -2- pyridylthios) benzoic acid is obtained with re-crystallizing in ethyl acetate.Aforesaid compound is heated in 2 hydroxy pyrimidine at 170 DEG C and obtains 5,6- dihydro pyridos [2,3-b] [Isosorbide-5-Nitrae] Benzothiazepine, is yellow solid.As described in reference implementation example 3, aforesaid compound is reacted with borane-dimethylsulfide and obtain product, be solid.- 2 '-carboxyl of reference implementation example 372- nitros-diphenylamines
The mixture of 13.7g ortho-aminobenzoic acids in 200 DEG C of oil baths under heating stirring, the o- bromo nitrobenzenes of 20.2g, 13.8g Anhydrous potassium carbonates and 0.1g metallic coppers, heating response mixture 2 hours is cooled down and the solid obtained by being washed with ether (3 × 100ml).Solid is dissolved in hot water and filtered.With 40ml hydrochloric acid acidified filtrates, solid obtained by collection and solid needed for being dried to obtain 20.5g, are solid, mp262-265 DEG C.- 2 '-carboxyl of reference implementation example 382- amino-diphenylamines
The 50ml methanol solutions of -2 '-carboxyl of 7.3g2- nitros-diphenylamines containing 10% palladium/charcoal are hydrogenated under 42 pounds of pressure 24 hours, by diatomite filter reactant mixture, filtrate evaporated in vacuo to it is dry obtain 6.6g needed for product, be solid, mp72-75 DEG C.Reference implementation example 395,11- dihydro -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza  -11- ketone
It is heated to reflux the 300ml xylene solutions of 6.6g2- amino -2 '-carboxyl diphenylamines 20 hours, it is evaporated in vacuo dimethylbenzene and obtains residue, it is evaporated in vacuo in 210ml toluene and obtain residue, gained residue is evaporated in vacuo residue of getting back in 50ml chloroforms.Dissolve the residue in 10ml tetrahydrofurans and be added in 400ml chilled hexanes, product needed for the solid obtained by collection obtains 4.3g is solid, mp121-123.Reference implementation example 405,11- dihydro -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diazas 
In nitrogen atmosphere to be cooled to 0 DEG C, stirring under 4.3g 5,11- dihydro -10H- dibenzo [b, e] [1,4] tetrahydrofuran solution of 4.0ml 10M dimethyl sulphides-borane complex is added in the 50ml tetrahydrofuran solutions of diaza  -11- ketone, ice bath is removed after 30 minutes and reactant mixture is stirred at room temperature 18 hours.Ice bath cools down reactant mixture and is added dropwise to 30ml absolute methanols, is evaporated in vacuo to dry.Add other 30ml methanol and evaporate and obtain residue, residue is quenched with the sodium hydroxides of 30ml 40%, then heated 45 minutes at 110 DEG C, be cooled to room temperature.Extracted with 200ml water diluted reaction mixture and with dichloromethane (3 × 100ml).Use 1N hydrochloric acid, the extract that water and the washing of 0.5N sodium hydroxides merge, State Administration of Traditional Chinese Medicine's organic layer is simultaneously evaporated in vacuo and obtains product needed for 3.2g, mp114-116.Reference implementation example 415H- dibenzo [b.e] azepines -6,11- diketone
The mixture of return stirring 2.50g -2 '-carboxylic acids of 2- aminobenzophenones and 50ml dimethylbenzene 23 hours, product needed for filtering mixture obtains 1.82g, is solid.Reference implementation example chloro- 5H- dibenzo [b.e] azepines -6, the 11- diketone of 422-
Stir 1.0g5H- dibenzo [b.e] azepines -6, the mixture of 11- diketone and 50ml acetic acid, chlorine is passed through into reactant mixture until saturation simultaneously, temperature is increased to 38 DEG C, precipitates and is formed after standing, filtering, washed and be air-dried with hexane and obtain 0.62g solids, required product is obtained by chromatogram purification, is solid, mp289-293 DEG C.Reference implementation example 432- chloro-6,11-dihydro -5H- dibenzo [b.e] azepines
To chloro- 5H- dibenzo [b.e] azepines -6 of 7.28g2- in argon gas atmosphere, in the mixture of 11- diketone and 25ml anhydrous tetrahydro furans, it is added dropwise to the tetrahydrofuran solution of 8.5ml (10M) boron-dimethyl sulphide, reactant mixture is stirred at room temperature 18 hours, heating reflux reaction mixture 3 hours is simultaneously cooled to room temperature.25ml methanol is carefully added under stirring, 100ml 2N sodium hydroxides are subsequently added into.Heating reflux reaction mixture 24 hours simultaneously collects solid, and the solid of gained is dissolved in dichloromethane and 2N citric acids are used, water washing and drying (sodium sulphate).It is evaporated in vacuo removing volatile matter and obtains 4.16g residues, product needed for being recrystallized to give 2.05g with ethylacetate-hexane is crystalline solid, mp137-141 DEG C.Reference implementation example 442- [2- (tributylstamlyl) -3- thienyls]-DOX
At room temperature to 15.6g (0.10mol) 2- (3- thienyls) -1 under stirring in nitrogen atmosphere, in the 100ml anhydrous ether solutions of 3- dioxolanes, it is added dropwise to n-BuLi (1.48N, hexane solution, 74.3ml), after backflow 15 minutes, reactant mixture is cooled to -78 DEG C and the 100ml anhydrous tetrahydrofuran solutions of tri-n-butyltin chloride (34.18g, 0.105mol) are added dropwise to.After the completion of addition, mixture is warming to room temperature and solvent is evaporated off, 100ml hexanes are added into oily residue, and filter out obtained precipitation (lithium chloride).Evaporate filtrate and vacuum distillation residue obtains 34.16g (77%) required product.Reference implementation example 452- [2- [(2- nitrobenzophenones) methyl] -3- thienyls]-DOX
The reflux in toluene 2- [2- (tributylstamlyl) -3- thienyls] -1 of gas is being removed in nitrogen atmosphere, 3- dioxolanes (8.8g, 20mmol), 2- nitrobenzyl bromides (4.5g, 22mmol) and four (triphenyl phasphine)-palladiums (0) (200mg) mixture 16 hours, after the completion of cooling reactant mixture filtered to room temperature and by diatomite.It is concentrated under reduced pressure and removes toluene and by silica gel column chromatography separation product, with 30% ethyl acetate: product needed for Hex obtains 4.5g, is thick liquid, mass spectrum：M+=292.Reference implementation example 464,10- dihydro -5H- thienos [3,2-c] [1] benzazepines
By the 4g2- [2- [(2- nitrobenzophenones) methyl] -3- thienyls] -1 under stirring, the acetone (50ml) and acetic acid (90% of 3- dioxolanes, 50ml) solution is heated to 60 DEG C, it is slowly added to zinc powder (10g), after adding, stirring reaction mixture 6 hours.After the completion of filtering reactant mixture and with acetone wash residual thing and concentrate.Fully washed with chloroform recovery brown residue and with water, dry organic layer (sodium sulphate) and filter and concentrate.By silica gel column chromatography separation product, with 20% ethyl acetate: product needed for Hex obtains 2.0g, is light yellow crystalline solid, mp86 DEG C, mass spectrum；M+202.Reference implementation example 474,5- dihydro -4,4- dimethyl -2- [3- [(2- nitrobenzophenones) methyl] -2- thienyl] oxazoles
To 4 at -70 DEG C in nitrogen atmosphere, 5- dihydros -4, oxazole (the 4.5g of 4- dimethyl -2- (2- thienyls) -, n-BuLi (2.5M hexane solution 11ml) is added dropwise in anhydrous ether solution 25mmol), in -78 DEG C of stirring reaction mixtures 45 minutes and it is added dropwise to tri-n-butyltin chloride (8.3g, 25mmol) anhydrous ether solution.The reactant mixture 1 hour of gained is stirred at room temperature and is quenched with water.Extracted by ether reactant mixture is used, is fully washed, is dried and concentrated with water.The purity of products therefrom is enough to be used in next step conversion.Make oil product 4 in toluene, 5- dihydros -4,4- dimethyl -2- [3- (tributylstamlyl) -2- thienyls]-oxazoles and 2- nitrobenzyl bromides (5.5g, 25mmol) mixing and backflow 16 hours in the presence of four (triphenyl phasphine)-palladiums (0) (200mg), make reactant mixture be cooled to room temperature and filter afterwards.Toluene is removed under reduced pressure and by silica gel column chromatography separation product, is brown oil, with 30% ethyl acetate: Hex obtains product needed for 5.7g；Mass spectrum；M+=316.Reference implementation example 489,10- dihydro -4H- thienos [3,2-c] [1] benzazepines -10- ketone
Backflow contains the 4 of 1N hydrochloric acid (30ml), 5- dihydros -4, [solution of 3- [(2- nitrobenzophenones) methyl] -2- thienyl] oxazoles 5g acetone/water (3: 1 100ml) 24 hours, concentrated reaction mixture is simultaneously dissolved the residue in glacial acetic acid (100ml) 4- dimethyl -2-.Glacial acetic acid is stirred at 70 DEG C and zinc powder (10g) is slowly added to, and continues to stir 6 hours at 70 DEG C.After the completion of, reactant mixture is cooled to room temperature and is filtered, acetic acid is removed under reduced pressure and chloroform recovery residue is used.Product needed for drying chloroform layer and being concentrated to give 2.9g, is brown solid, mass spectrum：M+215.Reference implementation example 499,10- dihydro -4H- thienos [2,3-c] [1] benzazepines
The tetrahydrofuran solution of return stirring 2.0g9,10- dihydro -4H- thienos [3,2-c] [1] benzazepines -10- ketone and lithium aluminium hydride reduction (500mg) 4 hours, afterwards, carefully makes reactant mixture be quenched and use chloroform recovery with frozen water.Organic layer is fully washed with water, with anhydrous sodium sulfate drying, filters and concentrates.By silica gel chromatography product, with 30% ethyl acetate: product needed for Hex obtains 1.2g, is light yellow solid, mass spectrum M+202.Reference implementation example 502- methylfuran -3- acyl chlorides
Flow back 4.0g 2- methylfuran -3- carboxylic acid methyl esters, the mixture of 30ml 2N sodium hydroxides and 15ml methanol 1.5 hours, and removal of solvent under reduced pressure obtains solid, and solid is extracted with dichloromethane (discarding).Solid is dissolved in water and solid is obtained with 2N acidified with citric acid solution, solid is washed with water and the crystal of 1.05g crystal 2- methylfuran -3- carboxylic acids is dried to obtain.Aforesaid compound (0.95g) and 3ml thionyl chlorides are flowed back 1 hour, solvent is removed, toluene (20ml, three times) is added and removes solvent and obtain product, is grease.Reference implementation example 512- [2- (tributylstamlyl) -3- thienyls]-DOX
At room temperature to 15.6g (0.10mol) 2- (3- thienyls) -1 under stirring in nitrogen atmosphere, in the 100ml anhydrous ether solutions of 3- dioxolanes, it is added dropwise to n-BuLi (1.48N, hexane solution, 74.3ml), after backflow 15 minutes, reactant mixture is cooled to -78 DEG C and the 100ml anhydrous tetrahydrofuran solutions of tri-n-butyltin chloride (34.18g, 0.105mol) are added dropwise to.After the completion of addition, mixture is warming to room temperature and solvent is evaporated off, 100ml hexanes are added into oily residue, and filter out the precipitation (lithium chloride) of gained.Simultaneously vacuum distillation residue obtains product needed for 34.16g (77%) to evaporation filtrate.Reference implementation example 526- aminopyridine-3-carboxylic acid methyl esters
Absolute methanol (400ml) is cooled down in ice bath and leads to HCl gases into mixture 25 minutes, and 30g6- aminopyridine-3-carboxylic acids are added into MeOH-HCl, is then stirred mixture and is heated 2 hours (all solid dissolvings) at 90 DEG C.Solvent is removed in vacuum and the solid of residual is dissolved in 100ml water, using in saturated sodium bicarbonate with acid solution (solid is separated), cooling mixture is simultaneously filtrated to get 30g white crystals, mp150-154 DEG C.Reference implementation example 536- [(5- fluoro-2-methylbenzenes formoxyl) amino] pyridine-3-carboxylic acid
The 10ml dichloromethane solutions of 6.38g5- fluoro-2-methylbenzene formyl chlorides are added into the 40ml dichloromethane solutions (being cooled down on ice bath) of 4.5g6- aminopyridine-3-carboxylic acids methyl esters and 5.53ml triethylamine mixtures, the mixture of gained is stirred at room temperature in argon gas atmosphere 18 hours, adds remaining 3.4g5- fluoro-2-methylbenzene formyl chloride.It is stirred at room temperature 3 hours, filtering mixture obtains 3.0g6- [[two (5- fluoro-2-methylbenzenes formoxyl)] amino] pyridine-3-carboxylic acid methyl esters.The filtrate was concentrated to dryness and residue is developed with hexane and ethyl acetate obtains the double acylated compounds of remaining 9.0g.
12.0g6- [[two (5- fluoro-2-methylbenzenes formoxyl)] amino] pyridine-3-carboxylic acid methyl esters is stirred at room temperature; the mixture of 60ml methanol-tetrahydrofuran (1: 1) and 23ml 5N sodium hydroxides 16 hours; vacuum concentrated mixture; diluted with 25ml water, cool down and be acidified with 1N hydrochloric acid.Filter mixture and solid is washed with water and obtain 6.3g products, be white solid.
As described in reference implementation example 53, but replace with appropriate aroyl chloride, heteroaryl acyl chlorides, cyclic alkanol chlorides, phenylacetyl chlorine and relevant suitable acyl chlorides, following 6- [(aroyl) amino] pyridine-3-carboxylic acids, 6- [ ( 4-hetaroylpyrazol ) amino ] pyridine-3-carboxylic acids and relevant 6- [ ( acylation ) amino ] pyridine-3-carboxylic acid can be prepared.Reference implementation case 546 - [(3 - methyl - 2 - thiophene carbonyl) amino] pyridine - 3 - carboxylic acid reference implementation case 556 - [(2 - methyl - 3 - thiophene carbonyl) amino] pyridine - 3 - carboxylic acid reference implementation case 566 - [(3 - methyl - 2 - furan based carbonyl) amino] pyridine - 3 - carboxylic acid reference implementation case 576 - [(2 - methyl - 3 - furan based carbonyl) amino] pyridine - 3 - carboxylic acid reference implementation case 586 - [(3 - fluoro - 2 - methyl benzene formyl) amino] pyridine - 3 - carboxylic acid reference implementation case 596 - [(2 - methyl benzene formyl) amino] pyridine - 3 - carboxylic acid reference implementation case 606 - [(2 - chloro - benzene formyl) amino] pyridine - 3 - carboxylic acid reference implementation case 616 - [(2 - fluoro - benzene formyl) amino] pyridine - 3 - carboxylic acid reference implementation case 626 - [(2-4 - fluorine benzene formyl chloride -) amino] pyridine - 3 - carboxylic acid reference example636- [ ( 2, 4- dichloro-benzoyls) amino] pyridine-3-carboxylic acid reference implementation example 646- [(the chloro- 2- fluoro benzoyls of 4-) amino] pyridine-3-carboxylic acid reference implementation example 656- [(3, 4, 5- trimethoxybenzoys) amino] pyridine-3-carboxylic acid reference implementation example 666- (2, 4- difluoro benzoyls, ), amino, ], pyridine-3-carboxylic acid reference implementation example 676-, [, (, 2- benzoyl bromides, ), amino, ], pyridine-3-carboxylic acid reference implementation example 686-, [, (, the chloro- 4- nitro benzoyls of 2-, ), amino, ], pyridine-3-carboxylic acid reference implementation example 696-, [, (, tetrahydrofuran base, ), -2- carbonyls, ), amino, ], pyridine-3-carboxylic acid reference implementation example 706-, [, (, tetrahydro-thienyl -2- carbonyls, ), amino, ], pyridine-3-carboxylic acid reference implementation example 716-, [, (, cyclohexyl-carbonyl, ), amino, ], pyridine-3-carboxylic acid reference implementation example 726-, [, (, hexamethylene -3- alkenyl carbonyls, ), amino, ], pyridine-3-carboxylic acid reference implementation example 736-, [, (, 5- fluoro-2-methylbenzene acetyl group, ), amino, ], pyridine-3-carboxylic acid reference implementation example 746-, [, (, 2- chloro acetyls, ), amino, ], pyridine-3-carboxylic acid reference implementation example 756-, [, (, cyclopentylcarbonyl, ), amino, ], pyridine-3-carboxylic acid reference implementation example 766-, [, (, Cyclohexylacetyl, ), amino, ], pyridine-3-carboxylic acid reference implementation example 776-, [, (, 3- methyl -2- thienyl acetyl group, ), amino, ], pyridine-3-carboxylic acid reference implementation example 786-, [, (, 2- methyl -3- thienyl acetyl group, ), amino, ], pyridine-3-carboxylic acid reference implementation example 796-, [, (, 3- methyl -2- furyl acetyl group, ), amino, ], pyridine-3-carboxylic acid, mp288-290 DEG C of reference implementation example 806-, [, (, 2- methyl-3-furyl acetyl group, ), amino, ], pyridine-3-carboxylic acid reference implementation example 816-, [, (, 3- methyl -2- tetrahydro-thienyl acetyl group, ), amino, ], pyridine-3-carboxylic acid reference implementation example 826-, [, (, 2- methyl -3- tetrahydro-thienyl acetyl group, ), amino, ], pyridine-3-carboxylic acid reference implementation example 836-, [, (, 2, 5- dichloro-benzoyls base) amino] pyridine-3-carboxylic acid reference implementation example 846- [(3, 5- dichloro-benzoyls base) amino] pyridine-3-carboxylic acid reference implementation example 856- [(2- methyl -4- chlorobenzene formacyls) amino] pyridine-3-carboxylic acid reference implementation example 866- [(2, 3- dimethylbenzoyls) amino] pyridine-3-carboxylic acid reference implementation example 876- [, (2- methoxybenzoyls base) amino] pyridine-3-carboxylic acid reference implementation example 886- [, (2- fluorine methoxybenzoyls base) amino] pyridine-3-carboxylic acid reference implementation example 896- [, (the chloro- 2- methoxybenzoyls bases of 4-) amino] pyridine-3-carboxylic acid reference implementation example 906- [[2-, (trifluoromethyl) benzoyl] amino] pyridine-3-carboxylic acid reference implementation example 916- [, (2, 6- dichloro-benzoyls base) amino] pyridine-3-carboxylic acid reference implementation example 926- [(2, 6- dimethylbenzoyls) amino] pyridine-3-carboxylic acid reference implementation example 936- [(2- methyl thios benzoyl) amino] pyridine-3-carboxylic acid reference implementation example 946- [(4- fluoro- 2- (trifluoromethyl) benzoyl) amino] pyridine-3-carboxylic acid reference implementation example 956- [(2, 3- dichloro-benzoyls base) amino] pyridine-3-carboxylic acid reference implementation example 966- [(4- fluoro-2-methylbenzenes formoxyl) amino] pyridine-3-carboxylic acid reference implementation example 976- [(2, 3, 5- trichlorobenzoyls) amino] pyridine-3-carboxylic acid reference implementation example 986- [(the fluoro- 2- chlorobenzene formacyls of 5-) amino] pyridine-3-carboxylic acid reference implementation example 996- [(2- fluoro- 5- (trifluoromethyl) benzoyl) amino] pyridine-3-carboxylic acid reference implementation example 1006- [(5- fluoro-2-methylbenzenes formoxyl) amino] pyridine -3- acyl chlorides
The mixture of backflow 6.2g 6- [(5- fluoro-2-methylbenzenes formoxyl) amino] pyridine-3-carboxylic acids and 23ml thionyl chlorides 1 hour; add remaining 12ml thionyl chloride and the mixture 0.5 hour of flowing back, vacuum concentrated mixture to dry doubling adds 30ml toluene into residue.Toluene is removed in vacuum, repeats this process (adding toluene and removing) and obtains 7.7g crude products, be solid.
As described in reference implementation example 100, following 6- ((acyl group) amino) pyridine -3- acyl chlorides can be prepared.Reference implementation example 1016- [(3- methyl -2- thienyl carbonyls] amino] pyridine -3- acyl chlorides reference implementation example 1026- [(2- methyl -3- thienyl carbonyls] amino] pyridine -3- acyl chlorides reference implementation example 1036- [(3- methyl -2- furyl carbonyls] amino] pyridine -3- acyl chlorides reference implementation example 1046- [(2- methyl-3-furyls carbonyl] amino] pyridine -3- acyl chlorides reference implementation example 1056- [(3- fluoro-2-methylbenzenes formoxyl) amino] pyridine -3- acyl chlorides reference implementation example 1066- [(2- methyl benzoyls) amino] pyridine -3- acyl chlorides reference implementation example 1076- [(2- chlorobenzene formacyls) amino] pyridine -3- acyl chlorides,White crystal reference implementation example 1086- [(2- fluoro benzoyls) amino] pyridine -3- acyl chlorides reference implementation example 1096- [(the chloro- 4- fluoro benzoyls of 2-) amino] pyridine -3- acyl chlorides reference implementation example 1106- [(2,4- dichloro-benzoyls base) amino] pyridine -3- acyl chlorides reference implementation example 1116- [(the chloro- 2- fluoro benzoyls of 4-) amino] pyridine -3- acyl chlorides reference implementation example 1126- [(3,4,5- trimethoxybenzoys) amino] pyridine -3- acyl chlorides reference implementation example 1136- [(2,4- difluoro benzoyls, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1146-, [, (, 2- benzoyl bromides, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1156-, [, (, the chloro- 4- nitro benzoyls of 2-, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1166-, [, (, tetrahydrofuran base -2- carbonyls, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1176-, [, (, tetrahydro-thienyl -2- carbonyls, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1186-, [, (, cyclohexyl-carbonyl, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1196-, [, (, hexamethylene -3- alkenyl carbonyls, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1206-, [, (, 2- methyl phenylacetyl groups, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1216-, [, (, 2- chloro acetyls, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1226-, [, (, cyclopentylcarbonyl, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1236-, [, (, hexamethylene acetyl group, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1246-, [, (, 3- methyl -2- thienyl acetyl group, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1256-, [, (, 2- methyl -3- thienyl acetyl group, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1266-, [, (, 3- methyl -2- furyl acetyl group, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1276-, [, (, 2- methyl-3-furyl acetyl group, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1286-, [, (, 2- methyl -5- fluorobenzene acetyl group, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1296-, [, (, 3- methyl -2- tetrahydro-thienyl acetyl group, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1306-, [, (, 2- methyl -3- tetrahydro-thienyl acetyl group, ), amino, ], pyridine -3- acyl chlorides reference implementation example 1316-, [, (, 2,5- dichloro-benzoyls base) amino] pyridine -3- acyl chlorides reference implementation example 1326- [(3,5- dichloro-benzoyls base) amino] pyridine -3- acyl chlorides reference implementation example 1336- [(2- methyl -4- chlorobenzene formacyls) amino] pyridine -3- acyl chlorides reference implementation example 1346- [(2,3- dimethylbenzoyls) amino] pyridine -3- acyl chlorides reference implementation example 1356- [, (2- methoxybenzoyls base) amino] pyridine -3- acyl chlorides reference implementation example 1366- [, (2- trifluoromethoxies benzoyl) amino] pyridine -3- acyl chlorides reference implementation example 1376- [, (the chloro- 2- methoxybenzoyls bases of 4-) amino] pyridine -3- acyl chlorides reference implementation example 1386- [[2-, (trifluoromethyl) benzoyl] amino] pyridine -3- acyl chlorides reference implementation example 1396- [, (2,6- dichloro-benzoyls base) amino] pyridine -3- acyl chlorides reference implementation example 1406- [(2,6- dimethylbenzoyls) amino] pyridine -3- acyl chlorides reference implementation example 1416- [(2- methylthio phenyls formoxyl) amino] pyridine -3- acyl chlorides reference implementation example 1426- [(4- fluoro- 2- (trifluoromethyl) benzoyl) amino] pyridine -3- acyl chlorides reference implementation example 1436- [(2,3- dichloro-benzoyls base) amino] pyridine -3- acyl chlorides reference implementation example 1446- [(4- fluoro-2-methylbenzenes formoxyl) amino] pyridine -3- acyl chlorides reference implementation example 1456- [(2,3,5- trichlorobenzoyls) amino] pyridine -3- acyl chlorides reference implementation example 1466- [(the fluoro- 2- chlorobenzene formacyls of 5-) amino] pyridine -3- acyl chlorides reference implementation example 1476- [(2- fluoro- 5- (trifluoromethyl) benzoyl) amino] pyridine -3- acyl chlorides
Following pairs of acylates (Table A) are prepared as described in reference implementation example 53 and by silica gel chromatography.Then it is sour (table B) by these compound hydrolysis as described in reference implementation example 53.
Table A
Figure A9619256801941
Reference implementation example number R1 R2 R3 R4 X M+
148 CH3 H H H H 388
149 CH3 H H H H 424
150 CH3 F F F H 426
151 H OCH3 OCH3 OCH3 H 540
152 Cl H H H H 430
153 F H H H H 396
154 Br H H H H 520
155 Cl H H H H 412
156 Ph H H H H 512
157 Cl H H Br H 474
158 CH3 H H H Br
159 CH3 H H H Br 468
M+Represent the molecular ion that FAB mass spectrums are obtained
Table B
Figure A9619256801951
Reference implementation example number R1 R2 R3 R4 X M+
160 CH3 H H H H 256
161 CH3 H H H H 274
162 CH3 F F F H 274
163 H OCH3 OCH3 OCH3 H 332
164 Cl H H H H 276
165 F H H H H 278
166 Br H H H H 322
167 Cl H H H H 294
168 Ph H H H H 318
169 Cl H H Br H 356
170 CH3 H H H Cl
171 CH3 H H H Br 336
M+Represent the molecular ion reference implementation example 1726- amino -5- bromopyridine -3- carboxylic acids that FAB mass spectrums are obtained
6- amino niacins (13.8g into stirring, bromine (16g is slowly added in glacial acetic acid (100ml) solution 0.1mol), acetic acid (20ml) solution 0.1mol), reactant mixture 8 hours is stirred at room temperature and acetic acid is removed under reduced pressure, the yellow solid residue of gained is soluble in water and use 30% NH4OH is carefully neutralized.Filter separated solid and be washed with water and obtain 18g solids；Mass spectrum：218(M+).Reference implementation example 1736- amino -5- bromopyridine -3- carboxylate methyl esters
6- amino -5- bromopyridine -3- carboxylic acids (10g, 50mmol) are dissolved in into list in saturation methanolizing HCl (100ml) to flow back 24 hours, removal of solvent under reduced pressure methanol is simultaneously dissolved the residue in cold water.With in 0.1N sodium hydroxides and the aqueous solution and filtering separated solid；Fully washed and be air-dried with water and obtain 10g products, be the solid, (M of mass spectrum 231+).Reference implementation example 1746- [(2- methyl phenylacetyl group) amino] pyridine-3-carboxylic acid
To the 5.0g6- amino-pyridine -3- carboxylate methyl esters of cooling (0 DEG C), 12.6mlN, the 10ml dichloromethane solutions of 12.2g2- methyl phenyllacetyl chlorides are added in the 40ml dichloromethane solutions of N- diisopropylethylamine mixtures, the mixture that gained is stirred at room temperature in argon gas atmosphere is stayed overnight.With 200ml dichloromethane and 50ml water diluted mixture and organic layer is separated, use 1M sodium acid carbonates, each 50ml washings organic layer of salt solution is dried (sodium sulphate).By hydrous magnesium silicate thin plate filtering solution, simultaneously the filtrate was concentrated to dryness.By silica gel column chromatography purification residues (9.0g), 8.6g solids are obtained as eluant, eluent with hexane-ethylacetate (3: 1).The solid is mainly 6- [[two (2- methyl phenylacetyl group)] amino] pyridine-3-carboxylic acid methyl esters; it is dissolved in 60ml tetrahydrofurans-methanol (1: 1) and 5N sodium hydroxides is added into this solution, mixture is stirred at room temperature and stays overnight and vacuum concentrated mixture.Add water (25ml) and stir mixture and share the acidifying of 1N hydrochloric acid.Cool down mixture and cross filter solid and be washed with water and obtain 5.9g gray solids.Reference implementation example 1756- [(2- methyl phenylacetyl group) amino] pyridine -3- acyl chlorides
Flowed back the mixture 1 hour of 4.5g6- [(2- methyl phenylacetyl group) amino] pyridine-3-carboxylic acids and 25ml thionyl chlorides, is then concentrated in vacuo to dry, and 20ml toluene is added into residue and solvent is removed in vacuum.Addition and the removing step of toluene are repeated, residual solids are dried in vacuo at room temperature and obtain 5.3g aterrimus solids.Reference implementation example 176 [1,1 '-xenyl] -2- xenyl acyl chlorides
Heated over steam bath 5.6g [1,1 '-xenyl] -2- carboxylic acids and 29ml thionyl chlorides mixture 0.5 hour and volatile matter is removed in vacuum.Add toluene (40ml) (twice) and solvent is removed in vacuum and obtain 6.8g yellow oils.Reference implementation example 1776- [[two ([1,1 '-xenyl] -2- bases-carbonyl)] amino] pyridine-3-carboxylic acid methyl esters
In argon gas atmosphere, the 30ml dichloromethane solutions of 2.64g6- aminopyridine-3-carboxylic acids methyl esters and 5.5ml diisopropylamines to cooling (0 DEG C) add 6.8g [1,1 '-xenyl] -2- acyl chlorides 10ml dichloromethane solutions, mixture is stirred at room temperature 2 days, is then diluted with 120ml dichloromethane and 50ml water.Organic layer is separated, is washed with 1M sodium acid carbonates and each 50ml of salt solution, is dried (sodium sulphate).By hydrous magnesium silicate thin plate filtering solution and it is concentrated in vacuo filtrate to dry and obtains solid.6.2g white crystals, mp180-188 DEG C are obtained with re-crystallizing in ethyl acetate.Reference implementation example 1786- [([1,1 '-xenyl] -2- bases-carbonyl) amino] pyridine-3-carboxylic acid
To the 6.0g6- [[two ([1 of cooling (0 DEG C), 1 '-xenyl] -2- bases-carbonyl)] amino] in mixture of the pyridine-3-carboxylic acid methyl esters in 40ml methanol and 30ml tetrahydrofurans, 18ml2N sodium hydroxides are slowly added to, the mixture that gained is stirred at room temperature is stayed overnight and PH is adjusted into 5 with glacial acetic acid.Mixture is concentrated, PH2-3 is acidified to 1N hydrochloric acid and is extracted with 250ml ethyl acetate, with 50ml salt water washing extracts, (sodium sulphate) is dried and solvent is removed in vacuum.The white solid remained using the development of 15ml ethyl acetate obtains 3.35g white crystals, mp215-217 DEG C.Reference implementation example 1796- [([1,1 '-xenyl] -2- bases carbonyl) amino] pyridine -3- acyl chlorides
The mixture of backflow 1.9g6- [([1,1 '-xenyl] -2- bases-carbonyl) amino] pyridine-3-carboxylic acids and 9ml thionyl chlorides 1 hour, is then concentrated in vacuo to dry.Toluene (15ml) (twice) is added into residue and solvent is removed in vacuum and obtains 2.1g light brown grease.Reference implementation example 1806- [(cyclohexyl-carbonyl) amino] pyridine-3-carboxylic acid
In argon gas atmosphere, the 50ml dichloromethane solutions of 5.0g6- aminopyridine-3-carboxylic acids methyl esters and 12.6ml diisopropylamines to cooling (0 DEG C) add the 10ml dichloromethane solutions of 9.7ml cyclohexyl acyl chlorides, mixture is stirred at room temperature to stay overnight, is then diluted with 200ml dichloromethane and 60ml water.Organic layer is separated, with 60ml salt water washings, is dried (sodium sulphate).By hydrous magnesium silicate thin plate filtering solution and it is concentrated in vacuo filtrate to dry and obtains 12.8g solids.
Cool down mixture of (0 DEG C) the above-mentioned solid (12.0g) in 150ml tetrahydrofurans-methanol (1: 1) and add 62ml 2N sodium hydroxides, mixture is stirred at room temperature 3 hours, is neutralized and be concentrated in vacuo with 10ml glacial acetic acids.Mixture (containing solid) is acidified to PH1 with 1N hydrochloric acid and extracted with 250ml ethyl acetate, and is extracted twice with 100ml ethyl acetate.The extract merged with 100ml salt water washing, dries (sodium sulphate) and is concentrated to give white solid.6.5g products are obtained with hexane development, are white solid.Reference implementation example 1812- [(4- ethyoxyls-oxo butyl) amino] methyl benzoate
The mixture of 19.2g2- Methyl anthranilates and 9.6g g- bromobutyrates is heated at 80-85 DEG C 24 hours, be cooled to room temperature and filter.With the solid obtained by dichloromethane is washed and 1N hydrochloric acid is used, water, 1N sodium acid carbonates and salt water washing filtrate remove solvent and obtain grease.Distillation grease and collection simultaneously discard boiling point in 45-75 DEG C and 130-160 DEG C of fraction, and residue is product (55.4g grease).Reference implementation example 1822- [N- (4- ethyoxyl -4- oxos butyl)-N- (2- Methyl benzenesulfonyls base) amino] methyl benzoate
In heated over steam bath 2.65g 2- [(4- ethyoxyls-oxo butyl) amino] methyl benzoate, the mixture of 2.0g2- toluene sulfonyl chlorides and pyridine 16 hours, vacuum concentrated mixture (removing pyridine) simultaneously adds 1N hydrochloric acid, with the mixture obtained by dichloromethane is extracted and use 1N hydrochloric acid, water, 1M sodium acid carbonates and salt water washing mixture, are dried (sodium sulphate).3.8g solids are obtained by hydrous magnesium silicate thin plate filtering solution and filtrate evaporated in vacuo, crystal, mp100-102 DEG C are obtained with ethyl alcohol recrystallization.Reference implementation example 1831,2- dihydro -5- hydroxyls -1- [(4- aminomethyl phenyls) sulfonyl] -3H-1- benzazepines -4- carboxylate methyl esters and ethyl ester
The 12ml tetrahydrofuran solutions of 0.838g 2- [N- (4- ethyoxyl -4- oxos butyl)-N- (2- Methyl benzenesulfonyls base) amino] methyl benzoate are added into the 0.448g potassium tert-butoxides (potassium tert-butoride) and the mixture of 2ml tetrahydrofurans for being cooled to 0 DEG C; mixture 4 hours (in argon gas atmosphere) is stirred at 0 DEG C, is poured into water and is neutralized with 2N citric acids.With dichloromethane extraction mixture and water is used, salt water washing extract is dried (magnesium sulfate), by hydrous magnesium silicate thin plate filtering solution and be concentrated in vacuo filtrate to dry and obtain 0.59g products (mixture of methyl esters and ethyl ester).Tetrahydrochysene-the 1- of reference implementation example 1841,2,3,4- [(2- aminomethyl phenyls) sulfonyl] -5H-1- benzazepines -5- ketone
Flow back 30g1; solution of the sample of 2- dihydro -5- hydroxyls -1- [(4- aminomethyl phenyls) sulfonyl] -3H-1- benzazepines -4- carboxylate methyl esters and ethyl ester mixture in 171ml concentrated hydrochloric acids and 171ml glacial acetic acid mixtures 24 hours; add remaining 170ml concentrated hydrochloric acid and the mixture 24 hours of flowing back; vacuum concentrated mixture is to close to drying, being diluted with water and the PH of solution is adjusted into 8 with saturated sodium bicarbonate.With dichloromethane extraction mixture and water is used, salt water washing extract and drying (sodium sulphate) by hydrous magnesium silicate thin plate filtering solution and are concentrated in vacuo filtrate and obtain 12.0g brown oils.Reference implementation example 1854- [(dimethylamino) methylene] -1,2,3,4- tetrahydrochysene -1- [(2- aminomethyl phenyls) sulfonyl] -5H-1- benzazepines -5- ketone
The heated over steam bath 1.89g1 in argon gas atmosphere; 2; 3; the 10ml dichloromethane solutions of 4- tetrahydrochysenes -1- [(2- aminomethyl phenyls) sulfonyl] -5H-1- benzazepines -5- ketone and 2.47ml tert-butoxies-two (dimethylamino) methane (Bredericks reagents) mixture 16 hours, vacuum concentrated mixture to dry doubling is dissolved the residue in dichloromethane.Thin plate is washed by hydrous magnesium silicate thin plate filtering solution and with 5% ethyl acetate/dichloromethane.The filtrate was concentrated to dryness and recrystallizes residue (1.96g) with dichloromethane/hexane obtains 0.85g crystal, mp180-185 DEG C.Part II crystal (0.85g) is reclaimed from mother liquor and remaining 0.3g is reclaimed from the washing lotion for washing hydrous magnesium silicate thin plate with ethyl acetate.Tetrahydrochysene-the 6- of reference implementation example 1861,4,5,6- [(2- aminomethyl phenyls) sulfonyl] pyrazolo [4,3-d] [1] benzazepines
Flow back 1.55g4- [(dimethylamino) methylene] -1 in argon gas atmosphere in steam bath; 2; 3; 4- tetrahydrochysenes -1- (2- aminomethyl phenyls) sulfonyl] -5H-1- benzazepines -5- ketone; the mixture of 0.25ml hydrazines and 60ml ethanol 2 hours, solvent is removed in vacuum after being stored at room temperature overnight.Dichloromethane neutralization water is dissolved the residue in, salt solution wash solution is dried (sodium sulphate).By hydrous magnesium silicate thin plate filtering solution and evaporate filtrate and obtain 1.4g crystal, mp76-79 DEG C.
On a large scale with 18.29g4- [(dimethylamino) methylene] -1; 2; 3; the dichloromethane solution of 4- tetrahydrochysenes -1- [(2- aminomethyl phenyls) sulfonyl] -5H-1- benzazepines -5- ketone reaction products is filtered by hydrous magnesium silicate thin plate; with with ethyl acetate washing and filtering thin plate; concentration filtrate obtains 16.5g products (thin-layer chromatography shows a spot) (silica gel), is eluted with hexane-ethylacetate (1: 2).The tetrahydro-pyrazole of reference implementation example 1871,4,5,6- simultaneously-[4,3-d] [1] benzazepines
1.0g1 is heated at 60 DEG C; 4; 5; 6- tetrahydrochysenes -6- [(2- aminomethyl phenyls) sulfonyl] pyrazolo [4; 3-d] mixture of [1] benzazepines in 60% (v/v) sulfuric acid/glacial acetic acid 12 hours be until removing tosyl; mixture is poured into 100ml ice and water and cooled down, solid sodium hydroxide (temperature keeps resisting 30 DEG C) is added portionwise under effective stirring and PH is adjusted to 8.With ethyl acetate extraction mixture and dried extract (sodium sulphate), remove solvent and obtain solid.Reference implementation example 18810,11- dihydrobenzos [b, f] [Isosorbide-5-Nitrae] oxazepin
To 7.35g lithium aluminium hydride reductions, 10.0g dibenzo [b, f] [Isosorbide-5-Nitrae] oxazepin -10 (11H) -one is added portionwise in the oar liquid of 100ml tetrahydrofurans, add remaining 100ml tetrahydrofuran and the mixture 6 hours of flowing back, be then stirred at room temperature overnight.It is added dropwise to 7.5ml water into the mixture of cooling, the sodium hydroxides of 7.5ml 15% and 7.5ml water three times.Filtering mixture simultaneously washs filter cake with tetrahydrofuran and dichloromethane, is concentrated in vacuo filtrate and obtains 10.1g solids to dry, the solid of gained is dissolved in dichloromethane and filtered by hydrous magnesium silicate thin plate.Filter cake is washed with dichloromethane and the filtrate was concentrated to dryness obtains 8.9g solids.7.5g crystal, mp69-71 DEG C are recrystallized to give with dichloromethane/hexane.The pyrido of reference implementation example 189 [2,3-b] [Isosorbide-5-Nitrae] Benzoxazepine -6 (5H) -one
Flow back 21.4g water sample acid phenenyl esters in argon gas atmosphere, 25.71g3- Amino-2-Chloropyridine and 20ml1,2, mixture 1 hour phenol and HCl (from backflow mixture) free with distillation simultaneously of 4- trichloro-benzenes are simultaneously collected into 1N sodium hydroxides, and hot mixt is poured into the solid that precipitation is collected by filtration in the neutralization of 200ml ethanol.Solid and drying are washed with ethanol, 6.0g products, mp268-270 DEG C are recrystallized to give with methanol-DMF (6: 1).Reference implementation example 1905,6- dihydro pyridos [2,3-b] [Isosorbide-5-Nitrae] Benzoxazepine
2.8g pyridos [2 are stirred at room temperature, 3-b] [Isosorbide-5-Nitrae] Benzoxazepine -6 (5H) -one, the mixture of 10ml tetrahydrofurans and 3ml 10M borane-dimethylsulfides/tetrahydrofuran stays overnight, it is then refluxed for 3 hours, 5ml methanol is added dropwise into mixture under an argon atmosphere.Solvent and the methanol added is removed in vacuum.Solvent is removed in vacuum and 12ml 2N sodium hydroxides are added into residue, backflow mixture hour is simultaneously extracted with ethyl acetate, uses 2N citric acids, water, salt water washing extract and drying (sodium sulphate).By hydrous magnesium silicate thin plate filtering solution and filtrate is concentrated in vacuo to dry.By silica gel (32 ° of g) post (2 " × 18 ") chromatography purification residues, 0.78g crystal, mp172-174 DEG C are obtained as solvent with hexane-ethylacetate (1: 1).Reference implementation example 191N- (2- hydroxy phenyls) -2- chloro-3-pyridyl formamides
Such as J.Med.Chem., 37,519 (1994) are described, in the 10ml tetrahydrofuran solutions that the 15ml tetrahydrofuran solutions of 1.09g2- amino-phenols are added dropwise to 2.1g triethylamines and 2.33g2- chloropyridine -3- benzoylchloride hydrochloride salt mixtures, mixture is stirred at room temperature in argon gas atmosphere 1 hour, is then refluxed for 1 hour.Solvent is removed in vacuum and residue is developed with water, crosses filter solid and is washed with water and obtains 1.02g solids.Crystal, mp145-146 DEG C are recrystallized to give with 2- propyl alcohol.The pyrido of reference implementation example 192 [2,3-b] [1,5] Benzoxazepine -5 (6H) ketone
The 100mlN of backflow 13.0gN- (2- hydroxy phenyls) -2- chloro-3-pyridyls formamides and 2.82g sodium methoxide mixtures in argon gas atmosphere, dinethylformamide solution 3 hours, add sodium methoxide (0.5g) and the mixture 2 hours of flowing back, be then stirred at room temperature 2 days.High vacuum removes solvent and the residue of brownish red is developed with cold methanol.Filter mixture and solid is washed with cold methanol and obtain 5.0g white solids, mp250-253 DEG C.Reference implementation example 1935,6- dihydro pyridos [2,3-b] [1,5] Benzoxazepine
1.65g pyridos [2,3-b] [1,5] Benzoxazepine -5 (6H) ketone is added portionwise into the 20ml oar liquid of the 0.886g lithium aluminium hydride reductions under stirring, is flowed back 18 hours with 30ml tetrahydrofurans diluted mixture and in argon gas atmosphere.1ml water is added into mixture, the sodium hydroxides of 1ml 15% and 1ml water three times is added portionwise and mixture is filtered.Solid is extracted with dichloromethane and solution is filtered by hydrous magnesium silicate thin plate.The filtrate was concentrated to dryness obtains crystal, mp125-129 DEG C.Reference implementation example 1949,10- dihydro -4H- thienos [2,3-c] [1] benzazepines
To the 9.0g4 for being cooled to -78 DEG C, 5- dihydros -4,4- dimethyl -2- (adds the hexane solution of 20ml 2.5M n-BuLis, mixture 15 minutes is stirred at -78 DEG C and is stirred 30 minutes in 0 DEG C of stirring in the 200ml tetrahydrofuran solutions of 2- thienyl) oxazoles.6.0g2- methyl Benzoxazepine -4- ketone is added into the solution under stirring, mixture 16 hours is stirred at room temperature and is quenched and is extracted with dichloromethane with icy water, concentrated extract to dry doubling adds the sulfuric acid of 100ml 4%.Backflow mixture 4 hours, is cooled to room temperature and is filtrated to get 9,10- dihydro -4,10- dioxo -4H- thienos [2,3-c] [1] benzazepines.Solid is washed with water and obtains 2.5g crystal, solid is dissolved in 100ml anhydrous tetrahydro furans and 1.0g lithium aluminium hydride reductions are added.Mixture obtained by backflow 16 hours, is cooled down and is added dropwise to icy water, and mixture is extracted after being diluted with water with methylene chloride-methanol (3: 1), dried extract (magnesium sulfate).Remove solvent and by silica gel chromatography residue, 1.8g solids are obtained using ethylacetate-hexane (1: 1) as solvent；Mass spectrum (CI) 202 (M+H).Reference implementation example 1954- [([1,1 '-xenyl] -2- carbonyls) amino] -3- methoxyl methyl benzoates
Mixture of 10.0g [1,1 '-xenyl] -2- carboxylic acids in 75ml dichloromethane and 12.52g  acyl chlorides is stirred at room temperature 15 hours, volatile matter is removed in vacuum and obtains 11.06g grease.Make the 25ml dichloromethane solutions and 1.81g 4- amino -3- methoxyl methyl benzoates and 1.30g N of the above-mentioned grease of 2.16g therein by being stirred at room temperature, N- diisopropylethylamine reacts 18 hours, with water, saturated sodium bicarbonate aqueous solution washing reaction mixture simultaneously dries organic layer (sodium sulphate), make organic layer by hydrous magnesium silicate thin plate and hexane is added into filtrate in boiling point, product needed for obtaining 3.2g, is crystalline solid, mp115-117 DEG C.Reference implementation example 1964- [([1,1 '-xenyl] -2- carbonyls) amino] -2- chloro benzoic ethers
By 2.37g [1,1 '-xenyl] the 10ml dichloromethane solutions of -2- acyl chlorides are added dropwise to ice-cold 1.84g4- amino -2- chloro benzoic ethers and 1.49g N, in the 50ml dichloromethane solutions of N- diisopropylethylamine, reactant mixture is stirred at room temperature 18 hours, with water, saturated sodium bicarbonate aqueous solution washing reaction mixture simultaneously dries organic layer (sodium sulphate), make organic layer by hydrous magnesium silicate thin plate and add hexane thereto in boiling point, obtain product needed for 1.1g, for crystalline solid, mp132-134 DEG C.M+=365.Reference implementation example 1974- [([1,1 '-xenyl] -2- carbonyls) amino] -2- chlorobenzoic acids
In heated over steam bath 3.0g 4- [([1,1 '-xenyl] -2- carbonyls) amino] the mixture of -2- chloro benzoic ethers in 75ml absolute ethyl alcohols and 2.0ml10N sodium hydroxides 3 hours, water is added thereto and obtains solution, and solution is extracted with dichloromethane.The solid and the product needed for 80 DEG C of vacuum drying obtain 0.1g obtained with acetic acid aqueous phase and collection, is crystalline solid, mp217-219 DEG C.Reference implementation example 1984- [([1,1 '-xenyl] -2- carbonyls)-amino] -3- methoxy benzoyl chlorides
The 5ml thionyl chloride solutions of heated over steam bath 2.69g 4- [([1,1 '-xenyl] -2- carbonyls) amino] -3- methoxy benzoic acids 1 hour in argon gas atmosphere.Volatile matter is removed in vacuum and obtains residue, developing residue with hexane obtains 2.58g crystalline solids, mp121-123 DEG C.M+=361.Reference implementation example 1994- [([1,1 '-xenyl] -2- carbonyls)-amino] methyl benzoate
Mixture of 10.0g [1,1 '-xenyl] -2- carboxylic acids in 75ml dichloromethane and 12.52g  acyl chlorides is stirred at room temperature 18 hours, volatile matter is removed in vacuum and obtains 11.66g residues.In the 100ml dichloromethane solutions that 0 DEG C of 25ml dichloromethane solution by above-mentioned grease 7.5g is added dropwise to 4.53 g4- Methyl anthranilates and 4.3gN, N- diisopropylethylamine.Reactant mixture 18 hours is stirred at room temperature and water is used, saturated sodium bicarbonate aqueous solution washing is dried (sodium sulphate).Make organic layer by hydrous magnesium silicate thin plate and hexane is added into filtrate in boiling point, product needed for obtaining 8.38g is crystalline solid, mp163-165 DEG C.Reference implementation example 2004- [([1,1 '-xenyl] -2- carbonyls)-amino] benzoic acid
Backflow is dissolved in 3.15g4- [([1,1 '-xenyl] -2- carbonyls)-amino] methyl benzoate sample 8 hours in 100ml ethanol and 2.5ml 10N sodium hydroxides, with [[Acid]] solid that the reactant mixture of cooling and collection are obtained is acidified, product needed for being dried to obtain 2.9g is solid, mp246-249 DEG C of reference implementation example 2014- [([1,1 '-xenyl] -2- carbonyls)-amino] chlorobenzoyl chloride
In heated over steam bath 1.39g 4- [([1,1 '-xenyl] -2- carbonyls)-amino] mixture of the benzoic acid in 2.0ml thionyl chlorides 1 hour, add cold hexane and immediately solid crystal, it is dried to obtain product needed for 1.34g, mp118-120 DEG C of reference implementation example 2022- (phenyl methyl) chlorobenzoyl chloride
In mixture of heated over steam bath 5.0g 2- (phenyl methyl) benzoic acid in 5ml thionyl chlorides 1 hour.Product needed for volatile matter obtains 5.74g is removed in vacuum, is grease.M+=227, it is methyl esters.Reference implementation example 2034- [[2- (phenyl methyl) benzoyl] amino] methyl benzoate
To 3.03g4- Methyl anthranilates and 3.12gN, 5.54g2- (phenyl methyl) chlorobenzoyl chlorides are added in the 75ml dichloromethane solutions of N- diisopropylethylamine and reactant mixture are stirred at room temperature 18 hours, with water, saturated sodium bicarbonate aqueous solution washing reaction mixture, is dried (sodium sulphate).Make organic layer by hydrous magnesium silicate thin plate and hexane is added into filtrate in boiling point, product needed for obtaining 5.04g is crystalline solid, mp138-139 DEG C.Reference implementation example 2044- [[2- (phenyl methyl) benzoyl] amino] sodium benzoate
In heated over steam bath 4.90g 4- [[2- (phenyl methyl) benzoyl] amino] mixture of methyl benzoate in 100ml absolute ethyl alcohols and 3.50ml 10N sodium hydroxides 3 hours; filtering aqueous phase simultaneously collects the solid of gained and is dried to obtain product needed for 4.25g, mp340-346 DEG C.Reference implementation example 2054- [[2- (phenyl methyl) benzoyl] amino] benzoic acid
4.0g 4- [[2- (phenyl methyl) benzoyl] amino] sodium benzoate is suspended in water and PH is adjusted to 5 with acetic acid, solid and product, mp246-247 DEG C, M needed for 80 DEG C of vacuum drying obtain 3.75g is collected by filtration+=332.Reference implementation example 2064- [[2- (phenyl methyl) benzoyl] amino] chlorobenzoyl chloride
In heated over steam bath 2.0g 4- [[2- (phenyl methyl) benzoyl] amino] mixture of benzoic acid in 2.0ml thionyl chlorides 1 hour, product needed for volatile matter obtains 1.53g is removed in vacuum, is grease.M+=346, it is methyl esters.Reference implementation example 2074- [[(2- phenyl methyls) benzoyl] amino] -2- chloro benzoic ethers
Mixture in heated over steam bath 5.0g 2- (phenyl methyl) benzoic acid 5.0ml thionyl chlorides 1 hour, is removed in vacuum volatile matter and obtains 5.70g grease.It is added to by the way that 18 hours 25ml dichloromethane solutions by the above-mentioned grease of 2.85g are stirred at room temperature containing 1.85g 4- amino -2- chloro benzoic ethers and 1.65g N, in the 50ml dichloromethane solutions of N- diisopropylethylamine, with water, saturated sodium bicarbonate aqueous solution washing reaction mixture simultaneously dries organic layer (sodium sulphate), make organic layer by hydrous magnesium silicate thin plate and hexane is added into filtrate in boiling point, product needed for obtaining 2.96g, is crystalline solid, mp133-135 DEG C.Reference implementation example 2084- [[(2- phenyl methyls) benzoyl] amino] -3- methoxyl methyl benzoates
The 25ml dichloromethane solutions of 2.85g 2- (phenyl methyl) chlorobenzoyl chloride are added dropwise to 1.84g 4- amino -3- methoxyl methyl benzoates and 1.61g N, in the 50ml dichloromethane solutions of N- diisopropylethylamine, reactant mixture is stirred at room temperature 18 hours, with water, saturated sodium bicarbonate aqueous solution washing reaction mixture simultaneously dries organic layer (sodium sulphate), make organic layer by hydrous magnesium silicate thin plate and add hexane thereto in boiling point, obtain product needed for 2.2g, for crystalline solid, mp129-131 DEG C.M+=376.Reference implementation example 2092- chloro- 4- [[(2- phenyl methyls) benzoyl] amino] benzoic acid
In the chloro- 4- of heated over steam bath 2.8g 2- [[(2- phenyl methyls) benzoyl] amino] mixture of methyl benzoate in 75ml absolute ethyl alcohols and 1.84ml 10N sodium hydroxides 3 hours; add water and obtain solution, with the solution obtained by dichloromethane is extracted.With acetic acid aqueous phase and collect gained solid, 80 DEG C vacuum drying obtain 2.6g needed for product, be crystalline solid, mp184-187 DEG C.M+H=366.Reference implementation example 2103- methoxyl groups -4- [[(2- phenyl methyls) benzoyl] amino] benzoic acid
In heated over steam bath 2.05g 4- [[(2- phenyl methyls) benzoyl] amino] mixture of -3- methoxyl methyl benzoates in 75ml absolute ethyl alcohols and 1.4ml 10N sodium hydroxides 3 hours; add water and obtain solution, with the solution obtained by dichloromethane is extracted.With acetic acid aqueous phase and collect gained solid, 80 DEG C vacuum drying obtain 1.87g needed for product, be crystalline solid, mp176-178 DEG C.M+H=362.Reference implementation example 2113- methoxyl groups -4- [[(2- phenyl methyls) benzoyl] amino] chlorobenzoyl chloride
Heated over steam bath 3- methoxyl groups -4- [[(2- phenyl methyls) benzoyl] amino] mixtures of the benzoic acid in 2.0ml thionyl chlorides 1 hour and hexane is added in argon gas atmosphere; solid obtained by collection is simultaneously dried to obtain product needed for 1.71g; for crystalline solid, mp130-135 DEG C of .M+=376, it is methyl esters.Reference implementation example 212 [4 '-(trifluoromethyl) -1,1 '-xenyl] -2- formyl chlorides
Mixture 1 hour of heated over steam bath 4 '-trifluoromethyl [1,1 '-xenyl] -2- carboxylic acids in 5.0ml thionyl chlorides and hexane is added in argon gas atmosphere, the solid obtained by collection and product needed for being dried to obtain 5.36g, are colorless oil.M+=280, it is methyl esters.Reference implementation example 2134- [([4 '-(trifluoromethyl) [1,1 '-xenyl] carbonyl) amino] methyl benzoate
To 3.13g [4 '-(trifluoromethyls) [1,1 '-xenyl] -2- acyl chlorides 25ml dichloromethane solutions in be added dropwise to ice-cold 1.84g PABAs methyl esters and 1.43gN, the 50ml dichloromethane solutions of N- diisopropylethylamine, reactant mixture 18 hours is stirred at room temperature and water is used, saturated sodium bicarbonate aqueous solution washing reaction mixture simultaneously dries organic layer (sodium sulphate), make organic layer by hydrous magnesium silicate thin plate and add hexane thereto in boiling point, obtain product needed for 3.36g, for crystalline solid, mp164-165 DEG C of .M+=396.Reference implementation example 2143- methoxyl groups -4- [([4 '-(trifluoromethyl) [1,1 '-xenyl] -2- carbonyls) amino] chlorobenzoyl chloride
Heated over steam bath 2.0g 3- methoxyl groups -4- [([4 '-(trifluoromethyls) [1 in argon gas atmosphere, 1 '-xenyl] -2- carbonyls) amino] mixture of the benzoic acid in 20ml thionyl chlorides 1 hour and add hexane, collect solid and be dried to obtain product needed for 1.92g, for crystalline solid, mp136-138 DEG C.Reference implementation example 2153- methoxyl groups -4- [([4 '-(trifluoromethyl) [1,1 '-xenyl] -2- carbonyls) amino] benzoic acid
In heated over steam bath 3.78g 3- methoxyl groups -4- [([4 '-(trifluoromethyls) [1,1 '-xenyl] -2- carbonyls) amino] mixture of the methyl benzoate in 75ml absolute ethyl alcohols and 2.20ml 10N sodium hydroxides 3 hours, add water and obtain solution, with the solution obtained by dichloromethane is extracted.With acetic acid aqueous phase and collect gained solid, 80 DEG C vacuum drying obtain 3.49g needed for product, be crystalline solid, mp213-215.Reference implementation example 2163- methoxyl groups -4- [([4 '-(trifluoromethyl) [1,1 '-xenyl] -2- carbonyls) amino] methyl benzoate
To 3.56g [4 '-(trifluoromethyls) [1,1 '-xenyl] -2- acyl chlorides 25ml dichloromethane solutions in be added dropwise to ice-cold 1.81g 4- amino -3- methoxyl methyl benzoates and 1.62g N, the 50ml dichloromethane solutions of N- diisopropylethylamine, reactant mixture 18 hours is stirred at room temperature and water is used, saturated sodium bicarbonate aqueous solution washing reaction mixture simultaneously dries organic layer (sodium sulphate), make organic layer by hydrous magnesium silicate thin plate and add hexane thereto in boiling point, obtain product needed for 3.9g, for crystalline solid, mp112-113 DEG C.The chloro- 4- of reference implementation example 2172- [([4 '-(trifluoromethyl) [1,1 '-xenyl] -2- carbonyls) amino] chlorobenzoyl chloride
In heated over steam bath 1.39g 2- chloro- 4- [([4 '-(trifluoromethyls) [1,1 '-xenyl] -2- carbonyls) amino] mixture of the benzoic acid in 2.0ml thionyl chlorides 1 hour and hexane is added, the solid obtained by collection is simultaneously dried to obtain product needed for 1.39g.The chloro- 4- of reference implementation example 2182- [([4 '-(trifluoromethyl) [1,1 '-xenyl] -2- carbonyls) amino] benzoic acid
In heated over steam bath 3.83g 2- chloro- 4- [([4 '-(trifluoromethyls) [1,1 '-xenyl] -2- carbonyls) amino] mixture of the methyl benzoate in 75ml absolute ethyl alcohols and 2.20ml 10N sodium hydroxides 3 hours, add water and obtain solution, with the solution obtained by dichloromethane is extracted.With acetic acid aqueous phase and collect gained solid, 80 DEG C vacuum drying obtain 3.42g needed for product, be crystalline solid, mp187-189 DEG C.The chloro- 4- of reference implementation example 2192- [([4 '-(trifluoromethyl) [1,1 '-xenyl] -2- carbonyls) amino] methyl benzoate
By 3.56g [4 '-(trifluoromethyls) [1, 1 '-xenyl] -2- acyl chlorides 10ml dichloromethane solutions in be added dropwise to the chloro- PABA methyl esters of ice-cold 1.86g 2- and 1.6g N, the 50ml dichloromethane solutions of N- diisopropylethylamine, reactant mixture 18 hours is stirred at room temperature and water is used, saturated sodium bicarbonate aqueous solution washing reaction mixture simultaneously dries organic layer (sodium sulphate), make organic layer by hydrous magnesium silicate thin plate (3X) and hexane is added into filtrate in boiling point, obtain product needed for 4.0g, for crystalline solid, mp130-132 DEG C.Reference implementation example 2204- [([4 '-(trifluoromethyl) [1,1 '-xenyl] carbonyl) amino] benzoic acid
In heated over steam bath 3.0g 4- [([4 '-(trifluoromethyls) [1,1 '-xenyl] -2- carbonyls) amino] mixture of the methyl benzoate in 75ml absolute ethyl alcohols and 2.0ml 10N sodium hydroxides 3 hours, add water and obtain solution, with the solution obtained by dichloromethane is extracted.With acetic acid aqueous phase and collect gained solid, 80 DEG C vacuum drying obtain 2.93g needed for product, be crystalline solid, mp243-245 DEG C.M+=385.Reference implementation example 2216- [[3- (2- picolyls) carbonyl] amino] pyridine-3-carboxylic acid methyl esters
3g 6- aminopyridine-3-carboxylic acids methyl esters and 4mlN into stirring, 6.4g 2- picoline -3- acyl chlorides and 25ml dichloromethane solutions are added dropwise in the 100ml dichloromethane solutions of N- diisopropylethylamine, reactant mixture 2 hours is stirred at room temperature and is quenched with water, organic layer is washed with water, dry (magnesium sulfate), filter and be concentrated in vacuo and obtain residue, it is stirred together with ether, solid obtained by collection is simultaneously air-dried and obtains product needed for 6.8g, M+=390.Reference implementation example 2226- [[3- (2- picolyls) carbonyl] amino] pyridine-3-carboxylic acid
To the tetrahydrofurans of 100ml 1: 1 of 6.5g 6- [[3- (2- picolyls) carbonyl] amino] pyridine-3-carboxylic acid methyl esters: add 20ml 5N sodium hydroxides in methanol solution, stirring reaction mixture, which is stayed overnight and is evaporated in vacuo, obtains residue, dissolves the residue in water and is neutralized with acetic acid.Filter separated solid and be air-dried and obtain product needed for 3.0g, M+=257.Reference implementation example 2236- [([1,1 '-xenyl] -2- carbonyls) amino]-pyridine-3-carboxylic acid methyl esters
3mlN is added into the 100ml dichloromethane solutions of 1.5g 6- aminopyridine-3-carboxylic acid methyl esters at room temperature, N- diisopropylethylamine is slowly added into 2.5g [1,1 '-xenyl] -2- acyl chlorides into the reactant mixture under stirring.Reactant mixture is stirred at room temperature 4 hours, is then quenched with water.Organic layer is fully washed with water and is dried with anhydrous magnesium sulfate, is filtered and is evaporated in vacuo and obtains solid residue.Residue is stirred together with ether, product needed for 3.0g is filtered and be dried to obtain：M+=332.Reference implementation example 2246- [([1,1 '-xenyl] -2- carbonyls) amino]-pyridine-3-carboxylic acid
To the tetrahydrofurans of 50ml 1: 1 of 2.5g 6- [([1,1 '-xenyl] -2- carbonyls) amino]-pyridine-3-carboxylic acid methyl esters: 10ml 5N sodium hydroxides are added in methanol solution, reactant mixture are then stirred at room temperature 16 hours.It is concentrated in vacuo reactant mixture and obtains residue, dissolves the residue in water and neutralized with acetic acid.Filter separated solid and be air-dried and obtain product needed for 2.0g, M+=318.Reference implementation example 2252- (2- pyridine radicals) methyl benzoate
Flow back 12g 2- (iodomethyl) methyl benzoate, 20g normal-butyl first stannanes and 2g tetra- (triphenyl phasphine) palladium (0) mixture remove disulfonic gas agitating solution 48 hours, it is concentrated in vacuo reactant mixture and obtains residue, pass through silica gel column chromatography purification residues, with 1: 1 ethyl acetate: product needed for Hex obtains 5.5g, is grease.M+=213.Reference implementation example 2262- (2- pyridine radicals) benzoic acid
Backflow 3.0g 2- (2- pyridine radicals) methyl benzoates and 600mg sodium hydroxides are in the methanol of 50ml 9: 1: the mixture in water 4 hours, are concentrated in vacuo reactant mixture and simultaneously dissolve the residue in 50ml cold water.With in glacial acetic acid and solution and the product that is filtrated to get, it is washed with water, is dried to obtain product needed for 2.5g：M+1=200.Embodiment 1N- [5- (dibenzo [b, f] [Isosorbide-5-Nitrae] oxazepin -10 (11H)-base carbonyl) -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
1.17g 6- [(5- fluoro-2-methylbenzenes formoxyl) amino]-pyridine -3- acyl chlorides is added in 0.39g 10 under stirring, 11- dihydro-dibenzos [b, f] [Isosorbide-5-Nitrae] oxazepin, the 5ml dichloromethane solutions of 1.1ml triethylamines.Reactant mixture is stirred at room temperature in argon gas atmosphere 16 hours, is diluted with 50ml dichloromethane and 20ml, separate organic layer, respectively with 20ml 1M sodium acid carbonates, salt water washing is dried (sodium sulphate).By hydrous magnesium silicate thin plate filtering solution and filtrate is concentrated in vacuo to dry.By silica gel chromatography residue, solid is afforded with ethylacetate-hexane (1: 1).0.335g gray crystals, mp180-186 DEG C are obtained with re-crystallizing in ethyl acetate.Embodiment 2N- [5- [(9,10- dihydro -4H- thienos [2,3-c] [1] benzazepines -9- bases) carbonyl] -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
As described in Example 1, in the presence of triethylamine, 9 are made; 10- dihydro -4H- thienos [2; 3-c] [1] benzazepines dichloromethane solution and 6- [(5- fluoro-2-methylbenzenes formoxyl) amino] pyridine -3- acyl chloride reactions, obtain product, be noncrystal yellow solid.Embodiment 3N- [5- [(4,10- dihydro -5H- thienos [3,2-c] [1] benzazepines -5- bases carbonyl) -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
As described in Example 1; make the dichloromethane solution and 6- [(5- fluoro-2-methylbenzenes formoxyl) amino] pyridine -3- acyl chloride reactions of 4,10- dihydro -5H- thienos [3,2-c] [1] benzazepines and triethylamine; product is obtained, is solid.Embodiment 4N- [5- pyridos [2,3-b] [Isosorbide-5-Nitrae] Benzoxazepine -5 (6H)-base carbonyl) -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
As described in Example 1; in the presence of triethylamine; make 5; 6- dihydro pyridos [2; 3-b] [Isosorbide-5-Nitrae] Benzoxazepine dichloromethane solution and 6- [(5- fluoro-2-methylbenzenes formoxyl) amino] pyridine -3- acyl chloride reactions, obtain product; for white crystal, mp187-189 DEG C.Embodiment 5N- [5- pyridos [2,3-b] [1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
As described in Example 1, in the presence of triethylamine, 5 are made; the dichloromethane solution of 6- dihydros [2,3-b] [1,5] Benzoxazepine reacts with 6- [(5- fluoro-2-methylbenzenes formoxyl) amino] dichloromethane; product is obtained, is Amorphous solids.Embodiment 6N- [5- [(6,11- dihydro -5H- dibenzo [b, e] azepines -5- bases) carbonyl] -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
As described in Example 1, in the presence of triethylamine, make the dichloromethane solution and 6- [(5- fluoro-2-methylbenzenes formoxyl) amino] pyridine -3- acyl chloride reactions of 6,11- dihydro -5H- dibenzo [b, e] azepines, obtain product, be solid.Embodiment 7N- [5- [4,5- dihydro -2- methylpyrazoles simultaneously [4,3-d] [1] benzazepines -6 (2H)-yl] carbonyl -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
As described in Example 1, in the presence of triethylamine, 2 are made; 4,5,6- tetrahydrochysene -2- methylpyrazoles simultaneously [4; 3-d] pyridine -3- acyl chloride reactions obtain product, are solid with 6- [(5- fluoro-2-methylbenzenes formoxyl) amino] for the dichloromethane solution of [1] benzazepines.Embodiment 8N- [5- [(6,7- dihydro -5H- dibenzo [b, d] azepines -5- bases) carbonyl -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
As described in Example 1, in the presence of triethylamine, making the dichloromethane solution of 6,7- dihydro -5H- dibenzo [b, d] azepines, pyridine -3- acyl chloride reactions obtain product, are solid with 6- [(5- fluoro-2-methylbenzenes formoxyl) amino].Embodiment 9N- [5- [(4,5- dihydro -6H- thienos [3,2-d] [1] benzazepines -6- bases) carbonyl -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
As described in Example 1; in the presence of triethylamine, make 4,5- dihydro -6H- thienos [3; 2-d] pyridine -3- acyl chloride reactions obtain product, are solid with 6- [(5- fluoro-2-methylbenzenes formoxyl) amino] for the dichloromethane solution of [1] benzazepines.Embodiment 10N- [5- [(5,10- dihydro -4H- thienos [3,2-c] [2] benzazepines -4- bases) carbonyl -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
As described in Example 1; in the presence of triethylamine, make 5,10- dihydro -4H- thienos [3; 2-c] pyridine -3- acyl chloride reactions obtain product, are solid with 6- [(5- fluoro-2-methylbenzenes formoxyl) amino] for the dichloromethane solution of [2] benzazepines.Embodiment 11N- [5- [(4,5- dihydro-pyrazolos [4,3-d] [1] benzazepines -6 (1H)-yl) carbonyl] -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
To 0.20mol 1; 4; 5; 6- tetrahydro-pyrazoles simultaneously [4; 3-d] [1] benzazepines; the 15ml dichloromethane solutions of 0.42mol 6- [(5- fluoro-2-methylbenzenes formoxyl) amino] pyridine -3- acyl chlorides are added in the solution of 0.80mol triethylamines, mixture 16 hours is stirred in argon gas atmosphere and is diluted with dichloromethane (25ml).With water, 1M sodium acid carbonates, salt water washing mixture and drying (sodium sulphate).Solvent is removed, the residue being dissolved in methanol-tetrahydrofuran (1: 1) and 1N sodium hydroxides are stirred 5 hours, with acetic acid and mixture and removing solvent.Water is added into residue and ethyl acetate extraction mixture is used.With water, 1N hydrochloric acid, 1M sodium hydroxides washing extract and drying (sodium sulphate).Solvent is removed in vacuum and by silica gel chromatography residue, using ethylacetate-hexane as solvent, obtains product, be solid.Embodiment 12N- [5- [(6,11- dihydro -5H- dibenzo [b, e] azepines -5- bases) carbonyl] -2- pyridine radicals] [1,1 '-xenyl] -2- formamides
To the 0.293g 6 of cooling (0 DEG C), 11- dihydro -5H- dibenzo [b, e] azepines and 625ml triethylamines 3.5ml dichloromethane solutions in add 0.657g 6- [([1,1 '-xenyl] -2- bases carbonyl) amino] and -3- pyridine acyl chlorides 1.5ml dichloromethane solutions, mixture 16 hours is stirred at room temperature in argon gas atmosphere and is diluted with 40ml dichloromethane and 20ml water.Separate organic layer and use 20ml 1M sodium acid carbonates, salt water washing and drying (sodium sulphate) respectively.By hydrous magnesium silicate thin plate filtering solution and filtrate is concentrated in vacuo to dry.By silica gel chromatography residue, glassy mass is obtained using ethylacetate-hexane (1: 1) as solvent.0.395g white crystals, mp134-142 DEG C are obtained with re-crystallizing in ethyl acetate.Embodiment 13N- [5- [(4,5- dihydro -2- methylpyrazoles simultaneously [4,3-d] [1] benzazepines -6 (2H)-yl) carbonyl] -2- pyridine radicals] [1,1 '-xenyl] -2- formamides
As described in Example 12, make 2,4,5,6- tetrahydrochysene -2- methylpyrazoles simultaneously [4,3-d] [1] benzazepines -3- pyridine acyl chloride reactions obtain product, are solid with 6- [([1,1 '-xenyl] -2- bases carbonyl) amino].Embodiment 14N- [5- [(6,7- dihydro -5H- dibenzo [b, d] azepines -5- bases) carbonyl -2- pyridine radicals] [1,1 '-xenyl] -2- formamides
As described in Example 12, making 6,7- dihydro -5H- dibenzo [b, d] azepines, -3- pyridine acyl chloride reactions obtain product, are solid with 6- [([1,1 '-xenyl] -2- bases carbonyl) amino].Embodiment 15N- [5- [(4,5- dihydro -6H- thienos [3,2-d] [1] benzazepines -6- bases) carbonyl -2- pyridine radicals] [1,1 '-xenyl] -2- formamides
As described in Example 12, making 4,5- dihydro -6H- thienos [3,2-d] [1] benzazepines, -3- pyridine acyl chloride reactions obtain product, are solid with 6- [([1,1 '-xenyl] -2- bases carbonyl) amino].Embodiment 16N- [5- [(5,10- dihydro -4H- thienos [3,2-c] [2] benzazepines -4- bases) carbonyl -2- pyridine radicals] [1,1 '-xenyl] -2- formamides
As described in Example 12, making 5,10- dihydro -4H- thienos [3,2-c] [2] benzazepines, -3- pyridine acyl chloride reactions obtain product, are solid with 6- [([1,1 '-xenyl] -2- bases carbonyl) amino].Embodiment 17N- [5- [(9,10- dihydro -4H- thienos [2,3-c] [1] benzazepines -9- bases) carbonyl] -2- pyridine radicals] [1,1 '-xenyl] -2- formamides
As described in Example 12, making 9,10- dihydro -4H- thienos [2,3-c] [1] benzazepines, -3- pyridine acyl chloride reactions obtain product, are solid with 6- [([1,1 '-xenyl] -2- bases carbonyl) amino].Embodiment 18N- [5- [(4,10- dihydro -5H- thienos [3,2-c] [1] benzazepines -5- bases carbonyl) -2- pyridine radicals] [1,1 '-xenyl] -2- formamides
As described in Example 12, making 4,10- dihydro -5H- thienos [3,2-c] [1] benzazepines, -3- pyridine acyl chloride reactions obtain product, are solid with 6- [([1,1 '-xenyl] -2- bases carbonyl) amino].Embodiment 19N- [5- [(4,5- dihydro-pyrazolos [4,3-d] [1] benzazepines -6 (1H)-yl) carbonyl] -2- pyridine radicals] [1,1 '-xenyl] -2- formamides
As described in Example 12, making 4,5- dihydro-pyrazolos [4,3-d] [1] benzazepines, -3- pyridine acyl chloride reactions obtain product, are solid with 6- [([1,1 '-xenyl] -2- bases carbonyl) amino].Embodiment 20N- [5- [(6,11- dihydro -5H- pyridos [2,3-b] [1,5] benzodiazepine  -6- bases) carbonyl] -2- pyridine radicals] -2- methylfuran -3- formamides
To the 0.296g 6 of cooling (0 DEG C), 11- dihydro -5H- pyridos [2,3-b] [1,5] the 4ml dichloromethane solutions of 6- [(2- methyl-3-furyls carbonyl) amino] -3- pyridine acyl chlorides are added in the 3ml dichloromethane solutions of benzodiazepine  and 624ml triethylamines, mixture 16 hours is stirred at room temperature and and solvent is removed in vacuum.1M sodium acid carbonates are added into residue and ethyl acetate extraction mixture is used.With water, 1M sodium acid carbonates, salt water washing extract and drying (sodium sulphate).Solvent is removed in vacuum, by silica gel chromatography residue, obtains product using ethylacetate-hexane (1: 1) as solvent, is solid.Embodiment 21N- [5- [5 (6H)-phenanthridinyls) carbonyl] -2- pyridine radicals] -2- methylfuran -3- formamides
As described in Example 20, making 5,6- dihydros-phenanthridines, -3- pyridine acyl chloride reactions obtain product, are solid with 6- [(2- methyl-3-furyls carbonyl) amino].Embodiment 22N- [5- [(5,11- dihydro -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- methylfuran -3- formamides
As described in Example 20, making 5,11- dihydro -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza , -3- pyridine acyl chloride reactions obtain product, are solid with 6- [(2- methyl-3-furyls carbonyl) amino].Embodiment 23N- [5- [(5,11- dihydro -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza  -10- bases) carbonyl] -2- pyridine radicals] [1,1 '-xenyl] -2- formamides
As described in Example 12, making 5,11- dihydro -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza , -3- pyridine acyl chloride reactions obtain product, are solid with 6- [([1,1 '-xenyl] -2- bases carbonyl) amino].Embodiment 245- (4- (4- butoxy) benzoyl -6,11- dihydro -5H- dibenzo [b, e] azepines
To 6,11- dihydro -5H- dibenzo [b, e] azepines (0.12g, triethylamine (0.12g is added in dichloromethane (2ml) solution 0.6mmol), 1.2mmol), it is subsequently added into 4- butyl phenyl ethers formyl chloride (0.15g, 0.72mmol), reactant mixture is stirred at room temperature 2 hours, then uses 4ml1N naoh treatments.Extract is washed with ethyl acetate (10ml) extraction mixture, and with 1N sodium hydroxides and salt solution (5ml), with anhydrous sodium sulfate drying, is filtered by hydrous magnesium silicate.Filtrate is evaporated, developing crude product with isooctane obtains 0.24g white solids；Mass spectrum (CI), 372 (MH+).Embodiment 2510- ([1,1 '-xenyl] -4- bases carbonyl) -5,11- dihydro -10H- dibenzo-[b, e] [Isosorbide-5-Nitrae] diaza 
To the 0.5g 5 of cooling (0 DEG C), 11- dihydro -10H- dibenzo-[b, e] [1,4] it is added dropwise to 0.67g [1 in diaza  50ml dichloromethane and the solution of 12ml diisopropylethylamine, 1 '-xenyl] -4- acyl chlorides 50ml dichloromethane solutions, mixture is stirred at room temperature 16 hours, add remaining 0.3g [1,1 '-xenyl] -4- acyl chlorides 30ml dichloromethane solutions and mixture is stirred at room temperature 16 hours, volatile matter is removed in vacuum and dissolves the residue in 150ml chloroforms.With 50ml water washing solution, dry (sodium sulphate) and remove solvent.By silica gel chromatography residue, 0.86g solids, mp152-154 DEG C are obtained using ethylacetate-hexane (1: 5) and ethylacetate-hexane (1: 3) as solvent；Mass spectrum (CI), 377 (MH+).Embodiment 2610- ([1,1 '-xenyl] -4- bases carbonyl) -10,11- dihydro-dibenzo-[b, f] [Isosorbide-5-Nitrae] oxazepin
To the 1.0g10 of cooling (0 DEG C) under argon gas atmosphere, 11- dihydro-dibenzo-[b, f] [1,4] it is added dropwise to 2.0g [1 in the 30ml dichloromethane solutions of oxazepin and 7ml triethylamines, 1 '-xenyl] -4- acyl chlorides, mixture 16 hours is stirred at room temperature and is diluted with 50ml chloroforms.30ml water, 2N hydrochloric acid, water, saturated sodium bicarbonate, water washing mixture and drying (sodium sulphate) are used respectively.Solvent is removed in vacuum and obtains 1.6g yellow solids, mp93-95 DEG C；Mass spectrum (CI), 378 (MH+).Embodiment 279- ([1,1 '-xenyl] -4- bases carbonyl) -9,10- dihydro -4H- thienos [2,3-c] [1] benzazepines
As described in Example 26,9,10- dihydro -4H- thienos [2,3-c] [1] benzazepines is obtained product with [1,1 '-xenyl] -4- acyl chloride reactions, be yellow solid；Mass spectrum (CI) 381 (MT).Embodiment 285- ([1,1 '-xenyl] -4- bases carbonyl) -6,7- dihydro -5H- dibenzo [b, d] azepines
As described in Example 26,6,7- dihydro -5H- dibenzo [b, d] azepines is obtained product with [1,1 '-xenyl] -4- acyl chloride reactions, be solid.Embodiment 296- ([1,1 '-xenyl] -4- bases carbonyl) -5,11- dihydro -6H- pyridos [2,3-e] [1] benzazepines
As described in Example 26,5,11- dihydro -6H- pyridos [2,3-e] [1] benzazepines is obtained product with [1,1 '-xenyl] -4- acyl chloride reactions, be solid.Embodiment 305- ([1,1 '-xenyl] -4- bases carbonyl) -5,6- dihydro pyridos [2,3-b] [Isosorbide-5-Nitrae] Benzothiazepine
As described in Example 26,5,6- dihydro pyridos [2,3-b] [Isosorbide-5-Nitrae] Benzothiazepine is obtained product with [1,1 '-xenyl] -4- acyl chloride reactions, be solid.Embodiment 3110- ([1,1 '-xenyl] -4- bases carbonyl) -10,11- dihydros [b, f] [Isosorbide-5-Nitrae] thia azepines
As described in Example 26,10,11- dihydros [b, f] [Isosorbide-5-Nitrae] thia azepines is obtained product with [1,1 '-xenyl] -4- acyl chloride reactions, be solid.Embodiment 3210- (4- benzoylbenzoyls) -10,11- dihydro-dibenzos [b, f] [Isosorbide-5-Nitrae] oxazepin
As described in Example 26,10,11- dihydro-dibenzos [b, f] [Isosorbide-5-Nitrae] oxazepin is reacted with 4- (benzoyl) chlorobenzoyl chloride and obtain product, be grey, mp103-106 DEG C；Mass spectrum (CI), 406 (MH+).Embodiment 335- (4- benzoylbenzoyls) 5,6,11,12- tetrahydrochysene dibenzo [b, f] azocine
As described in Example 26,5,6,11,12- tetrahydrochysene dibenzo [b, f] azocines is reacted with 4- (benzoyl) chlorobenzoyl chloride and obtain product, be solid, mp89-92 DEG C；Mass spectrum (CI), 418 (MH+).Embodiment 3410- [4- (benzoylbenzoyl)] -10,11- dihydros [b, f] [Isosorbide-5-Nitrae] thia azepines
As described in Example 26,10,11- dihydros [b, f] [1, H] thia azepines is reacted with 4- (benzoyl) chlorobenzoyl chloride and obtain product, be solid.Embodiment 355- [4- (benzoylbenzoyl)] -5,6- dihydro pyridos [2,3-b] [Isosorbide-5-Nitrae] Benzothiazepine
As described in Example 26,5,6- dihydro pyridos [2,3-b] [Isosorbide-5-Nitrae] Benzothiazepine is reacted with 4- (benzoyl) chlorobenzoyl chloride and obtain product, be solid.Embodiment 366- [(4- benzoylbenzoyls)] 5,11- dihydro -6H- pyridos [2,3-e] [1] benzazepines
As described in Example 26,5,11- dihydro -6H- pyridos [2,3-e] [1] benzazepines is reacted with 4- (benzoyl) chlorobenzoyl chloride and obtain product, be solid.Embodiment 375- [4- (benzoylbenzoyl)] -6,7- dihydro -5H- dibenzo [b, d] azepines
As described in Example 26,6,7- dihydro -5H- dibenzo [b, d] azepines is reacted with 4- (benzoyl) chlorobenzoyl chloride and obtain product, be solid.Embodiment 389- [(4- benzoylbenzoyls)] -9,10- dihydro -4H- thienos [2,3-c] [1] benzazepines
As described in Example 26,9,10- dihydro -4H- thienos [2,3-c] [1] benzazepines is reacted with 4- (benzoyl) chlorobenzoyl chloride and obtain product, be solid.Embodiment 395- [4- (benzoylbenzoyl)] -4,10- dihydro -5H- thienos [3,2-c] [1] benzazepines
As described in Example 26,4,10- dihydro -5H- thienos [3,2-c] [1] benzazepines is reacted with 4- (benzoyl) chlorobenzoyl chloride and obtain product, be solid.Embodiment 405- ([1,1 '-xenyl] -4- bases carbonyl) -4,10- dihydro -5H- thienos [3,2-c] [1] benzazepines
As described in Example 26,4,10- dihydro -5H- thienos [3,2-c] [1] benzazepines is obtained product with [1,1 '-xenyl] -4- base acyl chloride reactions, be solid.Embodiment 416- ([1,1 '-xenyl] -4- bases carbonyl)-Isosorbide-5-Nitrae, 5,6- tetrahydro-pyrazoles simultaneously [4,3-d] [1] benzazepines
As described in Example 26, make 2mmol 1,4,5,6- tetrahydro-pyrazoles simultaneously [4,3-d] [1] benzazepines and 5mmol [1,1 '-xenyl] -4- base acyl chloride reactions, product in methyl alcohol stirred 16 hours together with 2N sodium hydroxides and concentrated reaction mixture and extracted with ethyl acetate.Use 1M citric acids, sodium acid carbonate, water washing extract dries (sodium sulphate) and removes solvent and obtains embodiment product, is solid.Embodiment 42N- [4- [(5,6- dihydro-pyrazolos [4,3-d] [1] benzazepines -6 (1H)-yl) carbonyl] -3- chlorphenyls] [1,1 '-xenyl] -2- formamides
As described in Example 11,6- (the chloro- 4- amino benzoyls of 2-)-Isosorbide-5-Nitrae is made, simultaneously [4,3-d] [1] benzazepines obtains product to 5,6- tetrahydro-pyrazoles with [1,1 '-xenyl] -4- acyl chloride reactions, is solid.Embodiment 43N- [4- [(5,6- dihydro-pyrazolos [4,3-d] [1] benzazepines -6 (1H)-yl) carbonyl] -3- chlorphenyls] -2- (dimethylamino) pyridine-3-carboxamide
As described in Example 11,6- (the chloro- 4- amino benzoyls of 2-)-Isosorbide-5-Nitrae is made, simultaneously [4,3-d] [1] benzazepines obtains product to 5,6- tetrahydro-pyrazoles with 2- (dimethylamino) pyridine -3- acyl chloride reactions, is solid.Embodiment 44N- [4- [(5,6- dihydro-pyrazolos [4,3-d] [1] benzazepines -6 (1H)-yl) carbonyl] phenyl] -2- (dimethylamino)-pyridine-3-carboxamide
As described in Example 11,6- (4- amino benzoyls)-Isosorbide-5-Nitrae is made, simultaneously [4,3-d] [1] benzazepines obtains product to 5,6- tetrahydro-pyrazoles with 2- (dimethylamino) pyridine -3- acyl chloride reactions, is solid.Embodiment 45N- [5- [5,6,11,12- tetrahydrochysene dibenzo [b, f] azocine -5- bases) carbonyl] -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
0.246g 5 under cooling (0 DEG C) and stirring; 6; 11; 12- tetrahydrochysene dibenzo [b; f] azocine, 0.586g 6- are added in the 5ml dichloromethane solutions of 695ml triethylamines, and [(5- fluoro-2-methylbenzenes formoxyl) aminopyridine -3- acyl chlorides, stirs mixture 16 hours in argon gas atmosphere; diluted with 50ml dichloromethane and 20ml water, and separate organic layer.20ml sodium acid carbonates are used respectively, and salt water washing organic layer is dried (sodium sulphate).Make solution by hydrous magnesium silicate thin plate and be concentrated in vacuo filtrate to doing, residue (450mg) prepares plate chromatography purifying by silica gel and obtains solid.0.20g white crystals, mp198-200 DEG C are obtained with re-crystallizing in ethyl acetate.Embodiment 46N- [4- (dibenzo [b, f] [Isosorbide-5-Nitrae] oxazepin -10 (11H)-base carbonyl)-phenyl] [1,1 '-xenyl] -2- formamides
To 0.197g 10,11 dihydro-dibenzo [b, f] [1,4] oxazepin and 0.402g 4- [([1,1 '-xenyl] -2- carbonyls) amino] and chlorobenzoyl chloride 5ml dichloromethane solutions (on ice bath cool down) in be added dropwise to 0.154g N, the 2ml dichloromethane solutions of N- diisopropylethylamine, mixture is stirred at room temperature in argon gas atmosphere 2 hours, mixture is poured into water and organic layer is separated, use 2N sodium carbonate, water, salt water washing organic extract and drying (sodium sulphate).By hydrous magnesium silicate thin plate filtering solution and filter cake is washed with dichloromethane, the filtrate was concentrated to dryness obtains 0.65g solids.By thick silica gel thin-layer chromatography pure solid, 0.110g glassy mass, mp107-122 DEG C are obtained using hexane-ethylacetate (2: 1) as solvent.Elementary analysis.Measured value：C, 80.8；H, 4.9；N, 6.0.Embodiment 47N- [4- (dibenzo [b, f] [Isosorbide-5-Nitrae] oxazepin -10 (11H)-base carbonyl) -- 3- chlorphenyls] [1,1 '-xenyl] -2- formamides
0.263g 10,11- dihydros -10 (4- amino -2- chlorobenzene formacyls) dibenzo [b, f] [1 is stirred at room temperature; 4] oxazepin; the 7ml dichloromethane solutions of 0.195g [1,1 '-xenyl] -2- acyl chlorides and 0.116g DIPEAs 3 hours.The mixture of gained is poured into water and extracted with dichloromethane, 2N sodium carbonate, water, salt water washing extract and drying (sodium sulphate) is used.Pass through hydrous magnesium silicate thin plate filtering solution (washing thin plate with dichloromethane), the filtrate was concentrated to dryness obtains yellow solid, pass through thick silica gel plate chromatogram purification solid, 0.12g yellow glassy things, mp145-188 DEG C of elementary analysis are obtained using hexane-ethylacetate (1: 1) as solvent.Measured value：C, 73.6；H, 4.6；Cl, 6.4.Embodiment 48N- [5- (dibenzo [b, f] [Isosorbide-5-Nitrae] oxazepin -10 (11H)-base carbonyl) -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
As described in embodiment 46, in the presence of triethylamine, make 10; the dichloromethane solution of 11- dihydro-dibenzos [b, f] [Isosorbide-5-Nitrae] oxazepin obtains product with 2- [(2- methyl -5- fluoro benzoyls) amino] -5- pyridine radicals acyl chloride reactions; for crystal, mp180-186 DEG C.
As described in embodiment 46, following compounds can be prepared：Embodiment 49N- [4- (dibenzo [b, f] [1, 4] oxazepin -10 (11H)-base carbonyl) phenyl] -2- (2- pyridine radicals) benzamide embodiment 50N- [4- (dibenzo [b, f] [1, 4] oxazepin -10 (11H)-base carbonyl) phenyl] -2- (3- pyridine radicals) benzamide embodiment 51N- [4- (dibenzo [b, f] [1, 4] oxazepin -10 (11H)-base carbonyl) phenyl] -2- (4- pyridine radicals) benzamide embodiment 52N- [4- (dibenzo [b, f] [1, 4] oxazepin -10 (11H)-base carbonyl) the chloro- phenyl of -3-] -2- (2- thienyls) benzamide embodiment 53N- [4- (dibenzo [b, f] [1, 4] oxazepin -10 (11H)-base carbonyl) the chloro- phenyl of -3-] -2- (3- thienyls) benzamide
Following compounds can be prepared as described in embodiment 48：Embodiment 54N- [5- (dibenzo [b,f][1,4] oxazepin -10 (11H)-base carbonyl) -2- pyridine radicals] the chloro- 5- fluorobenzamides embodiment 55N- of -2- [5- (dibenzo [b,f][1,4] oxazepin -10 (11H)-base carbonyl) -2- pyridine radicals] -2- methyl -3- fluorobenzamide embodiments 56N- [5- (dibenzo [b,f][1,4] oxazepin -10 (11H)-base carbonyl) -2- pyridine radicals] -2- methyl benzamide embodiments 57N- [5- (dibenzo [b,f][1,4] oxazepin -10 (11H)-base carbonyl) -2- pyridine radicals] -2- chloro-3-pyridyl base formamide embodiment 58N- [5- (dibenzo [b,f][[1,4] oxazepin -10 (11H)-base carbonyl) -2- pyridine radicals] -2-Hydroxylbenzamide embodiment 59N- [5- (dibenzo [b,f][1,4] oxazepin -10 (11H)-base carbonyl) -2- pyridine radicals] -2- (dimethylamino) benzamide embodiment 60N- [5- (dibenzo [b,f][1,4] oxazepin -10 (11H)-base carbonyl) -2- pyridine radicals] -2- (dimethylamino) -3- pyridinyl carboxamide embodiments 61N- [5- (dibenzo [b,f][1,4] oxazepin -10 (11H)-base carbonyl) -2- pyridine radicals] the fluoro- 5- chlorobenzamides embodiment 62N- of -2- [5- (dibenzo [b,f][1,4] oxazepin -10 (11H)-base carbonyl) -2- pyridine radicals] [1,1- xenyls] -2- formamide embodiments 63N- [5- (dibenzo [b,f][1,4] oxazepin -10 (11H)-base carbonyl) -2- pyridine radicals] -2- (3- pyridine radicals) benzamide embodiment 64N- [5- (dibenzo [b,f][1,4] oxazepin -10 (11H)-base carbonyl) -2- pyridine radicals] -2- (2- pyridine radicals) benzamide embodiment 65N- [5- (dibenzo [b,f][1,4] oxazepin -10 (11H)-base carbonyl) -2- pyridine radicals] -2- (4- pyridine radicals) benzamide embodiment 66N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] [1,1 '-xenyl] -2- formamides
0.198g 5 is stirred at room temperature, 6- dihydro pyridos [2,3-b] [1,5] Benzoxazepine, 0.155gN, N- diisopropylethylamine and 0.404g 6- [([1,1 '-xenyl] -2- carbonyls) amino] mixture of pyridine -3- acyl chlorides in 12ml dichloromethane 3.5 hours, mixture is poured into water and extracted with dichloromethane.Use 2N sodium carbonate, water, salt water washing extract and drying (sodium sulphate).Make solution by hydrous magnesium silicate thin plate and the filtrate was concentrated to dryness, solid is dissolved in hexane-ethylacetate (1: 2) and by containing silicic acid magnesium sheet filtering solution, thin plate is washed with hexane-ethylacetate (1: 2) and the filtrate was concentrated to dryness obtains glassy mass, mp107-114 DEG C, elementary analysis：Measured value：C, 74.4；H, 5.7；N, 8.8.Embodiment 67N- [4- (pyrido [2,3-b] [1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- chlorphenyls] [1,1 '-xenyl] -2- formamides
0.198g 5 is stirred at room temperature, 6- dihydro pyridos [2,3-b] [1,5] Benzoxazepine, 0.155gN, N- diisopropylethylamine and 0.444g 4- [([1,1 '-xenyl] -2- carbonyls) amino] mixture of -2- chlorobenzoyl chlorides in 12ml dichloromethane 2.5 hours, mixture is poured into water and extracted with dichloromethane.Use 2N sodium carbonate, water, salt water washing extract and drying (sodium sulphate).Make solution by hydrous magnesium silicate thin plate, thin plate is washed with 50ml hexane-ethylacetates (1: 2) and the filtrate was concentrated to dryness, developing residue with ether obtains solid, mp205-217 DEG C.Elementary analysis：Measured value：C, 72.3；H, 4.2；N, 7.9；Cl, 6.7.
Following compounds can be prepared as described in embodiment 66：Embodiment 68N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- pyridine radicals] [1,1 '-xenyl] -2- formamide embodiments 69N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2- chlorobenzamide embodiments 70N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2- chloro- 5- fluorobenzoyls aniline. Example 71N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2-Hydroxylbenzamide embodiment 72N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2,5- difluorobenzamide embodiments 73N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2- methyl benzamide embodiments 74N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (dimethylamino) benzamide embodiment 75N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (methylamino) benzamide embodiment 76N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (amino methyl) benzamide embodiment 77N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2- methoxy benzamide embodiments 78N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2- chloro- 5- fluorobenzamides embodiment 79N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2- methyl -3- fluorobenzamide embodiments 80N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2- fluoro- 6- chlorobenzamides embodiment 81N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2,6 dichloro-benzamide embodiment 82N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2,5- dimethyl benzamide embodiments 83N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2- chloro-3-pyridyl base formamide embodiment 84N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (methylamino) -3- pyridinyl carboxamide embodiments 85N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (dimethylamino) -3- pyridinyl carboxamide embodiments 86N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (amino methyl) -4- pyridinyl carboxamide embodiments 87N- [5- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (dimethylamino) -4- pyridinyl carboxamides
Following compounds can be prepared as described in embodiment 67：Embodiment 88N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) the chloro- 6- aminomethyl phenyls of -3-] [1,1 '-xenyl] -2- formamide embodiments 89N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3,6- 3,5-dimethylphenyls] [1,1 '-xenyl] -2- formamide embodiments 90N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- aminomethyl phenyls] [1,1 '-xenyl] -2- formamide embodiments 91N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- chlorphenyls] [1,1 '-xenyl] -2- formamide embodiments 92N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) the chloro- 6- aminomethyl phenyls of -3-] -2- (2- thienyls) benzamide embodiment 93N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3,6- 3,5-dimethylphenyls] -2- (3- thienyls) benzamide embodiment 94N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- aminomethyl phenyls] -2- (2- thienyls) benzamide embodiment 95N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- chlorphenyls] -2- (2- thienyls) benzamide embodiment 96N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- chlorphenyls] -2- (3- thienyls) benzamide embodiment 97N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- chlorphenyls] -2- (2- furyls) benzamide embodiment 98N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- chlorphenyls] -2- (2- pyridine radicals) benzamide embodiment 99N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- chlorphenyls] -2- (3- pyridine radicals) benzamide embodiment 100N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- chlorphenyls] -2- (4- pyridine radicals) benzamide embodiment 101N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- chlorphenyls] -2- (3- furyls) benzamide embodiment 102N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- aminomethyl phenyls] [1,1 '-xenyl] -2- formamide embodiments 103N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- aminomethyl phenyls] -2- (3- thienyls) benzamide embodiment 104N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- aminomethyl phenyls] -2- (2- pyridine radicals) benzamide embodiment 105N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- aminomethyl phenyls] -2- (3- pyridine radicals) benzamide embodiment 106N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- aminomethyl phenyls] -2- (4- pyridine radicals) benzamide embodiment 107N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- aminomethyl phenyls] -2- (2- furyls) benzamide embodiment 108N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3,6- 3,5-dimethylphenyls] -2- (2- thienyls) benzamide
Following compounds can be prepared as described in embodiment 67：Embodiment 109N- [4- (pyridos [2,3-b ][1,5] Benzoxazepine -6 (5H)-base carbonyl) the fluoro- 6- aminomethyl phenyls of -3-] [1,1 '-xenyl] -2- formamide embodiments 110N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3,6- dichlorophenyls] [1,1 '-xenyl] -2- formamide embodiments 111N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- fluorophenyls] [1,1 '-xenyl] -2- formamide embodiments 112N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl)-phenyl] [1,1 '-xenyl] -2- formamide embodiments 113N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl)-phenyl] -2- (2- thienyls) benzamide embodiment 114N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl)-phenyl] -2- (3- thienyls) benzamide embodiment 115N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl)-phenyl] -2- (2- thienyls) benzamide embodiment 116N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- fluorophenyls] -2- (2- thienyls) benzamide embodiment 117N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl)-phenyl] -2- (3- thienyls) benzamide embodiment 118N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl)-phenyl] -2- (2- furyls) benzamide embodiment 119N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl)-phenyl] -2- (2- pyridine radicals) benzamide embodiment 120N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl)-phenyl] -2- (3- pyridine radicals) benzamide embodiment 121N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl)-phenyl] -2- (4- pyridine radicals) benzamide embodiment 122N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- fluorophenyls] -2- (3- furyls) benzamide embodiment 123N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- methyl -6- fluorophenyls] [1,1 '-xenyl] -2- formamide embodiments 124N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- aminomethyl phenyls] -2- (2- furyls) benzamide embodiment 125N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- aminomethyl phenyls] -2- (3- furyls) benzamide embodiment 126N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3,6- 3,5-dimethylphenyls] -2- (3- pyridine radicals) benzamide embodiment 127N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3,6- dichlorophenyls] -2- (4- pyridine radicals) benzamide embodiment 128N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl)-phenyl] -2- (3- furyls) benzamide embodiment 129N- [4- (pyridos [2,3-b][1,5] Benzoxazepine -6 (5H)-base carbonyl) -3- fluorophenyls] -2- (2- thienyls) benzamide embodiment 130N- [5- (pyridos [2,3-b][1,4] Benzoxazepine -5 (6H)-base carbonyl) -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
As described in embodiment 46; in N; in the presence of N- diisopropylethylamine (3mmol); make 5; 6- dihydro pyridos [2; 3-b] the dichloromethane solution reaction of [Isosorbide-5-Nitrae] Benzoxazepine (1mmol) and 2- [(2- methyl -5- fluoro benzoyls) amino] -5- pyridine radicals acyl chlorides (1.0mmol) obtains product, is glassy mass.Embodiment 131N- [5- (pyrido [2,3-b] [Isosorbide-5-Nitrae] Benzoxazepine -5 (6H)-base carbonyl) -2- pyridine radicals] [1,1 '-xenyl] -2- formamides
As described in embodiment 66, in N, in the presence of N- diisopropylethylamine (0.155g), make 5,6- dihydro pyridos [2,3-b] [Isosorbide-5-Nitrae] Benzoxazepine (0.198g) and 6- [([1,1 '-xenyl] -2- carbonyls) amino] and pyridine -3- acyl chlorides (0.404g) dichloromethane solution reaction obtain product, be solid.Embodiment 132N- [4- (pyrido [2,3-b] [Isosorbide-5-Nitrae] Benzoxazepine -5 (6H)-base carbonyl) -3- chlorphenyls] [1,1 '-xenyl] -2- formamides
As described in embodiment 66, in N, in the presence of N- diisopropylethylamine, make 0.198g 5,6- dihydro pyridos [2,3-b] [Isosorbide-5-Nitrae] Benzoxazepine and 4- [([1,1 '-xenyl] -2- carbonyls) amino] and -2- chlorobenzoyl chlorides dichloromethane solution reaction obtain product, be solid.Embodiment 133N- [4- (6,11- dihydro pyridos [2,3-b] [1,5] benzodiazepine  -6 (5H)-base carbonyl)-phenyl] [1,1 '-xenyl] -2- formamides
To 10.55g 6,11- dihydro pyridos [2,3-b] [1,5] in mixture of benzodiazepine  -5 (6H) -one in 40ml tetrahydrofurans, the tetrahydrofuran solution of 15ml 10M borane-dimethylsulfides is added, mixture is stirred at room temperature and is then refluxed within 2 hours (under hydrogen atmosphere) 4 hours.Add remaining 40ml tetrahydrofuran and mixture refluxed overnight.12ml methanol is added into the mixture of cooling and solvent is removed, 30ml 2N sodium hydroxides and under an argon atmosphere reflux solution 2 hours are added into residue.With ethyl acetate extraction mixture and with 2N lemon acid elution mixtures.Water layer is adjusted to alkalescence with 2N sodium hydroxides and extracted with ethyl acetate, with water, salt water washing extract and drying (sodium sulphate).By hydrous magnesium silicate thin bed filtration solution and the filtrate was concentrated to dryness obtains 4.65g brown solids.Product is obtained by silica gel chromatography solid, is solid.4.85g crude products sample is obtained into 2.68g 6 with ether development, 11- dihydro pyridos [2,3-b] [1,5] benzodiazepine , is solid.
0.296g 6 is stirred at room temperature, 11- dihydro pyridos [2,3-b] [1,5] benzodiazepine , 0.604g4- [([1,1 '-xenyl] -2- carbonyls) amino] mixture of chlorobenzoyl chloride and 0.232gN, N- diisopropylethylamine in 6ml dichloromethane 1.5 hours, the mixture of gained is poured into water and extracted with dichloromethane.With water, saturated sodium bicarbonate, salt water washing extract is dried (sodium sulphate).By hydrous magnesium silicate thin plate filtering solution, simultaneously the filtrate was concentrated to dryness.By thick-layer silica gel plate purification residues, product is obtained using hexane-ethylacetate (1: 2) as solvent, is solid, gray crystals, mp220-221 DEG C are obtained with re-crystallizing in ethyl acetate.Embodiment 134N- [4- (6,11- dihydro pyridos [2,3-b] [1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- chlorphenyls] [1,1 '-xenyl] -2- formamides
0.197g 6 is stirred at room temperature, 11- dihydro pyridos [2,3-b] H, 5] benzodiazepine , 0.444g4- [([1,1 '-xenyl] -2- carbonyls) amino] mixture of -2- chlorobenzoyl chlorides and 0.155gN, N- diisopropylethylamine in 8ml dichloromethane 1.5 hours, the mixture of gained is poured into water and extracted with dichloromethane.With water, saturated sodium bicarbonate, salt water washing extract is dried (sodium sulphate).By hydrous magnesium silicate thin plate filtering solution, simultaneously the filtrate was concentrated to dryness.By thick-layer silica gel plate purification residues, 0.160g solids, mp147-165 DEG C are obtained using hexane-ethylacetate (1: 2) as solvent.Assay value：C, 72.1；H, 5.1；N, 9.1；Cl, 6.3.Embodiment 135N- [4- (6,11- dihydro pyridos [2,3-b] [1,5] benzodiazepine  -6 (5H)-base carbonyl)-phenyl] [1,1 '-xenyl] -2- carboxamide hydrochlorides
Lead to hydrogen chloride (gas) into the methanol of the anhydrous coolings of 50ml 15 minutes.25ml methanolic hydrogen chloride samples are added in 0.30g N- [4- (6,11- dihydro pyridos [2,3-b] [1,5] benzodiazepine  -6 (5H)-base carbonyl)-phenyl] [1,1 '-xenyl] -2- formamides.Mixture 0.5 hour is stirred at 0 DEG C and it is warming to room temperature, is removed solvent and is dried in vacuo solid and obtains 0.31g solids, mp195-210 DEG C.
As described in embodiment 134, make 6,11- dihydro pyridos [2,3-b] [1,5] benzodiazepine  with suitable substituted or unsubstituted [(aryl carbonyl) amino] chlorobenzoyl chloride or with suitable substituted or unsubstituted [(aryl carbonyl) amino] pyridine radicals acyl chloride reaction, following compounds can be prepared.Embodiment 136N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- chlorphenyls] -2- (2- thienyls) benzamide embodiment 137N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- chlorphenyls] -2- (3- thienyls) benzamide embodiment 138N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) the chloro- 6- aminomethyl phenyls of -3-] -2- (2- thienyls) benzamide embodiment 139N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl)-phenyl] -2- (2- thienyls) benzamide embodiment 140N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl)-phenyl] -2- (3- thienyls) benzamide embodiment 141N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- aminomethyl phenyls] -2- (2- thienyls) benzamide embodiment 142N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3,6- Dimethvl-phenyls] -2- (2- thienyls) benzamide embodiment 143N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- aminomethyl phenyls] [1,1 '-xenyl] -2- formamide embodiment 144N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3,6- 3,5-dimethylphenyls] [1,1 '-xenyl] -2- formamide embodiment 145N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3,6- dichlorophenyls] [1,1 '-xenyl] -2- formamide embodiment 146N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- methyl -6- chlorphenyls] [1,1 '-xenyl] -2- formamide embodiment 147N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) the chloro- 6- fluorophenyls of -3-] [1,1 '-xenyl] -2- formamide embodiment 148N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- aminomethyl phenyls] [1,1 '-xenyl] -2- formamide embodiment 149N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- chlorphenyls] [1,1 '-xenyl] -2- formamide embodiment 150N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl)-phenyl] -2- (2- pyridine radicals) benzamide embodiment 151N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl)-phenyl] -2- (3- pyridine radicals) benzamide embodiment 152N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl)-phenyl] -2- (4- pyridine radicals) benzamide embodiment 153N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- chlorphenyls] -2- (2- pyridine radicals) benzamide embodiment 154N- [4- (6,1 1- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- chlorphenyls] -2- (3- pyridine radicals) benzamide embodiment 155N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- chlorphenyls] -2- (4- pyridine radicals) benzamide embodiment 156N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- aminomethyl phenyls] -2- (2- pyridine radicals) benzamide embodiment 157N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- aminomethyl phenyls] -2- (3- pyridine radicals) benzamide embodiment 158N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- aminomethyl phenyls] -2- (4- pyridine radicals) benzamide embodiment 159N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- methyl -6- fluorophenyls] -2- (2- thienyls) benzamide embodiment 160N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3,6- 3,5-dimethylphenyls] -2- (2- pyridine radicals) benzamide embodiment 161N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3,6- 3,5-dimethylphenyls] -2- (3- pyridine radicals) benzamide embodiment 162N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3,6- 3,5-dimethylphenyls] -2- (4- pyridine radicals) benzamide embodiment 163N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl)-phenyl] -2- methoxypyridine -3- formamide embodiment 164N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- chlorphenyls] -2- methylsulfanyl pyridine -3- formamide embodiment 165N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- aminomethyl phenyls] -2- picoline -3- formamide embodiment 166N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3,6- 3,5-dimethylphenyls] -2- picoline -3- formamide embodiment 167N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl)-phenyl] -2- picoline -3- formamide embodiment 168N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- chlorphenyls] -2- picoline -3- formamide embodiment 169N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) the chloro- 6- aminomethyl phenyls of -3-] -2- fluorine pyridine-3-carboxamide embodiment 170N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- chlorphenyls] -2- fluorine pyridine-3-carboxamide embodiment 171N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- aminomethyl phenyls] -2- chloropyridine -3- formamide embodiment 172N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3,6- 3,5-dimethylphenyls] -2- chloropyridine -3- formamide embodiment 173N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl)-phenyl] -3- picoline -2- formamide embodiment 174N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- chlorphenyls] -3- picoline -2- formamide embodiment 175N- [4- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- chlorphenyls] -2- chloropyridine -3- formamide embodiment 176N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] [1,1 '-xenyl] -2- formamides
mp278-281℃.Embodiment 177N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (2- thienyls) benzamide embodiment 178N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (3- thienyls) benzamide embodiment 179N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- fluorobenzamide embodiment 180N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (2- pyridine radicals) benzamide embodiment 181N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (3- pyridine radicals) benzamide embodiment 182N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (4- pyridine radicals) benzamide embodiment 183N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (2- furyls) benzamide embodiment 184N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (3- furyls) benzamide embodiment 185N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -3- chloropyridine -2- formamide embodiment 186N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- picoline -3- formamide embodiment 187N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -5- fluoro-2-methylbenzene formamide embodiment 188N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- chlorobenzamide embodiment 189N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] the chloro- 5- fluorobenzamides embodiment 190N- [5- (6 of -2-,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- methyl benzamide embodiment 191N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2,5- dimethyl benzamide embodiment 192N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] the chloro- 4- fluorobenzamides embodiment 193N- [5- (6 of -2-,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] the chloro- 6- fluorobenzamides embodiment 194N- [5- (6 of -2-,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- methyl -3- fluorobenzamide embodiment 195N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2-Hydroxylbenzamide embodiment 196N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- acetoxyl group benzamide embodiment 197N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- aminobenzamide embodiment 198N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (methylamino) benzamide embodiment 199N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (dimethylamino) benzamide embodiment 200N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- aminomethyl benzamide embodiment 201N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (diethylamino) benzamide embodiment 202N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (dimethylaminomethyl) benzamide embodiment 203N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (methyl mercapto) benzamide embodiment 204N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- chloropyridine -3- formamide embodiment 205N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- fluorine pyridine-3-carboxamide embodiment 206N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- methoxypyridine -3- formamide embodiment 207N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- methylsulfanyl pyridine -3- formamide embodiment 208N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals]-PA -3- formamide embodiment 209N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- Methylamino-pyridin -3- formamide embodiment 210N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- (dimethylamino) pyridine-3-carboxamide embodiment 211N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] thiophene-2-carboxamide derivatives embodiment 212N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] thiophene -3- formamide embodiment 213N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] furans -2- formamide embodiment 214N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- methylthiophene -3- formamide embodiment 215N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -3 methyl thiophene -2- formamide embodiment 216N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- chlorothiophene -3- formamide embodiment 217N- [5- (6,11- dihydro pyridos [2,3-b][1,5] benzodiazepine  -6 (5H)-base carbonyl) -2- pyridine radicals] -2- methylthiophene -3- formamide embodiment 218N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- chlorphenyls] [1,1 '-xenyl] -2- formamides
0.196g 5 is stirred at room temperature, 11- dihydro -10H- dibenzo [b, e] [1,4] diaza , 0.155gN, N- diisopropylethylamine and 0.444g 4- [([1,1 '-xenyl] -2- carbonyls) amino] mixture of -2- chlorobenzoyl chlorides in 12ml dichloromethane are stayed overnight, mixture are poured into water and extracted with dichloromethane.2N potassium carbonate is used, water, salt water washing extract is dried (sodium sulphate).By hydrous magnesium silicate thin plate filtering solution, the filtrate was concentrated to dryness and develops residue with ether and removes solvent.Residue, which is developed, with dichloromethane obtains 0.31g solids, mp158-184 DEG C.Elementary analysis：C33H24ClN3O21/2H2O；C, 73.7；H, 4.6；N, 7.5；Cl, 6.9.
As described in embodiment 218, pass through 5,11- dihydro -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza  can prepare following compounds with suitable substituted or unsubstituted [(aryl carbonyl) amino] chlorobenzoyl chloride or suitable substituted or unsubstituted [(aryl carbonyl) amino] pyridine radicals acyl chloride reaction.Embodiment 219N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl]-phenyl] [1,1 '-xenyl] -2- formamide embodiment 220N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- methylphenyls] [1,1 '-xenyl] -2- formamide embodiment 221N- [4- [(5,1 1- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3,6- 3,5-dimethylphenyls] [1,1 '-xenyl] -2- formamide embodiment 222N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- chlorphenyls] -2- (2- thienyls) benzamide embodiment 223N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- chlorphenyls] -2- (3- thienyls) benzamide embodiment 224N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- chlorphenyls] -2- (3- furyls) benzamide embodiment 225N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- chlorphenyls] -2- (2- furyls) benzamide embodiment 226N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- aminomethyl phenyls] -2- (2- thienyls) benzamide embodiment 227N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- aminomethyl phenyls] -2- (3- thienyls) benzamide embodiment 228N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- aminomethyl phenyls] [1,1 '-xenyl] -2- formamide embodiment 229N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3,6- 3,5-dimethylphenyls] [1,1 '-xenyl] -2- formamide embodiment 230N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- methyl -6- chlorphenyls] [1,1 '-xenyl] -2- formamide embodiment 231N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] the chloro- 6- fluorophenyls of -3-] [1,1 '-xenyl] -2- formamide embodiment 232N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- aminomethyl phenyls] [1,1 '-xenyl] -2- formamide embodiment 233N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] the chloro- 6- aminomethyl phenyls of -3-] [1,1 '-xenyl] -2- formamide embodiment 234N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- chlorphenyls] [1,1 '-xenyl] -2- formamide embodiment 235N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl]-phenyl] -2- (2- pyridine radicals) benzamide embodiment 236N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl]-phenyl] -2- (3- pyridine radicals) benzamide embodiment 237N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl]-phenyl] -2- (4- pyridine radicals) benzamide embodiment 238N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- chlorphenyls] -2- (2- pyridine radicals) benzamide embodiment 239N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- chlorphenyls] -2- (3- pyridine radicals) benzamide embodiment 240N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- chlorphenyls] -2- (4- pyridine radicals) benzamide embodiment 241N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- aminomethyl phenyls] -2- (2- pyridine radicals) benzamide embodiment 242N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- aminomethyl phenyls] -2- (3- pyridine radicals) benzamide embodiment 243N- [4- [(5,1 1- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- aminomethyl phenyls] -2- (4- pyridine radicals) benzamide embodiment 244N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3,6- 3,5-dimethylphenyls] -2- (2- pyridine radicals) benzamide embodiment 245N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3,6- 3,5-dimethylphenyls] -2- (3- pyridine radicals) benzamide embodiment 246N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3,6- 3,5-dimethylphenyls] -2- (4- pyridine radicals) benzamide embodiment 247N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] phenyl] -2- (phenyl methyl) benzamide embodiment 248N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] phenyl] -2- (3- Chlorophenylmethyls) benzamide embodiment 249N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- chlorphenyls] -2- (phenyl methyl) benzamide embodiment 250N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- chlorphenyls] -2- methoxypyridine -3- formamide embodiment 251N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- chlorphenyls] -2- (methyl mercapto) pyridine-3-carboxamide embodiment 252N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- aminomethyl phenyls] -2- picoline -3- formamide embodiment 253N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- aminomethyl phenyls] -3- picoline -2- formamide embodiment 254N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- aminomethyl phenyls] -2- chloropyridine -3- formamide embodiment 255N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3,6- 3,5-dimethylphenyls] -2- fluorine pyridine-3-carboxamide embodiment 256N- [4- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -3- methyl -6- chlorphenyls] -2- chloropyridine -3- formamide embodiment 257N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] [1,1 '-xenyl] -2- formamides
Mp280-285 DEG C of embodiment 258N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- (2- thienyls) benzamide embodiment 259N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- (3- thienyls) benzamide embodiment 260N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- (2- furyls) benzamide embodiment 261N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- (2- pyridine radicals) benzamide embodiment 262N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- (3- pyridine radicals) benzamide embodiment 263N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- (4- pyridine radicals) benzamide embodiment 264N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- (2- furyls) benzamide embodiment 265N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- (3- furyls) benzamide embodiment 266N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- methoxypyridine -6- formamide embodiment 267N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] pyridine-3-carboxamide embodiment 268N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- pyridine carboxamide embodiment 269N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- methyl -5- fluorobenzamide embodiment 270N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- chlorobenzamide embodiment 271N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] the chloro- 5- fluorobenzamides embodiment 272N- [5- [(5 of -2-,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- methyl benzamide embodiment 273N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2,5- dimethyl benzamide embodiment 274N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] the chloro- 4- fluorobenzamides embodiment 275N- [5- [(5 of -2-,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] the chloro- 6- fluorobenzamides embodiment 276N- [5- [(5 of -2-,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- methyl -3- fluorobenzamide embodiment 277N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2-Hydroxylbenzamide embodiment 278N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- acetoxyl group benzamide embodiment 279N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- aminobenzamide embodiment 280N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- (methylamino) benzamide embodiment 281N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- (amino methyl) benzamide embodiment 282N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- (dimethylamino) benzamide embodiment 283N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- chloropyridine -3- formamide embodiment 284N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- fluorine pyridine-3-carboxamide embodiment 285N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- methoxypyridine -3- formamide embodiment 286N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- (methyl mercapto) pyridine-3-carboxamide embodiment 287N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals]-PA -3- formamide embodiment 288N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- (methylamino) pyridine-3-carboxamide embodiment 289N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- (dimethylamino) pyridine-3-carboxamide embodiment 290N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -2- methylthiophene -3- formamide embodiment 300N- [5- [(5,11- dihydro -10H- dibenzo [b,e][1,4] diaza  -10- bases) carbonyl] -2- pyridine radicals] -3 methyl thiophene -2- formamide embodiment 301N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl]-phenyl] [1,1 '-xenyl] -2- formamides
It is stirred at room temperature 6,11- dihydro -5H- dibenzo [b, e] [1,4] azepines (0.195g), 4- [([1,1 '-xenyl] -2- carbonyls) amino] mixture of chlorobenzoyl chloride (0.41g) and 0.155gN, N- diisopropylethylamine in 12ml dichloromethane 3 hours, mixture is poured into water and extracted with dichloromethane.With water, saturated sodium bicarbonate, water, salt water washing extract is dried (sodium sulphate).By hydrous magnesium silicate thin plate filtering solution and with dichloromethane washing and filtering thin plate.The filtrate was concentrated to dryness obtains 0.66g yellow solids.By thick-layer silica gel plate chromatogram purification, using hexane-ethylacetate (1.5: 1) as solvent, crystal (0.165g) (being obtained by dichloromethane-ethyl acetate), mp224-225 DEG C are obtained.Embodiment 302N- [4- [(6,11- dihydro -5H- dibenzo [b, e] azepines -5- bases) carbonyl] -3- chlorphenyls] [1,1 '-xenyl] -2- formamides
0.195g 6 is stirred at room temperature, 11- dihydro -5H- dibenzo [b, e] azepines, 0.444g 4- [([1,1 '-xenyl] -2- carbonyls) amino] -2- chlorobenzoyl chlorides and 0.155gN, mixture of the N- diisopropylethylamine in 12ml dichloromethane 3 hours, mixture is poured into water and extracted with dichloromethane.With water, saturated sodium bicarbonate, water, salt water washing extract is dried (sodium sulphate).Remove solvent and by thick-layer silica gel plate chromatogram purification residue, using hexane-ethylacetate (1.5: 1) as solvent, obtain 0.32g crystal, mp120-125 DEG C.
As described in embodiment 302, make 6,11- dihydro -5H- dibenzo [b, e] azepines can prepare following compounds with suitable substituted or unsubstituted 4- [(aryl carbonyl) amino] chlorobenzoyl chlorides or with suitable substituted or unsubstituted 6- [(aryl carbonyl) amino] pyridine -3- acyl chloride reactions.Embodiment 303N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl]-phenyl] -2- (2- thienyls) benzamide embodiment 304N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl]-phenyl] -2- (3- thienyls) benzamide embodiment 305N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] phenyl] -3,6- dichlorophenyls] -2- (2- thienyls) benzamide embodiment 306N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3- chlorphenyls] -2- (2- thienyls) benzamide embodiment 307N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3- chlorphenyls] -2- (3- thienyls) benzamide embodiment 308N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] the chloro- 6- aminomethyl phenyls of -3-] -2- (2- thienyls) benzamide embodiment 309N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3- aminomethyl phenyls] -2- (2- thienyls) benzamide embodiment 310N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3,6- 3,5-dimethylphenyls] -2- (2- thienyls) benzamide embodiment 311N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3- aminomethyl phenyls] [1,1 '-xenyl] -2- formamide embodiment 312N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3,6- 3,5-dimethylphenyls] [1,1 '-xenyl] -2- formamide embodiment 313N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3- methyl -6- chlorphenyls] [1,1 '-xenyl] -2- formamide embodiment 314N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] the chloro- 6- aminomethyl phenyls of -3-] [1,1 '-xenyl] -2- formamide embodiment 315N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- aminomethyl phenyls] [1,1 '-xenyl] -2- formamide embodiment 316N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- chlorphenyls] [1,1 '-xenyl] -2- formamide embodiment 317N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] phenyl] -2- (2- pyridine radicals) benzamide embodiment 318N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] phenyl] -2- (3- pyridine radicals) benzamide embodiment 319N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] phenyl] -2- (4- pyridine radicals) benzamide embodiment 320N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3- chlorphenyls] -2- (2- pyridine radicals) benzamide embodiment 321N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3- chlorphenyls] -2- (3- pyridine radicals) benzamide embodiment 322N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3- aminomethyl phenyls] -2- (2- pyridine radicals) benzamide embodiment 323N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3- aminomethyl phenyls] -2- (3- pyridine radicals) benzamide embodiment 324N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3,6- 3,5-dimethylphenyls] -2- (2- pyridine radicals) benzamide embodiment 325N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3,6- 3,5-dimethylphenyls] -2- (3- pyridine radicals) benzamide embodiment 326N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3,6- 3,5-dimethylphenyls] -2- (4- pyridine radicals) benzamide embodiment 327N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3- chlorphenyls]-[3 '-methyl mercapto -1,1 '-xenyl] -2- formamide embodiment 328N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3- chlorphenyls]-[3 '-methoxyl group -1,1 '-xenyl] -2- formamide embodiment 329N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl]-phenyl]-[4 '-dimethylamino -1,1 '-xenyl] -2- formamide embodiment 330N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3- aminomethyl phenyls]-[3 '-chloro- 1,1 '-xenyl] -2- formamide embodiment 331N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3- chlorphenyls] -2- (3- furyls) benzamide embodiment 332N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] phenyl] -2- (2- furyls) benzamide embodiment 333N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl]-phenyl]-[3 '-chloro- 1,1 '-xenyl] -2- formamide embodiment 334N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3- chlorphenyls]-[3 '-chloro- 1,1 '-xenyl] -2- formamide embodiment 335N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3- aminomethyl phenyls]-[3 '-chloro- 1,1 '-xenyl] -2- formamide embodiment 336N- [5- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- pyridine radicals]-[3 '-chloro- 1,1 '-xenyl] -2- formamide embodiment 337N- [4- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -3- chlorphenyls]-[4 '-fluoro- 1,1 '-xenyl] -2- formamide embodiment 338N- [5- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- pyridine radicals] -2- chloropyridine -3- formamide embodiment 339N- [5- [(6,1 1- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- pyridine radicals] -2- fluorine pyridine-3-carboxamide embodiment 340N- [5- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- pyridine radicals]-PA -3- formamide embodiment 341N- [5- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- pyridine radicals] -2- (methylamino) pyridine-3-carboxamide embodiment 342N- [5- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- pyridine radicals] -2- (dimethylamino) pyridine-3-carboxamide embodiment 343N- [5- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- pyridine radicals] -3 methyl thiophene -2- formamide embodiment 344N- [5- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- pyridine radicals] -2- methylthiophene -3- formamide embodiment 345N- [5- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- pyridine radicals] -2- chlorobenzamide embodiment 346N- [5- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- pyridine radicals] the chloro- 5- fluorobenzamides embodiment 347N- [5- [(6 of -2-,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- pyridine radicals] the chloro- 6- fluorobenzamides embodiment 348N- [5- [(6 of -2-,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- pyridine radicals] -2- methyl -3- fluorobenzamide embodiment 349N- [5- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- pyridine radicals] -2- (methylamino) benzamide embodiment 350N- [5- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- pyridine radicals] -2-Hydroxylbenzamide embodiment 351N- [5- [(6,11- dihydro -5H- dibenzo [b,E] azepines -5- bases) carbonyl] -2- pyridine radicals] -2- (amino methyl) benzamide embodiment 352N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
As described in Example 1; in the presence of triethylamine (4mmol); make 6; 11- dihydro -5H- pyridos [2; 3-b] [1; 4] benzodiazepine  (2mmol) and 6- [(5- fluoro-2-methylbenzenes formoxyl) amino] pyridine -3- acyl chlorides (2.1mmol) dichloromethane solution reaction obtain product, are solid, mp102-104 DEG C.Embodiment 353N- [4- [(6,11- dihydro -5H- pyridos [2,3-b] [Isosorbide-5-Nitrae] benzodiazepine  -5- bases) carbonyl] -3- chlorphenyls] [1,1 '-xenyl] -2- formamides
As described in embodiment 134, in N, in the presence of N- diisopropylethylamine (0.155g), make 6,11- dihydro -5H- pyridos [2,3-b] [Isosorbide-5-Nitrae] benzodiazepine  (0.197g) and 4- [([1,1 '-xenyl] -2- carbonyls) amino] and -2- chlorobenzoyl chlorides (0.444g) 12ml dichloromethane solutions reaction obtain product, be solid.
As described in embodiment 352, make 6,11- dihydro -5H- pyridos [2,3-b] [Isosorbide-5-Nitrae] benzodiazepine  can prepare following compounds with suitable substituted or unsubstituted 4- [(aryl carbonyl) amino] chlorobenzoyl chlorides or with suitable substituted or unsubstituted 6- [(aryl carbonyl) amino] pyridine -3- acyl chloride reactions.Embodiment 354N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] phenyl] [1,1 '-xenyl] -2- formamide embodiment 355N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] phenyl] -2- (2- thienyls) benzamide embodiment 356N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -3- aminomethyl phenyls] [1,1 '-xenyl] -2- formamide embodiment 357N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -3- methyl -6- chlorphenyls] [1,1 '-xenyl] -2- formamide embodiment 358N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -3,6- 3,5-dimethylphenyls] [1,1 '-xenyl] -2- formamide embodiment 359N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -3- aminomethyl phenyls] -2- (2- thienyls) benzamide embodiment 360N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -3- chlorphenyls] -2- (2- thienyls) benzamide embodiment 361N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] phenyl] -2- (2- pyridine radicals) benzamide embodiment 362N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] phenyl] -2- (3- pyridine radicals) benzamide embodiment 363N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -3- chlorphenyls] -2- (2- pyridine radicals) benzamide embodiment 364N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -3- chlorphenyls] -2- (3- pyridine radicals) benzamide embodiment 365N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -3- aminomethyl phenyls] -2- (2- pyridine radicals) benzamide embodiment 366N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -3,6- 3,5-dimethylphenyls] -2- (3- pyridine radicals) benzamide embodiment 367N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] phenyl] -2- (4- pyridine radicals) benzamide embodiment 368N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] phenyl] -2- chloropyridine -3- formamide embodiment 369N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] phenyl] -2- fluorine pyridine-3-carboxamide embodiment 370N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -3- chlorphenyls] -2- chloropyridine -3- formamide embodiment 371N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] phenyl] -2- methoxypyridine -3- formamide embodiment 372N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -3- aminomethyl phenyls] -2- (methyl mercapto) pyridine-3-carboxamide embodiment 373N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -3- aminomethyl phenyls] -2- chloropyridine -3- formamide embodiment 374N- [4- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] phenyl]-PA -3- formamide embodiment 375N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] [1,1 '-xenyl] -2- formamide embodiment 376N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2- (2- thienyls) benzamide embodiment 377N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2- (3- thienyls) benzamide embodiment 378N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2- (2- pyridine radicals) benzamide embodiment 379N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2- (3- pyridine radicals) benzamide embodiment 380N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2- (4- pyridine radicals) benzamide embodiment 381N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2- (2- furyls) benzamide embodiment 382N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2- (3- furyls) benzamide embodiment 383N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2- chlorobenzamide embodiment 384N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] the chloro- 5- fluorobenzamides embodiment 385N- [5- [(6 of -2-,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2,5- dimethyl benzamide embodiment 386N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] the chloro- 6- fluorobenzamides embodiment 387N- [5- [(6 of -2-,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2- methyl -3- fluorobenzamide embodiment 388N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2-Hydroxylbenzamide embodiment 389N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2- aminobenzamide embodiment 390N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2- (methylamino) benzamide embodiment 391N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2- (dimethylamino) benzamide embodiment 392N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2- chloropyridine -3- formamide embodiment 393N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2- (dimethylamino) pyridine-3-carboxamide embodiment 394N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -2- methylthiophene -3- formamide embodiment 395N- [5- [(6,11- dihydro -5H- pyridos [2,3-b][1,4] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -3 methyl thiophene -2- formamide embodiment 396N- [4- [(4,5- dihydro-pyrazolos [4,3-d] [1] benzazepines -6 (1H)-yl) carbonyl] phenyl] [1,1 '-xenyl] -2- formamides
0.278g 4 is stirred at room temperature, 5- dihydro-pyrazolos [4,3-d] [1] benzazepines, 1.11g 4- [([1,1 '-xenyl] -2- carbonyls) amino] mixture of chlorobenzoyl chloride and 0.426g DIPEAs in 12ml dichloromethane-tetrahydrofuran (1: 1) stays overnight.Mixture is poured into water and extracted with dichloromethane.2N sodium carbonate, water, salt water washing extract and drying (sodium sulphate) are used, solvent is removed in vacuum and obtains 1.45g solids.2.78ml 2N sodium hydroxides are added into 25ml methanol-tetrahydrofuran (1: 1) solution of aforesaid solid and the solution 3.5 hours of gained is stirred at room temperature.Solvent is removed in vacuum, water is added into residue and dichloromethane extraction mixture is used.With water, 0.5N citric acids；Water, salt water washing extract and drying (sodium sulphate).Make solution by hydrous magnesium silicate thin plate and the filtrate was concentrated to dryness.The 0.17g crystal of residue (0.95g), mp225-260 DEG C are developed with ether-dichloromethane；Elementary analysis, C31H24N4O2·1/2H2O：C, 75.9；H, 5.1；N, 10.8.Embodiment 397N- [4- [(4,5- dihydro-pyrazolos [4,3-d] [1] benzazepines -6 (1H)-yl) carbonyl] -3- chlorphenyls] [1,1 '-xenyl] -2- formamides
0.185g 4 is stirred at room temperature, 5- dihydro-pyrazolos [4,3-d] [1] benzazepines, 0.814g 4- [([1,1 '-xenyl] -2- carbonyls) amino] mixture of -2- chlorobenzoyl chlorides and 0.284g DIPEAs in 9ml dichloromethane-tetrahydrofuran (1: 1) stays overnight.Mixture is poured into water and extracted with dichloromethane.2N sodium hydroxides, water, salt water washing extract and drying (sodium sulphate) are used, solvent is removed in vacuum and obtains 0.99g solids.1.75ml 2N sodium hydroxides are added into 15ml methanol-tetrahydrofuran (1: 1) solution of aforesaid solid and the solution 2 hours of gained is stirred at room temperature.Volatile matter is removed in vacuum and chloroform recovery mixture is used.Use 1N citric acids, water, salt water washing extract and drying (sodium sulphate).Make solution by the filtering of hydrous magnesium silicate thin plate and the filtrate was concentrated to dryness.By thick-layer silica gel plate chromatogram purification residue (0.76g), 0.37g white solids are obtained using hexane-ethylacetate (1: 2) as solvent.mp172-202℃；Elementary analysis, is found to be 1/2 hydrate：C, 70.1；H, 5.0；N, 9.8；Cl, 6.4. embodiment 398N- [5- [(4,5- dihydro-pyrazolos [4,3-d] [1] benzazepines -6 (1H)-yl) carbonyl] -2- pyridine radicals] [1,1 '-xenyl] -2- formamides
As described in embodiment 396, make 4,5- dihydro-pyrazolos [4,3-d] [1] benzazepines (0.1mmol) and 6- [([1,1 '-xenyl] -2- carbonyls) amino] pyridine -3- acyl chlorides (0.21mmol) reaction obtains product, is brown solid.Recrystallized with ethyl acetate/hexane, mp228-234 DEG C, be white crystal.Embodiment 399N- [5- [(4,5- dihydro-pyrazolos [4,3-d] [1] benzazepines -6 (1H)-yl) carbonyl] -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
As described in embodiment 396; make 0.10mmol 4; 5- dihydro-pyrazolos [4; 3-d] [1] benzazepines obtains product with the reaction of 6- [(5- fluoro-2-methylbenzenes formoxyl) amino] -2- pyridine -3- acyl chlorides (0.21mmol), is brown solid (0.15g).mp126-176℃；(the M of mass spectrum (FAB) 442++H).Embodiment 400N- [5- (4H- thienos [3,4-b] [1,5] benzodiazepine  -9 (10H)-base -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides
Such as J.B.Press et al are in J.Med.Chem., and 22 725 (1979) are described can to prepare 9,10- dihydro -4H- thienos [3,4-b] [1,5] benzodiazepine  -10 (9H) -one.The intermediate (4.8g) is dissolved in tetrahydrofuran in a nitrogen atmosphere and 4.2g lithium aluminium hydride reductions (LAH) are added portionwise thereto under agitation.Backflow mixture 18 hours is simultaneously quenched by being added dropwise to water.With chloroform recovery mixture and pass through diatomite filtrated extract.Organic layer is washed with water (200ml), (sodium sulphate) is dried and removes solvent.By thick-layer silica gel plate chromatogram purification residue, 1.2g9 is obtained using chloroform as eluant, eluent, 10- dihydro -4H- thienos [3,4-b] [1,5] benzodiazepine , is solid.Make aforesaid compound (0.5g) and contain 7mlN; the dichloromethane solution reaction of 1.06g 6- [(5- fluoro-2-methylbenzenes formoxyl) amino] pyridine -3- acyl chloride hydrochlorides of N- diisopropylethylamine; mixture is stirred at room temperature 16 hours; then water is used; 1N hydrochloric acid; saturated sodium bicarbonate solution, water washing and drying (sodium sulphate).Remove solvent and by silica gel chromatography residue, using ethylacetate-hexane (1: 3) as solvent, obtain 1.1g solids, mp89-92 DEG C.Embodiment 401N- [4- (4H- thienos [3,4-b] [1,5] benzodiazepine  -9 (10H)-yl)-phenyl] [1,1 '-xenyl] -2- formamides
As described in embodiment 400,9,10- dihydro -4H- thienos [3,4-b] [1,5] benzodiazepine  is reacted with 4- [([1,1 '-xenyl] -2- carbonyls) amino] chlorobenzoyl chloride and obtain product, be solid.Embodiment 402N- [4- (4H- thienos [3,4-b] [1,5] benzodiazepine  -9 (10H)-yl) -3- chlorphenyls] [1,1 '-xenyl] -2- formamides
As described in embodiment 400,9,10- dihydro -4H- thienos [3,4-b] [1,5] benzodiazepine  is reacted with 4- [([1,1 '-xenyl] -2- carbonyls) amino] -2- chlorobenzoyl chlorides and obtain product, be solid.Embodiment 403N- [5- (4H- thienos [3,4-b] [1,5] benzodiazepine  -9 (10H)-yl) -2- pyridine radicals] [1,1 '-xenyl] -2- formamides
As described in embodiment 400, making 9,10- dihydro -4H- thienos [3,4-b] [1,5] benzodiazepine ,-pyridine -3- acyl chloride reactions obtain product, are solid with 6- [([1,1 '-xenyl] -2- carbonyls) amino].Embodiment 4045,11- dihydros -10- [4- (2- thienyls) benzoyl] -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza 
The mixture 45 minutes of backflow 3g 4- (2- thienyls) benzoic acid and 30ml sulfonic acid chlorides simultaneously removes solvent.Dissolve the residue in carbon tetrachloride and solvent (2 times) is removed in vacuum, obtain 4- (2- thienyls) chlorobenzoyl chloride.To the 2.0g 5 of cooling (0 DEG C), 11- dihydro -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza  and 7mlN, N- diisopropylethylamine 30ml dichloromethane solutions in be added dropwise to the 30ml dichloromethane solutions of 3.15g 4- (2- thienyls) chlorobenzoyl chloride.Mixture 16 hours is stirred at room temperature and is diluted with 50ml chloroforms, 30ml water, 2N hydrochloric acid, saturated sodium bicarbonate, water washing solution and drying (sodium sulphate) are used respectively.Solvent is removed in vacuum and by silica gel (post) chromatogram purification residue (3.1g), 1.8g solids, mp114-116 DEG C are obtained using hexane-ethylacetate (2: 1) as eluant, eluent.Embodiment 4055,11- dihydros -10- [4- (3- thienyls) benzoyl] -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza 
To 2.0g 5, the 30ml dichloromethane solutions of 3.15g 4- (3- thienyls) chlorobenzoyl chloride are added dropwise in the 30ml dichloromethane solutions of 11- dihydro -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza  and 7mlN, N- diisopropylethylamine.Mixture 16 hours is stirred at room temperature and is diluted with dichloromethane (50ml), 30ml water, 2N hydrochloric acid, saturated sodium bicarbonate, water washing solution and drying (sodium sulphate) are used respectively.Solvent is removed in vacuum and solid is obtained by silica gel chromatography residue.To the binding tests of rats'liver V1 acceptors
Method according to Lesko etc. (1973) will be expressed and added by sucrose density gradient
Press the rat hepatocytes plasma membrane separation of element V1 receptor subtypes.By this film be quickly suspended in containing
0.2% bovine serum albumin(BSA) (BSA) and 0.1mM Phenylmethylsulfonyl fluorides (PMSF)
Freezed in 50.0mM Tris.HCl buffer solutions (PH7.4) and at -70 DEG C until for
Following binding tests.In binding tests, following substances are added to the microtitration of 96- holes
In each hole of flat board：Contain 10.0m MgCl2100ml 100.0mM Tris.HCl buffering
The mixture of liquid, the 0.2% inactive BSA of heating and protease inhibitors：Anti- fiber egg
White lyase inhibitor (leueptin), 1.0mg%；Aprotinin, 1.0mg%；1,10-
Phenanthroline, 2.0mg%；Trypsin inhibitor, 10.0mg% and 0.1mM PMSF,
0.8mM 20.0ml [phenylalanyl -3,4,5-3H] pitressin (S.A.
45.1 Ci/mmol), made by adding the 80ml tissue films containing 20mg histones
Reaction starts.Flat board is stood 120 minutes to reach balance in table top at room temperature, it is non-
Specific sample enters in the presence of the unmarked antagonist PHENYLPROPIONYL pitressins of 0.1mM
Row experiment, is added with volume 20.0ml.
Test compound is dissolved in 50% dimethyl sulfoxide (DMSO) and using the incubation volume of 20.0ml volumes addition to the last as 200.0ml.With reference to after the completion of, the content in each hole is filtered using Brandel, cellHarvester (Gaithersburg, MD).Radioactivity is deposited in filtering table by ligand-receptor complex, counted and be estimated by liquid scintillation on Packard LS counters, the efficiency of tritium is 65%, and graphic analyses IC is competed by LUNDON-250Data (LUNDON SOFTWARE, OH), and data are listed in Table I.To the binding tests of Rat renal marrow V2 acceptors
Rat renal myeloid tissue is separated, cuts into pieces and is infiltrated in the 0.154mM sodium chloride solutions containing 1.0mM EDTA, at this moment liquid phase there occurs many changes, until not containing blood in solution.Using Potter-Elvehjem homogenizers with teflon pestle the homogenized tissues in the 0.25M sucrose solutions containing 1.0mM EDTA and 0.1mM PMSF.Filtered and be homogenized by several layers of (4 layers) cheese cloth.Using pestle is pressed, filtrate is homogenized by dounce homogenizers again.The homogenate that finally reaches 15 minutes is centrifuged in 1500 × g.Discard the piller of core and 40,000 × g centrifuged supernatants 30 minutes, the piller formed contains black core, and lightpink shell.Pink casing part is suspended in a small amount of 50.0mM Tris.HCl buffer solutions (PH7.4).Protein content is determined by Lowry methods (Lowry et al., J.Biol.Chem., 1953).In -70 DEG C of 50.0mM Tris.HCl buffer solutions that film suspension is stored in containing 0.2% disactivation BSA and 0.1mM PMSF, every milliliter of suspension in 1.0ml sample aliquots is contained 10.0mg protein, be stored into always with binding tests later.
For binding tests, in the aperture that following material is added to 96 hole microtiter plates with ml volumes：Contain 0.2% hot disactivation BSA, 10.0mM MgCl2100.0ml 100.0mMTris.HCl buffer solutions and the mixture of protease inhibitors：Antifibrinolysin inhibitor (leupeptin) 1.0mg%；Aprotinin, 1.0mg%；1,10- phenanthroline, 2.0mg%；Trypsin inhibitor, 10.0mg% and 0.1mM PMSF, and 0.8nM 20.0ml [3H] arginine8, pitressin (S.A.75.0Ci/mmol), by adding 80.0ml tissue films (200.0mg tissue proteins) startup reaction.Flat board is stood 120 minutes to reach balance in table top, non-specific binding is carried out in the presence of the unlabelled parts of 1.0mM, addition volume is 20.0m1.Test compound is dissolved in 50% dimethyl sulfoxide (DMSO), and adds 20.0ml volumes and reaches last incubation volume 200ml.With reference to after the completion of, the content in each hole is filtered using Brandel, cellHarvester (Gaithersburg, MD).Radioactivity is deposited in filtering table by ligand-receptor complex, counted and be estimated by liquid scintillation on Packard LS counters, the efficiency of tritium is 65%, and graphic analyses IC is competed by LUNDON-250Data are simultaneously listed in Table I by data (LUNDON SOFTWARE, OH).The preparation of Radioligand Binding Assay (a) platelet membrane of human blood platelets film
Make to come from being thawed at room temperature (blood platelet source rich in hematoblastic refrigerated plasma (PRP) for Hudon Vaelley Blood Services：Hudson Vaelley Blood Services, Westchester Medical Center, Valhalla, NY).At 4 DEG C, in 16,000 × g centrifuges the test tube containing PRP 10 minutes, abandoning supernatant.By platelet suspension in isometric 50.0mMTris.HCl buffer solutions (PH7.5) containing 120mM NaCl and 20.0mM EDTA.Suspension is centrifuged 10 minutes in 16,000 × g again.Washing step is carried out more than once, discard washing lotion, make the blood platelet dissolved equal pulp in the 5.0mM Tris.HCl buffer solutions (PH7.5) that low ionic strength contains 5.0mMEDTA, in 39,000 × g centrifuges homogenate thing 10 minutes, obtained piller is resuspended in 70.0mM Tris.HCl buffer solutions and 39,000 × g is centrifuged 10 minutes again.Last piller is resuspended in the 50.0mMTris.HCl buffer solutions (PH7.4) containing 120mM NaCl and 5.0mM KCl, 1.0-2.0mg protein/ml suspension is obtained.(b) and human blood platelets film pitressin V1 receptor subtypes combination
0.2%BSA and protease inhibitors (aprotinin will be contained, antifibrinolysin inhibitor (leupeptin) etc.) 100ml 50.0mMTris.HCl buffer solutions be added in the aperture of 96 hole microtiter plates, then, add 20ml [3H] part：(Manning or Arg8Pitressin), obtain ultimate density scope 0.01-10.0nM.Start association reaction by adding 80.0ml platelet suspensions (about 100.0mg protein).By withdraw mix, all reagents are mixed several times repeatedly, in the unlabelled parts of 1.0mM (Manning or Arg8Pitressin) in the presence of determine non-specific binding, make mixture static 90 minutes at room temperature.At this moment Brandel is usedHarvester, is sucked by vacuum filter rapid filtration by GF/B and is incubated thing.The radioactivity obtained on filtering table is counted in liquid scintillator by adding liquid scintillation thing.To expressing people V with cDNA2The Apoptosis (LV-2) of vasopressin receptor transfection
The preparation of combination (a) film of film
By aspirating the culture medium removed in 175ml flasks, the flask contains the connection cell for growing to fusion, with 2 × 5ml flask of phosphate buffered saline (PBS) (PBS) rinsing containing connection cell, and each pumping liquid, finally, add Hank`s basal liquid (Specialty Medias of the 5ml without resolvase, Inc., Lafayette, NJ), and stand flask 2 minutes.All the elements thing in flask is poured into centrifuge tube, under 300 × g, make cell pelletization 15 minutes, aspirate Hank`s basal liquids, with Polytron, #6 grades are homogenized cell 10 seconds, and above-mentioned homogenizing is carried out in the 10.0mM Tris.HCl buffer solutions (PH7.4) containing 0.25M sucrose and 1.0mMEDTA, equal compound is centrifuged under 1500 × g 10 minutes, to remove ghost film.Under 100,000 × g, centrifuged supernatant 60 minutes makes receptor protein pelletization.After the completion of; the ball is resuspended in the 50.0mM Tris.HCl buffer solutions (PH7.4) of small size; protein content is determined by Lowly methods; and receptor membrane is suspended in the 50.0mM Tris.HCl buffer solutions (PH7.4) containing 0.1mM Phenylmethylsulfonyl fluorides compound (PMSF) and 0.2% bovine serum albumin(BSA) (BSA), obtain 2.5mg receptor proteins/ml suspension.(b) receptor binding assays
For binding tests, in the aperture that following thing is added to 96 hole microtiter plates with ml volumes：The 100.0mMTris.HCl buffer solutions of 100.0ml containing 0.2% hot disactivation BSA, 10.0mMMgCl2With the mixture of protease inhibitors：Antifibrinolysin inhibitor (leupeptin) 1.0mg%；Aprotinin, 1.0mg%；1,10- phenanthroline, 2.0mg%；Trypsin inhibitor, 10.0mg% and 0.1mM PMSF, and in 0.8nM 20.0ml [3H] arginine8, pitressin (S.A.75.0Ci/mmol), by adding 80.0ml tissue films (200.0mg tissue proteins) startup reaction.Flat board is stood 120 minutes to reach balance in table top, non-specific binding is carried out in the presence of 1.0 μM of unlabelled parts, addition volume is 20.0ml.Test compound is dissolved in 50% dimethyl sulfoxide (DMSO), and adds 20.0ml volumes and reaches last incubation volume 200ml.With reference to after the completion of, the content in each hole is filtered using Brandel, cellHarvester (Gaithersburg, MD).Radioactivity is deposited in filtering table by ligand-receptor complex, counted and be estimated by liquid scintillation on Packard LS counters, the efficiency of tritium is 65%, and graphic analyses IC is competed by LUNDON-250Data (LUNDON SOFTWARE, OH), data are shown in Table I：There are the pitressin V2 antagonist activities in consciousness Hydrated rats
There are consciousness Hydrated rats with the compound processing studied, oral or excipients (control) 0.1mg-100mg/kg.2-4 rat is handled with every kind of compound, after 1 hour, is applied with the arginine vasopressin (AVP, antidiuretichormone, ADH) being dissolved in peanut oil with 0.4 μ/kg amount intraperitoneal.In each experiment, there are two mouse not give arginine vasopressin, and be only given carrier (peanut oil) as the control that adds water.After 20 minutes, 30ml/kg deionized water is applied to every Oral Administration in Rats by gavage, and is separately positioned at and is equipped with the metabolic cage of pipeline and scaled glass cylinder, to collect urine 4 hours.Measure volume of urine and using the osmometers of Fiske mono-/ten (Fiske Asscc., Norwood, MA, USA) analysis osmolality.With ion-sodium of the special electrode in Beckman E3 (electrode) analyzer analyzes urine, potassium and chlorine.In following results, the reduction of volume of urine and the reduction of osmolality of AVP- controls indicate active.There are the pitressin V1 antagonist activities in consciousness rat
There to be consciousness rat to be limited in the posture lain on the back with elastic clip, pass through 2% procaine (0.2ml) subcutaneous osmotic, make local anaesthesia below afterbody, abdomen arteria caudalis is separated using asptic technique, the sleeve pipe (heat-melt) that PE10 and 20 pipes are constituted injects lower abdominal aorta.Sleeve pipe is fixed, test tube of hepari (1000i.u./cc), seal and sutured with 1 or 2 pin Dexon 4-0, to vein dispenser, sleeve pipe also is made in tail vein in the same manner.The time of operation is about 5 minutes, and other local anaesthesia (2% procaine or lidocaine) can be provided if desired.
Animal is placed in plastics limitation cage with erect posture, sleeve pipe is connected to Statcam P23Db pressure converters, record beating blood pressure.Before any medicine (compound) is applied, record the increase of the systolic pressure produced to the injection international unit (I.U.) (350I.U.=1mg) of arginine vasopressin 0.01 and 0.2, afterwards, compound 0.1-100mg/kg (10cc/kg) or intravenous administration 0.1-30mg/kg (1cc/kg) are studied to every Oral Administration in Rats.30,60,90,120.At 180,240 and 300 minutes, duplicate injection pitressin.Afterwards, the percentage as 100% antagonism for calculating compound is reacted using prodrug pitressin hypertensor.Ocytocin receptor combines the preparation of (a) film
Donor weighs about the diethylstilbestrol (DES) of 200-250g female Sprague-Dawley intramuscular injections (i.m.) 0.3mg/kg body weight.After 18 hours of anaesthetized with pentobarbital, rat is killed.Separating uterus, remove fat and connective tissue, and rinsed with 50ml physiological saline.In the 50ml0.01mMTris.HCl (PH7.4) containing 0.5mM dithiothreitol (DTT)s and 1.0mMEDTA, using with each 10 seconds the 6th grade of Polytron of 3 passages, the set tissue obtained in 6 rats is homogenized.Make equal compound by two (2) layer cheese cloth, and under 1000 × g, centrifugal filtrate 10 minutes.The supernatant of clarification is removed, and is centrifuged again 30 minutes under 165,000 × g.The piller containing ocytocin receptor of gained is suspended in the 50.0mM MTris.HCl (PH7.4) containing 5.0mM magnesium chlorides again, the suspensions of tissues that protein concentration is 2.5mg/ml is obtained.The preparation solution can be used for it is following [3H] oxytocins binding tests.(b) radioligand is combined
3,5- [3H] oxytocins ([3H] OT) and its acceptor combination be in microtiter plates using [3H] OT, at various concentrations, is containing 50.0m MgCl2And protease inhibitors mixture；BSA0.1mg；Aprotinin 1.0mg；1,10- phenanthroline, 2.0mg；Carried out in trypsase 10.0mg and PMSF0.3mg 50mM Tris.HCl buffer solutions (PH7,4).Non-specific knot is determined in the presence of 1.0 μM of unlabelled OT.
Association reaction is terminated after 60 minutes in 22 DEG C by fast filtering using Brandel  cell harvestors (Biomedicl Research and Developmentlaboratories, Inc., Gaithersburg, MD).Using 1.0nM [3H] OT and change substitution reagent concentration, be at war with experiment in equilibrium conditions.[3H] OT replaces 50% substitution reagent concentration (IC50) to calculate by computer assisted LUNDON-2 programs (LUNDON SOFT WARE INC., Ohio, USA) in its site.
Combination to rats'liver V1 acceptors and the binding tests or * and human body platelet V1 receptor subtypes of Rat renal marrow V2 acceptors, and * * with cDNA to expressing mankind V2The combination of Apoptosis (LV-2) film of acceptor transfection
Table I Example No. structure V1         V2
                                              IC50(μM)   IC50(μM)1             0.24           0.0542             0.059          0.0294
Figure A9619256802613
44% in 10 μM 20% in 10 μM
(Continued) Example No. structure V1          V2
                                    IC50(μM)    IC50(μM)12
Figure A9619256802621
90% in μM 24   *72% (μM)**26% (10 μM) 25
Figure A9619256802623
100% (1 μM) 39% (1 μM)
(Continued) Example No. structure V1         V2
                                             IC50(μM)   IC50(μM)26
Figure A9619256802631
46% (1 μM) 29% (10 μM) 27
Figure A9619256802632
                     *0.014       **1.8
(Continued) Example No. structure V1          V2
                                       IC50(μM)   IC50(μM)32 33% (10 μM) 33 10% (10 μM) 16% (10 μM) 45
Figure A9619256802643
34% (10 μM) 62% (10 μM)
Table II
There are the pitressin V2 antagonist activities in consciousness Hydrated rats
Example No. Dosage (mg/kg) N Volume of urine (ml/4 hours) Osmolality (MOsm/kg)
* 78 13.3±0.3 229±6
** 6 12.1±1 497±53
4 12.4±0.8 361+30
*** 76 2±0.2 1226±58
26 10 2 4.5 1058
45 10 2 6.6 979
4 10 2 6.8 878
2 10 2 16.5 591
32 10 2 9.3 726
2 10 2 16.5 591
24 10 2 4.3 1492
27 10 2 3.3 1317
* add water-compare
* adds water-compareed+DMSO (10%) (20%)
* * AVP- are compareed.Before experiment rather than experiment in can free water have consciousness rat pitressin antidiuresis (V2) react
To normotensive body weight 400-450g males or female Sprague-Dawley rats (Charles River Laboratories, Inc., Kingston, NY) LaboratoryRodent feeds 5001# (PMI Feed are provided, Inc., Richmond, IN) and can arbitrarily drink water.On the day of being tested, rat is respectively placed in the metabolic cage equipped with stainless steel railing (with separating feces and urine) and urine collecting pipeline.Compound, carrier or contrast agent are orally administered with various dosage.Food and drinking-water are not provided to rat in an experiment.Urine is collected with measuring graduates 4 hours, measure volume of urine after administration.Osmolality is analyzed with the osmometers of Fiske mono-/ten (FiskeAsscc., Norwood, MA, 02062).The sodium in urine, potassium and chlorine are analyzed on Beckman E3 (electrode 3) analyzer with ion-special electrode.The carrier of test compound is 20% dimethyl sulfoxide in 2.5% pre- boiling starch.The result of the experiment is listed in Table IV.
Table IV
Pitressin V2 antagonist activities in Conscious rats
Table IV
Example No. Dosage (mg/kg) N Volume of urine (ml/4 hours) Osmolality (MOsm/kg)
* 16 7-10±2 981±34
47 10 2 22.0 394
66 10 2 17.0 442
67 10 2 21.5 402
134 10 2 40.5 333
3 2 28 396
2 18.2 596
133 10 2 27.5 234
135 10 2 39.5 284
3 2 26.8 391
2 19.5 526
176 10 2 12.8 567
218 10 2 34 222
257 10 2 22.5 317
301 10 2 41.5 363
302 10 2 40 356
352 10 2 9.3 779
396 10 2 21.8 238
397 10 2 29.8 288
398 10 2 20.5 316
399 10 2 17.0 404
400 10 2 24.8 270
404 10 2 6 909
* compound is dissolved in DMSO by the control cornstarch of DMSO (20%) -2.5%, then dilutes (DMSO final concentration is 20%) with 2.5% cornstarch.All rats press 10mVkg dosage.
Table III
Oxytocins binding tests
Example No. Dosage (μM) % suppresses IC50(μM)
1 1 12 -
2 10 86 1.1
4 10 20 -
12 10 76 0.61
24 10 97 1.8
25 10 94 0.113
26 10 73 2.5
27 1 83 -
32 10 88 1.8
33 1 37 -
45 1 54 -
The compounds of this invention can pharmaceutically or in the form of the salt of physiologically acceptable acid or alkali be used with it, and these salt include but is not limited to and inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, the salt of phosphoric acid formation, with organic acid such as acetic acid, the salt of  acid, butanedioic acid, and maleic acid formation.Other salt include and alkali metal or alkaline-earth metal such as sodium, potassium, the salt that calcium or magnesium are formed, or the salt with organic base formation.The compounds of this invention can be with ester, and the form of carbamate and other convenient " prodrug " forms be used, when in the form of prodrug in use, it can change into activity form in vivo.
The compounds of this invention can be with one or more pharmaceutically acceptable carriers such as solvent in above-mentioned application, diluent, it is used in combination, and can be with tablet, capsule, dispersible pulvis, granula or form of suspension containing about 0.05%-5% suspending agents are oral, or it is oral with the syrup containing such as about 10-15% sucrose, or with the elixir containing such as about 20-50% ethanol orally etc.；With aseptic injectable solution or in isotonic medium containing about 0.05-5% suspending agents suspension in the form of parenteral.These pharmaceutical preparations can contain for example, from the active components of about 25- about 90% and carrier, the more usually active component containing about 5% and 60% weight.
The effective dose of the active component used depends on the particular compound used, the mode of administration and the order of severity of institute's treatment.But generally speaking, satisfied result can be obtained when applying the compounds of this invention with daily dose about 0.5- about 500mg/kg the weight of animals, it is preferably daily 2-4 times with the dosage of segmentation, or in the form of sustained release.For most mammals, total daily dose is in the range of about 1-100mg, preferably from about 2-80mg.It is adapted to the reactive compound containing the about 0.5-500mg closely mixed with solid or liquid pharmaceutical carriers in the applicable formulation of enteron aisle.The dose prescription be can adjust so that reach can preferable therapeutic effect.It can for example be applied daily by several fractionated doses or according to treatment in the urgent need to cutting down dosage in proportion.
These reactive compounds are orally available to be applied or by vein, and intramuscular or subcutaneous approach is applied.Solid carrier includes starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, and liquid-carrier includes sterilized water, polyethylene glycol, nonionic surfactant and edible oil such as corn oil, peanut oil and sesame oil, these properties and required specific administration form for being suitable to active component are adaptable, in the preparation of pharmaceutical composition, conventional assistant agent is preferably included, for example, flavoring agent, colouring agent, preservative, and antioxidant, such as vitamin E, ascorbic acid, BHT and BHA.
From the point of view of the easy degree for preparing and applying, preferred pharmaceutical composition is the capsule of solid composite, preferably tablet and hard-filled or liquid-filled.Oral administration of compound is preferred.
These compounds also can parenteral or intraperitoneal use.The preparation of the solution or suspension of the reactive compound existed with free alkali or pharmaceutical acceptable salt with surfactant such as hydroxypropyl cellulose can suitably mix progress in water.Prepared in the glycerine of dispersant also in oil, liquid, polyethylene glycol and its mixture.Storage and in use, containing preservative to suppress the growth of microorganism in these preparations under normal conditions.
Being adapted to the pharmaceutical dosage form of injection includes aseptic aqueous solution or dispersion liquid and for aseptic injectable solution or the aseptic powdery of the extemporaneous preparation of dispersion liquid.In all cases, all formulations all must be sterile, also, mobility reached with easy injectivity.It must be stable under preparation and storage requirement, it has to be possible to prevent the contamination of microorganism such as bacterium and fungi.Carrier can be solvent or contain, such as water, the suitable mixture of alcohol (such as glycerine, propane diols and liquid macrogol) above-mentioned substance, and vegetable oil decentralized medium.
The new non-peptide vasopressin antagonists of three rings of the invention can be used for treatment to need to reduce the situation of vasopressin levels, e.g., congestive heart failure, the disease symptomses and the increased symptom of angiemphraxis and coronary vasoconstriction of superfluous kidney fluid reabsorption.
Vasopressin antagonists of the present invention be particularly useful for the treatment of and/preventing hypertension, cardiac muscle can not entirely, coronary artery spasm, cardiac ischemia, Renal vascular spasm, liver strain, congestive heart failure, renal syndrome, encephaledema, cerebral ischemia, cerebral hemorrhage suffer a shock, thrombosis-property bleeding and exception water retention.
Specifically, oxytocin antagonist of the present invention can be used for preventing preterm from giving a birth and premature labor, these are the most important reasons of health problem and the death rate for causing baby.

Claims (142)

1. selected from compounds of formula I and its officinal salt, ester and its prodrug forms：
Figure A9619256800021
Formulas I wherein Y is selected from (CH2)n, O, S, NH, NCOCH3, N- low alkyl groups (C1-C3), CH- low alkyl groups (C1-C3), CHNH- low alkyl groups (C1-C3), CHNH2, CHN [low alkyl group (C1-C3)]2, CHO- low alkyl groups (C1-C3), CHS- low alkyl groups (C1-C3), wherein n is 0-2 integer；A-B is
Figure A9619256800022
Wherein m is 1-2 integer, and condition is when Y is-(CH2)n- and during n=2, m may also indicate that 0 and when n is 0, m may also indicate that 3, and condition is also included when Y is-(CH2)nDuring with n=2, M can not also be 2；R1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3, low alkyl group (C1-C3), O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：
Figure A9619256800023
Wherein Ar represents to be selected from following groups：O, S ,-NCH are represented with X3Or-NHR4Selected from hydrogen, low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3)；R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula parts
Figure A9619256800041
Wherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen, CH3, C2H5, or represent following formula parts：
Figure A9619256800042
-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen, CH3, C2H5；(b) formula part：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),
Figure A9619256800043
It is 0-3 with p；X represents O, S, NH, NCH3,Or key and R5And R7It is as defined above (c) formula part：
Figure A9619256800052
Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：
Figure A9619256800053
Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：
Figure A9619256800061
Figure A9619256800062
- S- low alkyl groups (C1-C3)Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicals
Figure A9619256800064
R8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or-NH- low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；W ' is selected from O, S, NH, N- low alkyl groups (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3)；R25Selected from following radicals：And group Represent：(1) phenyl or by one or two be selected from (C1-C3) low alkyl group, halogen, amino, (C1-C3) lower alkoxy or (C1-C3) low-grade alkyl amino the phenyl that arbitrarily replaces of substituent；(2) containing fragrant (undersaturated) heterocycle of heteroatomic 5- members selected from O, N or S；(3) fragrant (undersaturated) heterocycle of 6- members containing a nitrogen-atoms；(4) fragrant (undersaturated) heterocycle of 5- or 6- member containing two nitrogen-atoms；(5) fragrant (undersaturated) heterocycle of 5- members containing a nitrogen-atoms and an oxygen atom or a sulphur atom；5- or 6- circle heterocycles therein can be by (C1-C3) low alkyl group, formoxyl, following formula group：Halogen or (C1-C3) lower alkoxy is optionally substituted.
2. compound according to claim 1, wherein group
Figure A9619256800074
Represent to be selected from (C by one or two1-C3) low alkyl group, halogen, amino, (C1-C3) lower alkoxy and (C1-C3) the optionally substituted phenyl ring of lower alkyl amino, and n, m, W ', X, Y, A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
3. compound according to claim 1, wherein group
Figure A9619256800081
Represent fragrant (unsaturation) heterocycle of 6- members containing a nitrogen heteroatom, and n, m, W ', X, Y, A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
4. compound according to claim 1, wherein groupRepresent fragrant (unsaturation) heterocycle of 6- members containing two nitrogen heteroatoms, and n, m, W ', X, Y, A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
5. compound according to claim 1, wherein group
Figure A9619256800083
Represent fragrant (unsaturation) heterocycle of 5- members containing a sulfur heteroatom, and Y, A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
6. compound according to claim 1, wherein groupRepresent fragrant (unsaturation) heterocycle of 5- members containing an oxygen heteroatom, and Y, A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
7. compound according to claim 1, wherein groupRepresent fragrant (unsaturation) heterocycle of 5- members containing a nitrogen heteroatom, and Y, A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
8. compound according to claim 1, wherein groupRepresent fragrant (unsaturation) heterocycle of 5- members containing a nitrogen heteroatom, and Y, A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
9. compound according to claim 1, wherein group
Figure A9619256800092
Represent fragrant (unsaturation) heterocycle of fusion 5- members containing a nitrogen heteroatom and a sulfur heteroatom, and Y, A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
10. compound according to claim 1, wherein group
Figure A9619256800093
Represent fragrant (unsaturation) heterocycle of 5- members containing a nitrogen heteroatom and an oxygen heteroatom, and Y, A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
11. compound according to claim 1, wherein group
Figure A9619256800094
Represent to be selected from (C by one or two1-C3) low alkyl group, halogen, amino, (C1-C3) lower alkoxy and (C1-C3) the optionally substituted phenyl ring of lower alkyl amino, Y is selected from-CH2-,And A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1
12. compound according to claim 1, wherein group
Figure A9619256800101
Fragrant (unsaturation) heterocycle of 6- members containing a nitrogen heteroatom is represented, Y is selected from-CH2-,
Figure A9619256800102
And A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
13. compound according to claim 1, wherein groupFragrant (unsaturation) heterocycle of 6- members containing two nitrogen heteroatoms is represented, Y is selected from-CH2-,And A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
14. compound according to claim 1, wherein group
Figure A9619256800111
Fragrant (unsaturation) heterocycle of 5- members containing a sulfur heteroatom is represented, Y is selected from-CH2-,
Figure A9619256800112
And A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
15. compound according to claim 1, wherein group
Figure A9619256800113
Fragrant (unsaturation) heterocycle of 5- members containing an oxygen heteroatom is represented, Y is selected from-CH2-,
Figure A9619256800114
And A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
16. compound according to claim 1, wherein groupFragrant (unsaturation) heterocycle of 5- members containing a nitrogen heteroatom is represented, Y is selected from-CH2-,And A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
17. compound according to claim 1, wherein group
Figure A9619256800122
Fragrant (unsaturation) heterocycle of 5- members containing two nitrogen heteroatoms is represented, Y is selected from-CH2-,And A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
18. compound according to claim 1, wherein groupFragrant (unsaturation) heterocycle of 5- members containing a nitrogen heteroatom and a sulfur heteroatom is represented, Y is selected from-CH2-,
Figure A9619256800131
And A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
19. compound according to claim 1, wherein group
Figure A9619256800132
Fragrant (unsaturation) heterocycle of 5- members containing a nitrogen heteroatom and an oxygen heteroatom is represented, Y is selected from-CH2-,
Figure A9619256800133
And A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
20. compound according to claim 1, wherein group：
Figure A9619256800134
Represent to be selected from (C by one or two1-C3) low alkyl group, halogen, amino, (C1-C3) lower alkoxy and (C1-C3) the optionally substituted phenyl ring of lower alkyl amino, Y represents-(CH2)n-, n is 0 and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
21. compound according to claim 1, wherein group：
Figure A9619256800141
Fragrant (unsaturation) heterocycle of 6- members containing a nitrogen heteroatom is represented, Y represents-(CH2)n-, it is 0 and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
22. compound according to claim 1, wherein group：Fragrant (unsaturation) heterocycle of 6- members containing two nitrogen heteroatoms is represented, Y represents-(CH2)n-, n is 0 and A-B, Ra, Rb,R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
23. compound according to claim 1, wherein group：Fragrant (unsaturation) heterocycle of 5- members containing a sulfur heteroatom is represented, Y represents-(CH2)n-, n is 0 and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6 R7, R8, R9, R10, R25Definition with claim 1.
24. compound according to claim 1, wherein group：Fragrant (unsaturation) heterocycle of 5- members containing an oxygen heteroatom is represented, Y represents-(CH2)n-, n is 0 and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
25. compound according to claim 1, wherein group：
Figure A9619256800145
Fragrant (unsaturation) heterocycle of 5- members containing a nitrogen heteroatom is represented, Y represents-(CH2)n-, n is 0 and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
26. compound according to claim 1, wherein group：
Figure A9619256800146
Fragrant (unsaturation) heterocycle of 5- members containing two nitrogen heteroatoms is represented, Y represents-(CH2)n-, n is 0 and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
27. compound according to claim 1, wherein group：Fragrant (unsaturation) heterocycle of 5- members containing a nitrogen heteroatom and a sulfur heteroatom is represented, Y represents-(CH2)n-, n is 0 and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
28. compound according to claim 1, wherein group：
Figure A9619256800152
Fragrant (unsaturation) heterocycle of 5- members containing a nitrogen heteroatom and an oxygen heteroatom is represented, Y represents-(CH2)n-, n is 0 and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
29. compound according to claim 1, wherein group：
Figure A9619256800153
Phenyl or substituted phenyl are represented, Y is selected from O, S, NH, NCOCH3With N- low alkyl groups (C1-C3), and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
30. compound according to claim 1, wherein groupFragrant (unsaturation) heterocycle of 6- members containing a nitrogen heteroatom is represented, Y is selected from O, S, NH, NCOCH3With N- low alkyl groups (C1-C3), and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
31. compound according to claim 1, wherein groupFragrant (unsaturation) heterocycle of 6- members containing two nitrogen heteroatoms is represented, Y is selected from O, S, NH, NCOCH3With N- low alkyl groups (C1-C3), and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
32. compound according to claim 1, wherein group
Figure A9619256800162
Fragrant (unsaturation) heterocycle of 5- members containing a sulfur heteroatom is represented, Y is selected from O, S, NH, NCOCH3With N- low alkyl groups (C1-C3), and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
33. compound according to claim 1, wherein group：Fragrant (unsaturation) heterocycle of 5- members containing an oxygen heteroatom is represented, Y is selected from O, S, NH, NCOCH3With N- low alkyl groups (C1-C3), and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
34. compound according to claim 1, wherein groupFragrant (unsaturation) heterocycle of 5- members containing a nitrogen heteroatom is represented, Y is selected from O, S, NH, NCOCH3With N- low alkyl groups (C1-C3), and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
35. compound according to claim 1, wherein group
Figure A9619256800165
Fragrant (unsaturation) heterocycle of 5- members containing two nitrogen heteroatoms is represented, Y is selected from O, S, NH, NCOCH3With N- low alkyl groups (C1-C3), and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
36. compound according to claim 1, wherein group
Figure A9619256800171
Fragrant (unsaturation) heterocycle of 5- members containing a nitrogen heteroatom and a sulfur heteroatom is represented, Y is selected from O, S, NH, NCOCH3With N- low alkyl groups (C1-C3), and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
37. compound according to claim 1, wherein groupFragrant (unsaturation) heterocycle of 5- members containing a nitrogen heteroatom and an oxygen heteroatom is represented, Y is selected from O, S, NH, NCOCH3With N- low alkyl groups (C1-C3), and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 1.
38. according to the compound of claim, Y is selected from-(CH2)n-
Figure A9619256800173
Wherein n represents 0 or 1 integer；R3Represent groupWherein Ar is selected from groupAnd R6Selected from following radicalsWherein Ar ' is selected from groupW ' is O or S；And A-B, Ra, Rb, R1, R2, R4, R5, R7, R8, R9, R10, R25, X, cyclic hydrocarbon radical and group：
Figure A9619256800184
Definition with claim 1.
39. compound according to claim 1, Y is selected from-CH2-
Figure A9619256800191
R3Represent group
Figure A9619256800192
Wherein Ar is selected from group
Figure A9619256800193
And R6Selected from following radicals
Figure A9619256800201
Wherein Ar ' is selected from group
Figure A9619256800202
W ' is O or S；And A-B, Ra, Rb, R1, R2, R4, R5, R7, R8, R9, R10, R25, X, cyclic hydrocarbon radical and group：Definition with claim 1.
40. compound according to claim 1, Y is selected from-CH2-R3Represent groupWherein Ar is selected from group
Figure A9619256800211
And R6Selected from following radicalsWherein Ar ' is selected from groupW ' is O or S；And groupRepresent to be selected from (C by one or two1-C3) low alkyl group, halogen, amino, (C1-C3) lower alkoxy or (C1-C3) low-grade alkyl amino the phenyl ring that arbitrarily replaces of substituent, and A-B, Ra, Rb, R1, R2, R4, R5, R7, R8, R9, R10, R25, X, the definition of cyclic hydrocarbon radical is with claim 1.
41. compound according to claim 1, Y represents-(CH2)n-, wherein n represents integer 0；R3Represent groupWherein Ar is selected from group
Figure A9619256800222
And R6Selected from following radicals
Figure A9619256800223
Wherein Ar ' is selected from group
Figure A9619256800231
W ' is O or S；And groupRepresent to be selected from (C by one or two1-C3) low alkyl group, halogen, amino, (C1-C3) lower alkyl amino the phenyl ring that arbitrarily replaces of substituent, and A-B, Ra, Rb, R1, R2, R4, R5, R7, R8, R9, R10, R25, X, the definition of cyclic hydrocarbon radical is with claim 1.
42. compound according to claim 1, wherein Y are selected from O, S, NH, NCOCH3With N- low alkyl groups (C1-C3)；R3Represent groupWherein Ar is selected from group
Figure A9619256800234
And R6Selected from following radicalsWherein Ar ' is selected from groupW ' is O or S；And group
Figure A9619256800243
Represent to be selected from (C by one or two1-C3) low alkyl group, halogen, amino, (C1-C3) lower alkoxy or (C1-C3) low-grade alkyl amino the phenyl ring that arbitrarily replaces of substituent, and A-B, Ra, Rb, R1, R2, R4, R5, R7, R8, R9, R10, R25, X, the definition of cyclic hydrocarbon radical is with claim 1.
43. compound according to claim 1, wherein Y represent-(CH2)n-, wherein n represents integer 0；R3Represent groupWherein Ar is selected from group
Figure A9619256800251
And R6Selected from following radicalsWherein Ar ' is selected from groupW ' is O or S；And groupRepresent fragrant (unsaturation) heterocycle of 6- members containing a nitrogen heteroatom, and A-B, Ra, Rb, R1, R2, R4, R5, R7, R8, R9, R10, R25, X, the definition of cyclic hydrocarbon radical is with claim 1.
44. compound according to claim 1, wherein Y represent-CH2-；R3Represent group
Figure A9619256800261
Wherein Ar is selected from groupAnd R6Selected from following radicals
Figure A9619256800263
Wherein Ar ' is selected from group
Figure A9619256800264
W ' is O or S；And group
Figure A9619256800271
Represent fragrant (unsaturation) heterocycle of 6- members containing a nitrogen heteroatom, and A-B, Ra, Rb, R1, R2, R4, R5, R7, R8, R9, R10, R25, X, the definition of cyclic hydrocarbon radical is with claim 1.
45. compound according to claim 1, wherein Y represent-(CH2)n-, wherein n represents integer 0；R3Represent group
Figure A9619256800272
Wherein Ar is selected from groupAnd R6Selected from following radicals
Figure A9619256800274
Figure A9619256800281
Wherein Ar ' is selected from group
Figure A9619256800282
W ' is O or S；And group
Figure A9619256800283
Represent fragrant (unsaturation) heterocycle of 5- members containing a sulfur heteroatom, and A-B, Ra, Rb, R1, R2, R4, R5, R7, R8, R9, R10, R25, X, the definition of cyclic hydrocarbon radical is with claim 1.
46. compound according to claim 1, wherein Y represent-CH2-；R3Represent group
Figure A9619256800284
Wherein Ar is selected from groupAnd R6Selected from following radicals Wherein Ar ' is selected from groupW ' is O or S；And group
Figure A9619256800293
Represent fragrant (unsaturation) heterocycle of 5- members containing a sulfur heteroatom, and A-B, Ra, Rb, R1, R2, R4, R5, R7, R8, R9, R10, R25, X, the definition of cyclic hydrocarbon radical is with claim 1.
47. compound according to claim 1, wherein Y are selected from O, S, NH, NCOCH3With N- low alkyl groups (C1-C3)；R3Represent group
Figure A9619256800294
Wherein Ar is selected from group
Figure A9619256800301
And R6Selected from following radicalsWherein Ar ' is selected from group
Figure A9619256800303
W ' is O or S；And group
Figure A9619256800304
Represent fragrant (unsaturation) heterocycle of 5- members containing a sulfur heteroatom, and A-B, Ra, Rb, R1, R2, R4, R5, R7, R8, R9, R10, R25, X, the definition of cyclic hydrocarbon radical is with claim 1.
48. compound and its officinal salt selected from following formula：Wherein m represents integer 1 or 2；R1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3, low alkyl group (C1-C3), O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：Wherein Ar represents to be selected from following groups：
Figure A9619256800312
R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula parts
Figure A9619256800313
Figure A9619256800321
Wherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen ,-CH3Or-C2H5, or represent following formula parts：-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen ,-CH3Or-C2H5；(b) formula part：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),
Figure A9619256800331
It is 0-3 with p；X represents O, S, NH, NCH3,
Figure A9619256800332
Or key and R5And R7It is as defined above (c) formula part：
Figure A9619256800333
Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：
Figure A9619256800334
Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：
Figure A9619256800342
Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：
Figure A9619256800343
Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicals
Figure A9619256800351
R8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or-NH- low alkyl groups (C1-C3), N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；R25Selected from following radicals：W ' is selected from O, S, NH, N- low alkyl groups (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3) or NSO2Low alkyl group (C1-C3)。
49. compound and its officinal salt selected from following formula：
Figure A9619256800353
Wherein Y is selected from O, S, NH, and N- low alkyl group (C1-C3)；R1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3, low alkyl group (C1-C3), O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2, NH low alkyl groups (C1-C3) ,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：
Figure A9619256800361
Wherein Ar represents to be selected from following groups：
Figure A9619256800362
R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula parts
Figure A9619256800371
Wherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen, CH3, C2H5, or represent following formula parts：-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen, CH3Or C2H5；Formula part (b)：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),
Figure A9619256800381
It is 0-3 with p；X represents O, S, NH, NCH3,
Figure A9619256800382
Or key and R5And R7It is as defined above (c) formula part：
Figure A9619256800383
Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：
Figure A9619256800384
Figure A9619256800391
Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：
Figure A9619256800392
Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicals
Figure A9619256800401
R8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or-NH- low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；R25Selected from following radicals：
Figure A9619256800402
W ' is selected from O, S, NH, N- low alkyl groups (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3) or NSO2Low alkyl group (C1-C3)。
50. compound according to claim 1, the compound is N- [5- [(6,11- dihydro -5H- dibenzo [b, e] azepines -5- bases) carbonyl] -2- pyridine radicals] [1,1 '-xenyl] -2- formamides.
51. compound according to claim 1, the compound is N- [5- [(6,11- dihydro -5H- dibenzo [b, e] azepines -5- bases) carbonyl] -2- pyridine radicals] -2- dimethylamino naphthyridine -3- formamides.
52. compound according to claim 1, the compound is N- [5- [(9,10- dihydro -4H- thienos [2,3-c] [1] benzazepines -9- bases) carbonyl] -2- pyridine radicals] [1,1 '-xenyl] -2- formamides.
53. compound according to claim 1, the compound is N- [5- [(9,10- dihydro -4H- thienos [2,3-c] [1] benzazepines -9- bases) carbonyl] -2- pyridine radicals] -2- dimethylamino naphthyridine -3- formamides.
54. compound according to claim 1, the compound is N- [5- [(4,10- dihydro -5H- thienos [3,2-c] [1] benzazepines -5- bases) carbonyl] -2- pyridine radicals] [1,1 '-xenyl] -2- formamides.
55. compound according to claim 1, the compound is N- [5- [(4,10- dihydro -5H- thienos [3,2-c] [1] benzazepines -5- bases) carbonyl] -2- pyridine radicals] -2- dimethylamino naphthyridine -3- formamides.
56. compound according to claim 1, the compound is N- [5- [(9,10- dihydro -4H- thienos [2,3-c] [1] benzazepines -9- bases) carbonyl] -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides.
57. compound according to claim 1, the compound is N- [5- [(4,10- dihydro -5H- thienos [3,2-c] [1] benzazepines -5- bases) carbonyl] -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides.
58. compound according to claim 1, the compound is N- [5- [(4,5- dihydro-pyrazolos [4,3-d] [1] benzazepines -6 (1H)-yl) carbonyl] -2- pyridine radicals] -2- dimethylamino naphthyridine -3- formamides.
59. compound according to claim 1, the compound is N- [5- [(4,5- dihydro-pyrazolos [4,3-d] [1] benzazepines -6 (1H)-yl) carbonyl] -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides.
60. compound according to claim 1, the compound is N- [5- (pyrido [2,3-b] [Isosorbide-5-Nitrae] Benzoxazepine -5- (6H)-base carbonyl) -2- pyridines] -5- fluoro-2-methylbenzene formamides.
61. the pharmaceutical composition available for the treatment following diseases of mammal：Excessive kidney fluid reabsorption and congestive heart disease, cirrhosis, renal syndrome, tuberculosis and hyponatremia, said composition include claim 1 compound of suitable pharmaceutical acceptable carrier and effective dose.
62. the method for the following diseases for the treatment of：Excessive fluid reabsorption and congestive heart disease, cirrhosis, renal syndrome, tuberculosis and hyponatremia, this method include applying claim 1 compound for mitigating condition effective amount to the mammal.
63. prepare the method for compounds of formula I：
Figure A9619256800421
Formulas I wherein Y is selected from (CH2)n, O, S, NH, NCOCH3, N- low alkyl groups (C1-C3), CH- low alkyl groups (C1-C3), CHNH- low alkyl groups (C1-C3), CHNH2, CHN [low alkyl group (C1-C3)]2, CHO- low alkyl groups (C1-C3), CHS- low alkyl groups (C1-C3), wherein n is 0-2 integer；A-B is
Figure A9619256800422
Wherein m is 1-2 integer, and condition is when Y is-(CH2)n- and during n=2, m may also indicate that 0 and when n is 0, m may also indicate that 3, and condition is also included when Y is-(CH2)nDuring with n=2, M can not also be 2；R1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3, low alkyl group (C1-C3), O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：Wherein Ar represents to be selected from following groups：
Figure A9619256800424
Figure A9619256800431
R4Selected from hydrogen, low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3)；R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula parts
Figure A9619256800441
Wherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen, CH3, C2H5, or represent following formula parts：-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen, CH3, C2H5；Formula part (b)：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),It is 0-3 with p；X represents O, S, NH, NCH3,
Figure A9619256800451
Or key and R5And R7It is as defined above, (c) formula part：
Figure A9619256800452
Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：Or expression-CH2- K, wherein K represent halogen ,-OH, tetrahydrofuran, the heterocyclic radical of thiophane or following formula：
Figure A9619256800454
Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicals
Figure A9619256800462
R8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or-NH- low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；R25Selected from following radicals：
Figure A9619256800463
Figure A9619256800471
W ' is selected from O, S, NH, N- low alkyl groups (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3)；And groupRepresent：(1) phenyl or by one or two be selected from (C1-C3) low alkyl group, halogen, amino, (C1-C3) lower alkoxy or (C1-C3) low-grade alkyl amino the phenyl that arbitrarily replaces of substituent；(2) containing fragrant (undersaturated) heterocycle of heteroatomic 5- members selected from O, N or S；(3) fragrant (undersaturated) heterocycle of 6- members containing a nitrogen-atoms；(4) fragrant (undersaturated) heterocycle of 5- or 6- member containing two nitrogen-atoms；(5) fragrant (undersaturated) heterocycle of 5- members containing a nitrogen-atoms and an oxygen atom or a sulphur atom；5- or 6- circle heterocycles therein can be by (C1-C3) low alkyl group, formoxyl, following formula group：Halogen or (C1-C3) lower alkoxy is optionally substituted；This method includes：Make following formula: compound：
Figure A9619256800474
Reacted with following formula: compound：What wherein the formula part was represented is aroyl chloride or aryl carboxylic acid, by being converted into mixed acid anhydride or being activated using peptide coupling reagent, obtains compound of formula I.
64. compound and its officinal salt selected from following formula：R1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3, low alkyl group (C1-C3), O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：
Figure A9619256800483
Wherein Ar represents to be selected from following groups：
Figure A9619256800491
O, S ,-NCH are represented with X3Or-NH；R is independently selected from hydrogen, low alkyl group (C1-C3),
Figure A9619256800492
-(CH2)q- OH ,-(CH2)q- O- alkyl (C1-C3)；Q is 1,2 or 3；R4Selected from hydrogen, low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3)；R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula parts
Figure A9619256800493
Wherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen, CH3, C2H5, or represent following formula parts：
Figure A9619256800502
-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen, CH3, C2H5；Formula part (b)：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),
Figure A9619256800503
Figure A9619256800511
It is 0-3 with p；X represents O, S, NH, NCH3,
Figure A9619256800512
Or key and R5And R7It is as defined above (c) formula part：Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：
Figure A9619256800514
Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：
Figure A9619256800521
Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicals
Figure A9619256800523
Figure A9619256800531
R8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or-NH- low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；R25Selected from following radicals：
Figure A9619256800532
W ' is selected from O, S, NH, N- low alkyl groups (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3)。
65. compound and its officinal salt selected from following formula：
Figure A9619256800533
R1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3, low alkyl group (C1-C3), O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：
Figure A9619256800541
Wherein Ar represents to be selected from following groups：
Figure A9619256800542
R is independently selected from hydrogen, low alkyl group (C1-C3),-(CH2)q- OH ,-(CH2)q- O- alkyl (C1-C3)；Q is 1 or 2；R4Selected from hydrogen, low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3)；R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula partsWherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen, CH3, C2H5, or represent following formula parts：-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen ,-CH3Or-C2H5；Formula part (b)：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),
Figure A9619256800562
It is 0-3 with p；X represents O, S, NH, NCH3,
Figure A9619256800571
Or key and R5And R7It is as defined above (c) formula part：
Figure A9619256800572
Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：
Figure A9619256800573
Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：
Figure A9619256800575
Figure A9619256800581
Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicals
Figure A9619256800582
R8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or-NH- low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；R25Selected from following radicals： W ' is selected from O, S, NH, N- low alkyl groups (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3)。
66. compound and its officinal salt selected from following formula：R1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3, low alkyl group (C1-C3), O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：Wherein Ar represents to be selected from following groups：
Figure A9619256800601
R is independently selected from hydrogen, halogen, low alkyl group (C1-C3),
Figure A9619256800602
-(CH2)q- OH ,-(CH2)q- O- alkyl (C1-C3)；Q is 1 or 2；R4Selected from hydrogen, low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3)；R5Represent hydrogen ,-CH3,-C2H5, Cl, Br, F ,-O-CH3Or-O-C2H5；R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula parts
Figure A9619256800603
Figure A9619256800611
Wherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen, CH3, C2H5, or represent following formula parts：-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen ,-CH3Or-C2H5；Formula part (b)：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),
Figure A9619256800621
It is 0-3 with p；X represents O, S, NH, NCH3,
Figure A9619256800622
Or key and R5And R7It is as defined above (c) formula part：
Figure A9619256800623
Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：
Figure A9619256800624
Figure A9619256800631
Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：
Figure A9619256800632
Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：
Figure A9619256800633
Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicals R8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or-NH- low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；R25Selected from following radicals：W ' is selected from O, S, NH, N- low alkyl groups (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3)。
67. compound and its officinal salt selected from following formula：R1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3, low alkyl group (C1-C3), O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：Wherein Ar represents to be selected from following groups：
Figure A9619256800652
R is independently selected from hydrogen, halogen, low alkyl group (C1-C3),
Figure A9619256800653
-(CH2)q- OH ,-(CH2)q- O- alkyl (C1-C3)；Q is 1,2 or 3；R4Selected from hydrogen, low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3)；R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula partsWherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen, CH3, C2H5, or represent following formula parts：-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1 or 2；RbRepresent hydrogen ,-CH3Or-C2H5；Formula part (b)：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),It is 0-3 with p；X represents O, S, NH, NCH3,
Figure A9619256800673
Or key and R5And R7It is as defined above (c) formula part：
Figure A9619256800674
Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：
Figure A9619256800681
Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：
Figure A9619256800682
Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：
Figure A9619256800691
Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicals
Figure A9619256800692
R8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or-NH- low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；R25Selected from following radicals：
Figure A9619256800693
Figure A9619256800701
W ' is selected from O, S, NH, N- low alkyl groups (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3)。
68. compound and its officinal salt selected from following formula：Wherein A-B is represented
Figure A9619256800703
Wherein R1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3, low alkyl group (C1-C3), O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：Wherein Ar represents to be selected from following groups：
Figure A9619256800705
Figure A9619256800711
R is independently selected from hydrogen, halogen, low alkyl group (C1-C3),-(CH2)q- OH ,-(CH2)q- O- alkyl (C1-C3)；Q is 1,2 or 3；R4Selected from hydrogen, low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3)；R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula parts
Figure A9619256800713
Figure A9619256800721
Wherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen, CH3, C2H5, or represent following formula parts：-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen ,-CH3Or-C2H5；Formula part (b)：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),
P270 Fig. 2It is 0-3 with p；X represents O, S, NH, NCH3,
Figure A9619256800732
Or key and R5And R7It is as defined above (c) formula part：
Figure A9619256800733
Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C1-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：
Figure A9619256800734
Figure A9619256800741
Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：
Figure A9619256800743
Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicals R8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or-NH- low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；R25Selected from following radicals：W ' is selected from O, S, NH, N- low alkyl groups (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3)。
69. compound and its officinal salt selected from following formula：
Figure A9619256800753
Wherein Y represents-(CH2)n-, and n is integer 0 or 1；A-B is representedM is integer 1 wherein when n is 1, and m is integer 1 or 2 when n is 0；R1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3, low alkyl group (C1-C3), O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：
Figure A9619256800761
Wherein Ar represents to be selected from following groups：
Figure A9619256800762
R4Selected from hydrogen, low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3)；R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula parts
Figure A9619256800771
Wherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen ,-CH3, C2H5, or represent following formula parts：
Figure A9619256800781
-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen ,-CH3Or-C2H5；Formula part (b)：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),It is 0-3 with p；X represents O, S, NH, NCH3,Or key and R5And R7It is as defined above (c) formula part：
Figure A9619256800791
Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：
Figure A9619256800792
Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：
Figure A9619256800793
Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：
Figure A9619256800794
Figure A9619256800801
Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicals
Figure A9619256800802
R8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or-NH- low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；R25Selected from following radicals：
Figure A9619256800803
Figure A9619256800811
W ' is selected from O, S, NH, N- low alkyl groups (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3)。
70. compound and its officinal salt selected from following formula：
Figure A9619256800812
Wherein Y is selected from O, S, NH, and N- low alkyl group (C1-C3)；R1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3, low alkyl group (C1-C3), O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：
Figure A9619256800813
Wherein Ar represents to be selected from following groups：
Figure A9619256800821
R4Selected from hydrogen, low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3)；R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula parts Wherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen, CH3, C2H5, or represent following formula parts：
Figure A9619256800832
-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen ,-CH3Or-C2H5；Formula part (b)：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),It is 0-3 with p；X represents O, S, NH, NCH3,Or key and R5And R7It is as defined above (c) formula part：Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：
Figure A9619256800844
Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：
Figure A9619256800851
Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：
Figure A9619256800852
Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicalsR8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or-NH- low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；R25Selected from following radicals：W ' is selected from O, S, NH, N- low alkyl groups (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3)。
71. compound and its officinal salt selected from following formula：
Figure A9619256800862
Wherein Y is O, S, NH, and N- low alkyl group；It is with A-B
Figure A9619256800863
R1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3, low alkyl group (C1-C3), O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：
Figure A9619256800871
Wherein Ar represents to be selected from following groups：R4Selected from hydrogen, low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3)；R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula parts
Figure A9619256800881
Wherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen, CH3, C2H5, or represent following formula parts：-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen, CH3, C2H5；(b) formula part：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),It is 0-3 with p；X represents O, S, NH, NCH3,
Figure A9619256800892
Or key and R5And R7It is as defined above (c) formula part：
Figure A9619256800893
Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：
Figure A9619256800901
Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above：Ar ' is selected from following radicalsR8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or-NH- low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；R25Selected from following radicals：
Figure A9619256800912
W ' is selected from O, S, NH, N- low alkyl groups (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3)。
72. compound and its officinal salt selected from following formula：Wherein Y is O, S, NH, and N- low alkyl group (C1-C3)；It is with A-B
Figure A9619256800922
R1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3, low alkyl group (C1-C3), O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：
Figure A9619256800923
Wherein Ar represents to be selected from following groups：
Figure A9619256800924
R4Selected from hydrogen, low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3)；R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula partsWherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen, CH3, C2H5, or represent following formula parts：-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen ,-CH3Or-C2H5；Formula part (b)：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),It is 0-3 with p；X represents O, S, NH, NCH3,
Figure A9619256800943
Or key and R5And R7It is as defined above (c) formula part：
Figure A9619256800951
Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：
Figure A9619256800954
Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicalsR8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or-NH- low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；R25Selected from following radicals：
Figure A9619256800963
Figure A9619256800971
W ' is selected from O, S, NH, N- low alkyl groups (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3)。
73. according to the compound of claim 72, wherein A-B isR3Represent group：
Figure A9619256800973
Wherein Ar is selected from following radicals：And Y, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 72.
74. according to the compound of claim 72, wherein A-B is
Figure A9619256800975
Y is O；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 72.
75. according to the compound of claim 72, wherein A-B isR3Represent group：
Figure A9619256800977
Wherein Ar is selected from following radicals：
Figure A9619256800981
Y is 0；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 72.
76. according to the compound of claim 72, wherein A-B isY is NH；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 72.
77. according to the compound of claim 72, wherein A-B is P303 Fig. 5
Figure A9619256800983
R3Represent group：Wherein Ar is selected from following radicals：
Figure A9619256800985
It is NH with Y；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 72.
78. the compound selected from Formulas I, its officinal salt, ester and prodrug forms
Figure A9619256800986
Formulas I wherein Y represents (CH2)n, O, S, NH, NCOCH3, N- low alkyl groups (C1-C3), CH- low alkyl groups (C1-C3), CHNH- low alkyl groups (C1-C3), CHNH2, CHN [low alkyl group (C1-C3)]2, CHO- low alkyl groups (C1-C3), CHS- low alkyl groups (C1-C3), wherein n is 0-2 integer；A-B is
Figure A9619256800991
Wherein m is 1-2 integer, and condition is when Y is-(CH2)n- and during n=2, m may also indicate that 0 and when n is 0, m may also indicate that 3, and condition is also when Y is-(CH2)nDuring with n=2, m can not also be 2；R1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3；Low alkyl group (C1-C3)；O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：Wherein Ar represents to be selected from following groups：
Figure A9619256801001
X represents O, S, NCH3, or NHR4Represent hydrogen, low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3)；R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula partsWherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen, CH3, C2H5, or represent following formula parts：-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen ,-CH3Or-C2H5；Formula part (b)：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),
Figure A9619256801012
It is 0-3 with p；X represents O, S, NH, NCH3,Or key and R5And R7It is as defined above (c) formula part：Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：
Figure A9619256801022
Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：
Figure A9619256801023
Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：
Figure A9619256801031
Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicalsR8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or NH low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；W ' expressions O, S, NH, N- low alkyl group (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3)；R25Selected from following radicals：
Figure A9619256801041
And group
Figure A9619256801051
Represent：Fragrant (undersaturated) heterocycle of 6- members containing a nitrogen-atoms, described fragrant (undersaturated) heterocycle of 6- members containing a nitrogen-atoms can be by (C1-C3) low alkyl group, formoxyl, following formula group：
Figure A9619256801052
Halogen or (C1-C3) lower alkoxy is optionally substituted.
79. compound and its officinal salt selected from Formulas I
Figure A9619256801053
Wherein Y represents-(CH2)-, O, S, NH, NCOCH3, N- low alkyl groups (C1-C3), CH- low alkyl groups (C1-C3), CHNH- low alkyl groups (C1-C3), CHNH2, CHN [low alkyl group (C1-C3)]2, CHO- low alkyl groups (C1-C3), CHS- low alkyl groups (C1-C3)；A-B isR1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3；Low alkyl group (C1-C3)；O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：
Figure A9619256801055
Wherein Ar represents to be selected from following groups：
Figure A9619256801061
R4Represent hydrogen, low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3)；R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula partsWherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen, CH3, C2H5, or represent following formula parts：
Figure A9619256801072
-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen ,-CH3Or-C2H5；Formula part (b)：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),It is 0-3 with p；X represents O, S, NH, NCH3,
Figure A9619256801082
Or key and R5And R7It is as defined above (c) formula part：
Figure A9619256801083
Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：
Figure A9619256801093
Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicalsR8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or NH low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；R25Selected from following radicals：W ' expression O, S, NH, N- low alkyl groups (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3)。
80. according to the compound of claim 79, wherein A-B is
Figure A9619256801111
R3Represent group：Wherein Ar is selected from following formula parts：And Y, Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 79.
81. according to the compound of claim 79, wherein A-B is represented
Figure A9619256801114
Y represents-(CH2)-；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 79.
82. according to the compound of claim 79, wherein A-B is represented
Figure A9619256801115
Y is O；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 79.
83. according to the compound of claim 79, wherein A-B is representedY represents NH；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 79.
84. according to the compound of claim 79, wherein A-B is represented
Figure A9619256801121
R3Represent group：
Figure A9619256801122
Wherein Ar is selected from following formula parts：
Figure A9619256801123
Y represents-(CH2)-；；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 79.
85. according to the compound of claim 79, wherein A-B is represented
Figure A9619256801124
R3Represent group：Wherein Ar is selected from following formula parts：
Figure A9619256801126
Y represents O；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 79.
86. according to the compound of claim 79, wherein A-B is represented
Figure A9619256801131
R3Represent group：Wherein Ar is selected from following formula parts：
Figure A9619256801133
Y represents NH；；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 79.
87. selected from compounds of formula I and its officinal salt, ester and prodrug forms,
Figure A9619256801134
Formulas I wherein Y represents-(CH2)n-, O, S, NH, NCOCH3, N- low alkyl groups (C1-C3), CH- low alkyl groups (C1-C3), CHNH- low alkyl groups (C1-C3), CHNH2, CHN [low alkyl group (C1-C3)]2, CHO- low alkyl groups (C1-C3), CHS- low alkyl groups (C1-C3)；Wherein n is 0-2 integer；A-B isWherein m is 1-2 integer, and condition is when Y is-(CH2)n- and during n=2, m may also indicate that 0 and when n is 0, m may also indicate that 3, and condition is also when Y is-(CH2)nDuring with n=2, m can not also be 2；R1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3；Low alkyl group (C1-C3)；O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：
Figure A9619256801141
Wherein Ar represents to be selected from following groups：
Figure A9619256801142
O, S ,-NCH are represented with X3Or-NHR4Represent hydrogen, low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3)；R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula parts
Figure A9619256801151
Wherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen, CH3, C2H5, or represent following formula parts：
Figure A9619256801161
-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen ,-CH3Or-C2H5；Formula part (b)：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),It is 0-3 with p；X represents O, S, NH, NCH3,
Figure A9619256801171
Or key and R5And R7It is as defined above (c) formula part：Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：
Figure A9619256801173
Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：
Figure A9619256801181
Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicalsR8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or NH low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；W ' expression O, S, NH, N- low alkyl groups (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3), R25Selected from following radicals：And group：
Figure A9619256801192
Represent：Fragrant (undersaturated) heterocycle of 5- members containing a sulfur heteroatom, described fragrant (undersaturated) heterocycle of 5- members can be by (C1-C3) low alkyl group, formoxyl, following radicals, halogen or (C1-C3) lower alkoxy is optionally substituted.
88. selected from compounds of formula I and its officinal saltWherein Y represents-(CH2)-, O, S, NH, and N- low alkyl group (C1-C3)；A-B is representedR1Represent hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH ,-S- low alkyl groups (C1-C3) ,-SH ,-SO low alkyl groups (C1-C3) ,-SO2- low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3) ,-CF3；Low alkyl group (C1-C3)；O- low alkyl groups (C1-C3) ,-NO2,-NH2,-NHCO low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-SO2NH2；-SO2NH low alkyl groups (C1-C3) or-SO2N [low alkyl group (C1-C3)]2；R2Represent hydrogen, Cl, Br, F, I ,-OH, low alkyl group (C1-C3), O- low alkyl groups (C1-C3), or R1And R2It is common to represent methylene-dioxy or ethylenedioxy；R3Represent following radicals：
Figure A9619256801202
Wherein Ar represents to be selected from following groups：
Figure A9619256801203
R4Represent hydrogen, low alkyl group (C1-C3) ,-CO- low alkyl groups (C1-C3)；R5And R7Selected from hydrogen, (C1-C3) low alkyl group, (C1-C3) lower alkoxy and halogen；R6Selected from (a) following formula parts
Figure A9619256801211
Wherein cyclic hydrocarbon radical is defined as C3-C6Cycloalkyl, cyclohexenyl group or cyclopentenyl；RaRepresent hydrogen, CH3, C2H5, or represent following formula parts：-(CH2)2- O- low alkyl groups (C1-C3) or-CH2CH2OH；Q is 1,2 or 3；RbRepresent hydrogen ,-CH3Or-C2H5；Formula part (b)：-X-R10；Wherein R10Represent low alkyl group (C3-C8), low-grade alkenyl (C3-C8) ,-(CH2)p- cycloalkyl (C3-C6),
Figure A9619256801222
It is 0-3 with p；X represents O, S, NH, NCH3,
Figure A9619256801231
Or key and R5And R7It is as defined above (c) formula part：Wherein J represents Ra, side chain or non-branched low alkyl group (C3-C8), side chain or non-branched low-grade alkenyl (C3-C8), O- side chains or non-branched low alkyl group (C3-C8) ,-O- side chains or non-branched low-grade alkenyl (C3-C8), tetrahydrofuran, thiophane, or represent following radicals：
Figure A9619256801233
Or expression-CH2The heterocyclic radical of-K ', wherein K ' expressions halogen ,-OH, tetrahydrofuran, thiophane or following formula：Wherein D, E, F and G are selected from carbon or nitrogen and carbon atom therein can be by halogen, (C1-C3) low alkyl group, hydroxyl ,-CO- low alkyl groups (C1-C3), CHO, (C1-C3) lower alkoxy ,-CO2- low alkyl group (C1-C3) optionally replace, and RaAnd RbIt is as defined above；(d) it is selected from the group of following formulas：
Figure A9619256801241
Wherein RcSelected from halogen, (C1-C3) low alkyl group ,-O- low alkyl groups (C1-C3) and OH, RbIt is as defined above；Ar ' is selected from following radicals
Figure A9619256801242
R8And R9Independently represent hydrogen, low alkyl group (C1-C3)；O- low alkyl groups (C1-C3)；S- low alkyl groups (C1-C3) ,-CF3,-CN ,-OH ,-SCF3,-OCF3, halogen, NO2, amino or NH low alkyl groups (C1-C3) ,-N- [low alkyl group (C1-C3)]2,-N (Rb)(CH2)q-N(Rb)2；R25Selected from following radicals：
Figure A9619256801251
W ' expressions O, S, NH, N- low alkyl group (C1-C3), NCO- low alkyl groups (C1-C3) or NSO2- low alkyl group (C1-C3)。
89. according to the compound of claim 88, wherein A-B is
Figure A9619256801252
R3Represent group：
Figure A9619256801253
Wherein Ar is selected from following formula parts：
Figure A9619256801254
And Y, Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 88.
90. according to the compound of claim 88, wherein A-B is representedY represents-(CH2)-；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 88.
91. according to the compound of claim 88, wherein A-B is representedY is O；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 88.
92. according to the compound of claim 88, wherein A-B is representedY represents NH；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 88.
93. according to the compound of claim 88, wherein A-B is represented
Figure A9619256801264
R3Represent group：Wherein Ar is selected from following formula parts：
Figure A9619256801266
Y represents-(CH2)-；；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 88.
94. according to the compound of claim 88, wherein A-B is representedR3Represent group：
Figure A9619256801272
Wherein Ar is selected from following formula parts：
Figure A9619256801273
Y represents NH；；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 88.
95. according to the compound of claim 88, wherein A-B is represented
Figure A9619256801274
R3Represent group：
Figure A9619256801275
Wherein Ar is selected from following formula parts：
Figure A9619256801276
Y represents O；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 88.
96. compound according to claim 1, the compound is N- [4- (dibenzo [b, f] [Isosorbide-5-Nitrae] oxazepin -10 (11H)-base carbonyl)-phenyl] [1,1 '-xenyl] -2- formamides.
97. compound according to claim 1, the compound is N- [4- (dibenzo [b, f] [Isosorbide-5-Nitrae] oxazepin -10 (11H)-base carbonyl) -3- chlorphenyls] [1,1 '-xenyl] -2- formamides.
98. compound according to claim 1, the compound is N- [5- (dibenzo [b, f] [Isosorbide-5-Nitrae] oxazepin -10 (11H)-base carbonyl) -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides.
99. compound according to claim 1, the compound is N- [5- (dibenzo [b, f] [Isosorbide-5-Nitrae] oxazepin -10 (11H)-base carbonyl) -2- pyridine radicals] -2- (4- pyridine radicals) benzamide.
100. compound according to claim 1, the compound is N- [5- (pyrido [2,3-b] [1,5] Benzoxazepine -6 (5H)-base carbonyl) -2- pyridine radicals] [1,1 '-xenyl] -2- formamides.
101. compound according to claim 1, the compound is N- [5- (pyrido [2,3-b] [Isosorbide-5-Nitrae] Benzoxazepine -5 (6H)-base carbonyl) -2- pyridine radicals] [1,1 '-xenyl] -2- formamides.
102. compound according to claim 1, the compound is N- [4- (pyrido [2,3-b] [Isosorbide-5-Nitrae] Benzoxazepine -5 (6H)-base carbonyl) -3- chlorphenyls] [1,1 '-xenyl] -2- formamides.
103. compound according to claim 1, the compound is N- [4- (6,11- dihydro pyridos [2,3-b] [1,5] benzodiazepine  -6 (5H)-base carbonyl)-phenyl] [1,1 '-xenyl] -2- formamides.
104. compound according to claim 1, the compound is N- [4- (6,11 dihydro pyridos [2,3-b] [1,5] benzodiazepine  -6 (5H)-base carbonyl) -3- chlorphenyls] [1,1 '-xenyl] -2- formamides.
105. compound according to claim 1, the compound is N- [4- (6,11 dihydro pyridos [2,3-b] [1,5] benzodiazepine  -6 (5H)-base carbonyl)-phenyl] [1,1 '-xenyl] -2- carboxamide hydrochlorides.
106. compound according to claim 1, the compound is N- [4- [(5,11- dihydro -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza  -10- bases) carbonyl] -3- chlorphenyls] [1,1 '-xenyl] -2- formamides.
107. compound according to claim 1, the compound is N- [4- [(5,11- dihydro -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza  -10- bases) carbonyl]-phenyl] [1,1 '-xenyl] -2- formamides.
108. compound according to claim 1, the compound is N- [4- [(5,11- dihydro -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza  -10- bases) carbonyl] -3- aminomethyl phenyls] [1,1 '-xenyl] -2- formamides.
109. compound according to claim 1, the compound is N- [4- [(5,11- dihydro -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza  -10- bases) carbonyl] -2- aminomethyl phenyls] [1,1 '-xenyl] -2- formamides.
110. compound according to claim 1, the compound is N- [4- [(5,11- dihydro -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza  -10- bases) carbonyl] -2- chlorphenyls] [1,1 '-xenyl] -2- formamides.
111. compound according to claim 1, the compound is N- [4- [(6,11- dihydro -5H- dibenzo [b, e] azepines -5- bases) carbonyl]-phenyl] [1,1 '-xenyl] -2- formamides.
112. compound according to claim 1, the compound is N- [4- [(6,11- dihydro -5H- dibenzo [b, e] azepines -5- bases) carbonyl] -3- chlorphenyls] [1,1 '-xenyl] -2- formamides.
113. compound according to claim 1, the compound is N- [4- [(6,11- dihydro -5H- dibenzo [b, e] azepines -5- bases) carbonyl] -3- aminomethyl phenyls] [1,1 '-xenyl] -2- formamides.
114. compound according to claim 1, the compound is N- [4- [(6,11- dihydro -5H- dibenzo [b, e] azepines -5- bases) carbonyl] -2- chlorphenyls] [1,1 '-xenyl] -2- formamides.
115. compound according to claim 1, the compound is N- [5- [(6,11- dihydro -5H- pyridos [2,3-b] [Isosorbide-5-Nitrae] benzodiazepine  -5- bases) carbonyl] -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides.
116. compound according to claim 1, the compound is N- [4- [(6,11- dihydro -5H- pyridos [2,3-b] [1,4] benzodiazepine  -5- bases) carbonyl] -3- chlorphenyls] [1,1 '-xenyl] -2- formamides.
117. compound according to claim 1, the compound is N- [4- [(6,11- dihydro -5H- pyridos [2,3-b] [Isosorbide-5-Nitrae] benzodiazepine  -5- bases) carbonyl]-phenyl] [1,1 '-xenyl] -2- formamides.
118. compound according to claim 1, the compound is N- [4- [(6,11- dihydro -5H- pyridos [2,3-b] [1,4] benzodiazepine  -5- bases) carbonyl] -3- aminomethyl phenyls] [1,1 '-xenyl] -2- formamides.
119. compound according to claim 1, the compound is N- [4- [(4,5- dihydro-pyrazolos [4,3-d] [1] benzazepines -6 (1H)-yl) carbonyl] phenyl] [1,1 '-xenyl] -2- formamides.
120. compound according to claim 1, the compound is N- [4- [(4,5- dihydro-pyrazolos [4,3-d] [1] benzazepines -6 (1H)-yl) carbonyl] -3- chlorphenyls] [1,1 '-xenyl] -2- formamides.
121. compound according to claim 1, the compound is N- [5- [(4,5- dihydro-pyrazolos [4,3-d] [1] benzazepines -6 (1H)-yl) carbonyl] -2- pyridine radicals] [1,1 '-xenyl] -2- formamides.
122. compound according to claim 1, the compound is N- [5- [(4,5- dihydro-pyrazolos [4,3-d] [1] benzazepines -6 (1H)-yl) carbonyl] -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides.
123. compound according to claim 1, the compound is N- [5- (4H- thienos [3,4-b] [1,5] benzodiazepine  -9 (10H)-yl) -2- pyridine radicals] -5- fluoro-2-methylbenzene formamides.
124. compound according to claim 1, the compound is N- [4- (4H- thienos [3,4-b] [1,5] benzodiazepine  -9 (10H)-yl)-phenyl] [1,1 '-xenyl] -2- formamides.
125. compound according to claim 1, the compound is N- [4- (4H- thienos [3,4-b] [1,5] benzodiazepine  -9 (10H)-yl) -3- chlorphenyls] [1,1 '-xenyl] -2- formamides.
126. compound according to claim 1, the compound is N- [5- (4H- thienos [3,4-b] [1,5] benzodiazepine  -9 (10H)-yl) -2- pyridine radicals] [1,1 '-xenyl] -2- formamides.
127. compound according to claim 1, the compound is 5,11- dihydros -10- [4- (2- thienyls) benzoyl] -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza .
128. compound according to claim 1, the compound is 5,11- dihydros -10- [4- (3- thienyls) benzoyl] -10H- dibenzo [b, e] [Isosorbide-5-Nitrae] diaza .
129. according to the compound of claim 79, wherein A-B is
Figure A9619256801301
R3Represent group：Wherein Ar is selected from following formula parts：
Figure A9619256801311
And Y, Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 79.
130. according to the compound of claim 79, wherein A-B is represented
Figure A9619256801312
Y represents-(CH2)-；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 79.
131. according to the compound of claim 79, wherein A-B is represented
Figure A9619256801313
Y is O；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 79.
132. according to the compound of claim 79, wherein A-B is representedY represents NH；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 79.
133. according to the compound of claim 79, wherein A-B is representedR3Represent group：Wherein Ar is selected from following formula parts：Y represents-(CH2)-；；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 79.
134. according to the compound of claim 79, wherein A-B is representedR3Represent group：
Figure A9619256801324
Wherein Ar is selected from following formula parts：
Figure A9619256801325
Y represents O；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 79.
135. according to the compound of claim 79, wherein A-B is represented
Figure A9619256801326
R3Represent group：Wherein Ar is selected from following formula parts：Y represents NH；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 79.
136. according to the compound of claim 88, wherein A-B is
Figure A9619256801333
R3Represent group：Wherein Ar is selected from following formula parts：
Figure A9619256801335
And Y, Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 88.
137. according to the compound of claim 88, wherein A-B is represented
Figure A9619256801341
Y represents-(CH2)-；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 88.
138. according to the compound of claim 88, wherein A-B is representedY is O；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 88.
139. according to the compound of claim 88, wherein A-B is representedY represents NH；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 88.
140. according to the compound of claim 88, wherein A-B is representedR3Represent group：
Figure A9619256801351
Wherein Ar is selected from following formula parts：
Figure A9619256801352
Y represents-(CH2)-；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 88.
141. represent according to the compound of claim 88, wherein A-B
Figure A9619256801353
R3Represent group：Wherein Ar is selected from following formula parts：
Figure A9619256801355
Y represents NH；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 88.
142. represent according to the compound of claim 88, wherein A-B
Figure A9619256801356
R3Represent group：Wherein Ar is selected from following formula parts：
Figure A9619256801362
Y represents O；And Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25Definition with claim 88.
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