TW201728587A - Inhibitor of Bruton's tyrosine kinase - Google Patents

Abstract

The present invention relates to an inhibitor of Bruton's tyrosine kinase. A structure of the inhibitor is represented by formula (I). The inhibitor has a good selective inhibitory effect.

Description

Bruton tyrosine kinase inhibitor

The present invention relates to a Bruton tyrosine kinase inhibitor, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or a N - Oxide, belonging to the field of medicine.

Bruton's tyrosine kinase (Btk, hereinafter referred to as Btk) is a member of the Tec family of non-receptor tyrosine kinases. It is expressed in all hematopoietic cell types except T lymphocytes, natural killer cells and plasma cells, such as B cells, mast cells and macrophages, and is an important mediator of at least three key B cell survival mechanisms. Btk also acts as part of the B cell signaling pathway via the B-cell antigen receptor (BCR). This multiple action of Btk allows it to direct B-cell malignancies into lymphoid tissues, allowing tumor cells to survive the necessary microenvironment. Experimental data indicate that Btk also plays a role in the signaling pathways of monocytes, macrophages, neutrophils and mast cells. Btk inhibitors can also inhibit Fc-mediated cytokine release by monocytes as well as macrophages, as well as FcR-mediated cell degranulation. The lack of Btk has been shown to block B cell antigen receptor signaling, so compounds with Btk inhibitory activity can act as blocking B cell and/or mast cell-mediated related diseases such as cancer, autoimmune diseases, Effective treatments for thromboembolic diseases and inflammatory diseases, International Reviews of Immunology, 2012, 31, 119-132; Arthritis Research & Therapy, 2011, 13 , R115; Clin. Exp. Immunol. 1993, 94, 459; Chem. MedChem. 2007, 2, 58-61. A Btk inhibitor having the following formula (i) is disclosed in International Publication No. WO2008121742:

When L in the structure of formula (i) is selected from O, Ar is selected from benzene, Y is selected from acridine, Z is selected from carbonyl, and R ⁱ , R ⁱⁱ and R ⁱⁱⁱ are each selected from H, and an existing compound is obtained. Ibrutinib (trade name: Imbruvica) having the structure shown by the following formula (ii):

Ibrutinib was approved by the US FDA on November 13, 2013. Treatment is used to treat mantle cell lymphoma. In addition, ibrutinib has shown great potential in the treatment of chronic lymphocytic leukemia and multiple myeloma.

Another Btk inhibitor having the structure shown by formula (iii) below is disclosed in the publication No. CN102918040: The compound having such a structure has excellent Btk selective inhibitory activity and is a compound which is excellent in metabolic stability and can avoid hepatotoxicity, and thus can be used as a safety-preserving B cell and/or hypertrophy with non-Hodgkin's lymphoma. A therapeutic agent for cell-related diseases.

A Btk inhibitor having the following formula (iv) is disclosed in the patent application published as WO 2015048689:

The compound is also disclosed for the treatment of autoimmune, abnormal Use of diseases such as immunity and cancer.

As the research progresses, the structure of Btk inhibitors and the range of their indications have also undergone deeper changes.

It is an object of the present invention to provide a Bruton's tyrosine kinase inhibitor which has a selective inhibitory effect. For non-Hodgkin's lymphoma, B-cell non-Hodgkin's lymphoma is preferred, for example: diffuse Severe B-cell lymphoma, human B-lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia (WM) and B-cell chronic lymphocytic leukemia have good Inhibitory effect.

In one aspect, the invention provides a compound of the formula (I), a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, and a foreign product. Spinor or N-oxide:

Wherein: W is a 4-6 membered nitrogen-containing saturated heterocyclic group, a benzylidene (C ₃ -C ₆ )cycloalkyl group or a [3.3-5] nitrogen-containing saturated heterospirocyclic group; and R ¹ or R ² are each independently Is selected from H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy, phenyl, Substituted phenyl, benzene (C ₂ -C ₄ ) alkynyl, benzene (C ₁ -C ₄ )alkyl, benzylidene (C ₃ -C ₆ )cycloalkyl, substituted benzene (C ₁ -C ₄ ) alkane , phenoxyalkyl, substituted phenoxyalkyl, benzene (C ₁ -C ₄ ) alkoxy, substituted benzene (C ₁ -C ₄ ) alkoxy, benzene (C ₂ -C ₄ )alkenyl, substituted Benzene (C ₂ -C ₄ )alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, nitrogen-containing heterophenyl substituted (C ₁ -C ₄ ) alkoxy and One or more of them; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; a substituted phenyl group or a substituted nitrogen-containing heterophenyl group The substituents may each independently be selected from the group consisting of halogen, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl, aminemethanyl, B One or more of amidino group and (C ₁ -C ₄ )haloalkoxy group; any integer between n=0-4; R ^{3 is} selected from (C ₂ -C ₄ )alkenyl, (C ₂ - C ₄₎ alkynyl group, propenyl amine, N, N- disubstituted propenyl, one or more amines, and (C ₄ -C ₇₎ nitrogen-containing saturated heterocyclic group-substituted propenyl group, wherein the substituents on the amine The substituent includes one or more of a (C ₁ -C ₄ )alkyl group and a hydroxyl group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (II):

Wherein W is a 4-6 membered nitrogen-containing saturated heterocyclic group, a benzylidene (C ₃ -C ₆ )cycloalkyl group or a [3.3-5] nitrogen-containing saturated heterospirocyclic group; and R ¹ or R ² are each independently Is selected from H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy, phenyl, Substituted phenyl, benzene (C ₂ -C ₄ ) alkynyl, phenyl (C ₁ -C ₄ )alkyl, benzyl (C ₃ -C ₆ )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl a benzene (C ₁ -C ₄ ) alkoxy group, a substituted benzene (C ₁ -C ₄ ) alkoxy group, a benzene (C ₂ -C ₄ ) alkenyl group, a substituted benzene (C ₂ -C ₄ ) alkenyl group, Azaphenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkoxy and One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; any integer between n=0-4; R ^{3 is} selected from (C ₂ -C ₄ )alkenyl, (C ₂ -C ₄ )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C ₄ -C ₇ ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C ₁ -C ₄ )alkyl group and a hydroxyl group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (III):

Wherein R ¹ or R ² are each independently selected from H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C) ₄ ) haloalkoxy, phenyl, substituted phenyl, benzene (C ₁ -C ₄ )alkyl, benzylidene (C ₃ -C ₆ )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C ₁ -C ₄ ) alkoxy group, benzene (C ₂ -C ₄ ) alkenyl group, substituted benzene (C ₂ -C ₄ ) alkenyl group, nitrogen-containing heterophenyl group, substituted nitrogen-containing heterophenyl group, nitrogen-containing hetero a phenyl-substituted (C ₁ -C ₄ ) alkyl group, a nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ ) alkoxy group, and One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; any integer between n=0-4; R ^{3 is} selected from (C ₂ -C ₄ )alkenyl, (C ₂ -C ₄ )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C ₄ -C ₇ ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C ₁ -C ₄ )alkyl group and a hydroxyl group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (IV):

Wherein R ^{2 is} selected from the group consisting of phenyl, substituted phenyl, phenyl (C ₁ -C ₄ ) alkyl, substituted benzene (C ₁ -C ₄ ) alkyl, substituted benzene (C ₁ -C ₄ ) alkoxy a benzylidene (C ₃ -C ₆ )cycloalkyl group, a phenoxyalkyl group, a substituted phenoxyalkyl group, a benzene (C ₁ -C ₄ ) alkoxy group, a benzene (C ₂ -C ₄ )alkenyl group, Substituted benzene (C ₂ -C ₄ ) alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, nitrogen-containing heterophenyl substituted ( C ₁ -C ₄ ) alkoxy and One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; any integer between n=0-4; R ^{3 is} selected from (C ₂ -C ₄ )alkenyl, (C ₂ -C ₄ )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C ₄ -C ₇ ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C ₁ -C ₄ )alkyl group and a hydroxyl group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (V):

Wherein X and Y are each independently selected from CH or N, and R ^{4 is} selected from the group consisting of H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ - C ₄ ) one of a haloalkyl group, an amine carbenyl group, an ethenyl group, and a (C ₁ -C ₄ )haloalkoxy group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (VI):

Wherein R ^{4 is} selected from the group consisting of H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl, aminecaraki, B One of a guanamine group and a (C ₁ -C ₄ )haloalkoxy group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (VII):

Wherein R ^{4 is} selected from the group consisting of H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl, aminecaraki, B One of a guanamine group and a (C ₁ -C ₄ )haloalkoxy group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (VIII):

Wherein R ⁵ and R ⁶ are each independently selected from the group consisting of H, halogen, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl and One or more of (C ₁ -C ₄ )haloalkoxy groups.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (IX):

Wherein R ⁵ and R ⁶ are each independently selected from the group consisting of H, halogen, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl and One or more of (C ₁ -C ₄ )haloalkoxy groups.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (X):

Wherein X, Y and Z are each independently selected from CH or N; and R ⁵ and R ⁶ are each independently selected from H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl One or more of a cyano group, a (C ₁ -C ₄ )haloalkyl group, and a (C ₁ -C ₄ )haloalkoxy group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XI):

Wherein R ^{1 is} selected from the group consisting of phenyl, substituted phenyl, benzene (C ₂ -C ₄ ) alkynyl, phenyl (C ₁ -C ₄ )alkyl, substituted benzene (C ₁ -C ₄ )alkyl, substituted benzene ( C ₁ -C ₄ ) alkoxy, benzylidene (C ₃ -C ₆ )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C ₁ -C ₄ ) alkoxy, benzene (C ₂ -C ₄ )alkenyl, substituted benzene (C ₂ -C ₄ )alkenyl, nitrogen-containing heterophenyl, substituted aza-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, a nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ ) alkoxy group and One or more of them; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R ^{3 is} selected from (C ₂ -C ₄ ) alkene One or more of a (C ₂ -C ₄ )alkynyl group, an amine propylene group, an N,N-disubstituted amine propylene group, and a (C ₄ -C ₇ ) nitrogen-containing saturated heterocyclic group-substituted propylene group, wherein The substituent on the substituted amine includes one or more of a (C ₁ -C ₄ )alkyl group and a hydroxyl group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XII) shows:

Wherein X and Y are each independently selected from CH or N, and R ^{4 is} selected from the group consisting of H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ - C ₄ ) one of a haloalkyl group, an amine carbenyl group, an ethenyl group, and a (C ₁ -C ₄ )haloalkoxy group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XIII):

Wherein R ⁵ and R ⁶ are each independently selected from H, halogen, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl and One or more of (C ₁ -C ₄ )haloalkoxy groups.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XIV) shows:

Wherein R ⁵ and R ⁶ are each independently selected from the group consisting of H, halogen, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl and One or more of (C ₁ -C ₄ )haloalkoxy groups.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XV) shows:

Wherein X, Y and Z are each independently selected from CH or N; and R ⁵ and R ⁶ are each independently selected from H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl One or more of a cyano group, a (C ₁ -C ₄ )haloalkyl group, and a (C ₁ -C ₄ )haloalkoxy group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XVI) shows:

Wherein R ^{4 is} selected from the group consisting of H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl, aminecaraki, B One of a guanamine group and a (C ₁ -C ₄ )haloalkoxy group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XVII) shows:

Wherein R ^{4 is} selected from the group consisting of H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl, aminecaraki, B One of a guanamine group and a (C ₁ -C ₄ )haloalkoxy group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XVIII):

Wherein R ¹ or R ² are each independently selected from H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C) ₄ ) haloalkoxy, phenyl, substituted phenyl, benzene (C ₂ -C ₄ ) alkynyl, benzene (C ₁ -C ₄ )alkyl, substituted benzene (C ₁ -C ₄ )alkyl, benzene methylene (C ₃ -C ₆ )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C ₁ -C ₄ ) alkoxy, substituted benzene (C ₁ -C ₄ ) alkoxy, benzene (C ₂ -C ₄ )alkenyl, substituted benzene (C ₂ -C ₄ )alkenyl, nitrogen-containing heterophenyl, substituted aza-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, a nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ ) alkoxy group and One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; any integer between n=0-4; R ^{3 is} selected from (C ₂ -C ₄ )alkenyl, (C ₂ -C ₄ )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C ₄ -C ₇ ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C ₁ -C ₄ )alkyl group and a hydroxyl group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XIX) shows:

Wherein R ^{2 is} selected from the group consisting of phenyl, substituted phenyl, phenyl(C ₁ -C ₄ )alkyl, benzylidene(C ₃ -C ₆ )cycloalkyl, substituted benzene(C ₁ -C ₄ )alkyl, Benzene (C ₁ -C ₄ )alkoxy, substituted benzene (C ₁ -C ₄ )alkoxy, phenoxyalkyl, substituted phenoxyalkyl, phenyl(C ₂ -C ₄ )alkenyl, substituted benzene C ₂ -C ₄ )alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, nitrogen-containing heterophenyl substituted (C ₁ - C ₄ ) alkoxy and One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R ^{1 is} selected from the group consisting of H, (C ₁ -C ₄ An alkyl group, (C ₁ -C ₄ ) alkoxy group, (C ₁ -C ₄ )haloalkyl group or (C ₁ -C ₄ )haloalkoxy group; R ^{3 is} selected from (C ₂ -C ₄ )alkenyl group, One or more of (C ₂ -C ₄ )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl, and (C ₄ -C ₇ )nitrogen-containing saturated heterocyclic substituted propenyl, wherein The substituent on the substituted amine includes one or more of a (C ₁ -C ₄ )alkyl group and a hydroxyl group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XX):

Wherein R ^{2 is} selected from the group consisting of phenyl, substituted phenyl, phenyl(C ₁ -C ₄ )alkyl, benzylidene(C ₃ -C ₆ )cycloalkyl, substituted benzene(C ₁ -C ₄ )alkyl, Benzene (C ₁ -C ₄ )alkoxy, substituted benzene (C ₁ -C ₄ )alkoxy, phenoxyalkyl, substituted phenoxyalkyl, phenyl(C ₂ -C ₄ )alkenyl, substituted benzene C ₂ -C ₄ )alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, nitrogen-containing heterophenyl substituted (C ₁ - C ₄ ) alkoxy and One or more of them; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R ^{3 is} selected from (C ₂ -C ₄ ) alkene One or more of a (C ₂ -C ₄ )alkynyl group, an amine propylene group, an N,N-disubstituted amine propylene group, and a (C ₄ -C ₇ ) nitrogen-containing saturated heterocyclic group-substituted propylene group, wherein The substituent on the substituted amine includes one or more of a (C ₁ -C ₄ )alkyl group and a hydroxyl group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XXI) shows:

Wherein R ⁵ and R ⁶ are each independently selected from the group consisting of H, halogen, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl and One or more of (C ₁ -C ₄ )haloalkoxy groups.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XXII)

Wherein R ⁵ and R ⁶ are each independently selected from the group consisting of H, halogen, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl and One or more of (C ₁ -C ₄ )haloalkoxy groups.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XXIII):

Wherein R ⁵ and R ⁶ are each independently selected from the group consisting of H, halogen, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl and One or more of (C ₁ -C ₄ )haloalkoxy groups.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, such as (XXIV) shows:

Wherein X, Y and Z are each independently selected from CH or N; and R ⁵ and R ⁶ are each independently selected from H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl One or more of a cyano group, a (C ₁ -C ₄ )haloalkyl group, and a (C ₁ -C ₄ )haloalkoxy group.

Preferably, the compound, its cis-trans isomer, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxide, The compound is selected from one or more of the following compounds: 1-(3-(4-amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazole [3,4 -d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-(5-phenylthiophen-2-yl)- 1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-(4-() Phenoxymethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3 -(4-Amino-3-(5-methyl-4-(phenoxymethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine-1 -yl)prop-2-en-1-one; 1-(3-(4-amino-3-(5-(phenoxymethyl)thiophen-3-yl)-1H-pyrazole [3,4- d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-(4-((2-methyl))phenoxy) Thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4 -amino-3-(4-((m-methyl)phenoxymethyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl)acridin-1-yl )prop-2-en-1-one; 1-(3-(4-amino-3-(4-((p-methyl)phenoxymethyl)thiophen-2-yl)-1H-pyrazole [ 3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-(4-((2-methoxy)) Phenoxymethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; -(3-(4-Amino-3-(4-((3-methoxy)phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Acridine-1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-(4-(4-methoxy)phenoxymethyl)thiophene-2- -1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-() 2-((2-cyano)phenoxymethyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-ene 1-ketone; 1-(3-(4-cyano)-3-(2-((4-cyano)phenoxymethyl)thiophen-4-yl)-1H-pyrazole [3,4-d] Pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-(2-(3-cyano)phenoxymethyl)) Thiophen-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4-amino) 3-(2-(2-methoxyphenyl)oxymethylthiophen-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)propane- 2-en-1-one; 1-(3-(4-ammonia) 3-(2-(3-methoxyphenyl)oxymethylthiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)propane- 2-en-1-one; (R) -1-(3-(4-amino-3-(5-phenylthiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1- (R) -1-(3-(4-amino-3-(5-(phenoxymethyl))thiophen-3-yl) -1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3) -(5-((pyrimidin-4-yloxy)methyl)thiophen-3-yl)-1H-pyrazole [3,4-d]-pyrimidin-1-yl)acridin-1-yl) 2-en-1-one; 1-(3-(4-amino-3-(5-((2-methoxy-4-methylphenoxy)methyl)thiophen-3-yl)-) 1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-(5-() (2-methoxy-4-chlorophenoxy)methyl)thiophen-3-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)propane- 2-en-1-one; (R) -1-(3-(4-amino-3-(5-((2-methoxy-4-cyanophenoxy)methyl)thiophene-3- -1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino) -3-(5-((2-chloro-5-methoxyphenoxy)methyl)thiophen-3-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridine -1-yl)prop-2-ene-1- ; (R) -1- (3- ( 4- amino-3- (5 - ((3-chloro-5-methoxyphenoxy) methyl) thiophen-3-yl) lH-pyrazolo [ 3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(( 3-methoxy-4-cyanophenoxy)methyl)thiophen-3-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)propane- 2-en-1-one; (R) -1-(3-(4-Amino-3-(5-(2-methylphenoxymethyl)thiophen-3-yl)-1H-pyrazole [3 , 4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(4-) Tolyloxymethyl)thiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) 1-(3-(4-Amino-3-(5-(3-methylphenyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine -1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(3,4-dimethylphenyl)thiophen-2-yl) -1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-) 3-(5-(3-methoxyphenyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-ene 1-ketone; (R) -1-(3-(4-amino-3-(5-(4-methoxyphenyl)thiophen-2-yl)-1H-pyrazole [3,4-d Pyrimidin-1-yl)acridin-1-yl)prop-2-ene-1 -ketone; (R) -1-(3-(4-amino-3-(4-phenylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine -1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-phenylthiophen-3-yl)-1H-pyrazole [3, 4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(4-) Fluoromethylphenyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) 1-(3-(4-Amino-3-(5-(3-trifluorotoluene)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine- 1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(3,5-dimethylphenyl)thiophen-2-yl)-1H- Pyrazole [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (S) -1-(3-(4-amino-3-(5) -phenylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1- (3-(4-Amino-3-(5-(2-fluorophenyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl ) prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(3-fluorophenyl)thiophen-2-yl)-1H-pyrazole [3 , 4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(4-) Fluorophenyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl)pyridin-1- ) Prop-2-en-1-one; (R) -1- (3- ( 4- amino-3- (2- (3-methylphenyl) thiophen-4-yl) lH-pyrazolo [ 3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(2-(4) -Methoxyphenyl)thiophen-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R ) -1-(3-(4-Amino-3-(5-(3-methoxyphenyl)thiophen-3-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Acridine-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(2-fluorophenoxy)methyl)thiophene- 3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4 -amino-3-(5-((3-fluorophenoxy)methyl)thiophen-3-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl )prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-((4-fluorophenoxy)methyl)thiophen-3-yl)-1H) -pyrazol[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (S) -1-(3-(4-amino-3-() 5-(phenoxymethyl)thiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-acridin-1-yl)prop-2-en-1-one (R) -1-(3-(4-Amino-3-(2-(phenylethyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)- piperidin-1-yl) prop-2-en-1-one; (R & lt) trans-1- (3- (4- -3-(2-styrenethiophen-4-yl)-1H-pyrazo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; -(3-(4-Amino-3-(2-((3-methylphenyl)oxymethyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl) Acridine-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(2-pyridylaminomethyl)thiophen-2-yl) -1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-) 3-(5-(3-Pyridinylamino)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-ene 1-ketone; (R) -1-(3-(4-amino-3-(5-(4-pyridylaminomethyl)thiophen-2-yl)-1H-pyrazole [3,4-d Pyrimidine-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(anilinylcarbenyl)) Thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3- (4-Amino-3-(2-(2-pyridylaminomethyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl )prop-2-en-1-one; (R) -1-(3-(4-amino-3-(2-(3-pyridylaminomethyl)thiophen-4-yl)-1H-pyridyl Azole [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(2- (4-pyridinamine Acyl methyl) thiophen-4-yl) lH-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one; (R) -1 -(3-(4-Amino-3-(2-(anilinomethyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1- ())- 1-(3-(4-amino-3-(4-(2-pyridylaminomethyl) thiophen-2-yl)-1H- Pyrazole [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(4) -(3-pyridylaminocarbamimidyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1- Ketone; (R) -1-(3-(4-amino-3-(4-(4-pyridylaminomethyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidine -1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(4-(anilinomethyl)thiophene)- 2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4 -amino-3-(5-(pyridin-2-yl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)propan-2- En-1-one; (R) -1-(3-(4-amino-3-(5-(pyridin-3-yl)thiophen-2-yl)-1H-pyrazole [3,4-d] Pyrimidine-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(4-(pyridin-2-yl))thiophene -2-base)-1H- Oxazole [3,4-d] pyrimidine-1-yl) piperidin-1-yl) prop-2-en-1-one; (R & lt) -1- (3- (4-amino-3- (4- (pyridin-3-yl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (S ) -1- (3- (4-amino-3- (5- (pyridin-2-yl) thiophen-2-yl) lH-pyrazolo [3,4-d] pyrimidin-1-yl) piperidino -1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(6-cyanopyridin-2-yl)thiophen-2-yl) -1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -6-(5-(1-(1) - propylene acridine-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophen-2-yl)-pyridinium amide; (R) -6-( 5-(1-(1-Acryl-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophen-2-yl)-3-pyridine A Indoleamine; (R) -N-(6-(5-(1-(1-Acryl-3-yl)-4-amino-1H-pyrazole[3,4-d]pyrimidine-3- (R) -N-(6-(5-(1-(1-propenyl)-3-yl)-4-amino- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophen-2-yl)pyridin-3-yl)acetamide; (R) -1-(3-(4-amino-3-() 5-(6-methylpyridin-2-yl)thiophen-2-yl)-1H-pyrazo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-ene- 1-one; (R) -1- (3- ( 4- 3-(5-(5-methylpyridin-2-yl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)propan -2-en-1-one.

The present invention also provides a compound represented by the following formula (XXV) or a salt of the compound,

Wherein R ¹ or R ^{2 is} selected from the group consisting of H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkane Oxyl, phenyl, substituted phenyl, benzene (C ₂ -C ₄ ) alkynyl, phenyl (C ₁ -C ₄ )alkyl, benzylidene (C ₃ -C ₆ )cycloalkyl, substituted benzene (C ₁ -C ₄ )alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C ₁ -C ₄ ) alkoxy, substituted benzene (C ₁ -C ₄ ) alkoxy, benzene (C ₂ -C ₄ ) alkenyl, substituted benzene (C ₂ -C ₄ ) alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, aza-containing Phenyl substituted (C ₁ -C ₄ ) alkoxy and One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R ^{7 is} selected from H or Wherein R ^{3 is} selected from the group consisting of trifluoromethyl, tert-butoxy and benzyloxy; when R ⁷ is H, the salt of the compound of formula (XXV) may be hydrochloride, sulfate, acetate and One of the fluoroacetates. The compound of the formula (XXV) or a salt thereof is an intermediate compound of the compound of the formula (I) to the formula (XXIV).

Preferably, wherein the compound is as follows:

Wherein R ¹ or R ² are each independently selected from H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C) ₄ ) haloalkoxy, phenyl, substituted phenyl, benzene (C ₂ -C ₄ ) alkynyl, benzene (C ₁ -C ₄ )alkyl, benzyl (C ₃ -C ₆ )cycloalkyl, substituted Benzene (C ₁ -C ₄ )alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C ₁ -C ₄ ) alkoxy, substituted benzene (C ₁ -C ₄ ) alkoxy, benzene (C ₂ -C ₄ )alkenyl, substituted benzene (C ₂ -C ₄ )alkenyl, nitrogen-containing heterophenyl, substituted aza-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, a nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ ) alkoxy group and One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R ^{7 is} selected from H or Wherein R ^{3 is} selected from the group consisting of trifluoromethyl, tert-butoxy and benzyloxy; when R ⁷ is H, the salt of the compound of formula (XXVI) may be hydrochloride, sulfate, acetate and One of the fluoroacetates.

Preferably, wherein the compound is as follows:

Wherein R ^{1 is} selected from the group consisting of H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy, Phenyl, substituted phenyl, benzene (C ₂ -C ₄ ) alkynyl, benzene (C ₁ -C ₄ )alkyl, benzylidene (C ₃ -C ₆ )cycloalkyl, substituted benzene (C ₁ -C ₄ ) alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C ₁ -C ₄ ) alkoxy, substituted benzene (C ₁ -C ₄ ) alkoxy, benzene (C ₂ -C ₄ ) olefin a substituted benzene (C ₂ -C ₄ )alkenyl group, a nitrogen-containing heterophenyl group, a substituted nitrogen-containing heterophenyl group, a nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl group, a nitrogen-containing heterophenyl group substituted (C ₁ -C ₄ ) alkoxy group and One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R ^{7 is} selected from H or Wherein R ^{3 is} selected from the group consisting of trifluoromethyl, tert-butoxy and benzyloxy; when R ⁷ is H, the salt of the compound of formula (XXVII) may be hydrochloride, sulfate, acetate and One of the fluoroacetates.

The present invention also provides a compound represented by the following formula (XXVIII), wherein the compound is as follows:

Wherein R ^{8 is} selected from H, Br or a boronic acid group, and R ^{9 is} selected from the group consisting of H, methyl, cyano, amine indenyl or ethenyl. The compound of the formula (XXVIII) is an intermediate compound of the compound of the formula (I) - formula (XXIV).

Preferably, wherein the compound is as shown in the following formula (XXIX):

Wherein R ^{8 is} selected from H, Br or a boronic acid group, and R ^{9 is} selected from the group consisting of H, methyl, cyano, amine indenyl or ethenyl.

Preferably, wherein the compound is represented by the following formula (XXX):

Wherein R ^{8 is} selected from H, Br or a boronic acid group, and R ^{9 is} selected from the group consisting of H, methyl, cyano, amine indenyl or ethenyl.

Preferably, wherein the compound is represented by the following formula (XXXI):

Wherein R ^{8 is} selected from H, Br or a boronic acid group, and R ^{9 is} selected from the group consisting of H, methyl, cyano, amine indenyl or ethenyl.

Preferably, wherein the compound is as shown in the following formula (XXXII):

Wherein R ^{8 is} selected from H, Br or a boronic acid group, and R ^{9 is} selected from the group consisting of H, methyl, cyano, amine indenyl or ethenyl.

The invention also provides a compound of the invention, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation. Use in the preparation of a medicament for the treatment of a medicament associated with malignant tumors, autoimmune diseases and allergic diseases.

Preferably, the malignant tumor comprises one or more of lymphoma, plasmacytoma and leukemia.

Preferably, the lymphoma comprises non-Hodgkin's lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, intravascular large cell type B cell lymphoma, One or more of Kitt's lymphoma, AIDS-associated lymphoma, and marginal zone B-cell lymphoma.

Preferably, said non-Hodgkin's lymphoma comprises B-cell non-Hodgkin's lymphoma.

More preferably, the B-cell non-Hodgkin's lymphoma comprises one or more of diffuse large B-cell lymphoma and human B-lymphoma.

Preferably, the autoimmune diseases include one or more of arthritis, rheumatism, inflammatory bowel disease, and lupus erythematosus.

In a further aspect, the present invention provides a Bruton tyrosine kinase inhibitor composition comprising a compound of the invention, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a pair a mixture of polarisomers, a racemate or an N-oxide.

Fig. 1 is a graph showing the improvement of the disease in mice by the action of the compound of the present invention on rheumatoid arthritis mice.

The following examples are intended to exemplify the invention, and are not intended to limit the invention, and modifications, changes, variations and the like are possible within the scope of the invention.

Unless otherwise indicated, the term "bruton tyrosine kinase inhibitor" is provided herein to include having formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI). ), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI) a compound of the formula (XVII), formula (XVIII), formula (XIX), formula (XX), formula (XXI), formula (XXII), formula (XXIII), formula (XXIV), each compound Included are stereoisomers having the same structural formula, wherein the stereoisomers also include optical isomers and geometric isomers, optical isomers are also known as enantiomers, and geometric isomers are also known. Cis and trans isomers.

Optical enantiomers are optical enantiomers that have mirror images of each other.

A mixture of optical enantiomers refers to a mixture of two optical enantiomers which are chiral with each other in different molar ratios.

The racemate refers to the mixing of the two optical enantiomers which are chiral with each other in the same molar ratio, since the intermolecular action results in optical cancellation, and the resulting mixture is referred to as a racemate.

The cis-trans isomer means that the same atom is located on the same side and the opposite side of the carbon-carbon double bond, and the same atom is located on the same side of the carbon-carbon double bond. For cis, the same atom is located on the opposite side of the carbon-carbon double bond and is called trans.

The term "heterocyclyl" as used herein, unless otherwise indicated, refers to one or more of the carbon atoms of the cycloalkyl group constituting the ring being replaced by a heteroatom other than carbon to form a heterocyclic group, including but not limited to A nitrogen atom, an oxygen atom, a sulfur atom, and the like. The "cycloalkyl group" includes, without limitation, phenyl, cyclohexane, and the like. The "nitrogen-containing heterocyclic group" refers to a carbon atom constituting a ring which is substituted by one or more nitrogen atoms to form a heterocyclic group, and when the heterocyclic group formed is a saturated heterocyclic group, it is referred to as "saturated nitrogen-containing". Heterocyclic group"; when the heterocyclic group formed is an unsaturated heterocyclic group, it is referred to as "nitrogen-containing unsaturated heterocyclic group".

Unless otherwise stated, the term "benzimid (C ₃ -C ₆ )cycloalkyl" as used herein refers to a hydrogen atom of a methyl group on a benzyl group substituted by a (C ₃ -C ₆ )cycloalkyl group. The structure of a benzylidene cycloalkyl group in which two groups attached to a cycloalkyl group include, without being limited to, adjacent, interphase and relative positions.

The term "nitrogen-containing saturated heterospiro" as used herein, unless otherwise indicated, refers to two saturated cycloalkyl groups sharing one carbon atom to form a saturated spiro ring. A carbon atom (unshared carbon atom) on a saturated spiro ring is bonded to a nitrogen atom, and a saturated spiro ring is bonded to its adjacent group to form a nitrogen-containing saturated heterospinyl group, wherein the saturated heterospiro ring is named after the atom The number is determined by the number of carbon atoms or nitrogen atoms forming each ring skeleton, and does not contain two carbon atoms common to the ring.

Unless otherwise indicated, the term of "phenyl (C ₁ -C ₄₎ alkyl" refers to a hydrogen atom on the phenyl ring is substituted (C ₁ -C ₄₎ alkyl, phenyl formation (C ₁ -C ₄ ) Alkyl structures, including but not limited to benzyl, phenethyl, phenylpropyl, phenylisopropyl and phenylbutyl.

Unless otherwise indicated, the term of "phenyl (C _{2 -C. 4)} alkynyl group" refers to a hydrogen atom on the benzene ring is (C _{2 -C. 4)} substituted alkynyl group, formed by benzene (C ₂ -C ₄ ) alkynyl structures including, but not limited to, phenylacetylene, phenylpropyne, phenylbutyne, and the like. Unless otherwise stated, the term "substituted phenyl" as used herein refers to a substituted phenyl group substituted by a hydrogen atom on a phenyl group other than a hydrogen atom or a group.

Unless otherwise stated, the term "phenoxyalkyl" as used herein refers to a group formed by the attachment of a phenyl group and an alkyl group through an oxygen group, and the group is attached to the other groups externally via an alkyl group, including Limited to: phenoxymethyl, phenoxyethyl, phenoxypropyl and the like.

Unless otherwise stated, the term "substituted phenoxyalkyl" as used herein means that the phenyl group of the phenoxyalkyl group is substituted with an atom or group other than a hydrogen atom to form a substituted phenoxyalkyl group.

Unless otherwise stated, "amino substituted (C ₂ -C ₄ )alkenyl" as used herein refers to one or more hydrogen atoms of a (C ₂ -C ₄ )alkenyl group substituted by one or more amine groups. The resulting (C ₂ -C ₄ ) alkenyl group having an amine group, wherein the "hydrogen atom" includes both a hydrogen atom on the alkenyl group and a hydrogen group on a non-alkenyl group such as a methyl group or a methylene group. The atom, the "amine group" is an organic amine group formed by replacing a hydrogen atom of ammonia with a hydrocarbon group.

Unless otherwise stated, "benzene (C ₂ -C ₄ )alkenyl" means that one hydrogen atom on the phenyl ring is substituted with a (C ₂ -C ₄ ) alkenyl group to give a benzene ring (C ₂ -C) ₄ ) Alkenyl group, including but not limited to: styryl group, phenylpropenyl group, benzoisopropenyl group, phenylbutenyl group and the like.

Unless otherwise stated, the term "nitrogen-containing heterophenyl" as used herein means that one or more carbon atoms on the phenyl group are replaced by a nitrogen atom to form The phenyl group of the nitrogen hetero atom includes, but is not limited to, pyridyl, m-diazaphenyl, p-diazaphenyl and the like.

Unless otherwise stated, the term "plasma cell tumor" herein is a group of neoplastic diseases caused by proliferation of monoclonal plasma cells, including multiple myeloma, primary macroglobulinemia.

In certain embodiments, the test article of the invention may be a mammal, such as a dog, cat, cow, sheep, horse or human, preferably a human. The necessary therapeutic amount of the medicament of the present invention will vary depending on the particular disease and can be readily determined by one of ordinary skill in the art.

In certain embodiments, one or more compounds of the invention may be used in combination with one another, or a compound of the invention may be optionally used in combination with any other active agent for the preparation of a Bruton's tyrosine kinase inhibitor, If a group of compounds is used, the compounds can be administered simultaneously, separately or sequentially to the test article.

In certain embodiments, the compounds of the invention may be used in combination with one or more other anticancer agents. Anticancer agents that can be used include, but are not limited to, ibrutinib, statinidin, erlotinib, lapatinib, neratinib, lapatinib, cediranib, axitinib , pazopanib, sorafenib, aboxicept, rituximab, alemtuzumab, bevacizumab, panitumumab, trastuzumab, alkylating agent, nitrogen-based Drugs, folic acid antagonists, sputum antagonists, pyrimidine antagonists, spindle toxins, topoisomerase inhibitors, apoptosis inducers, angiogenesis inhibitors, podophyllotoxin, nitrosourea, antimetabolites, protein synthesis Inhibitors, kinase inhibitors, antiestrogens, cisplatin, carboplatin, interferon, aspartate, leuprolide, flutamide, megestrol, mitomycin, bleomycin ,Adriamycin, Irinotecan and paclitaxel. In one embodiment, the anticancer agent is an antiestrogen drug such as tamoxifen and fulvestrant (ICI 182, 780).

In certain embodiments, the pharmaceutical compositions of the invention are also useful for treating diseases in animals. A general veterinarian can administer a compound of the invention, or a veterinary salt thereof, or a veterinary solvent or prodrug thereof, in a suitable acceptable formulation, based on experience in the art. The veterinarian can determine the most appropriate route of administration for an animal.

The compounds of the invention are prepared by the following route 1:

In the above synthetic route, 5-amino-1H-pyrazole-4-cyano (compound 1') as a starting material is reacted with formamidine hydrochloride at 70-90 ° C, preferably 80 ° C. 1H-pyrazole [3,4-d]pyrimidin-4-amine (Compound 2') in an organic solvent (for example, dimethylformamide, acetic acid) with N-iodobutylimine or chlorine The iodine is reacted at 80 ° C, thereby performing an iodo reaction to obtain 3-iodo-1H-pyrazole [3,4-d]pyrimidin-4-amine (compound 3').

The reaction in the step 3 of Reaction Scheme 1 is well known, and 3-iodo-1H-pyrazole [3,4-d]pyrimidin-4-amine (Compound 3') is in an organic solvent such as tetrahydrofuran (THF). The hydroxy compound 4' is reacted at 50-70 ° C in the presence of triphenylphosphine and diisopropyl azodicarboxylate, whereby a bimolecular nucleophilic substitution (Mitsunobu substitution) reaction occurs to obtain a compound 5'. The compound 4' is a raw material having a chiral property, and therefore, in the course of the synthesis, a compound 4' having a suitable photoactivity can be selected as a raw material according to the light property of the target compound, whereby the obtained reaction intermediate compound also has a compound compound. 4' identical light properties. Compound 5' and compound 6' in an organic solvent (dimethylformamide, ethylene glycol dimethyl ether, tetrahydrofuran and 1,4-dioxane) in metallic palladium, For example: including tetrakis(triphenylphosphine)palladium Pd(PPh ₃ ) ₄ , bisphenylphosphine dichloropalladium Pd (Pd(PPh ₃ ) ₂ Cl ₂ and [1,1'-bis(diphenylphosphine) II The compound 7' is obtained by a coupling reaction at 60-80 ° C under the catalysis of any one or more of ferrocene palladium dichloride Pd(dppf)Cl ₂ .

The reaction of the step 5 in the reaction scheme 1 is known, and the compound 7' is reacted in an organic solvent (dichloromethane or tetrahydrofuran) in the presence of trifluoroacetic acid or hydrochloric acid at 0 ° C to room temperature. The deprotection reaction is carried out to obtain the compound 8'.

The reaction of the step 5 in Reaction Scheme 1 is well known, the compound 8', in an organic solvent (dichloromethane or dimethylformamide), with the corresponding carboxylic acid, or hydrazine chloride at 0 ° C to room temperature The reaction proceeds thereby, and a condensation reaction occurs to obtain a compound 9'.

The starting material 5-amino-1H-pyrazole-4-cyano CAS No. 16617-46-2 was purchased from Shanghai Haiqu Chemical Co., Ltd.

Compound 4' is 1-tert-butoxycarbonyl-3-hydroxyacridine CAS No. 85275-45-2, (S)-1-tert-butoxycarbonyl-3-hydroxyacridine CAS No. 143900-44-1 or (R)-1-tert-Butoxycarbonyl-3-hydroxyacridine CAS No. 143900-43-0 was purchased from Shanghai Haoyuan Reagent Co., Ltd.

Compound 6' was obtained by the following method: a solution of the corresponding bromo substituted thiophene compound in tetrahydrofuran was added dropwise to a solution of n-butyllithium (nBuLi) in tetrahydrofuran (THF) at 70 ° C under nitrogen. The reaction was carried out at -70 ° C for 2 hours, then methyl borate (B(OMe) ₃ ) was added, the reaction was continued at minus 70 ° C for 30 minutes, and the mixture was introduced to 1 mol/L hydrochloric acid at room temperature for 10 minutes. The organic phase obtained by extraction with ethyl acetate was dried and concentrated under reduced pressure to give a crude compound of the title compound, which was used for the next reaction without purification.

In the reaction in the present specification, the reaction accompanying the heating, as is common in the art, can be carried out using a water bath or an oil bath. In the reaction in the present specification, the reaction product can be purified by a usual purification means such as a fraction obtained by atmospheric or vacuum distillation, high performance liquid chromatography using tannin extract, thin layer chromatography, washing or the like. Purification can be carried out in each reaction or after multiple steps of the reaction.

Example 1

Preparation of 1H-pyrazole [3,4-d]pyrimidin-4-amine (Compound 2')

To a solution of 5-amino-1H-pyrazole-4-cyano (Compound 1 ') (20 g, 185.2 mmol) in EtOAc (EtOAc) (EtOAc) Then, it was reacted at 80 ° C for 10 hours, cooled to room temperature, and the solvent was concentrated under reduced pressure. The obtained solid product was washed with water and dried in vacuo to give the desired product (21.3 g, 85% yield), 1H-pyrazole [3, 4-d] Pyrimidine-4-amine (Compound 2').

Thin layer chromatography (TLC) detection: R _f 0.5 (dichloromethane: methanol = 5:1, unfolded phase)

Mass spectrometry: MS (ESI) m/z 136 (M + 1); NMR: 1H NMR (400 MHz, DMSO-d6), 6.96 (br s, 2H), 7.68 (s, 1H), 8.35 (s, 1 H) ), 13.24 (s, 1H).

Example 2: Preparation of 3-iodo-1H-pyrazole [3,4-d]pyrimidin-4-amine (Compound 3')

To a solution of 1H-pyrazole [3,4-d]pyrimidin-4-amine (20 g, 148 mmol) in acetic acid (500 mL) was added EtOAc (1 g, 148 mmol) and then react at 80 ° C. After 10 hours, it was cooled to room temperature, and the solvent was concentrated under reduced pressure. The obtained solid product was washed successively with Na ₂ CO ₃ saturated solution, Na ₂ SO ₃ saturated solution and water, and dried in vacuo to give 3-iodo-1H-pyrazole [3] , 4-d]pyrimidin-4-amine (compound 3', 30.9 g, 80% yield).

Thin layer chromatography: TLC: R _f 0.5 (dichloromethane: methanol = 5:1)

Mass spectrometry: MS (ESI) m/z 262 (M + 1); NMR: 1H NMR (400 MHz, DMSO-d6), 6.98 (br s, 2 H), 8.35 (s, 1 H), 13.20 (s) , 1H).

Preparation of Example 3 (Compound 4')

When ring 2 is acridine, m = 0, compound 4' is: 1-tert-butoxycarbonyl-3-hydroxyacridine

Compound 5' is: tert-butyl-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine-1-carboxylate

3-Iodo-1H-pyrazole [3,4-d]pyrimidin-4-amine at room temperature (combination Add 3 -tert-butoxycarbonyl-3-hydroxyacridine (compound 4'), (9.25 g, 46 mmol) in a solution of the title compound (10 g, 38.3 mmol) in tetrahydrofuran (150 mL). Photo-1,4-tert-butoxycarbonyl-3-hydroxyacridine), diisopropyl azodicarboxylate (9.30 g, 46 mmol) and triphenylphosphine (12.06 mmol, 46 mmol). Then, the reaction was carried out at 60 ° C for 5 hours, cooled to room temperature, and the crude product obtained by concentrating the solvent under reduced pressure was separated by liquid chromatography on a silica gel column eluting solvent: methylene chloride:methanol (40:1->10:1) The desired product tert-butyl-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-carboxylate (Compound 5', 2.8 g, yield: 75%).

TLC: R _f 0.5 (dichloromethane: methanol = 10:1) Mass spectrometric detection: MS (ESI) m/z 445 (M+1); NMR detection: 1H NMR (400 MHz, CDCl ₃ ) 1.67 (s, 9H); 1.70-2.40 (m, 4H), 2.95-4.95 (m, 5 H), 6.95 (br s, 2 H), 8.31 (s, 1 H). Example 4

Scheme 1 product 9 ', where R ^5, R ⁶ are H, a benzene ring, L ₁ is a methoxy group, wherein the methyl moiety is connected thiophene, connected with benzene group, L ₁ and thienyl The 5 positions are linked, the 2 position of the thiophene is linked to the 3 position of the pyrazole ring, m=0, the ring 2 is an acridine ring, and the 3 position of the acridine ring is linked to the nitrogen of the pyrazole ring, the acridine ring The nitrogen in the 1-position is attached to the carbonyl group and the R ³ is a vinyl group. The preparation is as follows:

Wherein Et ₃ N represents triethylamine and EDCl represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

When R ⁵ and R ⁶ are both H, ring 1 is benzene, and L ₁ is a methoxy group, wherein the methyl moiety is bonded to the thiophene, the oxy group is bonded to the benzene, L ₁ is bonded to the 5-position of the thiophene, and the boron and the thiophene are 2 Linked to the compound 6' is: (5-(phenoxymethyl)thiophen-2-yl)boronic acid.

Compound 6'(5-(phenoxymethyl)thiophen-2-yl)boronic acid to compound 1-1-(3-(4-amino-3-(5-(phenoxymethyl)thiophen-2-yl) -1H-pyrazole

Preparation of [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one

I. (5-(phenoxymethyl)thiophen-2-yl)boronic acid preparation method

To a solution of 2-bromothiophene-5-methanol (2 g, 10 mmol) (CAS 79387-71-6 purchased from Shanghai Titan Technology Co., Ltd.) in tetrahydrofuran (50 mL) was added phenol (1.46 g, 15 mmol) at room temperature. ), diisopropyl azodicarboxylate (3.1 g, 15 mmol) and triphenylphosphine (4 g, 15 mmol). Then, it was reacted at room temperature for 10 hours, and the crude product obtained by concentrating the solvent under reduced pressure was used. The liquid chromatography was carried out on a silica gel column, and the elution solvent was ethyl acetate: petroleum ether (1:20->1:10) to obtain 2-bromo-5-(phenoxymethyl)thiophene 1.95 g, yield: 70% ).

Thin layer chromatography: TLC: R _f 0.5 (ethyl acetate: petroleum ether = 1:15)

Mass spectrometric detection: MS (ESI) m/z 269 (M + 1); NMR: 1H NMR (400 MHz, CDCl ₃ ) 5.20 (s, 2 H), 6.50-6.75 (m, 2 H), 7.00-7.45 ( m, 5 H).

2-Bromo-5-(phenoxymethyl)thiophene (1.90 g, 7 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to n-butyllithium (5.6 mL, 2.5 mol/L) at 70 ° C under nitrogen. A solution of the alkane in tetrahydrofuran (15 mL). After reacting at -70 ° C for 2 hours, methyl borate (3.67 g, 35 mmol) was added, and the reaction was continued at -70 ° C for 30 minutes, and the mixture was stirred at room temperature to introduce 1 mol / L hydrochloric acid (30 mL), and stirred for 10 minutes. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and then evaporated. Used directly in the next step.

TLC: R _f 0.5 (ethyl acetate: petroleum ether = 1 : 5) Mass spectroscopy: MS (ESI) m/z 235 (M+1);

II. Tert-Butyl-3-(4-amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)indole Method for preparing pyridine-1-carboxylate

To tert-butyl-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-carboxylate (200 mg, 0.45 mmol) at room temperature (5-(phenoxymethyl)thiophen-2-yl)boronic acid (211 mg, 0.90 mmol), tetrakis(triphenylphosphine), in a solution of ethylene glycol dimethyl ether (5 mL) and water (2 mL) Palladium (26 mg, 0.02 mmol), Na ₂ CO ₃ (143 mg, 1.35 mmol). Then, the reaction was carried out at 80 ° C for 16 hours, cooled to room temperature, poured into 50 mL of water, extracted with ethyl acetate, and the organic layer was extracted with anhydrous Na ₂ SO ₄ and then evaporated. Chromatographic separation, eluting solvent petroleum ether: ethyl acetate (8:1→2:1) to give the desired product tert-butyl 3-(4-amino-3-(5-(phenoxymethyl)thiophene-2 -yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl)acridine-1-carboxylate (160 mg, yield 75%).

Thin layer chromatography: (TLC) detection: R _f 0.5 (petroleum ether: ethyl acetate = 2:1 unfolded phase)

Mass spectrometry: MS (ESI) m/z 507 (M + 1); NMR: 1H NMR (400 MHz, CDCl ₃ ), 1.68 (s, 9H), 0 (m, 1H), 2.28-2.45 (m, 2H) , 2.90-3.25 (m, 1H), 3.40-3.80 (m, 1H), 4.05-4.25 (m, 2H), 4.65-4.90 (m, 2H), 5.31 (s, 2H), 6.30-6.40 (m, 1H), 6.60-6.70 (m, 1H), 7.05-7.15 (m, 2H), 7.20-7.25 (m, 1H), 7.30-7.40 (m, 4H), 8.41 (s, 1H).

III. Preparation method of 3-(4-amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl)acridine

To tert-butyl 3-(4-amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazo[3,4-d]pyrimidin-1-yl)indole at 0 °C Trifluoroacetic acid (2 mL) was added to a solution of pyridine-1-carboxylate (160 mg, 0.32 mmol) in dichloromethane (4 mL), and then warmed to room temperature for 4 hours to give 3-(4-amino-3-( a trifluoroacetate salt of 5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine, or a solution of hydrochloric acid or sulfuric acid may be added to the solution. Acetic acid gives the corresponding hydrochloride, sulfate or acetate. The solvent was concentrated under reduced pressure to give crude product was dissolved in ethyl acetate (20mL), washed with a saturated solution of Na ₂ CO ₃ followed by drying with anhydrous Na ₂ SO _4, the solvent was concentrated under reduced pressure to give 3- (4-amino-3- (5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine crude product 80mg, directly used in the next reaction, the corresponding Hydrochloride, sulfate or acetate.

Thin layer chromatography: TLC: R _f 0.5 (dichloromethane: methanol = 5:1)

Mass spectrometry: MS (ESI) m/z 407 (M+1);

IV. 3-(4-Amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine to compound 1: 1-(3-(4-Amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1- Method for preparing propan-2-en-1-one

To 3-(4-amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)-1- at 0 °C Acrylic acid (23 mg, 0.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added sequentially to a solution of acridine (80 mg, 0.20 mmol) in dichloromethane (5 mL). (64mg, 0.30mmol) (CAS No. 25952-53-8, purchaser: Shanghai Bituo Biotechnology Co., Ltd.), 4-dimethylaminopyridine (DMAP) (13mg, 0.10mmol), then reacted at room temperature 2 purification (1:: methanol = 40 ethyl acetate) to give compound 1: hour, washed with water and then dried over anhydrous Na ₂ SO _4, the solvent under reduced pressure the crude product obtained by thin layer chromatography was concentrated, 1- (3- ( 4-amino-3-(5-(phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)propan-2- En-1-one (54 mg, yield 60%).

TLC: R _f 0.5 (ethyl acetate: methanol = 30: 1) MS (ESI ) m / z 461 (M + 1); 1 HNMR (400MHz, CDCl 3) (m, 1H), 2.27-2.41 (m, 2H), 2.89-3.24 (m, 1H), 3.40-3.78 (m, 1H), 4.07-4.28 (m, 2H), 4.65-4.91 (m, 2H), 5.31 (s, 2H), 5.70-5.77 ( m,1H), 5.83 (s, 2H), 6.31-6.40 (m, 1H), 6.59-6.67 (m, 1H), 7.04-7.10 (m, 2H), 7.19-7.25 (m, 1H), 7.30- 7.32 (m, 2H), 7.33-7.40 (m, 2H), 8.41 (s, 1H).

V. Intermediate compound and preparation method thereof

The intermediate compound was changed 6' in a similar manner to Example 4 to give the following compound, wherein the intermediate compound 6' may be selected from the group consisting of (4-(phenoxymethyl)thiophen-2-yl) Boric acid

(4-((5-Methylphenoxy)methyl)thiophen-2-yl)boronic acid

(5-(phenoxymethyl)thiophen-3-yl)boronic acid

(4-((o-tolyloxy)methyl)thiophen-2-yl)boronic acid

(4-((m-tolyloxy)methyl)thiophen-2-yl)boronic acid

(4-((p-tolyloxy)methyl)thiophen-2-yl)boronic acid

(4-((o-methoxyphenoxy)methyl)thiophen-2-yl)boronic acid

(4-((m-methoxyphenoxy)methyl)thiophen-2-yl)boronic acid

(4-((p-methoxyphenoxy)methyl)thiophen-2-yl)boronic acid

(5-((o-Cyanophenoxy)methyl)thiophen-3-yl)boronic acid

(5-((p-Cyanophenoxy)methyl)thiophen-3-yl)boronic acid

(5-((m-Cyanophenoxy)methyl)thiophen-3-yl)boronic acid

(5-((o-methoxyphenoxy)methyl)thiophen-3-yl)boronic acid

(5-((m-methoxyphenoxy)methyl)thiophen-3-yl)boronic acid

(5-((pyrimidin-4-yloxy)methyl)thiophen-3-yl)boronic acid

(5-((2-methoxy-4-methylphenoxy)methyl)thiophen-3-yl)boronic acid

(5-((2-methoxy-4-chlorophenoxy)methyl)thiophen-3-yl)boronic acid

(5-((2-methoxy-4-cyanophenoxy)methyl)thiophen-3-yl)boronic acid

(5-((2-chloro-5-methoxyphenoxy)methyl)thiophen-3-yl)boronic acid

(5-((3-chloro-5-methoxyphenoxy)methyl)thiophen-3-yl)boronic acid

(5-((3-Methoxy-4-cyanophenoxy)methyl)thiophen-3-yl)boronic acid

(5-((o-tolyloxy)methyl)thiophen-3-yl)boronic acid

(5-((p-tolyloxy)methyl)thiophen-3-yl)boronic acid

(5-((o-fluorophenoxy)methyl)thiophen-3-yl)boronic acid

(5-((m-Fluorophenoxy)methyl)thiophen-3-yl)boronic acid

(5-((p-Fluorophenoxy)methyl)thiophen-3-yl)boronic acid

((5-phenoxymethyl)thiophen-3-yl)boronic acid

The above synthesis method of the boric acid compound is similar to the preparation method of the compound 6' of Example 4 as (5-(phenoxymethyl)thiophen-2-yl)boronic acid.

Example 5

When R ⁵ and R ⁶ are both H, ring 1 is benzene, L ₁ is a single bond, benzene ring is bonded to the 5-position of thiophene, 1H-pyrazole [3,4-d]pyrimidin-1-yl and thiophene 3 Linked to a compound 6': ((5-phenyl)thiophen-3-yl)boronic acid

5.1 Preparation of intermediate ((5-phenyl)thiophen-3-yl)boronic acid: 3-bromo-5-(phenyl)thiophene (CAS No. 38071-58-8, purchased from Shanghai Bi De Pharmaceutical Technology Co., Ltd. (2 g, 8.3 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to a solution of n-butyllithium (6.7 mL, 2.5 mol/L in n-hexane) in tetrahydrofuran (15 mL) at 70 ° C under argon. The reaction was carried out at -70 ° C for 2 hours, then methyl borate (4.35 g, 42 mmol) was added, the reaction was continued at minus 70 ° C for 30 minutes, and the mixture was stirred at room temperature to introduce 1 mol/L hydrochloric acid (30 mL) and stirred for 10 minutes. After extracting with ethyl acetate, the organic layer was dried over anhydrous Na ₂ SO ₄ and then evaporated. In the next step.

Thin layer chromatography: TLC: R _f 0.5 (ethyl acetate: petroleum ether = 1:5)

Mass spectrometry: MS (ESI) m/z 205 (M + 1).

5.2 Preparation method of intermediate ((5-phenyl)thiophen-2-yl)boronic acid and ((4-phenyl)thiophen-2-yl)boronic acid

The synthesis method of ((5-phenyl)thiophen-2-yl)boronic acid and ((4-phenyl)thiophen-2-yl)boronic acid is the same as (5-(phenyl)thiophen-3-yl)boronic acid Preparation.

5.3 Preparation method of 2-bromo-4-(m-tolyl)thiophene

When R ⁵ and R ⁶ are both H, ring 1 is toluene, L ₁ is a single bond, benzene ring is bonded to the 5-position of thiophene, 1H-pyrazole [3,4-d]pyrimidin-1-yl and thiophene 3 The compound 6' is: ((5-(3-methylphenyl))thiophen-3-yl)boronic acid, prepared by the method of 2,4-dibromothiophene (4g, 16mmol) (purchased from West Asia Reagent, trade name 2,4-dibromothiophene, CAS No. 3140-92-9, commercial number: 1993) in toluene solution (50 mL) was added sequentially to m-toluic acid (2.25 g, 16 mmol), (CAS number: 17933- 03-8, trade name 3-toluene boric acid, purchased from Belling Technology, product number: 256729) Na ₂ CO ₃ (3.5 g, 33 mmol), Pd (PPh ₃ ) ₄ , (380 mg, 0.3 mmol) and H ₂ O ( 50 mL), then argon-substituted protection, warmed to 100 ° C for 12 hours, and TLC followed the reaction. Completion of the reaction, cooled to room temperature and extracted with ethyl acetate, dried organic extracts were dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure to give the crude product by column chromatography using silica gel, eluent ethyl acetate: petroleum ether (1: 50->1:20) 2 g (yield 50%) of 2-bromo-4-(m-tolyl)thiophene as a white solid.

TLC: R _f 0.5 (ethyl acetate: petroleum ether = 1:30)

MS (ESI) m / z 253 (M + 1); 1 HNMR (400MHz, CDCl 3) 2.38 (s, 3H), 7.15-7.60 (m, 6 H).

5.4 Preparation method of intermediate (4-(3-tolyl)thiophen-2-yl)boronic acid

2-Bromo-4-(3-methylphenyl)thiophene (2 g, 8 mmol) (prepared as 5.3) was dissolved in tetrahydrofuran (10 mL) and added dropwise to n-butyllithium (6.4 mL, 70 ° C, under nitrogen). A 2.5 mol/L solution of n-hexane in tetrahydrofuran (15 mL) was obtained. The reaction was carried out at minus 70 ° C for 2 hours, then trimethyl borate (4 g, 40 mmol) was added (CAS No.: 121-43-7, available from Best Reagent, trade name Trimethyl borate, commercial number: B00269101) The reaction was continued at minus 70 ° C for 30 minutes, and the mixture was stirred at room temperature to introduce 1 mol/L hydrochloric acid (30 mL), and stirred for 10 minutes. After extracting with ethyl acetate, the organic layer was dried over anhydrous Na ₂ SO ₄ and then evaporated. Used directly in the next step.

TLC: R _f 0.5 (ethyl acetate: petroleum ether = 1:5)

MS (ESI) m/z 195 (MH).

5.5 Preparation of intermediate ((5-(3-methoxyphenyl))thiophen-3-yl)boronic acid and ((5-(4-methoxyphenyl))thiophen-3-yl)boronic acid)

The method for synthesizing the above boric acid compound is the same as the method for preparing (4-(3-tolyl)thiophen-2-yl)boronic acid.

5.6 Preparation method of intermediate (5-(m-tolyl)thiophen-2-yl)boronic acid

When R ⁵ and R ⁶ are both H, ring 1 is 3-tolyl, L ₁ is a single bond, 3-tolyl is attached to the 5-position of thiophene, 1H-pyrazole [3,4-d]pyrimidin-1- The base is attached to the 2-position of the thiophene, and the compound 6' is (5-(m-tolyl)thiophen-2-yl)boronic acid by the preparation of 2,5-dibromothiophene (4 g, 16 mmol) (purchased from Qingdao). Tongyuan Pharmaceutical Co., Ltd., trade name 2,5-dibromothiophene, CAS No.: 3141-27-3) in toluene solution (50 mL) was added with m-tolueneboronic acid (2.25 g, 16 mmol) in sequence (CAS No.: 17933-03) -8, purchased from Shanghai Haiqu Chemical Co., Ltd., trade name toluene boronic acid), Na ₂ CO ₃ (3.5 g, 33 mmol), Pd (PPh ₃ ) ₄ , (380 mg, 0.3 mmol) and H ₂ O (50 mL) Then, it was replaced with argon gas, heated to 100 ° C for 12 hours, and TLC followed the reaction. Completion of the reaction, cooled to room temperature and extracted with ethyl acetate, dried organic extracts were dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure to give the crude product by column chromatography using silica gel, eluent ethyl acetate: petroleum ether (1: 50->1:20) 3.1 g (yield 75%) of 2-bromo-5-(m-tolyl)thiophene as a white solid.

TLC: R _f 0.5 (ethyl acetate: petroleum ether = 1:30)

MS (ESI) m / z 253 (M + 1); 1 HNMR (400MHz, CDCl 3) 2.33 (s, 3H), 7.10-7.70 (m, 6 H).

2-Bromo-5-(m-tolyl)thiophene (2 g, 8 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to n-butyllithium (6.4 mL, 2.5 mol/L n-hexane) at 70 ° C under nitrogen. Solution) in tetrahydrofuran (15 mL). The reaction was carried out at -70 ° C for 2 hours, then methyl borate (4 g, 40 mmol) was added, and the reaction was continued at minus 70 ° C for 30 minutes, and the mixture was stirred at room temperature to introduce 1 mol/L hydrochloric acid (30 mL) and stirred for 10 minutes. After extracting with ethyl acetate, the organic layer was dried over anhydrous Na ₂ SO ₄ and then evaporated to dryness to give the crude (5-(m-tolyl)thiophen-2-yl)boronic acid 1.20 g. Used directly in the next step.

TLC: R _f 0.5 (ethyl acetate: petroleum ether = 1:5)

MS (ESI) m/z 195 (MH).

5.7. Preparation method is similar to the intermediate of 5.6

The following intermediates were prepared in a similar manner to the intermediates of 5.6: (5-(3,4-dimethylphenyl)thiophen-2-yl)boronic acid

(5-(m-methoxyphenyl)thiophen-2-yl)boronic acid

(5-(p-methoxyphenyl)thiophen-2-yl)boronic acid

(5-(4-phenyl)thiophen-2-yl)boronic acid

(5-(p-Trifluoromethylphenyl)thiophen-2-yl)boronic acid

(5-(m-Trifluoromethylphenyl)thiophen-2-yl)boronic acid

(5-(3,5-dimethylphenyl)thiophen-2-yl)boronic acid

(5-phenyl)thiophen-2-yl)boronic acid

(5-(o-fluorophenyl)thiophen-2-yl)boronic acid

(5-(m-Fluorophenyl)thiophen-2-yl)boronic acid

(5-(p-fluorophenyl)thiophen-2-yl)boronic acid

The method for synthesizing the above boric acid compound is the same as the method for preparing (5-(m-tolyl)thiophen-2-yl)boronic acid.

5.8 Preparation method of intermediate (2-(styryl)thiophen-4-yl)boronic acid

When R ⁵ and R ⁶ are both H, ring 1 is a styryl group, L ₁ is a single bond, and the styryl group is linked to the thiophene at the 2-position by a single bond, 1H-pyrazole [3,4-d]pyrimidine-1 - The group is bonded to the 4-position of the thiophene, m = 0, the ring 2 is acridine, and the compound 6' is (2-(styryl)thiophen-4-yl)boronic acid. The preparation method is: 4-bromo-2-thiophene - Formaldehyde (4g, 21mmol) (CAS18791-75-8, available from Best Reagent Co., Ltd.) and benzyltriphenylphosphonium chloride (10.9g, 25mmol) dissolved in 50mL of isopropanol, then lithium hydroxide Monohydrate (1.32 g, 32 mmol). The temperature was raised to 85 ° C for 4 hours, and TLC (TLC detection, R _f 0.5 (ethyl acetate: petroleum ether = 1:50)) was followed to complete the reaction. After completion of the reaction, 50 mL of ethyl acetate was added, and the mixture was washed twice with 50 mL of water. The organic layer was dried and evaporated to dryness. 50 mL of ethyl acetate was added, and the mixture was washed with saturated sodium hydrogen sulfate (50 mL) and sodium sulfate (50 mL), and the organic layer was evaporated and evaporated to dryness. : petroleum ether (1:100->1:20) gave 4.7 g of trans-2-(styryl)thiophene-4-bromide, yield: 85%).

Thin layer chromatography: TLC: R _f 0.5 (ethyl acetate: petroleum ether = 1:15)

Mass spectrometry: MS (ESI) m/z 265 (M + 1); NMR: 1H NMR (400 MHz, CDCl ₃ ) 6.80-7.00 (m, 2 H), 7.08 (s, 1 H), 7.20 (s, 1H), 7.25-7.65 (m, 5 H).

Trans-2-(styryl)thiophene-4-bromo (2 g, 7.5 mmol) in tetrahydrofuran (10 mL) was added dropwise to n-butyllithium (6 mL, 2.5 mol/L n-hexane) at 70 ° C under nitrogen. Solution) in tetrahydrofuran (15 mL). The reaction was carried out at -70 ° C for 2 hours, then methyl borate (3.85 g, 38 mmol) was added, and the reaction was continued at minus 70 ° C for 30 minutes, and the mixture was stirred at room temperature to introduce 1 mol/L hydrochloric acid (30 mL) and stirred for 10 minutes. After extracting with ethyl acetate, the organic layer was dried over anhydrous Na ₂ SO ₄ and then evaporated to dryness to give 1.60 g of crude (2-(styryl)thiophen-4-yl)boronic acid. Used directly in the next step.

TLC: R _f 0.5 (ethyl acetate: petroleum ether = 1:5)

MS (ESI) m/z 231 (MH).

Preparation method of 5.9(2-(phenethyl)thiophen-4-yl)boronic acid

When R ⁵ and R ⁶ are both H, ring 1 is phenethyl, L ₁ is a single bond, phenethyl is attached to the 2-position of thiophene, 1H-pyrazole [3,4-d]pyrimidin-1-yl and The thiophene is bonded at the 4-position, m=0, ring 2 is acridine, and compound 6' is (2-(phenethyl)thiophen-4-yl)boronic acid.

Anti-2-(styryl)thiophene-4-bromo (2.5 g, 9.5 mmol) was dissolved in ethyl acetate (30 mL), then 10% palladium charcoal (1 g) was reacted in a hydrogen atmosphere at room temperature for 2 h, TLC (thin layer Chromatography, _Rf 0.5 (ethyl acetate: petroleum ether = 1:50) was followed to complete the reaction. The crude phase obtained by filtering off the palladium on carbon was separated by a liquid chromatography on a silica gel column. The eluting solvent was ethyl acetate: petroleum ether (1:100->1:20) to give 2-(phenylethyl) Base) thiophene-4-bromide 2g, yield: 80%.

Thin layer chromatography: TLC: R _f 0.5 (ethyl acetate: petroleum ether = 1:15)

Mass spectrometric detection: MS (ESI) m/z 267 (M + 1); NMR: 1H NMR (400 MHz, CDCl ₃ ) 2.65-2.90 (m, 4 H), 6.54 (s, 1 H), 6.66 (s, 1H), 7.20-7.45 (m, 5 H).

The crude product is 1.20g. Since the product is easily decomposed, it can be directly used in the next reaction without purification.

Thin layer chromatography TLC: R _f 0.5 (ethyl acetate: petroleum ether = 1:5)

MS (ESI) m/z 266 (MH).

2-(Phenylethyl)thiophene-4-bromo (2 g, 7.5 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to n-butyllithium (6 mL, 2.5 mol/L n-hexane) at 70 ° C under nitrogen. In a solution of tetrahydrofuran (15 mL). The reaction was carried out at -70 ° C for 2 hours, then methyl borate (3.85 g, 38 mmol) was added, and the reaction was continued at minus 70 ° C for 30 minutes, and the mixture was stirred at room temperature to introduce 1 mol/L hydrochloric acid (30 mL) and stirred for 10 minutes. After extracting with ethyl acetate, the organic layer was dried over anhydrous Na ₂ SO ₄ and then evaporated. Used for the next reaction.

TLC: _Rf 0.5 (EtOAc:EtOAc:EtOAc:

The compounds of the invention are also prepared by Scheme 3 below:

The reaction of the step 1 in the reaction scheme 3 is well known, and in the above synthetic route, the compound 5' as a starting material is prepared by the same method as in the route 1. Compound 5' and compound 10' in an organic solvent (dimethylformamide, ethylene glycol dimethyl ether, tetrahydrofuran and 1,4-dioxane) in metallic palladium, For example: including tetrakis(triphenylphosphine)palladium Pd(PPh ₃ ) ₄ , bisphenylphosphine dichloropalladium Pd(PPh ₃ ) ₂ Cl ₂ and [1,1'-bis(diphenylphosphino)ferrocene The reaction is carried out at 60-80 ° C under the catalysis of any one or more of palladium dichloride Pd(dppf)Cl ₂ to thereby effect a coupling reaction to obtain a compound 11'.

The reaction of the step 2 in the reaction scheme 3 is well known, and the compound 11' is reacted in tetrahydrofuran in the presence of tetrabutylammonium fluoride at 0 ° C to room temperature, thereby proceeding to carry out de-tert-butyl dimethyl The reaction of a decane protecting group gives compound 12'.

The reaction of the step 3 in the reaction scheme 3 is well known, and the compound 12' is sequentially added to the phosphate buffer (pH=6.7), 2,2,6,6-tetramethylacridine-nitrogen oxide (TEMPO) in acetonitrile. ), NaClO ₂ (sodium chlorite) and NaClO (sodium hypochlorite) are reacted at 35 ° C to carry out a hydroxy oxidation reaction to obtain a carboxylic acid compound 13'.

The reaction of step 4 in Scheme 2 is well known, compound 13', in an organic solvent (dichloromethane or dimethylformamide), in the condensing agent 1-ethyl-(3-dimethylaminopropane) Carbodiimide hydrochloride (EDCL) (CAS No. 25952-53-8, purchased from Jinan Panoru Chemical Co., Ltd.), 2-(7-azobenzotriazole)-N, N, N ',N'-Tetramethylurea hexafluorophosphate (HATU) (CAS No. 148893-10-1, purchased from Shanghai Ziyi Reagent Factory) or O-benzotriazole-N, N, N', N '-Tetramethylurea tetrafluoroborate (TBTU) (CAS number The reaction of the compound 14' at room temperature in the presence of 125700-67-6, purchased from Nanjing Peptide Biotechnology Co., Ltd., was carried out, and a condensation reaction was carried out to obtain a compound 15'. Wherein compound 14' can be selected from the group consisting of 2-aminopyridine, 3-aminopyridine, 4-aminopyridine or aniline.

The reaction of the step 5 in the reaction scheme 3 is known to be the same as the operation of the step 5 in the reaction scheme 1. The reaction of the step 6 in the reaction scheme 3 is known to be the same as the operation of the step 6 in the reaction scheme 1, wherein the starting aminopyridine is purchased from Beijing Vinda Chemical Co., Ltd., wherein the 3-aminopyridine product number is 462- 08-8, 2-aminopyridine commercial number is 504-29-0, 4-aminopyridine commercial number is 504-24-5.

Example 6

In step 1 of Scheme 3, when compound 10' is ((5-tert-butyldimethyloxymethylene)thiophen-2-yl)boronic acid, tert-butyldimethyl oxime in compound 11' The methyl group is attached to the 5-position of the thiophene, the 1H-pyrazole [3,4-d]pyrimidin-1-yl group is attached to the 2-position of the thiophene, m=0, the ring 2 is acridine, and the compound 11' is a tert-butyl group- 3-(4-Amino-3-(5-(tert-butyldimethylsulfoxymethylene)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)indole Pyridine-1-carboxylate. The preparation method is as follows: ( R )-tert-butyl-3-(-4-amino-3-iodo-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridine-1 at room temperature -5-(tert-Butyldimethyloxymethylene)thiophene-2 was added sequentially to a solution of the formic acid ester (300 mg, 0.68 mmol) in ethylene glycol dimethyl ether (5 mL) and water (2 mL). - yl) boronic acid (345mg, 1.35mmol), tetrakis triphenylphosphine palladium _{(39mg, 0.03mmol), Na 2} CO 3 (215mg, 2.1mmol). Then, the mixture was reacted at 80 ° C for 16 hours, cooled to room temperature, poured into 50 mL of water, and extracted with ethyl acetate. The organic layer was extracted with anhydrous Na ₂ SO ₄ and then evaporated. Chromatographic separation, elution solvent: petroleum ether: ethyl acetate (8:1→2:1) to give the desired product ( R ) tert-butyl-3-(4-amino-3-(5-(tert-butyl) Methyl methoxymethylene)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl)acridine-1-carboxylate (275 mg, yield 78%).

Thin layer chromatography: (TLC) detection: R _f 0.5 (petroleum ether: ethyl acetate = 3:1 unfolded phase)

Mass spectrometry: MS (ESI) m/z 545 (M + 1); NMR: ¹ H NMR (400 MHz, CDCl ₃ ): 0.20 (s, 3 H), 0.21 (s, 3 H), 1.59 (s, 9H) ), 1.69 (s, 9H), 1.60-2.45 (m, 4H), 2.90-4.90 (m, 5H), 5.31 (s, 2H), 6.30-6.40 (m, 1H), 6.60-6.70 (m, 1H) ), 7.00-7.15 (m, 2H), 8.40 (s, 1H).

The tert-butyldimethyloxymethylene group of compound 11' in step 2 of Scheme 3 is attached to the 5-position of thiophene, 1H-pyrazole [3,4-d]pyrimidin-1-yl and thiophene The two positions are linked, m=0, ring 2 is acridine, and compound 11' is ( R ) tert-butyl-3-(4-amino-3-(5-(tert-butyldimethyl oxime) Methyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine-1-carboxylate, compound 12' is ( R ) tert-butyl-3- (4-Amino-3-(5-(hydroxymethylene)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine-1-carboxylate, The preparation method is as follows: at room temperature to the compound 11', ( R ) tert-butyl-3-(4-amino-3-(5-(tert-butyldimethyl methoxymethylene)thiophene-2- -1H-pyrazol[3,4-d]pyrimidin-1-yl)acridine-1-carboxylate (250 mg, 0.46 mmol) in tetrahydrofuran (20 mL) 180 mg, 0.61 mmol). Then, it was reacted for 3 hours at room temperature, and a saturated ammonium chloride solution (50 mL) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and then evaporated. Chromatography separation, elution solvent petroleum ether: ethyl acetate (4:1 → 1:1) to obtain the desired product ( R ) tert-butyl-3-(4-amino-3-(5-(hydroxy- Thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine-1-carboxylate (158 mg, yield 80%).

Thin layer chromatography: (TLC) detection: R _f 0.5 (petroleum ether: ethyl acetate = 1:1 unfolded phase)

Mass spectrometry: MS (ESI) m/z 431 (M + 1); NMR: ¹ H NMR (400 MHz, CDCl ₃ ): 1.68 (s, 9H), 1.60 - 2.45 (m, 4H), 2.90 - 4.90 (m) , 5H), 5.34 (s, 2H), 6.30-6.45 (m, 1H), 6.62-6.70 (m, 1H), 7.00-7.15 (m, 2H), 8.41 (s, 1H).

The hydroxymethylene group of compound 12' in step 3 of Scheme 3 is attached to the 5-position of thiophene, and the 1H-pyrazole [3,4-d]pyrimidin-1-yl group is attached to the 2-position of thiophene, m=0 Ring 2 is acridine and compound 12' is ( R ) tert-butyl-3-(4-amino-3-(5-(hydroxymethylene)thiophen-2-yl)-1H-pyrazole [3 , 4-d]pyrimidin-1-yl)acridine-1-carboxylate, compound 13' is ( R ) tert-butyl-3-(3-(5-carboxylic acid thiophen-2-yl)-4- Amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine-1-carboxylate prepared by the method of 12', ( R ) tert-butyl- at room temperature 3-(4-Amino-3-(5-(hydroxymethylene)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine-1-carboxylate (150 mg, 0.34 mmol) in acetonitrile solution (5 mL) was added phosphate buffer (1.5 mL, pH=6.7), 2,2,6,6-tetramethyl acridine oxynitride (5 mg, 0.03 mmol), NaClO ₂ (80 mg, purity 80% in 0.5 mL water) and NaClO (0.015 mL, 5% in water). Then, the reaction was carried out at 35 ° C for 5 hours, and a phosphate buffer solution (10 mL, pH = 3.6) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ R ) tert-butyl-3-(3-(5-carboxylic acid thiophen-2-yl)-4-amino-1H-pyrazole [3,4-d]pyrimidin-1-yl)acridin-1-yl The ester (120 mg), (Compound 13') was used in the next step without further purification.

Thin layer chromatography: (TLC) detection: R _f 0.5 (dichloromethane: ethyl acetate = 1:2 unfolded phase)

Mass spectrometry: MS (ESI) m/z 445 (M + 1).

The compound of the compound 13' in the step 4 of Reaction Scheme 3 is ( R ) tert-butyl-3-(3-(5-carboxylic acid thiophen-2-yl)-4-amino-1H-pyrazole [3, 4 -d]pyrimidin-1-yl)acridine-1-carboxylate, compound 14' is ( R )-2-aminopyridine, and compound 15' is ( R )-3-(4-amino-3-(5) -(2-Pyridinylaminomethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-carboxylic acid tert-butyl ester, prepared by: To the compound 13' at room temperature, tert-butyl-3-(3-(5-carboxylic acid thiophen-2-yl)-4-amino-1H-pyrazole [3,4-d]pyrimidin-1-yl) Add a solution of the compound 14', 2-aminopyridine (76 mg, 0.81 mmol) (CAS number 504-) to a solution of acridine-1-carboxylate (120 mg, 0.27 mmol) in N,N-dimethylformamide (5 mL). 29-0, purchased from Alfa Aesar (China) Chemical Co., Ltd.), HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluoro Phosphate) (154 mg, 0.41 mmol) (CAS No.: 148893-10-1, purchased from Shanghai Shuo Biotech Co., Ltd.) and N,N-diisopropylethylamine (172 mg, 1.1 mmol). Then, it was reacted for 10 hours at room temperature, and a saturated ammonium chloride solution (20 mL) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and then evaporated. The chromatographic separation was carried out, and the eluting solvent was petroleum ether: ethyl acetate (4:1→1:1) to obtain the desired product compound 15'( R )-tert-butyl-3-(4-amino-3-(5- (2-Pyridinylaminomethyl) thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine-1-carboxylate (98 mg, yield 70%).

Thin layer chromatography: (TLC) detection: R _f 0.5 (petroleum ether: ethyl acetate = 1:1 unfolded phase)

Mass spectrometry: MS (ESI) m/z 521 (M + 1); NMR: ¹ H NMR (400 MHz, CDCl ₃ ): 1.66 (s, 9H), 1.60-2.45 (m, 4H), 2.85 - 4.95 (m) , 5H), 6.45-6.65 (m, 2H), 6.70-6.90 (m, 2H), 7.40-8.15 (m, 4H), 8.42 (s, 1H), 9.18 (s, 1H). Compound 16' in step 5 of Scheme 3 is ( R )-3-(4-amino-3-(5-(2-pyridylaminomethyl)thiophen-2-yl)-1H-pyrazole [ 3,4-d]pyrimidin-1-yl)-1-anthidine, which is prepared by the method of 15', ( R ) tert-butyl-3-(4-amino-3-() at room temperature 5-(2-Pyridinylaminomethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-carboxylate (90 mg, 0.17 mmol) To a solution of dichloromethane (5 mL) was added 2 mL of trifluoroacetic acid. Then, it was reacted at room temperature for 4 hours to obtain ( R )-3-(4-amino-3-(5-(2-pyridylaminomethyl)thiophen-2-yl)-1H-pyrazole [3, 4 -d]pyrimidin-1-yl)-1-pyridinium trifluoroacetate, or hydrochloric acid, sulfuric acid or acetic acid may be added to the solution to obtain the corresponding hydrochloride, sulfate or acetate. The solvent is concentrated under reduced pressure. the resulting crude product was dissolved in ethyl acetate (20mL), washed with a saturated solution of Na ₂ CO ₃ and then dried with anhydrous Na ₂ SO _4, to give the compound (R) by concentrating the solvent under reduced pressure using 3- (4-amino-3- (5-(2-pyridylamine-mercapto)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-anthracene (Compound 16'), 70 mg, Used directly in the next step of the reaction.

Thin layer chromatography: TLC: R _f 0.5 (dichloromethane: methanol = 5:1)

Mass spectrometry: MS (ESI) m/z 421 (M + 1).

The compound 17' in the step 6 of Reaction Scheme 3 is ( R )-1-(3-(4-amino-3-(5-(2-pyridylaminomethyl)thiophen-2-yl)-1H- Pyrazole [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one, prepared by ( R )-3-(4) at 0 °C -amino-3-(5-(2-pyridylaminomethyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl)-1-acridine (Compound 16' (70 mg, 0.17 mmol) in dichloromethane (5 mL) was added EtOAc (23 mg, 0.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( 64mg, 0.30mmol), 4- dimethylaminopyridine (13mg, 0.10mmol), followed by reaction for 2 hours at room temperature, washed with water and then dried over anhydrous Na ₂ SO _4, solvent was concentrated under reduced pressure to give the crude product by Purification by thin layer chromatography (ethyl acetate:methanol = 40:1) gave compound 17' (R) -1-(3-(4-amino-3-(5-(2-pyridylaminomethyl) thiophene) 2-yl)-1H-pyrazo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one (51 mg, yield 63%).

TLC: R _f 0.5 (ethyl acetate:methanol = 30:1)

MS (ESI) m / z 475 (M + 1); ¹ H NMR (400 MHz, CDCl ₃ )

1.60-2.45 (m, 4H), 2.89-4.95 (m, 5H), 5.25-5.65 (m, 3H), 6.55-6.95 (m, 4H), 7.30-7.32 (m, 2H), 7.30-8.15 (m , 4H), 8.42 (s, 1H), 9.14 (s, 1H).

The compound 10' was changed in a similar manner to Example 6 to give the compound 51-62 shown in the following Table 1, wherein the compound 10' may be selected from the following compounds: (5-(tert-Butyldimethyloxymethylene)thiophen-2-yl)boronic acid; (4-(tert-butyldimethyloxymethylene)thiophen-2-yl)boronic acid; (2 -(tert-butyldimethyloxymethylene)thiophen-4-yl)boronic acid

When tert-butyldimethyloxymethylene is attached to the 5-position of thiophene, the 2-position of thiophene is attached to the 3 position of the 1H-pyrazole [3,4-d]pyrimidinyl group, and the compound 10' is (5-(tert-butyl) Dimethylnonoxymethylene)thiophen-2-yl)boronic acid. Compound 10'(5-(tert-butyldimethyloxymethylene)thiophen-2-yl)boronic acid and its synthesis method are: 2-bromothiophene-5-methanol (4 g, 20 mmol) at room temperature (CAS is 79387-71-6 purchased from Shanghai Titan Technology Co., Ltd.) in N,N-dimethylformamide (50mL) solution with imidazole (2g, 30mmol) and tert-butyldimethyl chloride矽 (3.9 g, 25 mmol) (CAS No. 18162-48-6, purchased from Haimen Best Fine Chemical Co., Ltd.). Then, it was reacted for 2 hours at room temperature, 200 mL of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water (100 mL), and then the organic phase was dried over anhydrous sodium sulfate. The liquid chromatography was carried out on a silica gel column, and the eluting solvent was ethyl acetate: petroleum ether (1:30->1:15) to obtain 2-bromo-(5-tert-butyldimethylammoniomethyl)thiophene) (5.5 g, yield: 90%).

TLC: R _f 0.5 (ethyl acetate: petroleum ether = 1:10) Mass spectrometric detection: MS (ESI) m/z 307 (M+1); NMR detection: ¹ H NMR (400 MHz, CDCl ₃ ): 0.20 (s, 3 H), 0.21 (s, 3 H), 1.60 (s, 9 H), 5.21 (s, 2 H), 6.55-6.75 (m, 2 H).

2-Bromo-(5-tert-butyldimethyloxymethylene)thiophene (1.8 g, 5.9 mmol) was dissolved in tetrahydrofuran (15 mL) and added dropwise to n-butyllithium at a temperature of 70 ° C under nitrogen. A solution of mL, 2.5 mol/L in n-hexane) in tetrahydrofuran (10 mL). The reaction was carried out at -70 ° C for 2 hours, then methyl borate (3.15 g, 30 mmol) was added, and the reaction was continued at minus 70 ° C for 30 minutes, and the mixture was stirred at room temperature to introduce 1 mol/L hydrochloric acid (30 mL) and stirred for 10 minutes. Extracted with ethyl acetate, dried organic extracts were dried over anhydrous Na ₂ SO _4, concentrated under reduced pressure to give compound 10 '(5- (tert-butyldimethyl silicon oxide methylene) thiophen-2-yl) boronic acid crude 1.20g, because the product is easy to decompose, it can be directly used in the next reaction without refining.

Thin layer chromatography: TLC: R _f 0.5 (ethyl acetate: petroleum ether = 1:5)

Mass spectrometry: MS (ESI) m/z 273 (M + 1); (4-(tert-butyldimethyloxymethylene)thiophen-2-yl)boronic acid

(2-(tert-Butyldimethyloxymethylene)thiophen-4-yl)boronic acid

The above-described method for synthesizing a boric acid compound is the same as the method for producing the compound 10' (5-(tert-butyldimethylammoniomethylene)thiophen-2-yl)boronic acid.

Example 7

When R ⁵ and R ⁶ are both H, ring 1 is 2-pyridyl, L ₁ is a single bond, 2-pyridyl is attached to the 5-position of thiophene, and 1H-pyrazole [3,4-d]-pyrimidine-1 - The group is bonded to the 2-position of the thiophene, m=0, the ring 2 is acridine, and the compound 6' is (5-(2-pyridyl)thiophen-2-yl)boronic acid. The preparation method is as follows: 2 at room temperature -Bromopyridine (3 g, 19.1 mmol) (CAS No.: 109-04-6, available from Best Reagent, commercial number B012654) in a solution of ethylene glycol dimethyl ether (60 mL), water (30 mL), (thiophene) 2-yl)boronic acid (3.4 g, 26.7 mmol), tetratriphenylphosphine palladium (454 mg, 3.8 mmol) and Na ₂ CO ₃ (6.1 g, 57.3 mmol). After argon gas replacement for 3 times, the reaction was carried out at 80 ° C for 6 hours, cooled to room temperature, poured into 50 mL of water, extracted with ethyl acetate, and the organic layer was extracted with anhydrous Na ₂ SO ₄ and then evaporated. The crude product was separated by liquid chromatography on a silica gel column eluting with petroleum ether: ethyl acetate (100:1→60:1) to give the desired product 2-(2-pyridyl)thiophene (2.5 g, yield 83%) .

Thin layer chromatography: (TLC) detection: R _f 0.5 (petroleum ether: ethyl acetate = 8:1 unfolded phase); mass spectrometric detection: MS (ESI) m/z 162 (M+1); NMR: ¹ H NMR ( 400 MHz, CDCl ₃ ): 7.10-7.45 (m, 2H), 7.60-7.95 (m, 4H), 8.50-8.60 (m, 1H).

7.1 Preparation of 2-bromo-5-(2-pyridyl)thiophene: To a solution of 2-(2-pyridyl)thiophene (2.5 g, 15.5 mmol) in dichloromethane (100 mL) at 0 ° C A solution of bromine (2.50 g, 15.6 mmol) in dichloromethane (50 mL). After the completion of the dropwise addition for 1 hour, the mixture was stirred at room temperature for 2 hours, poured into saturated Na ₂ CO ₃ (200 mL), and the organic phase was separated, dried over anhydrous Na ₂ SO ₄ and then evaporated. The liquid chromatography was carried out, and the solvent was eluted with petroleum ether: ethyl acetate (100:1→80:1) to give the desired product 2-bromo-5-(2-pyridyl)thiophene (3 g, yield 81%).

Thin layer chromatography: (TLC) detection: R _f 0.5 (petroleum ether: ethyl acetate = 8:1 unfolded phase); mass spectrometry: MS (ESI) m/z 240 (M+1); NMR: 1H NMR (400 MHz) , CDCl3): 7.15-7.50 (m, 3H), 7.65-7.95 (m, 2H), 8.55-8.60 (m, 1H).

Preparation of (5-(2-pyridyl)thiophen-2-yl)boronic acid: 2-bromo-5-(2-pyridyl)thiophene (2 g, 8.3 mmol) dissolved in tetrahydrofuran (15 mL) Add to a solution of n-butyllithium (6.6 mL, 2.5 mol/L in n-hexane) in tetrahydrofuran (15 mL) at 70 °C. After completion of the dropwise addition for 30 minutes, the reaction was continued at minus 70 ° C for 2 hours, then trimethyl borate (5.2 g, 50 mmol) was added, the reaction was continued at minus 70 ° C for 30 minutes, and the temperature was raised to room temperature to introduce 1 mol/L hydrochloric acid. Stir in (20 mL) for 10 minutes. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and then evaporated. Used directly in the next step. Next, repeat route 1 steps 4-6.

TLC: Rf 0.5 (ethyl acetate: petroleum ether = 1:5)

MS (ESI) m/z 206 (M+1).

Route 4 for the preparation of the above intermediates is as follows:

In the above route, R _{7 is} selected from a methyl group, a cyano group, a formamidine amino group or an ethylamino group, and R ₇ may be at the 5- or 6-position of the pyridyl group. The pyridyl group and the thienyl group to which the position is desired can be obtained by selecting a thiophene boric acid substituted at a different position and selecting a bromopyridyl group at a different position.

7.2. Preparation method is similar to the intermediate of 7.1

(5-(3-pyridyl)thiophen-2-yl)boronic acid

5-(2-(6-methylpyridyl))thiophen-2-yl)boronic acid

5-(2-(5-methylpyridyl))thiophen-2-yl)boronic acid

(4-(2-pyridyl)thiophen-2-yl)boronic acid

(4-(3-pyridyl)thiophen-2-yl)boronic acid

The above methods for synthesizing boric acid compounds are similar to compounds A process for the preparation of 6'(5-(2-pyridyl)thiophen-2-yl)boronic acid.

7.3 When R ⁵ and R ⁶ are both H, ring 1 is 2-(6-cyanopyridyl), L ₁ is a single bond, and 2-(6-cyano)pyridinyl is attached to the 5-position of thiophene, 1H- Pyrazole [3,4-d]pyrimidin-1-yl is attached to the 2-position of thiophene, m=0, ring 2 is acridine, and compound 6' is (5-(6-cyanopyridin-2-yl)thiophene. -2-yl)boronic acid, prepared by the method: 5-bromo-((6-cyanopyridin-2-yl)thiophen-2-yl) is prepared in a similar manner to 2-bromo-5-(2-pyridyl)thiophene Preparation method. To a solution of 5-bromo-((6-cyanopyridin-2-yl)thiophen-2-yl) (3 g, 11.3 mmol) in ethylene glycol dimethyl ether (60 mL), water (30 mL) , bis (pinacol) diboron (2.88 g, 11.3 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium chloride dichloromethane complex (920 mg, 1.1 mmol) and NaOAc (3.1 g, 22.6 mmol). After argon gas replacement for 3 times, the reaction was carried out at 80 ° C for 12 hours, cooled to room temperature, poured into 50 mL of water, extracted with ethyl acetate, and the organic layer was extracted with anhydrous Na ₂ SO ₄ and then evaporated. The crude product was dissolved in 30 mL of ethyl acetate and added with 10 mL of 0.1 M hydrochloric acid. The mixture was stirred at room temperature for 5 h, and the mixture was adjusted to pH=6 with saturated Na ₂ CO ₃ , and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ The crude target product (5-(6-cyanopyridin-2-yl)thiophen-2-yl)boronic acid obtained by pressure concentration of the solvent was used in the next reaction without purification.

TLC: (TLC): Rf 0.5 ( petroleum ether: ethyl acetate = 6:1).

7.4 Preparation method Intermediates similar to 7.3

5-(2-(5-cyanopyridinyl)thiophen-2-yl)boronic acid

5-(2-(5-methylaminopyridyl)thiophen-2-yl)boronic acid

5-(2-(6-methylaminopyridinyl)thiophen-2-yl)boronic acid

5-(2-(5-(aminoethenyl)pyridyl)thiophen-2-yl)boronic acid

5-(2-(6-(aminoethenyl)pyridyl)thiophen-2-yl)boronic acid

According to the preparation method of the intermediate disclosed in Example 5, in combination with the synthetic route of the present invention, the compound 1-50 shown in the following Table 1 was obtained, and the preparation method of the intermediate disclosed in Example 6 was combined with the synthetic route of the present invention. Compounds 51-62 as shown in Table 1 below:

Example 8

BTK inhibitory activity and determination of Btk selectivity

Experimental Materials:

1. Bruton kinase inhibitor (BTK)

Yingjie Company, product number: PR5442A (Invitrogen-PR5442A)

2. Test kit

Cisbio, product number 62TK0PEJ

3. Test board

Platinum Elmer, product number: 6007299 (PerkinElmer-6007299)

4. Fluorescent plate reader / volume and universal microplate reader

Elmer, Platinum, trade number: 2104 (PerkinElmer-2104)

Experimental steps:

1. Compound dilution: test compound and positive compound Ibrutinib (Ibrutinib) was diluted 3 times with dimethyl hydrazine (DMSO) for a total of 11 concentrations, and the final system concentration was from 10 μM to 0.17 nM.

2. In a 10 L reaction system in which the buffer is 50 mM 4-hydroxyethylpyridazineethanesulfonic acid (Hepes) (pH 7.5), 5 mM MgCl ₂ , 0.01 mM Na ₃ VO ₄ , 1% bovine serum albumin (BSA), Includes 1nM Bruton's tyrosine kinase (Btk), 1M biotin peptide (biotin-TK peptide), 20M ATP, 50mM 4-hydroxyethylpyridinium ethanesulfonic acid (Hepes) in buffer (pH 7.5) The diluted dimethyl hydrazine (DMSO) solution of the test compound was added to a 96-well test plate and incubated at 23 ° C for 90 minutes. Then add 10 μl of 20 mM ethylenediaminetetraacetic acid (EDTA), 6.7 nM thymidine Btk-deficient antibody (TK) antibody, 62.5 nM stop solution (SA-XL665, purchased from Shanghai Baili Biotechnology Co., Ltd. (cisbio) ), incubate at 23 ° C for 60 minutes.

3. The fluorescence intensity of each well at 445 nm and 520 nm was measured using a fluorescent plate reader/capacitor and a universal microplate reader. The ratio of phosphorylation was determined by the coloration ratio at 445 nm (coumarin color development) relative to 520 nm (luciferon color development) according to the instructions attached to the kit.

4. Calculate the inhibition rate of the compound from the data read by the instrument, and then calculate the IC ₅₀ value. (Using IDBS's XLFIT5 Mode 205)

The inhibition rate (%) of the test compound was calculated using the following formula: Phosphorylation inhibition rate (%) = 1 - {(A _{C -} A _X ) / (A _{C -} A _B )} X 100

A _C : Phosphorylation rate when only dimethyl hydrazine (control) was added

A _X : Phosphorylation rate when adding test compound

A _B : Phosphorylation rate when ATP (blank) is added

The value (IC ₅₀ value) of the 50% inhibition rate of the test compound was calculated from the inhibition curve based on the inhibition rate at each concentration of the test compound.

The measurement of the inhibitory activity of other tyrosine kinase groups such as Lck uses various kinases instead of Btk, and operates in the same manner as the above method.

The above results indicate that the compound of the present invention has a good selective inhibitory effect on Btk.

Example 9

Human lymphoma Ramos cells (Ramos cells) Btk-specific signaling Determination of pathway activity

Test material

Ramos cell

Cell Culture Medium (RPMI1640) Invitrogen #11875093

Fetal bovine serum (FBS) Invitrogen #10099-141

Fluo-4 Calcium Flow Detection Kit Invitrogen #F10471

Immunoglobulin IgM Southern Biotech#2020-01

384-well plate (384-well plate) Grana (Greiner) #781946

2. Test procedure

Detecting IgM EC _80: The cells were collected, containing 0.1% FBS (fetal bovine serum) 1640 medium and resuspended cells were adjusted to a concentration of 5x10 ⁶ / mL. A 20 L/well cell suspension was added to the cell plate, and 40 L of Fluo-4 loading dye was added and incubated at 37 ° C for 50 minutes. IgM was diluted 3 fold to a final concentration of 10 g/mL to 0.0046 g/mL, and 10 L of IgM was transferred to the cell plate using a high throughput cell level screening system (FLIPR) and the fluorescence values were read. The drug concentration of IgM (EC ₈₀ ) was calculated.

Compound IC ₅₀ detection: Cells were harvested with 0.1% FBS containing medium cells were resuspended in 1640 and adjusted to a concentration of 5x10 ⁶ / mL. A 20 L/well cell suspension was added to the cell plate. The test compound and the positive compound Ibrutinib were diluted 3 fold to a final concentration of 10 M to 0.0046 M, and 10 L of the compound was transferred to a cell plate and incubated at 37 ° C for 60 minutes. Add 40L of Fluo-4 loading dye and incubate for 50 min at 37 °C. 10 L of 8 x EC ₈₀ IgM was transferred to the cell plates using a high throughput cell transfer screening system (FLIPR) and the fluorescence values were read. A graph of the inhibition rate was prepared using the drawing software (Prism) GraphPad Software, and the compound IC _{50 was} calculated.

The above results indicate that the compounds of the present invention have an inhibitory effect on the Btk-specific signaling pathway of Ramos cells over ibrutinib.

Example 10

Determination of proliferative activity of non-Hodgkin lymphoma cell lines

Test material

Ramos (Burkitts lymphoma cells)

HBL-1 (human diffuse large B lymphoma cells)

Daudi (Burkitts lymphoma cells)

DOHH-2 (human follicular lymphoma cells)

JeKo-1 (human mantle cell lymphoma cells)

OCI-LY-19 (Burkitts lymphoma cells)

Z-138 (human mantle cell lymphoma cells)

SU-DHL-4 (human diffuse large B lymphoma cells)

SU-DHL-10 (human diffuse large B lymphoma cells)

WSU-DLCL2 (human follicular lymphoma cells)

Microplate reader Molecular Devices Spectra MAX I3

Cell Culture Medium (RPMI1640) Thermo Scientific (Gibco) #C11875500BT

Fetal bovine serum FBS Yingjie company (Invitrogen) #10099-141

Cell Proliferation and Activity Detection Kit (CCK-8) Tongjin Chemical (Dojindo) #CK04B

384-well plate (384-well plate) Corning (Corning) #3701

2. Test procedure

The cells were collected, and the cells were resuspended in 1640 medium containing 10% FBS (fetal calf serum) and the concentration was adjusted to 3 x 10 ⁴ /mL. 50 μL/well of cell suspension was added to the cell plate. The test compound and the positive compound Ibrutinib were diluted 3-fold, and 5 μL of the compound solution was transferred to a cell plate to a final concentration of 50 μM or 1 μM to 0.128 nM or 0.0026 nM, and incubated at 37 ° C for 72 hours. Add 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonic acid benzene)-2H-tetrazole monosodium salt solution , that is, CCK-8 solution (purchased from Shanghai Qiansheng Biotechnology Co., Ltd., trade name CCK-8 kit, product number 40203ES60) 5 μL, and incubated at 37 ° C for 3 hours. The fluorescence value was read using a microplate reader. Use graphics software Prism5.0 (GraphPad Software) graph prepared cell proliferation, the compound is calculated IC _50.

Cell growth inhibition rate (%) = 1 - {(AC-AX) / (AC-AB)} X 100

AC: Negative control absorbance value when only dimethyl hydrazine (control) was added

AX: Add the absorbance value of the test compound well

AB: Absorbance value of blank control (blank)

The above results indicate that the compounds of the present invention have a significant inhibitory effect on the proliferation of non-Hodgkin lymphoma cells, and some of the compounds are significantly more active than ibrutinib.

Example 11

Pharmacodynamic study of compounds of the invention in type II collagen induced mouse arthritis model

Collagen-induced arthritis is an experimental animal model induced by species-specific collagen type II immunization. Because its genetic background and immunopathological changes are very similar to clinical rheumatoid arthritis, it is an ideal animal model for studying rheumatoid arthritis.

Model making method: DBA/1J mice, 7 weeks old, weighing 18-22 g, male, (purchased from Jinan Ono Bioengineering Co., Ltd., trade name DBA/1J mice, model: DBA/1J). Take appropriate amount of bovine type II collagen, dissolved in 0.01mol/L acetic acid (4mg collagen/ml), fully emulsified with an equal amount of complete Freund's adjuvant in an ice bath environment, 0.1ml per mouse (including collagen 200μg) The emulsion was intradermally injected at the base of the tail. On the 21st day, the same amount of collagen was emulsified by incomplete Freund's adjuvant, and the immunization was boosted once.

Materials and Methods: Test compound 17, compound 63, and compound 64 were dissolved in polyethylene glycol 400: castor oil ethoxylate (Kolliphor RH40) = 8:2 at a concentration of 200 mg/ml. (The ethoxylate of castor oil CAS No. 61788-85-0, purchased from BASF, Germany) DBA/1J mice were induced by oral administration of type II collagen-induced arthritis once daily at a dose of 25 mg/kg. The mice were divided into four groups: test compound 17, compound 63, compound 64 and vehicle, wherein the solvent group was administered at a ratio of 100 mg/kg by ethylene glycol 400: ethoxylate of castor oil = 8:2. The mice were administered once a day for 14 days.

Observation indicators and analysis: Arthritis index score. The arthritis index score was scored according to Wood's arthritis scoring criteria. 0 points, normal; 1 point, redness involves 1 finger joint; 2 points, redness involves more than 2 knuckles or the entire foot is slightly red and swollen; 3 points, the feet are red and swollen; 4 points, the feet are severely red and swollen, The joints are stiff and inelastic. The damage of each of the 4 paws was divided into 0-4 to calculate the total score of the limbs. The number of limbs in each group of rats with arthritis was expressed as a percentage, and the scores at different times (arthritis index) were also recorded. The incidence of arthritis and the onset of arthritis. As shown in Fig. 1, it can be seen from Fig. 1 that the arthritis condition of the mice is improved as the time of administration increases.

Inhibitory effect of the compound of Example 12 on the growth of chronic leukemia K562 cells in vitro

Detection of CellTiter-Glo® ATP luminescence activity in vitro of chronic leukemia K562 cells

Leukemia K562 cells were derived from ATCC and maintained at 37 ° C in a 5% CO ₂ atmosphere as well as in Dulbecco's medium (IMDM) and 10% fetal bovine serum. The cells were seeded at a density of 6*10 ³ cells/well in 96-well plates, and the test compound was dissolved in DMSO at concentrations of 0 μM, 0.3 μM, 0.5 μM, 1 μM, 2 μM, 3 μM, 5 μM, 10 μM, 20 μM, K562 cells were treated with 30 μM, 50 μM and 100 μM for 72 hours, and then the cells treated with the compound were detected using the CellTiter-Glo luminescence cell viability assay kit, and luminescence values were recorded.

The results of in vitro effects of some of the compounds of the present invention on leukemia K562 cell viability are listed in Table 6 below.

Claims (38)

A compound of the formula (I), a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation Object: Wherein: W is a 4-6 membered nitrogen-containing saturated heterocyclic group, a benzylidene (C ₃ -C ₆ )cycloalkyl group or a [3.3-5] nitrogen-containing saturated heterospirocyclic group; and R ¹ or R ² are each independently Is selected from H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy, phenyl, Substituted phenyl, benzene (C ₂ -C ₄ ) alkynyl, benzene (C ₁ -C ₄ )alkyl, benzylidene (C ₃ -C ₆ )cycloalkyl, substituted benzene (C ₁ -C ₄ ) alkane , phenoxyalkyl, substituted phenoxyalkyl, benzene (C ₁ -C ₄ ) alkoxy, substituted benzene (C ₁ -C ₄ ) alkoxy, benzene (C ₂ -C ₄ )alkenyl, substituted Benzene (C ₂ -C ₄ )alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, nitrogen-containing heterophenyl substituted (C ₁ -C ₄ ) alkoxy and One or more of them; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; a substituted phenyl group or a substituted nitrogen-containing heterophenyl group The substituents may each independently be selected from the group consisting of halogen, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl, aminemethanyl, B One or more of amidino group and (C ₁ -C ₄ )haloalkoxy group; any integer between n=0-4; R ^{3 is} selected from (C ₂ -C ₄ )alkenyl, (C ₂ - C ₄₎ alkynyl group, propenyl amine, N, N- disubstituted propenyl, one or more amines, and (C ₄ -C ₇₎ nitrogen-containing saturated heterocyclic group-substituted propenyl group, wherein the substituents on the amine The substituent includes one or more of a (C ₁ -C ₄ )alkyl group and a hydroxyl group. a compound according to claim 1 of the patent application, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation As shown in formula (II): Wherein W is a 4-6 membered nitrogen-containing saturated heterocyclic group, a benzylidene (C ₃ -C ₆ )cycloalkyl group or a [3.3-5] nitrogen-containing saturated heterospirocyclic group; and R ¹ or R ² are each independently Is selected from H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy, phenyl, Substituted phenyl, benzene (C ₂ -C ₄ ) alkynyl, phenyl (C ₁ -C ₄ )alkyl, benzyl (C ₃ -C ₆ )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl a benzene (C ₁ -C ₄ ) alkoxy group, a substituted benzene (C ₁ -C ₄ ) alkoxy group, a benzene (C ₂ -C ₄ ) alkenyl group, a substituted benzene (C ₂ -C ₄ ) alkenyl group, Azaphenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkoxy and One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; any integer between n=0-4; R ^{3 is} selected from (C ₂ -C ₄ )alkenyl, (C ₂ -C ₄ )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C ₄ -C ₇ ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C ₁ -C ₄ )alkyl group and a hydroxyl group. a compound according to the scope of claim 2, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation As shown in formula (III): Wherein R ¹ or R ² are each independently selected from H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C) ₄ ) haloalkoxy, phenyl, substituted phenyl, benzene (C ₁ -C ₄ )alkyl, benzylidene (C ₃ -C ₆ )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C ₁ -C ₄ ) alkoxy group, benzene (C ₂ -C ₄ ) alkenyl group, substituted benzene (C ₂ -C ₄ ) alkenyl group, nitrogen-containing heterophenyl group, substituted nitrogen-containing heterophenyl group, nitrogen-containing hetero a phenyl-substituted (C ₁ -C ₄ )alkyl group, a nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ ) alkoxy group, and One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; any integer between n=0-4; R ^{3 is} selected from (C ₂ -C ₄ )alkenyl, (C ₂ -C ₄ )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C ₄ -C ₇ ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C ₁ -C ₄ )alkyl group and a hydroxyl group. a compound according to claim 1 or 3, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or N - an oxide, as shown in formula (IV): Wherein R ^{2 is} selected from the group consisting of phenyl, substituted phenyl, phenyl (C ₁ -C ₄ ) alkyl, substituted benzene (C ₁ -C ₄ ) alkyl, substituted benzene (C ₁ -C ₄ ) alkoxy a benzylidene (C ₃ -C ₆ )cycloalkyl group, a phenoxyalkyl group, a substituted phenoxyalkyl group, a benzene (C ₁ -C ₄ ) alkoxy group, a benzene (C ₂ -C ₄ )alkenyl group, Substituted benzene (C ₂ -C ₄ ) alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, nitrogen-containing heterophenyl substituted ( C ₁ -C ₄ ) alkoxy and One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; any integer between n=0-4; R ^{3 is} selected from (C ₂ -C ₄ )alkenyl, (C ₂ -C ₄ )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C ₄ -C ₇ ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C ₁ -C ₄ )alkyl group and a hydroxyl group. a compound according to item 4 of the patent application, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation The object, as shown in formula (V): Wherein X and Y are each independently selected from CH or N, and R ^{4 is} selected from the group consisting of H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ - C ₄ ) one of a haloalkyl group, an amine carbenyl group, an ethenyl group, and a (C ₁ -C ₄ )haloalkoxy group. a compound according to claim 5, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation Object, as shown in formula (VI): Wherein R ^{4 is} selected from the group consisting of H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl, aminemethanyl, B One of a guanamine group and a (C ₁ -C ₄ )haloalkoxy group. a compound according to claim 5, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation As shown in formula (VII): Wherein R ^{4 is} selected from the group consisting of H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl, aminecaraki, B One of a guanamine group and a (C ₁ -C ₄ )haloalkoxy group. a compound according to claim 5, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation As shown in formula (VIII): Wherein R ⁵ and R ⁶ are each independently selected from the group consisting of H, halogen, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl and One or more of (C ₁ -C ₄ )haloalkoxy groups. a compound according to item 4 of the patent application, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation The object, as shown in formula (IX): Wherein R ⁵ and R ⁶ are each independently selected from the group consisting of H, halogen, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl and One or more of (C ₁ -C ₄ )haloalkoxy groups. a compound according to item 4 of the patent application, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation Object, as shown in formula (X): Wherein X, Y and Z are each independently selected from CH or N; and R ⁵ and R ⁶ are each independently selected from H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl One or more of a cyano group, a (C ₁ -C ₄ )haloalkyl group, and a (C ₁ -C ₄ )haloalkoxy group. a compound according to claim 1 or 3, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or N - an oxide, as shown in formula (XI): Wherein R ^{1 is} selected from the group consisting of phenyl, substituted phenyl, benzene (C ₂ -C ₄ ) alkynyl, phenyl (C ₁ -C ₄ )alkyl, substituted benzene (C ₁ -C ₄ )alkyl, substituted benzene ( C ₁ -C ₄ ) alkoxy, benzylidene (C ₃ -C ₆ )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C ₁ -C ₄ ) alkoxy, benzene (C ₂ -C ₄ )alkenyl, substituted benzene (C ₂ -C ₄ )alkenyl, nitrogen-containing heterophenyl, substituted aza-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, a nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ ) alkoxy group and One or more of them; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R ^{3 is} selected from (C ₂ -C ₄ ) alkene One or more of a (C ₂ -C ₄ )alkynyl group, an amine propylene group, an N,N-disubstituted amine propylene group, and a (C ₄ -C ₇ ) nitrogen-containing saturated heterocyclic group-substituted propylene group, wherein The substituent on the substituted amine includes one or more of a (C ₁ -C ₄ )alkyl group and a hydroxyl group. A compound according to claim 11 of the patent application, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation As shown in formula (XII): Wherein X and Y are each independently selected from CH or N, and R ^{4 is} selected from the group consisting of H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ - C ₄ ) one of a haloalkyl group, an amine carbenyl group, an ethenyl group, and a (C ₁ -C ₄ )haloalkoxy group. A compound according to claim 11 of the patent application, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation As shown in formula (XIII): Wherein R ⁵ and R ⁶ are each independently selected from the group consisting of H, halogen, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl and One or more of (C ₁ -C ₄ )haloalkoxy groups. A compound according to claim 11 of the patent application, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation As shown in formula (XIV): Wherein R ⁵ and R ⁶ are each independently selected from the group consisting of H, halogen, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl and One or more of (C ₁ -C ₄ )haloalkoxy groups. A compound according to claim 11 of the patent application, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation Object, as shown in formula (XV): Wherein X, Y and Z are each independently selected from CH or N; and R ⁵ and R ⁶ are each independently selected from H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl One or more of a cyano group, a (C ₁ -C ₄ )haloalkyl group, and a (C ₁ -C ₄ )haloalkoxy group. a compound according to claim 12, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation Object, as shown in formula (XVI): Wherein R ^{4 is} selected from the group consisting of H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl, aminecaraki, B One of a guanamine group and a (C ₁ -C ₄ )haloalkoxy group. a compound according to claim 12, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation As shown in formula (XVII): Wherein R ^{4 is} selected from the group consisting of H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl, aminecaraki, B One of a guanamine group and a (C ₁ -C ₄ )haloalkoxy group. a compound according to claim 1 of the patent application, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation As shown in formula (XVIII): Wherein R ¹ or R ² are each independently selected from H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C) ₄ ) haloalkoxy, phenyl, substituted phenyl, benzene (C ₂ -C ₄ ) alkynyl, benzene (C ₁ -C ₄ )alkyl, substituted benzene (C ₁ -C ₄ )alkyl, benzene methylene (C ₃ -C ₆ )cycloalkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C ₁ -C ₄ ) alkoxy, substituted benzene (C ₁ -C ₄ ) alkoxy, benzene (C ₂ -C ₄ )alkenyl, substituted benzene (C ₂ -C ₄ )alkenyl, nitrogen-containing heterophenyl, substituted aza-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, a nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ ) alkoxy group and One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; any integer between n=0-4; R ^{3 is} selected from (C ₂ -C ₄ )alkenyl, (C ₂ -C ₄ )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl and (C ₄ -C ₇ ) nitrogen-containing saturated heterocyclic ring One or more of the substituted propylene groups, wherein the substituent on the substituted amine includes one or more of a (C ₁ -C ₄ )alkyl group and a hydroxyl group. a compound according to claim 18, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation Object, as shown in formula (XIX): Wherein R ^{2 is} selected from the group consisting of phenyl, substituted phenyl, phenyl(C ₁ -C ₄ )alkyl, benzylidene(C ₃ -C ₆ )cycloalkyl, substituted benzene(C ₁ -C ₄ )alkyl, Benzene (C ₁ -C ₄ )alkoxy, substituted benzene (C ₁ -C ₄ )alkoxy, phenoxyalkyl, substituted phenoxyalkyl, phenyl(C ₂ -C ₄ )alkenyl, substituted benzene C ₂ -C ₄ )alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, nitrogen-containing heterophenyl substituted (C ₁ - C ₄ ) alkoxy and One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R ^{1 is} selected from the group consisting of H, (C ₁ -C ₄ An alkyl group, (C ₁ -C ₄ ) alkoxy group, (C ₁ -C ₄ )haloalkyl group or (C ₁ -C ₄ )haloalkoxy group; R ^{3 is} selected from (C ₂ -C ₄ )alkenyl group, One or more of (C ₂ -C ₄ )alkynyl, aminpropenyl, N,N-disubstituted aminepropenyl, and (C ₄ -C ₇ )nitrogen-containing saturated heterocyclic substituted propenyl, wherein The substituent on the substituted amine includes one or more of a (C ₁ -C ₄ )alkyl group and a hydroxyl group. a compound according to claim 19, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation The object, as shown in formula (XX): Wherein R ^{2 is} selected from the group consisting of phenyl, substituted phenyl, phenyl(C ₁ -C ₄ )alkyl, benzylidene(C ₃ -C ₆ )cycloalkyl, substituted benzene(C ₁ -C ₄ )alkyl, Benzene (C ₁ -C ₄ )alkoxy, substituted benzene (C ₁ -C ₄ )alkoxy, phenoxyalkyl, substituted phenoxyalkyl, phenyl(C ₂ -C ₄ )alkenyl, substituted benzene C ₂ -C ₄ )alkenyl, nitrogen-containing heterophenyl, substituted nitrogen-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, nitrogen-containing heterophenyl substituted (C ₁ - C ₄ ) alkoxy and One or more of them; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; R ^{3 is} selected from (C ₂ -C ₄ ) alkene One or more of a (C ₂ -C ₄ )alkynyl group, an amine propylene group, an N,N-disubstituted amine propylene group, and a (C ₄ -C ₇ ) nitrogen-containing saturated heterocyclic group-substituted propylene group, wherein The substituent on the substituted amine includes one or more of a (C ₁ -C ₄ )alkyl group and a hydroxyl group. a compound according to claim 20, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation Object, as shown in formula (XXI): Wherein R ⁵ and R ⁶ are each independently selected from the group consisting of H, halogen, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl and One or more of (C ₁ -C ₄ )haloalkoxy groups. a compound according to claim 14 of the patent application, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation As shown in formula (XXII): Wherein R ⁵ and R ⁶ are each independently selected from the group consisting of H, halogen, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl and One or more of (C ₁ -C ₄ )haloalkoxy groups. a compound according to claim 18, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation As shown in formula (XXIII): Wherein R ⁵ and R ⁶ are each independently selected from the group consisting of H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )haloalkyl and One or more of (C ₁ -C ₄ )haloalkoxy groups. a compound according to claim 18, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, a racemate or an N-oxidation Object, as shown in formula (XXIV): Wherein X, Y and Z are each independently selected from CH or N; and R ⁵ and R ⁶ are each independently selected from H, halogen, (C ₁ -C ₃ )alkoxy, (C ₁ -C ₄ )alkyl One or more of a cyano group, a (C ₁ -C ₄ )haloalkyl group, and a (C ₁ -C ₄ )haloalkoxy group. The compound according to any one of claims 1 to 24, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, and a foreign product. a snail or an N-oxide wherein the compound is selected from one or more of the following compounds: 1-(3-(4-amino-3-(5-(phenoxymethyl))thiophen-2-yl) -1H-pyrazole [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-(5) -phenylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-( 4-amino-3-(4-(phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)propan-2- En-1-one; 1-(3-(4-amino-3-(5-methyl-4-(phenoxymethyl)thiophen-2-yl)-1H-pyrazole [3,4-d] Pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-(5-(phenoxymethyl)thiophen-3-yl) -1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-(4- ((2-methyl)phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-ene-1 -ketone; 1-(3-(4-amino-3-(4-((m-methyl)phenoxymethyl)thiophen-2-yl)-1H-pyridyl) Iridazole [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-(4-((pair- Methyl)phenoxymethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; -(3-(4-Amino-3-(4-((2-methoxy)phenoxymethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1- (Acridine-1-yl)prop-2-en-1-one; 1-(3-(4-amino)-3-(4-((3-methoxy)phenoxymethyl)thiophene-2 -yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-) (4-((4-Methoxy)phenoxymethyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)propane-2 -en-1-one; 1-(3-(4-amino-3-(2-((2-cyano)phenoxymethyl)thiophen-4-yl)-1H-pyrazole [3,4- d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-(2-((4-cyano))phenoxy) Thiophen-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4 -amino-3-(2-((3-cyano)phenoxymethyl)thiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl )prop-2-en-1-one; 1-(3-(4-amino-3-(2-(2-methoxyphenyl)oxymethylthiophen-4-yl)-1H-pyrazole [3 ,4-d]pyrimidin-1-yl)acridine- 1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-(2-(3-methoxyphenyl)oxymethylthiophen-4-yl)-1H-pyridyl Azole [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-) Phenylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3 -(4-Amino-3-(5-(phenoxymethyl)thiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)-propene- 2-en-1-one; (R) -1-(3-(4-amino-3-(5-((pyrimidin-4-yloxy)methyl)thiophen-3-yl)-1H-pyridyl) Iridazole [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; 1-(3-(4-amino-3-(5-((2- Methoxy-4-methylphenoxy)methyl)thiophen-3-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)propan-2- Iso-1-one; 1-(3-(4-methoxy-4-(chlorophenoxy)methyl)thiophen-3-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-( (2-methoxy-4-cyanophenoxy)methyl)thiophen-3-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)propane -2-en-1-one; (R) -1-(3-(4-amino-3-(5-((2-chloro-5-methoxyphenoxy)methyl)thiophene-3- -1H-pyrazole [3,4-d]pyrimidine 1-yl) piperidin-1-yl) prop-2-en-1-one; (R) -1- (3- ( 4- amino-3- (5 - ((3-chloro-5- Oxyphenoxy)methyl)thiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-Amino-3-(5-((3-methoxy-4-cyanophenoxy)methyl)thiophen-3-yl)-1H-pyrazole [ 3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(2) - methyl-methylphenoxy) thiophen-3-yl) lH-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one; ( R) -1-(3-(4-Amino-3-(5-(4-methyloxymethyl)thiophen-3-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl Acridine-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(3-methylphenyl))thiophen-2-yl -1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-) 3-(5-(3,4-Dimethylphenyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)propane-2 -en-1-one; (R) -1-(3-(4-amino-3-(5-(3-methoxyphenyl)thiophen-2-yl)-1H-pyrazole [3,4 -d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(4-methoxy) Phenyl)thiophen-2-yl)-1H-pyrazole [3,4-d] L-yl) piperidin-1-yl) prop-2-en-1-one; (R) -1- (3- ( 4- amino-3- (4-phenyl-thiophen-2-yl) -1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3) -(5-phenylthiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) 1-(3-(4-Amino-3-(5-(4-trifluoromethylphenyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl) Acridine-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(3-trifluorotoluene)thiophen-2-yl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-) (5-(3,5-xylene)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1- Ketone; (S) -1-(3-(4-amino-3-(5-phenylthiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine- 1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(2-fluorophenyl)thiophen-2-yl)-1H-pyridyl Azole [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-) (3-fluorophenyl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R ) -1-(3-(4-Amino-3-(5-(4-fluorophenyl)thiophen-2-yl)-1H-pyridyl Azole [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(2- (3-methylphenyl) thiophen-4-yl) lH-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one; ( R) -1-(3-(4-Amino-3-(2-(4-methoxyphenyl)thiophen-4-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl Acridine-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(3-methoxyphenyl))thiophene-3- -1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino) -3-(5-((2-fluorophenoxy)methyl)thiophen-3-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)propyl -2-en-1-one; (R) -1-(3-(4-amino-3-(5-((3-fluorophenoxy)methyl)thiophen-3-yl)-1H-pyridyl Azole [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-) ((4-fluorophenoxy)methyl)thiophen-3-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-ene-1 -ketone; (S) -1-(3-(4-amino-3-(5-(phenoxymethyl)thiophen-3-yl)-1H-pyrazole[3,4-d]pyrimidine-1 -(a)pyridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(2-(phenylethyl))thiophen-4-yl) -1H-pyrazole [3,4-d]pyrimidin-1-yl)acridin-1-yl)propan-2- En-1-one; (R) trans- 1-(3-(4-amino-3-(2-styrenethiophen-4-yl)-1H-pyrazole[3,4-d]pyrimidin-1- Acridine-1-yl)prop-2-en-1-one; 1-(3-(1-(4-amino-3-(2-(3-methylphenyl)oxymethyl)thiophene- 4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one (R) -1-(3-(4- Amino-3-(5-(2-pyridylaminomethyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)propane-2 -en-1-one; (R) -1-(3-(4-amino-3-(5-(3-pyridylaminomethyl)thiophen-2-yl)-1H-pyrazole [3,4 -d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(4-pyridinamine) Mercapto)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1 -(3-(4-Amino-3-(5-(anilinocarbenyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1- ())- 1-(3-(4-amino-3-(2-(2-pyridylaminomethyl) thiophen-4-yl)-1H- Pyrazole [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(2) -(3-pyridylaminocarbamimidyl)thiophen-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1- Ketone; (R) -1- (3-(4-Amino-3-(2-(4-pyridylaminomethyl) thiophen-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine- 1-(1)-propan-2-en-1-one; (R) -1-(3-(4-amino-3-(2-(anilinylmethyl)thiophen-4-yl)-1H-pyridyl Azole [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(4-) (2-pyridylaminomethylindenyl)thiophen-2-yl)-1H-pyrazo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one (R) -1-(3-(4-Amino-3-(4-(3-pyridylaminomethyl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidine- 1-()-acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(4-(4-pyridylamino)methyl) Thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3- (4-Amino-3-(4-(anilinomethylindenyl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidin-1-yl)acridin-1-yl)propane- 2-en-1-one; (R) -1-(3-(4-amino-3-(5-(pyridin-2-yl)thiophen-2-yl)-1H-pyrazole [3,4- d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-(pyridin-3-yl)) Thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3) -(4-amino-3-(4-( 2-yl) thiophen-2-yl) lH-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one; (R & lt) 1-(3-(4-Amino-3-(4-(pyridin-3-yl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridine- 1-yl)prop-2-en-1-one; (S) -1-(3-(4-amino-3-(5-(pyridin-2-yl)thiophen-2-yl)-1H-pyridyl Azole [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one; (R) -1-(3-(4-amino-3-(5-) (6-cyanopyridin-2-yl)thiophen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1- Ketone; (R) -6-(5-(1-(1-Acryl-3-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophene- 2- ( )-pyridylamine; (R) -6-(5-(1-(1-propenyl)-3-yl)-4-amino-1H-pyrazole[3,4-d]pyrimidine -3-yl)thiophen-2-yl)-3-pyridinecarboxamide; (R) -N-(6-(5-(1-(1-propenyl)-3-yl)-4-amino -1H-pyrazolo[3,4-d]pyrimidin-3-yl)thiophen-2-yl)pyridin-2-yl)acetamide; (R) -N-(6-(5-(1-( Bing Xixi 1- piperidin-3-yl) -4-amino -1H- pyrazolo [3,4-d] pyrimidin-3-yl) thiophen-2-yl) pyridin-3-yl) acetyl amine; ( R) -1-(3-(4-Amino-3-(5-(6-methylpyridin-2-yl)thiophen-2-yl)-1H-pyrazole[3,4-d]pyrimidine-1 -yl)pyridin-1-yl)propane -2-en-1-one; (R) -1-(3-(4-amino-3-(5-(5-methylpyridin-2-yl)thiophen-2-yl)-1H-pyrazole [3,4-d]pyrimidin-1-yl)acridin-1-yl)prop-2-en-1-one. a compound represented by the following formula (XXV) or a salt of the compound, Wherein R ¹ or R ² are each independently selected from H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C) ₄ ) haloalkoxy, phenyl, substituted phenyl, benzene (C ₂ -C ₄ ) alkynyl, benzene (C ₁ -C ₄ )alkyl, benzyl (C ₃ -C ₆ )cycloalkyl, substituted Benzene (C ₁ -C ₄ )alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C ₁ -C ₄ ) alkoxy, substituted benzene (C ₁ -C ₄ ) alkoxy, benzene (C ₂ -C ₄ )alkenyl, substituted benzene (C ₂ -C ₄ )alkenyl, nitrogen-containing heterophenyl, substituted aza-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, a nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ ) alkoxy group and One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R ^{7 is} selected from H or Wherein R ^{3 is} selected from the group consisting of trifluoromethyl, tert-butoxy and benzyloxy; when R ⁷ is H, the salt of the compound of formula (XXV) may be hydrochloride, sulfate, acetate and One of the fluoroacetates. A compound according to claim 26, wherein the compound is as follows: Wherein R ¹ or R ² are each independently selected from H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C) ₄ ) haloalkoxy, phenyl, substituted phenyl, benzene (C ₂ -C ₄ ) alkynyl, benzene (C ₁ -C ₄ )alkyl, benzyl (C ₃ -C ₆ )cycloalkyl, substituted Benzene (C ₁ -C ₄ )alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C ₁ -C ₄ ) alkoxy, substituted benzene (C ₁ -C ₄ ) alkoxy, benzene (C ₂ -C ₄ )alkenyl, substituted benzene (C ₂ -C ₄ )alkenyl, nitrogen-containing heterophenyl, substituted aza-containing heterophenyl, nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl, a nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ ) alkoxy group and One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R ^{7 is} selected from H or Wherein R ^{3 is} selected from the group consisting of trifluoromethyl, tert-butoxy and benzyloxy; when R ⁷ is H, the salt of the compound of formula (XXVI) may be hydrochloride, sulfate, acetate and One of the fluoroacetates. A compound according to claim 26, wherein the compound is as follows: Wherein R _{1 is} selected from the group consisting of H, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )haloalkyl, (C ₁ -C ₄ )haloalkoxy, Phenyl, substituted phenyl, benzene (C ₂ -C ₄ ) alkynyl, benzene (C ₁ -C ₄ )alkyl, benzylidene (C ₃ -C ₆ )cycloalkyl, substituted benzene (C ₁ -C ₄ ) alkyl, phenoxyalkyl, substituted phenoxyalkyl, benzene (C ₁ -C ₄ ) alkoxy, substituted benzene (C ₁ -C ₄ ) alkoxy, benzene (C ₂ -C ₄ ) olefin a substituted benzene (C ₂ -C ₄ )alkenyl group, a nitrogen-containing heterophenyl group, a substituted nitrogen-containing heterophenyl group, a nitrogen-containing heterophenyl-substituted (C ₁ -C ₄ )alkyl group, a nitrogen-containing heterophenyl group substituted (C ₁ -C ₄ ) alkoxy group and One or more of the following; wherein R" is selected from one or more of a phenyl group, a substituted phenyl group, a nitrogen-containing heterophenyl group, and a substituted nitrogen-containing heterophenyl group; and R ^{7 is} selected from H or Wherein R ^{3 is} selected from the group consisting of trifluoromethyl, tert-butoxy and benzyloxy; when R ⁷ is H, the salt of the compound of formula (XXVII) may be its hydrochloride, sulfate, acetate and One of the trifluoroacetate salts. A compound of the formula (XXVIII) wherein the compound is as follows: Wherein R ^{8 is} selected from the group consisting of H, Br or a boronic acid group, and R ^{9 is} selected from the group consisting of H, methyl, cyano, amine indenyl or ethenyl. The compound according to claim 29, wherein the compound is represented by the following formula (XXIX): Wherein R ^{8 is} selected from H, Br or a boronic acid group, and R ^{9 is} selected from the group consisting of H, methyl, cyano, amine indenyl or ethenyl. The compound according to claim 29, wherein the compound is represented by the following formula (XXX): Wherein R ^{8 is} selected from H, Br or a boronic acid group, and R ^{9 is} selected from the group consisting of H, methyl, cyano, amine indenyl or ethenyl. The compound according to claim 29, wherein the compound is represented by the following formula (XXXI): Wherein R ^{8 is} selected from H, Br or a boronic acid group, and R ^{9 is} selected from the group consisting of H, methyl, cyano, amine indenyl or ethenyl. The compound according to claim 29, wherein the compound is represented by the following formula (XXXII): Wherein R ^{8 is} selected from H, Br or a boronic acid group, and R ^{9 is} selected from the group consisting of H, methyl, cyano, amine indenyl or ethenyl. A compound according to any one of claims 1 to 25, a cis-trans isomer thereof, a mixture of cis and trans isomers, an optical enantiomer, a mixture of enantiomers, and the like The use of racemates or N-oxides in the manufacture of a medicament for the treatment of diseases involving malignant tumors, autoimmune diseases and allergic diseases. The use according to claim 34, wherein the malignant tumor comprises one or more of lymphoma, plasmacytoma and leukemia. The use according to claim 36, wherein the lymphoma comprises non-Hodgkin's lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, intravascular One or more of large cell type B cell lymphoma, Burkitt's lymphoma, AIDS-associated lymphoma, and marginal zone B cell lymphoma; preferably, said non-Hodgkin's lymphoma comprises B cell non- Hodgkin's lymphoma; more preferably, the B-cell non-Hodgkin's lymphoma comprises one or more of diffuse large B-cell lymphoma and human B-lymphoma. The use according to claim 34, wherein the autoimmune disease comprises one or more of arthritis, rheumatism, inflammatory bowel disease and lupus erythematosus. A Bruton tyrosine kinase inhibitor composition comprising the compound of any one of claims 1 to 25, a cis-trans isomer thereof, a mixture of cis and trans isomers, and an optical alignment Isomer, mixture of enantiomers, racemate or N-oxide.