CN114276333B

CN114276333B - Dihydroquinoxaline bromodomain bivalent inhibitors

Info

Publication number: CN114276333B
Application number: CN202011039854.2A
Authority: CN
Inventors: 熊兵; 缪泽鸿; 陈丹琦; 王迎庆; 沈竞康; 宦霞娟; 吕铠铠; 胡剑萍
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2020-09-28
Filing date: 2020-09-28
Publication date: 2023-05-09
Anticipated expiration: 2040-09-28
Also published as: CN114276333A

Abstract

The invention relates to a dihydroquinoxaline bromodomain bivalent inhibitor with a structure shown in a general formula (I), a preparation method thereof, a composition containing the same and application thereof. The bivalent inhibitor can act on two bromodomains simultaneously, has a strong inhibition effect on bromodomain proteins, can be used for preparing medicines for treating a series of diseases and symptoms mediated by bromodomain proteins, and has a good treatment effect on tumors.

Description

Dihydroquinoxaline bromodomain bivalent inhibitors

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a dihydroquinoxaline bromodomain (bromodomain) bivalent inhibitor, a preparation method thereof, a composition containing the same and application of the compound in treating a series of diseases mediated by bromodomain proteins.

Background

In 2009, the Bradner group of Dana-Farber cancer institute reported the first small molecule inhibitor, (+) -JQ1, acting on BET bromodomain proteins, and several small molecule inhibitors of the BET family have been reported to date. Bromodomain protein inhibitors show a certain therapeutic potential in preclinical evaluation and clinical research, and the experimental result greatly encourages the enthusiasm of researchers, but suffers from low selectivity, drug resistance and other problems. Scientists have therefore continually explored new directions of research in recent years, with the desire to be able to solve the problems therein.

There remains a need in the art for the development of novel, more clinically valuable bromodomain inhibitors, which are expected to increase activity to effectively overcome the drug resistance problems of existing bromodomain protein inhibitors. The inventor of the present invention synthesizes a monovalent inhibitor through a suitable connection mode based on the work of a previously synthesized monovalent bromodomain inhibitor to obtain a divalent inhibitor, and unexpectedly discovers that the activity of the divalent inhibitor is significantly improved.

Disclosure of Invention

The invention provides a novel bromodomain bivalent inhibitor and pharmaceutically usable salts thereof, and a pharmaceutical composition containing the same. The bivalent inhibitor has a strong inhibition effect on bromodomain proteins and has a good treatment effect on tumors.

In a first aspect of the present invention there is provided a compound having the structure of formula (i):

wherein:

k is a bromodomain monovalent inhibitor group, for example, which may be selected from the following groups:

L ₁ is-C (=O) -or

G ₁ And G ₂ Each independently selected from: absence, -C (=o) -, substituted or unsubstituted C1-C4 alkylene; the substituted substituent is selected from: hydrogen, halogen, C1-C4 alkyl;

R ₁₉ and R is ₂₀ Each independently selected from: hydrogen, substituted or unsubstituted C1-C4 alkyl, said substituted substituents being selected from the group consisting of: hydrogen, C1-C4 alkyl;

L ₄ Selected from the group consisting of substituted or unsubstituted C1-C5 alkylene, substituted or unsubstituted C3-C10 cycloalkylene, said substituted substituents being selected from the group consisting of: fluorine, chlorine, bromine, hydroxyl, amino, nitro, cyano, C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, etc.), C1-C6 alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, etc.);

alternatively, L ₄ ，R ₁₉ ，R ₂₀ And the nitrogen atoms to which they are attached together form a substituted or unsubstituted 5-10 membered heterocyclic group, said substitution being meant to have 1-3 substituents, each substituent being independently selected from the group consisting of: halogen, hydroxy, nitro, cyano, C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), C1-C6 alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy);

x and Y are each independently selected from: c or N; preferably C;

R ₁ and R is ₁ ' may be the same or different from each other and are each independently selected from: hydrogen, C1-C6 alkyl (example)Such as methyl, ethyl, isopropyl), C3-C8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), phenyl-substituted C1-C2 alkyl (e.g., benzyl);

R ₂ and R is ₂ ' may be the same or different from each other and are each independently selected from: hydrogen, C1-C4 alkyl (e.g., methyl, ethyl), C2-C4 alkenyl substituted C1-C4 alkyl (e.g.

)；

R ₃ And R is ₃ ' may be the same or different from each other and are each independently selected from: a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted benzyl group, the substituted substituent being selected from the group consisting of: halogen (e.g., fluorine, chlorine, bromine), hydroxy, amino, nitro, cyano, C1-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl), C1-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy);

", indicates where substituents are attached.

In particular, L ₄ Selected from unsubstituted C1-C5 alkylene, unsubstituted C3-C10 cycloalkylene, or

L ₄ ，R ₁₉ ，R ₂₀ Together with the nitrogen atom to which they are attached form

/>

Wherein n4 and n5 are each independently selected from any integer between 0 and 4 (e.g., 0,1,2,3, 4), which may be the same as or different from each other;

n10, n11, n12 and n13 are each independently selected from any integer between 1 and 3 (e.g., 1,2, 3), and may be the same as or different from each other.

More particularly, L ₄ Is that

Or alternatively

Preferably G ₁ And G ₂ At least one of, or G ₁ And G ₂ Are all-C (=o) -.

In one embodiment, L in the above formula (I) ₁ Selected from the following groups:

Wherein,,

n1, n2 and n3 are each independently selected from any integer between 1 and 5 (e.g., 1,2,3,4, 5), which may be the same or different from each other;

n4, n5, n6, n7, n8 and n9 are each independently selected from any integer between 0 and 4 (e.g., 0,1,2,3, 4), which may be the same as or different from each other;

n10, n11, n12 and n13 are each independently selected from any integer between 1 and 3 (e.g., 1,2, 3), which may be the same as or different from each other;

L ₄ 、R ₁₉ and R is ₂₀ The definition of (a) is the same as that of the general formula (I).

In one embodiment, the compound of the structure of formula (I) is selected from the following compounds:

wherein,,

L ₅ selected from the group consisting of

Z ₁ Selected from-C (=O) -or- (CH) ₂ ) n-, n is an integer from 1 to 5;

Z ₂ selected from-C (=O) -or-CH ₂ -，

R ₁ And R is ₁ ' may be the same or different from each other and are each independently selected from hydrogen, C1-C4 alkyl (e.g., methyl, ethyl, isopropyl), C3-C8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), phenyl-substituted C1-C2 alkyl (e.g., benzyl); preferably selected from cyclopropyl, cyclobutyl, cyclopentyl, methyl, benzyl; preferably R ₁ And R is ₁ ' same;

R ₂ and R is ₂ ' may be the same or different from each other and are each independently selected from hydrogen, C1-C4 alkyl (e.g., methyl, ethyl, isopropyl), C2-C4 alkenyl substituted C1-C2 alkyl (e.g., vinyl ethyl); preferably selected from methyl, vinyl ethyl; preferably R ₂ And R is ₂ ' same;

R ₃ and R is ₃ ' may be the same or different from each other and are each independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, preferably selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl; the substituted substituents are selected from halogen (e.g. fluoro, chloro, bromo), hydroxy, amino, nitro, cyano, C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl), C1-C4 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy), preferably from halogen and methyl;

", indicates where substituents are attached.

In one embodiment, in formula II, R ₁ And R is ₁ ' is cyclopentyl, R ₂ And R is ₂ ' is methyl, R ₃ And R is ₃ ' is phenyl or p-methylphenyl, Z ₁ And Z ₂ Selected from-C (=O) -or-CH ₂ -。

In another embodiment, the compound of the structure of formula (I) is selected from the following compounds:

wherein,,

L ₅ 、Z ₁ 、Z ₂ 、R ₁ 、R ₂ and R is ₃ The same definition as in formula II.

In one embodiment, in formula III, R ₁ Is cyclopentyl, R ₂ Is methyl, R ₃ Is phenyl or p-methylphenyl, Z ₁ Is- (CH) ₂ ) n-, n is an integer from 1 to 5, Z ₂ Selected from-C (=O) -or-CH ₂ -。

Wherein,,

L ₅ 、Z ₁ 、Z ₂ 、R ₁ 、R ₂ 、R ₃ and R is ₃ ' the definition is the same as in formula II, R is selected from halogen.

In one embodiment, in formula IV, R ₁ Is cyclopentyl, R ₂ Is methyl, R ₃ And R is ₃ ' is phenyl or p-methylphenyl, Z ₁ And Z ₂ Selected from-C (=O) -or-CH ₂ -。

wherein R is ₁ 、R ₂ And R is ₃ The same definition as in formula II;

L ₅ the same definition as in formula II, or absent;

Z ₁ and general formula IIIn which the definitions are the same, or are absent or-CH ₂ -C(＝O)-，

Z ₂ The same definition as in formula II.

In one embodiment, in formula V, R ₁ Is cyclopentyl, R ₂ Is methyl, R ₃ Is phenyl, L ₅ Absence or as

Z ₁ Absent or-CH ₂ -C(＝O)-，Z ₂ is-C (=o) -.

wherein,,

R ₁ 、R ₂ and R is ₃ The same definition as in formula II;

L ₅ the same definition as in formula II, or absent;

Z ₁ as defined in formula II, either absent or-CH ₂ -C(＝O)-，

Z ₂ The same definition as in formula II.

In one embodiment, in formula VI, R ₁ Is cyclopentyl, R ₂ Is methyl, R ₃ Is phenyl, L ₅ Absence or as

Z ₁ Absent or-CH ₂ -C(＝O)-，Z ₂ is-C (=o) -.

In one embodiment, the compound of formula (I) is selected from the group consisting of:

/>

/>

in the present invention, the pharmaceutically acceptable salt may be, for example, sulfate, phosphate, hydrochloride, hydrobromide, acetate, oxalate, citrate, succinate, gluconate, tartrate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, benzoate, lactate, maleate, lithium, sodium, potassium or calcium salts, or the like.

In another aspect of the present invention, there is provided a pharmaceutical composition comprising one or more selected from the above compounds of the present invention and pharmaceutically acceptable salts thereof. The pharmaceutical composition optionally includes one or more pharmaceutical excipients. The pharmaceutical excipients include, for example, carriers, fillers, excipients, diluents, solvents, surfactants, binders, flavoring agents, sweeteners, sustained release agents, boosting agents, slip agents, coating agents, antioxidants, preservatives, flavoring agents and the like, but are not limited thereto, and can be appropriately selected by those skilled in the art according to the needs, such as formulation type, function and the like. The pharmaceutical composition of the present invention may be prepared into various dosage forms such as, but not limited to, tablets, pills, powders, injections, solutions, syrups, tinctures, capsules, sustained-release preparations, gels, drops, sprays, aerosols, and the like, as needed.

In a further aspect the present invention provides the use of a compound according to the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, for the preparation of an inhibitor of bromodomain recognition protein; or for the preparation of a medicament for the prophylaxis and/or treatment of a related disorder mediated by a bromodomain recognizing protein.

In a further aspect the present invention provides a compound according to the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the invention, for use in the preparation of an inhibitor of a bromodomain recognition protein; or for the prevention and/or treatment of related diseases mediated by bromodomain recognition proteins.

In a further aspect, the present invention provides a method of inhibiting a bromodomain recognition protein, or preventing and/or treating a related disorder mediated by a bromodomain recognition protein, comprising administering to a subject in need thereof a compound according to the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention.

In one embodiment, the related disorder mediated by a bromodomain recognition protein is selected from the group consisting of: malignant tumors, immunological diseases, cardiovascular system diseases, viral infections, neurodegenerative diseases or inflammation.

In another embodiment, the malignancy is selected from the group consisting of: acute lymphoblastic leukemia, acute myelogenous leukemia, B-cell chronic lymphocytic leukemia, chronic myelomonocytic leukemia, testicular nucleoprotein centerline cancer, small cell lung cancer, non-small cell lung cancer, B-cell lymphoma, prostate cancer, gastric cancer, colorectal cancer, renal cancer, liver cancer, breast cancer, pancreatic cancer.

Definition of terms:

the following terms, as used in the present specification and claims, have the meanings discussed below unless otherwise indicated.

C1-C6 means having 1-6 carbon atoms, C3-C10 means having 3-10 carbon atoms, and so on.

5-8 means 5-8 atoms on the ring, 5-10 means 5-10 atoms on the ring, and so on.

"alkyl" refers to a saturated aliphatic hydrocarbon group, which may be a branched or straight chain alkyl group.

"cycloalkyl" refers to an all-carbon monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

"alkoxy" means-O- (alkyl), such as methoxy, ethoxy;

"aryl" refers to an all-carbon monocyclic or fused-ring polycyclic group having a fully conjugated pi-electron system, examples of aryl being, but not limited to, phenyl, naphthyl, and the like;

"heterocyclyl" means a single, spiro, bridged or fused ring containing one, two, three, four or five ring heteroatoms selected from N, O, S, the remaining ring atoms, if present being C, such ring also having one or more double bonds, but such ring not having a fully conjugated pi electron system;

"heteroaryl" means a single cyclic or fused ring containing one, two, three or four ring heteroatoms selected from N, O, S, the remaining ring atoms, if present being C, and furthermore having a fully conjugated pi-electron system.

Compounds of formula I

In the invention, the compound shown in the general formula (I), the compound shown in the formula I and the compound shown in the formula I all refer to a bromodomain protein bivalent inhibitor with the following structure:

the compounds of the present invention of the above structure may exist as stereoisomers (including (enantiomers and diastereomers), solvates, hydrates and crystalline forms, for example

May be in the R configuration, S configuration or racemate form. Such stereoisomers, prodrugs, solvates, hydrates and crystalline forms are included within the scope of the compounds of the invention.

The compounds of the invention may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, including, but not limited to, optical isomers (including diastereomers and enantiomers), atropisomers, geometric isomers (cis-trans isomers), conformational isomers, and mixtures thereof (e.g., racemic mixtures), are included within the scope of the invention.

The compounds of the invention may also exist in different tautomeric forms, all of which are included within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconverted via a low energy barrier.

The compounds of the present invention may exist in unsolvated forms as well as solvated forms which comprise pharmaceutically acceptable solvents (e.g., water, ethanol, etc.), including solvated and unsolvated forms.

The compounds of the invention may also exist as prodrugs which are converted in vivo to the compounds of the invention and therefore, such prodrugs are included within the scope of the compounds of the invention.

The compounds of the present invention may also form protein-targeted degradation conjugates (PROTAC) or Antibody Drug Conjugates (ADC), and thus such PROTAC and ADC are also included within the scope of the compounds of the present invention.

The compounds of formula (I) have basic groups and thus can form pharmaceutically acceptable salts (i.e., pharmaceutically acceptable salts) with inorganic or organic acids, including pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable salts can be obtained by treating the free base of the compound of formula (I) with an inorganic or organic acid. Such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and such organic acids as ascorbic acid, nicotinic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, oxalic acid, malic acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like, without being limited thereto.

The compounds of the invention, pharmaceutically acceptable salts, solvates, prodrugs, protein targeted degradation conjugates or antibody drug conjugates thereof may also exist in one or more crystalline forms having similar or improved properties and are therefore included within the scope of the compounds of the invention.

Isotopically-labeled compounds of the present invention are also encompassed by the present invention except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, each of whichSuch as: ² hydrogen, hydrogen, ³ Hydrogen, hydrogen, ¹¹ Carbon (C), ¹³ Carbon (C), ¹⁴ Carbon (C), ¹³ Nitrogen (N), ¹⁵ Nitrogen (N), ¹⁵ Oxygen (O), ¹⁷ Oxygen (O), ¹⁸ Oxygen (O), ³¹ Phosphorus (P), ³² Phosphorus (P), ³⁵ Sulfur, sulfur, ¹⁸ Fluorine (F), ¹²³ Iodine (I), ¹²⁵ Iodine and its preparation method ³⁶ Chlorine.

Certain isotopically-labeled compounds of the present invention (e.g., with ³ H and ¹⁴ c-labeled) are used in compound and/or substrate tissue distribution assays. Particularly preferred is fluorination (i.e ³ H) And carbon-14 (i.e ¹⁴ C) Isotopes because of their ease of preparation and detection. Moreover, heavier isotopes such as deuterium (i.e ² H) Substitution may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) resulting from greater metabolic stability, and thus may be preferred in certain circumstances. Positron emitting isotopes, e.g ¹⁵ O、 ¹³ N、 ¹¹ C and C ¹⁸ F was used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labeled compounds of the present invention can generally be prepared following procedures analogous to those disclosed in the schemes and/or in the examples hereinbelow by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.

Preparation method

For purposes of illustration, the reaction schemes shown below provide possible routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the examples section below. The compounds of the invention may be synthesized by methods including those well known in the chemical arts, particularly in accordance with the description of the invention. The starting materials may be obtained commercially, or prepared by methods known in the art, or prepared according to the methods described herein.

For example, the method of preparation of the compounds of the present invention may be one of the following schemes:

reaction route one:

step a: nucleophilic substitution reaction of compound a with alanine (e.g., in the presence of potassium carbonate) to give compound B;

step b: compound B is reduced (e.g., in the presence of sodium dithionite and potassium carbonate) and intramolecular ring closure to give compound C;

step c: the compound C and ketone or aldehyde undergo reductive amination reaction (for example, in the presence of phenylsilane and dibutyltin dichloride) to obtain a compound D;

step d: compounds D and R ₂ I or R ₂ Br reaction (e.g. in the presence of sodium hydride) to give compound E;

step e: reacting compound E with pinacol ester of a bisborate (e.g., in the presence of potassium acetate and a [1, 1-bis (diphenylphosphorus) ferrocene ] palladium dichloride dichloromethane complex) to give compound F;

step f: compound F

By coupling reactions (e.g. between sodium bicarbonate and [1,1' -bis (diphenylphosphorus) ferrocene)]Palladium dichloride dichloromethane complex) to give compound G;

step g: hydrolysis of compound G (e.g., in the presence of lithium hydroxide monohydrate) gives compound H;

step h: compound H

The condensation reaction (e.g., in the presence of HATU) gives compound I.

Reaction route two:

step a: diamine linker protected by compound A and single-side tert-butyloxycarbonyl

Condensing under HATU condition to obtain compound B;

step b: removing tert-butoxycarbonyl (Boc) from the compound B in an HCl/dioxane solution to obtain a compound C;

step c: condensing the compound C and an optical isomer of the compound A under the HATU condition to obtain a compound D;

reaction route three:

step a: compound A is in LiAlH ₄ Reducing to obtain a compound B;

step b: compound B

In sodium bicarbonate and [1,1' -bis (diphenylphosphorus) ferrocene]Coupling reaction is carried out under the condition of palladium dichloride dichloromethane complex to obtain a compound C;

step c: reacting the compound C with MsCl to obtain a compound D;

step d: compound D

Nucleophilic substitution under the action of DIPEA to obtain a compound E;

the reaction route is four:

step a: hydrolyzing the compound A to obtain a compound B;

step b: compound B

Condensation under HATU conditions to give the chemicalA compound C;

step c: removing tert-butoxycarbonyl (Boc) from the compound C in HCl/dioxane solution to obtain a compound D;

step d: compound D

Obtaining a compound E through nucleophilic substitution reaction;

step e: compound E

In sodium bicarbonate and [1,1' -bis (diphenylphosphorus) ferrocene ]Coupling reaction is carried out under the condition of palladium dichloride dichloromethane complex to obtain a compound F;

reaction route five:

step a: and carrying out nucleophilic substitution reaction on the compound A and the compound B to obtain a compound C.

In the above scheme, each substituent is defined as the corresponding substituent in the above formula (I).

Detailed Description

The invention is further illustrated by the following examples. The following examples are merely illustrative of embodiments of the invention. It is to be understood that the embodiments of the invention are not limited to the specific details set forth in the following examples, as other variations will be apparent to those of ordinary skill in the art in light of the present disclosure.

The structure of the compound is changed into a nuclear magnetic resonance structure ¹ H-NMR) and/or Mass Spectrometry (MS). NMR measurement was performed using Mercury-400 nuclear magnetic resonance apparatus from Varian company, in which deuterated chloroform (CDC 1) was used as the solvent ₃ ) Deuterated methanol (CD) ₃ OD), deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Or deuterated acetonitrile (CD) ₃ CN), TMS is an internal standard. MS was measured using a Thermo Finnigan LCQ-Deca XP (ESI) liquid chromatograph-mass spectrometer.

Example 1

Step a 2-fluoro-4-bromonitrobenzene (30 g,136.4 mmol), D-alanine (15.8 g,177.3 mmol), potassium carbonate (24.5 g,177.3 mmol) were dissolved in 500mL ethanol: water = 3:1, heating and refluxing for 8 hours at 80 ℃, monitoring the reaction by a TLC plate, cooling to room temperature after the reaction is finished, evaporating the solvent, dissolving in water, adjusting the pH to 1-2 by using 1N HCl, precipitating a large amount of yellow solid, filtering, washing the solid by using 500mL of Petroleum Ether (PE), and drying in a vacuum drying box to obtain 34.7g of yellow solid, namely the compound 1B, with the yield of 88%.

¹ H NMR(400MHz，CDC1 ₃ ))δ8.35(d,J＝6.9Hz，1H)，8.06(d,J＝9.1Hz，1H)，6.90(s，1H)，6.85(d,J＝9.2Hz，1H)，4.33(p,J＝7.0Hz，1H)，1.67(d,J＝7.0Hz，3H).

Step B Compound 1B (34.7 g,120.0 mmol), potassium carbonate (16.6 g,120.0 mmol) was dissolved in 500mL of water, sodium dithionite (105 g,600.0 mmol) was slowly added in portions, reacted at 60℃for 8h, a large amount of solids was formed in the reaction solution, the reaction was monitored by TLC plates, cooled to room temperature after the completion of the reaction, filtered, the solids were washed with 500mL of water, and dried in a vacuum oven to give 11g of white solid, compound 1C, in 38% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.31(s,1H),6.82(d,J＝2.1Hz,1H),6.74(dd,J＝8.2,2.1Hz,1H),6.65(d,J＝8.3Hz,1H),6.29(s,1H),3.87–3.77(m,1H),1.25(d,J＝6.6Hz,3H).

Step C) Compound 1C (5.7 g,23.64 mmol), phenylsilane (8.5 mL,70.93 mmol), cyclopentanone (6.3 mL,70.93 mmol) and dibutyltin dichloride (11 g,35.46 mmol) were dissolved in 100mL Tetrahydrofuran (THF), reacted overnight at room temperature, the reaction was monitored by TLC plate, the solvent was evaporated after the reaction was completed, the silica gel was stirred and purified by flash chromatography column, gradient elution was performed using Ethyl Acetate (EA)/Petroleum Ether (PE) =10-30% to give 6.8g of colorless oily liquid as compound 1D, yield 93.2%.

¹ H NMR(400MHz,CDC1 ₃ )δ9.68(s,1H),6.92(d,J＝1.9Hz,1H),6.88(dd,J＝8.3,2.0Hz,1H),6.69(d,J＝8.2Hz,1H),4.10(q,J＝6.8Hz,1H),3.88–3.75(m,1H),2.08-1.94(m,2H),1.78-1.55(m,6H),1.14(d,J＝6.8Hz,3H).

Step D) Compound 1D (7.2 g,23.3 mmol) was dissolved in anhydrous 20mL Dimethylformamide (DMF), naH (1.9 g,46.6 mmol) was added in portions in an ice-water bath, stirred for 30min at 0deg.C, methyl iodide (2.2 mL,34.9 mmol) was slowly added, the reaction was monitored by TLC plate at room temperature for 2h, after the reaction was completed, the reaction solution was poured into 200mL ice-water to quench, 200mL x 2 Dichloromethane (DCM) to extract, the organic layers were combined, washed with 350mL saturated brine 1 time, dried over anhydrous sodium sulfate, the solvent evaporated, and the organic phase silica gel was purified by flash column eluting with EA/PE=10-20% gradient to give Compound 1E as a colorless oily liquid with a yield of 76.8%.

¹ H NMR(400MHz,DMSO-d ₆ )δ6.97(dd,J＝8.4,2.1Hz,1H),6.92(d,J＝2.1Hz,1H),6.78(d,J＝8.5Hz,1H)，4.17(d,J＝6.8Hz,1H)，3.81-3.72(m,1H),3.33(s,3H),2.08-1.96(m,2H),1.84-1.74(m,1H),1.72-1.58(m,5H),1.05(d,J＝6.8Hz,3H).

Step E Compound 1E (5 g,15.5 mmol), pinacol ester of Di-boric acid (4.4 g,17.0 mmol), potassium acetate (3 g,31.0 mmol) was dissolved in 100mL 1.4-dioxane and after 1min ventilation with N2 Pa (dppf) was added ₂ Cl ₂ (700 mg,0.775 mmol) and then N ₂ After 1min ventilation, reaction was carried out at 100 ℃ for 8h, monitored by TLC plate, after completion of the reaction the solvent was evaporated, silica gel was purified by flash column chromatography eluting with EA/pe=10-33% gradient to give 4.9g of compound 1F as colourless oil in 85.4% yield.

¹ H NMR(400MHz,CDC1 ₃ )δ7.38(dd,J＝7.9,1.3Hz,1H),7.30(d,J＝1.2Hz,1H),6.97(d,J＝8.0Hz,1H),4.17–4.09(m,1H),3.92(p,J＝7.5Hz,1H),3.39(s,3H),2.08–1.99(m,2H),1.83–1.75(m,1H),1.75–1.50(m,5H),1.37(s,12H),1.04(d,J＝6.9Hz,3H).

Step F Compound 1F (5.9 g,15.93 mmol), ethyl 5-bromo-1- (p-methylphenyl) -1,2, 4-triazole-3-carboxylate (5.4 g,17.41 mmol), sodium bicarbonate (2.7 g,32.14 mmol) in aqueous solution was dissolved in 100mL of THF and after 1min ventilation with N2, pa @ was addeddppf) ₂ Cl ₂ (1.3 g,1.59 mmol) and then N ₂ After 1min of aeration, the reaction was performed at 80℃for 8h, monitored by TLC plate, and after completion of the reaction, 200. 200mLH ₂ O/200mL of 2DCM was used for extraction, the organic layers were combined, washed with 200mL of saturated brine for 1 time, dried over anhydrous sodium sulfate, the solvent was evaporated, and the organic phase was purified by flash chromatography on silica gel eluting with EA/PE=10-33% gradient to give 1.4G of compound 1G as a white solid in 18.6% yield.

¹ H NMR(400MHz,CDC1 ₃ )δ7.33–7.24(m,4H),7.20(dd,J＝8.3,1.9Hz,1H),6.92(d,J＝8.4Hz,1H),6.87(d,J＝1.9Hz,1H),4.55(qd,J＝7.2,1.0Hz,2H),4.15(q,J＝6.8Hz,1H),3.47(q,J＝7.3Hz,1H),3.37(s,3H),2.42(s,3H),1.85–1.76(m,3H),1.73–1.66(m,1H),1.64–1.51(m,4H),1.47(t,J＝7.1Hz,3H),0.99(d,J＝6.8Hz,3H).

Step G Compound 1G (800 mg,1.69 mmol), lithium hydroxide monohydrate (280 mg,6.76 mmol) was dissolved in 50mL THF: h ₂ O=4: 1 in a mixed solvent at room temperature for 4 hours, monitoring the reaction by a TLC plate, and adjusting the pH to 1-2 by 1N HCl after the reaction is finished, 50mLH ₂ O/50mL 2EA extraction, combining organic layers, washing with 100mL saturated brine 1 time, drying over anhydrous sodium sulfate, evaporating the solvent, and purifying the organic phase over flash column on silica gel eluting with MeOH/DCM=1-10% gradient to give 750mg of compound 1H as a white solid in 99% yield.

¹ H NMR(400MHz,CDC1 ₃ )δ8.81(s,1H),7.30(dd,J＝8.2Hz,2H),7.26–7.19(m,3H),6.93(d,J＝8.2Hz,1H),6.84(s,1H),4.19(q,J＝6.7Hz,1H),3.50–3.40(m,1H),3.35(s,3H),2.39(s,3H),1.84–1.74(m,1H),1.71–1.62(m,1H),1.61–1.42(m,5H),1.36–1.24(m,1H),0.98(d,J＝6.8Hz,3H).8。

Step H Compound 1H (200 mg,0.45 mmol), DIPEA (0.81 mL,0.49 mmol) was dissolved in 10mL DMF, HATU (186.3 mg,0.49 mmol) was added, reacted at room temperature for 2H, piperazine (25 mg,0.2 mmol) was added, reacted at room temperature for 8H, the reaction was monitored by TLC plate and after the reaction was completed, 50mLH ₂ O/50mL of 2DCM is used for extraction, the organic layers are combined, the mixture is washed with 50mL of saturated saline for 1 time, dried with anhydrous sodium sulfate, the solvent is evaporated, and the organic phase is silica gel mixed with the samplePurification by flash column eluting with MeOH/dcm=1-10% gradient afforded 50mg of compound 1 as a white solid in 20% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.43–7.33(m,8H),7.25–7.11(m,4H),6.73(dd,J＝14.7,1.8Hz,2H),4.06(p,J＝6.8Hz,2H),3.95–3.72(m,8H),3.40–3.30(m,2H),3.27(d,J＝8.1Hz,6H),2.39(d,J＝8.3Hz,6H),1.75–1.58(m,8H),1.58–1.34(m,8H),0.88(dd,J＝9.9,6.7Hz,6H).

LC-MS(ESI)[M+H] ⁺ 941.68; retention time 6.019min, hplc purity = 98.927%.

Example 2

The compound of example 2 was prepared in the same manner as in example 1 except that 5-bromo-1- (2.4-dimethylphenyl) -1,2, 4-triazole-3-carboxylic acid ethyl ester was used in place of 5-bromo-1- (p-methylphenyl) -1,2, 4-triazole-3-carboxylic acid ethyl ester in step f of example 1, and the product was a white solid with a final step yield of 33%.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.38(dd,J＝14.6,8.0Hz,2H),7.33–7.08(m,8H),6.73(d,J＝11.7Hz,2H),4.11–4.00(m,2H),3.85(m,8H),3.33(m,2H),3.26(d,J＝8.1Hz,6H),2.37(d,J＝8.1Hz,6H),1.93(s,3H),1.92(s,3H),1.68(dd,J＝27.9,13.6Hz,2H),1.46(d,J＝16.1Hz,10H),1.22(d,J＝17.8Hz,4H),0.87(dd,J＝9.6,6.6Hz,6H).

LC-MS(ESI)[M+H] ⁺ 969.6; retention time 14.599min, hplc purity = 97.9%.

Example 3

The compound of example 3 was prepared in the same manner as in example 1 except that 5-bromo-1- (p-methylphenyl) -1,2, 4-triazole-3-carboxylic acid ethyl ester was replaced with 5-bromo-1- (β -naphthyl) -1,2, 4-triazole-3-carboxylic acid ethyl ester in step f of example 1, and the product was a white solid with a final step yield of 53%.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.23–7.94(m,8H),7.70–7.53(m,6H),7.36–7.24(m,2H),7.17(dd,J＝16.0,8.4Hz,2H),6.70–6.58(m,2H),4.03–3.89(m,6H),3.89–3.68(m,4H),3.26(d,J＝10.3Hz,6H),3.04(dt,J＝15.8,8.0Hz,2H),1.48–1.12(m,4H),1.10–0.89(m,4H),0.81(dd,J＝12.2,6.7Hz,6H).

LC-MS(ESI)[M+H] ⁺ 1013.4; retention time 13.903min, hplc purity = 98.9%.

Example 4

The compound of example 4 was produced in the same manner as in example 1 except that the cyclopentanone was replaced with benzaldehyde in step c of example 1, and the product was a white solid with a final step yield of 10%.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.40–7.15(m,18H),7.10(dd,J＝14.6,8.5Hz,2H),6.99–6.80(m,4H),4.29–4.08(m,4H),3.99–3.86(m,3H),3.85–3.68(m,3H),3.57(s,4H),3.29(d,J＝8.2Hz,6H),2.37(d,J＝8.3Hz,6H),0.99(dd,J＝11.6,6.7Hz,6H).

LC-MS(ESI)[M+H] ⁺ 985.4; retention time 9.516min, hplc purity = 92.35%.

Example 5

The compound of example 5 was prepared in the same manner as in example 1 except that N, N' -dimethylethylenediamine was used instead of piperazine in step h of example 1, and the product was a white solid with a final step yield of 21%.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.41–7.32(m,7H),7.30–7.21(m,3H),7.11–7.00(m,2H),6.73–6.61(m,2H),4.04(dd,J＝9.6,6.7Hz,2H),3.30(m,2H),3.27(d,J＝4.1Hz,3H),3.22(d,J＝7.2Hz,3H),3.15(d,J＝8.7Hz,3H),3.00(m,3H),2.39–2.31(m,6H),2.01(q,J＝6.9,6.4Hz,2H),1.63(d,J＝28.8Hz,4H),1.24(m,4H),1.39(d,J＝22.8Hz,10H),0.93–0.75(m,6H).

LC-MS(ESI)[M+H] ⁺ 943.68; retention time 5.780min, hplc purity = 100%.

Example 6

The compound of example 6 was prepared in the same manner as in example 1 except that piperazine was replaced with homopiperazine in step h of example 1, and the product was a white solid with a final step yield of 26%.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.43–7.32(m,10H),7.26(d,J＝8.2Hz,2H),6.78–6.71(m,2H),4.11–4.02(m,2H),3.96–3.87(m,2H),3.85–3.70(m,8H),3.30–3.24(m,6H),2.38(d,J＝6.4Hz,6H),1.66(dd,J＝35.7,15.4Hz,5H),1.52–1.33(m,11H),0.93–0.80(m,8H).

LC-MS(ESI)[M+H] ⁺ 955.75; retention time 5.939min, hplc purity = 97.435%.

Example 7

The compound of example 7 was prepared in the same manner as in example 1 except that the piperazine was replaced with trans-2, 5-dimethylpiperazine in step h of example 1, and the product was a white solid with a yield of 24% in the last step.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.39(ddd,J＝13.7,3.7,2.6Hz,8H),7.24–7.11(m,4H),6.80–6.69(m,2H),4.08(q,J＝7.8,7.0Hz,4H),3.33(m,18H),2.43–2.35(m,6H),1.67(d,J＝41.2Hz,5H),1.55–1.15(m,17H),0.94–0.77(m,6H).

LC-MS(ESI)[M+H] ⁺ 969.76; retention time 6.167min, hplc purity = 95.513%.

Example 8

The compound of example 8 was prepared in the same manner as in example 7 except that 5-bromo-1- (2.4-dimethylphenyl) -1,2, 4-triazole-3-carboxylic acid ethyl ester was substituted for 5-bromo-1- (p-methylphenyl) -1,2, 4-triazole-3-carboxylic acid ethyl ester in step f of example 7, and the product was a white solid with a final step yield of 69%.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.42–7.09(m,10H),6.79–6.69(m,2H),4.89(d,J＝65.6Hz,2H),4.05(h,J＝7.7,7.2Hz,4H),3.62(dd,J＝25.0,14.3Hz,2H),3.33(m,2H),3.29–3.18(m,6H),2.38(d,J＝7.4Hz,6H),1.96(dt,J＝29.0,8.9Hz,7H),1.78–1.61(m,2H),1.46(d,J＝14.7Hz,8H),1.35(t,J＝7.5Hz,2H),1.31–1.20(m,9H),0.92–0.74(m,6H).

LC-MS(ESI)[M+H] ⁺ 997.6; retention time 17.534min, hplc purity = 97.6%.

Example 9

The compound of example 9 was produced by the same method as in example 7, except that the cyclopentanone was replaced with cyclobutanone in step c of example 7, and the product was a white solid with a yield of 35% in the final step.

1H NMR(400MHz,DMSO-d6)δ7.39(ddd,J＝14.4,4.0,2.6Hz,8H),7.18–7.09(m,4H),6.70–6.53(m,2H),3.96(s,6H),3.33(s,12H),3.28(s,6H),2.51(p,J＝1.8Hz,6H),2.39(dd,J＝7.3,2.8Hz,4H),1.58(q,J＝12.7,8.6Hz,3H),1.46–1.13(m,6H),0.93–0.71(m,3H).

Example 10

The compound of example 10 was prepared in the same manner as in example 9 except that 5-bromo-1- (m-chlorophenyl) -1,2, 4-triazole-3-carboxylic acid ethyl ester was used instead of 5-bromo-1- (p-methylphenyl) -1,2, 4-triazole-3-carboxylic acid ethyl ester in step f of example 9, and the product was a white solid with a final step yield of 51%.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.76–7.55(m,5H),7.49(d,J＝17.4Hz,3H),7.23–7.12(m,4H),6.62–6.52(m,2H),4.16–3.82(m,3H),3.58–3.40(m,3H),3.29(d,J＝7.7Hz,6H),2.13(m,2H),1.96(dq,J＝19.1,9.5,8.6Hz,2H),1.76(m,3H),1.59(d,J＝11.4Hz,2H),1.31(ddt,J＝31.7,13.6,6.8Hz,9H),0.84(dd,J＝10.3,6.9Hz,6H).

LC-MS(ESI)[M+H] ⁺ 981.4; retention time 11.954min, hplc purity = 98.5%.

Example 11

The compound of example 11 was produced in the same manner as in example 1 except that piperazine was replaced with 1.3-propanediamine in step h of example 1, and the product was a white solid, and the final step yield was 37%.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.77(t,J＝6.1Hz,2H),7.37(d,J＝1.6Hz,8H),7.23(dd,J＝8.3,1.8Hz,2H),7.16(d,J＝8.5Hz,2H),6.73(d,J＝1.8Hz,2H),4.06(q,J＝6.7Hz,2H),3.33(m,6H),3.27(s,6H),2.38(s,6H),1.48(dd,J＝25.5,15.4Hz,9H),1.24(d,J＝4.0Hz,9H),0.93–0.75(m,8H).

LC-MS(ESI)[M+H] ⁺ 929.40; retention time 5.873min, hplc purity = 99.686%.

Example 12

The compound of example 12 was produced in the same manner as in example 1 except that piperazine was replaced with trans-1, 2-cyclohexanediamine in step h of example 1, and the product was a white solid with a final step yield of 42%.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.37(t,J＝8.9Hz,2H),7.42–7.29(m,8H),7.20(dd,J＝8.4,1.7Hz,2H),7.13(dd,J＝8.5,5.5Hz,2H),6.69(t,J＝1.4Hz,2H),4.13–3.89(m,2H),3.33(m,4H),2.36(s,6H),1.78–1.54(m,6H),1.53–1.32(m,16H),1.32–1.07(m,8H),0.86(dt,J＝9.9,6.9Hz,6H).

LC-MS(ESI)[M+H] ⁺ 969.69; retention time 6.611min, hplc purity = 95.199%.

Example 13

The compound of example 13 was prepared in the same manner as in example 1 except that ethylenediamine was used in place of piperazine in step h of example 1, and the product was a white solid with a final step yield of 29%.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.77(s,2H),7.42–7.29(m,8H),7.20(dd,J＝8.3,1.8Hz,2H),7.15(d,J＝8.4Hz,2H),6.73(d,J＝1.8Hz,2H),4.05(q,J＝6.7Hz,2H),3.51(d,J＝3.6Hz,4H),3.33(m,2H),3.27(s,6H),2.38(s,6H),1.76–1.56(m,4H),1.56–1.33(m,8H),1.21(d,J＝23.9Hz,4H),0.87(d,J＝6.7Hz,6H).

LC-MS(ESI)[M+H] ⁺ 915.67; retention time 5.829min, hplc purity = 98.751%.

Example 14

The compound of example 14 was prepared in the same manner as in example 1 except that (R) -5-methyl-homopiperazine was used instead of piperazine in step h of example 1, and the product was a white solid with a final step yield of 17%.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.39–7.33(m,8H),7.17(dp,J＝8.2,2.7,2.3Hz,4H),6.70(q,J＝2.4Hz,2H),4.93–4.70(m,1H),4.68–4.47(m,2H),4.37(ddd,J＝26.1,13.9,6.0Hz,1H),4.24–4.11(m,1H),4.10–3.99(m,4H),3.27(q,J＝3.9Hz,4H),3.23(m,6H),2.42–2.35(m,6H),1.65(d,J＝43.7Hz,2H),1.28–1.12(m,16H),0.94–0.82(m,9H).

LC-MS(ESI)[M+H] ⁺ 969.81; retention time 5.897min, hplc purity = 99.089%.

Example 15

The same procedures used in example 1 were repeated except for using (R) - (-) -2-methylpiperazine instead of piperazine in step h of example 1 to prepare the compound of example 15 as a white solid with a yield of 28% in the final step.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.44–7.30(m,8H),7.28–7.09(m,4H),6.81–6.66(m,2H),4.86(d,J＝61.7Hz,1H),4.68–4.14(m,3H),4.12–4.00(m,2H),3.71–3.45(m,1H),3.27(d,J＝7.6Hz,6H),3.23–3.12(m,2H),3.02(t,J＝12.5Hz,2H),2.38(d,J＝7.0Hz,6H),1.66(dd,J＝37.5,10.3Hz,2H),1.56–1.32(m,10H),1.32–1.09(m,7H),0.89(tt,J＝6.9,2.5Hz,6H).

LC-MS(ESI)[M+H] ⁺ 955.72; retention time 6.073min, hplc purity = 98.653%.

Example 16

The same procedures used in example 1 were repeated except for using 2, 6-diazaspiro [3.3] heptane instead of piperazine in step h of example 1 to prepare the compound of example 16 as a white solid, and the final step yield was 71%.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.37(s,8H),7.25–7.11(m,4H),6.71(s,2H),4.78(s,4H),4.32(s,4H),4.06(d,J＝7.8Hz,4H),3.57(s,6H),2.39(s,6H),1.45(d,J＝11.3Hz,8H),1.32–1.11(m,8H),0.89(d,J＝6.9Hz,6H).

LC-MS(ESI)[M+H] ⁺ 953.76; retention time 9.989min, hplc purity = 98.35%.

Example 17

The compound of example 17 was prepared in the same manner as in example 16 except that 5-bromo-1- (p-methylphenyl) -1,2, 4-triazole-3-carboxylic acid ethyl ester was replaced with 5-bromo-1- (β -naphthyl) -1,2, 4-triazole-3-carboxylic acid ethyl ester in step f of example 16, and the product was a white solid with a final step yield of 24%.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.17–8.09(m,3H),8.03(dd,J＝24.6,7.7Hz,4H),7.65(t,J＝6.5Hz,5H),7.55(dt,J＝8.6,1.9Hz,2H),7.32(d,J＝8.3Hz,2H),7.17(d,J＝8.4Hz,2H),6.61(s,2H),4.84(s,4H),4.35(d,J＝2.8Hz,4H),3.96(q,J＝6.6Hz,2H),3.26(s,6H),3.02(t,J＝7.8Hz,2H),1.44–1.27(m,5H),1.27–1.12(m,6H),1.11–0.84(m,7H),0.81(d,J＝6.7Hz,6H).

LC-MS(ESI)[M+H] ⁺ 1025.5; retention time 12.582min, hplc purity = 98.3%.

Example 18

The same procedures used in example 1 were repeated except for using 2, 7-diazaspiro [4.4] nonane instead of piperazine in step h of example 1 to prepare the compound of example 18 as a white solid, and the final yield was 17%.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.37(d,J＝9.8Hz,8H),7.25–7.17(m,2H),7.14(td,J＝9.2,8.6,3.2Hz,2H),6.77–6.68(m,2H),4.11–3.94(m,2H),3.96–3.82(m,2H),3.75–3.48(m,4H),3.29–3.21(m,10H),2.44–2.31(m,6H),2.09–1.88(m,4H),1.75–1.56(m,4H),1.44(d,J＝11.6Hz,8H),1.31–1.06(m,4H),0.94–0.83(m,6H).

LC-MS(ESI)[M+H] ⁺ 981.92; retention time 10.833min, hplc purity = 98.5%.

Example 19

The compound of example 19 was produced in the same manner as in example 1 except that in step c of example 1, aniline N and amide N were simultaneously methylated with 2 equivalents of methyl iodide to give compound 19A and step D was not performed, and in step e, compound 19A was used instead of compound 1D, and the product was a white solid with a final step yield of 70%.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.43–7.30(m,8H),7.07(dd,J＝11.4,8.4Hz,2H),6.99–6.90(m,2H),6.74(dd,J＝16.8,1.9Hz,2H),4.02(p,J＝6.9Hz,2H),3.96–3.72(m,8H),3.26(d,J＝7.5Hz,6H),2.60(d,J＝14.2Hz,6H),2.39(d,J＝8.7Hz,6H),0.96(dd,J＝10.2,6.7Hz,6H).

LC-MS(ESI)[M+H] ⁺ 833.4; retention time 4.448min, hplc purity = 97.4%.

Example 20

The compound of example 20 was prepared in the same manner as in example 19 except that the piperazine was replaced with trans-2, 5-dimethylpiperazine in step h of example 19, and the product was a white solid with a final step yield of 27%.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.44–7.27(m,8H),7.12–7.02(m,2H),6.95(dddd,J＝15.1,10.8,6.0,2.2Hz,2H),6.79–6.69(m,2H),4.04(q,J＝7.1Hz,4H),3.33(m,7H),3.27(dd,J＝7.0,1.9Hz,6H),2.64–2.56(m,6H),2.40(d,J＝7.7Hz,6H),1.42–1.22(m,6H),0.96(ddd,J＝8.2,6.7,1.7Hz,6H).

LC-MS(ESI)[M+H] ⁺ 861.5; retention time 5.379min, hplc purity = 98.9%.

Example 21

The same procedures used in example 19 were repeated except for using 2, 7-diazaspiro [4.4] nonane instead of piperazine in step h of example 19 to prepare the compound of example 21 as a white solid, and the final step yield was 81%.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.41–7.28(m,8H),7.09–7.01(m,2H),6.93(tt,J＝8.3,1.6Hz,2H),6.77–6.67(m,2H),4.08–3.93(m,4H),3.92–3.81(m,2H),3.74–3.51(m,4H),3.26(dd,J＝5.9,3.2Hz,6H),2.65–2.55(m,6H),2.43–2.34(m,6H),2.00(q,J＝8.2,7.8Hz,4H),1.00–0.87(m,6H).

LC-MS(ESI)[M+H] ⁺ 873.5; retention time 4.437min, hplc purity = 98.58%.

Example 22

The same procedure as in example 7 was used to prepare the compound of example 22, except that step d of example 7 (no methyl group was introduced into the amide N) was not performed, and the product of step c was used as a starting material in step e, and the product was a white solid in the final step yield of 39%.

LC-MS(ESI)[M+H] ⁺ 941.52; retention time 5.436min, hplc purity = 98.54%.

Example 23

Intermediate 23C is synthesized in the same manner as in 1H in example one, and D-alanine in step a of example one is replaced with L-alanine.

Step a Compound 1H (1.53 g,3.43 mmol), DIPEA (0.63 mL,3.78 mmol) was dissolved in 20mL of LDMF, HATU (1.5 g,3.78 mmol) was added, reacted at room temperature for 2H, N-Boc piperazine (704 mg,3.78 mmol) was added, reacted at room temperature for 8H, the reaction was monitored by TLC plate, and after the reaction was completed, 50mLH ₂ O/50mL of 2DCM, the organic layers were combined, washed 1 time with 100mL of saturated brine, dried over anhydrous sodium sulfate, the solvent evaporated, and the organic phase was purified on flash column eluting with MeOH/DCM=1-10% gradient to give 600mg of compound 23A as a white solid in 28.5% yield.

¹ H NMR(400MHz,CDC1 ₃ )δ7.51–7.46(m,2H),7.45–7.41(m,2H),7.15(dd,J＝8.3,1.9Hz,1H),6.93(d,J＝8.3Hz,1H),6.89(d,J＝1.8Hz,1H),4.17(q,J＝6.8Hz,1H),4.01–3.93(m,2H),3.84(d,J＝5.8Hz,2H),3.56(q,J＝6.5,5.9Hz,5H),3.38(s,3H),2.43(s,3H),1.83(dt,J＝10.9,5.7Hz,3H),1.69(td,J＝11.3,10.2,5.0Hz,1H),1.62–1.53(m,4H),1.50(s,9H),1.02(d,J＝6.8Hz,3H).

Step B) compound 23A (600 mg,0.98 mmol) was dissolved in 10mL 4n HCl/dioxane, reacted for 8h at room temperature, monitored by TLC plate, after the reaction was completed the reaction solution was poured into 20mL water, sodium hydroxide solid was neutralized to ph=7, 50mL x 2DCM was extracted, the organic layers were combined, washed 1 time with 50mL saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, the organic phase silica gel was purified by flash chromatography column eluting with MeOH/dcm=1-10% gradient to give 340mg of red solid, compound 23B, 67.3% yield.

¹ H NMR(400MHz,DMSO-d ₆ ) Delta 7.37 (s, 4H), 7.23-7.13 (m, 2H), 6.72 (d, j=1.8 hz, 1H), 4.06 (q, j=6.7 hz, 1H), 3.68 (dt, j=15.5, 5.3hz, 4H), 3.35 (td, j=15.2, 7.8hz, 1H), 3.27 (s, 3H), 2.83 (dt, j=20.4, 5.1hz, 4H), 2.38 (s, 3H), 1.75-1.37 (m, 6H), 1.31-1.12 (m, 2H), 0.88 (d, j=6.7 hz, 3H).

LC-MS(ESI)[M+H] ⁺ 514.52; retention time 2.006min, hplc purity = 99.75%.

Step C, compound 23C (200 mg,0.45 mmol), DIPEA (0.81 mL,0.49 mmol) was dissolved in 10mL of LDMF, HATU (186.3 mg,0.49 mmol) was added, reacted at room temperature for 2h, compound 23B (231 mg,0.45 mmol) was added, reacted at room temperature for 8h, the reaction was monitored by TLC plate, and after the reaction was completed, 50mLH ₂ O/50mL of 2DCM, combining the organic layers, washing with 50mL of saturated brine 1 time, drying over anhydrous sodium sulfate, evaporating the solvent, and purifying the organic phase over silica gel column using MeOH/DCM=1-10% gradient to afford 60mg of compound as a white solid in 14.2% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.44–7.31(m,8H),7.25–7.10(m,4H),6.77–6.68(m,2H),4.06(p,J＝6.8Hz,2H),3.97–3.69(m,8H),3.33(m,2H),3.27(d,J＝8.1Hz,6H),2.39(d,J＝8.2Hz,6H),1.72(d,J＝16.5Hz,4H),1.65–1.34(m,8H),1.22(d,J＝15.9Hz,4H),0.88(dd,J＝10.0,6.7Hz,6H).

Example 24

The procedure for the synthesis of compound 24A was the same as that for compound 23C of example 23, except that cyclopentanone was replaced with cyclobutanone. The procedure for the synthesis of compound 24D was the same as that for compound 1H of example 1, except that cyclopentanone was replaced with cyclobutanone in step c. Steps a-c of this example the compound of example 24 was prepared by the same method as in example 23, except that the N-Boc piperazine in step a of example 23 was replaced with N-Boc- (2 s,5 r) -2, 5-dimethylpiperazine. Compound 24 was a white solid with a final step yield of 45%.

1H NMR(400MHz,DMSO-d6)δ7.41(d,J＝4.3Hz,4H),7.37(d,J＝2.5Hz,4H),7.16–7.14(m,2H),7.11(dd,J＝4.9,1.9Hz,2H),6.66–6.58(m,2H),5.06–4.48(m,2H),4.33(dd,J＝25.0,13.5Hz,2H),4.04(dq,J＝9.9,7.2Hz,2H),3.94(q,J＝7.1Hz,2H),3.48(dt,J＝15.4,7.8Hz,2H),3.35(s,6H),3.27(dd,J＝7.8,1.7Hz,6H),2.51(p,J＝1.8Hz,6H),2.44–2.34(m,6H),1.40–1.32(m,3H),1.31–1.22(m,3H),0.84(ddd,J＝10.0,6.7,1.5Hz,6H).

LC-MS(ESI)[M+H] ⁺ 941.73; retention time 5.99min, hplc purity = 97.808%.

Example 25

Step a Compound 25A (1.6 g,5.2 mmol) was dissolved in 50mL dry THF and LiAlH was added slowly in portions under an ice-water bath ₄ (208 mg,5.2 mmol) was reacted at room temperature for 4h, monitored by TLC plate, after the reaction was completed, the reaction solution was poured into saturated ammonium chloride solution to quench, 100mL of 2EA was extracted, the organic layers were combined, washed with 150mL of saturated common salt water for 1 time, dried over anhydrous sodium sulfate, the solvent was evaporated, and the organic phase was stirred with silica gel and passed through a flash columnPurification, eluting with MeOH/dcm=1-10% gradient, afforded 860mg of compound 25B as a white solid in 62% yield.

LC-MS(ESI)[M+H] ⁺ 309.97; retention time 3.045min, hplc purity = 99.105%.

Step B Compound 25B (439 mg,1.59 mmol), (R) -6-bromo-4-cyclobutyl-1, 3-dimethyl-3, 4-dihydroquinoxalin-2 (1H) -one (513.5 mg,1.74 mmol), sodium bicarbonate (270 mg,3.21 mmol) in aqueous solution in 10mL THF, N ₂ After 1min of ventilation, pa (dppf) is added ₂ Cl ₂ (130 mg, 0.1599 mmol) and then N ₂ After 1min of aeration, the reaction was carried out at 80℃for 8h, monitored by TLC plate and after completion of the reaction, 50. 50mLH ₂ O/50mL of 2DCM, combining the organic layers, washing with 100mL of saturated brine 1 time, drying over anhydrous sodium sulfate, evaporating the solvent, and purifying the organic phase over silica gel column using EA/PE=10-33% gradient to afford 571mg of compound 25C as a white solid in 86% yield.

¹ H NMR(400MHz,CDC1 ₃ )δ7.28(d,J＝1.0Hz,1H),7.10(dd,J＝8.3,1.8Hz,2H),6.92(d,J＝8.3Hz,2H),6.67(d,J＝1.8Hz,2H),4.87(d,J＝6.0Hz,2H),4.07(q,J＝6.8Hz,1H),3.67–3.45(m,1H),3.37(d,J＝1.0Hz,3H),2.41(s,3H),1.67(qq,J＝18.8,9.4,8.6Hz,6H),0.95(d,J＝6.8Hz,3H).

Step C Compound 25C (2.2 g,5.2 mmol), DMAP (636 mg,5.2 mmol) was dissolved in 100mL dry DCM, msCl (1.2 g,10.4 mmol) was slowly added in ice-water bath and reacted at room temperature for 4h, the reaction was monitored by TLC plate and 100mLH after the reaction was completed ₂ O/100mL of 2DCM was used to extract, the organic layers were combined, washed with 100mL of saturated brine 1 time, dried over anhydrous sodium sulfate, the solvent evaporated, and the organic phase was purified by flash chromatography on silica gel eluting with MeOH/DCM=1-10% gradient to give 954mg of compound 25D as a white solid in 37% yield.

Step D Compound 25D (793 mg,1.6 mmol), DIPEA (207 mg,1.6 mmol) was dissolved in 10mL anhydrous DMF, and trans-2, 5-dimethylpiperazine (92 mg,0.8 mmol) was added and reacted at room temperature for 8h, the reaction was monitored by TLC plate, after the reaction was completed, 100mLH ₂ O/100mL of 2DCM extract, combine the organic layers, wash with 100mL of saturated brine1 times, dry over anhydrous sodium sulfate, evaporate the solvent, and purify the organic phase over silica gel by flash chromatography column eluting with MeOH/dcm=1-10% gradient to give 1.17g of compound 25 as a white solid in 80% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.41–7.29(m,8H),7.16–7.10(m,4H),6.57(d,J＝7.0Hz,2H),3.95(q,J＝6.7Hz,2H),3.74(m,9H),3.54–3.32(m,3H),3.32–3.24(m,6H),2.51(p,J＝1.8Hz,6H),2.39(d,J＝1.7Hz,6H),2.10(d,J＝8.3Hz,3H),2.06–1.85(m,3H),1.57(ddt,J＝32.2,16.6,9.3Hz,6H),0.83(d,J＝6.8Hz,6H).

Example 26

Step a Compound 25A (525 mg,1.69 mmol), lithium hydroxide monohydrate (284 mg,6.76 mmol) was dissolved in 50mL of THF: h ₂ O=4: 1 in a mixed solvent at room temperature for 4 hours, monitoring the reaction by a TLC plate, and adjusting the pH to 1-2 by 1N HCl after the reaction is finished, 50mLH ₂ O/50mL 2EA extraction, combining the organic layers, washing with 100mL saturated brine 1 time, drying over anhydrous sodium sulfate, evaporating the solvent, and purifying the organic phase over flash column on silica gel eluting with MeOH/DCM=1-10% gradient to give 472mg of compound 26A as a white solid in 99% yield.

Step b Compound 26A (968 mg,3.43 mmol), DIPEA (489 mg,3.78 mmol) were dissolved in 20 mM LDMF, HATU (1.44 g,3.78 mmol) was added, reacted at room temperature for 2h, N-Boc piperazine (704 mg,3.78 mmol) was added, reacted at room temperature for 8h, the reaction was monitored by TLC plate, and after the reaction was completed, 50mLH ₂ O/50mL of 2DCM was used to extract, the organic layers were combined, washed with 100mL of saturated brine 1 time, dried over anhydrous sodium sulfate, the solvent evaporated, and the organic phase was purified by flash chromatography on silica gel eluting with MeOH/DCM=1-10% gradient to give 468mg of compound 26B as a white solid in 28.5% yield.

LC-MS(ESI)[M+H] ⁺ 477.96; retention time 3.586min, hplc purity = 89.329%.

Step C) compound 26B (469 mg,0.98 mmol) was dissolved in 10mL 4n HCl/dioxane, reacted for 8h at room temperature, monitored by TLC plate, after the reaction was completed, the reaction solution was poured into 20mL water, sodium hydroxide solid was neutralized to ph=7, 50mL x 2DCM was extracted, the organic layers were combined, washed 1 time with 50mL saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, the organic phase silica gel was purified by flash chromatography column eluting with MeOH/dcm=1-10% gradient to give 250mg of red solid, compound 26C, 67.3% yield.

LC-MS(ESI)[M+H] ⁺ 334.17; retention time 2.524min, hplc purity = 91.755%.

Step d Compound 26C (605 mg,1.6 mmol), (5-bromo-1- (p-methylphenyl) -1H-1,2, 4-triazol-3-yl) methyl methanesulfonate (554 mg,1.6 mmol), DIPEA (207 mg,1.6 mmol) was dissolved in 10mL anhydrous DMF and reacted at room temperature for 8H, the reaction was monitored by TLC plate and after the reaction was complete 100mLH ₂ O/100mL of 2DCM was used to extract, the organic layers were combined, washed with 100mL of saturated brine 1 time, dried over anhydrous sodium sulfate, the solvent evaporated, and the organic phase was purified by flash chromatography on silica gel eluting with MeOH/DCM=1-10% gradient to give 747mg of compound 26D as a white solid in 80% yield.

LC-MS(ESI)[M+H] ⁺ 585.15; retention time 3.109min, hplc purity = 99.898%.

Step e Compound 26D (929 mg,1.59 mmol), (R) -6-bromo-4-cyclobutyl-1, 3-dimethyl-3, 4-dihydroquinoxalin-2 (1H) -one (533 mg,1.74 mmol), sodium bicarbonate (270 mg,3.21 mmol) in aqueous solution in 10mL of THF, N ₂ After 1min of ventilation, pa (dppf) is added ₂ Cl ₂ (130 mg, 0.1599 mmol) and then N ₂ After 1min of aeration, the reaction was carried out at 80℃for 8h, monitored by TLC plate and after completion of the reaction, 50. 50mLH ₂ O/50mL of 2DCM was used to extract, the organic layers were combined, washed with 100mL of saturated brine 1 time, dried over anhydrous sodium sulfate, the solvent evaporated, and the organic phase was purified by flash chromatography on silica gel eluting with a EA/PE=10-33% gradient to give 1.27g of compound 26 as a white solid in 86% yield.

¹ H NMR(400MHz,DMSO-d ₆ )δ7.39–7.26(m,8H),7.12(d,J＝11.4Hz,4H),6.59(dd,J＝11.4,1.4Hz,2H),3.95(qd,J＝6.7,3.2Hz,1H),3.73(d,J＝13.6Hz,2H),3.65(m,3H),3.53–3.42(m,2H),3.40–3.35(m,4H),3.27(d,J＝2.0Hz,6H),2.38(d,J＝3.5Hz,6H),2.17–2.06(m,5H),1.64–1.48(m,8H),1.44–1.28(m,5H),0.84(d,J＝6.7Hz,6H).

LC-MS(ESI)[M+H] ⁺ 927.62; retention time 3.742min, hplc purity = 99.262%.

Example 27

Step a) Compound 27A (2 g,7.11 mmol) was dissolved in 30mL anhydrous DMF, naH (580 mg,14.5 mmol) was added in portions in an ice-water bath, stirred for 30min at 0deg.C, 4-bromo-1-butene (1.5 g,10.67 mmol) was slowly added, reacted for 2h at room temperature, monitored by TLC plate, after completion of the reaction was quenched by pouring the reaction solution into 200mL ice-water, 100mL of x 2DCM was extracted, the organic layers were combined, washed 1 with 100mL saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, the organic phase silica gel was purified by flash chromatography column eluting with EA/PE=0-25% gradient to give 2g of white solid, compound 27B, 86% yield.

Step B Compound 27B (5.2 g,15.5 mmol), pinacol bisborate (4.4 g,17.0 mmol), potassium acetate (3 g,31.0 mmol) was dissolved in 100mL 1.4-dioxane with N ₂ After 1min of ventilation, pa (dppf) is added ₂ Cl ₂ (700 mg,0.775 mmol) and then N ₂ After 1min of aeration, the reaction was carried out at 100 ℃ for 8h, monitored by TLC plates, the solvent was evaporated after the reaction was completed, and the silica gel was purified by flash chromatography column eluting with EA/pe=10-33% gradient to give 5g of compound 27C as a colourless oil in 85.4% yield.

Step C Compound 27C (6.1 g,15.93 mmol), 5-bromo-1- (p-methylphenyl) -1,2, 4-triazole-3-carboxylic acid ethyl ester (5.4 g,17.41 mmol), sodium bicarbonate (2.7 g,32.14 mmol) in aqueous solution in 100mL of HF with N ₂ After 1min of ventilation, pa (dppf) is added ₂ Cl ₂ (1.3 g,1.59 mmol) and then N ₂ After 1min of aeration, the reaction was performed at 80℃for 8h, monitored by TLC plate, and after completion of the reaction, 200. 200mLH ₂ O/200mL of x 2DCM was extracted, and the organic layers were combined using200mL of saturated brine is washed with water for 1 time, dried over anhydrous sodium sulfate, the solvent is evaporated, the organic phase silica gel is stirred and purified by a flash chromatography column, and the mixture is eluted with an EA/PE=10-33% gradient to obtain 1.4g of a white solid, namely a compound 27D, with a yield of 18.6%.

¹ H NMR(400MHz,CDCl ₃ )δ7.35–7.22(m,4H),7.21–7.08(m,2H),6.92(dd,J＝8.6,3.6Hz,1H),5.32(s,3H),4.56(q,J＝7.1Hz,2H),4.06(dt,J＝13.2,6.7Hz,2H),3.88–3.72(m,3H),2.43(d,J＝12.0Hz,3H),1.47(q,J＝6.7Hz,3H),0.70(d,J＝5.6Hz,1H),0.58–0.43(m,2H),0.17(d,J＝10.2Hz,1H).

Step D Compound 27D (823mg, 1.69 mmol), lithium hydroxide monohydrate (280 mg,6.76 mmol) was dissolved in 50mL of THF: h ₂ O=4: 1 in a mixed solvent at room temperature for 4 hours, monitoring the reaction by a TLC plate, and adjusting the pH to 1-2 by 1N HCl after the reaction is finished, 50mLH ₂ O/50mL 2EA extraction, combining the organic layers, washing with 100mL saturated brine 1 time, drying over anhydrous sodium sulfate, evaporating the solvent, and purifying the organic phase over flash column on silica gel eluting with MeOH/DCM=1-10% gradient to give 765mg of compound 27E as a white solid in 99% yield.

Step E Compound 27E (206 mg,0.45 mmol), DIPEA (0.81 mL,0.49 mmol) was dissolved in 10mL of LDMF, HATU (186.3 mg,0.49 mmol) was added, reacted at room temperature for 2h, trans-2.5-dimethylpiperazine (23 mg,0.2 mmol) was added, reacted at room temperature for 8h, the reaction was monitored by TLC plate, and after the reaction was completed, 50mLH ₂ O/50mL of 2DCM, combining the organic layers, washing with 50mL of saturated brine 1 time, drying over anhydrous sodium sulfate, evaporating the solvent, and purifying the organic phase over silica gel column using MeOH/DCM=1-10% gradient to afford 88mg of compound 27 as a white solid in 20% yield.

¹ H NMR(400MHz,CDCl ₃ -d)δ7.38–7.24(m,7H),7.19(dt,J＝17.3,5.0Hz,4H),6.98–6.88(m,2H),5.90–5.77(m,2H),5.68–5.43(m,1H),5.15–5.02(m,4H),4.66–4.43(m,2H),4.08(dq,J＝13.5,6.8Hz,4H),3.92–3.60(m,6H),1.70(m,2H),1.60–1.41(m,6H),1.21–1.04(m,8H),0.70(m,6H),0.55(d,J＝11.0Hz,6H),0.19(d,J＝11.8Hz,4H).

LC-MS(ESI)[M+Na] ⁺ 1015.7; retention time 4.3838 min, hplc purity = 99.7%.

Example 28

Step a Compound 28A (4.6 g,15.5 mmol), pinacol bisborate (4.4 g,17.0 mmol), potassium acetate (3 g,31.0 mmol) was dissolved in 100mL 1.4-dioxane with N ₂ After 1min of ventilation, pa (dppf) is added ₂ Cl ₂ (700 mg,0.775 mmol) and then N ₂ After 1min ventilation, reaction was carried out at 100 ℃ for 8h, monitored by TLC plate, after completion of the reaction the solvent was evaporated, silica gel was purified by flash column chromatography eluting with EA/pe=10-33% gradient to give 4.5g of compound 28B as colourless oil in 85.4% yield.

Step B Compound 28B (5.5 g,15.93 mmol), 5-bromo-1- (p-methylphenyl) -1,2, 4-triazole-3-carboxylic acid ethyl ester (5.4 g,17.41 mmol), sodium bicarbonate (2.7 g,32.14 mmol) in aqueous solution in 100mL of HF with N ₂ After 1min of ventilation, pa (dppf) is added ₂ Cl ₂ (1.3 g,1.59 mmol) and then N ₂ After 1min of aeration, the reaction was performed at 80℃for 8h, monitored by TLC plate, and after completion of the reaction, 200. 200mLH ₂ O/200mL x 2dcm, combined organic layers, washed 1 with 200mL saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and the organic phase was purified by flash chromatography on silica gel eluting with EA/pe=10-33% gradient to give 1.3g of compound 28C as a white solid in 18.6% yield.

Step C Compound 28C (753 mg,1.69 mmol), lithium hydroxide monohydrate (280 mg,6.76 mmol) was dissolved in 50mL of THF: h ₂ O=4: 1 in a mixed solvent at room temperature for 4 hours, monitoring the reaction by a TLC plate, and adjusting the pH to 1-2 by 1N HCl after the reaction is finished, 50mLH ₂ O/50mL 2EA extraction, combining the organic layers, washing with 100mL saturated brine 1 time, drying over anhydrous sodium sulfate, evaporating the solvent, and purifying the organic phase over flash column on silica gel eluting with MeOH/DCM=1-10% gradient to give 698mg of compound 28D as a white solid in 99% yield.

Step d: compound 28D (1.44 g,3.43 mmol), DIPEA (489 mg,3.78 mmol) was dissolved in 20 mM LDMF, HATU (1.44 g,3.78 mmol) was added, reacted at room temperature for 2h, N-Boc piperazine (704 mg,3.78 mmol) was added, reacted at room temperature for 8h, the reaction was monitored by TLC plate, and after the reaction was completed, 50mLH ₂ O/50mL of 2DCM was used to extract, the organic layers were combined, washed with 100mL of saturated brine 1 time, dried over anhydrous sodium sulfate, the solvent evaporated, and the organic phase was purified by flash chromatography on silica gel eluting with MeOH/DCM=1-10% gradient to give 600mg of compound 28E as a white solid in 28.5% yield.

Step E) compound 28E (601 mg,0.98 mmol) was dissolved in 10mL 4n HCl/dioxane, reacted for 8h at room temperature, monitored by TLC plate, after the reaction was completed the reaction solution was poured into 20mL water, sodium hydroxide solid was neutralized to ph=7, 50mL x 2DCM was extracted, the organic layers were combined, washed 1 time with 50mL saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, the organic phase silica gel was purified by flash chromatography column eluting with MeOH/dcm=1-10% gradient to give 363mg of red solid, compound 28F, 67.3% yield.

Step F Compound 27E (206 mg,0.45 mmol), DIPEA (0.81 mL,0.49 mmol) was dissolved in 10mL of LDMF, HATU (186.3 mg,0.49 mmol) was added, reacted at room temperature for 2h, compound 28F (248 mg,0.45 mmol) was added, reacted at room temperature for 8h, the reaction was monitored by TLC plate, and after the reaction was completed, 50mLH ₂ O/50mL of 2DCM was used to extract, the organic layers were combined, washed with 50mL of saturated brine 1 time, dried over anhydrous sodium sulfate, the solvent evaporated, and the organic phase was purified by flash chromatography on silica gel eluting with MeOH/DCM=1-10% gradient to give 858mg of compound 28 as a white solid in 20% yield.

¹ H NMR(400MHz,CDCl ₃ -d)δ7.38–7.24(m,10H),7.19(dd,J＝17.2,3.3Hz,2H),6.98–6.83(m,2H),5.92–5.77(m,1H),5.56(m,1H),5.30(m,1H),5.14–5.05(m,2H),4.96(m,2H),4.68–4.43(m,2H),4.08(dq,J＝13.9,6.7Hz,3H),3.94–3.70(m,4H),3.45(d,J＝14.1Hz,2H),3.36(dd,J＝6.2,1.6Hz,3H),2.45(d,J＝6.0Hz,7H),1.59–1.40(m,7H),1.19–1.06(m,5H),0.71(s,3H),0.54(s,3H).

LC-MS(ESI)[M+Na] ⁺ 975.6; retention time 4.177min, HPLC purity = 97.788%.

Example 29

Compound 29A (719 mg,1.6 mmol), compound 29B (843 mg,1.6 mmol), DIPEA (207 mg,1.6 mmol) were dissolved in 10mL anhydrous DMF and reacted at room temperature for 8h, the reaction was monitored by TLC plate, after the reaction was completed, 100mLH ₂ O/100mL of 2DCM was used to extract, the organic layers were combined, washed with 100mL of saturated brine 1 time, dried over anhydrous sodium sulfate, the solvent evaporated, and the organic phase was purified by flash chromatography on silica gel eluting with MeOH/DCM=1-10% gradient to give 1g of compound 29 as a white solid in 81% yield.

LC-MS(ESI)[M+H] ⁺ 785.5; retention time 18.158min, hplc purity = 94.961%.

Example 30

Compound 30A (470 mg,1.6 mmol), compound 29B (843 mg,1.6 mmol), DIPEA (207 mg,1.6 mmol) were dissolved in 10mL anhydrous DMF and reacted at room temperature for 8h, the reaction was monitored by TLC plate and after the reaction was completed, 100mLH ₂ O/100mL of 2DCM was extracted, the organic layers were combined, washed with 100mL of saturated brine 1 time, dried over anhydrous sodium sulfate, the solvent evaporated, and the organic phase was purified by flash chromatography on silica gel eluting with MeOH/DCM=1-10% gradient to give 823mg of compound 30 as a white solid in 68% yield.

¹ H NMR(400MHz,CDCl ₃ -d)δ7.29(d,J＝4.0Hz,3H),7.17(d,J＝8.2Hz,1H),7.11(s,1H),7.07(d,J＝7.6Hz,1H),7.00(d,J＝7.7Hz,1H),6.95–6.87(m,3H),4.97(m,2H),4.16(t,J＝6.8Hz,1H),3.83(s,3H),3.76(s,2H),3.58(m,4H),3.48(q,J＝8.3,7.6Hz,1H),3.38(s,3H),2.43(s,3H),2.33(s,3H),2.19(s,3H),1.65(m,6H),1.32(d,J＝7.7Hz,2H),1.28(d,J＝3.6Hz,4H),1.17(m,2H),1.01(d,J＝6.8Hz,3H).

LC-MS(ESI)[M+H] ⁺ 757.52; protection deviceRetention time 17.981min, hplc purity = 83.48%.

Example 31

Compound 26A (127 mg,0.45 mmol), DIPEA (0.81 mL,0.49 mmol) were dissolved in 10mL of LDMF, HATU (186.3 mg,0.49 mmol) was added, reacted at room temperature for 2h, compound 29B (244 mg,0.45 mmol) was added, reacted at room temperature for 8h, the reaction was monitored by TLC plate, and after the reaction was completed, 50mLH ₂ O/50mL of 2DCM, combining the organic layers, washing with 50mL of saturated brine 1 time, drying over anhydrous sodium sulfate, evaporating the solvent, and purifying the organic phase over silica gel column using MeOH/DCM=1-10% gradient to afford 56mg of compound 31 as a white solid in 14.2% yield.

LC-MS(ESI)[M+H] ⁺ 805.32; retention time 9.095min, hplc purity = 94.877%.

Example 32

(R) -5- (4-cyclopentyl-1, 3-dimethyl-2-oxo-1, 2,3, 4-tetrahydroquinoxalin-6-yl) -1-phenyl-1, 2, 4-triazole-3-carboxylic acid (195 mg,0.45 mmol), DIPEA (0.81 mL,0.49 mmol) was dissolved in 10mL of LDMF, HATU (186.3 mg,0.49 mmol) was added, the reaction was carried out at room temperature for 2h, compound 32A (189 mg,0.45 mmol) was added, the reaction was monitored by TLC plate at room temperature for 8h, and after the reaction was completed, 50mLH ₂ O/50mL of 2DCM, combining the organic layers, washing with 50mL of saturated brine 1 time, drying over anhydrous sodium sulfate, evaporating the solvent, and purifying the organic phase over silica gel column using MeOH/DCM=1-10% gradient to afford 53mg of compound 32 as a white solid in 14.2% yield.

¹ H NMR(400MHz,CDCl ₃ -d)δ7.71(s,1H),7.54(s,1H),7.51–7.42(m,3H),7.38(d,J＝8.0Hz,2H),7.18(m,3H),7.04(m,2H),6.93(d,J＝8.3Hz,1H),6.89(s,1H),4.89(m,2H),4.56–4.35(m,1H),4.35–4.09(m,2H),3.94(s,4H),3.77(d,J＝5.8Hz,1H),3.37(s,3H),3.16–2.92(m,1H),2.78(m,2H),2.21(m,2H),2.13(s,2H),1.65–1.48(m,6H),1.39–1.27(m,7H),1.21(m,1H),1.01(d,J＝6.8Hz,3H).

LC-MS(ESI)[M+H] ⁺ 833.47; retention time 3.458 min, hplc purity = 100%.

Example 33

Compound 33A (215 mg,0.45 mmol), DIPEA (0.81 mL,0.49 mmol) was dissolved in 10mL of LDMF, HATU (186.3 mg,0.49 mmol) was added, reacted at room temperature for 2h, (R) -4-cyclopentyl-1, 3-dimethyl-6- (1-phenyl-3- (piperazinyl-1-carbonyl) -1,2, 4-triazole) -3, 4-dihydroquinoxalin-2-one (225 mg,0.45 mmol) was added, the reaction was monitored by TLC plate at room temperature for 8h, and after the reaction was completed, 50mLH ₂ O/50mL of 2DCM, combining the organic layers, washing with 50mL of saturated brine 1 time, drying over anhydrous sodium sulfate, evaporating the solvent, and purifying the organic phase over silica gel column using MeOH/DCM=1-10% gradient to afford 78mg of compound 33 as a white solid in 17.9% yield.

¹ H NMR(400MHz,CDCl ₃ -d)δ7.73–7.57(m,2H),7.47(d,J＝15.5Hz,5H),7.39–7.30(m,2H),7.16(t,J＝11.0Hz,2H),7.01(dd,J＝17.1,8.2Hz,1H),6.96–6.81(m,3H),4.42(d,J＝12.6Hz,1H),4.23(d,J＝14.5Hz,2H),4.16(t,J＝7.0Hz,1H),4.06(d,J＝20.4Hz,2H),3.92(d,J＝6.4Hz,6H),3.77(d,J＝14.4Hz,7H),3.37(d,J＝7.2Hz,5H),3.10(s,3H),2.75(m,2H),2.22(dd,J＝11.1,6.0Hz,2H),2.10(d,J＝9.3Hz,1H),1.91(m,3H),1.54(d,J＝18.1Hz,5H),1.29(d,J＝12.9Hz,3H),1.00(t,J＝7.6Hz,4H).

LC-MS(ESI)[M+H] ⁺ 959.62; retention time 3.067min, hplc purity = 100%.

Example 34

Compound 34A (150 mg,0.45 mmol), DIPEA (0.81 mL,0.49 mmol) was dissolved in 10mL of LDMFIn the above, HATU (186.3 mg,0.49 mmol) was added thereto, and the reaction was carried out at room temperature for 2 hours, and (R) -4-cyclopentyl-1, 3-dimethyl-6- (1-phenyl-3- (piperazinyl-1-carbonyl) -1,2, 4-triazole) -3, 4-dihydroquinoxalin-2-one (225 mg,0.45 mmol) was added thereto, and the reaction was monitored by TLC plate for 8 hours, and after the completion of the reaction, 50mLH ₂ O/50mL of 2DCM, combining the organic layers, washing with 50mL of saturated brine 1 time, drying over anhydrous sodium sulfate, evaporating the solvent, and purifying the organic phase over silica gel column using MeOH/DCM=1-10% gradient to afford 150mg of compound 34 as a white solid in 41.3% yield.

¹ H NMR(400MHz,CDCl ₃ -d)δ10.41(s,1H),8.13(s,1H),7.62(d,J＝14.4Hz,3H),7.46(d,J＝20.9Hz,6H),7.15(d,J＝8.4Hz,1H),6.95–6.80(m,2H),6.47(s,1H),5.88(td,J＝17.1,6.9Hz,3H),5.19–5.06(m,2H),4.19(dt,J＝27.8,7.2Hz,4H),3.97(s,3H),3.37(d,J＝1.9Hz,3H),3.23(s,1H),2.62(q,J＝7.4Hz,2H),1.53(m,4H),1.39–1.21(m,4H),1.21(s,4H),1.00(d,J＝6.7Hz,3H),0.90(t,J＝6.7Hz,1H).

LC-MS(ESI)[M+H] ⁺ 844.62; retention time 3.07min, hplc purity = 95.338%.

Example 35

/>

Compound 35A (202 mg,0.45 mmol), DIPEA (0.81 mL,0.49 mmol) was dissolved in 10mL of LDMF, HATU (186.3 mg,0.49 mmol) was added, reacted at room temperature for 2h, (R) -4-cyclopentyl-1, 3-dimethyl-6- (1-phenyl-3- (piperazinyl-1-carbonyl) -1,2, 4-triazole) -3, 4-dihydroquinoxalin-2-one (225 mg,0.45 mmol) was added, the reaction was monitored by TLC plate at room temperature for 8h, and after the reaction was completed, 50mLH ₂ O/50mL of 2DCM was used to extract, the organic layers were combined, washed with 50mL of saturated brine 1 time, dried over anhydrous sodium sulfate, the solvent evaporated, and the organic phase was purified by flash chromatography on silica gel eluting with MeOH/DCM=1-10% gradient to give 94mg of compound 35 as a white solid in 22.3% yield.

¹ H NMR(400MHz,CDCl ₃ -d)δ10.02(s,1H),8.03(s,1H),7.63(m,2H),7.55(d,J＝6.7Hz,2H),7.49(s,2H),7.44(d,J＝3.5Hz,1H),7.15(d,J＝7.8Hz,1H),6.94(d,J＝8.6Hz,1H),6.87(s,1H),6.49(s,1H),5.88(dt,J＝16.5,8.1Hz,1H),5.47–5.31(m,2H),5.11(dd,J＝24.2,13.6Hz,2H),4.23(t,J＝7.4Hz,2H),4.17(q,J＝6.8Hz,1H),4.06(d,J＝24.5Hz,2H),3.95(s,3H),3.89(d,J＝22.3Hz,3H),3.70(d,J＝28.3Hz,5H),3.46(m,5H),3.38(s,3H),2.62(d,J＝7.5Hz,2H),2.24(t,J＝7.7Hz,3H),1.82(s,3H),1.32–1.24(m,4H),1.01(d,J＝6.8Hz,3H),0.90(t,J＝6.5Hz,2H).

LC-MS(ESI)[M+H] ⁺ 970.5; retention time 2.815min, hplc purity = 97.631%.

Experimental examples

1. Molecular activity test method

The binding activity of the compound to the BRD4 protein bromodomain1 (hereinafter referred to as BRD4 BD 1) was tested using the fluorescence anisotropy test method (Fluorescence Anisotropy). The principle is based on the principle that the fluorescence polarization values in the horizontal direction and the vertical direction are calculated for relevant analysis by detecting the change of molecular weight before and after interaction of small molecules marked by fluorescein and other molecules. If the binding equilibrium between the fluorescent-labeled small molecule and the large molecule is established, the fluorescent-labeled small molecule moves slowly when excited, and the measured fluorescence polarization value increases. If the binding between the fluorescent-labeled small molecule and the large molecule is replaced by other ligands, the rotation or turnover speed of the fluorescent-labeled small molecule and the large molecule in a free state can be increased, the emitted light is depolarized relative to the excitation light plane, and the measured polarized light value is reduced, so that the fluorescence anisotropy of the sample can be calculated.

40ul of the experimental reaction system was provided with multiple wells, and the buffer was 50mM HEPES PH7.4,150mM Nacl,0.5mM CHAPS. The fluorogenic substrate was the positive compound JQ1 linked to the fluorescent molecule at a working concentration of 5nM, the BRD4 protein was expressed in E.coli at a working concentration of 10nM, the initial concentration of the compound was 1uM, the final concentration of DMSO was two thousandths, all components were mixed in 384 well plates (burning cat# CLS 3575) and left at 4℃overnight for 16 hours. After the reaction, the value of Anisotrollopy is measured, the average value of the compound holes is taken to calculate the inhibition rate, and the compound with the inhibition rate more than 50 percent under the condition is used for measuring the IC ₅₀ Values.

Test results: some of the test compounds showed higher molecular level inhibitory activity against either the BRD4 BD1 domain or the BRD4 full-length protein.

TABLE 1 inhibitory Activity of partial Compounds of the invention against BRD4 BD1 bromodomain proteins IC ₅₀ Value (nM)

Examples	BRD4 BD1 IC ₅₀ (nM)
		9	23.13
24	59.24
		25	27.28
32	2.91
		33	8.75
34	5.27
		35	4.38

TABLE 2 inhibitory Activity of partial Compounds of the invention against full-Length BRD4 protein IC ₅₀ Value (nM)

Examples	BRD4 IC ₅₀ (nM)
		1	6.2
5	6.5
		6	9.7
23	66.6

2. Method for testing cell activity

(1) Experimental principle:

CCK8 method: the CCK8 kit contains WST-8, and the compound can be reduced into yellow formazan products by dehydrogenase in living cell mitochondria under the action of electron carrier 1-methoxy-5-methylphenazine dimethyl sulfate. The number of formazan products generated is in direct proportion to living cells, and the more and the faster the cells proliferate, the darker the color; the more toxic the compound, the lighter the color will be as cell proliferation is inhibited. The light absorption value is measured by an enzyme-linked immunosorbent assay at the wavelength of 450nM, and the number of living cells can be indirectly reflected.

(2) Experimental materials: various tumor cell cultures (Gibco), CCK8 (Sigma), trichloroacetic acid (national medicine), glacial acetic acid (national medicine), tris base unbuffer (national medicine).

(3) The experimental steps are as follows:

cells in the logarithmic phase were inoculated at 100. Mu.l/well into 96-well plates and incubated at 37℃for 24 hours until the cells became adherent.

(II) 10 μl of drug at a diluted concentration was added to each well, and three replicates were set for each concentration. And a normal saline solvent control and a cell-free zeroing hole with corresponding concentration are arranged, and if the medicine has color, the cell-free zeroing hole with corresponding medicine concentration is to be made.

(III) all cell lines were cultured in complete medium supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin optimal for growth of the cells and placed at 37℃with 5% CO ₂ Is cultured in an incubator of (a).

(IV) if the cell activity is tested by CCK8 method, 10 μl/well of CCK8 reagent is added, and the light absorption value is measured by an enzyme-labeled instrument after culturing for 4 hours. If the cell activity is tested by SRB method, the culture solution is discarded, 100 μl/well of 10% TCA precooled at 4deg.C is added, and after 1 hour of fixation at 4deg.C, washing with distilled water for 5 times, and naturally drying in air.

(V) 100. Mu.l/well of SRB (4 mg/ml) solution in 1% glacial acetic acid was added and stained at room temperature for 15 minutes.

Removing supernatant, washing with 1% acetic acid for 5 times, and air drying.

(VII) 150. Mu.l/well Tris (10 mM) solution was added and left at room temperature for 5 minutes.

(VIII) the absorbance (OD) was measured at 560 nM.

(4) Data analysis:

(a) The calculation formula is as follows: inhibition = (OD value _{Control group} -OD value _{Administration group} value)/OD value _{Control group} X 100%............. (equation 5.3)

(b)IC ₅₀ The values were calculated using the Logit method.

(5) Test results:

the test part of the compounds show strong proliferation inhibition activity on TY82 thymus cancer cells and MM.1S myeloma cells, and the activity is improved by more than 10000 times compared with the monovalent inhibitor (HJP-178) obtained in the previous work of the inventor.

TABLE 3 partial Compound pairs of the inventionProliferation inhibitory Activity of tumor cell lines IC ₅₀ Value (nM)

3. The experimental method for oral metabolism of mice comprises the following steps: will dissolve in dimethylacetamide: test compound (10 mg/kg) in 0.5% HPMC (hydroxypropyl methylcellulose) (5:95, v/v) was formulated to a concentration of 1mg/mL and given to ICR mice by gavage administration (male, 18-22g, n=3). Blood samples (anticoagulant: EDTA-Na 2) were collected at 0.25,0.5,1,2,4,8 and 24 hours post-administration. 100 μl of methanol with internal standard: acetonitrile (1:1, v/v) solvent was added to 10. Mu.L of plasma and vortexed well. Centrifuge for 5 minutes, then mix 20 μl of supernatant with 20 μl of water for analysis. The samples were analyzed by Xex TQ-S triple quadrupole mass spectrometer (Waters, USA). Analysis was performed using ACQUITY UPLC BEH C18 (1.7 μm,2.0 mm. Times.50 mm, waters, USA). The elution was performed by a gradient of an eluent consisting of 5mM ammonium acetate in water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid. After analysis of the concentration of the test compounds, values for AUClast, aucnf_obs and mrtinf_obs were calculated from the time-concentration curve for each animal using Phoenix WinNonlin (CERTARA, USA). Cmax is determined as the maximum plasma concentration, tmax being the time to reach the maximum concentration.

Experimental results: test compounds 7, 10 and 24 all showed excellent oral absorption capacity.

TABLE 4 oral metabolism experiments in mice of partial Compounds of the invention (10 mg/kg)

	7	10	24	OTX-015
					T _1/2 (h)	4.89	4.09	4.29	0.99
T _max (h)	1.67	1.67	1.00	0.25
					C _max (ng/mL)	2535.5	1784.8	2456.5	1507
AUC _last (h*ng/mL)	19251.2	11756.0	18631.8	3078
					AUC _{INF_pred} (h*ng/mL)	19880.6	11932.9	19031.8	3088
MRT _last (h)	5.80	5.21	5.60	1.97

4. In vivo pharmacodynamics test method

(1) Experimental materials:

DMAC (20160316, shanghai Lingfeng chemical Co., ltd.), MC (methylcellulose M20, national pharmaceutical group chemical Co., ltd.) ultrapure water, laboratory animals (female, BALB/c nude mice SPF grade, beijing Vitolihua laboratory animal technologies Co., ltd.), the corresponding transplantable tumor cell line.

(2) The experimental method comprises the following steps:

cell culture: the corresponding tumor cells were routinely cultured in IMDM medium containing 10% fetal bovine serum at 5% co2 at 37 ℃. According to the growth condition of the cells, the cells are passaged 2 to 3 times per week.

And (II) establishing a model: tumor cells in the logarithmic growth phase were harvested by digestion with 0.25% pancreatin and centrifugation at 800 g. The cells were counted by resuspension in physiological saline. Cells were collected by centrifugation, suspended in a saline+matrigel (1:1) mixture and the cell concentration was adjusted to 6X 10 ⁷ cells/mL. Cells were aspirated with a 1mL syringe, injected under the anterior right limb axilla of nude mice, 0.1 mL/mouse, and the growth of animals and transplants was observed periodically.

(iii) animal group dosing: after 13 days of cell inoculation (Day 13), the tumor diameters of the animals were measured and the tumor volumes were calculated. Animals with excessively small, excessively large tumor volume or irregular tumor shape are eliminated, and the tumor volume is 112.39mm ³ ～185.83mm ³ Is divided into 12 solvent control groups and 6 other groups according to the tumor volume by adopting a random area method. Administration was initiated according to a group regimen for the weekThe period is 21 days or 28 days. During the administration period, tumor diameters were measured 2 times a week, animal weights were weighed, animal living states were observed, and abnormal conditions were recorded. The last dose was added on the day of the end of the trial, and each group was dosed with CO 1 and 8 hours after the last dose, respectively ₂ 3 animals were sacrificed at random (6 for each time point of the solvent control group), heart blood was collected, and about 200 μl/piece of EDTA-K2 anticoagulated plasma was collected; and the subcutaneous tumor tissue is rapidly peeled off, photographed and weighed, then sub-packaged into a homogenate tube according to the requirement, quickly frozen by liquid nitrogen and then transferred to a refrigerator at-80 ℃ for preservation and measurement. Animals were dissected and observed for abnormalities in the major organs.

(3) Data analysis:

(a) The calculation formula is as follows: tumor Volume (TV) =1/2×a×b ² … … … … … … … … … … (equation 5.6)

Wherein a represents a tumor major diameter; b represents the tumor minor diameter.

(b) The calculation formula is as follows: relative Tumor Volume (RTV) =v _t /V _initial X 100 (%) … … … … (equation 5.7)

Wherein V is _initial For measuring tumor volume at the time of group administration, V _t Tumor volume at each measurement.

(c) The calculation formula is as follows: relative tumor proliferation rate (T/C) = (T _RTV /C _RTV ) X 100% >. The term "(formula 5.8)

Wherein T is _RTV Representing relative tumor volume of treatment group, C _RTV The relative tumor volumes of the solvent control group are indicated.

(d) The calculation formula is as follows: tumor suppression ratio (GI) = [1- (TV) _t －TV _initial )/(CV _t －CT _initial )]X 100%....................... (equation 5.9)

Wherein TV is provided _t Tumor volume at each measurement of treatment group; TV set _initial Tumor volume representing treatment group at the time of group administration; CV (CV) _t Tumor volume at each measurement of control group is indicated; CT (computed tomography) _initial The tumor volume of the control group at the time of group administration was represented.

(e) The calculation formula is as follows: weight loss rate= (BW) _initial －BW _final )/BW _initial X 100% >. The (formula 5.10)

Wherein BW is _initial Indicating animal body weight at the time of group administration; BW (BW) _final Animal body weight at the end of the test.

(4) The statistical analysis method comprises the following steps:

test data were calculated and related statistical processing using Microsoft Office Excel 2007 software and comparisons between the two groups were made using t-test.

(5) Test results:

some of the tested compounds showed anti-tumor activity in mice superior to positive compounds (OTX-015, ABBV-075 and AZD 5153). Wherein OTX-015 and ABBV-075 are monovalent inhibitors and AZD5153 is a bivalent inhibitor.

TABLE 5 example 15 in vivo pharmacodynamic evaluation results in MV4-11 (human myelomonocytic leukemia cells) nude mice subcutaneous tumor suppression model

TABLE 6 in vivo pharmacodynamic evaluation results of example 9 and example 10 in the MV4-11 nude mice subcutaneous tumor inhibition model

The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description. The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims

1. A compound having the structure of formula (i), or a pharmaceutically acceptable salt thereof:

wherein:

k is selected from the following groups:

L ₁ is-C (=O) -or

L ₄ selected from the group consisting of substituted or unsubstituted C1-C5 alkylene, substituted or unsubstituted C3-C10 cycloalkylene, said substituted substituents being selected from the group consisting of: fluorine, chlorine, bromine, hydroxyl, amino, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy;

alternatively, L ₄ ，R ₁₉ ，R ₂₀ And the nitrogen atoms to which they are attached together form a substituted or unsubstituted 5-10 membered heterocyclic group, said substitution being meant to have 1-3 substituents, each substituent being independently selected from the group consisting of: halogen, hydroxy, nitro, cyano, C1-C6 alkylC1-C6 alkoxy;

x and Y are each independently selected from: c or N;

R ₁ and R is ₁ ' are the same or different from each other and are each independently selected from: hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl-substituted C1-C2 alkyl;

R ₂ and R is ₂ ' are the same or different from each other and are each independently selected from: hydrogen, C1-C4 alkyl, C2-C4 alkenyl substituted C1-C4 alkyl;

R ₃ And R is ₃ ' are the same or different from each other and are each independently selected from: a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted benzyl group, the substituted substituent being selected from the group consisting of: halogen, hydroxy, amino, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy;

", indicates where substituents are attached.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X and Y are C.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein,

L ₄ selected from unsubstituted C1-C5 alkylene, unsubstituted C3-C10 cycloalkylene, or

Wherein n4 and n5 are each independently selected from any integer between 0 and 4, which are the same or different from each other;

n10, n11, n12 and n13 are each independently selected from any integer between 1 and 3, and are the same or different from each other.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein,

L ₄ is that

Or alternatively

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein G ₁ And G ₂ At least one is present.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein G ₁ And G ₂ Are all-C (=o) -.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein,

L ₁ selected from the following groups:

wherein,,

n1, n2 and n3 are each independently selected from any integer between 1 and 5, which are the same or different from each other;

n4, n5, n6, n7, n8 and n9 are each independently selected from any integer between 0 and 4, and are the same or different from each other;

n10, n11, n12 and n13 are each independently selected from any integer between 1 and 3, and are the same or different from each other;

L ₄ 、R ₁₉ and R is ₂₀ Is defined as in the appended claims.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (i) is selected from the group consisting of:

wherein,,

L ₅ selected from the group consisting of

/>

Z ₁ Selected from-C (=O) -or- (CH) ₂ ) n-, n is an integer from 1 to 5;

Z ₂ selected from-C (=O) -or-CH ₂ -，

R ₁ And R is ₁ ' are the same or different from each other and are each independently selected from hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl, phenyl-substituted C1-C2 alkyl;

R ₂ and R is ₂ ' are the same or different from each other and are each independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl substituted C1-C2 alkyl;

R ₃ And R is ₃ ' are the same or different from each other and are each independently selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl; the substituted substituent is selected from halogen, hydroxy, amino, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy

"x" means that the substituents are attached at this point;

alternatively, the compound of the structure of formula (I) is selected from the following compounds:

wherein,,

L ₅ 、Z ₁ 、Z ₂ 、R ₁ 、R ₂ and R is ₃ The same definition as in formula II;

wherein,,

L ₅ 、Z ₁ 、Z ₂ 、R ₁ 、R ₂ 、R ₃ and R is ₃ ' is as defined in formula II, R is selected from halogen; alternatively, the compound of the structure of formula (I) is selected from the following compounds:

wherein R is ₁ 、R ₂ And R is ₃ The same definition as in formula II;

L ₅ the same definition as in formula II, or absent;

Z ₁ as defined in formula II, either absent or-CH ₂ -C(＝O)-，

Z ₂ The same definition as in formula II;

wherein,,

R ₁ 、R ₂ and R is ₃ The same definition as in formula II;

L ₅ the same definition as in formula II, or absent;

Z ₁ as defined in formula II, either absent or-CH ₂ -C(＝O)-，Z ₂ The same definition as in formula II.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R ₁ And R is ₁ ' each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, methyl, benzyl; and/or

R ₂ And R is ₂ ' each independently selected from methyl, vinyl ethyl; and/or

R ₃ And R is ₃ ' each independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl.

10. The compound according to claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein,

R ₁ and R is ₁ ' same; and/or

R ₂ And R is ₂ ' same; and/or

R ₃ And R is ₃ In' the substituted substituent is selected from halogen and methyl.

11. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein,

in formula II, R ₁ And R is ₁ ' is cyclopentyl, R ₂ And R is ₂ ' is methyl, R ₃ And R is ₃ ' is phenyl or p-methylphenyl, Z ₁ And Z ₂ Selected from-C (=O) -or-CH ₂ -；

In formula III, R ₁ Is cyclopentyl, R ₂ Is methyl, R ₃ Is phenyl or p-methylphenyl, Z ₁ Is- (CH) ₂ ) n-, n is an integer from 1 to 5, Z ₂ Selected from-C (=O) -or-CH ₂ -；

In formula IV, R ₁ Is cyclopentyl, R ₂ Is methyl, R ₃ And R is ₃ ' is phenyl or p-methylphenyl, Z ₁ And Z ₂ Selected from-C (=O) -or-CH ₂ -；

In the general formula V, R ₁ Is cyclopentyl, R ₂ Is methyl, R ₃ Is phenyl, L ₅ Absence or as

Z ₁ Absent or-CH ₂ -C(＝O)-，Z ₂ is-C (=o) -;

in formula VI, R ₁ Is cyclopentyl, R ₂ Is methyl, R ₃ Is phenyl, L ₅ Absence or as

Z ₁ Absent or-CH ₂ -C(＝O)-，Z ₂ is-C (=o) -.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (i) is selected from the group consisting of:

/>

/>

13. a pharmaceutical composition comprising one or more selected from the compounds of any one of claims 1-12 and pharmaceutically acceptable salts thereof, optionally comprising one or more pharmaceutical excipients.

14. Use of a compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the preparation of an inhibitor of bromodomain recognition protein; or for the preparation of a medicament for the prophylaxis and/or treatment of a disease associated with the bromodomain recognizing protein.

15. The use according to claim 14, wherein the related disorder mediated by bromodomain recognition proteins is selected from the group consisting of: malignant tumors, immunological diseases, cardiovascular system diseases, viral infections, neurodegenerative diseases or inflammation.

16. The use of claim 15, wherein the malignancy is selected from the group consisting of: acute lymphoblastic leukemia, acute myelogenous leukemia, B-cell chronic lymphocytic leukemia, chronic myelomonocytic leukemia, testicular nucleoprotein centerline cancer, small cell lung cancer, non-small cell lung cancer, B-cell lymphoma, prostate cancer, gastric cancer, colorectal cancer, renal cancer, liver cancer, breast cancer, pancreatic cancer.