WO2018041260A1 - Bromodomain recognition protein inhibitor and preparation method therefor and use thereof - Google Patents

Abstract

Disclosed are a compound of general formula (I), and a stereoisomer, a pharmaceutically acceptable salt, a prodrug, a solvate, a hydrate and a crystal form thereof. The compound of general formula (I) of the present invention can inhibit a bromodomain recognition protein, and can be used to regulate the epigenetic state of cells and treat a series of diseases and symptoms mediated by the bromodomain recognition protein. In particular, hematologic malignant tumors, midline carcinomas and inflammation, etc., can be treated.

Description

Bromine domain recognition protein inhibitor, preparation method and use thereof Technical field

The present invention relates to a novel class of bromodomain recognition protein inhibitors, and a preparation method and use thereof; and to the use of such compounds in the preparation of a medicament for treating a disease mediated by a bromodomain recognition protein, It relates to the application in the preparation of medicines for treating blood malignant tumors, midline cancer and inflammation.

Background technique

In 1964, Allfey et al. found that lysine acetylation can be used as a protein post-translational modification (PTM), and they simultaneously found acetylation and methylation of histones and proposed that these post-translational modifications regulate RNA synthesis. Histone acetylation neutralizes the positive charge on the ε-amino group of histone-specific lysine, resulting in weak binding of the negatively charged DNA to histones, and the chromatin structure becomes slack, and this relaxed state makes Polymerases, transcription factors, and other transcription-related complexes are close to DNA leading to transcriptional activation of genes. Therefore, acetylation of histones can activate the process of transcriptional expression of specific genes. Histone deacetylation is the opposite of histone acetylation, which can lead to the silencing of specific gene expression. Bromodomain proteins (BRDs) recognize lysine residues that are acetylated at the ends of histones, and their mechanism of action is to recruit protein complexes and thereby affect the transcription process. 61 bromodomains were found on 46 different proteins in the human genome, which can be divided into eight major families (as shown in Figure 1). Among them, there are many studies on the BET (Bromo-and Extra-terminal) family.

The BET family includes widely expressed BRD2, BRD3, BRD4 and BRDT specifically expressed in the testis.

The primary function of the BET family is to recruit transcriptional regulatory complexes to acetylated chromatin, thereby controlling specific gene networks involved in cell proliferation and cell cycle progression. For example, BRD4 and BRDT can regulate transcriptional elongation, mainly through interaction with positive transcription elongation factor (P-TEFb), leading to RNA polymerase II activation. BET family protein disorders are associated with many diseases, such as cancer, inflammation, etc., making BET protein an attractive drug target.

In 2010, two BET family selective inhibitors (+)-JQ1 were discovered (see Filippakopoulos, P.; Qi, J.; Picaud, S.; Shen, Y.; Smith, WB; Fedorov, O. ;Morse, EM;Keates,T.;Hickman,TT;Felletar,I.;Philpott,M.;Munro,S.;McKeown,MR;Wang,Y.;Christie,AL;West,N.;Cameron,MJ;Schwartz, B.;Heightman, TD; La Thangue, N.; French, CA; Wiest, O.; Kung, AL; Knapp, S.; Bradner, JESelective inhibition of BET bromodomains. Nature 2010, 468, 1067-1073. And I-BET762 (see Nicodeme, E.; Jeffrey, KL; Schaefer, U.; Beinke, S.; Dewell, S.; Chung, C.; Chandwani, R.; Marazzi, I.; Wilson, P.; Coste, H.; White, J.; Kirilovsky, J.; Rice, CM; Lora, JM; Prijha, RK; Lee, K.; Tarakhovsky, A. Suppression of inflammation by a synthetic histone mimic. Nature 2010, 468, 1119-1123.) (Structural formula below), causing widespread concern about bromine domain inhibitors. With the continuous efforts of researchers, more and more BET family selective inhibitors have been discovered and in recent years there have been more and more researches on inhibitors of non-BET family of bromodomain proteins. These bromodomain protein inhibitors can Helps better understand the function of the protein and its associated diseases.

In recent years, double inhibitors of kinase-bromodomain recognition proteins have also been studied, and BRD4 has been shown to have the properties of atypical kinases, which can phosphorylate the RNAC IIC-terminal serine at position 2. Among them, PLK1 inhibitor BI2536 and JAK2 inhibitor TG101209 have good activity against BRD4 with IC ₅₀ of 25 nM and 130 nM, respectively. These early discoveries allow for the rational design of dual inhibitors of kinase-bromodomain recognition proteins or selective bromodomain recognition protein inhibitors from kinase inhibitors, with selective inhibitors that reduce off-target side effects.

Summary of the invention

The inventors of the present invention rationally designed, synthesized and investigated selective bromodomain recognition protein inhibitors from dual inhibitors of kinase-bromodomain recognition proteins. The inventors obtained detailed information on the crystal structure (PDB ID: 4O74) in which the lactam structure in region 1 forms a key hydrogen bond with Asn140 in the BRD4KAc pocket, and two nitrogen atoms and kinase in region 2 The hinge region forms a critical hydrogen bond (Fig. 2A); the phenylamide structure and its attached group extend out of the binding pocket and do not enter the WPF subbinding site of the BRD4 binding site (Fig. 2B). By analyzing the structure, we retain the lactam structure that forms a key hydrogen bond with BRD4 and replace the N atom that forms a key hydrogen bond with the hinge region of the kinase as a C atom. A series of compounds described herein were thus synthesized and tested for activity of the compounds. The test results indicate that the compound has a very high BRD4 target binding activity and growth inhibitory activity of BRD4-sensitive cells. The inventors have also obtained the unique mode of action of the compounds in this application through crystal experiments and structural analysis of the complexes: the compounds unexpectedly entered the WPF sub-binding site with distinct binding modes, and the resolved crystal structure is shown in Figure 2C. Show.

Accordingly, it is an object of the present invention to provide a novel structure of a bromodomain recognition protein inhibitor, i.e., a compound represented by the formula (I), and stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates thereof. , hydrates and crystal forms which are useful for the treatment, prevention and inhibition of related diseases mediated by bromine domain recognition proteins;

Another object of the present invention is to provide a process for producing a compound represented by the general formula (I);

Still another object of the present invention is to provide a pharmaceutical composition comprising a compound represented by the general formula (I), and a stereoisomer, a pharmaceutically acceptable salt, a prodrug, a solvate, a hydrate or a crystalline form thereof;

A further object of the present invention is to provide the use of the compound represented by the general formula (I), and stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates or crystal forms thereof; A compound represented by the formula (I), and a stereoisomer, a pharmaceutically acceptable salt, a prodrug, a solvate, a hydrate or a crystal form thereof are selective inhibitors acting on a bromodomain recognition protein, which are capable of The bromodomain recognition protein recognizes the inhibition of lysine acetylation.

A further object of the present invention is to provide a compound represented by the general formula (I), and a stereoisomer, a pharmaceutically acceptable salt, a prodrug, a solvate, a hydrate or a crystal form thereof for the preparation of a blood malignant tumor. The use of drugs for diseases such as midline cancer and inflammation.

The present invention provides a compound represented by the formula (I), and stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates and crystal forms thereof:

among them:

X is C or N;

R ₁ is a hydrogen atom, a substituted or unsubstituted C1-C20 straight or branched alkyl group, a substituted or unsubstituted C1-C20 straight or branched alkoxy group, a substituted or unsubstituted C3-C10 cycloalkyl group The substituent is a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group;

R ₂ is a substituted or unsubstituted C1-C20 straight or branched alkyl group, a substituted or unsubstituted C1-C20 straight or branched alkoxy group, a substituted or unsubstituted C3-C10 cycloalkyl group, The substituent is halogen, hydroxy, amino, nitro, cyano, and the configuration of R ₂ may be R or S or a racemate;

R ₃ is a substituted or unsubstituted C1-C20 straight or branched alkyl group, a substituted or unsubstituted C1-C20 straight or branched alkoxy group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or An unsubstituted benzyl group, which is independently selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, 5-7 members containing 1-3 heteroatoms selected from N, O and S a heterocyclic group, a C1-C3 straight or branched alkyl group or a C1-C3 straight or branched alkoxy group;

或-CH₂-，其中R₅为氢原子，C1-C6直链或支链烷基；L is

Or -CH ₂ -, wherein R ₅ is a hydrogen atom, a C1-C6 straight or branched alkyl group;

R ₄ is a C1-C20 straight or branched alkyl group, a halogen-substituted C1-C20 straight or branched alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C3-C10 cycloalkane A substituted or unsubstituted C6-C20 aromatic ring, a substituted or unsubstituted C6-C20 aryl group, a substituted or unsubstituted C6-C12 aryl C1-C6 alkyl group, substituted or unsubstituted containing 1-3 selected 5-10 membered heterocyclic or heteroaryl group of a hetero atom of N, O and S, substituted or unsubstituted 5-10 membered heterocyclic group containing 1 to 3 hetero atoms selected from N, O and S Or a heteroaryl-substituted or unsubstituted C6-C12 aryl group, said substituents being independently selected from the group consisting of 1-4, halo, hydroxy, amino, nitro, cyano, C1-C6 straight or Branched alkyl or C1-C6 straight or branched alkoxy, or

时，R₄和R₅可以和它们连接的氮原子形成取代或未取代的含有N原子和0-2个O、S的杂原子的5-10元杂环基或杂芳基并取代或未取代的C6-C20芳基，所述取代基独立地选自如下1-2个基团：卤素、羟基、氨基、硝基、氰基、C1-C6直链或支链烷基或者C1-C6直链或支链烷氧基。When L is

When R ₄ and R ₅ may form a substituted or unsubstituted 5-10 membered heterocyclic or heteroaryl group containing a N atom and 0-2 O, S hetero atoms and a nitrogen atom to which they are attached, and substituted or not Substituted C6-C20 aryl, the substituents are independently selected from the group consisting of 1-2 groups: halogen, hydroxy, amino, nitro, cyano, C1-C6 straight or branched alkyl or C1-C6 Linear or branched alkoxy.

Preferably:

X is C or N;

R ₁ is a hydrogen atom, a C1-C6 linear or branched alkyl group or a halogen-substituted C1-C6 straight or branched alkyl group;

R ₂ is a C1-C6 linear or branched alkyl group or a halogen-substituted C1-C6 straight or branched alkyl group, and the configuration of R ₂ may be an R form or an S form or a racemate;

R ₃ is a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted benzyl group, and the substituents are independently selected from the following 1 - 5 groups: halogen, hydroxy, 5-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S, C1-C3 straight or branched alkyl or C1-C3 straight chain or Branched alkoxy group;

或-CH₂-，其中R₅为氢原子，C1-C3直链或支链烷基；L is

Or -CH ₂ -, wherein R ₅ is a hydrogen atom, a C1-C3 straight or branched alkyl group;

R ₄ is a C1-C6 straight or branched alkyl group, a halogen-substituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C3-C8 cycloalkane A substituted or unsubstituted C6-C12 aromatic ring, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C6-C12 aryl C1-C4 alkyl group, substituted or unsubstituted containing 1-3 selected 5-10 membered heterocyclic or heteroaryl group of a hetero atom of N, O and S, substituted or unsubstituted 5-10 membered heterocyclic group containing 1 to 3 hetero atoms selected from N, O and S Or a heteroaryl-substituted or unsubstituted C6-C10 aryl group, said substituents being independently selected from the group consisting of 1-4 groups: halogen, hydroxy, C1-C3 straight or branched alkyl or C1-C3 Linear or branched alkoxy, or

时，R₄和R₅可以和它们连接的氮原子形成取代或未取代的含有N原子和0-2个O、S的杂原子的5-10元杂环基或杂芳基并取代或未取代的C6-C12芳基，所述取代基独立地选自如下1-2个基团：卤素、羟基、C1-C3直链或支链烷基或者C1-C3直链或支链烷氧基。When L is

When R ₄ and R ₅ may form a substituted or unsubstituted 5-10 membered heterocyclic or heteroaryl group containing a N atom and 0-2 O, S hetero atoms and a nitrogen atom to which they are attached, and substituted or not Substituted C6-C12 aryl, said substituents being independently selected from the group consisting of 1-2 groups: halogen, hydroxy, C1-C3 straight or branched alkyl or C1-C3 straight or branched alkoxy .

Preferably:

X is C or N;

R ₁ is a hydrogen atom or a C1-C3 straight or branched alkyl group;

R ₂ is a C1-C6 linear or branched alkyl group, and the configuration of R ₂ may be an R type or an S type or a racemate;

R ₃ is a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted benzyl group, and the substituents are independently selected from the following 1 - 4 groups: halogen, 5-7 membered heterocyclic group containing 1-2 heteroatoms selected from N and O, C1-C3 straight or branched alkyl or C1-C3 straight or branched alkoxy base;

或-CH₂-，其中R₅为氢原子，C1-C3直链或支链烷基；L is

Or -CH ₂ -, wherein R ₅ is a hydrogen atom, a C1-C3 straight or branched alkyl group;

R ₄ is a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group and a substituted or unsubstituted C6-C12 aromatic ring, a substituted or unsubstituted C6-C12 aryl group, substituted or Unsubstituted C6-C12 aryl C1-C4 alkyl, substituted or unsubstituted 5-6 membered heterocyclic or heteroaryl group containing 1-3 heteroatoms selected from N, O and S, substituted or not Substituted 5-6 membered heterocyclic or heteroaryl substituted or unsubstituted C6-C10 aryl group containing from 1 to 3 heteroatoms selected from N, O and S, said substituents being independently selected from the group consisting of 1-3 groups: halogen, hydroxy, C1-C3 straight or branched alkyl or C1-C3 straight or branched alkoxy, or

时，R₄和R₅可以和它们连接的氮原子形成取代或未取代的含有N原子和0-2个O、S的杂原子的5-6元杂环基或杂芳基并取代或未取代的C6-C10芳基，所述取代基独立地选自如下1-2个基团：卤素、羟基、C1-C3直链或支链烷基或者C1-C3直链或支链烷氧基。When L is

When R ₄ and R ₅ may form a substituted or unsubstituted 5-6 membered heterocyclic or heteroaryl group containing a N atom and 0-2 O, S hetero atoms with or without a nitrogen atom to which they are attached, Substituted C6-C10 aryl, the substituents are independently selected from the group consisting of 1-2 groups: halogen, hydroxy, C1-C3 straight or branched alkyl or C1-C3 straight or branched alkoxy .

More preferably:

X is C or N;

R ₁ is a hydrogen atom, a methyl group or an ethyl group;

R ₂ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and the configuration of R ₂ may be R type or S type or racemic;

R ₃ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxyethyl, containing 1-2 selected from N and a 5- to 6-membered heterocyclic-substituted C1-C3 linear or branched alkyl group of a hetero atom of O (preferably morpholinoethyl, tetrahydrofuranylmethyl), halogen or C1-C3 alkoxy-substituted benzyl (preferably Br substituted benzyl or methoxybenzyl);

或-CH₂-，其中R₅为氢原子、甲基或乙基；L is

Or -CH ₂ -, wherein R ₅ is a hydrogen atom, a methyl group or an ethyl group;

R ₄ is a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group and a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted C6-C12 aryl group, substituted or Unsubstituted C6-C12 aryl C1-C3 alkyl, substituted or unsubstituted 5-6 membered heterocyclic or heteroaryl group containing from 1 to 2 heteroatoms selected from N and O, substituted or unsubstituted a C6-C10 aryl group having 1 to 6 membered heterocyclic or heteroaryl groups selected from 1 to 6 hetero atoms selected from N and O, the substituents being independently selected from the following 1-3 a group: a halogen, a C1-C3 straight or branched alkyl group or a C1-C3 straight or branched alkoxy group; preferably a cyclopentyl group, a cyclohexyl group, a methylcyclohexyl group, a phenyl group, a methylphenyl group, a chlorine group Phenyl, fluorophenyl, methoxyphenyl, isoxazolyl, 1,2,4-trimethylpyrazol-3-yl, methylbenzyl, 2,4-dimethylphenyl, 3 -fluoro-4-methylphenyl, 2,4,6-trimethylphenyl or pyrimidinyl, or

时，R₄和R₅可以和它们连接的氮原子形成取代或未取代的含有N原子和非必须的O原子的5-6元杂环基或杂芳基并取代或未取代的C6-C10芳基，所述取代基独立地选自如下1-2个基团：卤素、C1-C3直链或支链烷基或者C1-C3直链或支链烷氧基；优选R₄和R₅可以和它们连接的氮原子形成二氢吲哚基、甲基取代的二氢吲哚基、F取代的二氢吲哚基或

When L is

When R ₄ and R ₅ may form a substituted or unsubstituted 5-6 membered heterocyclic or heteroaryl group containing a N atom and an optional O atom with a nitrogen atom to which they are bonded, and substituted or unsubstituted C6-C10 An aryl group, said substituent being independently selected from the group consisting of 1-2 groups: halogen, C1-C3 straight or branched alkyl or C1-C3 straight or branched alkoxy; preferably R ₄ and R ₅ The nitrogen atom to which they are attached may form a dihydroindenyl group, a methyl-substituted indanyl group, an F-substituted indanyl group or

Preferably, when L is -CH ₂ -, R ₄ contains an N atom.

Most preferably, the compound is selected from the group consisting of

The compound represented by the formula (I) may contain an asymmetric or chiral center and thus may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, including but not limited to Isomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, are included within the scope of the invention.

The compounds of the formula (I) may also exist in different tautomeric forms, all of which are included in the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are converted to each other via a low energy barrier.

The compound of formula (I) may exist in unsolvated as well as solvated forms containing pharmaceutically acceptable solvents such as water, ethanol, and the like, and the compounds of the present invention include both solvated and unsolvated forms.

The compound represented by the formula (I) has a basic group and thus can form a pharmaceutically acceptable salt (ie, a pharmaceutically acceptable salt) with an inorganic or organic acid, including a pharmaceutically acceptable acid addition salt, by using an inorganic The pharmaceutically acceptable salt can be obtained by treating the free base of the compound of the formula (I) with an acid or an organic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and the organic acid such as ascorbic acid. , niacin, 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, benzene Sulfonic acid, p-toluenesulfonic acid, etc.

For illustrative purposes, the reaction schemes shown below provide possible pathways for the synthesis of the compounds of the invention as well as key intermediates. For a more detailed description of the individual reaction steps, please see the Examples section below. The compounds of the formula (I) of the present invention can be synthesized by methods including those well known in the chemical arts, especially in accordance with the description of the present invention. The starting materials are generally available from commercial sources such as Sigma Aldrich or are readily prepared using methods well known to those skilled in the art.

The compound in the reaction scheme includes a salt thereof, for example, a salt as defined by the compound of the formula (I), etc., i.e., a free base of the compound treated with an organic acid or a mineral acid, to give a salt of the corresponding compound.

The preparation method of the above compound represented by the structural formula (I) includes

Reaction route 1:

Step a: Compound 1A is reacted with amino acid NH ₂ R ₂ COOH to obtain Compound 1B;

Step b: Compound 1B is reacted under the conditions of tin dichloride dihydrate to obtain compound 1C;

Step c: compound 1C and R ₁ I are reacted under sodium hydride to obtain compound 1D;

Step d: Compound 1D with sulfonamide R ₄ SO ₂ NH ₂ in allyl palladium chloride dimer, 2-di-tert-butylphosphino-2', 4',6'-triisopropylbiphenyl and potassium carbonate Compound 1E is obtained by a coupling reaction under the conditions;

Step e: Compound 1E is reacted with R ₅ I under sodium hydride to give compound 1F.

Reaction route two:

Step a: compound 2A is reacted with a primary amine R ₃ NH ₂ to obtain a compound 2B;

Step b: compound 2B is reacted under iron powder and ammonium chloride to obtain compound 2C;

反应得到中间体，2)中间体在N,N-二异丙基乙胺条件下通过分子内亲核反应得到化合物2D；Step c: 1) Compound 2C with a different 2-bromoalkanoyl bromide

The reaction gives an intermediate, 2) the intermediate is obtained by intramolecular nucleophilic reaction under N,N-diisopropylethylamine to obtain compound 2D;

Step d: compound 2D is reacted with R ₁ I to obtain compound 2E;

Step e: Compound 2E with sulfonamide R ₄ SO ₂ NH ₂ in allyl palladium chloride dimer, 2-di-tert-butylphosphino-2', 4',6'-triisopropylbiphenyl and potassium carbonate The compound of the formula 2F is obtained by a coupling reaction under the conditions;

Step f: compound 2F and R ₅ I are reacted under sodium hydride to obtain compound 2G;

Alternatively, after steps a-d, steps e and f are not performed, but the following steps are performed:

Step g: 1) Compound 2E is coupled with tert-butyl carbamate under conditions of Pd(OAc) ₂ , 2-dicyclohexylphosphine-2', 4',6'-triisopropylbiphenyl and cesium carbonate. The reaction gives the intermediate, 2) the intermediate is deprotected under the action of trifluoroacetic acid to obtain the compound 2H;

Step h: compound 2H is reacted with different acid chloride R ₄ COCl to obtain compound 2I;

Step i: Compound 2I is reacted with R ₅ I under sodium hydride to give compound 2J.

Reaction route three:

Step a: compound 3A is reacted with thionyl chloride and methanol to obtain compound 3B;

Step b: compound 3B is reacted with different primary amines R ₃ NH ₂ to obtain compound 3C;

Step c: compound 3C is reacted under iron powder and ammonium chloride to obtain compound 3D;

反应得到中间体，2)中间体在N,N-二异丙基乙胺条件下通过分子内亲核反应得到化合物3E；Step d: 1) Compound 3D with a different 2-bromoalkanoyl bromide

The reaction gives an intermediate, 2) the intermediate is obtained by intramolecular nucleophilic reaction under N,N-diisopropylethylamine to obtain compound 3E;

Step e: compound 3E and R ₁ I are reacted under sodium hydride to obtain compound 3F;

Step f: compound 3F is obtained by hydrolysis reaction under lithium hydroxide to obtain compound 3G;

Step g: Compound 3G is reacted with an amine R ₄ R ₅ NH to give compound 3H by condensation reaction.

Reaction route four:

反应得到化合物4B；Step a: Compound 4A and 2-bromoalkanoyl bromide

Reaction gives compound 4B;

Step b: compound 4B is reacted with an amine R ₃ NH ₂ to obtain a compound 4C;

Step c: Compound 4C is obtained by intramolecular nucleophilic reaction under N,N-diisopropylethylamine to obtain compound 4D;

Step d: compound 4D and R ₁ I are reacted under sodium hydride to obtain compound 4E;

Step e: Compound 4E with sulfonamide R ₄ SO ₂ NH ₂ in allyl palladium chloride dimer, 2-di-tert-butylphosphino-2', 4',6'-triisopropylbiphenyl and potassium carbonate Compound 4F is obtained by a coupling reaction;

Step f: compound 4F and R ₅ I are reacted under sodium hydride to obtain compound 4G;

Alternatively, after steps a-d, steps e and f are not performed, but the following steps are performed:

Step g: Compound 4E and amine R ₄ R ₅ NH in triethylamine, 4-dimethylaminopyridine, hexacarbonyl molybdenum, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride And reacting with 1,8-diazabicycloundec-7-ene to obtain compound 4H;

Alternatively, after steps a-d, without performing steps e and f or g, the following steps are performed:

Step h: 1) Compound 4E is coupled with tert-butyl carbamate under conditions of Pd(OAc) ₂ , 2-dicyclohexylphosphine-2', 4',6'-triisopropylbiphenyl and cesium carbonate. The reaction gives the intermediate, 2) the intermediate is deprotected under the action of trifluoroacetic acid to obtain the compound 4I;

Step i: Compound 4I is reacted with an acid chloride R ₄ COCl to obtain a compound 4J;

Step j: Compound 4J is reacted with R ₅ I under sodium hydride to obtain compound 4K.

In Reaction Schemes 1 to 4, R _{1 -} R ₄ , L and X are the same as defined above.

Reaction route five:

Step a: compound 5A and amine R ₄ H by reductive amination reaction to obtain compound 5B;

Step b: compound 5B is reacted with different amines R ₃ NH ₂ to obtain compound 5C;

Step c: compound 5C is reacted with tin dichloride dihydrate and concentrated hydrochloric acid to obtain compound 5D;

反应得到中间体，2)中间体在N,N-二异丙基乙胺条件下通过分子内亲核反应得到化合物5E；Step d: 1) Compound 5D with a different 2-bromoalkanoyl bromide

The reaction gives an intermediate, 2) the intermediate is obtained by intramolecular nucleophilic reaction under N,N-diisopropylethylamine to obtain compound 5E;

Step e: Compound 5E is reacted with R ₁ I under sodium hydride to give compound 5F.

In Reaction Scheme 5, R ₁ -R ₄ and X are as described above, and R ₄ contains an N atom.

Preliminary studies indicate that the following diseases, disorders and/or disorders are mediated by bromodomain recognition protein inhibitors: hematological malignancies, midline cancer, and inflammation.

Therefore, the compound represented by the general formula (I) of the present invention, and stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates and crystal forms thereof, are suitable for the treatment of mitochondrial recognition protein inhibitors. Disease, condition and/or dysfunction.

The present invention provides a method of treating a disease, condition and/or dysfunction mediated by a bromodomain recognition protein inhibitor, the method comprising administering to a patient an effective amount of a compound represented by the general formula (I), Stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates, and crystalline forms.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the formula (I), and stereoisomers thereof, pharmaceutically acceptable salts, prodrugs, solvates, hydrates and crystal forms thereof One or more of the following, together with at least one excipient, diluent or carrier.

Further, the compound represented by the general formula (I) of the present invention, and stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates or crystal forms thereof can be used in monotherapy or combination therapy. When used in union In the course of treatment, the compound represented by the formula (I) of the present invention, and stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates and crystal forms thereof are usually combined with a therapy based on small molecule compounds, radiation, and antibodies. (eg Herceptin and Rituxima) are used together with anti-cancer vaccination, gene therapy, cell therapy, hormone therapy or cytokine therapy.

A typical formulation is prepared by mixing the compound of the formula (I) of the present invention with a carrier, diluent or excipient. Suitable carriers, diluents or excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oil, A substance such as a solvent or water. The particular carrier, diluent or excipient used will depend on the mode and purpose for which the compound of the invention is applied. The solvent is generally selected based on a solvent which is considered safely (GRAS) to a mammal in the art. In general, safe solvents are non-toxic aqueous solvents such as water, as well as other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include mixtures of one or more of water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and the like. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, a coloring agent, sweetener, flavoring agent, flavoring agent or other known additive to provide a beautiful presentation of the drug (ie, a compound of the invention or a pharmaceutical composition thereof), or to assist the pharmaceutical product (also That is, the manufacture of drugs.

This formulation can be prepared using conventional dissolution mixing procedures. For example, in the presence of one or more of the above-mentioned excipients, a block-like drug substance (i.e., a compound represented by the formula (I) of the present invention or a stabilized form of the compound (e.g., with a ring) The dextrin derivative or a complex of other known complexing agents) is dissolved in a suitable solvent. The compound represented by the general formula (I) of the present invention is typically formulated into a pharmaceutical dosage form to provide easy control of the drug. The dose, and provides the patient with an easy to handle product.

In accordance with the methods of the invention, a compound of the invention or a combination of a compound of the invention and at least one other agent (referred to herein as "combination") is preferably administered in the form of a pharmaceutical composition. Thus, the compounds or combinations of the invention can be administered orally, rectally, transdermally, parenterally (e.g., intravenously, intramuscularly, or subcutaneously) intracerebrocerally, intravaginally, intraperitoneally, intravesically, locally (e.g., Powder, ointment or droplets, buccal or nasal dosage forms, administered separately or together to a patient.

Compositions suitable for parenteral injection, generally comprising a pharmaceutically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and for reconstitution into a sterile injectable solution or dispersion Bacteria powder. Suitable aqueous or non-aqueous vehicles or diluents (including solvents and carriers), including mixtures of one or more of water, ethanol, polyol (propylene glycol, polyethylene glycol, glycerol, etc.); vegetable oils (such as olives) Oil); and injectable organic esters such as ethyl oleate. For example, by using one A coating such as lecithin, in the case of a dispersion, maintains the desired particle size, or maintains a suitable fluidity by using a surfactant.

These compositions may also contain excipients such as preservatives, wetting agents, emulsifying agents and dispersing agents. Microbial contamination of the composition can be avoided by various bactericides and fungicides, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. These compositions may also include isotonic agents such as sugars, sodium chloride, and the like. The absorption of the injectable pharmaceutical compositions can also be extended by the use of agents which delay absorption, such as aluminum monostearate and gelatin.

Solid dosage forms for oral administration can include capsules, tablets, powders, and granules. In a solid dosage form, the compound or combination of the invention is admixed with at least one inert excipient, diluent or carrier. Suitable excipients, diluents or carriers include those such as sodium citrate or dicalcium phosphate, or (a) fillers or extenders (such as starch, lactose, sucrose, mannitol, silicic acid, etc.); b) binders (such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc.); (c) wetting agents (such as glycerin, etc.); (d) disintegrants (such as Agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicate, sodium carbonate, etc.); (e) solution blockers (such as paraffin, etc.); (f) accelerated absorbers (such as quaternary ammonium compounds) ()) wetting agents (such as acetyl alcohol, glyceryl monostearate, etc.); (h) adsorbents (such as kaolin, bentonite, etc.); and / or i) lubricants (such as talc, stearin) Calcium acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc.). In the case of capsules and tablets, the dosage form may also include a buffer. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose as well as high molecular weight polyethylene glycols and the like as excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compound of the present invention or a composition thereof, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, acetic acid Ethyl ester, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide; oils (such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.) Glycerin; tetrahydrofurfuryl alcohol; fatty acid ester of polyethylene glycol and sorbitan; or a mixture of several of these.

In addition to these inert diluents, the compositions may also include excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and flavoring agents.

In the case of a suspension, in addition to the compound or combination of the present invention, a carrier such as a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystals may be further included. Cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or a mixture of several of these.

Compositions for rectal or vaginal administration preferably include suppositories, which may be prepared by admixing a compound or combination of the present invention with a suitable non-irritating excipient or carrier, such as a cocoa butter, Ethylene glycol or suppository wax, which is solid at room temperature and liquid at body temperature, and thus can be melted in the rectum or vagina to release the active compound.

The dosage form of the compound of the present invention and the compound of the present invention in combination with a blood cancer or an inflammatory drug for topical administration may include ointments, powders, sprays, and inhalants. The medicament can be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent or carrier, and any preservative, buffer or propellant required. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be encompassed within the scope of the invention.

It is known that the compounds (or compositions) of the invention can be placed in drinking water whereby a therapeutic dose of the compound is ingested along with the daily water supply. The compound can be metered directly into the drinking water, preferably in the form of a liquid water-soluble concentrate such as an aqueous solution of a water-soluble salt.

A paste formulation can be prepared by dispersing the drug in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.

A pill containing an effective amount of a compound, pharmaceutical composition or combination of the present invention may be prepared by mixing a compound or composition of the present invention with a diluent such as a carbow wax, palm wax or the like; A lubricant such as magnesium stearate or calcium stearate to enhance the pelleting process.

The present invention also provides the compound represented by the general formula (I), and a stereoisomer, a pharmaceutically acceptable salt, a prodrug, a solvate, a hydrate or a crystal form thereof as a selectivity of a bromodomain recognition protein. Uses of inhibitors, and in the preparation of a medicament for treating a disease associated with recognition of a protein by a bromodomain. Related diseases mediated by bromodomain recognition proteins include, but are not limited to, hematological malignancies, midline cancer, and diseases such as inflammation.

The present invention also provides a compound represented by the formula (I), and a stereoisomer, a pharmaceutically acceptable salt, a prodrug, a solvate, a hydrate or a crystal form thereof for the preparation of a hematological malignancy, a midline cancer, and The use of drugs for diseases such as inflammation.

The present invention also provides a compound represented by the general formula (I), and a stereoisomer, a pharmaceutically acceptable salt thereof, a prodrug, a solvate thereof, for treating a related disease mediated by a bromodomain recognition protein, Hydrate or crystalline form.

The invention also encompasses isotopically-labeled compounds of the invention, in addition to 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 common in nature. The same is true. Examples of isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as: ² hydrogen, ³ hydrogen, ¹¹ carbon, ¹³ carbon, ¹⁴ carbon, respectively. , ¹³ nitrogen, ¹⁵ nitrogen, ¹⁵ oxygen, ¹⁷ oxygen, ¹⁸ oxygen, ³¹ phosphorus, ³² phosphorus, ³⁵ sulfur, ¹⁸ fluorine, ¹²³ iodine, ¹²⁵ iodine and ³⁶ chlorine.

Certain isotopically-labeled compounds of the invention (such as those labeled with ³ H and ¹⁴ C) are used in compound and/or substrate tissue distribution assays. Deuterated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred because they are easy to prepare and detect. Moreover, substitution of heavier isotopes such as deuterium (ie, ² H) may provide certain therapeutic advantages resulting from greater metabolic stability (eg, increased in vivo half-life or reduced dosage requirements) and, in some cases, may be Preferred. Positron emission isotopes such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁸ F are used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the invention can generally be prepared by replacing the non-isotopically labeled reagent with an isotopically labeled reagent, following procedures similar to those disclosed in the Schemes and/or the Examples below.

DRAWINGS

Figure 1 is a schematic diagram of the gene tree of a human bromodomain protein.

2A is a design of a selective BDR4 inhibitor from a dual inhibitor of PLK-BRD4; FIG. 2B is a binding mode of BI2536 to BRD4; and FIG. 2C is a mode of binding of compound 8 to BRD4.

detailed description

Without further elaboration, it is believed that the invention may The following examples are provided to further illustrate the invention and are not intended to limit the scope of the invention in any way.

Starting materials can be obtained commercially, or by methods known in the art, or prepared according to the methods described herein.

Rf 75快速制备色谱仪，载体采用青岛海洋化工厂的200-300目硅胶。The structure of the compound is determined by nuclear magnetic resonance ( ¹ H-NMR) and/or mass spectrometry (MS). The NMR measurement was carried out by a Varian company's Mercury-400 NMR spectrometer, and the solvent was deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), deuterated dimethyl sulfoxide (DMSO-d ₆ ) or deuterated. Acetonitrile (CD ₃ CN), TMS is an internal standard. The measurement of MS was carried out using a Thermo Finnigan LCQ-Deca XP type (ESI) liquid chromatography-mass spectrometer. Separation and purification of the product by column chromatography using ISCO

Rf 75 rapid preparation chromatograph, the carrier uses 200-300 mesh silica gel from Qingdao Ocean Chemical Plant.

Preparation examples:

Example 1

Reagents and conditions: a) (R)-2-aminobutyric acid, potassium carbonate, ethanol, water, 80 ° C, 3 hours; b) tin dichloride dihydrate, ethanol, concentrated hydrochloric acid, 80 ° C, 3 hours; ) 0 ° C, sodium hydride, 30 minutes, methyl iodide, room temperature, 2 hours; d) p-toluenesulfonamide, allyl palladium chloride dimer, tBuXPhos, potassium carbonate, 2-methyltetrahydrofuran, 80 ° C, 24 hour.

a) Compound A (2 g, 9.09 mmol) and (R)-2-aminobutyric acid (0.937 g, 9.09 mmol) were dissolved in 10 mL of ethanol, then 6N aqueous potassium carbonate solution (2.51 g, 18.18 mmol), refluxed at 80 ° C After 3 hours, the reaction was monitored by TLC. After the reaction was completed, the pH was adjusted to 7-8 with dilute hydrochloric acid, and the solvent was evaporated to ethyl ether (20 mL*2) and 20 mL of water, and the organic layer was combined and re-extracted with 40 mL of brine. The organic phase was dried over anhydrous sodium sulfate and the organic layer was evaporated to dryness to give 2.7 g of white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.41 - 8.32 (m, 1 H), 8.07 (dd, J = 9.2, 0..9 Hz, 1H), 6.93-6.89 (m, 1H), 6.84 (ddd, J = 9.1, 1.9, 0.9 Hz, 1H), 4.24 (q, J = 6.5 Hz, 1H), 2.20 - 1.97 (m, 2H), 1.09 (t, J = 7.4 Hz, 3H).

b) Compound B (1.5 g, 4.95 mmol) was dissolved in 15 mL of ethanol, and then a solution of tin dichloride dihydrate (4.47 g, 19.79 mmol) dissolved in 5 mL of ethanol and 1.0 mL of concentrated hydrochloric acid was added to the above solution, and refluxed at 80 ° C. After 3 hours, the reaction was monitored by TLC. After the reaction was completed, the pH was adjusted to 7-8 with 2N sodium hydroxide, filtered, and the filtrate was evaporated to dryness and extracted with ethyl acetate (20 mL*2) and 20 mL of water. 40 mL of water was back-extracted once, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness to yield 1.24 g of white solid C, yield 98.41%. _{^{1 H NMR (400MHz, CDCl 3}} ) δ8.78 (s, 1H), 6.90-6.78 (m, 2H), 6.60 (d, J = 8.1Hz, 1H), 4.06-3.97 (m, 1H), 3.87 ( Dd, J = 7.3, 5.1 Hz, 1H), 1.91-1.73 (m, 2H), 1.03 (dd, J = 8.1, 6.7 Hz, 3H).

c) Compound C (1.2 g, 4.70 mmol) was dissolved in 5 mL of N,N-dimethylformamide (DMF), cooled to 0 ° C, sodium hydride (0.452 g, 18.82 mmol), and stirred at 0 ° C for half an hour Methyl iodide (1.17 mL, 18.8 mmol) was added at 0 ° C, and then reacted at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction, pH was adjusted to 7-8 with dilute hydrochloric acid, and ethyl acetate (20mL*2) and The organic layer was extracted with aq.

d) Compound D (0.3 g, 1.06 mmol) and p-toluenesulfonamide (0.272 g, 1.59 mmol) and potassium carbonate (0.293 g, 2.12 mmol) were dissolved in 2 mL of 2-methyltetrahydrofuran and ventilated with nitrogen. Allyl palladium chloride dimer (8 mg, 0.021 mmol), tBuXPhos (9 mg, 0.021 mmol) was added, and the mixture was purged with nitrogen, then reacted at 80 ° C for 24 hours. The reaction was monitored by TLC. (10 mL*2) and 10 mL of water were extracted, and the organic layer was combined, and the organic layer was extracted with 20 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, and the organic phase was mixed with silica gel and purified by flash column using ethyl acetate / petroleum ether = A gradient of 0 to 30% eluted to give 0.2 g of a white solid E, Compound 1, yield 50.63%. MS (ESI) [M + H ] +: 374.18; 1 H NMR (400MHz, CDCl 3) δ7.67 (d, J = 8.3Hz, 2H), 7.37 (s, 1H), 7.20 (d, J = 8.1 Hz, 2H), 6.68 (d, J = 8.5 Hz, 1H), 6.49 (dd, J = 8.4, 2.3 Hz, 1H), 6.40 (d, J = 2.3 Hz, 1H), 3.83 (dd, J = 7.5 , 5.1 Hz, 1H), 3.29 (s, 3H), 2.81 (s, 3H), 2.35 (s, 3H), 1.68 - 1.56 (m, 1H), 1.53 - 1.43 (m, 1H), 0.78 (t, J=7.5Hz, 3H).

Example 2

The compound of Example 2 was prepared in the same manner as in Example 1 except that (S)-2-aminopropionic acid was used instead of (R)-2-aminobutanoic acid in the step.

MS (ESI) [M+H] ⁺ : 360.16. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (d, J = 8.3 Hz, 2H), 7.48 (s, 1H), 7.23 (d, J = 8.1 Hz, 2H), 6.74 (d, J = 8.5 Hz , 1H), 6.56 (dd, J = 8.5, 2.2 Hz, 1H), 6.45 (d, J = 2.2 Hz, 1H), 3.98 (q, J = 6.8 Hz, 1H), 3.31 (s, 3H), 2.76 (s, 3H), 2.38 (s, 3H), 1.07 (d, J = 6.8 Hz, 3H).

Example 3

Substituting (S)-2-aminopropionic acid for (R)-2-aminobutyric acid in step a; the same as in Example 1 except that o-chlorobenzenesulfonamide was substituted for p-toluenesulfonamide in step d The compound of Example 3 was prepared by the method.

MS (ESI) [M+H] ⁺ : 380.21. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.39 (s, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 5.9 Hz, 2H), 7.49 (t, J = 6.3 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 6.43 (s, 1H), 3.93 (d, J = 6.6 Hz, 1H), 3.15 (s, 3H), 2.66 (s, 3H), 0.88 (d, J = 6.5 Hz, 3H).

Example 4

The compound of Example 4 was prepared in the same manner as in Example 1 except that (S)-2-aminobutyric acid was used instead of (R)-2-aminobutyric acid in the step.

MS (ESI) [M+H] ⁺ : 374.16. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.66 (d, J = 8.2Hz, 2H), 7.20 (d, J = 8.2Hz, 3H), 6.69 (d, J = 8.4Hz, 1H), 6.48 (dd , J=8.4, 2.1 Hz, 1H), 6.39 (d, J=2.0 Hz, 1H), 3.83 (dd, J=7.5, 5.2 Hz, 1H), 3.30 (s, 3H), 2.81 (s, 3H) , 2.36 (s, 3H), 1.69 - 1.56 (m, 1H), 1.47 (dt, J = 21.6, 7.4 Hz, 1H), 0.79 (t, J = 7.5 Hz, 3H).

Example 5

The compound of Example 5 was prepared in the same manner as in Example 1 except that p-fluorobenzenesulfonamide was substituted for p-toluenesulfonamide in the step d.

MS (ESI) [M+H] ⁺ : 378.43. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 - 7.75 (m, 2H), 7.14 - 7.07 (m, 2H), 6.96 (s, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.45 ( Dd, J = 8.4, 2.3 Hz, 1H), 6.39 (d, J = 2.3 Hz, 1H), 3.86 (dd, J = 7.5, 5.1 Hz, 1H), 3.32 (s, 3H), 2.84 (s, 3H) ), 1.72 - 1.59 (m, 1H), 1.51 (dt, J = 13.9, 7.4 Hz, 1H), 0.81 (t, J = 7.5 Hz, 3H).

Example 6

Substituting (S)-2-aminobutyric acid for (R)-2-aminobutyric acid in step a; using the same as in Example 1 except that fluorobenzenesulfonamide was substituted for p-toluenesulfonamide in step d The compound of Example 6 was prepared by the method.

MS (ESI) [M+H] ⁺ : 378. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 - 7.75 (m, 2H), 7.14 - 7.06 (m, 2H), 7.04 (s, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.45 ( Dd, J = 8.4, 2.3 Hz, 1H), 6.39 (d, J = 2.3 Hz, 1H), 3.86 (dd, J = 7.5, 5.1 Hz, 1H), 3.32 (s, 3H), 2.84 (s, 3H) ), 1.66 (ddd, J = 14.0, 7.5, 5.1 Hz, 1H), 1.51 (dt, J = 14.0, 7.4 Hz, 1H), 0.81 (t, J = 7.5 Hz, 3H).

Example 7

The compound of Example 7 was prepared in the same manner as in Example 1 except that the (R)-2-aminobutyric acid was replaced by D-leucine in the step a.

MS (ESI) [M+H] ⁺ : 402. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.66 (d, J = 7.9Hz, 2H), 7.18 (t, J = 6.4Hz, 2H), 6.70 (d, J = 6.6Hz, 1H), 6.56-6.48 (m, 1H), 6.40 (s, 1H), 3.87 (t, J = 7.1 Hz, 1H), 3.30 - 3.22 (m, 3H), 2.78 (d, J = 2.8 Hz, 3H), 2.34 (d, J = 6.1 Hz, 3H), 2.06 - 1.99 (m, 2H), 1.64 - 1.51 (m, 1H), 0.86 (ddd, J = 25.6, 8.0, 2.9 Hz, 6H).

Examples 8 and 9

Reagents and conditions: a) cyclopropylamine, 1,2-dichloroethane, refluxed at 80 ° C for 12 hours; b) iron powder, ammonium chloride solution, ethanol, 80 ° C reaction for 1 hour; c) 1.2-bromopropionyl bromide , N,N-diisopropylethylamine (DIPEA), dichloromethane, reaction at room temperature for 2 hours; 2. acetonitrile, DIPEA, reaction at 80 ° C overnight; d) sodium hydride, N, N-dimethylformamide ( DMF), methyl iodide, reacted at room temperature for 1 hour; e) p-toluenesulfonamide, allyl palladium chloride dimer, 2-di-tert-butylphosphino-2', 4', 6'-triisopropyl Biphenyl (tBuXPhos), potassium carbonate, 2-methyltetrahydrofuran, reacted at 80 ° C for 24 hours; f) cesium carbonate, tert-butyl carbamate, Pd(OAc) ₂ , 2-dicyclohexylphosphine-2', 4', 6'-Triisopropylbiphenyl (Xphos), dioxane, reacted at 100 ° C overnight; g) p-methylbenzoyl chloride, triethylamine, dichloromethane, and allowed to react at room temperature overnight.

Preparation of the compound of Example 8:

a) Compound A (10 g, 45.45 mmol) was dissolved in 30 mL of 1 ,2-dichloroethane, then cyclopropylamine (6.29 mL, 90.91 mmol) was added, then refluxed at 80 ° C for 12 hours, and the reaction was monitored by TLC. The solvent was extracted with methylene chloride (40 mL*2) and 40 mL of water. The organic layer was combined, and the organic layer was re-extracted with 80 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate. 87.33%. _{^{1 H NMR (400MHz, CDCl 3}} ) δ8.05 (s, 1H), 7.96 (d, J = 9.1Hz, 1H), 7.45 (d, J = 2.0Hz, 1H), 6.77 (dd, J = 9.1, 2.0 Hz, 1H), 2.60–2.50 (m, 1H), 0.97–0.88 (m, 2H), 0.69–0.61 (m, 2H).

b) Compound B (10 g, 38.90 mmol) was dissolved in 25 mL of ethanol, a solution of ammonium chloride (10.41 g, 194.55 mmol) in water (10 mL) was added, then iron powder (10.89 g, 194.55 mmol) was added and reacted at 80 ° C The reaction was monitored by TLC. After the reaction was completed, the iron powder was filtered off with celite, extracted with ethyl acetate (40mL*2) and 40mL of water, and the organic layer was combined and re-extracted with 80 mL of saturated brine. Dry over sodium sulfate and dry the organic phase to give 5.2 g of a red oily liquid C, yield 58.89%. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.13 (d, J = 2.1Hz, 1H), 6.79 (dd, J = 8.1,2.1Hz, 1H), 6.53 (d, J = 8.1Hz, 1H), 3.59 –3.03 (m, 2H), 2.45–2.32 (m, 1H), 0.76 (q, J = 6.4 Hz, 2H), 0.57–0.44 (m, 2H).

c) Compound C (5.2 g, 22.90 mmol) was dissolved in EtOAc EtOAc (EtOAc m. After the reaction was carried out for 2 hours at room temperature, the reaction was monitored by EtOAc (EtOAc) (EtOAc) The organic phase was evaporated to dryness to give the title compound, which was dissolved in 20 mL of acetonitrile, and then added to 8 mM EtOAc, and then reacted at 80 ° C overnight. The reaction was monitored by TLC. After the reaction, the solvent was evaporated to dryness with dichloromethane (40 mL*2) and 40 mL of water The organic layer was extracted, and the organic layer was extracted with a saturated aqueous solution of 80 mL. The organic phase was dried over anhydrous sodium sulfate, and the organic phase was purified by silica gel chromatography, eluting with ethyl acetate / petroleum ether = 0 to 30% gradient. 2 g of a white solid D were obtained in a yield of 31.06%. MS (ESI) [M + H ] +: 281.17; 1 H NMR (400MHz, CDCl 3) δ9.10 (s, 1H), 7.18 (d, J = 1.8Hz, 1H), 6.91 (dd, J = 8.2 , 1.9 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 4.04 (q, J = 6.8 Hz, 1H), 2.45 - 2.35 (m, 1H), 1.24 (d, J = 6.9 Hz, 3H) ), 1.00 (td, J = 10.5, 6.2 Hz, 1H), 0.84 - 0.75 (m, 1H), 0.63 (dt, J = 10.2, 5.1 Hz, 1H), 0.56 (ddd, J = 14.2, 8.1, 4.1) Hz, 1H).

d) Compound D (2 g, 7.11 mmol) was dissolved in 8 mL of DMF, cooled to 0 ° C, sodium hydride (0.512 g, 21.34 mmol) was added, and the reaction was stirred at 0 ° C for half an hour, then iodomethane (0.67 mL, 10.67 mmol) was added, then The reaction was carried out for 1 hour at room temperature, and the reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to 0 ° C, and then diluted with hydrochloric acid to adjust pH to 7-8, and then extracted with dichloromethane (20 mL*2) and 20 mL of water. 40 mL of water was back-extracted once, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was combined with silica gel and purified by flash column, eluting with ethyl acetate / petroleum ether = 0~25% gradient to give 1.8 g of white solid E. 85.71%. MS (ESI) [M + H ] +: 295.15; 1 H NMR (400MHz, CDCl 3) δ7.14 (d, J = 2.2Hz, 1H), 6.91 (dd, J = 8.5,2.1Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 4.04 (p, J = 7.0 Hz, 1H), 3.24 (s, 3H), 2.36 - 2.27 (m, 1H), 1.10 (d, J = 6.9 Hz, 3H) ), 0.91 (dtd, J = 10.8, 6.3, 4.7 Hz, 1H), 0.79 - 0.68 (m, 1H), 0.60 - 0.51 (m, 1H), 0.46 (ddt, J = 10.4, 6.5, 4.1 Hz, 1H) ).

e) Compound E (0.2 g, 0.68 mmol) and p-toluenesulfonamide (0.174 g, 1.02 mmol) and potassium carbonate (0.187 g, 1.36 mmol) were dissolved in 2 mL of 2-methyltetrahydrofuran and ventilated with nitrogen. Allyl palladium chloride dimer (6 mg, 0.014 mmol), tBuXPhos (6 mg, 0.014 mmol) was added, and then ventilated with nitrogen, then reacted at 80 ° C for 24 hours, and the reaction was monitored by TLC. (10 mL*2) and 10 mL of water were extracted, and the organic layer was combined, and the organic layer was extracted with 20 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, and the organic phase was mixed with silica gel and purified by flash column using ethyl acetate / petroleum ether = A gradient of 0 to 30% eluted to give 0.15 g of white solid F, Compound 8, yield 57.47%. MS (ESI) [M+H] ⁺ : 386.22; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (s, 1H), 7.71 (d, J = 7.5 Hz, 2H), 7.21. (d, J = 7.4 Hz, 2H), 6.91 (s, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 4.08 (d, J = 6.2 Hz, 1H), 3.27 ( s, 3H), 2.36 (s, 3H), 2.27 (s, 1H), 1.10 (d, J = 6.2 Hz, 3H), 0.83 (s, 1H), 0.73 (s, 1H), 0.55 (s, 1H) ), 0.30 (s, 1H).

Preparation of the compound of Example 9:

The preparation methods of steps a) to d) are the same as those used in the preparation of Example 8,

f) Compound E (0.2 g, 0.68 mmol), cesium carbonate (0.314 g, 0.96 mmol) and tert-butyl carbamate (0.12 g, 1.03 mmol) dissolved in 2 mL of dioxane, ventilated with nitrogen, ventilated Then Pd(OAc) ₂ (0.046 g, 0.068 mmol) and XPhos (0.052 g, 0.11 mmol) were added, and the mixture was purged with nitrogen. After the exchange, the reaction was carried out at 100 ° C overnight, monitored by TLC plate, and ethyl acetate was used after the reaction. (10 mL*2) and 10 mL of water were extracted, and the organic layer was combined, and the organic layer was extracted with 20 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, and the organic phase was mixed with silica gel and purified by flash column using ethyl acetate / petroleum ether = Gradient elution from 0 to 30% gave 0.16 g of a yellow solid. The yellow solid was dissolved in 3 mL of dry methylene chloride, cooled to 0 ° C, 1 mL of trifluoroacetic acid was added, and then reacted at room temperature for 2 hours, and monitored by TLC plate. After the reaction, the mixture was cooled to 0 ° C, and the pH was adjusted to 7-8 with saturated NaHCO ₃ , and then extracted with ethyl acetate (10 mL*2) and 10 mL of water. The organic layer was combined and re-extracted once with 20 mL of saturated brine. Drying with sodium sulfate and mixing with organic phase silica gel by flash column chromatography using ethyl acetate/petroleum ether = 0 to 35% gradient Elution gave 0.1 g of a white solid G with a total yield of 63.69%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.18 (d, J = 2.2 Hz, 1H), 6.97 (dd, J = 8.5, 2.2 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 4.08 (q, J = 6.8 Hz, 1H), 3.29 (s, 3H), 2.42 - 2.32 (m, 1H), 1.15 (d, J = 6.9 Hz, 3H), 1.00 - 0.92 (m, 1H), 0.81 - 0.74 (m, 1H), 0.65–0.57 (m, 1H), 0.55–0.47 (m, 1H).

g) Compound G (0.1 g, 0.43 mmol) was dissolved in dichloromethane (2 mL), p-methylbenzoic acid chloride (0.075mL, 0.56mmol) and triethylamine (0.18mL, 1.29mmol). After the reaction, the mixture was extracted with dichloromethane (10 mL*2) and 10 mL of water. The organic layer was combined and extracted with 20 mL of saturated brine. Purification by flash column chromatography eluting with EtOAc EtOAc EtOAc (EtOAc) MS (ESI) [M+H] ⁺ : 350.23; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.79 (s, 1H), 7.77 (s, 1H), 7.60 (s, 1H) ), 7.28 (s, 1H), 7.26 (s, 1H), 7.08 (dd, J = 8.5, 2.2 Hz, 1H), 6.87 (d, J = 8.6 Hz, 1H), 4.10 (q, J = 6.8 Hz) , 1H), 3.33 (s, 3H), 2.45 - 2.37 (m, 4H), 1.16 (d, J = 6.8 Hz, 3H), 1.04 - 0.96 (m, 1H), 0.81 - 0.72 (m, 1H), 0.64–0.51 (m, 2H).

Example 10

The compound of Example 10 was prepared in the same manner as in Example 8 except that the cyclopentylamine was replaced with cyclopentylamine in the step a;

MS (ESI) [M+H] ⁺ : 400.18. ^{1 H NMR (400MHz, DMSO-} d 6) δ10.29 (s, 1H), 9.77 (s, 1H), 7.55 (d, J = 8.3Hz, 2H), 7.31 (d, J = 8.1Hz, 2H) , 6.63 (d, J = 8.2 Hz, 1H), 6.45 (dd, J = 8.2, 2.1 Hz, 1H), 6.43 (s, 1H), 3.83 (q, J = 6.7 Hz, 1H), 3.50 (p, J=7.4 Hz, 1H), 2.31 (s, 3H), 1.88–1.72 (m, 2H), 1.70–1.59 (m, 2H), 1.57–1.45 (m, 3H), 1.39–1.27 (m, 1H) , 0.88 (d, J = 6.7 Hz, 3H).

Example 11

The compound of Example 11 was prepared in the same manner as in Example 8 except that the cyclopentylamine was used instead of the cyclopropylamine in the step a.

MS (ESI) [M+H] ⁺ : 414.17. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.3 Hz, 2H), 7.21. (d, J = 8.0 Hz, 2H), 7.08 (s, 1H), 6.75 (d, J = 8.4 Hz) , 1H), 6.57 (d, J = 2.2 Hz, 1H), 6.54 (dd, J = 8.4, 2.3 Hz, 1H), 4.15 (q, J = 6.8 Hz, 1H), 3.59 (p, J = 7.3 Hz) , 1H), 3.29 (s, 3H), 2.36 (s, 3H), 1.96 - 1.84 (m, 2H), 1.72 (dd, J = 11.4, 6.1 Hz, 1H), 1.66 - 1.50 (m, 4H), 1.46–1.34 (m, 1H), 0.97 (d, J = 6.8 Hz, 3H).

Example 12

The compound of Example 12 was prepared in the same manner as in Example 8 except that the cyclopentylamine was replaced by cyclopentylamine in the step a;

MS (ESI) [M+H] ⁺ : 428.21. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.64 (d, J = 8.3Hz, 2H), 7.22 (d, J = 8.4Hz, 2H), 6.78 (d, J = 8.5Hz, 1H), 6.76 (s , 1H), 6.54 (d, J = 2.3 Hz, 1H), 6.51 (dd, J = 8.4, 2.3 Hz, 1H), 4.10 (q, J = 6.7 Hz, 1H), 4.02 (dq, J = 14.4, 7.3 Hz, 1H), 3.78 (dq, J = 14.1, 7.0 Hz, 1H), 3.59 (p, J = 7.3 Hz, 1H), 2.37 (s, 3H), 1.95 - 1.83 (m, 2H), 1.78 - 1.69 (m, 1H), 1.69–1.63 (m, 2H), 1.61–1.55 (m, 2H), 1.42 (dt, J = 16.1, 6.9 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H) , 0.96 (d, J = 6.8 Hz, 3H).

Example 13

The compound of Example 13 was prepared in the same manner as in Example 8 except that isopropylamine was used instead of cyclopropylamine in the step.

MS (ESI) [M+H] ⁺ : 388. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.66 (d, J = 8.3Hz, 2H), 7.51 (s, 1H), 7.20 (d, J = 8.0Hz, 2H), 6.74 (d, J = 8.5Hz , 1H), 6.60 (d, J = 2.2 Hz, 1H), 6.55 (dd, J = 8.5, 2.2 Hz, 1H), 4.18 - 4.13 (m, 1H), 3.69 (dq, J = 13.3, 6.6 Hz, 1H), 3.28 (s, 3H), 2.35 (s, 3H), 1.17 (dd, J = 8.0, 6.8 Hz, 6H), 1.01 (d, J = 6.8 Hz, 3H).

Example 14

The compound of Example 14 was prepared in the same manner as in Example 8 except that 2-methylpropan-1-amine was used instead of cyclopropylamine in the step.

MS (ESI) [M+H] ⁺ : 402.21. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.67 (d, J = 8.2Hz, 2H), 7.48 (s, 1H), 7.21 (d, J = 8.1Hz, 2H), 6.73 (d, J = 8.5Hz , 1H), 6.53 (dd, J = 8.5, 2.1 Hz, 1H), 6.39 (d, J = 2.0 Hz, 1H), 3.95 (q, J = 6.8 Hz, 1H), 3.30 (s, 3H), 3.07 (dd, J=13.7, 5.5 Hz, 1H), 2.49 (dd, J=13.7, 8.8 Hz, 1H), 2.36 (s, 3H), 1.81–1.65 (m, 1H), 1.01 (d, J=6.8) Hz, 3H), 0.86 (dd, J = 8.3, 6.8 Hz, 6H).

Example 15

The compound of Example 15 was prepared in the same manner as in Example 8 except that 2-methoxyethylamine was used instead of cyclopropylamine in the step.

MS (ESI) [M+H] ⁺ : 404. _{^{1 H NMR (400MHz, CDCl 3}} ) δ8.18 (s, 1H), 7.62 (d, J = 8.0Hz, 2H), 7.13 (d, J = 7.9Hz, 2H), 6.68 (d, J = 8.5Hz , 1H), 6.56 (d, J = 8.5 Hz, 1H), 6.51 (s, 1H), 4.05 (q, J = 6.5 Hz, 1H), 3.47 - 3.40 (m, 2H), 3.40 - 3.32 (m, 1H), 3.24 (s, 3H), 3.20 (d, J = 6.1 Hz, 3H), 3.10 (dd, J = 13.2, 5.7 Hz, 1H), 2.28 (s, 3H), 0.99 (d, J = 6.7) Hz, 3H).

Example 16

The compound of Example 16 was prepared in the same manner as in Example 8 except that 2-morpholine ethane-1-amine was used instead of cyclopropylamine in the step.

MS (ESI) [M+H] ⁺ : 459. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.78 (d, J = 8.5 Hz, 1H), 6.69 (s) , 1H), 6.54 (d, J = 2.3 Hz, 1H), 6.50 (dd, J = 8.4, 2.3 Hz, 1H), 4.10 (q, J = 6.7 Hz, 1H), 4.02 (dq, J = 14.3, 7.1 Hz, 1H), 3.78 (dq, J = 14.3, 7.2 Hz, 1H), 3.58 (p, J = 7.3 Hz, 1H), 2.38 (s, 3H), 1.95 - 1.83 (m, 2H), 1.78 - 1.69 (m, 1H), 1.66 - 1.50 (m, 5H), 1.42 (ddd, J = 16.0, 13.4, 6.9 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H).

Example 17

The compound of Example 17 was prepared in the same manner as in Example 8 except that (tetrahydrofuran-2-yl)methylamine was used instead of cyclopropylamine in the step.

MS (ESI) [M+H] ⁺ : 430.21. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.64 (dd, J = 8.3,6.6Hz, 2H), 7.29 (d, J = 3.0Hz, 1H), 7.20 (d, J = 8.1Hz, 2H), 6.72 (t, J = 8.1 Hz, 1H), 6.57 - 6.50 (m, 1H), 6.47 (dd, J = 8.4, 2.2 Hz, 1H), 4.16 (q, J = 6.8 Hz, 1H), 4.03 - 3.95 ( m, 1H), 3.85 (ddd, J = 15.2, 11.0, 6.9 Hz, 1H), 3.75 - 3.68 (m, 1H), 3.34 (dd, J = 14.2, 3.3 Hz, 1H), 3.27 (d, J = 3.7 Hz, 3H), 2.99 - 2.90 (m, 1H), 2.36 (s, 3H), 2.00 (ddd, J = 10.3, 8.2, 5.1 Hz, 1H), 1.91 - 1.79 (m, 2H), 1.60 - 1.46 (m, 1H), 1.05 (dd, J = 6.8, 2.6 Hz, 3H).

Example 18

The compound of Example 18 was prepared in the same manner as in Example 8 except that (2-methoxyphenyl)methylamine was used instead of cyclopropylamine in the step.

MS (ESI) [M+H] ⁺ : 466.07. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.47 (d, J = 8.3Hz, 2H), 7.39 (s, 1H), 7.26-7.20 (m, 1H), 7.18 (d, J = 7.5Hz, 1H) , 7.11 (d, J = 8.1 Hz, 2H), 6.88 (d, J = 8.1 Hz, 1H), 6.84 (t, J = 7.5 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 6.55 (d, J = 2.2 Hz, 1H), 6.46 (dd, J = 8.5, 2.2 Hz, 1H), 4.45 (d, J = 15.4 Hz, 1H), 4.10 - 4.01 (m, 2H), 3.86 (s, 3H), 3.28 (s, 3H), 2.33 (s, 3H), 1.11 (d, J = 6.8 Hz, 3H).

Example 19

The compound of Example 19 was prepared in the same manner as in Example 8 except that p-methoxybenzenesulfonamide was substituted for p-toluenesulfonamide in the step.

MS (ESI) [M+H] ⁺ : 402. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74 - 7.67 (m, 2H), 6.92 - 6.87 (m, 2H), 6.84 (d, J = 2.3 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 6.66 (s, 1H), 6.53 (dd, J = 8.5, 2.4 Hz, 1H), 4.06 (q, J = 6.9 Hz, 1H), 3.83 (s, 3H), 3.27 (s, 3H), 2.28 (td, J = 6.6, 3.3 Hz, 1H), 1.12 (d, J = 6.8 Hz, 3H), 0.86 (dt, J = 10.9, 6.3 Hz, 1H), 0.80 - 0.70 (m, 1H), 0.58 (dt, J = 10.3, 4.5 Hz, 1H), 0.36 (dt, J = 10.3, 5.2 Hz, 1H).

Example 20

Reagents and conditions: a) thionyl chloride (SOCl ₂ ), methanol, reflux at 12 ° C for 12 hours; b) cyclopropylamine, 1,2-dichloroethane, reflux at 80 ° C for 12 hours; c) iron powder, chlorination Ammonium solution, ethanol, reacted at 80 ° C for 1 hour; d) 1.2-bromopropionyl bromide, N,N-diisopropylethylamine (DIPEA), dichloromethane, reacted at room temperature for 2 hours; 2. Acetonitrile, DIPEA, 80 °C reaction overnight; e) sodium hydride, N, N-dimethylformamide (DMF), methyl iodide, reaction at room temperature for 1 hour; f) lithium hydroxide, THF / H ₂ O, reaction at room temperature overnight; g) 2- (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA), N, N-dimethylformamide (DMF) was reacted overnight at room temperature.

a) Compound A (10g, 54.02mmol) was dissolved in 26mL of methanol was cooled to 0 deg.] C, was added SOCl ₂ (19.62mL, 270.11mmol), refluxed for 60 ℃ 12 hours and monitored by TLC plate, the solvent was evaporated after the reaction, was cooled to 0 deg.] C, saturated with NaHCO ₃ adjusted to pH 7-8, then extracted with dichloromethane (40mL * 2) and 40mL of water, the organic layers were combined, back extracted with 80mL saturated brine once, the organic phase dried over anhydrous sodium Drying and drying the organic phase gave 10.2 g of pale yellow solid B. _{^{1 H NMR (400MHz, CDCl 3}} ) δ8.11 (t, J = 7.8Hz, 1H), 7.97 (s, 1H), 7.94 (d, J = 3.0Hz, 1H), 3.98 (s, 3H).

b) Compound B (10 g, 50.25 mmol) was dissolved in 50 mL of 1,2-dichloroethane, cyclopropylamine (6.95 mL, 100.50 mmol) was added, then refluxed at 80 ° C for 12 hours, monitored by TLC plate, steamed after the reaction. The organic solvent was extracted with dichloromethane (50 mL*2) and 50 mL of water. The organic layer was combined, and then extracted with 100 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and evaporated. The rate is 85.93%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.15 (d, J = 8.8 Hz, 1H), 8.03 (s, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.22 (dd, J = 8.8, 1.8 Hz, 1H), 3.89 (s, 3H), 2.68 (td, J = 6.6, 3.0 Hz, 1H), 0.94 - 0.84 (m, 2H), 0.70 - 0.60 (m, 2H).

c) Compound C (10 g, 42.33 mmol) was dissolved in 30 mL of ethanol, a solution of ammonium chloride (11.32 g, 211.65) in water (10 mL) was added, then iron powder (11.86 g, 211.67 mmol) was added and reacted at 80 ° C for 1 hour. The mixture was monitored by TLC. After the reaction was completed, the iron powder was filtered off with celite, extracted with ethyl acetate (40 mL*2) and 40 mL of water, and the organic layer was combined and extracted once with 80 mL of saturated brine. The sodium was dried and the organic phase was evaporated to dryness to give 5.2 g of yel. MS (ESI) [M+H] ⁺ : 207.

d) Compound D (5.2 g, 25.21 mmol) was dissolved in dry EtOAc EtOAc EtOAc (EtOAc:EtOAc. Then, it was reacted for 2 hours at room temperature, and it was monitored by a TLC plate. After the reaction, it was extracted with dichloromethane (40 mL*2) and 40 mL of water, and the organic layer was combined, and the organic layer was re-extracted with 80 mL of saturated brine. The intermediate was evaporated to dryness. The intermediate was dissolved in 20 mL of acetonitrile, then 9 m LDIPEA was added, and then reacted at 80 ° C overnight, and monitored by TLC plate. After completion of the reaction, the solvent was evaporated to dryness and extracted with dichloromethane (40 mL*2) and 40 mL of water. The organic layer was combined and re-extracted with 80 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, and the organic phase was purified by silica gel chromatography, eluting with ethyl acetate / petroleum ether = 0-40% gradient. 3 g of white solid E, yield 45.73%. MS (ESI) [M + H ] +: 261.20; 1 H NMR (400MHz, CDCl 3) δ8.61 (s, 1H), 7.75 (d, J = 1.6Hz, 1H), 7.53 (dd, J = 8.1 , 1.8 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 4.13 - 4.05 (m, 1H), 3.90 (s, 3H), 2.52 - 2.45 (m, 1H), 1.24 (d, J = 6.9 Hz, 3H), 1.10–1.02 (m, 1H), 0.86–0.78 (m, 1H), 0.68–0.60 (m, 1H), 0.60–0.51 (m, 1H).

e) Compound E (3 g, 11.53 mmol) was dissolved in 8 mL DMF, cooled to 0 ° C, sodium hydride (0.83 g, 34.58 mmol) was added, and the reaction was carried out at 0 ° C for half an hour, then iodomethane (1.08 mL, 17.30 mmol) was added, then The reaction was carried out for 1 hour at room temperature, monitored by TLC plate, cooled to 0 ° C after completion of the reaction, adjusted to pH 7-8 with dilute hydrochloric acid, then extracted with dichloromethane (20 mL*2) and 20 mL of water, and the organic layer was combined with saturated salt 40 mL of water was back-extracted once, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was combined with silica gel and purified by flash column chromatography eluting with ethyl acetate / petroleum ether = 0 to 25% to give 2.8 g of colorless transparent liquid F. The yield was 88.61%. MS (ESI) [M + H ] +: 275.18; 1 H NMR (400MHz, CDCl 3) δ7.75 (d, J = 1.9Hz, 1H), 7.59 (dd, J = 8.3,1.9Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.12 (q, J = 6.9 Hz, 1H), 3.89 (s, 3H), 3.35 (s, 3H), 2.48 - 2.42 (m, 1H), 1.15 (d) , J=6.9 Hz, 3H), 1.03 (dtd, J=9.7, 6.3, 4.6 Hz, 1H), 0.84–0.76 (m, 1H), 0.66–0.58 (m, 1H), 0.56–0.48 (m, 1H) ).

f) Compound F (2.8 g, 10.22 mmol) was dissolved in 15 mL of tetrahydrofuran and 5 mL of water, and lithium hydroxide monohydrate (1.72 g, 40.88 mmol) was added and then allowed to react overnight at room temperature, monitored by TLC plate, and pH adjusted with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL*2) and 20 mL of water. The organic layer was combined, and the organic layer was re-extracted with 40 mL of brine. The yield was 90.23%. MS (ESI) [M + H ] +: 261.08; 1 HNMR (400MHz, CDCl 3) δ7.83 (d, J = 1.9Hz, 1H), 7.70 (dd, J = 8.3,1.9Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.17 (q, J = 6.9 Hz, 1H), 3.39 (s, 3H), 2.55 - 2.43 (m, 1H), 1.19 (d, J = 6.9 Hz, 3H) , 1.06 (tt, J = 11.1, 5.4 Hz, 1H), 0.88 - 0.77 (m, 1H), 0.66 (dt, J = 10.0, 4.7 Hz, 1H), 0.60 - 0.51 (m, 1H).

g) Compound G (0.2 g, 0.77 mmol) was dissolved in 2 mL DMF, HATU (0.29 g, 0.77 mmol) was added and reacted at room temperature for half an hour, then p-methylaniline (0.1 g, 0.92 mmol) and DIPEA (0.14 mL, The reaction mixture was stirred at room temperature overnight, and then was applied to ethyl acetate (20 mL*2) and 40 mL of water. The organic layer was combined, and the organic layer was re-extracted with 40 mL of brine. The organic phase was mixed with silica gel and purified by flash column eluting with ethyl acetate / petroleum ether = 0 to 35% to give 0.1 g of white solid H, compound 20, yield 37.31%. MS (ESI) [M+H] ⁺ : 350.16; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8. s (s, 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.33 (dd, J = 8.2, 1.8 Hz, 1H), 7.15 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 8.3 Hz, 1H), 4.12 (q, J = 6.8) Hz, 1H), 3.34 (s, 3H), 2.43 (ddd, J = 9.9, 6.6, 3.7 Hz, 1H), 2.33 (s, 3H), 1.15 (d, J = 6.8 Hz, 3H), 0.99 (td , J = 10.6, 6.2 Hz, 1H), 0.78 (td, J = 11.2, 6.4 Hz, 1H), 0.60 (dt, J = 10.0, 4.5 Hz, 1H), 0.51 (dt, J = 14.3, 7.1 Hz, 1H).

Example 21

The compound of Example 21 was prepared in the same manner as in Example 20 except that N-methylcyclohexylamine was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 356.24. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.10 (s, 1H), 6.89 (s, 2H), 4.09 (q, J = 6.8Hz, 1H), 3.62-3.46 (m, 1H), 3.33 (s, 3H), 3.02–2.75 (m, 3H), 2.43–2.33 (m, 1H), 1.70 (d, J=29.8 Hz, 4H), 1.47 (d, J=58.7 Hz, 4H), 1.13 (d, J) = 6.8 Hz, 3H), 1.05 (s, 2H), 0.97 - 0.85 (m, 1H), 0.77 (td, J = 11.3, 6.4 Hz, 1H), 0.60 (td, J = 10.2, 4.6 Hz, 1H) , 0.49 (td, J = 10.2, 4.1 Hz, 1H).

Example 22

The compound of Example 22 was prepared in the same manner as in Example 20 except that N-ethylcyclohexylamine was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 370.26. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.07 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 4.10 (q, J = 6.8 Hz) , 1H), 3.52 (d, J = 8.4 Hz, 1H), 3.43 (d, J = 12.8 Hz, 2H), 3.34 (s, 3H), 2.44 - 2.33 (m, 1H), 1.75 (s, 4H) , 1.52 (dd, J = 17.9, 8.1 Hz, 3H), 1.25 (d, J = 12.2 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H), 1.06 (s, 3H), 0.92 (dt, J = 10.7, 6.3 Hz, 1H), 0.78 (dt, J = 11.4, 6.3 Hz, 1H), 0.62 (td, J = 10.1, 4.8 Hz, 1H), 0.50 (td, J = 10.2, 4.1 Hz, 1H) ).

Example 23

The compound of Example 23 was prepared in the same manner as in Example 20 except that in the g.

MS (ESI) [M+H] ⁺ : 327.35. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.74 (dd, J = 4.5, 1.4 Hz, 1H), 8.47 (dd, J = 8.4, 1.4 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H) , 7.88 (dd, J = 8.4, 2.0 Hz, 1H), 7.47 (dd, J = 8.4, 4.5 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 4.19 (q, J = 6.9 Hz, 1H), 3.41 (s, 3H), 2.49 (ddd, J = 10.0, 6.6, 3.6 Hz, 1H), 1.21 (d, J = 6.9 Hz, 3H), 1.07 - 1.00 (m, 1H), 0.86 - 0.81 (m, 1H), 0.69 - 0.62 (m, 1H), 0.56 (ddd, J = 10.3, 5.1, 3.2 Hz, 1H).

Example 24

The compound of Example 24 was prepared in the same manner as in Example 20 except that 1,3,5-trimethyl-1H-pyrazolyl-4-amine was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 368. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.67 (d, J = 1.9Hz, 1H), 7.63 (s, 1H), 7.37 (dd, J = 8.3,1.9Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 4.10 (q, J = 6.8 Hz, 1H), 3.67 (s, 3H), 3.33 (s, 3H), 2.47 - 2.39 (m, 1H), 2.13 (s, 3H), 2.10 ( s, 3H), 1.13 (d, J = 6.9 Hz, 3H), 1.03 - 0.93 (m, 1H), 0.77 (ddd, J = 11.0, 10.3, 6.4 Hz, 1H), 0.59 (dt, J = 10.4, 4.6 Hz, 1H), 0.55–0.46 (m, 1H).

Example 25

The compound of Example 25 was prepared in the same manner as in Example 20 except that p-methylbenzylamine was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 364.17. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.64 (s, 1H), 7.23 (d, J = 7.8 Hz, 3H), 7.12 (d, J = 7.8 Hz, 2H), 6.86 (d, J = 8.3 Hz) , 1H), 6.75 (d, J = 4.9 Hz, 1H), 4.57 (d, J = 5.3 Hz, 2H), 4.10 (q, J = 6.8 Hz, 1H), 3.31 (s, 3H), 2.45 - 2.36 (m, 1H), 2.32 (s, 3H), 1.12 (d, J = 6.8 Hz, 3H), 0.97 (td, J = 10.7, 6.0 Hz, 1H), 0.76 (td, J = 11.1, 6.1 Hz, 1H), 0.57 (dd, J = 9.9, 4.6 Hz, 1H), 0.50 (dd, J = 10.0, 4.1 Hz, 1H).

Example 26

The compound of Example 26 was prepared in the same manner as in Example 20 except that o-methoxyaniline was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 366.11. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 (s, 1H), 8.53 (dd, J = 7.9, 1.6 Hz, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.3, 2.0 Hz, 1H), 7.07 (td, J = 7.7, 1.7 Hz, 1H), 7.02 (dd, J = 7.8, 1.4 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.91 ( Dd, J = 8.0, 1.3 Hz, 1H), 4.15 (q, J = 6.8 Hz, 1H), 3.92 (s, 3H), 3.37 (s, 3H), 2.53 - 2.45 (m, 1H), 1.18 (d , J = 6.9 Hz, 3H), 1.09 - 0.98 (m, 1H), 0.84 (ddd, J = 9.4, 7.6, 4.8 Hz, 1H), 0.65 (dt, J = 10.1, 4.4 Hz, 1H), 0.60 - 0.52 (m, 1H).

Example 27

The compound of Example 27 was prepared in the same manner as in Example 20 except that N-methyl-p-methylaniline was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 364.21. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.03 (d, J = 7.9 Hz, 2H), 6.99 (d, J = 8.4 Hz, 1H), 6.94 (s, 2H), 6.92 (s, 1H), 6.75 (d, J = 8.2 Hz, 1H), 4.00 (q, J = 6.7 Hz, 1H), 3.48 (s, 3H), 3.27 (s, 3H), 2.28 (s, 3H), 2.12 (s, 1H) 1.02 (d, J = 6.8 Hz, 3H), 0.68 (d, J = 6.4 Hz, 2H), 0.49 (d, J = 8.2 Hz, 1H), 0.11 (d, J = 9.0 Hz, 1H).

Example 28

The compound of Example 28 was prepared in the same manner as in Example 20 except that the p-methylaniline was replaced with 2,4-dimethylaniline in the step g.

MS (ESI) [M+H] ⁺ : 364.21. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.81 (d, J = 7.8Hz, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 7.35 (dd, J = 8.2,1.8Hz, 1H) , 7.07 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 8.3 Hz, 1H), 4.16 (q, J = 6.8 Hz, 1H), 3.39 (s, 3H), 2.53 - 2.45 (m, 1H), 2.32 (d, J = 4.6 Hz, 6H), 1.19 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 4.4 Hz, 1H), 0.83 (dt, J = 11.2, 6.2 Hz, 1H), 0.64 (dd, J = 10.3, 4.3 Hz, 1H), 0.57 (d, J = 3.9 Hz, 1H).

Example 29

The compound of Example 29 was prepared in the same manner as in Example 20 except that phenylamine was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 336.17. ^{1 H NMR (400MHz, DMSO-} d 6) δ10.14 (s, 1H), 7.77 (d, J = 8.0Hz, 2H), 7.66 (s, 1H), 7.57 (d, J = 8.3Hz, 1H) , 7.35 (t, J = 7.8 Hz, 2H), 7.17 (d, J = 8.3 Hz, 1H), 7.09 (t, J = 6.9 Hz, 1H), 4.05 (q, J = 6.7 Hz, 1H), 3.31 (s, 3H), 2.55 (d, J = 3.1 Hz, 1H), 1.09 (d, J = 6.8 Hz, 3H), 1.04 - 0.95 (m, 1H), 0.80 (d, J = 5.5 Hz, 1H) , 0.64 (d, J = 4.1 Hz, 1H), 0.43 (d, J = 3.8 Hz, 1H).

Example 30

The compound of Example 30 was prepared in the same manner as in Example 20 except that N-methylaniline was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 350.21. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21 (t, J = 7.6 Hz, 2H), 7.12 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 7.5 Hz, 2H), 6.98 (dd , J = 8.2, 1.8 Hz, 1H), 6.91 (d, J = 1.7 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 3.97 (q, J = 6.8 Hz, 1H), 3.49 (s) , 3H), 3.24 (s, 3H), 2.13 - 2.03 (m, 1H), 0.99 (d, J = 6.8 Hz, 3H), 0.70 - 0.60 (m, 2H), 0.49 - 0.41 (m, 1H), 0.13–0.04 (m, 1H).

Example 31

The compound of Example 31 was prepared in the same manner as in Example 20 except that p-methoxyaniline was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 366.24. _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.81 (s, 1H), 7.67 (s, 1H), 7.55 (d, J = 8.6Hz, 2H), 7.32 (dd, J = 8.2,1.4Hz, 1H) , 6.94 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 8.9 Hz, 2H), 4.14 (q, J = 6.8 Hz, 1H), 3.81 (s, 3H), 3.37 (s, 3H) , 2.53–2.41(m,1H), 1.17(d,J=6.8Hz,3H),1.07–0.96(m,1H),0.81(td,J=11.4,6.3Hz,1H),0.63(dt,J =10.1, 4.7 Hz, 1H), 0.55 (dd, J = 10.1, 4.2 Hz, 1H).

Example 32

The compound of Example 32 was prepared in the same manner as in Example 20 except that p-methylcyclohexylamine was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 356.21. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (t, J = 2.1 Hz, 1H), 7.17 (td, J = 8.2, 1.9 Hz, 1H), 6.90 (dd, J = 10.8, 8.3 Hz, 1H) , 6.07 (dd, J = 103.5, 8.1 Hz, 1H), 4.20 (s, 1H), 4.12 (qd, J = 6.8, 3.1 Hz, 1H), 3.34 (d, J = 4.0 Hz, 3H), 2.47 ( Tt, J = 6.3, 3.3 Hz, 1H), 2.13 - 2.02 (m, 1H), 1.90 - 1.52 (m, 8H), 1.16 - 1.12 (m, 3H), 1.01 (dt, J = 10.7, 6.1 Hz, 1H), 0.92 (dd, J = 15.2, 6.5 Hz, 3H), 0.84 - 0.75 (m, 1H), 0.65 - 0.58 (m, 1H), 0.54 (dt, J = 10.2, 4.3 Hz, 1H).

Example 33

The compound of Example 33 was prepared in the same manner as in Example 20 except that instead of p-methylaniline.

MS (ESI) [M+H] ⁺ : 342. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.59 (d, J = 1.9Hz, 1H), 7.17 (dd, J = 8.2,1.9Hz, 1H), 6.89 (d, J = 8.3Hz, 1H), 5.97 (d, J = 8.0 Hz, 1H), 4.12 (q, J = 6.9 Hz, 1H), 4.04 - 3.89 (m, 1H), 3.35 (s, 3H), 2.52 - 2.42 (m, 1H), 2.03 ( d, J = 12.0 Hz, 2H), 1.76 (d, J = 4.4 Hz, 1H), 1.65 (d, J = 13.2 Hz, 1H), 1.43 (dd, J = 24.3, 12.2 Hz, 2H), 1.29 - 1.18 (m, 4H), 1.15 (d, J = 6.9 Hz, 3H), 1.02 (dt, J = 10.9, 6.2 Hz, 1H), 0.79 (dt, J = 11.1, 6.5 Hz, 1H), 0.62 (dt , J = 10.6, 4.2 Hz, 1H), 0.53 (ddd, J = 14.5, 8.4, 4.3 Hz, 1H).

Example 34

The compound of Example 34 was prepared in the same manner as in Example 20 except that N-methyl-p-methylcyclohexylamine was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 370.29. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.09 (s, 1H), 6.88 (s, 2H), 4.08 (q, J = 6.8Hz, 1H), 3.49 (s, 1H), 3.32 (s, 3H) , 2.92 (s, 3H), 2.89 - 2.74 (m, 1H), 2.37 (s, 1H), 1.74 (s, 4H), 1.51 (dd, J = 29.9, 21.7 Hz, 4H), 1.13 (d, J = 6.8 Hz, 3H), 1.00 - 0.87 (m, 3H), 0.83 - 0.71 (m, 2H), 0.60 (d, J = 4.5 Hz, 1H), 0.48 (d, J = 4.1 Hz, 1H).

Example 35

The compound of Example 35 was prepared in the same manner as in Example 20 except that N-ethyl-p-methylaniline was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 378.21. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.03 (s, 1H), 7.01 (s, 1H), 6.97 (dd, J = 8.2, 1.9 Hz, 1H), 6.92 (d, J = 2.4 Hz, 2H) , 6.90 (s, 1H), 6.73 (d, J = 8.3 Hz, 1H), 4.04 - 3.86 (m, 3H), 3.25 (s, 3H), 2.27 (s, 3H), 2.17 - 2.06 (m, 1H) ), 1.20 (t, J = 7.1 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 0.75 - 0.61 (m, 2H), 0.52 - 0.41 (m, 1H), 0.18 - 0.07 (m, 1H).

Example 36

The compound of Example 36 was prepared in the same manner as in Example 20 except that in the g.

MS (ESI) [M+H] ⁺ : 372.26. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32 (s, 1H), 7.21. (d, J = 7.5 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 7.09 (d, J = 1.8 Hz) , 1H), 7.01 (s, 1H), 6.96 (s, 1H), 6.94 (s, 1H), 4.13 (q, J = 6.9 Hz, 3H), 3.37 (s, 3H), 3.13 (t, J = 8.2 Hz, 2H), 2.40 (d, J = 3.4 Hz, 1H), 1.18 (d, J = 6.8 Hz, 3H), 0.87 (s, 1H), 0.79 (dd, J = 12.9, 7.8 Hz, 1H) , 0.61 (dd, J = 10.0, 4.7 Hz, 1H), 0.50 (s, 1H).

Example 37

The compound of Example 37 was prepared in the same manner as in Example 20 except that 5-methyldihydroindole was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 376.26. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.32 (s, 1H), 7.10 (s, 1H), 7.08 (s, 1H), 7.03 (s, 1H), 6.95 (s, 1H), 6.93 (s, 1H), 4.13 (dd, J = 13.5, 6.7 Hz, 3H), 3.37 (s, 3H), 3.09 (t, J = 8.3 Hz, 2H), 2.40 (s, 1H), 2.30 (s, 3H), 1.18 (d, J = 6.8 Hz, 3H), 0.89 (s, 1H), 0.79 (d, J = 4.9 Hz, 1H), 0.62 (d, J = 4.5 Hz, 1H), 0.51 (s, 1H).

Example 38

The compound of Example 38 was prepared in the same manner as in Example 20 except that 5-fluoroindoline was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 380.24. ^{1 H NMR (400MHz, DMSO)} δ7.28 (s, 1H), 7.16 (s, 1H), 7.13 (s, 3H), 7.00 (s, 1H), 4.11 (t, J = 8.3Hz, 2H), 4.03 (q, J = 6.8 Hz, 1H), 3.29 (s, 3H), 3.10 (t, J = 8.2 Hz, 2H), 2.47 (s, 1H), 1.09 (d, J = 6.8 Hz, 3H), 0.95 (s, 1H), 0.77 (d, J = 5.0 Hz, 1H), 0.61 (d, J = 4.4 Hz, 1H), 0.39 (s, 1H).

Example 39

The compound of Example 39 was prepared in the same manner as in Example 20 except that 4-methyldihydroindole was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 376. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.31 (s, 1H), 7.10 (d, J = 1.8Hz, 1H), 7.08 (d, J = 1.8Hz, 1H), 6.96 (s, 1H), 6.93 (s, 1H), 6.85 (s, 1H), 4.13 (dd, J = 13.6, 6.7 Hz, 3H), 3.37 (s, 3H), 3.03 (t, J = 8.2 Hz, 2H), 2.40 (d, J = 3.1 Hz, 1H), 2.25 (s, 3H), 1.18 (d, J = 6.8 Hz, 3H), 0.87 (s, 1H), 0.78 (d, J = 5.2 Hz, 1H), 0.61 (dd, J = 9.5, 5.1 Hz, 1H), 0.50 (s, 1H).

Example 40

The compound of Example 40 was prepared in the same manner as in Example 20 except that the cyclopentylamine was replaced by cyclopentylamine in the step b; and the p-methylaniline was replaced with 2,4-dimethylaniline in the step g.

MS (ESI) [M+H] ⁺ : 3921.21. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.77 (d, J = 7.6Hz, 1H), 7.62 (s, 1H), 7.45 (s, 1H), 7.30 (dd, J = 8.3,1.8Hz, 1H) , 7.06 (d, J = 7.9 Hz, 2H), 6.99 (d, J = 8.3 Hz, 1H), 4.23 (q, J = 6.8 Hz, 1H), 3.96 - 3.84 (m, 1H), 3.40 (s, 3H), 2.31 (d, J = 6.7 Hz, 6H), 2.13 - 1.99 (m, 2H), 1.84 - 1.74 (m, 1H), 1.74 - 1.70 (m, 1H), 1.68 - 1.55 (m, 4H) , 1.07 (d, J = 6.8 Hz, 3H).

Example 41

The compound of Example 41 was prepared in the same manner as in Example 20 except that the cyclopentylamine was used instead of the cyclopropylamine in the step b.

MS (ESI) [M+H] ⁺ : 390.14. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21 (d, J = 7.4 Hz, 1H), 7.09 (s, 1H), 7.07 (s, 1H), 7.04 (s, 1H), 7.01 (s, 1H) , 6.98 (s, 1H), 6.96 (s, 1H), 4.22 (q, J = 6.8 Hz, 1H), 4.14 (t, J = 7.9 Hz, 2H), 3.85 - 3.71 (m, 1H), 3.40 ( s, 3H), 3.13 (t, J = 8.2 Hz, 2H), 1.98 (d, J = 6.0 Hz, 2H), 1.73 (d, J = 12.4 Hz, 1H), 1.68 - 1.51 (m, 5H), 1.06 (d, J = 6.8 Hz, 3H).

Example 42

The compound of Example 42 was prepared in the same manner as in Example 20 except that the cyclopentylamine was used instead of the cyclopropylamine in the step b.

MS (ESI) [M+H] ⁺ : 378. _{^{1 H NMR (400MHz, CDCl 3}} ) δ8.18 (s, 1H), 7.54 (d, J = 8.1Hz, 2H), 7.44 (s, 1H), 7.31 (d, J = 7.1Hz, 1H), 7.13 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 8.3 Hz, 1H), 4.18 (q, J = 6.8 Hz, 1H), 3.87 - 3.76 (m, 1H), 3.35 (s, 3H) , 2.31 (s, 3H), 2.05 - 1.95 (m, 2H), 1.74 (d, J = 6.1 Hz, 1H), 1.66 - 1.52 (m, 5H), 1.01 (d, J = 6.8 Hz, 3H).

Example 43

In addition to replacing cyclopropylamine with cyclopentylamine in step b; replacing 2-bromopropionyl bromide with 2-bromobutyryl bromide in step d; replacing p-methylaniline with 2,4-dimethylaniline in step g The compound of Example 43 was prepared in the same manner as in Example 20 except for the procedure.

MS (ESI) [M+H] ⁺ : 406.21. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.75 (d, J = 7.4Hz, 1H), 7.63 (s, 1H), 7.48 (s, 1H), 7.31 (dd, J = 8.3,1.9Hz, 1H) , 7.06 (s, 1H), 7.04 (s, 1H), 6.97 (d, J = 8.3 Hz, 1H), 3.95 (q, J = 7.2 Hz, 2H), 3.40 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H), 2.07 - 1.96 (m, 2H), 1.82 - 1.72 (m, 2H), 1.70 - 1.49 (m, 6H), 0.89 (t, J = 7.5 Hz, 3H).

Example 44

In addition to the use of cyclopentylamine in place of cyclopropylamine in step b; in place of 2-bromobutyryl bromide in place of 2-bromopropionyl bromide; in step g, in addition to indoline instead of p-methylaniline, The compound of Example 44 was prepared in the same manner as in Example 20.

MS (ESI) [M+H] ⁺ : 404.27. ^{1 H NMR (400MHz, DMSO)} δ7.27 (s, 1H), 7.25 (s, 1H), 7.12 (t, J = 9.2Hz, 3H), 7.08 (s, 1H), 7.01 (t, J = 7.3 Hz, 1H), 4.05 (td, J = 8.8, 3.9 Hz, 2H), 3.91 - 3.83 (m, 2H), 3.32 (s, 3H), 3.08 (t, J = 8.3 Hz, 2H), 1.93 (d , J = 6.4 Hz, 2H), 1.70 - 1.51 (m, 5H), 1.47 - 1.28 (m, 3H), 0.80 (t, J = 7.4 Hz, 3H).

Example 45

The compound of Example 45 was prepared in the same manner as in Example 20 except that the pyrimidine-4-amine was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 338.38. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.74 (dd, J = 4.5, 1.4 Hz, 1H), 8.47 (dd, J = 8.4, 1.4 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H) , 7.89 (dd, J = 8.4, 2.0 Hz, 1H), 7.47 (dd, J = 8.4, 4.5 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 4.19 (q, J = 6.8 Hz, 1H), 3.42 (s, 3H), 2.53–2.46 (m, 1H), 1.18 (s, 3H), 1.07–0.99 (m, 1H), 0.87–0.81 (m, 1H), 0.67 (dt, J= 10.1, 4.8 Hz, 1H), 0.61 - 0.53 (m, 1H).

Example 46

The compound of Example 46 was prepared in the same manner as in Example 20 except that 2-fluoroaniline was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 353. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47 (t, J = 8.0 Hz, 1H), 8.08 (s, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.2, 1.9 Hz, 1H), 7.18 (dd, J = 13.7, 5.5 Hz, 1H), 7.15 - 7.04 (m, 2H), 6.99 (d, J = 8.3 Hz, 1H), 4.16 (q, J = 6.8 Hz, 1H), 3.38 (s, 3H), 2.56 - 2.45 (m, 1H), 1.19 (d, J = 6.8 Hz, 3H), 1.05 (dt, J = 10.9, 5.2 Hz, 1H), 0.88 - 0.80 (m) , 1H), 0.65 (dt, J = 10.1, 4.4 Hz, 1H), 0.56 (dt, J = 10.2, 4.1 Hz, 1H).

Example 47

The compound of Example 47 was prepared in the same manner as in Example 20 except that 3-fluoro-4-methylaniline was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 368. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (d, J = 12.5 Hz, 1H), 7.66 (d, J = 1.9 Hz, 1H), 7.56 (dd, J = 11.5, 1.9 Hz, 1H), 7.31 (dd, J = 8.3, 1.9 Hz, 1H), 7.21 - 7.17 (m, 1H), 7.13 (t, J = 8.2 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 4.14 (q, J = 6.8 Hz, 1H), 3.36 (s, 3H), 2.52 - 2.39 (m, 1H), 2.25 (s, 3H), 1.16 (d, J = 6.9 Hz, 3H), 1.00 (dd, J = 12.2) , 7.4 Hz, 1H), 0.86 - 0.76 (m, 1H), 0.67 - 0.58 (m, 1H), 0.58 - 0.49 (m, 1H).

Example 48

The compound of Example 48 was prepared in the same manner as in Example 20 except that instead of p-tolylamine.

MS (ESI) [M+H] ⁺ : 328. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (d, J = 1.9 Hz, 1H), 7.16 (dd, J = 8.2, 2.0 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.06 (d, J = 7.1 Hz, 1H), 4.44 - 4.32 (m, 1H), 4.12 (q, J = 6.9 Hz, 1H), 3.34 (s, 3H), 2.52 - 2.40 (m, 1H), 2.17 - 2.03 (m, 2H), 1.76–1.68 (m, 2H), 1.68–1.62 (m, 2H), 1.56–1.43 (m, 2H), 1.15 (d, J=6.9 Hz, 3H), 1.02 (ddd, J = 10.9, 8.5, 5.5 Hz, 1H), 0.84 - 0.73 (m, 1H), 0.67 - 0.56 (m, 1H), 0.57 - 0.47 (m, 1H).

Example 49

The compound of Example 49 was prepared in the same manner as in Example 20 except that N-methylcyclopentylamine was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 342.24. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.15 (s, 1H), 6.91 (d, J = 1.4Hz, 2H), 4.19 (s, 1H), 4.11 (q, J = 6.8Hz, 1H), 3.34 (s, 3H), 2.93 (s, 3H), 2.44 - 2.37 (m, 1H), 1.68 (s, 7H), 1.52 (d, J = 6.9 Hz, 1H), 1.15 (d, J = 6.9 Hz, 3H), 0.99–0.90 (m, 1H), 0.78 (ddd, J=11.2, 10.4, 6.5 Hz, 1H), 0.68–0.57 (m, 1H), 0.51 (ddt, J=10.2, 6.3, 4.1 Hz, 1H).

Example 50

The compound of Example 50 was prepared in the same manner as in Example 20 except that 2,4,6-trimethylaniline was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 378. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.71 (d, J = 1.9Hz, 1H), 7.40 (dd, J = 8.2,1.9Hz, 1H), 7.32 (s, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.94 (s, 2H), 4.16 (q, J = 6.9 Hz, 1H), 3.39 (s, 3H), 2.54 - 2.46 (m, 1H), 2.29 (s, 3H), 2.26 ( s, 6H), 1.19 (d, J = 6.9 Hz, 3H), 1.06 - 0.99 (m, 1H), 0.82 (dd, J = 12.9, 7.9 Hz, 1H), 0.64 (dd, J = 10.3, 4.4 Hz , 1H), 0.58 (dd, J = 10.2, 4.1 Hz, 1H).

Example 51

The compound of Example 51 was prepared in the same manner as in Example 20 except that in the step g, 2,5-dimethyldihydroindole was used instead of p-methylaniline.

MS (ESI) [M+H] ⁺ : 390.21. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.27 (s, 1H), 7.22 (s, 1H), 7.07 (d, J = 7.8Hz, 1H), 7.03 (s, 1H), 6.97-6.89 (m, 1H), 6.83 (s, 1H), 4.78 (s, 1H), 4.19 - 4.06 (m, 1H), 3.44 - 3.32 (m, 4H), 2.59 (d, J = 15.5 Hz, 1H), 2.37 (s , 1H), 2.28 (s, 3H), 1.33 - 1.22 (m, 3H), 1.17 (d, J = 6.8 Hz, 3H), 0.98 - 0.86 (m, 1H), 0.81 - 0.69 (m, 1H), 0.61 (dd, J = 10.4, 4.2 Hz, 1H), 0.55 (dd, J = 10.3, 4.0 Hz, 1H).

Example 52

The compound of Example 52 was prepared in the same manner as in Example 20 except that 2-methylindole was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 376.26. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21 (s, 1H), 7.19 (s, 1H), 7.09 (d, J = 8.7 Hz, 1H), 7.02 (s, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.95 (s, 1H), 6.94 - 6.89 (m, 1H), 4.77 (s, 1H), 4.17 - 4.06 (m, 1H), 3.43 (dd, J = 17.3, 8.1 Hz, 1H) ), 3.36 (d, J = 3.4 Hz, 3H), 2.63 (dd, J = 15.8, 2.9 Hz, 1H), 2.35 (s, 1H), 1.25 (d, J = 12.0 Hz, 3H), 1.16 (dd) , J = 6.8, 2.2 Hz, 3H), 0.96 - 0.83 (m, 1H), 0.79 - 0.69 (m, 1H), 0.65 - 0.57 (m, 1H), 0.57 - 0.48 (m, 1H).

Example 53

The compound of Example 53 was prepared in the same manner as in Example 20 except that in the step b, 3-bromobenzylamine was used in place of the cyclopropylamine; and the aniline was used instead of p-methylaniline in the step g.

MS (ESI) [M+H] ⁺ : 464.21. _{^{1 H NMR (400MHz, CDCl 3}} ) δ7.69 (s, 1H), 7.60 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.42 (d, J = 8.2Hz, 1H) , 7.36 (t, J = 6.4 Hz, 2H), 7.33 (dd, J = 6.7, 1.5 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.23 (s, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 4.62 (d, J = 14.8 Hz, 1H), 4.15 (d, J = 14.9 Hz, 1H), 4.02 (q, J = 6.8 Hz, 1H), 3.44 (s, 3H), 1.14 (d, J = 6.8 Hz, 3H).

Examples 54 and 55

Reagents and conditions: a) 2-bromopropionyl bromide, sodium carbonate, dichloromethane, reaction at room temperature for 2 hours; b) cyclopropylamine, acetonitrile, N,N-diisopropylethylamine (DIPEA), reflux at 80 ° C 12 H) N,N-diisopropylethylamine (DIPEA), N,N-dimethylformamide (DMF), reacted at 150 ° C overnight; d) sodium hydride, N,N-dimethylformamide (DMF), methyl iodide, reacted at room temperature for 1 hour; e) p-toluenesulfonamide, allyl palladium chloride dimer, 2-di-tert-butylphosphino-2', 4', 6'-triisopropyl Base benzene (tBuXPhos), potassium carbonate, 2-methyltetrahydrofuran, reacted at 80 ° C for 24 hours; f) 2,4-dimethylaniline, 4-dimethylaminopyridine, hexacarbonyl molybdenum, [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride, 1,8-diazabicycloundec-7-ene (DBU), triethylamine, dioxane, reflux at 85 ° C hour.

Preparation of the compound of Example 54:

a) Compound A (1 g, 3.97 mmol) was dissolved in dry 10 mL dichloromethane, cooled to 0 <0>C, sodium carbonate (0.42 g, 3.97 mmol) and 2-bromopropionyl bromide (0.5 mL, 4.77 mmol). Then, the reaction was carried out for 2 hours at room temperature, and the reaction was monitored by TLC. After the reaction, the mixture was extracted with dichloromethane (20 mL*2) and 20 mL of water. The phase was evaporated to dryness to give a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.70 (s, 1H), 8.54 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 4.59 (q, J = 7.1 Hz) , 1H), 1.99 (d, J = 7.1 Hz, 3H).

b) Compound B (1 g, 2.59 mmol) was dissolved in 8 mL of EtOAc (EtOAc) (EtOAc (EtOAc) After that, the solvent was evaporated to dryness, and the mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjj Elution with ethyl acetate/petroleum ether = 0 to 10% gave 0.8 g of white solid C, yield 85.11%. MS (ESI) [M + H ] +: 362.02; 1 H NMR (400MHz, CDCl 3) δ10.03 (s, 1H), 8.67 (dd, J = 9.3,8.5Hz, 1H), 7.39 (t, J = 8.8 Hz, 1H), 3.43 (p, J = 7.2 Hz, 1H), 2.39 - 2.26 (m, 1H), 1.43 (dd, J = 9.3, 7.2 Hz, 3H), 0.54 (ddd, J = 12.2, 4.9, 3.3 Hz, 1H), 0.47 (tdd, J = 9.2, 7.4, 4.0 Hz, 3H).

c) Compound C (0.8 g, 2.22 mmol) was dissolved in EtOAc EtOAc EtOAc (EtOAc) (20mL*2) and 20mL of water were extracted, and the organic layer was combined, and the organic layer was re-extracted with 40 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, and the organic phase was mixed with silica gel and purified by flash column using ethyl acetate / petroleum ether = A gradient of 0 to 20% eluted to give 0.5 g of a white solid D, yield 79.37%. ^{1 H NMR (400MHz, DMSO-} d 6) δ10.61 (s, 1H), 6.93 (d, J = 7.9Hz, 1H), 6.89 (d, J = 7.8Hz, 1H), 4.00 (q, J = 6.9 Hz, 1H), 2.65 - 2.58 (m, 1H), 1.21 (d, J = 6.9 Hz, 3H), 0.94 (dt, J = 11.5, 6.6 Hz, 1H), 0.68 (dt, J = 9.3, 6.7) Hz, 1H), 0.61 (dd, J = 10.6, 5.5 Hz, 1H), 0.46 (dd, J = 10.3, 4.6 Hz, 1H).

d) Compound D (0.5 g, 1.77 mmol) was dissolved in 4 mL of DMF, cooled to 0 ° C, sodium hydride (0.13 g, 5.31 mmol). Then, the reaction was carried out for 1 hour at room temperature, and the reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to 0 ° C, and then diluted with hydrochloric acid to adjust pH to 7-8, and then extracted with dichloromethane (15 mL*2) and 15 mL of water. 30 mL of saturated brine was back-extracted once, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was mixed with silica gel and purified by flash column, eluting with ethyl acetate / petroleum ether = 0 to 25% gradient to give 0.4 g of colorless transparent liquid E, the yield was 76.19%. MS (ESI) [M+H] ⁺ : 296.18; ¹ H NMR (400 MHz, CDCl3) δ 6.81 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 4.08 (q) , J = 6.9 Hz, 1H), 3.17 (s, 3H), 2.61 - 2.50 (m, 1H), 1.16 (d, J = 6.9 Hz, 3H), 0.98 - 0.89 (m, 1H), 0.68 - 0.57 ( m, 1H), 0.50–0.36 (m, 2H).

e) Compound E (0.2 g, 0.68 mmol) and p-toluenesulfonamide (0.175 g, 1.02 mmol) and potassium carbonate (0.19 g, 1.36 mmol) were dissolved in 2-methyltetrahydrofuran. Allyl palladium chloride dimer (6 mg, 0.014 mmol), tBuXPhos (6 mg, 0.014 mmol), then ventilated with nitrogen, then reacted at 80 ° C for 24 hours. The reaction was monitored by TLC. 10 mL*2) and 10 mL of water were extracted, and the organic layer was combined and extracted with 20 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, and the organic phase was mixed with silica gel and purified by flash column using ethyl acetate / petroleum ether = A gradient of -30% eluted to give 0.15 g of white solid F, Compound 54, yield 57.25%. MS (ESI) [M + H ] +: 387.19; 1 H NMR (400MHz, CDCl 3) δ7.79 (d, J = 8.3Hz, 2H), 7.28 (s, 2H), 7.04 (s, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 4.14 (q, J = 6.8 Hz, 1H), 3.25 (s, 3H), 2.47 (dd, J = 7.0) , 3.3 Hz, 1H), 2.40 (s, 3H), 1.21 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 5.3 Hz, 1H), 0.75 - 0.64 (m, 1H), 0.49 (d , J = 5.1 Hz, 1H), 0.36 (d, J = 4.9 Hz, 1H).

Preparation of the compound of Example 55:

The preparation methods of steps a) to d) are the same as those used in the preparation of Example 54,

f) Compound E (0.2 g, 0.68 mmol), 2,4-dimethylaniline (0.165 g, 1.36 mmol), triethylamine (0.189 mL, 1.36 mmol) and 4-dimethylaminopyridine (0.083 g, 0.68) Methyl) was dissolved in dioxane, and after venting with nitrogen, hexacarbonyl molybdenum (0.09 g, 0.34 mmol) was added, and after nitrogen gas exchange, [1,1'-bis(diphenylphosphino)ferrocene was added. Palladium dichloride (55 mg, 0.068 mmol), after venting with nitrogen, 1,8-diazabicycloundec-7-ene (0.153 mL, 1.02 mmol) was added, and then ventilated with nitrogen, then 85 After reacting for 24 hours, the reaction was monitored by TLC. After the reaction, the mixture was combined with ethyl acetate (10 mL*2) and 10 mL of water, and the organic layer was combined, and the mixture was re-extracted with 20 mL of brine. The silica gel was purified by flash column chromatography eluting with ethyl acetate / pet ether <RTI ID=0.0></RTI></RTI><RTIgt; MS (ESI) [M + H ] +: 365.22; 1 H NMR (400MHz, CDCl 3) δ9.94 (s, 1H), 8.23 (d, J = 8.2Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 7.03 (s, 1H), 4.29 (q, J = 6.8 Hz, 1H), 3.36 ( s, 3H), 2.82–2.69 (m, 1H), 2.37 (s, 3H), 2.31 (s, 3H), 1.33 (d, J = 6.9 Hz, 3H), 1.11–1.03 (m, 1H), 0.87 –0.85 (m, 2H), 0.67 (d, J = 3.7 Hz, 1H).

Example 56

The compound of Example 56 was prepared in the same manner as in Example 55 except that in the step f, 5-methyldihydroindole was used instead of 2,4-dimethylaniline.

MS (ESI) [M+H] ⁺ : 377.21. _{^{1 H NMR (400MHz, CDCl 3}} ) δ8.19 (d, J = 7.8Hz, 1H), 7.55 (d, J = 8.1Hz, 1H), 7.17 (d, J = 8.1Hz, 1H), 7.07 (s , 1H), 7.05 (s, 1H), 4.80 (dd, J = 20.2, 9.3 Hz, 1H), 4.37 - 4.30 (m, 1H), 4.25 (q, J = 6.9 Hz, 1H), 3.35 (s, 3H), 3.11 (t, J = 8.2 Hz, 2H), 2.69 (s, 1H), 2.33 (s, 3H), 1.27 (d, J = 6.9 Hz, 3H), 0.98 (s, 1H), 0.78 ( s, 1H), 0.61 (s, 2H).

Example 57

The compound of Example 57 was prepared in the same manner as in Example 55, except that in the step f, was used instead of 2, 4-dimethylaniline.

MS (ESI) [M+H] ⁺ : 353.21. _{^{1 H NMR (400MHz, CDCl 3}} ) δ8.33 (s, 1H), 7.57 (s, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 7.20 (d, J = 8.0Hz, 1H) , 7.09 (s, 1H), 4.82 (s, 1H), 4.41 - 4.32 (m, 1H), 4.28 (d, J = 6.7 Hz, 1H), 3.38 (s, 3H), 3.18 (t, J = 8.1 Hz, 2H), 2.72 (s, 1H), 1.30 (d, J = 6.9 Hz, 3H), 1.01 (s, 1H), 0.80 (s, 1H), 0.63 (s, 2H).

Example 58

The compound of Example 58 was prepared in the same manner as in Example 55 except that in the step f, 4-methyldihydroindole was used instead of 2,4-dimethylaniline.

MS (ESI) [M+H] ⁺ : 377.21. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J = 7.3 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.89 (d) , J = 7.3 Hz, 1H), 4.82 (d, J = 10.5 Hz, 1H), 4.34 (dt, J = 11.8, 7.9 Hz, 1H), 4.25 (q, J = 6.8 Hz, 1H), 3.34 (s) , 3H), 3.05 (t, J = 8.3 Hz, 2H), 2.69 (s, 1H), 2.26 (s, 3H), 1.27 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 11.4 Hz) , 1H), 0.78 (s, 1H), 0.61 (s, 2H).

Example 59

The compound of Example 59 was prepared in the same manner as in Example 55 except that in the step f, 2,5-dimethyldihydroindole was used instead of 2,4-dimethylaniline.

MS (ESI) [M+H] ⁺ : 391.17. _{^{1 H NMR (400MHz, CDCl 3}} ) δ8.26 (s, 1H), 7.58 (s, 1H), 7.17 (d, J = 8.0Hz, 1H), 7.05 (s, 1H), 5.79 (s, 1H) , 4.25 (s, 1H), 3.42 (d, J = 8.7 Hz, 1H), 3.39 (s, 1H), 3.35 (s, 3H), 2.64 (s, 2H), 2.33 (s, 3H), 1.29 ( s, 6H), 1.05 - 0.90 (m, 1H), 0.77 (s, 1H), 0.60 (s, 2H).

Example 60

Reagents and conditions: a) indoline, sodium triacetoxyborohydride, 1,2-dichloroethane, 0 ° C, 2 hours; b) cyclopropylamine, 1,2-dichloroethane, 80 ° C Reflux for 12 hours; c) tin dichloride dihydrate, concentrated hydrochloric acid, 0 ° C - room temperature, 3 hours; d) 1.2-bromopropionyl bromide, N,N-diisopropylethylamine (DIPEA), dichloromethane , reaction at room temperature for 2 hours; 2. acetonitrile, DIPEA, reaction at 80 ° C overnight; e) sodium hydride, N,N-dimethylformamide (DMF), methyl iodide, reaction at room temperature for 1 hour.

a) Compound A (1.7 g, 10.07 mmol) was dissolved in 10 mL of 1,2-dichloroethane, cooled to 0 ° C, dihydroindole (1 g, 8.39 mmol) was added, and the reaction was carried out at 0 ° C for half an hour. Sodium oxyborohydride (2.14 g, 10.07 mmol), which was then reacted at 0 ° C for 2 hrs, and was monitored with a TLC plate. After completion of the reaction, it was extracted with dichloromethane (20 mL*2) and 20 mL of saturated sodium hydrogencarbonate. The crystalline silica gel was purified by flash column chromatography eluting with ethyl acetate / petroleum ether = 0 to 3% to yield 1.7 g of a red oily liquid B, yield 74.43%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (t, J = 8.0 Hz, 1H), 7.39 - 7.29 (m, 2H), 7.16 (d, J = 7.2 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 6.75 (t, J = 7.4 Hz, 1H), 6.40 (d, J = 7.8 Hz, 1H), 4.32 (s, 2H), 3.41 (t, J = 8.2 Hz, 2H), 3.06 (t, J = 8.3 Hz, 2H).

b) Compound B (1.7 g, 6.24 mmol) was dissolved in 10 mL of 1,2-dichloroethane, cyclopropylamine (0.86 mL, 12.48 mmol) was added, and then reacted at 80 ° C for 12 hours, monitored by TLC plate, after the reaction The solvent was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjj ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.18 - 8.08 (m, 2H), 7.30 (s, 1H), 7.13 (d, J = 7.3 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H) , 6.74–6.67 (m, 2H), 6.49 (d, J = 7.8 Hz, 1H), 4.27 (s, 2H), 3.40 (t, J = 8.3 Hz, 2H), 3.03 (t, J = 8.3 Hz, 2H), 2.59–2.47 (m, 1H), 0.84 (q, J=6.7 Hz, 2H), 0.65–0.57 (m, 2H).

c) Compound C (1.8 g, 5.82 mmol) was dissolved in 4 mL of concentrated hydrochloric acid, and a solution of dichlorodichloride dihydrate (6.24 g, 27.65 mmol) in concentrated hydrochloric acid (4 mL). After the reaction, the pH was neutralized with saturated sodium hydrogencarbonate to 7-8, and then extracted with ethyl acetate (20 mL*2) and 20 mL of water. The organic layer was combined, and the mixture was re-extracted once with 40 mL of saturated brine. The sodium was dried and the organic phase was evaporated to dryness to give a white oil (D.

d) Compound D (1.4 g, 5.01 mmol) was dissolved in EtOAc EtOAc (EtOAc) Then, it was reacted at room temperature for 2 hours, and it was monitored with a TLC plate. After the reaction, it was extracted with dichloromethane (20 mL*2) and 20 mL of water, and the organic layer was combined, and the organic layer was re-extracted with 40 mL of saturated brine. purification by silica-gel flash chromatography column mixed sample using ethyl acetate / petroleum ether = 0 to 15% gradient, to give the intermediate as a yellow solid ^{200mg, 1 H NMR (400MHz, CDCl} 3) δ7.72 (s, 1H) , 7.20 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 7.10 (d, J = 7.1 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 7.0 Hz, 1H), 6.67 (t, J = 7.4 Hz, 1H), 6.55 (d, J = 7.8 Hz, 1H), 4.58 (q, J = 7.0 Hz, 1H), 4.24 (s, 2H), 3.33 (t, J = 8.3 Hz, 2H), 2.98 (t, J = 8.3 Hz, 2H), 2.43 (dt, J = 10.1, 3.4 Hz, 1H), 1.97 (d, J = 7.0 Hz, 3H), 0.71 (q, J = 6.5 Hz, 2H), 0.51 - 0.45 (m, 2H). This intermediate was dissolved in 2 mL of acetonitrile, 1 m LDIPEA was added, then reacted at 80 ° C overnight, monitored by TLC plate, and evaporated to dryness after solvent Extract with dichloromethane (10 mL * 2) and 10 mL of water, combine the organic layers, And 20mL brine back-extracted once, and the organic phase was dried over anhydrous sodium sulfate, the organic phase was evaporated to dryness to give 0.15g directly without purification as a pale yellow powder E, the total yield of 8.98%.

e) Compound E (0.1 g, 0.30 mmol) was dissolved in 2 mL DMF, cooled to 0 ° C, sodium hydride (22 mg, 0.90 mmol) was added, and reacted at 0 ° C for half an hour, and iodomethane (37 uL, 0.60 mmol) was added at 0 °C. Then, it was reacted at room temperature for 1 hour, and it was monitored with a TLC plate. After the reaction was completed, the pH was neutralized to 7-8 with saturated sodium hydrogencarbonate, and then extracted with ethyl acetate (10 mL*2) and 20 mL of water. 20 mL of brine was back-extracted once, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether = 0 to 25% to give 40 mg of white powder F. 60, yield 38.38%. MS (ESI) [M+H] ⁺ : 347. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.10 (s, 2H), 7.06 (d, J = 7.8 Hz, 1H), 6.87 (s, 2H), 6.67 (t, J = 7.3 Hz, 1H), 6.56 ( d, J = 7.8 Hz, 1H), 4.24 (q, J = 14.8 Hz, 2H), 4.10 (q, J = 6.8 Hz, 1H), 3.39 - 3.28 (m, 5H), 2.98 (t, J = 8.4) Hz, 2H), 2.35 (s, 1H), 1.17 (d, J = 6.8 Hz, 3H), 0.86 (dd, J = 12.1, 6.4 Hz, 1H), 0.79 - 0.71 (m, 1H), 0.65 - 0.57 (m, 1H), 0.48 (d, J = 4.4 Hz, 1H).

Pharmacological test example

A method for testing bromodomain recognition protein BRD4 inhibitor enzyme activity

The binding activity of the compound to BRD4 (I) was tested using a fluorescence anisotropy test (Fluorescence Anisotropy, FA). The principle of FA test is to calculate the fluorescence polarization values in the horizontal and vertical directions by detecting the change of molecular weight before and after the interaction of fluorescein-labeled small molecules with other molecules. If the equilibrium of the binding between the fluorescently labeled small molecule and the macromolecule is established, it will move slowly when excited, and the measured fluorescence polarization value will increase. If the binding between the fluorescently labeled small molecule and the macromolecule is replaced by another ligand, its rotation or flipping speed in the free state will be faster, and the emitted light will be depolarized relative to the plane of the excitation light, and the measured polarized light value Decrease to calculate the fluorescence anisotropy of the sample.

Fluorescent substrate 1 is (+)-JQ1 attached to a fluorescent molecule and has a working concentration of 5 nM. BRD4(I) protein working concentration is 40nM, total reaction system is 40μL, buffer is 50mM 4-hydroxyethylpiperazineethanesulfonic acid (HEPES) pH 7.4, 150mM NaCl, 0.5mM 3-[3-(cholamide) Propyl)dimethylamino]propanesulfonic acid inner salt (CHAPS). The initial screening concentration of the compound was 1 μM, and the IC ₅₀ of the compound having an inhibition rate greater than 60% under this condition was determined. The final concentration of DMSO was chosen to be 5%, taking into account the solubility of the compound and the effect of DMSO on the assay. All measurements were made under these conditions. After mixing all the components, the anisotropy value was measured after the reaction was allowed to stand at room temperature for 4 hours or at 4 ° C overnight. The test used Corning's all-black, low-side, NBS surface 384-well microplate (Cat. No. CLS3575). The test instrument was a BioTek synergy 2 detector with an excitation of 485 nM and an emission of 530 nM. Use buffer as the blank value for the system reading.

Numerical processing: inhibition rate = (C-F) / (C-B) × 100% (Equation 1)

Where: C: anisotropic value of the complete binding of the fluorescent substrate to the protein

B: Fluorescent substrate anisotropy background value

F: anisotropy value at the corresponding concentration of the compound

The S curve is taken as the concentration of the compound and the corresponding inhibition rate. To give the corresponding compound of IC _50.

BRD4 enzyme activity detection method Fluorescent substrate 1 used in FA

Pharmacological data: The pharmacological test results of the compounds of the present invention are published in Table 1 below, and the control used in the test is a bromodomain egg recognition white BRD4 inhibitor (+)-JQ1.

Table 1 bromodomain protein BRD4 inhibitor enzyme activity test results

It can be seen from Table 1 that many of the compounds have good molecular activity, and in particular, the molecular activities of the compounds 27, 30, 35, 37 and 41 are slightly stronger than those of the positive (+)-JQ1. The relationship between the total structure and effect can be found that the substituent at the R ₁ position has a better methyl activity, the hydrogen atom and the ethyl group activity are all decreased; the substituent at the R ₂ position has a better methyl group activity, and the ethyl and isobutyl groups have lower activities. Moreover, the configuration of the substituent has little effect on the activity; the R ₃ substituent has a better cyclopropyl activity, and the isopropyl and cyclopentyl substitution activities are slightly decreased, isobutyl, 2-methoxyethyl, etc. The activity of other larger substituents is lower; the R ₄ position is better when the parent benzene ring is bonded to the carboxylic acid and the carboxylic acid is bonded to a different amino group to form an amide, wherein the amide nitrogen atom is substituted by a methyl group or an ethyl group. The unsubstituted activity is further improved.

2. Bromine domain recognition protein BRD4 inhibitor cell activity test method

Cell viability assays were tested for HT-29, MM.1S and TY-82 cell lines. The test methods were (1) HT-29 cells: human colon cancer HT-29 cells were treated with compound for 72 h. SRB method was used to detect the proliferation inhibition effect of compound and its degree; (2) MM.1S cells: human myeloma cells MM.1S, compound treatment for 72h, using ATP depletion method to detect the proliferation inhibition effect of the compound and its extent; 3) TY-82 cells: NUT-BRD4 midline cancer TY-82 cells were treated with compound for 72 hours, and the proliferation inhibition effect of the compounds was examined by SRB method.

Pharmacological data: The pharmacological test results of some of the compounds of the present invention are disclosed in Table 2 below, and the control used in the test is a bromodomain egg recognition white BRD4 inhibitor (+)-JQ1.

According to Table 2, it can be seen that the sensitivity of the compound to the MM.1S and TY-82 cell lines is higher than that of the HT-29 cell line, and the activities of the compounds 37 and 39 on the TY-82 cell line are very good, that is, when R _{The 4} -position is a mother benzene ring to which a carboxylic acid is attached and the carboxylic acid is bonded to a 4-methyl group or a 5-methyl porphyrin to have a very good activity.

3. Test method for metabolic stability and enzyme inhibition properties of compounds in liver microsomes

3.1 metabolic stability test test method

The system was 150 μl of liver microsomes (final concentration 0.5 mg/ml) for metabolic stability incubation. The system contained reduced coenzyme II (NADPH) (final concentration 1 mM) and 1 μM compound, positive control or negative control, respectively at 0 min. The reaction was terminated with acetonitrile containing (imiprozine, batch number: 3221; tinidazole, lot number: T3021) at 5 min, 10 min and 30 min, vortexed for 10 min, centrifuged at 15000 rpm for 10 min, and 50 μl of the supernatant was injected into a 96-well plate. The metabolic stability of the compound was calculated by measuring the relative reduction in the original drug.

3.2 Direct inhibition test (DI test) test method

Directly inhibited incubation with 100 μl of human liver microsomes (final concentration 0.2 mg/ml) containing NADPH (final concentration 1 mM), 10 μM compound, positive inhibitor cocktail cocktail (ketoconazole 10 μM, quinine) Din Quinidine 10 μM, Sulfaphenazole 100 μM, Naphthoflavone 10 μM, tranylcypromine 1000 μM, negative control 10 μM DMSO and mixed probe substrate (midazolam 10 μM, testosterone 100 μM, dextromethorphan Dextromethophan) 10 μM, Diclofenac 20 μM, phenacetin Phenacetin 100 μM, Mephenytoin 100 μM, and the reaction was stopped after incubation for 20 min. The relative activity of the enzyme was calculated by measuring the relative amount of production of the metabolite.

3.3 Mechanism inhibition test (TDI test) test method

Systemic inhibition of incubation with 200 μl of human liver microsomes (final concentration 0.2 mg/ml), 10 μM compound, mixed positive inhibitor (Taoleandomycin 10 μM, Paroxetine 10 μM, Tienilic Acid) Add NADPH (final concentration 1 mM) and mixed probe substrate after incubation with NADPH (final concentration 1 mM) or PBS for 10 min, 5 min, 10 min and 30 min after addition of 10 μM, furalineline 10 μM or 10 μM negative control PRO. (midazolam Midazolam 5 μM, testosterone Testosterone 50 μM, dextromethorphan Dextromethophan 5 μM, diclofenac 10 μM, phenacetin Phenacetin 50 μM, S-(+)-mefentoin S-(+)-mephenytoin 50 μM ), the reaction was terminated after incubation for 10 min. The positive inhibitor CYP2C19 was made alone, the inhibitor S-(+)-fluoxetine S-(+)-fluoxetine 100 μM. The enzyme activity was calculated by measuring the relative amount of metabolite produced. Calculate k _obs .

Pharmacological data: The pharmacological test results of some of the compounds of the present invention are disclosed in Table 3 below.

Table 3 Test results of metabolic stability and enzyme inhibition properties of liver microsomes

It can be seen from Table 3 that the R ₄ position is a parent benzene ring to which a carboxylic acid is bonded and the carboxylic acid is bonded to a different amino group to form an amide, which has good in vitro metabolic stability, especially with p-toluidine and 2,4-dimethylaniline. An amide formed by 3-fluoro-4-methylaniline.

Claims (10)

A compound represented by the formula (I), and stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates and crystal forms thereof:

among them: X is C or N; R ₁ is a hydrogen atom, a substituted or unsubstituted C1-C20 straight or branched alkyl group, a substituted or unsubstituted C1-C20 straight or branched alkoxy group, a substituted or unsubstituted C3-C10 cycloalkyl group The substituent is a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group; R ₂ is a substituted or unsubstituted C1-C20 straight or branched alkyl group, a substituted or unsubstituted C1-C20 straight or branched alkoxy group, a substituted or unsubstituted C3-C10 cycloalkyl group, The substituent is halogen, hydroxy, amino, nitro, cyano, and the configuration of R ₂ is R or S or a racemate; R ₃ is a substituted or unsubstituted C1-C20 straight or branched alkyl group, a substituted or unsubstituted C1-C20 straight or branched alkoxy group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or An unsubstituted benzyl group, which is independently selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, 5-7 members containing 1-3 heteroatoms selected from N, O and S a heterocyclic group, a C1-C3 straight or branched alkyl group or a C1-C3 straight or branched alkoxy group; L is

Or -CH ₂ -, wherein R ₅ is a hydrogen atom, a C1-C6 straight or branched alkyl group; R ₄ is a C1-C20 straight or branched alkyl group, a halogen-substituted C1-C20 straight or branched alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C3-C10 cycloalkane A substituted or unsubstituted C6-C20 aromatic ring, a substituted or unsubstituted C6-C20 aryl group, a substituted or unsubstituted C6-C12 aryl C1-C6 alkyl group, substituted or unsubstituted containing 1-3 selected 5-10 membered heterocyclic or heteroaryl group of a hetero atom of N, O and S, substituted or unsubstituted 5-10 membered heterocyclic group containing 1 to 3 hetero atoms selected from N, O and S Or a heteroaryl-substituted or unsubstituted C6-C12 aryl group, said substituents being independently selected from the group consisting of 1-4, halo, hydroxy, amino, nitro, cyano, C1-C6 straight or Branched alkyl or C1-C6 straight or branched alkoxy, or When L is

When R ₄ and R ₅ and the nitrogen atom to which they are attached form a substituted or unsubstituted 5-10 membered heterocyclic or heteroaryl group containing a N atom and 0-2 O, S hetero atoms and substituted or unsubstituted a C6-C20 aryl group, the substituents being independently selected from the group consisting of 1-2 groups: halogen, hydroxy, amino, nitro, cyano, C1-C6 straight or branched alkyl or C1-C6 straight Chain or branched alkoxy. The compound represented by the formula (I) according to claim 1, and stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates and crystal forms thereof, wherein X is C or N; R ₁ is a hydrogen atom, a C1-C6 linear or branched alkyl group or a halogen-substituted C1-C6 straight or branched alkyl group; R ₂ is a C1-C6 linear or branched alkyl group or a halogen-substituted C1-C6 straight or branched alkyl group, and the configuration of R ₂ is an R type or an S type or a racemate; R ₃ is a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted benzyl group, and the substituents are independently selected from the following 1 - 5 groups: halogen, hydroxy, 5-7 membered heterocyclic group containing 1-3 heteroatoms selected from N, O and S, C1-C3 straight or branched alkyl or C1-C3 straight chain or Branched alkoxy group; L is

Or -CH ₂ -, wherein R ₅ is a hydrogen atom, a C1-C3 straight or branched alkyl group; R ₄ is a C1-C6 straight or branched alkyl group, a halogen-substituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C3-C8 cycloalkane A substituted or unsubstituted C6-C12 aromatic ring, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C6-C12 aryl C1-C4 alkyl group, substituted or unsubstituted containing 1-3 selected 5-10 membered heterocyclic or heteroaryl group of a hetero atom of N, O and S, substituted or unsubstituted 5-10 membered heterocyclic group containing 1 to 3 hetero atoms selected from N, O and S Or a heteroaryl-substituted or unsubstituted C6-C10 aryl group, said substituents being independently selected from the group consisting of 1-4 groups: halogen, hydroxy, C1-C3 straight or branched alkyl or C1-C3 Linear or branched alkoxy, Or When L is

When R ₄ and R ₅ and the nitrogen atom to which they are attached form a substituted or unsubstituted 5-10 membered heterocyclic or heteroaryl group containing a N atom and 0-2 O, S hetero atoms and substituted or unsubstituted The C6-C12 aryl group is independently selected from the group consisting of 1-2 groups: halogen, hydroxy, C1-C3 straight or branched alkyl or C1-C3 straight or branched alkoxy. The compound represented by the formula (I) according to claim 1, and stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates and crystal forms thereof, wherein X is C or N; R ₁ is a hydrogen atom or a C1-C3 straight or branched alkyl group; R ₂ is a C1-C6 straight or branched alkyl group, and the configuration of R ₂ is an R type or an S type or a racemate; R ₃ is a substituted or unsubstituted C1-C6 straight or branched alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted benzyl group, and the substituents are independently selected from the following 1 - 4 groups: halogen, 5-7 membered heterocyclic group containing 1-2 heteroatoms selected from N and O, C1-C3 straight or branched alkyl or C1-C3 straight or branched alkoxy base; L is

Or -CH ₂ -, wherein R ₅ is a hydrogen atom, a C1-C3 straight or branched alkyl group; R ₄ is a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group and a substituted or unsubstituted C6-C12 aromatic ring, a substituted or unsubstituted C6-C12 aryl group, substituted or Unsubstituted C6-C12 aryl C1-C4 alkyl, substituted or unsubstituted 5-6 membered heterocyclic or heteroaryl group containing 1-3 heteroatoms selected from N, O and S, substituted or not Substituted 5-6 membered heterocyclic or heteroaryl substituted or unsubstituted C6-C10 aryl group containing from 1 to 3 heteroatoms selected from N, O and S, said substituents being independently selected from the group consisting of 1-4 groups: halogen, hydroxy, C1-C3 straight or branched alkyl or C1-C3 straight or branched alkoxy, or When L is

When R ₄ and R ₅ and the nitrogen atom to which they are attached form a substituted or unsubstituted 5-6 membered heterocyclic or heteroaryl group containing a N atom and 0-2 O, S hetero atoms and substituted or unsubstituted The C6-C10 aryl group is independently selected from the group consisting of 1-2 groups: halogen, hydroxy, C1-C3 straight or branched alkyl or C1-C3 straight or branched alkoxy. The compound represented by the formula (I) according to claim 1, and stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates and crystal forms thereof, wherein X is C or N; R ₁ is a hydrogen atom, a methyl group or an ethyl group; R ₂ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and the configuration of R ₂ is R or S or a racemate; R ₃ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxyethyl, containing 1-2 selected from N and a 5- to 6-membered heterocyclic-substituted C1-C3 linear or branched alkyl group of a hetero atom of O (preferably morpholinoethyl, tetrahydrofuranylmethyl), halogen or C1-C3 alkoxy-substituted benzyl (preferably Br substituted benzyl or methoxybenzyl); L is

Or -CH ₂ -, wherein R ₅ is a hydrogen atom, a methyl group or an ethyl group; R ₄ is a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group and a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted C6-C12 aryl group, substituted or Unsubstituted C6-C12 aryl C1-C3 alkyl, substituted or unsubstituted 5-6 membered heterocyclic or heteroaryl group containing from 1 to 2 heteroatoms selected from N and O, substituted or unsubstituted a C6-C10 aryl group having 1 to 6 membered heterocyclic or heteroaryl groups selected from 1 to 6 hetero atoms selected from N and O, the substituents being independently selected from the following 1-3 a group: a halogen, a C1-C3 straight or branched alkyl group or a C1-C3 straight or branched alkoxy group; preferably a cyclopentyl group, a cyclohexyl group, a methylcyclohexyl group, a phenyl group, a methylphenyl group, a chlorine group Phenyl, fluorophenyl, methoxyphenyl, isoxazolyl, 1,2,4-trimethylpyrazol-3-yl, methylbenzyl, 2,4-dimethylphenyl, 3 -fluoro-4-methylphenyl, 2,4,6-trimethylphenyl or pyrimidinyl, or When L is

When R ₄ and R ₅ and the nitrogen atom to which they are attached form a substituted or unsubstituted 5-6 membered heterocyclic or heteroaryl group containing a N atom and an optional O atom, and a substituted or unsubstituted C6-C10 aryl group. The substituent is independently selected from the group consisting of 1-2 groups: halogen, C1-C3 straight or branched alkyl or C1-C3 straight or branched alkoxy; preferably R ₄ and R ₅ may And the nitrogen atom to which they are attached form a dihydroindenyl group, a methyl-substituted indanyl group, an F-substituted indanyl group or

The compound represented by the formula (I) according to claim 1, and stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates and crystal forms thereof, wherein The compound is selected from:

A method of producing a compound represented by the formula (I) according to claim 1, which comprises Reaction route 1:

Step a: Compound 1A is reacted with amino acid NH ₂ R ₂ COOH to obtain Compound 1B; Step b: Compound 1B is reacted under the conditions of tin dichloride dihydrate to obtain compound 1C; Step c: compound 1C and R ₁ I are reacted under sodium hydride to obtain compound 1D; Step d: Compound 1D with sulfonamide R ₄ SO ₂ NH ₂ in allyl palladium chloride dimer, 2-di-tert-butylphosphino-2', 4',6'-triisopropylbiphenyl and potassium carbonate Compound 1E is obtained by a coupling reaction under the conditions; Step e: Compound 1E is reacted with R ₅ I under sodium hydride to obtain compound 1F. or Reaction route two:

Step a: compound 2A is reacted with a primary amine R ₃ NH ₂ to obtain a compound 2B; Step b: compound 2B is reacted under iron powder and ammonium chloride to obtain compound 2C; Step c: 1) Compound 2C with a different 2-bromoalkanoyl bromide

The reaction gives an intermediate, 2) the intermediate is obtained by intramolecular nucleophilic reaction under N,N-diisopropylethylamine to obtain compound 2D; Step d: compound 2D is reacted with R ₁ I to obtain compound 2E; Step e: Compound 2E with sulfonamide R ₄ SO ₂ NH ₂ in allyl palladium chloride dimer, 2-di-tert-butylphosphino-2', 4',6'-triisopropylbiphenyl and potassium carbonate The compound of the formula 2F is obtained by a coupling reaction under the conditions; Step f: compound 2F and R ₅ I are reacted under sodium hydride to obtain compound 2G; Alternatively, after steps a-d, steps e and f are not performed, but the following steps are performed: Step g: 1) Compound 2E is coupled with tert-butyl carbamate under conditions of Pd(OAc) ₂ , 2-dicyclohexylphosphine-2', 4',6'-triisopropylbiphenyl and cesium carbonate. The reaction gives the intermediate, 2) the intermediate is deprotected under the action of trifluoroacetic acid to obtain the compound 2H; Step h: compound 2H is reacted with different acid chloride R ₄ COCl to obtain compound 2I; Step i: Compound 2I is reacted with R ₅ I under sodium hydride to obtain compound 2J. or Reaction route three:

Step a: compound 3A is reacted with thionyl chloride and methanol to obtain compound 3B; Step b: compound 3B is reacted with different primary amines R ₃ NH ₂ to obtain compound 3C; Step c: compound 3C is reacted under iron powder and ammonium chloride to obtain compound 3D; Step d: 1) Compound 3D with a different 2-bromoalkanoyl bromide

The reaction gives an intermediate, 2) the intermediate is obtained by intramolecular nucleophilic reaction under N,N-diisopropylethylamine to obtain compound 3E; Step e: compound 3E and R ₁ I are reacted under sodium hydride to obtain compound 3F; Step f: compound 3F is obtained by hydrolysis reaction under lithium hydroxide to obtain compound 3G; Step g: Compound 3G is reacted with an amine R ₄ R ₅ NH to obtain a compound 3H by condensation reaction. or Reaction route four:

Step a: Compound 4A and 2-bromoalkanoyl bromide

Reaction gives compound 4B; Step b: compound 4B is reacted with an amine R ₃ NH ₂ to obtain a compound 4C; Step c: Compound 4C is obtained by intramolecular nucleophilic reaction under N,N-diisopropylethylamine to obtain compound 4D; Step d: compound 4D and R ₁ I are reacted under sodium hydride to obtain compound 4E; Step e: Compound 4E with sulfonamide R ₄ SO ₂ NH ₂ in allyl palladium chloride dimer, 2-di-tert-butylphosphino-2', 4',6'-triisopropylbiphenyl and potassium carbonate Compound 4F is obtained by a coupling reaction; Step f: compound 4F and R ₅ I are reacted under sodium hydride to obtain compound 4G; Alternatively, after steps a-d, steps e and f are not performed, but the following steps are performed: Step g: Compound 4E and amine R ₄ R ₅ NH in triethylamine, 4-dimethylaminopyridine, hexacarbonyl molybdenum, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride And reacting with 1,8-diazabicycloundec-7-ene to obtain compound 4H; Alternatively, after steps a-d, without performing steps e and f or g, the following steps are performed: Step h: 1) Compound 4E is coupled with tert-butyl carbamate under conditions of Pd(OAc) ₂ , 2-dicyclohexylphosphine-2', 4',6'-triisopropylbiphenyl and cesium carbonate. The reaction gives the intermediate, 2) the intermediate is deprotected under the action of trifluoroacetic acid to obtain the compound 4I; Step i: Compound 4I is reacted with an acid chloride R ₄ COCl to obtain a compound 4J; Step j: Compound 4J is reacted with R ₅ I under sodium hydride to obtain compound 4K. In Reaction Schemes 1 to 4, R _{1 -} R ₄ , L and X are the same as defined in claim 1. or Reaction route five:

Step a: compound 5A and amine R ₄ H by reductive amination reaction to obtain compound 5B; Step b: compound 5B is reacted with different amines R ₃ NH ₂ to obtain compound 5C; Step c: compound 5C is reacted with tin dichloride dihydrate and concentrated hydrochloric acid to obtain compound 5D; Step d: 1) Compound 5D with a different 2-bromoalkanoyl bromide

The reaction gives an intermediate, 2) the intermediate is obtained by intramolecular nucleophilic reaction under N,N-diisopropylethylamine to obtain compound 5E; Step e: Compound 5E is reacted with R ₁ I under sodium hydride to obtain compound 5F. In Reaction Scheme 5, R _{1 -} R ₃ , L and X are the same as defined in Claim 1, and R ₄ is a substituted or unsubstituted 5-half-containing hetero atom selected from N, O and S. 10-membered heterocyclic or heteroaryl, substituted or unsubstituted C6- substituted or unsubstituted 5-10 membered heterocyclic or heteroaryl containing 1-3 heteroatoms selected from N, O and S a C12 aryl group, the substituents being independently selected from the group consisting of 1-4 groups: halogen, hydroxy, amino, nitro, cyano, C1-C6 straight or branched alkyl or C1-C6 straight or branched Alkenyloxy, and R ₄ contains an N atom. A pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the formula (I) according to claim 1, and stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates thereof, and One or more of the crystalline forms, and at least one excipient, diluent or carrier. A compound represented by the formula (I) according to claim 1, and stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates and crystal forms thereof for preparing a bromodomain recognition protein Use in selective inhibitors. A compound represented by the formula (I) according to claim 1, and stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates and crystal forms thereof, for the preparation of a treatment identified by a bromine domain The use of proteins in protein-mediated related diseases. The use according to claim 9, wherein the related diseases mediated by the bromodomain recognition protein include hematological malignancies, midline cancer, and inflammatory diseases.

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