CN107629057B

CN107629057B - BET protein inhibitor and application thereof

Info

Publication number: CN107629057B
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: 2020-03-27
Anticipated expiration: 2036-07-19
Also published as: CN107629057A

Abstract

The present invention relates to compounds of general formula (I) which inhibit BET proteins, in particular BRD4, and their use in hyperproliferative diseases, primarily the prevention or treatment of neoplastic diseases, benign hyperplasias, inflammatory diseases, autoimmune diseases, sepsis, viral infections, vascular diseases and neurological diseases.

Description

BET protein inhibitor and application thereof

Technical Field

The present invention relates to the field of pharmaceutical manufacturing, and in particular to compounds useful as inhibitors of one or more bromodomain-containing proteins.

Background

Epigenetics (epigenetics) is one of the current very popular drug discovery topics. Histone acetylation is an important component of epigenetic research. Bromodomain (BRD) is a class of conserved protein domains that specifically recognize acetylated lysine (KAc) in histones, and by binding acetylated lysine to promote protein enrichment at specific gene transcription sites, alter RNA polymerase II activity, regulate gene transcription expression (Kuc and Allis, Bioessays, 1998, 20: 615-.

Currently, 61 BRD domains found in humans are present in 42 proteins, and the BRD proteins are classified into 8 major families according to the function of the parent protein, and the BET protein family is the class 2 of the BRD protein family. BET proteins include the four members BRD2, BRD3, BRD4, and BRDT (Wu and Chiang, J.biol. chem., 2007, 282: 13141-. The first three are widely expressed in all body cells, the latter only in testis tissue.

BET proteins play an important role in a variety of tumors. For example, hematopoietic tumors (acute myelocytic leukemia, lymphoma, multiple myeloma, B-cell acute lymphoblastic leukemia, etc.) can inhibit MYC expression by interfering the combination of BRD4 and oncogene MYC, thereby causing tumor cell apoptosis. The fusion between BET proteins (BRD3 or BRD4) and NUT (a protein that is normally expressed only in the testis) results in an aggressive form of squamous cell carcinoma, which is called NUT midline carcinoma (French, cancer gene, cytogene, 2010, 203: 16-20). The fusion protein prevents cell differentiation and promotes proliferation (Yan et al, biol. chem., 2011, 286: 27663-27675), and the growth of the in vivo model thus obtained is inhibited by BRD 4-inhibitors (Fil ppakleptolos et al, Nature, 2010, 468: 1067-1073).

The broader biological functions of BET proteins have been reported in many documents. Proteins containing bromodomains are involved in transcriptional regulation, leading to oncogene rearrangement, resulting in highly oncogenic fusion proteins, which play an important role in the development of a variety of malignant cancers. In addition, bromodomains also contain the protein regulatory nuclear factor-kB (NF-kB), a key transcription factor in the mediated inflammatory response. They are also involved in the replication of the viral genome and in the regulation of transcription of certain viral proteins. Taken together, targeting these proteins may be beneficial for developing new therapeutic strategies targeting cancer, inflammation and viral infections. Currently, small molecule inhibitors directed against this receptor are in clinical stage and are mainly used in the treatment of cancer and autoimmune diseases.

Disclosure of Invention

One of the objects of the present invention is to provide a novel class of BET protein inhibitor compounds or pharmaceutically acceptable salts thereof.

The invention also aims to provide application of the compounds as novel BET protein inhibitors in preparing medicines for preventing or treating diseases related to BET protein, mainly tumor diseases, benign hyperplasia, inflammatory diseases, autoimmune diseases, septicemia, viral infection, vascular diseases and neurological diseases. The prevention or treatment of neoplastic diseases includes, but is not limited to, acute myelogenous leukemia, lymphoma, multiple myeloma, B-cell acute lymphoid leukemia, midline carcinoma, glioma, solid tumor, breast cancer, colorectal cancer, prostate cancer, cervical cancer, non-small cell lung cancer, melanoma, and the like.

To achieve the above objects, the present invention provides a derivative represented by the following general formula I:

wherein:

ring A is aryl or heteroaryl;

R₁represents hydrogen, halogen, C₁-C₃Alkyl of (C)₁-C₃Alkoxy group of (a);

R₂represents methyl, trifluoromethyl, cyano, halogen;

y represents

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

R₃represents C₁-C₃Alkyl group of (A) or (B),

R₄Represents hydrogen, methyl, halogen, hydroxyl, cyano, trifluoromethyl;

R₅represents hydrogen, C₁-C₃Alkyl groups of (a);

m is 0, 1;

n is 0, 1, 2;

the invention also provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier, and at least one compound of formula (I) and pharmaceutically acceptable salts thereof as described herein for use as BET protein inhibitors.

"aryl or heteroaryl" as used herein refers to phenyl, pyridyl, thienyl, furyl, pyrimidinyl, pyrazinyl, thiazolyl, imidazolyl; the halogen refers to F, Cl, Br and I; said "C₁-C₃The "alkyl group" of (a) means a methyl group, an ethyl group, an n-propyl group or an isopropyl group; said "C₁-C₃The "alkoxy group" of (a) means a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.

Typical compounds of the present invention include, but are not limited to, the following compounds of table 1:

or a pharmaceutically acceptable salt thereof.

Examples of pharmaceutically acceptable salts include inorganic and organic salts, such as hydrochloride, hydrobromide, sulfate, phosphate, citrate, tartrate, succinate, maleate, fumarate, tonsil and oxalate salts.

The compounds of the invention can be prepared by the following general synthesis method:

the final product I, i.e.the substituted aminoarone (I) was prepared according to the procedures reported in the literature (C Chung, H Coste et al J. Med. chem.2011, 54 (11): 3827-3838 and HARBESONSCOTT L et al WO2015120393A1)₁) With Fmoc-L-aspartyl chloride-4-methyl ester (I)₂) The amide intermediate (I) is prepared by condensation reaction₃)，I₃The target product I is prepared through the steps of deprotection, ring closing, vulcanization, condensation, cyclization, hydrolysis, condensation and the like.

The invention provides application of the compounds as novel BET protein inhibitors in preparation of medicines for preventing or treating diseases related to BET proteins, mainly tumor diseases, benign hyperplasia, inflammatory diseases, autoimmune diseases, septicemia, viral infections, vascular diseases and neurological diseases. The prevention or treatment of neoplastic diseases includes, but is not limited to, acute myelogenous leukemia, lymphoma, multiple myeloma, B-cell acute lymphoid leukemia, midline carcinoma, glioma, solid tumor, breast cancer, colorectal cancer, prostate cancer, cervical cancer, non-small cell lung cancer, melanoma, and the like.

The derivative can be formed into a composition for treating related cancers and other diseases by oral administration, injection and the like in the process of treating diseases.

The composition comprises a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The mentioned carriers refer to the carriers conventional in the pharmaceutical field, such as: diluents, excipients such as water, etc.; binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.; fillers such as starch and the like; disintegrating agents such as calcium carbonate, sodium bicarbonate; in addition, other adjuvants such as flavoring agents and sweeteners may also be added to the composition.

For oral administration, it can be prepared into conventional solid preparations such as tablet, powder or capsule; for injection, it can be prepared into injection.

The various dosage forms of the composition of the present invention can be prepared by conventional methods in the medical field, wherein the content of the active ingredient is 0.1-99.5% (by weight).

The administration amount of the present invention may vary depending on the route of administration, age, body weight of the patient, type and severity of the disease to be treated, etc., and the daily dose thereof is 0.005 to 30mg/kg body weight (oral administration) or 0.005 to 30mg/kg body weight (injection).

Examples

The present invention is further illustrated below with reference to specific examples, which are not intended to limit the scope of the invention.

Example 1

The compound (I-1) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (methylsulfonyl) acetamide

Step 1: intermediate I₃The preparation of (1): [ 2-amino-5- (methyloxy) phenyl](4-chlorophenyl) methanone (I)₁5.0g, 19.1mmol) and diisopropylethylamine (4.9g, 38.2mmol) were added to dichloromethane (50mL) and Fmoc-L-aspartyl chloride-4-methyl ester (I) was added dropwise with stirring at room temperature₂7.4g, 19.1mmol), stirring at room temperature after additionReacting for 5H, adding H into the reaction solution₂O (50mL) is stirred and extracted, and the organic layer is dried, filtered and concentrated to obtain an intermediate I₃(10.5g, yield 90%), MS (m/z): 614[ M + H]⁺。

Step 2: intermediate I₄The preparation of (1): amides I₃(10g, 16.3mmol) and triethylamine (24.7g, 245mmol) were added to dichloromethane (100mL) and heated to reflux temperature for 5 h. The solvent was concentrated to dryness and the residue was taken up in dichloroethane (50mL), acetic acid (9.8g, 163mmol) and heated to 60 ℃ for 2 h. The reaction mixture was washed with 1N diluted hydrochloric acid aqueous solution (30mL), dried over anhydrous sodium sulfate, and concentrated to dryness. Pulping residue with anhydrous ethanol (20mL) for 30min, filtering, and vacuum drying to obtain intermediate I₄(4.9g, yield 81.2%), MS (m/z): 374[ M + H]⁺。

And step 3: intermediate I₅The preparation of (1): phosphorus pentasulfide (4.8g, 21.7mmol), sodium carbonate (2.3g, 21.7mmol) were added to dichloroethane (50mL) and the mixture was stirred at room temperature for 1 h. I is₄(4.5g, 12.1mmol) was added to the above reaction mixture, and the mixture was heated to 70 ℃ for reaction for 5 hours. Cooled to room temperature and filtered. Filtrate is subjected to H₂Washing with O (50mL), separating, drying the organic layer with anhydrous sodium sulfate, and concentrating to dryness to obtain crude sulfamide intermediate I₅(3.3g, yield 71%), MS (m/z): 390[ M + H ]]⁺. The crude product was used in the next reaction without further purification.

And 4, step 4: intermediate I₆The preparation of (1): sulfamide intermediate I₅(3g, 7.7mmol) was dissolved in tetrahydrofuran (30mL), cooled to 0-5 deg.C, and hydrazine hydrate (1.1g, 23.1mmol) was added dropwise with stirring and reacted at this temperature for 5 h. Triethylamine (2.3g, 23.1mmol) was added to the reaction solution, acetyl chloride (1.8g, 23.1mmol) was added dropwise while maintaining at 0-5 deg.C, and the reaction was allowed to warm to room temperature for 2 h. Addition of H₂O (30 mL)/ethyl acetate (50mL) is stirred and extracted, liquid is separated, an organic layer is dried by anhydrous sodium sulfate, and the mixture is concentrated to be dry to obtain a crude intermediate I₆(3.2g, yield 98%), MS (m/z): 430[ M + H ]]⁺。

And 5: triazole intermediates I₇The preparation of (1): i is₆(3.2g, 7.5mmol) was added to tetrahydrofuran (30mL) and acetic acid (30mL) and the reaction was stirred at room temperature for 24 h. Concentrating the reaction solution under reduced pressure to dryness to obtain the residueThe mixture was extracted with saturated aqueous sodium bicarbonate (30 mL)/dichloromethane (50mL), and the organic layer was extracted with H₂Washing with O (30mL), washing with saturated saline (30mL), concentrating to dryness, and passing through silica gel column (mobile phase dichloromethane/methanol: 100/1) to obtain triazole intermediate I₇(2.5g, yield 81.5%), MS (m/z): 412[ M + H]⁺。

Step 6: acid intermediate I₈The preparation of (1): triazole intermediates I₇(2.5g, 6.1mmol) tetrahydrofuran (10mL), H₂O (30mL), a 30% aqueous solution of sodium hydroxide was added dropwise with stirring at room temperature, and the mixture was heated to 40 to 45 ℃ to react for 5 hours. Cooling to 0-5 deg.C, adding 1N hydrochloric acid aqueous solution dropwise to adjust pH to 4-5, separating out solid, stirring for 30min, filtering, and vacuum drying filter cake to obtain acid intermediate (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid I₈(2.3g, yield 95%), MS (m/z): 398[ M + H]⁺。

And 7: preparation of a target product I-1: acid intermediate I₈(0.5g, 1.26mmol), benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate (HBTU, 0.52g, 1.38mmol), methanesulfonic acid amine (0.13g, 1.38mmol), N, N-diisopropylethylamine (DIPEA, 0.32g, 2.52mmol), and DMF (5mL) were added to the reaction flask and stirred at room temperature for 2 h. Dropwise addition of H₂O (5mL) and dichloromethane (20mL) are stirred and extracted, the organic layer is washed by saturated saline (30mL) again, the organic layer is concentrated to be dry, and the crude product passes through a silica gel column (mobile phase dichloromethane/methanol: 100/1) to obtain (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N-methanesulfonamide (I-1) as a 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)。

Example 2

The compound (I-2) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (aminosulfonyl) acetamide

Synthesis of Compound I-2 the procedure of example 1 was followed, starting from (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ]][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And tert-butyl N- (aminosulfonyl) carbamate by the reaction of step 7 of example 1 to obtain (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]The intermediate is subjected to BOC removal protection by 3N ethyl acetate hydrochloride to obtain a light white solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N- (aminosulfonyl) 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)。

Example 3

The compound (I-3) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (ethylsulfonyl) acetamide

Synthesis of Compound I-3 the procedure of example 1 was followed, starting from (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And an ethyl sulfonic acid amine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-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)。

Example 4

The compound (I-4) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (methylaminosulfonyl) acetamide

Synthesis of Compound I-4 the procedure of example 1 was followed, starting from (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And methylamino sulfamide, the white solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f) is obtained after the reaction according to the example 1][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N- (methylaminosulfonyl) 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)。

Example 5

The compound (I-5) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (propylsulfonyl) acetamide

Synthesis of Compound I-5 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And propyl sulfonic acid amine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N- (propylsulfonyl) 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)。

Example 6

The compound (I-6) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (ethylamino sulfonyl) acetamide

Synthesis of Compound I-6 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And ethylamino sulfamide, and a light white solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f) is obtained after the reaction is carried out according to the example 1][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N- (ethylaminosulfonyl) 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)。

Example 7

The compound (I-7) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (isopropylsulfonyl) acetamide

Synthesis of Compound I-7 the procedure of example 1 was followed, starting from (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And isopropyl sulfonic acid amine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N- (isopropylsulfonyl) 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)。

Example 8

The compound (I-8) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (propylaminosulfonyl) acetamide

Synthesis of Compound I-8 by the method of example 1, starting with (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And propylamino sulfamide, and a light white solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f) is obtained after the reaction is carried out according to the example 1][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N- (propylaminosulfonyl) 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)。

Example 9

The compound (I-9) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (methylsulfonyl) acetamide

Synthesis of Compound I-9 the procedure of example 1 was followed, starting from (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (prepared from 2-amino-4' -chlorobenzophenone as the starting material, see example 1 for a synthetic method) and methanesulfonic acid amine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N- (methylsulfonyl) 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)。

Example 10

The compound (I-10) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (aminosulfonyl) acetamide

Synthesis of Compound I-10 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and tert-butyl N- (aminosulfonyl) carbamate were reacted as in step 7 of example 1 to give (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f [][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]The intermediate is subjected to BOC removal protection by 3N ethyl acetate hydrochloride to obtain a white gray solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N- (aminosulfonyl) 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)。

Example 11

The compound (I-11) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (ethylsulfonyl) acetamide

Synthesis of Compound I-11 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and ethyl sulfonamide react according to the step 7 of the embodiment 1 to obtain the off-white solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N- (ethylsulfonyl) acetamide (I-11). MS (m/z): 459[ M + H ]]⁺。¹HNMR(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)。

Example 12

The compound (I-12) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (methylaminosulfonyl) acetamide

Synthesis of Compound I-12 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and methylamino sulfamide, white solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f ] is obtained after the reaction according to the example 1][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N- (methylaminosulfonyl) acetamide (I-12). MS (m/z): 460[ M + H ]]⁺。¹HNMR(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)。

Example 13

The compound (I-13) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (propylsulfonyl) acetamide

Synthesis of Compound I-13 by the method of example 1, starting with (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and propyl sulfonamide react according to the step 7 of the embodiment 1 to obtain the off-white solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N- (propylsulfonyl) acetamide (I-13). MS (m/z): 473[ M + H ]]⁺。¹HNMR(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)。

Example 14

The compound (I-14) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (ethylamino sulfonyl) acetamide

Synthesis of Compound I-14 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and ethylamino sulfamide, white solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f ] is obtained after reaction according to example 1][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N- (ethylaminosulfonyl) acetamide (I-14). MS (m/z): 474[ M + H]⁺。¹HNMR(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)。

Example 15

The compound (I-15) (S) -2- [6- (4-chlorophenyl) -1-cyano-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (propylsulfonyl) acetamide

Synthesis of Compounds 1-15 the procedure of example 1 was followed, starting with (S) -2- [6- (4-chlorophenyl) -1-cyano-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and propylamine sulfonamide. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -1-cyano-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-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)。

Example 16

The compound (I-16) (S) -2- [6- (4-chlorophenyl) -1-fluoro-2-methyl-4H-benzo [ f ] [1, 2, 4] imidazo [1, 2-a ] [1, 4] diazepin-4-yl ] -N- (ethylamino sulfonyl) acetamide

Synthesis of Compound I-16 by the method of example 1, starting with (S) -2- [6- (4-chlorophenyl) -1-fluoro-2-methyl-4H-benzo [ f)][1，2，4]Imidazo [1, 2-a ]][1，4]Diazepin-4-yl]Acetic acid and ethylamine sulfamide to obtain a white solid target product (S) -2- [6- (4-chlorphenyl) -1-fluoro-2-methyl-4H-benzo [ f)][1，2，4]Imidazo [1, 2-a ]][1，4]Diazepin-4-yl]-N- (ethylaminosulfonyl) 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)。

Example 17

The compound (I-17) (S) -2- [6- (4-chlorophenyl) -8-chloro-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (ethylsulfonyl) acetamide

Synthesis of Compound I-17 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -8-chloro-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and ethyl amine sulfonate. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -8-chloro-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-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)。

Example 18

The compound (I-18) (S) -2- [6- (4-chlorophenyl) -9-fluoro-1, 8-dimethyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (ethylamino sulfonyl) acetamide

Synthesis of Compound I-18 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -9-fluoro-1, 8-dimethyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and ethylamine sulfamide to obtain a light white solid target product (S) -2- [6- (4-chlorphenyl) -9-fluorine-1, 8-dimethyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N- (ethylaminosulfonyl) 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)。

Example 19

The compound (I-19) (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -N- (methylsulfonyl) acetamide

Synthesis of Compound I-19 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]Acetic acid (synthesis method see example 1, prepared from (2-amino-4, 5-dimethyl-3-thiophene) (4-chlorophenyl) methanone) and methanesulfonic acid amine. Obtaining a light yellow solid target product (S) -2- [4- (4-chlorphenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-N- (methylsulfonyl) 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)。

Example 20

The compound (I-20) (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -N- (aminosulfonyl) acetamide

Synthesis of Compound I-20 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]Acetic acid and tert-butyl N- (aminosulfonyl) carbamate were reacted as in step 7 of example 1 to give (S) -2- [6- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]The intermediate is subjected to BOC removal protection by 3N ethyl acetate hydrochloride to obtain a white gray solid target product (S) -2- [4- (4-chlorphenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-N- (aminosulfonyl) 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)。

Example 21

The compound (I-21) (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -N- (ethylsulfonyl) acetamide

Synthesis of Compound I-21 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]Acetic acid and ethyl amine sulfonate. Obtaining a light yellow solid target product (S) -2- [4- (4-chlorphenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-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)。

Example 22

The compound (I-22) (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -N- (methylaminosulfonyl) acetamide

Synthesis of Compound I-22 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]Acetic acid and methylamino sulfonamide to obtain a white solid target product (S) -2- [4- (4-chlorphenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-N- (methylaminosulfonyl) 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)。

Example 23

The compound (I-23) (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 24] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -N- (propylsulfonyl) acetamide

Synthesis of Compound I-23 by the method of example 1, starting with (S) -2- [6- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]Acetic acid and ethyl amine sulfonate. Obtaining a light yellow solid target product (S) -2- [4- (4-chlorphenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-N- (propylsulfonyl) acetamide (I-23). MS (m/z): 507M + 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)。

Example 24

The compound (I-24) (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -N- (ethylamino sulfonyl) acetamide

Synthesis of Compound I-24 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]Acetic acid and ethylamine sulfamide to obtain a white solid target product (S) -2- [4- (4-chlorphenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-N- (ethylaminosulfonyl) 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)。

Example 25

The compound (I-25) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (3-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [4, 3-A ] pyrazine) ethanone

Synthesis of Compound I-25 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And 3-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (3-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]Pyrazine) ethanone (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)。

Example 26

The compound (I-26) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (3-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [4, 3-A ] pyrazine) ethanone

Synthesis of Compound I-26 the procedure of example 1 was followed, starting from (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And 3-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (3-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]Pyrazine) ethanone (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)。

Example 27

The compound (I-27) (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -1- (3-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [4, 3-A ] pyrazine) ethanone

Synthesis of Compound I-27 by the method of example 1, starting with (S) -2- [6- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]Acetic acid and 3-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [4- (4-chlorphenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-1- (3-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]Pyrazine) ethanone (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)。

Example 28

The compound (I-28) (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -1- (3-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [4, 3-A ] pyrazine) ethanone

Synthesis of Compound I-28 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]Acetic acid and 3-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [4- (4-chlorphenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-1- (3-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]Pyrazine) ethanone (I-28). MS (m/z): 576[ M + H]⁺。¹HNMR(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)。

Example 29

The compound (I-29) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (2-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [1, 5-A ] pyrazine) ethanone

Synthesis of Compound I-29 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And 2-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (2-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]Pyrazine) ethanone (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)。

Example 30

The compound (I-30) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (2-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [1, 5-A ] pyrazine) ethanone

Synthesis of Compound I-30 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And 2-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (2-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]Pyrazine) ethanone (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)。

Example 31

The compound (I-31) (S) -2- [6- (4-chlorophenyl) -9-chloro-1-fluoro-8-isopropoxy-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (methylsulfonyl) acetamide

Synthesis of Compound I-31 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -9-chloro-1-fluoro-8-isopropoxy-4H-benzo [ f][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and methylsulfonyl amine to obtain light white solid target product (S) -2- [6- (4-chlorphenyl) -9-chloro-1-fluoro-8-isopropoxy-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N- (methylsulfonyl) 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)。

Example 32

The compound (I-32) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-pyrido [2, 3-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (methylsulfonyl) acetamide

Synthesis of Compound I-32 the procedure of example 1 was followed, starting from (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-pyrido [2, 3-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and methanesulfonic acid amine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-pyrido [2, 3-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N- (methylsulfonyl) 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)。

Example 33

The compound (I-33) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-pyrimido [4, 5-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -N- (methylsulfonyl) acetamide

Synthesis of Compound I-33 by the method of example 1, starting with (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-pyrimido [4, 5-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and methanesulfonic acid amine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-pyrimido [4, 5-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-N- (methylsulfonyl) 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)。

Example 34

The compound (I-34) (S) -2- [5- (4-chlorophenyl) -10-methyl-7H-pyrazino [2, 3-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-7-yl ] -N- (methylsulfonyl) acetamide

The compound I-34 was synthesized as in example 1 starting from (S) -2- [5- (4-chlorophenyl) -10-methyl-7H-pyrazino [2, 3-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-7-yl]Acetic acid and methanesulfonic acid amine. Obtaining a light yellow solid target product (S) -2- [5- (4-chlorphenyl) -10-methyl-7H-pyrazino [2, 3-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-7-yl]-N- (methylsulfonyl) 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)。

Example 35

The compound (I-35) (S) -2- [4- (4-chlorophenyl) -9-methyl-6H-furo [2, 3-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -N- (methylsulfonyl) acetamide

Synthesis of Compound I-35 was carried out as in example 1 starting from (S) -2- [4- (4-chlorophenyl) -9-methyl-6H-furo [2, 3-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]Acetic acid and methanesulfonic acid amine. Obtaining a light yellow solid target product (S) -2- [4- (4-chlorphenyl) -9-methyl-6H-furo [2, 3-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-N- (methylsulfonyl) 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)。

Example 36

The compound (I-36) (S) -2- [4- (4-chlorophenyl) -9-methyl-6H-thiazolo [4, 5-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -N- (methylsulfonyl) acetamide

Synthesis of Compound I-36 was carried out as in example 1 starting from (S) -2- [4- (4-chlorophenyl) -9-methyl-6H-thiazolo [4, 5-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]Acetic acid and methanesulfonic acid amine. Obtaining a light yellow solid target product (S) -2- [4- (4-chlorphenyl) -9-methyl-6H-thiazolo [4, 5-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-N- (methylsulfonyl) 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)。

Example 37

The compound (I-37) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (3-cyano-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [4, 3-A ] pyrazine) ethanone

Synthesis of Compound I-37 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And 3-cyano-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (3-cyano-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]Pyrazine) ethanone (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)。

Example 38

The compound (I-38) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (3-hydroxy-5, 6-tetrahydroimidazo [1, 5-a ] pyrazin-7 (8H) -yl) ethanone

Synthesis of Compound I-38 the procedure is as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And 3-hydroxy-5, 6, 7, 8-tetrahydroimidazo [1, 5-a ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (3-hydroxy-5, 6-tetrahydroimidazo [1, 5-a)]Pyrazin-7 (8H) -yl) ethanone (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)。

Example 39

The compound (I-39) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (3-fluoro-5, 6-dihydroimidazo [1, 5-a ] pyrazin-7 (8H) -yl) ethanone

Synthesis of Compound I-39 the procedure of example 1 was followed starting from (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ]][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And 3-fluoro-5, 6, 7, 8-tetrahydroimidazo [1, 5-a ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (3-fluoro-5, 6-tetrahydroimidazo [1, 5-a)]Pyrazin-7 (8H) -yl) ethanone (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)。

Example 40

The compound (I-40) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (2-methyl-5, 6-dihydropyrrolo [1, 5-a ] pyrazin-5 (4H) -yl) ethanone

Synthesis of Compound I-40 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And 2-methyl-4, 5, 6, 7-tetrahydropyrrolo [1, 5-a ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (2-methyl-5, 6-dihydropyrrolo [1, 5-a)]Pyrazin-5 (4H) -yl) ethanone (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)。

EXAMPLE 41

The compound (I-41) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (2-chloro-5, 6-dihydroimidazo [1, 2-a ] pyrazin-7 (8H) -yl) ethanone

Synthesis of Compound I-41 by the method of example 1, starting with (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And 2-chloro-5, 6, 7, 8-tetrahydroimidazo [1, 2-a ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (2-chloro-5, 6-dihydroimidazo [1, 2-a)]Pyrazin-7 (8H) -yl) ethanone (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)。

Example 42

The compound (I-42) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (5, 6-dihydroimidazo [1, 2-a ] pyrazin-7 (8H) -yl) ethanone

Synthesis of Compound I-42 the procedure of example 1 was followed, starting from (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) And 5, 6, 7, 8-tetrahydroimidazo [1, 2-a ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (5, 6-dihydroimidazo [1, 2-a)]Pyrazin-7 (8H) -yl) ethanone (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)。

Example 43

The compound (I-43) (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -1- (2-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [1, 5-A ] pyrazine) ethanone

Synthesis of Compound I-43 the procedure of example 1 was followed, starting from (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]Acetic acid and 2-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [4- (4-chlorphenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-1- (2-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]Pyrazine) ethanone (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)。

example 44

The compound (I-44) (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -1- (2-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [1, 5-A ] pyrazine) ethanone

Synthesis of Compound I-44 was carried out as in example 1 starting from (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]Acetic acid and 2-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [4- (4-chlorphenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-1- (2-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]Pyrazine) ethanone (I-44). MS (m/z): 576[ M + H]⁺。¹HNMR(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)。

Example 45

The compound (I-45) (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -1- (3-fluoro-5, 6-tetrahydroimidazo [1, 2-a ] pyrazin-7 (8H) -yl) ethanone

Synthesis of Compound I-45 was carried out as in example 1 starting from (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]Acetic acid and 3-fluoro-5, 6, 7, 8-tetrahydroimidazo [1, 2-a ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [4- (4-chlorphenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-1- (3-fluoro-5, 6-tetrahydroimidazo [1, 2-a)]Pyrazin-7 (8H) -yl) ethanone (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)。

Example 46

The compound (I-46) (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -1- (5, 6-tetrahydroimidazo [1, 2-a ] pyrazin-7 (8H) -yl) ethanone

Synthesis of Compound I-46 was carried out as in example 1 starting from (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]Acetic acid and 5, 6, 7, 8-tetrahydroimidazo [1, 2-a ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [4- (4-chlorphenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-1- (5, 6-tetrahydroimidazo [1, 2-a ]]Pyrazin-7 (8H) -yl) ethanone (I-46). MS (m/z): 507M + 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)。

Example 47

The compound (I-47) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (3-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [4, 3-A ] pyrazine) ethanone

Synthesis of Compound I-47 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and 3-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo compounds[4，3-a][1，4]Diazepin-4-yl]-1- (3-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]Pyrazine) ethanone (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)。

Example 48

The compound (I-48) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (3-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [4, 3-A ] pyrazine) ethanone

Synthesis of Compound I-48 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and 3-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (3-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]Pyrazine) ethanone (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)。

Example 49

The compound (I-49) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (2-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [1, 5-A ] pyrazine) ethanone

Synthesis of Compound I-49 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and 2-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diaza derivativesAndroid-4-yl]-1- (2-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]Pyrazine) ethanone (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)。

Example 50

The compound (I-50) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (2-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [1, 5-A ] pyrazine) ethanone

Synthesis of Compound I-50 was carried out as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and 2-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (2-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]Pyrazine) ethanone (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)。

Example 51

The compound (I-51) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (3-fluoro-5, 6-dihydroimidazo [1, 5-a ] pyrazin-7 (8H) -yl) ethanone

Synthesis of Compound I-51 the procedure is as in example 1 starting from (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and 3-fluoro-5, 6, 7, 8-tetrahydroimidazo [1, 5-a ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (3-fluoro-5, 6-dihydroimidazo [1,5-a]pyrazin-7 (8H) -yl) ethanone (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)。

Example 52

The compound (I-52) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (3-cyano-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [4, 3-A ] pyrazine) ethanone

Synthesis of Compound I-52 the procedure of example 1 was followed, starting from (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and 3-cyano-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]A pyrazine. Obtaining a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (3-cyano-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]Pyrazine) ethanone (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)。

Example 53

The compound (I-53) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (1H-indol-1-yl) ethanone

The synthesis of compound I-53 was carried out as follows: the starting material is (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) Reacting with thionyl chloride to obtain (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetyl chloride reacts with indole under the action of triethylamine to prepare a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo compounds[4，3-a][1，4]Diazepin-4-yl]-1- (1H-indol-1-yl) ethanone (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)。

Example 54

The compound (I-54) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone

The synthesis of compound I-54 was carried out as in example 53: the starting material is (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) With 1H-pyrrolo [2, 3-b ]]Pyridine reaction is carried out to obtain light yellow solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (1H-pyrrolo [2, 3-b)]Pyridine) ethanone (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)。

Example 55

The compound (I-55) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (9H-purin-9-yl) ethanone

The synthesis of compound I-55 was carried out as in example 53: the starting material is (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid reacts with 9H-purine to prepare a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (9H-purin-9-yl) ethanone (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)。

Example 56

The compound (I-56) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (7H-pyrrolo [2, 3-d ] pyrimidin-7-yl) ethanone

The synthesis of compound I-55 was carried out as in example 53: the starting material is (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid with 7H-pyrrolo [2, 3-d]Pyrimidine to obtain a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (7H-pyrrolo [2, 3-d)]Pyrimidin-7-yl) ethanone (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)。

Example 57

The compound (I-57) (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -1- (1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) ethanone

The synthesis of compound I-57 was carried out as in example 53: the starting material is (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid with 1H-pyrazolo [3, 4-d]Pyrimidine to obtain light yellow solid target product (S) -2- [4- (4-chlorphenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-1- (1H-pyrazolo [3, 4-d)]Pyrimidin-1-yl) ethanone (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)。

Example 58

The compound (I-58) (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -1- (1H-pyrazolo [3, 4-b ] pyrazin-1-yl) ethanone

The synthesis of compounds I-58 was carried out as described in example 53: the starting material is (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid with 1H-pyrazolo [3, 4-b]Pyrazine to obtain a light yellow solid target product (S) -2- [4- (4-chlorphenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-1- (1H-pyrazolo [3, 4-b)]Pyrazin-1-yl) ethanone (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)。

Example 59

The compound (I-59) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-1-yl) ethanone

The synthesis of compound I-59 was carried out as in example 53: the starting material is (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) With 2, 3-dihydro-1H-pyrrolo [2, 3-b ]]Pyridine reaction to obtain light white solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (2, 3-dihydro-1H-pyrrolo [2, 3-b)]Pyridin-1-yl) ethanone (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)。

Example 60

The compound (I-60) (S) -2- [6- (4-chlorophenyl) -8-methoxy-1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (6, 7-dihydro-5H-pyrrolo [2, 3-d ] pyrimidin-5-yl) ethanone

The synthesis of compound I-60 was carried out as in example 53: the starting material is (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid (I)₈) With 6, 7-dihydro-5H-pyrrolo [2, 3-d]Pyrimidine reaction is carried out to obtain light white solid target product (S) -2- [6- (4-chlorphenyl) -8-methoxyl-1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (6, 7-dihydro-5H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) ethanone (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)。

Example 61

The compound (I-61) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (3, 4-dihydroisoquinolin-2 (1H) -yl) ethanone

The synthesis of compound I-61 was carried out as described in example 53: the starting material is (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid reacts with 3, 4-dihydroisoquinoline to prepare a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (3, 4-dihydroisoquinolin-2 (1H) -yl) ethanone (I-61). MS (m/z): 483[ M + H]⁺。¹HNMR(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)。

Example 62

The compound (I-62) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) ethanone

The synthesis of compound I-62 was carried out as in example 53: the starting material is (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid reacts with 7, 8-dihydro-1, 6-naphthyridine to prepare a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (7, 8-dihydro-1, δ -naphthyridin-6 (5H) -yl) ethanone (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)。

Example 63

The compound (I-63) (S) -2- [6- (4-chlorophenyl) -1-methyl-4H-benzo [ f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-4-yl ] -1- (3, 4-dihydro-2, 6-naphthyridin-2 (1H) -yl) ethanone

The synthesis of compound I-63 was carried out as described in example 53: the starting material is (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid reacts with 3, 4-dihydro-2, 6-naphthyridine to prepare a light yellow solid target product (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]-1- (3, 4-dihydro-2, 6-naphthyridin-2 (1H) -yl) ethanone (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)。

Example 64

The compound (I-64) (S) -2- [4- (4-chlorophenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f ] [1, 2, 4] triazolo [4, 3-a ] [1, 4] diazepin-6-yl ] -1- (3, 4-dihydro-2, 7-naphthyridin-2 (1H) -yl) ethanone

The synthesis of compounds I-64 was carried out as in example 53: the starting material is (S) -2- [6- (4-chlorphenyl) -1-methyl-4H-benzo [ f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-4-yl]Acetic acid and 3, 4-dihydro-2, 7-naphthyridine to prepare a light yellow solid target product (S) -2- [4- (4-chlorphenyl) -2, 3, 9-trimethyl-6H-thieno [3, 2-f)][1，2，4]Triazolo [4, 3-a][1，4]Diazepin-6-yl]-1- (3, 4-dihydro-2, 7-naphthyridin-2 (1H) -yl) ethanone (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)。

Example 65

Biological assay

BRD4 activity assay:

the compounds of the examples disclosed in this application were tested for their BRD4 effect using time-resolved fluorescence resonance energy transfer (TR-FRET) method, and recombinant human BRD4(BD1) was expressed and purified from e.coli with His tag at the N-terminus. The assay was performed by mixing bromodomain protein, 0-10 μ M compound and GRGK (Ac) GGK (Ac) GLGK (Ac) GGAK (Ac) RHGGSK-biotin in a buffer containing 25mM HEPES pH 7.5, 100mM NaCl, 0.1% BSA, 0.05% CHAPS and detection reagents. When the protein, compound and peptide fragment reach the binding equilibrium, a detection reagent containing a streptavidin-labeled Tb cryptate and an XL 665-labeled anti-6 XHis antibody is added. After further incubation for 1h, the TR-FRET signal was recorded with a BMGPHERAstar FS instrument. Using the four parameter nonlinear regression equation of Graphpad Prism software: y ═ max + (min-max)/(1 + (X/IC)₅₀)^Hill) Percent inhibition was fitted to obtain the IC of each compound₅₀The value is obtained. X is the log concentration of the compound, Y is the percent inhibition at that concentration, and Hill is the Hill slope factor.

MV4-1 cell proliferation assay:

by passing

Reagents (Invitrogen) determine cell viability.

MV4-11 cells (acute myeloid leukemia) were seeded at a concentration of 5000 cells/well in 100. mu.L growth medium (RPMI1640, 10% FCS) in 96-well microtiter plates. After incubation at 37 ℃ overnight, the fluorescence values (C1 values) were determined. The plates were then treated with dilutions of various substances and incubated at 37 ℃ for 72h before the fluorescence value (C0 value) was determined. For data analysis, the C1 value was subtracted from the C0 value and the results of cells treated with multiple dilutions of the substance or buffer solution only were compared. Thereby computing the IC₅₀The value is obtained.

The results of the above experiments are shown in table 2.

Table 2. test results:

Claims

1. a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

2. Use of the compound of claim 1 and pharmaceutically acceptable salts thereof for the preparation of BET protein inhibitors for the prevention or treatment of BET protein related diseases.

3. Use according to claim 2, characterized in that the BET protein-related diseases refer to BET protein-related tumor diseases, benign hyperplasias, inflammatory diseases, autoimmune diseases, sepsis, viral infections, vascular diseases and neurological diseases.

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.