CN104513235B - Substituted amino-metadiazine compound and its application method and purposes - Google Patents

Abstract

The present invention relates to new amino-metadiazine compound the extremely related disorder for the treatment of PI3 kinases or the purposes of the medicine of disease are used as to using its free form or pharmaceutically acceptable salt to dosage form.The present invention also relates to include the pharmaceutical composition of the compounds of this invention, and use the medicine composite for curing mammal, particularly treat the purposes of the extremely related human disorder of PI3 kinases or disease, such as, the treatment of the immunity and inflammatory disease of the PI3 kinases regulation to be played a major role in leukocyte function, and the treatment of the proliferative diseases related to PI3 kinase activities, including but not limited to leukaemia and solid tumor.

Description

Substituted amino-metadiazine compound and its application method and purposes

Invention field

The invention belongs to drug field, and in particular to a kind of noval chemical compound as kinase activity inhibitor, prepare them Method, the pharmaceutical composition comprising the compound and the compound and its pharmaceutical composition treating a variety of different diseases Application in disease.More specifically, compound of the present invention can be used as phosphoinositide 3-kinase family (PI3- Kinases, PI3Ks, such as PI3K δ, PI3K α, PI3K β and PI3K γ) activity or function inhibitor.

Background of invention

Phosphoinositide 3-kinase (PI3- kinases or PI3Ks), as a family of lipid kinase, enter in many cells Journey, such as the survival of cell, important adjustment effect is played in breeding and differentiation.As receptor tyrosine kinase (RTKs) and G Major influence factors in the conduction of protein-coupled receptor (GPCRs) downstream, by producing phosphatide, PI3Ks will come from all kinds of growths The signal transduction of factor and the factor to intracellular, activation Ser-ine-threonine protein kinase AKT (also referred to as protein kinase B (PKB)) and Other downstream passages.Tumor suppressor gene or PTEN (homologous acid phosphatase-tensin) are most important in PI3K signal paths Reverse conditioning agent (" Small-molecule inhibitors of the PI3K signaling network. " Future Med.Chem.,2011,3,5,549-565)。

Up to the present, the PI3Ks of 8 kinds of mammals has been identified, based on gene order, structure, adapter molecule, table Reach, the difference of activation mechanism and substrate can be divided into three classes (I, II and III).Wherein, again can be according to letter according to I classes PI3Ks Number path and regulatory protein are divided into IA and the classes of IB two.IA classes PI3Ks (PI3K α, PI3K β and PI3K δ) is by catalytic subunit P110 (being p110 α, p110 β and p110 δ respectively) and regulator subunit p85 (such as：P85 α, p85 β, p55 δ, p55 α and p50 α) the heterodimeric nanocrystal composition of composition.P110 subunits with catalytic activity using ATP phosphorylations phosphatidylinositols (PI, PtdIns), PI4P and PI (4,5) P2.The response of these signals is transmitted typically by receptor tyrosine kinase (RTKs).IB classes PI3K γ signal be by g protein coupled receptor (GPCRs) transmit, be made up of catalytic subunit p110 γ, with p110 γ Related regulation subunit is different from IA class hypotypes.

To the function and the related signal path in phosphatide of regulation of effector enzyme be I classes PI3Ks (e.g., PI3K δ, PI3Kdelta after) being activated, second messenger is generated on membrane phospholipid.I classes PI3Ks using membrane phospholipid PI (4,5) P2 be converted into as PI (3,4,5) P3 of second messenger.PI and PI (4) P is also PI3K substrate, and they can also be phosphorylated and turn respectively Turn to PI3P and PI (3,4) P2.In addition, these phosphoinositides specific by 5'- and 3'- specificity phosphatases can also be urged Change effect changes into other phosphoinositides.So, signal passes in the cell for active two kinds direct or indirect of the generation of PI3K enzymes Lead in approach as second messenger 3'- phosphoinositides hypotype (Nature Reviews Molecular Cell Biology, 2010,11,329)。

The expression way of PI3K α and PI3K two kinds of hypotypes of β is generally existing, but mainly found in leucocyte The expression way of both hypotypes of PI3K δ and PI3K γ can be more confined from.PI3K δ and PI3K γ relatively limited expression way, Except showing that the accumulative data to mice study also can show that the two hypotypes in adaptability and innate immune system Important function (J.Med.Chem., 2012,55,20,8559-8581).

In B and T cell, PI3Ks plays an important roll, the family by the Tec families of activator protein EGFR-TK Race includes proleulzin-induction type T- cell kinases in Bruton ' s EGFR-TKs (BTK) and T cell in B cell (ITK).Once PI3K is activated, BTK or ITK transpositions to plasma membrane, they are then by Src tyrosine phosphorylations there.Activation One of ITK main target is Phospholipase C-gamma (PLC γ 1), and PI (4,5) P2 is hydrolyzed to PI (3,4,5) P3 and starts to make by it Intracellular calcium improves and can activate the protein kinase C diglyceride (DAG) in the T cell of activation.

PI3K δ kinases, which completely knocks in (knock-in) mouse, can also survive, and their phenotype is limited to immune signal The defects of conduction (Okkenhaug et al., Science, 2002,297, p.1031-4).These transgenic mices have carried Understanding in depth for functions of the PI3K δ in B- cells and T- cellular signal transductions is supplied.Especially, PIs of the PI3K δ for CD28 (3,4,5) it is required that P3, which forms downstream and/or φt cell receptor (TCR) signal,.TCR PI3K signal transductions downstream it is important Effect is the activation to Akt, and it makes the anti-apoptotic factor and for a variety of different transcription factors caused by cell factor Phosphorylation.As a result, the T cell with inactive PI3K δ lacks in terms of breeding with Th1 and Th2 cytokine secretions.T is thin Born of the same parents reduce value and duration of the TCR by the threshold value of antigenic activation and increase breeder reaction by CD28 activation.These effects Should all be to PI3K δ-dependence increase in the transcription for include IL2 (an important SCIF) by many genes Mediated.

Therefore, the expection of PI3K inhibitor via it in regulation and breathing problem, such as asthma, COPD and cystic fibrosis Effect in the inflammatory reaction cell-mediated T- of association provides treatment benefit.The therapy that additionally, there are T- cells guiding can There is provided save Corticosteroids (corticosteroid sparing) characteristic instruction (Lancet, 1992,339, p.324- 8) it, is prompted to merge either as independent (standalone) or with suction or oral glucocorticosteroid, it is possible to provide Useful therapy in breathing problem.PI3K inhibitor also can be with other routine treatments, such as long acting beta-2-agonists (LABA) one Rise and be used for asthma.

In vascular system, PI3K δ are expressed by endothelial cell, and by adjusting these cells in being responded with TNF α Pre- attachment (neutrophil) state participate in neutrophil migration (trafficking) (Blood, 2004,103,9, p.3448).TNF αs of the PI3K δ in endothelial cell can be proved by the pharmacology inhibitory action of Akt phosphorylation and PDK1 activity The effect of the signal transduction of induction.In addition, PI3K δ are related to vascular permeability and air flue tissue edema by VEGF paths (Allergy Clin.Immunol.,2006,118,2,p.403).These observations show that PI3K δ suppress extra in asthma Benefit, the leucocyte that the benefit is associated by merging with asthma is overflowed and vascular permeability is reduced and realized.In addition, PI3K δ are active Mast cell function for both in vitro and in vivo be need (Nature, 2004,431, p.1007；J. Immunol., 2008,180,4, p.2538), also prompting PI3K to suppress should be to allergic reaction indication, such as asthma, allergic rhinitis and spy Answer atopic dermatitis that there is treatment benefit.

PI3K δ offer in B cell proliferation, antibody-secreting, B- cellular antigens and the conduction of IL-4 receptor signals, B cell antigen Effect in function also obtain determination (J.Immunol., 2007,178,4, p.2328-35；Blood,2006,107,2,p.642- 50), and it is shown in autoimmune disease, such as the effect in rheumatic arthritis or systemic loupus erythematosus.Therefore, PI3K inhibitor also has the effect of preferable to above-mentioned indication.

PI3K δ pharmacological inhibitory action suppresses agar glycosyl of the neutrophil cell to ICAM coatings of fMLP- dependences The chemotaxis (Sadhu etc., J.Immunol., 2003,170,5, p.2647-54) of the deflection system of matter integrin-dependence. PI3K δ suppression regulation neutrophil activation, adhesion and migration, without influence neutrophil cell mediation to golden yellow Staphylococcic phagocytosis and bactericidal activity (Sadhu etc., Biochem.Biophys.Res.Commun, 2003,308,4, p.764-9).In a word, the data shows that PI3K δ suppress that the neutrophilia to required for congenital immunity defence should be unable to be suppressed comprehensively Granulocyte function.Effects of the PI3K δ in neutrophil cell is provided including treatment tissue remodeling (such as COPD and rheumatic pass Section is scorching) inflammation disease more room.

PI3K γ have been determined as the medium of the regulation of G β-γ-dependence of JNK activity, and G β-γ are heterotrimers The subunit (J.Biol.Chem., 1998,273,5, p.2505-8) of G-protein (heterotrimeric G proteins). Recently, (Laffargue etc., Immunity, 2002,16,3, p.441-51) have been described PI3K γ by a variety of G (i)- Acceptor transfer (relays) inflammatory signals (inflammatory signals) of coupling, and its to mast cell function and Stimulant in leucocyte and immunology context be it is important, the stimulant include such as cell factor, chemotactic because Son, adenosine, antibody, integrin, agglutination factor, growth factor, virus or hormone (Immunity, 2002,16,3, p.441- 51；J.Cell Sci., 2001,114 (Pt 16), p.2903-10 with Curr.Opinion Cell Biol., 2002,14,2, p.203-13)。

It has been best understood by now, the imbalance of oncogene and tumor suppressor gene, such as given birth to by increased cell Long and propagation or increase cell survival promote malignant tumour to be formed.Now it is also known that road, the signal mediated by PI3K families pass Guiding path plays an important roll in multiple cell processes including breeding and surviving, and the imbalance of these paths is various Human cancer and Other diseases the origin cause of formation (Annual Rev. Cell Dev.Biol., 2001,17, p.615-675 and J.Cell Science,2003,116,15,p.3037-3040)。

In addition, also there is good evidence to show that I class PI3K enzymes also directly or indirectly facilitate various human cancers Tumour (Vivanco and Sawyers, Nature Reviews Cancer, 2002,2,7, p.489-501) occurs.For example, PI3K δ suppression is disorderly for hematologic, such as acute myelogenous leukemia have preferable therapeutic action (Oncogene, 2006,25,50,p.6648-59).In addition, in p110 α (PIK3CA genes) activated mutant from it is a variety of different other swollen Knurl, such as colon cancer, breast cancer and lung cancer it is associated (Science, 2004,304,5670, p.554；Nature Reviews Cancer,2009,9,551)。

Also result of study shows, PI3K is related to the central sensitization (central in painful inflammatory disease Sensitization determination (J. of Neuroscience, 2008,28,16, p.4261-4270)).

Various retrovirus and DNA base activated viral PI3K paths, as host between pre- anti-virus infection period The mode of cell death and finally explore for its duplication host cell synthesis mechanism (Virology, 2006,344,1, p.131-8；And Nat.Rev.Microbiol., 2008,6,4, p.265-75).Therefore, PI3K inhibitor is except more determining Outside oncolytic (oncolytic) and anti-inflammation indication, can also have ntiviral characteristic.These antivirus actions cause in disease The inflammation of poison induction prospect interesting in deteriorating.For example, common cold ERC group virus (HRV) causes the respiratory tract more than 50% Infection, but the complication of these infection can have more meaning in some crowds.This especially in breathing problem, such as asthma or It is especially such in the case of chronic obstructive pulmonary disease (COPD).It is thin that the rhinovirus infection of epithelial cell causes PI3K to rely on Intracellular cytokine and chemokine secretion (J.Biol.Chem., 2005,280,44, p.36952).The inflammatory reaction during infection with exhaling The deterioration for inhaling symptom is related.Therefore, PI3K inhibitor can suppress the immune response of (dampen) other benign virus amplification.Mostly Number HRV bacterial strains infect bronchial epithelial cell by initial combination to ICAM-1 acceptors.Then, further made by cell endocytic With HRV-ICAM-1 compounds are included into intracellular (internalised) and have shown that this measure will to PI3K activity Ask (J.Immunol., 2008,180,2, p. 870-880).Therefore, PI3K inhibitor also can be by suppressing cell entry host Cell and prevent viral infection.

PI3K inhibitor can be used for reducing other types of respiratory infections, including fungal infection aspergillosis (Mucosal Immunol.,2010,3,2, p.193-205).In addition, the mouse that PI3K δ lack is to assorted by the very large profit of protozoon parasite Graceful protozoon (Leishmania.major) infected with stronger resistance (J.Immunol., 2009,183,3, p.1921- 1933).In view of the effect to virus infection, these reports prompting PI3K inhibitor can be used for treating various infection.

Research shows, PI3K suppress can also to promote regulatory T cells differentiation (Sauer etc., Proc.Natl.Acad.Sci.USA, 2008,105,22, p.7797-7802), prompt PI3K inhibitor can in autoimmunity or In allergic reaction indication, by inducing the immunological tolerance former to autoantigen or allergic reaction and for therapeutic purposes.Closely Phase, insensitive association (the Am.J. Respir.Crit.Care of glucocorticoid that PI3K δ hypotypes have also induced with smoking Med.,2009,179,7,p.542-548).This research show COPD patient, its differently to glucocorticosteroid response not It is good, benefit can be obtained from the combination of PI3K inhibitor and glucocorticosteroid.

PI3K also has been directed to other breathing problems, such as idiopathic pulmonary fibrosis (IPF).IPF is fibre modification disease Disease, with progressive decreased lung function and caused by respiratory failure, the death rate increases.In IPF, Circulating fibrocyte (circulating fibrocytes) is oriented to lung via Chemokine receptor CXCR4.Signal transductions of the PI3K for CXCR4 It is both required (Int.J. Biochem.and Cell Biol., 2009,41, p.1708-1718) with expression.Therefore, By reducing CXCR4 expression and blocking its effector functions, PI3K inhibitor can suppress fibrocyte and raise to lung and thus Fibrotic processes, a kind of disease of height less than foot therapy demand are slowed down based on IPF.

The Κ β of PI3K α and Ρ Ι 3 are in the homeostasis and drug inhibition for maintaining the molecular target related to cancer Play the role of indispensable (Maira etc., Expert Opin.Ther.Targets, 2008,12,223).

Signal transductions and molecular growth path-dependent (Nature, 2006,441,366) of the PI3K α also with insulin.ΡΙ3 The selective inhibitory of Κ δ hypotypes is expected to be avoided that some potential side effects, such as hyperglycaemia and metabolism or growth failure.

Some groups have been developed for the alternative cpd to PI3K γ, and its effect is for autoimmune disease Immunodepressant (Nature Reviews, 2006,5,903-918).It is worth noting that, AS 605240 is had been demonstrated in class It is effective (Nature Medicine, 2005,11,936-943) in the mouse model of rheumatic arthritis, and in system The breaking-out (Nature Medicine, 2005,11,933-935) of disease can be postponed in the model of property lupus erythematosus.

PI3K δ-selective depressant has been described recently.Most selective compound includes quinolinone purine inhibitors (PIK39 and IC87114), IC87114 suppress PI3K δ on high nanomolar range (three digits), and have to PI3K δ big In 100 times of selectivity, there are 52 times of selectivity to PI3K β, but selectivity (about 8 times) is lacked to PI3K γ.It is to examination Any protein kinase tested is not shown active (Cell, 2006,125,733-747).Use PI3K δ-alternative cpd or something lost Pass gene control mouse (PI3K δ^D910A) prove, in addition to being played a crucial role in B and t cell activation, PI3K δ also parts It is related to neutrophil migration and the breathing of sensitization neutrophil, and cause the mast cell threshing of antigen-IgE mediations Part blocks (Blood, 2005,106,1432-1440；Nature,2002,431, 1007-1011).Therefore, PI3K δ are to make Occurring for the important medium that many critical inflammatories react, the inflammatory reaction, which it is known that, participates in abnormal inflammatory disease, including but It is not limited to autoimmune disease and allergy.In order to support the viewpoint, produced from the experiment using Genetic tools and medicament Ever-increasing 1) PI3K δ checkings data are given birth to.Therefore, using PI3K δ alternative cpd IC87114 and PI3K δ^D910AIt is small Verified PI3K δ rise mouse, Ali et al. (Nature, 2002,431,1007-1011) in the mouse model of anaphylactia Key effect.In the case of in the absence of function δ, passive cutaneous anaphylaxis (PCA) substantially reduces, and can be attributed to anti- The mast cells activation of original-IgE inductions and the reduction of threshing.In addition, in the asthma of the airway inflammation induced using ovalbumin Mouse model in, with IC87114 suppress δ have been demonstrated to significantly improve inflammation (FASEB, 2006,20:455-465).Different groups The same model using allergy airway inflammation in, using these data of compound in PI3K δ^D910AIt is phase in mutant mice (Eur.J.Immunol., the 2007,37,416-424) of mutual certification.

Need to be provided as the new PI3K inhibitor of good drug candidate.Specifically, preferable compound should be with PI3K acceptors effectively combine, while hardly show compatibility to other acceptors, and show the function as activator Activity.The compound should be fully absorbed by intestines and stomach, metabolic stability and have good pharmacokinetic property.When targeting maincenter During acceptor in nervous system, they can freely pass through blood-brain barrier, and selectively ought target in peripheral neverous system Acceptor when, they would not pass through blood-brain barrier.They should be non-toxic and show few side effect.In addition, the ideal Drug candidate should exist with stable, non-hygroscopic and the physical form easily prepared.The compounds of this invention shows specific water The flat PI3K α for different paralogous (paralogs), beta, gamma and δ selectivity.Particularly, specified level is shown The selectivity for the Κ δ of Ρ Ι 3.

The compounds of this invention all has treatment potential to a series of illnesss being widely present, particularly to LADA Disease, diseases associated with inflammation, anaphylactia, the disease related to immune system or infection, airway disorders, such as asthma and chronic resistance Plug property tuberculosis (COPD), graft-rejection, tumour, such as hematopoietic system cancer or solid tumor.

The invention further relates to the treatment method that other one or more pharmaceutical active compounds are used alone or in combination, this is controlled Treatment method includes the treatment of following disease or obstacle, breathing problem, including asthma, COPD (COPD) and spy Hair property pulmonary fibrosis (IPF)；Virus infection, including viral respiratory infection and viral respiratory disease deteriorate, and such as roar Asthma and COPD；Non-viral respiratory tract infection, including aspergillosis and leishmaniasis；Anaphylactia, including allergic rhinitis and spy Answer atopic dermatitis；Autoimmune disease, including rheumatoid arthritis and multiple sclerosis；Inflammatory disease, including inflammatory Enteropathy；Angiocardiopathy, including DVT and atherosclerosis (Future Med. Chem., 2013,5,4,479-492； Biochemical Society Transactions,2004,32,378)；Malignant hematologic disease；Nerve degenerative diseases；Pancreas It is scorching；Multiple organ failure；Nephrosis；Platelet aggregation；Cancer；Sperm motility；Graft rejection；Graft rejection；Injury of lungs；And pain Bitterly, neuralgia, sugar including after the pain related to rheumatoid arthritis or osteoarthritis, backache, systemic inflammatorome pain, liver Urinate characteristic of disease DPN, neuro-inflammatory pain (wound), trigeminal neuralgia and central pain；Malignant hematologic disease, including Acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), the white blood of chronic myelognous Sick (CML), T cell ALL (T-ALL), B cell ALL (B-ALL), Fei Huoqi Golden lymthoma (NHL), B cell lymphoma, solid tumor (e.g., breast cancer).

Abstract of invention

The invention discloses a kind of noval chemical compound can be used as kinase activity inhibitor, can particularly be used as PI3- kinase activities Inhibitor.Compound as PI3- kinase inhibitors can be used for the treatment extremely caused disease of kinases, and particularly PI3- swashs The extremely caused disease of enzyme, such as treating and preventing the disease by PI3- kinases mechanisms mediates.It is it should be noted that described Kinases includes abnormal kinase extremely and/or kinase expression is abnormal.Such disease includes at least one of：Respiratory tract disease Disease, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF)；Virus infection, including viral exhale Inhale road infection and viral respiratory disease deteriorates, such as asthma and COPD；Non-viral respiratory tract infection, including aspergillosis and profit Assorted graceful disease；Allergic diseases, including allergic rhinitis and atopical dermatitis；Autoimmune disease, including rheumatoid Property arthritis and multiple sclerosis；Inflammatory disease, including inflammatory bowel disease；Angiocardiopathy, including DVT and Atherosclerosis Change；Malignant hematologic disease；Nerve degenerative diseases；Pancreatitis；Multiple organ failure；Nephrosis；Platelet aggregation；Cancer；Sperm motility； Graft rejection；Graft rejection；Injury of lungs；And pain, including the pain related to rheumatoid arthritis or osteoarthritis, the back of the body Bitterly, neuralgia, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia after systemic inflammatorome pain, liver Pain and central pain.

In some embodiments, the compounds of this invention is shown exceedes other kinases to the selectivity of PI3- kinases.

In other embodiments, the compounds of this invention can be PI3K δ effective inhibitor.

In other embodiments, the compounds of this invention is shown exceedes other PI3- kinases to PI3K δ selectivity Type.

On the one hand, the present invention relates to a kind of compound, it is chemical combination shown in the compound of structure shown in formula (I) or formula (I) The stereoisomer of thing, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug,

Wherein each X, Y, R³And R⁴With definition as described in the present invention.

In some embodiments, X C_3-7Heterocyclic radical, C_3-7Heterocyclic radical-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl- C_1-4Alkylidene, include the former molecular heteroaryl of 1,2,3 or 4 be independently selected from O, S and N heteroatomic 5-10 or (5-10 The individual molecular heteroaryl of original)-C_1-4Alkylidene, wherein the X is optionally by 1,2,3,4 or 5 R¹Group is substituted；

Y is

Wherein described Y is optionally by 1,2,3 or 4 R²Group is substituted；

Each R¹And R²It independently is H, D, F, Cl, Br, CN, NO₂, oxo (=O) ,-C (=O) R^a,-C (=O) OR^a,-C (= O)NR^aR^b,-OC (=O) NR^aR^b,-OC (=O) OR^a,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-S (=O)₂R^a,-N (R^c) S (=O)₂R^a,-N (R^c)-(C_1-4Alkylidene)-S (=O)₂R^a, R^bR^aNC (=O)-C_1-4Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-4Alkylidene, R^aOC (=O) N (R^c)-C_1-4Alkylidene, R^bR^aNC (= O)O-C_1-4Alkylidene, R^bR^aNS (=O)₂-C_1-4Alkylidene, R^aS (=O)₂N(R^c)-C_1-4Alkylidene, OR^a, NR^aR^b, R^aO-C_1-4 Alkylidene, R^bR^aN-C_1-4Alkylidene, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8Cycloalkyl-C_1-4Alkylidene, C_3-7Heterocyclic radical, C_3-7Heterocyclic radical-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, include 1,2,3 or 4 independence Heteroatomic 5-10 former molecular heteroaryl or (5-10 former molecular heteroaryl)-C selected from O, S and N_1-4Alkylene Base, wherein each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8Cycloalkyl-C_1-4Alkylidene, C_3-7Heterocyclic radical, C_3-7Heterocyclic radical-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 The individual molecular heteroaryl of original)-C_1-4Alkylidene is independently unsubstituted or is substituted by 1,2,3 or 4 substituent, described to take Dai Ji is independently selected from D, F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；

Each R³And R⁴It independently is H, D, F, CN, NO₂,-C (=O) R^a,-C (=O) OR^a,-C (=O) NR^aR^b, R^bR^aNC (= O)-C_1-4Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-4Alkylidene, R^aOC (=O) N (R^c)-C_1-4Alkylidene, R^bR^aNC (=O) O- C_1-4Alkylidene, R^bR^aNS (=O)₂-C_1-4Alkylidene, R^bS (=O)₂N(R^c)-C_1-4Alkylidene, R^aO-C_1-4Alkylidene, R^bR^aN- C_1-4Alkylidene, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8Cycloalkyl-C_1-4Alkylidene, C_3-7Heterocyclic radical, C_3-7Heterocyclic radical-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, O, S and N are independently selected from comprising 1,2,3 or 4 Heteroatomic 5-10 former molecular heteroaryl or (5-10 former molecular heteroaryl)-C_1-4Alkylidene, wherein described each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8Cycloalkyl-C_1-4Alkylidene, C_3-7Heterocyclic radical, C_3-7Heterocyclic radical-C_1-4 Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 original is molecular Heteroaryl)-C_1-4Alkylidene is independently unsubstituted or is substituted by 1,2,3 or 4 substituent, and the substituent independently selects From D, F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；Or R³, R⁴With with they Connected carbon atom together, forms the former molecular carbocyclic ring of substituted or non-substituted 3-8 or heterocycle；With

Each R^a, R^bAnd R^cIt independently is H, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4It is sub- Alkyl, C_3-6Heterocyclic radical, C_3-6Heterocyclic radical-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, include 1,2,3 or 4 It is independently selected from O, S and N heteroatomic 5-10 former molecular heteroaryl or (5-10 former molecular heteroaryl)-C_1-4 Alkylidene, wherein each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkylidene, C_3-6It is miscellaneous Ring group, C_3-6Heterocyclic radical-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 former molecular heteroaryl)-C_1-4Alkylidene is independently unsubstituted or is substituted by 1,2,3 or 4 substituent, institute Substituent is stated independently selected from D, F, Cl, CN, N₃, OH, NH₂, C_1-6Alkyl, C_1-6Haloalkyl, C_1-6Alkoxy or C_1-6Alkyl Amino；Or R^a, R^bTogether with the nitrogen-atoms being connected with them, the former molecular heterocycle of substituted or non-substituted 3-8 is formed.

In other embodiments, X C_3-7Heterocyclic radical includes 1,2,3 or 4 miscellaneous original for being independently selected from O, S and N The former molecular heteroaryl of 5-10 of son, wherein the X is optionally by 1,2,3 or 4 R¹Group is substituted.

In other embodiments, each R¹And R²It independently is H, D, F, Cl, CN, oxo (=O) ,-C (=O) NR^aR^b,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-N (R^c) S (= O)₂R^a,-N (R^c)-(C_1-4Alkylidene)-S (=O)₂R^a, R^bR^aNC (=O)-C_1-4Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-4It is sub- Alkyl, R^bR^aNS (=O)₂-C_1-4Alkylidene, R^aS (=O)₂N(R^c)-C_1-4Alkylidene, OR^a, NR^aR^b, R^aO-C_1-4Alkylidene, R^bR^aN-C_1-4Alkylidene, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8Cycloalkyl-C_1-4Alkylidene, C_3-7Heterocycle Base, C_3-7Heterocyclic radical-C_1-4Alkylidene, phenyl, phenyl-C_1-4Alkylidene is independently selected from the miscellaneous of O, S and N comprising 1,2,3 or 4 The former molecular heteroaryl of 5-6 of atom, wherein each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8Ring Alkyl-C_1-4Alkylidene, C_3-7Heterocyclic radical, C_3-7Heterocyclic radical-C_1-4Alkylidene, phenyl, phenyl-C_1-4Alkylidene and comprising 1,2,3 or 4 former molecular heteroaryls of be independently selected from O, S and N heteroatomic 5-6 are independently unsubstituted or by 1,2,3 or 4 Substituent is substituted, and the substituent is independently selected from D, F, CN, OR^a, NR^aR^b, C_1-3Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene.

In other embodiments, each R³And R⁴It independently is H, D, F, CN ,-C (=O) NR^aR^b, R^bR^aNC (=O)- C_1-2Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-2Alkylidene, R^aOC (=O) N (R^c)-C_1-2Alkylidene, R^bR^aNC (=O) O-C_1-2 Alkylidene, R^bR^aNS (=O)₂-C_1-2Alkylidene, R^bS (=O)₂N(R^c)-C_1-2Alkylidene, R^aO-C_1-2Alkylidene, R^bR^aN-C_1-2 Alkylidene, C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-2Alkylidene, C_3-5Heterocyclic radical, C_3-5It is miscellaneous Ring group-C_1-2Alkylidene, phenyl, phenyl-C_1-2Alkylidene, include 1,2,3 or 4 be independently selected from O, S and N heteroatomic 5 Former molecular heteroaryl or (5 molecular heteroaryls of original)-C_1-2Alkylidene, wherein each C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-2Alkylidene, C_3-5Heterocyclic radical, C_3-5Heterocyclic radical-C_1-2Alkylidene, phenyl, benzene Base-C_1-2Alkylidene, 5 molecular heteroaryls of original and (5 molecular heteroaryls of original)-C_1-2Alkylidene is not taken independently In generation, is substituted by 1,2,3 or 4 substituent, and the substituent is independently selected from D, F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkane Base, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；Or R³, R⁴Together with the carbon atom being connected with them, formed it is substituted or The former molecular carbocyclic ring of non-substituted 3-8 or heterocycle.

In other embodiments, each R^a, R^bAnd R^cIt independently is H, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6 Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkylidene, C_3-6Heterocyclic radical, C_3-6Heterocyclic radical-C_1-4Alkylidene includes 1,2,3 or 4 independence The heteroatomic 5-10 former molecular heteroaryl selected from O, S and N, wherein each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynes Base, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkylidene, C_3-6Heterocyclic radical, C_3-6Heterocyclic radical-C_1-4Alkylidene and 5-10 atom group Into heteroaryl it is independently unsubstituted or substituted by 1,2,3 or 4 substituent, the substituent independently selected from D, F, CN, N₃, OH, NH₂, C_1-3Alkyl, C_1-3Haloalkyl, C_1-4Alkoxy or C_1-4Alkyl amino.

In other embodiments, X is

Wherein described X is optionally by 1,2 or 3 R¹Group is substituted.

In other embodiments, Y is

Wherein described Y is optionally by 1 or 2 R²Group is substituted.

In other embodiments, each R¹And R²It independently is H, F, Cl, CN, oxo (=O) ,-C (=O) NR^aR^b, -N(R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-N (R^c) S (=O)₂R^a, OR^a, NR^aR^b, C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-2Alkylidene, C_3-5Heterocyclic radical, C_3-5 Heterocyclic radical-C_1-2Alkylidene, phenyl or phenyl-C_1-2Alkylidene, wherein each C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Ring Alkyl, C_3-6Cycloalkyl-C_1-2Alkylidene, C_3-5Heterocyclic radical, C_3-5Heterocyclic radical-C_1-2Alkylidene, phenyl and phenyl-C_1-2Alkylidene is only On the spot unsubstituted or substituted by 1,2,3 or 4 substituent, the substituent is independently selected from F, CN, OR^a, NR^aR^bOr C_1-3Alkyl.

In other embodiments, each R³And R⁴It independently is H, D, F, CN, C_1-3Alkyl, C_3-6Cycloalkyl, C_3-5It is miscellaneous Ring group or C_3-5Heterocyclic radical-C_1-2Alkylidene, wherein each C_1-3Alkyl, C_3-6Cycloalkyl, C_3-5Heterocyclic radical and C_3-5Heterocyclic radical- C_1-2Alkylidene is independently unsubstituted or is substituted by 1,2,3 or 4 substituent, the substituent independently selected from D, F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；Or R³, R⁴The carbon being connected with them Atom together, forms the former molecular carbocyclic ring of substituted or non-substituted 3-8 or heterocycle.

In other embodiments, each R^a, R^bAnd R^cIt independently is H, C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6 Cycloalkyl, C_3-5Heterocyclic radical includes 1,2,3 or 4 former molecular heteroaryl of be independently selected from O, S and N heteroatomic 5-6 Base, wherein each C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Cycloalkyl, C_3-5Heterocyclic radical and 5-6 former molecular heteroaryl Base is independently unsubstituted or is substituted by 1,2,3 or 4 substituent, and the substituent is independently selected from F, CN, OH, NH₂, C_1-3Alkyl, C_1-3Haloalkyl, C_1-3Alkoxy or C_1-3Alkyl amino.

On the one hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes above-claimed cpd of the present invention. In some embodiments of the present invention, the compound further includes pharmaceutically acceptable carrier, excipient, diluent, Assistant agent, medium, or combinations thereof.In some embodiments, pharmaceutical composition provided by the invention further includes one Kind or a variety of therapeutic agents.In other embodiments, pharmaceutical composition can be liquid, and solid is semi-solid, gel or spray Mist formulation.

On the other hand, the purposes the invention provides above-claimed cpd or aforementioned pharmaceutical compositions in medicine is prepared, its Described in medicine be used for protect, handle, treat or mitigate PI3- kinases exception relevant diseases.

In some embodiments, PI3- kinases of the present invention is PI3K δ kinases.

In other embodiments, PI3- kinases exception relevant disease of the present invention is breathing problem, disease Poison infection, non-viral respiratory tract infection, anaphylactia, autoimmune disease, inflammatory disease, angiocardiopathy, pernicious blood Liquid disease, nerve degenerative diseases, pancreatitis, multiple organ failure, nephrosis, platelet aggregation, cancer, sperm motility, graft rejection, Graft rejection, injury of lungs and pain.

In other embodiments, PI3- kinases exception relevant disease of the present invention is asthma, COPD Property tuberculosis (COPD), viral respiratory infection, viral respiratory disease deteriorate, aspergillosis, leishmaniasis, allergia nose Inflammation, allergic dermatitis, rheumatic arthritis, multiple sclerosis, inflammatory bowel disease, DVT, atherosclerosis, hematologic Disease, nerve degenerative diseases, pancreatitis, multiple organ failure, nephrosis, platelet aggregation, cancer, sperm motility, graft rejection, move Plant repels, injury of lungs, the pain related to rheumatoid arthritis or osteoarthritis, backache, systemic inflammatorome pain, after liver Neuralgia, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia and central pain.

On the other hand, the purposes the invention provides above-claimed cpd or aforementioned pharmaceutical compositions in medicine is prepared, its Described in medicine be used for the kinases of inhibition of phosphatidylinositol3-3 (PI3- kinases) activity, including：Make the sheet of PI3- kinases and effective dose The disclosed compound of invention or pharmaceutical composition thereof of the present invention；In some embodiments, contact procedure can be entered One step includes the cell of contact expression PI3- kinases；In the other embodiment of this method, inhibitory action occurs enduring In the object of one or more type PI3- kinases obstacle relevant diseases.One or more type PI3- involved in the present invention swash The extremely related disease of enzyme includes autoimmune disease, rheumatic arthritis, respiratory disease, allergic reaction and various The cancer of type.

In some embodiments, method of the present invention includes applying second therapeutic agent to study subject.

In other embodiments, PI3- kinases exception relevant disease is selected from rheumatic arthritis, ankylosing spondylitis, Osteoarthritis, psoriatic arthritis, psoriasis, diseases associated with inflammation and autoimmune disease；In other embodiments, PI3- Kinase mediated disease is selected from angiocardiopathy, atherosclerosis, hypertension, Deep vain thrombosis, apoplexy, cardiac muscle stalk Plug, unstable angina, thromboembolism, pulmonary embolism, thrombolysis disease, Acute arterial ischeamia, peripheral thrombus obstruction and coronary artery Disease.In other embodiments, PI3- kinases exceptions relevant disease is selected from cancer, colon cancer, glioblastoma, endometrium Cancer, liver cancer, lung cancer, melanoma, kidney, thyroid cancer, lymthoma, lymphoproliferative disorder, ED-SCLC, squamous cell Lung cancer, glioma, breast cancer, prostate cancer, oophoroma, cervical carcinoma and leukaemia.In other embodiments, PI3- kinases The disease of mediation is selected from type ii diabetes；In other embodiments, PI3- kinases exception relevant disease is selected from respiratory tract disease Disease, bronchitis, asthma and chronic obstructive pulmonary disease；In other embodiments, study subject is people.

On the other hand, the present invention relates to the treatment method of PI3- kinase mediated diseases, the treatment method is including the use of this The step of invention compound or pharmaceutical composition are administered.

On the other hand, the present invention relates to rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, The treatment of psoriasis, diseases associated with inflammation or autoimmune disease, the treatment is including the use of the compounds of this invention or medicine group The step of compound is administered.

On the other hand, the present invention relates to including asthma, COPD (COPD) and idiopathic pulmonary fibrosis (IPF) treatment of breathing problem such as, it is described to treat the step being administered including the use of the compounds of this invention or pharmaceutical composition Suddenly.

On the other hand, the present invention relates to IBD, inflammatory ocular disease, inflammation or unstable bladder disease, The skin disease of inflammatory component, chronic inflammation, systemic loupus erythematosus (SLE), myasthenia gravis, acute diseminated encephalomyelitis, Idiopathic blood platelet reduction property purpura, multiple sclerosis, Sjogren syndrome and autoimmune hemolytic anemia, mistake The treatment of quick property and pleoergy disease, it is described to treat the step being administered including the use of the compounds of this invention or pharmaceutical composition Suddenly.

On the other hand, it is involved in the present invention to be mediated by PI3K activity, dependent on PI3K activity or related to PI3K activity The activity of the treatment of cancer, especially PI3K δ, the treatment include the compound of any of above and following embodiment is administered Step.

On the other hand, the present invention relates to the treatment method selected from following cancer：Acute myelogenous leukemia, spinal cord development are different Normal syndrome, myeloproliferative disease, chronic myelogenous leukemia, T cell ALL, B cell acute lymphoblastic are thin Born of the same parents' leukaemia, NHL, B cell lymphoma, solid tumor and breast cancer, the treatment method is including the use of the present invention The step of compound or pharmaceutical composition are administered.

On the other hand, the present invention relates to the compounds of this invention as the application in terms of medicine.

On the other hand, the answering in terms of the disease mediated medicines for the treatment of PI3K are prepared the present invention relates to the compounds of this invention With.

On the other hand, the present invention relates to the compounds of this invention prepare treat rheumatoid arthritis, ankylosing spondylitis, Osteoarthritis, psoriatic arthritis, psoriasis, diseases associated with inflammation, including asthma, COPD (COPD) and special hair Property pulmonary fibrosis (IPF) etc. breathing problem, the application of medicine in terms of autoimmune disease and cancer.

Unless otherwise mentioned, the present invention includes the stereoisomer of all the compounds of this invention, geometric isomer, mutually variation Structure body, solvate, hydrate, metabolite, salt and pharmaceutically acceptable prodrug.

In some embodiments, the salt refers to pharmaceutically acceptable salt.Term " pharmaceutically acceptable " refers to Material or composition must be with other compositions comprising preparation and/or with the mammals of its treatment chemically and/or toxicology It is upper compatible.

The compound of the present invention also includes the form of its salt, and the salt is not necessarily pharmaceutically acceptable salt, but can be with For preparing and/or purifying the compound of the present invention and/or the intermediate of the enantiomer for separating the compounds of this invention.

The compounds of this invention including its salt can also be obtained with its hydrate forms, or be crystallized including other for it Solvent.The compounds of this invention can form the solvate with acceptable solvent (including water) inherently or by designing； Therefore, present invention additionally comprises its solvation and unsolvated form.

On the other hand, the invention provides the preparation of compound shown in formula (I), separation and the method purified.The present inventionization Compound may include the form of several asymmetric centers or its generally described raceme mixture.The present invention also enters one Step includes racemic mixture, partial racemic compound and isolated enantiomer and diastereomer.

The compounds of this invention can be with one in possible isomers, rotational isomer, atropisomer, dynamic isomer Kind form or the form of its mixture are present, and the present invention can further include isomers, the rotational isomeric of the compounds of this invention Body, atropisomer, the mixture of dynamic isomer, or isomers, rotational isomer, atropisomer, dynamic isomer Part mixes or the separated isomers opened, rotational isomer, atropisomer, dynamic isomer.

On the other hand, compound of the present invention is including the use of chemical combination defined in the present invention of various isotope marks Thing, for example, radio isotope wherein be present, such as³H,¹⁴C and¹⁸F those compounds, or the same position of on-radiation wherein be present Element, such as²H and¹³C compound.

On the other hand, the method for preparation, separation and the purifying of the compound included the present invention relates to formula (I).

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.

Detailed description of the invention book

Definition and general terms

The present invention will in detail list the document corresponding to the content of the materialization of determination, and embodiment is all accompanied by structure The note of formula and chemical formula.The present invention, which has, expectedly covers all choices, variant and coordinate, and these may be as power Profit is included in existing invention field like that defined in requiring.Those skilled in the art will identify it is many similar or equivalent to Method described herein and material, these can apply in the practice of the present invention.The present invention is limited to absolutely not method and thing The description of matter.There is many documents and similar material to distinguish or contradict with the present patent application, including but be not limited to art The definition of language, the usage of term, the technology of description, or the scope controlled as the present patent application.

Unless otherwise noted, technology used in the present invention and scientific terminology and the technical field of the invention technical staff It is conventional understand that there is identical implication, unless otherwise noted, all patents public affairs cited in full content are disclosed in the present invention Open publication and be integrally incorporated the present invention by reference.

The present invention will apply defined below unless other aspects show.According to the purpose of the present invention, chemical element is according to member Plain periodic table, CAS versions and chemicals handbook, 75,^thEd, 1994 define.In addition, organic chemistry General Principle is shown in “Organic Chemistry”,Thomas Sorrell, University Science Books,Sausalito:1999, and“March's Advanced Organic Chemistry”,by Michael B.Smith and Jerry March, John Wiley&Sons,New York:2007, therefore all contents of the invention have all merged bibliography.

Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.It is tested right As also referring to primate (such as people), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc..Some In embodiment, the study subject is primate.In other other embodiments, the study subject is people.

Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.

Present invention additionally comprises the compounds of this invention of isotope marks, its in addition to following facts with it is of the present invention those Compound phase is same：One or more atoms are different from the original of natural common atomic quality or mass number by atomic mass or mass number Filial generation is replaced.The Exemplary isotopes that can be also introduced into the compounds of this invention include the same position of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine Element, such as²H,³H,¹³C,¹⁴C,¹⁵N,¹⁶O,¹⁷O,³¹P,³²P,³⁶S,¹⁸F and³⁷Cl。

The compounds of this invention and the compound comprising other of aforementioned isotopes and/or other atoms isotope Pharmaceutically acceptable salt is included within the scope of the present invention.The compounds of this invention of isotope marks, such as the same position of radioactivity Element, such as³H and¹⁴C, which is incorporated into the compounds of this invention, can be used for medicine and/or substrate tissue distributional analysis.Due to it is easily prepared with And detection, tritium generation, i.e.³H, and carbon-14, i.e.,¹⁴C, isotope are particularly preferred.In addition, with weight isotope, such as deuterium, i.e.,²H Substitution, it is possible to provide some are derived from the advantage in the treatment of bigger metabolic stability, such as increased Half-life in vivo or reduction Volume requirements.Therefore, it is probably preferable in some cases.

The Stereochemical definitions and convention that the present invention uses are generally according to S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley＆Sons, Inc., New York, 1994.The compounds of this invention can contain asymmetric center or chiral centre, therefore with different three-dimensional different Configuration formula is present.It is expected that all stereoisomeric forms in any ratio of the compounds of this invention, including but not limited to diastereo-isomerism Body, enantiomter and atropisomer (atropisomer) and their mixture such as racemic mixture, it is also contained in this Within invention scope.Many organic compounds exist with optical active forms, i.e., they, which have, sends out the plane of linearly polarized light The ability of raw rotation.When description has optically active compound, represented using prefix D and L or R and S with regard in molecule The absolute configuration of molecule for chiral centre (or multiple chiral centers).Prefix d and l or (+) and (-) are to be used for appointed compound The symbol of caused linearly polarized light rotation, wherein (-) or l represent that compound is left-handed.Prefix is (+) or d compound is Dextrorotation.For given chemical constitution, in addition to these stereoisomers each other mirror image, these stereoisomers are identical 's.Specific stereoisomer is alternatively referred to as enantiomter, and the mixture of the isomers is commonly referred to as enantiomerism The mixture of body.The 50 of enantiomter:50 mixtures are referred to as racemic mixture or racemic modification, when in chemical reaction or side When there is no stereoselectivity or stereospecificity in method, the racemic mixture or racemic modification may occur in which.

According to the selection of raw material and method, the compounds of this invention can be with one in possible isomers or theirs is mixed The form of compound is present, such as pure optical isomer, or as isomer mixture, it is such as different as racemic and non-corresponding Structure body mixture, this depends on the quantity of asymmetric carbon atom.Chiral synthesis can be used in (R)-or (S)-isomers of optical activity Prepared by son or chiral agents, or split using routine techniques.If this compound contains a double bond, substituent may be E or Z Configuration；If containing dibasic cycloalkyl in this compound, the substituent of cycloalkyl may be cis or trans (cis- or Trans-) configuration.

The compounds of this invention can contain asymmetric center or chiral centre, therefore be deposited with different stereoisomer forms .It is expected that all stereoisomer forms of the compounds of this invention, including but not limited to diastereoisomer, mapping Isomers and atropisomer (atropisomer) and geometry (or conformation) isomers and their mixture, as racemic is mixed Compound, within the scope of the present invention.

Unless otherwise noted, the structure that describes of the present invention be also represented by including this structure all isomers (e.g., enantiomer, Diastereomer atropisomer (atropisomer) and geometry (or conformation)) form；For example, the R and S structures of each asymmetric center Type, (Z) and (E) double bond isomer, and (Z) and (E) rotamer.Therefore, the single spatial chemistry of the compounds of this invention Isomers and mixture of enantiomers, non-enantiomer mixture and geometric isomer (or rotamer) mixture are in this hair Within the scope of bright.

What term " dynamic isomer " or " tautomeric form " referred to have different-energy can build (low by low energy Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of dynamic isomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include by proton migration the mutual inversion of phases that carries out, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the restructuring of some bonding electrons come The mutual inversion of phases carried out.The instantiation of ketoenol tautomerization is pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyls The change of dynamic isomer.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific Example is the change of pyridine -4- alcohol and pyridine -4 (1H) -one dynamic isomer.Unless otherwise noted, the institute of the compounds of this invention There are tautomeric forms to be within the scope of the present invention.

" nitrogen oxides " used in the present invention refers to when compound contains several amine functional groups, can be by 1 or more than 1 Nitrogen-atoms aoxidize to form N- oxides.The particular example of N- oxides is the N- oxides or nitrogen heterocyclic ring nitrogen-atoms of tertiary amine N- oxides.Available oxidant example, as hydrogen peroxide or peracid (such as peroxycarboxylic acid) handle corresponding amine and form N- oxides (referring to Advanced Organic Chemistry, Wiley Interscience, the 4th edition, Jerry March, pages). Especially, N- oxides can be prepared (Syn.Comm.1977,7,509-514) with L.W.Deady method, wherein for example lazy Property solvent, such as dichloromethane in, react amines and m- chlorine benzylhydroperoxide (MCPBA).

" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention are formed Thing.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.

" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology known to art Adopt as stating and experimentally characterized.Such product can be by, by aoxidizing, being reduced, water to drug compound The methods of solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc., obtains.Correspondingly, the present invention includes compound Metabolite, including by the present invention compound metabolite caused by a period of time is fully contacted with mammal.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in art on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:It is 1-19. described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Other method such as ion-exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, alginates, resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphurs Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that appropriate alkali obtains includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.The present invention is also intended to contemplate any The quaternary ammonium salt that the compound of included N group is formed.Water-soluble or oil-soluble or dispersion product can be turned into by quaternary ammonium With obtaining.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

Term " prodrug " used in the present invention, represent a compound and be converted into compound shown in formula (I) in vivo. Such conversion is hydrolyzed or is that precursor structure is influenceed through enzymatic conversion in blood or tissue in blood by pro-drug.This hair Bright pro-drug compounds can be ester, and ester can be as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, you can be acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.Completely begged on pro-drug By may be referred to documents below：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。

The shape that any asymmetric atom (for example, carbon etc.) of the compounds of this invention can be enriched with racemic or enantiomer Formula is present, such as (R)-, (S)-or (R, S)-configuration be present.In certain embodiments, each asymmetric atom (R)- Or there is at least 50% enantiomeric excess in terms of (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, extremely Few 80% enantiomeric excess, at least at least 90% enantiomeric excess, 95% enantiomeric excess, or at least 99% enantiomeric excess. If it would be possible, substituent on the atom with unsaturated double-bond can by cis-(Z)-or trans-(E)-in the form of deposit .

Therefore, as described in the present invention, compound of the invention can be with possible isomers, rotational isomeric The form of a kind of form or its mixture in body, atropisomer, dynamic isomer is present, for example, substantially pure geometry (cis or trans) isomers, diastereoisomer, optical isomer (enantiomer), racemic modification or its form of mixtures.

Any isomer mixture of gained can be separated into according to the physical chemical differences of component pure or substantially pure Geometry or optical isomer, diastereoisomer, racemic modification, such as separated by chromatography and/or fractional crystallization.

The racemic modification of any gained end-product or intermediate can be passed through into those skilled in the art with known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Thing can also be separated by chiral chromatogram, e.g., use the high pressure liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can prepare (e.g., Jacques, et al., Enantiomers, Racemates and by asymmetric syntheses Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2^ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L. Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；and Wilen, S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed., Univ.of Notre Dame Press,Notre Dame,IN 1972)。

As described in the invention, compound of the invention optionally can be substituted by one or more substituents, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can exchange use to " optionally substituting " this term with " substituted or non-substituted ".Term is " optionally Ground ", " optional " or " optional " refer to then described event or situation can with but may not occur, and the description is including wherein The situation of the event or situation occurs, and the situation of the event or situation does not occur wherein.In general, term " optionally " Whether it is located at before term " substituted ", all represents to give one or more of structure hydrogen atom by specific substituent institute Substitution.Unless otherwise indicated, an optional substituted radical can be substituted in each commutable position of group.When More than one position can be substituted by one or more substituents selected from specific group in given structural formula, then substitution Base with identical or different can substitute in each position.Wherein described substituent can be, but be not limited to, D, F, Cl, Br, CN, N₃, OH, NH₂, NO₂, oxo (=O) ,-C (=O) R^a,-C (=O) OR^a,-C (=O) NR^aR^b,-OC (=O) NR^aR^b,-OC (=O) OR^a,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-S (=O)₂R^a,-N (R^c) S (=O)₂R^a,-N (R^c)-(C_1-4Alkylidene)-S (=O)₂R^a, R^bR^aNC (=O)-C_1-4Alkylidene, R^bR^aNC (= O)N(R^c)-C_1-4Alkylidene, R^aOC (=O) N (R^c)-C_1-4Alkylidene, R^bR^aNC (=O) O-C_1-4Alkylidene, R^bR^aNS (=O)₂- C_1-4Alkylidene, R^aS (=O)₂N(R^c)-C_1-4Alkylidene, OR^a, NR^aR^b, R^aO-C_1-4Alkylidene, R^bR^aN-C_1-4Alkylidene, C_1-6Alkane Base, C_1-6Haloalkyl, C_1-6Alkoxy, C_1-6Alkyl amino, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8Cycloalkyl-C_1-4 Alkylidene, C_3-7Heterocyclic radical, C_3-7Heterocyclic radical-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, include 1,2,3 or 4 Individual heteroatomic 5-10 former molecular heteroaryl for being independently selected from O, S and N or (5-10 former molecular heteroaryl)- C_1-4Alkylidene, wherein, the R^a, R^bAnd R^cWith defining as described herein.

In addition, it is necessary to explanation, unless otherwise explicitly point out, used describing mode in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, it both may be used To refer in different groups, do not influence mutually, can also represent in phase between expressed specific option between same-sign In same group, do not influenceed mutually between expressed specific option between same-sign.

In each several part of this specification, the substituent that the present invention discloses compound discloses according to radical species or scope.It is special Do not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.For example, term “C_1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

In each several part of the present invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.If for example, the structure needs linking group and for being somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then is represented respectively it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.

Terminology used in the present invention " alkyl " or " alkyl group ", represent saturated straight chain or side chain containing 1-20 carbon atom Monovalence hydrocarbon atomic group.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom, and some of them are implemented Example is that alkyl group contains 1-10 carbon atom, and other embodiment is that alkyl group contains 1-8 carbon atom, in addition one A little embodiments are that alkyl group contains 1-6 carbon atom, and other embodiment is that alkyl group contains 1-4 carbon atom, Other embodiment is that alkyl group contains 1-3 carbon atom.

The example of alkyl group includes, but is not limited to, methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), n-propyl (n- Pr ,-CH₂CH₂CH₃), isopropyl (i-Pr ,-CH (CH₃)₂), normal-butyl (n-Bu ,-CH₂CH₂CH₂CH₃), isobutyl group (i-Bu ,- CH₂CH(CH₃)₂), sec-butyl (s-Bu ,-CH (CH₃)CH₂CH₃), the tert-butyl group (t-Bu ,-C (CH₃)₃), n-pentyl (- CH₂CH₂CH₂CH₂CH₃), 2- amyl groups (- CH (CH₃)CH₂CH₂CH₃), 3- amyl groups (- CH (CH₂CH₃)₂), 2- methyl -2- butyl (- C (CH₃)₂CH₂CH₃), 3- methyl -2- butyl (- CH (CH₃)CH(CH₃)₂), 3- methyl isophthalic acids-butyl (- CH₂CH₂CH(CH₃)₂), 2- first Base -1- butyl (- CH₂CH(CH₃)CH₂CH₃), n-hexyl (- CH₂CH₂CH₂CH₂CH₂CH₃), 2- hexyls (- CH (CH₃) CH₂CH₂CH₂CH₃), 3- hexyls (- CH (CH₂CH₃)(CH₂CH₂CH₃)), 2- methyl -2- amyl groups (- C (CH₃)₂CH₂CH₂CH₃), 3- Methyl -2- amyl groups (- CH (CH₃)CH(CH₃)CH₂CH₃), 4- methyl -2- amyl groups (- CH (CH₃)CH₂CH(CH₃)₂), 3- methyl -3- Amyl group (- C (CH₃)(CH₂CH₃)₂), 2- methyl -3- amyl groups (- CH (CH₂CH₃)CH(CH₃)₂), 2,3- dimethyl -2- butyl (- C (CH₃)₂CH(CH₃)₂), 3,3- dimethyl -2- butyl (- CH (CH₃)C(CH₃)₃), n-heptyl, n-octyl, etc., wherein described Alkyl group can be independently unsubstituted or substituted by one or more substituents described in the invention.

Term " alkyl " used in the present invention and its prefix " alkane ", the saturated carbon chains all comprising straight chain and side chain.

Term " alkylidene " represents to remove from the saturated hydrocarbyl of straight or branched the saturation obtained by two hydrogen atoms Bivalent hydrocarbon radical group.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom, and other embodiment is, sub- Alkyl group contains 1-6 carbon atom, and other embodiment is that alkylidene group contains 1-4 carbon atom, and other is real Applying example is, alkylidene group contains 1-2 carbon atom.Such example includes methylene (- CH₂-), ethylidene (- CH₂CH₂-), Isopropylidene (- CH (CH₃)CH₂-) etc., wherein the alkylidene group can be independently unsubstituted or one or more Substituent described in the invention is substituted.

Term " alkenyl " represents 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or 2-4 carbon original The monovalent hydrocarbon of the straight or branched of son, wherein at least one position is undersaturated condition, i.e., a C-C is sp²Double bond, wherein The group of alkenyl can be independently unsubstituted or substituted by one or more substituents described in the invention, including base There are negation " just " or " E " " Z " positioning in group, wherein specific example includes, but is not limited to, vinyl (- CH=CH₂), alkene Propyl group (- CH₂CH=CH₂) etc..

Term " alkynyl " represents 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or 2-4 carbon atom Straight or branched monovalent hydrocarbon, wherein at least one position is undersaturated condition, i.e., a C-C is the keys of sp tri-, wherein alkynes Base group can be independently unsubstituted or substituted by one or more substituents described in the invention, specific example bag Include, but be not limited to, acetenyl (- C ≡ CH), propargyl (- CH₂C ≡ CH), 1- propinyls (- C ≡ C-CH₃) etc..

Term " alkoxy " represents that alkyl group is connected by oxygen atom with molecule remainder, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-20 carbon atom, some of real Applying example is, alkoxy base contains 1-10 carbon atom, and other embodiment is that it is former that alkoxy base contains 1-8 carbon Son, other embodiment are that alkoxy base contains 1-6 carbon atom, and other embodiment is that alkoxy base contains 1-4 carbon atom, other embodiment are that alkoxy base contains 1-3 carbon atom.

The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH₃), ethyoxyl (EtO ,- OCH₂CH₃), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH₂CH₂CH₃), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH₃)₂), 1- butoxy (n-BuO, n- butoxy ,-OCH₂CH₂CH₂CH₃), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH₂CH(CH₃)₂), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH₃)CH₂CH₃), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH₃)₃), 1- amoxys (n- amoxys ,-OCH₂CH₂CH₂CH₂CH₃), 2- amoxys (- OCH (CH₃) CH₂CH₂CH₃), 3- amoxys (- OCH (CH₂CH₃)₂), 2- methyl -2- butoxy (- OC (CH₃)₂CH₂CH₃), 3- methyl -2- fourths Epoxide (- OCH (CH₃)CH(CH₃)₂), 3- methyl-l- butoxy (- OCH₂CH₂CH(CH₃)₂), 2- methyl-l- butoxy (- OCH₂CH(CH₃)CH₂CH₃), etc., wherein the alkoxy base can be independently unsubstituted or by this one or more hair Bright described substituent is substituted.

Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represent alkyl, and alkenyl or alkoxy base are by one Individual or multiple halogen atoms are substituted, and such example includes, but is not limited to, trifluoromethyl, trifluoromethoxy etc..

Term " carbocyclic ring ", " carbocylic radical " or " annular aliphatic " refer to have one or more tie points be connected to molecule its Remaining part point, non-aromatic, saturation or part are undersaturated, contain 3-12 carbon atom, or 3-10 carbon atom, or 3-8 Carbon atom, or monocyclic, the bicyclic and three-ring system of 3-6 carbon atom.Bicyclic system includes that spiral shell is bicyclic and condensed-bicyclic.Suitably Carbon ring group includes, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of carbon ring group further comprises, but never It is limited to, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyls, 1- cyclopenta -2- alkenyls, 1- cyclopenta -3- alkenyls, ring Hexyl, 1- cyclohexyl -1- alkenyls, 1- cyclohexyl -2- alkenyls, 1- cyclohexyl -3- alkenyls, cyclohexadienyl, suberyl, ring are pungent Base, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..

Term " cycloalkyl " refers to the remainder for having one or more tie points to be connected to molecule, saturation, contains 3- Monocyclic, the bicyclic or three-ring system of 12 carbon atoms.Some of embodiments, cycloalkyl are the ring bodies containing 3-10 carbon atom System；Other embodiment, cycloalkyl are the member ring systems containing 3-8 carbon atom；Other embodiment, cycloalkyl are to contain 3-6 The member ring systems of individual carbon atom；Other embodiment, cycloalkyl are the member ring systems containing 5-6 carbon atom；And the cycloalkyl base Group can be independently unsubstituted or substituted by one or more substituents described in the invention.

Term " cycloalkyl alkylidene " represents that alkyl group can be substituted by one or more groups of naphthene base, wherein alkane Base and group of naphthene base have implication as described in the present invention.Some of embodiments are, cycloalkyl alkylidene group refer to " compared with Rudimentary cycloalkyl alkylidene " group, i.e. group of naphthene base are connected to C_1-6Alkyl group on.Other embodiment is ring Alkyl group is connected to C_1-4Alkyl group on.Other embodiment is that group of naphthene base is connected to C_1-3Alkyl group On.Other embodiment is that group of naphthene base is connected to C_1-2Alkyl group on.Such example includes, but and unlimited In, cyclopropylethyl, cyclopentyl-methyl, cyclohexyl methyl etc..The cycloalkyl alkylidene group can not taken independently In generation, is substituted by one or more substituents described in the invention.

Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " and " condensed ring radical " are used interchangeably here, all referring to full And/or undersaturated bridged-ring system, the bridged-ring system are related to the bicyclic system of non-aromatic.Member ring systems can include independent Or conjugation unsaturated system, but its core texture does not include aromatic rings or heteroaromatic (but aromatic series can be used as thereon Substituent).Term " loop coil base ", " loop coil ", " spiral shell bicyclic group " or " spiral shell is bicyclic " are used interchangeably here, represent a ring Originating from particularly ring-shaped carbon on another ring, for example, as described by following formula a, the bridged-ring system of a saturation (ring B and B ') it is referred to as " condensed-bicyclic ", on the contrary ring A and ring B shares a carbon atom in the member ring systems of two saturations, then is referred to as " loop coil " or " spiral shell is bicyclic ".Each ring in loop coil can be carbocyclic ring or heterocycle.Such example includes, but is not limited to 5- Azaspiro [2.4] heptane -5- bases, (R) -4- azaspiros [2.4] heptane -6- bases etc..Term " bridged ring ", " bridged ring base " or " bridge Ring " it is used interchangeably here, all referring to the polycyclic system of shared two or more carbon atom.

Term " heterocycle ", " heterocyclic radical " or " heterocycle " are used interchangeably here, bicyclic all referring to monocyclic, or three rings System, one or more atoms are replaced by hetero atom individually optionally in its middle ring, ring can be it is fully saturated or comprising One or more degrees of unsaturation, but the definitely not fragrant same clan, there is the remainder that one or more tie points are connected to molecule.Its Bicyclic system includes that spiral shell is bicyclic and condensed-bicyclic, and one of ring can be monocyclic carbocyclic ring or single heterocycle.One of them is more Individual ring hydrogen atom is substituted by one or more substituents described in the invention individually optionally.Some of embodiments " heterocycle ", " heterocyclic radical " or " heterocycle " group be 4-8 it is former it is molecular it is monocyclic (3-7 carbon atom and selected from N, O, P, S 1-3 hetero atom, optionally substituted to obtain picture S=O, SO by one or more oxygen atoms in this S or P₂, PO, PO₂ Group)；Other embodiment is " heterocycle ", and " heterocyclic radical " or " heterocycle " group is 4-7 former molecular monocyclic (3-6 carbon atom and selected from N, O, P, is optionally substituted S 1-3 hetero atom in this S or P by one or more oxygen atoms Obtain as S=O, SO₂, PO, PO₂Group)；Other embodiment is " heterocycle ", and " heterocyclic radical " or " heterocycle " group is 3-7 former molecular monocyclic (2-6 carbon atom and selected from N, O, P, S 1-3 hetero atom, in this S or P optionally by one Individual or multiple oxygen atoms substitute to obtain as S=O, SO₂, PO, PO₂Group)；Other embodiment is " heterocycle ", " heterocycle Base " or " heterocycle " group be 3-6 it is former it is molecular it is monocyclic (2-5 carbon atom and selected from N, O, P, S 1-3 hetero atom, Optionally substituted to obtain picture S=O, SO by one or more oxygen atoms in this S or P₂, PO, PO₂Group, when it is described be 3 During former molecular ring, only one of which hetero atom)；Other embodiment is " heterocycle ", " heterocyclic radical " or " heterocycle " Group is 4-6 former molecular monocyclic (3-5 carbon atom and optional in this S or P selected from N, O, P, S 1-3 hetero atom Ground substitutes to obtain as S=O, SO by one or more oxygen atoms₂, PO, PO₂Group)；Other embodiment is, " miscellaneous Ring ", " heterocyclic radical " or " heterocycle " group are 3-6 former molecular monocyclic (2-5 carbon atoms and selected from N, O, P, S 1-3 Individual hetero atom, optionally substituted to obtain picture S=O, SO by one or more oxygen atoms in this S or P₂, PO, PO₂Group, when It is described when being the molecular ring of three originals, only one of which hetero atom), or 7-10 former molecular bicyclic (4-9 carbon Atom and selected from N, O, P, S 1-3 hetero atom, optionally substitute to obtain as S by one or more oxygen atoms in this S or P =O, SO₂, PO, PO₂Group).

Heterocyclic radical can be carbon-based or hetero atom base." heterocyclic radical " equally also includes heterocyclic group and saturation or part insatiable hunger With ring or heterocyclic fused formed group.The example of heterocycle includes, but is not limited to, pyrrolidinyl, tetrahydrofuran base, dihydro Furyl, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, Thioxane base, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, glycidyl, Azacycloheptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, 4,5- bis- Qing Evil Oxazolyl, 2- pyrrolinyls, 3- pyrrolinyls, indolinyl, 2H- pyranoses, 4H- pyranoses, dioxane hexyl, 1,3- Dioxy amyl group, pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidinyl imidazolinyl, imidazolidinyl, 1, 2,3,4- tetrahydro isoquinolyls.The example of heterocyclic group also includes, two carbon originals on 1,1- dioxidothiomorpholinyl, and its middle ring Son is substituted such as hybar X base by oxygen atom.

Term " heterocycloalkylene " represents that alkyl group can be substituted by one or more heterocyclyl groups, wherein alkane Base and heterocyclyl groups have implication as described in the present invention.Some of embodiments are, heterocycloalkylene group refer to " compared with Rudimentary heterocycloalkylene " group, i.e. heterocyclyl groups are connected to C_1-6Alkyl group on.Other embodiment is, miscellaneous Cyclic groups are connected to C_1-4Alkyl group on.Other embodiment is that heterocyclyl groups are connected to C_1-2Alkyl group On.Such example includes, but is not limited to, 2- pyrrolidines ethyls, 3- azetidine methyl etc..The heterocyclic radical is sub- Alkyl group can be independently unsubstituted or substituted by one or more substituents described in the invention.

Term " n former molecular ", wherein n is integer, the number of ring member nitrogen atoms in molecule is typically described, described The number of ring member nitrogen atoms is n in molecule.For example, piperidyl is 6 molecular Heterocyclylalkyls of original, and 1,2,3,4- tetralyl It is the molecular carbocylic radical group of 10 originals.

Term " hetero atom " refers to O, S, N, P and Si, including the form of N, S and any oxidation state of P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, for example, N is (as in 3,4- dihydro-2 h-pyrrole bases N), NH (as the NH in pyrrolidinyl) or NR (NR in the pyrrolidinyl substituted as N-).

Term " halogen " refers to F, Cl, Br or I.

Term " N₃" represent a nitrine structure.This group can be connected with other groups, for example, can be with a first Base is connected to form triazonmethane (MeN₃), or it is connected to form phenylazide (PhN with a phenyl₃)。

Term " aryl " can be used alone or as " aralkyl ", a big portion of " aralkoxy " or " aryloxy alkyl " Point, expression contains 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom is monocyclic, bicyclic, and the carbon of three rings Member ring systems, wherein, at least one member ring systems are aromatic, and each of which member ring systems include 3-7 former molecular ring, and There are one or more attachment points to be connected with the remainder of molecule.Term " aryl " can be exchanged with term " aromatic rings " and used, As aromatic rings can include phenyl, naphthyl and anthryl.The aromatic yl group can be independently unsubstituted or one or more Substituent described in the invention is substituted.

Term " aryl alkylene " represent alkyl group can be substituted by one or more aromatic yl groups, wherein alkyl and Aromatic yl group has implication as described in the present invention, and some of embodiments are that arylalkylene groups refer to the " virtue of lower level Base alkylidene " group, i.e. aromatic yl group are connected to C_1-6Alkyl group on.Other embodiment is arylalkylene groups Refer to contain C_1-4Alkyl " benzene alkylene ".Other embodiment is that arylalkylene groups refer to that aromatic yl group is connected to C_1-2Alkyl group on.Wherein instantiation includes benzyl, diphenyl methyl, phenethyl etc..The arylalkylene groups Can be independently unsubstituted or be substituted by one or more substituents described in the invention.

Term " heteroaryl " can be used alone or as most of " heteroaryl alkyl " or " heteroarylalkoxy ", Expression contains 5-14 annular atom, or 5-12 annular atom, or 5-10 annular atom, or 5-6 annular atom is monocyclic, bicyclic, And three-ring system, wherein at least one member ring systems are aromatic, and at least one member ring systems include one or more hetero atoms, Each of which member ring systems include 5-7 former molecular ring, and have one or more attachment points to be connected with molecule remainder. Term " heteroaryl " can exchange use with term " hetero-aromatic ring " or " heteroaromatics ".In some embodiments, heteroaryl Base is comprising 1,2,3 or 4 former molecular heteroaryl of be independently selected from O, S and N heteroatomic 5-12.In other realities Apply in scheme, heteroaryl is comprising 1,2,3 or 4 former molecular heteroaryl of be independently selected from O, S and N heteroatomic 5-10 Base.In other embodiments, heteroaryl is to include 1,2,3 or 4 heteroatomic 5-6 atom for being independently selected from O, S and N The heteroaryl of composition.In other embodiments, heteroaryl is to include 1,2,3 or 4 hetero atom for being independently selected from O, S and N 5 molecular heteroaryls of original.

Other embodiment is that heteroaryl includes following monocyclic groups, but is not limited to these monocyclic groups：2- furans Mutter base, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- is different Oxazolyl, 2- oxazolyls, 4- oxazolyls, 5- oxazolyls, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridines Base, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, pyridazinyl (such as 3- pyridazinyls), 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, tetrazole radical (such as 5H- tetrazole radicals, 2H- tetrazole radicals), triazolyl (such as 2- triazolyls, 5- triazolyls, 4H-1,2,4- tri- Oxazolyl, 1H-1,2,4- triazolyls, 1,2,3-triazoles base), 2- thienyls, 3- thienyls, pyrazolyl (e.g., 2- pyrazolyls and 3- Pyrazolyl), isothiazolyl, 1,2,3- oxadiazolyl, 1,2,5- oxadiazolyl, 1,2,4- oxadiazolyl, 1,3,4- oxadiazolyl, 1,2,3- thio biphosphole base, 1,3,4- thio biphosphole base, 1,2,5- thio biphosphole base, pyrazinyl, 1,3,5-triazines base；Also include Following bicyclic radicals, but it is not limited to these bicyclic radicals：Benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- indyls), purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinolyls), and isoquinolyl (such as 1- isoquinolines Quinoline base, 3- isoquinolyls or 4- isoquinolyls).The heteroaryl groups optionally described in the invention are taken by one or more Substituted for base.

Term " heteroarylalkylenyl " represents that alkyl group can be substituted by one or more heteroaryl groups, wherein alkane Base and heteroaryl groups have implication as described in the present invention, and some of embodiments are, heteroarylalkylenyl group refer to " compared with Rudimentary heteroarylalkylenyl " group, i.e. heteroaryl groups are connected to C_1-6Alkyl group on.Other embodiment is, miscellaneous Aromatic yl group is connected to C_1-4Alkyl group on.Other embodiment is that heteroaryl groups are connected to C_1-2Alkyl group On.Wherein instantiation includes 2- picolyls, 3- furylethyls etc..The heteroarylalkylenyl group can independently not It is substituted or is substituted by one or more substituents described in the invention.

Term " carboxyl ", no matter it is single use or is used in conjunction with other terms, such as " carboxyalkyl ", expression-CO₂H；Term " carbonyl ", no matter it is single use or is used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", represents-(C=O)-.

Term " alkyl amino " includes " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino group independently Ground is substituted by one or two alkyl group.Some of embodiments are that alkyl amino is one or two C_1-6Alkyl connects The alkylamino group of lower level on to nitrogen-atoms.Other embodiment is that alkyl amino is C_1-3Lower level alkyl Amino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but not It is limited to, N- methylaminos, N- ethylaminos, N, N- dimethylaminos, N, N- lignocaines etc..

Term " fragrant amino " represents that amino group is substituted by one or two aromatic yl group, and such example includes, but It is not limited to N- phenylaminos.Some of embodiments are that the aromatic ring in fragrant amino can be further substituted.

Term " aminoalkyl " includes the C substituted by one or more amino_1-10Straight or branched alkyl group.Wherein Some embodiments are that aminoalkyl is the C substituted by one or more amino groups_1-6" aminoalkyl of lower level ", so Example include, but is not limited to, aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.

As described in the invention, the member ring systems formed in substituent one key connection of picture to the ring at center are (such as formula b and formula Shown in c-1, c-2 and c-3) represent substituent any commutable position on ring and can substitute.For example, formula b represents B rings Upper any position that may be substituted, as shown in formula c-1, c-2 and c-3：

Used term is " undersaturated " in the present invention represents to contain one or more degrees of unsaturation in group.

Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded from otherwise Content.

As described herein, term " pharmaceutically acceptable carrier " includes any solvent, decentralized medium, coating agents, Surfactant, antioxidant, preservative (such as antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizing agent, bonding Agent, excipient, dispersant, lubricant, sweetener, flavor enhancement, colouring agent, or its composition, these carriers are all affiliated technologies Known (such as Remington's Pharmaceutical Sciences, the 18th Ed.Mack of art personnel Printing Company, described in 1990, pp.1289-1329).Except any conventional carrier feelings incompatible with active component Outside condition, cover its purposes in treatment or pharmaceutical composition.

" therapeutically effective amount " of term the compounds of this invention refers to that the biology or medicinal response, example of study subject will be triggered Such as reduce or inhibitory enzyme or protein active or improve symptom, relax symptom, slow down or delay progression of disease or prevention disease The amount of used the compounds of this invention.It is applied in some non-limiting embodiments, term " therapeutically effective amount " refers to work as The used amount to the effective the compounds of this invention of the following during study subject：(1) at least partly relax, suppress, prevention And/or improve (i) by disease PI3K imbalance mediations or that (ii) is relevant with PI3K activity or (iii) is characterized by PI3K activity Trouble or illness or disease；Or (2) mitigate or suppressed PI3K activity.In other non-limiting embodiments, " treatment has term Effect amount " refers to when being applied to cell or tissue or non-cellular biological material or medium, at least partly mitigates illness or suppression The amount of the effective the compounds of this invention of PI3K；Or at least mitigate illness to a certain extent or suppress PI3K activity.Term " therapeutically effective amount ", can also be in the same manner using taking office except for illustrating the content of the embodiments above on PI3K What protein/polypeptide/enzyme of his correlation.

Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (slow down or prevent mitigate disease or the development of its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stablizes body Parameter) or above-mentioned two aspects regulation disease or illness.In other embodiments, " treatment " refers to prevention or delay disease or disease Breaking-out, generation or the deterioration of disease.

When term " blocking group " or " PG " refer to a substituent with other reacted with functional groups, commonly used to hinder It is disconnected or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected with amino group to block Or the feature of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyls (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent of base is used for blocking or protecting the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl Blocking group " refers to that the substituent of carboxyl is used for blocking or protect the feature of carboxyl, in general carboxyl-protecting group includes- CH₂CH₂SO₂Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The description of group in general refers to document：T W.Greene,Protective Groups in Organic Synthesis, John Wiley&Sons, New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.

The description of the compound of the present invention

The invention discloses a kind of new compound, kinase activity inhibitor can be used as, can particularly be used as PI3- kinases The inhibitor of activity.Compound as PI3- kinase inhibitors can be used for treatment abnormal with kinases, and particularly PI3- kinases is different Chang Xiangguan disease, such as treating and preventing the disease by PI3- kinases mechanisms mediates.Such disease is included below extremely It is one of few：Breathing problem, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF)；Virus sense Dye, including viral respiratory infection and viral respiratory disease deteriorate, such as asthma and COPD；Non-viral respiratory tract sense Dye, including aspergillosis and leishmaniasis；Allergic diseases, including allergic rhinitis and atopical dermatitis；Autoimmunity Property disease, including rheumatoid arthritis and multiple sclerosis；Inflammatory disease, including inflammatory bowel disease；Angiocardiopathy, including blood Bolt disease and atherosclerosis；Malignant hematologic disease；Nerve degenerative diseases；Pancreatitis；Multiple organ failure；Nephrosis；Platelet aggregation Collection；Cancer；Sperm motility；Graft rejection；Graft rejection；Injury of lungs；And pain, including closed with rheumatoid arthritis or bone Neuralgia, diabetic neuropathy, neuro-inflammatory pain after the scorching related pain of section, backache, systemic inflammatorome pain, liver (wound), trigeminal neuralgia and central pain bitterly.

In some embodiments, the compounds of this invention can be shown swashs to the selectivity of PI3- kinases more than other types Enzyme.

In other embodiments, the compounds of this invention can be as PI3K δ effective inhibitor.

In other embodiments, the compounds of this invention can be shown exceedes other types to PI3K δ selectivity PI3- kinases.

On the one hand, the present invention relates to a kind of compound, it is chemical combination shown in the compound of structure shown in formula (I) or formula (I) The stereoisomer of thing, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug：

Wherein：Each X, Y, R³And R⁴With definition as described in the present invention.

In some embodiments, X C_3-7Heterocyclic radical, C_3-7Heterocyclic radical-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl- C_1-4Alkylidene, include the former molecular heteroaryl of 1,2,3 or 4 be independently selected from O, S and N heteroatomic 5-10 or (5-10 The individual molecular heteroaryl of original)-C_1-4Alkylidene, wherein the X is optionally by 1,2,3,4 or 5 R¹Group is substituted；

Y is

Wherein described Y is optionally by 1,2,3 or 4 R²Group is substituted；

Each R¹And R²It independently is H, D, F, Cl, Br, CN, NO₂, oxo (=O) ,-C (=O) R^a,-C (=O) OR^a,-C (= O)NR^aR^b,-OC (=O) NR^aR^b,-OC (=O) OR^a,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-S (=O)₂R^a,-N (R^c) S (=O)₂R^a,-N (R^c)-(C_1-4Alkylidene)-S (=O)₂R^a, R^bR^aNC (=O)-C_1-4Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-4Alkylidene, R^aOC (=O) N (R^c)-C_1-4Alkylidene, R^bR^aNC (= O)O-C_1-4Alkylidene, R^bR^aNS (=O)₂-C_1-4Alkylidene, R^aS (=O)₂N(R^c)-C_1-4Alkylidene, OR^a, NR^aR^b, R^aO-C_1-4 Alkylidene, R^bR^aN-C_1-4Alkylidene, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8Cycloalkyl-C_1-4Alkylidene, C_3-7Heterocyclic radical, C_3-7Heterocyclic radical-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, include 1,2,3 or 4 independence Heteroatomic 5-10 former molecular heteroaryl or (5-10 former molecular heteroaryl)-C selected from O, S and N_1-4Alkylene Base, wherein each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8Cycloalkyl-C_1-4Alkylidene, C_3-7Heterocyclic radical, C_3-7Heterocyclic radical-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 The individual molecular heteroaryl of original)-C_1-4Alkylidene is independently unsubstituted or is substituted by 1,2,3 or 4 substituent, described to take Dai Ji is independently selected from D, F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；

Each R³And R⁴It independently is H, D, F, CN, NO₂,-C (=O) R^a,-C (=O) OR^a,-C (=O) NR^aR^b, R^bR^aNC (= O)-C_1-4Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-4Alkylidene, R^aOC (=O) N (R^c)-C_1-4Alkylidene, R^bR^aNC (=O) O- C_1-4Alkylidene, R^bR^aNS (=O)₂-C_1-4Alkylidene, R^bS (=O)₂N(R^c)-C_1-4Alkylidene, R^aO-C_1-4Alkylidene, R^bR^aN- C_1-4Alkylidene, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8Cycloalkyl-C_1-4Alkylidene, C_3-7Heterocyclic radical, C_3-7Heterocyclic radical-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, O, S and N are independently selected from comprising 1,2,3 or 4 Heteroatomic 5-10 former molecular heteroaryl or (5-10 former molecular heteroaryl)-C_1-4Alkylidene, wherein described each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8Cycloalkyl-C_1-4Alkylidene, C_3-7Heterocyclic radical, C_3-7Heterocyclic radical-C_1-4 Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 original is molecular Heteroaryl)-C_1-4Alkylidene is independently unsubstituted or is substituted by 1,2,3 or 4 substituent, and the substituent independently selects From D, F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；Or R³, R⁴With with they Connected carbon atom together, forms the former molecular carbocyclic ring of substituted or non-substituted 3-8 or heterocycle；With

Each R^a, R^bAnd R^cIt independently is H, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4It is sub- Alkyl, C_3-6Heterocyclic radical, C_3-6Heterocyclic radical-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, include 1,2,3 or 4 It is independently selected from O, S and N heteroatomic 5-10 former molecular heteroaryl or (5-10 former molecular heteroaryl)-C_1-4 Alkylidene, wherein each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkylidene, C_3-6It is miscellaneous Ring group, C_3-6Heterocyclic radical-C_1-4Alkylidene, C_6-10Aryl, C_6-10Aryl-C_1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 former molecular heteroaryl)-C_1-4Alkylidene is independently unsubstituted or is substituted by 1,2,3 or 4 substituent, institute Substituent is stated independently selected from D, F, Cl, CN, N₃, OH, NH₂, C_1-6Alkyl, C_1-6Haloalkyl, C_1-6Alkoxy or C_1-6Alkyl Amino；Or R^a, R^bTogether with the nitrogen-atoms being connected with them, the former molecular heterocycle of substituted or non-substituted 3-8 is formed.

In other embodiments, X C_3-7Heterocyclic radical includes 1,2,3 or 4 miscellaneous original for being independently selected from O, S and N The former molecular heteroaryl of 5-10 of son, wherein the X is optionally by 1,2,3 or 4 R¹Group is substituted.

In other embodiments, each R¹And R²It independently is H, D, F, Cl, CN, oxo (=O) ,-C (=O) NR^aR^b,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-N (R^c) S (= O)₂R^a,-N (R^c)-(C_1-4Alkylidene)-S (=O)₂R^a, R^bR^aNC (=O)-C_1-4Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-4It is sub- Alkyl, R^bR^aNS (=O)₂-C_1-4Alkylidene, R^aS (=O)₂N(R^c)-C_1-4Alkylidene, OR^a, NR^aR^b, R^aO-C_1-4Alkylidene, R^bR^aN-C_1-4Alkylidene, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8Cycloalkyl-C_1-4Alkylidene, C_3-7Heterocycle Base, C_3-7Heterocyclic radical-C_1-4Alkylidene, phenyl, phenyl-C_1-4Alkylidene is independently selected from the miscellaneous of O, S and N comprising 1,2,3 or 4 The former molecular heteroaryl of 5-6 of atom, wherein each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl, C_3-8Ring Alkyl-C_1-4Alkylidene, C_3-7Heterocyclic radical, C_3-7Heterocyclic radical-C_1-4Alkylidene, phenyl, phenyl-C_1-4Alkylidene and comprising 1,2,3 or 4 former molecular heteroaryls of be independently selected from O, S and N heteroatomic 5-6 are independently unsubstituted or by 1,2,3 or 4 Substituent is substituted, and the substituent is independently selected from D, F, CN, OR^a, NR^aR^b, C_1-3Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene.

In other embodiments, each R³And R⁴It independently is H, D, F, CN ,-C (=O) NR^aR^b, R^bR^aNC (=O)- C_1-2Alkylidene, R^bR^aNC (=O) N (R^c)-C_1-2Alkylidene, R^aOC (=O) N (R^c)-C_1-2Alkylidene, R^bR^aNC (=O) O-C_1-2 Alkylidene, R^bR^aNS (=O)₂-C_1-2Alkylidene, R^bS (=O)₂N(R^c)-C_1-2Alkylidene, R^aO-C_1-2Alkylidene, R^bR^aN-C_1-2 Alkylidene, C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-2Alkylidene, C_3-5Heterocyclic radical, C_3-5It is miscellaneous Ring group-C_1-2Alkylidene, phenyl, phenyl-C_1-2Alkylidene, include 1,2,3 or 4 be independently selected from O, S and N heteroatomic 5 Former molecular heteroaryl or (5 molecular heteroaryls of original)-C_1-2Alkylidene, wherein each C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-2Alkylidene, C_3-5Heterocyclic radical, C_3-5Heterocyclic radical-C_1-2Alkylidene, phenyl, benzene Base-C_1-2Alkylidene, 5 molecular heteroaryls of original and (5 molecular heteroaryls of original)-C_1-2Alkylidene is not taken independently In generation, is substituted by 1,2,3 or 4 substituent, and the substituent is independently selected from D, F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkane Base, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；Or R³, R⁴Together with the carbon atom being connected with them, formed it is substituted or The former molecular carbocyclic ring of non-substituted 3-8 or heterocycle.

In other embodiments, each R^a, R^bAnd R^cIt independently is H, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-6 Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkylidene, C_3-6Heterocyclic radical, C_3-6Heterocyclic radical-C_1-4Alkylidene includes 1,2,3 or 4 independence The heteroatomic 5-10 former molecular heteroaryl selected from O, S and N, wherein each C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynes Base, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-4Alkylidene, C_3-6Heterocyclic radical, C_3-6Heterocyclic radical-C_1-4Alkylidene and 5-10 atom group Into heteroaryl it is independently unsubstituted or substituted by 1,2,3 or 4 substituent, the substituent independently selected from D, F, CN, N₃, OH, NH₂, C_1-3Alkyl, C_1-3Haloalkyl, C_1-4Alkoxy or C_1-4Alkyl amino.

In other embodiments, X is

Wherein described X is optionally by 1,2 or 3 R¹Group is substituted.

In other embodiments, Y is

Wherein described Y is optionally by 1 or 2 R²Group is substituted.

In other embodiments, each R¹And R²It independently is H, F, Cl, CN, oxo (=O) ,-C (=O) NR^aR^b, -N(R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-N (R^c) S (=O)₂R^a, OR^a, NR^aR^b, C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl-C_1-2Alkylidene, C_3-5Heterocyclic radical, C_3-5 Heterocyclic radical-C_1-2Alkylidene, phenyl or phenyl-C_1-2Alkylidene, wherein each C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Ring Alkyl, C_3-6Cycloalkyl-C_1-2Alkylidene, C_3-5Heterocyclic radical, C_3-5Heterocyclic radical-C_1-2Alkylidene, phenyl and phenyl-C_1-2Alkylidene is only On the spot unsubstituted or substituted by 1,2,3 or 4 substituent, the substituent is independently selected from F, CN, OR^a, NR^aR^bOr C_1-3Alkyl.

In other embodiments, each R³And R⁴It independently is H, D, F, CN, C_1-3Alkyl, C_3-6Cycloalkyl, C_3-5It is miscellaneous Ring group or C_3-5Heterocyclic radical-C_1-2Alkylidene, wherein each C_1-3Alkyl, C_3-6Cycloalkyl, C_3-5Heterocyclic radical and C_3-5Heterocyclic radical- C_1-2Alkylidene is independently unsubstituted or is substituted by 1,2,3 or 4 substituent, the substituent independently selected from D, F, Cl, Br, CN, OR^a, NR^aR^b, C_1-6Alkyl, R^aO-C_1-4Alkylidene or R^bR^aN-C_1-4Alkylidene；Or R³, R⁴The carbon being connected with them Atom together, forms the former molecular carbocyclic ring of substituted or non-substituted 3-8 or heterocycle.

In other embodiments, each R^a, R^bAnd R^cIt independently is H, C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6 Cycloalkyl, C_3-5Heterocyclic radical includes 1,2,3 or 4 former molecular heteroaryl of be independently selected from O, S and N heteroatomic 5-6 Base, wherein each C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Cycloalkyl, C_3-5Heterocyclic radical and 5-6 former molecular heteroaryl Base is independently unsubstituted or is substituted by 1,2,3 or 4 substituent, and the substituent is independently selected from F, CN, OH, NH₂, C_1-3Alkyl, C_1-3Haloalkyl, C_1-3Alkoxy or C_1-3Alkyl amino.

In other embodiments, the present invention relates to the compound of one of or its stereoisomer, Geometric isomer, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug, But it is not limited to these compounds：

On the other hand, the purposes the invention provides above-claimed cpd of the present invention in medicine is prepared, wherein the medicine For the kinases of inhibition of phosphatidylinositol3-3 (PI3- kinases) activity, including：Make the presently disclosed of PI3- kinases and effective dose Compound contact；In some embodiments, contact procedure can further comprise the cell of contact expression PI3- kinases；The party In the other embodiment of method, inhibitory action occurs enduring one or more type PI3- kinases obstacle relevant diseases In object.The extremely related disease of one or more type PI3- kinases involved in the present invention includes autoimmune disease, Rheumatic arthritis, respiratory disease, allergic reaction and various types of cancers.

In some embodiments, method of the present invention includes applying therapeutic agent to object.

In other embodiments, disease kinase mediated PI3- is selected from rheumatic arthritis, ankylosing spondylitis, bone Arthritis, psoriatic arthritis, psoriasis, at least one of diseases associated with inflammation and autoimmune disease；Other are implemented In scheme, disease kinase mediated PI3- is selected from angiocardiopathy, atherosclerosis, hypertension, Deep vain thrombosis, in Wind, miocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolysis disease, Acute arterial ischeamia, peripheral thrombus obstruction and At least one of coronary artery disease.In other embodiments, disease kinase mediated PI3- is selected from cancer, colon cancer, Glioblastoma, carcinoma of endometrium, liver cancer, lung cancer, melanoma, kidney, thyroid cancer, lymthoma, lymphoproliferative disorder, In ED-SCLC, prognosis of squamous cell lung cancer, glioma, breast cancer, prostate cancer, oophoroma, cervical carcinoma and leukaemia at least It is a kind of.In other embodiments, disease kinase mediated PI3- is selected from type ii diabetes；In other embodiments, Disease kinase mediated PI3- is selected from breathing problem, bronchitis, at least one of asthma and chronic obstructive pulmonary disease； In other embodiments, study subject is people.

On the other hand, the present invention relates to the treatment of PI3- kinase mediated diseases, the treatment to include any of above reality of administration The step of applying the compound of scheme.

On the other hand, the present invention relates to rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, The treatment of psoriasis, diseases associated with inflammation or autoimmune disease, the treatment include the change of any of above embodiment is administered The step of compound.

On the other hand, the present invention relates to including asthma, COPD (COPD) and idiopathic pulmonary fibrosis (IPF) treatment of breathing problem such as, the step for the treatment of includes the compound of any of above embodiment is administered.

On the other hand, the present invention relates to IBD, inflammatory ocular disease, inflammation or unstable bladder disease, The skin disease of inflammatory component, chronic inflammation, systemic loupus erythematosus (SLE), myasthenia gravis, acute diseminated encephalomyelitis, Idiopathic blood platelet reduction property purpura, multiple sclerosis, Sjogren syndrome and autoimmune hemolytic anemia, mistake The treatment of quick property and pleoergy, described treatment the step of including the compound of any of above and following embodiment is administered.

On the other hand, it is involved in the present invention to be mediated by PI3- kinase activities, swash dependent on PI3- kinase activities or with PI3- The activity of the treatment, especially PI3K δ of the related cancer of enzymatic activity, the treatment include any of above and following embodiment party of administration The step of compound of case.

On the other hand, the present invention relates to the treatment selected from following cancer：Acute myelogenous leukemia, spinal cord development are extremely comprehensive Simulator sickness, myeloproliferative disease, chronic myelogenous leukemia, T cell ALL, B cell acute lymphoblastic are white Blood disease, NHL, B cell lymphoma, solid tumor and breast cancer, it is any of above and following that the treatment includes administration The step of compound of embodiment.

On the other hand, the present invention relates to the compound of any of above embodiment as the application in terms of medicine.

On the other hand, the present invention relates to the compound of any of above embodiment PI3- kinase mediated diseases curative The application of thing manufacture view.

On the other hand, the present invention relates to the compound of any of above embodiment to prepare treatment rheumatoid arthritis, Ankylosing spondylitis, osteoarthritis, psoriatic arthritis, psoriasis, diseases associated with inflammation, including asthma, COPD Disease breathing problem, autoimmune disease and the cancer such as (COPD) and idiopathic pulmonary fibrosis (IPF).

Unless otherwise indicated, the present invention relates to the stereoisomer of all the compounds of this invention, geometric isomer, mutually variation Structure body, solvate, hydrate, metabolite, salt and pharmaceutically acceptable prodrug.

In some embodiments, the salt refers to pharmaceutically acceptable salt.Term " pharmaceutically acceptable " refers to Material or composition must be with other compositions comprising preparation and/or with the mammals of its treatment chemically and/or toxicology It is upper compatible.

The compound of the present invention also includes other salt of such compound, and other salt are not necessarily pharmaceutically acceptable Salt, and may be used as the compound for preparing and/or purifying the present invention and/or the compound for separating the present invention The intermediate of enantiomer.

Pharmaceutically useful acid-addition salts can be formed with inorganic acid and organic acid, such as acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Thing/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.

The inorganic acid of salt can be obtained by its derivative to be included such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.

The organic acid of salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, butanedioic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..

Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.

The inorganic base that salt can be obtained by its derivative includes, such as the metal of the I races of ammonium salt and periodic table to XII races. In some embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.

The organic base of salt can be obtained by its derivative includes primary amine, secondary amine and tertiary amine, the amine of substitution including naturally occurring Substituted amine, cyclic amine, deacidite etc..Some organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.

The officinal salt of the present invention can be synthesized with conventional chemical processes by parent compound, alkalescence or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate etc.) reaction, or by counting the free alkali form of these compounds and chemistry It is prepared by the suitable acid reaction of amount amount.Such reaction is generally carried out in water or organic solvent or the mixture of the two.One As, in appropriate cases, it is necessary to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.In example As " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts：Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the suitable salt of other can be found in.

Moreover, the compounds of this invention including its salt can also be obtained with its hydrate forms, or it is used for it including other The solvent of crystallization.The compounds of this invention can form the solvation with acceptable solvent (including water) inherently or by designing Thing；Therefore, the invention is intended to including solvation and unsolvated form.

The compounds of this invention might have the shape of several asymmetric centers or generally described raceme mixture Formula.The present invention further includes racemic mixture, the mixture of partial racemization and isolated enantiomer and non-right Reflect body.

The compound of the present invention can be with possible isomers, rotational isomer, atropisomer, dynamic isomer A kind of form or the form of its mixture are present, and the present invention can further include isomers, rotational isomer, resistance turn isomery The mixture of body, dynamic isomer, or the part mixes of isomers, rotational isomer, atropisomer, dynamic isomer Or isomers, rotational isomer, atropisomer, the dynamic isomer separated.

Any structural formula that the present invention provides is also intended to the form and isotope mark for representing that these compounds are not labeled The form of note.The structure that the formula that there is the compound of isotope marks the present invention to provide is described, except one or more atoms Replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention include Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, the isotope of fluorine and chlorine, such as²H,³H,¹¹C,¹³C,¹⁴C,¹⁵N,¹⁸F,³¹P,³²P,³⁶S,³⁷Cl or¹²⁵I。

On the other hand, compound of the present invention includes the compound defined in the present invention of various isotope marks, For example, radio isotope wherein be present, such as³H,¹⁴C and¹⁸F those compounds, or non radioactive isotope wherein be present, Such as²H and¹³C.The compound of such isotope marks can be used for metabolism research (to use¹⁴C), Reaction kinetics research (use example Such as²H or³H), detection or imaging technique, surveyed such as positron emission tomography (PET) or including medicine or substrate tissue distribution Fixed single photon emission computed tomography (SPECT), or available in the radiotherapy of patient.¹⁸The compound pair of F marks It is especially desirable for PET or SPECT researchs.Formula (I) compound of isotope marks can pass through those skilled in the art Known routine techniques or embodiment in the present invention and preparation process are described is substituted using suitable isotope labeling reagent Originally prepared by used unmarked reagent.

In addition, higher isotope particularly deuterium is (i.e.,²H or D) substitution some treatment advantages can be provided, these advantages are Brought by metabolic stability is higher.For example, Half-life in vivo increase or volume requirements reduce or therapeutic index obtains improving band Come.It should be appreciated that the deuterium in this context is seen as the substituent of formula (I) compound.Isotope enrichment factor can be used To define the concentration of such higher isotope particularly deuterium.Term " isotope enrichment factor " used in the present invention refers to meaning Determine the ratio between the isotope abundance of isotope and natural abundance.If the substituent of the compounds of this invention is designated as deuterium, The compound has at least 3500 (at each specified D-atoms 52.5% deuterium incorporation), at least for each D-atom specified 4000 (60% deuterium incorporations), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% deuterium incorporations), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporations), at least 6466.7 The isotope enrichment of (97% deuterium incorporation), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuterium incorporations) The factor.The pharmaceutically useful solvate of the present invention includes such as D that wherein recrystallisation solvent can be isotope substitution₂O, acetone-d₆、 Or DMSO-d₆Those solvates.

The composition of the compound of the present invention, preparation and administration

On the one hand, the compound shown in formula (I), the change listed by the present invention are included the characteristics of pharmaceutical composition of the invention Compound, or embodiment 1-65 compound, and pharmaceutically acceptable carrier, assistant agent or excipient.In the composition of the present invention The amount of compound can effectively, detectably suppress biological sample or the protein kinase of patient's body.

The compound of the present invention exists in a free form or in the form of suitable, pharmaceutically acceptable derivates.Pharmacy Upper acceptable derivates include, but is not limited to, pharmaceutically acceptable prodrug, salt, ester, esters salt, can directly or Be grounded be administered according to needs of patient other any adducts or derivative, the present invention other in terms of described by compound or Their metabolite or residue.

As described in the invention, pharmaceutical composition of the present invention or pharmaceutically acceptable composition further wrap Containing pharmaceutically acceptable carrier, assistant agent or excipient, applied as of the invention, including be suitable for distinctive target formulation , any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickener, emulsifying agent, Preservative, solid binder or lubricant, etc..As described in documents below：Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy, Lippincott Williams& Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J. Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, document above disclosure with It is for reference that its full text is incorporated in the present invention.Literature cited is described for preparing pharmaceutically acceptable composition not herein Preparation method known to same carrier and composition.Except the conventional carrier medium incompatible with the compound of the present invention, such as Bad biological effect can be produced or harmful interaction occurs with any other component in pharmaceutically acceptable composition, Other any conventional carrier mediums and their purposes are also the scope that the present invention is considered.

The pharmaceutical composition of the present invention can prepare and be packaged as form in bulk, wherein can extract out safely, effectively agent Compound or its pharmaceutically acceptable salt shown in the formula (I) of amount, patient can be administered in the form of powder or syrup.Or Person, pharmaceutical composition of the present invention can be prepared or be packaged in unit dosage forms, wherein, each unit dosage forms are containing shown in formula (I) Compound or its pharmaceutically acceptable salt.When being prepared into unit dosage forms, pharmaceutical composition of the invention usually contains 0.5mg To the compound or its pharmaceutically acceptable salt shown in 1g or 1mg to 700mg or 5mg to 100mg formula (I).

The pharmaceutical composition of the present invention is typically containing the compound or its pharmaceutically acceptable salt shown in formula (I).

Term " pharmaceutically acceptable excipient " in the present invention refers to and given pharmaceutical composition shape or compatibility Pharmaceutically acceptable material, composition or carrier.In mixing, every kind of excipient must be with other in pharmaceutical composition Component is compatible, so as to avoid when giving patient, the effect of substantially reducing the compounds of this invention or its pharmaceutically acceptable salt And cause the interaction of pharmaceutically unacceptable composition.In addition, every kind of excipient must all have sufficiently high purity So that it is pharmaceutically acceptable.Compound or its pharmaceutically acceptable salt shown in formula (I) and pharmaceutically acceptable Excipient or assistant agent, it is usually formulated as being applied to giving the formulation with patient by required method of administration.For example, suitable for The formulation of lower method of administration：(1) be administered orally, as tablet, capsule, caplet agent, pill, containing tablet, pulvis, syrup, elixir, Supensoid agent, solution, emulsion, sachet and sachet；(2) parenteral, as sterile solution agent, supensoid agent and for redissolution Pulvis；(3) percutaneous dosing, such as transdermal patch；(4) rectally, such as suppository；(5) inhalation, as aerosol, solution and Dry powder doses；(6) local administration, such as cream, ointment, washing lotion, solution, paste, spray, foaming agent and gel.

Suitable pharmaceutically acceptable excipient will be different regarding selected specific formulation.In addition, them can be directed in group The specific function played in compound selects suitable pharmaceutically acceptable excipient.For example, it can help to give birth to according to them Produce the ability of equal one dosage type low temperature and select some pharmaceutically acceptable excipient.Them can be directed to when giving patient, contributed to The compounds of this invention or its pharmaceutically acceptable salt are carried or transported from an organ of human body or partly to the another of human body Individual organ or partial ability select some pharmaceutically acceptable excipient.Them, which can be directed to, strengthens the energy of patient compliance Power selects some pharmaceutically acceptable excipient.

Suitable pharmaceutically acceptable excipient includes following kind of excipient：Diluent, filler, adhesive, Disintegrant, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweetener, rectify Taste agent, odor mask, colouring agent, anticaking agent, NMF, chelating agent, plasticiser, tackifier, antioxidant, preservative, stably Agent, surfactant and buffer.It would be recognized by those skilled in the art that some pharmaceutically acceptable excipient can play it is more In a kind of function, and alternative function can be played, this depends on what be present in the presence of how much excipient and preparation in the formulation Kind other compositions.

Those skilled in the art grasp the knowledge and technology of this area so that they can be selected for the appropriate of the present invention Amount, suitable, pharmaceutically acceptable excipient.In addition, those skilled in the art be able to can pharmaceutically connect from many descriptions The place for the excipient received obtains resource, and available for the suitable pharmaceutically acceptable excipient of selection.Such as： Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。

Pharmaceutical composition of the present invention is prepared using technique well known by persons skilled in the art and method.Commonly used in the art Certain methods refer to： Remington's Pharmaceutical Sciences(Mack Publishing Company).

On the other hand, prepared the present invention relates to one kind comprising the compound shown in a formula (I) or its is pharmaceutically acceptable Salt and one or more pharmaceutically acceptable excipient containing blending ingredients pharmaceutical composition method.It is this to include The pharmaceutical composition of compound or its pharmaceutically acceptable salt shown in one formula (I) can be made under room temperature, condition of normal pressure It is standby to obtain.

In some embodiments, the compound shown in formula (I) or its pharmaceutically acceptable salt be prepared to orally to The formulation of medicine.In other embodiments, the compound shown in formula (I) or its pharmaceutically acceptable salt are prepared to suck The formulation of administration.In other embodiments, the compound shown in formula (I) or its pharmaceutically acceptable salt are prepared to fit In the formulation of nasal-cavity administration.

On the one hand, the present invention relates to solid oral administrations formulation, such as：Tablet or capsule, it is included safely, effectively Compound or its pharmaceutically acceptable salt, diluent or filler shown in the formula (I) of dosage.Suitable diluent and fill out Filling agent includes：(e.g., cornstarch, potato starch and pregel form sediment for lactose, sucrose, glucose, mannitol, D-sorbite, starch Powder), calcium sulfate, calcium monohydrogen phosphate.Oral dosage form can also further include adhesive.Suitable adhesive includes starch (e.g., cornstarch, potato starch and pregelatinized starch), gelatin, Arabic gum, sodium alginate, alginic acid, tragacanth, melon That glue, PVP, cellulose and their derivative (e.g., microcrystalline cellulose).Oral dosage form can also include disintegrant. Suitable disintegrant, include PVPP, sodium starch glycolate, cross-linked carboxymethyl cellulose, alginic acid, carboxymethyl cellulose Plain sodium.Oral solid dosage formulation, lubricant can also be included.Suitable lubricant includes magnesium stearate, calcium stearate, tristearin Acid and talcum powder.

If appropriate, microencapsulation can be carried out to the dosage unit preparations of oral administration.By the way that particulate matter is coated Or be embedded in polymer, wax etc., it can extend or control the release of the pharmaceutical composition.

Compound or its pharmaceutically acceptable salt shown in formula (I) can also be with the solubilities as target medicine carrier Polymer is coupled.Suitable polymer includes：PVP, pyran co-polymer, poly- hydroxypropyhnethacrylamide- Cascophen, polyhydroxyethylaspart or the polyoxyethylene poly-D-lysine substituted by palmitic acid residues.In addition, Compound or its pharmaceutically acceptable salt shown in formula (I) can also with a series of achievable controlled release drug administrations, can biology drop The polymer of solution is combined.Such as：PLA, polycaprolactone, multi-hydroxybutyrate, poe, polyacetals, poly- dihydropyran, The crosslinking of polybutylcyanoacrylate and hydrogel or amphiphilic block copolymer.

On the other hand, the present invention relates to liquid oral form of administration.Liquid oral dosage form, such as：Solution, syrup, Elixir, can be made in a unit, in such a given metering containing the compounds of this invention of scheduled volume or its Pharmaceutically acceptable salt.Syrup is that the compounds of this invention or its pharmaceutically acceptable salt are dissolved in into suitably seasoned water It is made in solution, and elixir is made by using nontoxic alcoholic vehicle.Supensoid agent is by the compounds of this invention or its pharmacy Upper acceptable salt suspension is made in non-toxic carrier.Can also add solubilizer and emulsifying agent such as ethoxylated isostearyl alcohol and Polyoxyethylene sorbitol ether, preservative, flavor enhancement such as peppermint oil, natural sweetener or saccharin or other artificial sweetening agents etc..

On the other hand, the present invention relates to it is a kind of can to patient carry out inhalation formulation, as dry powder doses, aerosol, Supensoid agent or liquid composite.In some embodiments, the present invention relates to can to patient carry out inhalation formulation, such as Dry powder doses.In other embodiments, the present invention relates to carry out inhalation in aerosol to patient.Pass through suction Mode contain the compounds of this invention or its pharmaceutically acceptable salt of fine powder form to the dry powder composite of pulmonary administration With one or more pharmaceutically acceptable excipient of fine powder form.To those skilled in the art, it is particularly suitable The pharmaceutically acceptable excipient used in dry powder doses includes, lactose, starch, mannitol, monose, disaccharides or polysaccharide.Point Dissipating good powder can be obtained by way of micronized and grinding.In general, size reduces (such as micronized) chemical combination The size of thing is by D₅₀Value limits, about 1 to 10 microns (for example, being measured with laser diffractometry).

Described dry powder patient can be administered by the inhalator (RDPI) of reservoir dry powder, and the inhalator, which has, is suitable to storage Deposit (non-dosing) drug reservoir of multiple dry powder forms.RDPI generally include to measure from storage each drug dose to The equipment of medicine position.For example, the measuring equipment can include jigger, it can be moved to the second place from first position, At first position, jigger can be full of the medicine from storage, and in the second place, the drug dose measured can be by patient Suction.

Or described dry powder can be stored in capsule (e.g., gelatin or plasthetics), cartridge case or blister pack So that multidose dry powder inhaler (MDPI) uses in (blister packs).MDPI is inhalator, and wherein medicine is comprised in Containing (or carry) multiple limiting doses (or part thereof) in the multiple-unit container of medicine.When described dry powder is with blister pack Form in the presence of, it includes multiple bubble-caps (blister) containing dry powder form medicament.Typically, described bubble-cap is with rule Mode arranges, and discharges medicine therefrom to facilitate.For example, described bubble-cap can generally be arranged in collar plate shape bubble in a circular manner In cover packaging, or described bubble-cap can be elongated, such as including strip or banding.Each capsule, cartridge case or bubble-cap can examples The compounds of this invention or its pharmaceutically acceptable salt such as containing 20 μ g-10mg.

Aerosol can be promoted by by the compounds of this invention or its pharmaceutically acceptable salt, being suspended or dissolved in liquefaction Prepared in agent.Suitable propellant includes halogenated hydrocarbons, hydro carbons and other liquefied gases.Representational propellant includes： Arcton 11 (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), HFC-134a (HFA-134a), 1,1- Difluoroethanes (HFA-152a), dichloromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, perfluorinated butane, perflenapent, butane, iso-butane and pentane.Comprising the compounds of this invention or its Patient is administered typically via quantitative pressure inhalator (MDI) for the aerosol of pharmaceutically acceptable salt.These devices are these Known to art personnel.

Aerosol can excipient pharmaceutically acceptable containing other, being typically used together with MDI such as surface work Property agent, lubricant, cosolvent and other excipient, to improve the physical stability of preparation, improve valve performance, improve dissolving Degree improves taste.

Therefore, the invention provides the medicinal aerosol as another aspect of the present invention, it includes chemical combination of the present invention Thing or its pharmaceutically acceptable salt and fluorocarbon, hydrogeneous CFC are as propellant, optional and surfactant And/or cosolvent is combined.

According to another aspect of the present invention, the invention provides a kind of medicinal aerosol, propellant to be selected from 1,1,1,2- tetra- Fluoroethane, 1,1,1,2,3,3,3- seven fluorine n-propane and their mixture.

The preparation of the present invention can also add suitable buffer buffering.

For sucking or being blown into the capsule and cartridge case of administration, such as gelatina, can be configured to containing the powder suitable for suction The preparation of mixture, the mixture of powders include the compounds of this invention or its pharmaceutically acceptable salt and suitable mealiness base Matter, such as lactose or starch.Each capsule and cartridge case usually contain 20 μ g-10mg the compounds of this invention or its is pharmaceutically acceptable Salt.In addition, capsule or cartridge case can comprise only the compounds of this invention or its pharmaceutically acceptable salt and be free of other figurations Agent such as lactose.

The ratio of reactive compound of the present invention or its pharmaceutically acceptable salt in topical composition depends on institute The specific formulation prepared, ratio as a rule used is in the range of 0.001-10% weight ratio.Typically for most of doses Suitable proportion used in type is from 0.005%-1%, such as is in the range of 0.01%-0.5% in some embodiments. But ratio used in the powder in inhalant and insufflation is in the range of 0.1%-5%.

It is the unit metered dose of aerosol or " penetrating " dosage is contained 20 μ g- that the preferable dosage of aerosol, which is formulated, 10mg, the preferably approximately salt of 20 μ g-500 μ g the compounds of this invention or its pharmaceutical acceptable.Administration can be one day one It is secondary or one day for several times, such as 2,3,4 or 8 times, administration every time is such as 1,2 or 3 unit dose.The total daily dose of aerosol is 100 μ g-10mg, preferably in the range of 200 μ g-2000 μ g.Capsule or cartridge case are total to suck or be blown into the day of administration release Dosage and metered dose are generally twice in the dosage of aerosol.

In suspension aerosol, the granule size of particle (such as particulate) should meet with aerosol form inhalation Afterwards, whole medicines can enter lung；Therefore, particle diameter should be less than 100 microns, and preferably particle diameter is less than 20 microns, especially It is particle diameter in 1-10 microns, such as 1-5 microns, preferably particle diameter is in the range of 2-3 microns.

The formulation of the present invention can by appropriate containers by medicine and the compounds of this invention or its is pharmaceutically acceptable Salt be dispersed or dissolved in propellant and prepare, such as aided in using sonication or high-shear mixer.This was prepared Journey will be carried out in the environment of control air humidity.

The chemistry of aerosol of the present invention, physical stability and acceptability pharmaceutically can be by those skilled in the art Determined using techniques well known.For example, compound, after long-term storage, stability can be analyzed by HPLC and determined. Physical stability data can be obtained by other conventional analysis test methods, for example, being commented by leak test, valve for medicine Fixed (opening the weight averagely discharged every time), dose reproducibility evaluation (opening the active principle discharged every time) and spray Distributional analysis.

The stability of the suspension aerosol of the present invention can be determined by routine techniques, for example, by measuring floccules Degree distribution, using back-illuminated light scattering apparatus or by measuring particle size distribution, by colliding step by step (cascade impaction) Or " binary collision " (twin impinger) assay." binary collision " determination method of the present invention refers to that " use device A exists In pressurizing vessel measure eject medicament precipitation ", this definition is shown in British Pharmacopoeia 1988, the A204-207 pages, annex XVII C.This technology can calculate the inhalable particle part in aerosol.One kind is used to calculate inhalable particle Method be this is using above-mentioned " binary collision " by " fine grained classification " method, open every time from collision cell collective low to Active component amount, be expressed as opening the percentage of the active component total amount ejected every time.

Term " metered dose inhaler " or MDI refer to a combination, include a tank, the protection cap covered in tank, a He Gai Formula metering valve on son.MDI systems include suitable transfer device.Suitable transfer device includes, and such as a valve drives Device, a cylindric or coniform passage, patient can be delivered to by metering valve from filling tank by this passage medicine Nose or face in, such as blow gun actuator.

MDI tanks generally comprise a container that can bear propellant vapour pressure, e.g., plastics or plastic-faced vial Preferably metal can, for example, aluminium pot, or aluminium alloy can, it can be by anodization, varnish application and/or plastics Coating, (for example, introducing bibliography patent WO 96/32099 herein, which part or all inner surfaces are coated with one Or multiple fluorocarbon polymers and one or more non-fluorocarbon polymers), container metering jam pot cover mouth.Lid can be by super The mode that sound wave welding, screw are fixed or crimped is fixed on tank.MDI (dose inhaler) shown in this article can pass through this area (referenced patent WO96/32099) is made in known method.Preferably, it is furnished with lid on cartridge case, wherein, medication dosing valve is positioned at lid On son, described lid is crimped on cartridge case.

In some embodiments of the present invention, one layer of fluoropolymer is coated by the metallic interior surface of tank, more preferably, Coating is the mixture of fluoropolymer and non-fluorinated polymer.In other embodiments of the present invention, the metallic interior surface of tank Copolymer mixture coated with polytetrafluoroethylene (PTFE) and polyethersulfone resin.In other embodiments, table in the whole metal of tank Face is each coated with the copolymer mixture of polytetrafluoroethylene (PTFE) and polyethersulfone resin.The design of metering valve is intended to open every time and can all provided The formulation of metering, and contain a packing ring for preventing propellant from being leaked at valve.Packing ring can include any suitable bullet Property material, such as low density polyethylene (LDPE), chlorobutyl, brombutyl, ethylene propylene diene rubber, the butadiene-acrylonitrile of black or white Rubber, butyl rubber and neoprene.Suitable valve can be from purchase obtains at manufacturer known to aerosol industry, such as Valois, French (such as DF10, DF30, DF60), Bespak pic, Britain such as (BK300, BK357) and 3M-TM Neotechnic Ltd, Britain (such as Spraymiser).

In various embodiments, metered dose inhaler can also be used for being incorporated in other structures, such as, but not limited to, be used for Storage, the external packing box comprising metered dose inhaler, specifically may be referred to United States Patent (USP) US 6, and 119,853,6,179,118,6, 315,112,6,352,152,6,390,291, and 6,679,374, the patent related to batching counter also has but is not limited to, United States Patent (USP) US 6,360,739 and 6,431,168.

Medicinal aerosol can be used to manufacture conventional batch production method well known to those skilled in the art and equipment to carry out The large-scale production of wound packages medicine.Thus, for example in a kind of method for producing suspension aerosol in batches, metering valve is crimped on Empty cylinder is formed on one aluminium pot.Granulated drug is fitted into filling container, and suitable excipient and liquefied propellant are passed through Filling container pressurization is filled with manufacture container.Drug suspension is mixed before filling machine circulation is entered, by aliquot Drug suspension be filled with by metering valve in cylinder.In the embodiment of other batch production Liquid Aerosols, it will measure Valve, which is crimped on an aluminium pot, forms empty cylinder.The medicine of dissolving is fitted into filling container, and by suitable excipient and liquefied Propellant is filled with manufacture container by filling container pressurization.

In process of production, the liquid preparation per equal portions is added in the container of opening at temperature cold enough, with true Protect preparation will not evaporation loss, after powder charge again by metering valve crimping to the container.

Generally, in the producing by batch of medicine, the cylinder of each filling is examined, weighed, stamps lot number, before release test It is fitted into disk and deposits.Suspension and solution containing the compounds of this invention or its pharmaceutically acceptable salt can also pass through spraying Patient is administered device.Solvent or suspension for atomization are all pharmaceutically acceptable liquid, such as water, salting liquid, alcohol or two First alcohol, such as ethanol, isopropanol, glycerine, propane diols, polyethylene glycol or their mixture.In salting liquid salt used be to There is no or has the salt of seldom pharmacological activity after medicine.Organic salt, such as alkali metal salt or ammonium halide salt, such as sodium chloride, potassium chloride Or organic salt, such as potassium, sodium and ammonium salt and organic acids such as ascorbic acid, citric acid, acetic acid, tartaric acid may be used to this mesh 's.

Other pharmaceutically acceptable excipient can also be used in suspension or solution.The compounds of this invention or its pharmaceutically The stability of acceptable salt, can be by adding inorganic acid such as hydrochloric acid, nitric acid, sulfuric acid and/or phosphoric acid；Organic acid such as Vitamin C Acid, citric acid, acetic acid, tartaric acid etc., complexometric reagent such as EDTA or citric acid and its salt, or antioxidant such as vitamin E and anti- Bad hematic acid.In the formulation, above excipient can be used alone or together can pharmaceutically be connect with stablizing the compounds of this invention or its The salt received.Preservative such as benzalkonium chloride, benzoic acid and its salt can also be added in preparation.Especially, surface-active can be added Agent is used for the physical stability for improving suspending agent.Surfactant such as, lecithin, dioctyl sulfo-succinic acid disodium, oleic acid and Sorbitan ester.

Another aspect of the present invention is related to the formulation of intranasal administration.

The formulation of intranasal administration includes giving the pressurized aerosol formulation and aqueous solution preparation of nose by force (forcing) pump.It is non-pressurised And gained a special interest suitable for the preparation of intranasal administration.For this purpose, suitable preparation is to be used as diluent or load using water Body.The conventional excipients that the liquid dosage form of preparation lung or intranasal administration uses have buffer, tension regulator etc..Aqueous solution system Agent can also be by Neulized inhalation to intranasal administration.The compounds of this invention or its pharmaceutically acceptable salt can be configured to using stream The liquid preparation of body distributor transmission administration, fluid distributor contains a distribution nozzle and aperture, when the power that user applies When being applied to the pump configuration of fluid distributor, the liquid preparation of dosing is distributed by distributing nozzle or dispensing aperture.This Kind fluid distributor is generally provided with accommodating the storage tank of multiple dosing liquid preparations, and dosage can pass through the action point of continuous pump Match somebody with somebody.Configurable distribution nozzle or aperture to insert in user nostril, for by liquid preparation spray distribution into nasal cavity.It is foregoing to carry And fluid distributor be the type illustrated in patent WO05/044354, entire contents are incorporated in the present invention by quoting.Should Distributor has the housing for accommodating fluid discharging apparatus, and fluid discharging apparatus, which includes, to be arranged on the container for accommodating liquid preparation Force (forcing) pump.Housing have it is at least one can finger manipulation side lever, the side lever can move inward relative to housing, with cam band Container in dynamic housing is upward, and the preparation of dosing is pumped out into pump rod by the nose nozzle of housing so as to cause pump pressure to contract (stem).Especially preferred fluid distributor is the general type illustrated in patent WO05/044354 Figure 30-40.

It is suitable for the pharmaceutical composition of intranasal administration, carrier therein is solid, including particle diameter is for example in 20-500 microns Corase meal；It can be administered in such a way, powder fills in a reservoir, holds close to nasal cavity, quick by nasal passage Suction.Suitable composition, the aqueous solution or oil solution comprising the compounds of this invention or its pharmaceutically acceptable salt, wherein carrying Body is liquid, is administered using nasal spray or is administered as nasal drop.

It is adapted to the pharmaceutical composition of percutaneous dosing can be used with the patch form of separation, for close with the epidermis of patient Contact one section of longer time.For example, the discharge active component from paster can be penetrated into by ion, its common description is shown in Pharmaceutical Research,3(6),318 (1986)。

Ointment, emulsion, suspension, washing lotion, pulvis, molten can also be configured to suitable for the pharmaceutical composition being locally administered Liquid, paste, gel, spray, aerosol or finish.Ointment, emulsion and gel can use water or oleaginous base plus conjunction Suitable thickener and/or gel are prepared.Matrix such as atoleine, for example poly- second of vegetable oil such as peanut oil, castor oil or solvent Glycol.Thickener and gel will be selected according to the property of matrix, include paraffin, aluminum stearate, hexadecanol and octadecyl alcolol Mixture, polyethylene glycol, lanolin, beeswax, the derivative and/or glycerin monostearate of carbopol and cellulose, and/ Or nonionic emulsifier.

Lotion can use water or oleaginous base to prepare, and typically contain one or more emulsifying agents, stabilizer, disperse Agent, suspending agent or thickener.

External powder agent needs to add suitable powdered substrate, such as talcum powder, lactose or starch when preparing.Dropping liquid is matched somebody with somebody System typically uses water or non-aqueous base, additionally containing one or more dispersants, chaotropic agent, suspending agent or preservative.

The preparation of local application can daily to affected part in single or divided doses, use impermeable plastic wound dressing in skin affected part.Even Continuous, long-term administration can be realized by pasting drug-reservoir.

The pharmaceutical composition for treating eye or other outside organizations such as face, skin can be with local application's cream and breast The form application of agent.When being configured to ointment, the compounds of this invention or its pharmaceutically acceptable salt can use paraffin or can be with The miscible ointment bases of water.In addition, the compounds of this invention or its pharmaceutically acceptable salt can use oil-in-water or Water-In-Oil Substrate preparation into emulsion.

Pharmaceutical composition for parenteral includes water and non-aqueous sterile injection liquid, its can contain antioxidant, Buffer solution, bacteriostatic agent and solute, it causes the preparation and the isotonic and aqueous and anhydrous nothing of the blood of specified recipient Bacterium suspension can contain suspending agent and thickener.Described composition can be such as close in unit dose or multi-dose container Deposit, and can be stored in lyophilized (freeze-drying) condition in the ampoule and medicine bottle of envelope, it only needs immediately to add before use Enter sterile liquid carrier, such as water for injection.Extemporaneous injection solutions and suspension can be by sterile powder, granula and tablet systems It is standby.

The compound and pharmaceutical composition of the present invention can be with one or more other therapeutic agents use in conjunction, the treatment Agent is selected from antiinflammatory, anticholinergic drug (particularly M1/M2/M3 receptor antagonists), β₂- 3 adrenergic receptor agonists, resist Infectious agent, such as antibiotic or antivirotic or antihistamine.The present invention further provides a kind of composition, and it includes a kind of formula (I) compound shown in or its pharmaceutically acceptable salt and one or more other active therapeutic agents, the active therapeutic agent Selected from anti-inflammatory agent, such as steroidal anti-inflammatory drugses, non-steroid anti-inflammatory drug, anticholinergic drug, β₂- 3 adrenergic receptor agonists, Anti-infective such as antivirotic or antiseptic, or antihistamine.Another aspect of the present invention is related to some compositions, and it includes formula (I) compound shown in or its pharmaceutically acceptable salt, and β₂- 3 adrenergic receptor agonists, anticholinergic drug and/or PDE-4 inhibitor and/or antihistamine.

In some embodiments, the present invention includes a kind of the compounds of this invention safe to use, effective dose or its pharmacy Upper acceptable salt and one or more active therapeutic agents, the method for disease extremely related treatment PI3K.

Some specific compounds of the present invention have the selectivity better than other PI3K to PI3K δ.Therefore, it is of the invention another On the one hand a kind of pharmaceutical composition is provided, it includes the compound or its medicine that act on shown in PI3K δ formula (I) of selectivity Receivable salt and other PI3K are acted on, the compound or its pharmaceutical acceptable as shown in PI3K γ formula (I) Salt.

On the other hand, the present invention also includes composition, and it includes one or two kinds of other therapeutic agents.

To those skilled in the art, situations below is clear, i.e.,：In appropriate circumstances, other therapeutic agents Can be the form such as alkali metal salt, ammonium salt of salt, or the salt as sour addition, or the form of prodrug, or the form of ester Such as lower alkyl esters, or the form of solvate for example optimizes activity and/stability and/or physical characteristic, as dissolubility, The hydrate of therapeutic component.Following situation is equally clear, i.e., in appropriate circumstances, active therapeutic ingredient is with optics Pure form application.

In some embodiments, the present invention provides a kind of product, and it includes the chemical combination shown in formula (I) as combination preparation Thing and at least one other therapeutic agents, contained composition are used to treat simultaneously, respectively or successively.In other embodiments In, what is treated is the disease or illness extremely related to PI3K.Product as combination preparation includes composition, the combination Thing contains the compound and other therapeutic agents shown in the formula (I) of the present invention in identical pharmaceutical composition, or containing independent Formula (I) of the present invention shown in compound and other therapeutic agents, such as in the form of medicine box.

In some embodiments, the present invention provides a kind of pharmaceutical composition, and it includes the compound shown in formula (I) and its His therapeutic agent.Optionally, described pharmaceutical composition can also include above-described pharmaceutically acceptable carrier.

In some embodiments, present invention additionally comprises a kind of medicine box, it contains two or more single drug regimens Thing, wherein at least one composition contain the compound shown in formula (I) of the present invention.In other embodiments, medicine box includes For depositing the different utensils of described various pharmaceutical compositions, such as container, separated bottle or separated paper tinsel bag respectively. Such example is blister package.It is generally used for package troche, capsule etc..

The medicine box of the present invention, available for different formulations, such as orally and parenterally formulation, for difference Spacing of doses applies single composition, or is stepped up single composition for another kind relatively.In order to increase compliance, The medicine box of the present invention generally all contains operation instruction.

In the therapeutic alliance of the present invention, the compounds of this invention and other therapeutic agents can be by identical or different factories Family prepares or prepared.Moreover, the compounds of this invention and other therapeutic agents can be collectively incorporated into a therapeutic combination：(i) exist Before combination product is issued into doctor (such as medicine box containing the compounds of this invention and other therapeutic agents) (ii) Before administration is faced, (iii) is carried out by doctor oneself (or in the case where doctor instructs) and carried out by patient oneself, such as is being applied successively During the compounds of this invention and other treatment.

Correspondingly, it is abnormal in treatment PI3K the invention provides compound shown in formula (I) or its pharmaceutically acceptable salt Purposes in related disease or illness, medicine therein are prepared for being co-administered with other therapeutic agents.The present invention also carries The purposes for the other therapeutic agents for treating the extremely related diseases of PI3K or illness is supplied, wherein described medicine and formula (I) compound is co-administered.

It is used for the use for treating the extremely related diseases of PI3K or illness present invention also offers the compound shown in formula (I) On the way, the compound wherein shown in formula (I) and other therapeutic agents are prepared to the preparation for combined administration.Present invention also offers Other therapeutic agents are used for the purposes for treating the extremely related diseases of PI3K or illness, wherein described other therapeutic agents and the present invention Compound shown in formula (I) is prepared to the preparation for combined administration.

Present invention also offers purposes of formula (I) compound in treatment PI3K extremely related disease or illness, wherein Patient previously with other therapeutic agents treated by (such as in 24 hours).Present invention also offers other therapeutic agents to exist The purposes in PI3K extremely related disease and illness is treated, wherein previously (such as in 24 hours) use formula (I) to patient Shown compound is treated.Compound shown in formula (I) as unique active component or with other assistant agents or medicine It is used cooperatively, wherein assistant agent or medicine such as immunodepressant, immunomodulator or other antiinflammatories, same for treating or preventing Kind or the acute or chronic rejection of heterograft or the medicine of inflammation or autoimmune disease, or chemotherapeutant, such as Malignant cell antiproliferative.For example, the compound shown in formula (I) of the present invention is applied jointly with neural pherylarsin oxide With for example, cyclosporin A or FK506；MTOR inhibitors, such as rapamycin, 40-O- (2- ethoxys)-rapamycin, CCI779, ABT578, AP23573, TAFA-93 etc., biolimus-7 or biolimus-9, ascosin, there is immunosupress The ABT-281 of activity, ASM981, cortin, endoxan, azathioprene, methotrexate, leflunomide, imidazoles are stood Guest, mycophenolic acid or its salt, mycophenolate, 15-deoxyspergualine or immunosuppressive homologues, analog or derivative Thing, PKC inhibitor etc., as described in patent WO 02/38561or WO 03/82859, embodiment compound 56 or 70, or JAK3 kinase inhibitors, such as：N- benzyl -3- benzals -1,4- dihydroxy-cyanoacetamide-alpha-cyanos-(3,4- dihydroxy) - N- benzyls cinnamamide (tyrphostin AG 490), prodigiosin 25-C (PNU156804), 4- (4 '-hydroxy benzenes Base)-amido-6,7-dimethoxy quinazoline (WHI-P131), 4- (the bromo- 4'- hydroxy phenyls of 3', 5'- bis-)-amino -6,7- bis- Methoxyquinazoline hydrochloride WHI-P97, KRX-211,3- (3R, 4R) -4- methyl -3- [methyl-(7H- pyrrolo-es [2,3-d] pyrimidine - 4- yls)-amino]-piperidin-1-yl } -3- oxo-propionitriles, the form presence of free form or pharmaceutically acceptable salt, such as list Citric acid (also referred to as CP-690,550), or the compound in patent WO 04/052359 or WO 05/066156, immunosupress Agent monoclonal antibody, the monoclonal antibody of leukocyte receptors, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or their part, and other immunomodulatory compounds, there is the extracellular knots of CTLA4 At least one of restructuring binding molecule in structure domain or its mutant, such as the CTLA4lg being connected with non-CTLA4 protein sequences (such as being referred to as ATCC 68629) or its variant (for example, LEA29Y) or other adhesion molecule inhibitors such as LFA-1 antagonists The antagonists of ICAM-1 or -3, VCAM-4 antagonists or VLA-4 antagonists or antihistamine, or pectoral, bronchodilator, blood Angiotensin receptor blocking pharmacon or anti-infective.

Compound shown in formula (I) of the present invention and other immunodepressant/immunomodulators, antiinflammatory, chemotherapeutant Or anti-infective co-administration, wherein immunodepressant/immunomodulator, antiinflammatory, chemotherapeutant or anti-infective are common The dosage of medication depends on the type of drug combination, is steroid compound or calcineurin inhibitors, and be used for The specific medicine for the treatment of and treatment etc..

In one embodiment, the present invention includes containing formula (I) compound or its pharmaceutically acceptable salt, and β₂- kidney The combination of upper parathyrine receptor stimulating agent.

β₂The example of-adrenoceptor agonists includes salmeterol (salmeterol), and (it can be racemic chemical combination Thing or single enantiomter, such as R- enantiomters), salbutamol (salbutamol) (its can be racemic compound or Single enantiomter, such as R- enantiomters), (it can be racemic compound or single to Formoterol (formoterol) Diastereoisomer, such as R, R- diastereoisomers), salmefamol (salmefamol), fenoterol (fenoterol), card Mo Teluo (carmoterol), Yi Tanteluo (etanterol), naminterol (naminterol), Clenbuterol (clenbuterol), pirbuterol (pirbuterol), Flerobuterol (flerbuterol), Reproterol (reproterol), bambuterol (bambuterol), QAB-149 (indacaterol), Terbutaline (terbutaline) And their salt, such as the xinafoate (1- hydroxy-2-naphthoic acids salt) of salmeterol, the sulfate of salbutamol or free The fumarate of alkali or Formoterol.In some embodiments, long-acting beta₂- adrenoceptor agonists, for example, carrying Effect bronchiectasis is provided with up to 12 hours or the compound of longer time, is preferable.

β₂- adrenoceptor agonists can be with the form of pharmaceutically acceptable sour forming salt.It is described pharmaceutically The acid of receiving is selected from sulfuric acid, hydrochloric acid, fumaric acid, carbonaphthoic acid (such as 1- or 3- hydroxy-2-naphthoic acids), cinnamic acid, the meat of substitution Cinnamic acid, triphenylacetic acid, sulfamic acid, p-aminobenzene sulfonic acid, 3- (1- naphthyls) acrylic acid, benzoic acid, 4- methoxy benzoic acids, 2- or 4-HBA, 4- chlorobenzoic acids and 4- Phenylbenzoic acids.

Suitable antiinflammatory includes corticosteroid.Available for formula (I) compound or its pharmaceutically acceptable salt group The suitable corticosteroid closed is those oral and suction corticosteroids, and its has the prodrug of anti-inflammatory activity.Example Including methylprednisolone, prednisolone (prednisolone), dexamethasone (dexamethasone), fluticasone propionate (fluticasone propionate), 6 alpha, 9 alpha-difluoro-11 β-hydroxy-16 alpha-methyl-17-alphas-[(4- methyl-1,3-thiazoles- 5- carbonyls) epoxide] -3- oxo-androst-Isosorbide-5-Nitrae-diene -17 β-thiocarboxylic acid S- fluorine methyl esters, 6 α, 9 α-two fluoro- 17 α-[(2- furans Mutter carbonyl) epoxide]-16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of-11 beta-hydroxy-thiocarboxylic acid S- fluorine methyl esters (furancarboxylic acids Fluticasone), 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-- 17 α of methyl-3- oxos-propionyloxy-androsta-Isosorbide-5-Nitrae-β of diene-17- Thiocarboxylic acid S- (2- oXo-tetrahydro furans-3S- bases) ester, 6 α, the 9 alpha-difluoro-11 betas-hydroxy-16 alpha-α of methyl-3- oxos-17- (2,2,3,3- tetramethyls cyclopropyl carbonyl) epoxide--17 β of androstane -1,4- diene-thiocarboxylic acid S- cyano methyl esters and 6 α, 9 α - The two fluoro- α of-16 Alpha-Methyl of 11 beta-hydroxy-17-(1- ethyls cyclopropyl carbonyl) epoxide-3- oxos-β of androstane-1,4- diene-17- Thiocarboxylic acid S- methyl fluoride esters, beclomethasone ester (such as 17- propionic esters or 17,21- dipropionic acid fat), budesonide (budesonide), flunisolide (flunisolide), Mometasone ester (such as momestasone furoate), Triamcinolone acetonide (triamcinolone acetonide), sieve fluoronaphthalene moral (rofleponide), ciclesonide (ciclesonide) (16 α, 17- [[(R)-cyclohexylmethylene] is double (epoxide)] -11 β, 21- dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene -3,20- diketone), propionic acid cloth replaces Can special (butixocort propionate), RPR-106541 and ST-126.Preferable corticosteroid includes propionic acid fluorine for card Loose (fluticasone propionate), 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-methyl-17-alpha-[(4- methyl isophthalic acids, 3- thiazoles - 5- carbonyls) epoxide] -3- oxo-androst-Isosorbide-5-Nitrae-diene -17 β-thiocarboxylic acid S- methyl fluoride esters, the fluoro- 17 α-[(2- of 6 α, 9 α-two Furanylcarbonyl) epoxide] -11 β-hydroxy-16 alpha--17 β of methyl -3- oxo-androst -1,4- diene-thiocarboxylic acid S- methyl fluorides Ester, the α of-16 Alpha-Methyl-3- oxos of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-17-(2,2,3,3- tetramethyls cyclopropyl carbonyl) epoxide-hero - 17 β of steroid-1,4- diene-thiocarboxylic acid S- cyano methyl esters and the α of-16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-17-(1- methyl Cyclopropyl carbonyl) -17 β of epoxide -3- oxo-androst -1,4- diene-thiocarboxylic acid S- fluorine methyl esters.In some embodiments, skin Matter steroids is 6 α, fluoro- 17 α of 9 α-two-Alpha-Methyl -3- oxo-androst -1 of [(2- furanylcarbonyls) epoxide] -11 beta-hydroxy -16, - 17 β of 4- diene-thiocarboxylic acid S- methyl fluoride esters.

Transcription inhibition is swashed with selectivity (compared with transcriptional activation), available for therapeutic alliance with glucocorticoid Moving the nonsteroidal compound of activity includes those compounds covereding in following patent：WO03/082827、WO98/ 54159、WO04/005229、 WO04/009017、WO04/018429、WO03/104195、WO03/082787、WO03/ 082280、WO03/059899、WO03/101932、WO02/02565、WO01/16128、WO00/66590、WO03/086294、 WO04/026248, WO03/061651 and WO03/08277.More nonsteroidal compounds WO2006/000401, It is included in WO2006/000398 and WO2006/015870.

The example of antiinflammatory includes nonsteroidal anti-inflammatory drug (NSAID's).

NSAID's example includes nasmil, sodium nedocromil (nedocromil sodium), phosphodiesterase (PDE) inhibitor (such as theophylline, PDE4 inhibitor, or mixed type PDE3/PDE4 inhibitor), leukotriene antagonist, leukotriene close Into inhibitor (such as montelukast), iNOS inhibitor, trypsase and elastatinal, Beta 2 integrin antagonist With adenosine receptor agonist or antagonist (e.g., adenosine 2a receptor stimulating agents), (such as chemokine receptors is short of money for cytokine antagonist Anti-agent, including CCR3 antagonists), cytokine synthesis inhibitor, or 5-LO inhibitor.Wherein, iNOS (inductivities one Nitric oxide synthase) inhibitor is preferably administered orally.The example of iNOS inhibitor includes those in WO93/13055, WO98/ 30537th, the compound disclosed in WO02/50021, WO95/34534 and WO99/62875.CCR3 inhibitor include those Compound disclosed in WO02/26722.

In one embodiment, offer formula (I) compound of the present invention is in the group with phosphodiesterase 4 (PDE4) inhibitor Application in conjunction, the especially application in the case where being suitable for sucking preparation.PDE4 specificity for this aspect of the present invention Inhibitor can be known suppression PDE4 enzymes or be found any compound as PDE4 inhibitor, and they are only PDE4 inhibitor, it is not to suppress other members in PDE families, such as PDE3 and PDE5 compound.Compound includes cis -4- cyanogen Base -4- (3- cyclopentyloxy -4- methoxyphenyls) hexamethylene -1- carboxylic acids, 2- carbomethoxy -4- cyano group -4- (3- cyclopropyl first Epoxide -4- difluoro-methoxies phenyl) hexamethylene -1- ketone and cis-[4- cyano group -4- (3- cyclo propyl methoxy -4- difluoromethoxies Base phenyl) hexamethylene -1- alcohol]；Also cis -4- cyano group -4- [3- (ring propoxyl group) -4- methoxyphenyls] hexamethylene -1- is included Carboxylic acid (also referred to as Xi Luosi) and its salt, ester, prodrug or physical form, it was in 09 month 1996 No. 03 United States Patent (USP) US authorized Disclosed in 5,552,438, this patent and its disclosed compound are by quoting and being integrally incorporated in the present invention.

The example of anticholinergic is compounds that those are used as muscarinic receptor antagonist, particularly those as M1 or M3 receptor antagonists, M₁/M₃Or M₂/M₃Receptor dual antagonist or M₁/M₂/M₃The compound of the general antagonist of acceptor.Inhalation Example compound include ipratropium (for example, as bromide, CAS 22254-24-6,For Trade name is sold), oxygen support ammonium (for example, as bromide, CAS 30286-75-0) and tiotropium (for example, as bromide, CAS 136310-93-5,Sold for trade name)；Be also interested in also have Revatropate (for example, As hydrobromate, CAS 262586-79-8) and LAS-34273 disclosed in WO01/04118.The example of oral administration Compound includes pirenzepine (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or its hydrobromate CAS 133099-07-7, sold by trade name of Enablex), oxybutynin (CAS 5633-20-5, Sold for trade name), terodiline (CAS 15793-40-5), Tolterodine (CAS 124937-51-5, or its tartrate CAS 124937-52-6,Sold for trade name), Austria is for ammonium (for example, as bromide, CAS 26095- 59-0, withSold for trade name), trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478- 37-1, or its succinate CAS 242478-38-2, i.e. compound YM-905,Sold for trade name Sell).

In some embodiments, the invention provides one kind to include formula (I) compound or its pharmaceutically acceptable salt, with The combination of H1 antagonists.The example of H1 antagonists includes, but not limited to Amlexanox (amelexanox), this western imidazoles (astemizole), azatadine (azatadine), azelastine (azelastine), Acrivastine (acrivastine), Brompheniramine (brompheniramine), cetirizine (cetirizine), levocetirizine (levocetirizine), second Fluorine profit piperazine (efletirizine), chloropheniramine (chlorpheniramine), clemastine (clemastine), marezine (cyclizine), Carebastine (carebastine), cyproheptadine (cyproheptadine), carbinoxamine (carbinoxamine), descarboethoxyloratadine (descarboethoxyloratadine), doxylamine (doxylamine), diformazan indenes (dimethindene), Ebastine (ebastine), epinastine (epinastine), second Fluorine profit piperazine (efletirizine), fexofenadine (fexofenadine), hydroxyzine (hydroxyzine), Ketotifen (ketotifen), Loratadine (loratadine), levocabastine (levocabastine), Mizolastine (mizolastine), mequitazine (mequitazine), Mianserin (mianserin), the primary STING of promise (noberastine), meclizine (meclizine), Tecastemizole (norastemizole), olopatadine (olopatadine), piperacetazine (picumast), it is more special than Lamine (pyrilamine), phenergan (promethazine) Fei Nading (terfenadine), Tripelennamine (tripelennamine), temelastine (temelastine), nedeltran (trimeprazine) and triprolidine (triprolidine), preferred cetirizine (cetirizine), levocetirizine (levocetirizine), Efletirizine (efletirizine) and fexofenadine (fexofenadine).At another In embodiment, the invention provides one kind to include formula (I) compound or its pharmaceutically acceptable salt, with H3 antagonists (and / or inverse agonist) combination.The example of H3 antagonists includes those disclosed in WO2004/035556 and WO2006/045416 Compound.Available for other histamine receptor antagonists for combine of compound with the present invention including H4 receptor antagonists (and/or Inverse agonist), such as in Jablonowski et al., J.Med.Chem.46:Chemical combination disclosed in 3957-3960 (2003) Thing.

Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with The combination of PDE-4 inhibitor.

Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with β₂- The combination of adrenoceptor agonists.

Therefore, on the other hand, the present invention, which provides one kind, includes the compound or its pharmaceutically acceptable salt of formula (I), with The combination of corticosteroid.

Therefore, on the other hand, the invention provides one kind to include the compound or its pharmaceutically acceptable salt of formula (I), With the combination of nonsteroidal GR activators.

Therefore, on the other hand, the invention provides one kind to include the compound or its pharmaceutically acceptable salt of formula (I), With the combination of anticholinergic drug.

Therefore, on the other hand, the invention provides one kind to include the compound or its pharmaceutically acceptable salt of formula (I), With antihistaminic combination.

Therefore, on the other hand, the invention provides one kind to include the compound or its pharmaceutically acceptable salt of formula (I), With PDE4 inhibitor and β₂The combination of-adrenoceptor agonists.

Therefore, on the other hand, the invention provides one kind to include the compound or its pharmaceutically acceptable salt of formula (I), With the combination of anticholinergic drug and PDE-4 inhibitor.

Combination of the above can easily be prepared into pharmaceutical composition to use, therefore, including defined above group Close and represent another aspect of the present invention with the pharmaceutical composition of pharmaceutically acceptable diluent or carrier.

Single compounds of these combinations can give with alone or in combination pharmaceutical dosage forms order of administration or simultaneously Medicine.In some embodiments, single compound component is administered simultaneously with the pharmaceutical dosage forms of combination.Known treatment agent Suitable dosage be easy to be understood by the person skilled in the art.

Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with it The pharmaceutical composition of his therapeutically active agent combination.

Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with The pharmaceutical composition of PDE4 inhibitor combination.

Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with β 2- The pharmaceutical composition of adrenoceptor agonists combination.

Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with skin The pharmaceutical composition of matter steroid combination.

Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, and non- The pharmaceutical composition of steroid GR agonist combinations.

Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with resisting The pharmaceutical composition of cholinergic agent combination.

Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with resisting The pharmaceutical composition of histamine drug combination.

Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with PDE4 inhibitor and the pharmaceutical composition of β 2- adrenoceptor agonists combination.

Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with resisting Cholinergic agent and the pharmaceutical composition of PDE4 inhibitor combination.

Formula (I) compound can also be advantageously utilised in the combination with other compounds, or and other therapeutic agents, it is especially anti- In the combination of multiplication agent.Such antiproliferative includes, but not limited to aromatase inhibitor；Antiestrogenic；Topoisomerase I Inhibitor；Topoisomerase II inhibitors；Microtubule active agent；Alkylating agent；Histon deacetylase (HDAC) inhibitor；Inducing cell point The compound of change process；Cyclooxygenase-2 inhibitors；MMP inhibitor；MTOR inhibitors；Antitumor antimetabolite；Platinum compounds； The compound of the compound of targeting/reduction albumen or lipid kinase activity and other anti-angiogenesis；Targeting, reduce or suppress egg White or lipid phosphate esterase active compound；Gonadorelin excitomotor；Antiandrogen；Methionine aminopeptidase inhibitor；It is double Phosphonate；BRM；Antiproliferation antibodies；Heparanase inhibitors；The carcinogenic hypotype inhibitor of Ras；Telomerase presses down Preparation；Proteasome inhibitor；Treat the medicament of neoplastic hematologic disorder；Targeting, the compound for reducing or suppressing Flt-3 activity；Hsp90 Inhibitor；TemozolomideAnd Calciumlevofolinate.

Term used herein " aromatase inhibitor ", refers to suppress compound caused by estrogen, that is, it is male to suppress substrate Alkene diketone and testosterone change into the compound of oestrone and estradiol respectively.The term includes, but are not limited to：Steroid, especially It is atamestane (atamestane), Exemestane (exemestane) and formestane (formestane)；And particularly Non-steroids, especially aminoglutethimide (aminoglutethimide), Rogletimide (roglethimide), pyrrole Rumi Special (pyridoglutethimide), Trilostane (trilostane), Testolactone (testolactone), ketoconazole (ketoconazole), fluorine chlorazol (vorozole), Fadrozole (fadrozole), Anastrozole (anastrozole) and come Bent azoles (letrozole).Exemestane can be with commercially available, such as the form administration that trade mark is Arnold new (AROMASIN).Fu Mei Smooth (formestane) can be with commercially available, if trade mark is the form administration of Lentaron (LENTARON).Fadrozole (fadrozole) can be with commercially available, the form if trade mark is AFEMA is administered.Anastrozole (anastrozole) can be with Commercially available, if trade mark is the form administration of Arimidex (ARIMIDEX).Letrozole (letrozole) can be with commercially available, such as business It is designated as fluon (FEMARA) or FEMAR form administration.Aminoglutethimide (aminoglutethimide) can be with commercially available, such as Trade mark is administered for the form of Elipten AG (ORIMETEN).The combination that the present invention includes aromatase inhibitor chemotherapeutic is used in particular for controlling Treat the tumour that hormone receptor is positive, such as tumor of breast.

Term used herein " antiestrogenic ", refers to the compound in Estrogen Receptor antagonising oestrogen effectiveness. The term includes, but not limited to TAM (tamoxifen), fulvestrant (fulvestrant), Raloxifene And raloxifene hydrochloride (raloxifene hydrochloride) (raloxifene).TAM (tamoxifen) can So that with commercially available, the form if trade mark is Nolvadex/Nolvadex-D (NOLVADEX) is administered.Raloxifene hydrochloride (raloxifene Hydrochloride) can be with commercially available, the form if trade mark is Yi Weite (EVISTA) is administered.Fulvestrant (fulvestrant) can be or commercially available with United States Patent (USP) US 4, the formulation disclosed in 659,516, as trade mark is FASLODEX form administration.The combination that the present invention includes antiestrogenic chemotherapeutic is particularly useful for the treatment of ERs in sun The tumour of property, such as tumor of breast.

Term used herein " antiandrogen " refers to any material that can suppress male sex hormone biological action, and it is wrapped Include, but be not limited to, Bicalutamide (bicalutamide, trade name CASODEX), its formulation can according to United States Patent (USP) US 4, 636,505 prepare.

Term used herein " Gonadorelin excitomotor " includes, but not limited to abarelix (abarelix), Ge She Rayleigh (goserelin) and goserelin acetate.Goserelin is disclosed in United States Patent (USP) US 4,100,274, can be with Commercially available, if trade mark is the form administration of Zoladex (ZOLADEX).Abarelix (abarelix) can be according to United States Patent (USP) Method disclosed in US 5,843,901 prepares formulation.

Term used herein " topoisomerase I inhibitor ", include, but are not limited to TPT (topotecan), it is lucky Horse replaces health (gimatecan), Irinotecan (irinotecan), camptothecine (camptothecian) and the like, 9- nitre Base camptothecine (9-nitrocamptothecin) and macromolecular camptothecin conjugated compound PNU-166148 (WO 99/17804 In compound A1).Irinotecan can be with commercially available, if trade mark is the form administration of CPT-11 (CAMPTOSAR).Topology is replaced Health can be with commercially available, if trade mark is the form administration with U.S. new (HYCAMTIN).

Term used herein " Topoisomerase II inhibitors " includes, but are not limited to anthracycline compound, such as how soft ratio Star (doxorubicin), its Lipidosome, the triumphant Lay of trade name (CAELYX)；Daunomycin (daunorubicin)；Table It is soft than star (epirubicin)；Idarubicin (idarubicin)；The not soft pyrrole star (nemorubicin) of naphthalene；Anthraquinones rice support anthracene Quinone (mitoxantrone) and Losoxantrone (losoxantrone)；Podophillotoxines etoposide (etoposide) and for Buddhist nun Moor glycosides (teniposide).Etoposide can be with commercially available, if trade mark is the form administration of Etopophos (ETOPOPHOS).Replace Buddhist nun moors glycosides can be with commercially available, and the form if trade mark is VM 26-BRISTOL is administered.Doxorubicin can be with commercially available, such as business It is designated as the form administration of adriamycin (ADRIBLASTIN) or adriamycin (ADRIAMYCIN).Epirubicin can be with city Sell, if trade mark is the form administration of Pharmorubicin RD (PHARMORUBICIN).Idarubicin can be with commercially available, as trade mark does good Only it is administered up to the form of (ZAVEDOS).Mitoxantrone can be with commercially available, such as the form that trade mark is NSC-279836 (NOVANTRON) Administration.

Term " microtubule active agent " refers to microtubule stabilizer, microwave destabiliser and microtubule polymerization inhibitor.It includes, but not It is limited to taxanes, such as taxol (paclitaxel) and Docetaxel (docetaxel)；Vinca alkaloids, such as Changchun Alkali (vinblastine), especially vinblastine sulfate, especially vincristine, vincristine sulphate and vinorelbine (vinorelbine)；discodermolides；Colchicin；And Epothilones and its derivative, such as epothilone B or D Or derivatives thereof.Taxol can be with commercially available, if trade mark is the form administration of PTX (TAXOL).Docetaxel can be with Commercially available, if trade mark is that safe Supreme Being is plain (TAXOTERE).Vinblastine sulfate can be with commercially available, if trade mark is VINBLASTIN R.P. form administration.Vincristine sulphate can be with commercially available, and the form if trade mark is FARMISTIN is administered. Discodermolide can obtain according to the method disclosed in United States Patent (USP) US 5,010,099.It is additionally included in WO 98/ 10121st, United States Patent (USP) US 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, the and of WO 98/22461 Epothilones analog derivative disclosed in WO 00/31247, particularly preferred ebomycin A and/or B.

Term used herein " alkylating agent " includes, but not limited to endoxan (cyclophosphamide), different ring phosphorus Acid amides (ifosfamide), melphalan (melphalan) or Nitrosourea (nitrosourea, such as BCNU or carmustine).Ring phosphinylidyne Amine can be with commercially available, if trade mark is the form administration of cyclophosphamide (CYCLOSTIN).Ifosfamide can be with commercially available, such as Trade mark is administered for the form of Holoxan (HOLOXAN).

Term " histon deacetylase (HDAC) inhibitor " or " hdac inhibitor " refer to inhibition of histone deacetylase, and Compound with antiproliferative activity.It is included in the compound disclosed in WO 02/22577, especially N- hydroxyls -3- [4- [[(2- ethoxys) [2- (1H- indol-3-yls) ethyl]-amino] methyl] phenyl] -2E-2- acrylamides, N- hydroxyls -3- [4- [[[2- (2- Methyl-1H-indole -3- bases)-ethyl]-amino] methyl] phenyl] -2E-2- acrylamides and its pharmaceutically may be used The salt of receiving.Especially include Vorinostat (SAHA).

Term " antitumor antimetabolite " includes, but not limited to 5-fluor-uracil (5-fluorouracil) or 5-FU； Capecitabine (capecitabine)；Gemcitabine (gemcitabine)；DNA demethylation reagents, such as U-18496 (5- ) and Decitabine (decitabine) azacytidine；Methotrexate (MTX) (methotrexate) and Edatrexate (edatrexate)；And antifol, such as pemetrexed (pemetrexed).Capecitabine can be with commercially available, such as business It is designated as the form administration of Xeloda (XELODA).Gemcitabine can be with commercially available, such as the form that trade mark is gemzar (GEMZAR) Administration.This term also includes monoclonal antibody Herceptin (trastuzumab), can be with commercially available, if trade mark is He Sai The form administration in spit of fland (HERCEPTIN).

Term used herein " platinum compounds " includes, but are not limited to carboplatin (carboplatin), cDDP (cis- Platin), cis-platinum (cisplatinum) and oxaliplatin (oxaliplatin).Carboplatin can be with commercially available, as trade mark isForm administration.Oxaliplatin can be with commercially available, and the form if trade mark is OXA (ELOXATIN) is given Medicine.

Term used herein " the change of targeting/reduction albumen or lipid kinase activity or albumen or lipid phosphatase activity Compound, or the compound of other anti-angiogenesis " include, but not limited to protein tyrosine kinase and/or serine and/or Threonine inhibitor, or lipid kinase inhibitors, such as

A) target, reduce or suppress the compound of platelet derived growth factor receptor (PDGFR) activity；Targeting, reduce Or suppress the compound of PDGFR activity, especially suppressing the compound of pdgf receptor includes N- phenyl -2- pyrimidines-amine derivative Thing, such as Imatinib (imatinib), SU101, SU6668, GFB-111 etc.；

B) target, reduce or suppress the active compound of fibroblast growth factor acceptor (FGFR)；

C) target, reduce or suppress the active compound of IGF-1-1 (IGF-1R)；Targeting, reduce Or suppress the compound of IGF-1R activity, especially suppressing the compound of IGF-1 receptor actives includes those in patent WO 02/ Compound disclosed in 092599；

D) targeting, reduction or the compound for suppressing Trk receptor tyrosine kinase family actives；

E) targeting, reduction or the compound for suppressing Axl family active；

F) targeting, reduction or the compound for suppressing c-Met receptor actives；

G) targeting, reduction or the compound for suppressing Kit/SCFR receptor tyrosine kinase activities；

H) target, reduce or suppress the active chemical combination of C-kit receptor tyrosine kinases (part in PDGFR families) Thing；Targeting, the compound for reducing or suppressing C-kit receptor tyrosine kinase family actives, especially suppress the change of c-Kit acceptors Compound, including Imatinib (imatinib) etc.；

I) target, reduce or suppress c-Abl families and their gene fusion products, such as the change of BCR-Abl kinase activities Compound；Targeting, the compound for reducing or suppressing c-Abl family members and their Gene Fusion things include N- phenyl -2- pyrimidines - Amine derivative, such as Imatinib, PD180970, AG957, NSC 680410, the PD173955 from ParkeDavis

J) target, Raf family members in reduction or suppression protein kinase C (PKC) and serine/threonine kinases, MEK, SRC, JAK, FAK, PDK and Ras/MAPK family member, Pl (3) kinase families member, or Pl (3) kinases associated kinase family Member, and/or the compound of cell cycle protein dependent kinase family (CDK) member activity；Particularly those are special in the U.S. Sharp US 5, the staurosporine derivatives disclosed in 093,330, such as midostaurin (midostaurin)；More compounds are real Example also includes, UCN-01；Safingol (safingol)；BAY 43-9006；Bryostatin 1；Piperazine Li Fuxin (Perifosine)； Ilmofosine (llmofosine)；RO 318220 and RO 320432； GO 6976；Isis 3521；LY333531/ LY379196；Isoquinoline compound, such as in WO 00/09495 those disclosed；FTIs； PD184352；Or QAN697 (a kind of P13K inhibitor)；

K) target, reduce or suppress the active compound of protein tyrosine kinase inhibitor；Targeting, reduce or suppress The compound of protein tyrosine kinase inhibitor activity includes Gleevec (GLEEVEC) or tyrosine phosphorylation presses down Preparation；The preferred low molecule amount (Mr of tyrphostin<1500) compound, or its pharmaceutically acceptable salt, especially Compound selected from the eyeball class of the eyeball class of benzyl allyl two or S- aryl sheet the third two or Double bottom thing quinolines, is further selected from tyrosine phosphorus Acidification inhibitors A23/RG-50810, AG 99, tyrphostin AG 213, tyrphostin AG 1748, tyrphostin AG 490, tyrphostin B44, tyrphostin B44 (+) Enantiomer, tyrphostin AG 555, AG 494, tyrphostin AG 556, AG957 and Adaphostin (4- { [(2,5- dihydroxy phenyls) methyl] amino }-benzoic acid Buddha's warrior attendant alkyl ester, NSC 680410, adaphostin)；With

I) target, reduce or suppress receptor tyrosine kinase epidermal growth factor receptor family (EGFR, ErbB2, ErbB3, ErbB4 equal or heterodimer) activity compound；Targeting, reduce or suppress Epidermal Growth Factor Receptor Family Compound refer in particular to suppress EGF receptor family member (such as EGF receptor, ErbB2, ErbB3, ErbB4, or can with EGF or The material that EGF associated ligands combine) compound, albumen or antibody, is particularly summarized in the following documents or it is specific openly Compound, albumen or monoclonal antibody：WO 97/02266 (such as embodiment 39), EP 0 564 409, WO 99/03854, EP 0520722、EP 0 566 226、EP 0 787 722、EP 0 837 063、US 5,747,498、WO 98/10767、WO 97/30034th, WO 97/49688 and WO 97/38983, WO 96/30347 (such as CP 358774), WO 96/33980 is (as changed Compound ZD 1839), WO 95/03283 (such as compound ZM105180), Herceptin (Trastuzumab), Cetuximab, Yi Rui Sand, Erlotinib, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, E7.6.3, and the 7H- pyrrolo-es being disclosed in WO 03/013541-[2,3-d] pyrimidine derivatives.

In addition, anti-angiogenic compounds include having other active mechanisms (for example, with albumen or lipid kinase suppressing not It is related) compound, such as Thalidomide (THALOMID) and TNP-470.

Targeting, reduction or the compound of suppression albumen or lipid kinase activity are the inhibitor of phosphatase -1, and phosphatase 2A presses down Preparation, PTEN inhibitor or CDC25 inhibitor, such as okadaic acid or derivatives thereof.

The compound of Cell differentiation inducing activity process is vitamin A acid, α-, γ-or Delta-Tocopherol, α-, γ-or δ-fertility triolefin Phenol.

Term used herein " cyclooxygenase-2 inhibitors " includes, but not limited to Cox-2 inhibitor, and 5- is alkyl-substituted 2- fragrant aminos phenylacetic acid and its derivative, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, are examined with cutting down Former times, or 5- alkyl -2- fragrant amino phenylacetic acids, such as 5- methyl -2- (the chloro- 6'- fluoroanilinos of 2'-) phenylacetic acids or Lu meter Kao Former times

Term used herein " diphosphonate " includes, but not limited to Etidronic Acid, Clodronate, Tiludronic Acid, pa rice phosphine Acid, alendronic acid, ibandronic acid, Risedronic Acid and zoledronic acid.Etidronic Acid can with commercially available, as trade name Supreme Being sieve how (DIDRONEL) form administration.Clodronate can be with commercially available, as the form of trade name Bonefos (BONEFOS) is administered.Replace Shandong phosphonic acids can be with commercially available, as trade name SKELID form is administered；Pamidronic acid (Pamidronic acid) can be with Commercially available, such as trade name Aredia (AREDIA^TM) form administration；Alendronic acid can be with commercially available, such as trade name good fortune The form administration of kind U.S. (FOSAMAX)；Ibandronic acid can be with commercially available, such as trade name Bang Luoli (BONDRANAT) shape Formula is administered；Risedronic Acid can be with commercially available, as the form of trade name ANTU good (ACTONEL) is administered；Zoledronic acid can be with With commercially available, such as the form administration in trade name pool safe (ZOMETA).

Term " mTOR inhibitors " refers to suppress mammal rapamycin (mTOR) target protein have antiproliferative activity Compound, such as sirolimus (sirolimus,), everolimus (Certican^TM), CCI-779 and ABT578.

Term used herein " heparanase inhibitors " refers to, targets, reduces or suppress acetylsulfuric acid depolymerized heparin Compound.This term includes, but unlimited PI-88.

Term used herein " BRM " refers to lymphokine or interferon, such as interferon gamma.

Term used herein " the carcinogenic hypotypes of Ras (such as H-Ras, K-Ras or N-Ras) inhibitor " refers to target, reduced Or suppress the compound of Ras carcinogenic activities, such as " farnesyl transferase inhibitor ", such as L-744832, DK8G557 or R115777(Zarnestra)。

Term used herein " telomerase inhibitor " refers to the compound for targetting, reducing or suppressing telomerase activation.Target Refer in particular to suppress the compound of telornerase receptor, such as telomere mycin to, the compound that reduces or suppress telomerase activation.

Term used herein " methionine aminopeptidase inhibitor " refers to target, reduce or suppress methionine aminopeptidase activity Compound.The compound of targeting, reduction or suppression methionine aminopeptidase activity includes bengamide or derivatives thereof.

Term used herein " proteasome inhibitor " refers to target, reduces or the chemical combination of protease inhibition body activity Thing.The compound of targeting, reduction or protease inhibition body activity includes PS-341 and MLN 341.

Term used herein " NMPI " or " MMP inhibitor " include, but not limited to glue Former albumen peptides and non-peptide inhibitor, tetracycline derivant, such as hydroxamic acid peptide inhibitor Batimastat (batimastat) With its equivalent homologue Marimastat (marimastat, BB-2516) of oral bio, Pu Masita (prinomastat, AG3340), Mei Tasita (metastat, NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B Or AAJ996.

Term used herein " reagent for being used for treating neoplastic hematologic disorder " includes, but not limited to FMS- sample EGFR-TKs Inhibitor.Targeting, the compound for reducing or suppressing FMS- samples tyrosine kinase receptor (Flt-3R) activity；Interferon, 1-b-D- Arabinofuranosyl adenin cytimidine (ara-c) and bisulfan；With ALK inhibitor, such as targeting, reduce or suppress anaplastic lymphoma and swash The compound of enzyme.

Targeting, reduce or suppress FMS- samples tyrosine kinase receptor (Flt-3R) compound especially suppress Flt-3 by The compound of body kinase families member, albumen or antibody, such as PKC412, midostaurin (midostaurin), staurosporin Derivative, SU11248 and MLN518.

Term used herein " HSP90 inhibitor " includes, but are not limited to target, reduce or suppress HSP90 endogenous The compound of atpase activity；The chemical combination degraded by ubiquitin protein body enzymatic pathway, targetted, reduce or suppress HSP90 client proteins Thing.Targeting, the compound for the Endogenous ATP enzymatic activity for reducing or suppressing HSP90 refer in particular to suppress HSP90 Endogenous ATP The compound of enzymatic activity, albumen or antibody, for example, 17- allyl aminos, 17-AAG (17AAG), its The compound of his geldanamycin correlation, red shell rhzomorph and hdac inhibitor.

Term used herein " antiproliferation antibodies " includes, but not limited to Herceptin (Herceptin^TM), toltrazuril Monoclonal antibody-DM1, Tarceva (Tarceva^TM), bevacizumab (Avastin^TM), RituximabPR064553 And 2C4 antibody (anti-CD40).Antibody means complete monoclonal antibody, polyclonal antibody, by the complete antibody of at least two The multi-specificity antibody and antibody fragment (as long as they have desired bioactivity) of formation.For the white blood of acute myeloid sample For the treatment of sick (AML), the leukemia therapy of formula (I) compound and standard can be used in combination, especially with for AML The therapy for the treatment of is used in combination.Specifically, can by formula (I) compound and such as farnesyl tranfering enzyme inhibitor and/or its He be used for AML treatment medicine for example daunorubicin, adriamycin, Ara-C, VP-16, Teniposide, mitoxantrone, idarubicin, Carboplatin and PKC412 administering drug combinations.

Formula (I) compound can also be advantageously utilised in the combination with other compounds or with the combination of other therapeutic agents, Especially other anti-malarial agents.Such anti-malarial agents include, but are not limited to chloroguanide (proguanil), Chlorproguanil (chlorproguanil), TMP (trimethoprim), chloroquine (chloroquine), Mefloquine (mefloquine), Lumefantrine (lumefantrine), Atovaquone (atovaquone), pyrimethamine-sulfanilamide (SN) (pyrimethamine- Sulfadoxine), pyrimethamine-chlorobenzene (pyrimethamine-dapsone), halofantrine (halofantrine), quinine (quinine), quinindium (quinidine), amodiaquine (amodiaquine), amopyroquine (amopyroquine), sulfanilamide (SN) Class medicine, qinghaosu, Arteflene (arteflene), Artemether, Artesunate, primaquine, suck NO, L-arginine, dipropyl Alkene triamine NONO esters (NO donor), Rosiglitazone (PPARy activators), activated carbon, hematopoietin, levamisol, And Malaridine.

Formula (I) compound can also be advantageously used in the combination with other compounds or the combination of other therapeutic agents, example Such as treat the other therapeutic agents of leishmaniasis, trypanosomiasis, toxoplasmosis and cerebral cysticercosis.Such medicament includes, but are not limited to Nivaquin, atovaquone-proguanil, Artemether-lumenfantrine, quinine sulfate, Artesunate, quinine, fortimicin (doxycycline), clindamycin (clindamycin), meglumine antimony (meglumine antimoniate), gluconic acid Antimony sodium (sodium stibogluconate), Miltefosine (miltefosine), ketoconazole (ketoconazole), pentamidine (pentamidine), amphotericin B (AmB), AmB liposomes, paromomycin (paromomycine), Eflornithine (eflornithine), nifurtimox (nifurtimox), suramin (suramin), melarsoprol (melarsoprol), sprinkle Ni Songlong (prednisolone), benzimidazole, sulphadiazine, pyrimethamine, abactrim, radonil, Ah Miramycin (azitromycin), Atovaquone, dexamethasone, praziquantel, albendazole (albendazole), beta-lactam, Fluoroquinolones medicine, macrolides medicine, aminoglycoside medicine, sulphadiazine and pyrimethamine.

The structure of active component and its preparation can be from classic " The determined by code name, common name or trade name Merck Index (Merck index) " current edition (such as M.J.O ' Neil et al. compile ' The MerckIndex ', the 13rd Version, Merck Research Laboratories, 2001) or from database (such as Patents International (such as IMS World Publications)) in know.

Compound above-described, being applied in combination with formula (I) compound, can be pressed by those skilled in the art Prepare and be administered according to the method described in above-mentioned document.Formula (I) compound can also be combined with therapeutic process, improve curative effect.Example Such as, hormone therapy or special radiotherapy are given.Formula (I) compound is used especially as radiosensitizer, it is especially useful in right The weak oncotherapy of those radiotherapeutic responses.

" combination " represents the medicine box of the fixed Combination in single dose unit form or the part for combined administration, its Middle formula (I) compound and combined partner can be applied in same time individual application or respectively at a certain time interval With, particularly make combined partner show cooperation, for example act synergistically.Term " co-administration " as used in the present invention or " group Single individual (such as the patient) for being applied to selected COMBINATION OF THE INVENTION and needing it to be administered in combination is included in conjunction administration " etc., and wraps Wherein material is included without going through identical route of administration or the therapeutic scheme being administered simultaneously.Term " medicine group as used in the present invention Close product " represent more than one active components to be mixed or combined resulting product, and both included the fixation of active component Combination also includes non-fixed combinations.Term " fixed Combination " represent active component as shown in formula (I) compound and COMBINATION OF THE INVENTION with Single entities or the form of dosage are administered simultaneously in patient.Term " non-fixed combinations " represents active component such as formula (I) shownization Compound and COMBINATION OF THE INVENTION are successively applied to patient with limiting simultaneously, jointly or without special time as corpus separatum, wherein should It is applied in the treatment level of significance that patient's body provides two kinds of compounds.The latter applies also for HAART, such as using 3 Kind or more kind active component.

The purposes of the compounds of this invention and pharmaceutical composition

The compounds of this invention is the inhibitor of the inhibitor of kinase activity, particularly PI3- kinase activities.For PI3- kinases The compound of inhibitor can be used for treating wherein potential pathology (at least part of) and be attributed to improperly PI3- kinase activities Disorder, such as asthma and chronic obstructive pulmonary disease (COPD)." improperly PI3- kinase activities " refers to and in specific patient In desired normal PI3- kinase activities have any PI3- kinase activities of deviation.Improperly PI3- kinases can be taken, for example, The abnormal increase of activity, or PI3- kinases distort or controlled not normal form.Improperly activity can be due to for these, such as causes Improperly or not controlled make the overexpression of protein kinase being activated or mutation.Therefore, on the other hand, the present invention relates to treatment Disorderly or disease the method.

Such disorderly or disease includes, but is not restricted to, respiratory disease, including asthma, chronic obstructive Tuberculosis and idiopathic pulmonary fibrosis (IPF)；Virus infection, including viral respiratory infection and viral respiratory disease are disliked Change, such as asthma and COPD；Non-viral respiratory tract infection, including aspergillosis and leishmaniasis；Anaphylactia, including allergy Property rhinitis and atopic dermatitis；Autoimmune disease, including rheumatoid arthritis and multiple sclerosis；Diseases associated with inflammation, Including IBD；Angiocardiopathy, including DVT and atherosclerosis；Malignant hematologic disease；Nerve degenerative diseases； Pancreatitis；MOF；Kidney trouble；Platelet aggregation；Cancer；Sperm motility；Graft rejection；Graft rejection； Injury of lungs；And pain, including the pain related to rheumatoid arthritis or osteoarthritis, backache, systemic inflammatorome pain, Neuralgia, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia and central pain after liver. In one embodiment, such disorder includes, respiratory disease, including asthma and chronic obstructive pulmonary disease (COPD)；Anaphylaxis Disease, including allergic rhinitis and atopic dermatitis；Autoimmune disease, including rheumatoid arthritis and multiple hard Change；Diseases associated with inflammation, including IBD；Angiocardiopathy, including DVT and atherosclerosis；Malignant hematologic disease； Nerve degenerative diseases；Pancreatitis；MOF；Kidney trouble；Platelet aggregation；Cancer；Sperm motility；Transplanting row Reprimand；Graft rejection；Injury of lungs；And pain, including the pain related to rheumatoid arthritis or osteoarthritis, backache, Neuralgia, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia after systemic inflammatorome pain, liver And central pain.

The treatment method of the present invention include giving patient in need with compound shown in the formula of safety and effective dose (I) or Its pharmaceutically acceptable salt.Each embodiment of the present invention is included by giving patient in need with safety and effective dose Compound or its pharmaceutically acceptable salt shown in formula (I), any disorderly or disease method that the treatment present invention mentions.

Compound shown in formula (I) can be given to study subject or its is pharmaceutically acceptable by any suitable method of administration Salt, including Formulations for systemic administration and local administration both.Formulations for systemic administration include orals administration, parenteral, cutaneous penetration and directly Enteral administration.Parenteral refer to except enteral or it is transdermal in addition to method of administration, typically inject or infuse.Parenteral Including intravenous, intramuscular and hypodermic injection or transfusion.Local administration includes being applied to skin, and intraocular, ear, vagina Interior, suction and intranasal administration.Suction refers to being administered to the intrapulmonary of patient, is sucked whether through oral cavity suction or nasal cavity. In certain embodiments, compound or its pharmaceutically acceptable salt shown in formula (I) can be administered orally.In other embodiments In, can compound or its pharmaceutically acceptable salt shown in administration by inhalation formula (I).In further embodiments, can be through intranasal Give compound shown in formula (I) or its pharmaceutically acceptable salt.

It can once give or give formula (I) compound or its pharmaceutically acceptable salt according to a dosage regimen, in institute State in dosage regimen, it is specified that period in give some dosage at various time intervals.For example, can give 1 time daily, 2 times, 3 times or 4 dosage.In certain embodiments, 1 dosage is given daily.In further embodiments, 2 dosage are given daily. Dosage can be given until reaching required therapeutic effect or indefinitely maintaining desired therapeutic effect.Chemical combination shown in formula (I) The suitable dosage regimen of thing or its pharmaceutically acceptable salt depends on the pharmacokinetic property of the compound, such as inhales Receipts, distribution and half-life period, it can be determined by professional and technical personnel.In addition, suitable dosage regimen, including scheme it is lasting when Between, for formula (I) compound or its pharmaceutically acceptable salt, depending on the disorder treated or disease, receiving The disorder for the treatment of or the order of severity of disease, the age of patients receiving treatment and health, the medical history, same of patient under consideration When the property of therapy, the effect of expected treatment and some factors in the knowledge and technical skill of professional and technical personnel.Specialty Technical staff, which is also understood that according to reaction of the individual patient to dosage regimen or elapses individual patient over time, to be needed to change When, in order to be sufficiently accurate it may be desired to adjust suitable dosage regimen.

The present invention compound can with one or more other drugs simultaneously, before or after be administered.The change of the present invention Compound can be administered alone by identical or different method of administration, or together be given in same pharmaceutical composition with other drugs Medicine.

The pharmaceutical composition of the present invention or combination can be about 1-1000mg active components for about 50-70kg individual, Or the unit dose of about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg active component Amount.The treatment effective dose of compound, pharmaceutical composition or its combination depends on species, body weight, age and the individual disease of individual Disease, disorder or disease or severity to be treated.The doctor of this area common skill, clinician or animal doctor can be easily It is determined that the effective dose of each active component for preventing, treating or suppressing disorderly or progression of disease.Dosage cited above is special Property used favourable mammal, such as mouse, rat, dog, monkey or isolated organ, tissue and its sample external and Confirmed in vivo studies.The compound of the present invention can use in vitro as a solution, such as the aqueous solution, also can be in suspension Or the vein that the form of the aqueous solution enterally, parenterally and preferably passes through uses in vivo.The scope of interior therapeutic effective dose depends on giving The approach of medicine, between about 0.01-500mg/kg, or about between 1-100mg/kg.

In addition, compound shown in formula (I) can be administered with pro-drug.Term used in the present invention, chemistry " prodrug " of the compound of formula (I) is its feature for the compound for finally discharging chemical formula (I) when delivering medicine to patient in vivo Derivative.During with the compound of prodrug administration chemistry formula (I), those skilled in the art can implement one kind in following manner and with On：(a) onset time is changed inside compound；(b) acting duration inside compound is changed；(c) compound is changed Inside conveying or distribution；(d) solubility inside compound is changed；And (e) overcomes the side effect or its that compound faced His difficult point.For preparing the typical functional derivatives of prodrug, comprising in vivo chemically or the mode of enzyme cracks The variant of compound.Comprising preparing these variants of phosphate, acid amides, ester, monothioester, carbonate and carbaminate to ability It is well-known for field technique personnel.

On the one hand, the invention provides disease extremely related PI3K or the treatment method of disorder.The treatment method bag Include by giving patient in need with the formula of safety and effective dose (I) compound or its pharmaceutically acceptable salt, treatment is originally Invent any disorderly or disease the method mentioned.

In some embodiments, the extremely related disease of PI3- kinases or disorder include：Breathing problem, as asthma, Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) etc.；Virus infection, including viral respiratory infection and Viral respiratory disease deteriorates, such as asthma and COPD；Non-viral respiratory tract infection, including aspergillosis and leishmaniasis；Cross Quick reactive disorder, including allergic rhinitis and atopical dermatitis；Autoimmune disease, including rheumatoid arthritis and Multiple sclerosis；Inflammatory disease, including inflammatory bowel disease；Angiocardiopathy, including DVT and atherosclerosis；Hematologic Disease；Nerve degenerative diseases；Pancreatitis；Multiple organ failure；Nephrosis；Platelet aggregation；Cancer；Sperm motility；Graft rejection；Move Plant repels；Injury of lungs；And pain, including the pain related to rheumatoid arthritis or osteoarthritis, backache, systemic inflammatorome Neuralgia, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia and central after property pain, liver Pain.

The compounds of this invention can be used for disease or the sense of the immune system of one or more functions of the treatment with B cell Dye, for example, antibody tormation, antibody present, cell factor generation or lymphoid organ formed abnormal or worthless illness, disease or The method of illness, the illness, disease or illness include rheumatoid arthritis, pemphigus vulgaris, essential thrombocytopenia and subtracted Few property purpura, systemic loupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren syndrome, Autoimmune hemolytic are poor Blood, ANCA associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic auto-immune nettle rash, Allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), Goodpasture's syndrome, AMR (antibody-mediated transplanting Repel), the cancer in super acute, the acute and chronic graft rejection of B cell mediation and hematopoiesis source, including but not limited to multiple bone Myeloma；Acute myeloid leukaemia；Chronic myelogenous leukemia；Lymphocytic leukemia；Myeloid leukemia；Non-Hodgkin's lymph Knurl；Lymthoma；Polycythemia vera；Primary thrombocytosis；Myelofibrosis with metaplasia outside marrow；With watt Er Dengsitelun diseases.

The present invention includes one or more functions such as superoxides release for the treatment of wherein neutrophil cell, is excited born of the same parents Tell or migration is abnormal or the method for worthless illness, disease or illness, the illness, disease or illness include rheumatoid Property arthritis, sepsis, lung or respiratory disorder are such as asthma, inflammatory skin diseases such as psoriasis.

The present invention includes one or more functions such as migration for the treatment of wherein basophilic granulocyte and mast cell Or allergen-IgE- mediations threshing is abnormal or the method for worthless illness, disease or illness, the illness, disease or disease Disease include anaphylactia (atopic dermatitis, contact dermatitis, allergic rhinitis) and other illnesss such as COPD, asthma or Pulmonary emphysema.

The present invention includes one or more functions such as cell factor generation or cell-mediated thin for the treatment of wherein T cell Cellular toxicity is abnormal or the method for worthless illness, disease or illness, the illness, disease or illness include rheumatoid and closed Save the cancer in acute or chronic repulsion or the hematopoiesis source of inflammation, multiple sclerosis, cell tissue or organ graft.

In addition, the present invention includes the method for the treatment of neurodegenerative disease, angiocardiopathy and platelet aggregation.

In addition, the present invention includes treatment disease of skin such as porphyria cutanea tarda, polymorphous light eruption (polymorphous light eruption), dermatomyositis, urticaria solaris, oral lichen planus, panniculitis, chorionitis, The method of urticarial vasculitis.

In addition, the present invention includes the method for the treatment of chronic inflammatory disease such as sarcoidosis, granuloma annulare.

In other embodiments, illness or disorder are selected from (as PI3K is mediated)：Polycythemia vera, primary Piastrenemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS (ARDS), Loew Le are comprehensive Simulator sickness, eosinophilic pneumonia, parasite (particularly metazoa) infect (including increased tropical eosinophils), bronchus Pulmonary aspergilosis, PAN (including Qiu-this syndrome), eosinophilic granuloma, the influence as caused by drug response The disorder relevant with acidophic cell of air flue, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, blister Rash sample dermatitis, chorionitis, leucoderma, allergic vasculitis, nettle rash, bullous pemphigoid, lupus erythematosus, pemphigus (pemphisus), posterior bullous epidermis release, (such as hemolytic anemia, aplastic are poor for autoimmune hematological disease Blood, pure red cell anaemia and essential thrombocytopenia are reduced), systemic loupus erythematosus, polychondritis, chorionitis, Wegener Granulomatosis, dermatomyositis, CAH, myasthenia gravis, steven-Johnson syndrome, idiopathic sprue, itself Immunity inflammatory bowel disease (such as ulcerative colitis and Crohn disease), endocrine ophthalmopathy, Graves disease, sarcoidosis, lung Steep inflammation, chronic anaphylaxis pneumonia, multiple sclerosis, PBC, (front and rear) uveitis, interstitial lung Fibrosis, psoriatic arthritis, glomerulonephritis, angiocardiopathy, atherosclerosis, hypertension, dvt shape Into, it is apoplexy, miocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolysis disease, Acute arterial ischeamia, outer All thrombotic occlusions and coronary artery disease, reperfusion injury, retinopathy, such as diabetic retinopathy or hyperbaric oxygen draw The retinopathy risen, and illness, such as glaucoma characterized by raising intraocular pressure or aqueous humor secretion.

In some embodiments, disorder extremely related PI3K is pain.

In another embodiment, the compounds of this invention can be used for treatment to be selected from following illness or illness：Primary Cutaneous B cell lymphoma, immunity bubble disease (immunobullous disease), pemphigus vulgaris, fallen leaves property day Blister sore, Brazilian pemphigus (Fogo selvagem), tumour form sign pemphigus (paraneoplastic Pemphigus), bullous pemphigoid, mucosal pemphigus, acquired epidermolysis bullosa, the anti-place of chronic graft Main disease, dermatomyositis, systemic loupus erythematosus, vasculitis, polyangitis, low complement courage and uprightness urticarial vasculitis (hypocomplementemic urticarial vasculitis), anti-neutrophil cell cytoplasmic antibody associated vessels Inflammation, cryoglobulinemia, Schnitzler syndromes, macroglobulinemia Waldenstron, angioedema, hickie, it is System property lupus erythematosus, ITP, multiple sclerosis, cold coagulation disease, Autoimmune hemolytic are poor Blood, anti-neutrophil cell cytoplasmic antibody associated vasculitis, graft versus host disease(GVH disease), cryoglobulinemia and thrombotic blood are small Plate reduces disease.

In other embodiments, the present invention can be used for treating, prevent or alleviating autoimmunity disease and inflammatory disease Disease, particularly teiology includes the inflammatory condition of LADA component, such as arthritis (such as it is rheumatoid arthritis, slow Property enter fertility arthritis (arthritis chronic progrediente) and arthritis deformans) and rheumatic disease, bag Include the inflammatory condition and rheumatic disease for involving bone lesion；Inflammatory pain, spondyloarthropathy (including ankylosing spondylitis, Lai Te That syndrome, adjuvant arthritis, psoriatic arthritis and enteropathic arthritis (enterophathics arthritis), Hypersensitivity (including air flue hypersensitivity and skin hypersensitivity) and allergy.The specific LADA disease of antibody of the present invention can be used Disease includes autoimmune hematological illness (including such as hemolytic anemia, alpastic anemia, pure red cell anaemia and spy Hair property thrombopenia), Acquired hemophilia A, cold coagulation disease, cryoglobulinemia, thrombotic thrombocytopenic it is purple Purplish or white patches on the skin, Sjogren syndrome, systemic loupus erythematosus, inflammatory muscular disorders, polychondritis, scleroderma, anti-neutrophil cell kytoplasm Antibody associated vasculitis, DPN, opsoclonia-myoclonic syndrome, wegener granulomatosis, the musculus cutaneus of IgM mediations Inflammation, CAH, myasthenia gravis, psoriasis, Si-about syndrome, pemphigus vulgaris, pemphigus foliaceus, spy (including for example ulcerative colitis, regional enteritis and intestines easily swash are comprehensive for hair property sprue, autoimmune inflammatory enteropathy Simulator sickness), endocrine ophthalmocace change, Graves disease, sarcoidosis, multiple sclerosis, neuromyelitis optica, primary biliary liver it is hard Change, juvenile-onset diabetes (type i diabetes), uveitis (anterior uveitis, intermediate uveitis and posterior uveitis and complete Uveitis), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulus Ephritis (with without nephrotic syndrome, such as including idiopathic nephrotic syndrome or minute nephropathy), tumour, skin With cornea inflammatory disease, myositis, bone graft relaxation, metabolic disorder such as atherosclerosis, diabetes and dyslipidemia (dislipidemia)。

In some embodiments, the invention provides the therapeutical uses of compound shown in formula (I), other embodiments In, treatment of the described treatment for the disease related to PI3K inhibitory action.In other embodiments, can treat Disease is selected from above-mentioned list of diseases, including autoimmune disease, diseases associated with inflammation, anaphylactia, airway disorders (e.g., heavy breathing Asthma and COPD), graft rejection；Antibody tormation, antibody present, cell factor generates or lymphoid organ formation is abnormal or can not The illness or disease taken, including rheumatoid arthritis, pemphigus vulgaris, ITP, systematicness Lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren syndrome, autoimmune hemolytic anemia, ANCA associated vessels Inflammation, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic auto-immune nettle rash, allergy (idiopathic skin Inflammation, contact dermatitis, allergic rhinitis), Goodpasture's syndrome, AMR (antibody-mediated graft rejection), B cell mediation Super acute, acute and chronic graft rejection and hematopoiesis source cancer, including but not limited to Huppert's disease；Leukaemia；It is acute Myelogenous leukemia；Chronic myelogenous leukemia；Lymphocytic leukemia；Myeloid leukemia；NHL；Lymthoma； Polycythemia vera；Primary thrombocytosis；Myelofibrosis with metaplasia outside marrow；With Walden Si Telun Disease.Wherein described illness or disease are selected from rheumatoid arthritis (RA), pemphigus vulgaris (PV), essential thrombocytopenia and reduced Property purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune hemolytic anemia (AIHA), acquired blood friend Sick A types (AHA), systemic loupus erythematosus (SLE), multiple sclerosis (MS), myasthenia gravis (MG), Sjogren syndrome (SS), ANCA associated vasculitis, cryoglobulinemia, chronic auto-immune nettle rash (CAU), allergy (atopic dermatitis, connect Touch property dermatitis, allergic rhinitis), Goodpasture's syndrome, graft rejection and make haematogenous cancer；Equally it can treat and exempt from Epidemic disease related disease of science or infection, such as severe malaria, cerebral malaria, trypanosomiasis, leishmaniasis, toxoplasmosis and cerebral cysticercosis Disease.

Therefore, in some more particular embodiments, the present invention relates to the compound of any of above embodiment in PI3K The application of disease mediated medicine manufacture view；In other embodiments, the medicine is that treatment suppresses with PI3K Act on the medicine of related disease；In other embodiments, the disease that can be treated is selected from above-mentioned list of diseases, including Autoimmune disease, diseases associated with inflammation, anaphylactia, airway disorders (e.g., asthma and COPD), graft rejection；Antibody tormation, It is abnormal or worthless illness or disease that antibody, which is presented, cell factor generation or lymphoid organ are formed, including rheumatoid Arthritis, pemphigus vulgaris, ITP, systemic loupus erythematosus, multiple sclerosis, severe flesh without Power, Sjogren syndrome, autoimmune hemolytic anemia, ANCA associated vasculitis, cryoglobulinemia, Thrombotic Thrombocytopenic Reduction property purpura, chronic auto-immune nettle rash, allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), Gourde(G) Super acute, the acute and chronic graft rejection and make that Paasche mound syndrome, AMR (antibody-mediated graft rejection), B cell mediate Blood source cancer, including but not limited to Huppert's disease；Leukaemia；Acute myeloid leukaemia；Chronic myelogenous leukemia；Lymph is thin Born of the same parents' property leukaemia；Myeloid leukemia；NHL；Lymthoma；Polycythemia vera；Idiopathic thrombocythemia Disease；Myelofibrosis with metaplasia outside marrow；And Waldenstrom.Wherein described illness or disease are selected from rheumatoid Arthritis (RA), pemphigus vulgaris (PV), ITP (ITP), thrombotic thrombocytopenic are purple Purplish or white patches on the skin (TTP), autoimmune hemolytic anemia (AIHA), Acquired hemophilia A type (AHA), systemic loupus erythematosus (SLE), Multiple sclerosis (MS), myasthenia gravis (MG), Sjogren syndrome (SS), ANCA associated vasculitis, cryoglobulinemia, Chronic auto-immune nettle rash (CAU), allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), Goodpasture Syndrome, graft rejection and make haematogenous cancer；The disease related to immunopathology or infection can be equally treated, it is such as serious Malaria, cerebral malaria, trypanosomiasis, leishmaniasis, toxoplasmosis and cerebral cysticercosis.

General building-up process

For the description present invention, embodiment is listed below.But it is to be understood that the invention is not restricted to these embodiments, it is The method that the practice present invention is provided.

Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent such as formula (I).Following reaction scheme and embodiment are used to this is further illustrated The content of invention.

The professional of art will be recognized that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and other methods of the compound for preparing the present invention are considered as the model in the present invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention Completed by method of modifying, such as appropriate protection interference group, by using other known reagent except described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the invention.

The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified during use, unless other aspects show.In general reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Teng Long chemical reagent Co., Ltd, and Haiyang Chemical Plant, Qingdao's purchase It can buy.

Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMA and N, N- Dimethylformamide is to dry to use in advance through anhydrous sodium sulfate.

Reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects below Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.

Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.The survey of proton nmr spectra Strip part is：Under room temperature condition, Brooker (Bruker) 400MHz or 600MHz nuclear magnetic resonance spectrometer, with CDC1₃、DMSO-d₆、CD₃OD Or acetone-d₆For solvent (in units of ppm), reference standard is used as by the use of TMS (0ppm) or chloroform (7.26ppm).It is more when occurring When weight peak, following abbreviation will be used：S (singlet, unimodal), d (doublet, bimodal), t (triplet, it is triple Peak), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), Dt (doublet of triplets, double triplets).Coupling constant, represented with J, unit is hertz (Hz).

The test condition of Algorithm (MS) data is：Quadrupole HPLC-MS (the pillars of Agilent 6120 Model：Zorbax SB-C18,2.1 × 30mm, 3.5 μm, 6min, flow velocity 0.6mL/min, mobile phase：5%-95% (contains The CH of 0.1% formic acid₃CN) (H of 0.1% formic acid is being contained₂O the ratio in)), detected in 210nm/254nm with UV, use electron spray Ionization pattern (ESI).

The characteristic manner of compound purity is：The preparative high performance liquid chromatographies of Agilent 1260 (Pre-HPLC) or The preparative high performance liquid chromatographies of Calesep Pump 250 (Pre-HPLC) (pillar model：NOVASEP, 50/80mm, DAC), 210nm/254nm is detected with UV.

The use of brief word below is through the present invention：

ATP atriphos

AcOH,HAc,HOAc,CH₃COOH acetic acid, acetic acid

AcOK,CH₃COOK potassium acetates

AIBN azodiisobutyronitriles

BBr₃Boron tribromide

Bu₄NF tetrabutyl ammonium fluorides

Burgess reagent (Burgess Reagent) N- (triethyl ammonium sulphonyl) methyl carbamate

2,2'- pairs-(diphenyl phosphine) -1,1'- dinaphthalenes of BINAP

BSA bovine serum albumin(BSA)s

BOC, Boc tert-butoxycarbonyl

N-BuOH n-butanols

N-BuLi n-BuLis

(n-Bu)₃SnCl tri-n-butyltin chlorides

Ca(SO₃CF₃)₂Trifluoromethyl calcium sulfate

Cs₂CO₃Cesium carbonate

CCl₄Carbon tetrachloride

CHCl₃Chloroform

CDCl₃Deuterochloroform

CH₂Cl₂, DCM dichloromethane

CH₃CN acetonitriles

CH₃CHCN propionitrile

(CH₃)₂CHCN isobutyronitriles

CH₃Cl chloromethanes

CH₃I iodomethane

CsF cesium fluorides

CH₃SO₂Cl, MsCl methylsufonyl chloride

Cu copper

CuI cuprous iodides

DCC N, N'- dicyclohexylcarbodiimides

Carbon -7- the alkene of DBU 1,8- diazabicylos [5.4.0] 11

D₂Deuterium

DIBAL diisobutyl aluminium hydrides

DIAD diisopropyl azodiformates

DIEA, DIPEA, iPr₂Net N, N- diisopropylethylamine

DEAD diethyl azodiformates

DMF DMFs, dimethylformamide

DMAP DMAPs

DMSO dimethyl sulfoxide (DMSO)s

DMFDMA N,N-dimethylformamide dimethylacetals

DPPA diphenyl phosphate azides

DTT DTTs

EDC, EDCI 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides

EDTA ethylenediamine tetra-acetic acids

EtOAc, EA ethyl acetate

Et₃N, TEA triethylamine

Et₂O ether

EtOH ethanol

FBS hyclones

G grams

H hours

HATU 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters

HBr hydrobromic acids

HBTU O- BTAs-N, N, N', N'- tetramethylurea hexafluorophosphates

HCl hydrochloric acid

HOAT N- hydroxyl -7- azepine BTAs

HOBt I-hydroxybenzotriazole hydrates

H₂Hydrogen

H₂O water

H₂O₂Hydrogen peroxide

H₃PO₄Phosphoric acid

H₂SO₄Sulfuric acid

HNO₃Nitric acid

HCOOK potassium formates

HCOONH₄Ammonium formate

HMDS hmds

I₂Iodine

Fe iron

The silicon substrate base lithium of LiHMDS hexamethyls two

LDA lithium diisopropyl amidos

MBP myelin alkaline proteins

MCPBA metachloroperbenzoic acids

MeCN,CH₃CN acetonitriles

MgSO₄Magnesium sulfate

Mg ATP adenosine triphosphate magnesium

MeOH,CH₃OH methanol

MeI,CH₃I iodomethane

MOPS 3- (N- morpholinoes) propane sulfonic acid

ML, ml milliliter

Min minutes

N₂Nitrogen

NH₃Ammonia

NMP 1-METHYLPYRROLIDONEs

NaHCO₃Sodium acid carbonate

NaBH₄Sodium borohydride

NaBH₃CN sodium cyanoborohydrides

NaOtBu sodium tert-butoxides

NaOMe,NaOCH₃,CH₃ONa sodium methoxides

NaOH sodium hydroxides

NaClO₂Sodium chlorite

NaCl sodium chloride

NaH₂PO₄Sodium dihydrogen phosphate

NaH sodium hydrides

NaI sodium iodides

Na₂SO₄Sodium sulphate

Na₂S₂O₃Sodium thiosulfate

NBS N- bromo-succinimides

NIS N- N-iodosuccinimides

NCS N- chlorosuccinimides

NEt₃Triethylamine

Nonidet promises are lotion

NH₃Ammonia

NH₄Cl sal-ammoniacs

NH₂OHHCl hydroxylamine hydrochlorides

(NH₄)₂Ce(NO₃)₆Ammonium ceric nitrate

Pd/C palladiums/carbon

Pd₂(dba)₃Three (dibenzalacetone) two palladium

Pd(OAc)₂Palladium

Pd(OH)₂Palladium dydroxide

Pd(PPh₃)₄Tetrakis triphenylphosphine palladium

Pd(PPh₃)₂Cl₂Double (triphenylphosphine) palladium chlorides

Pd(dppf)Cl₂1,1 '-two (diphenylphosphino) ferrocene palladium chlorides

P(t-Bu)₃Three (tert-butyl group) phosphines

PE petroleum ethers (60-90 DEG C)

PBS phosphate buffered saline (PBS)s

POCl₃POCl3

PhI(OAc)₂Iodobenzene diacetate

K₂CO₃Potassium carbonate

KOH potassium hydroxide

RT, rt, r.t. room temperature

Rt retention times

SOCl₂Thionyl chloride

SO₂Cl₂Sulfonic acid chloride

T-BuOK potassium tert-butoxides

TBTU O- BTAs-N, N, N', N'- tetramethylurea tetrafluoro boric acid esters

THF tetrahydrofurans

TFA trifluoroacetic acids

TBAI tetrabutylammonium iodides

TBS trimethylolaminomethane buffered salines

TEAC bis- (tetraethyl ammonium) carbonate

Tris trishydroxymethylaminomethanes

TsCl paratoluensulfonyl chlorides

X-Phos 2- dicyclohexyl phosphorus -2', 4', 6'- tri isopropyl biphenyls

Zn zinc

μ L microlitre

Following synthetic schemes lists the experimental procedure for preparing compound disclosed in the present invention.Wherein, each R¹、R²、R³、R⁴ There is definition as described in the present invention with X, " PG " is suitable alkynyl blocking group.

Synthetic schemes 1

Intermediate(7)It can be prepared by the method described in synthetic schemes 1.First, benzoic acid derivative(1) And SOCl₂In non-polar solven (e.g., toluene), at a reflux temperature reaction generation acid chloride intermediate, acid chloride intermediate again and Amino-compound(2)Reaction generation compound(3).Compound(4)Elder generation and SOCl₂In non-polar solven, at a reflux temperature Reaction generation acid chloride intermediate, acid chloride intermediate is again and compound(3)Reaction generation compound(5).Nitro compound(5)In zinc Reduction and cyclisation generation compound occur in the presence of powder and sour (such as acetic acid)(6).Compound(6)Finally in the effect of acid Under, take off the blocking group generation intermediate on amino(7)。

Synthetic schemes 2

Intermediate(7)It can also be prepared by the method described in synthetic schemes 2.Benzoic acid derivative(8)First and SOCl₂In non-polar solven (such as toluene), reaction generation acid chloride intermediate at a reflux temperature, acid chloride intermediate is again and amino Compound(2)Reaction generation compound(9).Compound(9)In the presence of EDCI or HATU with compound(4)Generation condensation is anti- Compound should be generated(10), compound(10)Cyclization generation intermediate finally occurs under the catalytic action of iodine(7)。

Synthetic schemes 3

Synthetic schemes 3 also illustrates intermediate(7)Preparation method.First, N- hydroxysuccinimides(11)And chemical combination Thing(4)Generation condensation reaction generates compound(12).Compound(12)Further and amino-compound(9)Generation cyclization is given birth to Into bis-heterocyclic compounds(6).Finally, compound(6)Under the action of an acid, the blocking group generation intermediate on amino is taken off(7)。

Synthetic schemes 4

Compound in the present invention can be prepared by the method described in above-mentioned synthetic schemes 4.Synthesize herein In scheme, compound(13)Elder generation and NH₃Methanol solution reaction generation amino-compound(14).Compound(14)In alkalescence condition Lower and intermediate(7)React generation compound(15).Compound(15)In aldehyde radical can be in oxidant (such as NaClO₂) In the presence of be oxidized to carboxyl, carboxylic acid compound(16)Further with compound(17)Condensation generation compound(18).Finally, Compound(18)Cyclization generation kinase targets suppression can occur under burgess reagent (Burgess reagent) effect Preparation(19)。

Synthetic schemes 5

Compound in the present invention can also be prepared by the method described in above-mentioned synthetic schemes 5.Compound(20)Iodide reaction generation compound occurs with NIS(21).Bromo compound(22)With compound(23)In alkali (such as normal-butyl Lithium) in the presence of with compound(23)React generation compound(24).Compound(24)In suitable Pd catalyst (such as Pd (PPh₃)₂Cl₂) the lower generation coupling reaction generation compound of effect(25).Finally, compound(25)In the basic conditions, backflow temperature Spend lower and intermediate(7)Reaction generation targeted kinase inhibitor(26)。

Synthetic schemes 6

Compound as shown in chemical formula (I) formula can be prepared by the method described in synthetic schemes 6. Compound(13)Elder generation and SO₂Cl₂Reaction generation chloride compounds(27).Compound(27)Again with compound(17)React generationization Compound(28).Compound(28)The compound of generation amino substitution is reacted with ammonia(29).Compound(29)Can be in burgess Reagent (Burgess reagent) effect is lower to occur cyclization generation compound(30).Finally, compound(30)In alkaline bar Under part, under reflux temperature with intermediate(7)Reaction generation targeted kinase inhibitor(31)。

Synthetic schemes 7

Compound as shown in chemical formula (I) formula can also be prepared into by the method described in synthetic schemes 7 Arrive.Acetonitrile(32)First and hydroxylamine hydrochloride reacts generation compound in the basic conditions(33).Compound(33)With compound(27) Reaction generation compound(34).Compound(34)The compound of generation amino substitution is reacted with ammonia(35).Compound(35) Bu₄Cyclisation generation compound occurs in the presence of NF(36).Finally, compound(36)In the basic conditions, under reflux temperature With intermediate(7)Reaction generation targeted kinase inhibitor(37)。

Synthetic schemes 8

The preparation method of the compound as shown in chemical formula (I) formula is also illustrated in synthetic schemes 8.Compound(27)Elder generation and compound(38)Reaction generation compound(39).Compound(39)The compound of generation amino substitution is reacted with ammonia(40).Compound(40)In hydroxyl in chlorinating agent (such as POCl₃Or SOCl₂) Cl is changed under effect.Chlorinated compound(41) Cyclization generation compound occurs under alkalescence condition(42).Finally, compound(42)In the basic conditions, under reflux temperature with Intermediate(7)Reaction generation targeted kinase inhibitor(43)。

Synthetic schemes 9

The preparation method of the compound as shown in chemical formula (I) formula is also illustrated in synthetic schemes 9.Compound(27)Generation amide compound is reacted with ammonia(44).Compound(44)Reacted with sodium methoxide and generate the acyl of methoxy substitution Amines(45).Compound(45)Generation compound is reacted with DMFDMA(46).Compound(46)With compound(47)In acid Property under the conditions of occur cyclization generation compound(48).Compound(48)Compound is generated in the presence of concentrated hydrochloric acid and acetic acid(49).Compound(49)In hydroxyl in chlorinating agent (such as POCl₃Or SOCl₂) Cl generation compounds are changed under effect(50)。 Compound(50)Reacted with the methanol solution of ammonia and a Cl in compound is changed into amino.Finally, compound(51) Under alkalescence condition, under reflux temperature with intermediate(7)Reaction generation targeted kinase inhibitor(52)。

Synthetic schemes 10

Synthetic schemes 10 also illustrates intermediate(7)Preparation method.First, compound(8)With triphosgene in backflow temperature React generation compound under degree(53).Compound(53)Further and amino-compound(2)React generation compound(9).Compound(9)With compound(4)Condensation reaction generation compound occurs in the presence of HATU and alkali(10).Compound(10)In N, the double trimethylsilyl acetamides of O-, cyclization generation dicyclic compound occurs in the presence of DMAP and alkali(6).Most Afterwards, compound(6)Under the action of an acid, the blocking group generation intermediate on amino is taken off(7)。

Synthetic schemes 11

Targeted kinase inhibitor(60)It can be prepared by the method described in synthetic schemes 11.First, chemical combination Thing(13)React generation compound at a reflux temperature with sodium methoxide(54).Compound(54)Again in the presence of a base with hydroxylamine hydrochloride Reaction generation compound(55).Next, compound(55)In (NH₄)₂Ce(NO₃)₆It is catalyzed lower and cyano compound(56)Occur Addition cyclization generates compound(57).Compound(57)Flowed back again in the presence of chlorinating agent (such as POCl3), will thereon The methoxyl group in face changes into chlorine, generates compound(58).Compound(58)The reaction generation mono amino substitution under ammonia atmosphere Compound(59).Compound(59)Finally and intermediate(7)React generation targeted kinase inhibitor in the basic conditions(60)。

Synthetic schemes 12

Targeted kinase inhibitor(67)It can be prepared by the method described in synthetic schemes 12.Compound(13) Generation formaldehyde oxime compound is first reacted with hydroxylamine hydrochloride in the basic conditions(61).Compound(61)Again with N- chloro succinyl Imines (NCS) reaction generation compound(62).Compound(62)In the basic conditions with alkynyl compounds(63)Generation cyclisation is anti- Compound should be generated(64).Compound(64)The compound of reaction generation mono amino substitution under ammonia atmosphere(65).Alkynyl is protected Shield group " PG " includes but is not limited to TMS, TES or TIPS.Compound(65)In alkynyl blocking group " PG " can be in alkali The aqueous solution, take off in the presence of TBAF or CsF etc. protection group generation compound (66).Finally, compound(66)With intermediate(7) Reaction generation targeted kinase inhibitor in the basic conditions(67)。

Synthetic schemes 13

Targeted kinase inhibitor(72)It can be prepared by the method described in synthetic schemes 13.Compound(44) Elder generation and compound(68)Reaction generation compound(69).Compound(69)Flowed back again in the presence of chlorinating agent (such as POCl3), Methoxyl group above it is changed into chlorine, generates compound(70).Next, compound(70)Generation is reacted under ammonia atmosphere The compound of mono amino substitution(71).Compound(71)Finally and intermediate(7)React generation target in the basic conditions Kinase inhibitor(72)。

Synthetic schemes 14

Targeted kinase inhibitor(78)It can be prepared by the method described in synthetic schemes 14.Compound(73) Reduction reaction generation compound first occurs(74).Compound(74)Reacted again with methylating reagent and the hydrogen on hydroxyl is converted into first Base generates compound(75).Compound(75)Flowed back again in the presence of chlorinating agent (such as POCl3), by the methoxyl group above it Chlorine is changed into, generates compound(76).Next, compound(76)The chemical combination of reaction generation mono amino substitution under ammonia atmosphere Thing(77).Compound(77)Finally in the basic conditions with intermediate(7)Reaction generation targeted kinase inhibitor(78)。

Synthetic schemes 15

Targeted kinase inhibitor(81)It can be prepared by the method described in synthetic schemes 15.Compound(79) With the methanol solution reaction generation amides compound of ammonia(80).Compound(80)In the basic conditions with intermediate(7)Reaction Generate targeted kinase inhibitor(81)。

Synthetic schemes 16

Targeted kinase inhibitor(85)It can be prepared by the method described in synthetic schemes 16.Compound(46) Cyclization generation compound occurs with hydroxylamine hydrochloride in the basic conditions(82).Compound(82)In methoxyl group in chlorination base POCl₃In the presence of change into chlorine, generate compound(83).Compound(83)First reacted with ammonia by a chlorine in compound Amino is changed into, generates compound(84).Compound(84)Finally in the basic conditions with intermediate(7)Reaction, generate target Kinase inhibitor(85)。

Embodiment

Following examples are used to illustrate the present invention, but are not limited to the scope of the present invention.

Embodiment 1 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) Propyl group) chloro- 3- phenylquinazolines -4 (3H) -one of -5-

The chloro- N- phenylbenzamaides of step 1) 2- amino -6-

Compound 2- amino -6- chlorobenzoic acids (10.30g, 60.0mol) are dissolved in toluene (250mL), then in room Under the conditions of temperature, thionyl chloride (24mL, 330.4mmol) is added dropwise, reactant mixture is stirred overnight at 120 DEG C, then subtracted Pressure is concentrated to give the grease of brown, and the grease is directly used in and reacted in next step without being further purified.

The grease of acyl chlorides derived above is dissolved in chloroform (250mL), then thereto add aniline (12mL, 131.4mmol), reactant mixture stirring reaction at 80 DEG C after 5 hours, is cooled to room temperature, then is concentrated under reduced pressure, gained residue Through silica gel column chromatography (PE/EtOAc (v/v)=10/1) purify, obtain title compound for faint yellow solid (10.66g, 72.0%).

MS(ESI,pos.ion)m/z:247.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.71 (br.s, 1H), 7.65 (d, J=7.9Hz, 2H), 7.41 (t, J =7.9Hz, 2H), 7.21 (t, J=7.4Hz, 1H), 7.13 (t, J=8.1Hz, 1H), 6.80 (d, J=7.9Hz, 1H), 6.66 (d, J=8.2Hz, 1H).

Step 2) (S) -2,5- dioxo pyrrolidin -1- bases 2- (tertbutyloxycarbonyl) amino) methyl butyrate

By compound 1- hydroxyl pyrrolidine -2,5- diketone (5.80g, 50.4mmol) and (S) -2- ((tertbutyloxycarbonyl) ammonia Base) butyric acid (10.00g, 49.2mmol) is dissolved in THF (120mL), then at 0 DEG C, add thereto DCC (10.20g, 49.4mmol), reactant mixture is stirred overnight at 0 DEG C, is then filtered, and filter cake is washed with ethyl acetate (50mL × 3), will be obtained Filtrate decompression concentration, add ethyl acetate (500mL) residue is dissolved, gained mixture uses saturation NaHCO successively₃It is water-soluble Liquid (100mL) and saline solution (100mL) washing, isolated organic phase anhydrous Na₂SO₄Dry, be then concentrated under reduced pressure.Institute Residue through silica gel column chromatography (PE/EtOAc (v/v)=3/1) purify, obtain title compound for white solid (14.57g, 98.6%).

MS(ESI,pos.ion)m/z:201.2[M–Boc+H]⁺, 323.2 [M+Na]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):5.03 (d, J=6.9Hz, 1H), 4.66 (d, J=7.4Hz, 1H), 2.86 (s, 4H), 2.02 (m, 1H), 1.90 (m, 1H), 1.48 (s, 9H), 1.09 (t, J=7.3Hz, 3H).

Step 3) (S)-(1- (the chloro- 4- oxos -3- phenyl -3,4- dihydroquinazolines -2- bases of 5-) propyl group) carbamic acid uncle Butyl ester

By the chloro- N- phenylbenzamaides (4.58g, 18.56mmol) of compound 2- amino -6- and (S) -2,5- dioxo pyrroles Cough up alkane -1- bases 2- (tertbutyloxycarbonyl) amino) methyl butyrate (8.36g, 27.85mmol) is dissolved in toluene (100mL), then Dimethylamino naphthyridine (3.40g, 27.85mmol) and diisopropylethylamine (3.60g, 27.85mmol) are added thereto.Reaction Mixture stirring reaction 24 hours at 120 DEG C, are subsequently cooled to room temperature, then be concentrated under reduced pressure.Gained residue is through silica gel column layer (PE/EtOAc (v/v)=10/1) purifying is analysed, it is yellow solid (1.90g, 24.7%) to obtain title compound.

MS(ESI,pos.ion)m/z:414.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.89(br.s,1H),7.67(m,2H),7.57(m,3H),7.47(d, J=7.1Hz, 1H), 7.30 (s, 1H), 5.86 (br.s, 1H), 4.42 (m, 1H), 1.44 (s, 9H), 1.24 (q, J=8.0Hz, 1H), 1.18 (q, J=8.0Hz, 1H), 0.80 (t, J=7.4Hz, 3H).

Chloro- 3- phenylquinazolines -4 (3H) -one of step 4) (S) -2- (1- aminopropyls) -5-

By compound (S)-(1- (the chloro- 4- oxos -3- phenyl -3,4- dihydroquinazolines -2- bases of 5-) propyl group) carbamic acid The tert-butyl ester (1.90g, 4.6mmol) is dissolved in dichloromethane (50mL), then at ambient temperature, is slowly added to thereto The ethyl acetate solution (0.5M, 40mL, 20mmol) of hydrogen chloride.Reactant mixture is stirred at room temperature overnight, then is depressurized dense Contracting.Residue is dissolved in the in the mixed solvent of water (50mL) and dichloromethane (50mL), gained mixture saturated sodium carbonate The aqueous solution is adjusted to pH=10, is then extracted with dichloromethane (150mL × 3), the organic phase saturated aqueous common salt of merging (100mL × 3) are washed, and use anhydrous Na₂SO₄Dry, be concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v) =1/1) purify, it is yellow solid (550mg, 38.2%) to obtain title compound.

MS(ESI,pos.ion)m/z:314.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.60 (m, 5H), 7.49 (dt, J=7.5,1.3Hz, 1H), 7.34 (m, 1H), 7.30 (m, 1H), 3.55 (q, J=6.0Hz, 1H), 1.82 (m, 1H), 1.56 (td, J=14.2,7.1Hz, 1H), 0.83 (t, J=7.4Hz, 3H).

Step 5) 4- amino -6- chlorine pyrimidine -5-formaldehydes

By compound 4,6- dichloro pyrimidine -5- formaldehyde (19.50g, 110mmol) is suspended in toluene (220mL), Ran Houxiang The methanol solution (7M, 27mL, 189mmol) of ammonia is wherein added, reactant mixture is heated to 60 DEG C of simultaneously stirring reaction 1 hours, The methanol solution (7M, 18mL, 126mmol) of second batch ammonia is added, gained mixture continues stirring reaction 3 hours at 60 DEG C Afterwards, room temperature is cooled to, and is concentrated under reduced pressure, residue is diluted in EtOAc (50mL), gained mixture stirring 1 hour, then Filter, it is yellow solid (20.50g, 100%) to obtain title compound.

MS(ESI,pos.ion)m/z:158.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):10.25(s,1H),8.73(br.s,1H),8.57(br.s,1H), 8.40(s,1H)。

Step 6) (R) -4- amino -6- ((1- (the chloro- 4- oxos -3- phenyl -3,4- dihydroquinazolines -2- bases of 5-) propyl group) Amino) pyrimidine -5-formaldehyde

By chloro- 3- phenylquinazolines -4 (3H) -one (530mg, 1.69mmol) of compound (S) -2- (1- aminopropyls) -5- It is dissolved in n-butanol (20mL) with 4- amino -6- chlorine pyrimidine -5-formaldehydes (320mg, 2.03mmol), then adds thereto DIPEA(437mg,3.38mmol).Reactant mixture stirring reaction at 120 DEG C after 30 hours, is down to room temperature, then depressurizes dense Contracting, gained residue purify through silica gel column chromatography (PE/EtOAc (v/v)=1/1), and it is yellow solid to obtain title compound (250mg, 34.0%).

MS(ESI,pos.ion)m/z:435.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):10.25(s,1H),8.03(s,1H),7.68(s,1H),7.67(d,J =4.0Hz, 2H), 7.61 (m, 4H), 7.53 (dd, J=6.5,2.5Hz, 1H), 5.18 (td, J=7.7,4.1Hz, 1H), 1.78 (dd, J=14.6,7.5Hz, 2H), 0.90 (t, J=6.8Hz, 3H).

Step 7) (R) -4- amino -6- ((1- (the chloro- 4- oxos -3- phenyl -3,4- dihydroquinazolines -2- bases of 5-) propyl group) Amino) pyrimidine -5- formic acid

By compound (R) -4- amino -6- ((1- (the chloro- 4- oxos -3- phenyl -3,4- dihydroquinazolines -2- bases of 5-) third Base) amino) pyrimidine -5-formaldehyde (240mg, 0.55mmol) is dissolved in DCM (8mL), DMSO is then added thereto (431mg, 5.52mmol), H₃PO₄(0.75M, 2mL, 1.50mmol) and sodium chlorite (100mg, 1.10mmol), reaction mixing Reaction 5 hours is stirred at room temperature in thing, then adds DMSO (500mg, 6.40mmol), H₃PO₄(0.75M,6mL, 4.50mmol) continue stirring reaction at room temperature with sodium chlorite (200mg, 2.20mmol), gained mixture 2 hours, be used in combination Saturated sodium bicarbonate aqueous solution is adjusted to pH=5-6, then uses CH₂Cl₂(100mL × 3) extract.The organic phase salt of merging Water (100mL × 3) washs, then uses anhydrous Na₂SO₄Dry, be concentrated under reduced pressure, obtain title compound thing for yellow solid (300mg, 100%), without further purifying, it is directly used in and reacts in next step.

MS(ESI,pos.ion)m/z:451.2[M+H]⁺。

Step 8) (S)-N'- acetyl group -4- amino -6- ((1- (the chloro- 4- oxos -3- phenyl -3,4- dihydroquinazolines of 5- - 2- yls) propyl group) amino) pyrimidine -5- formylhydrazines

By compound (R) -4- amino -6- ((1- (the chloro- 4- oxos -3- phenyl -3,4- dihydroquinazolines -2- bases of 5-) third Base) amino) pyrimidine -5- formic acid (373mg, 0.828mmol) and hydrazine acetate (343mg, 4.637mmol) be dissolved in DCM (15mL) In, EDCI (317mg, 1.656mmol) and HOAT (225mg, 1.656mmol) is then added thereto, and reactant mixture is 45 Stirring reaction 24 hours at DEG C, then add acethydrazide (343mg, 4.637mmol) DCM (15mL) solution, EDCI (317mg, 1.656mmol) and HOAT (225mg, 1.656 mmol), reactant mixture continues to be stirred overnight at 45 DEG C, then Reaction is quenched with water (20mL), and mixture is extracted with DCM (100mL × 3), and the organic phase of merging is with saline solution (100mL × 3) Washing, uses anhydrous Na₂SO₄Dry, be concentrated under reduced pressure, gained residue purifies through preparative high performance liquid chromatography post, obtains titled Compound is yellow solid (130mg, 31.0%).

MS(ESI,pos.ion)m/z:507.0[M+H]⁺。

Step 9) (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) third Base) chloro- 3- phenylquinazolines -4 (3H) -one of -5-

By compound (S)-N'- acetyl group -4- amino -6- ((1- (chloro- 4- oxos -3- phenyl -3,4- dihydros quinoline azoles of 5- Quinoline -2- bases) propyl group) amino) pyrimidine -5- formylhydrazines (40mg, 0.08mmol) are dissolved in THF (2mL), then add thereto Burgess reagent (40mg, 0.16mmol), reactant mixture react 1 hour in 100 DEG C of microwaves, are then concentrated under reduced pressure, gained Residue through silica gel column chromatography (PE/EtOAc (v/v)=1/3) purify, obtain title compound for buff white solid (25mg, 65.8%).

MS(ESI,pos.ion)m/z:489.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):9.56 (s, 1H), 8.02 (s, 1H), 7.74 (m, 1H), 7.65 (d, J= 4.5Hz, 2H), 7.56 (m, 5H), 7.37 (m, 1H), 7.33 (m, 1H), 5.23 (td, J=7.7,4.7Hz, 1H), 2.77 (s, 3H), 1.85 (dd, J=14.6,7.1Hz, 2H), 1.01 (d, J=6.7Hz, 3H).

Embodiment 2 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) Propyl group) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

The chloro- N- cyclopropyl -6- nitrobenzamides of step 1) 2-

At room temperature, the chloro- 6- nitrobenzoic acids (10g, 49.61mmol) of compound 2- are suspended in toluene (50mL), Then SOCl is added dropwise into the yellow solution₂(5.28mL, 74.41mmol), after dripping, reactant mixture is placed in Reacted overnight at 110 DEG C, be then concentrated under reduced pressure, residue is dissolved in Isosorbide-5-Nitrae-dioxane (30mL), at 5 DEG C, Xiang Qi Middle addition cyclopropylamine (3.43mL, 49.61mmol) and NaHCO₃The 1,4- dioxane (30mL) of (8.34g, 99.22mmol) Suspension, gained mixture be stirred at room temperature reaction 24 hours after, filter, filtrate is through being concentrated under reduced pressure to give title compound Thing is yellow powder (11.66g, 98%), without being further purified, is directly used in and reacts in next step.

MS(ESI,pos.ion)m/z:241.0[M+H]⁺。

Step 2) (S)-(1- (the chloro- N- cyclopropyl -6- nitrobenzamides of 2-) -1- oxo-butanes -2- bases) carbamic acid The tert-butyl ester

The chloro- N- cyclopropyl -6- nitrobenzamides (1.19g, 4.9mmol) of compound 2- are dissolved in toluene (20mL) In, SOCl is then added dropwise thereto₂(3.35mL,49.2mmol).After adding, reaction solution is stirred overnight at 120 DEG C, Then brown oil (2.79g, 100%) is concentrated under reduced pressure to give, it is not purified, it is directly used in and reacts in next step.

Compound Boc-L-2- aminobutyric acids (1.50g, 7.38mmol) and DIPEA (1.68g, 12.98mmol) are dissolved In dichloromethane (10mL), then at 0 DEG C, the dichloromethane (30mL) of brown oil obtained above is added thereto Solution, gained reaction solution be stirred at room temperature reaction 24 hours after, successively with 4% aqueous citric acid solution (100mL), saturation NaHCO₃The aqueous solution (100mL) and saline solution (30mL) washing, liquid separation, obtained organic phase anhydrous Na₂SO₄Dry, decompression Concentration.Gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=8/1), and it is yellow solid to obtain title compound (1.41g, 67.6%).

MS(ESI,pos.ion)m/z:326.2[M-Boc+H]⁺。

Step 3) (S)-(1- (the chloro- 3- cyclopropyl -4- oxos -3,4- dihydroquinazolines -2- bases of 5-) propyl group) carbamic acid The tert-butyl ester

By compound (S)-(1- (the chloro- N- cyclopropyl -6- nitrobenzamides of 2-) -1- oxo-butanes -2- bases) amino first Tert-butyl acrylate (1.41g, 3.31 mmol) is dissolved in acetic acid (25mL), then thereto add zinc powder (1.13g, 17.31mmol), after adding, reaction solution is stirred at room temperature overnight, and then adds NaHCO₃PH=7-8 is neutralized to, institute Obtain mixture to be extracted with ethyl acetate (200mL × 3), the organic phase anhydrous Na of merging₂SO₄Dry, be concentrated under reduced pressure, residue It is white solid (863mg, 69%) to obtain title compound through silica gel column chromatography (PE/EtOAc (v/v)=50/6) purifying.

MS(ESI,pos.ion)m/z:378.1[M+H]⁺。

Chloro- 3- cyclopropyl quinazoline -4 (3H) -one of step 4) (S) -2- (1- aminopropyls) -5-

By compound (S)-(1- (the chloro- 3- cyclopropyl -4- oxos -3,4- dihydroquinazolines -2- bases of 5-) propyl group) amino first Tert-butyl acrylate (3.01g, 7.97 mmol) is dissolved in ethyl acetate (11mL), then at room temperature, adds hydrogen chloride thereto Ethyl acetate (3.5M, 15mL) solution, mixture be stirred at room temperature reaction 5.5 hours, be then dissolved in water (150mL) In, gained mixture is extracted with ethyl acetate (100mL).Liquid separation, add NaHCO₃Obtained aqueous phase is adjusted to pH=6 by powder, Then extracted again with EtOAc and MeOH mixed solvent (EtOAc/MeOH (v/v)=100/2,200mL × 3), merging has Machine is mutually washed with saline solution (100mL), uses anhydrous Na₂SO₄Dry, be concentrated under reduced pressure, it is yellow powder to obtain title compound (2.11g, 96%).

MS(ESI,pos.ion)m/z:278.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.67 (t, J=7.9Hz, 1H), 7.52 (d, J=8.1Hz, 1H), 7.47 (d, J=7.8Hz, 1H), 4.43-4.30 (m, 1H), 3.06-2.95 (m, 1H), 1.88-1.74 (m, 1H), 1.62- 1.49 (m, 1H), 1.27-1.15 (m, 2H), 1.00-0.90 (m, 4H), 0.73 (dd, J=8.5,3.6Hz, 1H).

Step 5) 4,6- dichloro pyrimidine -5- formyl chlorides

By compound 4,6- dichloro pyrimidine -5- formaldehyde (10g, 56.5mmol), SO₂Cl₂(11.44g, 84.75mmol), AIBN (0.464g, 2.83 mmol) and CCl₄The mixture of (100mL) stirring reaction at 80 DEG C after 5 hours, is cooled to room Temperature, filter, it is yellow oil (11.9g, 99.6%) that filtrate decompression is concentrated to give into title compound.

Step 6) N'- acetyl group -4,6- dichloro pyrimidine -5- formylhydrazines

Compounds acetic acid hydrazine (1.39g, 18.74mmol) is suspended in CH₂Cl₂In (40mL), then at 0 DEG C, thereto DIPEA (4.84g, 37.48mmol) is added, next adds 4,6- dichloro pyrimidine -5- formyl chlorides (4g, 18.74mmol) Dichloromethane (20mL) solution.Reaction solution stirring reaction 30 minutes at 0 DEG C, then add EtOAc (400mL) and dilute, and according to Secondary saturation NH₄The Cl aqueous solution (150 mL) and saline solution (100mL) washing, liquid separation, obtained organic phase anhydrous Na₂SO₄It is dry It is dry, and be concentrated under reduced pressure.Gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=1/2), and it is white to obtain title compound Color solid (1.78g, 38%).

MS(ESI,neg.ion):246.9[M-H]^-；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):10.92 (d, J=2.5Hz, 1H), 10.48 (d, J=2.6Hz, 1H),9.03(s,1H), 1.93(s,3H)。

Step 7) N'- acetyl group -4- amino -6- chlorine pyrimidine -5- formylhydrazines

By compound N '-acetyl group -4,6- dichloro pyrimidine -5- formylhydrazines (1.78g, 7.20mmol) are suspended in tetrahydrofuran In (80mL), ammonia is then filled with thereto.After reaction is stirred at room temperature 4 hours in reaction solution, filter, then filtrate decompression is dense Contracting, gained residue purify through silica gel column chromatography (PE/EtOAc (v/v)=1/2), and it is white solid to obtain title compound (1.06g, 64.2%).

MS(ESI,pos.ion):230.0[M+H]⁺。

The chloro- 5- of step 8) 6- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine -4- amine

By compound N '-acetyl group -4- amino -6- chlorine pyrimidine -5- formylhydrazines (1.08g, 4.7mmol) are dissolved in toluene In (50mL), burgess reagent (2.41g, 10.11mmol) is then added thereto, and reaction solution is heated to flowing back and stirred anti- Answer 1 hour, be subsequently cooled to room temperature, reaction solution is divided into two layers, and upper strata is clear liquid, and lower floor is dark brown syrup thing, will divide The limpid liquid in upper strata separated out is concentrated under reduced pressure, and the residue of concentration is diluted in EtOAc (50mL), and gained mixture is with water (20mL) Washed with saline solution (20mL), organic phase anhydrous Na₂SO₄Dry, be concentrated under reduced pressure.Lower floor syrup thing silica gel column chromatography (PE/ EtOAc (v/v)=2/1) purifying, the residue of concentration and the syrup thing purified are mixed, then use silica gel column chromatography (PE/EtOAc (v/v)=2/1) is purified, and it is white solid (242mg, 24.3%) to obtain title compound.

MS(ESI,pos.ion):211.9[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):8.44(s,1H),8.30(s,1H),7.85-7.71(m,1H), 2.65(s,3H)。

Step 9) (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) third Base) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By the chloro- 5- of compound 6- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine -4- amine (50mg, 0.24mmol) and (S) chloro- 3- cyclopropyl quinazoline -4 (3H) -one (68.9mg, 0.25mmol) of -2- (1- aminopropyls) -5- are suspended in n-BuOH In (4mL), DIPEA (61mg, 0.470mmol) is then added thereto.Reaction solution is heated to reflux 6 hours, is then down to room Temperature, then be concentrated under reduced pressure.Residue is diluted with EtOAc (20mL), gained mixture saturation NH₄The Cl aqueous solution (5mL) and salt Water (5mL) washs, organic phase anhydrous Na₂SO₄Dry, be concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/ V)=1/2) purify, it is white solid (48mg, 44.9%) to obtain title compound.

MS(ESI,pos.ion):453.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.80 (d, J=7.6Hz, 1H), 8.04 (s, 1H), 7.68 (t, J= 8.0Hz, 1H), 7.54-7.43 (m, 2H), 7.27 (s, 2H), 6.09 (td, J=7.8,4.8Hz, 1H), 3.21-3.09 (m, 1H),2.61(s,3H),2.17-2.03(m, 1H),1.96-1.81(m,1H),1.32-1.26(m,2H),1.16-1.07(m, 1H), 0.98 (t, J=7.4Hz, 3H), 0.89-0.81 (m, 1H).

Embodiment 3 (S) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Propyl group) chloro- 3- phenylquinazolines -4 (3H) -one of -5-

Step 1) (Z)-N'- hydroxyl second is narrowed

By compound hydroxylamine hydrochloride (10.16g, 146.16mmol), Anhydrous potassium carbonate (20.20g, 146.16mmol) and Reaction 1 hour is stirred at room temperature in EtOH (40mL) suspension, adds acetonitrile (2.00g, 48.72mmol).Reaction is mixed Compound is heated to reflux 17 hours, then filters, filtrate decompression is concentrated, obtain title compound for faint yellow solid (2.72g, 75.4%).

MS(ESI,pos.ion):75.2[M+H]⁺。

Step 2) (E)-N'- ((4,6- dichloro pyrimidine -5- carbonyls) epoxide) second is narrowed

By compound 4,6- dichloro pyrimidine -5- formyl chlorides (3.62g, 17.4mmol) are suspended in dichloromethane (20mL), Then at 0 DEG C, add thereto (Z)-N'- hydroxyl second narrow (1.27g, 17.14mmol) and DIPEA (4.43g, 34.28mmol) dichloromethane (20mL) solution of mixture.Reaction solution stirring reaction after 1 hour at 0 DEG C, add water by its Dilute (40mL).Liquid separation, obtained organic phase use the NaHCO of saturation successively₃The aqueous solution (40mL) and saline solution (40mL) washing, Use anhydrous Na₂SO₄Dry, be concentrated under reduced pressure, gained residue is through silica gel column chromatography (CH₂Cl₂/ MeOH (v/v)=250/1) purifying, It is faint yellow solid (2.45g, 25%) to obtain title compound.

MS(ESI,pos.ion):248.9[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.87(s,1H),4.95(s,2H),2.05(s,3H)。

Step 3) (E)-N'- ((4- amino -6- chlorine pyrimidine -5- carbonyls) epoxide) second is narrowed

Compound (E)-N'- ((4,6- dichloro pyrimidine -5- carbonyls) epoxide) second is narrowed (3.1g, 12.45mmol) and is dissolved in In tetrahydrofuran (50mL), ammonia is then filled with thereto, and reaction solution is stirred at room temperature overnight, and is then filtered.Filter cake is hanged Float over mixed solution (EtOH/H₂O (v/v)=1/5,12mL) in, gained mixture stirs 6 hours, refilters to obtain titled Compound is pale solid (1.9g, 66.6%).

MS(ESI,pos.ion):230.2[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.07(s,1H),8.27(s,1H),7.55(s,2H),6.44(s, 2H),1.79(s,3H)。

The chloro- 5- of step 4) 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine

Compound (E)-N'- ((4- amino -6- chlorine pyrimidine -5- carbonyls) epoxide) second is narrowed into (200mg, 0.87mmol) to suspend In DMSO (4mL), Bu is then added thereto₄NF tetrahydrofuran solution (1M, 2.61mL, 2.61mmol), mixture exists It is stirred overnight at room temperature, then adds EtOAc (30mL) dilutions, gained mixture uses water (15mL × 2) and saline solution successively (15mL) is washed, liquid separation, obtained organic phase anhydrous Na₂SO₄Dry, be concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=4/1) is purified, and it is white solid (21mg, 11.4%) to obtain title compound.

MS(ESI,pos.ion):212.0[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):8.41(s,1H),8.03(s,1H),2.47(s,3H)。

The chloro- N- phenylbenzamaides of step 5) 2- amino -6-

Compound 2- amino -6- chlorobenzoic acids (10g, 58.28mmol) are suspended in toluene (60mL), then in room temperature Under, SOCl is added into reaction solution₂(17mL,233.1mmol).Reactant mixture is heated to backflow simultaneously stirring reaction 4 hours, Room temperature is subsequently cooled to, and is concentrated under reduced pressure.Gained residue is dissolved in DCM (100mL), and at 0 DEG C, added thereto Aniline (4.8mL, 52.45mmol) and Et₃N (15.5mL, 116.56mmol) DCM (50mL) solution.Gained mixture is in room It is stirred overnight under temperature, then uses saline solution (100mL) and saturation NaHCO successively₃The aqueous solution (100mL) washs, and subtracts each other organic Pressure concentration, gained residue purify through silica gel column chromatography (PE/EtOAc (v/v)=1/1), and it is faint yellow to obtain title compound Solid (2.6g, 18%).

MS(ESI,pos.ion)m/z:247.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.71 (br.s, 1H), 7.63 (d, J=8.0Hz, 2H), 7.38 (t, J =7.8Hz, 2H), 7.18 (t, J=7.4Hz, 1H), 7.10 (t, J=8.1Hz, 1H), 6.77 (d, J=7.9Hz, 1H), 6.63 (d, J=8.2Hz, 1H), 4.68 (s, 2H).

Step 6) (S)-(1- ((3- chloro- 2- (phenylcarbamoyl) phenyl) amino) -1- oxo-butanes -2- bases) amino T-butyl formate

By compound (S) -2- ((tertbutyloxycarbonyl) amino) butyric acid (2.3g, 11.19mmol), the chloro- N- benzene of 2- amino -6- Yl-benzamide (2.6g, 10.66mmol) and DIPEA (5.5mL, 31.62mmol) are dissolved in DCM (40mL), then- 10 DEG C, HATU (4.81g, 12.65mmol) is added thereto, and mixture stirring reaction at -10 DEG C after 1 hour, rises to room Temperature, backflow simultaneously stirring reaction 24 hours, then be down to room temperature are then heated to, then use H successively₂O (200mL × 2) and saturation NaHCO₃The aqueous solution (200mL) washs, and the organic phase that liquid separation is obtained is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/ EtOAc (v/v)=4/1) purifying, it is yellow solid (3.3g, 72%) to obtain title compound.

MS(ESI,neg.ion)m/z:430.0[M-H]^-；

¹H NMR(600MHz,CDCl₃)δ(ppm):9.43(br.s,1H),8.13-8.11(m,1H),7.95(m,1H), 7.64-7.62 (d, J=7.8 Hz, 2H), 7.39-7.37 (t, J=7.8Hz, 2H), 7.35-7.32 (t, J=7.8Hz, 1H), 7.21-7.18(m,2H),4.99(br.s,1H),4.15 (br.s,1H),1.91-1.90(m,1H),1.67-1.63(m,1H), 1.39 (s, 9H), 0.94-0.91 (t, J=7.2Hz, 3H).

Chloro- 3- phenylquinazolines -4 (3H) -one of step 7) (S) -2- (1- aminopropyls) -5-

By compound (S)-(1- ((3- chloro- 2- (phenylcarbamoyl) phenyl) amino) -1- oxo-butanes -2- bases) ammonia Base t-butyl formate (2.0g, 4.63 mmol) is dissolved in DCM (50mL), then under nitrogen protection, sequentially adds iodine (823mg, 3.24mmol), HMDS (2.9mL, 13.89mmol) is added with syringe.Gained mixture was stirred at room temperature At night, then add saturated aqueous sodium thiosulfate (200mL) and reaction is quenched, the organic phase that liquid separation is obtained is concentrated under reduced pressure, institute Obtain residue to purify through silica gel column chromatography (DCM/MeOH (v/v)=50/1), it is faint yellow solid to obtain title compound (500mg, 34%).

MS(ESI,pos.ion.)m/z:314.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):10.41(br.s,1H),9.11(br.s,1H),8.37-8.34(d,J =8.4Hz, 1H), 8.27-8.25 (d, J=8.0Hz, 1H), 7.62-7.35 (m, 4H), 7.28-7.26 (d, J=8.4Hz, 1H), 7.20-7.18 (d, J=8.0Hz, 11H), 3.44-3.41 (m, 1H), 1.96-1.90 (m, 1H), 1.66-1.60 (m, 1H), 0.99-0.96 (t, J=6.8Hz, 3H).

Step 8) (S) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) third Base) chloro- 3- phenylquinazolines -4 (3H) -one of -5-

By the chloro- 5- of compound 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (30mg, 0.142mmol) and (S) chloro- 3- phenylquinazolines -4 (3H) -one (47mg, 0.149mmol) of -2- (1- aminopropyls) -5- are suspended in n-BuOH In (2mL), DIPEA (37 mg, 0.284mmol) is then added thereto.Reactant mixture is heated to backflow and stirring reaction 12 hours, room temperature is then down to, then be concentrated under reduced pressure.Residue is dissolved in EtOAc (15mL), gained mixture is successively with full And NH₄The Cl aqueous solution (10mL) and saturated aqueous common salt (10mL) washing.The organic phase anhydrous Na that liquid separation obtains₂SO₄Dry, subtract Pressure concentration.Gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=2/1), and it is faint yellow to obtain title compound Solid (47mg, 67.8%).

MS(ESI,pos.ion)m/z:489.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.04 (d, J=7.0Hz, 1H), 7.99 (s, 1H), 7.80 (t, J= 8.0Hz,1H), 7.71-7.43(m,7H),4.96-4.87(m,1H),2.50(s,3H),1.96-1.86(m,1H),1.70- 1.59 (m, 1H), 0.76 (t, J=7.4Hz, 3H).

Embodiment 4 (S) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Propyl group) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By chloro- 3- cyclopropyl quinazoline -4 (3H) -one of compound (S) -2- (1- aminopropyls) -5- (110mg, 0.396mmol) it is suspended in the chloro- 5- of 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (92mg, 0.436mmol) In n-BuOH (5mL), DIPEA (102mg, 0.792mmol) is then added thereto.It is small that gained mixture is heated to reflux 2 When, room temperature is subsequently cooled to, then be concentrated under reduced pressure, gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=2/1), It is white solid (168mg, 93.7%) to obtain title compound.

MS(ESI,pos.ion)m/z:453.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.17 (d, J=7.5Hz, 1H), 8.10 (s, 1H), 7.72 (t, J= 8.0Hz, 1H), 7.59-7.47 (m, 2H), 6.16 (td, J=7.2,5.3Hz, 1H), 3.14 (ddd, J=11.2,7.2, 4.2Hz, 1H), 2.50 (s, 3H), 2.12 (ddt, J=14.7,12.4,7.4Hz, 1H), 1.91 (tt, J=14.5,7.3Hz, 1H), 1.31-1.25 (m, 2H), 0.94 (t, J=7.4Hz, 3H), 0.88-0.76 (m, 2H).

Embodiment 52- ((S) -1- ((6- amino -5- ((S) -4- methyl -4,5- dihydro-oxazole -2- bases) pyrimidine-4-yl) ammonia Base) propyl group) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

Step 1) (S) -4,6- two chloro- N- (1- hydroxy propane -2- bases) pyrimidine -5- formamides

By compound 4,6- dichloro pyrimidine -5- formyl chlorides (1.63g, 7.71mmol) are suspended in dichloromethane (4mL), so Afterwards at 0 DEG C, thereto add (S) -2- aminopropane -1- alcohol (0.579g, 7.71mmol) and DIPEA (1.50g, Dichloromethane (6mL) solution 11.57mmol).Reaction solution stirring reaction 1 hour at 0 DEG C, is then concentrated under reduced pressure, residue Through silica gel column chromatography (CH₂Cl₂/ MeOH (v/v)=50/1) purifying, syrup is obtained, syrup is dissolved in acetic acid second In ester, gained mixture is washed with hydrochloric acid (1M, 15mL), and water layer is extracted with EtOAc (10mL × 4) again, and the organic phase of merging is used Anhydrous Na₂SO₄Dry, be concentrated under reduced pressure, it is yellow solid (1.28g, 66.5%) to obtain title compound thing.

MS(ESI,pos.ion)m/z:249.9[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.81 (s, 1H), 6.56 (d, J=6.6Hz, 1H), 4.38-4.22 (m, 1H), 3.82 (dd, J=11.1,3.7Hz, 1H), 3.69 (dd, J=11.1,4.7Hz, 1H), 2.37 (s, 1H), 1.33 (d, J =6.8Hz, 3H).

The chloro- N- of step 2) (S) -4- amino -6- (1- hydroxy propane -2- bases) pyrimidine -5- formamides

By compound (S) -4,6- two chloro- N- (1- hydroxy propane -2- bases) pyrimidine -5- formamides (1.3g, 5.20mmol) It is suspended in THF (20mL), is then full of ammonia thereto, reaction 6 hours is stirred at room temperature in reaction solution, filters, and filter cake is used Ethyl acetate EtOAc (10mL) rinse, gained filtrate through be concentrated under reduced pressure to give title compound for yellow solid (1.125g, 93.8%).

MS(ESI,pos.ion)m/z:231.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):8.40 (d, J=8.4Hz, 1H), 8.21 (s, 1H), 7.15 (s, 2H), 4.92 (t, J=5.5Hz, 1H), 3.98 (dt, J=14.7,6.6Hz, 1H), 3.38 (t, J=5.9Hz, 2H), 1.08 (d, J=6.8Hz, 3H).

Step 3) (S) -4- amino -6- chloro- N- (n-propyl chloride -2- bases) pyrimidine -5- formamides

By the chloro- N- of compound (S) -4- amino -6- (1- hydroxy propane -2- bases) pyrimidine -5- formamides (500mg, 2.17mmol) it is suspended in CHCl₃In (10 mL), SOCl is then added thereto₂(0.78mL, 10.84mmol), by mixture plus Hot simultaneously stirring reaction 2 hours of extremely flowing back, are subsequently cooled to room temperature, then are concentrated under reduced pressure, and residue is dissolved in into CH₂Cl₂With MeOH's In the mixed solvent (CH₂Cl₂/ MeOH (v/v)=25/1,15mL), gained mixture filters through silicagel pad, filter cake CH₂Cl₂With MeOH(CH₂Cl₂/ MeOH (v/v)=20/1,200mL) to rinse, filtrate is yellow solid through being concentrated under reduced pressure to give title compound (0.54g, 100%).

MS(ESI,pos.ion)m/z:249.0[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):8.76 (d, J=7.7Hz, 1H), 8.22 (s, 1H), 7.15 (s, 2H), 4.20 (ddd, J=19.5,13.1,6.7Hz, 1H), 3.73 (dd, J=10.7,4.9Hz, 1H), 3.67 (dd, J= 10.7,6.1Hz, 1H), 1.21 (d, J=6.7Hz, 3H).

The chloro- 5- of step 4) (S) -6- (4- methyl -4,5- dihydro-oxazole -2- bases) pyrimidine -4- amine

By compound (S) -4- amino -6- chloro- N- (n-propyl chloride -2- bases) pyrimidine -5- formamides (690mg, 2.77mmol) be suspended in dry THF (20mL), then at 0 DEG C, thereto add NaH (222mg, 5.54mmol, 60% is dispersed in kerosene) THF (5mL) mixture.Reaction solution is warmed to room temperature and stirred 30 minutes, is then dissolved in In EtOAc (50mL), gained mixture is washed with water (20mL) and saline solution (20mL) successively, organic phase anhydrous Na₂SO₄It is dry It is dry, it is concentrated under reduced pressure, gained residue is through silica gel column chromatography (CH₂Cl₂/ MeOH (v/v)=100/1) purifying, obtain title compound Thing is yellow solid (438mg, 74.4%).

MS(ESI,pos.ion)m/z:213.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):9.15(br.s,1H),8.30(s,1H),6.03(br.s,1H),4.55 (dd, J=9.4,8.3Hz, 1H), 4.46-4.36 (m, 1H), 4.00 (t, J=8.1Hz, 1H), 1.38 (d, J=6.6Hz, 3H)。

Step 5) 2- ((S) -1- ((6- amino -5- ((S) -4- methyl -4,5- dihydro-oxazole -2- bases) pyrimidine-4-yl) ammonia Base) propyl group) chloro- 3- cyclopropane quinazoline -4 (3H) -one of -5-

By the chloro- 5- of compound (S) -6- (4- methyl -4,5- dihydro-oxazole -2- bases) pyrimidine -4- amine (50mg, 0.235mmol) and chloro- 3- cyclopropyl quinazoline -4 (3H) -one (72mg, 0.259mmol) of (S) -2- (1- aminopropyls) -5- are outstanding Float in n-BuOH (2mL), then add DIPEA (61mg, 0.470mmol) thereto.It is small that gained mixture is heated to reflux 8 When, room temperature is subsequently cooled to, then be concentrated under reduced pressure, residue is dissolved in EtOAc (15mL), gained mixture uses water successively (10mL) and saline solution (10mL) wash, liquid separation, obtained organic phase anhydrous Na₂SO₄Dry, be concentrated under reduced pressure, gained residue Purified through silica gel column chromatography (PE/EtOAc (v/v)=1/1), it is pale solid (85mg, 79.7%) to obtain title compound.

MS(ESI,pos.ion)m/z:454.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):9.37 (d, J=7.4Hz, 1H), 8.02 (s, 1H), 7.57-7.49 (m, 2H), 7.42 (d, J=7.4 Hz, 1H), 6.16 (dd, J=13.0,7.3Hz, 1H), 4.58-4.50 (m, 1H), 4.47-4.37 (m, 1H), 3.96 (t, J=7.8Hz, 1H), 3.14-3.05 (m, 1H), 2.06-2.03 (m, 1H), 1.98-1.91 (m, 1H), 1.44-1.40 (m, 2H), 1.39 (d, J=6.6Hz, 3H), 1.03 (t, J=7.4Hz, 3H), 0.93-0.85 (m, 2H).

Embodiment 62- ((S) -1- ((6- amino -5- ((S) -4- methyl -4,5- dihydro-oxazole -2- bases) pyrimidine-4-yl) ammonia Base) propyl group) chloro- 3- phenylquinazolines -4 (3H) -one of -5-

By the chloro- 5- of compound (S) -6- (4- methyl -4,5- dihydro-oxazole -2- bases) pyrimidine -4- amine (30mg, 0.141mmol) suspended with chloro- 3- phenylquinazolines -4 (3H) -one (47mg, 0.148mmol) of (S) -2- (1- aminopropyls) -5- In n-BuOH (2mL), DIPEA (36mg, 0.282mmol) is then added thereto, and gained mixture is heated to backflow simultaneously Stirring reaction 8 hours, is subsequently cooled to room temperature, then is diluted with EtOAc (15mL), gained mixture successively with water (10mL) and Saline solution (10mL) washs, liquid separation, obtained organic phase anhydrous Na₂SO₄Dry, be concentrated under reduced pressure.Gained residue is through silica gel Column chromatography (PE/EtOAc (v/v)=3/2) purifies, and it is pale solid (54mg, 78.1%) to obtain title compound.

MS(ESI,pos.ion)m/z:490.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.41 (d, J=6.8Hz, 1H), 7.86 (s, 1H), 7.76 (t, J= 8.0Hz, 1H), 7.62-7.49 (m, 7H), 7.45 (s, 1H), 7.17 (s, 1H), 4.66 (td, J=7.8,4.2Hz, 1H), 4.57-4.52 (m, 1H), 4.38-4.29 (m, 1H), 3.94 (t, J=8.0Hz, 1H), 1.90-1.82 (m, 1H), 1.64- 1.57 (m, 1H), 1.27 (d, J=6.6Hz, 3H), 0.74 (t, J=7.4Hz, 3H).

Embodiment 7 (S) -2- (1- ((6- amino -5- (5- Jia Ji oxazole -2- bases) pyrimidine-4-yl) amino) propyl group) -5- Chloro- (3H) -one of 3- cyclopropyl quinazoline -4

Step 1) 4,6- bis- chloro- N- (2- oxopropyls) pyrimidine -5- formamides

By compound 4,6- dichloro pyrimidine -5- formyl chlorides (4.0g, 18.92mmol) are dissolved in dichloromethane (30mL), Then at 0 DEG C, DIPEA (7.34g, 56.76mmol) is added dropwise thereto, next adds 1- aminopropane -2- ketone Dichloromethane (20mL) solution of hydrochloride (2.28g, 20.81mmol).Mixture after 0 DEG C of stirring reaction 1 hour, then according to Secondary saturation NH₄The Cl aqueous solution (40mL) and saline solution (40mL) washing, liquid separation, obtained organic phase anhydrous Na₂SO₄Dry, It is concentrated under reduced pressure.Gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=5/1), and it is yellowish to obtain title compound Color solid (2.53g, 53.9%).

MS(ESI,pos.ion)m/z:247.9[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.85 (s, 1H), 6.76 (s, 1H), 4.43 (d, J=4.4Hz, 2H), 2.33(s,2H)。

Step 2) 4- amino -6- chloro- N- (2- oxopropyls) pyrimidine -5- formamides

Compound 4,6- bis- chloro- N- (2- oxopropyls) pyrimidine -5- formamides (2.57g, 10.36mmol) are dissolved in In THF (50mL), ammonia is then full of thereto.Reaction 4 hours is stirred at room temperature in mixture, is then concentrated under reduced pressure, gained Residue is through silica gel column chromatography (CH₂Cl₂/ MeOH (v/v)=50/1) purifying, it is yellow solid to obtain title compound (1.71g, 72%).

MS(ESI,pos.ion)m/z:229.1[M+H]⁺。

The chloro- 5- of step 3) 6- (5- Jia Ji oxazole -2- bases) pyrimidine -4- amine

Compound 4- amino -6- chloro- N- (2- oxopropyls) pyrimidine -5- formamides (1.44g, 6.30mmol) are dissolved in In toluene (40mL), then at room temperature, burgess reagent (3.23g, 13.55mmol) is added thereto.Reaction solution is heated to 120 DEG C and stirring reaction are down to room temperature after 2.5 hours, then are concentrated under reduced pressure, and gained residue is through silica gel column chromatography (CH₂Cl₂/ MeOH (v/v)=250/1) purifying, it is faint yellow solid (450mg, 34.3%) to obtain title compound.

MS(ESI,pos.ion)m/z:211.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):9.11 (s, 1H), 8.32 (s, 1H), 6.95 (d, J=0.7Hz, 1H), 5.96 (s, 1H), 2.47 (d, J=0.7Hz, 3H).

Step 4) (S) -2- (1- ((6- amino -5- (5- Jia Ji oxazole -2- bases) pyrimidine-4-yl) amino) propyl group) -5- is chloro- 3- cyclopropyl quinazoline -4 (3H) -one

By the chloro- 5- of compound 6- (5- Jia Ji oxazole -2- bases) pyrimidine -4- amine (50mg, 0.237mmol) and (S) -2- (1- Aminopropyl) chloro- 3- cyclopropyl quinazoline -4 (3H) -one (69mg, 0.249mmol) of -5- are suspended in n-BuOH (5mL), so Add DIPEA (61mg, 0.475mmol) thereto afterwards.Gained mixture is heated to reflux 18 hours, is subsequently cooled to room temperature, and It is concentrated under reduced pressure, residue is dissolved in EtOAc (15 mL), gained mixture uses saturation NH successively₄The Cl aqueous solution (15mL) and Saline solution (15mL) washs, liquid separation, obtained organic phase anhydrous Na₂SO₄Dry, be concentrated under reduced pressure, residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/1) is purified, and it is faint yellow solid (66mg, 61.5%) to obtain title compound.

MS(ESI,pos.ion)m/z:452.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.97 (d, J=7.9Hz, 1H), 8.10 (s, 1H), 7.62-7.37 (m, 3H), 6.92 (s, 1H), 6.31 (dd, J=13.2,7.5Hz, 1H), 3.19-3.05 (m, 1H), 2.50 (s, 3H), 2.10- 1.98 (m, 2H), 1.48-1.40 (m, 2H), 1.06 (t, J=7.4Hz, 3H), 0.95-0.84 (m, 2H).

Embodiment 8 (S) -2- (1- ((6- amino -5- (5- Jia Ji oxazole -2- bases) pyrimidine-4-yl) amino) propyl group) -5- Chloro- 3- phenylquinazolines -4 (3H) -one

By the chloro- 5- of compound 6- (5- Jia Ji oxazole -2- bases) pyrimidine -4- amine (40mg, 0.19mmol) and (S) -2- (1- ammonia Base propyl group) chloro- 3- phenylquinazolines -4 (3H) -one (62.57mg, 0.199mmol) of -5- are dissolved in n-BuOH (2mL), then DIPEA (49.09mg, 0.380mmol) is added thereto, reaction solution stirring reaction 9 hours at 120 DEG C, is subsequently cooled to room Temperature, then be concentrated under reduced pressure, residue is dissolved in EtOAc (20mL), gained mixture uses saturation NH successively₄The Cl aqueous solution (5mL) and saline solution (5mL) wash.Liquid separation, obtained organic phase anhydrous Na₂SO₄Dry, be concentrated under reduced pressure, residue is through silica gel Column chromatography (PE/EtOAc (v/v)=1/1) purifies, and it is yellow solid (17mg, 18.5%) to obtain title compound.

MS(ESI,pos.ion)m/z:488.11[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.17 (d, J=7.5Hz, 1H), 8.10 (s, 1H), 7.72 (t, J= 8.0Hz, 1H), 7.59-7.47 (m, 2H), 6.16 (td, J=7.2,5.3Hz, 1H), 3.14 (ddd, J=11.2,7.2, 4.2Hz, 1H), 2.50 (s, 3H), 2.12 (ddt, J=14.7,12.4,7.4Hz, 1H), 1.91 (tt, J=14.5,7.3Hz, 1H), 1.31-1.25 (m, 2H), 0.94 (t, J=7.4Hz, 3H), 0.88-0.76 (m, 2H).

Embodiment 92- ((1S) -1- ((6- amino -5- (1- methyl isophthalic acid H-1,2,4- triazole -5- bases) pyrimidine-4-yl) ammonia Base) propyl group) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

Step 1) 4,6- dichloro pyrimidine -5- formamides

By compound 4,6- dichloro pyrimidine -5- formyl chlorides (2.11g, 10.0mmol) are dissolved in THF (20mL), Ran Houxiang Ammonia is wherein filled with, reaction solution reacts 5 minutes at room temperature.Then filter, then filtrate decompression is concentrated.Gained residue is through silicon Plastic column chromatography (pure EtOAc) purifies, and it is white solid (1.43g, 74%) to obtain title compound.

MS(ESI,pos.ion)m/z:192.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.85(s,1H),6.23(br s,1H),5.96(br s,1H)。

Step 2) 4,6- dimethoxypyridin -5- formamides

By compound 4,6- dichloro pyrimidine -5- formamides (1.65g, 8.6mmol) are dissolved in methanol (30mL), Ran Houxiang Sodium methoxide (1.15g, 21.3mmol) is wherein added, then mixture is heated to 40 DEG C of simultaneously stirring reaction 12 hours, then will mixing Thing is filtered, and filtrate decompression is concentrated, and gained residue purifies through silica gel column chromatography (pure EtOAc), and obtaining title compound is White solid (1.30g, 83%).

MS(ESI,pos.ion)m/z:184.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.47(s,1H),6.30(br s,1H),5.98(br s,1H),4.07 (s,6H)。

Step 3) N- ((dimethylamino) methylene) -4,6- dimethoxypyridin -5- formamides

By compound 4,6- dimethoxypyridin -5- formamides (732.6mg, 4.0mmol) and N,N-dimethylformamide The mixture of dimethylacetal (10 mL) is placed in stirring reaction at room temperature and is concentrated under reduced pressure after 1 hour, then by reactant mixture, obtains It is white solid (952.0mg, 100%) to title compound, without further purifying, is directly used in and reacts in next step.

MS(ESI,pos.ion)m/z:239.0[M+H]⁺。

Step 4) 4,6- dimethoxys -5- (1- methyl isophthalic acid H-1,2,4- triazole -5- bases) pyrimidine

By compound N-((dimethylamino) methylene) -4,6- dimethoxypyridin -5- formamides (952mg, 4.0mmol) it is dissolved in acetic acid (15 mL), then adds methyl hydrazine (1.84g, 40mmol) thereto.Reactant mixture is in room The lower stirring reaction of temperature 2 hours, is then concentrated under reduced pressure, residue is dissolved in ethyl acetate (100mL), gained mixture is successively With saturation NaHCO₃The aqueous solution (20mL) and saline solution (30mL) washing, the organic phase that liquid separation is obtained are concentrated under reduced pressure, and gained is residual Thing is stayed to be purified through silica gel column chromatography (pure EtOAc), it is yellow solid (0.65g, 74%) to obtain title compound.

MS(ESI,pos.ion)m/z:222.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.57(s,1H),8.04(s,1H),4.00(s,6H),3.75(s, 3H)；

¹³C NMR(150MHz,CDCl₃)δ(ppm):168.6,158.8,151.3,146.6,93.3,54.9,35.9；

2D-NMR(HMBC):(8.57,168.6),(8.04,146.6),(4.00,168.6),(3.75,146.6)。

Step 5) 5- (1- methyl isophthalic acid H-1,2,4- triazole -5- bases) pyrimidine -4,6- glycol

By compound 4,6- dimethoxys -5- (1- methyl isophthalic acid H-1,2,4- triazole -5- bases) pyrimidine (650mg, 2.94mmol), the mixture of concentrated hydrochloric acid (6mL) and acetic acid (6mL) is heated to 100 DEG C, and stirring reaction is after 3 hours, then recover to Room temperature, then it is concentrated under reduced pressure, it is white solid (568mg, 100%) to obtain title compound, without being further purified, is directly used Reacted in next step.

MS(ESI,pos.ion)m/z:194.0[M+H]⁺。

Bis- chloro- 5- of step 6) 4,6- (1- methyl isophthalic acid H-1,2,4- triazole -5- bases) pyrimidine

By compound 5- (1- methyl isophthalic acid H-1,2,4- triazole -5- bases) pyrimidine -4,6- glycol (568mg, 2.94mmol) It is suspended in DMF (1.0mL) in toluene (15mL), then adds POCl thereto₃(901.6mg,5.88mmol).By reaction solution 100 DEG C of simultaneously stirring reaction 3.5 hours are heated to, are subsequently cooled to room temperature, then are concentrated under reduced pressure, residue is dissolved in ethyl acetate In (100mL), gained mixture uses saturation NaHCO successively₃The aqueous solution (20mL) and saturated aqueous common salt (30mL) washing, organic phase Use anhydrous Na₂SO₄Dry, be concentrated under reduced pressure, gained residue purifies through silica gel column chromatography (EtOAc), obtains title compound as Huang Color grease (650mg, 96%).

MS(ESI,pos.ion)m/z:229.9[M+H]⁺。

The chloro- 5- of step 7) 6- (1- methyl isophthalic acid H-1,2,4- triazole -5- bases) pyrimidine -4- amine

By bis- chloro- 5- of compound 4,6- (1- methyl isophthalic acid H-1,2,4- triazole -5- bases) pyrimidines (650mg, 2.8mmol) and Reaction 24 hours is stirred at room temperature in the mixture of the methanol solution (7M, 20mL) of ammonia, then filters, filtrate decompression is concentrated, Gained residue purifies through silica gel column chromatography (DCM/MeOH (v/v)=20/1), and it is white solid to obtain title compound (180mg, 31%).

MS(ESI,pos.ion)m/z:211.0[M+H]⁺。

Step 8) 2- ((1S) -1- ((6- amino -5- (1- methyl isophthalic acid H-1,2,4- triazole -5- bases) pyrimidine-4-yl) ammonia Base) propyl group) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By the chloro- 5- of compound 6- (1- methyl isophthalic acids H-1,2,4- triazole -5- bases) pyrimidine -4- amine (80mg, 0.38mmol), (S) chloro- 3- cyclopropyl quinazoline -4 (3H) -one (116.1mg, 0.42mmol) of -2- (1- aminopropyls) -5-, N, N- diisopropyls Back flow reaction is after 24 hours at 120 DEG C for the mixture of base ethamine (147.3mg, 1.14mmol) and n-butanol (3mL), decompression Concentration, residue is dissolved in ethyl acetate (100mL), gained mixture uses saturation NH successively₄The Cl aqueous solution (20mL) and Saline solution (20mL × 2) washs, the organic phase anhydrous Na that liquid separation obtains₂SO₄Dry, be concentrated under reduced pressure, gained residue is through silicon Plastic column chromatography (EtOAc) purifies, and it is white solid (30mg, 17.5%) to obtain title compound.

MS(ESI,pos.ion)m/z:452.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.24 (s, 1H), 8.18 (s, 1H), 7.54 (t, J=7.8Hz, 1H), 7.43 (d, J=7.8Hz, 1H), 7.36 (d, J=7.8Hz, 1H), 6.13 (s, 2H), 5.98 (s, 1H), 3.89 (s, 3H), 3.10-2.99 (m, 1H), 2.05-1.97 (m, 1H), 1.84-1.75 (m, 2H), 1.23-1.15 (m, 2H), 0.98 (t, J= 7.2Hz,3H),0.95-0.90(m,2H)。

Embodiment 102- ((1S) -1- ((6- amino -5- (1- methyl isophthalic acid H-1,2,4- triazole -5- bases) pyrimidine-4-yl) Amino) propyl group) chloro- 3- phenylquinazolines -4 (3H) -one of -5-

By the chloro- 5- of compound 6- (1- methyl isophthalic acids H-1,2,4- triazole -5- bases) pyrimidine -4- amine (40mg, 0.19mmol), (S) chloro- 3- phenylquinazolines -4 (3H) -one (59.6mg, 0.19mmol) of -2- (1- aminopropyls) -5-, N, N- diisopropyls The mixture of ethamine (73.6mg, 0.57mmol) and n-butanol (2 mL) is heated to 120 DEG C, and stirring reaction 40 hours, then Filter, filter cake is rinsed with methanol (10mL) and ethyl acetate (10 mL) successively, and filtrate decompression is concentrated, residue is dissolved in In ethyl acetate (20mL), gained mixture uses saturation NH successively₄The Cl aqueous solution (10mL) and saline solution (10mL × 2) washing, The organic phase anhydrous Na that liquid separation obtains₂SO₄Dry, be concentrated under reduced pressure, gained residue purifies through silica gel column chromatography (EtOAc), obtains It is white solid (20mg, 22%) to title compound.

MS(ESI,pos.ion)m/z:488.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.16(s,1H),8.13(s,1H),7.67-7.54(m,5H),7.54- 7.42 (m, 5H), 3.90 (s, 3H), 1.89-1.77 (m, 1H), 1.64-1.51 (m, 2H), 0.77 (t, J=7.2Hz, 3H).

Embodiment 11 (S) -2- (1- ((6- amino -5- (pyridine -2- bases) pyrimidine-4-yl) amino) propyl group) chloro- 3- rings of -5- Propyl group quinazoline -4 (3H) -one

The chloro- 5- iodine pyrimidines -4- ammonia of step 1) 6-

Compound 6- chlorine pyrimidine -4- amino (1.29g, 10mmol) is dissolved in DMF (8mL), then added thereto NIS (2.25g, 10mmol), reactant mixture stirring reaction 8 hours at 100 DEG C, is subsequently cooled to room temperature, then depressurizes dense Contracting.Residue is dissolved in EtOAc (300mL), the Na of gained mixture saturation₂S₂O₄The NaHCO of the aqueous solution/saturation₃ Mixed solution (v/v, 1/2,100mL × 3) washing of the aqueous solution, then washed successively with water (150mL × 3) and saline solution (100mL) Wash, the organic phase anhydrous Na for then obtaining liquid separation₂SO₄Dry, be concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/ EtOAc (v/v)=5/1) purifying, it is white solid (1.20g, 46.97%) to obtain title compound.

MS(ESI,pos.ion.)m/z:255.8[M+H]⁺。

The normal-butyl 2- pyridine radicals tin of step 2) three

Compound 2- bromopyridines (2.09g, 13.33mmol) are dissolved in anhydrous THF (10mL), by the colourless anti-of gained After answering liquid to substitute gas (nitrogen) 3 times, stirred 30 minutes at -78 DEG C, be then slowly added into n-BuLi (2.4M, 6mL, 14.4mmol), reaction solution is moved into room temperature and stirred 30 minutes, reactant mixture is then moved to -78 DEG C again, and delay thereto It is slow to add tributyltin chloride (3.67g, 13.33 mmol).After gained mixture stirs 1 hour at -78 DEG C, room is then moved to Be stirred overnight under temperature, then add water (200mL) dilution, gained mixture with EtOAc (100mL × 3) extract, merging it is organic Mutually washed successively with water (100mL × 2) and saline solution (100mL), use anhydrous Na₂SO₄Dry, be concentrated under reduced pressure, gained residue warp Silicagel column (PE/EtOAc (v/v)=10/1) purifies, and it is pale yellow oil (2.92g, 59.53%) to obtain title compound.

MS(ESI,pos.ion.)m/z:370.1[M+H]⁺。

The chloro- 5- of step 3) 6- (pyridine -2- bases) pyrimidine -4- amine

By the chloro- 5- iodine pyrimidines -4- amine (511mg, 2.0mmol) of compound 6-, Pd (PPh₃)₂Cl₂(140mg,0.2mmol) It is suspended in CuI (38mg, 0.2mmol) in DMF (10mL), then adds triethylamine (405mg, 4.0mmol) thereto, then Add DMF (5mL) solution of three normal-butyl 2- pyridine radicals tin (1.47g, 4.0mmol), mixture stirring reaction at 120 DEG C 2.5 hours, room temperature is subsequently cooled to, adds EtOAc (300mL) dilutions, gained mixture is washed with water (200mL × 3), will be divided The organic phase that liquid obtains is concentrated under reduced pressure, and gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=10/1), is marked Topic compound is faint yellow solid (58.9mg, 14.25%).

MS(ESI,pos.ion.)m/z:207.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.72 (dd, J=4.9,0.8Hz, 1H), 8.36 (s, 1H), 7.87 (td, J=7.8,1.8Hz, 1H), 7.79-7.74 (m, 1H), 7.36 (ddd, J=7.5,4.9,1.1Hz, 1H), 6.12 (s, 2H)。

Step 4) (S) -2- (1- ((6- amino -5- (pyridine -2- bases) pyrimidine-4-yl) amino) propyl group) chloro- 3- rings third of -5- Base quinazoline -4 (3H) -one

By chloro- 3- cyclopropyl quinazoline -4 (3H) -one of compound (S) -2- (1- aminopropyls) -5- (93.56mg, 0.34mmol) it is dissolved in the chloro- 5- of 6- (pyridine -2- bases) pyrimidine -4- amine (34.8mg, 0.17mmol) in n-BuOH (2mL), Then diisopropylethylamine (148 mg, 1.14mmol) is added thereto, and mixture flows through night next time at 130 DEG C, then cools down To room temperature, then it is concentrated under reduced pressure, gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=2/3), obtains titled Compound is yellow solid (21mg, 27.6%).

MS(ESI,pos.ion.)m/z:448.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.81 (d, J=4.8Hz, 1H), 8.14 (s, 1H), 7.95-7.84 (m, 1H), 7.55-7.51 (m, 1H), 7.42 (d, J=7.8Hz, 1H), 7.37 (d, J=8.1Hz, 1H), 7.34-7.29 (m, 1H), 6.99 (d, J=8.2Hz, 1H), 5.64 (s, 2H), 4.18-4.06 (m, 1H), 3.13-2.99 (m, 1H), 2.05-1.94 (m, 1H), 1.85-1.74 (m, 1H), 1.50-1.40 (m, 2H), 1.05-0.99 (m, 1H), 1.00 (t, J=6.8Hz, 3H), 0.94-0.90(m,1H)。

Embodiment 12 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) Propyl group) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

Step 1) 4,6- dimethoxypyridin -5- formaldehyde

By compound 4,6- dichloro pyrimidine -5- formaldehyde (20g, 113.0mmol) is suspended in dry methanol (100mL), At 0 DEG C, sodium methoxide (27.47g, 508.5mmol) absolute methanol (100mL) solution is slowly added into reaction solution.Will be anti- Answer liquid to be warming up to 70 DEG C, and stir 2 hours, be cooled back to 0 DEG C, then add aqueous hydrochloric acid solution (1M, 300mL) and reaction is quenched, Add saturation NaHCO₃Obtained mixture is neutralized to pH=7 by the aqueous solution, and mixture is extracted with ethyl acetate (500mL × 3) Take, the organic phase anhydrous Na of merging₂SO₄Dry, be concentrated under reduced pressure, gained residue is through silica gel column chromatography (ether/ethyl acetate (v/v)=4/1) purify, it is white solid (8.37g, 44%) to obtain title compound.

MS(ESI,pos.ion)m/z:169.1[M+H]⁺。

Step 2) 4,6- dimethoxypyridin -5- formaldoximes

By compound 4,6- dimethoxypyridin -5- formaldehyde (3.0g, 17.8mmol) is dissolved in ethyl acetate (50mL), At room temperature, water (30mL) solution of hydroxylamine hydrochloride (1.24g, 17.8mmol) is added thereto, then adds sodium acetate (1.46g,17.8mmol).Reaction solution is stirred at room temperature 2 hours, is then washed with water (100mL × 2), and organic phase is with anhydrous Na₂SO₄Dry, be concentrated under reduced pressure, it is white solid (3.2g, 97%) to obtain title compound.

MS(ESI,pos.ion)m/z:184.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):11.47(s,1H),8.47(s,1H),8.08(s,1H),3.96(s, 6H)。

Step 3) 3- (4,6- dimethoxypyridin -5- bases) -5- methyl isophthalic acids, 2,4- oxadiazoles

Under room temperature and nitrogen protection, to equipped with 4,6- dimethoxypyridin -5- formaldoximes (3.0g, 16.4mmol) and (NH₄)₂Ce(NO₃)₆Acetonitrile (100mL) is added in the three-necked flask of (18.0g, 32.8mmol), reaction solution is heated to 70 DEG C simultaneously After stirring reaction 4 hours, filter, and filtrate decompression is concentrated, gained yellow residue is through silica gel column chromatography (petroleum ether/acetic acid Ethyl ester (v/v)=4/1) purifying, it is white solid (0.58g, 16%) to obtain title compound.

MS(ESI,pos.ion)m/z:223.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.68(s,1H),3.93(s,6H),2.67(s,3H)。

Step 4) 3- (4,6- dichloro pyrimidine -5- bases) -5- methyl isophthalic acids, 2,4- oxadiazoles

By compound 3- (4,6- dimethoxypyridin -5- bases) -5- methyl isophthalic acids, 2,4- oxadiazoles (391mg, 1.76mmol) It is suspended in DMF (3.0mL) in toluene (20mL), then adds POCl3 (2.04g, 13.3mmol), reaction solution thereto React under reflux conditions, and with thin-layered chromatography (PE/EtOAc, v/v, 4/1)) monitoring reacts, after react, reaction mixed Compound is concentrated under reduced pressure, and gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=8/1), and obtaining title compound is White solid (0.36mg, 89%).

MS(ESI,pos.ion)m/z:231.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.16(s,1H),2.78(s,3H)。

The chloro- 5- of step 5) 6- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine -4- amine

At room temperature, by compound 3- (4,6- dichloro pyrimidine -5- bases) -5- methyl isophthalic acids, 2,4- oxadiazoles (355mg, 1.54mmol) it is dissolved in dry tetrahydrofuran (25mL), and is full of ammonia thereto, reaction solution is stirred at room temperature instead Should, and use thin-layered chromatography (PE/EtOAc, v/v, 4/1)) monitoring reaction, after having reacted, mixture is filtered, gained filtrate Through being concentrated under reduced pressure, it is white solid (325mg, 100%) to obtain title compound.

MS(ESI,pos.ion)m/z:212.05[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):8.35(s,1H),7.88(br.s.,1H),7.06(br.s.,1H), 2.67(s,3H)。

Step 6) (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) third Base) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By the chloro- 5- of compound 6- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine -4- amine (42.3mg, 0.2mmol), (S) chloro- 3- cyclopropyl quinazoline -4 (3H) -one (55.5mg, 0.2mmol) of -2- (1- aminopropyls) -5-, N, N- diisopropyls The mixture of ethamine (77.5mg, 0.6mmol) and n-butanol (2.5 mL) is heated to 125 DEG C, and back flow reaction is after 12 hours, then subtracts Pressure concentration, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/1)) purifying, title compound is obtained as white Solid (78mg, 86%).

MS(ESI,pos.ion)m/z:453.2[M+H]⁺；HPLC:98%；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.89 (d, J=7.7Hz, 1H), 8.13 (s, 1H), 7.61-7.48 (m, 2H), 7.46-7.38 (m, 1H), 6.30 (td, J=7.7,5.3Hz, 1H), 3.20-3.04 (m, 1H), 2.74 (s, 3H), 2.18-2.05 (m, 1H), 2.04-1.95 (m, 1H), 1.49-1.39 (m, 2H), 1.25-1.19 (m, 1H), 1.06 (t, J= 7.4Hz,3H),0.96-0.91(m,1H)；

¹³C NMR(100MHz,CDCl₃)δ(ppm):174.2,166.0,161.6,161.5,160.3,159.7,149.3, 133.8,133.2,129.2, 126.4,118.3,82.7,52.7,28.1,27.0,12.4,10.6,10.3,10.2。

Embodiment 13 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) Propyl group) chloro- 3- phenylquinazolines -4 (3H) -one of -5-

By the chloro- 5- of compound 6- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine -4- amine (35.0mg, 0.165mmol), (S) chloro- 3- phenylquinazolines -4 (3H) -one (52.0mg, 0.165mmol) of -2- (1- aminopropyls) -5-, N, N- diisopropyls The mixture of ethamine (60.6mg, 0.47mmol) and n-butanol (2.5mL) is heated to 125 DEG C of simultaneously back flow reaction 20 hours, now There is white precipitate precipitation, then filter reactant mixture, filter cake is rinsed with n-butanol (4mL) and ethanol (4mL) successively, is obtained Title compound is white solid (50mg, 62%).

MS(ESI,pos.ion)m/z:489.1[M+H]⁺；HPLC：99.7%；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.73 (d, J=7.1Hz, 1H), 7.96 (s, 1H), 7.76 (t, J= 8.0Hz, 1H), 7.64- 7.54 (m, 7H), 7.51 (s, 2H), 4.85 (td, J=7.5,4.3Hz, 1H), 2.76 (s, 3H), 2.04-1.82 (m, 1H), 1.72-1.59 (m, 1H), 0.77 (t, J=7.4Hz, 3H)；

¹³C NMR(100MHz,DMSO-d₆)δ(ppm):175.8,165.8,161.7,159.8,159.4,158.7, 158.6,149.8,136.8,135.0, 133.3,130.0,129.8,129.71,129.67,129.5,127.1,118.2, 81.6,53.8,10.3。

Embodiment 14 (S) -2- (1- ((6- amino -5- (isoxazole -3-bases) pyrimidine-4-yl) amino) propyl group) the chloro- 3- of -5- Cyclopropyl quinazoline -4 (3H) -one

Step 1) 4,6- dichloro pyrimidine -5- formaldoximes

By compound 4,6- dichloro pyrimidine -5- formaldehyde (7.20g, 40.6mmol) is dissolved in ethyl acetate (100mL), so Add water (30mL) solution of hydroxylamine hydrochloride (2.82g, 40.6mmol) thereto afterwards, then at room temperature, add acetic acid Water (30mL) solution of sodium (3.34g, 40.6mmol).Reaction 4 hours is stirred at room temperature in mixture, then with water (100mL × 2) wash, the organic phase anhydrous Na that liquid separation obtains₂SO₄Dry, be concentrated under reduced pressure, it is faint yellow solid to obtain title compound (6.0g, 77%).

MS(ESI,pos.ion)m/z:192.1[M+H]⁺。

The chloro- N- hydroxy pyrimidines -5- carboximidoyl chlorides of step 2) 4,6- bis-

By compound 4,6- dichloro pyrimidine -5- formaldoximes (4.0g, 20.8mmol) are dissolved in DMF (18mL), then 0 At DEG C, N- chlorosuccinimides (3.05g, 22.9mmol) are slowly added into reaction solution, mixture are moved into room temperature, and stir Mix 1 hour, add ethyl acetate (100mL) dilution, gained mixture is washed with saline solution (50mL × 4).What liquid separation obtained Organic phase anhydrous sodium sulfate drying, it is pale yellow oil (4.7g, 100%) to be concentrated under reduced pressure to give title compound.

MS(ESI,pos.ion)m/z:225.9[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):13.14(s,1H),9.08(s,1H)。

Step 3) 3- (4,6- dichloro pyrimidine -5- bases) -5- (trimethylsilyl) isoxazoles

The chloro- N- hydroxy pyrimidines -5- carboximidoyl chlorides (4.71g, 20.8mmol) of compound 4,6- bis- are dissolved in THF In (60mL), then at room temperature, trimethylsilyl acetylene (6.13g, 62.4mmol) is added to it, is next slow added into three Tetrahydrofuran (5mL) solution of ethamine (4.2g, 41.6mmol), mixture are stirred at room temperature overnight, then filtered.By gained Filtrate decompression concentrates, and concentrated residues thing purifies through silica gel column chromatography (PE/EtOAc (v/v)=4/1), and obtaining title compound is Pale yellow oil (4.30g, 72%).

MS(ESI,pos.ion)m/z:288.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.86(s,1H),6.60(s,1H),0.43(s,9H)。

The chloro- 5- of step 4) 6- (5- (trimethylsilyl) isoxazole -3-bases) pyrimidine -4- amine

By compound 3- (4,6- dichloro pyrimidine -5- bases), (trimethylsilyl) isoxazoles (2.0g, 6.94mmol) are molten by -5- Solution is in dry tetrahydrofuran (50mL), then at room temperature, and is full of ammonia thereto, reactant mixture is at room temperature After stirring reaction 5 hours, filter, it is white solid (1.88g, 100%) that filtrate decompression is concentrated to give into title compound.

MS(ESI,pos.ion)m/z:269.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):8.29(s,1H),7.78(br.s,1H),7.04(s,1H),6.88 (br.s,1H),0.37(s, 9H)。

The chloro- 5- (isoxazole -3-bases of step 5) 6-) pyrimidine -4- amine

By the chloro- 5- of compound 6- (5- (trimethylsilyl) isoxazole -3-bases) pyrimidine -4- amine (1.0g, 3.72mmol) DMF/H is dissolved in CsF (1.13g, 7.44 mmol)₂In O (5mL/1mL), reaction 0.5 hour is stirred at room temperature in mixture Afterwards, ethyl acetate (100mL) dilution is added, gained mixture is washed with saline solution (50mL × 4), the organic phase that liquid separation obtains With anhydrous sodium sulfate drying, it is concentrated under reduced pressure, gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=2/1), obtains Title compound is white solid (210mg, 29%).

MS(ESI,pos.ion)m/z:197.0[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.14 (d, J=1.6Hz, 1H), 8.31 (s, 1H), 7.75 (br.s., 1H), 6.94 (br.s., 1H), 6.89 (d, J=1.6Hz, 1H).

Step 6) (S) -2- (1- ((6- amino -5- (isoxazole -3-bases) pyrimidine-4-yl) amino) propyl group) the chloro- 3- rings of -5- Propyl group quinazoline -4 (3H) -one

By the chloro- 5- (isoxazole -3-bases of compound 6-) pyrimidine -4- amine (35.0mg, 0.178mmol), (S) -2- (1- amino Propyl group) chloro- 3- cyclopropyl quinazoline -4 (3H) -one (59.3mg, 0.214mmol) of -5- and N, N- diisopropylethylamine (69.0mg, 0.534mmol) is dissolved in n-butanol (2.0 mL), after reactant mixture flows back 45 hours at 125 DEG C, decompression Concentration, gained residue purify through silica gel column chromatography (PE/EtOAc (v/v)=1/1), and it is white solid to obtain title compound (28mg, 36%).

MS(ESI,pos.ion)m/z:438.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.65 (d, J=1.5Hz, 1H), 8.17 (s, 1H), 7.55 (t, J= 8.0Hz, 1H), 7.44 (d, J=7.7Hz, 1H), 7.43 (d, J=7.7Hz, 1H), 7.04 (d, J=1.5Hz, 1H), 6.73 (d, J=8.3Hz, 1H), 6.23 (td, J=8.0,4.7 Hz, 1H), 5.66 (br.s., 2H), 3.11-3.05 (m, 1H), 2.11-2.01 (m, 1H), 1.91-1.80 (m, 1H), 1.50-1.41 (m, 2H), 1.02 (t, J=7.4Hz, 3H), 0.96- 0.87(m,2H)；

¹³C NMR(150MHz,CDCl₃):δ(ppm):161.5,160.4,160.3,159.4,158.8,158.1, 156.6,148.8,133.9,133.4, 129.4,126.0,118.2,104.2,86.1,52.2,27.9,26.8,10.7, 10.2,10.1。

Embodiment 15 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) Propyl group) -5- methyl -3- (o-tolyl) quinazoline -4 (3H) -one

Step 1) 2- methyl -6- nitros-N- (o-tolyl) benzamide

Compound 2- methyl -6- nitrobenzoic acids (5.43g, 30mmol) are suspended in toluene (45mL), then in room Under temperature, SOCl is disposably added thereto₂(4.5mL,60mmol).Reaction solution backflow overnight, then is concentrated under reduced pressure.Residue is molten Solution is in Isosorbide-5-Nitrae-dioxane (30 mL), then at 0 DEG C, be added dropwise into obtained mixture ortho-aminotoluene (3.22g, 30mmol) and NaHCO₃Isosorbide-5-Nitrae-dioxane (30mL) suspension of (6.34g, 75 mmol), then adds ethyl acetate (400mL) and water (200mL) diluted mixture, the organic phase washed with water (200mL) and saline solution (300mL) that liquid separation obtains are washed To wash, with anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=3/2), It is pink powder (7.44g, 92%) to obtain title compound.

MS(ESI,pos.ion)m/z:271.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.08 (d, J=8.2Hz, 1H), 7.94 (d, J=8.0Hz, 1H), 7.62 (d, J=7.6Hz, 1H), 7.52 (t, J=7.9Hz, 1H), 7.33 (t, J=7.6Hz, 1H), 7.27 (d, J=7.5Hz, 1H), 7.19 (dd, J=14.1,6.6Hz, 1H), 7.15 (s, 1H), 2.61 (s, 3H), 2.31 (s, 3H).

Step 2) (S)-(1- (2- methyl -6- nitros-N- (o-tolyl) benzamido) -1- oxo-butanes -2- bases) T-butyl carbamate

Compound 2- methyl -6- nitros-N- (o-tolyl) benzamides (7.44g, 27.5mmol) are suspended in toluene In (150mL), DMF (0.5mL) and SOCl is then added dropwise successively thereto₂(15.84mL, 220mmol), reaction solution backflow After overnight, it is concentrated under reduced pressure, gained residue is dissolved in dichloromethane (100mL), obtains yellow solution A.

By compound (S) -2- ((tertbutyloxycarbonyl) amino) butyric acid (5.6g, 27.5mmol) and DIPEA (10mL, 60.5mmol) it is dissolved in dry dichloromethane (100mL), then at 0 DEG C, solution A is added into reaction solution, gained mixes Close liquid and reaction 24 hours is stirred at room temperature, then successively with acetic acid/water (1/100, (v/v), 100mL × 3), unsaturated carbonate Hydrogen sodium water solution (100mL) and saline solution (100mL) washing, organic phase anhydrous sodium sulfate drying, are concentrated under reduced pressure, gained is residual Stay thing through silica gel column chromatography (PE/EtOAc (v/v)=10/1) purify, obtain title compound for faint yellow solid (11.35g, 91%).

MS(ESI,pos.ion)m/z:478.1[M+Na]⁺。

Step 3) (1- (5- methyl -4- oxos -3- (o-tolyl) -3,4- dihydroquinazoline -2- bases) propyl group) amino first Tert-butyl acrylate

By compound (S)-(1- (2- methyl -6- nitros-N- (o-tolyl) benzamido) -1- oxo-butanes -2- Base) t-butyl carbamate (11.2g, 24.6mmol) is dissolved in acetic acid (60mL), zinc powder is then disposably added thereto (6.43g, 98.4mmol), reactant mixture stirring reaction 24 hours at 35 DEG C, then filters, filtrate decompression is concentrated, then Ethyl acetate (300mL) dilution residue is added, gained mixture uses saturated sodium bicarbonate aqueous solution NaHCO successively₃(100mL × 2) wash, organic phase anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained residue is through silica gel column layer with saline solution (100mL) (PE/EtOAc (v/v)=50/3) purifying is analysed, it is white solid (5.4g, 54%) to obtain title compound.

MS(ESI,pos.ion)m/z:408.2[M+H]⁺。

Step 4) 2- (1- aminopropyls) -5- methyl -3- (o-tolyl) quinazoline -4 (3H) -one

By compound (1- (5- methyl -4- oxos -3- (o-tolyl) -3,4- dihydroquinazoline -2- bases) propyl group) amino T-butyl formate (5.4g, 13.3 mmol) is dissolved in ethyl acetate (20mL), then at room temperature, disposable thereto to add Enter the ethyl acetate solution (3.5M, 70mL) of hydrogen chloride, after reaction is stirred at room temperature 3.5 hours in mixture, gained is suspended Liquid is dissolved in water (400mL), liquid separation, and aqueous phase is extracted with ethyl acetate (100mL × 2), and then adding sodium bicarbonate powder will It is neutralized to pH=7, then is extracted with mixed solvent ethyl acetate/methanol (6/1 (v/v), 100mL × 3), the organic phase of merging Washed with saline solution (100mL), with anhydrous sodium sulfate drying, be concentrated under reduced pressure, it is brown oil to obtain title compound (4.09g, 100%), the grease are made up of two kinds of isomers that ratio is A/B=4/7.

MS(ESI,pos.ion)m/z:308.2[M+H]⁺；

Isomers A:¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.72-7.66(m,1H),7.57-7.52(m,1H), 7.48-7.43(m,2H), 7.43-7.36(m,1H),7.36-7.26(m,2H),3.13-3.05(m,1H),2.74(s,3H), 2.02(s,1H),1.79-1.63(m,1H), 1.50-1.27(m,1H),0.75-0.67(m,3H)；

Isomers B:¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.72-7.66(m,1H),7.57-7.52(m,1H), 7.48-7.43(m,2H), 7.43-7.36(m,1H),7.36-7.26(m,2H),2.99-2.92(m,1H),2.74(s,3H), 2.08(s,2H),1.79-1.63(m,1H), 1.50-1.27(m,1H),0.75-0.67(m,3H)。

Step 5) (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) third Base) -5- methyl -3- (o-tolyl) quinazoline -4 (3H) -one

By the chloro- 5- of compound 6- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine -4- amine (31.0mg, 0.15mmol), 2- (1- aminopropyls) -5- methyl -3- (o-tolyl) quinazoline -4 (3H) -one (50.0mg, 0.16mmol) and N, N- bis- are different Propylethylamine (57.4mg, 0.44mmol) is dissolved in n-butanol (2.0mL), and reaction solution is heated into 125 DEG C and back flow reaction 12 hours, after having reacted, reactant mixture is concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/ 1) purify, it is faint yellow solid (50.0mg, 70%) to obtain title compound, and the faint yellow solid is A/B=10/9 by ratio Two kinds of isomers form.

MS(ESI,pos.ion)m/z:483.2[M+H]⁺；HPLC：92% (isomers A and B total purity)；

Isomers A:¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.93 (d, J=8.3Hz, 1H), 7.92 (s, 1H), 7.66-7.58(m,2H), 7.48-7.35(m,3H),7.28-7.21(m,2H),5.26-5.14(m,1H),2.98(s,3H), 2.85(s,3H),2.21(s,3H),1.83-1.67(m, 4H),0.91-0.83(m,3H)；

Isomers B:¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.76 (d, J=7.5Hz, 1H), 7.95 (s, 1H), 7.66-7.58(m,2H), 7.48-7.35(m,3H),7.28-7.21(m,2H),5.26-5.14(m,1H),2.91(s,3H), 2.85(s,3H),2.07(s,3H),1.83-1.67(m, 4H),0.91-0.83(m,3H)。

Embodiment 16 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) Propyl group) -4 (3H) -one of -3- cyclopropyl -5- Fluquinconazoles quinoline

The fluoro- N- cyclopropyl -6- nitrobenzamides of step 1) 2-

At room temperature, compound 2- fluoride-6-nitrobenzoic acids (2.0g, 10.8mmol) are suspended in toluene (11mL), Then thionyl chloride (3.0mL, 32.4mmol) is added dropwise into reaction solution, after adding, reactant mixture stirs at 110 DEG C Overnight, brown oil is then concentrated under reduced pressure to give, not purified be directly used in of the grease is reacted in next step.

By cyclopropylamine (1.2mL, 16.2mmol) and NaHCO₃(1.8g, 21.6mmol) is dissolved in 1,4- dioxane In (7mL), then at 5 DEG C, Isosorbide-5-Nitrae-dioxane (7mL) solution of resulting brown oil above, gained are added thereto Mixture is stirred at room temperature overnight, and is then filtered, and gained filtrate decompression is concentrated, and residue is through silica gel column chromatography (PE/ EtOAc (v/v)=1/1) purifying, it is Light brown solid (2.44g, 100%) to obtain title compound.

MS(ESI,pos.ion)m/z:225.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.78(s,1H),8.05-7.98(m,1H),7.81-7.68(m, 2H),2.79(m,1H), 0.76-0.69(m,2H),0.53-0.48(m,2H)。

Step 2) (S)-(1- (the fluoro- 6- nitrobenzamides bases of N- cyclopropyl -2-) -1- oxo-butanes -2- bases) amino first Tert-butyl acrylate

The fluoro- N- cyclopropyl -6- nitrobenzamides (1.0g, 4.46mmol) of compound 2- are suspended in toluene (15mL) In, thionyl chloride (3.0mL, 40.14mmol) and DMF (0.5mL), after adding, reaction solution is then added dropwise thereto successively It is stirred overnight at 120 DEG C, is then concentrated under reduced pressure, obtain brown oil, the grease is directly used in without being further purified React in next step.

Compound Boc-L-2- aminobutyric acids (1.20g, 5.58mmol) and DIPEA (1.73g, 13.38mmol) are dissolved In dichloromethane (8mL), then at 0 DEG C, the dichloromethane (23mL) for adding resulting brown oil above thereto is molten Liquid, after adding, reactant mixture is stirred at room temperature overnight, then successively with 1% acetic acid aqueous solution (100mL), unsaturated carbonate Hydrogen sodium water solution (100mL) and saline solution (100mL) washing, organic phase anhydrous sodium sulfate drying, are concentrated under reduced pressure.Gained remains Thing through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purify, obtain title compound for yellow oil (1.72g, 94%).

MS(ESI,pos.ion)m/z:310.1[M-Boc+H]⁺。

Step 3) (S)-(1- (the fluoro- 3- cyclopropyl -4- oxos -3,4- dihydroquinazolines -2- bases of 5-) propyl group) carbamic acid The tert-butyl ester

By compound (S)-(1- (the fluoro- 6- nitrobenzamides bases of N- cyclopropyl -2-) -1- oxo-butanes -2- bases) amino T-butyl formate (3.88g, 9.48 mmol) is dissolved in acetic acid (52mL), then thereto disposably add zinc powder (2.50g, 38.23mmol), after reaction is stirred at room temperature 11 hours in reactant mixture, filters, filtrate decompression is concentrated, add acetic acid second Ester (150mL) dissolution residual substance, gained mixture are neutralized to pH=7-8 with the sodium acid carbonate concentrated solution of saturation.Organic phase is eaten Salt solution (150mL × 2) washs, and with anhydrous sodium sulfate drying, is concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purify, it is brown oil (2.87g, 83%) to obtain title compound.

MS(ESI,pos.ion)m/z:362.2[M+H]⁺。

(3H) -one of step 4) (S) -2- (1- aminopropyls) -3- cyclopropyl -5- Fluquinconazoles quinoline -4

By compound (S)-(1- (the fluoro- 3- cyclopropyl -4- oxos -3,4- dihydroquinazolines -2- bases of 5-) propyl group) amino first Tert-butyl acrylate (2.87g, 7.94 mmol) is dissolved in ethyl acetate (12mL), then at room temperature, disposable thereto to add The ethyl acetate solution (3.5M, 20mL) of hydrogen chloride.After reaction is stirred at room temperature 2 hours in mixture, water (200mL) is added Dilution, add saturated sodium bicarbonate aqueous solution and gained mixture is adjusted to pH=7-8, aqueous phase mixed solvent EtOAc/MeOH (50/1, v/v, 100mL × 3) are extracted, and the organic phase of merging is washed with saline solution (150mL), with anhydrous sodium sulfate drying, decompression Concentration, it is pale brown oil thing (1.79g, 86%) to obtain title compound.

MS(ESI,pos.ion)m/z:262.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.62 (td, J=8.1,5.5Hz, 1H), 7.41 (d, J=8.2Hz, 1H),7.11-7.03(m,1H), 4.62-4.55(m,1H),2.95-2.88(m,1H),1.95-1.84(m,1H),1.73- 1.61 (m, 1H), 1.44-1.36 (m, 1H), 1.36-1.29 (m, 1H), 1.03 (t, J=7.4Hz, 3H), 0.97-0.89 (m, 2H)。

Step 5) (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) third Base) -4 (3H) -one of -3- cyclopropyl -5- Fluquinconazoles quinoline

By the chloro- 5- of compound 6- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine -4- amine (25.0mg, 0.118mmol), (S) (3H) -one (33.9mg, 0.130mmol) of -2- (1- aminopropyls) -3- cyclopropyl -5- Fluquinconazoles quinoline -4 and N, N- bis- are different Propylethylamine (45.8mg, 0.354mmol) is dissolved in n-butanol (2.0mL), reactant mixture is heated into 125 DEG C, and return Stream reaction 22 hours, after having reacted, mixture is concentrated under reduced pressure, gained residue is through preparative thin layer chromatography (DCM/MeOH, v/ V, 50/1) purifying, it is faint yellow solid (32.0 mg, 62%) to obtain title compound.

MS(ESI,pos.ion)m/z:437.2[M+H]⁺；HPLC：98.7%；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.92 (d, J=7.7Hz, 1H), 8.13 (s, 1H), 7.61 (td, J= 8.2,5.4Hz, 1H), 7.42 (d, J=8.2Hz, 1H), 7.28 (s, 1H), 7.07 (dd, J=10.1,8.6Hz, 1H), 6.32 (td, J=7.7,5.4Hz, 1H), 3.15-3.07 (m, 1H), 2.74 (s, 3H), 2.16-2.06 (m, 1H), 2.05-1.96 (m, 1H), 1.26-1.19 (m, 2H), 1.06 (t, J=7.4Hz, 3H), 0.97-0.86 (m, 2H)；

¹³C NMR(151MHz,CDCl₃)δ(ppm):174.2,165.9,161.9,161.4,160.6,160.54, 160.52,160.1,159.7,158.4, 148.9,134.22,134.15,123.0,122.9,113.1,113.0,110.9, 110.8,82.6,52.7,28.2,26.7,12.4,10.6,10.3,10.2。

Embodiment 17 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) Propyl group) -4 (3H) -one of -3- cyclopropyl -5- Fluquinconazoles quinoline

Step 1) 2- methyl-N- cyclopropyl -6- nitrobenzamides

Compound 2- methyl -6- nitrobenzoic acids (3.0g, 16.6mmol) are suspended in toluene (17mL), then in room Under temperature, thionyl chloride (3.7mL, 49.7mmol) is added dropwise thereto, after adding, reactant mixture stirs at 110 DEG C Overnight, then it is concentrated under reduced pressure, obtains brown oil, the grease is directly used in and reacted in next step without being further purified.

Cyclopropylamine (1.8mL, 24.8mmol) and sodium acid carbonate (2.8g, 33.1mmol) are suspended in 1,4- dioxane In (10mL), then at 5 DEG C, dioxane (10mL) solution of brown oil obtained in the previous step is added to suspension In, after reaction is stirred at room temperature 10 hours in gained mixture, filter, then filtrate decompression is concentrated, residue is through silica gel column layer (PE/EtOAc (v/v)=2/1) purifying is analysed, it is Light brown solid (3.2g, 88%) to obtain title compound.

MS(ESI,pos.ion)m/z:221.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.55 (s, 1H), 7.95 (d, J=8.1Hz, 1H), 7.67 (d, J= 7.5Hz, 1H), 7.54 (t, J=7.9Hz, 1H), 2.87-2.64 (m, 1H), 2.32 (s, 3H), 0.75-0.66 (m, 2H), 0.52-0.45(m,2H)。

Step 2) (S)-(1- (2- methyl-N- cyclopropyl -6- nitrobenzamides base) -1- oxo-butanes -2- bases) amino T-butyl formate

Compound 2- methyl-N- cyclopropyl -6- nitrobenzamides (3.2g, 14.5mmol) are suspended in toluene (48mL), thionyl chloride (10mL, 130.8mmol) is added dropwise thereto while stirring, adds DMF (0.5mL), add it Afterwards, reactant mixture is stirred overnight at 120 DEG C, is then concentrated under reduced pressure to give brown oil, and the grease is not purified, directly Connect for reacting in next step.

Compound Boc-L-2- aminobutyric acids (3.8g, 18.8mmol) and DIPEA (8mL, 43.6mmol) are dissolved in two In chloromethanes (26 mL), then at 0 DEG C, dichloromethane (73mL) solution of above brown oil, reaction are added thereto After reaction is stirred at room temperature 5 hours in mixture, then successively with 1% acetic acid aqueous solution (150mL × 2), saturation NaHCO₃Water Solution (150mL × 2) and saline solution (150mL × 2) washing, organic phase anhydrous sodium sulfate drying, are concentrated under reduced pressure, gained residual Thing through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purify, obtain title compound for brown oil (5.9g, 99%).

MS(ESI,pos.ion)m/z:306.1[M-Boc+H]⁺。

Step 3) (S)-(1- (5- methyl -3- cyclopropyl -4- oxo -3,4- dihydroquinazoline -2- bases) propyl group) amino first Tert-butyl acrylate

By compound (S)-(1- (2- methyl-N- cyclopropyl -6- nitrobenzamides base) -1- oxo-butanes -2- bases) ammonia Base t-butyl formate (5.9g, 14.5mmol) is dissolved in acetic acid (72mL), then thereto disposably add zinc powder (3.8g, 58.0mmol), after reactant mixture is stirred at room temperature overnight, filter, then filtrate decompression is concentrated, gained residue is dissolved in In ethyl acetate (150mL), then add saturated sodium bicarbonate into gained mixture and be adjusted to pH=7-8, liquid separation, organic phase Washed with saline solution (150mL × 2), with anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/ EtOAc (v/v)=5/1) purifying, it is brown oil (3.9 g, 75.8%) to obtain title compound.

MS(ESI,pos.ion)m/z:358.2[M+H]⁺。

(3H) -one of step 4) (S) -2- (1- aminopropyls) -3- cyclopropyl -5- methylquinazolins -4

By compound (S)-(1- (5- methyl -3- cyclopropyl -4- oxo -3,4- dihydroquinazoline -2- bases) propyl group) amino T-butyl formate (3.9g, 11.0 mmol) is dissolved in ethyl acetate (15mL), then adds the acetic acid second of hydrogen chloride thereto Ester solution (3.5M, 50mL).Reaction 2 hours is stirred at room temperature in gained mixture, is then diluted in water (100mL) and acetic acid second In ester (200mL), gained mixture is adjusted to pH=7-8, liquid separation, aqueous phase mixed solvent with saturated sodium bicarbonate aqueous solution EtOAc/MeOH (50/1, v/v, 100mL × 3) is extracted, and the organic phase of merging is washed with saline solution (150mL × 2), with anhydrous sulphur Sour sodium is dried, and is concentrated under reduced pressure, it is pale brown oil thing (3.0g, 100.0%) to obtain title compound.

MS(ESI,pos.ion)m/z:258.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.54-7.49 (m, 1H), 7.46 (d, J=8.0Hz, 1H), 7.19 (d, J=7.3Hz, 1H), 4.80 (t, J=6.0Hz, 1H), 2.95-2.87 (m, 1H), 2.84 (s, 3H), 2.00-1.94 (m, 1H), 1.86-1.77 (m, 1H), 1.44-1.36 (m, 1H), 1.33-1.27 (m, 1H), 1.09-1.04 (m, 1H), 1.03 (t, J= 7.4Hz,3H),0.94-0.87(m,1H)。

Step 5) (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) third Base) -4 (3H) -one of -3- cyclopropyl -5- Fluquinconazoles quinoline

By the chloro- 5- of compound 6- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine -4- amine (27.7mg, 0.130mmol), (S) (3H) -one (37.0mg, 0.144mmol) of -2- (1- aminopropyls) -3- cyclopropyl -5- methylquinazolins -4 and N, N- are different Propylethylamine (50.0mg, 0.390mmol) is dissolved in n-butanol (2.0mL), heats the mixture to 125 DEG C and back flow reaction 20 hours, after having reacted, reactant mixture is concentrated under reduced pressure, gained residue is through preparative thin-layer chromatography (DCM/MeOH (v/v) =50/1) purify, it is faint yellow solid (36.0mg, 64%) to obtain title compound.

MS(ESI,pos.ion)m/z:433.3[M+H]⁺；HPLC:96%；

¹H NMR(600MHz,CDCl₃)δ(ppm):9.03 (d, J=7.8Hz, 1H), 8.13 (d, J=7.4Hz, 1H), 7.54 (t, J=7.7Hz, 1H), 7.48 (d, J=8.0Hz, 1H), 7.19 (d, J=7.2Hz, 1H), 6.35-6.30 (m, 1H), 3.09 (ddd, J=11.1,7.1,4.2Hz, 1H), 2.86 (s, 3H), 2.74 (s, 3H), 2.15-2.07 (m, 1H), 2.05- 1.98 (m, 1H), 1.19-1.11 (m, 2H), 1.04 (t, J=7.4Hz, 3H), 0.94-0.83 (m, 2H)；

¹³C NMR(151MHz,CDCl₃)δ(ppm):174.1,165.9,164.1,161.4,159.6,158.9,158.3, 148.3,140.8,133.0, 129.2,125.2,119.6,82.5,52.6,28.1,26.6,23.0,12.3,10.6,10.2, 10.0；

Embodiment 18 (S) -2- (1- ((6- amino -5- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine-4-yl) ammonia Base) propyl group) -4 (3H) -one of -3- cyclopropyl -5- methylquinazolins

By the chloro- 5- of compound 6- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine -4- amine (35mg, 0.165mmol) (3H) -one (55mg, 0.214mmol) of (S) -2- (1- aminopropyls) -3- cyclopropyl -5- methylquinazolins -4 is suspended in positive fourth In alcohol (2mL), DIPEA (43mg, 0.331mmol) is then added thereto, reactant mixture is heated to flowing back, and stir Reaction 36 hours, monitored and reacted with thin-layered chromatography (PE/EtOAc, v/v, 1/3), after having reacted, reaction solution is cooled to room Temperature, then be concentrated under reduced pressure and remove solvent, ethyl acetate (15mL) dilution gained residue is added, gained mixture uses water successively (15mL) and saturated aqueous common salt (10mL) wash, and liquid separation, organic phase anhydrous sodium sulfate drying, are concentrated under reduced pressure, gained residue Through silica gel column chromatography (PE/EtOAc (v/v)=1/1) after purification, then using preparative thin layer chromatography (DCM/MeOH (v/v)= 20/1) it is further purified, it is faint yellow solid (36mg, 50.2%) to obtain title compound.

MS(ESI,pos.ion)m/z:432.3[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):9.67(s,1H),8.16(s,1H),8.13(s,1H),7.61–7.39 (m, 2H), 7.18 (d, J=6.3Hz, 1H), 6.40-6.25 (m, 1H), 4.06 (s, 3H), 3.09 (s, 1H), 2.86 (s, 3H), 2.13-2.00 (m, 2H), 1.46-1.38 (m, 2H), 1.05 (t, J=6.3Hz, 3H), 0.91-0.83 (m, 2H).

Embodiment 19 (R) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Propyl group) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

The chloro- N- cyclopropyl -6- nitrobenzamides of step 1) 2-

The chloro- 6- nitrobenzoic acids (5.0g, 24.8mmol) of compound 2- are suspended in toluene (25mL), then in room temperature Under, thionyl chloride (5.5mL, 74.4mmol) and DMF (1mL) are added dropwise into the yellow suspension, after adding, reaction mixing Thing is stirred overnight at 110 DEG C, is then concentrated under reduced pressure, and obtains brown oil, and the brown oil is not purified, is directly used in React in next step.

By cyclopropylamine (2.6mL, 37.2mmol) and NaHCO₃(4.2g, 49.6mmol) is suspended in 1,4- dioxane In (15mL), then at 5 DEG C, Isosorbide-5-Nitrae-dioxane (15mL) solution of brown oil above, gained mixing are added thereto Thing is stirred at room temperature overnight, filter, by filtrate decompression be concentrated to give title compound for Light brown solid (5.2g, 87.0%).

MS(ESI,pos.ion)m/z:241.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.78(s,1H),8.05–7.98(m,1H),7.81–7.68(m, 2H),2.79(m,1H), 0.76–0.69(m,2H),0.53–0.48(m,2H)。

Step 2) (R)-(1- (the chloro- N- cyclopropyl -6- nitrobenzamides of 2-) -1- oxo-butanes -2- bases) carbamic acid The tert-butyl ester

The chloro- N- cyclopropyl -6- nitrobenzamides (5.2g, 21.6mmol) of compound 2- are suspended in toluene (72mL) In, thionyl chloride (14.5mL, 194.5mmol) is then added dropwise thereto, after adding, reactant mixture is heated to 120 DEG C and be stirred overnight, be then concentrated under reduced pressure, obtain brown oil, gained grease is not purified, is directly used in anti-in next step Should.

Boc-D-2- aminobutyric acids (5.7g, 28.1mmol) and DIPEA (8.4g, 64.8mmol) are dissolved in dichloromethane In (36mL), then at 0 DEG C, dichloromethane (110mL) solution of gained grease above is slowly added into thereto, gained mixes After compound is stirred at room temperature overnight, then successively with 1% aqueous acetic acid (150mL), saturated sodium bicarbonate aqueous solution (100m × 2) wash, liquid separation, organic phase anhydrous sodium sulfate drying, be concentrated under reduced pressure with saline solution (150mL), obtain title compound as Huang Color grease (7.7g, 83.4%).

MS(ESI,pos.ion)m/z:326.1[M-Boc+H]⁺。

Step 3) (R)-(1- (the chloro- 3- cyclopropyl -4- oxos -3,4- dihydro-quinazolin-2-yls of 5-) propyl group) carbamic acid The tert-butyl ester

By compound (R)-(1- (the chloro- N- cyclopropyl -6- nitrobenzamides bases of 2-) -1- oxo-butanes -2- bases) amino T-butyl formate (7.6g, 18.0 mmol) is dissolved in acetic acid (72mL), then thereto disposably add zinc powder (4.7g, 72.1mmol), reactant mixture is stirred at room temperature overnight, and filters, filtrate decompression is concentrated to give into dark brown solid.Will dark palm fibre Color solid dissolving adds saturated sodium bicarbonate aqueous solution and gained mixture is adjusted into pH=7-8 in ethyl acetate (200mL), The organic phase that liquid separation obtains is washed with saturated aqueous common salt (150mL × 2), with anhydrous sodium sulfate drying, is concentrated under reduced pressure, is obtained title Compound is dark brown solid (5.3g, 78.0%).

MS(ESI,pos.ion)m/z:378.2[M+H]⁺。

Chloro- 3- cyclopropyl quinazoline -4 (3H) -one of step 4) (R) -2- (1- aminopropyls) -5-

By compound (R)-(1- (the chloro- 3- cyclopropyl -4- oxos -3,4- dihydroquinazolines -2- bases of 5-) propyl group) amino first Tert-butyl acrylate (5.2g, 13.7mmol) is dissolved in ethyl acetate (30mL), then disposably adds the second of hydrogen chloride thereto Acetate solution (3.5M, 35mL), after reaction is stirred at room temperature 3 hours in mixture, add ethyl acetate (100mL) and water (80mL) dilutes, and gained mixture is neutralized to pH=7-8 with saturated sodium bicarbonate, liquid separation, aqueous phase with mixed solvent ethyl acetate/ Methanol (50/1, v/v, 100mL × 2) is extracted, and the organic phase of merging is washed with saline solution (200mL × 2), done with anhydrous sodium sulfate It is dry, it is concentrated under reduced pressure, it is brown oil (3.2g, 83.7%) to obtain title compound.

MS(ESI,pos.ion)m/z:278.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.58-7.50 (m, 2H), 7.42 (dd, J=7.2,1.5Hz, 1H), 4.56 (dd, J=7.3,5.4 Hz, 1H), 3.00-2.88 (m, 1H), 1.95-1.83 (m, 1H), 1.73-1.61 (m, 1H), 1.44-1.37 (m, 1H), 1.37-1.30 (m, 1H), 1.03 (t, J=7.4Hz, 3H), 0.98-0.87 (m, 2H).

Step 5) (R) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) third Base) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By the chloro- 5- of compound 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (32mg, 0.151mmol) and (R) chloro- 3- cyclopropyl quinazoline -4 (3H) -one (47mg, 0.169mmol) of -2- (1- aminopropyls) -5- are suspended in n-butanol In (3mL), DIPEA (39 mg, 0.302mmol) is then added thereto, reactant mixture is heated to flowing back, and stir anti- Answer 24 hours, monitored and reacted using thin-layered chromatography (PE/EtOAc, v/v, 1/3), after having reacted, mixture is cooled to room Temperature, then be concentrated under reduced pressure.Residue is diluted in ethyl acetate (15mL), gained mixture uses water (15mL) and saline solution successively (10mL) is washed.Organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/EtOAc (v/ V)=3/2) purify, it is dark yellow solid (66mg, 96.4%) to obtain title compound.

MS(ESI,pos.ion):453.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.93 (d, J=6.2Hz, 1H), 8.16 (s, 1H), 7.69 (br s, 1H),7.65–7.51(m,2H), 7.44(s,1H),6.40–6.24(m,1H),5.92(s,1H),3.10(s,1H),2.60(d, J=63.7Hz, 3H), 2.20-2.06 (m, 1H), 2.06-1.93 (m, 1H), 1.45 (s, 2H), 1.05 (t, J=6.7Hz, 3H),0.96–0.81(m,2H)。

Embodiment 20 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) Propyl group) -4 (3H) -one of -3- cyclopropyl -5- methylquinazolins

By the chloro- 5- of compound 6- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine -4- amine (32mg, 0.151mmol), (S) (3H) -one (42mg, 0.163mmol) of -2- (1- aminopropyls) -3- cyclopropyl -5- methylquinazolins -4 is suspended in n-butanol In (2mL), DIPEA (39 mg, 0.302mmol) is then added thereto, and reactant mixture is heated to backflow and stirring reaction 24 hours, monitored and reacted with thin-layered chromatography (PE/EtOAc, v/v, 1/3), reactant mixture is then cooled to room temperature, depressurized Concentration, add ethyl acetate (15mL) and dilute residue, gained mixture is washed with water (15mL) and saline solution (10mL) successively Wash.Liquid separation, organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/EtOAc (v/v) =1/1) purify, it is dark yellow solid (44mg, 67.3%) to obtain title compound.

MS(ESI,pos.ion)m/z:433.2[M+H]⁺；HPLC：96%；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.89 (d, J=7.6Hz, 1H), 8.19 (s, 1H), 7.56 (t, J= 7.7Hz, 1H), 7.46 (d, J=8.0Hz, 1H), 7.22 (d, J=7.3Hz, 1H), 6.39-6.30 (m, 1H), 3.10-3.01 (m,1H),2.87(s,3H),2.77(s,3H), 2.18–2.08(m,1H),2.05–1.95(m,1H),1.49–1.41(m, 2H), 1.11-1.04 (m, 1H), 1.02 (t, J=7.4Hz, 3H), 0.93-0.89 (m, 1H).

Embodiment 21 (S) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Propyl group) -4 (3H) -one of -3- cyclopropyl -5- methylquinazolins

By the chloro- 5- of compound 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (32mg, 0.151mmol) and (S) (3H) -one (42mg, 0.163mmol) of -2- (1- aminopropyls) -3- cyclopropyl -5- methylquinazolins -4 is suspended in positive fourth In alcohol (2mL), DIPEA (39mg, 0.302mmol) is then added into reactant, reactant mixture is heated to flowing back, and stir Reaction 22 hours is mixed, is monitored and reacted with thin-layered chromatography (PE/EtOAc, v/v, 1/3).After having reacted, reaction solution is cooled to Room temperature, and be concentrated under reduced pressure, add ethyl acetate (15mL) and dilute residue, gained mixture uses water (15mL) and salt successively Water (10mL) washs.Liquid separation, organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/ EtOAc (v/v)=2/1) purifying, it is faint yellow solid (56mg, 85.6%) to obtain title compound.

MS(ESI,pos.ion)m/z:433.3[M+H]⁺；HPLC：98%；

¹H NMR(400MHz,CDCl₃)δ(ppm):9.05 (d, J=7.6Hz, 1H), 8.17 (s, 1H), 7.63-7.45 (m, 2H), 7.20 (d, J=7.0 Hz, 1H), 6.33 (td, J=7.3,5.5Hz, 1H), 3.13-3.01 (m, 1H), 2.87 (s, 3H), 2.55(s,3H),2.19–2.10(m,1H), 2.05–1.95(m,1H),1.45–1.40(m,2H),1.15–1.07(m,1H), 1.02 (t, J=7.4Hz, 3H), 0.93-0.89 (m, 1H).

Embodiment 22 (S) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Propyl group) -3- (2- fluorophenyls) quinazoline -4 (3H) -one

By the chloro- 5- of compound 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (31mg, 0.147mmol) and (S) -2- (1- aminopropyls) -3- (2- fluorophenyls) quinazoline -4 (3H) -one (48mg, 0.161mmol) is suspended in n-butanol In (2mL), DIPEA (38mg, 0.293mmol) is then added thereto, and reactant mixture is heated to backflow and stirring reaction 13 hours, monitored and reacted with thin-layered chromatography (PE/EtOAc, v/v, 2/3).After having reacted, reactant mixture is cooled to room Temperature, then be concentrated under reduced pressure, add ethyl acetate (15mL) and dilute residue, gained mixture uses water (15mL) and saline solution successively (10mL) is washed, and organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (PE/EtOAc (v/ V)=3/1) purify, it is that white solid is (65mg, 93.9%) to obtain title compound, and compound is A/B=5/4's by ratio Two kinds of isomers are formed.

MS(ESI,pos.ion)m/z:473.3[M+H]⁺；HPLC：98% (isomers A and B total purity)；

Isomers A:¹H NMR(400MHz,CDCl₃)δ(ppm):8.79 (d, J=7.5Hz, 1H), 8.31 (d, J= 7.8Hz,1H),8.04(s, 1H),7.90–7.69(m,2H),7.66–7.46(m,3H),7.45–7.30(m,2H),5.36– 5.16(m,1H),2.55(s,3H),2.00–1.78(m, 2H),0.93–0.86(m,3H)；

Isomers B:¹H NMR(400MHz,CDCl₃)δ(ppm):8.79 (d, J=7.5Hz, 1H), 8.31 (d, J= 7.8Hz,1H),7.94(s, 1H),7.90–7.69(m,2H),7.66–7.46(m,3H),7.45–7.30(m,2H),5.36– 5.16(m,1H),2.53(s,3H),2.00–1.78(m, 2H),0.93–0.87(m,3H)；

Embodiment 23 (S) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Propyl group) -4 (3H) -one of -3- cyclopropyl -5- Fluquinconazoles quinoline

By the chloro- 5- of compound 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (31mg, 0.147mmol) and (S) fluoro- 3- cyclopropyl quinazoline -4 (3H) -one (40mg, 0.154mmol) of -2- (1- aminopropyls) -5- are suspended in n-butanol In (2mL), DIPEA (38 mg, 0.294mmol) is then added thereto, and reactant mixture is heated to backflow and stirring reaction 13 hours, and monitored and reacted with thin-layered chromatography (PE/EtOAc, v/v, 2/3).After having reacted, reactant mixture is cooled to Room temperature, and be concentrated under reduced pressure, ethyl acetate (15mL) dilution is added into residue, gained mixture is successively with water (15mL) and food Salt solution (10mL) washs.Organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/ EtOAc (v/v)=2/1) purifying, it is faint yellow solid (49mg, 76.6%) to obtain title compound.

MS(ESI,pos.ion)m/z:437.2[M+H]⁺；HPLC:99%；

¹H NMR(600MHz,CDCl₃)δ(ppm):9.50 (d, J=6.1Hz, 1H), 8.21 (s, 1H), 7.67 (dd, J= 13.1,7.8Hz, 1H), 7.47 (d, J=8.1Hz, 1H), 7.18-7.04 (m, 1H), 6.37 (dd, J=11.9,6.6Hz, 1H),3.11–3.00(m,1H),2.58(s,3H), 2.21–2.12(m,1H),2.11–1.96(m,1H),1.53–1.40(m, 2H), 1.14-1.06 (m, 1H), 1.03 (t, J=7.3Hz, 3H), 1.01-0.95 (m, 1H).

Embodiment 24 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) Propyl group) -3- (2- fluorophenyls) quinazoline -4 (3H) -one

Step 1) N- (2- fluorophenyls) -2- nitrobenzamides

Compound 2- nitrobenzoic acids (5.01g, 30mmol) are suspended in toluene (60mL), then at room temperature, to Thionyl chloride (4.9mL, 67.5mmol) is disposably added in the yellow suspension, it is small that gained mixture reacts 10 at 110 DEG C When, then it is concentrated under reduced pressure, residue is dissolved in Isosorbide-5-Nitrae-dioxane (30mL), at 5 DEG C, 2- fluorine is added dropwise thereto Aniline (3.36g, 30mmol) and NaHCO₃Isosorbide-5-Nitrae-dioxane (30mL) suspension of (6.34g, 75.5mmol), gained mix Compound is stirred at room temperature overnight, and the water quenching for adding 200 mL is gone out reaction, then filters gained mixture.Filter cake water (100mL × 2) are rinsed, then under vacuum in 50 DEG C of dryings, obtain title compound for faint yellow solid (7.55g, 97%).

MS(ESI,pos.ion.)m/z:261.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):10.52(s,1H),8.22–8.10(m,1H),7.94–7.83(m, 2H),7.83–7.69(m, 2H),7.37–7.17(m,3H)。

Step 2) (S)-(1- (N- (2- fluorophenyls) -2- nitrobenzamides base) -1- oxo-butanes -2- bases) carbamic acid The tert-butyl ester

Compound N-(2- fluorophenyls) -2- nitrobenzamides (5.20g, 20mmol) are suspended in toluene (60mL), Then DMF (146mg) and SOCl is added thereto₂(18.88g, 160mmol), after reactant mixture backflow overnight, then depressurize dense Contracting, obtains burgundy grease, and not purified be directly used in is reacted in next step.

By compound (S) -2- ((tertbutyloxycarbonyl) amino) butyric acid (4.08g, 20mmol) and DIPEA (7mL, 42mmol) It is dissolved in anhydrous DCM (100mL), at 0 DEG C, is slowly added to the dichloromethane of gained burgundy grease above thereto (100mL) solution, reaction 24 hours is stirred at room temperature in gained mixture, then uses AcOH/H successively₂O(1/100,v/v,100mL × 3), saturated sodium bicarbonate aqueous solution (100mL) and saline solution (100mL) washing, organic phase anhydrous sodium sulfate drying, decompression Concentration, gained residue purify through silica gel column chromatography (PE/EtOAc (v/v)=5/1), obtain title compound and consolidate for dark yellow Body (5.1g, 57%).

MS(ESI,pos.ion.)m/z:468.1[M+Na]⁺。

Step 3) (S)-(1- (3- (2- fluorophenyls) -4- oxo -3,4- dihydroquinazoline -2- bases) propyl group) carbamic acid uncle Butyl ester

By compound (S)-(1- (N- (2- fluorophenyls) -2- nitrobenzamides base) -1- oxo-butanes -2- bases) amino first Tert-butyl acrylate (5.1g, 11.4 mmol) is dissolved in acetic acid (58mL), and thereto disposably add zinc powder (3.0g, 45.8mmol).Reaction 24 hours is stirred at room temperature in reactant mixture, then filters, filtrate decompression is concentrated.Gained residue Be dissolved in ethyl acetate (100mL), and successively with saturated sodium bicarbonate aqueous solution (100mL × 2) and saline solution (100mL × 2) wash, organic phase anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained residue through silica gel column chromatography (PE/EtOAc (v/v)= 10/1) purify, it is yellow solid (2.7g, 59%) to obtain title compound.

MS(ESI,pos.ion.)m/z:398.2[M+H]⁺。

Step 4) (S) -2- (1- aminopropyls) -3- (2- fluorophenyls) quinazoline -4 (3H) -one

By compound (S)-(1- (3- (2- fluorophenyls) -4- oxo -3,4- dihydroquinazoline -2- bases) propyl group) carbamic acid The tert-butyl ester (2.7g, 6.8mmol) is dissolved in ethyl acetate (10mL), then at room temperature, disposably adds chlorination thereto The ethyl acetate solution (3.5M, 50mL) of hydrogen.After reaction is stirred at room temperature 2 hours in mixture, suspension is formed, by suspension It is dissolved in water (200mL), liquid separation, aqueous phase is extracted with ethyl acetate (100mL × 2), is added sodium acid carbonate and is adjusted it to pH= 7, then extracted with mixed solvent ethyl acetate/methanol (6/1 (v/v), 100 mL × 3), the organic phase saline solution of merging (100mL) wash, with anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained residue through silica gel column chromatography (PE/EtOAc (v/v)= 1/20) purify, it is yellow oil (2.02g, 100%) to obtain title compound.

MS(ESI,pos.ion.)m/z:298.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.14 (dd, J=7.9,1.1Hz, 1H), 7.90 (ddd, J=8.6, 7.3,1.6Hz, 1H), 7.75 (d, J=7.7Hz, 1H), 7.67-7.60 (m, 2H), 7.60-7.48 (m, 2H), 7.46-7.40 (m, 1H), 3.16 (dd, J=7.5,4.8Hz, 1H), 1.85-1.73 (m, 1H), 1.47-1.33 (m, 1H), 0.75 (t, J= 7.4Hz,3H)。

Step 5) (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) third Base) -3- (2- fluorophenyls) quinazoline -4 (3H) -one

By the chloro- 5- of compound 6- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine -4- amine (30mg, 0.142mmol) and (S) -2- (1- aminopropyls) -3- (2- fluorophenyls) quinazoline -4 (3H) -one (44mg, 0.149mmol) is suspended in n-butanol In (2mL), DIPEA (37mg, 0.284mmol) is then added thereto, reactant mixture is heated to reflux 19 hours, and with thin Layer chromatography (PE/EtOAc, v/v, 1/3) monitoring reaction, after having reacted, is cooled to room temperature, and be concentrated under reduced pressure by reactant mixture Solvent is removed, residue is dissolved in ethyl acetate (15mL), and gained mixture uses water (15mL) and saline solution (10mL) respectively Washing, organic phase anhydrous sodium sulfate drying, filters and is concentrated under reduced pressure, concentrated residues thing is through silica gel column chromatography (PE/EtOAc (v/ V)=1/1) purify, it is title compound (42mg, 62.7%) to obtain dark yellow solid, and the compound is A/B=7/5 by ratio Two kinds of isomers form.

MS(ESI,pos.ion)m/z:473.2[M+H]⁺；HPLC：97.1% (isomers A and B total purity)；

Isomers A:¹H NMR(600MHz,DMSO-d₆)δ(ppm):8.74 (d, J=6.8Hz, 1H), 8.15 (d, J= 7.6Hz,1H),7.96(s, 1H),7.91(s,1H),7.75–7.68(m,2H),7.68–7.50(m,3H),7.49–7.35(m, 1H),7.21(br s,2H),5.08–4.97(m, 1H),2.62(s,3H),1.88–1.78(m,1H),1.72–1.59(m, 1H), 0.78 (t, J=6.9Hz, 3H)；

Isomers B:¹H NMR(600MHz,DMSO-d₆)δ(ppm):8.63 (d, J=7.8Hz, 1H), 8.15 (d, J= 7.6Hz,1H),7.91(s, 1H),7.77(s,1H),7.75–7.68(m,2H),7.68–7.50(m,3H),7.49–7.35(m, 1H),7.21(br s,2H),5.08–4.97(m, 1H),2.59(s,3H),1.88–1.78(m,1H),1.72–1.59(m, 1H), 0.84 (t, J=6.9Hz, 3H).

Embodiment 25 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) Propyl group) -4 (3H) -one of -3- cyclopropyl -5- Fluquinconazoles quinoline

By the chloro- 5- of compound 6- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine -4- amine (30mg, 0.142mmol) and (S) fluoro- 3- cyclopropyl quinazoline -4 (3H) -one (40mg, 0.153mmol) of -2- (1- aminopropyls) -5- are suspended in n-butanol In (2mL), DIPEA (37 mg, 0.284mmol) is then added thereto, and reactant mixture is heated to backflow and stirring reaction 23 hours, and monitored and reacted with thin-layered chromatography (PE/EtOAc, v/v, 1/3).After having reacted, reaction solution is cooled to room temperature, Then it is concentrated under reduced pressure, adds ethyl acetate (15mL) and dilute residue, gained mixture uses water (15mL) and saline solution successively (10mL) is washed, and organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/ V)=3/5) purify, it is pale solid (45mg, 72.7%) to obtain title compound.

MS(ESI,pos.ion)m/z:437.1[M+H]⁺；HPLC:98%；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.54 (d, J=8.0Hz, 1H), 8.16 (s, 1H), 7.63 (td, J= 8.2,5.4Hz, 1H), 7.41 (d, J=8.2Hz, 1H), 7.08 (dd, J=10.1,8.6Hz, 1H), 6.35 (td, J=7.6, 5.3Hz,1H),3.16–3.04(m,1H),2.74(s, 3H),2.18–2.06(m,1H),2.05–1.94(m,1H),1.49– (1.39 m, 2H), 1.22-1.13 (m, 1H), 1.05 (t, J=7.4Hz, 3H), 0.94-0.81 (m, 1H).

Embodiment 26 (S) -2- (1- ((6- amino -5- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine-4-yl) ammonia Base) propyl group) -4 (3H) -one of -3- cyclopropyl -5- Fluquinconazoles quinoline

By the chloro- 5- of compound 6- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine -4- amine (31mg, 0.147mmol) Fluoro- 3- cyclopropyl quinazoline -4 (3H) -one (41mg, 0.157mmol) of (S) -2- (1- aminopropyls) -5- are suspended in n-butanol In (2mL), DIPEA (38mg, 0.294mmol) is then added thereto, and reactant mixture is heated to backflow and stirring reaction 29 hours, monitored and reacted with thin-layered chromatography (DCM/MeOH, v/v, 25/1), after having reacted, reactant mixture is cooled to room Temperature, then be concentrated under reduced pressure, ethyl acetate (15mL) dilution residue is added, gained mixture uses water (15mL) and saline solution successively (10mL) is washed.Organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/EtOAc (v/ V)=1/3) purify, it is faint yellow solid (49mg, 76.5%) to obtain title compound. MS(ESI,pos.ion)m/z: 436.2[M+H]⁺；HPLC:98.5%；

¹H NMR(400MHz,CDCl₃)δ(ppm):9.50 (d, J=7.5Hz, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.59 (dd, J=13.2,7.7Hz, 1H), 7.40 (d, J=8.1Hz, 1H), 7.10-7.01 (m, 1H), 6.36-6.25 (m, 1H), 4.05 (s, 3H), 3.14 (s, 1H), 2.13-2.01 (m, 2H), 1.47-1.41 (m, 2H), 1.08 (t, J=7.2Hz, 3H),0.96–0.89(m,2H)。

Embodiment 27 (S) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Propyl group) -5- methyl -3- (o-tolyl) quinazoline -4 (3H) -one

By the chloro- 5- of compound 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (30mg, 0.142mmol) and 2- (1- aminopropyls) -5- methyl -3- (o-tolyl) quinazoline -4 (3H) -one (44mg, 0.142mmol) is suspended in n-butanol In (2mL), DIPEA (37mg, 0.284mmol) is then added thereto, and reactant mixture is heated to backflow and stirring reaction 22 hours, monitored and reacted with thin-layered chromatography (PE/EtOAc, v/v, 1/1).After having reacted, reaction solution is cooled to room temperature, then It is concentrated under reduced pressure, residue is diluted in ethyl acetate (15mL), gained mixture uses water (15mL) saturated aqueous common salt successively (10mL) is washed, and liquid separation, organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/ EtOAc (v/v)=5/1) purifying, it is that pale solid is (56mg, 81.9%) to obtain title compound, and the compound is by ratio Formed for A/B=3/2 two kinds of isomers.

MS(ESI,pos.ion)m/z:483.3[M+H]⁺；HPLC：97.0% (isomers A and B total purity)；

Isomers A:¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.13 (d, J=7.9Hz, 1H), 7.89 (s, 1H), 7.78-7.70 (m, 1H), 7.60-7.54 (m, 1H), 7.50-7.42 (m, 3H), 7.42-7.27 (m, 2H), 4.94 (td, J= 7.5,4.7Hz, 1H), 2.73 (s, 3H), 2.49 (s, 3H), 1.96 (s, 3H), 1.89-1.43 (m, 2H), 0.74 (t, J= 7.4Hz,3H)。

Isomers B:¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.07 (d, J=7.3Hz, 1H), 7.95 (s, 1H), 7.78–7.70(m,1H), 7.60–7.54(m,1H),7.50–7.42(m,3H),7.42–7.27(m,2H),5.17–5.07(m, 1H), 2.73 (s, 3H), 2.48 (s, 3H), 2.10 (s, 3H), 1.89-1.43 (m, 2H), 0.74 (t, J=7.4Hz, 3H).

Embodiment 28 (S) -2- (1- ((6- amino -5- (5- Jia Ji oxazole -2- bases) pyrimidine-4-yl) amino) propyl group) -5- Methyl -3- (o-tolyl) quinazoline -4 (3H) -one

By the chloro- 5- of compound 6- (5- Jia Ji oxazole -2- bases) pyrimidine -4- amine (30mg, 0.142mmol) and 2- (1- amino Propane) -5- methyl -3- (o-tolyl) quinazoline -4 (3H) -one (44mg, 0.142mmol) is suspended in n-butanol (2mL), And DIPEA (37mg, 0.284mmol) is added thereto, reactant mixture is heated to reflux 21 hours, and uses thin-layered chromatography (PE/EtOAc, v/v, 1/1) monitoring reaction.After having reacted, reactant mixture is cooled to room temperature, then is concentrated under reduced pressure, will be remained Thing is diluted in ethyl acetate (15mL), and gained mixture is washed with water (15 mL) and saline solution (10mL) successively, and organic phase is used Anhydrous sodium sulfate drying, it is concentrated under reduced pressure, gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=2/1), obtains Title compound is pale solid (48mg, 70.0%), and the compound is by two kinds of isomers structures that ratio is A/B=4/5 Into.

MS(ESI,pos.ion)m/z:482.2[M+H]⁺；HPLC：94.3% (isomers A and B total purity)；

Isomers A:¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.19 (d, J=8.2Hz, 1H), 7.84 (s, 1H), 7.75–7.67(m,1H), 7.59–7.49(m,1H),7.48–7.38(m,3H),7.38–7.27(m,2H),7.25(br s, 2H),7.10(s,1H),5.07–4.98(m,1H), 2.73(s,3H),2.44(s,3H),2.09(s,3H),1.81–1.47(m, 2H),0.80–0.70(m,3H)。

Isomers B:¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.19 (d, J=8.2Hz, 1H), 7.77 (s, 1H), 7.75–7.67(m,1H), 7.59–7.49(m,1H),7.48–7.38(m,3H),7.38–7.27(m,2H),7.25(br s, 2H),7.10(s,1H),4.96–4.87(m,1H), 2.73(s,3H),2.44(s,3H),1.97(s,3H),1.81–1.47(m, 2H),0.80–0.70(m,3H)。

Embodiment 29 (S) -2- (1- ((6- amino -5- (4- Jia Ji oxazole -2- bases) pyrimidine-4-yl) amino) propyl group) -5- Methyl -3- (o-tolyl) quinazoline -4 (3H) -one

Step 1) 4,6- dichloro pyrimidine -5- formamides

By compound 4,6- dichloro pyrimidine -5- formyl chlorides (9.9g, 46.82mmol) are dissolved in tetrahydrofuran (100mL), Then be full of ammonia thereto, reaction solution is stirred at room temperature reaction 20 minutes, and with thin-layered chromatography (PE/EtOAc, v/v, 1/1) monitoring reaction.After having reacted, mixture is filtered, filter cake is rinsed with tetrahydrofuran (20mL), and gained filtrate decompression is dense Contracting, residue purify through silica gel column chromatography (PE/EtOAc (v/v)=1/1), and it is dark yellow solid to obtain title compound (6.2g, 69.0%).

MS(ESI,pos.ion)m/z:192.1[M+H]⁺。

Step 2) 4,6- dimethoxypyridin -5- formamides

By compound 4,6- dichloro pyrimidine -5- formamides (5.5g, 28.65mmol) are dissolved in absolute ethyl alcohol (65mL), And the methanol solution (30%, 12.9g, 71.61mmol) of sodium methoxide is added, reaction mixture is heated to reflux 5 hours, then subtracted Pressure concentration.Concentrated residues thing is suspended in water (50mL), gained mixture is neutralized to pH=6-7 with 4M HCl/water solution, then Mixture is filtered, filter cake is rinsed with ethyl acetate (10mL) and ethanol (5mL) successively, then is dried under reduced pressure to obtain title compound For yellow solid (3.9g, 74.3%).

MS(ESI,pos.ion)m/z:184.1[M+H]⁺。

Step 3) 2- (4,6- dimethoxypyridin -5- bases) -4- Jia Ji oxazoles

Compound 4,6- dimethoxypyridin -5- formamides (500mg, 2.73mmol) are suspended in the bromo- 2,2- diformazans of 1- Epoxide propane (5mL), heat the mixture to 130 DEG C and stirring reaction 1.5 hours, with thin-layered chromatography (PE/EtOAc, v/v, 2/1) monitoring reaction.After having reacted, add ethyl acetate (30mL) dilute reaction solution, gained mixture successively with water (30mL) and Saline solution (30mL) washs, and organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (PE/ EtOAc (v/v)=8/1) purifying, it is white solid (229mg, 37.9%) to obtain title compound.

MS(ESI,pos.ion)m/z:222.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.51 (s, 1H), 7.53 (d, J=1.0Hz, 1H), 7.28 (s, 1H), 4.04(s,6H),2.29(s, 3H)；

¹³C NMR(151MHz,CDCl₃)δ(ppm):168.74(s),157.80(s),154.00(s),137.37(s), 135.04(s),94.71(s),54.97 (s),11.72(s).

Step 4) 2- (4,6- dichloro pyrimidine -5- bases) -4- Jia Ji oxazoles

Compound 2- (4,6- dimethoxypyridin -5- bases) -4- Jia Ji oxazoles (549mg, 2.48mmol) are suspended in dry In dry toluene (20mL), then thereto add POCl3 (2.3mL, 24.8mmol) and DMF (0.5mL, 6.46mmol), gained mixture is heated to backflow simultaneously stirring reaction 18 hours, is then concentrated under reduced pressure, residue is dissolved in In ethyl acetate (100mL), gained mixture is washed, liquid separation with water (100 mL), and aqueous phase is extracted with ethyl acetate (100mL × 2) Take, the organic phase of merging is washed with saline solution (100mL), with anhydrous sodium sulfate drying, is concentrated under reduced pressure.Gained residue is through silica gel Column chromatography (PE/EtOAc (v/v)=1/4) purifies, and it is white solid (257mg, 45.1%) to obtain title compound.

MS(ESI,pos.ion)m/z:230.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.89 (s, 1H), 7.64 (d, J=1.2Hz, 1H), 2.34 (d, J= 1.2Hz,3H)。

The chloro- 5- of step 5) 6- (4- Jia Ji oxazole -2- bases) pyrimidine -4- amine

Compound 2- (4,6- dichloro pyrimidine -5- bases) -4- Jia Ji oxazoles (550mg, 2.39mmol) are dissolved in dry In tetrahydrofuran (15mL), and ammonia is filled with thereto, reaction 1 hour is stirred at room temperature in reactant mixture, and with thin layer color Spectrometry (PE/EtOAc, v/v, 2/1) monitoring reaction.After having reacted, mixture is filtered, filter cake is rushed with tetrahydrofuran (20mL) Wash.Gained filtrate decompression is concentrated, residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=5/1), obtains title compound Thing is white solid (331mg, 65.7%).

MS(ESI,pos.ion)m/z:211.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):9.16 (s, 1H), 8.33 (s, 1H), 7.56 (d, J=1.2Hz, 1H), 5.93 (s, 1H), 2.29 (d, J=1.2Hz, 3H).

Step 6) (S) -2- (1- ((6- amino -5- (4- Jia Ji oxazole -2- bases) pyrimidine-4-yl) amino) propyl group) -5- first Base -3- (o-tolyl) quinazoline -4 (3H) -one

By the chloro- 5- of compound 6- (4- Jia Ji oxazole -2- bases) pyrimidine -4- amine (31mg, 0.147mmol) and 2- (1- amino Propyl group) -5- methyl -3- (o-methyl-phenyl) quinazoline -4 (3H) -one (48mg, 0.155mmol) is suspended in n-butanol (3mL) In, DIPEA (38mg, 0.294mmol) is then added thereto, and reactant mixture is heated to backflow and stirring reaction 22 is small When, monitored and reacted with thin-layered chromatography (PE/EtOAc, v/v, 1/1).After having reacted, reactant mixture is cooled to room temperature, and It is concentrated under reduced pressure, adds ethyl acetate (15mL) and dilute residue, gained mixture uses water (15mL) and saturated aqueous common salt successively (10mL) wash, organic phase anhydrous sodium sulfate drying, be concentrated under reduced pressure, residue through silica gel column chromatography (PE/EtOAc (v/v)= 2/1) purify, it be faint yellow solid (55mg, 77.6%) to obtain title compound, the compound by ratio for A/B=3/2 two Kind isomers is formed.

MS(ESI,pos.ion)m/z:482.3[M+H]⁺；HPLC：93.1% (isomers A and B total purity)；

Isomers A:¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.32 (d, J=8.1Hz, 1H), 7.95 (d, J= 1.3Hz, 1H), 7.80 (s, 1H), 7.76-7.67 (m, 1H), 7.58 (t, J=7.8Hz, 1H), 7.50-7.38 (m, 3H), 7.37-7.27 (m, 2H), 4.96-4.87 (m, 1H), 2.74 (s, 3H), 2.25 (d, J=1.1Hz, 3H), 1.97 (s, 3H), 1.83-1.48 (m, 2H), 0.76 (t, J=7.3Hz, 3H).

Isomers B:¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.23 (d, J=7.2Hz, 1H), 7.97 (d, J= 1.3Hz, 1H), 7.87 (s, 1H), 7.76-7.67 (m, 1H), 7.58 (t, J=7.8Hz, 1H), 7.50-7.38 (m, 3H), 7.37-7.27 (m, 2H), 5.13-5.02 (m, 1H), 2.74 (s, 3H), 2.24 (d, J=1.1Hz, 3H), 2.10 (s, 3H), 1.83-1.48 (m, 2H), 0.76 (t, J=7.3Hz, 3H).

Embodiment 30 (S) -2- (1- ((6- amino -5- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine-4-yl) ammonia Base) propyl group) -5- methyl -3- (o-tolyl) quinazoline -4 (3H) -one

By the chloro- 5- of compound 6- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine -4- amine (30mg, 0.142mmol) (S) -2- (1- aminopropyls) -5- methyl -3- (o-tolyl) quinazoline -4 (3H) -one (46mg, 0.150mmol) is suspended in In n-butanol (2mL), DIPEA (37mg, 0.284mmol) is then added thereto, reactant mixture is heated to flowing back and stirred Reaction 22 hours is mixed, is monitored and reacted with thin-layered chromatography (DCM/MeOH, v/v, 100/3), after having reacted, by reactant mixture Room temperature is cooled to, and is concentrated under reduced pressure, ethyl acetate (15mL) is added and dilutes residue, gained mixture uses water successively (15mL) and saline solution (10mL) wash, and organic phase anhydrous sodium sulfate drying, are concentrated under reduced pressure, residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/1) is purified, and it is white solid (53mg, 75.8%) to obtain title compound, the compound by than Example is formed for two kinds of isomers of A/B=3/2.

MS(ESI,pos.ion)m/z:482.2[M+H]⁺；HPLC:95.4% (isomers A and B total purity)；

Isomers A:¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.53 (d, J=8.2Hz, 1H), 8.74 (s, 1H), 8.13(s,1H),7.74 (s,1H),7.72–7.65(m,1H),7.55(s,1H),7.49–7.37(m,3H),7.38–7.24 (m,2H),7.06(s,1H),4.96–4.88(m, 1H),4.01(s,3H),2.73(s,3H),1.98(s,3H),1.86–1.51 (m,2H),0.81–0.73(m,3H)。

Isomers B:¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.49 (d, J=7.5Hz, 1H), 8.74 (s, 1H), 8.13(s,1H),7.82 (s,1H),7.72–7.65(m,1H),7.53(s,1H),7.49–7.37(m,3H),7.38–7.24 (m,2H),7.06(s,1H),5.06–4.98(m, 1H),4.00(s,3H),2.73(s,3H),2.09(s,3H),1.86–1.51 (m,2H),0.81–0.73(m,3H)。

Embodiment 31 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) Propyl group) -5- methyl -3- (o-tolyl) quinazoline -4 (3H) -one

By the chloro- 5- of compound 6- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine -4- amine (30mg, 0.142mmol) and 2- (1- aminopropyls) -5- methyl -3- (o-tolyl) quinazoline -4 (3H) -one (46mg, 0.149mmol) is suspended in positive fourth In alcohol (2mL), and DIPEA (37 mg, 0.284mmol) is added thereto, reactant mixture is heated to reflux 15 hours, and is used Thin-layered chromatography (PE/EtOAc, v/v, 1/3) monitoring reaction.After having reacted, reactant mixture is cooled to room temperature, and depressurize dense Contracting, residue is diluted in ethyl acetate (15mL), and gained mixture is washed with water (15mL) and saline solution (10mL) successively, Organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure, and gained residue is pure through silica gel column chromatography (PE/EtOAc (v/v)=2/1) Change, it is white solid (53mg, 77.5%) to obtain title compound, and the compound is A/B=4/5 two kind isomers by ratio Form.

MS(ESI,pos.ion)m/z:483.2[M+H]⁺；HPLC：97.3% (total purity of two kinds of isomers of A and B)；

Isomers A:¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.75 (d, J=8.3Hz, 1H), 7.89 (s, 1H), 7.76–7.67(m,1H), 7.58–7.49(m,1H),7.49–7.39(m,3H),7.37–7.31(m,1H),7.30–7.21(m, 1H),5.05–4.98(m,1H),2.73(s,3H), 2.61(s,3H),2.10(s,3H),1.90–1.48(m,2H),0.79– 0.70(m,3H)。

Isomers B:¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.73 (d, J=7.6Hz, 1H), 7.83 (s, 1H), 7.76–7.67(m,1H), 7.58–7.49(m,1H),7.49–7.39(m,3H),7.37–7.31(m,1H),7.30–7.21(m, 1H),4.94–4.87(m,1H),2.73(s,3H), 2.61(s,3H),1.98(s,3H),1.90–1.48(m,2H),0.79– 0.70(m,3H)。

Embodiment 32 (S) -2- (1- ((6- amino -5- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine-4-yl) ammonia Base) propyl group) chloro- 3- phenylquinazolines -4 (3H) -one of -5-

By the chloro- 5- of compound 6- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine -4- amine (30mg, 0.142mmol) Chloro- 3- phenylquinazolines -4 (3H) -one (47mg, 0.150mmol) of (S) -2- (1- aminopropyls) -5- are suspended in n-BuOH In (1.5mL), DIPEA (37mg, 0.285mmol) is then added thereto.Gained mixture is heated to reflux 24 hours, and With thin-layered chromatography (CH₂Cl₂/ MeOH, v/v, 100/3) monitoring reaction, after having reacted, mixture is cooled to room temperature, and subtract Pressure concentration, add EtOAc (20mL) and dilute gained residue, gained mixture uses water (10mL) and saline solution (10mL) successively Washing, organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/ 4) purify, it is white solid (41mg, 59.0%) to obtain title compound.

MS(ESI,pos.ion)m/z:488.1[M+H]⁺；Purity：97.8%；

¹H NMR(600MHz,CDCl₃)δ(ppm):9.35(s,1H),8.14(s,1H),7.96(s,1H),7.63–7.48 (m, 6H), 7.48-7.31 (m, 2H), 5.02 (s, 1H), 4.09 (d, J=59.2Hz, 3H), 2.01-1.92 (m, 2H), 0.92 (t, J=7.1Hz, 3H).

Embodiment 33 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) Ethyl) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

The chloro- N- cyclopropyl -6- nitrobenzamides of step 1) 2-

The chloro- 6- nitrobenzoic acids (5.0g, 24.8mmol) of compound 2- are suspended in toluene (50mL), then in room temperature Under, SOCl is disposably added thereto₂(5.85g, 49.6mmol), after adding, reactant mixture stirring reaction 6 at 110 DEG C Hour, and be concentrated under reduced pressure, gained yellow oil is dissolved in Isosorbide-5-Nitrae-dioxane (30mL), obtains light yellow suspension.

By cyclopropylamine (1.42g, 24.8mmol) and NaHCO₃(4.17g, 49.6mmol) is suspended in 1,4- dioxane In (30mL), then at 0 DEG C, gained light yellow suspension, gained mixture were stirred at room temperature before addition thereto At night, 350mL water being then slowly added into, obtains suspension, gained suspension is filtered, gained solid is rinsed with water (100mL), And under vacuum in 50 DEG C of dryings, it is faint yellow solid (3.9g, 65.36%) to obtain title compound.

MS(ESI,pos.ion)m/z:241.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.09 (d, J=8.2Hz, 1H), 7.73 (d, J=7.8Hz, 1H), 7.52 (t, J=8.2Hz, 1H), 5.95 (s, 1H), 2.95 (m, 1H), 0.92 (m, 2H), 0.76 (m, 2H).

Step 2) (S)-(1- (the chloro- N- cyclopropyl -6- nitrobenzamides bases of 2-) -1- oxopropan -2- bases) amino first Tert-butyl acrylate

The chloro- N- cyclopropyl -6- nitrobenzamides (5.31g, 22.1mmol) of compound 2- are suspended in toluene (50mL) In, then at room temperature, SOCl is disposably added thereto₂(6.4mL, 88.4mmol), reactant mixture stir at 120 DEG C Overnight, pale brown oil thing is then concentrated under reduced pressure to give, the pale brown oil thing is dissolved in the DCM of 50mL dryings, obtained Yellow solution.

By compound (S) -2- ((tertbutyloxycarbonyl) amino) propionic acid (4.18g, 22.1mmol) and DIPEA (5.71g, 44.2mmol) it is dissolved in the DCM of 100mL dryings, then at 0 DEG C, the yellow for being slowly added to be previously obtained thereto is molten Liquid.Reaction 24 hours is stirred at room temperature in gained mixture, is then washed successively with water (100mL) and saline solution (100mL), point Liquid, organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=7/1) Purifying, it is yellow solid (6.58g, 72.4%) to obtain title compound.

MS(ESI,neg.ion)m/z:410.0[M-H]^-。

Step 3) (S)-(1- (the chloro- 3- cyclopropyl -4- oxos -3,4- dihydroquinazolines -2- bases of 5-) ethyl) carbamic acid The tert-butyl ester

By compound (S)-(1- (the chloro- N- cyclopropyl -6- nitrobenzamides bases of 2-) -1- oxopropan -2- bases) amino T-butyl formate (6.58g, 16.0 mmol) is dissolved in acetic acid (32mL), then thereto disposably add zinc powder (4.16g, 63.6mmol), reactant mixture stirring reaction 24 hours at 35 DEG C, then filter, filtrate decompression are concentrated, and add EtOAc (300mL) dilutes residue, and gained mixture uses saturation NaHCO successively₃The aqueous solution (100mL × 2) and saline solution (200mL) Washing, organic phase anhydrous sodium sulfate drying, and being concentrated under reduced pressure, gained residue through silica gel column chromatography (PE/EtOAc (v/v)= 8/1) purify, it is faint yellow solid (4.74g, 81.25%) to obtain title compound. MS(ESI,pos.ion)m/z:364.2 [M+H]⁺。

Chloro- 3- cyclopropyl quinazoline -4 (3H) -one of step 4) (S) -2- (1- amino-ethyls) -5-

By compound (S)-(1- (the chloro- 3- cyclopropyl -4- oxos -3,4- dihydroquinazolines -2- bases of 5-) ethyl) amino first Tert-butyl acrylate (4.7g, 12.9mmol) is dissolved in EtOAc (10mL), then at room temperature, disposably adds chlorination thereto The ethyl acetate solution (10mL, 3.5M) of hydrogen.Reactant mixture is stirred at room temperature overnight, and gained suspension is dissolved in In 150mL water, aqueous phase is extracted with EtOAc (30mL × 3), and uses Na₂CO₃Powder is neutralized to pH=8, then with EtOAc (100mL × 4) extract, the organic phase of merging is washed with saline solution (200mL), anhydrous sodium sulfate drying, and is concentrated under reduced pressure, and obtains title compound Thing is faint yellow solid (2.57g, 75.6%).

MS(ESI,pos.ion)m/z:264.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.54 (m, 2H), 7.43 (m, 1H), 4.87 (dd, J=13.0, 6.4Hz, 1H), 2.94 (m, 1H), 1.52 (d, J=6.6Hz, 3H), 1.38 (m, 2H), 0.95 (m, 2H).

Step 5) (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) second Base) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By chloro- 3- cyclopropyl quinazoline -4 (3H) -one of compound (S) -2- (1- amino-ethyls) -5- (80mg, 0.30mmol) and the chloro- 5- of 6- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine -4- amine (60mg, 0.28mmol) is dissolved in n- In BuOH (5mL), DIPEA (90 mg, 0.70mmol) is then added thereto, mixture is heated to reflux 24 hours, and with thin Layer chromatography (PE/EtOAc, v/v, 1/2) monitoring reaction.Then mixture is cooled to room temperature, and be concentrated under reduced pressure, gained residual Thing purifies through silica gel column chromatography (PE/EtOAc (v/v)=1/2), and it is white solid (67mg, 51%) to obtain title compound.

MS(ESI,pos.ion):439.2[M+H]⁺；HPLC:98.1%；

¹H NMR(400MHz,CDCl₃)δ(ppm):9.01 (d, J=6.7Hz, 1H), 8.15 (s, 1H), 7.55 (d, J= 3.9Hz, 2H), 7.43 (d, J=3.9Hz, 1H), 6.39-6.22 (m, 1H), 3.11 (s, 1H), 2.74 (s, 3H), 1.78 (s, 2H), 1.67 (d, J=6.4Hz, 3H), 1.44 (m, 2H), 0.96 (m, 2H).

Embodiment 34 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) Propyl group) the chloro- 3- of -5- (3- fluorophenyls) quinazoline -4 (3H) -one

The chloro- N- of step 1) 2- (3- fluorophenyls) -6- nitrobenzamides

The chloro- 6- nitrobenzoic acids (5.0g, 24.8mmol) of compound 2- are suspended in toluene (25mL), then thereto Add SOCl₂(5.5mL, 74.4mmol), mixture are stirred overnight at 110 DEG C, are then concentrated under reduced pressure, and obtain brown oil Thing.By 3- fluoroanilines (4.1g, 37.2mmol) and NaHCO₃(4.2g, 49.6mmol) is suspended in 1,4- dioxane (15mL) In, then at 5 DEG C, it is slowly added to Isosorbide-5-Nitrae-dioxane (15mL) solution of brown oil being previously obtained, gained mixing Thing is stirred at room temperature overnight, and is then concentrated under reduced pressure.Add ethyl acetate (200mL) and water (80mL) is dilute by gained residue Release, liquid separation, organic phase is washed with saline solution (150mL × 2), with anhydrous sodium sulfate drying, is concentrated under reduced pressure, is obtained title compound For buff white solid (7.3g, 100%).

MS(ESI,pos.ion)m/z:295.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.18 (d, J=18.6Hz, 1H), 7.86-7.73 (d, 1H), 7.70- 7.46 (m, 3H), 7.36 (dd, J=14.6,8.0Hz, 1H), 6.92 (dd, J=25.7,16.2,1H), 3.70 (s, 1H).

Step 2) 2- amino -6- chloro- N- (3- fluorophenyls) benzamide

The chloro- N- of compound 2- (3- fluorophenyls) -6- nitrobenzamides (4.0g, 13.6mmol) are suspended in absolute ethyl alcohol In (70mL), iron powder (3.8g, 67.8mmol) and HCOONH are then added thereto₄The water of (8.23g, 130.57mmol) (14mL) solution, after gained mixture is stirred overnight at 95 DEG C, filter.Filtrate decompression is concentrated, residue is through silica gel column layer (PE/EtOAc (v/v)=5/1) purifying is analysed, it is buff white solid (1.5g, 42%) to obtain title compound.

MS(ESI,pos.ion)m/z:265.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):10.65 (s, 1H), 7.74 (d, J=11.7Hz, 1H), 7.45 (d, J =8.2Hz, 1H), 7.37 (dd, J=15.1,8.0Hz, 1H), 7.10 (t, J=8.1Hz, 1H), 6.93 (dd, J=11.9, 4.9Hz, 1H), 6.67 (dd, J=30.2,7.9 Hz, 1H), 5.36 (s, 2H).

Step 3) (S)-(1- ((the chloro- 2- of 3- ((3- fluorophenyls) carbamoyl) phenyl)-amino) -1- oxo-butanes -2- Base) t-butyl carbamate

By compound 2- amino -6- chloro- N- (3- fluorophenyls) benzamides (1.5g, 5.67mmol) and Boc-L-2- amino Butyric acid (1.21g, 5.95 mmol) is dissolved in DCM (20mL), then at -10 DEG C, thereto add DIPEA (2.20g, 17.01mmol) with HATU (2.59 g, 6.80mmol), after thermotonus 1 hour, heat the mixture to and flow back and stir Overnight, water (150mL × 2) and saturation NaHCO are then used successively₃The aqueous solution (150mL × 2) washs, and organic phase is concentrated under reduced pressure, institute Obtain residue to purify through silica gel column chromatography (PE/EtOAc (v/v)=5/1), it is faint yellow solid to obtain title compound (1.7g, 66.7%).

MS(ESI,pos.ion)m/z:350.2[M-Boc+H]⁺。

Step 4) (S)-(1- (the chloro- 3- of 5- (3- fluorophenyls) -4- oxo -3,4- dihydroquinazoline -2- bases) propyl group) amino T-butyl formate

By compound (S)-(1- ((the chloro- 2- of 3- ((3- fluorophenyls) carbamoyl) phenyl)-amino) -1- oxo-butanes - 2- yls) t-butyl carbamate (1.6 g, 3.60mmol) and triethylamine (15mL, 108mmol) be dissolved in CH₃CN(100mL) In, then under nitrogen protection, N, the double trimethylsilyl acetamides (13mL, 36mmol) of O-, by institute are added thereto with syringe Mixture is heated to 85 DEG C, and stirring reaction 33 hours is subsequently cooled to room temperature, and is concentrated under reduced pressure, and gained residue is through silicon Plastic column chromatography (PE/EtOAc (v/v)=8/1) purifies, and it is faint yellow solid (1.28g, 82.3%) to obtain title compound.

MS(ESI,pos.ion)m/z:432.1[M+H]⁺。

Chloro- 3- (3- fluorophenyls) quinazoline -4 (3H) -one of step 5) (S) -2- (1- aminopropyls) -5

By compound (S)-(1- (the chloro- 3- of 5- (3- fluorophenyls) -4- oxo -3,4- dihydroquinazoline -2- bases) propyl group) ammonia Base t-butyl formate (1.28g, 2.96 mmol) is suspended in 10mL EtOAc, and adds the ethyl acetate of hydrogen chloride thereto Solution (3.0M, 8mL, 24.00mmol), mixture is stirred at room temperature reaction 4 hours, is then concentrated under reduced pressure, and residue is molten Solution is in EtOAc (50mL), resulting solution saturation NaHCO₃The aqueous solution is neutralized to pH=7-8.Organic phase saline solution (100mL × 2) are washed, then with anhydrous sodium sulfate drying, are concentrated under reduced pressure, obtain title compound for white solid (982mg, 100%).

MS(ESI,pos.ion)m/z:332.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.79 (t, J=8.0Hz, 1H), 7.67-7.61 (m, 2H), 7.57 (d, J=7.7Hz, 1H), 7.50 (d, J=9.6Hz, 1H), 7.46-7.36 (m, 2H), 7.33 (d, J=7.9Hz, 1H), 3.17-3.15 (s, 1H), 1.40 (m, 2H), 0.72 (t, J=7.3Hz, 3H).

Step 6) (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) third Base) the chloro- 3- of -5- (3- fluorophenyls) quinazoline -4 (3H) -one

By compound (S) -2- (1- aminopropyls) -5- chloro- 3- (3- fluorophenyls) quinazoline -4 (3H) -one (98.9mg, 0.298mmol) it is dissolved in the chloro- 5- of 6- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine -4- amine (60mg, 0.284mmol) In 5mL n-BuOH, DIPEA (0.15mL, 0.568mmol) is then added thereto, mixture is stirred overnight at 120 DEG C, Filter, filter cake is washed with 1mL ethanol, and it is white solid (40mg, 27.7%) to obtain title compound.

MS(ESI,pos.ion)m/z:507.1[M+H]⁺；HPLC:99.8%；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):8.64 (d, J=7.1Hz, 1H), 7.95 (d, J=15.8Hz, 1H), 7.82-7.73 (m, 1H), 7.72-7.54 (m, 3H), 7.44 (m, 2H), 7.21 (s, 2H), 4.87-4.76 (m, 1H), 2.62 (s, 3H), 2.03-1.92 (m, 2H), 0.87-0.85 (t, J=12Hz, 3H).

Embodiment 35 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) Propyl group) -5- chloro- 3- (o-tolyl) quinazoline -4 (3H) -one

Chloro- 6- nitros-N- (o-tolyl) benzamides of step 1) 2-

The chloro- 6- nitrobenzoic acids (5.0g, 24.8mmol) of compound 2- are suspended in toluene (25mL), then in room temperature Under, SOCl is added dropwise thereto₂(5.5mL, 74.4mmol) and DMF (3mL), after adding, reactant mixture is at 110 DEG C It is stirred overnight, is then concentrated under reduced pressure, obtains pale brown oil thing.

By ortho-aminotoluene (4.0g, 37.2mmol) and NaHCO₃(4.2g, 49.6mmol) is suspended in 1,4- dioxane In (15mL), then at 5 DEG C, thereto add before gained pale brown oil thing Isosorbide-5-Nitrae-dioxane (5mL) solution, Reaction 7 hours is stirred at room temperature in gained mixture, then adds ethyl acetate (300mL) and water (300mL) dilutes, liquid separation, Organic phase washed with saline solution (200mL), with anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained residue is through silica gel column chromatography (DCM) purify, it is pale solid (6.3g, 87.4%) to obtain title compound.

MS(ESI,pos.ion)m/z:291.0[M+H]⁺。

Step 2) 2- amino -6- chloro- N- (o-tolyl) benzamide

Chloro- 6- nitros-N- (o-tolyl) benzamides (4.0g, 13.7mmol) of compound 2- are suspended in absolute ethyl alcohol In (70mL), iron powder (3.8g, 67.9mmol) and HCOONH are then added thereto₄The 14mL of (8.7g, 137.6mmol) is water-soluble Liquid, gained mixture are warming up to 95 DEG C and are stirred overnight.Then ethyl acetate (400mL) and water (20mL) dilution, aqueous phase are added Being extracted with ethyl acetate (100mL × 2), the organic phase of merging washed with saline solution (150mL × 3), with anhydrous sodium sulfate drying, It is concentrated under reduced pressure, gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=5/1), and it is greyish white to obtain title compound Color solid (2.7g, 75.8%).

MS(ESI,pos.ion)m/z:261.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.89 (s, 1H), 7.51 (d, J=7.8Hz, 1H), 7.36-7.17 (m, 2H), 7.14 (t, J=7.4Hz, 1H), 7.09 (t, J=8.0Hz, 1H), 6.71 (d, J=8.2Hz, 1H), 6.64 (d, J =18.0Hz, 1H), 5.33 (s, 2H), 2.30 (s, 3H).

Step 3) (S)-(1- ((the chloro- 2- of 3- (o-tolylamino formoxyl) phenyl) amino) -1- oxo-butanes -2- bases) T-butyl carbamate

By compound 2- amino -6- chloro- N- (o-tolyl) benzamide (2.7g, 10.4mmol), Boc-L-2- amino Butyric acid (2.2g, 10.8 mmol) and DIPEA (5.4mL, 31.1mmol) are suspended in DCM (40mL), then at -10 DEG C, to HATU (4.7 g, 12.4mmol) is wherein added, mixture stirring reaction at -10 DEG C after 1 hour, is again heated to and flows back and stir Mix overnight, then use water (200mL × 2) and saturation NaHCO successively₃The aqueous solution (200mL × 2) is washed, liquid separation, and organic phase is used Anhydrous sodium sulfate drying, and be concentrated under reduced pressure.Gained residue purifies through silica gel column chromatography (EtOAc), and obtaining title compound is Faint yellow solid (3.25g, 70.3%).

MS(ESI,pos.ion)m/z:346.2[M-Boc+H]⁺。

Step 4) (S)-(1- (chloro- 4- oxos -3- (the o-tolyl) -3,4- dihydroquinazoline -2- bases of 5-) propyl group) amino T-butyl formate

By compound (S)-(1- ((the chloro- 2- of 3- (o-tolylamino formoxyl) phenyl) amino) -1- oxo-butanes -2- Base) t-butyl carbamate (1.7g, 3.80mmol) is dissolved in CH₃In CN (120mL), triethylamine is then added thereto (27mL,190mmol).Nitrogen purification is passed through into reactant mixture, then N, the double trimethylsilyl acetamides of O- are added with syringe (19mL, 76.25mmol), after adding, mixture under nitrogen protection, in 90 DEG C of stirring reactions 3 days in seal pipe, then subtracts Pressure concentration, gained residue purify through silica gel column chromatography (PE/EtOAc (v/v)=10/1), and it is yellow to obtain title compound Solid (1.26g, 77%).

MS(ESI,pos.ion)m/z:428.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.85-7.75 (m, 1H), 7.66 (dd, J=12.9,8.2Hz, 1H), 7.59 (dd, J=11.0,8.0Hz, 1H), 7.53-7.29 (m, 4H), 7.19 (dd, J=40.9,7.9Hz, 1H), 3.91–3.74(m,1H),2.09(s,3H),1.56-1.46(m, 2H),1.35(s,9H),0.66(m,3H)。

Step 5) (S) -2- (1- aminopropyls) -5- chloro- 3- (o-tolyl) quinazoline -4 (3H) -one

By compound (S)-(1- (chloro- 4- oxos -3- (the o-tolyl) -3,4- dihydroquinazoline -2- bases of 5-) propyl group) ammonia Base t-butyl formate (1.24g, 2.90 mmol) is suspended in EtOAc (10mL), then adds the acetic acid second of hydrogen chloride thereto Ester solution (3M, 8mL, 24.00mmol), gained mixture are stirred at room temperature overnight, are then concentrated under reduced pressure, residue is dissolved In EtOAc (100mL), gained mixture saturation NaHCO₃The aqueous solution is neutralized to pH=7-8.Liquid separation, aqueous phase EtOAc (100mL × 2) are extracted, and the organic phase of merging is washed with saturated aqueous common salt (150mL × 2), then is concentrated under reduced pressure, and removes 90% Solvent, PE (50mL) is added dropwise into the residue after concentration, after adding, gained mixture is stirred at room temperature 30 minutes, then Filter, the concentration of gained filtrate decompression, it is light brown syrup (850 mg, 89%) to obtain title compound.

MS(ESI,pos.ion)m/z:328.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.81-7.77 (t, J=8.0Hz, 1H), 7.68-7.66 (m, 1H), 7.57-7.55 (m, 1H), 7.50-7.34 (m, 4H), 3.10-3.06 (t, J=6.6Hz, 1H), 2.09 (s, 3H), 1.49- 1.27(m,2H),0.72(m,3H)。

Step 6) (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) third Base) -5- chloro- 3- (o-tolyl) quinazoline -4 (3H) -one

By compound (S) -2- (1- aminopropyls) -5- chloro- 3- (o-tolyl) quinazoline -4 (3H) -one (97.6mg, 0.298mmol) it is suspended in the chloro- 5- of 6- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine -4- amine (60mg, 0.284mmol) In 5mL n-BuOH, DIPEA (0.15mL, 0.568mmol) is then added thereto, 120 DEG C is heated the mixture to and stirs Overnight, then filter, filter cake is washed with 1mL ethanol, and it is white solid (38.8mg, 27.2%) to obtain title compound.

MS(ESI,pos.ion)m/z:503.1[M+H]⁺；HPLC:99.0%；

1H NMR(400MHz,DMSO-d₆)δ(ppm):8.93 (d, J=8.0Hz, 1H), 7.92 (s, 1H), 7.84-7.78 (m,1H),7.69–7.57 (m,2H),7.54–7.38(m,5H),4.93-4.88(m,1H),2.61(s,3H),2.01(s, 3H), 1.87-1.54 (m, 2H), 0.75 (t, J=7.4 Hz, 3H).

Embodiment 36 (S) -2- (1- ((6- amino -5- (2- methyl -2H- tetrazole -5- bases) pyrimidine-4-yl) amino) third Base) the chloro- 3- of -5- (3- fluorophenyls) quinazoline -4 (3H) -one

Compound (S) -2- (1- aminopropyls) -5- chloro- 3- (3- fluorophenyls) quinazoline -4 (3H) -one (30mg, 0.09mmol), the chloro- 5- of 6- (2- methyl -2H- tetrazole -5- bases) pyrimidine -4- amine (19mg, 0.09mmol), DIPEA (41mg, 130 DEG C of simultaneously stirring reaction 24 hours 0.31mmol) are heated to n-BuOH (1mL) mixture, are subsequently cooled to room temperature, and subtract Pressure concentration, gained residue purify through silica gel column chromatography (DCM/MeOH (v/v)=100/1), obtain crude product, crude product is again It is further purified by preparative thin layer chromatography (DCM/MeOH, v/v, 25/1), it is white solid to obtain title compound (27mg, 59%).

MS(ESI,pos.ion)m/z:507[M+H]⁺；HPLC:90%；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.79-8.77 (d, J=6.8Hz, 1H), 7.97-7.95 (d, J= 8.8Hz, 1H), 7.78-7.74 (dd, J=8.0,7.8Hz, 1H), 7.627.43 (m, 6H), 4.88-4.85 (m, 1H), 4.52 (s, 2H), 4.43 (s, 1H), 2.02-1.99 (m, 1H), 1.75-1.66 (m, 1H), 0.82-0.79 (dd, J=6.8,6.0Hz, 3H)。

Embodiment 37 (S) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Propyl group) -4 (3H) -one of -5- methyl -3- phenylquinazolines

Step 1) 2- methyl -6- nitro-N-phenylbenzamides

Compound 2- methyl -6- nitrobenzoic acids (5g, 27.6mmol) are dissolved in toluene (50mL), then in room temperature Under, SOCl is disposably added into gained yellow suspension₂(6.51g, 54.7mmol), after adding, reactant mixture is at 110 DEG C Under be stirred overnight, be then concentrated under reduced pressure to give yellow oil, the yellow oil be dissolved in Isosorbide-5-Nitrae-dioxane (30mL) In.At 5 DEG C, resulting solution is added dropwise to aniline (2.51g, 27.6mmol) and NaHCO₃(5.85g, 69.6mmol's) In Isosorbide-5-Nitrae-dioxane (30mL) suspension, reaction 24 hours is stirred at room temperature in gained mixture, then adds water (200mL) Reaction is quenched, mixture is extracted with EtOAc (200mL × 3), and the organic phase of merging is washed with saline solution (200mL), then is depressurized dense Contracting, gained residue purify through silica gel column chromatography (PE/EtOAc (v/v)=8/3), and it is faint yellow solid to obtain title compound (6.5g, 92%).

MS(ESI,pos.ion.)m/z:257.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.98 (d, J=8.2Hz, 1H), 7.75 (s, 1H), 7.56 (d, J= 19.6Hz, 3H), 7.45 (t, J=7.9Hz, 1H), 7.37 (t, J=7.7Hz, 2H), 7.20 (t, J=7.4Hz, 1H), 2.49 (s,3H)。

Step 2) (S)-(1- (2- methyl -6- nitro-N-phenylbenzamides base) -1- oxo-butanes -2- bases) amino first Tert-butyl acrylate

Compound 2- methyl -6- nitro-N-phenylbenzamides (6.5g, 25.4mmol) are suspended in toluene (100mL) In, SOCl is then added dropwise thereto₂(7.3mL,101.6mmol).After adding, reaction solution stirring reaction at 120 DEG C 12 hours, then it is concentrated under reduced pressure, obtained brown oil is not purified, is directly used in and reacts in next step.

Compound Boc-L-2- aminobutyric acids (5.17g, 25.4mmol) and DIPEA (9.85g, 76.2mmol) are dissolved in In DCM (50mL), then at 0 DEG C, DCM (50mL) solution of brown oil obtained above is added thereto.Add it Afterwards, after reaction is stirred at room temperature 24 hours in reactant mixture, successively with 4% aqueous citric acid solution (100mL × 3), saturation NaHCO₃The aqueous solution (100mL × 2) and saline solution (100mL) washing, organic phase are crossed with anhydrous sodium sulfate drying, are concentrated under reduced pressure, Gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=9/1), and it is yellow oil to obtain title compound (7.47g, 66.54%).

MS(ESI,pos.ion.)m/z:464.2[M+Na]⁺。

Step 3) (S)-(1- (5- methyl -4- oxo -3- phenyl -3,4- dihydroquinazoline -2- bases) propyl group) carbamic acid The tert-butyl ester

By compound (S)-(1- (2- methyl -6- nitro-N-phenylbenzamides base) -1- oxo-butanes -2- bases) amino T-butyl formate (7.37g, 16.7 mmol) is dissolved in acetic acid (30mL), then thereto disposably add zinc powder (4.37g, 66.8mmol), after adding, reactant mixture is stirred overnight at 35 DEG C, is then filtered, then filtrate decompression is concentrated, and will be remained Thing is dissolved in EtOAc (200mL), and gained mixture uses saturation NaHCO successively₃The aqueous solution (200mL × 2), water (200mL) and Saline solution (100mL) washs, and organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/ EtOAc (v/v)=25/2) purifying, it is pale yellow powder (2.82g, 43%) to obtain title compound.

MS(ESI,pos.ion.)m/z:394.2[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.68 (t, J=7.7Hz, 1H), 7.63-7.55 (m, 2H), 7.52 (dd, J=17.9,7.8 Hz, 2H), 7.46 (d, J=7.7Hz, 1H), 7.38 (d, J=7.6Hz, 1H), 7.29 (d, J= 7.3Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 3.95 (td, J=9.1,3.8Hz, 1H), 2.72 (s, 3H), 1.71 (m, 1H),1.54(m,1H),1.34(s,9H),0.63(t,3H)。

(3H) -one of step 4) (S) -2- (1- aminopropyls) -5- methyl -3- phenylquinazolines -4

By compound (S)-(1- (5- methyl -4- oxo -3- phenyl -3,4- dihydroquinazoline -2- bases) propyl group) amino first Tert-butyl acrylate (2.82g, 7.2mmol) is dissolved in EtOAc (80mL), at room temperature, disposably adds hydrogen chloride thereto Ethyl acetate solution (3.5M, 21mL).Mixture is stirred at room temperature overnight, and is then dissolved in water (300mL).Aqueous phase is used EtOAc (100mL) is extracted, and adds NaHCO₃Powder is neutralized to pH=8, is then extracted again with EtOAc (150mL × 3).Merge Organic phase washed with saline solution (100mL), then with anhydrous sodium sulfate drying, be concentrated under reduced pressure, it is yellow to obtain title compound Powder (2.05g, 97.2%).

MS(ESI,pos.ion.)m/z:294.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.62 (dd, J=13.5,6.0Hz, 1H), 7.61-7.56 (m, 3H), 7.53 (t, J=7.4Hz, 1H), 7.33-7.27 (m, 2H), 7.25 (d, J=7.2Hz, 1H), 3.41 (dt, J=63.0, 31.5Hz, 1H), 2.84 (s, 3H), 1.93-1.81 (m, 1H), 1.61-1.44 (m, 1H), 0.82 (t, J=7.4Hz, 3H).

Step 5) (S) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) third Base) -4 (3H) -one of -5- methyl -3- phenylquinazolines

By (3H) -one (59mg, 0.2mmol) of compound (S) -2- (1- aminopropyls) -5- methyl -3- phenylquinazolines -4 N-BuOH (2mL) is suspended in the chloro- 5- of 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (42mg, 0.2mmol) In, DIPEA (52 mg, 0.4mmol) is then added thereto.By reactant mixture backflow overnight, and with thin-layered chromatography (PE/ EtOAc, v/v, 1/3) monitoring reaction, after having reacted, reactant mixture is cooled to room temperature, and be concentrated under reduced pressure.Residue is dilute Release in EtOAc (10mL), gained mixture is washed with water (10 mL × 2) and saline solution (10mL) successively, and organic phase is with anhydrous Sodium sulphate is dried, and is concentrated under reduced pressure.Gained residue purifies through thin-layered chromatography (PE/EtOAc (v/v)=2/1), obtains title Compound is white solid (79mg, 84.3%).

MS(ESI,pos.ion):469.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):9.37 (d, J=7.3Hz, 1H), 8.06 (s, 1H), 7.69-7.53 (m, 5H), 7.35 (dd, J=17.7,9.4Hz, 2H), 7.28 (m, 1H), 5.23 (m, 1H), 2.85 (s, 3H), 2.58 (s, 3H), 2.23 (m, 6.4Hz, 1H), 1.65 (m, 1H), 0.86 (t, J=7.4Hz, 3H).

Embodiment 38 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) Propyl group) -4 (3H) -one of -5- methyl -3- phenylquinazolines

By (3H) -one of compound (S) -2- (1- aminopropyls) -5- methyl -3- phenylquinazolines -4 (40mg, 0.14mmol) it is suspended in the chloro- 5- of 6- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine -4- amine (28.9mg, 0.14mmol) In n-BuOH (2mL), DIPEA (36.2mg, 0.28mmol) is then added thereto, and reactant mixture is heated to backflow simultaneously It is stirred overnight, is monitored and reacted with thin-layered chromatography (PE/EtOAc, v/v, 1/4), after having reacted, mixture is cooled to room temperature, And be concentrated under reduced pressure, EtOAc (10mL) dilution residues are added, obtained mixture uses water (10mL × 2) and saline solution successively (10mL) is washed, and organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure, gained residue is through thin-layered chromatography (PE/EtOAc (v/ V)=2/1) purify, it is white solid (45mg, 68.8%) to obtain title compound.

MS(ESI,pos.ion):469.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.69 (d, J=7.3Hz, 1H), 7.95 (s, 1H), 7.67 (t, J= 7.8Hz, 1H), 7.63-7.43 (m, 6H), 7.29 (d, J=7.3Hz, 1H), 4.89-4.76 (m, 1H), 2.72 (s, 3H), 2.61 (s, 3H), 1.97-1.84 (m, 1H), 1.74-1.60 (m, 1H), 0.76 (t, J=7.3Hz, 3H).

Embodiment 39 (S) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Propyl group) fluoro- 3- phenylquinazolines -4 (3H) -one of -5-

The fluoro- 6- nitro-N-phenylbenzamides of step 1) 2-

Compound 2- fluoride-6-nitrobenzoic acids (5.55g, 30mmol) are suspended in toluene (50mL), then in room temperature Under, SOCl is disposably added thereto₂(7.08g, 60mmol), after adding, reactant mixture stirring reaction 8 at 110 DEG C Hour, yellow oil is then concentrated under reduced pressure to give, yellow oil is dissolved in Isosorbide-5-Nitrae-dioxane (40mL), Ran Hou At 5 DEG C, aniline (2.79 g, 30mmol) and NaHCO are added dropwise thereto₃The 1,4- dioxane of (5.04g, 60mmol) The suspension of (40mL), gained mixture are stirred at room temperature overnight, and then add water (350mL) and reaction is quenched, then will mixing Thing is filtered, and filter cake is rinsed with water (100mL × 2), and under vacuo in 50 DEG C of dryings, it is dark brown solid to obtain title compound (5.6g, 71.6%).

MS(ESI,pos.ion.)m/z:261.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.02 (d, J=8.2Hz, 1H), 7.63 (dd, J=13.8,8.2Hz, 4H), 7.52 (dd, J=17.2,9.0Hz, 1H), 7.42 (t, J=7.8Hz, 2H), 7.23 (t, J=7.4Hz, 1H).

The fluoro- N- phenylbenzamaides of step 2) 2- amino -6-

The fluoro- 6- nitro-N-phenylbenzamides (5.6g, 21.5mmol) of compound 2- are dissolved in ethanol (150mL), Then iron powder (6.08g, 107.5mmol) is added thereto, and property adds HCOONH again₄The water of (13.55g, 215mmol) (30mL) solution, gained suspension stirring reaction 7 hours at 80 DEG C, then filters, filtrate decompression is concentrated while hot, and concentration is residual Thing is stayed to be dissolved in EtOAc (300mL), mixture is washed with water (200mL × 2) and saline solution (200mL) successively, liquid separation, is had Machine mutually uses anhydrous sodium sulfate drying, and is concentrated under reduced pressure, and gained residue is pure through silica gel column chromatography (PE/EtOAc (v/v)=40/1) Change, it is white solid (2.7g, 54.4%) to obtain title compound.

Step 3) (S)-(1- ((3- fluoro- 2- (phenylcarbamoyl) phenyl) amino) -1- oxo-butanes -2- bases) amino T-butyl formate

By the fluoro- N- phenylbenzamaides (700mg, 3.0mmol) of compound 2- amino -6- and (S) -2- ((tertiary butyloxycarbonyls Base) amino) butyric acid (610 mg, 3.0mmol) is suspended in DCM (11mL), then at -10 DEG C, HATU is added thereto (1.37g, 3.6mmol) and DIPEA (1.16g, 9.0mmol).Gained mixture stirs 1 hour at -10 DEG C, is then heated to Flow back and be stirred overnight, reactant mixture is cooled to room temperature, and use water (20mL × 2) and saturation NaHCO successively₃The aqueous solution (20mL × 2) are washed, and organic phase anhydrous sodium sulfate drying, are concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=10/1) purify, it is yellow solid (1.14g, 91.46%) to obtain title compound.

MS(ESI,neg.ion.)m/z:414.2[M-H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):11.73 (s, 1H), 8.55 (d, J=8.5Hz, 1H), 8.40 (d, J= 14.4Hz, 1H), 7.64 (d, J=8.2Hz, 1H), 7.47 (dd, J=16.8,9.4Hz, 1H), 7.42 (t, J=7.7Hz, 2H), 7.27 (m, 1H), 7.23 (t, J=7.4Hz, 1H), 6.93 (dd, J=12.3,8.4Hz, 1H), 5.13 (s, 1H), 4.27 (s, 1H), 1.77 (m, 1H), 1.47 (m, 1H), 1.44 (s, 9H), 1.02 (t, J=7.4Hz, 3H).

Step 3) (S)-(1- (5- fluorin-4-oxygens generation -3- phenyl -3,4- dihydroquinazoline -2- bases) propyl group) carbamic acid uncle Butyl ester

By compound (S)-(1- ((3- fluoro- 2- (phenylcarbamoyl) phenyl) amino) -1- oxo-butanes -2- bases) ammonia Base t-butyl formate (4.0g, 9.63 mmol) is dissolved in acetonitrile (250mL) and triethylamine (48.72g, 481.5mmol), will After mixture substitutes gas (nitrogen), at room temperature, N, the double trimethylsilyl acetamides (29.38g, 144.45mmol) of O- are added.Instead Answer mixture to flow through night next time at 90 DEG C, and monitored and reacted with LC-MS, after having reacted, reactant mixture is concentrated under reduced pressure, added Enter EtOAc (100mL) to dissolve residue, gained mixture is washed with water (100mL × 2) and saline solution (100mL) successively, is had Machine mutually uses anhydrous sodium sulfate drying, is concentrated under reduced pressure, and gained residue is pure through silica gel column chromatography (PE/EtOAc (v/v)=20/1) Change, it is white solid (2.57g, 67%) to obtain title compound.

MS(ESI,pos.ion.)m/z:398.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.72 (m, 1H), 7.62 (t, J=7.2Hz, 1H), 7.55 (m, 3H), 7.39 (d, J=7.1Hz, 1H), 7.29 (m, 1H), 7.14 (m, 1H), 5.47 (d, J=8.3Hz, 1H), 4.43 (m, 1H), 1.75 (m, 1H), 1.53 (m, 1H), 1.45 (s, 9H), 0.78 (t, J=7.4Hz, 3H).

Fluoro- 3- phenylquinazolines -4 (3H) -one of step 4) (S) -2- (1- aminopropyls) -5-

By compound (S)-(1- (5- fluorin-4-oxygens generation -3- phenyl -3,4- dihydroquinazoline -2- bases) propyl group) carbamic acid The tert-butyl ester (220mg, 0.55 mmol) is dissolved in EtOAc (2mL), then at room temperature, disposably adds hydrogen chloride thereto Ethyl acetate solution (2.5mL, 3.88M).Gained mixture is stirred at room temperature overnight, gained suspension after having reacted It is dissolved in water (20mL), aqueous phase is extracted with EtOAc (20 mL), and adds Na₂CO₃Powder is adjusted to pH=8, then uses EtOAc (20mL × 3) are extracted, and the organic phase of merging washed with saline solution (20 mL), with anhydrous sodium sulfate drying, and are concentrated under reduced pressure, are obtained It is white powder (163mg, 100%) to title compound.

MS(ESI,pos.ion.)m/z:298.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.83 (td, J=8.2,5.6Hz, 1H), 7.56 (m, 5H), 7.43 (m, 1H), 7.28 (dd, J=11.0,8.2Hz, 1H), 3.14 (dd, J=7.5,5.4Hz, 1H), 1.72 (m, 1H), 1.36 (m, 1H), 0.69 (t, J=7.4Hz, 3H).

Step 5) (S) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) third Base) fluoro- 3- phenylquinazolines -4 (3H) -one of -5-

By fluoro- 3- phenylquinazolines -4 (3H) -one (42mg, 0.14mmol) of compound (S) -2- (1- aminopropyls) -5- N-BuOH (2mL) is suspended in the chloro- 5- of 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (30mg, 0.14mmol) In, DIPEA (36 mg, 0.28mmol) is then added thereto.Reactant mixture backflow overnight, and with thin-layered chromatography (PE/ EtOAc, v/v, 1/4) monitoring reaction, reactant mixture is then cooled to room temperature, then filtered, gained filter cake EtOH (10mL × 2) are rinsed, and it is white solid (45.3mg, 68.5%) to obtain title compound.

MS(ESI,pos.ion):473.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.04 (d, J=6.9Hz, 1H), 7.99 (s, 1H), 7.86 (dd, J =13.5,8.1Hz, 1H), 7.58 (m, 5H), 7.52 (d, J=8.2Hz, 1H), 7.31 (dd, J=10.3,8.6Hz, 1H), 4.93 (dd, J=11.4,6.9Hz, 1H), 2.50 (s, 3H), 1.92 (m, 1H), 1.66 (m, 1H), 0.76 (t, J=7.4Hz, 3H)。

Embodiment 40 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) Propyl group) fluoro- 3- phenylquinazolines -4 (3H) -one of -5-

By fluoro- 3- phenylquinazolines -4 (3H) -one of compound (S) -2- (1- aminopropyls) -5- (50.5mg, 0.17mmol) it is suspended in the chloro- 5- of 6- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine -4- amine (35.6mg, 0.17mmol) In n-BuOH (2mL), DIPEA (44mg, 0.34mmol) is then added thereto.By reactant mixture backflow overnight, and with thin Layer chromatography (PE/EtOAc, v/v, 1/4) monitoring reaction, is then cooled to room temperature by reactant mixture, obtains white suspension, Suspension is filtered again, the solid of collection is rinsed with EtOH (10mL × 2), obtain title compound for white solid (49mg, 61%).

MS(ESI,pos.ion):473.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.66 (d, J=7.2Hz, 1H), 7.96 (s, 1H), 7.82 (td, J =8.2,5.6Hz, 1H), 7.58 (m, 5H), 7.46 (d, J=8.1Hz, 1H), 7.29 (dd, J=10.7,8.3Hz, 1H), 7.19 (s, 2H), 4.81 (td, J=7.8,4.2Hz, 1H), 2.61 (s, 3H), 1.94 (m, 1H), 1.69 (m, 1H), 0.76 (t, J=7.3Hz, 1H).

Embodiment 41 (S) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Ethyl) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By chloro- 3- cyclopropyl quinazoline -4 (3H) -one of compound (S) -2- (1- amino-ethyls) -5- (37mg, 0.14mmol) and the chloro- 5- of 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (30mg, 0.14mmol) is suspended in n- In BuOH (2mL), DIPEA (36.2mg, 0.28mmol) is then added thereto.Reactant mixture backflow overnight, and uses thin layer Chromatography (PE/EtOAc, v/v, 1/4) monitoring reaction, is then cooled to room temperature by reactant mixture, and is concentrated under reduced pressure, by gained Residue is dissolved in ethyl acetate EtOAc (20mL), and gained mixture is washed with water (10mL) and saline solution (10mL) successively, Organic phase anhydrous sodium sulfate drying, is then concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/ 1) purify, it is dark white solid (45.3mg, 68.5%) to obtain title compound.

MS(ESI,pos.ion):439.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.32 (d, J=6.8Hz, 1H), 8.12 (s, 1H), 7.74 (t, J= 8.0Hz, 1H), 7.54 (dd, J=9.5,8.1Hz, 1H), 6.11 (p, J=6.5Hz, 1H), 3.14 (m, 1H), 2.51 (s, 3H), 1.59 (d, J=6.6Hz, 3H), 1.26 (d, J=6.8Hz, 2H), 0.85 (d, J=6.9Hz, 2H).

Embodiment 42 (S) -2- (1- ((6- amino -5- (2- methyl -2H- tetrazole -5- bases) pyrimidine-4-yl) amino) second Base) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By chloro- 3- cyclopropyl quinazoline -4 (3H) -one of compound (S) -2- (1- amino-ethyls) -5- (52.7mg, 0.2mmol) and the chloro- 5- of 6- (2- methyl -2H- tetrazole -5- bases) pyrimidine -4- amine (42.3mg, 0.2mmol) is suspended in n- In BuOH (2mL), DIPEA (51.7 mg, 0.4mmol) is then added thereto.Reactant mixture is heated to flowing back and stirred Overnight, monitored and reacted with thin-layered chromatography (PE/EtOAc, v/v, 1/4), reactant mixture is then cooled to room temperature, and depressurize Concentration, residue is dissolved in ethyl acetate (15mL), mixture is washed with water (10 mL × 2) and saline solution (10mL) successively Wash, organic phase anhydrous sodium sulfate drying, and be concentrated under reduced pressure, gained residue purifies through thin-layered chromatography (DCM), is marked Topic compound is faint yellow solid (23mg, 26.2%).

MS(ESI,pos.ion):439.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):9.78 (d, J=7.0Hz, 1H), 8.22 (s, 1H), 7.58 (m, 2H), 7.46 (m, 1H), 6.36 (p, J=6.7Hz, 1H), 4.56 (s, 3H), 3.08 (m, 1H), 1.71 (d, J=6.6Hz, 3H), 1.10(m,2H),0.99(m,2H)。

Embodiment 43 (S) -2- (1- ((6- amino -5- (2- methyl -2H- tetrazole -5- bases) pyrimidine-4-yl) amino) third Base) fluoro- 3- phenylquinazolines -4 (3H) -one of -5-

By the chloro- 5- of compound 6- (2- methyl -2H- tetrazole -5- bases) pyrimidine -4- amine (30mg, 0.142mmol) and (S) - Fluoro- 3- phenylquinazolines -4 (3H) -one (44mg, 0.148mmol) of 2- (1- aminopropyls) -5- are suspended in n-BuOH (3mL) In, DIPEA (37 mg, 0.284mmol) is then added thereto.Gained mixture is heated to reflux 25 hours, and with thin layer color Spectrometry (PE/EtOAc, v/v, 1/4) monitoring reaction, is then cooled to room temperature by mixture, then is concentrated under reduced pressure, by gained residue It is suspended in EtOH (1.5mL), and filters, filter cake is rinsed with EtOH (1 mL), and is dried under reduced pressure, and it is light to obtain title compound Yellow solid (38mg, 56.7%).

MS(ESI,pos.ion):473.2[M+H]⁺；HPLC:93.6%；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.83 (d, J=7.2Hz, 1H), 7.98 (s, 1H), 7.86-7.78 (m, 1H), 7.65-7.52 (m, 5H), 7.48 (d, J=7.9Hz, 1H), 7.29 (dd, J=10.7,8.4Hz, 1H), 4.89 (td, J=7.6,4.3Hz, 1H), 4.54 (s, 3H), 2.04-1.89 (m, 1H), 1.75-1.61 (m, 1H), 0.78 (t, J= 7.4Hz,3H)。

Embodiment 44 (S)-2- (1- ((6- amino-5- (1- methyl isophthalic acid H-1,2,4- triazole-3- bases) pyrimidine-4-yl) ammonia Base) ethyl) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By the chloro- 5- of compound 6- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine -4- amine (30mg, 0.142mmol) Chloro- 3- cyclopropyl quinazoline -4 (3H) -one (40mg, 0.150mmol) of (S) -2- (1- amino-ethyls) -5- are suspended in n-BuOH In (3mL), DIPEA (37mg, 0.285mmol) is then added thereto.Reactant mixture is heated to backflow and stirring reaction 21 hours, and using thin-layered chromatography (CH₂Cl₂/ MeOH, v/v, 25/1) monitoring reaction, mixture is cooled to room temperature, and subtract Pressure concentration, residue is diluted in EtOAc (15mL), gained mixture is washed with water (15mL) and saline solution (10mL) successively Wash, organic phase anhydrous sodium sulfate drying, and be concentrated under reduced pressure, gained residue through silica gel column chromatography (DCM/MeOH (v/v)= 200/3) purify, it is faint yellow solid (33mg, 52.9%) to obtain title compound.

MS(ESI,pos.ion):438.2[M+H]⁺；HPLC:97.4%；

¹H NMR(400MHz,CDCl₃)δ(ppm):9.76 (d, J=7.3Hz, 1H), 8.18 (s, 1H), 8.12 (s, 1H), 7.61-7.49 (m, 2H), 7.43 (dd, J=6.1,2.8Hz, 1H), 6.43-6.24 (m, 1H), 4.07 (s, 3H), 3.18- 3.04 (m, 1H), 1.68 (d, J=6.6Hz, 3H), 1.21-1.11 (m, 1H), 1.02-0.80 (m, 3H).

Embodiment 45 (S) -2- (1- ((6- amino -5- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine-4-yl) ammonia Base) propyl group) the chloro- 3- of -5- (2- fluorophenyls) quinazoline -4 (3H) -one

The chloro- N- of step 1) 2- (2- fluorophenyls) -6- nitrobenzamides

The chloro- 6- nitrobenzoic acids (5.0g, 24.8mmol) of compound 2- are suspended in toluene (25mL), then thereto Add SOCl₂(5.5mL, 74.4mmol), mixture are stirred overnight at 110 DEG C, are then concentrated under reduced pressure, and obtain brown oil Thing.At 5 DEG C, by 2- fluoroanilines (4.1g, 37.2mmol) and NaHCO₃(4.2g, 49.6mmol) is suspended in 15mL 1,4- bis- In the ring of oxygen six, and Isosorbide-5-Nitrae-dioxane (15mL) solution of resulting brown oil above is slowly added to thereto, gained mixing Thing is stirred at room temperature overnight, then add EtOAc (200mL) and water (80mL) dilute, organic phase with saline solution (150mL × 2) wash, then with anhydrous sodium sulfate drying, be concentrated under reduced pressure, it is buff white solid (8.0g, 100%) to obtain title compound.

MS(ESI,pos.ion)m/z:295.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):10.65 (s, 1H), 8.26 (dd, J=8.3,0.7Hz, 1H), 8.10-7.97 (m, 2H), 7.77 (t, J=8.2Hz, 1H), 7.40-7.16 (m, 3H).

Step 2) 2- amino -6- chloro- N- (2- fluorophenyls) benzamide

The chloro- N- of compound 2- (2- fluorophenyls) -6- nitrobenzamides (4.0g, 13.6mmol) are suspended in absolute ethyl alcohol In (70mL), iron powder (3.8g, 67.8mmol) is then added thereto, adds HCOONH₄(8.23g, 130.57mmol's) Water (14mL) solution, gained mixture are stirred overnight at 95 DEG C, filter, gained filtrate decompression is concentrated, gained residue warp Silica gel column chromatography (PE/EtOAc (v/v)=5/1) purifies, and it is buff white solid (1.51g, 42%) to obtain title compound.

MS(ESI,pos.ion)m/z:265.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):10.29 (s, 1H), 7.83 (td, J=7.8,1.7Hz, 1H), 7.33-7.15 (m, 3H), 7.10 (t, J=8.0Hz, 1H), 6.68 (dd, J=30.4,8.0Hz, 2H), 5.34 (s, 2H).

Step 3) (S)-(1- ((the chloro- 2- of 3- ((2- fluorophenyls) carbamoyl) phenyl) amino) -1- oxo-butanes -2- Base) t-butyl carbamate

By compound 2- amino -6- chloro- N- (2- fluorophenyls) benzamides (1.5g, 5.67mmol) and 2- ((tertiary butyloxycarbonyls Base) amino) butyric acid (1.21 g, 5.95mmol) is dissolved in DMF (20mL), then at room temperature, DIPEA is added thereto (2.20g, 17.01mmol) and HATU (2.59g, 6.80mmol).Mixture is stirred at room temperature overnight, and then uses water successively (150mL × 2) and saturation NaHCO₃The aqueous solution (150mL × 2) washs, and liquid separation, organic phase is concentrated under reduced pressure, gained residue warp Silica gel column chromatography (PE/EtOAc (v/v)=5/1) purifies, and it is faint yellow solid (0.72g, 28%) to obtain title compound.

MS(ESI,pos.ion)m/z:350.2[M-Boc+H]⁺。

Step 4) (S)-(1- (the chloro- 3- of 5- (2- fluorophenyls) -4- oxo -3,4- dihydroquinazoline -2- bases) propyl group) amino T-butyl formate

By compound (S)-(1- ((the chloro- 2- of 3- ((2- fluorophenyls) carbamoyl) phenyl) amino) -1- oxo-butanes - 2- yls) t-butyl carbamate (1.6g, 3.60mmol) and triethylamine (15mL, 108mmol) be dissolved in CH₃CN(100mL) In, then under nitrogen protection, N, the double trimethylsilyl acetamides (13mL, 36mmol) of O- are added thereto with syringe.Gained Mixture stirring reaction 33 hours at 85 DEG C, are subsequently cooled to room temperature, and are concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=8/1) is purified, and it is faint yellow solid (0.63g, 41%) to obtain title compound.

MS(ESI,pos.ion)m/z:432.1[M+H]⁺。

Step 5) (S) -2- (1- aminopropyls) -5- chloro- 3- (2- fluorophenyls) quinazoline -4 (3H) -one

By compound (S)-(1- (the chloro- 3- of 5- (2- fluorophenyls) -4- oxo -3,4- dihydroquinazoline -2- bases) propyl group) ammonia Base t-butyl formate (1.28g, 2.96 mmol) is suspended in EtOAc (10mL), then adds the acetic acid second of hydrogen chloride thereto Ester solution (3.0M, 8mL, 23.68mmol).Reaction 4 hours is stirred at room temperature in mixture, is then concentrated under reduced pressure, by residue It is dissolved in EtOAc (50mL), obtained mixture saturation NaHCO₃The aqueous solution be adjusted to pH=7-8, organic phase salt Water (100mL × 2) washs, and with anhydrous sodium sulfate drying, then be concentrated under reduced pressure, it is white solid to obtain title compound (0.81g, 81%), the solid are made up of two kinds of isomers of A and B, and its ratio is 2/1 (A/B).

MS(ESI,pos.ion)m/z:332.1[M+H]⁺；

Isomers A:¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.85–7.77(m,1H),7.73–7.56(m,4H), 7.56-7.48 (m, 1H), 7.48-7.40 (m, 1H), 3.22 (t, J=6.4Hz, 1H), 1.90 (s, 2H), 1.82-1.57 (m, 1H), 1.48-1.29 (m, 1H), 0.69 (t, J=7.3 Hz, 3H).

Isomers B:¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.85–7.77(m,1H),7.73–7.56(m,4H), 7.56-7.48 (m, 1H), 7.47-7.39 (m, 1H), 3.11 (dd, J=7.5,4.8Hz, 1H), 1.90 (s, 2H), 1.82- 1.57 (m, 1H), 1.48-1.29 (m, 1H), 0.75 (t, J=7.4Hz, 3H).

Step 6) (S) -2- (1- ((6- amino -5- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine-4-yl) ammonia Base) propyl group) the chloro- 3- of -5- (2- fluorophenyls) quinazoline -4 (3H) -one

By the chloro- 5- of compound 6- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine -4- amine (30mg, 0.142mmol) (S) -2- (1- aminopropyls) -5- chloro- 3- (2- fluorophenyls) quinazoline -4 (3H) -one (50mg, 0.150mmol) is suspended in n- In BuOH (3mL), DIPEA (37mg, 0.285mmol) is then added thereto.Gained mixture is heated to flowing back and stirred Reaction 29 hours, and monitored and reacted with thin-layered chromatography (DCM/MeOH, v/v, 25/1), it is after having reacted, reactant mixture is cold But to room temperature, and it is concentrated under reduced pressure, residue is diluted with EtOAc (15mL), and gained mixture uses water (15mL) and saline solution successively (10mL) is washed, organic phase anhydrous sodium sulfate drying, and is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=200/3) purify, it is white solid (35 mg, 48.6%) to obtain title compound, and the solid is by two kinds of isomeries of A and B Body is formed, and its ratio is 3/2 (A/B).

MS(ESI,pos.ion):506.1[M+H]⁺；HPLC:93.6% (total purity of two kinds of isomers of A and B)；

Isomers A:¹H NMR(400MHz,CDCl₃)δ(ppm):9.35(s,1H),8.14(s,1H),7.95(s,1H), 7.70-7.43 (m, 5H), 7.35-7.29 (m, 2H), 5.09 (td, J=7.9,5.2Hz, 1H), 4.05 (s, 3H), 2.11- 1.94(m,2H),0.99–0.89(m,5H)。

Isomers B:¹H NMR(400MHz,CDCl₃)δ(ppm):9.35(s,1H),8.10(s,1H),7.83(s,1H), 7.70-7.43 (m, 5H), 7.35-7.29 (m, 2H), 5.28 (td, J=7.5,6.6Hz, 1H), 4.02 (s, 3H), 2.11- 1.94(m,2H),0.99–0.89(m,5H)。

Embodiment 46 (S) -2- (1- ((6- amino -5- (5- (methoxy) -1- methyl isophthalic acid H-1,2,4- triazoles -3- Base) pyrimidine-4-yl) amino) propyl group) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

Step 1) (3- (4,6- dimethoxypyridin -5- bases) -1- methyl isophthalic acid H-1,2,4- triazole -5- bases) methanol

By compound 3- (4,6- dimethoxypyridin -5- bases) -1- methyl isophthalic acid H-1,2,4- triazole -5- Ethyl formates (380mg, 1.30mmol) is suspended in THF (8mL), and at 0 DEG C, LiAlH is added portionwise₄(49mg,1.30mmol).Gained mixes Compound is stirred 1 hour at 0 DEG C, is then slowly added into water (50mg), and mixture is stirred 15 minutes at 0 DEG C, then added few The anhydrous sodium sulfate of amount, mixture continue stirring 15 minutes, then add the NaOH aqueous solution (5M, 0.04mL), mixture is again Continue stirring 30 minutes, then filter, filtrate decompression is concentrated, residue is through silica gel column chromatography (CH₂Cl₂/ MeOH (v/v)= 50/1) purify, it is white solid (79 mg) to obtain a part of title compound.Gained filter cake is suspended in EtOAc (20mL), And be stirred at room temperature 30 minutes, mixture is filtered, for gained filtrate through being concentrated under reduced pressure, it is white to obtain another part title product Color solid (153mg) (gross production rate:71.3%).

MS(ESI,pos.ion)m/z:252.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.51(s,1H),4.85(s,2H),4.02(s,3H),3.99(s, 6H)。

Step 2) 4,6- dimethoxys -5- (5- (methoxy) -1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine

By compound (3- (4,6- dimethoxypyridin -5- bases) -1- methyl isophthalic acid H-1,2,4- triazole -5- bases) methanol (232mg, 0.92mmol) is suspended in THF (15mL), and then at 0 DEG C, adding NaH thereto, (60% is dispersed in mineral oil In, 55mg, 1.39mmol).Reactant mixture stirring reaction 40 minutes at 0 DEG C, add CH₃I(157mg,1.11mmol) THF (1mL) solution, gained mixture is warmed to room temperature, and reaction 4 hours is stirred at room temperature, then with saturation NH₄Cl is water-soluble Reaction is quenched in liquid (15mL), and gained mixture is extracted with EtOAc (10mL × 3).Aqueous phase is acidified to pH with 4M HCl/water solution =2-3, then extracted with EtOAc (10mL × 3).The organic phase of merging is concentrated under reduced pressure, residue is through silica gel column chromatography (PE/ EtOAc (v/v)=1/10) purifying, it is white solid (49 mg, 19.9%) to obtain title compound.

MS(ESI,pos.ion)m/z:266.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.51(s,1H),4.70(s,2H),4.02(s,3H),3.98(s, 6H),3.46(s,3H)。

Bis- chloro- 5- of step 3) 4,6- (5- (methoxy) -1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine

Compound 4,6- dimethoxys -5- (5- (methoxy) -1- methyl isophthalic acid H-1,2,4- triazole -3- bases) is phonetic Pyridine (56mg, 0.21mmol) is suspended in dry toluene (5mL), then adds POCl thereto₃(0.2mL,2.11mmol) With DMF (0.2mL).Gained mixture is heated to backflow simultaneously stirring reaction 22 hours, supernatant separated, and depressurizes Concentration, obtains yellow residue.Then the residue of the burgundy of lower floor is suspended in water (10mL), mixture EtOAc (10mL × 3) are extracted, and the organic phase of merging is washed with saline solution (10mL), then is concentrated under reduced pressure, and obtain another part yellow residual Thing, two parts residue is merged, it is not purified, it is directly used in and reacts in next step.

MS(ESI,pos.ion)m/z:274.0[M+H]⁺。

The chloro- 5- of step 4) 6- (5- (methoxy) -1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine -4- amine

The yellow residue that upper step (step 3) obtains is dissolved in THF (5mL), gained reaction solution is in NH₃Under atmosphere in 30 DEG C of stirring reactions 18 hours, and monitored and reacted with thin-layered chromatography (PE/EtOAc, v/v, 1/4), after having reacted, by mixture Filtering, and with EtOAc (15mL) rinse, gained filtrate decompression is concentrated, obtain title compound be yellow solid (52mg, two Walk yield：95.6%).

MS(ESI,pos.ion)m/z:255.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.33(s,1H),4.71(s,2H),4.05(s,3H),3.47(s, 3H)。

StepRapid 5) (S) -2- (1- ((6- amino -5- (5- (methoxy) -1- methyl isophthalic acid H-1,2,4- triazoles -3- Base) pyrimidine-4-yl) amino) propyl group) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By the chloro- 5- of compound 6- (5- (methoxy) -1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine -4- amine Chloro- 3- cyclopropyl quinazoline -4 (3H) -one of (26mg, 0.102mmol) and (S) -2- (1- aminopropyls) -5- (31mg, 0.112mmol) it is suspended in n-BuOH (2mL), then adds thereto in DIPEA (26mg, 0.204mmol), by mixture Backflow simultaneously stirring reaction 22 hours are heated to, with thin-layered chromatography (CH₂Cl₂/ MeOH, v/v, 25/1) monitoring reaction.Will mixing Thing is cooled to room temperature, then is concentrated under reduced pressure, and gained residue is diluted in EtOAc (15 mL), and successively with water (15mL) and food Salt solution (10mL) washs, organic phase anhydrous sodium sulfate drying, then is concentrated under reduced pressure, and residue is through silica gel column chromatography (CH₂Cl₂/ MeOH (v/v)=25/1) purifying, it is faint yellow solid (31mg, 61.2%) to obtain title compound.

MS(ESI,pos.ion)m/z:496.2[M+H]⁺；HPLC:96.1%；

¹H NMR(400MHz,CDCl₃)δ(ppm):9.50 (d, J=7.6Hz, 1H), 8.10 (s, 1H), 7.58-7.46 (m, 2H), 7.42 (dd, J=6.9,2.0Hz, 1H), 6.37-6.24 (m, 1H), 4.71 (s, 2H), 4.04 (s, 3H), 3.45 (s, 3H), 3.18-3.05 (m, 1H), 2.12-1.99 (m, 2H), 1.45-1.41 (m, 2H), 1.07 (t, J=7.4Hz, 3H), 0.90–0.86(m,2H)。

Embodiment 47 (S) -2- (1- ((6- amino -5- (isoxazole -3-bases) pyrimidine-4-yl) amino) propyl group) -3- rings third Base -5- methylquinazolins -4 (3H) -one

By the chloro- 5- (isoxazole -3-bases of compound 6-) pyrimidine -4- amino (50mg, 0.25mmol), (S) -2- (1- amino Propyl group) -4 (3H) -one (78.5mg, 0.31mmol) of -3- cyclopropyl -5- methylquinazolins, DIPEA The mixture of (98.5mg, 0.76mmol) and n-butanol (3.0mL) is sealed in tube sealing, and is reacted 36 hours in 150 DEG C, reaction After complete, reactant mixture is concentrated under reduced pressure, gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=1/2), obtains Title compound is faint yellow solid (45mg, 42%).

MS(ESI,pos.ion)m/z:418.2[M+H]⁺；HPLC:99.5%；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.66 (d, J=1.5Hz, 1H), 8.17 (s, 1H), 7.54 (t, J= 7.7Hz, 1H), 7.38 (d, J=8.0Hz, 1H), 7.20 (d, J=7.3Hz, 1H), 7.10 (d, J=1.5Hz, 1H), 6.75 (d, J=8.2Hz, 1H), 6.24 (td, J=7.8,4.8 Hz, 1H), 5.71 (br.s., 2H), 3.05 (ddd, J=11.1, 7.2,4.2Hz,1H),2.86(s,3H),2.10-2.01(m,1H),1.90-1.80(m, 1H),1.50-1.39(m,2H), 1.00 (t, J=7.4Hz, 3H), 0.94-0.85 (m, 2H)；

¹³C NMR(151MHz,CDCl₃)δ(ppm):164.0,160.2,159.4,159.0,158.7,158.1,156.6, 147.7,140.8,133.2, 129.3,124.9,119.4,104.2,86.1,51.9,27.9,26.4,23.0,10.6, 10.1,9.9。

Embodiment 48 (S) -2- (1- ((6- amino -5- (isoxazole -3-bases) pyrimidine-4-yl) amino) propyl group) -3- rings third (3H) -one of base -5- Fluquinconazoles quinoline -4

By the chloro- 5- (isoxazole -3-bases of compound 6-) pyrimidine -4- amine (39.3mg, 0.20mmol), (S) -2- (1- amino Propyl group) fluoro- 3- cyclopropyl quinazoline -4 (3H) -one (62.7mg, 0.24mmol) of -5-, DIPEA (77.5mg, 0.6mmol) mixture with n-butanol (2.5mL) is sealed in tube sealing, and is reacted 36 hours at 150 DEG C, will after having reacted Reactant mixture is concentrated under reduced pressure, and gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=1/2), obtains titled Compound is white solid (30mg, 36%).

MS(ESI,pos.ion)m/z:422.2[M+H]⁺；HPLC:94.1%；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.65 (d, J=1.2Hz, 1H), 8.16 (s, 1H), 7.62 (td, J= 8.1,5.4Hz, 1H), 7.34 (d, J=8.2Hz, 1H), 7.08 (dd, J=10.0,8.5Hz, 1H), 7.04 (d, J=1.2Hz, 1H), 6.72 (d, J=8.3Hz, 1H), 6.24 (td, J=8.1,4.7Hz, 1H), 5.67 (br.s., 2H), 3.07 (ddd, J= 11.1,7.2,4.2Hz,1H),2.09-2.00(m,1H),1.90-1.80(m, 1H),1.51-1.40(m,2H),1.03(t,J =7.4Hz, 3H), 0.98-0.85 (m, 2H)；

¹³C NMR(151MHz,CDCl₃)δ(ppm):161.9,160.7,160.41,160.36,160.3,160.1, 159.4,158.8,158.0,156.6, 148.5,134.4,134.3,122.7,122.6,113.3,113.2,110.8, 110.7,104.1,86.4,52.2,28.0,26.5,10.6,10.2,10.1。

Embodiment 49 (R) -2- (1- ((6- amino -5- (isoxazole -3-bases) pyrimidine-4-yl) amino) propyl group) the chloro- 3- of -5- Cyclopropyl quinazoline -4 (3H) -one

By the chloro- 5- (isoxazole -3-bases of compound 6-) pyrimidine -4- amine (39.3mg, 0.2mmol), (R) -2- (1- aminopropans Base) chloro- 3- cyclopropyl quinazoline -4 (3H) -one (66.7mg, 0.24mmol) of -5-, DIPEA (77.5mg, 0.60mmol) mixture with n-butanol (2.0mL) is sealed in tube sealing, and is reacted 30 hours at 150 DEG C, after having reacted, Reactant mixture is concentrated under reduced pressure, gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=1/2), obtains title Compound is white solid (47mg, 54%).

MS(ESI,pos.ion)m/z:438.2[M+H]⁺；HPLC:99.51%；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.65 (d, J=1.6Hz, 1H), 8.16 (s, 1H), 7.54 (t, J= 8.0Hz, 1H), 7.46-7.40 (m, 2H), 7.04 (d, J=1.6Hz, 1H), 6.70 (d, J=8.4Hz, 1H), 6.23 (td, J =8.1,4.7Hz, 1H), 5.63 (br.s., 2H), 3.08 (ddd, J=11.1,7.1,4.2Hz, 1H), 2.11-2.00 (m, 1H), 1.89-1.80 (m, 1H), 1.50-1.41 (m, 2H), 1.03 (t, J=7.4Hz, 3H), 0.95-0.88 (m, 2H)；

¹³C NMR(151MHz,CDCl₃)δ(ppm):161.5,160.38,160.35,159.4,158.8,158.1, 156.6,148.8,133.9,133.4, 129.3,125.9,118.1,104.1,86.3,52.1,27.8,26.8,10.7, 10.2,10.1。

Embodiment 50 (S) -2- (1- ((6- amino -5- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine-4-yl) ammonia Base) propyl group) the chloro- 3- of -5- (4- fluorophenyls) quinazoline -4 (3H) -one

The chloro- N- of step 1) 2- (4- fluorophenyls) -6- nitrobenzamides

The chloro- 6- nitrobenzoic acids (5g, 24.8mmol) of compound 2- are suspended in toluene (50mL), then in room temperature Under, SOCl is disposably added into gained yellow suspension₂(5.85g, 49.6mmol), after adding, reactant mixture is at 120 DEG C Under be stirred overnight, then be concentrated under reduced pressure, residue be dissolved in Isosorbide-5-Nitrae-dioxane (30mL), then at 5 DEG C, gained mixed Compound is added dropwise to 4- fluoroanilines (2.76g, 24.8mmol) and NaHCO₃The 1,4- dioxane of (4.17g, 49.6mmol) In (30mL) suspension, reaction 7 hours is stirred at room temperature in gained mixture, and the water quenching for then adding 250mL is gone out reaction, is obtained The suspension of yellow.Suspension is filtered, gained solid is rinsed with water (100 mL × 2), and is dried under 50 DEG C of vacuum conditions, It is Light brown solid (6.37g, 87.1%) to obtain title compound.

MS(ESI,pos.ion.)m/z:295.0[M+H]⁺。

Step 2) 2- amino -6- chloro- N- (4- fluorophenyls) benzamide

The chloro- N- of compound 2- (4- fluorophenyls) -6- nitrobenzamides (5.78g, 19.6mmol) are dissolved in ethanol In (145mL), iron powder (5.47g, 98mmol) is added thereto while stirring, and once add into gained suspension HCOONH₄Water (30mL) solution of (12.3g, 196mmol), gained mixture stirring reaction 7 hours at 80 DEG C, then mistake while hot Filter, filtrate decompression is concentrated, residue is dissolved in 300mL EtOAc, and gained mixture is respectively with water (200mL) and food Salt solution (200mL) washs, organic phase anhydrous sodium sulfate drying, then is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (PE/ EtOAc (v/v)=10/1) purifying, it is white solid (2.85g, 55.1%) to obtain title compound.

MS(ESI,pos.ion)m/z:265.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):10.49 (s, 1H), 7.75 (m, 2H), 7.18 (t, J=8.9Hz, 2H), 7.09 (t, J=8.1 Hz, 1H), 6.70 (d, J=8.2Hz, 1H), 6.64 (m, 1H), 5.36 (s, 2H).

Step 3) (S)-(1- ((the chloro- 2- of 3- ((4- fluorophenyls) carbamoyl) phenyl) amino) -1- oxo-butanes -2- Base) t-butyl carbamate

By compound 2- amino -6- chloro- N- (4- fluorophenyls) benzamide (3.57g, 13.5mmol) and (S) -2- ((uncles Butoxy carbonyl) amino) butyric acid (3.03g, 14.9mmol) is suspended in DCM (50mL), then at -10 DEG C, adds thereto HATU (5.67g, 14.9mmol) and DIPEA (5.23g, 40.5mmol).After gained mixture stirs 1 hour at -10 DEG C, It is warming up to 45 DEG C and is stirred overnight.After having reacted, mixture is down to room temperature, and use saturation NaHCO successively₃The aqueous solution (200mL × 2), water (150mL) and saline solution (200mL) washing, liquid separation, organic phase anhydrous sodium sulfate drying, and be concentrated under reduced pressure.Gained Residue through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purify, obtain title compound for white solid (2.78g, 45.9%).

MS(ESI,neg.ion.)m/z:448.1[M-H]⁺.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):10.65 (s, 1H), 9.44 (s, 1H), 7.84 (d, J=8.1Hz, 1H), 7.74 (m, 2H), 7.47 (t, J=8.1Hz, 1H), 7.36 (d, J=8.0Hz, 1H), 7.19 (t, J=8.8Hz, 2H), 7.11 (d, J=7.2Hz, 1H), 4.00 (dd, J=12.8,7.5Hz, 1H), 1.68 (m, 1H), 1.51 (m, 1H), 1.33 (s, 9H), 0.81 (t, J=7.4Hz, 3H)

Step 4) (S)-(1- (the chloro- 3- of 5- (4- fluorophenyls) -4- oxo -3,4- dihydroquinazoline -2- bases) propyl group) amino T-butyl formate

By compound (S)-(1- ((the chloro- 2- of 3- ((4- fluorophenyls) carbamoyl) phenyl) amino) -1- oxo-butanes - 2- yls) t-butyl carbamate (2.779g, 6.2mmol) be dissolved in anhydrous acetonitrile (250mL) and triethylamine (18.92g, In 186mmol), resulting solution N₂Purification, then add N, the double trimethylsilyl acetamides of O- thereto at room temperature (18.92g, 93mmol), gained reactant mixture flow through night next time at 90 DEG C, are monitored and reacted with thin-layered chromatography, after having reacted, Reaction solution is concentrated under reduced pressure, concentrated residues thing is dissolved in EtOAc (300mL), and gained mixture uses water (100mL × 2) successively Wash, liquid separation, organic phase anhydrous sodium sulfate drying, and be concentrated under reduced pressure with saline solution (100mL).Gained residue is through silicagel column (PE/EtOAc (v/v)=10/1) purifying is chromatographed, it is faint yellow solid (2.51g, 93.5%) to obtain title compound.

MS(ESI,pos.ion.)m/z:432.2[M+H]⁺。

Step 5) (S) -2- (1- aminopropyls) -5- chloro- 3- (4- fluorophenyls) quinazoline -4 (3H) -one

By compound (S)-(1- (the chloro- 3- of 5- (4- fluorophenyls) -4- oxo -3,4- dihydroquinazoline -2- bases) propyl group) ammonia Base t-butyl formate (2.51g, 5.8 mmol) is dissolved in DCM (10mL), then at room temperature, disposably adds chlorine thereto Change the ethyl acetate solution (3.88M, 8.3 mL) of hydrogen, mixture is stirred at room temperature overnight, and gained suspension is dissolved in 200mL Water in, aqueous phase is extracted with EtOAc (100mL), and uses Na₂CO₃Powder is neutralized to pH=8, is then extracted again with EtOAc (100mL) Taking, the organic phase of merging is washed with saline solution (50mL), then with anhydrous sodium sulfate drying, and be concentrated under reduced pressure, obtain title compound Thing is white powder (1.7g, 87.9%).

MS(ESI,pos.ion)m/z:332.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.65(m,2H),7.50(m,1H),7.28(m,4H),3.42(m, 1H), 1.81 (m, 1H), 1.54 (tt, J=14.7,7.4Hz, 1H), 0.84 (t, J=7.4Hz, 3H).

Step 6) (S) -2- (1- ((6- amino -5- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine-4-yl) ammonia Base) propyl group) the chloro- 3- of -5- (4- fluorophenyls) quinazoline -4 (3H) -one

By compound (S) -2- (1- aminopropyls) -5- chloro- 3- (4- fluorophenyls) quinazoline -4 (3H) -one (66mg, 0.2mmol) it is suspended in the chloro- 5- of 6- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine -4- amine (42mg, 0.2mmol) In n-BuOH (2mL), DIPEA (51.7mg, 0.4mmol) is then added thereto, and reactant mixture is heated to flowing back and stirred Overnight, and monitored and reacted with thin-layered chromatography (DCM/MeOH, v/v, 10/1), after having reacted, reactant mixture is cooled to room temperature, It is concentrated under reduced pressure again, residue is dissolved in EtOAc (20mL), gained mixture uses water (20mL × 2) and saline solution successively (10mL) is washed, organic phase anhydrous sodium sulfate drying, then is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (CH₂Cl₂/ MeOH (v/v)=100/1) purifying, it is white solid (35mg, 34.6%) to obtain title compound.

MS(ESI,pos.ion)m/z:506.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.25 (d, J=7.1Hz, 1H), 8.24 (s, 1H), 7.83 (s, 1H), 7.50 (dd, J=11.2,7.2Hz, 3H), 7.36 (d, J=6.8Hz, 1H), 7.24 (s, 1H), 7.17 (dd, J= 15.0,7.5Hz, 2H), 4.84 (d, J=5.0Hz, 1H), 3.96 (s, 3H), 1.84 (m, 1H), 1.77 (m, 1H), 0.85 (t, J =7.3Hz, 3H).

Embodiment 51 (S) -2- (1- ((6- amino -5- (1- methyl isophthalic acid H- pyrazole-3-yls) pyrimidine-4-yl) amino) third Base) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By the chloro- 5- of compound 6- (1- methyl isophthalic acid H- pyrazole-3-yls) pyrimidine -4- amine (30mg, 0.143mmol) and (S) -2- Chloro- 3- cyclopropyl quinazoline -4 (3H) -one (42mg, 0.150mmol) of (1- aminopropyls) -5- are suspended in n-BuOH (1.5mL) In, DIPEA (74 mg, 0.572mmol) is then added thereto.Gained mixture is heated to backflow simultaneously stirring reaction 48 hours, With thin-layered chromatography (CH₂Cl₂/ MeOH, v/v, 125/3) monitoring reaction, after having reacted, reactant mixture is cooled to room temperature, And be concentrated under reduced pressure, gained residue purifies through silica gel column chromatography (PE/EtOAc=1/3), and it is entitled to obtain title compound Faint yellow solid (24mg, 37.2%).

MS(ESI,pos.ion)m/z:451.1[M+H]⁺；HPLC:99.5%；

¹H NMR(600MHz,DMSO-d₆) δ (ppm) 7.92 (d, J=6.8Hz, 2H), 7.76-7.62 (m, 1H), 7.64- 7.38(m,3H),6.67 (s,1H),6.35(s,2H),6.00(s,1H),3.97(s,3H),3.12(s,1H),2.05–1.96 (m, 1H), 1.80 (d, J=6.2Hz, 1H), 1.35-1.27 (m, 2H), 1.09 (s, 1H), 0.93 (s, 3H), 0.87-0.81 (m,1H).

Embodiment 52 (S) -2- (1- ((6- amino -5- (4- Jia Ji oxazole -2- bases) pyrimidine-4-yl) amino) propyl group) -5- Chloro- (3H) -one of 3- cyclopropyl quinazoline -4

By the chloro- 5- of compound 6- (4- Jia Ji oxazole -2- bases) pyrimidine -4- amine (31mg, 0.147mmol) and (S) -2- (1- Aminopropyl) chloro- 3- cyclopropyl quinazoline -4 (3H) -one (50mg, 0.180mmol) of -5- are suspended in n-BuOH (3mL), so Add DIPEA (38mg, 0.294mmol) thereto afterwards, gained mixture is heated to backflow simultaneously stirring reaction 16 hours, and use is thin Layer chromatography (PE/EtOAc, v/v, 1/1) monitoring reaction, after having reacted, is cooled to room temperature, then depressurize dense by reactant mixture Contracting, gained residue are dissolved in EtOAc (15mL), and gained mixture is washed with water (15mL) and saline solution (10mL) successively, Organic phase anhydrous sodium sulfate drying, then be concentrated under reduced pressure, organic phase anhydrous sodium sulfate drying, then be concentrated under reduced pressure, gained residual Thing through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purify, obtain title compound for faint yellow solid (64mg, 96.2%).

MS(ESI,pos.ion)m/z:452.1[M+H]⁺；HPLC:96.2%；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 9.32 (d, J=7.5Hz, 1H), 8.00 (s, 1H), 7.97 (d, J= 1.3Hz, 1H), 7.73-7.64 (m, 1H), 7.51 (td, J=8.4,1.0Hz, 2H), 7.37 (s, 2H), 6.12 (td, J= 7.2,5.0Hz, 1H), 3.18-3.08 (m, 1H), 2.25 (d, J=1.1Hz, 3H), 2.16-2.02 (m, 1H), 1.93-1.83 (m, 1H), 1.31-1.26 (m, 2H), 1.11-1.03 (m, 1H), 0.96 (t, J=7.4Hz, 3H), 0.85-0.82 (m, 1H).

Embodiment 53 (S) -2- (1- ((6- amino -5- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine-4-yl) ammonia Base) propyl group) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By the chloro- 5- of compound 6- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine -4- amine (30mg, 0.142mmol) Chloro- 3- cyclopropyl quinazoline -4 (3H) -one (42mg, 0.150mmol) of (S) -2- (1- aminopropanes) -5- are suspended in n-BuOH In (1.5mL), DIPEA (37mg, 0.285mmol) is then added thereto, and gained mixture is heated to reflux 24 hours, is used in combination Thin-layered chromatography (CH₂Cl₂/ MeOH, v/v, 125/3) monitoring reaction, after having reacted, mixture is cooled to room temperature and depressurized dense Contracting, gained residue purify through silica gel column chromatography (PE/EtOAc (v/v)=1/3), and it is faint yellow solid to obtain title compound (35mg, 54.4%)

MS(ESI,pos.ion)m/z:452.1[M+H]⁺；HPLC:93.4%；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):9.56 (d, J=7.5Hz, 1H), 8.76 (s, 1H), 8.16 (s, 1H), 7.94 (s, 1H), 7.65 (t, J=8.0Hz, 1H), 7.48 (dd, J=8.3,1.7Hz, 2H), 7.10 (s, 1H), 6.13- 5.96(m,1H),4.02(s,3H),3.21–3.11(m, 1H),2.15–2.02(m,1H),1.96–1.82(m,1H),1.32– 1.24 (m, 2H), 1.17-1.07 (m, 1H), 1.01 (t, J=7.3Hz, 3H), 0.88-0.81 (m, 1H).

Embodiment 54 (S) -2- (1- ((6- amino -5- (2- methyl -2H- tetrazole -5- bases) pyrimidine-4-yl) amino) third Base) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By the chloro- 5- of compound 6- (2- methyl -2H- tetrazole -5- bases) pyrimidine -4- amine (31mg, 0.147mmol) and (S) - Chloro- 3- cyclopropyl quinazoline -4 (3H) -one (43mg, 0.154mmol) of 2- (1- aminopropyls) -5- are suspended in n-BuOH (3mL) In, DIPEA (38 mg, 0.293mmol) is then added thereto, and gained mixture is heated to backflow and stirring reaction 29 is small When, and monitored and reacted with thin-layered chromatography (PE/EtOAc, v/v, 1/4), after having reacted, mixture is cooled to room temperature, then subtract Pressure concentration, residue is diluted in EtOAc (15mL), gained mixture is washed with water (15mL) and saline solution (10mL) successively Wash, organic phase anhydrous sodium sulfate drying, then be concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=2/ 1) purify, it is white solid (39mg, 58.8%) to obtain title compound.

MS(ESI,pos.ion)m/z:453.2[M+H]⁺；HPLC:98.3%；

¹H NMR(400MHz,CDCl₃)δ(ppm):9.02 (d, J=7.6Hz, 1H), 8.17 (s, 1H), 7.57-7.48 (m, 2H), 7.42 (dd, J=6.4,2.6Hz, 1H), 6.34 (td, J=7.7,5.3Hz, 1H), 4.52 (s, 3H), 3.17-3.05 (m,1H),2.20–2.08(m,1H),2.06–1.97 (m,1H),1.48–1.40(m,2H),1.27–1.21(m,1H),1.08 (t, J=7.4Hz, 3H), 0.91-0.86 (m, 1H)

Embodiment 55 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) Propyl group) -4 (3H) -one of -3- cyclopropyl -5- Fluquinconazoles quinoline

By the chloro- 5- of compound 6- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine -4- amine (23.0mg, 0.11mmol), (S) -2- (1- aminopropyls) -3- (2- fluorophenyls) quinazoline -4 (3H) -one (38.8mg, 0.13mmol) and N, N- diisopropyl Base ethamine (42.3mg, 0.33mmol) is added in n-butanol (2.0mL), and gained mixture is heated into 125 DEG C and stirred anti- Answer 24 hours, after having reacted, reactant mixture be concentrated under reduced pressure, gained residue with thin-layer chromatography (DCM/MeOH (v/v)= 50/1) purify, it is faint yellow solid (20mg, 39%) to obtain title compound, and the faint yellow solid is by two kinds of isomers of A and B Form, its ratio is A/B=3/4.

MS(ESI,pos.ion)m/z:473.2[M+H]⁺；HPLC:99.1% (total purity of two kinds of isomers of A and B)；

Isomers A:¹H NMR(600MHz,CDCl₃) δ 8.76 (d, J=7.3Hz, 1H), 7.88 (s, 1H), 7.84-7.69 (m, 2H), 7.60-7.44 (m, 3H), 7.41-7.30 (m, 2H), 7.20 (t, J=8.8Hz, 1H), 5.80 (br.s, 1H), 5.32-5.26 (m, 1H), 2.71 (s, 3H), 2.16-2.08 (m, 1H), 2.02-1.88 (m, 1H), 0.95 (t, J=7.4Hz, 3H).

Isomers B:¹H NMR(600MHz,CDCl₃) δ 8.31 (d, J=7.8Hz, 1H), 7.99 (s, 1H), 7.84-7.69 (m, 3H), 7.60-7.44 (m, 3H), 7.41-7.30 (m, 2H), 5.18 (td, J=7.7,5.0Hz, 1H), 2.74 (s, 3H), 2.45 (br.s, 1H), 2.02-1.88 (m, 1H), 1.81 (tt, J=14.9,7.4Hz, 1H), 0.91 (t, J=7.3Hz, 3H)

Embodiment 56 (S) -2- (1- ((6- amino -5- (3- ethyl -1,2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Propyl group) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

Step 1) N'- the third amidines of hydroxyl

Hydroxylamine hydrochloride (18.9g, 272.7mmol) and Anhydrous potassium carbonate (37.6g, 272.7mmol) are suspended in EtOH/ H₂In O (200 mL/50mL), after mixture is stirred at room temperature 1 hour, propionitrile (10.0g, 181.8mmol) is added.Gained Mixture is heated to backflow simultaneously stirring reaction 20 hours, and is monitored and reacted with thin-layered chromatography (DCM/MeOH, v/v, 50/1).Instead After having answered, inorganic salts are filtered to remove, gained filtrate decompression concentration, obtain title compound for faint yellow solid (13.5g, 81%).

Step 2) N'- ((4,6- dichloro pyrimidine -5- carbonyls) epoxide) third is narrowed

By compound 4,6- dichloro pyrimidine -5- formyl chlorides (20.0g, 94.8mmol) are suspended in dichloromethane (100mL), Then at 0 DEG C, the two of N'- the third amidines of hydroxyl (8.3g, 94.8mmol) and DIPEA (25.1g, 190.6mmol) is added thereto Chloromethanes (100mL) mixture, reaction solution stirring reaction 2 hours at 0 DEG C, and with thin-layered chromatography (DCM/MeOH, v/v, 100/1) monitoring reaction, after having reacted, reaction solution is diluted in water (100mL), liquid separation, organic phase uses saturation NaHCO successively₃ The aqueous solution (100mL) and saline solution (100mL) washing, and with anhydrous sodium sulfate drying, then be concentrated under reduced pressure, gained residue passes through Silica gel column chromatography (DCM/MeOH (v/v)=500/1) purifies, and it is yellow solid (13.7g, 55%) to obtain title compound.

MS(ESI,pos.ion)m/z:263.1[M+H]⁺。

Step 3) N'- ((4- amino -6- chlorine pyrimidine -5- carbonyls) epoxide) third is narrowed

By compound N '-((4,6- dichloro pyrimidine -5- carbonyls) epoxide) third amidine (3.1g, 11.8mmol) is dissolved in THF In (30mL), ammonia is then filled with thereto, reaction solution is stirred at room temperature overnight, and with thin-layered chromatography (DCM/MeOH, v/ V, 100/1) monitoring reaction, after having reacted, reactant mixture is concentrated under reduced pressure, gained residue is diluted in EtOH (2mL) and water The in the mixed solvent of (10mL), after gained mixture is stirred 1 hour, then filter, it is white solid to obtain title compound (2.5g, 88%).

MS(ESI,pos.ion)m/z:244.1[M+H]⁺。

The chloro- 5- of step 4) 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine

By compound N '-((4- amino -6- chlorine pyrimidine -5- carbonyls) epoxide) third amidine (7.5g, 30.8mmol) is suspended in In DMSO (50mL), and Bu is added thereto₄NF tetrahydrofuran solution (1M, 60mL, 60.0mmol), gained mixture is in room It is stirred overnight under temperature, and (PE/EtOAc, v/v, 1/1) reaction is monitored with thin-layered chromatography, after having reacted, reaction solution is diluted in In EtOAc (100mL), gained mixture is washed with water (50mL × 2) and saline solution (100mL), liquid separation, the anhydrous sulphur of organic phase Sour sodium is dried, then is concentrated under reduced pressure.Residue purifies (PE/EtOAc (v/v)=6/1) through silica gel column chromatography and obtains title compound For white solid (1.1g, 16%).

MS(ESI,pos.ion)m/z:226.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.41 (s, 1H), 2.84 (q, J=7.5Hz, 2H), 1.30 (t, J= 7.5Hz,3H)。

Step 5) (S) -2- (1- ((6- amino -5- (3- ethyl -1,2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) third Base) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By chloro- 3- cyclopropyl quinazoline -4 (3H) -one of compound (S) -2- (1- aminopropyls) -5- (70mg, 0.252mmol) it is suspended in the chloro- 5- of 6- (3- ethyl -1,2,4- oxadiazole -5- bases) pyrimidine -4- amine (55mg, 0.243mmol) In n-BuOH (4mL), and DIPEA (75 mg, 0.580mmol) is added thereto, gained residue is heated to reflux 12 hours, and Monitored and reacted with thin-layered chromatography (PE/EtOAc, v/v, 1/1), after having reacted, mixture is cooled to room temperature, then depressurize dense Contracting, gained residue purify through silica gel column chromatography (PE/EtOAc (v/v)=2/1), and it is white solid to obtain title compound (74mg, 65%).

MS(ESI,pos.ion)m/z:467.1[M+H]⁺；HPLC:98.9%；

¹H NMR(600MHz,CDCl₃) δ 8.96 (d, J=7.3Hz, 1H), 8.15 (s, 1H), 7.54 (d, J=4.2Hz, 2H), 7.47-7.38 (m, 1H), 6.33 (m 1H), 3.10 (m, 1H), 2.90 (q, J=15.0,7.5Hz, 2H), 2.16 (m, 1H), 1.99 (m 1H), 1.44 (t, J=7.5Hz, 3H), 1.27 (m, 2H), 1.05 (t, J=7.3Hz, 3H), 0.96-0.86 (m,2H)

Embodiment 57 (S) -2- (1- ((6- amino -5- (3- isopropyl -1,2,4- oxadiazole -5- bases) pyrimidine-4-yl) ammonia Base) ethyl) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

Step 1) N'- hydroxy-isobutyrics are narrowed

Hydroxylamine hydrochloride (11.1g, 159.7mmol) and Anhydrous potassium carbonate (23.9g, 173.7mmol) are suspended in EtOH/ H₂In O (150 mL/50mL), after reaction is stirred at room temperature 1 hour in mixture, then add isobutyl cyanogen (10.0g, 144.7mmol), gained reactant mixture is heated to backflow and stirring reaction 20 hours, with thin-layered chromatography (DCM/MeOH, V/v, 50/1) monitoring reaction, after having reacted, the inorganic salts in mixture are filtered, gained filtrate obtains title through being concentrated under reduced pressure Compound is faint yellow solid (11.8g, 80%).

MS(ESI,pos.ion)m/z:103.2[M+H]⁺。

Step 2) N'- ((4,6- dichloro pyrimidine -5- carbonyls) epoxide) isobutyl is narrowed

Compound 4,6- dichloro pyrimidine -5- formyl chlorides (21.1g, 100.1mmol) are suspended in CH₂Cl₂In (100mL), so Afterwards at 0 DEG C, N'- hydroxy-isobutyrics are added thereto and narrow (10.3g, 100.1mmol) and DIPEA (25.8g, 200.2mmol) Dichloromethane (100mL) mixture, gained reaction solution stirring reaction 2 hours at 0 DEG C, and with thin-layered chromatography (DCM/ MeOH, v/v, 100/1) monitoring reaction, after having reacted, reaction solution is diluted in water (100mL), liquid separation, organic phase is used successively Saturation NaHCO₃The aqueous solution (100mL) and saline solution (100mL) washing, with anhydrous sodium sulfate drying, then are concentrated under reduced pressure.Gained is residual Stay thing through silica gel column chromatography (DCM/MeOH (v/v)=500/1) purify, obtain title compound for yellow oil (12.4g, 45%).

MS(ESI,pos.ion)m/z:277.1[M+H]⁺。

Step 3) N'- ((4- amino -6- chlorine pyrimidine -5- carbonyls) epoxide) isobutyl is narrowed

By compound N '-((4,6- dichloro pyrimidine -5- carbonyls) epoxide) isobutyl narrows (12.4g, 44.7mmol) and is dissolved in THF In (100mL), and ammonia being filled with, reaction solution is stirred at room temperature overnight, and is monitored and reacted with thin-layered chromatography (DCM), After having reacted, reactant mixture is concentrated under reduced pressure, residue is diluted in the in the mixed solvent of THF (2mL) and water (50mL), institute After reaction is stirred at room temperature 1 hour in mixture, then filter, it is white solid (9.8g, 85%) to obtain title compound.

MS(ESI,pos.ion)m/z:258.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ:8.27(s,1H),7.55(s,2H),6.32(s,2H),2.40(m,1H), 1.13 (d, J=7.0Hz, 6H)

The chloro- 5- of step 4) 6- (3- isopropyl -1,2,4- oxadiazole -5- bases) pyrimidine -4- amine

By compound N '-((4- amino -6- chlorine pyrimidine -5- carbonyls) epoxide) isobutyl narrows (7.5g, 29.1mmol) and is suspended in In DMSO (20mL), Bu is then added thereto₄NF tetrahydrofuran solution (1M, 60mL, 60.0mmol).Gained mixture exists It is stirred overnight at room temperature, and is monitored and reacted with thin-layered chromatography (PE/EtOAc, v/v, 1/1).After having reacted, reaction solution is diluted In EtOAc (100mL), gained mixture is washed with water (100mL) and saline solution (100mL) successively.Liquid separation, organic phase nothing Aqueous sodium persulfate is dried, then is concentrated under reduced pressure, and residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=7/1), obtains titled Compound is white solid (0.9g, 14%).

MS(ESI,pos.ion)m/z:240.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ8.47(s,1H),8.43(s,1H),8.10(s,1H),3.18(m,1H), 1.34 (d, J=6.9Hz, 6H).

Step 5) (S) -2- (1- ((6- amino -5- (3- isopropyl -1,2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Ethyl) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By chloro- 3- cyclopropyl quinazoline -4 (3H) -one of compound (S) -2- (1- amino-ethyls) -5- (70mg, 0.27mmol) it is suspended in the chloro- 5- of 6- (3- isopropyl -1,2,4- oxadiazole -5- bases) pyrimidine -4- amine (65mg, 0.28mmol) In n-BuOH (4mL), DIPEA (75 mg, 0.58mmol) is then added thereto.Gained mixture is heated to reflux 20 hours, and Monitored and reacted with thin-layered chromatography (PE/EtOAc, v/v, 1/1), after having reacted, mixture is cooled to room temperature, then depressurize dense Contracting, gained residue purify through silica gel column chromatography (DCM/MeOH (v/v)=100/1), and it is white solid to obtain title compound (82mg, 65%).

MS(ESI,pos.ion)m/z:467.1[M+H]⁺；HPLC:99.2%；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.24 (d, J=7.1Hz, 1H), 8.12 (s, 1H), 7.72 (t, J= 8.0Hz, 1H), 7.52 (m, 4H), 6.19 (m, 1H), 3.20 (m, 1H), 3.13 (m, 1H), 1.59 (d, J=6.6Hz, 3H), 1.36 (d, J=6.9Hz, 6H), 1.26 (m, 1H), 1.03 (m, 1H), 0.91-0.78 (m, 2H).

Embodiment 58 (S) -3- (4- amino -6- ((1- (chloro- 3- cyclopropyl -4- oxos -3,4- dihydroquinazolines -2- of 5- Base) propyl group) amino) pyrimidine -5- bases) -1- methyl isophthalic acid H-1,2,4- triazole -5- formamides

Step 1) 3- (4- amino -6- chlorine pyrimidine -5- bases) -1- methyl isophthalic acid H-1,2,4- triazole -5- formamides

By compound 3- (4- amino -6- chlorine pyrimidine -5- bases) -1- methyl isophthalic acid H-1,2,4- triazole -5- Ethyl formates The mixture of the methanol solution of (100mg, 0.354mmol) and ammonia (10mL) is sealed in tube sealing, then tube sealing is placed at 65 DEG C Stirring reaction 5 hours, then filters mixture, and filter cake is white solid (85mg, 94%) through being dried to obtain title compound.

MS(ESI,pos.ion)m/z:254.1[M+H]⁺。

Step 2) (S) -3- (4- amino -6- ((1- (the chloro- 3- cyclopropyl -4- oxos -3,4- dihydroquinazolines -2- bases of 5-) Propyl group) amino) pyrimidine -5- bases) -1- methyl isophthalic acid H-1,2,4- triazole -5- formamides

By chloro- 3- cyclopropyl quinazoline -4 (3H) -one of compound (S) -2- (1- aminopropyls) -5- (97.7mg, 0.352mmol) and 3- (4- amino -6- chlorine pyrimidine -5- bases) -1- methyl isophthalic acid H-1,2,4- triazole -5- formamides (85mg, 0.335mmol) it is suspended in 5mL n-BuOH, then adds DIPEA (86.6mg, 0.670mmol) thereto, mixture adds Heat overnight, is subsequently cooled to room temperature, filters, gained filter cake 2mL alcohol flushing, obtain title compound to 125 DEG C of reactions For white solid (30mg, 18%).

MS(ESI,pos.ion)m/z:495.2[M+H]⁺；HPLC:95%；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.17 (d, J=7.5Hz, 1H), 8.63 (s, 1H), 8.32 (s, 1H), 8.08 (s, 1H), 7.96 (s, 1H), 7.67 (t, J=8.0Hz, 1H), 7.49 (m, 2H), 7.07 (s, 1H), 6.15 (m, 1H),4.29(s,3H),3.21–3.13(m,1H),2.06 (m,1H),1.94(m,1H),1.28(m,2H),1.07(m,1H), 0.99 (t, J=7.3Hz, 3H), 0.90-0.78 (m, 1H).

Embodiment 59 (S) -2- (1- ((6- amino -5- (5- isopropyl -1,2,4- oxadiazole -3- bases) pyrimidine-4-yl) ammonia Base) ethyl) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

Step 1) 4,6- dimethoxypyridin -5- formaldehyde

By compound 4,6- dichloro pyrimidine -5- formaldehyde (5g, 28.25mmol) is suspended in dry MeOH (100mL), so Add K thereto afterwards₂CO₃(7.8g, 56.5mmol), reaction solution stirring reaction 1 hour at 90 DEG C, is then concentrated under reduced pressure, by institute The in the mixed solvent that residue is dissolved in water (100mL) and DCM (100mL), liquid separation are obtained, aqueous phase is extracted with DCM (50mL × 3), The organic phase of merging is concentrated under reduced pressure, residue is diluted in DCM/PE (1mL/20mL), gained mixture stirs at room temperature Reaction 3 hours is mixed, then filters, obtains yellow solid, the yellow solid is through silica gel column chromatography (PE/EtOAc (v/v)=5/1) Purifying, it is white solid (2.2 g, 46.3%) to obtain title compound.

MS(ESI,pos.ion)m/z:169.1[M+H]⁺。

Step 2) 4,6- dimethoxypyridin -5- formaldoximes

Compound 4,6- dimethoxypyridin -5- formaldehyde (2.2g, 13.08mmol) is dissolved in ethyl acetate (45mL) In, NH is then added thereto₂OHHCl (910g, 13.08mmol) water (18mL) solution, at room temperature, add sodium acetate (1.07g,13.08mmol).Reaction solution stirs 3 hours at 28 DEG C, then filters.Gained filter cake is rinsed with 30mL water, and Dried under 60 DEG C of vacuum conditions, it is white solid (2.2g, 91.8%) to obtain title compound.

MS(ESI,pos.ion)m/z:184.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆):δ11.47(s,1H),8.47(s,1H),8.08(s,1H),3.96(s,6H)。

Step 3) 3- (4,6- dimethoxypyridin -5- bases) -5- isopropyl -1,2,4- oxadiazoles

Under room temperature and nitrogen protection, to equipped with 4,6- dimethoxypyridin -5- formaldoximes (50mg, 0.273mmol) and (NH₄)₂Ce(NO₃)₆(CH is added in the three-necked flask of (300mg, 0.546mmol)₃)₂CHCN (3mL), reactant mixture heating To 70 DEG C and stirring reaction 4 hours, then filter, filtrate decompression concentrated, then residue is dissolved in EtOAc (10mL), Gained mixture uses saturation Na successively₂CO₃The aqueous solution (10mL) and saline solution (10mL) washing, liquid separation, organic phase are depressurized dense Contracting, gained residue purify through silica gel column chromatography (PE/EtOAc (v/v)=3/1), and it is yellow solid to obtain title compound (24mg, 35.1%).

MS(ESI,pos.ion)m/z:251.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.54 (s, 1H), 4.01 (s, 6H), 3.33 (m, 1H), 1.50 (d, J= 7.0Hz,6H)。

Step 4) 3- (4,6- dichloro pyrimidine -5- bases) -5- isopropyl -1,2,4- oxadiazoles

By compound 3- (4,6- dimethoxypyridin -5- bases) -5- isopropyl -1,2,4- oxadiazoles (573mg, 2.29mmol) it is suspended in DMF (6.0mL) in toluene (50mL), then adds POCl thereto₃(6mL, 62.64mmol), After reaction solution is heated to reflux 24 hours, then it is concentrated under reduced pressure and removes solvent, obtained crude on silica gel column chromatography (PE/EtOAc (v/v)=10/1) purify, it is yellow oil (350mg, 58.9%) to obtain title compound.

The chloro- 5- of step 5) 6- (5- isopropyl -1,2,4- oxadiazole -3- bases) pyrimidine -4- amine

Compound 3- (4,6- dichloro pyrimidine -5- bases) -5- isopropyl -1,2,4- oxadiazoles (350mg, 1.35mmol) is molten Solution at room temperature, and is filled with ammonia, with thin-layered chromatography (PE/EtOAc, v/v, 3/ thereto in dry THF (10 mL) 1) monitoring reaction.After having reacted, reactant mixture is filtered, filtrate decompression is concentrated, it is yellow solid to obtain title compound (325mg, 100%).

MS(ESI,pos.ion)m/z:240.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.35(s,1H),7.11(s,2H),3.37(m,1H),1.38(d,J =7.0Hz, 6H).

Step 6) (S) -2- (1- ((6- amino -5- (5- isopropyl -1,2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) Ethyl) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By chloro- 3- cyclopropyl quinazoline -4 (3H) -one of compound (S) -2- (1- amino-ethyls) -5- (50mg, 0.19mmol) suspended with the chloro- 5- of 6- (5- isopropyl -1,2,4- oxadiazole -3- bases) pyrimidine -4- amine (45.5mg, 0.19mmol) In 5mL n-BuOH, DIPEA (49.2mg, 0.38mmol) is then added thereto.Heat the mixture to 120 DEG C and stir Mix overnight, be then concentrated under reduced pressure, residue is dissolved in EtOAc (10mL), gained mixture is washed with water (10mL), will Organic phase is concentrated under reduced pressure, and gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=1/3), obtains title compound For white solid (35mg, 39.5%).

MS(ESI,pos.ion)m/z:467.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.95-8.93 (d, J=7.3Hz, 1H), 8.06 (s, 1H), 7.72- (7.68 t, J=8.0Hz, 1H), 7.54 (s, 2H), 7.50 (m, 2H), 6.21-6.15 (m, 1H), 3.43-3.40 (m, 1H), 3.16-3.13 (m, 1H), 2.03-1.97 (m, 1H), 1.59-1.57 (d, J=6.6Hz, 3H), 1.43-1.42 (d, J= 7.0Hz,6H),1.06-1.04(m,1H),0.88-0.84(m,2H)。

Embodiment 60 (S) -2- (1- ((6- amino -5- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine-4-yl) ammonia Base) propyl group) -3- (2- fluorophenyls) quinazoline -4 (3H) -one

By the chloro- 5- of compound 6- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine -4- amine (30mg, 0.142mmol) (S) -2- (1- aminopropyls) -3- (2- fluorophenyls) quinazoline -4 (3H) -one (44mg, 0.150mmol) is suspended in n-BuOH In (1mL), DIPEA (37mg, 0.284mmol) is then added into reaction solution, heats the mixture to backflow and stirring reaction 22 hours, reaction was monitored with thin-layered chromatography (DCM/MeOH, v/v, 100/3), is subsequently cooled to room temperature, is concentrated under reduced pressure, and was added EtOAc (15mL) dilutes residue, and gained mixture is washed with water (15mL) and saline solution (10mL) successively, liquid separation, and organic phase is used Anhydrous sodium sulfate drying, then it is concentrated under reduced pressure, gained residue purifies through silica gel column chromatography (PE/EtOAc (v/v)=1/1) It is white solid (15mg, 22.3%) to title compound, product is by mixture that isomers A/ isomers B is 3/2.

MS(ESI,pos.ion):472.2[M+H]⁺；HPLC:95.4% (isomers A and isomers B total purity)；

Isomer A:¹H NMR(400MHz,CDCl₃)δ(ppm):8.31 (d, J=7.7Hz, 1H), 8.15 (s, 1H), 7.95(s,1H),7.82-7.68 (m,2H),7.58-7.44(m,3H),7.39-7.30(m,2H),5.21-5.12(m,1H), 4.05 (s, 3H), 3.68 (t, J=2.5Hz, 2H), 0.99-0.93 (m, 3H).

Isomer B:¹H NMR(400MHz,CDCl₃)δ(ppm):8.31 (d, J=7.7Hz, 1H), 8.10 (s, 1H), 7.84(s,1H),7.82-7.68 (m,2H),7.58-7.44(m,3H),7.39-7.30(m,2H),5.35-5.26(m,1H), 4.02 (s, 1H), 3.68 (t, J=2.5Hz, 2H), 0.99-0.93 (m, 3H).

Embodiment 61 (S) -2- (1- ((6- amino -5- (5- ethyl -1,2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) Ethyl) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

Step 1) 4,6- dimethoxypyridin -5- formaldehyde

By compound 4,6- dichloro pyrimidine -5- formaldehyde (5g, 28.25mmol) is suspended in dry methanol (100mL), so Potassium carbonate (7.8g, 56.5mmol) is added in backward reaction solution, reaction solution is heated to 90 DEG C of simultaneously stirring reaction 1 hours, decompression Concentration, then add water (100mL) and the mixed solvent of dichloromethane (100mL) dissolves residue, gained mixture is with two Chloromethanes (50mL × 3) is extracted, and the organic phase of merging is concentrated under reduced pressure, and DCM/PE (1/20, v/v, 10mL) is added in residue And be stirred at room temperature 3 hours, filter, it is yellow solid to obtain crude product, and crude product successively analyses (PE/EtOAc through silica gel again (v/v) it is white solid (2.2g, 46.3%) that=5/1) purifying, which obtains title compound,.

MS(ESI,pos.ion)m/z:169.1[M+H]⁺。

Step 2) 4,6- dimethoxypyridin -5- formaldoximes

Compound 4,6- dimethoxypyridin -5- formaldehyde (2.2g, 13.08mmol) is dissolved in ethyl acetate (45mL) In, then at room temperature, NH is added into reaction solution₂OHHCl (910g, 13.08mmol) water (8mL) solution, next Sodium acetate (1.07g, 13.08mmol) is added, 28 DEG C of simultaneously stirring reaction 3 hours is heated the mixture to, filters, filter cake is used 30mL is washed, and then in 60 DEG C of dryings in vacuum drying chamber, it is white solid (2.2g, 91.8%) to obtain title compound.

MS(ESI,pos.ion)m/z:184.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆):δ11.47(s,1H),8.47(s,1H),8.08(s,1H),3.96(s,6H)。

Step 3) 3- (4,6- dimethoxypyridin -5- bases) -5- ethyl -1,2,4- oxadiazoles

Room temperature condition and nitrogen protection under, to equipped with 4,6- dimethoxypyridin -5- formaldoximes (2.0g, 10.93mmol) and (NH₄)₂Ce(NO₃)₆CH is added in the there-necked flask of (12.0g, 21.86mmol)₃CHCN (37mL), then will Mixture is heated to 70 DEG C of simultaneously stirring reaction 6 hours, filters, filtrate decompression is concentrated, residue is dissolved in into ethyl acetate In (50mL), gained mixture with saturated aqueous sodium carbonate (50mL × 2) and saline solution (50mL × 2) with being washed successively, liquid separation, Organic phase is concentrated under reduced pressure, gained residue obtains title compound through silica gel column chromatography (PE/EtOAc (v/v)=10/1) purifying Thing is yellow solid (805mg, 31.0%).

MS(ESI,pos.ion)m/z:237.2[M+H]⁺。

Step 4) 3- (4,6- dichloro pyrimidine -5- bases) -5- ethyl -1,2,4- oxadiazoles

By compound 3- (4,6- dimethoxypyridin -5- bases) -5- ethyl -1,2,4- oxadiazoles (650mg, 2.75mmol) It is suspended in DMF (6.0mL) in toluene (14mL), POCl is then added into reaction solution₃(6mL, 62.75mmol), it will react Liquid is heated to 120 DEG C of simultaneously stirring reaction 10 hours, is then concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/ V) it is yellow slurry (320mg, 51.4%) that=10/1) purifying, which obtains title compound,.

MS(ESI,pos.ion)m/z:245.1[M+H]⁺。

The chloro- 5- of step 5) 6- (5- ethyl -1,2,4- oxadiazole -3- bases) pyrimidine -4- amine

Compound 3- (4,6- dichloro pyrimidine -5- bases) -5- ethyl -1,2,4- oxadiazoles (320mg, 1.31mmol) are dissolved In THF (10mL) and then in room temperature condition, it is passed through into reaction solution after ammonia reacts 1 hour, filters, filtrate decompression is concentrated, It is faint yellow solid (330mg, 100%) to obtain title compound.

MS(ESI,pos.ion)m/z:226.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ:8.35(s,1H),7.85(s,1H),7.07(s,1H),3.05-2.99(q,J =7.6Hz, 2H), 1.36-1.32 (t, J=7.6Hz, 3H).

Step 6) (S) -2- (1- ((6- amino -5- (5- ethyl -1,2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) second Base) chloro- 3- cyclopropyl quinazoline -4 (3H) -one of -5-

By chloro- 3- cyclopropyl quinazoline -4 (3H) -one of compound (S) -2- (1- amino-ethyls) -5- (50mg, 0.19mmol) it is suspended in the chloro- 5- of 6- (5- ethyl -1,2,4- oxadiazole -3- bases) pyrimidine -4- amine (43mg, 0.19mmol) In 4mL n-BuOH, DIPEA (49.1mg, 0.38mmol) is then added into reaction solution.Reactant mixture is heated to 120 DEG C and be stirred overnight, be then concentrated under reduced pressure, residue be dissolved in EtOAc (15mL), gained mixture with water (10mL × 2) wash, liquid separation, organic phase anhydrous sodium sulfate drying, be then concentrated under reduced pressure, gained residue purifies through Flash silica column chromatography It is yellow solid (31mg, 36%) to obtain title compound.

MS(ESI,pos.ion)m/z:453.3[M+H]⁺；

1H NMR (400MHz, CDCl3) δ 9.01 (d, J=7.4Hz, 1H), 8.14 (s, 1H), 7.53 (m, 2H), 7.46- 7.39 (m, 1H), 6.33 (m, 1H), 6.01-5.39 (s, 2H), 3.12 (m, 1H), 3.04 (q, J=7.6Hz, 2H), 1.65 (d, J=9.6Hz, 3H), 1.50 (t, J=7.6Hz, 3H), 1.46-1.39 (m, 2H), 0.90 (m, 2H).

Embodiment 622- ((S) -1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Propyl group) the chloro- 3- of -5- ((1R, 2S) -2- fluorine cyclopropyl) quinazoline -4 (3H) -one

The chloro- N- of step 1) 2- ((1R, 2S) -2- fluorine cyclopropyl) -6- nitrobenzamides

The chloro- 6- nitrobenzoic acids (806mg, 4.0mmol) of compound 2- are suspended in toluene (10mL), then in room temperature Condition, SOCl is disposably added into reaction solution₂(952mg, 8.0mmol), reaction solution is heated to 110 DEG C and stirring reaction 9 Hour, it is concentrated under reduced pressure, gained yellow oil is dissolved in Isosorbide-5-Nitrae-dioxane (10mL), obtains yellow suspension.

By compound (1R, 2S) -2- fluorine cyclopropylamine toluene fulfonates (1.0g, 4.0mmol) and NaHCO₃(1.34g, 16.0mmol) it is suspended in Isosorbide-5-Nitrae-dioxane (10mL), then at 5 DEG C, above-mentioned gained yellow is added dropwise into reaction solution Suspension, reaction solution are stirred at room temperature overnight, and then add the dilution of 100mL water, gained mixture with ethyl acetate (50mL × 3) extract, the organic phase of merging is washed with saline solution (100mL), with anhydrous sodium sulfate drying, is then concentrated under reduced pressure to give titled Compound is faint yellow solid (940mg, 90.86%).

MS(ESI,pos.ion)m/z:259.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):8.12 (d, J=8.3Hz, 1H), 7.75 (d, J=8.0Hz, 1H), 7.55 (t, J=8.2Hz, 1H), 6.08 (s, 1H), 4.80 (ddd, J=63.6,8.8,5.7Hz, 1H), 3.08 (td, J= 9.4,5.3Hz, 1H), 1.32 (dt, J=14.9,8.3Hz, 1H), 1.24 (m, 1H).

Step 2) ((S) -1- (the chloro- N- of 2- ((1R, 2S) -2- fluorine cyclopropyl) -6- nitrobenzamides base) -1- oxo fourths Alkane -2- bases) t-butyl carbamate

The chloro- N- of compound 2- ((1R, 2S) -2- fluorine cyclopropyl) -6- nitrobenzamides (940mg, 3.63mmol) is outstanding Float in toluene (20mL), then at ambient temperature, SOCl is disposably added into reaction solution₂(2mL, 27.57mmol), Reactant mixture is heated to 120 DEG C of simultaneously stirring reaction 10 hours, is concentrated under reduced pressure, obtains light brown grease, it is then that its is molten Solution obtains yellow solution in 10mL anhydrous methylene chloride.

By compound (S) -2- ((tertbutyloxycarbonyl) amino) butyric acid (734mg, 3.63mmol) and DIPEA (1.41g, 10.89mmol) it is dissolved in 10mL anhydrous methylene chlorides, then at 0 DEG C, it is molten that above-mentioned gained yellow is slowly added into reaction solution Then liquid, obtained mixture are washed with water (30mL × 3) and saline solution (10mL) in room temperature condition stirring reaction 24 hours, point Liquid, organic phase anhydrous sodium sulfate drying, then be concentrated under reduced pressure, gained residue through silica gel column chromatography (PE/EtOAc (v/v)= 10/1) it is yellow oil (0.83g, 52.34%) that purifying, which obtains title compound,.

MS(ESI,pos.ion)m/z:466.1[M+Na]⁺。

Step 3) ((S) -1- (the chloro- 3- of 5- ((1R, 2S) -2- fluorine cyclopropyl) -4- oxo -3,4- dihydroquinazoline -2- bases) Propyl group) t-butyl carbamate

By compound ((S) -1- (the chloro- N- of 2- ((1R, 2S) -2- fluorine cyclopropyl) -6- nitrobenzamides base) -1- oxos Butane -2- bases) t-butyl carbamate (730mg, 1.64mmol) is dissolved in acetic acid (5mL), then into reaction solution once Property add zinc powder (420mg, 6.58mmol), then reaction solution is filtered in 35 DEG C of stirring reactions 24 hours, filtrate decompression is dense Contracting, residue is dissolved in EtOAc (30mL), gained mixture saturated sodium bicarbonate aqueous solution (10mL) and saline solution (10mL) is washed, liquid separation, organic phase anhydrous sodium sulfate drying, then is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/ EtOAc (v/v)=10/1) to obtain title compound be faint yellow solid (226mg, 4.81%) for purifying.

MS(ESI,pos.ion)m/z:396.2[M+H]⁺。

Step 4) 2- ((S) -1- aminopropyls) chloro- 3- of -5- ((1R, 2S) -2- fluorine cyclopropyl) quinazoline -4 (3H) -one

By compound ((S) -1- (the chloro- 3- of 5- ((1R, 2S) -2- fluorine cyclopropyl) -4- oxo -3,4- dihydroquinazolines -2- Base) propyl group) t-butyl carbamate (233mg, 0.59mmol) is dissolved in EtOAc (6mL), then in room temperature condition, to anti- Answer in liquid and disposably to add ethyl acetate (3.5M, 6mL) solution of hydrogen chloride, reaction solution was in room temperature condition stirring reaction 6 hours After form suspension, gained suspension is dissolved in 50mL water, aqueous phase first with ethyl acetate (20mL × 3) extract, remaining water It is added to powdered sodium carbonate to be adjusted to pH=8, is then extracted again with ethyl acetate (30mL × 4), the organic phase of merging is used Saline solution (50mL) is washed, with anhydrous sodium sulfate drying, be concentrated under reduced pressure to give title compound for faint yellow solid (151mg, 86.54%).

MS(ESI,pos.ion)m/z:296.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.61-7.53 (m, 2H), 7.45 (dd, J=6.7,2.3Hz, 1H), 4.97 (ddd, J=62.8,8.7,5.4Hz, 1H), 4.28 (t, J=6.2Hz, 1H), 3.04 (dd, J=13.9,5.4Hz, 1H), 2.04-1.94 (m, 1H), 1.75 (dt, J=18.0,5.4Hz, 2H), 1.55-1.42 (m, 1H), 1.02 (t, J= 7.4Hz,3H)。

Step 5) 2- ((S) -1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) third Base) the chloro- 3- of -5- ((1R, 2S) -2- fluorine cyclopropyl) quinazoline -4 (3H) -one

By compound 2- ((S) -1- aminopropyls) chloro- 3- of -5- ((1R, 2S) -2- fluorine cyclopropyl) quinazoline -4 (3H) -one The chloro- 5- of (59mg, 0.2mmol) and 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (42mg, 0.2mmol) is outstanding Float in n-BuOH (10mL), DIPEA (52mg, 0.4mmol) is then added into reaction solution, reactant mixture is heated to back Simultaneously stirring reaction 6 hours are flowed, reaction is monitored with thin-layered chromatography (PE/EtOAc, v/v, 2/1), is subsequently cooled to room temperature, and subtract Pressure concentration, it is white powder that gained residue obtains title compound through silica gel column chromatography (PE/EtOAc (v/v)=1/4) purifying Last (58mg, 61.58%).

MS(ESI,pos,ion):471.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.70 (s, 1H), 8.15 (s, 1H), 7.58 (d, J=4.3Hz, 2H), 7.45 (m, 1H), 6.10 (d, J=5.1Hz, 1H), 5.07 (ddd, J=63.2,8.7,5.5Hz, 1H), 3.17 (dd, J= 13.4,6.3Hz,1H),2.52(s,3H),2.16(m, 1H),2.06(m,1H),1.84(m,1H),1.69(m,1H),1.07 (t, J=7.4Hz, 3H).

Embodiment 63 (S) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Ethyl) fluoro- 3- phenylquinazolines -4 (3H) -one of -5-

Step 1) (S)-(1- ((3- fluoro- 2- (phenylcarbamoyl) phenyl) amino) -1- oxopropan -2- bases) amino T-butyl formate

By the fluoro- N- phenylbenzamaides (2.31g, 10mmol) of compound 2- amino -6- and (S) -2- ((tertbutyloxycarbonyl) Amino) propionic acid (2.08g, 11mmol) is suspended in DCM (40mL), then at -10 DEG C, HATU is added into reaction solution (4.56g, 12mmol) and DIPEA (3.88g, 30mmol), reactant mixture are stirred 1 hour at -10 DEG C, are then heated to back Flow and be stirred overnight.Mixture is cooled to room temperature, successively with water (200mL × 2) and saturation NaHCO₃The aqueous solution (200mL × 2) wash, liquid separation, organic phase anhydrous sodium sulfate drying, then be concentrated under reduced pressure, gained residue purifies through silica gel column chromatography to be marked Topic compound is white solid (1.14g, 67.8%).

MS(ESI,neg.ion)m/z:400.1[M-H]^-。

Step 2) (S)-(1- (5- fluorin-4-oxygens generation -3- phenyl -3,4- dihydroquinazoline -2- bases) ethyl) carbamic acid uncle Butyl ester

By compound (S)-(1- ((3- fluoro- 2- (phenylcarbamoyl) phenyl) amino) -1- oxopropan -2- bases) ammonia Base t-butyl formate (2.85g, 7.1 mmol), the mixture of acetonitrile (180mL) and triethylamine (21.55g, 481.5mmol) is taken out Take a breath (N₂) 3 times, then at room temperature, add N into reaction solution, the double trimethylsilyl acetamides (29.38g, 213mmol) of O-, Reactant mixture was flowed back liquid, is monitored and reacted with LC-MS, after react, mixture is concentrated under reduced pressure, addition EtOAc (70mL) dissolves residue, and gained mixture is washed with water (70mL × 2) and saline solution (50mL) successively, liquid separation, and organic phase is used Anhydrous sodium sulfate drying, then be concentrated under reduced pressure, gained residue through silica gel column chromatography purify to obtain title compound for (1.0g, 36.6%).

MS(ESI,pos.ion)m/z:384.2[M+H]⁺。

Fluoro- 3- phenylquinazolines -4 (3H) -one of step 3) (S) -2- (1- amino-ethyls) -5-

By compound (S)-(1- (5- fluorin-4-oxygens generation -3- phenyl -3,4- dihydroquinazoline -2- bases) ethyl) carbamic acid The tert-butyl ester (1.0g, 2.61mmol) is dissolved in EtOAc (8mL), then at ambient temperature, is disposably added into reaction solution The ethyl acetate solution (11mL, 3M) of hydrogen chloride, reactant mixture is stirred at room temperature overnight, and gained suspension is dissolved in 20mL In water, aqueous phase is extracted with ethyl acetate (20mL), and remaining aqueous phase adds powdered sodium carbonate and adjusted to pH=8, then uses acetic acid Ethyl ester (20mL × 3) extracts.The organic phase of merging is washed with saline solution (20 mL), with anhydrous sodium sulfate drying, is concentrated under reduced pressure to give Title compound is white powder (440mg, 59.4%)

MS(ESI,pos.ion)m/z:284.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.89 (td, J=8.2,5.6Hz, 1H), 7.66-7.46 (m, 6H), 7.34 (dd, J=10.8,8.3Hz, 1H), 5.92 (s, 2H), 3.63 (q, J=6.6Hz, 1H), 1.23 (d, J=6.7Hz, 3H)。

Step 4) (S) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) second Base) fluoro- 3- phenylquinazolines -4 (3H) -one of -5-

By fluoro- 3- phenylquinazolines -4 (3H) -one of compound (S) -2- (1- amino-ethyls) -5- (30mg, 0.105mmol), the chloro- 5- of 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (22mg, 0.105mmol), DIPEA (27mg, 0.211mmol) and n-BuOH (1ml) mixture are heated to 125 DEG C of simultaneously stirring reaction 1 hours, are subsequently cooled to room Temperature, filter, filter cake is washed with ethyl acetate (2mL), and it is white solid to be then dried to obtain title compound under vacuum (32.7mg, 67%).

MS(ESI,pos.ion)m/z:459.0[M+H]⁺；HPLC:99%；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):9.23-9.21 (d, J=6.5Hz, 1H), 7.99 (s, 1H), 7.92- 7.86 (ddd, J=8.4,8.4,6.4Hz, 1H), 7.60-7.54 (m, 8H), 7.35-7.30 (dd, J=10.4,8.4Hz, 1H), 4.93 (m, 1H), 2.50 (s, 3H), 1.36 (d, J=6.6Hz, 3H).

Embodiment 64 (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) Ethyl) chloro- 3- phenylquinazolines -4 (3H) -one of -5-

Step 1) 5- chlorine 1H- benzos [d] [1,3] oxazine -2,4- diketone

Compound 2- amino -6- chlorobenzoic acids (1.00g, 5.83mmol) are suspended in Isosorbide-5-Nitrae-dioxane (20mL), Then two (trichloromethyl) carbonic esters (605mg, 2.04mmol) are added into reaction solution, reactant mixture is heated to backflow simultaneously Stirring reaction 3 hours, is subsequently cooled to room temperature, filters, and filter cake is washed with petroleum ether (50mL), and then vacuum drying obtains titled Compound is Light brown solid (954mg, 83%).

MS(ESI,pos.ion)m/z:198.0[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):11.85 (s, 1H), 7.67-7.64 (dd, J=7.8,8.4Hz, 1H), 7.31-7.30 (d, J=7.8Hz, 1H), 7.11-7.10 (d, J=8.4Hz, 1H).

The chloro- N- phenylbenzamaides of step 2) 2- amino -6-

By compound 5- chlorine 1H- benzos [d], [1,3] oxazine -2,4- diketone (1.00g, 5.06mmol) are suspended in 1,4- bis- The ring of oxygen six (20mL), aniline (471mg, 5.06mmol) is then added into reaction solution, reactant mixture is heated to backflow simultaneously Stirring reaction 12 hours, is subsequently cooled to room temperature, is concentrated under reduced pressure, gained residue through silica gel column chromatography (PE/EtOAc (v/v)= 1/2) it is light yellow solid (1.12g, 90%) that purifying, which obtains title compound,

MS(ESI,pos.ion)m/z:247.0[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.71 (br.s, 1H), 7.63 (d, J=8.0Hz, 2H), 7.38 (t, J =7.8Hz, 2H), 7.18 (t, J=7.4Hz, 1H), 7.10 (t, J=8.1Hz, 1H), 6.77 (d, J=7.9Hz, 1H), 6.63 (d, J=8.2Hz, 1H), 4.68 (s, 2H).

Step 3) (S)-(1- ((3- chloro- 2- (phenylcarbamoyl) phenyl) amino) -1- oxopropan -2- bases) amino T-butyl formate

At 0 DEG C, to the chloro- N- phenylbenzamaides (600mg, 2.43mmol) of compound 2- amino -6-, (S) -2- ((tertiary fourths Oxygen carbonyl) amino) in propionic acid (552mg, 2.92mmol) and the mixture of dichloromethane (10mL) add DIPEA (1.27mL, 7.30mmol) and HATU (1.11g, 2.92mmol), reactant mixture is heated to backflow simultaneously after 0 DEG C of stirring reaction 1 hour It is stirred overnight, is subsequently cooled to room temperature, is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=40/7) It is white solid (934mg, 92%) that purifying, which obtains title compound,.

MS(ESI,neg.ion)m/z:416.0[M-H]^-；

¹H NMR(400MHz,CDCl₃)δ(ppm):9.49 (s, 1H), 8.15 (br.s, 1H), 8.13-8.11 (d, J= 8.4Hz, 1H), 7.68-7.66 (d, J=7.6Hz, 2H), 7.41-7.37 (t, J=7.6Hz, 2H), 7.37-7.33 (t, J= 8.4Hz, 1H), 7.23-7.19 (m, 2H), 5.03-5.02 (d, J=4.8Hz, 1H), 4.29 (m, 1H), 1.40 (s, 9H), (1.40-1.39 d, J=5.6Hz, 3H).

Step 4) (S)-(1- (the chloro- 4- oxos -3- phenyl -3,4- dihydroquinazolines -2- bases of 5-) ethyl) carbamic acid uncle Butyl ester

By compound (S)-(1- ((3- chloro- 2- (phenylcarbamoyl) phenyl) amino) -1- oxopropan -2- bases) ammonia Base t-butyl formate (400mg, 0.96mmol), DMAP (117mg, 0.96mmol) and DIPEA (0.33mL, 1.91mmol) are molten Solution is in CH₃In CN (3mL), then at ambient temperature, N is added into reaction solution, the double trimethylsilyl acetamides of O- (2.34mL, 9.6mmol), reactant mixture is heated to backflow simultaneously stirring reaction 4 hours, room temperature is subsequently cooled to, adds 10mL saturated carbons Reaction is quenched in sour hydrogen sodium water solution, and obtained mixture is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/EtOAc (v/v) it is faint yellow solid (253mg, 66%) that=10/1) purifying, which obtains title compound,.

MS(ESI,pos.ion)m/z:400.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.63-7.61(m,2H),7.59-7.57(m,1H),7.55-7.51 (m, 2H), 7.48-7.46 (dd, J=6.4,3.6Hz, 1H), 7.39-7.37 (d, J=7.2Hz, 1H), 7.29-7.27 (m, 1H), 5.59-5.57 (d, J=7.2Hz, 1H), 4.52-4.49 (m, 1H), 1.42 (s, 9H), 1.26-1.26 (d, J= 6.8Hz,3H)。

Chloro- 3- phenylquinazolines -4 (3H) -one of step 5) (S) -2- (1- amino-ethyls) -5-

By compound (S)-(1- (the chloro- 4- oxos -3- phenyl -3,4- dihydroquinazolines -2- bases of 5-) ethyl) carbamic acid The tert-butyl ester (367mg, 0.92 mmol) is dissolved in ethyl acetate (10mL), then at ambient temperature, is added into reaction solution The ethyl acetate solution (8mL, 24mmol, 3M) of hydrogen chloride, reactant mixture subtract after room temperature condition stirring reaction 40 hours Pressure concentration, add 26mL water and dissolve residue, gained mixture is extracted with EtOAc/PE (10mL/5mL), and aqueous phase adds carbonic acid Hydrogen sodium powder end is adjusted to pH=8.5, is then extracted again with dichloromethane (75mL × 2), and the organic phase of merging is satisfied with 50mL Washed with salt, with anhydrous sodium sulfate drying, be then concentrated under reduced pressure to give title compound for faint yellow solid (253mg, 92%).

MS(ESI,pos.ion)m/z:300.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.63-7.61(m,2H),7.59-7.51(m,3H),7.47-7.45 (dd, J=6.6,2.5Hz, 1H), 7.28-7.26 (m, 2H), 3.68 (q, J=6.6Hz, 1H), 1.28-1.26 (d, J= 6.6Hz,3H)。

Step 6) (S) -2- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) second Base) chloro- 3- phenylquinazolines -4 (3H) -one of -5-

By chloro- 3- phenylquinazolines -4 (3H) -one of compound (S) -2- (1- amino-ethyls) -5- (35mg, 0.116mmol), the chloro- 5- of 6- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine -4- amine (24.7mg, 0.116mmol), DIPEA (30mg, 0.233mmol) and n-BuOH (1mL) mixture are heated to 125 DEG C of simultaneously stirring reaction 4 hours, then cool down To room temperature, it is concentrated under reduced pressure, gained residue is suspended in ethyl acetate (2mL) and water (2mL), filters, filter cake vacuum is done The dry title compound that obtains is white solid (42mg, 76%).

MS(ESI,pos.ion)m/z:475.0[M+H]⁺；HPLC:99%；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.54(m,1H),8.01(s,1H),7.59-7.45(m,6H),7.33- 7.26(m,1H),6.40 (br.s,2H),5.13(m,1H),2.71(s,3H),1.46(m,3H)。

Embodiment 65 (S) -2- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Ethyl) chloro- 3- phenylquinazolines -4 (3H) -one of -5-

By chloro- 3- phenylquinazolines -4 (3H) -one of compound (S) -2- (1- amino-ethyls) -5- (35mg, 0.116mmol), the chloro- 5- of 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (24.7mg, 0.116mmol), DIPEA (30mg, 0.233mmol) and n-BuOH (1mL) mixture are heated to 125 DEG C of simultaneously stirring reaction 4 hours, then cool down To room temperature, it is concentrated under reduced pressure, gained residue is suspended in EtOAc (2mL) and water (2mL), filters, after filter cake is dried in vacuo It is white solid (25mg, 45%) to obtain title compound.

MS(ESI,pos.ion)m/z:475.0[M+H]⁺；HPLC:98%；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.80-8.78 (d, J=6.9Hz, 1H), 8.03 (s, 1H), 7.66- 7.51 (m, 5H), 7.48-7.43 (m, 2H), 7.35-7.33 (m, 1H), 5.14 (dddd, J=6.4,6.4,6.4,6.4Hz, 1H), 2.52 (s, 3H), 1.46 (d, J=6.7Hz, 3H).

Biologic test

The LC/MS/MS systems of analysis include 1200 serial vacuum degassing furnaces of Agilent, and binary syringe pump, orifice plate is certainly Dynamic sampler, post insulating box, charged spray ionize the Agilent G6430 three-level level Four bar mass spectrographs in (ESI) source.Quantitative analysis Carried out under MRM patterns, the parameter of MRM conversions is as in Table A：

Table A

More reaction detection scannings	490.2→383.1
		Fragmentation voltage	230V
Capillary voltage	55V
		Dryer temperature	350℃
Atomizer	40psi
		Drier flow velocity	10L/min

Analysis uses the Agilent μM posts of XDB-C18,2.1 × 30mm, 3.5, injects 5 μ L samples.Analysis condition：Mobile phase Aqueous formic acid (A) and 0.1% formic acid methanol solution (B) for 0.1%.Flow velocity is 0.4mL/min.Eluent gradient such as table Shown in B：

Table B

Time	The gradient of Mobile phase B
		0.5min	5%
1.0min	95%
		2.2min	95%
2.3min	5%
		5.0min	Stop

In addition, also having the serial LC/MS/MS spectrometers of Agilent 6330 for analysis, noted equipped with G1312A binary Penetrate pump, G1367A automatic samplers and G1314C UV detectors；LC/MS/MS spectrometers use ESI radioactive sources.Use standard Liquid carries out suitable cation model treatment and MRM conversion to each analyte and carries out optimal analysis.Make during analysis With Capcell MP-C18 posts, specification is：100 × 4.6mm I.D., 5 μM (Phenomenex, Torrance, California,USA).Mobile phase is 5mM ammonium acetates, 0.1% methanol aqueous solution (A)：5mM ammonium acetates, 0.1% methanol acetonitrile Solution (B) (70:30, v/v)；Flow velocity is 0.6mL/min；Column temperature is maintained at room temperature；Inject 20 μ L samples.

Embodiment A：Stability of the compound in people and rat liver microsomes

People or rat liver microsomes are placed in polypropylen tubes and are incubated, and guides its duplication.It is typical to be incubated mixed liquor Including people or rat liver microsomes (0.5mg protein/mL), target compound (5 μM) and the NADPH that cumulative volume is 200 μ L (1.0mM) kaliumphosphate buffer (PBS, 100mM, pH value 7.4), compound is dissolved in DMSO, and using PBS by its Dilution, the concentration for making its final DMSO solution are 0.05%.And be incubated in the water-bath communicated at 37 DEG C with air, in advance It is incubated in 3 minutes backward mixed liquors and adds albumen and start to react.At different time points (0,5,10,15,30 and 60min), Add same volume ice-cold acetonitrile terminating reaction.Sample is preserved at -80 DEG C until carrying out LC/MS/MS analyses.

Concentration of the compound in people or rat liver microsomes mixtures incubated is determined by LC/MS/MS method 's.The range of linearity of concentration range is determined by each test-compound.

It is parallel to be incubated experiment and use the microsome being denatured to hatch at 37 DEG C as negative control, react when different Between point (0,15 and 60min) terminate.

Dextromethorphan (70 μ Μ) is used as positive control, hatches at 37 DEG C, react different time point (0,5,10, 15,30 and 60min) terminate.All include positive and negative control sample in each assay method, to ensure that microsome hatches body The integrality of system.In addition, stability data of the compound of the present invention in people or rat liver microsomes also can be by following examination Test to obtain.People or rat liver microsomes are placed in polypropylen tubes and are incubated, and guides its duplication.Typical mixtures incubated bag Include people or rat liver microsomes (ultimate density：0.5mg albumen/mL), compound (ultimate density：1.5 μM) and cumulative volume be 30 μ L K- cushioning liquid (EDTA containing 1.0mM, 100mM, pH 7.4).Compound is dissolved in DMSO, and with K- cushioning liquid Dilution, the ultimate density for making DMSO are 0.2%.After preincubate 10 minutes, 15 μ L NADPH (ultimate densities are added：2mM) carry out Enzymatic reaction, whole experiment are carried out in 37 DEG C of incubation tube.At different time points (0,15,30 and 60 minute), add 135 μ L acetonitriles (containing IS) terminating reaction.Centrifuged 10 minutes with 4000rpm, except deproteinized, collect supernatant liquor, use LC-MS/MS Analysis.

In above-mentioned experiment, ketanserin (1 μM) is selected as positive control, hatches at 37 DEG C, reacts in the different time Point terminates for (0,15,30 and 60 minute).All include positive control sample in each assay method, to ensure that microsome is hatched The integrality of system.

Data analysis

For each reaction, concentration of the compound in people or rat liver microsomes are incubated is pressed (as a percentage) With respect to the plotted as percentage of zero time point, internal liver clearance rate CL is inferred with this_int(ref.:Naritomi Y, Terashita S,Kimura S,Suzuki A, Kagayama A,Sugiyama Y.Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition 2001,29: 1316-1324)。

Stability data of the embodiment of the present invention of table 1 in people and rat liver microsomes

The result of table 1 shows that the compounds of this invention has good stability in the hepatomicrosome of people and rat.

Embodiment B：Pharmacokinetic Evaluation after mouse, rat, dog and monkey injection and oral the compounds of this invention

The present invention is commented pharmacokinetic of the compounds of this invention in mouse, rat, dog or monkey body Estimate.The compounds of this invention is with the aqueous solution or the aqueous solution of 2%HPMC+1% Tween-80s, 5%DMSO+5% saline solution, and 4% MC or capsule form are administered.It is administered for intravenous injection, animal gives 1 or 2mg/kg dosage.For oral dose (p.o.), rat and mouse are 5 or 10 mg/kg, and dog and monkey are 10mg/kg.It is 0.25,0.5,1.0,2.0 at time point, Blood (0.3mL) is taken within 3.0,4.0,6.0,8.0,12 and 24 hours, and is centrifuged 10 minutes under 3,000 or 4,000rpm.Collect blood Solution is starched, and is preserved at -20 DEG C or -70 DEG C until carrying out above-mentioned LC/MS/MS analyses.

Pharmacokinetic data of the embodiment of the present invention of table 2 in rat body

The result of table 2 shows that the compounds of this invention is good in rat body absorption, and half-life period is reasonable.

Embodiment C：Kinase activity assays

The compounds of this invention can be evaluated as the activity of PI3K and mTOR kinase inhibitors by following experiments 's.

The general description of kinase assay

Kinase assay by detect incorporation γ-³³P-ATP myelin basic protein (MBP) is come what is completed.Prepare 20 μ g/ ML MBP (Sigma #M-1891) trishydroxymethylaminomethane buffer salt solutions (TBS；50mM Tris pH 8.0,138mM NaCl, 2.7mM KCl), white 384 orifice plate (Greiner) of high associativity is coated with, per the μ L of hole 60.4 DEG C, it is incubated 24 hours.Afterwards With 100 μ L TBS board-washings 3 times.Kinase reaction is in kinase buffer liquid (the 5mM Hepes pH 7.6,15mM that cumulative volume is 34 μ L NaCl, 0.01% bovine serum albumin(BSA) (Sigma #I-5506), 10mM MgCl₂, 1mM DTT, 0.02%TritonX-100) Middle progress.Compound is dissolved in DMSO, added in each hole, DMSO ultimate density is 1%.Each twice of data determination, The measure of each compound is at least tested twice.For example the ultimate density of enzyme is 10nM or 20nM.Addition does not have markd ATP (10 μM) and γ-³³The ATP of P marks is (per hole 2 × 10⁶Cpm, 3000Ci/mmole) start to react.Reaction is shaken at room temperature Swing and carry out 1 hour.384 orifice plates with 7 × PBS, then add the scintillation solution per the μ L of hole 50.With Wallac Trilux Counter testing result.To those of ordinary skill in the art, this is only one kind in numerous detection methods, others side Method also may be used.

The IC that above-mentioned test method can be inhibited₅₀And/or inhibition constant K_i。IC₅₀It is defined as under test conditions, suppression Make compound concentration during 50% enzymatic activity.The curve for including 10 concentration points is made using 1/2log extension rate, is estimated IC₅₀Value by following compound concentration (for example, make a typical curve：10μM,3μM,1μM,0.3μM,0.1μM,0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM and 0 μM).

The ordinary test scheme of PI3 kinases

PI3K (p110 α/p85 α) (h) [cold test]

PI3K (p110 α/p85 α) (h) is containing 10 μM of phosphoric acid acyl inositol -4,5- diphosphonic acid and MgATP, (concentration is according to need Ask determination) cushioning liquid in be incubated.After adding ATP solution, start to react.After being incubated 30 minutes at room temperature, add thereto Enter the terminate liquid containing EDTA and biotin phosphatidylinositols -3,4,5- triphosphoric acids and carry out terminating reaction.Finally, detection buffering is added Liquid, include the anti-GST monoclonal antibodies of europium mark, the GRP1PH domains and streptavidin-allophycocyanin of GST marks.Orifice plate when Between reading under resolved fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal by equation HTRF=10000 × (Em665nm/Em620nm) determine.

PI3K (p110 β/p85 α) (h) [cold test]

PI3K (p110 β/p85 α) (h) is containing 10 μM of phosphoric acid acyl inositol -4,5- diphosphonic acid and MgATP, (concentration is according to need Ask determination) cushioning liquid in be incubated.After adding ATP solution, start to react.After being incubated 30 minutes at room temperature, add thereto Enter the terminate liquid containing EDTA and biotin phosphatidylinositols -3,4,5- triphosphoric acids and carry out terminating reaction.Finally, detection buffering is added Liquid, include the anti-GST monoclonal antibodies of europium mark, the GRP1PH domains and streptavidin-allophycocyanin of GST marks.Orifice plate when Between reading under resolved fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal by equation HTRF=10000 × (Em665nm/Em620nm) determine.

PI3K (p110 δ/p85 α) (h) [cold test]

PI3K (p110 δ/p85 α) (h) is containing 10 μM of phosphoric acid acyl inositol -4,5- diphosphonic acid and MgATP, (concentration is according to need Ask determination) cushioning liquid in be incubated.After adding ATP solution, start to react.After being incubated 30 minutes at room temperature, add thereto Enter the terminate liquid containing EDTA and biotin phosphatidylinositols -3,4,5- triphosphoric acids and carry out terminating reaction.Finally, detection buffering is added Liquid, include the anti-GST monoclonal antibodies of europium mark, the GRP1PH domains and streptavidin-allophycocyanin of GST marks.Orifice plate when Between reading under resolved fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal by equation HTRF=10000 × (Em665nm/Em620nm) determine.

PI3K (p120 γ) (h) [cold test]

PI3K (p120 γ) (h) is containing 10 μM of phosphoric acid acyl inositol -4,5- diphosphonic acid and MgATP, (concentration is true according to demand It is incubated in cushioning liquid calmly).After adding ATP solution, start to react.After being incubated 30 minutes at room temperature, add contain thereto There are EDTA and the terminate liquid of biotin phosphatidylinositols -3,4,5- triphosphoric acids to carry out terminating reaction.Finally, detection buffer solution is added, Include the anti-GST monoclonal antibodies of europium mark, the GRP1PH domains and streptavidin-allophycocyanin of GST marks.Orifice plate is in the time point Reading under fluorescence mode is distinguished, homogeneous phase time discrimination fluorescence (HTRF) signal is by equation HTRF=10000 × (Em665nm/ Em620nm) determine.

mTOR(h)

MTOR (h) is in the HEPES that 50mM pH value is 7.0,1mM EDTA, 0.01% polysorbas20,2mg/mL substrates, 3mM chlorine Change manganese and [γ-³³P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing. Start to react after adding MnATP mixtures.After being incubated 40 minutes at room temperature, 3% phosphoric acid solution is added thereto and is terminated instead Should.10 μ L reaction solutions are distributed on P30 filters in mottled, and cleaned 3 times in 5 minutes with 75mM phosphoric acid, and dry It is put into methanol solution and preserves at once before dry and scinticounting.

Kinase assay in the present invention be by Millipore companies of Britain come complete (Millipore UK Ltd, Dundee Technology Park, Dundee DD21SW,UK)。

The kinase inhibition data of the embodiment of the present invention of table 3

NT：Represent that sample is not tested

The result of table 3 shows that the compounds of this invention has good selectivity to the different subtype in PI3- kinase families.

The kinase inhibiting activity of the compounds of this invention can also pass through KINOMEscan^TMTest, it is mainly based upon quantitative The part and the experiment of kinases competitive binding ability that determination sample and fixed, active site are oriented to.This is tested complete Into needing to combine following three elements：Kinases, the part and testing sample of fixation of DNA- marks.Testing sample and fixed ligands The ability of competitive binding kinases can be determined by determining the amount of the PCR in DNA marker.

For most of experiments, the T7 phage strains of kinases-mark are the large intestine bars that origin comes from BL21 bacterial strains Bacterium host is prepared.I.e. first by Escherichia coli culture arrive exponential phase, then infected with T7 bacteriophages, and by its Lysate is centrifuged, filtered, removes cell fragment until cracking in 32 DEG C of hatchings under continuous concussion.It is remaining in HEK-293 And then kinases caused by intracellular is marked with DNA, the detection for qPCR.It is coated with magnetic bead and the life of Streptavidin After the smaller ligand of thing elementization reacts 30 minutes at room temperature, the affine resin for kinase assay is generated.The magnetic being coordinated The excessive biotin of integument blocks, with blocking buffer (SEABLOCK^TM(Pierce), 1%BSA, 0.05% Tween-20, 1mM DTT) the free part of washing removing, to reduce non-specific binding.Association reaction is all by kinases, the parent being coordinated Magnetic bead and testing sample with property is in 1 × combination buffer (20%SEABLOCK^TM, 0.17 × PBS, 0.05% Tween-20, 6mM DTT) in complete.All reactions are carried out in 96 orifice plates of the polystyrene that final volume is 0.135mL.The hole of experiment Plate is hatched 1 hour under continuous concussion in room temperature condition, the magnetic bead of compatibility with lavation buffer solution (1 × PBS, 0.05% Tween-20) washing, being then resuspended to elution buffer, (1 × PBS, 0.05% Tween-20,0.5 μM is non-biotinylated affine Property part) in, and hatch 30 minutes in room temperature condition under continuous concussion.Kinase concentration in eluent is determined by qPCR.

Kinase assay in the present invention is by the KINOMEscan of DiscoveRx companies^TMAnalysis Service is completed (42501Albrae St. Fremont,CA 94538,USA)。

In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or the spy for combining the embodiment or example description Point is contained at least one embodiment or example of the present invention.In this manual, to the schematic representation of above-mentioned term not Identical embodiment or example must be directed to.Moreover, specific features, structure, material or the feature of description can be with office Combined in an appropriate manner in one or more embodiments or example.In addition, in the case of not conflicting, the skill of this area Art personnel can be tied the different embodiments or example and the feature of different embodiments or example described in this specification Close and combine.

Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changed, replacing and modification.

Claims (18)

1. a kind of compound, it is the compound or pharmaceutically acceptable salt of structure shown in formula (I),

Wherein, X is

Wherein described X is optionally by 1,2 or 3 R¹Group is substituted,

Y is

Each R¹It independently is H, D, F, Cl, Br, CN, NO₂, oxo (=O) ,-C (=O) R^a,-C (=O) OR^a,-C (=O) NR^aR^b,-OC (=O) NR^aR^b,-OC (=O) OR^a,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-S (=O)₂R^a,-N (R^c) S (=O)₂R^a, OR^a, NR^aR^b, R^aO-C_1-4Alkylidene, R^bR^aN-C_1-4Alkylene Base, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Cycloalkyl or C_3-7Heterocyclic radical；

Each R³And R⁴It independently is H, C_1-6Alkyl, C_2-6Alkenyl or C_2-6Alkynyl；With

Each R^a, R^bAnd R^cIt independently is H, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl or C_3-6Cycloalkyl.

2. compound according to claim 1, wherein each R¹It independently is H, F, Cl, CN, oxo (=O) ,-C (=O) NR^aR^b,-N (R^c) C (=O) NR^aR^b,-N (R^c) C (=O) OR^a,-N (R^c) C (=O) R^a,-S (=O)₂NR^aR^b,-N (R^c) S (=O)₂R^a, OR^a, NR^aR^b, C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, C_3-6Cycloalkyl or C_3-5Heterocyclic radical.

3. compound according to claim 1, wherein each R³And R⁴It independently is H or C_1-3Alkyl.

4. compound according to claim 1, wherein each R^a, R^bAnd R^cIt independently is H, C_1-3Alkyl or C_3-6Cycloalkyl.

5. a kind of compound, there is the compound or pharmaceutically acceptable salt of one of structure：

6. a kind of pharmaceutical composition, it includes the compound described in claim any one of 1-5.

7. pharmaceutical composition according to claim 6, is further included：Pharmaceutically acceptable carrier, excipient, dilution Agent, assistant agent, medium or combinations thereof.

8. the pharmaceutical composition according to claim 6 or 7, further comprising one or more therapeutic agents.

9. prepared by the pharmaceutical composition described in compound or claim any one of 6-8 described in claim any one of 1-5 Purposes in medicine, wherein the medicine is used to protecting, handle, treat or mitigating PI3- kinases exception relevant diseases.

10. purposes according to claim 9, wherein the PI3- kinases exception relevant disease is breathing problem, virus Non-respiratory tract disease caused by infection, anaphylactia, autoimmune disease, inflammatory disease, angiocardiopathy, nerve move back Row disease, pancreatitis, multiple organ failure, nephrosis, platelet aggregation, cancer, sperm motility pathologic is low, graft rejection, Injury of lungs or pain.

11. purposes according to claim 10, wherein the breathing problem includes non-viral breathing problem.

12. purposes according to claim 10, wherein the angiocardiopathy includes malignant hematologic disease.

13. purposes according to claim 10, wherein the graft rejection includes graft rejection.

14. purposes according to claim 9, wherein the PI3- kinase-associated conditions are asthma, chronic obstructive pulmonary disease, Viral respiratory infection, viral respiratory disease deteriorate, aspergillosis, leishmaniasis, allergic rhinitis, allergic skin Inflammation, rheumatic arthritis, multiple sclerosis, inflammatory bowel disease, DVT, atherosclerosis, malignant hematologic disease, nervus retrogression Disease, pancreatitis, multiple organ failure, nephrosis, platelet aggregation, cancer, sperm motility pathologic is low, graft rejection, lung damage Hinder, the pain related to rheumatoid arthritis or osteoarthritis, backache, systemic inflammatorome pain, neuralgia after liver, diabetes Nerve lesion, neuro-inflammatory pain, trigeminal neuralgia or central pain.

15. purposes according to claim 14, wherein the graft rejection includes graft rejection.

16. prepared by the pharmaceutical composition described in compound or claim any one of 6-8 described in claim any one of 1-5 Purposes in medicine, the medicine are used to suppress PI3- kinase activities.

17. purposes according to claim 16, further comprising the compound or power made described in claim any one of 1-5 Profit requires that the pharmaceutical composition described in any one of 6-8 contacts with biological sample.

18. purposes according to claim 16, wherein the PI3- kinases is PI3K δ.