CN107629057A

CN107629057A - BET protein inhibitors and its application

Info

Publication number: CN107629057A
Application number: CN201610572967.6A
Authority: CN
Inventors: 金华; 郑永勇; 周峰; 黄美花; 孟欣
Original assignee: Shanghai Xunhe Pharmaceutical Technology Co Ltd
Current assignee: Shanghai Xunhe Pharmaceutical Technology Co Ltd
Priority date: 2016-07-19
Filing date: 2016-07-19
Publication date: 2018-01-26
Anticipated expiration: 2036-07-19
Also published as: CN107629057B

Abstract

The present invention relates to suppress BET albumen, particularly suppress BRD4 logical formula (I) compound, and its for excess proliferative disease, be primarily referred to as preventing or treat tumor disease, hyperplasia of prostate, inflammatory disease, autoimmune disease, septicemia, virus infection, vascular diseases and neurogenic disease.

Description

BET protein inhibitors and its application

Technical field

The present invention relates to field of medicine preparing technology, more particularly to the suppression as one or more brominated domain proteins The compound of preparation.

Background technology

Epigenetics (Epigenetic) is one of current very popular drug discovery theme.Acetylation of histone is The important component of epigenetic research.Bromodomain (BRD) is that one kind being capable of acetylation in specific recognition histone The conserved protein domain of lysine (KAc), protein enrichment is promoted to turn in specific gene by being combined with acetylated lysine Site is recorded, changes the activity of rna plymerase ii, and the transcriptional expression of regulatory gene (Kuc and Allis, Bioessays, 1998,20： 615-626)。

At present, the 61 kinds of BRD domains found in human body are present in 42 kinds of albumen, according to the difference of female protein function, BRD albumen is divided into 8 extended familys, and BET protein families are the 2nd classes of BRD protein families.BET albumen include BRD2, BRD3, Tetra- members of BRD4 and BRDT (Wu and Chiang, J.Biol.chem., 2007,282：13141-13145).The extensive table of first three Only limit up in all body cells, the latter and be expressed in testis tissue.

BET albumen plays a significant role in kinds of tumors.Such as hematopoietic system cancer (acute myelocytic leukemia, lymph Knurl, Huppert's disease, B cell acute lymphatic leukaemia etc.), by disturbing BRD4 and oncogene MYC combination, can suppress MYC expression, and then cause apoptosis of tumor cells.BET albumen (BRD3 or BRD4) and NUT (are generally only expressed in testis Albumen) between fusion cause the aggressive form of squamous cell carcinoma, it is referred to as NUT center line cancers (French, Cancer Genet, Cytogenet., 2010,203：16-20).The fusion protein prevent cell differentiation and promote propagation (Yan et al., Biol.Chem., 2011,286：27663-27675), the growth of thus obtained In vivo model is suppressed by BRD4- inhibitor (Fil ppakepoulos et al., Nature, 2010,468：1067-1073).

The wider biological function of BET albumen is reported in many documents.Albumen comprising bromine domain participates in turning Record regulation and control, cause oncogene to be reset, and obtain high carcinogenic fusion protein, this plays important in the development of a variety of malignant cancers Effect.In addition, bromine domain, also comprising albumen regulation Nuclear-factor kappa B (NF-kB), this, which is that a kind of inflammatory reaction of mediation is crucial, turns Record the factor.They also participate in virus genomic duplication and adjust the transcription of some virus proteins.In summary, these eggs are targetted In vain for developing target on cancer, the new therapeutic strategy that inflammation and virus infect is probably beneficial.It is directed to this at present The micromolecular inhibitor of acceptor enters clinical stage, and it is mainly used in the treatment of cancer and autoimmune disease.

The content of the invention

An object of the present invention is to provide a kind of new BET inhibitor compounds or its pharmaceutically useful salt.

The second object of the present invention is to provide such compound and is preparing prevention or treatment as novel B ET protein inhibitors With the purposes in the medicine of BET protein related diseases, be primarily referred to as preventing or treat tumor disease, hyperplasia of prostate, inflammatory disease, Autoimmune disease, septicemia, virus infection, vascular diseases and neurogenic disease.Prevention or the treatment tumor disease includes But it is not limited to acute myeloid leukaemia, lymthoma, Huppert's disease, B cell acute lymphatic leukaemia, center line cancer, neuroglia Matter knurl, solid tumor, breast cancer, colorectal cancer, prostate cancer, cervical carcinoma, non-small cell lung cancer, melanoma etc..

To achieve the above object, the invention provides the derivative or its pharmaceutically useful salt that below formula I is represented：

Wherein：

A rings are aryl or heteroaryl；

R₁Represent hydrogen, halogen, C₁-C₃Alkyl, C₁-C₃Alkoxy；

R₂Represent methyl, trifluoromethyl, cyano group, halogen；

Y is represented

X, Z, U, V, W represent C or N respectively；

R₃Represent C₁-C₃Alkyl,

R₄Represent hydrogen, methyl, halogen, hydroxyl, cyano group, trifluoromethyl；

R₅Represent hydrogen, C₁-C₃Alkyl；

M is 0,1；

N is 0,1,2；

Present invention also offers pharmaceutical composition, the pharmaceutical composition includes at least one pharmaceutical carrier, and at least one Herein described formula (I) compound and its pharmaceutical salts, using the application as BET protein inhibitors.

" aryl or heteroaryl " described herein refers to phenyl, pyridine radicals, thienyl, furyl, pyrimidine radicals, pyrazine Base, thiazolyl, imidazole radicals；" halogen " refers to F, Cl, Br, I；Described " C₁-C₃Alkyl " refer to methyl, ethyl, positive third Base or isopropyl；Described " C₁-C₃Alkoxy " refer to methoxyl group, ethyoxyl, positive propoxy or isopropoxy.

The typical compound of the present invention includes, but are not limited to table 1 below compound：

Or its pharmaceutically useful salt.

The example of officinal salt includes inorganic salts and organic salt, such as hydrochloride, hydrobromate, sulfate, phosphate, lemon Lemon hydrochlorate, tartrate, succinate, maleate, fumarate, tonsillotome hydrochlorate and oxalates.

The compound of the present invention can use following synthesis to lead to method and prepare：

According to document (J.Med.Chem.2011 such as C Chung, H Coste, 54 (11)：3827-3838 and HARBESON The WO2015120393A1 such as SCOTT L) in report program prepare end-product I, i.e. substituted-amino arone (I₁) and Fmoc-L- days The chloro- 4- methyl esters (I of winter aminoacyl₂) through condensation reaction amide intermediate (I is made₃), I₃Through deprotection, cyclization, vulcanization, condensation, ring Target product I is made in the steps such as conjunction, hydrolysis, condensation.

The present invention provides such compound and is preparing prevention as novel B ET protein inhibitors or treating and BET albumen phases Purposes in the medicine of related disorders, it is primarily referred to as preventing or treats tumor disease, hyperplasia of prostate, inflammatory disease, autoimmunity disease Disease, septicemia, virus infection, vascular diseases and neurogenic disease.Prevention or the treatment tumor disease includes but is not limited to anxious Property myelogenous leukemia, lymthoma, Huppert's disease, B cell acute lymphatic leukaemia, center line cancer, glioma, entity Knurl, breast cancer, colorectal cancer, prostate cancer, cervical carcinoma, non-small cell lung cancer, melanoma etc..

The derivative of the present invention can pass through the sides such as oral, injection in treatment of diseases is implemented with the formation of composition Formula, for treating associated cancer and other diseases.

The composition includes the above-claimed cpd or its pharmaceutically useful salt and medically acceptable load of therapeutically effective amount Body.

The carrier addressed refers to the conventional carrier of pharmaceutical field, such as：Diluent, excipient such as water etc.；Adhesive such as fibre Tie up plain derivative, gelatin, polyvinylpyrrolidone etc.；Filler such as starch etc.；Burst apart agent such as calcium carbonate, sodium acid carbonate；In addition, Other adjuvants such as flavouring agent and sweetener can also be added in the composition.

For it is oral when, conventional solid pharmaceutical preparation such as tablet, pulvis or capsule etc. can be prepared into；During for injecting, Parenteral solution can be prepared into.

It is prepared by the method that the various formulations of the composition of the present invention can use medical domain conventional, wherein activity into The content divided is 0.1%~99.5% (weight ratio).

The amount of application of the present invention can be according to route of administration, the age of patient, body weight, the type for the disease treated and serious Degree etc. is changed, and its daily dose is 0.005-30mg/kg body weight (oral) or 0.005-30mg/kg body weight (injection).

Embodiment

With reference to specific embodiment, the present invention is further elaborated, but these embodiments are not intended to limit the model of the present invention Enclose.

Embodiment 1

Compound (I-1) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (methyl sulphonyl) acetamide

Step 1：Intermediate compound I₃Preparation：[2- amino -5- (methyl epoxide) phenyl] (4- chlorphenyls) ketone (I₁, 5.0g, 19.1mmol), diisopropylethylamine (4.9g, 38.2mmol) is added in dichloromethane (50mL), and lower dropwise addition Fmoc- is stirred at room temperature The chloro- 4- methyl esters (I of L- aspartoyls₂, 7.4g, 19.1mmol), rear room temperature stirring reaction 5h is added, reaction solution adds H₂O (50mL) is stirred Extraction is mixed, organic layer is dry, filters, is concentrated to give intermediate compound I₃(10.5g, yield 90%), MS (m/z)：614[M+H]⁺。

Step 2：Intermediate compound I₄Preparation：Acid amides I₃(10g, 16.3mmol), triethylamine (24.7g, 245mmol) add two In chloromethanes (100mL), reflux temperature reaction 5h is heated to.Concentrated solvent adds dichloroethanes (50mL), second to doing in residue Sour (9.8g, 163mmol), it is heated to 60 DEG C of reaction 2h.Reaction solution 1N diluted hydrochloric acid aqueous solutions (30mL) are washed, and anhydrous sodium sulfate is done It is dry, it is concentrated to dryness.Residue absolute ethyl alcohol (20mL) is beaten 30min, filtering, is dried in vacuo to obtain intermediate compound I₄(4.9g, yield 81.2%), MS (m/z)：374[M+H]⁺。

Step 3：Intermediate compound I₅Preparation：Phosphoric sulfide (4.8g, 21.7mmol), sodium carbonate (2.3g, 21.7mmol) add Enter in dichloroethanes (50mL), 1h is stirred at room temperature in the mixture.I₄(4.5g, 12.1mmol) is added in above-mentioned reaction solution, heating To 70 DEG C of reaction 5h.It is cooled to room temperature, filters.Filtrate is through H₂O (50mL) is washed, liquid separation, and organic layer is through anhydrous sodium sulfate drying, concentration It is extremely dry to obtain crude product sulphamide intermediate compound I₅(3.3g, yield 71%), MS (m/z)：390[M+H]⁺.The crude product is not added with purifying, directly For the next step.

Step 4：Intermediate compound I₆Preparation：Sulphamide intermediate compound I₅(3g, 7.7mmol) is dissolved in tetrahydrofuran (30mL), drop Temperature stirs lower dropwise addition hydrazine hydrate (1.1g, 23.1mmol), in this thermotonus 5h after adding to 0-5 DEG C.Three are added in reaction solution Ethamine (2.3g, 23.1mmol), and kept for 0-5 DEG C chloroacetic chloride (1.8g, 23.1mmol) is added dropwise, and it is warmed to room temperature reaction 2h.Add Enter H₂O (30mL)/ethyl acetate (50mL) stirring extraction, liquid separation, organic layer are concentrated to dryness to obtain crude product through anhydrous sodium sulfate drying Intermediate compound I₆(3.2g, yield 98%), MS (m/z)：430[M+H]⁺。

Step 5：Triazole intermediate compound I₇Preparation：I₆(3.2g, 7.5mmol) adds tetrahydrofuran (30mL) and acetic acid In (30mL), reaction 24h is stirred at room temperature.Reaction solution is concentrated under reduced pressure into dry, residue addition saturated sodium bicarbonate aqueous solution (30mL)/dichloromethane (50mL) extracts, organic layer H again₂O (30mL) is washed, saturated aqueous common salt (30mL) is washed, and is concentrated to dryness, slightly Product cross silicagel column (mobile phase dichloromethane/methanol：100/1) triazole intermediate compound I is obtained₇(2.5g, yield 81.5%), MS (m/z)： 412[M+H]⁺。

Step 6：Sour intermediate compound I₈Preparation：Triazole intermediate compound I₇(2.5g, 6.1mmol) addition tetrahydrofuran (10mL), H₂In O (30mL), 30% sodium hydrate aqueous solution of lower dropwise addition is stirred at room temperature, and is warming up to 40-45 DEG C of reaction 5h.It is cooled to 0-5 DEG C, 1N aqueous hydrochloric acid solutions are added dropwise and adjust pH value 4-5, solid separates out, and is stirred for 30min, filters, and filter cake vacuum drying, obtains sour centre Body (S) -2- [6- (4- chlorphenyls) -8- methoxyl groups -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] phenodiazines Miscellaneous Zhuo -4- bases] acetic acid I₈(2.3g, yield 95%), MS (m/z)：398[M+H]⁺。

Step 7：Target product I-1 preparation：Sour intermediate compound I₈(0.5g, 1.26mmol), BTA-N, N, N ', N '-tetramethylurea hexafluorophosphate (HBTU, 0.52g, 1.38mmol), pyrovinic acid amine (0.13g, 1.38mmol), N, N- bis- Wopropyl ethyl amine (DIPEA, 0.32g, 2.52mmol), DMF (5mL) are added in reaction bulb, and 2h is stirred at room temperature.H is added dropwise₂O (5mL), dichloromethane (20mL), stirring extraction, organic layer again wash by saturated aqueous common salt (30mL), is concentrated to dryness, crude product crosses silica gel Post (mobile phase dichloromethane/methanol：100/1) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] are obtained [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- Methanesulfomides (I-1), white solid (322mg, yield 53.9%).MS(m/z)：475[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.88 (br, 1H), 7.78-7.74 (m, 2H), 7.68- 7.65 (m, 2H), 7.58 (s, 1H), 7.38-7.36 (d, J=8.0Hz, 1H), 7.23-7.21 (d, J=8.0Hz, 1H), 5.27 (m, 1H), 5.14-5.05 (m, 1H), 4.76-4.72 (m, 1H), 3.85 (s, 3H), 3.01 (s, 3H), 2.43 (s, 3H).

Embodiment 2

Compound (I-2) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (amino-sulfonyl) acetamide

Compound I-2 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- methoxies Base -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid (I₈) and N- (amino Sulfonyl) t-butyl carbamate, obtain (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- first after being reacted by the step 7 of embodiment 1 Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (t-butyl carbamate base sulphonyl Base) acetamide, the intermediate again through 3N hydrochloric ethyl acetates take off BOC protection after, obtain pale white solid target product (S) -2- [6- (4- chlorphenyls) -8- methoxyl groups -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] - N- (amino-sulfonyl) acetamide (I-2).MS(m/z)：476[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.82 (br, 1H), 7.77-7.74 (m, 2H), 7.69-7.65 (m, 2H), 7.56 (s, 1H), 7.41 (br, 2H), 7.37-7.35 (d, J=8.0Hz, 1H), 7.24-7.22 (d, J=8.0Hz, 1H), 5.27 (m, 1H), 5.12-5.05 (m, 1H), 4.77-4.72 (m, 1H), 3.87 (s, 3H), 2.44 (s, 3H).

Embodiment 3

Compound (I-3) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (ethylsulfonyl) acetamide

Compound I-3 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- methoxies Base -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid (I₈) and ethylsulfonic acid Amine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (ethylsulfonyl) acetamide (I-3).MS(m/z)：489[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.83 (br, 1H), 7.79-7.76 (m, 2H), 7.69-7.64 (m, 2H), 7.57 (s, 1H), 7.38- 7.36 (d, J=8.0Hz, 1H), 7.24-7.22 (d, J=8.0Hz, 1H), 5.27 (m, 1H), 5.13-5.06 (m, 1H), 4.78- 4.75 (m, 1H), 3.88 (s, 3H), 3.52-3.49 (q, J=4.0Hz, 2H), 2.42 (s, 3H), 1.25-1.23 (t, J= 4.0Hz, 3H).

Embodiment 4

Compound (I-4) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (aminosulfonyl) acetamide

Compound I-4 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- methoxies Base -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid (I₈) and methylamino sulphur Acid amides, desired product as white solid (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- are obtained after being reacted by embodiment 1 Benzo [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (aminosulfonyl) acetamide (I-4).MS (m/z)：490[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.84 (br, 1H), 7.78-7.76 (m, 2H), 7.71-7.68 (m, 2H), 7.55 (s, 1H), 7.43 (br, 1H), 7.36-7.34 (d, J=8.0Hz, 1H), 7.24-7.22 (d, J=8.0Hz, 1H), 5.26 (m, 1H), 5.14-5.07 (m, 1H), 4.78-4.72 (m, 1H), 3.88 (s, 3H), 2.44 (s, 3H), 2.35 (s, 3H).

Embodiment 5

Compound (I-5) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (sulfonyl propyl base) acetamide

Compound I-5 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- methoxies Base -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid (I₈) and propyl sulfonic acid Amine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (sulfonyl propyl base) acetamide (I-5).MS(m/z)：503[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.82 (br, 1H), 7.79-7.75 (m, 2H), 7.69-7.64 (m, 2H), 7.56 (s, 1H), 7.38- 7.36 (d, J=8.0Hz, 1H), 7.23-7.21 (d, J=8.0Hz, 1H), 5.26 (m, 1H), 5.11-5.06 (m, 1H), 4.76- 4.71 (m, 1H), 3.89 (s, 3H), 3.55-3.53 (t, J=4.0Hz, 2H), 2.45 (s, 3H), 2.05-2.02 (m, 2H), (1.24-1.22 t, J=4.0Hz, 3H).

Embodiment 6

Compound (I-6) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (ethylamino sulfonyl) acetamide

Compound I-6 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- methoxies Base -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid (I₈) and ethylamino- sulphur Acid amides, by embodiment 1 react after pale white solid target product (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl - 4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (ethylamino sulfonyl) acetamide (I- 6).MS(m/z)：504[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.82 (br, 1H), 7.79-7.76 (m, 2H), 7.73-7.69 (m, 2H), 7.56 (s, 1H), 7.46 (br, 1H), 7.36-7.34 (d, J=8.0Hz, 1H), 7.23-7.21 (d, J=8.0Hz, 1H), 5.25 (m, 1H), 5.13-5.07 (m, 1H), 4.76-4.72 (m, 1H), 3.85 (s, 3H), 3.50-3.48 (q, J= 4.0Hz, 2H), 2.46 (s, 3H), 1.23-1.21 (t, J=4.0Hz, 3H).

Embodiment 7

Compound (I-7) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (isopropelsulfonyl) acetamide

Compound I-7 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- methoxies Base -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid (I₈) and isopropyl sulphur Acid amide.Faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2, 4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (isopropelsulfonyl) acetamide (I-7).MS(m/z)：503[M+ H]⁺。¹H NMR(DMSO-d₆)：δ：8.85 (br, 1H), 7.89-7.85 (m, 2H), 7.72-7.69 (m, 2H), 7.59 (s, 1H), 7.43-7.41 (d, J=8.0Hz, 1H), 7.26-7.24 (d, J=8.0Hz, 1H), 5.29 (m, 1H), 5.10-5.06 (m, 1H), 4.77-4.71 (m, 1H), 3.88 (s, 3H), 3.61 (m, 1H), 2.47 (s, 3H), 1.36 (s, 6H).

Embodiment 8

Compound (I-8) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (the third amino-sulfonyl) acetamide

Compound I-8 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- methoxies Base -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid (I₈) and Propylamino sulphur Acid amides, by embodiment 1 react after pale white solid target product (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl - 4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (the third amino-sulfonyl) acetamide (I- 8).MS(m/z)：518[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.85 (br, 1H), 7.77-7.74 (m, 2H), 7.71-7.66 (m, 2H), 7.58 (s, 1H), 7.43 (br, 1H), 7.37-7.35 (d, J=8.0Hz, 1H), 7.24-7.22 (d, J=8.0Hz, 1H), 5.26 (m, 1H), 5.12-5.07 (m, 1H), 4.77-4.74 (m, 1H), 3.88 (s, 3H), 3.51-3.49 (t, J= 4.0Hz, 2H), 2.45 (s, 3H), 1.61-1.59 (m, 2H), 0.89-0.87 (t, J=4.0Hz, 3H).

Embodiment 9

Compound (I-9) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (methyl sulphonyl) acetamide

Compound I-9 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid (synthetic method referring to embodiment 1, It is made using 2- amino -4 '-chlorobenzophenone as raw material) and pyrovinic acid amine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (methyl sulphurs Acyl group) acetamide (I-9).MS(m/z)：444[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.85 (br, 1H), 7.78-7.75 (m, 2H), 7.70-7.66 (m, 2H), 7.56-7.51 (m, 4H), 5.25 (m, 1H), 5.12-5.07 (m, 1H), 4.78-4.73 (m, 1H), 3.15 (s, 3H), 2.44 (s, 3H).

Embodiment 10

Compound (I-10) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (amino-sulfonyl) acetamide

Compound I-10 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and N- (amino-sulfonyl) amino T-butyl formate, (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] are obtained after being reacted by the step 7 of embodiment 1 Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (t-butyl carbamate base sulfonyl) acetamide, the intermediate is again Through 3N hydrochloric ethyl acetates take off BOC protection after, obtain lime color solid target compound (S) -2- [6- (4- chlorphenyls) -1- methyl - 4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (amino-sulfonyl) acetamide (I-I0). MS(m/z)：446[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.83 (br, 1H), 7.77-7.73 (m, 2H), 7.69-7.65 (m, 2H), 7.56-7.51 (m, 4H), 7.48 (br, 1H), 7.43 (br, 2H), 5.26 (m, 1H), 5.11-5.05 (m, 1H), 4.78- 4.72 (m, 1H), 2.42 (s, 3H).

Embodiment 11

Compound (I-11) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (ethylsulfonyl) acetamide

Compound I-11 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and ethyl sulphonyl ammonia, by embodiment Pale solid target product (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] are obtained after the reaction of 1 step 7 Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (ethylsulfonyl) acetamide (I-11).MS(m/z)：459[M+H ]⁺。¹H NMR(DMSO-d₆)：δ：8.86 (br, 1H), 7.78-7.73 (m, 2H), 7.71-7.67 (m, 2H), 7.57-7.53 (m, 4H), 7.49 (br, 1H), 5.27 (m, 1H), 5.09-5.05 (m, 1H), 4.77-4.72 (m, 1H), 3.53-3.49 (q, J= 4.0Hz, 2H), 2.43 (s, 3H), 1.26-1.24 (t, J=4.0Hz, 3H).

Embodiment 12

Compound (I-12) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (aminosulfonyl) acetamide

Compound I-12 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and methylamino sulfuryl amine, by implementation Example 1 obtains desired product as white solid (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols after reacting [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (aminosulfonyl) acetamide (I-12).MS(m/z)：460[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.85 (br, 1H), 7.76-7.73 (m, 2H), 7.68-7.65 (m, 2H), 7.57-7.52 (m, 4H), 7.47 (br, 1H), 7.41 (br, 1H), 5.27 (m, 1H), 5.10-5.05 (m, 1H), 4.77-4.72 (m, 1H), 2.44 (s, 3H), 2.35 (s, 3H).

Embodiment 13

Compound (I-13) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (sulfonyl propyl base) acetamide

Compound I-13 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and sulfonyl propyl ammonia, by embodiment Pale solid target product (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] are obtained after the reaction of 1 step 7 Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (sulfonyl propyl base) acetamide (I-13).MS(m/z)：473[M+H ]⁺。¹H NMR(DMSO-d₆)：δ：8.84 (br, 1H), 7.79-7.73 (m, 2H), 7.72-7.67 (m, 2H), 7.59-7.54 (m, 4H), 7.51 (br, 1H), 5.26 (m, 1H), 5.07-5.03 (m, 1H), 4.76-4.72 (m, 1H), 3.54-3.52 (t, J= 4.0Hz, 2H), 2.45 (s, 3H), 2.04-2.01 (m, 2H), 1.22-1.20 (t, J=4.0Hz, 3H).

Embodiment 14

Compound (I-14) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (ethylamino sulfonyl) acetamide

Compound I-14 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and ethylamino- sulfonamide, by implementation Example 1 obtains desired product as white solid (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols after reacting [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (ethylamino sulfonyl) acetamide (I-14).MS(m/z)：474[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.84 (br, 1H), 7.75-7.72 (m, 2H), 7.69-7.66 (m, 2H), 7.56-7.52 (m, 4H), 7.49 (br, 1H), 7.44 (br, 1H), 5.27 (m, 1H), 5.08-5.05 (m, 1H), 4.76-4.72 (m, 1H), 3.51-3.49 (q, J=4.0Hz, 2H), 2.44 (s, 3H), 1.23-1.21 (t, J=4.0Hz, 3H).

Embodiment 15

Compound (I-15) (S) -2- [6- (4- chlorphenyls) -1- cyano group -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (sulfonyl propyl base) acetamide

Compound 1-15 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -1- cyanogen Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and Propylamino sulfonamide.Obtain yellowish Color solid target compound (S) -2- [6- (4- chlorphenyls) -1- cyano group -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] Diazepine -4- bases]-N- (ethylsulfonyl) acetamide (I-15).MS(m/z)：499[M+H]⁺。¹H NMR(DMSO-d₆)：δ： 8.84 (br, 1H), 7.78-7.76 (m, 2H), 7.69-7.65 (m, 2H), 7.57-7.52 (m, 4H), 7.48 (br, 1H), 7.43 (br, 1H), 5.27 (m, 1H), 5.12-5.06 (m, 1H), 4.79-4.74 (m, 1H), 3.51-3.49 (t, J=4.0Hz, 2H), 1.62-1.59 (m, 2H), 0.88-0.86 (t, J=4.0Hz, 3H).

Embodiment 16

Compound (I-16) (S) -2- [fluoro- 2- methyl -4H- benzos [f] [1,2,4] imidazos of 6- (4- chlorphenyls) -1- [1,2-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (ethylamino sulfonyl) acetamide

Compound I-16 synthesis is carried out by the method for embodiment 1, and initiation material is that [6- (4- chlorphenyls) -1- is fluoro- by (S) -2- 2- methyl -4H- benzos [f] [1,2,4] imidazo [1,2-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and ethylamino- sulfonamide, obtain Desired product as white solid (S) -2- [fluoro- 2- methyl -4H- benzos [f] [1,2,4] imidazos [1,2- of 6- (4- chlorphenyls) -1- A] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (ethylamino sulfonyl) acetamide (I-16).MS(m/z)：490[M+H]⁺。¹H NMR (DMSO-d₆)：δ：8.85 (br, 1H), 7.78-7.74 (m, 2H), 7.72-7.69 (m, 2H), 7.57-7.53 (m, 4H), 7.51 (br, 1H), 7.46 (br, 1H), 5.26 (m, 1H), 5.07-5.03 (m, 1H), 4.78-4.74 (m, 1H), 3.50-3.48 (q, J =4.0Hz, 2H), 2.26 (s, 3H), 1.22-1.20 (t, J=4.0Hz, 3H).

Embodiment 17

Compound (I-17) (S) -2- [chloro- 1- methyl -4H- benzos [f] [1,2,4] triazols of 6- (4- chlorphenyls) -8- [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (ethylsulfonyl) acetamide

Compound I-17 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- chlorine Base -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and ethylsulfonic acid amine. Obtain faint yellow solid target product (S) -2- [chloro- 1- methyl -4H- benzos [f] [1,2,4] triazols of 6- (4- chlorphenyls) -8- [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (ethylsulfonyl) acetamide (I-17).MS(m/z)：493[M+H]⁺。¹H NMR (DMSO-d₆)：δ：8.84 (br, 1H), 7.78-7.75 (m, 2H), 7.69-7.65 (m, 2H), 7.58 (s, 1H), 7.38-7.36 (d, J=8.0Hz, 1H), 7.23-7.21 (d, J=8.0Hz, 1H), 5.26 (m, 1H), 5.12-5.06 (m, 1H), 4.77-4.74 (m, 1H), 3.53-3.50 (q, J=4.0Hz, 2H), 2.43 (s, 3H), 1.24-1.22 (t, J=4.0Hz, 3H).

Embodiment 18

Compound (I-18) (S) -2- [fluoro- 1,8- dimethyl -4H- benzos [f] [1,2,4] triazoles of 6- (4- chlorphenyls) -9- And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (ethylamino sulfonyl) acetamide

Compound I-18 synthesis is carried out by the method for embodiment 1, and initiation material is that [6- (4- chlorphenyls) -9- is fluoro- by (S) -2- 1,8- dimethyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and ethylamino- sulphonyl Amine, obtain pale white solid target product (S) -2- [fluoro- 1,8- dimethyl -4H- benzos [f] [1,2,4] of 6- (4- chlorphenyls) -9- Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (ethylamino sulfonyl) acetamide (I-18).MS(m/z)：506[M+ H]⁺。¹H NMR(DMSO-d₆)：δ：8.84 (br, 1H), 7.81-7.77 (m, 2H), 7.72-7.69 (m, 2H), 7.55 (s, 1H), 7.49 (br, 1H), 7.44 (br, 1H), 7.36 (s, 1H), 7.12 (s, 1H), 5.27 (m, 1H), 5.11-5.07 (m, 1H), 4.77-4.74 (m, 1H), 3.51-3.49 (q, J=4.0Hz, 2H), 2.45 (s, 3H), 2.35 (s, 3H), 1.23-1.21 (t, J =4.0Hz, 3H).

Embodiment 19

Compound (I-19) (S) -2- [trimethyl -6H- thienos [3,2-f] [1,2,4] of 4- (4- chlorphenyls) -2,3,9- Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases]-N- (methyl sulphonyl) acetamide

Compound I-19 synthesis by the method for embodiment 1 carry out, initiation material be (S) -2- [6- (4- chlorphenyls) -2,3, 9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] acetic acid (synthetic method Referring to embodiment 1, it is made with (2- amino -4,5- dimethyl -3- thiophene) (4- chlorphenyls) ketone for raw material) and pyrovinic acid Amine.Faint yellow solid target product (S) -2- [trimethyl -6H- thienos [3,2-f] of 4- (4- chlorphenyls) -2,3,9- [1,2, 4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases]-N- (methyl sulphonyl) acetamide (I-19).MS(m/z)：479[M+ H]⁺。¹H NMR(DMSO-d₆)：δ：8.87 (br, 1H), 7.79-7.75 (m, 2H), 7.72-7.69 (m, 2H), 5.27 (m, 1H), 5.09-5.06 (m, 1H), 4.83-4.79 (m, 1H), 3.13 (s, 3H), 2.43 (s, 3H), 2.37 (s, 3H), 2.22 (s, 3H).

Embodiment 20

Compound (I-20) (S) -2- [trimethyl -6H- thienos [3,2-f] [1,2,4] of 4- (4- chlorphenyls) -2,3,9- Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases]-N- (amino-sulfonyl) acetamide

Compound I-20 synthesis by the method for embodiment 1 carry out, initiation material be (S) -2- [6- (4- chlorphenyls) -2,3, 9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] acetic acid and N- (amino Sulfonyl) t-butyl carbamate, by the step 7 of embodiment 1 react after (S) -2- [6- (4- chlorphenyls) -2,3,9- trimethyls - 6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases]-N- (t-butyl carbamate base sulphurs Acyl group) acetamide, the intermediate again through 3N hydrochloric ethyl acetates take off BOC protection after, obtain lime color solid target compound (S) -2- [4- (4- chlorphenyls) -2,3,9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine - 6- yls]-N- (amino-sulfonyl) acetamide (I-20).MS(m/z)：480[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.86 (br, 1H), 7.79-7.76 (m, 2H), 7.73-7.69 (m, 2H), 7.48 (br, 2H), 5.25 (m, 1H), 5.06-5.03 (m, 1H), 4.83-4.79 (m, 1H), 2.44 (s, 3H), 2.35 (s, 3H), 2.21 (s, 3H).

Embodiment 21

Compound (I-21) (S) -2- [trimethyl -6H- thienos [3,2-f] [1,2,4] of 4- (4- chlorphenyls) -2,3,9- Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases]-N- (ethylsulfonyl) acetamide

Compound I-21 synthesis by the method for embodiment 1 carry out, initiation material be (S) -2- [6- (4- chlorphenyls) -2,3, 9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] acetic acid and ethyl sulphur Acid amide.Faint yellow solid target product (S) -2- [trimethyl -6H- thienos [3,2-f] of 4- (4- chlorphenyls) -2,3,9- [1, 2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases]-N- (ethylsulfonyl) acetamide (I-21).MS(m/z)：493[M +H]⁺。¹H NMR(DMSO-d₆)：δ：8.86 (br, 1H), 7.79-7.75 (m, 2H), 7.71-7.68 (m, 2H), 5.27 (m, 1H), 5.08-5.05 (m, 1H), 4.78-4.74 (m, 1H), 3.54-3.51 (q, J=4.0Hz, 2H), 2.43 (s, 3H), 2.35 (s, 3H), 2.21 (s, 3H), 1.24-1.22 (t, J=4.0Hz, 3H).

Embodiment 22

Compound (I-22) (S) -2- [trimethyl -6H- thienos [3,2-f] [1,2,4] of 4- (4- chlorphenyls) -2,3,9- Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases]-N- (aminosulfonyl) acetamide

Compound I-22 synthesis by the method for embodiment 1 carry out, initiation material be (S) -2- [6- (4- chlorphenyls) -2,3, 9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] acetic acid and methylamino Sulfonamide, obtain desired product as white solid (S) -2- [trimethyl -6H- thienos [3,2-f] of 4- (4- chlorphenyls) -2,3,9- [1, 2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases]-N- (aminosulfonyl) acetamide (I-22).MS(m/z)：494 [M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.86 (br, 1H), 7.75-7.73 (m, 2H), 7.69-7.66 (m, 2H), 7.49 (br, 1H), 5.27 (m, 1H), 5.07-5.04 (m, 1H), 4.82-4.79 (m, 1H), 3.12 (s, 3H), 2.47 (s, 3H), 2.35 (s, 3H), 2.21 (s, 3H).

Embodiment 23

Compound (I-23) (S) -2- [trimethyl -6H- thienos [3,24] [1,2,4] three of 4- (4- chlorphenyls) -2,3,9- Azoles simultaneously [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases]-N- (sulfonyl propyl base) acetamide

Compound I-23 synthesis by the method for embodiment 1 carry out, initiation material be (S) -2- [6- (4- chlorphenyls) -2,3, 9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] acetic acid and ethyl sulphur Acid amide.Faint yellow solid target product (S) -2- [trimethyl -6H- thienos [3,2-f] of 4- (4- chlorphenyls) -2,3,9- [1, 2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases]-N- (sulfonyl propyl base) acetamide (I-23).MS(m/z)：507[M +H]⁺。¹H NMR(DMSO-d₆)：δ：8.85 (br, 1H), 7.78-7.76 (m, 2H), 7.72-7.69 (m, 2H), 5.25 (m, 1H), 5.07-5.05 (m, 1H), 4.77-4.74 (m, 1H), 3.55-3：53 (t, J=4.0Hz, 2H), 2.44 (s, 3H), 2.37 (s, 3H), 2.20 (s, 3H), 2.03-2.00 (m, 2H), 1.23-1.21 (t, J=4.0Hz, 3H).

Embodiment 24

Compound (I-24) (S) -2- [trimethyl -6H- thienos [3,2-f] [1,2,4] of 4- (4- chlorphenyls) -2,3,9- Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases]-N- (ethylamino sulfonyl) acetamide

Compound I-24 synthesis by the method for embodiment 1 carry out, initiation material be (S) -2- [6- (4- chlorphenyls) -2,3, 9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] acetic acid and ethylamino- Sulfonamide, obtain desired product as white solid (S) -2- [trimethyl -6H- thienos [3,2-f] of 4- (4- chlorphenyls) -2,3,9- [1, 2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases]-N- (ethylamino sulfonyl) acetamide (I-24).MS(m/z)：508 [M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.82 (br, 1H), 7.76-7.73 (m, 2H), 7.68-7.65 (m, 2H), 7.52 (br, 1H), 5.26 (m, 1H), 5.06-5.03 (m, 1H), 4.81-4.79 (m, 1H), 3.51-3.49 (q, J=4.0Hz, 2H), 2.45 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H), 1.22-1.20 (t, J=4.0Hz, 3H).

Embodiment 25

Compound (I-25) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (3- methyl -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine) second Ketone

Compound I-25 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- first Oxy-1-methyl-4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine-4- bases] acetic acid (I₈) and 3- first Base -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorobenzenes Base) -8- methoxyl groups -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (3- first Base -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine) ethyl ketone (I-25).MS(m/z)：518[M+H]⁺。¹H NMR (DMSO-d₆)：δ：7.78-7.76 (m, 2H), 7.67-7.64 (m, 2H), 7.58 (s, 1H), 7.37-7.35 (d, J=8.0Hz, 1H), 7.23-7.21 (d, J=8.0Hz, 1H), 5.27 (m, 1H), 5.12-5.08 (m, 1H), 4.79-4.76 (m, 1H), 4.45 (s, 2H), 3.88 (s, 3H), 3.62-3.56 (m, 4H), 2.44 (s, 3H), 2.39 (s, 3H).

Embodiment 26

Compound (I-26) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (3- trifluoromethyls -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrrole Piperazine) ethyl ketone

Compound I-26 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- first Oxy-1-methyl-4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine-4- bases] acetic acid (I₈) and 3- trifluoros Methyl -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorobenzenes Base) -8- methoxyl groups -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (3- tri- Methyl fluoride -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine) ethyl ketone (I-26).MS(m/z)：572[M+H]⁺。¹H NMR (DMSO-d₆)：δ：7.77-7.75 (m, 2H), 7.68-7.65 (m, 2H), 7.57 (s, 1H), 7.36-7.34 (d, J=8.0Hz, 1H), 7.22-7.20 (d, J=8.0Hz, 1H), 5.26 (m, 1H), 5.11-5.08 (m, 1H), 4.78-4.76 (m, 1H), 4.46 (s, 2H), 3.87 (s, 3H), 3.61-3.56 (m, 4H), 2.45 (s, 3H).

Embodiment 27

Compound (I-27) (S) -2- [trimethyl -6H- thienos [3,2-f] [1,2,4] of 4- (4- chlorphenyls) -2,3,9- Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- (3- methyl -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrrole Piperazine) ethyl ketone

Compound I-27 synthesis by the method for embodiment 1 carry out, initiation material be (S) -2- [6- (4- chlorphenyls) -2,3, 9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] acetic acid and 3- methyl - 5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine.Faint yellow solid target product (S) -2- [4- (4- chlorphenyls) -2, 3,9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- (3- methyl - 5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine) ethyl ketone (I-27).MS(m/z)：522[M+H]⁺。¹H NMR(DMSO- d₆)：δ：7.79-7.76 (m, 2H), 7.68-7.65 (m, 2H), 5.29 (m, 1H), 5.13-5.09 (m, 1H), 4.79-4.76 (m, 1H), 4.42 (s, 2H), 3.61-3.55 (m, 4H), 2.44 (s, 3H), 2.39 (s, 3H), 2.35 (s, 3H), 2.20 (s, 3H).

Embodiment 28

Compound (I-28) (S) -2- [trimethyl -6H- thienos [3,2-f] [1,2,4] of 4- (4- chlorphenyls) -2,3,9- Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- (3- trifluoromethyls -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] Pyrazine) ethyl ketone

Compound I-28 synthesis by the method for embodiment 1 carry out, initiation material be (S) -2- [6- (4- chlorphenyls) -2,3, 9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] acetic acid and 3- trifluoros Methyl -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine.Obtain faint yellow solid target product (S) -2- [4- (4- chlorobenzenes Base) -2,3,9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- (3- trifluoromethyls -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine) ethyl ketone (I-28).MS(m/z)：576[M+H]⁺。¹H NMR(DMSO-d₆)：δ：7.78-7.75 (m, 2H), 7.68-7.65 (m, 2H), 5.27 (m, 1H), 5.12-5.09 (m, 1H), 4.78-4.75 (m, 1H), 4.43 (s, 2H), 3.62-3.57 (m, 4H), 2.43 (s, 3H), 2.36 (s, 3H), 2.21 (s, 3H).

Embodiment 29

Compound (I-29) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (2- methyl -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [1,5-A] pyrazine) second Ketone

Compound I-29 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- first Oxy-1-methyl-4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine-4- bases] acetic acid (I₈) and 2- first Base -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [1,5-A] pyrazine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorobenzenes Base) -8- methoxyl groups -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (2- first Base -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [1,5-A] pyrazine) ethyl ketone (I-29).MS(m/z)：518[M+H]⁺。¹H NMR (DMSO-d₆)：δ：7.79-7.76 (m, 2H), 7.68-7.65 (m, 2H), 7.57 (s, 1H), 7.36-7.34 (d, J=8.0Hz, 1H), 7.22-7.20 (d, J=8.0Hz, 1H), 5.28 (m, 1H), 5.11-5.09 (m, 1H), 4.79-4.76 (m, 1H), 4.46 (s, 2H), 3.89 (s, 3H), 3.64-3.58 (m, 4H), 2.45 (s, 3H), 2.38 (s, 3H).

Embodiment 30

Compound (I-30) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (2- trifluoromethyls -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [1,5-A] pyrrole Piperazine) ethyl ketone

Compound I-30 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- first Oxy-1-methyl-4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine-4- bases] acetic acid (I₈) and 2- trifluoros Methyl -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [1,5-A] pyrazine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorobenzenes Base) -8- methoxyl groups -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (2- tri- Methyl fluoride -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [1,5-A] pyrazine) ethyl ketone (I-30).MS(m/z)：572[M+H]⁺。¹H NMR (DMSO-d₆)：δ：7.78-7.75 (m, 2H), 7.69-7.65 (m, 2H), 7.56 (s, 1H), 7.35-7.33 (d, J=8.0Hz, 1H), 7.21-7.19 (d, J=8.0Hz, 1H), 5.27 (m, 1H), 5.11-5.09 (m, 1H), 4.78-4.76 (m, 1H), 4.45 (s, 2H), 3.87 (s, 3H), 3.63-3.57 (m, 4H), 2.44 (s, 3H).

Embodiment 31

Compound (I-31) (S) -2- [the fluoro- 8- isopropoxies -4H- benzos [f] of 6- (4- chlorphenyls) chloro- 1- of -9- [1,2, 4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (methyl sulphonyl) acetamide

Compound I-31 synthesis is carried out by the method for embodiment 1, and initiation material is that [6- (4- chlorphenyls) -9- is chloro- by (S) -2- Fluoro- 8- isopropoxies -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases of 1-] acetic acid and methyl sulphur Acid amide, obtain pale white solid target product (S) -2- [fluoro- 8- isopropoxies -4H- benzos [f] of 6- (4- chlorphenyls) chloro- 1- of -9- [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (methyl sulphonyl) acetamide (I-31).MS(m/z)： 541[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.81 (br, 1H), 7.83-7.79 (m, 2H), 7.73-7.69 (m, 2H), 7.51 (s, 1H), 7.45 (s, 1H), 5.28 (m, 1H), 5.21 (m, 1H), 5.08-5.05 (m, 1H), 4.78-4.75 (m, 1H), 3.15 (s, 3H), 1.35 (s, 6H).

Embodiment 32

Compound (I-32) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- pyridos [2,3-f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (methyl sulphonyl) acetamide

Compound I-32 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- pyridos [2,3-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and pyrovinic acid amine. Faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- pyridos [2,3-f] [1,2,4] triazol [4, 3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (methyl sulphonyl) acetamide (I-32).MS(m/z)：446[M+H]⁺。¹H NMR (DMSO-d₆)：δ：8.83 (br, 1H), 8.65 (m, 1H), 8.47 (m, 1H), 7.79-7.76 (m, 2H), 7.71 (m, 1H), 7.68-7.66 (m, 2H), 5.27 (m, 1H), 5.09-5.06 (m, 1H), 4.75-4.72 (m, 1H), 3.10 (s, 3H), 2.45 (s, 3H)。

Embodiment 33

Compound (I-33) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- pyrimidos [4,5-f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (methyl sulphonyl) acetamide

Compound I-33 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- pyrimidos [4,5-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and pyrovinic acid amine. Faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- pyrimidos [4,5-f] [1,2,4] triazol [4, 3-a] [Isosorbide-5-Nitrae] diazepine -4- bases]-N- (methyl sulphonyl) acetamide (I-33).MS(m/z)：447[M+H]⁺。¹H NMR (DMSO-d₆)：δ：9.65 (s, 1H), 9.15 (s, 1H), 8.86 (br, 1H), 7.81-7.77 (m, 2H), 7.68-7.65 (m, 2H), 5.28 (m, 1H), 5.07-5.05 (m, 1H), 4.77-4.75 (m, 1H), 3.08 (s, 3H), 2.44 (s, 3H).

Embodiment 34

Compound (I-34) (S) -2- [5- (4- chlorphenyls) -10- methyl -7H- pyrazines simultaneously [2,3-f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -7- bases]-N- (methyl sulphonyl) acetamide

Compound I-34 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [5- (4- chlorphenyls) -10- first Base -7H- pyrazines simultaneously [2,3-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -7- bases] acetic acid and pyrovinic acid amine. Faint yellow solid target product (S) -2- [5- (4- chlorphenyls) -10- methyl -7H- pyrazines simultaneously [2,3-f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -7- bases]-N- (methyl sulphonyl) acetamide (I-34).MS(m/z)：447[M+H]⁺。¹H NMR (DMSO-d₆)：δ：8.82 (br, 1H), 8.81 (m, 2H), 7.82-7.79 (m, 2H), 7.68-7.65 (m, 2H), 5.27 (m, 1H), 5.08-5.05 (m, 1H), 4.78-4.75 (m, 1H), 3.09 (s, 3H), 2.44 (s, 3H).

Embodiment 35

Compound (I-35) (S) -2- [4- (4- chlorphenyls) -9- methyl -6H- furans simultaneously [2,3-f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases]-N- (methyl sulphonyl) acetamide

Compound I-35 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [4- (4- chlorphenyls) -9- first Base -6H- furans simultaneously [2,3-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] acetic acid and pyrovinic acid amine. Faint yellow solid target product (S) -2- [4- (4- chlorphenyls) -9- methyl -6H- furans simultaneously [2,3-f] [1,2,4] triazol [4, 3-a] [Isosorbide-5-Nitrae] diazepine -6- bases]-N- (methyl sulphonyl) acetamide (I-35).MS(m/z)：435[M+H]⁺。¹H NMR (DMSO-d₆)：δ：8.83 (br, 1H), 7.83-7.79 (m, 3H), 7.69-7.66 (m, 2H), 6.58-6.56 (d, J=8.0Hz, 1H), 5.26 (m, 1H), 5.08-5.06 (m, 1H), 4.77-4.75 (m, 1H), 3.08 (s, 3H), 2.45 (s, 3H).

Embodiment 36

Compound (I-36) (S) -2- [4- (4- chlorphenyls) -9- methyl -6H- thiazoles simultaneously [4,5-f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases]-N- (methyl sulphonyl) acetamide

Compound I-36 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [4- (4- chlorphenyls) -9- first Base -6H- thiazoles simultaneously [4,5-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] acetic acid and pyrovinic acid amine. Faint yellow solid target product (S) -2- [4- (4- chlorphenyls) -9- methyl -6H- thiazoles simultaneously [4,5-f] [1,2,4] triazol [4, 3-a] [Isosorbide-5-Nitrae] diazepine -6- bases]-N- (methyl sulphonyl) acetamide (I-36).MS(m/z)：452[M+H]⁺。¹H NMR (DMSO-d₆)：δ：9.12 (s, 1H), 8.84 (br, 1H), 7.81-7.79 (m, 2H), 7.68-7.65 (m, 2H), 5.27 (m, 1H), 5.07-5.04 (m, 1H), 4.78-4.75 (m, 1H), 3.10 (s, 3H), 2.45 (s, 3H).

Embodiment 37

Compound (I-37) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (3- cyano group -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine) second Ketone

Compound I-37 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- first Oxy-1-methyl-4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine-4- bases] acetic acid (I₈) and 3- cyanogen Base -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorobenzenes Base) -8- methoxyl groups -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (3- cyanogen Base -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine) ethyl ketone (I-37).MS(m/z)：529[M+H]⁺。¹H NMR (DMSO-d₆)：δ：7.78-7.75 (m, 2H), 7.69-7.65 (m, 2H), 7.58 (s, 1H), 7.37-7.35 (d, J=8.0Hz, 1H), 7.21-7.19 (d, J=8.0Hz, 1H), 5.27 (m, 1H), 5.11-5.08 (m, 1H), 4.79-4.76 (m, 1H), 4.45 (s, 2H), 3.88 (s, 3H), 3.62-3.57 (m, 4H), 2.44 (s, 3H).

Embodiment 38

Compound (I-38) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (3- hydroxyls -5,6- imidazolidine simultaneously [1,5-a] pyrazine -7 (8H)-yl) second Ketone

Compound I-38 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- first Oxy-1-methyl-4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine-4- bases] acetic acid (I₈) and 3- hydroxyls Base -5,6,7,8- imidazolidines simultaneously [1,5-a] pyrazine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -8- first Oxy-1-methyl-4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine-4- bases]-1- (3- hydroxyls-5,6- Imidazolidine simultaneously [1,5-a] pyrazine -7 (8H)-yl) ethyl ketone (I-38).MS(m/z)：519[M+H]⁺。¹H NMR(DMSO-d₆)：δ： 8.15 (br, 1H), 7.79-7.76 (m, 2H), 7.68-7.65 (m, 2H), 7.59 (s, 1H), 7.37-7.35 (d, J=8.0Hz, 1H), 7.29 (s, 1H), 7.21-7.19 (d, J=8.0Hz, 1H), 5.26 (m, 1H), 5.10-5.07 (m, 1H), 4.79-4.76 (m, 1H), 4.46 (s, 2H), 3.89 (s, 3H), 3.61-3.57 (m, 4H), 2.45 (s, 3H).

Embodiment 39

Compound (I-39) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (fluoro- 5, the 6- glyoxalidine of 3- simultaneously [1,5-a] pyrazine -7 (8H)-yl) ethyl ketone

Compound I-39 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- first Oxy-1-methyl-4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine-4- bases] acetic acid (I₈) and 3- it is fluoro- 5,6,7,8- imidazolidines simultaneously [1,5-a] pyrazine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -8- methoxies Base -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (fluoro- 5, the 6- tetrahydrochysenes of 3- Imidazo [1,5-a] pyrazine -7 (8H)-yl) ethyl ketone (I-39).MS(m/z)：521[M+H]⁺。¹H NMR(DMSO-d₆)：δ： 7.78-7.75 (m, 2H), 7.69-7.65 (m, 2H), 7.57 (s, 1H), 7.36-7.34 (d, J=8.0Hz, 1H), 7.21-7.19 (d, J=8.0Hz, 1H), 7.10 (s, 1H), 5.27 (m, 1H), 5.09-5.06 (m, 1H), 4.79-4.76 (m, 1H), 4.45 (s, 2H), 3.88 (s, 3H), 3.62-3.57 (m, 4H), 2.43 (s, 3H).

Embodiment 40

Compound (I-40) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (2- methyl -5,6- pyrrolin simultaneously [1,5-a] pyrazine -5 (4H)-yl) second Ketone

Compound I-40 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- first Oxy-1-methyl-4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine-4- bases] acetic acid (I₈) and 2- first Base -4,5,6,7- nafoxidines simultaneously [1,5-a] pyrazine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -8- first Oxy-1-methyl-4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine-4- bases]-1- (2- methyl-5,6- Pyrrolin simultaneously [1,5-a] pyrazine -5 (4H)-yl) ethyl ketone (I-40).MS(m/z)：517[M+H]⁺。¹H NMR(DMSO-d₆)：δ： 7.85-7.82 (m, 2H), 7.73-7.70 (m, 2H), 7.59 (s, 1H), 7.37-7.35 (d, J=8.0Hz, 1H), 7.22-7.20 (d, J=8.0Hz, 1H), 6.35 (s, 1H), 5.29 (m, 1H), 5.07-5.04 (m, 1H), 4.79-4.76 (m, 1H), 4.47 (s, 2H), 3.89 (s, 3H), 3.64-3.61 (m, 4H), 2.43 (s, 3H), 2.20 (s, 3H).

Embodiment 41

Compound (I-41) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (chloro- 5, the 6- glyoxalidine of 2- simultaneously [1,2-a] pyrazine -7 (8H)-yl) ethyl ketone

Compound I-41 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- first Oxy-1-methyl-4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine-4- bases] acetic acid (I₈) and 2- it is chloro- 5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -8- methoxies Base -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (chloro- 5, the 6- dihydros of 2- Imidazo [1,2-a] pyrazine -7 (8H)-yl) ethyl ketone (I-41).MS(m/z)：537[M+H]⁺。¹HNMR(DMSO-d₆)：δ：7.83- 7.80 (m, 2H), 7.74-7.71 (m, 2H), 7.58 (s, 1H), 7.38-7.36 (d, J=8.0Hz, 1H), 7.23-7.21 (d, J =8.0Hz, 1H), 6.75 (s, 1H), 5.27 (m, 1H), 5.06-5.03 (m, 1H), 4.78-4.75 (m, 1H), 4.45 (s, 2H), 3.88 (s, 3H), 3.65-3.61 (m, 4H), 2.45 (s, 3H).

Embodiment 42

Compound (I-42) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (5,6- glyoxalidine simultaneously [1,2-a] pyrazine -7 (8H)-yl) ethyl ketone

Compound I-42 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -8- first Oxy-1-methyl-4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine-4- bases] acetic acid (I₈) and 5,6,7, 8- imidazolidines simultaneously [1,2-a] pyrazine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] (5,6- glyoxalidine are simultaneously [1,2-a] by -1- Pyrazine -7 (8H)-yl) ethyl ketone (I-42).MS(m/z)：503[M+H]⁺。¹H NMR(DMSO-d₆)：δ：(7.85-7.82 m, 2H), 7.75-7.72 (m, 2H), 7.59 (s, 1H), 7.37-7.35 (d, J=8.0Hz, 1H), 7.21-7.19 (d, J=8.0Hz, 1H), 6.98-6.96 (d, J=8.0Hz, 1H), 6.74-6.72 (d, J=8.0Hz, 1H), 5.25 (m, 1H), 5.03-5.01 (m, 1H), 4.77-4.75 (m, 1H), 4.46 (s, 2H), 3.87 (s, 3H), 3.63-3.58 (m, 4H), 2.43 (s, 3H).

Embodiment 43

Compound (I-43) (S) -2- [trimethyl -6H- thienos [3,2-f] [1,2,4] of 4- (4- chlorphenyls) -2,3,9- Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- (2- methyl -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [1,5-A] pyrrole Piperazine) ethyl ketone

Compound I-43 synthesis by the method for embodiment 1 carry out, initiation material be (S) -2- [4- (4- chlorphenyls) -2,3, 9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] acetic acid and 2- methyl - 5,6,7,8- tetrahydrochysenes [1,2,4] triazole [1,5-A] pyrazine.Faint yellow solid target product (S) -2- [4- (4- chlorphenyls) -2, 3,9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- (2- methyl - 5,6,7,8- tetrahydrochysenes [1,2,4] triazole [1,5-A] pyrazine) ethyl ketone (I-43).MS(m/z)：522[M+H]⁺。¹H NMR(DMSO- d₆)：δ：7.78-7.75 (m, 2H), 7.69-7.66 (m, 2H), 5.28 (m, 1H), 5.11-5.07 (m, 1H), 4.78-4.74 (m, 1H), 4.46 (s, 2H), 3.61-3.56 (m, 4H), 2.45 (s, 3H), 2.38 (s, 3H), 2.34 (s, 3H), 2.19 (s, 3H).

Embodiment 44

Compound (I-44) (S) -2- [trimethyl -6H- thienos [3,2-f] [1,2,4] of 4- (4- chlorphenyls) -2,3,9- Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- (2- trifluoromethyls -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [1,5-A] Pyrazine) ethyl ketone

Compound I-44 synthesis by the method for embodiment 1 carry out, initiation material be (S) -2- [4- (4- chlorphenyls) -2,3, 9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] acetic acid and 2- trifluoros Methyl -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [1,5-A] pyrazine.Obtain faint yellow solid target product (S) -2- [4- (4- chlorobenzenes Base) -2,3,9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- (2- trifluoromethyls -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [1,5-A] pyrazine) ethyl ketone (I-44).MS(m/z)：576[M+H]⁺。¹H NMR(DMSO-d₆)：δ：7.81-7.77 (m, 2H), 7.69-7.65 (m, 2H), 5.27 (m, 1H), 5.10-5.06 (m, 1H), 4.79-4.74 (m, 1H), 4.45 (s, 2H), 3.62-3.57 (m, 4H), 2.44 (s, 3H), 2.35 (s, 3H), 2.21 (s, 3H).

Embodiment 45

Compound (I-45) (S) -2- [trimethyl -6H- thienos [3,2-f] [1,2,4] of 4- (4- chlorphenyls) -2,3,9- Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- (fluoro- 5,6- imidazolidines [1,2-a] pyrazine -7 (the 8H)-yls of 3-) second Ketone

Compound I-45 synthesis by the method for embodiment 1 carry out, initiation material be (S) -2- [4- (4- chlorphenyls) -2,3, 9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] acetic acid and 3- fluoro- 5, 6,7,8- imidazolidines simultaneously [1,2-a] pyrazine.Obtain faint yellow solid target product (S) -2- [4- (4- chlorphenyls) -2,3,9- tri- Methyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- (fluoro- 5, the 6- tetrahydrochysenes of 3- Imidazoles [1,2-a] pyrazine -7 (8H)-yl) ethyl ketone (I-45).MS(m/z)：525[M+H]⁺。¹H NMR(DMSO-d₆)：δ：7.82- 7.78 (m, 2H), 7.68-7.64 (m, 2H), 7.05 (s, 1H), 5.26 (m, 1H), 5.09-5.06 (m, 1H), 4.78-4.74 (m, 1H), 4.46 (s, 2H), 3.61-3.57 (m, 4H), 2.45 (s, 3H), 2.36 (s, 3H), 2.20 (s, 3H).

Embodiment 46

Compound (I-46) (S) -2- [trimethyl -6H- thienos [3,2-f] [1,2,4] of 4- (4- chlorphenyls) -2,3,9- Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- (5,6- imidazolidines [1,2-a] pyrazine -7 (8H)-yl) ethyl ketone

Compound I-46 synthesis by the method for embodiment 1 carry out, initiation material be (S) -2- [4- (4- chlorphenyls) -2,3, 9- trimethyl -6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] acetic acid and 5,6,7, 8- imidazolidines simultaneously [1,2-a] pyrazine.Faint yellow solid target product (S) -2- [4- (4- chlorphenyls) -2,3,9- trimethyls - 6H- thienos [3,2-f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- (5,6- imidazolidines [1,2- A] pyrazine -7 (8H)-yl) ethyl ketone (I-46).MS(m/z)：507[M+H]⁺。¹H NMR(DMSO-d₆)：δ：7.83-7.80 (m, 2H), 7.69-7.66 (m, 2H), 6.99-6.97 (d, J=8.0Hz, 1H), 6.75-6.73 (d, J=8.0Hz, 1H), 5.27 (m, 1H), 5.08-5.06 (m, 1H), 4.77-4.74 (m, 1H), 4.45 (s, 2H), 3.60-3.56 (m, 4H), 2.44 (s, 3H), 2.35 (s, 3H), 2.19 (s, 3H).

Embodiment 47

Compound (I-47) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (3- methyl -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine) ethyl ketone

Compound I-47 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and 3- methyl -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (3- methyl -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine) ethyl ketone (I-47).MS(m/z)：488[M+H]⁺。¹H NMR(DMSO-d₆)：δ：(7.82-7.78 m, 2H), 7.69-7.65 (m, 2H), 7.56-7.52 (m, 4H), 5.26 (m, 1H), 5.10-5.07 (m, 1H), 4.78-4.75 (m, 1H), 4.46 (s, 2H), 3.63-3.58 (m, 4H), 2.45 (s, 3H), 2.41 (s, 3H).

Embodiment 48

Compound (I-48) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (3- trifluoromethyls -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine) ethyl ketone

Compound I-48 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and 3- trifluoromethyls -5,6,7,8- Tetrahydrochysene [1,2,4] triazole [4,3-A] pyrazine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- Benzo [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (3- trifluoromethyls -5,6,7,8- tetrahydrochysenes [1, 2,4] triazole [4,3-A] pyrazine) ethyl ketone (I-48).MS(m/z)：542[M+H]⁺。¹H NMR(DMSO-d₆)：δ：7.82-7.77 (m, 2H), 7.69-7.66 (m, 2H), 7.57-7.54 (m, 4H), 5.27 (m, 1H), 5.09-5.06 (m, 1H), 4.79-4.76 (m, 1H), 4.45 (s, 2H), 3.58-3.54 (m, 4H), 2.44 (s, 3H).

Embodiment 49

Compound (I-49) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (2- methyl -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [1,5-A] pyrazine) ethyl ketone

Compound I-49 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and 2- methyl -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [1,5-A] pyrazine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (2- methyl -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [1,5-A] pyrazine) ethyl ketone (I-49).MS(m/z)：588[M+H]⁺。¹H NMR(DMSO-d₆)：δ：(7.82-7.77 m, 2H), 7.69-7.67 (m, 2H), 7.58-7.55 (m, 4H), 5.27 (m, 1H), 5.08-5.05 (m, 1H), 4.80-4.76 (m, 1H), 4.46 (s, 2H), 3.63-3.59 (m, 4H), 2.43 (s, 3H), 2.37 (s, 3H).

Embodiment 50

Compound (I-50) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (2- trifluoromethyls -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [1,5-A] pyrazine) ethyl ketone

Compound I-50 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and 2- trifluoromethyls -5,6,7,8- Tetrahydrochysene [1,2,4] triazole [1,5-A] pyrazine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- Benzo [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (2- trifluoromethyls -5,6,7,8- tetrahydrochysenes [1, 2,4] triazole [1,5-A] pyrazine) ethyl ketone (I-50).MS(m/z)：542[M+H]⁺。¹H NMR(DMSO-d₆)：δ：7.78-7.74 (m, 2H), 7.69-7.66 (m, 2H), 7.59-7.56 (m, 4H), 5.25 (m, 1H), 5.07-5.05 (m, 1H), 4.77-4.75 (m, 1H), 4.46 (s, 2H), 3.62-3.57 (m, 4H), 2.45 (s, 3H).

Embodiment 51

Compound (I-51) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (fluoro- 5, the 6- glyoxalidine of 3- simultaneously [1,5-a] pyrazine -7 (8H)-yl) ethyl ketone

Compound I-51 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and the tetrahydrochysene miaows of 3- fluoro- 5,6,7,8- Azoles simultaneously [1,5-a] pyrazine.Faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1, 2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (fluoro- 5, the 6- glyoxalidine of 3- simultaneously [1,5-a] pyrazine -7 (8H) - Base) ethyl ketone (I-51).MS(m/z)：491[M+H]⁺。¹H NMR(DMSO-d₆)：δ：7.78-7.76 (m, 2H), 7.69-7.67 (m, 2H), 7.57-7.54 (m, 4H), 5.26 (m, 1H), 5.08-5.06 (m, 1H), 4.79-4.77 (m, 1H), 4.46 (s, 2H), 3.63-3.57 (m, 4H), 2.44 (s, 3H).

Embodiment 52

Compound (I-52) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (3- cyano group -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine) ethyl ketone

Compound I-52 synthesis is carried out by the method for embodiment 1, and initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and 3- cyano group -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine.Obtain faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (3- cyano group -5,6,7,8- tetrahydrochysenes [1,2,4] triazole [4,3-A] pyrazine) ethyl ketone (I-52).MS(m/z)：499[M+H]⁺。¹H NMR(DMSO-d₆)：δ：(7.81-7.78 m, 2H), 7.68-7.66 (m, 2H), 7.58-7.54 (m, 4H), 5.26 (m, 1H), 5.08-5.06 (m, 1H), 4.79-4.76 (m, 1H), 4.46 (s, 2H), 3.57-3.53 (m, 4H), 2.45 (s, 3H).

Embodiment 53

Compound (I-53) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (1H- indoles -1- bases) ethyl ketone

Compound I-53 synthesis is carried out as follows：Initiation material is (S) -2- [6- (4- chlorphenyls) -8- methoxies Base -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid (I₈) and thionyl chloride Obtained (the S) -2- of reaction [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [1, 4] diazepine -4- bases] chloroacetic chloride, the production of faint yellow solid target is made again under triethylamine effect with indole reaction in the acyl chlorides Thing (S) -2- [6- (4- chlorphenyls) -8- methoxyl groups -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] phenodiazines Miscellaneous Zhuo -4- bases] -1- (1H- indoles -1- bases) ethyl ketone (I-53).MS(m/z)：497[M+H]⁺。¹H NMR(DMSO-d₆)：δ： 8.15-8.12 (m, 3H), 7.87-7.84 (m, 2H), 7.76-7.73 (m, 2H), 7.58 (s, 1H), 7.38-7.35 (m, 2H), 7.27-7.22 (m, 3H), 5.27 (m, 1H), 5.04-5.01 (m, 1H), 4.78-4.75 (m, 1H), 3.88 (s, 3H), 2.44 (s, 3H)。

Embodiment 54

Compound (I-54) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (1H- pyrrolo-es [2,3-b] pyridine -1- bases) ethyl ketone

Compound I-54 synthesis is carried out by the method for embodiment 53：Initiation material is (S) -2- [6- (4- chlorphenyls) -8- first Oxy-1-methyl-4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine-4- bases] acetic acid (I₈) and 1H- pyrroles Simultaneously [2,3-b] pyridine reaction is coughed up, faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- first is made Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (1H- pyrrolo-es [2,3-b] pyridine) Ethyl ketone (I-54).MS(m/z)：498[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.22-8.19 (m, 2H), 7.88-7.85 (m, 2H), 7.78-7.75 (m, 2H), 7.57 (s, 1H), 7.37-7.34 (m, 2H), 7.15-7.12 (m, 2H), 6.17 (m, 1H), 5.26 (m, 1H), 5.05-5.02 (m, 1H), 4.79-4.75 (m, 1H), 3.87 (s, 3H), 2.45 (s, 3H).

Embodiment 55

Compound (I-55) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (9H- purine -9- bases) ethyl ketone

Compound I-55 synthesis is carried out by the method for embodiment 53：Initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and 9H- purine react, be made light Yellow solid target product (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [1, 4] diazepine -4- bases] -1- (9H- purine -9- bases) ethyl ketone (I-55).MS(m/z)：470[M+H]⁺。¹H NMR(DMSO-d₆)： δ：9.36 (s, 1H), 9.17 (s, 1H), 8.67 (s, 1H), 7.87-7.84 (m, 2H), 7.78-7.76 (m, 2H), 7.52-7.48 (m, 4H), 5.27 (m, 1H), 5.06-5.02 (m, 1H), 4.79-4.75 (m, 1H), 2.44 (s, 3H).

Embodiment 56

Compound (I-56) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (7H- pyrrolo-es [2,3-d] pyrimidin-7-yl) ethyl ketone

Compound I-55 synthesis is carried out by the method for embodiment 53：Initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and 7H- pyrrolo-es [2,3-d] be phonetic Pyridine, faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols are made [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (7H- pyrrolo-es [2,3-d] pyrimidin-7-yl) ethyl ketone (I-56).MS(m/z)： 469[M+H]⁺。¹H NMR(DMSO-d₆)：δ：9.26 (s, 1H), 8.67 (s, 1H), 7.88-7.85 (m, 2H), 7.79-7.77 (m, 2H), 7.53-7.49 (m, 4H), 7.13-7.11 (d, J=8.0Hz, 1H), 6.15-6.13 (d, J=8.0Hz, 1H), 5.27 (m, 1H), 5.06-5.03 (m, 1H), 4.79-4.76 (m, 1H), 2.45 (s, 3H).

Embodiment 57

Compound (I-57) (S) -2- [trimethyl -6H- thienos [3,2-f] [1,2,4] of 4- (4- chlorphenyls) -2,3,9- Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- (1H- pyrazolos [3,4-d] pyrimidine -1- bases) ethyl ketone

Compound I-57 synthesis is carried out by the method for embodiment 53：Initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and 1H- pyrazolos [3,4-d] be phonetic Pyridine, be made faint yellow solid target product (S) -2- [trimethyl -6H- thienos [3,2-f] of 4- (4- chlorphenyls) -2,3,9- [1, 2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- (1H- pyrazolos [3,4-d] pyrimidine -1- bases) ethyl ketone (I-57). MS(m/z)：504[M+H]⁺。¹H NMR(DMSO-d₆)：δ：9.27 (s, 1H), 8.72 (s, 1H), 8.03 (s, 1H), 7.87-7.85 (m, 2H), 7.78-7.76 (m, 2H), 5.26 (m, 1H), 5.04-5.03 (m, 1H), 4.79-4.75 (m, 1H), 2.45 (s, 3H), 2.37 (s, 3H), 2.21 (s, 3H).

Embodiment 58

Compound (I-58) (S) -2- [trimethyl -6H- thienos [3,2-f] [1,2,4] of 4- (4- chlorphenyls) -2,3,9- Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- (1H- pyrazolos [3,4-b] pyrazine -1- bases) ethyl ketone

Compound I-58 synthesis is carried out by the method for embodiment 53：Initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and 1H- pyrazolos [3,4-b] pyrrole Piperazine, be made faint yellow solid target product (S) -2- [trimethyl -6H- thienos [3,2-f] of 4- (4- chlorphenyls) -2,3,9- [1, 2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- (1H- pyrazolos [3,4-b] pyrazine -1- bases) ethyl ketone (I-58). MS(m/z)：504[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.62 (m, 2H), 8.12 (s, 1H), 7.88-7.86 (m, 2H), 7.79-7.77 (m, 2H), 5.27 (m, 1H), 5.06-5.02 (m, 1H), 4.79-4.75 (m, 1H), 2.44 (s, 3H), 2.36 (s, 3H), 2.20 (s, 3H).

Embodiment 59

Compound (I-59) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (2,3- dihydro -1H- pyrrolo-es [2,3-b] pyridine -1- bases) ethyl ketone

Compound I-59 synthesis is carried out by the method for embodiment 53：Initiation material is (S) -2- [6- (4- chlorphenyls) -8- first Oxy-1-methyl-4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine-4- bases] acetic acid (I₈) and 2,3- bis- Hydrogen -1H- pyrrolo-es [2,3-b] pyridine reacts, and pale white solid target product (S) -2- [6- (4- chlorphenyls) -8- methoxies are made Base -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (2,3- dihydro -1H- pyrroles Cough up simultaneously [2,3-b] pyridine -1- bases) ethyl ketone (I-59).MS(m/z)：500[M+H]⁺。1H NMR(DMSO-d₆)：δ：7.89-7.86 (m, 3H), 7.76-7.73 (m, 3H), 7.59 (s, 1H), 7.38-7.35 (m, 3H), 5.28 (m, 1H), 5.05-5.01 (m, 1H), 4.79-4.75 (m, 1H), 4.45-4.42 (m, 2H), 3.88 (s, 3H), 3.04-3.02 (m, 2H), 2.44 (s, 3H).

Embodiment 60

Compound (I-60) (S) -2- [6- (4- chlorphenyls) -8- methoxyl group -1- methyl -4H- benzos [f] [1,2,4] triazoles And [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (6,7- dihydro -5H- pyrrolo-es [2,3-d] pyrimidine -5- bases) ethyl ketone

Compound I-60 synthesis is carried out by the method for embodiment 53：Initiation material is (S) -2- [6- (4- chlorphenyls) -8- first Oxy-1-methyl-4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine-4- bases] acetic acid (I₈) and 6,7- bis- Hydrogen -5H- pyrrolo-es [2,3-d] pyrimidine reacts, and pale white solid target product (S) -2- [6- (4- chlorphenyls) -8- methoxies are made Base -1- methyl -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (6,7- dihydro -5H- pyrroles Cough up simultaneously [2,3-d] pyrimidine -5- bases) ethyl ketone (I-60).MS(m/z)：501[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.64 (s, 1H), 7.88-7.85 (m, 3H), 7.75-7.73 (m, 2H), 7.58 (s, 1H), 7.47-7.45 (d, J=8.0Hz, 1H), 7.15- 7.13 (d, J=8.0Hz, 1H), 5.27 (m, 1H), 5.04-5.01 (m, 1H), 4.79-4.75 (m, 1H), 4.44-4.40 (m, 2H), 3.87 (s, 3H), 3.04-3.01 (m, 2H), 2.45 (s, 3H).

Embodiment 61

Compound (I-61) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- ((the 1H)-yl of 3,4- dihydro-isoquinoline -2) ethyl ketone

Compound I-61 synthesis is carried out by the method for embodiment 53：Initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and 3,4- dihydro-isoquinoline react, Faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3- are made A] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- ((the 1H)-yl of 3,4- dihydro-isoquinoline -2) ethyl ketone (I-61).MS(m/z)：483[M+H ]⁺。¹H NMR(DMSO-d₆)：δ：7.88-7.86 (m, 2H), 7.77-7.74 (m, 3H), 7.53-7.48 (m, 5H), 7.21-7.18 (m, 2H), 5.28 (m, 1H), 5.07-5.04 (m, 1H), 4.81-4.78 (m, 1H), 4.67 (s, 2H), 3.89-3.86 (m, 2H), 3.16-3.12 (m, 2H), 2.45 (s, 3H).

Embodiment 62

Compound (I-62) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- ((the 5H)-yl of 7,8- dihydro -1,6- naphthyridines -6) ethyl ketone

Compound I-62 synthesis is carried out by the method for embodiment 53：Initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and 7,8- dihydro -1,6- naphthyridines it is anti- Should, faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols are made [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- (7,8- dihydros -1, δ-naphthyridines -6 (5H)-yl) ethyl ketone (I-62).MS(m/z)： 484[M+H]⁺。¹H NMR(DMSO-d₆)：δ：7.92-7.88 (m, 3H), 7.79-7.74 (m, 4H), 7.56-7.52 (m, 4H), 5.28 (m, 1H), 5.08-5.05 (m, 1H), 4.83-4.79 (m, 1H), 4.68 (s, 2H), 3.88-3.85 (m, 2H), 3.17- 3.14 (m, 2H), 2.44 (s, 3H).

Embodiment 63

Compound (I-63) (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- ((the 1H)-yl of 3,4- dihydro -2,6- naphthyridines -2) ethyl ketone

Compound I-63 synthesis is carried out by the method for embodiment 53：Initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and 3,4- dihydro -2,6- naphthyridines it is anti- Should, faint yellow solid target product (S) -2- [6- (4- chlorphenyls) -1- methyl -4H- benzos [f] [1,2,4] triazols are made [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] -1- ((the 1H)-yl of 3,4- dihydro -2,6- naphthyridines -2) ethyl ketone (I-63).MS(m/z)： 484[M+H]⁺。¹H NMR(DMSO-d₆)：δ：7.91-7.88 (m, 3H), 7.78-7.74 (m, 4H), 7.57-7.52 (m, 4H), 7.03 (m, 1H), 5.29 (m, 1H), 5.07-5.05 (m, 1H), 4.84-4.81 (m, 1H), 4.67 (s, 2H), 3.89-3.85 (m, 2H), 3.18-3.14 (m, 2H), 2.45 (s, 3H).

Embodiment 64

Compound (I-64) (S) -2- [trimethyl -6H- thienos [3,2-f] [1,2,4] of 4- (4- chlorphenyls) -2,3,9- Triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- ((the 1H)-yl of 3,4- dihydro -2,7- naphthyridines -2) ethyl ketone

Compound I-64 synthesis is carried out by the method for embodiment 53：Initiation material is (S) -2- [6- (4- chlorphenyls) -1- first Base -4H- benzos [f] [1,2,4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -4- bases] acetic acid and 3,4- dihydro -2,7- naphthyridines, Be made faint yellow solid target product (S) -2- [trimethyl -6H- thienos [3,2-f] of 4- (4- chlorphenyls) -2,3,9- [1,2, 4] triazol [4,3-a] [Isosorbide-5-Nitrae] diazepine -6- bases] -1- ((the 1H)-yl of 3,4- dihydro -2,7- naphthyridines -2) ethyl ketone (I-64). MS(m/z)：518[M+H]⁺。¹H NMR(DMSO-d₆)：δ：8.72 (s, 1H), 8.12-8.10 (d, J=8.0Hz, 1H), 7.89- 7.86 (m, 2H), 7.78-7.76 (m, 2H), 7.10-7.08 (d, J=8.0Hz, 1H), 5.29 (m, 1H), 5.07-5.04 (m, 1H), 4.79-4.76 (m, 1H), 4.66 (s, 2H), 3.88-3.85 (m, 2H), 2.45 (s, 3H), 2.37 (s, 3H), 2.20 (s, 3H)。

Embodiment 65

Biological test

BRD4 active testings：

Using time-resolved fluorescence resonance energy transfer (TR-FRET) method, to disclosure embodiment compound BRD4 effects are tested, from expression in escherichia coli of the N-terminal with His labels and the people source BRD4 (BD1) of purification of Recombinant. In buffer solution containing 25mM HEPES pH 7.5,100mM NaCl, 0.1%BSA, 0.05%CHAPS and detection reagent, mix It is GRGK (Ac) GGK (Ac) GLGK (Ac) GGAK (Ac) to close Bu Luomo domain proteins, 0-10 μM of compound and sequence RHGSGSK- biotins are measured.After albumen, compound and peptide fragment reach with reference to balance, addition contains Streptavidin mark The detection reagent of the anti-6XHis antibody of Tb cryptates and the XL665 mark of note.Continue after being incubated 1h, use BMG PHERAstar FS instrument record TR-FRET signals.Utilize four parameter nonlinear regression equations of Graphpad Prism softwares： Y=maximums+(minimum value-maximum)/(1+ (X/IC₅₀)^Hill) suppression percentage is fitted, and then obtain each chemical combination The IC of thing₅₀Value.X is the log concentration of compound, and Y is the suppression percentage under the concentration, and Hill is Hill slope factors.

MV4-1 cell proliferation experiments：

Pass throughReagent (Invitrogen) determines cell viability.

MV4-11 cells (acute myeloid leukaemia) are seeded in 96 hole microtiter plates with the concentration of 5000 cells/wells On 100 μ L growth mediums (RPMI1640,10%FCS) in.After being incubated overnight at 37 DEG C, fluorescent value (C1 values) is determined. Then many kinds of substance dilution process plate is used, and 72h is incubated at 37 DEG C, then determines fluorescent value (C0 values).For data Analysis, from C0 values deduct C1 values, and by it is being handled with many kinds of substance dilution or only with cushioning liquid processing cell results It is compared.So as to calculate IC₅₀Value.

Above-mentioned experimental result is as shown in table 2.

The test result of table 2.：

Claims

1. compound or its pharmaceutically useful salt shown in the logical formula (I) of one kind：

Wherein：

A rings are aryl or heteroaryl；

R₁Represent hydrogen, halogen, C₁-C₃Alkyl, C₁-C₃Alkoxy；

R₂Represent methyl, trifluoromethyl, cyano group, halogen；

Y is represented

X, Z, U, V, W represent C or N respectively；

R₃Represent C₁-C₃Alkyl,

R₅Represent hydrogen, C₁-C₃Alkyl；

M is 0,1；

N is 0,1,2.

2. logical formula (I) compound according to claim 1, it is characterised in that described " aryl or heteroaryl " refers to benzene Base, pyridine radicals, thienyl, furyl, pyrimidine radicals, pyrazinyl, thiazolyl, imidazole radicals；" halogen " refers to F, Cl, Br, I； Described " C₁-C₃Alkyl " refer to methyl, ethyl, n-propyl or isopropyl；Described " C₁-C₃Alkoxy " refer to methoxy Base, ethyoxyl, positive propoxy or isopropoxy.

A kind of 3. logical formula (I) compound according to claim 1, it is characterised in that compound being selected from the group：

Or its pharmaceutically useful salt.

4. logical formula (I) compound and its pharmaceutically useful salt any one of claim 1-3 be as BET protein inhibitors, And for preventing or treating the disease related to BET albumen.

5. the disease treatment purposes described in claim 4, be primarily referred to as the tumor disease related to BET albumen, hyperplasia of prostate, Inflammatory disease, autoimmune disease, septicemia, virus infection, vascular diseases and neurogenic disease.

A kind of 6. pharmaceutical composition, it is characterised in that the formula described in the claim any one of 1-3 comprising therapeutically effective amount (I) compound and pharmaceutically acceptable carrier or excipient.