CN105936635A

CN105936635A - Compound as phosphatidylinositol 3-kinase delta inhibitor and application thereof

Info

Publication number: CN105936635A
Application number: CN201610125706.XA
Authority: CN
Inventors: 王勇; 刘晓蓉; 黄丹丹; 张雁; 开玉美
Original assignee: Nanjing Sanhome Pharmaceutical Co Ltd
Current assignee: Nanjing Sanhome Pharmaceutical Co Ltd
Priority date: 2015-03-06
Filing date: 2016-03-07
Publication date: 2016-09-14
Anticipated expiration: 2036-03-07
Also published as: CN105936635B

Abstract

The invention belongs to the field of medical chemistry, relates to a compound as a phosphatidylinositol 3-kinase (PI3K) delta inhibitor and an application thereof, and particularly, provides the compound represented by the formula I or isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, preparation methods of the compounds, pharmaceutical compositions containing the compounds, and an application of the compounds or the compositions in treatment of cancer, tissue hyperplasia diseases or inflammatory diseases. The compound has good inhibition activity to PI3K[delta], has high selectivity, and is extremely promising to become a therapeutic agent for the cancer, tissue hyperplasia diseases and inflammatory diseases.

Description

Compounds as phosphatidylinositol 3-kinase inhibitors and uses thereof

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to a compound serving as a phosphatidylinositol 3-kinase (PI3K) inhibitor or an isomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound or the composition in treating cancers, tissue proliferation diseases or inflammatory diseases.

Background

PI3K (phosphatidylinositol 3-kinase) is a member of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3' -OH group on phosphatidylinositols. Depending on the structure and phosphorylated substrates, PI3K can be classified into three types I, II, and III, with type I PI3K being the focus of current research and playing an important role in modulating immune cells with PI3K activity that contribute to the pro-tumorigenic effects of inflammatory cells (Coussens and Werb, Nature, 2002, 420, 860-867), and having therapeutic value in the treatment of various forms of cancer disease, including solid tumors (e.g., carcinomas and sarcomas), leukemias, and lymphoid malignancies. Type I PI3K consists of p110 units and p85 units, four of the currently known p110 subunits, namely p110 α, p110 β, p110 γ and p110, where p110 is predominantly expressed in spleen and hematopoietic cells including leukocytes such as T cells, dendritic cells, neutrophils, mast cells, B cells and macrophages. PI3K is involved in whole mammalian immune system functions such as T cell function, dendritic cell function, neutrophil activity, mast cell activation, B cell activation. Thus, PI3K is also involved in a variety of diseases associated with abnormal immune responses, such as allergies, inflammatory diseases, inflammation-mediated angiogenesis, rheumatoid arthritis, autoimmune diseases such as lupus erythematosus, asthma, emphysema, and other respiratory diseases.

The research on the drugs targeting the PI3K pathway has been carried out for many years, and some clinical success is achieved, especially recently, selective PI3K inhibitors are found to have obvious curative effect in the treatment of diseases such as cancer. However, there is still a need to develop more superior PI3K inhibitors, in particular selective PI3K inhibitors, in order to specifically modulate and/or mediate the transduction of PI3K and related protein kinases for the treatment of diseases associated with PI3K kinase mediated events.

Disclosure of Invention

The invention aims to provide a compound with PI3K inhibitory activity shown in a general formula I, or an isomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,

wherein,

y is selected from O and N (R)¹) Wherein R is¹Selected from the group consisting of hydrogen, alkyl, haloalkyl, and cycloalkyl;

X¹、X²、X³、X⁴are each independently selected from N and C (R)²) Wherein R is²Selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, nitro, carboxy, cyano, amino, monoalkylamino, and dialkylamino;

R^cselected from the group consisting of alkylene, alkenylene, alkynylene and cycloalkylene, which may be substituted with one or more alkyl, haloalkyl, hydroxy, hydroxyalkyl, halogen, oxo, alkoxy, carboxy, cyano, amino, monoalkylamino or dialkylamino groups;

Cy¹selected from aryl and heteroaryl groups, which may be substituted with one or more halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, monoalkylamino, monoalkylaminoalkyl, dialkylamino, dialkylaminoalkyl, alkanoyl, alkylacylalkyl, alkoxyacyl, alkoxyacylalkyl, alkylacyloxy, alkylacyloxyalkyl, aminoacyl, aminoacylalkyl, monoalkylaminoacylalkyl, dialkylaminoacylalkyl, alkylacylamino or alkylacylaminoalkyl groups;

R^aselected from H and alkyl, and R^bSelected from six-to twelve-membered nitrogen-containing heteroaryl and-C (O) -six-to twelve-membered nitrogen-containing heteroaryl, or R^a、R^bTogether with the N atom to which they are attached, form a six-to twelve-membered nitrogen-containing heteroaryl group, wherein the six-to twelve-membered nitrogen-containing heteroaryl group and-C (O) -six-to twelve-membered nitrogen-containing heteroaryl group may be substituted with one or more halogens, hydroxy groups, oxo groups, amino groups, carboxy groups, cyano groups, nitro groups, alkyl groups, cycloalkyl groups, heterocycloalkyl groups, alkoxy groups, haloalkyl groups, hydroxyalkyl groups, aminoalkyl groups, carboxyalkyl groups, cyanoalkyl groups, nitroalkyl groups, cycloalkylalkyl groups, heterocycloalkylalkyl groups, alkoxyalkyl groups, monoalkylamino groups, monoalkylaminoalkyl groups, dialkylamino groups, dialkylaminoalkyl groups, alkanoyl groups, alkylacylalkyl groups, alkoxyacyl groups, alkoxyacylalkyl groups, alkylacyloxy groups, alkylacyloxyalkyl groups, aminoacyl groups, aminoalkylaminoalkyl groups, monoalkylaminoacyl groups, monoalkyl aminoacyl groups, monoalkyl groups, or a combination thereof, A bisalkylaminoacyl, bisalkylaminoacylalkyl, alkylacylamino, or alkylacylaminoalkyl substituent.

It is another object of the present invention to provide a process for preparing the compounds of formula I of the present invention or isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof.

It is a further object of the present invention to provide compositions comprising a compound of formula I of the present invention or an isomer, a pharmaceutically acceptable salt, solvate or prodrug thereof and a pharmaceutically acceptable carrier, and compositions comprising a compound of formula I of the present invention or an isomer, a pharmaceutically acceptable salt, solvate or prodrug thereof and another inhibitor or inhibitors of PI 3K.

The invention also provides a method for treating and/or preventing tumor, tissue proliferation diseases or inflammatory diseases by using the compound of the general formula I or the isomer, the pharmaceutically acceptable salt, the solvate or the prodrug thereof, and application of the compound of the general formula I or the isomer, the pharmaceutically acceptable salt, the solvate or the prodrug thereof in preparing medicaments for treating and/or preventing tumor, tissue proliferation diseases or inflammatory diseases.

Aiming at the above purpose, the invention provides the following technical scheme:

in a first aspect, the present invention provides a compound of formula I or an isomer, a pharmaceutically acceptable salt, solvate or prodrug thereof,

wherein,

Cy¹selected from aryl and heteroaryl groups which may be substituted with one or more halogens, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, monoalkylamino, monoalkylaminoalkyl, dialkylamino, dialkylaminoalkyl, alkanoyl, alkylacylalkyl, alkoxyacyl, alkoxyalkoxy, nitro, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkoxyalkyl, monoalkylamino, monoalkylaminoalkyl, dialkylamino, dialkylaminoalkyl, alkyl acyl, alkyl acylalkyl, alkoxyacyl, alkoxyalkoxy, alkoxy, or a combination thereofSubstituted with acylalkyl, alkylacyloxy, alkylacyloxyalkyl, aminoacyl, aminoacylalkyl, monoalkylaminoacyl, monoalkylaminoacylalkyl, dialkylaminoacyl, dialkylaminoacylalkyl, alkylacylamino or alkylacylaminoalkyl groups; and

In some particular embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

X¹、X²、X³、X⁴are all C (R)²)。

In other specific embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

X¹、X²、X³、X⁴one of them is N, the other three are C (R)²)。

X¹、X²、X³、X⁴two of them are N and the other two are C (R)²)。

X¹、X²、X³、X⁴three of them are N, the other one is C (R)²)。

In some preferred embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

y is selected from O and N (R)¹) Wherein R is¹Selected from hydrogen, C_1-6Alkyl, halo C_1-6Alkyl and C_3-6A cycloalkyl group;

further preferably, Y is selected from O and N (R)¹) Wherein R is¹Selected from hydrogen, C_1-3Alkyl, halo C_1-3Alkyl and C_3-6A cycloalkyl group;

even more preferably, Y is selected from O and N (R)¹) Wherein R is¹Selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

R²selected from hydrogen, hydroxy, halogen, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-6Alkylamino and di-C_1-6An alkylamino group;

further preferably, R²Selected from hydrogen, hydroxy, halogen, C_1-3Alkyl, halo C_1-3Alkyl, hydroxy C_1-3Alkyl radical, C_1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-3Alkylamino and di-C_1-3An alkylamino group;

even more preferably, R²Selected from the group consisting of hydrogen, hydroxy, halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxy, cyano, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino and ethylpropylamino.

R^cis selected from C_1-10Alkylene, alkylidene_3-10Cycloalkyl, C_2-10Alkenyl and alkylidene_2-10Alkynyl, said alkylene_1-10Alkyl, alkylene C_3-10Cycloalkyl, C_2-10Alkenyl and alkylidene_2-10Alkynyl may be substituted by one or more C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, halogen, oxo, C_1-6Alkoxy, carboxyl, cyano, amino, mono C_1-6Alkylamino or di-C_1-6Alkyl amino substitution;

further preferably, R^cIs selected from C_1-6Alkylene, alkylidene_3-6Cycloalkyl, C_2-6Alkenyl and alkylidene_2-6Alkynyl, said alkylene_1-6Alkyl, alkylene C_3-6Cycloalkyl, C_2-6Alkenyl and alkylidene_2-6Alkynyl may be substituted by one or more C_1-3Alkyl, halo C_1-3Alkyl, hydroxy C_1-3Alkyl, halogen, oxo, C_1-3Alkoxy, carboxyl, cyano, amino, mono C_1-3Alkylamino or di-C_1-3Alkyl amino substitution;

even more preferably, R^cIs C_1-3Alkylene radical of the formula C_1-3Alkylene groups may be substituted by one or more C_1-3Alkyl, halo C_1-3Alkyl, hydroxy C_1-3Alkyl, halogen, oxo, C_1-3Alkoxy, carboxyl, cyano, amino, mono C_1-3Alkylamino or di-C_1-3Alkyl amino substitution.

Even more preferably, R^cSelected from the group consisting of methylene, ethylene and propylene, said methylene, ethylene and propylene being optionally substituted with one or more methyl, ethyl, propyl, isopropyl, oxo groups.

Cy¹selected from aryl and heteroaryl, which may be substituted by one or more halogens, hydroxy, amino, carboxy, cyano, nitro, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Heterocycloalkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl, cyano C_1-6Alkyl, nitro C_1-6Alkyl, cycloalkyl C_1-6Alkyl radical, C_3-8Heterocycloalkyl radical C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl, mono C_1-6Alkylamino radical, mono C_1-6Alkylamino radical C_1-6Alkyl, di-C_1-6Alkylamino, di-C_1-6Alkylamino radical C_1-6Alkyl radical, C_1-6Alkyl acylBase, C_1-6Alkyl acyl radical C_1-6Alkyl radical, C_1-6Alkoxyacyl group, C_1-6Alkoxy acyl radical C_1-6Alkyl radical, C_1-6Alkyl acyloxy, C_1-6Alkyl acyloxy radical C_1-6Alkyl, aminoacyl C_1-6Alkyl, mono C_1-6Alkylaminoacyl, mono C_1-6Alkylaminoacyl radical C_1-6Alkyl, di-C_1-6Alkylaminoacyl, di-C_1-6Alkylaminoacyl radical C_1-6Alkyl radical, C_1-6Alkylacylamino or C_1-6Alkylacylamino C_1-6Alkyl substitution;

further preferably, Cy¹Selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrrolyl, thienyl, furyl, indolyl, isoindolyl and quinolinyl, which may be substituted with one or more of halogen, hydroxy, amino, carboxy, cyano, nitro, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Heterocycloalkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl, cyano C_1-6Alkyl, nitro C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Heterocycloalkyl radical C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl, mono C_1-6Alkylamino radical, mono C_1-6Alkylamino radical C_1-6Alkyl, di-C_1-6Alkylamino, di-C_1-6Alkylamino radical C_1-6Alkyl radical, C_1-6Alkyl acyl radical, C_1-6Alkyl acyl radical C_1-6Alkyl radical, C_1-6Alkoxyacyl group, C_1-6Alkoxy acyl radical C_1-6Alkyl radical, C_1-6Alkyl acyloxy, C_1-6Alkyl acyloxy radical C_1-6Alkyl, aminoacyl C_1-6Alkyl, mono C_1-6Alkylaminoacyl, mono C_1-6Alkylaminoacyl radical C_1-6Alkyl, di-C_1-6Alkylaminoacyl, di-C_1-6Alkylaminoacyl radical C_1-6Alkyl radical, C_1-6Alkylacylamino or C_1-6Alkylacylamino C_1-6Alkyl substitution;

still more preferably, Cy is¹Selected from phenyl, pyridyl and pyrimidinyl, which may be substituted with one or more of halogen, hydroxy, amino, carboxy, cyano, nitro, C_1-3Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl radical, C_1-3Alkoxy, halo C_1-3Alkyl, hydroxy C_1-3Alkyl, amino C_1-3Alkyl, carboxyl C_1-3Alkyl, cyano C_1-3Alkyl, nitro C_1-3Alkyl radical, C_3-6Cycloalkyl radical C_1-3Alkyl radical, C_3-6Heterocycloalkyl radical C_1-3Alkyl radical, C_1-3Alkoxy radical C_1-3Alkyl, mono C_1-3Alkylamino radical, mono C_1-3Alkylamino radical C_1-3Alkyl, di-C_1-3Alkylamino, di-C_1-3Alkylamino radical C_1-3Alkyl radical, C_1-3Alkyl acyl radical, C_1-3Alkyl acyl radical C_1-3Alkyl radical, C_1-3Alkoxyacyl group, C_1-3Alkoxy acyl radical C_1-3Alkyl radical, C_1-3Alkyl acyloxy, C_1-3Alkyl acyloxy radical C_1-3Alkyl, aminoacyl C_1-3Alkyl, mono C_1-3Alkylaminoacyl, mono C_1-3Alkylaminoacyl radical C_1-3Alkyl, di-C_1-3Alkylaminoacyl, di-C_1-3Alkylaminoacyl radical C_1-3Alkyl radical, C_1-3Alkylacylamino or C_1-3Alkylacylamino C_1-3Alkyl substitution.

R^aselected from H and C_1-6Alkyl, and R^bSelected from six-to twelve-membered nitrogen-containing heteroaryl and-C (O) -six-to twelve-membered nitrogen-containing heteroaryl, or R^a、R^bTogether with the N atom to which they are attached, form a six-to twelve-membered nitrogen-containing heteroaryl group, wherein the six-to twelve-membered nitrogen-containing heteroaryl group and-C (O) -six-to twelve-membered nitrogen-containing heteroaryl group may be substituted with one or more halogens, hydroxy groups, oxo groups, amino groups, carboxy groups, cyano groups, nitro groups, alkyl groups, cycloalkyl groups, heterocycloalkyl groups, alkoxy groups, haloalkyl groups, hydroxyalkyl groups, aminoalkyl groups, carboxyalkyl groups, cyanoalkyl groups, nitroalkyl groups, cycloalkylalkyl groups, heterocycloalkylalkyl groups, alkoxyalkyl groups, monoalkylamino groups, monoalkylaminoalkyl groups, dialkylamino groups, dialkylaminoalkyl groups, alkanoyl groups, alkylacylalkyl groups, alkoxyacyl groups, alkoxyacylalkyl groups, alkylacyloxy groups, alkylacyloxyalkyl groups, aminoacyl groups, aminoalkylaminoalkyl groups, monoalkylaminoacyl groups, monoalkyl aminoacyl groups, monoalkyl groups, or a combination thereof, A bisalkylaminoacyl, bisalkylaminoacylalkyl, alkylacylamino, or alkylacylaminoalkyl substitution;

further preferably, R^aSelected from H and C_1-3Alkyl, and R^bSelected from six-to twelve-membered nitrogen-containing heteroaryl and-C (O) -six-to twelve-membered nitrogen-containing heteroaryl, or R^a、R^bTogether with the N atom to which they are attached form a six-to twelve-membered nitrogen-containing heteroaryl group, wherein the six-to twelve-membered nitrogen-containing heteroaryl and-C (O) -nitrogen-containing heteroaryl groups may be substituted with one or more halogens, hydroxy, oxo, amino, carboxy, cyano, nitro, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl, cyano C_1-6Alkyl, nitro C_1-6Alkyl radical, C_3-6Cycloalkyl radical C_1-6Alkyl radical, C_3-6Heterocycloalkyl radical C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl, mono C_1-6Alkylamino radical, mono C_1-6Alkylamino radical C_1-6Alkyl, di-C_1-6Alkylamino, di-C_1-6Alkylamino radical C_1-6Alkyl radical, C_1-6Alkyl acyl radical, C_1-6Alkyl acyl radical C_1-6Alkyl radical, C_1-6Alkoxyacyl group, C_1-6Alkoxy acyl radical C_1-6Alkyl radical, C_1-6Alkyl acyloxy, C_1-6Alkyl acyloxy radical C_1-6Alkyl, aminoacyl C_1-6Alkyl, mono C_1-6Alkylaminoacyl, mono C_1-6Alkylaminoacyl radical C_1-6Alkyl, di-C_1-6Alkylaminoacyl, di-C_1-6Alkylaminoacyl radical C_1-6Alkyl radical, C_1-6Alkylacylamino or C_1-6Alkylacylamino C_1-6Alkyl substitution.

R^aselected from H and C_1-3Alkyl, and R^bSelected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyridopyrrolyl, pyridopyrazolyl, pyridoimidazolyl, pyridotriazolyl, pyrimidopyrrolyl, pyrimidoimidazolyl, pyrimidoiazolyl, pyrimidoiotriazolyl, pyrazinoipyrrolyl, pyrazinoimidazolyl, pyrazinoipyrazolyl, pyrazinoitriazolyl, pyridazinoiyrrolyl, pyridazinoimidazolyl, pyridazinazolyl and pyridazinoiriazolyl, said pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyridopyrrolyl, pyridopyrazolyl, pyridoimidazolyl, pyridotriazolazolyl, pyrimidoipyrrolyl, pyrimidoimidazolyl, pyrimidoizolyl, pyrazinoizolyl, pyrazinoitriazolyl, pyridazinoizolyl, pyridopyrrolyl, pyrimidoizolyl, the pyridazinoimidazolyl, pyridazinazolyl and pyridazinotriazolyl radicals may be substituted by one or more halogen, hydroxy, oxo, amino, carboxy, cyano, nitro, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl, cyano C_1-6Alkyl, nitro C_1-6Alkyl radical, C_3-6Cycloalkyl radical C_1-6Alkyl radical, C_3-6Heterocycloalkyl radical C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl, mono C_1-6Alkylamino radical, mono C_1-6Alkylamino radical C_1-6Alkyl, di-C_1-6Alkylamino, di-C_1-6Alkylamino radical C_1-6Alkyl radical, C_1-6Alkyl acyl radical, C_1-6Alkyl acyl radical C_1-6Alkyl radical, C_1-6Alkoxyacyl group, C_1-6Alkoxy acyl radical C_1-6Alkyl radical, C_1-6Alkyl acyloxy, C_1-6Alkyl acyloxy radical C_1-6Alkyl, aminoacyl C_1-6Alkyl, mono C_1-6Alkylaminoacyl, mono C_1-6Alkylaminoacyl radical C_1-6Alkyl, di-C_1-6Alkylaminoacyl, di-C_1-6Alkylaminoacyl radical C_1-6Alkyl radical, C_1-6Alkylacylamino or C_1-6Alkylacylamino C_1-6Alkyl substitution.

R^ais H, and R^bSelected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridopyrazolyl and pyrimidoimidazolyl, which pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridopyrazolyl and pyrimidoimidazolyl may be substituted by one or more halogen, hydroxy, oxo, amino, carboxy, cyano, nitro, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl, cyano C_1-6Alkyl, nitro C_1-6Alkyl radical, C_3-6Cycloalkyl radical C_1-6Alkyl radical, C_3-6Heterocycloalkyl radical C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl, mono C_1-6Alkylamino radical, monoC_1-6Alkylamino radical C_1-6Alkyl, di-C_1-6Alkylamino, di-C_1-6Alkylamino radical C_1-6Alkyl radical, C_1-6Alkyl acyl radical, C_1-6Alkyl acyl radical C_1-6Alkyl radical, C_1-6Alkoxyacyl group, C_1-6Alkoxy acyl radical C_1-6Alkyl radical, C_1-6Alkyl acyloxy, C_1-6Alkyl acyloxy radical C_1-6Alkyl, aminoacyl C_1-6Alkyl, mono C_1-6Alkylaminoacyl, mono C_1-6Alkylaminoacyl radical C_1-6Alkyl, di-C_1-6Alkylaminoacyl, di-C_1-6Alkylaminoacyl radical C_1-6Alkyl radical, C_1-6Alkylacylamino or C_1-6Alkylacylamino C_1-6Alkyl substitution.

R^a、R^btogether with the N atom to which they are attached form a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyridopyrrolyl, pyridopyrazolyl, pyridoimidazolyl, pyridotriazolyl, pyrimidopyrrolyl, pyrimidoimidazolyl, pyrimidopyrazolyl, pyrimidotriazolyl, pyrazinopyrrolyl, pyrazinoimidazolyl, pyrazinopyrazolyl, pyrazinotriazolyl, pyridazinopyrrolyl, pyridazinoimidazolyl, pyridazinazolyl or pyridazinotriazolyl group, said pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyridopyrrolyl, pyridopyrazolyl, pyridoimidazolyl, pyridotriazolyl, pyrimidopyrrolyl, pyrimidoimidazolyl, pyrimidopyrazolyl, pyrimidotriazolyl, pyrazinoimidazolyl, pyrazinoizolyl, pyrazinoitriazolyl, pyrazinoiriazolyl, pyrazinoizolyl, pyrazinoiriazolyl, pyridotriazolyl, pyridopyrroloiyl, pyridopyrroloiazolyl, pyridinopyrrolyl, pyridinotriazolyl, The pyridazinopyrrolyl, pyridazinoimidazolyl or pyridazinpyrazolyl, pyridazinotriazolyl group may be substituted by one or more halogen, hydroxy, oxo, amino, carboxy, cyano, nitro, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl, cyano C_1-6Alkyl, nitro C_1-6Alkyl radical, C_3-6Cycloalkyl radical C_1-6Alkyl radical, C_3-6Heterocycloalkyl radical C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl, mono C_1-6Alkylamino radical, mono C_1-6Alkylamino radical C_1-6Alkyl, di-C_1-6Alkylamino, di-C_1-6Alkylamino radical C_1-6Alkyl radical, C_1-6Alkyl acyl radical, C_1-6Alkyl acyl radical C_1-6Alkyl radical, C_1-6Alkoxyacyl group, C_1-6Alkoxy acyl radical C_1-6Alkyl radical, C_1-6Alkyl acyloxy, C_1-6Alkyl acyloxy radical C_1-6Alkyl, aminoacyl C_1-6Alkyl, mono C_1-6Alkylaminoacyl, mono C_1-6Alkylaminoacyl radical C_1-6Alkyl, di-C_1-6Alkylaminoacyl, di-C_1-6Alkylaminoacyl radical C_1-6Alkyl radical, C_1-6Alkylacylamino or C_1-6Alkylacylamino C_1-6Alkyl substitution.

R^ais H; and

R^ba group selected from:

wherein said May be substituted by one or more halogen, hydroxy, oxo, amino, carboxy, cyano, nitro, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl, cyano C_1-6Alkyl, nitro C_1-6Alkyl radical, C_3-6Cycloalkyl radical C_1-6Alkyl radical, C_3-6Heterocycloalkyl radical C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl, mono C_1-6Alkylamino radical, mono C_1-6Alkylamino radical C_1-6Alkyl, di-C_1-6Alkylamino, di-C_1-6Alkylamino radical C_1-6Alkyl radical, C_1-6Alkyl acyl radical, C_1-6Alkyl acyl radical C_1-6Alkyl radical, C_1-6Alkoxyacyl group, C_1-6Alkoxy acyl radical C_1-6Alkyl radical, C_1-6Alkyl acyloxy, C_1-6Alkyl acyloxy radical C_1-6Alkyl, aminoacyl C_1-6Alkyl, mono C_1-6Alkylaminoacyl, mono C_1-6Alkylaminoacyl radical C_1-6Alkyl, di-C_1-6Alkylaminoacyl, di-C_1-6Alkylaminoacyl radical C_1-6Alkyl radical, C_1-6Alkylacylamino or C_1-6Alkylacylamino C_1-6Alkyl substitution.

In some particular embodiments, the compounds of the present invention are of formula I or an isomer, N-oxide, pharmaceutically acceptable salt, solvate, prodrug or chemically protected form thereof, wherein:

y is selected from O and N (R)¹) Wherein R is¹Selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

X¹、X²、X³、X⁴are all C (R)²) Wherein R is²Selected from hydrogen, hydroxy, halogen, C_1-3Alkyl, halo C_1-3Alkyl, hydroxy C_1-3Alkyl radical, C_1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-3Alkylamino and di-C_1-3An alkylamino group;

R^cselected from the group consisting of methylene, ethylene and propylene, said methylene, ethylene and propylene being optionally substituted with one or more methyl, ethyl, propyl, isopropyl, oxo groups;

Cy¹selected from phenyl, pyridyl and pyrimidinyl, which may be substituted with one or more of halogen, hydroxy, amino, carboxy, cyano, nitro, C_1-3Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl radical, C_1-3Alkoxy, halo C_1-3Alkyl, hydroxy C_1-3Alkyl, amino C_1-3Alkyl, carboxyl C_1-3Alkyl, cyano C_1-3Alkyl, nitro C_1-3Alkyl radical, C_3-6Cycloalkyl radical C_1-3Alkyl radical, C_3-6Heterocycloalkyl radical C_1-3Alkyl radical, C_1-3Alkoxy radical C_1-3Alkyl, mono C_1-3Alkylamino radical, mono C_1-3Alkylamino radical C_1-3Alkyl, di-C_1-3Alkylamino, di-C_1-3Alkylamino radical C_1-3Alkyl radical, C_1-3Alkyl acyl radical, C_1-3Alkyl acyl radical C_1-3Alkyl radical, C_1-3Alkoxyacyl group, C_1-3Alkoxy acyl radical C_1-3Alkyl radical, C_1-3Alkyl acyloxy, C_1-3Alkyl acyloxy radical C_1-3Alkyl, aminoacyl C_1-3Alkyl, mono C_1-3Alkylaminoacyl, mono C_1-3Alkylaminoacyl radical C_1-3Alkyl, di-C_1-3Alkylaminoacyl, di-C_1-3Alkylaminoacyl radical C_1-3Alkyl radical, C_1-3Alkylacylamino or C_1-3Alkylacylamino C_1-3Alkyl substitution;

R^aselected from H and C_1-3An alkyl group; and

R^ba group selected from:

the present invention provides the following specific compounds:

or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process for the preparation of a compound of the general formula of the present invention, comprising:

1. preparation of a compound of formula I wherein Y is O:

a) carrying out esterification reaction on the compound of the formula (1) and the compound of the formula (2) to obtain an intermediate of the formula (3);

b) reacting the intermediate of formula (3) with a strong base (such as sodium hydride) to provide an intermediate of formula (4);

c) cyclizing the intermediate of the formula (4) under an acidic condition to obtain an intermediate of the formula (5);

d) carrying out halogenation reaction on the intermediate of the formula (5) to obtain an intermediate of a formula (6);

e) the intermediate of formula (6) is subjected to conventional reaction to obtain the compound of general formula (I).

Wherein, the conventional reaction of step e) includes, but is not limited to, a reaction such as amination of the intermediate of formula (6) with Y-R^bCarrying out nucleophilic reaction to obtain a compound of a general formula (I); or the intermediate of the formula (6) is subjected to ester formation, hydrolysis and oxidation and then reacts with tert-butyl sulfinamide to obtain the intermediateThe intermediate is then reacted with an alkyl reagent and further reacted with Y-R^bCarrying out nucleophilic reaction to obtain a compound of a general formula (I); or cyanation and re-hydrolysis of the intermediate of formula (6) with NH₂-R^bCondensing to obtain the compound of the general formula (I) and the like.

Wherein, X¹、X²、X³、X⁴、Cy¹、R^bAnd R^cHave the meaning in the general formula I; r^aRepresents hydrogen; m represents an alkyl group, preferably C_1-6Alkyl, more preferably C_1-3An alkyl group; m' represents an alkylene group wherein one H of M is substituted by X; m "represents a group remaining after one carbon atom is removed from M, and when M is a methyl group, M" represents H; x, Y represents halogen, preferably chlorine, bromine or iodine.

2. Y is N (R)¹) Preparation of a compound of general formula I:

a') reacting a compound of formula (11) with triphosgene to give an intermediate of formula (12);

b') reacting the intermediate of formula (12) with a compound of formula (13) to give an intermediate of formula (14);

c') subjecting the intermediate of formula (14) to a reduction reaction to obtain an intermediate of formula (15);

d') subjecting the intermediate of formula (15) to an oxidation reaction to obtain an intermediate of formula (16);

e') addition reaction of the intermediate of formula (16) with an alkylating agent to give an intermediate of formula (17);

f') subjecting the intermediate of formula (17) to an oxidation reaction to obtain an intermediate of formula (18);

g') reacting the intermediate of formula (18) with hydroxylamine to give an intermediate of formula (19);

h') subjecting the intermediate of formula (19) to a reduction reaction to obtain an intermediate of formula (20);

i') reacting the intermediate of formula (20) with an amino protecting group to give an intermediate of formula (21);

j') intermediate of formula (21) and R¹-X nucleophilic reaction to give an intermediate of formula (22);

k') an intermediate deaminating protecting group of formula (22), with X-R^bAnd (3) carrying out nucleophilic reaction to obtain the compound shown in the general formula I.

Wherein, X¹、X²、X³、X⁴、Cy¹、R^bAnd R¹Have the meaning in the general formula I; r^aRepresents H; r^cRepresents an alkylene group which may be further substituted by an alkyl group, when R is^cWhen representing a methylene group, the intermediate of formula (16) is reacted directly with hydroxylamine and the compounds of formula I are obtained by the processes of steps h '), I'), j ') and k'); t represents an alkyl group, preferably C_1-6Alkyl, more preferably C_1-3An alkyl group; x represents a halogen, preferably chlorine, bromine or iodine.

In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or an isomer, a pharmaceutically acceptable salt, solvate or prodrug thereof.

In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of the present invention, or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, further comprising one or more selected from the group consisting of: tyrosine protease inhibitors, EGFR inhibitors, VEGFR inhibitors, Bcr-Abl inhibitors, c-kit inhibitors, c-Met inhibitors, Raf inhibitors, MEK inhibitors, histone deacetylase inhibitors, VEGF antibodies, EGF antibodies, HIV protein kinase inhibitors, HMG-CoA reductase inhibitors, and the like.

In some embodiments, the present invention provides a compound of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, and a pharmaceutical composition comprising a compound of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof for treating and/or preventing cancer, a tissue proliferative disease or an inflammatory disease.

The compound of the present invention or its isomer, pharmaceutically acceptable salt, solvate or prodrug can be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulations may be administered by any route, for example by infusion or bolus injection, by a route of absorption through epithelial or cutaneous mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of the formulation for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulation. In a fourth aspect, the present invention provides a compound represented by formula I, or an isomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, or a pharmaceutical composition containing the same in the preparation of a medicament for treating and/or preventing cancer, tissue proliferative diseases or inflammatory diseases, wherein the cancer is selected from melanoma, papillary thyroid tumors, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymphoma, carcinomas of the liver, kidney, bladder, prostate, breast and pancreas, and sarcomas, and primary and recurrent solid tumors of the skin, colon, thyroid, lung and ovary or leukemia, the inflammatory disease is selected from allergy, asthma, rheumatoid arthritis, osteoarthritis, allergic conjunctivitis, allergic keratitis, dry eye, chronic obstructive disease (COPD), lupus erythematosus, psoriasis, multiple sclerosis, end-stage renal disease, etc. In some embodiments, the present invention relates to a method of treating cancer, tissue proliferative disorders or inflammatory disorders selected from the group consisting of allergy, asthma, rheumatoid arthritis, osteoarthritis, allergic conjunctivitis, allergic keratitis, dry eye, chronic obstructive disease (COPD), lupus erythematosus, psoriasis, inflammatory bowel disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, or an isomer, a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising the same, wherein the cancer is selected from the group consisting of melanoma, papillary thyroid tumors, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, malignant lymphoma, carcinomas and sarcomas of the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors of the skin, colon, thyroid, lung and ovary, or leukemia, Multiple sclerosis and end stage renal disease.

Description of the terms

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "halogen" as used herein means fluorine, chlorine, bromine or iodine.

"alkyl" according to the present invention means a straight-chain or branched saturated aliphatic hydrocarbon group, preferably a straight-chain or branched group having 1 to 6 carbon atoms, further preferably a straight-chain or branched group having 1 to 3 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment. "haloalkyl" in the context of the present invention means an alkyl group substituted with at least one halogen.

According to the invention"alkylene" refers to a group resulting from the formal removal of one hydrogen atom from an alkyl group, such as methylene (-CH)₂-, ethylene (-CH)₂-CH₂-, propylene (-CH)₂-CH₂-CH₂-) etc., as used herein, said "C-ene_1-10Alkyl "means C_1-10Alkyl radicals formally leaving one hydrogen atom removed, said "C-ene_1-6Alkyl "means C_1-6Alkyl formally removes a hydrogen atom from the remaining radical.

The "alkenylene group" in the present invention means a group obtained by formally removing one hydrogen atom from an alkenyl group, such as an ethenylene group (-CH-), an propenylene group (-CH-), and the like₂-or-CH₂-CH ═ CH —), etc., and in the present context, said "sub-C —"_2-10Alkenyl "means C_2-10Alkenyl radicals formally removed from one hydrogen atom to leave a radical, said "C-ene_2-6Alkenyl "means C_2-6Alkenyl groups formally remove one hydrogen atom from the remaining group.

"alkynylene" in the present invention means a group in which an alkynyl group is formally removed by one hydrogen atom, such as ethynylene (-C.ident.C-), propynyl (-C.ident.C-CH)₂-or-CH₂-C ≡ C-) and the like, in the present context, said "sub-C ≡ C-)_2-10Alkynyl "means C_2-10Alkynyl radical being the radical left by formal removal of one hydrogen atom, said "C-ene_2-6Alkynyl "means C_2-6Alkynyl groups formally remove one hydrogen atom from the remaining group.

"Cycloalkylene" in the context of the present invention refers to a cycloalkyl group which is formally interrupted by a hydrogen atom, e.g. cyclopropyleneCyclo-butylene groupEtc., as used herein, the term "sub-C" refers to_3-10Cycloalkyl "means C_3-10Cycloalkyl being formally removed by oneThe group remaining from a hydrogen atom, said "C being_3-6Cycloalkyl "means C_3-6Cycloalkyl formally removes a hydrogen atom from the remaining radical.

The "cycloalkyl group" in the present invention means a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term "heterocycloalkyl group" as used herein refers to a saturated cyclic hydrocarbon group containing a heteroatom.

"alkoxy" according to the present invention means-O-alkyl. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy and the like. An alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment. "aryl" as used herein refers to an aromatic system which may comprise a single ring or fused polycyclic ring, preferably a single ring or fused bicyclic ring, having from 6 to 18 carbon atoms, preferably from about 6 to about 14 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, fluorenyl, indanyl. The term "heteroaryl" as used herein refers to an aryl group having at least one carbon atom replaced by a heteroatom, said heteroatom being O, S, N. Suitable heteroaryl groups include, but are not limited to, imidazolyl, benzimidazolyl, imidazopyridinyl, quinazolinyl, pyrrolyl, imidazolonyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, and the like. Among them, the "six-to twelve-membered heteroaryl group" of the present invention means a heteroaryl group consisting of 6 to 12 atoms, at least one of which is a heteroatom. Suitable six-to twelve-membered heteroaryl groups include, but are not limited to, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidopyrazolyl, pyrimidoimidazolyl, and the like.

The term "solvate" as used herein refers in the conventional sense to a complex of a solute (e.g., active compound, salt of active compound) and a solvent (e.g., water). Solvent means a solvent known or readily determined by one skilled in the art. In the case of water, the solvate is often referred to as a hydrate, e.g., a monohydrate, a dihydrate, a trihydrate, and the like.

The "prodrug" of the present invention refers to a compound which is converted into a compound of the formula (i) by a reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, i.e., a compound which is converted into a compound of the formula (i) by oxidation, reduction, hydrolysis or the like by an enzyme, a compound which is converted into a compound of the formula (i) by a hydrolysis reaction of gastric acid or the like, or the like.

The "pharmaceutical composition" of the present invention is intended to comprise a mixture of any one of the compounds described herein, including the corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts, or chemically protected forms thereof, and one or more pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism. The compositions are generally useful for the preparation of medicaments for the treatment and/or prevention of diseases mediated by one or more kinases.

The "pharmaceutically acceptable carrier" of the present invention refers to a carrier that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes all solvents, diluents or other excipients, dispersants, surfactant isotonicity agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like. Unless any conventional carrier medium is incompatible with the compounds of the present invention. Some examples of carriers that may be pharmaceutically acceptable include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, and cellulose acetate; malt, gelatin, and the like.

"excipient" herein refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.

The term "use in a medicament for treating and/or preventing cancer, tissue proliferative disease or inflammatory disease" refers to the improvement of cancer, tissue proliferative disease or inflammatory disease, the inhibition of the growth, development and/or metastasis of cancer, or the reduction of risk of cancer, tissue proliferative disease or inflammatory disease, and the administration of a therapeutically and/or prophylactically effective amount of a compound of the invention to inhibit, slow down or reverse the growth, development or spread of cancer in a subject, the improvement of cancer, tissue proliferative disease or inflammatory disease, or the reduction of risk of cancer, including cancer, such as bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer (including small cell lung cancer), esophagus cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, pancreatic cancer, colon cancer, bladder cancer, breast cancer, bladder cancer, kidney cancer, liver, Prostate and skin cancers (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage, including, for example, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma; tumors of mesenchymal origin, including, for example, fibrosarcoma, rhabdomyosarcoma; hematopoietic tumors of myeloid lineage, including, for example, acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia; tumors of the central and peripheral nervous system, including, for example, astrocytomas, neuroblastomas, gliomas, and schwannomas; and other tumors, including, for example, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma, keratoacanthoma, thyroid follicular cancer, and kaposi's sarcoma. The inflammatory disease is selected from allergy, asthma, rheumatoid arthritis, osteoarthritis, allergic conjunctivitis, allergic keratitis, dry eye, chronic obstructive disease (COPD), lupus erythematosus, psoriasis, multiple sclerosis, end-stage renal disease, etc.

The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds of the present invention which are safe and effective for use in a mammalian body and which possess the requisite biological activity.

Detailed Description

The following representative examples are intended to better illustrate the present invention and are not intended to limit the scope of the present invention.

Example 13- (9H-purin-6-ylaminomethyl) -2-phenyl-4H-chromen-4-one

Step 12 preparation of benzoyloxypropiophenone

2-Hydroxypropiophenone (5g,33.33mmol), benzoyl chloride (11.7g, 83.33mmol) and potassium carbonate (23g, 166.6mmol) were added to 120ml of acetone, heated in an oil bath to reflux overnight, and checked by TLC to the end of the reaction. After the reaction is finished, spin-drying the solvent; water was added, extraction was performed with ethyl acetate, and the mixture was dried over anhydrous sodium sulfate and concentrated to obtain 6.5g of an oil with a yield of 76.7%.

Step 23 preparation of methyl-2-phenyl-4H-chromen-4-one

2-benzoyloxypropiophenone (6.5g, 25.6mmol) was dissolved in 80ml DMSO, placed in an ice water bath to cool, and sodium hydrogen (3.1g, 76.7mmol) was added in portions. Stirring for about 2h at room temperature, tracking and monitoring by TLC, finishing the reaction, adding water into the reaction liquid, adjusting the pH value to weak acidity by using dilute hydrochloric acid, extracting by using ethyl acetate, drying by using anhydrous sodium sulfate, and concentrating to obtain oily matter so as to obtain an intermediate 1- (2-cyanophenyl) -2-methyl-3-phenyl-1, 3-diacetone. To the oil was added 80ml of acetic acid and a few drops of concentrated hydrochloric acid, the reaction was refluxed for about 3h, and the reaction was followed by TLC. And (2) spin-drying the reaction liquid, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating to prepare sand, and purifying by column chromatography to obtain a white solid 5g, wherein the yield is as follows: 82.7 percent.

Step 33 preparation of bromomethyl-2-phenyl-4H-chromen-4-one

3-methyl-2-phenyl-4H-chromen-4-one (300mg, 1.27mmol), N-bromosuccinimide (NBS, 225mg, 1.27mmol) and benzoyl peroxide (BPO, 30mg, 0.12mmol) were dissolved in 15ml of carbon tetrachloride, heated in an oil bath under reflux overnight, monitored by TLC follow-up and the reaction was complete. Adding water into the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating to obtain sand, and purifying by column chromatography to obtain a white solid 157mg, wherein the yield is as follows: 39.4 percent.

Step 43 preparation of aminomethyl-2-phenyl-4H-chromen-4-one hydrochloride

3-bromomethyl-2-phenyl-4H-chromen-4-one (157mg, 0.5mmol) was dissolved in 5ml DMF, 2ml ammonia was added, and the mixture was stirred at room temperature overnight. TLC monitoring, the reaction was complete. Adding water into the reaction liquid, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating the organic layer to about 5ml, adding saturated ethyl acetate hydrogen chloride solution, gradually separating out off-white solid, performing suction filtration, and drying to obtain 82mg of a product, wherein the yield is as follows: 57.1 percent.

Step 53 preparation of (9H-purin-6-ylaminomethyl) -2-phenyl-4H-chromen-4-one

3-aminomethyl-2-phenyl-4H-chromen-4-one hydrochloride (100mg, 0.34mmol), 6-bromopurine (76mg, 0.38mmol) and DIEA (135mg, 1.04mmol) were dissolved in 3ml of tert-butanol, heated to reflux overnight in an oil bath and monitored by TLC for the end of the reaction. Water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to sand, and purified by preparative HPLC to give 15mg of white solid, yield: 11.7 percent.

¹H NMR(300MHz,DMSO-d₆):12.91-12.90(d,1H,J＝3.1Hz),8.14-8.08(m,3H),7.87-7.78(m,3H),7.70-7.67(m,1H),7.57-7.51(m,5H),4.53(s,2H).ES:m/z 370.1[M+H]⁺。

Example 24-amino-5-cyano-6- (4-oxo-2-phenyl-4H-chromen-3-yl) methylaminopyrimidine

3-aminomethyl-2-phenyl-4H-chromen-4-one hydrochloride (80mg, 0.28mmol) prepared in step 4 of example 1, 4-amino-5-cyano-6-chloropyrimidine (47mg, 0.30mmol) and potassium carbonate (116mg, 0.84mmol) were dissolved in 3ml of DMF and reacted overnight at room temperature with TLC follow-up to monitor the end of the reaction. Water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to sand, and purified by preparative HPLC to give 12mg of a white solid, yield: 11.6 percent.

¹H NMR(300MHz,DMSO-d₆):8.13-8.12(d,1H,J＝4.23Hz),7.94(s,1H),7.85-7.82(t,1H,J＝4.27Hz),7.74-7.72(d,2H,J＝3.54Hz),7.69-7.67(d,1H,J＝4.95Hz),7.57-7.52(m,4H),7.23(s,1H),7.18(s,2H),4.40(s,2H).ES:m/z 370.1[M+H]⁺。

Example 32, 4-diamino-5-cyano-6- (4-oxo-2-phenyl-4H-chromen-3-yl) methylaminopyrimidine

3-aminomethyl-2-phenyl-4H-chromen-4-one hydrochloride (100mg, 0.34mmol) prepared in step 4 of example 1,2, 4-diamino-5-cyano-6-chloropyrimidine (70mg, 0.38mmol) and potassium carbonate (140mg, 1mmol) were dissolved in 3ml DMF and the reaction was heated to 100 ℃ in an oil bath overnight and monitored by TLC for the end of the reaction. Water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to sand, and purified by preparative HPLC to give 15mg of white solid, yield: 11.5 percent.

¹H NMR(300MHz,DMSO-d₆):8.14-8.11(d,1H,J＝7.86Hz),7.86-7.82(t,1H,J＝7.03Hz),7.76-7.73(t,2H,J＝3.66Hz),7.69-7.67(d,1H,J＝8.46Hz),7.59-7.51(m,4H),6.65(s,1H),6.49(s,2H),6.22(s,2H),4.32-4.30(d,2H,J＝3.69Hz).ES:m/z 385.0[M+H]⁺。

Example 43- (1- (9H-purin-6-aminoethyl)) -2-phenyl-4H-chromen-4-one

Step 13 preparation of Acetooxymethyl-2-phenyl-4H-chromen-4-one

3-bromomethyl-2-phenyl-4H-chromen-4-one (33.1g, 0.105mol) obtained in step 3 of example 1 and sodium acetate (43g, 0.527mol) were dissolved in 700ml DMF and heated to 75 ℃ in an oil bath for 4H and monitored by TLC for completion of the reaction. Slowly pouring the reaction solution into water, separating out solid, filtering, and directly putting the wet product into the next step.

Step 23 preparation of hydroxymethyl-2-phenyl-4H-chromen-4-one

The wet product obtained in the above step was added to 530ml of THF and 200ml of water, sodium hydroxide (12.65g, 0.315mol) was added thereto, and the reaction was allowed to proceed overnight at room temperature, followed by TLC to monitor the completion of the reaction. Most of THF is removed by rotary evaporation, yellow solid is gradually precipitated, and 22.1g of solid is obtained by suction filtration and drying, and the yield of the two steps is 83.5%.

Step 33 preparation of formyl-2-phenyl-4H-chromen-4-one

3-hydroxymethyl-2-phenyl-4H-chromen-4-one (22.1g, 87.7mmol) and o-iodoxybenzoic acid (IBX, 27g, 96.4mmol) were dissolved in 500ml DMSO and reacted overnight at room temperature with TLC follow-up to monitor the end of the reaction. The reaction solution was poured into a large amount of water to precipitate a white solid. The solid was added to water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and spin dried to give 15.2g of a yellow-white solid with a yield of 68.7%.

Step 42 preparation of methyl-N- ((4-oxo-2-phenyl-4H-chromen-3-yl) methylene) propane-2-sulfinamide

3-formyl-2-phenyl-4H-chromen-4-one (1g, 4mmol), tert-butylsulfinamide (0.53g, 4.4mmol) and cesium carbonate (1.95g, 6mmol) were dissolved in 25ml DCM and reacted overnight at room temperature with TLC follow-up monitoring of the end of the reaction. The reaction solution was spin-dried, extracted with ethyl acetate, dried over anhydrous sodium sulfate to give a yellow-white solid 0.8g, yield 56.6%.

Step 53- (1-aminoethyl) -2-phenyl-4H-chromen-4-one hydrochloride preparation

2-methyl-N- ((4-oxo-2-phenyl-4H-chromen-3-yl) methylene) propane-2-sulfinamide (5.3g, 15mmol) was dissolved in 60ml THF, replaced three times with argon, cooled in a cold trap at-20 ℃ and a THF solution of methylmagnesium chloride (10ml, 30mmol) was slowly added, the reaction was allowed to proceed for 2H in the cold trap and the end of the reaction was monitored by TLC follow-up. Quenching the reaction solution by saturated ammonium chloride aqueous solution, extracting by ethyl acetate, drying by anhydrous sodium sulfate, dissolving the dried oily substance by a small amount of ethyl acetate, dropwise adding an ethyl acetate solution of hydrogen chloride, gradually precipitating gray solid, stirring for a while, performing suction filtration, and drying to obtain 3.8g of solid, wherein the yield of the two steps is 84.2%.

Step 63 preparation of 1- (9H-purin-6-aminoethyl)) -2-phenyl-4H-chromen-4-one

3- (1-aminoethyl) -2-phenyl-4H-chromen-4-one hydrochloride (700mg,3.32mmol), 6-bromopurine (925mg,4.65mmol) and potassium carbonate (1.6g,11.62mmol) were dissolved in 20ml DMF and reacted at 100 ℃ in an oil bath for 24H and the end of the reaction was monitored by TLC follow-up. Adding water into the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, spinning to obtain sand, and separating by column chromatography to obtain white solid 32mg with yield of 2.5%.

¹H NMR(300MHz,DMSO-d₆):9.25(s,1H),8.55(s,1H),8.45(s,1H),8.14-8.11(d,1H,J＝8.1Hz),7.86-7.81(t,1H,J＝8.1Hz),7.75(s,2H),7.66-7.63(m,5H),7.55-7.50(t,1H,J＝7.5Hz),5.34-5.30(t,1H,J＝6.3Hz),1.75-1.73(d,3H,J＝6.3Hz).ES:m/z 384.2[M+H]⁺。

Example 54-amino-5-cyano-6- (1- (4-oxo-2-phenyl-4H-chromen-3-yl) ethylamino) pyrimidine

3- (1-aminoethyl) -2-phenyl-4H-chromen-4-one hydrochloride (700mg,3.32mmol), 4-amino-5-cyano-6-chloropyrimidine (716mg,4.65mmol) and potassium carbonate (1.6g,11.62mmol) obtained in step 5 of example 4 were dissolved in 20ml of DMF, reacted at 100 ℃ in an oil bath for 24H, and the reaction was monitored by TLC for completion. Adding water into the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, spinning to obtain sand, and separating by column chromatography to obtain white solid 200mg with yield of 52.2%.

¹H NMR(300MHz,DMSO-d₆):8.18-8.15(d,1H,J＝7.5Hz),7.91(s,1H),7.87-7.82(t,1H,J＝7.6Hz),7.71-7.67(m,2H),7.63(s,4H),7.57-7.52(t,1H,J＝7.9Hz),7.30(s,3H),5.39-5.35(t,1H,J＝6.9Hz),1.50-1.48(d,3H,J＝6.6Hz).ES:m/z 383.9[M+H]⁺。

Example 62, 4-diamino-5-cyano-6- (1- (4-oxo-2-phenyl-4H-chromen-3-yl) ethylamino) pyrimidine

3- (1-aminoethyl) -2-phenyl-4H-chromen-4-one hydrochloride (700mg,3.32mmol), 2, 4-diamino-5-cyano-6-chloropyrimidine (716mg,4.65mmol) and potassium carbonate (1.6g,11.62mmol) obtained in step 5 of example 4 were dissolved in 20ml of DMF and reacted at 100 ℃ in an oil bath for 24H, followed by TLC to monitor the end of the reaction. Adding water into the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, spinning to obtain sand, and separating by column chromatography to obtain a white solid 20mg with a yield of 5.2%.

¹H NMR(300MHz,DMSO-d₆):8.16-8.15(d,1H,J＝4.2Hz),7.86-7.83(t,1H,J＝4.6Hz),7.73-7.72(m,2H),7.66-7.63(m,4H),7.56-7.53(t,1H,J＝4.5Hz),6.92-6.90(d,1H,J＝5.5Hz),6.57(s,2H),6.00(br,2H),5.40-5.34(m,1H),1.44-1.43(d,3H,J＝4.1Hz).ES:m/z 399.0[M+H]⁺。

Example 74-amino-5-cyano-6- (1- (8-chloro-4-oxo-2-phenyl-4H-chromen-3-yl) ethylamino) pyrimidine

Step 13-preparation of bromomethyl-8-chloro-2-phenyl-4H-chromen-4-one

The preparation method was the same as that of 3-bromomethyl-2-phenyl-4H-chromen-4-one prepared in steps 1 to 3 of example 1, except that 2-hydroxypropiophenone as a raw material was replaced with 2-hydroxy-3-chlorophenylacetone.

Step 23- (1-aminoethyl) -8-chloro-2-phenyl-4H-chromen-4-one hydrochloride preparation

Preparation method the same as that of 3- (1-aminoethyl) -2-phenyl-4H-chromen-4-one hydrochloride prepared in steps 1-5 of example 4 was used, except that 3-bromomethyl-2-phenyl-4H-chromen-4-one as a starting material was replaced with 3-bromomethyl-8-chloro-2-phenyl-4H-chromen-4-one.

Step 34 preparation of amino-5-cyano-6- (1- (8-chloro-4-oxo-2-phenyl-4H-chromen-3-yl) ethylamino) pyrimidine

3- (1-aminoethyl) -8-chloro-2-phenyl-4H-chromen-4-one hydrochloride (200mg,0.59mmol), 4-amino-5-cyano-6-chloropyrimidine (101mg,0.65mmol) and potassium carbonate (244mg,1.77mmol) were dissolved in 20ml DMF and reacted at 100 ℃ in an oil bath for 24H with TLC follow-up monitoring of the end of the reaction. Adding water into the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, spinning to obtain sand, and separating by column chromatography to obtain white solid 35mg with yield of 14.2%.

¹H NMR(300MHz,DMSO-d₆):8.12-8.10(d,1H,J＝7.8Hz),8.03-8.00(d,1H,J＝7.8Hz),7.92(s,1H),7.76-7.74(m,2H),7.65(s,3H),7.56-7.51(t,1H,J＝7.9Hz),7.30(s,2H),7.20-7.17(d,1H,J＝8.6Hz),5.44-5.36(m,1H),1.52-1.50(d,3H,J＝6.8Hz).ES:m/z418.1[M+H]⁺。

Example 82, 4-diamino-5-cyano-6- (1- (8-chloro-4-oxo-2-phenyl-4H-chromen-3-yl) ethylamino) pyrimidine

3- (1-aminoethyl) -8-chloro-2-phenyl-4H-chromen-4-one hydrochloride (200mg,0.59mmol), 2, 4-diamino-5-cyano-6-chloropyrimidine (101mg,0.65mmol) and potassium carbonate (244mg,1.77mmol) obtained in step 2 of example 7 were dissolved in 20ml of DMF and reacted at 100 ℃ in an oil bath for 24H with TLC follow-up monitoring of the end of the reaction. Adding water into the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, spinning to obtain sand, and separating by column chromatography to obtain white solid 23mg with yield of 9.0%.

¹H NMR(300MHz,DMSO-d₆):8.12-8.09(d,1H,J＝7.2Hz),8.03-8.01(d,1H,J＝7.6Hz),7.76-7.75(d,2H,J＝2.8Hz),7.67-7.66(d,3H,J＝2.3Hz),7.56-7.50(t,1H,J＝7.9Hz),6.84-6.81(d,1H,J＝9.0Hz),6.60(s,2H),6.12(br,2H),5.47-5.39(m,1H),1.45-1.43(d,3H,J＝6.8Hz).ES:m/z 433.2[M+H]⁺。

Example 94-amino-5-cyano-6- (1- (8-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl) ethylamino) pyrimidine

Step 13- (1-aminoethyl) -8-fluoro-2-phenyl-4H-chromen-4-one hydrochloride preparation

The preparation process was the same as that of 3- (1-aminoethyl) -8-chloro-2-phenyl-4H-chromen-4-one hydrochloride prepared in step 1-2 of example 7, except that 2-hydroxy-3-chlorophenylacetone was used instead of 2-hydroxy-3-fluorophenylacetone as the starting material.

Step 24 preparation of amino-5-cyano-6- (1- (8-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl) ethylamino) pyrimidine

3- (1-aminoethyl) -8-fluoro-2-phenyl-4H-chromen-4-one hydrochloride (200mg,0.59mmol), 4-amino-5-cyano-6-chloropyrimidine (101mg,0.65mmol) and potassium carbonate (244mg,1.77mmol) were dissolved in 20ml DMF and reacted at 100 ℃ in an oil bath for 24H with TLC follow-up monitoring of the end of the reaction. Adding water into the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, spinning to obtain sand, and separating by column chromatography to obtain white solid 51mg with yield of 21.5%.

¹H NMR(300MHz,DMSO-d₆):7.97-7.92(m,2H),7.85-7.78(t,1H,J＝9.5Hz),7.74-7.72(m,2H),7.64-7.63(m,3H),7.55-7.51(m,1H),7.32(s,2H),7.20-7.17(d,1H,J＝8.3Hz),5.43-5.35(m,1H),1.52-1.49(d,3H,J＝6.8Hz).ES:m/z 402.1[M+H]⁺。

Example 102, 4-diamino-5-cyano-6- (1- (8-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl) ethylamino) pyrimidine

3- (1-aminoethyl) -8-fluoro-2-phenyl-4H-chromen-4-one hydrochloride (190mg,0.59mmol), 2, 4-diamino-5-cyano-6-chloropyrimidine (101mg,0.65mmol) and potassium carbonate (244mg,1.77mmol) obtained in step 1 of example 9 were dissolved in 20ml of DMF and reacted at 100 ℃ in an oil bath for 24H with TLC follow-up monitoring of the end of the reaction. Adding water into the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, spinning to obtain sand, and separating by column chromatography to obtain white solid 32mg with yield of 13.0%.

¹H NMR(300MHz,DMSO-d₆):7.92-7.88(m,2H),7.85-7.75(m,2H),7.70-7.65(m,2H),7.61-7.56(m,3H),7.50-7.46(m,1H),7.27(s,2H),7.17-7.13(d,1H,J＝8.0Hz),5.40-5.32(m,1H),1.55-1.50(d,3H,J＝6.6Hz).ES:m/z 417.1[M+H]⁺。

Example 113- ((4-amino-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) -2-phenyl-4H-chromen-4-one

4-Aminopyrazolo [3,4-d ] pyrimidine (71mg, 0.47mmol) was dissolved in 3ml of DMF, NaH (23mg, 0.57mmol) was added, the reaction was carried out at room temperature for a while, 3-bromomethyl-2-phenyl-4H-chromen-4-one (150mg, 0.47mmol) obtained in step 3 of example 1 was added, the reaction was carried out at room temperature, and the completion of the reaction was monitored by TLC tracing. Water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to sand, and purified by preparative HPLC to give 18mg of a white solid, yield: 10.4 percent.

¹H NMR(300MHz,DMSO-d₆):8.50(s,1H),8.13-8.06(m,2H),8.00-7.98(d,2H,J＝3.9Hz),7.89-7.86(t,1H,J＝4.5Hz),7.75-7.73(d,1H,J＝5.0Hz),7.64-7.62(m,4H),7.56-7.53(t,2H,J＝4.5Hz),5.35(s,2H).ES:m/z 370.1[M+H]⁺。

Example 123-amino-N- (4-oxo-2-phenyl-4H-chromen-3-yl) methyl-2-carboxamide-pyrazine

3-aminomethyl-2-phenyl-4H-chromen-4-one hydrochloride (400mg, 1.59mmol) prepared in step 4 of example 1, 3-aminopyrazine-2-carboxylic acid (243mg, 1.75mmol), EDC hydrochloride (396mg, 2.07mmol), DMAP (38mg, 0.32mmol) and DIEA (410mg, 3.18mmol) were dissolved in 10ml DMF and reacted overnight at room temperature with TLC follow-up monitoring of the end of the reaction. Water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to sand, and purified by preparative HPLC to give 55mg of a white solid, yield: 9.2 percent.

¹H NMR(400MHz,DMSO-d₆):8.78-8.76(t,1H,J＝5.4Hz),8.43(s,1H),8.20-8.19(d,1H,J＝2.4Hz),8.15-8.12(dd,1H,J₁＝1.6Hz,J₂＝8.0Hz),7.87-7.83(m,1H),7.80-7.78(m,3H),7.70-7.68(d,1H,J＝8.0Hz),7.64-7.62(m,3H),7.56-7.52(m,2H),4.39(s,2H).ES:m/z 373.1[M+H]⁺。

Example 132-amino-N- (4-oxo-2-phenyl-4H-chromen-3-yl) methyl-3-carboxamide-pyrazolo [1,5-a ] pyrimidine

3-aminomethyl-2-phenyl-4H-chromen-4-one hydrochloride (130mg, 0.45mmol) prepared in step 4 of example 1, 2-aminopyrazolo [1,5-a ] pyrimidine-3-carboxylic acid (81mg, 0.45mmol), PyBOP (345mg, 0.68mmol) and DIEA (172mg, 1.35mmol) were dissolved in 5ml DMF and reacted overnight at room temperature with TLC follow-up monitoring of the end of the reaction. Water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to sand, and purified by preparative HPLC to give 25mg of white solid, yield: 13.51 percent.

¹H NMR(300MHz,DMSO-d₆):8.87-8.85(d,1H,J＝6.6Hz),8.47-8.45(d,1H,J＝4.4Hz),8.22-8.18(t,1H,J＝5.4Hz),8.15-8.12(d,1H,J＝7.5Hz),7.85-7.82(m,3H),7.69-7.66(d,1H,J＝8.5Hz),7.61-7.60(m,3H),7.55-7.50(t,1H,J＝7.5Hz),6.96-6.92(m,1H),6.44(s,2H),4.49-4.48(d,2H,J＝5.4Hz).ES:m/z 411.9[M+H]⁺。

Example 14N- (2-Aminopyridin-4-yl) -2- (4-oxo-2-phenyl-4H-chromen-3-yl) acetamide

Step preparation of 12- (4-oxo-2-phenyl-4H-chromen-3-yl) acetonitrile

3-bromomethyl-2-phenyl-4H-chromen-4-one (1g, 3.18mmol) prepared in step 3 of example 1 and tetraethylammonium cyanide (1g, 6.37mmol) were dissolved in 25ml dry DMF and reacted at room temperature for about 2H, followed by TLC and the reaction was complete. Adding water into the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating to obtain sand, and purifying by column chromatography to obtain a white solid 488mg, wherein the yield is as follows: 58.77 percent.

Step 22- (4-oxo-2-phenyl-4H-chromen-3-yl) acetic acid preparation

2- (4-oxo-2-phenyl-4H-chromen-3-yl) acetonitrile (200mg, 0.76mmol) was dissolved in 2ml dioxane and 1ml water, 1ml concentrated sulfuric acid was added, the reaction was heated to reflux for about 5H in an oil bath, followed by TLC and the reaction was complete. Adding water into the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating to obtain sand, and purifying by column chromatography to obtain a white solid 121mg, wherein the yield is as follows: 56.8 percent.

Step 3 preparation of N- (2-aminopyridin-4-yl) -2- (4-oxo-2-phenyl-4H-chromen-3-yl) acetamide

2- (4-oxo-2-phenyl-4H-chromen-3-yl) acetic acid (80mg, 0.214mmol), 2, 4-diaminopyridine (35mg, 0.235mmol), PyBOP (222mg, 0.321mmol) and DIEA (110mg, 0.642mmol) were dissolved in 2ml DMF and reacted overnight at room temperature with TLC follow-up to monitor the end of the reaction. Water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to sand, and purified by preparative HPLC to give 17mg of a white solid, yield: 21.4 percent.

¹H NMR(300MHz,DMSO-d₆):10.12(s,1H),8.28(s,1H),8.09-8.08(d,1H,J＝4.7Hz),7.86-7.83(t,1H,J＝4.6Hz),7.77-7.72(m,3H),7.70-7.68(m,2H),7.60-7.59(m,3H),7.55-7.52(d,1H,J＝4.5Hz),7.26(s,1H),6.23-6.22(d,1H,J＝3.1Hz),3.52(s,2H).ES:m/z 372.1[M+H]⁺。

Example 15N- (2-Aminopyridin-3-yl) -2- (4-oxo-2-phenyl-4H-chromen-3-yl) acetamide

2- (4-oxo-2-phenyl-4H-chromen-3-yl) acetic acid (80mg, 0.214mmol), 2, 3-diaminopyridine (35mg, 0.235mmol), PyBOP (222mg, 0.321mmol) and DIEA (110mg, 0.642mmol), prepared in step 2 of example 14, were dissolved in 2ml DMF and reacted overnight at room temperature with TLC following the completion of the reaction. Water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to sand, and purified by preparative HPLC to give 13mg of a white solid, yield: 16.4 percent.

¹H NMR(500MHz,DMSO-d₆):9.39(s,1H),8.11-8.09(d,1H,J＝7.9Hz),7.86-7.83(m,1H),7.81-7.78(m,3H),7.71-7.69(d,1H,J＝8.4Hz),7.61-7.60(m,3H),7.54-7.51(t,1H,J＝7.5Hz),7.49-7.47(d,1H,J＝7.5Hz),6.55-6.52(m,1H),5.74(s,2H),3.54(s,2H).ES:m/z 372.1[M+H]⁺。

Example 16N- (2-oxo-1, 2-dihydropyridin-3-yl) -2- (4-oxo-2-phenyl-4H-chromen-3-yl) acetamide

2- (4-oxo-2-phenyl-4H-chromen-3-yl) acetic acid (80mg, 0.214mmol), 3-amino-2-hydroxypyridine (35mg, 0.235mmol), PyBOP (222mg, 0.321mmol) and DIEA (110mg, 0.642mmol), prepared in step 2 of example 14, were dissolved in 2ml DMF and reacted overnight at room temperature with TLC follow-up to monitor the end of the reaction. Water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to sand, and purified by preparative HPLC to give 15mg of white solid, yield: 18.9 percent.

¹H NMR(500MHz,DMSO-d₆):11.92(s,1H),9.46(s,1H),8.20-8.18(d,1H,J＝7.1Hz),8.09-8.07(d,1H,J＝7.9Hz),7.86-7.83(t,1H,J＝7.7Hz),7.78-7.76(m,2H),7.70-7.69(d,1H,J＝8.4Hz),7.60-7.59(m,3H),7.54-7.51(t,1H,J＝7.5Hz),7.09-7.07(d,1H,J＝5.9Hz),6.20-6.17(t,1H,J＝6.8Hz),3.62(s,2H).ES:m/z 373.1[M+H]⁺。

Example 174-amino-5-cyano-6- ((1- (8-chloro-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethyl) amino) pyrimidine

Step 13-preparation of Chloroindigylic anhydride

2-amino-3-chlorobenzoic acid (34.2g, 0.2mol) and 175ml acetonitrile are added into a 500ml three-necked bottle, heated to 55 ℃, and then a dichloromethane solution of triphosgene (29.6g, 0.1mol) is dropwise added into 150ml dichloromethane), and pyridine (50ml, 0.6mol) is dropwise added at the same time, the dropwise addition is finished within about 30min, the reaction is carried out for 5h, and the TLC tracking reaction is carried out until the reaction is complete. And (3) carrying out suction filtration on the reaction liquid while the reaction liquid is hot, washing a filter cake with 100ml of ethyl acetate, desolventizing the filtrate to obtain a black oily substance, adding an ice-water mixture, separating out a large amount of solids, carrying out suction filtration, drying, recrystallizing an ethyl acetate petroleum ether system, carrying out suction filtration, and drying to obtain 30.8g of a gray solid with the yield of 78.2%.

Step preparation of 28-chloro-4-oxo-2-phenyl-1, 4-dihydroquinoline-3-carboxylic acid ethyl ester

Adding benzoyl ethyl acetate (19.2g, 0.1mol) and 50ml DMF into a 250ml three-necked bottle, cooling to-20 ℃, then adding 60% NaH (4.0g, 0.1mol) in batches with a large amount of bubbles, keeping the temperature not more than 0 ℃, continuing stirring for 15min after about 30min, heating to room temperature, and stirring for later use. Dissolving 3-chloroisatoic anhydride (19.7g, 0.1mol) in 100ml DMF, dropwise adding into the reaction solution through a constant pressure dropping funnel, keeping the reaction system anhydrous and anaerobic, after 30min, completing dropwise adding, heating the reaction solution to 150 ℃, stirring, and tracking the reaction by TLC until the reaction is complete. The reaction solution was desolventized under reduced pressure to obtain a black oily substance, which was then added to the ice-water mixture, extracted with 150ml of ethyl acetate × 3, the organic layers were combined, dried to remove solvent sand, and separated by column chromatography to obtain a pale yellow solid 18.3g, with a yield of 55.9%.

Step 38 preparation of chloro-3-hydroxymethyl-2-phenylquinolin-4- (1H) -one

Adding 8-chloro-4-oxo-2-phenyl-1, 4-dihydroquinoline-3-carboxylic acid ethyl ester (16.4g, 0.05mol) and 100ml of THF into a 250ml three-neck flask, stirring for dissolving, cooling to-20 ℃, adding lithium aluminum hydride (3.8g, 0.1mol) in batches, bubbling out, controlling the adding speed, keeping the temperature not to exceed 0 ℃, completing the addition for about 15min, then heating to room temperature, stirring for 2h, and tracking by TLC until the reaction is complete. The reaction was stopped and 3.8g of sodium sulfate decahydrate were added in portions with release of air bubbles, and the addition rate was controlled to prevent flushing. After the addition, the reaction is carried out for 0.5h under stirring at room temperature, the filtration is carried out, the solid is washed for 3 times by tetrahydrofuran, the filtrate is desolventized, and the solid is obtained after spin drying, wherein the yield is 88.6 percent.

Step 48 preparation of chloro-4-oxo-2-phenyl-1, 4-dihydroquinoline-3-carbaldehyde

8-chloro-3-hydroxymethyl-2-phenylquinolin-4- (1H) -one (11.4g, 0.04mol) and 100ml of DMSO were added to a 250ml three-necked flask, dissolved with stirring, IBX (14g, 0.05mol) was added, the temperature was raised to 35 ℃ and stirred for 5H, and the reaction was followed by TLC until the reaction was complete. Stopping the reaction, adding 300ml of ethyl acetate, heating to reflux for 15min, carrying out suction filtration while hot, washing the solid with hot ethyl acetate for 3 times, combining filtrates, adding 200ml of water, carrying out layering, extracting the water layer with 100ml of multiplied by 2 ethyl acetate, combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, and evaporating under reduced pressure to remove the solvent to obtain 9.9g of light yellow solid with the yield of 87.5%.

Step 58 preparation of chloro-3- (1-hydroxyethyl) -2-phenylquinolin-4 (1H) -one

Adding 8-chloro-4-oxo-2-phenyl-1, 4-dihydroquinoline-3-formaldehyde (8.5g, 0.03mol) and 50ml of anhydrous tetrahydrofuran into a 100ml two-neck bottle, stirring and dissolving, cooling to-35 ℃, protecting argon, then adding a methyl magnesium chloride tetrahydrofuran solution (3M in concentration) (3ml, 0.09mol) by using an injector, heating to 0 ℃ after the addition is finished, stirring for 2h, and tracking the reaction by TLC until the reaction is complete. The reaction was stopped, 5ml of ethanol was added to quench the reaction, the solvent was distilled off under reduced pressure, 200ml of water and 100ml of ethyl acetate were added, the layers were separated, the aqueous layer was extracted with 100ml of × 2 ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 8.2g of a pale yellow solid, with a yield of 91.2%.

Step 63 preparation of acetyl-8-chloro-2-phenylquinolin-4 (1H) -one

8-chloro-3- (1-hydroxyethyl) -2-phenylquinolin-4 (1H) -one (6g, 0.02mol) and 60ml of DMSO were added to a 100ml three-necked flask, dissolved with stirring, followed by the addition of IBX (8.4g, 0.03mol), warmed to 35 ℃ with stirring for 5H, and the reaction was followed by TLC until completion. Stopping the reaction, adding 300ml of ethyl acetate, heating to reflux for 15min, carrying out hot suction filtration, washing the solid with hot ethyl acetate for 3 times, combining filtrates, adding 200ml of water, carrying out layering, extracting a water layer with 100ml of multiplied by 2 ethyl acetate, combining organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, and evaporating under reduced pressure to remove the solvent to obtain 5.4g of light yellow solid with the yield of 90.2%.

Step 78 preparation of chloro-3- (1- (hydroxyimino) ethyl) -2-phenylquinolin-4 (1H) -one

3-acetyl-8-chloro-2-phenylquinolin-4 (1H) -one (4.5g, 0.015mol) and 50ml of anhydrous methanol were added to a 100ml three-necked flask, stirred to dissolve, then hydroxylamine hydrochloride (6.3g, 0.09mol) and sodium acetate (9.8g, 0.12mol) were added, the temperature was raised to 45 ℃, stirred for 5H, and the reaction was followed by TLC until the reaction was complete. Stopping the reaction, removing the solvent under reduced pressure, adding 100ml of water into the residue, separating out a large amount of light yellow solid, performing suction filtration, washing with water, and drying the filter cake to obtain 4.8g of beige solid with the yield of 87.1%.

Step 83- (1-aminoethyl) -8-chloro-2-phenylquinolin-4 (1H) -one preparation

8-chloro-3- (1- (hydroxyimino) ethyl) -2-phenylquinolin-4 (1H) -one (3.1g, 0.01mol) and 50ml of acetic acid were charged into a 100ml three-necked flask, dissolved with stirring, followed by addition of activated zinc powder (3.3g, 0.05mol) and 10ml of methanol, warming to 45 ℃, stirring for 5H, and the reaction was followed by TLC until completion. Stopping reaction, performing suction filtration, washing a filter cake by using a large amount of ethyl acetate, removing a solvent under reduced pressure, adding 50ml of water and 100ml of ethyl acetate into a residue, removing an organic layer, adjusting the pH value of a water layer to 12 by using 5M sodium hydroxide, separating out a large amount of light yellow solid, performing suction filtration, washing by using water, and drying the filter cake to obtain 1.7g of light yellow solid with the yield of 58.1%.

Step 94 preparation of amino-5-cyano-6- ((1- (8-chloro-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethyl) amino) pyrimidine

3- (1-aminoethyl) -8-chloro-2-phenylquinolin-4 (1H) -one (1.5g, 0.005mol) and 50ml of isopropanol were charged into a 100ml three-necked flask, dissolved with stirring, and then 4-amino-5-cyano-6-chloropyrimidine (0.93g,0.006mol) and potassium carbonate (2.1g, 0.015mol) were added, the temperature was raised to 80 ℃ and refluxed with stirring for 5H, and the reaction was followed by TLC until completion of Compound 9. Stopping reaction, filtering, washing filter cake with a large amount of ethyl acetate, removing solvent under reduced pressure, adding methanol and silica gel into residue to prepare sand, and separating by column chromatography to obtain white solid 1.3g with yield of 62.2%.

¹H NMR(500MHz,DMSO-d₆):11.06(s,1H),8.23-8.21(d,1H,J＝10.0Hz),8.01-7.99(d,1H,J＝10.0Hz),7.90(s,1H),7.88(s,1H),7.59-7.52(m,5H),7.40-7.43(t,1H,J＝7.5Hz),7.24(s,2H),5.14-5.17(m,1H),1.39-1.37(d,3H,J＝10.0Hz).ES:m/z 416.9[M+H]⁺。

Example 184-amino-5-cyano-6- ((1- (4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethyl) amino) pyrimidine

The preparation method was the same as that of example 17, except that 2-amino-3-chlorobenzoic acid as a raw material was replaced with 2-aminobenzoic acid to obtain the objective compound with a yield of 66.6%.

¹H NMR(500MHz,DMSO-d₆):11.06(s,1H),8.36-8.35(d,1H,J＝5.0Hz),8.21-8.20(d,1H,J＝5.0Hz),7.87(s,1H),7.81-7.82(m,2H),7.62-7.63(m,3H),7.44-7.51(m,3H),7.17(s,2H),4.90-4.87(m,1H),1.29-1.31(d,3H,J＝10.0Hz).ES:m/z 383.1[M+H]⁺。

Example 194-amino-5-cyano-6- ((1- (5-chloro-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethyl) amino) pyrimidine

The preparation process was the same as that in example 17, except that 2-amino-3-chlorobenzoic acid was replaced with 2-amino-6-chlorobenzoic acid to give the objective compound in a yield of 58.6%.

¹H NMR(500MHz,DMSO-d₆):11.05(s,1H),8.24-8.22(d,1H,J＝10.0Hz),8.02-8.00(d,1H,J＝10.0Hz),7.91(s,1H),7.86(s,1H),7.55-7.51(m,5H),7.41-7.44(t,1H,J＝7.5Hz),7.24(s,2H),5.14-5.17(m,1H),1.38-1.36(d,3H,J＝10.0Hz).ES:m/z 416.9[M+H]⁺。

Example 204-amino-5-cyano-6- ((1- (8-fluoro-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethyl) amino) pyrimidine

The preparation method was the same as that of example 17, except that 2-amino-3-chlorobenzoic acid as a starting material was replaced with 2-amino-3-fluorobenzoic acid to obtain the objective compound in a yield of 62.1%.

¹H NMR(500MHz,DMSO-d₆):11.06(s,1H),8.22-8.20(d,1H,J＝10.0Hz),8.02-8.00(d,1H,J＝10.0Hz),7.91(s,1H),7.88(s,1H),7.59-7.53(m,5H),7.40-7.43(t,1H,J＝7.5Hz),7.24(s,2H),5.14-5.16(m,1H),1.39-1.37(d,3H,J＝10.0Hz).ES:m/z 400.9[M+H]⁺。

Example 214-amino-5-cyano-6- ((1- (4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) propyl) amino) pyrimidine

The preparation method was the same as that of example 17, except that 2-amino-3-chlorobenzoic acid as a raw material was replaced with 2-aminobenzoic acid, and methyl magnesium chloride was replaced with ethyl magnesium chloride, to obtain the objective compound with a yield of 52.6%.

¹H NMR(500MHz,DMSO-d₆):11.06(s,1H),8.34-8.35(d,1H,J＝5.0Hz),8.21-8.22(d,1H,J＝5.0Hz),7.88(s,1H),7.80-7.81(m,2H),7.62-7.63(m,3H),7.44-7.51(m,3H),7.17(s,2H),5.09-5.12(m,1H),1.80-1.84(m,2H),0.59-0.62(m,3H).ES:m/z 397.2[M+H]⁺。

Example 224-amino-5-cyano-6- (((8-chloro-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) methyl) amino) pyrimidine

Step preparation of 18-chloro-4-oxo-2-phenyl-1, 4-dihydroquinoline-3-carbaldehyde oxime

8-chloro-4-oxo-2-phenyl-1, 4-dihydroquinoline-3-carbaldehyde prepared in steps 1 to 4 of example 17 (4.3g, 0.015mol) and 50ml of anhydrous methanol were charged into a 100ml three-necked flask, dissolved with stirring, and then hydroxylamine hydrochloride (6.3g, 0.09mol) and sodium acetate (9.8g, 0.12mol) were added, the temperature was raised to 45 ℃ and stirred for 5 hours, and the reaction was followed by TLC until the reaction was complete. Stopping reaction, removing solvent under reduced pressure, adding 100ml of water into residue, separating out a large amount of light yellow solid, performing suction filtration, washing with water, and drying filter cake to obtain beige solid 4.0g, wherein the yield is 88.9%.

Step 23 preparation of aminomethyl-8-chloro-2-phenylquinolin-4 (1H) -one

8-chloro-4-oxo-2-phenyl-1, 4-dihydroquinoline-3-carbaldehyde oxime (3.0g, 0.01mol) and 50ml of acetic acid were added to a 100ml three-necked flask, stirred to dissolve, then activated zinc powder (3.3g, 0.05mol) and 10ml of methanol were added, the temperature was raised to 45 ℃, stirred for 5h, and the reaction was followed by TLC until the reaction was complete. Stopping reaction, performing suction filtration, washing a filter cake by using a large amount of ethyl acetate, removing a solvent under reduced pressure, adding 50ml of water and 100ml of ethyl acetate into a residue, removing an organic layer, adjusting the pH value of a water layer to 12 by using 5M sodium hydroxide, separating out a large amount of light yellow solid, performing suction filtration, washing by using water, and drying the filter cake to obtain 1.56g of light yellow solid with the yield of 55.2%.

Step 34 preparation of amino-5-cyano-6- (((8-chloro-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) methyl) amino) pyrimidine

3-aminomethyl-8-chloro-2-phenylquinolin-4 (1H) -one (1.42g, 0.005mol) and 50ml of isopropanol were charged into a 100ml three-necked flask, dissolved with stirring, and then 4-amino-5-cyano-6-chloropyrimidine (0.93g,0.006mol) and potassium carbonate (2.1g, 0.015mol) were added, the temperature was raised to 80 ℃ and refluxed with stirring for 5 hours, and the reaction was followed by TLC until completion of the reaction of Compound 9. Stopping reaction, filtering, washing filter cake with a large amount of ethyl acetate, removing solvent under reduced pressure, adding methanol and silica gel into residue to prepare sand, and separating by column chromatography to obtain white solid 1.37g with yield of 68.1%.

¹H NMR(500MHz,DMSO-d₆):10.78(s,1H),8.18-8.17(d,1H,J＝5.0Hz),7.86-7.85(d,1H,J＝5.0Hz),7.57-7.53(m,4H),7.33-7.38(t,1H,J＝7.5Hz),6.36-6.43(m,3H),6.14(s,2H),4.21(s,2H).ES:m/z 403.1[M+H]⁺。

Example 234-amino-5-cyano-6- (((8-chloro-2-phenyl-1, 4-dihydroquinolin-3-yl) methyl) amino) pyrimidine

Step preparation of 14-oxo-2-phenyl-1, 4-dihydroquinoline-3-carbaldehyde

The preparation process was identical with the preparation process of 8-chloro-4-oxo-2-phenyl-1, 4-dihydroquinoline-3-carbaldehyde prepared in steps 1 to 4 of example 17, except that the starting material 2-amino-3-chlorobenzoic acid was replaced with 2-aminobenzoic acid to prepare the objective compound.

Step 23 preparation of aminomethyl-2-phenylquinolin-4 (1H) -one

Preparation method the same as that of 3-aminomethyl-8-chloro-2-phenylquinolin-4 (1H) -one prepared in step 1-2 of example 22, except that the starting material, 8-chloro-4-oxo-2-phenyl-1, 4-dihydroquinoline-3-carbaldehyde, was replaced with 4-oxo-2-phenyl-1, 4-dihydroquinoline-3-carbaldehyde prepared in the above step to prepare the objective compound.

Step 34 preparation of amino-5-cyano-6- (((8-chloro-2-phenyl-1, 4-dihydroquinolin-3-yl) methyl) amino) pyrimidine

3-aminomethyl-2-phenylquinolin-4 (1H) -one (1.25g, 0.005mol) and 50ml of isopropanol were added to a 100ml three-necked flask, stirred to dissolve, and then 4-amino-5-cyano-6-chloropyrimidine (0.93g,0.006mol) and potassium carbonate (2.1g, 0.015mol) were added, the temperature was raised to 80 ℃, stirred under reflux for 5H, and the reaction was followed by TLC until the reaction was complete. Stopping reaction, filtering, washing filter cake with a large amount of ethyl acetate, removing solvent under reduced pressure, adding methanol and silica gel into residue to prepare sand, and separating by column chromatography to obtain white solid 1.37g with yield of 68.1%.

¹H NMR(500MHz,DMSO-d₆):10.80(s,1H),8.18-8.17(d,1H,J＝5.0Hz),7.88-7.87(d,1H,J＝5.0Hz),7.56-7.54(m,5H),7.36-7.39(t,1H,J＝7.5Hz),6.43(s,3H),6.10(s,2H),4.23(s,2H).ES:m/z 368.9[M+H]⁺。

Example 244-amino-5-cyano-6- (((8-fluoro-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) methyl) amino) pyrimidine

Step 13 preparation of aminomethyl-8-fluoro-2-phenylquinolin-4 (1H) -one

The preparation process was the same as that of 3-aminomethyl-2-phenylquinolin-4 (1H) -one obtained in step 1-2 of example 23, except that 2-aminobenzoic acid, the starting material, was replaced with 2-amino-3-fluorobenzoic acid to give the objective compound.

Step 24 preparation of amino-5-cyano-6- (((8-fluoro-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) methyl) amino) pyrimidine

3-aminomethyl-8-fluoro-2-phenylquinolin-4 (1H) -one (1.34g, 0.005mol) and 50ml of isopropanol were added to a 100ml three-necked flask, stirred to dissolve, and then 4-amino-5-cyano-6-chloropyrimidine (0.93g,0.006mol) and potassium carbonate (2.1g, 0.015mol) were added, the temperature was raised to 80 ℃, stirred under reflux for 5H, and the reaction was followed by TLC until the reaction was complete. Stopping reaction, filtering, washing filter cake with a large amount of ethyl acetate, removing solvent under reduced pressure, adding methanol and silica gel into residue to prepare sand, and separating by column chromatography to obtain white solid 1.23g with yield of 63.8%.

¹H NMR(500MHz,DMSO-d₆):10.78(s,1H),8.18-8.17(d,1H,J＝5.0Hz),7.86-7.85(d,1H,J＝5.0Hz),7.57-7.53(m,4H),7.33-7.38(t,1H,J＝7.5Hz),6.36-6.43(m,3H),6.14(s,2H),4.21(s,2H).ES:m/z 387.1[M+H]⁺。

Example 252, 4-diamino-5-cyano-6- (((2-phenyl-1, 4-dihydroquinolin-3-yl) methyl) amino) pyrimidine

3-aminomethyl-2-phenylquinolin-4 (1H) -one (1.25g, 0.005mol) obtained in step 2 of example 23 and 50ml of isopropanol were charged into a 100ml three-necked flask, dissolved with stirring, followed by addition of 2, 4-diamino-5-cyano-6-chloropyrimidine (1.01g, 0.006mol) and DBU (2.1g, 0.015mol), warming to 80 ℃, reflux with stirring for 5H, and the reaction was followed by TLC until completion. Stopping reaction, removing solvent under reduced pressure, adding methanol and silica gel into residue to make sand, and separating by column chromatography to obtain white solid 0.70g with yield of 36.3%.

¹H NMR(500MHz,DMSO-d₆):10.81(s,1H),8.18-8.17(d,1H,J＝5.0Hz),7.89-7.88(d,1H,J＝5.0Hz),7.56-7.54(m,4H),7.36-7.39(t,1H,J＝7.5Hz),6.43(s,3H),6.10(s,2H),6.02(s,2H),4.23(s,2H).ES:m/z 384.1[M+H]⁺。

Example 262, 4-diamino-5-cyano-6- ((8-chloro-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) methyl) amino) pyrimidine

3-aminomethyl-8-chloro-2-phenylquinolin-4 (1H) -one (1.42g, 0.005mol) prepared in step 2 of example 22 and 50ml of isopropanol were charged into a 100ml three-necked flask, dissolved with stirring, followed by addition of 2, 4-diamino-5-cyano-6-chloropyrimidine (1.01g, 0.006mol) and potassium carbonate (2.1g, 0.015mol), warming to 80 ℃, refluxing with stirring for 5H, and TLC was followed until the reaction was complete. Stopping reaction, filtering, washing filter cake with a large amount of ethyl acetate, removing solvent under reduced pressure, adding methanol and silica gel into residue to prepare sand, and separating by column chromatography to obtain white solid 0.62g with yield of 29.6%.

¹H NMR(500MHz,DMSO-d₆):10.78(s,1H),8.17-8.18(d,1H,J＝5.0Hz),7.85-7.86(d,1H,J＝5.0Hz),7.51-7.54(m,3H),7.33-7.38(t,1H,J＝7.5Hz),6.36-6.43(m,3H),6.16(s,2H),6.08(s,2H),4.21(s,2H).ES:m/z 418.1[M+H]⁺。

Example 274-amino-5-cyano-6- ((1- (8-chloro-1-methyl-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethyl) amino) pyrimidine

Step preparation of tert-butyl 11- (8-chloro-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethylcarbamate

3- (1-aminoethyl) -8-chloro-2-phenylquinolin-4 (1H) -one prepared in step 8 of example 17 (1.5g, 0.005mol) and 20ml of THF were charged into a 100ml three-necked flask, dissolved with stirring, then 10ml of 1M sodium hydroxide solution was added, the temperature was lowered to 0 ℃ and then 5ml of tetrahydrofuran solution of di-tert-butyl dicarbonate (1.38g, 0.006mol) was added dropwise, stirred at room temperature for 1H, and the reaction was followed by TLC until completion. The reaction was stopped, the tetrahydrofuran was removed by rotary evaporation, 50ml of water and 50ml of ethyl acetate were added to the residue, the aqueous layer was extracted with 25ml of × 2 ethyl acetate again, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and column chromatography was carried out to obtain 1.65g of a white solid, with a yield of 82.8%.

Step 21 preparation of tert-butyl (8-chloro-1-methyl-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethylcarbamate

Tert-butyl 1- (8-chloro-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethylcarbamate (1.59g, 0.004mol), potassium carbonate (1.69g, 0.012mol), methyl iodide (2.84g, 0.020mol) and 25ml DMF were added to a 100ml three-necked flask, the temperature was raised to 45 ℃ and stirred for 2 hours, TLC followed until the reaction was complete, the reaction was stopped, suction filtration was performed, the cake was washed with ethyl acetate, the filtrate was freed of the solvent under reduced pressure, 50ml of ethyl acetate and 50ml of water were added and extracted, the aqueous layer was washed with 25ml of ethyl x 2 acetate, the organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried, and 1.53g of a white solid after the desolvation was obtained in 92.6% yield.

Step 33 preparation of (1-aminoethyl) -8-chloro-1-methyl-2-phenylquinolin-4 (1H) -one hydrochloride

Tert-butyl 1- (8-chloro-1-methyl-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethylcarbamate (1.24g, 0.003mol) and 20ml of an ethanol solution of hydrogen chloride (HCl concentration 6.2M) were added to a 100ml three-necked flask, stirred at room temperature for 1h and the reaction was followed by TLC until completion. Stopping the reaction, removing the solvent by rotary evaporation, adding 50ml of absolute ethyl alcohol into the residue, removing the solvent by rotary evaporation again to obtain 1.21g of crude product, and directly putting the crude product into the next reaction. .

Step preparation of 44-amino-5-cyano-6- ((1- (8-chloro-1-methyl-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethyl) amino) pyrimidine

The crude 3- (1-aminoethyl) -8-chloro-1-methyl-2-phenylquinolin-4 (1H) -one hydrochloride (1.21g) and 50ml of isopropanol were charged to a 100ml three-necked flask and dissolved with stirring, followed by the addition of 4-amino-5-cyano-6-chloropyrimidine (0.36g, 0.036mol) and potassium carbonate (1.25g, 0.09mol), warming to 80 deg.C, refluxing with stirring for 5H, and the reaction was followed by TLC until completion of Compound 9. Stopping reaction, filtering, washing filter cake with a large amount of ethyl acetate, removing solvent under reduced pressure, adding methanol and silica gel into residue to prepare sand, and separating by column chromatography to obtain white solid 0.93g with yield of 72.1%.

¹H NMR(500MHz,DMSO-d₆):8.36-8.35(d,1H,J＝5.0Hz),8.21-8.20(d,1H,J＝5.0Hz),7.87(s,1H),7.81-7.82(m,2H),7.62-7.63(m,2H),7.44-7.51(m,3H),7.17(s,2H),4.90-4.87(m,1H),3.42(s,3H),1.29-1.31(d,3H,J＝10.0Hz).ES:m/z 430.9[M+H]⁺。

Example 284-amino-5-cyano-6- ((1- (8-fluoro-1-methyl-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethyl) amino) pyrimidine

Step preparation of 13- (1-aminoethyl) -8-fluoro-2-phenylquinolin-4 (1H) -one

The preparation process was identical to the preparation of 3- (1-aminoethyl) -8-chloro-2-phenylquinolin-4 (1H) -one prepared in steps 1 to 8 of example 17, except that the starting material, 2-amino-3-chlorobenzoic acid, was replaced with 2-amino-3-fluorobenzoic acid to prepare the objective compound.

Step 23- (1-aminoethyl) -8-fluoro-1-methyl-2-phenylquinolin-4 (1H) -one hydrochloride preparation

Preparation method the same as that for the hydrochloride of 3- (1-aminoethyl) -8-chloro-1-methyl-2-phenylquinolin-4 (1H) -one prepared in steps 1 to 3 of example 27 except that the starting hydrochloride of 3- (1-aminoethyl) -8-chloro-2-phenylquinolin-4 (1H) -one was replaced with the hydrochloride of 3- (1-aminoethyl) -8-fluoro-2-phenylquinolin-4 (1H) -one prepared in the above step to prepare the objective compound.

Step 34 preparation of amino-5-cyano-6- ((1- (8-fluoro-1-methyl-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethyl) amino) pyrimidine

The crude 3- (1-aminoethyl) -8-fluoro-1-methyl-2-phenylquinolin-4 (1H) -one hydrochloride (1.18g) and 50ml of isopropanol were charged to a 100ml three-necked flask and dissolved with stirring, followed by the addition of 4-amino-5-cyano-6-chloropyrimidine (0.36g, 0.036mol) and potassium carbonate (1.25g, 0.09mol), warming to 80 deg.C, refluxing with stirring for 5H, and the reaction was followed by TLC until completion of Compound 9. Stopping reaction, filtering, washing filter cake with a large amount of ethyl acetate, removing solvent under reduced pressure, adding methanol and silica gel into residue to prepare sand, and separating by column chromatography to obtain white solid 0.93g with yield of 72.1%.

¹H NMR(500MHz,DMSO-d₆):8.38-8.37(d,1H,J＝5.0Hz),8.20-8.19(d,1H,J＝5.0Hz),7.87(s,1H),7.81-7.83(m,2H),7.61-7.63(m,2H),7.44-7.50(m,3H),7.16(s,2H),4.90-4.86(m,1H),3.41(s,3H),1.29-1.31(d,3H,J＝10.0Hz).ES:m/z 415.2[M+H]⁺。

Example 294-amino-5-cyano-6- ((1- (1-methyl-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) methyl) amino) pyrimidine

Step 13 preparation of- (1-aminomethyl) -1-methyl-2-phenylquinolin-4 (1H) -one hydrochloride

Preparation method the same as that for the hydrochloride of 3- (1-aminoethyl) -8-chloro-1-methyl-2-phenylquinolin-4 (1H) -one, prepared in steps 1 to 3 of example 27, except that the starting hydrochloride of 3- (1-aminoethyl) -8-chloro-2-phenylquinolin-4 (1H) -one was replaced with 3-aminomethyl-2-phenylquinolin-4 (1H) -one, prepared in step 2 of example 23, was used to prepare the title compound.

Step preparation of 24-amino-5-cyano-6- ((1- (1-methyl-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) methyl) amino) pyrimidine

The crude 3- (1-aminomethyl) -1-methyl-2-phenylquinolin-4 (1H) -one hydrochloride (1.12g) and 50ml of isopropanol were added to a 100ml three-necked flask and dissolved with stirring, followed by addition of 4-amino-5-cyano-6-chloropyrimidine (0.36g, 0.036mol) and potassium carbonate (1.25g, 0.09mol), warming to 80 deg.C, reflux with stirring for 5H, and TLC follow-up of the reaction to completion. Stopping reaction, filtering, washing filter cake with a large amount of ethyl acetate, removing solvent under reduced pressure, adding methanol and silica gel into residue to prepare sand, and separating by column chromatography to obtain white solid 0.79g with yield of 68.5%.

¹H NMR(500MHz,DMSO-d₆):8.17-8.18(d,1H,J＝5.0Hz),7.86-7.87(d,1H,J＝5.0Hz),7.48-7.53(m,5H),7.36-7.39(t,1H,J＝7.5Hz),6.43(s,3H),6.10(s,2H),4.23(s,2H),3.41(s,3H).ES:m/z 383.2[M+H]⁺。

Example 302, 4-diamino-5-cyano-6- ((1- (4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethyl) amino) pyrimidine

The preparation process was the same as that of example 17, except that 2-amino-3-chlorobenzoic acid as a raw material was replaced with 2-aminobenzoic acid, and 4-amino-5-cyano-6-chloropyrimidine as a raw material was replaced with 2, 4-diamino-5-cyano-6-chloropyrimidine, to obtain the objective compound in a yield of 45.1%.

¹H NMR(500MHz,DMSO-d₆):11.05(s,1H),8.35-8.34(d,1H,J＝5.0Hz),8.22-8.21(d,1H,J＝5.0Hz),7.81-7.82(m,2H),7.61-7.62(m,3H),7.45-7.52(m,3H),6.11(s,2H),6.03(s,2H),4.90-4.87(m,1H),1.29-1.31(d,3H,J＝10.0Hz).ES:m/z 398.2[M+H]⁺。

Example 312, 4-diamino-5-cyano-6- ((1- (8-chloro-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethyl) amino) pyrimidine

The preparation method was the same as that of example 17, except that 4-amino-5-cyano-6-chloropyrimidine as a raw material was replaced with 2, 4-diamino-5-cyano-6-chloropyrimidine to prepare a target compound in a yield of 32.1%.

¹H NMR(500MHz,DMSO-d₆):11.05(s,1H),8.20-8.22(d,1H,J＝10.0Hz),8.00-8.02(d,1H,J＝10.0Hz),7.91(s,1H),7.53-7.58(m,5H),7.40-7.43(t,1H,J＝7.5Hz),6.12(s,2H),6.04(s,2H),5.14-5.17(m,1H),1.35-1.37(d,3H,J＝10.0Hz).ES:m/z 432.1[M+H]⁺。

Example 324-amino-5-cyano-6- ((1- (1-methyl-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethyl) amino) pyrimidine

The preparation method was the same as that of example 28, except that 2-amino-3-fluorobenzoic acid, which was the starting material, was replaced with 2-aminobenzoic acid to obtain the objective compound in a yield of 81.1%.

¹H NMR(500MHz,DMSO-d₆):8.36-8.35(d,1H,J＝5.0Hz),8.21-8.20(d,1H,J＝5.0Hz),7.87(s,1H),7.81-7.82(m,2H),7.62-7.63(m,2H),7.44-7.51(m,4H),7.17(s,2H),4.90-4.87(m,1H),3.42(s,3H),1.29-1.31(d,3H,J＝10.0Hz).ES:m/z 397.2[M+H]⁺。

Example 332, 4-diamino-5-cyano-6- ((1- (1-methyl-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethyl) amino) pyrimidine

The preparation method was the same as that of example 28, except that the starting material 2-amino-3-fluorobenzoic acid was replaced with 2-aminobenzoic acid, and the starting material 4-amino-5-cyano-6-chloropyrimidine was replaced with 2, 4-diamino-5-cyano-6-chloropyrimidine, to obtain the objective compound in a yield of 81.1%.

¹H NMR(500MHz,DMSO-d₆):8.36-8.35(d,1H,J＝5.0Hz),8.22-8.21(d,1H,J＝5.0Hz),7.81-7.83(m,2H),7.62-7.64(m,2H),7.44-7.50(m,4H),6.12(s,2H),6.04(s,2H),4.87-4.90(m,1H),3.42(s,3H),1.29-1.31(d,3H,J＝10.0Hz).ES:m/z 412.2[M+H]⁺。

Example 344-amino-5-cyano-6- ((1- (1-methyl-4-oxo-2- (3-fluorophenyl) -1, 4-dihydroquinolin-3-yl) ethyl) amino) pyrimidine

The preparation method was the same as that of example 28, except that 2-amino-3-fluorobenzoic acid as a raw material was replaced with 2-aminobenzoic acid, and benzoylethyl ester as a raw material was replaced with 3-fluorobenzoylethyl ester, to obtain the objective compound in a yield of 32.8%.

¹H NMR(500MHz,DMSO-d₆):8.33-8.32(d,1H,J＝5.0Hz),8.18-8.19(d,1H,J＝5.0Hz),7.87(s,1H),7.83-7.84(m,3H),7.55-7.58(m,1H),7.49-7.53(m,3H),7.19(s,2H),4.88-4.91(m,1H),3.43(s,3H),1.31-1.33(d,3H,J＝10.0Hz).ES:m/z 415.2[M+H]⁺。

Example 352, 4-diamino-5-cyano-6- ((1- (8-chloro-1-methyl-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) ethyl) amino) pyrimidine

The preparation method was the same as that of example 28, except that 2-amino-3-fluorobenzoic acid as a raw material was replaced with 2-amino-3-chlorobenzoic acid, and 4-amino-5-cyano-6-chloropyrimidine as a raw material was replaced with 2, 4-diamino-5-cyano-6-chloropyrimidine, to obtain the objective compound with a yield of 33.5%.

¹H NMR(500MHz,DMSO-d₆):8.21-8.23(d,1H,J＝10.0Hz),8.00-8.03(d,1H,J＝10.0Hz),7.92(s,1H),7.53-7.55(m,5H),7.40-7.43(t,1H,J＝7.5Hz),6.15(s,2H),6.01(s,2H),5.14-5.17(m,1H),3.43(s,3H),1.35-1.37(d,3H,J＝10.0Hz).ES:m/z 446.1[M+H]⁺。

Example 362, 4-diamino-5-cyano-6- ((8-fluoro-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) methyl) amino) pyrimidine

The preparation method was the same as that of example 23, except that 2-aminobenzoic acid, which was a raw material, was replaced with 2-amino-3-fluorobenzoic acid to prepare a target compound in a yield of 22.8%.

¹H NMR(500MHz,DMSO-d₆):10.78(s,1H),8.17-8.18(d,1H,J＝5.0Hz),7.86-7.87(d,1H,J＝5.0Hz),7.52-7.55(m,3H),7.35-7.39(t,1H,J＝7.5Hz),6.36-6.43(m,2H),6.16(s,2H),6.08(s,2H),4.21(s,2H).ES:m/z 387.1[M+H]⁺。

Example 374 preparation of amino-5-cyano-6- (((5-chloro-4-oxo-2-phenyl-1, 4-dihydroquinolin-3-yl) methyl) amino) pyrimidine

The preparation method was the same as that of example 23, except that 2-aminobenzoic acid, the starting material, was replaced with 2-amino-6-chlorobenzoic acid to obtain the objective compound in a yield of 88.1%.

¹H NMR(500MHz,DMSO-d₆):10.78(s,1H),8.18-8.17(d,1H,J＝5.0Hz),7.82-7.85(d,1H,J＝5.0Hz),7.52-7.56(m,4H),7.33-7.38(t,1H,J＝7.5Hz),6.36-6.41(m,3H),6.11(s,2H),4.20(s,2H).ES:m/z 403.1[M+H]⁺。

Example 382, 4-diamino-5-cyano-6- (1- (2- (3-fluorophenyl) -4-oxo-4H-chromen-3-yl) ethylamino) pyrimidine

Step 13 preparation of bromomethyl-2- (3-fluorophenyl) -4H-chromen-4-one

The preparation method was the same as that of 3-bromomethyl-2-phenyl-4H-chromen-4-one prepared in steps 1 to 3 of example 1, except that benzoyl chloride as a raw material was replaced with 3-fluorobenzoyl chloride, to obtain the objective compound.

Step 22, preparation of 4-diamino-5-cyano-6- (1- (2- (3-fluorophenyl) -4-oxo-4H-chromen-3-yl) ethylamino) pyrimidine

The preparation method was the same as that of example 7, steps 2-3, except that 3-bromomethyl-8-chloro-2-phenyl-4H-chromen-4-one was replaced with 3-bromomethyl-2- (3-fluorophenyl) -4H-chromen-4-one prepared in the above step, and 4-amino-5-cyano-6-chloropyrimidine was replaced with 2, 4-diamino-5-cyano-6-chloropyrimidine, to obtain the objective compound in a yield of 3.1%.

¹H NMR(300MHz,DMSO-d₆):8.17-8.14(d,1H,J＝7.8Hz),7.88-7.83(t,1H,J＝7.5Hz),7.72-7.46(m,6H),6.87-6.84(d,1H,J＝9.0Hz),6.50(s,2H),6.07(br,2H),5.37-5.30(t,1H,J＝6.9Hz),1.44-1.42(d,3H,J＝6.6Hz).ES:m/z 417.1[M+H]⁺。

Example 392, 4-diamino-5-cyano-6- (1- (2- (3, 5-difluorophenyl) -4-oxo-4H-chromen-3-yl) ethylamino) pyrimidine

The preparation method was the same as that of example 38, except that 3-fluorobenzoyl chloride as a raw material was replaced with 3, 5-difluorobenzoyl chloride, to obtain the objective compound with a yield of 7.9%.

¹H NMR(300MHz,DMSO-d₆):8.17-8.14(d,1H,J＝7.9Hz),7.89-7.83(t,1H,J＝7.7Hz),7.68-7.65(d,1H,J＝8.5Hz),7.58-7.52(m,4H),6.81-6.78(d,1H,J＝8.8Hz),6.60(s,2H),6.08(br,2H),5.37-5.27(m,1H),1.45-1.43(d,3H,J＝6.7Hz).ES:m/z 435.1[M+H]⁺。

Example 402, 4-diamino-5-cyano-6- (1- (4-oxo-2-phenyl-4H-chromen-3-yl) propylamino) pyrimidine

The preparation method was the same as that of example 38, except that 3-fluorobenzoyl chloride as a raw material was replaced with benzoyl chloride, and methyl magnesium chloride as a raw material was replaced with ethyl magnesium chloride, to obtain the objective compound with a yield of 5.7%.

¹H NMR(300MHz,DMSO-d₆):8.17-8.14(d,1H,J＝7.8Hz),7.89-7.86(t,1H,J＝7.7Hz),7.77-7.53(m,7H),7.09-7.04(s,1H),6.77(s,2H),6.21(br,2H)，5.31-5.23(m,1H),1.85-1.83(m,2H),0.67-0.62(t,3H,J＝7.0Hz).ES:m/z 413.1[M+H]⁺。

Comparative example 14-amino-5-cyano-6- (1- (3- (3, 5-difluorophenyl) -6-fluoro-1-methyl-4-oxo-1, 4 dihydroquinolin-2-yl) ethylamino) pyrimidine

The title compound was prepared according to the method disclosed in WO2010/151735 example 17 and identified by hydrogen spectroscopy and mass spectroscopy. The in vitro kinase activity of this compound was determined using the method of the following Experimental example 1, and the results showed that the IC of this compound to PI3K₅₀The value was 20nM and the selectivity was poor.

Experimental example 1 evaluation of kinase Activity of Compound in vitro

1. Experimental Material

A compound: the compounds of the present invention prepared in the above examples were each formulated in DMSO to 10mM, and then diluted to 1. mu.M, 100nM, 10nM, 1nM, 0.1nM, and 0.01nM in this order.

Reagents PI3K α (p110 α/p85a) from Invitrogen, Cat.No. PV4788, PIK3C (p110/p85a) from Millipore, Cat.No.14-604-K, PIK3C β (p110 β) from Millipore, Cat.No.14-603-K, PIK3C gamma (pp110 gamma) from Invitrogen, Cat.No. PR8641C, dimethyl sulfoxide (DMSO) from Sigma USA, EDTA from Sigma USA, 1 × kinase buffer (50mMHEPES, pH 7.5, 0.0015% Brij-35,10mM MgCl₂2mM DTT), prepared just before use; stop solutions (100mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3, 50mM EDTA) were prepared just before use.

The instrument comprises the following steps: LabChip EZ Reader, available from Caliper, USA.

2. Experimental methods

2.1. Taking 10 mu l of compound solution with each concentration to a 96-well plate, and adding 90 mu l of 1 Xkinase buffer solution; a DMSO control and a non-enzyme live control were also set, each containing only 10. mu.l DMSO and 90. mu.l 1 Xkinase buffer. Mixing the solutions at room temperature for 10min, and transferring 5 μ l to 384-well plate;

2.2. dissolving kinase in 1 Xkinase buffer solution to prepare 2.5 Xkinase solution, and transferring 10. mu.l of 2.5 Xkinase solution to 384-well plate containing compound at each concentration; DMSO control group was added with 10. mu.l of 2.5 Xkinase solution; no enzyme active control group was added with 10. mu.l of kinase-free 1 Xkinase buffer. Incubating at room temperature for 10 min;

2.3. dissolving FAM-labeled polypeptide and ATP in 1 × kinase buffer solution to obtain 2.5 × substrate solution, transferring 10 μ l of 2.5 × substrate solution to the 384-well plate, and incubating at 28 deg.C for 1 hr;

2.4. adding 25 mul of stop solution into each hole to stop the reaction;

2.5. placing the sample on a LabChip EZ Reader to read conversion rate data, and calculating the inhibition rate (I%), wherein the formula is that I% ═ Max-Com)/(Max-Min) × 100, Max is the conversion rate of a DMSO control group, Min is the conversion rate of an enzyme-free control group, Com is the conversion rate of a compound treatment group, XLFit treatment is carried out on the data, and IC is obtained by fitting₅₀。IC₅₀Values represent the concentration of compound corresponding to 50% inhibition of enzyme activity by the compound compared to the group treated without the compound. IC of partial compound₅₀The results are shown in Table 1. IC of Compounds of the invention for PI3K enzyme₅₀Values at nM level showed significant selective inhibitory activity against PI3K enzyme.

TABLE 1

"-" indicates not measured.

From the above experimental results, it can be seen that the compound of the present invention has a good inhibitory activity against PI3K, and also has a low inhibitory effect against PI3K α, PI3K β and PI3K γ, and is highly selective, and is highly expected to be a therapeutic agent for cancer, a therapeutic agent for tissue proliferative disease, or a therapeutic agent for inflammatory disease, which has a higher therapeutic effect and fewer side effects.

Experimental example 2 evaluation of cell Activity of Compounds in vitro

1. Experimental Material

Test compounds: the compounds of the present invention prepared in the above examples, each of which was formulated in DMSO at 10mM, were then sequentially diluted 3-fold at 20000.00nM, 6666.67nM, 2222.22nM, 740.74nM, 246.91nM, 27.43nM, 9.14nM, 3.05 nM.

Lymphoma cell lines SU-DHL-5 and SU-DHL-6 were purchased from the American Type Culture Collection (ATCC).

Reagent: RPMI-1640, available from Invitrogen, USA; FBS, available from Invitrogen, usa; EDTA, available from Sigma, USA;luminescent Cell visual Assay Kit, available from Progema, USA; backsseal film available from Perkin Elmer, usa.

2. Experimental methods

2.1 cell culture:

cell recovery: the cells were lysed in a 37 ℃ water bath, transferred to 15ml of pre-warmed medium, centrifuged at 1000rpm for 5 minutes, the medium was discarded, the cells were resuspended in 15ml of fresh medium, transferred to a T75 flask, placed at 37 ℃ in 5% CO₂The culture was performed in the incubator (1), and after 24 hours, the cells were replaced with fresh medium.

Cell passage: transferring the recovered cells into a 50ml sterile centrifuge tube, centrifuging at 1000rpm for 5 minutes, discarding the culture medium, counting the uniformly dispersed cells, adjusting the appropriate cell concentration to 15ml fresh culture medium, adding into a T75 culture flask, placing at 37 ℃ in 5% CO₂Cultured in an incubator.

2.2 Experimental procedures:

t75 cells grown to 1 × 10 cells in flasks⁵-1×10⁶After the number of cells/ml has been counted,resuspended cells were resuspended in fresh medium (RPMI1640+ 20% FBS) and counted the resuspended cells were adjusted to the following 8 concentration gradients 1 × 10⁴Individual cells/ml, 2 × 10⁴Individual cells/ml, 3 × 10⁴Individual cells/ml, 5 × 10⁴Individual cells/ml, 8 × 10⁴Individual cells/ml, 1 × 10⁵Individual cells/ml, 1.5 × 10⁵Individual cells/ml and 2 × 10⁵Cell suspension of the above concentration was added to a 96-well cell culture plate, and 100. mu.l (1 × 10, respectively) was added to each well³Individual cell/well, 2 × 10³Individual cell/well, 3 × 10³Individual cell/well, 5 × 10³Individual cell/well, 8 × 10³Individual cell/well, 1 × 10⁴Individual cell/well, 1.5 × 10⁴Individual cell/well and 2 × 10⁴Individual cells/well). Two multiple holes are formed for each concentration, and three plates are laid. Adding 100 mul to the hole to be measured after 72hLuminescent Cell visual availability buffer. Shake the mixture gently. After 10 minutes, a backsaid membrane is attached to the bottom of the Assay plate, the Assay plate is placed on an Envison to read fluorescence readings, the cell survival rate (cell survivor (%)) is calculated, the formula is (Com-Min)/(Max-Min), wherein Max is the reading of a solvent control group, Min is the reading of a cell-free control group, Com is the reading of a compound treatment group, data are processed by XLfit, and IC is obtained by fitting₅₀The results are shown in Table 2.

TABLE 2

"-" indicates no detection.

As can be seen from the experiments, the compound of the invention shows good inhibitory activity on SU-DHL-5 and SU-DHL-6 lymphoma cells, and is very promising to be used as a lymphoma therapeutic agent.

The inventors of the present invention found that the compounds of the present invention have very high subtype selectivity for PI3K kinase. In addition, the compound of the invention has very good bioavailability, long half-life period and good drug property.

Although the present invention has been described in detail above, those skilled in the art will appreciate that various modifications and changes can be made to the present invention without departing from the spirit and scope of the invention. The scope of the invention is not to be limited by the above detailed description but is only limited by the claims.

Claims

1. A compound shown in a general formula I or an isomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,

wherein:

Cy¹selected from aryl and heteroaryl groups, which may be substituted with one or more halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, cyanoalkyl, nitroalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, monoalkylamino, monoalkylaminoalkyl, dialkylamino, dialkylaminoalkyl, alkanoyl, alkylacylalkyl, alkoxyacyl, alkoxyacylalkyl, alkylacyloxy, alkylacyloxyalkyl, aminoacyl, aminoacylalkyl, monoalkylaminoacylalkyl, dialkylaminoacylalkyl, alkylacylamino or alkylacylaminoalkyl groups; and

R^aselected from H and alkyl, and R^bSelected from six-to twelve-membered nitrogen-containing heteroaryl and-C (O) -six-to twelve-membered nitrogen-containing heteroaryl, or R^a、R^bTogether with the N atom to which they are attached form a six-to twelve-membered nitrogen-containing heteroaryl group, wherein the six-to twelve-membered nitrogen-containing heteroaryl group and-C (O) -six-to twelve-membered nitrogen-containing heteroaryl group may be substituted with one or more halogens, hydroxy groups, oxo groups, amino groups, carboxy groups, cyano groups, nitro groups, alkyl groups, cycloalkyl groups, heterocycloalkyl groups, alkoxy groups, haloalkyl groups, hydroxyalkyl groups, aminoalkyl groups, carboxyalkyl groups, cyanoalkyl groups, nitroalkyl groups, cycloalkylalkyl groups, heterocycloalkylalkyl groups, alkoxyalkyl groups, monoalkylamino groups, monoalkylaminoalkyl groups, dialkylaminoalkyl groupsAmino, bisalkylaminoalkyl, alkanoyl, alkylacylalkyl, alkoxyacyl, alkoxyacylalkyl, alkylacyloxy, alkylacyloxyalkyl, aminoacyl, aminoacylalkyl, monoalkylaminoacyl, monoalkylaminoacylalkyl, bisalkylaminoacylacyl, bisalkylaminoacylalkyl, alkylacylamino or alkylacylaminoalkyl substitution.

2. The compound of claim 1, or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

X¹，X²，X³，X⁴are all C (R)²) Wherein R is²Selected from hydrogen, hydroxy, halogen, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-6Alkylamino and di-C_1-6An alkylamino group;

Cy¹selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrrolyl, thienyl, furyl, indolyl, isoindolyl and quinolinyl, which may be substituted with one or more of halogen, hydroxy, amino, carboxy, cyano, nitro, C_1-6Alkyl radical、C_3-8Cycloalkyl radical, C_3-8Heterocycloalkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl, cyano C_1-6Alkyl, nitro C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Heterocycloalkyl radical C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl, mono C_1-6Alkylamino radical, mono C_1-6Alkylamino radical C_1-6Alkyl, di-C_1-6Alkylamino, di-C_1-6Alkylamino radical C_1-6Alkyl radical, C_1-6Alkyl acyl radical, C_1-6Alkyl acyl radical C_1-6Alkyl radical, C_1-6Alkoxyacyl group, C_1-6Alkoxy acyl radical C_1-6Alkyl radical, C_1-6Alkyl acyloxy, C_1-6Alkyl acyloxy radical C_1-6Alkyl, aminoacyl C_1-6Alkyl, mono C_1-6Alkylaminoacyl, mono C_1-6Alkylaminoacyl radical C_1-6Alkyl, di-C_1-6Alkylaminoacyl, di-C_1-6Alkylaminoacyl radical C_1-6Alkyl radical, C_1-6Alkylacylamino or C_1-6Alkylacylamino C_1-6Alkyl substitution; and

R^aselected from H and C_1-6Alkyl, and R^bSelected from six-to twelve-membered nitrogen-containing heteroaryl and-C (O) -six-to twelve-membered nitrogen-containing heteroaryl, or R^a、R^bTogether with the N atom to which they are attached form a six-to twelve-membered nitrogen-containing heteroaryl group, wherein the six-to twelve-membered nitrogen-containing heteroaryl group and-C (O) -six-to twelve-membered nitrogen-containing heteroaryl group may be substituted with one or more halogens, hydroxy groups, oxo groups, amino groups, carboxy groups, cyano groups, nitro groups, alkyl groups, cycloalkyl groups, heterocycloalkyl groups, alkoxy groups, haloalkyl groups, hydroxyalkyl groups, aminoalkyl groups, carboxyalkyl groups, cyanoalkyl groups, nitroalkyl groups, cycloalkylalkyl groups, heterocycloalkylalkyl groups, alkoxyalkyl groups, monoalkylamino groups, monoalkylaminoalkyl groups, dialkylamino groups, dialkylaminoalkyl groups, alkanoyl groups, alkylacylalkyl groups, alkoxyacyl groups, alkoxyacylalkyl groups, alkylacyloxyalkoxyaryl groupsAlkyl acyloxyalkyl, aminoacyl, aminoacylalkyl, monoalkylaminoacyl, monoalkylaminoacylalkyl, dialkylaminoacyl, dialkylaminoacylalkyl, alkylacylamino or alkylacylaminoalkyl substitution.

3. The compound according to claim 1 or 2, or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein Y is selected from O and N (R)¹) Wherein R is¹Selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

4. A compound according to any one of claims 1-3, or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein X¹，X²，X³，X⁴Are all C (R)²) Wherein R is²Selected from the group consisting of hydrogen, hydroxy, halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxy, cyano, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino and ethylpropylamino.

5. The compound according to any one of claims 1-4, or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R^cSelected from the group consisting of methylene, ethylene and propylene, said methylene, ethylene and propylene being optionally substituted by one or more methyl, ethyl, propyl, isopropyl or oxo groups.

6. The compound according to any one of claims 1-5, or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, whereinCy¹Selected from phenyl, pyridyl and pyrimidinyl, which may be substituted with one or more of halogen, hydroxy, amino, carboxy, cyano, nitro, C_1-3Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl radical, C_1-3Alkoxy, halo C_1-3Alkyl, hydroxy C_1-3Alkyl, amino C_1-3Alkyl, carboxyl C_1-3Alkyl, cyano C_1-3Alkyl, nitro C_1-3Alkyl radical, C_3-6Cycloalkyl radical C_1-3Alkyl radical, C_3-6Heterocycloalkyl radical C_1-3Alkyl radical, C_1-3Alkoxy radical C_1-3Alkyl, mono C_1-3Alkylamino radical, mono C_1-3Alkylamino radical C_1-3Alkyl, di-C_1-3Alkylamino, di-C_1-3Alkylamino radical C_1-3Alkyl radical, C_1-3Alkyl acyl radical, C_1-3Alkyl acyl radical C_1-3Alkyl radical, C_1-3Alkoxyacyl group, C_1-3Alkoxy acyl radical C_1-3Alkyl radical, C_1-3Alkyl acyloxy, C_1-3Alkyl acyloxy radical C_1-3Alkyl, aminoacyl C_1-3Alkyl, mono C_1-3Alkylaminoacyl, mono C_1-3Alkylaminoacyl radical C_1-3Alkyl, di-C_1-3Alkylaminoacyl, di-C_1-3Alkylaminoacyl radical C_1-3Alkyl radical, C_1-3Alkylacylamino or C_1-3Alkylacylamino C_1-3Alkyl substitution.

7. The compound according to any one of claims 1-6, or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

R^ais H; and

R^bselected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridopyrazolyl and pyrimidoimidazolyl, which pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridopyrazolyl and pyrimidoimidazolyl may be substituted by one or more halogen, hydroxy, oxo, amino, carboxy, cyano, nitro, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Heterocycloalkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl, cyano C_1-6Alkyl, nitro C_1-6Alkyl radical, C_3-6Cycloalkyl radical C_1-6Alkyl radical, C_3-6Heterocycloalkyl radical C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl, mono C_1-6Alkylamino radical, mono C_1-6Alkylamino radical C_1-6Alkyl, di-C_1-6Alkylamino, di-C_1-6Alkylamino radical C_1-6Alkyl radical, C_1-6Alkyl acyl radical, C_1-6Alkyl acyl radical C_1-6Alkyl radical, C_1-6Alkoxyacyl group, C_1-6Alkoxy acyl radical C_1-6Alkyl radical, C_1-6Alkyl acyloxy, C_1-6Alkyl acyloxy radical C_1-6Alkyl, aminoacyl C_1-6Alkyl, mono C_1-6Alkylaminoacyl, mono C_1-6Alkylaminoacyl radical C_1-6Alkyl, di-C_1-6Alkylaminoacyl, di-C_1-6Alkylaminoacyl radical C_1-6Alkyl radical, C_1-6Alkylacylamino or C_1-6Alkylacylamino C_1-6Alkyl substitution.

8. The compound of claim 1, or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the compound is selected from the group consisting of:

9. a pharmaceutical composition comprising a compound of any one of claims 1 to 8, or an isomer, pharmaceutically acceptable salt, solvate, prodrug thereof and a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1 to 8, or an isomer, a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the treatment and/or prophylaxis of cancer, a tissue proliferative disorder or an inflammatory disorder.

11. The use according to claim 10, wherein the cancer is selected from melanoma, papillary thyroid tumors, cholangiocarcinomas, colon cancer, ovarian cancer, lung cancer, malignant lymphomas, carcinomas and sarcomas of the liver, kidney, bladder, prostate, breast and pancreas, and primary and recurrent solid tumors or leukemias of the skin, colon, thyroid, lung and ovary, and the inflammatory disease is selected from allergy, asthma, rheumatoid arthritis, osteoarthritis, allergic conjunctivitis, allergic keratitis, dry eye, chronic obstructive disease, lupus erythematosus, psoriasis, multiple sclerosis and end-stage renal disease.