CN105924434A

CN105924434A - Substituted aminopyrimidine compound and usage method and application thereof

Info

Publication number: CN105924434A
Application number: CN201610108890.7A
Authority: CN
Inventors: 习宁; 王亮; 冯学金; 吴双; 张涛; 王婷瑾
Original assignee: Add And Open Up Scientific Co; Guangdong HEC Pharmaceutical
Current assignee: Add And Open Up Scientific Co; Guangdong HEC Pharmaceutical; Calitor Sciences LLC
Priority date: 2015-02-28
Filing date: 2016-02-26
Publication date: 2016-09-07

Abstract

The present invention relates to a substituted aminopyrimidine compound and a usage method and application thereof, and in particular to application of the novel aminopyrimidine compound and free-form salts or pharmaceutically acceptable salts and preparations thereof as the medicaments for the treatment of PI3-kinase abnormality-related disorder or diseases. The invention also relates to the pharmaceutical compositions comprising the compound, and application of the pharmaceutical compositions to the treatment of mammals, particularly for the treatment of PI3-kinase abnormality-related human disorder or diseases, such as treatment of PI3-kinase regulated immune and inflammatory diseases, wherein PI3-kinase plays a major role in leukocyte function, and the treatment of of PI3- kinase-related proliferative diseases including but not limited to leukemia and solid tumors.

Description

Substituted amino-metadiazine compound and using method thereof and purposes

Invention field

The invention belongs to drug world, be specifically related to a class as kinase activity inhibitor noval chemical compound, prepare them Method, the pharmaceutical composition comprising described compound and described compound and pharmaceutical composition in the multiple different diseases for the treatment of Application in disease.More specifically, compound of the present invention can be as phosphoinositide 3-kinase family (PI3- Kinases, PI3Ks, such as PI3K δ, PI3K α, PI3K β and PI3K γ) activity or the inhibitor of function.

Background of invention

Phosphoinositide 3-kinase (PI3-kinases or PI3Ks), as a family of lipid kinase, enters at many cells Journey, such as the survival of cell, plays important regulation effect in breeding and breaking up.As receptor tyrosine kinase (RTKs) and G Major influence factors in the conduction of protein-coupled receptor (GPCRs) downstream, by producing phospholipid, PI3Ks will be from all kinds of growths The signal of factor and the factor is transmitted to intracellular, activate Ser-ine-threonine protein kinase AKT (also referred to as protein kinase B (PKB)) and Other downstream passages.Antioncogene or PTEN (homology phosphatase-tensin) are most important in PI3K signal path Reversely regulator (" Small-molecule inhibitors of the PI3K signaling network. " Future Med.Chem.,2011,3,5,549-565)。

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

To the function of effector enzyme and the relevant signal path in phospholipid of regulation be I class PI3Ks (e.g., PI3K δ, PI3Kdelta), after being activated, membrane phospholipid generates second message,second messenger.I class PI3Ks membrane phospholipid PI (4,5) P2 is converted into as PI (3,4,5) P3 of second message,second messenger.PI and PI (4) P is also the substrate of PI3K, and they can also be phosphorylated and convert respectively For PI3P and PI (3,4) P2.It addition, these phosphoinositides can also pass through 5'-specificity and the catalysis of 3'-specificity phosphatase Effect changes into other phosphoinositides.So, the generation that the activity of PI3K enzyme is direct or indirect two kinds is at Cellular Signaling Transduction Mediated In approach as second message,second messenger 3'-phosphoinositide hypotype (Nature Reviews Molecular Cell Biology, 2010,11,329)。

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

In B and T cell, the PI3Ks Tec family by activator protein tyrosine kinase, there is important function, described family Race includes the Bruton ' s tyrosine kinase (BTK) in B cell and the interleukin-2 in T cell-induction type T-cell kinase (ITK).Once PI3K activates, BTK or ITK transposition is to plasma membrane, and they are subsequently by Src tyrosine phosphorylation there.The ITK activated One of main target be Phospholipase C-gamma (PLC γ 1), PI (4,5) P2 is hydrolyzed to PI (3,4,5) P3 and starts to make cell by it The Protein kinase C diglyceride (DAG) that interior calcium level improves and can activate in the T cell of activation.

PI3K δ kinases is knocked in (knock-in) mice completely and also can be survived, and their phenotype is limited to immunity signal Conduction defect (Okkenhaug et al., Science, 2002,297, p.1031-4).These transgenic mices provide The understanding in depth of PI3K δ function in B-cell and T-cellular signal transduction.Especially, PI3K δ for CD28 PI (3, 4,5) P3 forms downstream and/or φt cell receptor (TCR) signal is required.The important function in the PI3K signal conduction downstream of TCR Being the activation to Akt, it makes the anti-apoptotic factor and the multiple different transcription factor phosphoric acid produced for cytokine Change.As a result, the T cell with inactive PI3K δ lacks in terms of propagation and Th1 and Th2 cytokine secretion.T cell is led to Cross activating of CD28 and reduce value and the persistent period that TCR by the threshold value of antigenic activation and increases breeder reaction.These effects are all It is to include PI3K δ-dependency is increased by the transcribing of IL2 (an important SCIF) being situated between by many genes Lead.

Therefore, the expection of PI3K inhibitor is regulating and respiratory tract disease, such as asthma, COPD and cystic fibrosis via it Effect in the inflammatory reaction cell-mediated for T-of association provides treatment benefit.The therapy that additionally, there are T-cell guiding can There is provided save Corticosteroids (corticosteroid sparing) characteristic instruction (Lancet, 1992,339, p.324- 8), point out itself or as independent (standalone) or with suck or oral glucose corticosteroid merge, it is possible to provide Therapy useful in respiratory tract disease.PI3K inhibitor also can be with other routine treatment, such as long acting beta-2-agonists (LABA) Rise for asthma.

In vascular system, PI3K δ is expressed by endotheliocyte, and by regulating these cells in responding with TNF α Pre-attachment (neutrophil) state participate in neutrophil migration (trafficking) (Blood, 2004,103,9, p.3448).The PI3K δ TNF α at endotheliocyte can be proved by pharmacology's inhibitory action of Akt phosphorylation and PDK1 activity The effect of the signal conduction of induction.It addition, PI3K δ relates to the vascular permeability by VEGF path and air flue tissue edema (Allergy Clin.Immunol.,2006,118,2,p.403).These observations show PI3K δ extra in asthma of suppression Benefit, this benefit is overflowed and vascular permeability minimizing realization by merging the leukocyte associated with asthma.It addition, PI3K δ is active For the mastocyte function of both in vitro and in vivo be need (Nature, 2004,431, p.1007；J.Immunol., 2008,180,4, p.2538), also prompting PI3K suppression should be to anaphylaxis indication, such as asthma, allergic rhinitis and spy Atopic dermatitis is answered to have treatment benefit.

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

The neutrophil cell that the pharmacological inhibitory action suppression fMLP-of PI3K δ the relies on agar glycosyl to ICAM coating The chemotaxis of the deflection system of matter integrin-dependence (Sadhu etc., J.Immunol., 2003,170,5, p.2647-54). PI3K δ suppression regulation neutrophil activation, adhere to and migrate, and do not affect 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, this data display PI3K δ suppression should be unable to suppress the neutrophilia required for defending innate immunity comprehensively Granulocyte function.The PI3K δ treatment that act as in neutrophil cell includes that tissue remodeling is (such as COPD and rheumatism joint Scorching) etc. inflammation disease provide the broader visual field.

PI3K γ has been determined as the medium of the regulation of the G β-γ-dependence of JNK activity, and G β-γ is heterotrimer The subunit of G-protein (heterotrimeric G proteins) (J.Biol.Chem., 1998,273,5, p.2505-8).? Closely, (Laffargue etc., Immunity, 2002,16,3, p.441-51) have been described with PI3K γ by multiple G (i)-coupling Receptor transfer (relays) inflammatory signals (inflammatory signals), and it is to mastocyte function with in vain Stimulus object in cell and immunology context is important, and described stimulus object includes such as cytokine, chemotactic factor, gland Glycosides, antibody, integrin, aggregation factor, somatomedin, 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)。

Being best understood by now, oncogene and the imbalance of tumor suppressor gene, the such as cell by increasing is raw Length and propagation or increase cell survival promote malignant tumor to be formed.Now it is also known that road, the signal mediated by PI3K family is passed Guiding path has important function in the multiple cell processes including propagation and existence, 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)。

It addition, also there is good evidence to show, I class PI3K enzyme facilitates various human cancer the most directly or indirectly Tumor occur (Vivanco and Sawyers, Nature Reviews Cancer, 2002,2,7, p.489-501).Such as, The suppression of PI3K δ is disorderly for hematologic, such as acute myelogenous leukemia have preferable therapeutical effect (Oncogene, 2006,25,50,p.6648-59).Additionally, in p110 α (PIK3CA gene) activated mutant and multiple other different tumor, Such as colon cancer, breast carcinoma and pulmonary carcinoma be associated (Science, 2004,304,5670, p.554；Nature Reviews Cancer,2009,9,551)。

Having had result of study to show, PI3K relates to the central sensitization (central in painful inflammatory diseases Determination sensitization) (J.of Neuroscience, 2008,28,16, p.4261-4270).

Various retrovirus and DNA base activated viral PI3K path, as host during prophylaxis of viral infections The mode of cell death and finally explore for its host cell synthesis mechanism replicated (Virology, 2006,344,1, p.131-8；And Nat.Rev.Microbiol., 2008,6,4, p.265-75).Therefore, PI3K inhibitor is molten except more determine Outside tumor (oncolytic) and anti-inflammation indication, also can have ntiviral characteristic.These antivirus actions cause in virus The prospect that the inflammation of induction is interesting in deteriorating.Such as, common cold ERC group virus (HRV) causes the respiratory tract sense more than 50% Dye, but these complication infected can in some crowd more meaning.This is especially in respiratory tract disease, such as asthma or slow In the case of property obstructive pulmonary disease (COPD) the most such.The rhinovirus infection of epithelial cell cause cell that PI3K relies on because of Son and chemokine secretion (J.Biol.Chem., 2005,280,44, p.36952).This inflammatory reaction breathes disease during infecting The deterioration of shape is correlated with.Therefore, PI3K inhibitor can suppress the immunoreation that (dampen) other benign virus are amplified.Great majority HRV bacterial strain infects bronchial epithelial cell by being initially bound to ICAM-1 receptor.Then, endocytosis is passed through further HRV-ICAM-1 complex is included in intracellular (internalised) and to have shown that PI3K activity is had by this measure required (J.Immunol.,2008,180,2,p.870-880).Therefore, PI3K inhibitor also can be by suppression cell entry host cell And stop virus infection.

PI3K inhibitor can be used for reducing other type of respiratory infections, including fungal infection aspergillosis (Mucosal Immunol.,2010,3,2,p.193-205).It addition, the mice that PI3K δ lacks is to by the very large Li Shiman of protozoon parasite The infection of protozoon (Leishmania.major) have higher resistance (J.Immunol., 2009,183,3, p.1921- 1933).In view of the effect infecting virus, these report prompting PI3K inhibitor can be used for treating various infection.

Research shows, PI3K suppression also can promote regulatory T cells differentiation (Sauer etc., Proc.Natl.Acad.Sci.USA, 2008,105,22, p.7797-7802), prompting PI3K inhibitor can in autoimmune or In anaphylaxis indication, by induction to the former immunologic tolerance of autoantigen or anaphylaxis for therapeutic purposes.Closely Phase, the glucocorticoid insensitive association (Am.J.Respir.Crit.Care that PI3K δ hypotype has the most been induced with smoking Med.,2009,179,7,p.542-548).This research display COPD patient, it is differently to glucocorticoid response not Good, benefit can be obtained from the combination with glucocorticoid of the PI3K inhibitor.

PI3K also has been directed to other respiratory tract disease, such as idiopathic pulmonary fibrosis (IPF).IPF is fibre modification disease Disease, increases with Progressive symmetric erythrokeratodermia decreased lung function and the mortality rate caused due to respiratory failure.In IPF, Circulating fibrocyte (circulating fibrocytes) guides pulmonary via Chemokine receptor CXCR4.PI3K conducts for the signal of CXCR4 The most required with expression (Int.J.Biochem.and Cell Biol., 2009,41, p.1708-1718).Therefore, Expressing by reducing CXCR4 and block its effector functions, PI3K inhibitor can suppress fibrocyte to raise to pulmonary and thus Slow down fibrotic processes based on IPF, the disease of a kind of height not met Treatment need.

PI3K α and Ρ Ι 3 Κ β is in the homeostasis maintaining the molecular target relevant to cancer and drug inhibition There is indispensable effect (Maira etc., Expert Opin.Ther.Targets, 2008,12,223).

PI3K α also conducts and molecular growth path-dependent (Nature, 2006,441,366) with the signal of insulin.ΡΙ3 The selective inhibitory of Κ δ hypotype is expected to be avoided that the side effect that some are potential, such as hyperglycemia and metabolism or growth failure.

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

PI3K δ-selective depressant is described the most.Most selective compound includes quinolinone purine inhibitors (PIK39 and IC87114), IC87114 is at high nanomolar range (three figure places) upper suppression PI3K δ, and has PI3K δ and be more than The selectivity of 100 times, has 52 times of selectivitys, but PI3K γ is lacked selectivity (about 8 times) PI3K β.It is to test Any protein kinase do not show activity (Cell, 2006,125,733-747).Use PI3K δ-alternative cpd or heredity Gene Handling mice (PI3K δ^D910A) prove, in addition to playing a crucial role in B and t cell activation, PI3K δ also relates in part to Neutrophil migration and sensitization neutrophil are breathed, and cause the part of mastocyte threshing that antigen-IgE mediates Block (Blood, 2005,106,1432-1440；Nature,2002,431,1007-1011).Therefore, PI3K δ is as a lot The important medium of critical inflammatory reaction occurs, described inflammatory reaction it is known that participation abnormal inflammatory disease, includes but not limited to Autoimmune disease and anaphylaxis.In order to support this viewpoint, create not from the experiment using Genetic tools and medicament Disconnected increase 1) PI3K δ verifies data.Therefore, PI3K δ alternative cpd IC87114 and PI3K δ is used^D910AMice, Ali etc. People (Nature, 2002,431,1007-1011) has turned out PI3K δ and plays a crucial role in the mouse model of anaphylactic disease. In the case of there is not function δ, passive cutaneous anaphylaxis, PCA (PCA) substantially reduces, and can lure owing to antigen-IgE The mast cells activation led and the minimizing of threshing.It addition, the mice mould of the asthma at the airway inflammation using ovalbumin induction In type, have been demonstrated to significantly improve inflammation (FASEB, 2006,20:455-465) with IC87114 suppression δ.The use of different groups In the same model of quick airway inflammation, utilize these data of compound at PI3K δ^D910AMutant mice is mutually authenticated (Eur.J.Immunol.,2007,37,416-424)。

Need to be provided as the new PI3K inhibitor of good drug candidate.Specifically, preferred compound should be with PI3K receptor combines effectively, other receptor demonstrates affinity simultaneously hardly, and demonstrates the function as agonist Activity.This compound should be fully absorbed by gastrointestinal tract, metabolic stability and have good pharmacokinetic property.When targeting maincenter During receptor in nervous system, they can freely pass through blood brain barrier, and when selectivity targets in peripheral nervous system Receptor time, they would not pass through blood brain barrier.They are answered avirulence and show few side effect.Additionally, described ideal Drug candidate should exist with the physical form of stable, non-hygroscopic and easily preparation.The compounds of this invention demonstrates specific water The flat PI3K α for different paralogous (paralogs), beta, gamma and the selectivity of δ.Particularly, specified level is demonstrated The selectivity for Ρ Ι 3 Κ δ.

Abstract of invention

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

The invention still further relates to be used alone or in combination the Therapeutic Method of other one or more pharmaceutical active compounds, this is controlled Treatment method includes the treatment of following disease or obstacle, and respiratory tract disease, including asthma, chronic obstructive pulmonary disease (COPD) and spy The property sent out pulmonary fibrosis (IPF)；Virus infects, and deteriorates including viral respiratory tract infection and viral respiratory disease, such as roars Breathe heavily and COPD；Non-viral respiratory tract infection, including aspergillosis and leishmaniasis；Anaphylactic disease, including allergic rhinitis and spy Answer atopic dermatitis；Autoimmune disease, including rheumatoid arthritis and multiple sclerosis；Inflammatory diseases, including inflammatory Enteropathy；Cardiovascular disease, including thrombosis and atherosclerosis (Future Med.Chem., 2013,5,4,479 492； Biochemical Society Transactions,2004,32,378)；Malignant hematologic disease；Neurodegenerative diseases；Pancreas Scorching；Multiple organ failure, MOF；Nephropathy；Platelet aggregation；Cancer；Motility of sperm is abnormal；Transplant rejection；Transplant rejection；Injury of lung；With Pain, including neuralgia after the pain relevant to rheumatoid arthritis or osteoarthritis, backache, systemic inflammatorome pain, liver, Diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia and central pain；Malignant hematologic disease, bag Including acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myelognous is white Disorders of blood (CML), T cell acute lymphoblastic leukemia (T-ALL), B cell acute lymphoblastic leukemia (B-ALL), non-suddenly Strange gold lymphoma (NHL), B cell lymphoma, solid tumor (e.g., breast carcinoma).

The invention discloses a class noval chemical compound and can serve as PI3-kinase activity especially as kinase activity inhibitor Inhibitor.Compound as PI3-inhibitors of kinases can be used for treating the abnormal disease caused of kinases, and particularly PI3-swashs The abnormal disease caused of enzyme, such as treating and preventing by the disease of PI3-kinases mechanisms mediate.It should be noted that it is described Kinases is abnormal includes that abnormal kinase and/or kinase expression are 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 infects, including viral breathing Road infects and viral respiratory disease deteriorates, such as asthma and COPD；Non-viral respiratory tract infection, including aspergillosis and Li Shi Graceful disease；Allergic diseases, including allergic rhinitis and atopical dermatitis；Autoimmune disease, including rheumatoid Arthritis and multiple sclerosis；Inflammatory diseases, including inflammatory bowel；Cardiovascular disease, including thrombosis and atherosclerosis； Malignant hematologic disease；Neurodegenerative diseases；Pancreatitis；Multiple organ failure, MOF；Nephropathy；Platelet aggregation；Cancer；Motility of sperm is different Often；Transplant rejection；Transplant rejection；Injury of lung；And pain, including the pain relevant to rheumatoid arthritis or osteoarthritis Bitterly, neuralgia after backache, systemic inflammatorome pain, liver, diabetic neuropathy, neuro-inflammatory pain (wound), three Fork neuralgia and central pain.

In some embodiments, the compounds of this invention shows that selectivity kinase whose to PI3-exceedes other kinases.

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

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

On the one hand, the present invention relates to a kind of compound, it is compound or its stereoisomer of one of, mutually Tautomeric, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug:

On the one hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises above-claimed cpd of the present invention.? In some embodiments of the present invention, described compound comprises pharmaceutically acceptable carrier further, excipient, diluent, Adjuvant, vehicle, or combinations thereof.In some embodiments, the pharmaceutical composition that the present invention provides comprises one further Plant or multiple therapeutic agent.In other embodiments, pharmaceutical composition can be liquid, solid, semi-solid, gel or spray Mist dosage form.

On the other hand, the invention provides above-claimed cpd or the aforementioned pharmaceutical compositions purposes in preparing medicine, its Described in medicine be used for protecting, process, treat or alleviate PI3-kinases exception relevant disease.

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 respiratory tract disease, sick Poison infects, non-viral respiratory tract infection, anaphylactic disease, autoimmune disease, inflammatory diseases, cardiovascular disease, pernicious blood Liquid is sick, neurodegenerative diseases, pancreatitis, multiple organ failure, MOF, nephropathy, platelet aggregation, cancer, and motility of sperm is abnormal, transplants Repel, transplant rejection, injury of lung and pain.

In other embodiments, PI3-kinases exception relevant disease of the present invention is asthma, chronic obstruction Property pneumonopathy (COPD), viral respiratory tract infection, viral respiratory disease deteriorate, aspergillosis, leishmaniasis, allergia nose Inflammation, allergic dermatitis, rheumatic arthritis, multiple sclerosis, inflammatory bowel, thrombosis, atherosclerosis, hematologic Disease, neurodegenerative diseases, pancreatitis, multiple organ failure, MOF, nephropathy, platelet aggregation, cancer, motility of sperm is abnormal, the row of transplanting Scolding, transplant rejection, injury of lung, the pain relevant to rheumatoid arthritis or osteoarthritis, backache, systemic inflammatorome aches Bitterly, neuralgia after liver, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia and central pain.

On the other hand, the invention provides above-claimed cpd or the aforementioned pharmaceutical compositions purposes in preparing medicine, its Described in medicine for inhibition of phosphatidylinositol3-3 kinases (PI3-kinases) activity, including: make the basis of PI3-kinases and effective dose Compound disclosed in invention or pharmaceutical composition thereof of the present invention；In some embodiments, contact procedure can be entered One step includes that the kinase whose cell of PI3-is expressed in contact；In the other embodiment of the method, inhibitory action occurs standing In the object of one or more type PI3-kinases obstacle relevant diseases.One or more types PI3-involved in the present invention swash Enzyme the most relevant abnormal disease includes autoimmune disease, rheumatic arthritis, respiratory system disease, anaphylactic reaction and various The cancer of type.

In some embodiments, the method that the present invention relates to includes using study subject the second therapeutic agent.

In other embodiments, PI3-kinases exception relevant disease be 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 cardiovascular disease, atherosclerosis, hypertension, venous thrombosis, apoplexy, cardiac muscle stalk Plug, unstable angina, thromboembolism, pulmonary infarction, thrombolytic disease, Acute arterial ischeamia, peripheral thrombus obstruction and coronary artery Disease.In other embodiments, PI3-kinases exception relevant disease is selected from cancer, colon cancer, glioblastoma, endometrium Cancer, hepatocarcinoma, pulmonary carcinoma, melanoma, renal carcinoma, thyroid carcinoma, lymphoma, lymphoproliferative disorder, small cell lung cancer, squamous cell Pulmonary carcinoma, glioma, breast carcinoma, carcinoma of prostate, ovarian cancer, cervical cancer and leukemia.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 Therapeutic Method of PI3-kinase mediated disease, described Therapeutic Method includes using this The step that 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, described treatment includes using the compounds of this invention or medicine group The step that compound is administered.

On the other hand, the present invention relates to include asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) treatment of respiratory tract disease such as, described treatment includes the step using the compounds of this invention or pharmaceutical composition to be administered Suddenly.

On the other hand, the present invention relates to inflammatory bowel, inflammatory ocular disease, inflammation or unstable bladder disease, The dermatosis of inflammatory component, chronic inflammatory disease, systemic lupus erythematosus (sle) (SLE), myasthenia gravis, acute disseminated encephalomyelitis, Idiopathic blood platelet minimizing property purpura, multiple sclerosis, Sjogren syndrome and autoimmune hemolytic anemia, mistake Quick property and the treatment of pleoergy disease, described treatment includes the step using the compounds of this invention or pharmaceutical composition to be administered Suddenly.

On the other hand, involved in the present invention mediated by PI3K activity, depend on PI3K activity or relevant to PI3K activity The treatment of cancer, the activity of especially PI3K δ, described treatment includes being administered the compound of any of above and following embodiment Step.

On the other hand, the present invention relates to the Therapeutic Method selected from following cancer: acute myelogenous leukemia, spinal cord development is different Often syndrome, myeloproliferative disease, chronic lymphocytic leukemia, T cell acute lymphoblastic leukemia, B cell acute lymphoblastic is thin Born of the same parents' leukemia, non-Hodgkin lymphoma, B cell lymphoma, solid tumor and breast carcinoma, described Therapeutic Method includes using the present invention The step that 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 present invention relates to the compounds of this invention answering in terms of the medicine that preparation treatment PI3K is disease mediated With.

On the other hand, the present invention relates to the compounds of this invention and preparing treatment rheumatoid arthritis, ankylosing spondylitis, Osteoarthritis, psoriatic arthritis, psoriasis, diseases associated with inflammation, including asthma, chronic obstructive pulmonary disease (COPD) and special Respiratory tract disease, autoimmune disease and the application of cancer aspect medicine such as property pulmonary fibrosis (IPF).

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

In some embodiments, described salt refers to pharmaceutically acceptable salt.Term " pharmaceutically acceptable " refers to Material or compositions must be with other compositions and/or with its mammal treated chemically and/or toxicology comprising preparation Upper compatible.

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

The compounds of this invention, include that its salt can also obtain with its hydrate forms, or include that other crystallize for it Solvent.The compounds of this invention inherently or can have the solvate of acceptable solvent (including water) by design forming； Therefore, present invention additionally comprises its solvation and unsolvated form.

On the other hand, the invention provides the preparation of compound disclosed in this invention, separate and the method for purification.This Bright compound may comprise several asymmetric center or the form of its most described raceme mixture.The present invention is also Comprise enantiomer and the diastereomer of racemic mixture, partial racemic compound and isolated further.

The compounds of this invention can be with in possible isomer, rotamer, atropisomer, tautomer Presented in the form of kind or its mixture, the present invention can comprise the isomer of the compounds of this invention, rotational isomeric further Body, atropisomer, the mixture of tautomer, or isomer, rotamer, atropisomer, tautomer Part mixes or separated open isomer, rotamer, atropisomer, tautomer.

On the other hand, compound of the present invention includes using chemical combination defined in the various isotope-labeled present invention , such as, wherein there is radiosiotope in thing, as³H,¹⁴C and¹⁸Those compounds of F, or wherein there is on-radiation coordination Element, as²H and¹³The compound of C.

On the other hand, the method that the present invention relates to the preparation of compound disclosed in this invention, separation and purification.

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspects and 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 list the document corresponding to the content of the materialization determined in detail, and embodiment is all attended by structure Formula and the diagram of chemical formula.The present invention has and expectedly contains all of choice, variant and coordinate, and these may be as right Existing invention field it is included in like that defined in requirement.Those skilled in the art will identify many similar or equivalent to This described method and material, these can apply in the practice of the present invention.The present invention is limited to absolutely not method and material Description.Have a lot of document and similar material distinguish with the present patent application or conflict, including but be not limited to term Definition, 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 Conventional understand that there is identical implication, unless otherwise noted, public in all patents cited in the open full content of the present invention Open publication and be integrally incorporated the present invention by reference.

The present invention by defined below for application unless other aspects show.According to the purpose of the present invention, chemical element is according to unit Element periodic chart, CAS version and chemical drugs handbook, 75,^thEd, 1994 define.It 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 of content of the present invention has all merged list of references.

Term used in the present invention " study subject " refers to animal.The most described animal is mammal.Tested right As also referring to primate (such as people), cattle, sheep, goat, horse, Canis familiaris L., cat, rabbit, rat, mice, fish, bird etc..At some In embodiment, described study subject is primate.In additionally other embodiments, described study subject is people.

Term used in the present invention " patient " refers to people's (including adult and child) or other animals.Implement at some In scheme, " patient " refers to people.

Present invention additionally comprises isotope-labeled the compounds of this invention, its in addition to following facts with of the present invention those Compound is identical: one or more atoms are different from the former of natural common atomic quality or mass number by atomic mass or mass number Filial generation is replaced.Also can introduce the Exemplary isotopes in the compounds of this invention and include the coordination of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine Element, as²H,³H,¹³C,¹⁴C,¹⁵N,¹⁶O,¹⁷O,³¹P,³²P,³⁶S,¹⁸F and³⁷Cl。

Comprise other isotopic the compounds of this invention of aforementioned isotopes and/or other atoms and described compound Pharmaceutically acceptable salt is included within the scope of the present invention.Isotope-labeled the compounds of this invention, such as radioactivity coordination Element, as³H and¹⁴C is incorporated in the compounds of this invention and can be used for medicine and/or substrate tissue distributional analysis.Due to easily prepared with And detection, tritium generation, i.e.³H, and carbon-14, i.e.¹⁴C, isotope is particularly preferred.Additionally, with the isotope of weight, such as deuterium, i.e.²H Replace, it is possible to provide some advantages being derived from the treatment of bigger metabolic stability, the Half-life in vivo such as increased or minimizing Volume requirements.Therefore, it is probably in some cases preferably.

The Stereochemical definitions of present invention use and convention 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 stands with different Body isomeric form exists.It is expected that all stereoisomeric forms in any ratio of the compounds of this invention, include but not limited to that diastereomeric is different Structure body, enantiomer and atropisomer (atropisomer) and their mixture such as racemic mixture, be also contained in Within the scope of the invention.Many organic compound exist with optical active forms, and i.e. they have the plane making linearly polarized light The ability rotated.When description has optically active compound, prefix D and L or R and S is used to represent with regard in molecule Chiral centre (or mulitiple chiral centers) for the absolute configuration of molecule.Prefix d and l or (+) and (-) are for specifying chemical combination Caused by thing linearly polarized light rotate symbol, wherein (-) or l represent that compound is left-handed.Prefix be (+) or the compound of d It is dextrorotation.For given chemical constitution, in addition to these stereoisomers mirror image each other, these stereoisomers are phases With.Concrete stereoisomer is alternatively referred to as enantiomer, and the so-called mapping of mixture of described isomer is different The mixture of structure body.The 50:50 mixture of enantiomer is referred to as racemic mixture or racemic modification, when at chemical reaction or When method does not has stereo selectivity or stereospecificity, may occur in which described racemic mixture or racemic modification.

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

The compounds of this invention can contain asymmetric center or chiral centre, therefore deposits with different stereoisomer forms ?.It is expected that all stereoisomer forms of the compounds of this invention, include but not limited to diastereomer, mapping Isomer and atropisomer (atropisomer) and geometry (or conformation) isomer and their mixture, as raceme mixes Compound, the most within the scope of the present invention.

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

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

" nitrogen oxides " used in the present invention refers to when compound is containing several amine functional group, can be by 1 or more than 1 Nitrogen-atoms oxidation formed N-oxide.The particular example of N-oxide is N-oxide or the nitrogen heterocyclic ring nitrogen-atoms of tertiary amine N-oxide.Available oxidant example, forms N-oxide as hydrogen peroxide or peracid (such as peroxycarboxylic acid) process corresponding amine (seeing Advanced Organic Chemistry, Wiley Interscience, the 4th edition, Jerry March, pages). Especially, N-oxide can be prepared (Syn.Comm.1977,7,509-514) by the method for L.W.Deady, the most such as lazy In property solvent, such as dichloromethane, amines is made to react with m-chlorine benzylhydroperoxide (MCPBA).

" solvate " of the present invention refers to the association that the compound of one or more solvent molecule and the present invention is formed Thing.The solvent 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 complex that water is formed.

" metabolite " refers to that concrete compound or its salt is in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention Adopt as stating and experimentally characterize.Such product can be by passing through oxidation, reduction, water to drug compound Solving, amidated, desamido-effect, esterification, degreasing, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes compound Metabolite, be fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.

" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention.Medicine On, acceptable salt is known to us at art, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. it is 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 hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Additive method such as ion exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, alginate, resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, Camphora sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalene sulphur Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionic acid salt, bitterness Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that suitable 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 the group of comprised N is formed.Water solublity 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 farther includes to fit When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenide, hydroxide, carboxylate, sulphuric acid Compound, phosphoric acid compound, nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

Term used in the present invention " prodrug ", represents a compound and is converted into chemical combination disclosed in this invention in vivo Thing.Such conversion is hydrolyzed in blood by prodrug or is that precursor structure is affected through enzymatic conversion in blood or tissue. Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, fat as prodrug Fat race (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention One compound comprises hydroxyl, i.e. can be acylated the compound obtaining prodrug form.Other prodrug form It is that the di on parent obtains including phosphate ester, such as these phosphate compounds.Complete about prodrug Discussion be referred to documents below: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.14 of 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 (such as, carbon etc.) of the compounds of this invention can be enriched with raceme or enantiomer Formula exists, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom (R)- Or (S)-configuration aspect has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, extremely Few 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. If it would be possible, the substituent group having on the atom of unsaturated double-bond can be deposited with cis-(Z)-or trans-(E)-form ?.

Therefore, as described in the present invention as, the compound of the present invention can be with possible isomer, rotational isomeric Presented in a kind of form in body, atropisomer, tautomer or its mixture, the purest geometry (cis or trans) isomer, diastereomer, optical isomer (enantiomer), racemic modification or its form of mixtures.

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

By known method, the racemic modification of any gained end-product or intermediate can be passed through those skilled in the art The method being familiar with splits into optical antipode, e.g., by separating its diastereoisomeric salt obtained.Racemic product Thing can also be separated by chiral chromatogram, e.g., uses the high pressure liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomer can prepare (e.g., Jacques, et al., Enantiomers, Racemates and by asymmetric synthesis 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, the compound of the present invention can optionally be replaced by one or more substituent groups, as General formula compound above, or as example special inside embodiment, subclass, and the compounds that the present invention is comprised. Should be appreciated that " optionally substituted " this term and " substituted or non-substituted " this term can exchange use.Term is " optionally Ground ", " optional " or " optionally " refer to subsequently described in event or situation can but may not occur, and this description includes wherein There is the situation of this event or situation, and the situation of this event or situation does not wherein occur.It is said that in general, term " optionally " Whether, before being positioned at term " substituted ", all represent that the one or more hydrogen atoms in given structure are by concrete substituent group institute Replace.Unless other aspects show, an optional substituted radical can replace in each commutable position of group.When In given structural formula, more than one position can be selected from one or more substituent groups of concrete group and replaced, then replacement Base can replace in each position identical or differently.Wherein said substituent group it may be that but be not limited to, D, F, Cl, Br, CN, N₃, OH, NH₂, NO₂, oxo (=O) ,-C (=O) OCH₃,-C (=O) NH₂,-OC (=O) NH₂,-NHC (=O) NH₂,-NHC (=O) OCH₃,-OCH₃,-NH₂, CH₃O-C_1-4Alkylidene, H₂N-C_1-4Alkylidene, C_1-6Alkyl, C_3-6Cycloalkyl, C_3-6Cycloalkyl- C_1-4Alkylidene, or C_6-10Aryl.

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

At each several part of this specification, the come into the open substituent group of compound of the present invention is open according to radical species or scope.Special Not pointing out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.Such as, term “C_1-6Alkyl " refer in particular to individually disclosed methyl, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

At each several part of the present invention, describe connection substituent group.When this structure clearly needs linking group, for this Ma Kushi variable cited by group is interpreted as linking group.Such as, if this structure needs linking group and for this The Ma Kushi group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively The alkylidene group connected or arylene group.

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

The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), n-pro-pyl (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 group (-CH (CH₃)CH₂CH₂CH₃), 3-amyl group (-CH (CH₂CH₃)₂), 2-methyl-2-butyl (-C (CH₃)₂CH₂CH₃), 3-methyl-2-butyl (-CH (CH₃)CH(CH₃)₂), 3-methyl isophthalic acid-butyl (-CH₂CH₂CH(CH₃)₂), 2-first Base-1-butyl (-CH₂CH(CH₃)CH₂CH₃), n-hexyl (-CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (-CH (CH₃) CH₂CH₂CH₂CH₃), 3-hexyl (-CH (CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-amyl group (-C (CH₃)₂CH₂CH₂CH₃), 3-first Base-2-amyl group (-CH (CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-amyl group (-CH (CH₃)CH₂CH(CH₃)₂), 3-methyl-3-penta Base (-C (CH₃)(CH₂CH₃)₂), 2-methyl-3-amyl group (-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 said Alkyl group can be the most unsubstituted or replaced by one or more substituent groups described in the invention.

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

Term " alkylidene " represents remove obtained by two hydrogen atoms from the saturated hydrocarbyl of straight or branched saturated 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, alkylidene group contains 1-4 carbon atom, and other is real Executing example is, alkylidene group contains 1-2 carbon atom.Such example includes methylene (-CH₂-), ethylidene (-CH₂CH₂-), Isopropylidene (-CH (CH₃)CH₂-) etc., wherein said alkylidene group can be the most unsubstituted or one or more Substituent group described in the invention is replaced.

Term " cycloalkyl " refers to that one or more junction point is connected to the remainder of molecule, saturated, containing 3- The monocycle of 12 carbon atoms, dicyclo or three-ring system.Some of them embodiment, cycloalkyl is the ring body containing 3-10 carbon atom System；Other embodiment, cycloalkyl is the member ring systems containing 3-8 carbon atom；Other embodiment, cycloalkyl is containing 3-6 The member ring systems of individual carbon atom；Other embodiment, cycloalkyl is the member ring systems containing 5-6 carbon atom；And described cycloalkyl base Group can be the most unsubstituted or replaced by one or more substituent groups described in the invention.

Term " cycloalkyl alkylidene " represents that alkyl group can be replaced 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 them embodiment is, cycloalkyl alkylidene group refers to " relatively Rudimentary cycloalkyl alkylidene " group, i.e. group of naphthene base be 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 does not limit In, cyclopropylethyl, cyclopentyl-methyl, cyclohexyl methyl etc..Described cycloalkyl alkylidene group can not taken Generation or replaced by one or more substituent groups described in the invention.

Term " n former molecular ", wherein n is integer, typically describes the number of ring member nitrogen atoms in molecule, described In molecule, the number of ring member nitrogen atoms is n.Such as, piperidyl is 6 former molecular Heterocyclylalkyls, and 1,2,3,4-tetralyl It is 10 former molecular carbocylic radical groups.

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

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

Term " aryl " can be used alone or as " aralkyl ", the big portion of the one of " aralkoxy " or " aryloxy alkyl " Point, represent containing 6-14 annular atoms, or 6-12 annular atoms, or the monocycle of 6-10 annular atoms, dicyclo, and the carbocyclic ring of three rings System, wherein, at least one member ring systems is aromatic, and each of which member ring systems comprises 3-7 former molecular ring, and has One or more attachment points are connected with the remainder of molecule.Term " aryl " can use with term " aromatic rings " exchange, as Aromatic rings can include phenyl, naphthyl and anthryl.Described aromatic yl group can be the most unsubstituted or by one or more Substituent group described by invention is replaced.

As described in the invention, substituent group draws the member ring systems formed on a ring being bonded the center of receiving (such as formula a institute Show) represent substituent group any commutable position on ring and can replace.Such as, formula a represents and any on A ring may be replaced Position, as shown in formula b-1, b-2 and b-3:

The term " undersaturated " used in the present invention represents in group containing one or more degrees of unsaturation.

It is open language that term " comprises ", i.e. includes the content specified by the present invention, but is not precluded from otherwise Content.

As described herein, term " pharmaceutically acceptable carrier " includes any solvent, disperse medium, coating agents, Surfactant, antioxidant, preservative (such as antibacterial agent, antifungal), isotonic agent, salt, drug stabilizing agent, bonding Agent, dispersant, lubricant, sweeting agent, flavoring agent, coloring agent, or a combination thereof thing, these carriers are all art technology Personnel's is known (such as Remington's Pharmaceutical Sciences, 18th Ed.Mack Printing Company, described in 1990, pp.1289-1329).Except in the case of any conventional carrier and active component are incompatible, contain Its purposes in treatment or pharmaceutical composition.

" therapeutically effective amount " of term the compounds of this invention refers to cause biology or medicinal response, the example of study subject As reduced or inhibitory enzyme or protein active or improve symptom, relax condition of illness, slow down or delay progression of disease or prevention disease etc. The amount of used the compounds of this invention.In some non-limiting embodiments, term " therapeutically effective amount " refers to when being applied to The amount of the compounds of this invention effective to the following used during study subject: (1) is at least partly relaxed, suppresses, prevented And/or improve (i) by PI3K imbalance mediation or (ii) is relevant with PI3K activity or (iii) is characterized with PI3K activity disease Suffer from or disease or disease；Or (2) alleviate or suppress PI3K activity.In other non-limiting embodiments, " treatment has term Effect amount " refer to, when being applied to cell or tissue or non-cellular biological material or medium, at least partly alleviate disease or suppression The amount of the effective the compounds of this invention of PI3K；Or alleviate disease or the activity of suppression PI3K the most to a certain extent.Term " therapeutically effective amount " is except being used for illustrating the content of the embodiments above about PI3K, it is also possible to application is taken office in the same manner Protein/polypeptide/enzyme that what he is correlated with.

Any disease or disease " treated " in term as used in the present invention, and some embodiment middle fingers improve disease wherein Disease or disease (i.e. slow down or stop or palliate a disease or the development of its at least one clinical symptoms).In other embodiments In, " treatment " refers to relax or improve at least one body parameter, including the body parameter may not discovered by patient.At another In a little embodiments, " treatment " refers to (such as stablize perceptible symptom) from health or physiologically (such as stablize health Parameter) or above-mentioned two aspect regulation disease or diseases.In other embodiments, " treat " and refer to prevention or postpone disease or disease The outbreak of disease, occur or deteriorate.

The when that term " blocking group " or " PG " referring to a substituent group and other reacted with functional groups, it is commonly used to resistance Disconnected or protect special functional.Such as, " blocking group of amino " refers to that a substituent group is connected with amino group and blocks Or amino functional in protection compound, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenes Asia methoxycarbonyl group (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent group of base is used for blocking or protect the functional of hydroxyl, suitable blocking group to include acetyl group and silicyl." carboxyl Blocking group " refer to the substituent group of carboxyl for blocking or protect the functional of carboxyl, general carboxyl-protecting group includes- CH₂CH₂SO₂Ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxyl methyl, 2-is (to toluene Sulfonyl) ethyl, 2-(p-nitrophenyl sulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The description that group is 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 the compound that a class is new, PI3-kinases can be can serve as especially as kinase activity inhibitor The inhibitor of activity.Compound as PI3-inhibitors of kinases can be used for treatment with kinases extremely, and particularly PI3-kinases is different The most relevant disease, such as treating and preventing by the disease of PI3-kinases mechanisms mediate.Such disease include with down to One of few: respiratory tract disease, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF)；Virus sense Dye, deteriorates including viral respiratory tract infection and viral respiratory disease, such as asthma and COPD；Non-viral respiratory tract sense Dye, including aspergillosis and leishmaniasis；Allergic diseases, including allergic rhinitis and atopical dermatitis；Autoimmune Property disease, including rheumatoid arthritis and multiple sclerosis；Inflammatory diseases, including inflammatory bowel；Cardiovascular disease, including blood Bolt disease and atherosclerosis；Malignant hematologic disease；Neurodegenerative diseases；Pancreatitis；Multiple organ failure, MOF；Nephropathy；Platelet aggregation Collection；Cancer；Motility of sperm is abnormal；Transplant rejection；Transplant rejection；Injury of lung；And pain, including with rheumatoid arthritis or Neuralgia, diabetic neuropathy, neuro-inflammatory after pain that osteoarthritis is relevant, backache, systemic inflammatorome pain, liver Property pain (wound), trigeminal neuralgia and central pain.

In some embodiments, the compounds of this invention can show that selectivity kinase whose to PI3-exceedes other type and swash Enzyme.

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

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

On the other hand, the invention provides the above-claimed cpd of the present invention purposes in preparing medicine, wherein said medicine For inhibition of phosphatidylinositol3-3 kinases (PI3-kinases) activity, including: make the presently disclosed of PI3-kinases and effective dose Compound contact；In some embodiments, contact procedure can farther include contact and express the kinase whose cell of PI3-；The party In the other embodiment of method, inhibitory action occurs standing one or more type PI3-kinases obstacle relevant diseases In object.The abnormal relevant disease of one or more type PI3-kinases involved in the present invention includes autoimmune disease, Rheumatic arthritis, respiratory system disease, anaphylactic reaction and various types of cancer.

In some embodiments, the method that the present invention relates to includes object administering therapeutic agent.

In other embodiments, disease kinase mediated for PI3-is selected from rheumatic arthritis, ankylosing spondylitis, bone At least one in arthritis, psoriatic arthritis, psoriasis, diseases associated with inflammation and autoimmune disease；Other are implemented In scheme, disease kinase mediated for PI3-be selected from cardiovascular disease, atherosclerosis, hypertension, venous thrombosis, in Wind, myocardial infarction, unstable angina, thromboembolism, pulmonary infarction, thrombolytic disease, Acute arterial ischeamia, peripheral thrombus obstruction and At least one in coronary artery disease.In other embodiments, the disease selected from cancer that PI3-is kinase mediated, colon cancer, Glioblastoma, carcinoma of endometrium, hepatocarcinoma, pulmonary carcinoma, melanoma, renal carcinoma, thyroid carcinoma, lymphoma, lymphoproliferative disorder, In small cell lung cancer, prognosis of squamous cell lung cancer, glioma, breast carcinoma, carcinoma of prostate, ovarian cancer, cervical cancer and leukemia at least A kind of.In other embodiments, kinase mediated for PI3-disease is selected from type ii diabetes；In other embodiments, Disease kinase mediated for PI3-is selected from respiratory tract disease, bronchitis, at least one in 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 disease, described treatment includes being administered any of above reality Execute the step of 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, described treatment includes the change being administered any of above embodiment The step of compound.

On the other hand, the present invention relates to include asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) treatment of respiratory tract disease such as, described treatment includes the step being administered the compound of any of above embodiment.

On the other hand, the present invention relates to inflammatory bowel, inflammatory ocular disease, inflammation or unstable bladder disease, The dermatosis of inflammatory component, chronic inflammatory disease, systemic lupus erythematosus (sle) (SLE), myasthenia gravis, acute disseminated encephalomyelitis, Idiopathic blood platelet minimizing property purpura, multiple sclerosis, Sjogren syndrome and autoimmune hemolytic anemia, mistake Quick property and the treatment of pleoergy, described treatment includes the step being administered the compound of any of above and following embodiment.

On the other hand, involved in the present invention mediated by PI3-kinase activity, depend on PI3-kinase activity or swash with PI3- The treatment of the cancer that enzymatic activity is relevant, the activity of especially PI3K δ, described treatment includes being administered any of above and following embodiment party The step of the compound of case.

On the other hand, the present invention relates to the treatment selected from following cancer: acute myelogenous leukemia, spinal cord development is abnormal comprehensive Simulator sickness, myeloproliferative disease, chronic lymphocytic leukemia, T cell acute lymphoblastic leukemia, B cell acute lymphoblastic is white Disorders of blood, non-Hodgkin lymphoma, B cell lymphoma, solid tumor and breast carcinoma, described treatment includes being administered any of above and following reality Execute the step of the compound of scheme.

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 curative at PI3-kinase mediated disease of any of above embodiment The application of thing manufacture view.

On the other hand, the compound that the present invention relates to any of above embodiment treats rheumatoid arthritis in preparation, Ankylosing spondylitis, osteoarthritis, psoriatic arthritis, psoriasis, diseases associated with inflammation, including asthma, Chronic obstructive pulmonary disease Sick respiratory tract disease, 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, make a variation mutually Structure body, solvate, hydrate, metabolite, salt and pharmaceutically acceptable prodrug.

The compound of the present invention also includes other salt of such compound, and these other salt are not necessarily pharmaceutically acceptable Salt, and may serve as preparation and/or purify the present invention compound and/or for separating the compound of the present invention The intermediate of enantiomer.

Pharmaceutically useful acid-addition salts can be formed with mineral acid and organic acid, such as acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Thing/hydrochlorate, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, Fructus Mali pumilae 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.

Such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc. can be included by its derivative mineral acid obtaining salt.

Can by its derivative organic acid obtaining salt include such as acetic acid, propanoic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, succinic 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.

Can be included by its derivative inorganic base obtaining salt, the metal of the I race of such as ammonium salt and periodic chart to XII race.? In some embodiment, this salt is derived from sodium, potassium, ammonium, calcium, magnesium, ferrum, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salt.

Can be included that primary amine, secondary amine and tertiary amine, substituted amine include naturally occurring by its derivative organic base obtaining salt Substituted amine, cyclic amine, deacidite etc..Some organic amine includes, such as, and 2-aminopropane., benzathine benzylpenicillin (benzathine), choline salt (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine And trometamol.

The officinal salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes. It is said that in general, such salt can free acid form Yu stoichiometry by making these compounds suitable alkali (as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate etc.) reaction, or by making free alkali form and the chemistry meter of these compounds The suitable acid reaction of amount amount is prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two.One As, in the case of suitably, need to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.In example Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook: character, select and apply (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.

And, the compounds of this invention, include that its salt can also obtain with its hydrate forms, or include that other are for it The solvent of crystallization.The compounds of this invention inherently or can have the solvation of acceptable solvent (including water) by design forming Thing；Therefore, the invention is intended to include solvation and unsolvated form.

The compounds of this invention there may be several asymmetric center or the shape of the most described raceme mixture Formula.The present invention comprises racemic mixture further, the mixture of partial racemization and the enantiomer of isolated and non-right Reflect body.

The compound of the present invention can be with in possible isomer, rotamer, atropisomer, tautomer Presented in a kind of form or its mixture, the present invention can comprise isomer further, rotamer, resistance turn isomery Body, the mixture of tautomer, or isomer, rotamer, atropisomer, the part mixes of tautomer Or the isomer separated, rotamer, atropisomer, tautomer.

Any structural formula that the present invention is given is also intended to represent form and the isotope mark that these compounds are not labeled The form of note.Isotope-labeled compound has the structure of the formula description that the present invention provides, except one or more atoms Replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can introduce in the compounds of this invention includes The isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, as²H,³H,¹¹C,¹³C,¹⁴C,¹⁵N,¹⁸F,³¹P,³²P,³⁶S,³⁷Cl or¹²⁵I。

On the other hand, compound of the present invention includes with compound defined in the various isotope-labeled present invention, Such as, wherein there is radiosiotope, as³H,¹⁴C and¹⁸Those compounds of F, or wherein there is non radioactive isotope, As²H and¹³C.Such isotope-labeled compound can be used for metabolism research and (uses¹⁴C), kinetics research (makes use-case As²H or³H), detection or imaging technique, as positron emission tomography (PET) or include medicine or substrate tissue distribution survey Fixed SPECT (single photon emission computed tomography) (SPECT), or can be used in the radiotherapy of patient.¹⁸The compound pair of F labelling It is especially desirable for PET or SPECT research.Isotope-labeled compound disclosed in this invention can pass through this area Embodiment in routine techniques that technical staff is familiar with or the present invention and preparation process is described uses suitable isotope labelling Reagent substitutes original used unmarked reagent to be prepared.

Additionally, higher isotope particularly deuterium is (i.e.,²H or D) replacement can provide some treat advantage, these advantages are Brought by metabolic stability is higher.Such as, Half-life in vivo increases or volume requirements reduces or therapeutic index obtains improving band Come.Should be appreciated that the deuterium in this context is seen as doing the substituent group of compound shown in invention.Isotope enrichment can be used The factor defines the concentration of such higher isotope particularly deuterium.Term used in the present invention " the isotope enrichment factor " refers to Specified ratio between isotopic isotope abundance and natural abundance.If the substituent group of the compounds of this invention is designated as Deuterium, this compound has at least 3500 (each specify the deuterium of 52.5% at D-atom to mix), extremely for each D-atom specified Few 4000 (deuterium of 60% mixes), at least 4500 (deuterium of 67.5% mixes), at least 5000 (deuterium of 75% mixes), at least 5500 The deuterium of 82.5% (mix), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuterium of 95% mixes), at least 6466.7 (deuterium of 97% mixes), at least 6600 (deuterium of 99% mixes) or the isotope enrichment of at least 6633.3 (deuterium of 99.5% mixes) The factor.The pharmaceutically useful solvate of the present invention includes that wherein recrystallisation solvent can be the substituted such as D of isotope₂O, acetone-d₆、 Or DMSO-d₆Those solvates.

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

On the one hand, the feature of the pharmaceutical composition of the present invention includes compound disclosed in this invention, and pharmaceutically can connect The carrier being subject to, adjuvant or excipient.In the compositions of the present invention, the amount of compound can effectively, detectably suppress biological sample Or protein kinase in the patient.

The compound of the present invention in a free form or exists with suitable, pharmaceutically acceptable derivates form.Pharmacy Upper acceptable derivates includes, but is not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of esters, can directly or Ground connection according to patient need be administered other any adducts or derivant, other aspects of the present invention described by compound or Their metabolite or residue.

As described in the invention, pharmaceutical composition of the present invention or pharmaceutically acceptable compositions are wrapped further Containing pharmaceutically acceptable carrier, adjuvant or excipient, as the present invention is applied, including being suitable for distinctive target formulation , any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickening agent, 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 is open It is for reference that content is incorporated in the present invention in full with it.Literature cited describes for preparing pharmaceutically acceptable combination herein Preparation method known to the different carrier of thing and compositions.Except the conventional carrier matchmaker incompatible with the compound of the present invention It is situated between, such as, can produce bad biological effect or with any other component in pharmaceutically acceptable compositions, harmful phase occur Interaction, the carrier medium of other any routines and their purposes are also the scopes that the present invention is considered.

The pharmaceutical composition of the present invention to prepare and can be packaged as form in bulk, wherein can extract safely, effectively agent The compound disclosed in this invention of amount or its pharmaceutically acceptable salt, can give patient with the form of powder or syrup Medicine.Or, pharmaceutical composition of the present invention can be prepared or be packaged in unit dosage forms, and wherein, each unit dosage forms all contains this Bright disclosed compound or its pharmaceutically acceptable salt.When being prepared as unit dosage forms, the pharmaceutical composition of the present invention is usual Compound disclosed in this invention containing 0.5mg to 1g or 1mg to 700mg or 5mg to 100mg or it is pharmaceutically acceptable Salt.

The pharmaceutical composition of the present invention typically contains compound disclosed in this invention or its pharmaceutically acceptable salt.

Term " pharmaceutically acceptable excipient " in the present invention refers to and gives pharmaceutical composition shape or the compatibility Pharmaceutically acceptable material, compositions or carrier.When mixing, every kind of excipient must be with other in pharmaceutical composition Component is compatible, thus avoids when giving patient, is substantially reduced effect of the compounds of this invention or its pharmaceutically acceptable salt And cause the interaction of the most unacceptable compositions.It addition, every kind of excipient all must have sufficiently high purity So that it is pharmaceutically acceptable.Compound shown in formula (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable Excipient or adjuvant, be usually formulated as being applicable to give the dosage form with patient by required route of administration.Such as, it is adaptable to The dosage form of lower route of administration: (1) oral administration, as tablet, capsule, caplet agent, pill, containing tablet, powder, syrup, elixir, Suspensoid, solution, Emulsion, sachet and sachet；(2) parenteral, as sterile solution agent, suspensoid and for redissolve Powder；(3) percutaneous dosing, such as transdermal patch；(4) rectally, such as suppository；(5) inhalation, as aerosol, solution and Dry powder doses；(6) topical, such as ointment, ointment, washing liquid, solution, paste, spray, foam and gel.

Suitable pharmaceutically acceptable excipient will be different regarding selected concrete dosage form.Additionally, can be for them in group The specific function played in compound is to select suitable pharmaceutically acceptable excipient.Such as, life can be contributed to according to them Produce the ability of equal one dosage type low temperature and select some pharmaceutically acceptable excipient.Can contribute to for them when giving patient Carry or transport the compounds of this invention or its pharmaceutically acceptable salt from human body organ or part to another of human body The ability of individual organ or part selects some pharmaceutically acceptable excipient.The energy of patient compliance can be strengthened for them Power selects some pharmaceutically acceptable excipient.

Suitable pharmaceutically acceptable excipient comprises following kind of excipient: diluent, filler, binding agent, Disintegrating agent, lubricant, fluidizer, granulating agent, coating materials, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweeting agent, rectify Taste agent, odor mask, coloring agent, anticaking agent, wetting agent, chelating agen, plasticiser, viscosifier, antioxidant, preservative, stable Agent, surfactant and buffer agent.It would be recognized by those skilled in the art that some pharmaceutically acceptable excipient can play many In a kind of function, and can play alternative function, this depends on there are how many these excipient in the formulation and what preparation exists Plant other compositions.

Those skilled in the art grasp the knowledge and technology of this area so that it is suitable that they can select for the present invention Amount, excipient suitable, pharmaceutically acceptable.Pharmaceutically can connect additionally, those skilled in the art can describe from many The local of the excipient being subject to obtains resource, and can be used for selecting suitable pharmaceutically acceptable excipient.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 uses technique well known by persons skilled in the art and method to prepare.Commonly used in the art Certain methods refers to: Remington's Pharmaceutical Sciences (Mack Publishing Company).

On the other hand, the present invention relates to one prepare and comprise a compound disclosed in this invention or it pharmaceutically can connect The salt being subject to and one or more contain the method for pharmaceutical composition of pharmaceutically acceptable excipient of blending ingredients.This bag Pharmaceutical composition containing the compound shown in a formula (I) or its pharmaceutically acceptable salt can be under room temperature, condition of normal pressure Prepare.

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

On the one hand, the present invention relates to solid oral administrations dosage form, such as: tablet or capsule, it comprises safely, effectively The compound shown in formula (I) of dosage or its pharmaceutically acceptable salt, diluent or filler.Suitably diluent and filling Agent includes: (e.g., corn starch, potato starch and pregel form sediment for lactose, sucrose, glucose, mannitol, Sorbitol, starch Powder), calcium sulfate, calcium hydrogen phosphate.Oral dosage form can also further comprise binding agent.Suitably binding agent comprises starch (e.g., corn starch, potato starch and pregelatinized starch), gelatin, arabic gum, sodium alginate, alginic acid, tragakanta, melon That glue, polyvidone, cellulose and their derivant (e.g., microcrystalline Cellulose).Oral dosage form can also comprise disintegrating agent. Suitably disintegrating agent, comprises polyvinylpolypyrrolidone, sodium starch glycolate, cross-linked carboxymethyl cellulose, alginic acid, carboxymethyl cellulose Element sodium.Oral solid dosage dosage form, it is also possible to include lubricant.Proper lubrication agent includes magnesium stearate, calcium stearate, tristearin Acid and Pulvis Talci.

If appropriate, micro encapsulation can be carried out with the dosage unit preparations that oral disposition is administered.By by particulate matter coating Or be embedded in polymer, wax etc., can extend or control the release of this pharmaceutical composition.

Compound shown in formula (I) or its pharmaceutically acceptable salt can also be with the solubilities as target medicine carrier Polymer coupling.Suitably polymer comprises: polyvinyl pyrrolidone, pyran co-polymer, poly-hydroxypropyhnethacrylamide- Cascophen, polyhydroxyethylaspart or the polyoxyethylene poly-D-lysine replaced by palmitic acid residues.Additionally, Compound shown in formula (I) or its pharmaceutically acceptable salt can also with a series of realize controlled release drug administration, can biological drop The polymer solved combines.Such as: polylactic acid, polycaprolactone, multi-hydroxybutyrate, poe, polyacetals, poly-dihydropyran, Polybutylcyanoacrylate and the crosslinking of 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 prepare 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 suitably seasoned water Solution prepares, and elixir is by using nontoxic alcoholic vehicle to prepare.Suspensoid is by the compounds of this invention or its pharmacy Upper acceptable salt suspension prepares in non-toxic carrier.Can also add solubilizing agent and emulsifying agent such as ethoxylated isostearyl alcohol and Polyoxyethylene sorbitol ether, preservative, flavoring agent such as Oleum menthae, natural sweetener or saccharin or other artificial sweetening agents etc..

On the other hand, the present invention relates to a kind of dosage form that patient can be carried out inhalation, as dry powder doses, aerosol, Suspensoid or liquid composite.In some embodiments, the present invention relates to can patient be carried out the dosage form of inhalation, as Dry powder doses.In other embodiments, the present invention relates to patient is carried out in aerosol inhalation.By sucking Mode the dry powder composite of pulmonary administration is contained the compounds of this invention or its pharmaceutically acceptable salt of fine powder form One or more pharmaceutically acceptable excipient with fine powder form.To those skilled in the art, particularly suitable The pharmaceutically acceptable excipient used in dry powder doses comprises, lactose, starch, mannitol, monosaccharide, disaccharide or polysaccharide.Point Dissipate good powder to obtain by the way of micronized and grinding.It is said that in general, size reduces (such as micronized) chemical combination The size of thing is by D₅₀Value limits, about 1 to 10 microns (such as, measuring with laser diffractometry).

Described dry powder can by the inhaler (RDPI) of reservoir dry powder to patient be administered, this inhaler have be suitable to storage Deposit (non-dosing) drug reservoir of multiple dry powder form.RDPI generally include measure from storage each drug dose to The equipment of medicine position.Such as, this measuring equipment can comprise jigger, and it can move to the second position from primary importance, First position, jigger can be full of the medicine from storage, and in second position, the drug dose measured can be by patient Suck.

Or, described dry powder can be stored in capsule (e.g., gelatin or plasthetics), cartridge case or blister pack (blister packs) uses for multidose dry powder inhaler (MDPI).MDPI is inhaler, and its Chinese medicine is comprised in Containing in the multiple-unit container of (or carrying) multiple limiting dose (or its part) medicine.When described dry powder is with blister pack In the presence of form, it includes the multiple bubble-caps (blister) containing dry powder form medicament.Typically, described bubble-cap is with rule side Formula arranges, and discharges medicine from which to facilitate.Such as, described bubble-cap generally can be arranged in collar plate shape bubble-cap in a circular manner Bubble-cap in packaging or described can be elongated, such as, include strip or banding.Each capsule, cartridge case or bubble-cap can be such as The compounds of this invention containing 20 μ g-10mg or its pharmaceutically acceptable salt.

Aerosol can be suspended or dissolved in liquefaction advance by by the compounds of this invention or its pharmaceutically acceptable salt Agent is prepared.Suitably propellant includes halogenated hydrocarbons, hydro carbons and the gas of other liquefaction.Representational propellant includes: Arcton 11 (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-Difluoroethane (HFA-152a), dichloromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, perfluorinated butane, perflenapent, butane, iso-butane and pentane.Comprise the compounds of this invention or its Patient is administered by the aerosol of pharmaceutically acceptable salt typically via quantitative pressure inhaler (MDI).These devices are these Known to the skilled person.

Aerosol can be lived on excipient such as surface pharmaceutically acceptable containing other, that be typically used together with MDI Property agent, lubricant, cosolvent and other excipient, to improve the physical stability of preparation, improve valve performance, improve and dissolve Spend or improve taste.

Therefore, the invention provides the medicinal aerosol as another aspect of the present invention, it comprises chemical combination of the present invention Thing or its pharmaceutically acceptable salt and fluorocarbon, hydrogeneous Chlorofluorocarbons (CFCs) as propellant, optional and surfactant And/or cosolvent combines.

According to a further aspect in the invention, the invention provides a kind of medicinal aerosol, propellant is 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 applicable buffer agent buffering.

For sucking or be blown into capsule and the cartridge case of administration, such as gelatina, can be configured to containing the powder being suitable to suction The preparation of mixture, this mixture of powders comprises 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 the compounds of this invention of 20 μ g-10mg or it is pharmaceutically acceptable Salt.It addition, capsule or cartridge case can comprise only the compounds of this invention or its pharmaceutically acceptable salt and not contain other figuration Agent such as lactose.

Reactive compound of the present invention or its pharmaceutically acceptable salt ratio in topical composition depend on institute The concrete dosage form of preparation, ratio as a rule used is in the weight ratio of 0.001-10%.Typically for most of doses Suitable proportion used by type is from 0.005%-1%, is the most in some embodiments in the range of 0.01%-0.5%.But It is that ratio used by the powder in inhalant and insufflation is in the range of 0.1%-5%.

It is to make the unit metered dose of aerosol or " spraying into " dosage contain 20 μ g-that the preferred dosage of aerosol is formulated 10mg, the compounds of this invention of preferably approximately 20 μ g-500 μ g or the salt of its pharmaceutical acceptable.Administration can be one day one Secondary or one day for several times, such as 2,3,4 or 8 times, be administered as such as 1,2 or 3 unit dose every time.The TDD of aerosol is at 100 μ G-10mg, preferably in the range of 200 μ g-2000 μ g.Capsule or cartridge case are administered, to suck or to be blown into, the day total agent discharged Amount and metered dose are generally twice in the dosage of aerosol.

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

The dosage form of the present invention can by appropriate containers by medicine and the compounds of this invention or it is pharmaceutically acceptable Salt be dispersed or dissolved in propellant preparation, such as use sonication or high-shear mixer to assist.This was prepared Journey to be carried out in the environment controlling air humidity.

The chemistry of the aerosol of the present invention, physical stability and acceptability pharmaceutically can be by those skilled in the art Techniques well known is used to be measured.Such as, compound is after long-term storage, and stability can be analyzed by HPLC and measure. Physical stability data can be obtained by the analysis test method of other routines, such as, is commented for medicine by leak test, valve Fixed (weight that each unlatching averagely discharges), dose reproducibility evaluation (every time opening the active principle discharged) and spray medicine Distributional analysis.

The stability of the suspension aerosol of the present invention can be measured by routine techniques, such as, by measuring floccules Degree distribution, uses backlight scatterometer or by measuring particle size distribution, by collision (cascade impaction) step by step Or " binary collision " (twin impinger) assay." binary collision " of the present invention algoscopy refers to " use device A to exist Pressurizing vessel measures and is ejected to obtain the precipitation of medicament ", this definition is shown at British Pharmacopoeia 1988, the A204-207 page, annex XVII C.This technology can calculate the inhalable granule part in aerosol.One is used for calculating inhalable granule Method be that this is the method using above-mentioned " binary collision " by " fine grained classification ", open every time from collision cell collective low to The amount of active component, be expressed as opening the percent of the active component total amount ejected every time.

Term " metered dose inhaler " or MDI refer to a combination, comprise a tank, one cover at the protection cap of tank, He Gai Formula metering valve on son.MDI system comprises suitable transfer device.Suitably transfer device comprises, as a valve drives Device, a cylindric or cone shape passage, can be delivered to patient from filling tank by metering valve by this passage medicine Nose or face in, such as blow gun actuator.

MDI tank generally comprises a container that can bear propellant vapour pressure, e.g., plastics or plastic-faced vial Preferably canister, such as, aluminium pot, or aluminium alloy can, it can be through anodization, varnish application and/or plastics Coating, (such as, introducing list of references patent WO 96/32099, the most part or all of inner surface is coated with one herein Or multiple fluorocarbon polymers and one or more non-fluorocarbon polymers), this 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 shown in this article (dose inhaler) can pass through this area Known method prepares (referenced patent WO 96/32099).Preferably, cartridge case being furnished with lid, wherein, medication dosing valve is positioned at lid On son, described lid is crimped on cartridge case.

In some embodiments of the present invention, the metallic interior surface of tank is coated by one layer of fluoropolymer, 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 It is coated with the copolymer mixture of politef and polyethersulfone resin.In other embodiments, table in the whole metal of tank Face is each coated with the copolymer mixture of politef and polyethersulfone resin.The design of metering valve is intended to open every time all can be provided The dosage form of metering, and containing a packing ring preventing propellant from leaking at valve.Packing ring can comprise any suitable bullet Property material, the such as butadiene-acrylonitrile of Low Density Polyethylene, chlorobutyl, brombutyl, ethylene propylene diene rubber, black or white Rubber, butyl rubber and neoprene.Suitably valve can obtain at manufacturer known to aerosol industry in purchase, as Valois, France (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 combined in other structures, such as but not limited to, it is used for Storage, comprise the external packing box of metered dose inhaler, be specifically referred to United States Patent (USP) US 6,119,853,6,179,118,6, 315,112,6,352,152,6,390,291, and 6,679,374, the patent relevant with 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 is carried out The large-scale production of wound packages medicine.It is thus possible, for instance in a kind of method producing suspension aerosol in batches, metering valve is crimped on Empty cylinder is formed on one aluminium pot.Granulated drug is loaded and fills in container, and the propellant of suitable excipient and liquefaction is passed through Fill container pressurization to be filled with in manufacture container.Drug suspension was mixed, by aliquot before entering filling machine circulation Drug suspension be filled with in cylinder by metering valve.In the embodiment of other batch production Liquid Aerosol, will metering Valve is crimped on an aluminium pot the empty cylinder of formation.The medicine that will dissolve loads fills in container, and by suitable excipient and liquefaction Propellant is filled with in manufacture container by filling container pressurization.

In process of production, the liquid preparation of every equal portions joins in the container of opening at a temperature of the coldest, with really Protect preparation will not evaporation loss, after powder charge again by metering valve crimp to the container.

Generally, in the producing by batch of medicine, the cylinder of each filling is checked, weighs, stamped lot number, before release test Loading dish is deposited.Can also be by spraying containing the compounds of this invention or the suspension of its pharmaceutically acceptable salt and solution Patient is administered by device.Solvent or suspension for atomization are all pharmaceutically acceptable liquid, such as water, saline solution, alcohol or two Unit's alcohol, such as ethanol, isopropanol, glycerol, propylene glycol, Polyethylene Glycol or their mixture.Salt used in saline solution be to After medicine not or have the salt of little pharmacologically active.Organic salt, such as alkali metal salt or ammonium halide salt, such as sodium chloride, potassium chloride Or organic salt, as potassium, sodium and ammonium salt and organic acids such as ascorbic acid, citric acid, acetic acid, tartaric acid etc. 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 mineral acid example hydrochloric acid, nitric acid, sulphuric 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 salt thereof, or antioxidant such as vitamin E are with anti- Bad hematic acid.In the formulation, above excipient can be used alone or together with stable the compounds of this invention or its pharmaceutically can connect The salt being subject to.Preparation can also add preservative such as benzalkonium chloride, benzoic acid and salt thereof.Especially, surface activity can be added Agent is for improving the physical stability of suspending agent.Surfactant such as, lecithin, dioctyl sulfo-succinic acid disodium, oleic acid and Sorbitan ester.

Another aspect of the present invention relates to the dosage form of intranasal administration.

The dosage form of intranasal administration includes pressurized aerosol formulation and the aqueous solution preparation being given nose by force (forcing) pump.Non-pressurised And the preparation being applicable to intranasal administration gains a special interest.For this purpose it is proposed, suitably preparation is using water as diluent or load Body.The conventional excipients that the liquid dosage form of preparation pulmonary or intranasal administration uses has buffer agent, 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 use stream The liquid preparation that the transmission of body allotter is administered, fluid distributor contains a distributing 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 Planting fluid distributor and be generally provided with accommodating the storage tank of multiple dosing liquid preparation, dosage can be divided by continuous pump action Join.Configurable distributing nozzle or aperture are to insert in user nostril, for by liquid preparation spray distribution to nasal cavity.Aforementioned carry And fluid distributor be the type illustrated in patent WO 05/044354, entire contents is incorporated in the present invention by quoting. This allotter has the housing accommodating fluid discharging apparatus, and fluid discharging apparatus comprises on the container being arranged on receiving liquid preparation Force (forcing) pump.Housing have at least one can the side lever of finger manipulation, this side lever can move inward relative to housing, with cam Drive the container in housing upwards, thus cause pump pressure to contract and the preparation of dosing is pumped out pump rod by the nose nozzle of housing (stem).Especially preferred fluid distributor is the general type illustrated in Figure 30-40 of patent WO 05/044354.

Being suitable for the pharmaceutical composition of intranasal administration, carrier therein is solid, including particle diameter such as at 20-500 micron Corase meal；Can be administered in such a way, powder fills in a reservoir, holds close to nasal cavity, quick by nasal passage Suck.Suitably compositions, comprises the compounds of this invention or the aqueous solution of its pharmaceutically acceptable salt or oil solution, Qi Zhongzai Body is liquid, is administered using nasal spray or is administered as nasal drop.

The pharmaceutical composition being suitable for percutaneous dosing can use with the patch form separated, for close with the epidermis of patient Contact one longer period.For example, it is possible to penetrate into release of active ingredients from paster by ion, its common description is shown in Pharmaceutical Research,3(6),318(1986)。

It is applicable to the pharmaceutical composition of topical and can also be configured to ointment, Emulsion, suspension, washing liquid, powder, molten Liquid, paste, gel, spray, aerosol or oil preparation.Ointment, Emulsion and gel can add with water or oleaginous base and close Suitable thickening agent and/or gel preparation.Substrate such as liquid paraffin, vegetable oil such as Oleum Arachidis hypogaeae semen, Oleum Ricini or the most poly-second of solvent Glycol.Thickening agent and gel to select according to the character of substrate, comprise paraffin, aluminium stearate, hexadecanol and octadecanol The derivant of mixture, Polyethylene Glycol, lanoline, Cera Flava, carbopol and cellulose and/or glyceryl monostearate, and/ Or nonionic emulsifier.

Lotion can be prepared with water or oleaginous base, and typically contains one or more emulsifying agents, stabilizer, dispersion Agent, suspending agent or thickening agent.

Need to add suitable powdered substrate, such as Pulvis Talci, lactose or starch during external powder agent preparation.Joining of dropping liquid System generally uses water or non-aqueous base, additionally contains one or more dispersants, chaotropic agent, suspending agent or preservative.

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

The pharmaceutical composition for the treatment of 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 ointment base that water is miscible.It addition, the compounds of this invention or its pharmaceutically acceptable salt can use oil-in-water or Water-In-Oil Substrate preparation become Emulsion.

Pharmaceutical composition for parenteral comprises water and non-aqueous sterile injection liquid, its can contain antioxidant, Buffer, antibacterial and solute, its make described preparation with the blood of specified receiver isotonic and aqueous and anhydrous nothing Bacterium suspension can contain suspending agent and thickening agent.Described compositions can be the closeest at unit dose or multi-dose container Depositing in the ampoule of envelope and medicine bottle, and can store in lyophilizing (lyophilization) condition, it only needs to add the most immediately Enter sterile liquid carrier, such as water for injection.Extemporaneous injection solutions and suspension can be by sterile powder, granule and tablet systems Standby.

The compound of the present invention and pharmaceutical composition can be with one or more other therapeutic agents use in conjunction, described treatments Agent is selected from antiinflammatory, anticholinergic (particularly M1/M2/M3 receptor antagonist), β₂-3 adrenergic receptor agonists, anti- Infectious agent, such as antibiotic or antiviral agent or antihistaminic.The present invention further provides a kind of compositions, it comprises a kind of formula (I) compound shown in or its pharmaceutically acceptable salt and one or more other active therapeutic agent, described active therapeutic agent Selected from anti-inflammatory agent, such as steroidal anti-inflammatory drugs, nonsteroidal antiinflammatory drug, anticholinergic, β₂-3 adrenergic receptor agonists, Anti-infective such as antiviral agent or antibacterial, or antihistaminic.Another aspect of the present invention relates to some compositions, and it is contained (I) compound shown in or its pharmaceutically acceptable salt, and β₂-3 adrenergic receptor agonists, anticholinergic and/or PDE-4 inhibitor and/or antihistaminic.

In some embodiments, the present invention comprises the compounds of this invention or its pharmacy that a kind of use is safely, effectively measured Upper acceptable salt and one or more active therapeutic agents, the method for the abnormal relevant disease for the treatment of PI3K.

Some specific compounds of the present invention have the selectivity being better than other PI3K to PI3K δ.Therefore, the present invention's is another On the one hand providing a kind of pharmaceutical composition, it comprises the compound shown in formula (I) or its medicine optionally acting on PI3K δ Receivable salt and act on other PI3K on, compound as shown in the formula (I) of PI3K γ or it is pharmaceutically acceptable Salt.

On the other hand, the present invention also comprises compositions, and it comprises one or both other therapeutic agents.

To those skilled in the art, situations below is clearly, it may be assumed that in appropriate circumstances, other therapeutic agents Can be to be the form such as alkali metal salt, ammonium salt of salt, or the salt as acid addition, or the form of prodrug, or the form of ester Such as lower alkyl esters, or the form of solvate such as optimizes activity and/stability and/or physical characteristic, as dissolubility, The hydrate of therapeutic component.Following situation is clearly equally, and the most 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 comprises the chemical combination shown in formula (I) as combination preparation Thing and at least one other therapeutic agent, contained composition simultaneously, or be used for successively treating respectively.In other embodiments In, treated is relevant disease abnormal to PI3K or disease.Product as combination preparation comprises compositions, described combination Thing contains the compound shown in formula (I) of the present invention in identical pharmaceutical composition and other therapeutic agents, or containing individually The compound shown in formula (I) of the present invention and other therapeutic agents, such as with the form of medicine box.

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

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

The medicine box of the present invention, can be used for different dosage forms, such as orally and parenterally dosage form, for difference Spacing of doses uses single compositions, or is stepped up single compositions for another kind relatively.In order to increase compliance, The medicine box of the present invention the most 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's preparation or preparation.And, the compounds of this invention and other therapeutic agents can be collectively incorporated in a therapeutic combination: (i) exists Before combination product is issued to doctor (such as the medicine box containing the compounds of this invention and other therapeutic agents) (ii) Before facing and using, doctor oneself (or under doctor instructs) carry out (iii) and carried out by patient oneself, such as, using successively During the compounds of this invention and other treatment.

Correspondingly, the invention provides compound shown in formula (I) or its pharmaceutically acceptable salt abnormal at treatment PI3K Purposes in relevant disease or disease, medicine therein is prepared for jointly using with other therapeutic agents.The present invention also carries The purposes of the other therapeutic agents treating the abnormal relevant disease of PI3K or disease, wherein said medicine and formula are supplied (I) described compound is used jointly.

Present invention also offers the compound shown in formula (I) for treating the abnormal relevant disease of PI3K or the use of disease On the way, the compound shown in its Chinese style (I) and other therapeutic agents are prepared to the preparation for combined administration.Present invention also offers Other therapeutic agents is for treating the abnormal relevant disease of PI3K or the purposes of disease, wherein said other therapeutic agents and the present invention Compound shown in formula (I) is prepared to the preparation for combined administration.

Present invention also offers formula (I) compound purposes in the abnormal relevant disease for the treatment of PI3K or disease, wherein Patient previously (such as in 24 hours) is treated by other therapeutic agents.Present invention also offers other therapeutic agents to exist Purposes in the abnormal relevant disease for the treatment of PI3K and disease, wherein patient previously (such as in 24 hours) has used formula (I) Shown compound is treated.Compound shown in formula (I) as unique active component or with other adjuvant or medicine With the use of, wherein adjuvant or medicine such as immunosuppressant, immunomodulator or other antiinflammatories, for treatment or prevention with Kind or the acute or chronic rejection of xenotransplantation or inflammation or the medicine of autoimmune disease, or chemotherapeutant, as Malignant cell antiproliferative.Such as, the compound shown in formula (I) of the present invention is executed jointly with neural pherylarsin oxide With, such as, cyclosporin A or FK506；MTOR inhibitors, such as rapamycin, 40-O-(2-ethoxy)-rapamycin, CCI779, ABT578, AP23573, TAFA-93 etc., biolimus-7 or biolimus-9, ascosin, there is immunosuppressant The ABT-281 of activity, ASM981,17-hydroxy-11-dehydrocorticosterone, cyclophosphamide, azathioprene, methotrexate, leflunomide, imidazoles stands Guest, mycophenolic acid or its salt, mycophenolate, 15-deoxyspergualine or immunosuppressant homologue, analog or derivative Thing, pkc inhibitor etc., as described in patent WO 02/38561 or WO 03/82859, embodiment compound 56 or 70, or JAK3 inhibitors of kinases, such as: N-benzyl-3-benzal-Isosorbide-5-Nitrae-dihydroxy-cyanoacetamide-alpha-cyano-(3,4-dihydroxy)- N-benzyl cinnamamide (tyrphostin AG 490), prodigiosin 25-C (PNU156804), 4-(4 '-hydroxy benzenes Base)-amido-6,7-dimethoxy quinazoline (WHI-P131), 4-(3', 5'-bis-bromo-4'-hydroxy phenyl)-amino-6,7-bis- Methoxyquinazoline hydrochloride WHI-P97, KRX-211,3-{ (3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine- 4-yl)-amino]-piperidin-1-yl }-3-oxo-propionitrile, presented in free form or pharmaceutically acceptable salt, such as list Compound in citric acid (also referred to as CP-690,550), or patent WO 04/052359 or WO 05/066156, immunosuppressant 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, have CTLA4 extracellular knot Structure territory or at least one of restructuring binding molecule of its mutant, the CTLA4lg being such as connected with non-CTLA4 protein sequence (being such as referred to as ATCC 68629) or its variant (such as, LEA29Y) or other adhesion molecule inhibitors such as LFA-1 antagonist ICAM-1 or-3 antagonist, VCAM-4 antagonist or VLA-4 antagonist or antihistaminic, or antitussive, bronchodilator, blood Angiotensin receptor blocking agent or anti-infective.

Compound shown in formula (I) of the present invention and other immunosuppressant/immunomodulator, antiinflammatory, chemotherapeutant Or anti-infective co-administration, wherein immunosuppressant/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 is used for The concrete medicine for the treatment of and treatment situation etc..

In one embodiment, the present invention includes compound disclosed in this invention or its pharmaceutically acceptable salt, And β₂The combination of-adrenoceptor agonists.

β₂The example of-adrenoceptor agonists includes that (it can be raceme chemical combination to salmaterol (salmeterol) Thing or single enantiomer, such as R-enantiomer), albuterol (salbutamol) (its can be racemic compound or Single enantiomer, such as R-enantiomer), (it can be racemic compound or single to formoterol (formoterol) Diastereomer, such as R, R-diastereomer), 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 the xinafoate (1-hydroxy-2-naphthoic acid salt) of their salt, such as salmaterol, the sulfate of albuterol or free Alkali or the fumarate of formoterol.In some embodiments, long-acting beta₂-adrenoceptor agonists, such as, carries Reach 12 hours for effective bronchiectasis or the compound of longer time, be preferred.

β₂-adrenoceptor agonists can be with the form of pharmaceutically acceptable acid formation salt.Described pharmaceutically may be used The acid accepted is selected from sulphuric acid, hydrochloric acid, fumaric acid, carbonaphthoic acid (such as 1-or 3-hydroxy-2-naphthoic acid), cinnamic acid, substituted meat Cinnamic acid, triphenylacetic acid, sulfamic acid, p-aminobenzene sulfonic acid, 3-(1-naphthyl) acrylic acid, benzoic acid, 4-methoxybenzoic acid, 2-or 4-HBA, 4-chlorobenzoic acid and 4-Phenylbenzoic acid.

Suitably antiinflammatory includes corticosteroid.Can be used for compound disclosed in this invention or its pharmaceutically can connect The suitable corticosteroid that the salt being subject to combines is those corticosteroid that are oral and that suck, and before there is anti-inflammatory activity Medicine.Example includes methylprednisolone, prednisolone (prednisolone), dexamethasone (dexamethasone), propanoic acid fluorine For Kazon (fluticasone propionate), 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-16 Alpha-Methyl-17 α-[(4-methyl isophthalic acid, 3- Thiazole-5-carbonyl) epoxide]-3-oxo-androst-Isosorbide-5-Nitrae-diene-17 β-thiocarboxylic acid S-fluorine methyl ester, 6 α, 9 fluoro-17 α of α-two- [(2-furanylcarbonyl) epoxide]-11 beta-hydroxy-16 Alpha-Methyl-3-oxo-androst-1,4-diene-17 β-thiocarboxylic acid S-fluorine first Ester (fluticasone furoate), 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-methyl-3-oxo-17 α-propionyloxy-androsta-Isosorbide-5-Nitrae-two Alkene-17 β-thiocarboxylic acid S-(2-oXo-tetrahydro furan-3S-base) ester, 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-methyl-3-oxygen Generation-17 α-(2,2,3,3-tetramethyl cyclopropyl carbonyl) epoxide-androstane-1,4-diene-17 β-thiocarboxylic acid S-cyano methyl ester and 6 Alpha, 9 alpha-difluoro-11 beta-hydroxy-16 Alpha-Methyl-17 α-(1-ethyl cyclopropyl carbonyl) epoxide-3-oxo-androst-1,4-diene- 17 β-thiocarboxylic acid S-methyl fluoride ester, beclomethasone ester (such as 17-propionic ester 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] double (epoxide)]-11 β, 21-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone), propanoic acid cloth replaces Can special (butixocort propionate), RPR-106541 and ST-126.Preferably corticosteroid includes that propanoic acid fluorine is for card Pine (fluticasone propionate), 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-methyl-17-alpha-[(4-methyl isophthalic acid, 3-thiophene Azoles-5-carbonyl) epoxide]-3-oxo-androst-Isosorbide-5-Nitrae-diene-17 β-thiocarboxylic acid S-methyl fluoride ester, 6 α, 9 fluoro-17 α of α-two- [(2-furanylcarbonyl) epoxide]-11 beta-hydroxy-16 Alpha-Methyl-3-oxo-androst-1,4-diene-17 β-thiocarboxylic acid S-fluorine first Base ester, 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-16 Alpha-Methyl-3-oxo-17 α-(2,2,3,3-tetramethyl cyclopropyl carbonyl) epoxide- Androstane-1,4-diene-17 β-thiocarboxylic acid S-cyano methyl ester and 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-16 Alpha-Methyl-17 α-(1-first Cyclopropyl carbonyl) epoxide-3-oxo-androst-1,4-diene-17 β-thiocarboxylic acid S-fluorine methyl ester.In some embodiments, Corticosteroid is 6 α, 9 fluoro-17 α of α-two-[(2-furanylcarbonyl) epoxide]-11 beta-hydroxy-16 Alpha-Methyl-3-oxo-androst- 1,4-diene-17 β-thiocarboxylic acid S-methyl fluoride ester.

Transcription inhibition is had selectivity (compared with transcriptional activation), can be used for therapeutic alliance have glucocorticoid swash The nonsteroidal compound of dynamic activity includes those compounds covereding in following patent: WO 03/082827, WO 98/ 54159、WO 04/005229、WO 04/009017、WO 04/018429、WO 03/104195、WO 03/082787、WO 03/ 082280、WO 03/059899、WO 03/101932、WO 02/02565、WO 01/16128、WO 00/66590、WO 03/ 086294, WO 04/026248, WO 03/061651 and WO 03/08277.More nonsteroidal compound is at WO 2006/ 000401, WO 2006/000398 and WO 2006/015870 is included.

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

The example of NSAID's includes sodium cromoglicate, sodium nedocromil (nedocromil sodium), phosphodiesterase (PDE) inhibitor (such as theophylline, PDE4 inhibitor, or mixed type PDE3/PDE4 inhibitor), leukotriene antagonist, leukotriene closes Become inhibitor (such as montelukast), iNOS inhibitor, trypsin and elastase inhibitor, Beta 2 integrin antagonist With adenosine receptor agonist or antagonist (e.g., adenosine 2a receptor stimulating agent), cytokine antagonist is (as chemokine receptors is short of money Anti-agent, including CCR3 antagonist), cytokine synthesis inhibitor, or 5-LO inhibitor.Wherein, iNOS (inductivity one Nitric oxide synthase) administration of inhibitor preferred oral.The example of iNOS inhibitor includes that those are at WO 93/13055, WO 98/ 30537, the compound disclosed in WO 02/50021, WO 95/34534 and WO 99/62875.CCR3 inhibitor include those Compound disclosed in WO 02/26722.

In one embodiment, the present invention provide compound disclosed in this invention with phosphodiesterase 4 (PDE4) Application in the combination of inhibitor, the especially application in the case of being suitable for suction preparation.For this aspect of the present invention PDE4 specific inhibitor can be known suppression PDE4 enzyme or be found any compound as PDE4 inhibitor, they It is only PDE4 inhibitor, is not other members in suppression PDE family, such as the compound of PDE3 and PDE5.Compound includes suitable Formula-4-cyano group-4-(3-cyclopentyloxy-4-methoxyphenyl) hexamethylene-1-carboxylic acid, 2-carbomethoxy-4-cyano group-4-(3-ring Propylmethoxy-4-difluoro-methoxy phenyl) hexamethylene-1-ketone and cis-[4-cyano group-4-(3-cyclo propyl methoxy-4-two Fluorine methoxyphenyl) hexamethylene-1-alcohol]；Also cis-4-cyano group-4-[3-(ring propoxyl group)-4-methoxyphenyl] hexamethylene is included Alkane-1-carboxylic acid (also referred to as Xi Luosi) and salt, ester, prodrug or physical form, it is special in 1996 09 month No. 03 U.S. authorized Profit US 5, disclosed in 552,438, this patent and compound disclosed in it are by quoting and being integrally incorporated in the present invention.

The example of anticholinergic is that those are used as the compound of muscarinic receptor antagonist, particularly those as M1 or M3 receptor antagonist, M₁/M₃Or M₂/M₃Receptor dual antagonist or M₁/M₂/M₃The compound of the general antagonist of receptor.Inhalation Example compound include ipratropium (such as, as bromide, CAS 22254-24-6, withFor Trade name is sold), oxygen torr ammonium (such as, as bromide, CAS 30286-75-0) and tiotropium (such as, as bromide, CAS 136310-93-5, withSell for trade name)；(such as, be also interested in also has Revatropate As hydrobromate, CAS 262586-79-8) and LAS-34273 disclosed in WO 01/04118.The example of oral administration Compound includes pirenzepine (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or its hydrobromate CAS 133099-07-7, sells with Enablex for trade name), oxibutynin (CAS 5633-20-5, with Sell for trade name), terodiline (CAS 15793-40-5), tolterodine (CAS 124937-51-5, or its tartrate CAS 124937-52-6, withSell for trade name), Austria replaces ammonium (such as, as bromide, CAS 26095-59-0, withSell 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, withFor business The name of an article is sold).

In some embodiments, the invention provides one and include that compound disclosed in this invention or its pharmacy can connect The salt being subject to, with the combination of H1 antagonist.The example of H1 antagonist includes, but not limited to ammonia and carrys out promise (amelexanox), west this Imidazoles (astemizole), azatadine (azatadine), azelastine (azelastine), acrivastine (acrivastine), brompheniramine (brompheniramine), cetirizine (cetirizine), levocetirizine (levocetirizine), Efletirizine (efletirizine), chlorpheniramine (chlorpheniramine), clemastine (clemastine), marezine (cyclizine), carebastine (carebastine), Cyproheptadine (cyproheptadine), carbinoxamine (carbinoxamine), descarboethoxyloratadine (descarboethoxyloratadine), doxylamine (doxylamine), diformazan indenes (dimethindene), ebastine (ebastine), epinastine (epinastine), Efletirizine (efletirizine), fexofenadine (fexofenadine), hydroxyzine (hydroxyzine), ketotifen (ketotifen), loratadine (loratadine), Zuo Ka Bath spit of fland (levocabastine), mizolastine (mizolastine), mequitazine (mequitazine), mianserin (mianserin), the primary STING of promise (noberastine), meclizine (meclizine), Tecastemizole (norastemizole), olopatadine (olopatadine), piperacetazine (picumast), ratio Lamine (pyrilamine), Phenergan (promethazine), terfenadine (terfenadine), tripelennamine (tripelennamine), for beautiful this Spit of fland (temelastine), alimemazine (trimeprazine) and triprolidine (triprolidine), preferably cetirizine (cetirizine), levocetirizine (levocetirizine), Efletirizine (efletirizine) and fexofenadine (fexofenadine).In another one embodiment, the invention provides one and include compound disclosed in this invention Or its pharmaceutically acceptable salt, with the combination of H3 antagonist (and/or inverse agonist).The example of H3 antagonist include those Compound disclosed in WO 2004/035556 and WO 2006/045416.Can be used for the present invention compound combination other Histamine receptor antagonists includes H4 receptor antagonist (and/or inverse agonist), such as at Jablonowski et al., J.Med.Chem., the compound disclosed in 46:3957-3960 (2003).

Therefore, on the other hand, the present invention provides one to include compound disclosed in this invention or it is pharmaceutically acceptable Salt, with the combination of PDE-4 inhibitor.

Therefore, on the other hand, the present invention provides one to include compound disclosed in this invention or it is pharmaceutically acceptable Salt, with β₂The combination of-adrenoceptor agonists.

Therefore, on the other hand, the present invention provide a kind of include compound disclosed in this invention or its pharmaceutically can connect The salt being subject to, with the combination of corticosteroid.

Therefore, on the other hand, the invention provides a kind of include compound disclosed in this invention or its pharmaceutically may be used The salt accepted, with the combination of nonsteroidal GR agonist.

Therefore, on the other hand, the invention provides a kind of include compound disclosed in this invention or its pharmaceutically may be used The salt accepted, with the combination of anticholinergic.

Therefore, on the other hand, the invention provides a kind of include compound disclosed in this invention or its pharmaceutically may be used The salt accepted, with antihistaminic combination.

Therefore, on the other hand, the invention provides a kind of include compound disclosed in this invention or its pharmaceutically may be used The salt accepted, with PDE4 inhibitor and β₂The combination of-adrenoceptor agonists.

Therefore, on the other hand, the invention provides one include compound disclosed in this invention or its pharmaceutically can connect The salt being subject to, with anticholinergic and the combination of PDE-4 inhibitor.

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

The individualized compound of these combinations with alone or in combination pharmaceutical dosage forms order of administration or can be given simultaneously Medicine.In some embodiments, individualized polymer component is to be administered simultaneously with the pharmaceutical dosage forms of combination.Known treatment agent Applicable dosage be prone to be understood by the person skilled in the art.

Therefore, on the other hand, the present invention provides one to include compound disclosed in this invention or it is pharmaceutically acceptable Salt, the pharmaceutical composition combined with other therapeutically active agent.

Therefore, on the other hand, the present invention provides one to include compound disclosed in this invention or it is pharmaceutically acceptable Salt, with PDE4 inhibitor combination pharmaceutical composition.

Therefore, on the other hand, the present invention provides one to include compound disclosed in this invention or it is pharmaceutically acceptable Salt, with beta-2-adrenoreceptor agonists combination pharmaceutical composition.

Therefore, on the other hand, the present invention provides one to include compound disclosed in this invention or it is pharmaceutically acceptable Salt, with the pharmaceutical composition of corticosteriods.

Therefore, on the other hand, the present invention provides one to include compound disclosed in this invention or it is pharmaceutically acceptable Salt, with the pharmaceutical composition of nonsteroidal GR agonist combinations.

Therefore, on the other hand, the present invention provides one to include compound disclosed in this invention or it is pharmaceutically acceptable Salt, with anticholinergic combination pharmaceutical composition.

Therefore, on the other hand, the present invention provides one to include compound disclosed in this invention or it is pharmaceutically acceptable Salt, with antihistaminic combination pharmaceutical composition.

Therefore, on the other hand, the present invention provides one to include compound disclosed in this invention or it is pharmaceutically acceptable Salt, the pharmaceutical composition combined with PDE4 inhibitor and beta-2-adrenoreceptor agonists.

Therefore, on the other hand, the present invention provides one to include compound disclosed in this invention or it is pharmaceutically acceptable Salt, the pharmaceutical composition combined with anticholinergic and PDE4 inhibitor.

Compound disclosed in this invention can also be advantageously utilised in the combination with other compounds, or and other treatment In the combination of agent, especially antiproliferative.Such antiproliferative includes, but not limited to aromatase inhibitor；Estrogen antagonist； Topoisomerase I inhibitor；Topoisomerase II inhibitors；Microtubule active agent；Alkylating agent；Histon deacetylase (HDAC) suppresses Agent；The compound of Cell differentiation inducing activity process；Cyclooxygenase-2 inhibitors；MMP inhibitor；MTOR inhibitors；Anti-tumor metabolism Medicine；Platinum compounds；The compound of targeting/reduction albumen or lipid kinase activity and the compound of other angiogenesis inhibitor；Targeting, Reduce or suppress albumen or the compound of lipid phosphate esterase active；Gonadorelin excitomotor；Androgen antagonist；Methionine ammonia peptide Enzyme inhibitor；Diphosphonate；Biological response modifier；Antiproliferation antibodies；Heparanase inhibitors；The carcinogenic hypotype of Ras suppresses Agent；Telomerase inhibitor；Proteasome inhibitor；The medicament for the treatment of neoplastic hematologic disorder；Targeting, reduce or suppress Flt-3 activity Compound；Hsp90 inhibitor；TemozolomideAnd calcium folinate.

Term used herein " aromatase inhibitor ", refers to the compound suppressing estrogen to produce, i.e. suppression substrate is male Alkene diketone and testosterone change into the compound of estrone and estradiol respectively.This 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, and the form if trade mark is Arnold new (AROMASIN) is administered.Formestane (formestane) can be with commercially available, the form if trade mark is Lentaron (LENTARON) is administered.Fadrozole (fadrozole) Can be with commercially available, the form if trade mark is AFEMA is administered.Anastrozole (anastrozole) can be with commercially available, such as trade mark Form for Arimidex (ARIMIDEX) is administered.Letrozole (letrozole) can be with commercially available, if trade mark is fluon (FEMARA) or FEMAR form be administered.Aminoglutethimide (aminoglutethimide) can be with commercially available, if trade mark is difficult to understand The form of U.S. fixed (ORIMETEN) is administered.The present invention includes that the combination of aromatase inhibitor chemotherapeutic is particularly useful for the treatment of hormone and is subject to The tumor that body is positive, such as breast tumor.

Term used herein " estrogen antagonist ", refers to the compound in Estrogen Receptor antagonising oestrogen effectiveness. This term includes, but not limited to tamoxifen (tamoxifen), fulvestrant (fulvestrant), raloxifene And raloxifene hydrochloride (raloxifene hydrochloride) (raloxifene).Tamoxifen (tamoxifen) can With 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 with United States Patent (USP) US 4, the dosage form disclosed in 659,516, or commercially available, as trade mark is The form of FASLODEX is administered.The present invention includes that the combination of estrogen antagonist chemotherapeutic is particularly useful for the treatment of estrogen receptor and is positive Tumor, such as breast tumor.

Term used herein " androgen antagonist " refers to any material that can suppress androgen biological action, its bag Include, but be not limited to, bicalutamide (bicalutamide, trade name CASODEX), its dosage form can according to United States Patent (USP) US 4, 636,505 prepare.

Term used herein " gonadorelin excitomotor " includes, but not limited to 1: PN: WO02056903 PAGE: 25 claimed protein (abarelix), Ge She Rayleigh (goserelin) and goserelin acetate.Goserelin, in United States Patent (USP) US 4, is disclosed in 100,274, can be with city Selling, the form if trade mark is Zoladex (ZOLADEX) is administered.1: PN: WO02056903 PAGE: 25 claimed protein (abarelix) can be according to United States Patent (USP) US Method disclosed in 5,843,901 prepares dosage form.

Term used herein " topoisomerase I inhibitor ", includes, but are not limited to topotecan (topotecan), lucky Horse replaces health (gimatecan), irinotecan (irinotecan), camptothecine (camptothecian) and the like, 9-nitro Camptothecine (9-nitrocamptothecin) and macromolecular camptothecin conjugated compound PNU-166148 are (in WO 99/17804 Compound A1).Irinotecan can be with commercially available, and the form if trade mark is CPT-11 (CAMPTOSAR) is administered.Topotecan can With with commercially available, such as trade mark it be and the form of U.S. new (HYCAMTIN) is administered.

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 Soft than star (epirubicin)；Idarubicin (idarubicin)；Naphthalene the most soft pyrrole star (nemorubicin)；Anthraquinones rice torr anthracene Quinone (mitoxantrone) and losoxantrone (losoxantrone)；Podophillotoxines etoposide (etoposide) and for Buddhist nun Pool glycosides (teniposide).Etoposide can be with commercially available, and the form if trade mark is Etopophos (ETOPOPHOS) is administered.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 The form being designated as adriamycin (ADRIBLASTIN) or amycin (ADRIAMYCIN) is administered.Epirubicin can be with city Selling, the form if trade mark is Pharmorubicin RD (PHARMORUBICIN) is administered.Idarubicin can be with commercially available, as trade mark does good The form only reaching (ZAVEDOS) is administered.Mitoxantrone can be with commercially available, such as the form that trade mark is NSC-279836 (NOVANTRON) It is administered.

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 paclitaxel (paclitaxel) and Docetaxel (docetaxel)；Vinca alkaloids, such as Changchun Alkali (vinblastine), especially vinblastine sulfate, vincristine, especially vincristine sulfate and vinorelbine (vinorelbine)；discodermolides；Colchicine；And Epothilones and its derivant, such as epothilone B or D Or derivatives thereof.Paclitaxel can be with commercially available, and the form if trade mark is taxol (TAXOL) is administered.Docetaxel can be with Commercially available, if trade mark is safe Supreme Being's element (TAXOTERE).Vinblastine sulfate can be with commercially available, if trade mark is VINBLASTIN R.P. form is administered.Vincristine sulfate 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/ 10121, United States Patent (USP) US 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and 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 cyclophosphamide (cyclophosphamide), different ring phosphorus Amide (ifosfamide), melphalan (melphalan) or Nitrosourea (nitrosourea, such as BCNU or carmustine).Ring phosphinylidyne Amine can be with commercially available, and the form if trade mark is cyclophosphamide (CYCLOSTIN) is administered.Ifosfamide can with commercially available, as Trade mark is that the form of ifosfamide (HOLOXAN) is administered.

Term " Antibiotic FR 901228 " or " hdac inhibitor " refer to inhibition of histone deacetylase, and There is the compound of antiproliferative activity.It is included in the compound disclosed in WO 02/22577, especially N-hydroxyl-3-[4- [[(2-ethoxy) [2-(1H-indol-3-yl) ethyl]-amino] methyl] phenyl]-2E-2-acrylamide, N-hydroxyl-3-[4- [[[2-(2-Methyl-1H-indole-3-base)-ethyl]-amino] methyl] phenyl]-2E-2-acrylamide and pharmaceutically can connecing The salt being subject to.Especially include Vorinostat (SAHA).

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

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

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

A) targeting, reduces or suppresses the compound of platelet derived growth factor receptor (PDGFR) activity；Targeting, reduction Or the compound of suppression PDGFR activity, especially suppress the compound of pdgf receptor to include N-phenyl-2-pyrimidine-amine derivatives, Such as imatinib (imatinib), SU101, SU6668, GFB-111 etc.；

B) targeting, reduce or suppress fibroblast growth factor acceptor (FGFR) activity compound；

C) targeting, reduce or suppress IGF-1-1 (IGF-1R) activity compound；Targeting, reduction Or the compound of suppression IGF-1R activity, the especially compound of suppression IGF-1 receptor active include that those are in patent WO 02/ Compound disclosed in 092599；

D) targeting, reduce or suppress the compound of Trk receptor tyrosine kinase family active；

E) targeting, reduce or suppress the compound of Axl family active；

F) targeting, reduce or suppress the compound of c-Met receptor active；

G) targeting, reduce or suppress the compound of Kit/SCFR receptor tyrosine kinase activity；

H) targeting, reduce or suppress C-kit receptor tyrosine kinase (part in PDGFR family) activity chemical combination Thing；Targeting, reduce or suppress the compound of C-kit receptor tyrosine kinase family active, especially suppress the change of c-Kit receptor Compound, including imatinib (imatinib) etc.；

I) targeting, reduce or suppress c-Abl family and their gene fusion product, such as the change of BCR-Abl kinase activity Compound；Targeting, reduce or suppress the compound of c-Abl family member and their gene fusion things include N-phenyl-2-pyrimidine- Amine derivative, such as imatinib, PD180970, AG957, NSC 680410, PD173955 from ParkeDavis；

J) targeting, reduce or suppress Raf family member in Protein kinase C (PKC) and serine/threonine kinases, MEK, SRC, JAK, FAK, PDK and Ras/MAPK family member, PI (3) kinase families member, or PI (3) kinases associated kinase family become Member, and/or the compound of cell cycle protein dependent kinase family (CDK) member activity；Particularly those are in United States Patent (USP) US 5,093, the staurosporine derivatives disclosed in 330, such as midostaurin (midostaurin)；More examples of compounds Also include, UCN-01；Safingol (safingol)；BAY 43-9006；Bryostatin 1；Piperazine Li Fuxin (Perifosine)；She Mo Fuxin (llmofosine)；RO 318220 and RO 320432；GO 6976；Isis 3521；LY333531/LY379196； Isoquinoline compound, as in WO 00/09495 those disclosed；FTIs；PD184352；Or QAN697 (a kind of P13K presses down Preparation)；

K) targeting, reduce or suppress protein tyrosine kinase inhibitor activity compound；Targeting, reduce or suppress The compound of protein tyrosine kinase inhibitor activity includes that Gleevec (GLEEVEC) or tyrosine phosphorylation press down Preparation；Tyrphostin preferably less than molecular weight (Mr < 1500) compound, or its pharmaceutically acceptable salt, especially Selected from benzyl allyl two eyeball class or S-aryl this third two eyeball class or compound of Double bottom thing quinolines, 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 phenyl) methyl] amino }-benzoic acid Buddha's warrior attendant alkyl ester, NSC 680410, adaphostin)；With

I) targeting, reduce or suppress receptor tyrosine kinase epidermal growth factor receptor family (EGFR, ErbB2, ErbB3, ErbB4 all 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 EGF associated ligands combine material) compound, albumen or antibody, summarized the most in the following documents or specifically disclosed 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 97/30034, WO 97/49688 and WO 97/38983, WO 96/30347 (such as CP 358774), WO 96/33980 is (such as chemical combination Thing 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 7H-pyrrolo-[2, the 3-d] pyrimidine derivatives being disclosed in WO 03/013541.

Additionally, anti-angiogenic compounds includes that having other active mechanisms (such as, suppresses not with albumen or lipid kinase Relevant) compound, such as Thalidomide (THALOMID) and TNP-470.

Targeting, the compound reducing or suppressing albumen or lipid kinase activity are phosphatase-1 inhibitor, 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 retinoic 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-alkyl is substituted 2-virtue aminophenyl acetic acid and its derivant, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, examine with cutting down Former times, or 5-alkyl-2-virtue aminophenyl acetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino) phenylacetic acid or Lu meter Kao Former times.

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

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

Term used herein " heparanase inhibitors " refers to, targeting, reduces or suppresses acetylsulfuric acid depolymerized heparin Compound.This term includes, but does not limit PI-88.

Term used herein " biological response modifier " refers to lymphokine or interferon, such as interferon gamma.

Term used herein " Ras carcinogenic hypotype (such as H-Ras, K-Ras or N-Ras) inhibitor " refers to targeting, reduction Or the compound of suppression Ras carcinogenic activity, such as " farnesyl transferase inhibitor ", such as L-744832, DK8G557 or R115777(Zarnestra)。

Term used herein " telomerase inhibitor " refers to targeting, reduces or suppress the compound of telomerase activation.Target To, reduce or suppress the compound of telomerase activation refer in particular to suppress telornerase receptor compound, such as telomere mycin.

Term used herein " methionine aminopeptidase inhibitor " refers to targeting, reduces or suppresses methionine aminopeptidase activity Compound.Targeting, reduce or suppress methionine aminopeptidase activity compound include bengamide or derivatives thereof.

Term used herein " proteasome inhibitor " refers to targeting, reduction 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 " matrix metallo-proteinase inhibitor " 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 oral bio equivalence homologue Marimastat (marimastat, BB-2516), Pu Masita (prinomastat, AG3340), Mei Tasita (metastat, NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996。

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

Targeting, reduce or suppress the compound of FMS-sample tyrosine kinase receptor (Flt-3R) especially to suppress Flt-3 to be subject to The compound of body kinase families member, albumen or antibody, such as PKC412, midostaurin (midostaurin), D-82041 DEISENHOFEN Derivant, SU11248 and MLN518.

Term used herein " HSP90 inhibitor " includes, but are not limited to targeting, reduces or suppress the endogenous of HSP90 The compound of atpase activity；By ubiquitin protein body enzymatic pathway degraded, targeting, reduce or suppress the chemical combination of HSP90 client protein Thing.Targeting, reduce or suppress the compound of Endogenous ATP enzymatic activity of HSP90 to refer in particular to suppress the Endogenous ATP of HSP90 The compound of enzymatic activity, albumen or antibody, such as, 17-allyl amino, 17-AAG (17AAG), its The compound that his geldanamycin is relevant, red shell rhzomorph and hdac inhibitor.

Term used herein " antiproliferation antibodies " includes, but not limited to Herceptin (Herceptin^TM), toltrazuril Monoclonal antibody-DM1, Erlotinib (Tarceva^TM), bevacizumab (Avastin^TM), RituximabPR064553 And 2C4 antibody (anti-CD40).Antibody mean complete monoclonal antibody, polyclonal antibody, by least 2 complete antibody The multi-specificity antibody formed and antibody fragment (as long as they have desired biological activity).Blood white for acute myeloid sample From the point of view of the treatment of sick (AML), the leukemia therapy of compound disclosed in this invention with standard can be used in combination, especially It is used in combination with the therapy treated for AML.Specifically, compound disclosed in this invention can be turned with such as farnesyl- Move enzyme inhibitor and/or other medicine such as daunorubicin, amycin, Ara-C, VP-16, teniposide, rice treated for AML Torr anthraquinone, idarubicin, carboplatin and PKC412 administering drug combinations.

Compound disclosed in this invention can also be advantageously utilised in the combination with other compounds or and other therapeutic agents Combination in, especially other anti-malarial agents.Such anti-malarial agents includes, but are not limited to proguanil (proguanil), chlorproguanil (chlorproguanil), trimethoprim (trimethoprim), chloroquine (chloroquine), mefloquine (mefloquine), Benflumetol (lumefantrine), atovaquone (atovaquone), pyrimethamine-sulfanilamide (pyrimethamine- Sulfadoxine), pyrimethamine-chlorobenzene (pyrimethamine-dapsone), halofantrine (halofantrine), quinine (quinine), quinidine (quinidine), amodiaquine (amodiaquine), amopyroquine (amopyroquine), sulfanilamide Class medicine, arteannuin, arteflene (arteflene), Artemether, artesunate, primaquine, suck NO, L-arginine, dipropyl Alkene triamine NONO ester (NO donor), rosiglitazone (PPARy agonist), activated carbon, erythropoietin, levamisole, And malaridine.

Compound disclosed in this invention can also be advantageously used in the combination with other compounds or other therapeutic agents In combination, such as, treat the other therapeutic agents of leishmaniasis, african trypanosomiasis, toxoplasmosis and cerebral cysticercosis.Such medicament includes, But it is not limited to Nivaquine (M B), atovaquone-proguanil, Artemether-lumenfantrine, quinine sulfate, artesunate, quinine, doxycycline (doxycycline), clindamycin (clindamycin), meglumine antimony (meglumine antimoniate), gluconic acid Antimony sodium (sodium stibogluconate), miltefosine (miltefosine), ketoconazole (ketoconazole), pentamidine (pentamidine), amphotericin B (AmB), AmB liposome, paromomycin (paromomycine), eflornithine (eflornithine), nifurtimox (nifurtimox), suramin (suramin), melarsoprol (melarsoprol), sprinkle Ni Songlong (prednisolone), benzimidazole, sulfadiazine, pyrimethamine, compound sulfamethoxazole methyl isoxazole, sulfamethoxazole, Ah Miramycin (azitromycin), atovaquone, dexamethasone, praziquantel, albendazole (albendazole), beta-lactam, Fluoroquinolones medicine, macrolides medicine, aminoglycoside medicine, sulfadiazine and pyrimethamine.

Structure and preparation thereof by active component determined by code name, common name or trade name can be from classic " The 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 data base's (such as Patents International (example Such as IMS World Publications)) in know.

Compound above-described, that can be applied in combination with compound disclosed in this invention, can be by this area skill Art personnel, prepare according to the method described in above-mentioned document and are administered.Compound disclosed in this invention can also with treated Cheng Lianyong, improves curative effect.Such as, hormone therapy or special radiotherapy are given.Compound disclosed in this invention is especially It is used as radiosensitizer, it is especially useful in the oncotherapy weak to those radiotherapeutic responses.

" combine " fixed Combination represented in single dosage unit form or the medicine box of the part for combined administration, its In compound disclosed in this invention and combined partner can be in same time individual application or can be between the regular hour Use respectively every interior, particularly make combined partner show cooperation, such as synergism.Term as used in the present invention is " common Use " or " combined administration " etc. include the single individuality being applied to selected COMBINATION OF THE INVENTION need a combination thereof to use and (such as suffer from Person), and include that wherein material is without going through identical route of administration or the therapeutic scheme used simultaneously.Art as used in the present invention Language " pharmaceutical combination product " represents the product mixed by more than one active component or obtained by combination, and has both included activity one-tenth The fixed Combination divided also includes non-fixed combinations.Term " fixed Combination " represents active component compound and group as shown in formula (I) The form accompanying by single entities or dosage in partnership is applied to patient simultaneously.Term " non-fixed combinations " represents active component such as formula (I) compound shown in and COMBINATION OF THE INVENTION all as corpus separatum simultaneously, common or limit ground without special time and be successively applied to suffer from Person, wherein this is applied in the treatment effect level providing two kinds of compounds in the patient.The latter applies also for HAART, Such as use 3 kinds or more kinds of active component.

The compounds of this invention and the purposes of pharmaceutical composition

The compounds of this invention is the inhibitor of kinase activity, the inhibitor of particularly PI3-kinase activity.For PI3-kinases The compound of inhibitor can be used for treating the most potential pathology (at least part of) owing to PI3-kinase activity improperly Disorder, such as asthma and chronic obstructive pulmonary disease (COPD)." PI3-kinase activity improperly " refers to and concrete patient In desired normal PI3-kinase activity have any PI3-kinase activity of deviation.PI3-kinases can be taked improperly, such as, lives Property exception increase, PI3-kinases distortion or control not normal form.These improperly activity can result from, such as cause not When or the process LAN of the most controlled protein kinase being activated or sudden change.Therefore, on the other hand, the present invention relates to treat institute The method stating disorder or disease.

Such disorder or disease comprise, but are not restricted to, respiratory system disease, including asthma, chronic obstructive Pneumonopathy and idiopathic pulmonary fibrosis (IPF)；Virus infects, and dislikes including viral respiratory tract infection and viral respiratory disease Change, such as asthma and COPD；Non-viral respiratory tract infection, including aspergillosis and leishmaniasis；Anaphylactic disease, including allergy Property rhinitis and atopic dermatitis；Autoimmune disease, including rheumatoid arthritis and multiple sclerosis；Diseases associated with inflammation, Including inflammatory bowel；Cardiovascular disease, including thrombosis and atherosclerosis；Malignant hematologic disease；Neurodegenerative diseases； Pancreatitis；Multiple organ dysfunction syndrome；Kidney disease；Platelet aggregation；Cancer；Motility of sperm is abnormal；Transplant rejection；Graft is arranged Scold；Injury of lung；And pain, including the pain relevant to rheumatoid arthritis or osteoarthritis, backache, systemic inflammatorome pain Bitterly, neuralgia, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia and central pain after liver. In one embodiment, such disorder comprises, respiratory system disease, including asthma and chronic obstructive pulmonary disease (COPD)；Allergy Property disease, including allergic rhinitis and atopic dermatitis；Autoimmune disease, including rheumatoid arthritis and multiple firmly Change；Diseases associated with inflammation, including inflammatory bowel；Cardiovascular disease, including thrombosis and atherosclerosis；Malignant hematologic disease； Neurodegenerative diseases；Pancreatitis；Multiple organ dysfunction syndrome；Kidney disease；Platelet aggregation；Cancer；Motility of sperm is abnormal；Move Plant repulsion；Transplant rejection；Injury of lung；And pain, including the pain relevant to rheumatoid arthritis or osteoarthritis, the back of the body Bitterly, neuralgia, diabetic neuropathy, neuro-inflammatory pain (wound), nervi trigeminus after systemic inflammatorome pain, liver Pain and central pain.

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

Compound shown in formula (I) can be given by any suitable route of administration to study subject or it is pharmaceutically acceptable Salt, including Formulations for systemic administration and topical.Formulations for systemic administration includes oral administration, parenteral, transdermal administration and straight Enteral administration.Parenteral refers to the route of administration in addition to enteral or transdermal, it is common that injects or infuses.Parenteral Including intravenous, intramuscular and subcutaneous injection or transfusion.Topical includes being applied to skin, and ophthalmic, ear, vagina In, suck and intranasal administration.Suck and refer to be administered in the lung of patient, suck whether through oral cavity or nasal cavity sucks. 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.

Can once give or give formula (I) compound or its pharmaceutically acceptable salt, in institute according to a dosage regimen State in dosage regimen, it is stipulated that period in give some dosage at various time intervals.Such as, 1 time can be given every day, 2 times, 3 times or 4 dosage.In certain embodiments, 1 dosage is given every day.In further embodiments, 2 dosage are given every day. 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 this compound, such as, inhale Receiving, be distributed and the half-life, it can be determined by professional and technical personnel.Additionally, suitable dosage regimen, during including scheme lasting Between, for formula (I) compound or its pharmaceutically acceptable salt, depend on treated disorder or disease, accept Treatment disorder or the order of severity of disease, the age of patients receiving treatment and health, the medical history of patient under consideration, with Time therapy character, expection treatment effect and some factors in the knowledge and technical skill of professional and technical personnel.Specialty Technical staff it is also understood that according to individual patient to the reaction of dosage regimen or over time passage individual patient need change Time, in order to be sufficiently accurate it may be desired to adjust suitable dosage regimen.

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

The pharmaceutical composition of the present invention or combination can be about 1-1000mg active component for the individuality of about 50-70kg, Or the unit dose of the active component of about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg Amount.The treatment effective dose of compound, pharmaceutical composition or a combination thereof depends on that the species of individuality, body weight, age and individuality are sick Disease, disorder or disease or severity to be treated.The doctor of this area common skill, clinician or veterinary can be easily Determine the effective dose of each active component for preventing, treat or suppress disorderly or progression of disease.Dosage cited above is special Property used favourable mammal, such as mice, rat, Canis familiaris L., monkey or isolated organ, tissue and specimen thereof external and In vivo test confirms.The compound of the present invention can use the most in vitro, such as aqueous solution, it is possible in suspension Or the vein of the form of aqueous solution enterally, parenterally and preferably warp uses in vivo.The scope of interior therapeutic effective dose depend on to The approach of medicine, between about 0.01-500mg/kg, or about between 1-100mg/kg.

Additionally, compound disclosed in this invention can be administered with prodrug.Term used in the present invention, this Chemical chemical combination disclosed in this invention is discharged the most in vivo when " prodrug " of the compound disclosed in invention is to deliver medicine to patient Its functional derivatives of thing.During compound disclosed in this invention with prodrug administration, those skilled in the art can implement following One in mode and more than: the internal onset time of (a) modification compound；During the internal effect lasts of (b) modification compound Between；The internal conveying of (c) modification compound or distribution；The internal dissolubility of (d) modification compound；And (e) overcomes compound institute The side effect faced or other difficult points.For preparing the typical functional derivatives of prodrug, be included in internal chemically Or the variant of compound that the mode of enzyme cracks.Comprise and prepare phosphate, amide, ester, monothioester, carbonate and carbaminate These variants be well-known to those skilled in the art.

On the one hand, the invention provides the abnormal relevant disease of PI3K or the Therapeutic Method of disorder.Described Therapeutic Method bag Include by giving patient in need that with safety and the compound disclosed in this invention of effective dose or it is pharmaceutically acceptable Salt, any one disorderly or method of disease that the treatment present invention mentions.

In some embodiments, PI3-kinases the most relevant abnormal disease or disorder include: respiratory tract disease, as asthma, Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) etc.；Virus infects, including viral respiratory tract infection and disease Toxicity respiratory tract disease deteriorates, such as asthma and COPD；Non-viral respiratory tract infection, including aspergillosis and leishmaniasis；Allergy Reactive disorder, including allergic rhinitis and atopical dermatitis；Autoimmune disease, including rheumatoid arthritis with many The property sent out hardening；Inflammatory diseases, including inflammatory bowel；Cardiovascular disease, including thrombosis and atherosclerosis；Hematologic Sick；Neurodegenerative diseases；Pancreatitis；Multiple organ failure, MOF；Nephropathy；Platelet aggregation；Cancer；Motility of sperm is abnormal；The row of transplanting Scold；Transplant rejection；Injury of lung；And pain, including the pain relevant to rheumatoid arthritis or osteoarthritis, backache, complete Neuralgia after body inflammatory pain, liver, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia and Central pain.

The compounds of this invention can be used for treating immune disease or the sense of one or more functions with B cell Dye, such as antibody tormation, antibody are presented, cytokine generates or lymphatic organ formed abnormal or worthless illness, disease or The method of disease, described illness, disease or disease include that rheumatoid arthritis, pemphigus vulgaris, essential thrombocytopenia subtract Few property purpura, systemic lupus erythematosus (sle), multiple sclerosis, myasthenia gravis, sjogren syndrome, Autoimmune hemolytic are lean Blood, ANCA associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic auto-immune urticaria, Anaphylaxis (atopic dermatitis, contact dermatitis, allergic rhinitis), Goodpasture's syndrome, AMR (antibody-mediated transplanting Repel), B cell mediation transplant rejection super acute, acute and chronic and the cancer in hemopoietic source, include but not limited to multiple bone Myeloma；Acute myeloid leukaemia；Chronic myelogenous leukemia；Lymphocytic leukemia；Myeloid leukemia；Non-Hodgkin′s lymph Tumor；Lymphoma；Polycythemia vera；Primary thrombocytosis；There is the myelofibrosis of the outer metaplasia of bone marrow；With watt Er Dengsitelun is sick.

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

The present invention includes one or more functions such as migration treating wherein basophilic granulocyte and mastocyte Or the abnormal or worthless illness of threshing, disease or the method for disease, described illness, disease or the disease of allergen-IgE-mediation Disease include anaphylactic disease (atopic dermatitis, contact dermatitis, allergic rhinitis) and other diseases such as COPD, asthma or Emphysema.

The present invention includes treating one or more functions such as cytokine of wherein T cell and generates or cell-mediated thin Abnormal or the worthless illness of cellular toxicity, disease or the method for disease, described illness, disease or disease include that rheumatoid closes Joint inflammation, multiple sclerosis, cell tissue or the acute or chronic repulsion of organ graft or the cancer in hemopoietic source.

Additionally, the present invention includes treating neurodegenerative disease, cardiovascular disease and the method for platelet aggregation.

Additionally, the present invention includes treating dermatosis such as porphyria cutanea tarda, polymorphous light eruption (polymorphous light eruption), dermatomyositis, solar urticaria, oral lichen planus, panniculitis, scleroderma, The method of urticarial vasculitis.

Additionally, the method that the present invention includes treating chronic inflammatory disease such as sarcoidosis, granuloma annulare.

In other embodiments, disease or disorder (as PI3K mediates) are selected from: polycythemia vera, constitutional Thrombocytosis, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS (adult respiratory distress syndrome), Loew are strangled and are combined Simulator sickness, eosinophilic pneumonia, parasite (particularly metazoa) infect (including TPE), bronchus Pulmonary aspergillosis, polyarteritis nodosa (including Qiu-this syndrome), eosinophilic granuloma, the impact that caused by drug reaction The disorder relevant with oxyphil cell of air flue, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, bleb Rash sample dermatitis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus (pemphisus), sick (such as hemolytic anemia, aplastic is lean for epidermolysis bullosa acquisita, autoimmune hematological Blood, pure red cell anaemia and essential thrombocytopenia reduce), systemic lupus erythematosus (sle), polychondritis, scleroderma, Wegener Granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, steven-Johnson syndrome, idiopathic sprue, self Immunity inflammatory bowel (such as ulcerative colitis and Crohn disease), endocrine ophthalmopathy, Graves disease, sarcoidosis, lung Bubble inflammation, chronic anaphylaxis pneumonia, multiple sclerosis, primary biliary cirrhosis, (front and rear) uveitis, interstitial lung Fibrosis, psoriatic arthritis, glomerulonephritis, cardiovascular disease, atherosclerosis, hypertension, dvt shape One-tenth, apoplexy, myocardial infarction, unstable angina, thromboembolism, pulmonary infarction, thromboembolism disease, Acute arterial ischeamia, outer All thrombotic occlusion and coronary artery disease, reperfusion injury, retinopathy, such as diabetic retinopathy or hyperbaric oxygen draw The retinopathy risen, and disease, the such as glaucoma being characterized is secreted with liter high intraocular pressure or aqueous humor.

In some embodiments, the abnormal relevant disorder of PI3K is pain.

In another embodiment, the compounds of this invention can be used for treatment selected from following illness or disease: constitutional Cutaneous B cell lymphoma, immunity blister disease (immunobullous disease), pemphigus vulgaris, fallen leaves sky Bleb skin ulcer, Brazilian pemphigus (Fogo selvagem), tumor form sign pemphigus (paraneoplastic Pemphigus), bullous pemphigoid, MMP, acquired epidermolysis bullosa, the anti-place of chronic graft Main disease, dermatomyositis, systemic lupus erythematosus (sle), vasculitis, polyangitis, low complement courage and uprightness urticarial vasculitis (hypocomplementemic urticarial vasculitis), anti-neutrophil cell cytoplasmic antibody associated vessels Inflammation, cryoglobulinemia, Schnitzler syndrome, macroglobulinemia Waldenstron, angioedema, white macula, it is System property lupus erythematosus, idiopathic thrombocytopenic purpura, multiple sclerosis, cold agglutinin disease, Autoimmune hemolytic are lean Blood, anti-neutrophil cell cytoplasmic antibody associated vasculitis, graft versus host disease, cryoglobulinemia and thrombotic blood are little Plate reduces disease.

In other embodiments, the present invention can be used for treating, prevent or alleviate autoimmune disease and inflammatory disease Disease, particularly etiology includes the inflammatory condition of autoimmunity component, and such as arthritis is (such as rheumatoid arthritis, slow Property enter fertility arthritis (arthritis chronic progrediente) and osteoarthrisis deformans knee) and rheumatism, bag Include inflammatory condition and the rheumatism involving bone lesion；Inflammatory pain, spondyloarthropathy (include ankylosing spondylitis, Lai Te Your syndrome, reactive arthritis, psoriatic arthritis and enteropathic arthritis (enterophathics arthritis), super Quick property (including air flue hypersensitivity and skin hypersensitivity) and anaphylaxis.The concrete autoimmune disease of antibody of the present invention can be used (such as hemolytic anemia, aplastic anemia, pure red cell anaemia and Te Fa is included including autoimmune hematological disease Property thrombocytopenia), Acquired hemophilia A, cold agglutinin disease, cryoglobulinemia, thrombotic thrombocytopenic purpura, Sjogren syndrome, systemic lupus erythematosus (sle), inflammatory muscular disorders, polychondritis, scleroderma, anti-neutrophil cell kytoplasm are anti- Body associated vasculitis, IgM mediation neuropathy, opsoclonus-myoclonic syndrome, wegener granulomatosis, dermatomyositis, Chronic active hepatitis, myasthenia gravis, psoriasis, Si-about syndrome, pemphigus vulgaris, pemphigus foliaceus, idiopathic Sprue, autoimmune inflammatory enteropathy (include that such as ulcerative colitis, segmental enteritis and intestinal easily swash comprehensive Levy), endocrine ophthalmocace change, Graves disease, sarcoidosis, multiple sclerosis, optic neuromyelitis, primary biliary liver 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 glomerule Nephritis (with without nephrotic syndrome, such as include idiopathic nephrotic syndrome or MCN), tumor, skin , metabolic disorder such as atherosclerosis, diabetes and dyslipidemia lax with cornea inflammatory diseases, myositis, bone graft (dislipidemia)。

In some embodiments, the invention provides the therapeutic use of presently disclosed compound, other are implemented In scheme, described treatment is for the treatment of the disease relevant to PI3K inhibitory action.In other embodiments, can control The disease treated is selected from above-mentioned list of diseases, including autoimmune disease, diseases associated with inflammation, anaphylactic disease, airway disorders (e.g., asthma and COPD), transplant rejection；Antibody tormation, antibody are presented, cytokine generates or lymphatic organ formation is abnormal Or worthless disease or disease, including rheumatoid arthritis, pemphigus vulgaris, idiopathic thrombocytopenic purpura, Systemic lupus erythematosus (sle), multiple sclerosis, myasthenia gravis, sjogren syndrome, autoimmune hemolytic anemia, ANCA are relevant Property vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic auto-immune urticaria, anaphylaxis (special send out Property dermatitis, contact dermatitis, allergic rhinitis), Goodpasture's syndrome, AMR (antibody-mediated transplant rejection), B cell The transplant rejection super acute, acute and chronic of mediation and hemopoietic source cancer, include but not limited to multiple myeloma；Leukemia； Acute myeloid leukaemia；Chronic myelogenous leukemia；Lymphocytic leukemia；Myeloid leukemia；Non-Hodgkin lymphoma；Lymph Tumor；Polycythemia vera；Primary thrombocytosis；There is the myelofibrosis of the outer metaplasia of bone marrow；With Walden this Special human relations are sick.Wherein said disease or disease are selected from rheumatoid arthritis (RA), pemphigus vulgaris (PV), essential thrombocytopenia Minimizing property purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune hemolytic anemia (AIHA), acquired Hemophilia A (AHA), systemic lupus erythematosus (sle) (SLE), multiple sclerosis (MS), myasthenia gravis (MG), sjogren syndrome (SS), ANCA associated vasculitis, cryoglobulinemia, chronic auto-immune urticaria (CAU), anaphylaxis (idiopathic skin Inflammation, contact dermatitis, allergic rhinitis), Goodpasture's syndrome, transplant rejection and make haematogenous cancer；Equally control Treat the disease relevant to immunopathology or infection, such as severe malaria, cerebral malaria, african trypanosomiasis, leishmaniasis, toxoplasmosis and brain Cysticercosis.

Therefore, in some more particular embodiments, the present invention relates to the compound of any of above embodiment at PI3K The application of disease mediated medicine manufacture view；In other embodiments, described medicine is that treatment suppresses with PI3K The medicine of the disease that effect is relevant；In other embodiments, the disease that can treat is selected from above-mentioned list of diseases, including Autoimmune disease, diseases associated with inflammation, anaphylactic disease, airway disorders (e.g., asthma and COPD), transplant rejection；Antibody tormation, Antibody is presented, cytokine generates or lymphatic organ formation is abnormal or worthless disease or disease, including rheumatoid Arthritis, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus (sle), multiple sclerosis, serious symptom flesh without Power, sjogren syndrome, autoimmune hemolytic anemia, ANCA associated vasculitis, cryoglobulinemia, Thrombotic Thrombocytopenic Minimizing property purpura, chronic auto-immune urticaria, anaphylaxis (atopic dermatitis, contact dermatitis, allergic rhinitis), Gourde(G) Paasche mound syndrome, AMR (antibody-mediated transplant rejection), B cell mediation transplant rejection super acute, acute and chronic and make Blood source cancer, includes but not limited to multiple myeloma；Leukemia；Acute myeloid leukaemia；Chronic myelogenous leukemia；Lymph is thin Born of the same parents' property leukemia；Myeloid leukemia；Non-Hodgkin lymphoma；Lymphoma；Polycythemia vera；Idiopathic thrombocythemia Disease；There is the myelofibrosis of the outer metaplasia of bone marrow；And Waldenstrom.Wherein said disease or disease are selected from rheumatoid Arthritis (RA), pemphigus vulgaris (PV), idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic are purple Purplish or white patches on the skin (TTP), autoimmune hemolytic anemia (AIHA), Acquired hemophilia A type (AHA), systemic lupus erythematosus (sle) (SLE), Multiple sclerosis (MS), myasthenia gravis (MG), sjogren syndrome (SS), ANCA associated vasculitis, cryoglobulinemia, slow Property autoimmune urticaria (CAU), anaphylaxis (atopic dermatitis, contact dermatitis, allergic rhinitis), Goodpasture combine Simulator sickness, transplant rejection and make haematogenous cancer；Equally treat the disease relevant to immunopathology or infection, such as serious malaria Disease, cerebral malaria, african trypanosomiasis, leishmaniasis, toxoplasmosis and cerebral cysticercosis.

General building-up process

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

Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation.Following reaction scheme and embodiment are used for being further illustrated by present disclosure.

The professional of art is it will be appreciated that chemical reaction described in the invention can be used to prepare perhaps suitably Other compounds of many present invention, and it is considered as the model in the present invention for other method of the compound of preparing the present invention Within enclosing.Such as, the synthesis according to the compound of those non-illustrations of the present invention can be successfully by those skilled in the art Completed by method of modifying, as group is disturbed in suitable protection, by utilizing reagent known to other except described in the invention , or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applicable to the preparation of other compounds of the present invention.

The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, the most not through being further purified, unless other aspects show during use.General reagent is western Gansu Province chemical industry from Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Tianjin good fortune chemistry in morning Chemical reagent work, Wuhan Xin Huayuan development in science and technology company limited, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao purchase Can buy.

Anhydrous tetrahydro furan, dioxane, toluene, ether is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, normal hexane, N,N-dimethylacetamide and N, N- Dimethylformamide is to be dried in advance through anhydrous sodium sulfate to use.

Hereinafter reaction is usually and overlaps a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb the most suitable rubber closure, substrate is squeezed into by syringe.Glass drying oven 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, and the nuclear magnetic resonance spectrometer of Brooker (Bruker) 400MHz or 600MHz, with CDC1₃、DMSO-d₆、CD₃OD Or acetone-d₆For solvent (in units of ppm), with TMS (0ppm) or chloroform (7.26ppm) as reference standard.Many when occurring The when of weight peak, by use following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triple Peak), hept (heptet, septet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant, represents with J, and unit is conspicuous Hereby (Hz).

The test condition of Algorithm (MS) data is: Agilent 6120Quadrupole HPLC-MS (pillar Model: Zorbax SB-C18,2.1 × 30mm, 3.5 μm, 6min, flow velocity is 0.6mL/min, and flow phase: 5%-95% (contains The CH of 0.1% formic acid₃CN) at (H containing 0.1% formic acid₂O) ratio in), detect at 210nm/254nm UV, use electron spray Ionization pattern (ESI).

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

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

ATP adenosine triphosphate

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

AcOK,CH₃COOK potassium acetate

BBr₃Boron tribromide

Bu₄NF tetrabutyl ammonium fluoride

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

BINAP 2,2'-pair-(diphenyl phosphine)-1,1'-dinaphthalene

BSA bovine serum albumin

BOC, Boc tert-butoxycarbonyl

N-BuOH n-butyl alcohol

N-BuLi n-BuLi

(n-Bu)₃SnCl tri-n-butyltin chloride

Ca(SO₃CF₃)₂Trifluoromethyl calcium sulfate

Cs₂CO₃Cesium carbonate

CCl₄Carbon tetrachloride

CHCl₃Chloroform

CDCl₃Deuterochloroform

CH₂Cl₂, DCM dichloromethane

CH₃CN acetonitrile

CH₃CHCN propionitrile

(CH₃)₂CHCN isopropyl cyanide

CH₃Cl chloromethanes

CH₃I iodomethane

CsF cesium fluoride

CH₃SO₂Cl, MsCl methylsufonyl chloride

Cu copper

CuI Hydro-Giene (Water Science).

DCC N, N'-dicyclohexylcarbodiimide

DBU 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene

DIBAL diisobutyl aluminium hydride

DIAD diisopropyl azodiformate

DIEA,DIPEA,iPr₂Net N, N-diisopropylethylamine

DEAD diethyl azodiformate

DMF DMF, dimethylformamide

DMAP DMAP

DMSO dimethyl sulfoxide

DMFDMA N,N-dimethylformamide dimethylacetal

DPPA diphenyl phosphate azide

DTT DTT

EDC, EDCI 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride

EDTA ethylenediaminetetraacetic acid

EtOAc, EA ethyl acetate

Et₃N, TEA triethylamine

Et₂O ether

EtOH ethanol

FBS hyclone

G gram

H hour

HATU 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester

HBr hydrobromic acid

HBTU O-BTA-N, N, N', N'-tetramethylurea hexafluorophosphate

HCl hydrochloric acid

HOAT N-hydroxyl-7-azepine BTA

HOBt I-hydroxybenzotriazole hydrate

H₂Hydrogen

H₂O water

H₂O₂Hydrogen peroxide

H₃PO₄Phosphoric acid

H₂SO₄Sulphuric acid

HNO₃Nitric acid

HCOOK potassium formate

HCOONH₄Ammonium formate

HMDS hmds

I₂Iodine

Fe ferrum

The silica-based lithium of LiHMDS hexamethyl two

LDA lithium diisopropyl amido

MBP myelin basic protein

MCPBA metachloroperbenzoic acid

MeCN,CH₃CN acetonitrile

MgSO₄Magnesium sulfate

Mg ATP adenosine triphosphate magnesium

MeOH,CH₃OH methanol

MeI,CH₃I iodomethane

MOPS 3-(N-morpholino) propane sulfonic acid

ML, ml milliliter

Min minute

N₂Nitrogen

NH₃Ammonia

NMP N-Methyl pyrrolidone

NaHCO₃Sodium bicarbonate

NaBH₄Sodium borohydride

NaBH₃CN sodium cyanoborohydride

NaOtBu sodium tert-butoxide

NaOMe,NaOCH₃,CH₃ONa Feldalat NM

NaOH sodium hydroxide

NaClO₂Sodium chlorite

NaCl sodium chloride

NaH₂PO₄Sodium dihydrogen phosphate

NaH sodium hydride

NaI sodium iodide

Na₂SO₄Sodium sulfate

Na₂S₂O₃Sodium thiosulfate

NBS N-bromo-succinimide

NIS N-N-iodosuccinimide

NCS N-chlorosuccinimide

NEt₃Triethylamine

Nonidet promise is lotion

NH₃Ammonia

NH₄Cl ammonia chloride

NH₂OH HCl oxammonium hydrochloride.

(NH₄)₂Ce(NO₃)₆Ammonium ceric nitrate

Pd/C palladium/carbon

Pd₂(dba)₃Three (dibenzalacetone) two palladium

Pd(OAc)₂Palladium

Pd(OH)₂Palladium dydroxide

Pd(PPh₃)₄Tetrakis triphenylphosphine palladium

Pd(PPh₃)₂Cl₂Double (triphenylphosphine) palladium chloride

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

Pd(dppf)Cl₂·CH₂Cl₂1,1 '-two (diphenylphosphino) ferrocene palladium chloride dichloromethane complex

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

PE petroleum ether (60-90 DEG C)

PBS phosphate buffered saline (PBS)

POCl₃Phosphorus oxychloride

K₂CO₃Potassium carbonate

KOH potassium hydroxide

RT, rt, r.t. room temperature

Rt retention time

SOCl₂Thionyl chloride

SO₂Cl₂Sulfonic acid chloride

T-BuOK potassium tert-butoxide

TBTU O-BTA-N, N, N', N'-tetramethylurea Tetrafluoroboric acid ester

THF oxolane

TFA trifluoroacetic acid

TBAI tetrabutylammonium iodide

TBS TBS

Tris trishydroxymethylaminomethane

TsCl paratoluensulfonyl chloride

Zn zinc

μ L microlitre

Following synthetic schemes lists the experimental procedure of compound disclosed in the preparation present invention.Wherein, R¹And R²The most independent Ground is H, F, Cl, H₂N-C_1-4Alkylidene, optionally substituted C_1-3Alkyl, optionally substituted C_3-6Cycloalkyl or optionally substituted benzene Base；R³And R⁴It is each independently H or optionally substituted C_1-3Alkyl；W is N or CH.

Synthetic schemes 1

Intermediate(7)Can be synthesized by the method described by synthetic schemes 1.First, benzoic acid(1)Elder generation and SOCl₂? React under reflux temperature and in non-polar solven (such as toluene), the product obtained adds compound(2)Continue reaction to obtain Compound(3).It follows that compound (3) elder generation and SOCl₂At a reflux temperature with reaction in non-polar solven (such as toluene), To product in add compound(4)Continue reaction and obtain compound(5).Then, the substituted compound of nitro(5)At zinc powder Compound is generated with there is reduction and cyclization in the presence of acid (such as acetic acid)(6).Finally, compound(6)In acid condition Take off the blocking group on amino and generate intermediate(7)。

Synthetic schemes 2

Intermediate(7)Can also be synthesized by the method described by synthetic schemes 2.First, compound(3)Occur reduction anti- Compound should be generated(8).Compound(8)Acid with Boc protection(4)Coupling reaction generationization is there is in the presence of EDCI or HATU Compound(9).It follows that compound(9)At the double trimethylsilyl acetamide of N, O-(10), occur cyclisation anti-in the presence of DMAP and alkali Compound should be generated(6).Finally, compound(6)Take off the blocking group on amino in acid condition and generate intermediate(7)。

Synthetic schemes 3

Intermediate(16)Can also be synthesized by the method described by synthetic schemes 3.Benzoic acid(11)Elder generation and SOCl₂Or (COCl)₂At a reflux temperature with reaction in non-polar solven (such as toluene), the mixture obtained adds compound(2)? To compound(12).Compound(4)With compound(13)The reacting generating compound (such as triethylamine) in the presence of a base(14).Chemical combination Thing(14)With compound(15)Generate mixture A under nitrogen protection.Compound(12)In the presence of alkali (such as n-BuLi) and nitrogen Mixture B is generated under gas shielded.Then, mixture A first reacts with mixture B, and the product obtained generates middle again with acid reaction Body(16).

Synthetic schemes 4

Targeted kinase inhibitor(25)Can be prepared by the method described by synthetic schemes 4.First, compound(17)With SOCl₂Reaction is converted into chloride compounds(19).Then, chloride compounds(19)With compound(20)In alkalescence condition Lower reacting generating compound(21).It follows that compound(21)With NH₃Reacting generating compound(22).Compound(22)Closing It is cyclized (in the presence of burgess reagent (Burgess reagent) or Trifluoromethanesulfonic anhydride and pyridine) under conditions of Shi Reacting generating compound(23).Finally, compound(23)In the basic conditions, with intermediate(24)React raw at a reflux temperature Become targeted kinase inhibitor(25)。

Synthetic schemes 5

Targeted kinase inhibitor(31)Can be prepared by the method described by synthetic schemes 5.First, acetonitrile(26) First with oxammonium hydrochloride. reacting generating compound in the basic conditions(27).Then, compound(27)With compound(19)Reaction is raw Become compound(28).It follows that compound(28)The generation substituted compound of amino is reacted with ammonia(29).Compound(29)? Bu₄Cyclisation is occurred to generate compound in the presence of NF(30).Finally, compound(30)In the basic conditions with intermediate(24) Reaction generates targeted kinase inhibitor at a reflux temperature(31)。

Synthetic schemes 6

Targeted kinase inhibitor(39)Can be prepared by the method described in synthetic schemes 6.First, compound(32)With Feldalat NM reacting generating compound at a reflux temperature(33).Compound(33)Anti-with oxammonium hydrochloride. the most in the presence of a base Compound should be generated(34).It follows that compound(34)At (NH₄)₂Ce(NO₃)₆It is catalyzed lower and cyano compound(35)Add Annellated reacting generating compound(36).Compound(36)Reflux in the presence of chlorinating agent (such as phosphorus oxychloride) again, above it Methoxyl group change into chlorine, generate compound(37).Compound(37)Under ammonia atmosphere, reaction generates mono amino substitutedization Compound(38).Finally, compound(38)With intermediate(24)React generation targeted kinase inhibitor in the basic conditions(39)。

Synthetic schemes 7

Targeted kinase inhibitor(49)Can be prepared by the method described in synthetic schemes 7.First, compound(40)With compound(41)React generation compound(42).Compound(42)Occur with tributyltin chloride in the presence of a base Reacting generating compound(43).Compound(43)With compound in the presence of Pd catalyst(44)Coupling reaction is occurred to generate chemical combination Thing(45).Compound(45)Reflux in acid condition, the methoxyl group above it is changed into hydroxyl, generate compound(46)。 It follows that compound(46)Reflux in the presence of phosphorus oxychloride again, the hydroxyl above it is changed into chlorine, generate compound(47).Compound(47)Under ammonia atmosphere, reaction generates the substituted compound of mono amino(48).Finally, compound(48)In with Mesosome(24)React generation targeted kinase inhibitor in the basic conditions(49)。

Synthetic schemes 8

Targeted kinase inhibitor(59)Can be prepared by the method described in synthetic schemes 8.First, compound(50)With compound(51)Reacting generating compound(52).Then, compound(52)With compound(53)Reacting generating compound(54).It follows that compound(54)With chloride compounds(19)Reacting generating compound(55).Compound(55)Again and NH₃Instead Compound should be generated(56).Compound(56)Compound is generated in the presence of alkali and triphenylphosphine(57).Compound(57)In acid Take off the blocking group on amino under the conditions of property and generate compound(58).Finally, compound(58)With intermediate(24)In alkalescence Under the conditions of react generation targeted kinase inhibitor(59)。

Detailed description of the invention

Embodiment 1 (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-5-chloro-3-cyclopropyl quinazoline-4 (3H)-one

By compound (S)-2-(1-amino-ethyl)-5-chloro-3-cyclopropyl quinazoline-4 (3H)-one (100.3mg, 0.379mmol), the chloro-5-of 6-(5-methyl isophthalic acid, 3,4-diazole-2-bases) pyrimidine-4-amine (89.6mg, 0.417mmol), DIPEA The mixture of (99.8mg, 0.379mmol) and n-BuOH (4mL) is heated to 125 DEG C, and stirring reaction 6 hours at this temperature, Being then cooled to room temperature, concentrating under reduced pressure, it is white solid that gained residue obtains target compound through silica gel column chromatography purification (160mg, 95%).

MS(ESI,pos.ion)m/z:439.2[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆) δ (ppm): 8.88 (d, J=7.0Hz, 1H), 8.06 (s, 1H), 7.70 (t, J= 8.0Hz, 1H), 7.50 (d, J=8.0Hz, 2H), 7.29 (s, 2H), 6.13-6.05 (m, 1H), 3.16 (m, 1H), 2.62 (s, 3H), 1.59 (d, J=6.6Hz, 3H), 1.26 (m, J=5.6Hz, 2H), 1.07 (m, J=6.8Hz, 1H), 0.87 (m, J= 10.1Hz,1H)。

Embodiment 2 (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-5-fluoro-3-phenylquinazoline-4 (3H)-one

By compound (S)-2-(1-amino-ethyl)-5-fluoro-3-phenylquinazoline-4 (3H)-one (53.5mg, 0.189mmol), the chloro-5-of 6-(5-methyl isophthalic acid, 3,4-diazole-2-bases) pyrimidine-4-amine (58.7mg, 0.277mmol) and The DIPEA (53.5mg, 0.414mmol) mixture in n-BuOH (2mL) is heated to 125 DEG C and stirs reaction 26 hours, so After be cooled to room temperature, concentrating under reduced pressure, gained residue obtains title through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purification Compound is white solid (59mg, 68.2%).

MS(ESI,pos.ion)m/z:459.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.75 (d, J=6.8Hz, 1H), 7.96 (s, 1H), 7.89-7.81 (m, 1H), 7.59 (s, 2H), 7.57 (d, J=4.9Hz, 3H), 7.50 (d, J=8.2Hz, 1H), 7.36-7.22 (m, 3H), 4.88 (dd, J=13.3,6.6Hz, 1H), 2.62 (s, 3H), 1.38 (d, J=6.6Hz, 3H).

Embodiment 3 (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-3-cyclopropyl-5-Fluquinconazole quinoline-4 (3H)-one

Step 1) (S)-(1-(2-fluoro-N-cyclopropyl-6-nitrobenzamide base)-1-oxopropan-2-base) amino first Tert-butyl acrylate

Fluoro-for compound 2-N-cyclopropyl-6-nitrobenzamide (2.0g, 8.9mmol) is suspended in toluene (20mL), Then in reactant liquor, SOCl is disposably added in room temperature₂(2.46g, 20.7mmol), mixture is stirred overnight at 120 DEG C, subtracts Pressure is concentrated to give light brown grease, is dissolved in by gained grease in anhydrous methylene chloride (30mL), obtains yellow solution.Will (S)-2-((tertbutyloxycarbonyl) amino) propanoic acid (1.86g, 9.83mmol) and DIPEA (2.5g, 19mmol) are dissolved in anhydrous two In chloromethanes (20mL), then at 0 DEG C, gained solution is slowly added in above-mentioned yellow solution, mixture is warming up to room Temperature also stirs reaction 24 hours, washes with water (30mL) and saturated aqueous common salt (30mL) the most successively, and separatory, organic facies is with anhydrous Sodium sulfate is dried, concentrating under reduced pressure, and gained residue obtains titled through silica gel column chromatography (PE/EtOAc (v/v)=8/1) purification Compound is yellow solid (1.63g, 48%).

MS(ESI,pos.ion)m/z:296.2[M-Boc+2H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.03 (s, 1H), 7.57-7.47 (m, 1H), 7.42 (t, J=8.3Hz, 1H), 5.31 (t, 1H), 1.40 (d, J=8.1Hz, 12H), 1.29-0.75 (m, 5H).

Step 2) (S)-(1-(5-fluoro-3-cyclopropyl-4-oxo-3,4-dihydroquinazoline-2-base) ethyl) carbamic acid The tert-butyl ester

By compound (S)-(1-(2-fluoro-N-cyclopropyl-6-nitrobenzamide base)-1-oxopropan-2-base) amino T-butyl formate (1.63g, 4.12mmol) is dissolved in acetic acid (12mL), then disposably adds zinc in the reactant liquor of stirring Powder (1.14g, 17.4mmol), gained mixture was 35 DEG C of stirring reactions 24 hours, and then sucking filtration, by filtrate reduced in volume, institute Residue through silica gel column chromatography (PE/EtOAc (v/v)=10/1) purification obtain title compound be faint yellow solid (0.6g, 40%).

MS(ESI,pos.ion)m/z:348.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 7.60 (dt, J=8.1,4.1Hz, 1H), 7.39 (d, J=8.2Hz, 1H), 7.06 (dd, J=10.4,8.4Hz, 1H), 5.72-5.54 (m, 2H), 2.96-2.91 (m, 1H), 1.47 (d, J= 6.3Hz, 3H), 1.45 (s, 8H), 1.37 (t, J=11.1Hz, 2H), 1.31-1.18 (m, 2H).

Step 3) (S)-2-(1-amino-ethyl)-5-fluoro-3-cyclopropyl quinazoline-4 (3H)-one

By compound (S)-(1-(5-fluoro-3-cyclopropyl-4-oxo-3,4-dihydroquinazoline-2-base) ethyl) amino first Tert-butyl acrylate (0.6g, 2mmol) is dissolved in ethyl acetate (1.5mL), then disposably adds in reactant liquor at room temperature condition Entering the EtOAc solution (4M, 1.25mL) of HCl, mixture is stirred at room temperature overnight, and gained residue is dissolved in water (30mL), Aqueous phase ethyl acetate (40mL × 2) extracts, and adds Na₂CO₃Aqueous phase is regulated to pH=8, gained mixture acetic acid second by powder Ester (100mL × 3) extracts, and the organic facies saturated aqueous common salt (200mL) of merging is washed, and is dried with anhydrous sodium sulfate, concentrating under reduced pressure Obtaining title compound is faint yellow solid (0.16g, 40%).

MS(ESI,pos.ion)m/z:248.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 7.61 (td, J=8.2,5.5Hz, 1H), 7.40 (d, J=8.2Hz, 1H), 7.05 (dd, J=10.5,8.3Hz, 1H), 4.76 (dd, J=6.6Hz, 1H), 2.99-2.83 (m, 1H), 1.45 (d, J= 6.6Hz,3H),1.40-1.28(m,2H),0.94-0.87(m,2H)。

Step 4) (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) second Base)-3-cyclopropyl-5-Fluquinconazole quinoline-4 (3H)-one

By compound (S)-2-(1-amino-ethyl)-5-fluoro-3-cyclopropyl quinazoline-4 (3H)-one (150mg, 0.607mmol), the chloro-5-of 6-(5-methyl isophthalic acid, 3,4-diazole-2-bases) pyrimidine-4-amine (141.5mg, 0.669mmol) and The DIPEA (256mg, 2.05mmol) mixture in n-BuOH (5ml) is heated to backflow and stirs reaction 17 hours, the coldest But to room temperature, concentrating under reduced pressure, gained residue obtains titled through silica gel column chromatography (DCM/MeOH (v/v)=100/1) purification Compound faint yellow solid (100mg, 39%).

MS(ESI,pos.ion)m/z:423.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.64 (d, J=7.2Hz, 1H), 8.14 (s, 1H), 7.62 (td, J= 8.1,5.4Hz, 1H), 7.41 (d, J=8.2Hz, 1H), 7.07 (dd, J=10.4,8.3Hz, 1H), 6.31 (p, J=6.7Hz, 1H), 3.12-2.97 (m, 1H), 2.72 (s, 3H), 1.65 (d, J=6.6Hz, 3H), 1.43 (dt, J=6.9,3.4Hz, 2H), 1.15-1.05(m,1H),1.01-0.91(m,1H)。

Embodiment 4 (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-3-cyclopropyl-5-methylquinazolin-4 (3H)-one

Step 1) (S)-N-(2-aminopropionyl)-N-cyclopropyl-2-methyl-6-nitrobenzamide

Compound N-cyclopropyl-2-methyl-6-nitrobenzamide (4.6g, 21mmol) is suspended in toluene (50mL) In, in reactant liquor, disposably add SOCl the most at ambient temperature₂(6.4mL, 88.4mmol), mixture stirs at 120 DEG C Mix overnight, be concentrated under reduced pressure to give pale brown oil thing, this grease is dissolved in dichloromethane (50mL) obtains faint yellow molten Liquid.

By compound (2S)-2-(t-butoxycarbonyl amino) propanoic acid (4.18g, 22.1mmol) and DIPEA (5.71g, 44.2mmol) it is dissolved in 100mL anhydrous methylene chloride, is then slowly added to above-mentioned gained yellow solution, mixture at 0 DEG C Stirring reaction 24 hours, washes with water (100mL) and saturated aqueous common salt (100mL), separatory the most successively at ambient temperature, organic Being dried with anhydrous sodium sulfate, concentrating under reduced pressure, gained residue obtains through silica gel column chromatography (PE/EtOAc (v/v)=7/1) purification It is yellow solid (6.58g, 72.4%) to title compound.

MS(ESI,pos.ion)m/z:292.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.06(s,1H),7.68(s,1H),7.54(s,1H),7.28(s, 1H), 5.02 (s, 1H), 2.96 (s, 1H), 2.27 (d, J=46.8Hz, 3H), 1.99 (s, 1H), 1.34 (s, 9H), 1.26 (d, J =11.4Hz, 2H), 1.18 (t, J=7.1Hz, 2H).

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

By compound (S)-N-(2-aminopropionyl)-N-cyclopropyl-2-methyl-6-nitrobenzamide (7.8g, 27mmol) being dissolved in acetic acid (54mL), then disposably add zinc (7g, 107.7mmol) in reactant, mixture is 35 DEG C stirring reaction 24 hours, then sucking filtration, by gained filtrate reduced in volume, residue is dissolved in ethyl acetate (300mL), The saturated NaHCO of gained mixture₃Aqueous solution (100mL × 2) and saturated aqueous common salt (200mL) are washed, and separatory, organic facies is with anhydrous Sodium sulfate is dried, concentrating under reduced pressure, and gained residue obtains titled through silica gel column chromatography (PE/EtOAc (v/v)=8/1) purification Compound is faint yellow solid (6g, 65%).

MS(ESI,pos.ion)m/z:344.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 7.58 (t, J=7.7Hz, 1H), 7.37 (d, J=8.0Hz, 1H), 7.29 (d, J=7.5Hz, 1H), 7.21 (d, J=7.4Hz, 1H), 5.33 (p, J=6.6Hz, 1H), 3.02-2.92 (m, 1H), 2.73 (s, 3H), 1.40 (d, J=6.8Hz, 3H), 1.37 (s, 9H), 1.26-1.20 (m, 2H), 1.00-0.77 (m, 2H).

Step 3) (S)-2-(1-amino-ethyl)-3-cyclopropyl-5-methylquinazolin-4 (3H)-one

By compound (S)-(1-(3-cyclopropyl-5-methyl-4-oxo-3,4-dihydroquinazoline-2-base) ethyl) amino T-butyl formate (0.32g, 1.3mmol) is dissolved in ethyl acetate (10mL), the most at ambient temperature, in reactant one Secondary property adds the ethyl acetate solution (4M, 10mL) of hydrogen chloride, and mixture stirred overnight at room temperature, gained float is dissolved in water (150mL) in, aqueous phase ethyl acetate (30mL × 3) is washed, and adds powdered sodium carbonate and regulates to pH=8, gained mixture second Acetoacetic ester (100mL × 4) extracts, and the organic facies saturated aqueous common salt (200mL) of merging is washed, and is dried with anhydrous sodium sulfate, decompression It is concentrated to give title compound pale white solid, the most purified, it is directly used in next step reaction.

MS(ESI,pos.ion)m/z:244.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 7.44 (t, J=7.7Hz, 1H), 7.26 (d, J=8.0Hz, 1H), 7.06 (d, J=7.3Hz, 1H), 2.91-2.84 (m, 1H), 2.59 (s, 3H), 2.36 (s, 1H), 1.22 (d, J=6.5Hz, 3H),1.12-0.99(m,2H),0.80-0.55(m,2H)。

Step 4) (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) second Base)-3-cyclopropyl-5-methylquinazolin-4 (3H)-one

To compound (S)-2-(1-amino-ethyl)-3-cyclopropyl-5-methylquinazolin-4 (3H)-one (121mg, 0.5mmol) with the chloro-5-of 6-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-amine (119mg, 0.5mmol) at n-BuOH (10mL) adding DIPEA (129mg, 0.99mmol) in mixture, gained mixture is stirred overnight at 120 DEG C, concentrating under reduced pressure, It is beige solid that gained residue obtains title compound through Flash silica column chromatography (PE/EtOAc (v/v)=1/3) purification (100mg, 45%).

MS(ESI,pos.ion)m/z:419.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.91 (d, J=7.1Hz, 1H), 8.07 (s, 1H), 7.61 (t, J= 7.7Hz, 1H), 7.39 (d, J=8.1Hz, 1H), 7.24 (d, J=7.3Hz, 1H), 3.18-3.07 (m, 1H), 2.74 (s, 3H), 2.62 (s, 3H), 2.51 (s, 1H), 1.58 (d, J=6.6Hz, 3H), 1.25 (d, J=7.8Hz, 2H), 1.11-0.76 (m, 2H)。

Embodiment 5 (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-5-methyl-3-phenylquinazoline-4 (3H)-one

Step 1) 2-amino-6-Methyl-N-phenyl Benzoylamide

At room temperature condition, to compound 2-methyl-6-nitro-N-phenylbenzamide (1.97g, 7.69mmol), activity Ethanol (15mL, the 258mmol) mixture of carbon (0.22g) and iron chloride (11.0mg, 0.0678mmol) is added dropwise over hydration Hydrazine (1.35g, 27.0mmol), then 80 DEG C of stirring reactions 2.5 hours, then adds hydrazine hydrate (2.7g, 54.0mmol), Gained mixture is at 80 DEG C of stirring reactions 1 hour, sucking filtration, and filter cake EtOH (30mL) washes, and by filtrate reduced in volume, gained remains Thing use water/acetone (20mL/2mL) dilution, gained suspension is stirred at room temperature 1 hour, sucking filtration, after filter cake water (20mL) is washed, Obtaining title compound 65 DEG C of vacuum drying is white solid (1.01g, 55.6%).MS(ESI,pos.ion)m/z:227.1 [M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 7.64 (d, J=8.0Hz, 2H), 7.49 (s, 1H), 7.40 (t, J= 8.0Hz, 2H), 7.19 (t, J=8.0Hz, 1H), 7.11 (t, J=6.0Hz, 1H), 6.65 (d, J=8.0Hz, 1H), 6.60 (d, J=8.0Hz, 1H), 4.21 (s, 2H), 2.43 (s, 3H).

Step 2) (S)-(1-((3-methyl-2-(phenylcarbamoyl) phenyl) amino)-1-oxopropan-2-base) ammonia Base t-butyl formate

By compound 2-amino-6-Methyl-N-phenyl Benzoylamide (1.0g, 4.4mmol), (2S)-2-(tertbutyloxycarbonyl Amino) propanoic acid (1.0g, 5.3mmol) and HATU (2.05g, 5.39mmol) be dissolved in dichloromethane (6mL), then at 0 DEG C, Being added dropwise over DIPEA (1.16g, 8.89mmol) in reactant, mixture, 0 DEG C of stirring reaction 1 hour, is heated to 45 DEG C also Stirring reaction 20 hours, is then cooled to room temperature, concentrating under reduced pressure, and residue is dissolved in ethyl acetate (30mL), and gained mixes Thing successively with water (25mL × 2), NaOH aqueous solution (2.5M, 25mL × 2), HCl/water solution (1.0M, 25mL × 2) and saturated food Saline (25mL × 2) is washed, separatory, and organic facies anhydrous sodium sulfate is dried, concentrating under reduced pressure, and obtaining title compound is white solid (1.59g, 91%).

MS(ESI,neg.ion)m/z:396.20[M-H]^?；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.75 (s, 1H), 7.94 (s, 1H), 7.65 (d, J=8.0Hz, 3H), 7.39 (t, J=8.0Hz, 2H), 7.33 (t, J=8.0Hz, 1H), 7.19 (t, J=6.0Hz, 1H), 7.12 (d, J=8.0Hz, 1H), 4.93 (d, J=4.0Hz, 1H), 4.26 (s, 1H), 2.47 (s, 3H), 1.42 (s, 9H), 1.33-1.28 (m, 3H).

Step 3) (S)-(1-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazoline-2-base) ethyl) carbamic acid The tert-butyl ester

By compound (S)-(1-((3-methyl-2-(phenylcarbamoyl) phenyl) amino)-1-oxopropan-2-base) T-butyl carbamate (1.0g, 2.5mmol), DMAP (304.3mg, 2.491mmol) and DIPEA (648.7m g, 5.019mmol) it is dissolved in CH₃In CN (5mL), the most at ambient temperature, in reactant liquor add BSA (2.55g, 12.5mmol), heating the mixture to backflow and stir reaction 5 hours, TLC display material unreacted is complete, again adds BSA (2.55g, 12.5mmol), and continue, reflux temperature stirring reaction 1.5 hours, to be cooled to room temperature, reactant is poured into second In acetoacetic ester (50mL), gained mixture is successively with hydrochloride aqueous solution (1M, 30mL × 2) and saturated aqueous common salt (30mL × 2) Washing, separatory, organic facies anhydrous sodium sulfate is dried, and being concentrated under reduced pressure to give title compound is yellow solid (610mg, 64%). MS(ESI,pos.ion)m/z:380.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 7.70-7.24 (m, 9H), 4.13 (t, J=6.0Hz, 1H), 2.71 (s, 3H), 1.32 (s, 9H), 1.18 (d, J=8.0Hz, 3H).

Step 4) (S)-2-(1-amino-ethyl)-5-methyl-3-phenylquinazoline-4 (3H)-one

By compound (S)-(1-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazoline-2-base) ethyl) amino first Tert-butyl acrylate (500mg, 1.318mmol) is dissolved in ethyl acetate (12mL), then disposably adds chlorination in reactant liquor The ethyl acetate solution (4M, 4mL) of hydrogen, is stirred at room temperature reaction 4 hours, and aqueous phase ethyl acetate (30mL) extracts, and adds carbonic acid Aqueous phase is neutralized to pH=8 by sodium powder, then extracts by ethyl acetate (20mL x 3), the organic facies saturated aqueous common salt of merging (20mL) washing, be dried with anhydrous sodium sulfate, being concentrated under reduced pressure to give title compound is white solid (320mg, 86.42%).

MS(ESI,pos.ion)m/z:280.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 7.65-7.52 (m, 5H), 7.31 (d, J=4.0Hz, 2H), 7.25 (d, J=8.0Hz, 1H), 3.73-3.68 (m, 1H), 2.84 (s, 3H), 1.30 (d, J=8.0Hz, 3H).

Step 5) (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) second Base)-5-methyl-3-phenylquinazoline-4 (3H)-one

By compound (S)-2-(1-amino-ethyl)-5-methyl-3-phenylquinazoline-4 (3H)-one (100.0mg, 0.3559mmol), the chloro-5-of 6-(5-methyl isophthalic acid, 3,4-diazole-2-bases) pyrimidine-4-amine (75.8mg, 0.358mmol) dissolves In n-BuOH (2mL), then disposably adding DIPEA (92.6mg, 0.716mmol) in reactant liquor, mixture is in backflow Temperature stirring reaction 23 hours, is then cooled to room temperature, sucking filtration, is dissolved in ethyl acetate by filter cake, by gained solution decompression Concentrating, it is white solid that gained residue obtains title compound through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purification (102.0mg, 62.82%).

MS(ESI,pos.ion)m/z:455.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 7.79 (d, J=8.0Hz, 5H), 7.95 (s, 1H), 7.70 (t, J= 8.0Hz, 1H), 7.60-7.50 (m, 6H), 7.31 (d, J=8.0Hz, 1H), 7.26 (s, 2H), 4.92-4.85 (m, 1H), 2.73 (s, 3H), 2.62 (s, 3H), 1.37 (d, J=4.0Hz, 3H), 1.24 (s, 1H).

Embodiment 6 (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Propyl group)-3-cyclopropyl quinazoline-4 (3H)-one

Step 1) N-cyclopropyl-2-nitrobenzamide

Under room temperature condition, to stirring 2-nitrobenzoic acid (3.2g, 19mmol) and DMF (0.17g, 2.3mmol) mixture in oxolane (25mL) disposably adds SOCl₂(4.92g, 41.4mmol), mixture heats To 60 DEG C and stir reaction 6 hours, be then concentrated under reduced pressure to give yellow oil, this grease be dissolved in dichloromethane (6mL) obtain faint yellow float, at 0 DEG C, this faint yellow float is added dropwise to cyclopropylamine (1.18g, 20.5mmol) And Et₃N (3.56g, 35.2mmol) is in the float of dichloromethane (4mL), after 0 DEG C of stirring is reacted 2 hours, and concentrating under reduced pressure, Gained residue water (50mL) is pulled an oar 20 minutes, sucking filtration, and filter cake water (10mL) is washed, and obtains titled 50 DEG C of vacuum drying Compound is faint yellow solid (3.4g, 96%).

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.02 (d, J=8.1Hz, 1H), 7.64 (dd, J=9.2,5.4Hz, 1H), 7.54 (t, J=7.5Hz, 1H), 7.47 (d, J=7.4Hz, 1H), 6.11 (s, 1H), 2.97-2.70 (m, 1H), 0.85 (m,2H),0.66(m,2H)。

Step 2) (S)-(1-(N-cyclopropyl-2-nitrobenzamide base)-1-oxo-butanes-2-base) the tertiary fourth of carbamic acid Ester

Compound N-cyclopropyl-2-nitrobenzamide (1.5g, 7.3mmol) is dissolved in toluene (15mL), then Disposably adding thionyl chloride (1.73g, 14.5mmol) in reactant liquor, mixture is in 120 DEG C of stirring reactions 6 hours, decompression It is concentrated to give yellow solution A；

By compound (2S)-2-(t-butoxycarbonyl amino) butanoic acid (1.50g, 7.38mmol) and DIPEA (1.90g, 14.7mmol) it is dissolved in dichloromethane (32mL), stirs 15 minutes at 0 DEG C, then by the dichloro of above-mentioned gained yellow solution A Methane (16mL) solution joins in gained solution, reaction 18 hour is stirred at room temperature, the most successively with water (30mL) and saturated Saline solution (30mL) is washed, separatory, and organic facies anhydrous sodium sulfate is dried, concentrating under reduced pressure, and gained residue is through silica gel column chromatography It is yellow solid (1.83g, 64%) that (PE/EtOAc (v/v)=7/1) purification obtains title compound.

MS(ESI,pos.ion)m/z:292.2[M-Boc+2H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.19 (d, J=8.0Hz, 1H), 7.71 (t, J=8.0Hz, 1H), 7.59 (t, J=8.0Hz, 1H), 7.33 (d, J=8.0Hz, 1H), 5.40-5.19 (m, 1H), 4.95 (d, J=8.0Hz, 1H), 4.17-4.12 (m, 1H), 2.86 (s, 1H), 1.97-1.91 (m, 1H), 1.44 (s, 9H), 1.28 (t, J=8.0Hz, 2H), 1.10-0.96(m,5H)。

Step 3) (S)-(1-(3-cyclopropyl-4-oxo-3,4-dihydroquinazoline-2-base) propyl group) t-butyl carbamate

By compound (S)-(1-(N-cyclopropyl-2-nitrobenzamide base)-1-oxo-butanes-2-base) carbamic acid uncle Butyl ester (1.8g, 4.4mmol) is dissolved in glacial acetic acid (10mL), then in reactant liquor disposable add Zn powder (1.22g, 18.7mmol), at 35 DEG C of stirring reactions 15 hours, then concentrating under reduced pressure, gained residue is dissolved in ethyl acetate (50mL) In, sucking filtration, filtrate uses saturated NaHCO successively₃Aqueous solution (30mL × 2) and saturated aqueous common salt (50mL) are washed, separatory, and organic facies is used Anhydrous sodium sulfate is dried, concentrating under reduced pressure, and gained residue is marked through silica gel column chromatography (PE/EtOAc (v/v)=8/1) purification Topic compound is yellow liquid (0.6g, 40%).

MS(ESI,pos.ion)m/z:344.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.23 (d, J=8.0Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.62 (d, J=8.0Hz, 1H), 7.45 (t, J=8.0Hz, 1H), 3.01 (t, J=4.0Hz, 1H), 1.98-1.92 (m, 1H), 1.79-1.63 (m, 2H), 1.47 (s, 9H), 1.42 (t, J=4.0Hz, 2H), 0.95-0.86 (m, 5H).

Step 4) (S)-2-(1-aminopropyl)-3-cyclopropyl quinazoline-4 (3H)-one

By compound (S)-(1-(3-cyclopropyl-4-oxo-3,4-dihydroquinazoline-2-base) propyl group) tertiary fourth of carbamic acid Ester (509.1mg, 1.483mmol) is dissolved in ethyl acetate (9mL), then at room temperature condition, disposably adds in reactant liquor Entering ethyl acetate (4M, the 4.5mL) solution of hydrogen chloride, mixture is stirred at room temperature reaction 5 hours；

It is neutralized to pH=8, aqueous phase ethyl acetate (50mL by above-mentioned gained float adds saturated aqueous sodium carbonate × 4) extraction, the organic facies saturated aqueous common salt (50mL × 2) of merging is washed, and is dried with anhydrous sodium sulfate, is concentrated under reduced pressure to give mark Topic compound is yellow liquid (212mg, 58.77%).

MS(ESI,pos.ion)m/z:244.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.06 (t, J=8.0Hz, 1H), 7.79-7.75 (m, 1H), 7.60 (d, J=8.0Hz, 1H), 7.46 (t, J=8.0Hz, 1H), 4.43 (q, J=8.0Hz, 1H), 3.08-3.02 (m, 1H), 1.91- 1.79(m,1H),1.61-1.54(m,1H),1.24-1.21(m,2H),0.98-0.93(m,4H),0.79-0.75(m,1H)。

Step 5) (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) third Base)-3-cyclopropyl quinazoline-4 (3H)-one

By compound (S)-2-(1-aminopropyl)-3-cyclopropyl quinazoline-4 (3H)-one (200mg, 0.8220mmol), The chloro-5-of 6-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-amine (178mg, 0.84mmol) is dissolved in n-butyl alcohol (5mL) In, in reactant liquor, then disposably adding DIPEA (215mg, 1.6636mmol), mixture is little 120 DEG C of stirring reactions 12 Time, concentrating under reduced pressure, it is white that gained residue obtains title compound through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purification Color solid (206mg, 58.32%).

MS(ESI,pos.ion)m/z:419.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.52 (d, J=8.0Hz, 1H), 8.25 (t, J=8.0Hz, 1H), 8.17 (s, 1H), 7.74-7.70 (m, 1H), 7.62 (d, J=8.0Hz, 1H), 7.45 (t, J=8.0Hz, 1H), 6.42-6.37 (m, 1H), 4.15 (q, J=8.0Hz, 1H), 3.16-3.11 (m, 1H), 2.75 (s, 3H), 2.16-1.98 (m, 3H), 1.48- 1.44 (m, 2H), 1.04 (t, J=8.0Hz, 3H), 0.97-0.89 (m, 2H).

Embodiment 7 (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Propyl group)-3-phenylquinazoline-4 (3H)-one

Step 1) 2-nitro-N-phenylbenzamide

Compound 2-nitrobenzoic acid (6.2g, 37.1mmol) and N,N-dimethylformamide (0.25mL) are suspended in two In chloromethanes (40mL), the most at ambient temperature, being added dropwise over oxalyl chloride (6.5mL, 77mmol) in reactant liquor, room temperature is stirred Mix reaction 5 hours, then concentrating under reduced pressure, gained residue is dissolved in Isosorbide-5-Nitrae-dioxane (10mL), at 0 DEG C, by gained Solution is added dropwise to aniline (3.47g, 37.3mmol) and the 1,4-dioxane of sodium bicarbonate (7.86g, 490mmol) (30mL) with in the mixture of water (40mL), gained mixture is moved to room temperature, and continues stirring reaction 2 hours, be subsequently adding Water (100mL), sucking filtration, filter cake vacuum drying is obtained title compound faint yellow solid (8.1g, 90%).

MS(ESI,pos.ion)m/z:243.0[M+H]；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.07-8.05 (d, J=8.0Hz, 1H), 7.69-7.65 (t, J= 7.4Hz, 1H), 7.60-7.55 (m, 4H), 7.33-7.29 (t, J=7.6Hz, 2H), 7.13-7.11 (t, J=7.2Hz, 1H).

Step 2) (S)-(1-(2-nitro-N-phenylbenzamide base)-1-oxo-butanes-2-base) t-butyl carbamate

Compound 2-nitro-N-phenylbenzamide (1.50g, 6.19mmol) is suspended in toluene (10mL), then In reactant liquor, add thionyl chloride (2.25mL, 31.2mmol), heat the mixture to backflow, and be stirred overnight, then subtract Pressure concentrates, and is dissolved in by residue in dichloromethane (2mL), at 0 DEG C, gained solution joins (2S)-2-(tertbutyloxycarbonyl Amino) butanoic acid (1.01g, 4.97mmol) and triethylamine (628mg, 6.2061mmol) dichloromethane (2mL) mixture in, Gained mixture stirs 2 hours at 0 DEG C, is then warmed to room temperature, and continues stirring reaction 24 hours, and mixture uses water successively (20mL), saturated sodium bicarbonate aqueous solution (20mL), and saturated saturated aqueous common salt (20mL) washes, separatory, organic facies is reduced pressure dense Contracting, it is faint yellow solid that gained residue obtains title compound through silica gel column chromatography (PE/EtOAc (v/v)=10/1) purification (1.8g, 68%).

MS(ESI,pos.ion)m/z:328.0[M-Boc+2H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.16-8.14 (d, J=8.0Hz, 1H), 7.70-7.66 (dd, J= 7.6,7.2Hz, 1H), 7.54-7.42 (m, 7H), 4.90-4.98 (d, J=7.2Hz, 1H), 4.54 (m, 1H), 1.87-1.79 (m, 1H), 1.47-1.40 (m, 1H), 1.40 (s, 9H), 0.83-0.79 (t, J=7.2Hz, 3H).

Step 3) (S)-(1-(4-oxo-3-phenyl-3,4-dihydroquinazoline-2-base) propyl group) t-butyl carbamate

By compound (S)-(1-(2-nitro-N-phenylbenzamide base)-1-oxo-butanes-2-base) tertiary fourth of carbamic acid Ester (1.80g, 4.21mmol) is suspended in acetic acid (10mL), then at room temperature condition, in reactant liquor add zinc powder (1.42g, 21.7mmol), reaction 22 hour being stirred at room temperature, then with suction filtered through kieselguhr, by filtrate reduced in volume, gained residue is through silica gel It is faint yellow solid (1.18g, 74%) that column chromatography (PE/EtOAc (v/v)=10/1) purification obtains title compound.

MS(ESI,pos.ion)m/z:380.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.28-8.26 (d, J=7.2Hz, 1H), 7.79-7.75 (dt, J= 1.2,8.4Hz, 1H), 7.72-7.70 (d, J=7.6Hz, 1H), 7.61-7.46 (m, 4H), 7.38-7.36 (d, J=6.8Hz, 1H), 7.30-7.26 (m, 1H), 5.55-5.53 (d, J=8.0Hz, 1H), 4.45-4.40 (m, 1H), 1.771.69 (m, 1H), 1.55-1.48 (m, 1H), 1.42 (s, 9H), 0.77-0.73 (t, J=7.4Hz, 3H).

Step 4) (S)-2-(1-aminopropyl)-3-phenylquinazoline-4 (3H)-one

By compound (S)-(1-(4-oxo-3-phenyl-3,4-dihydroquinazoline-2-base) propyl group) t-butyl carbamate (1.18g, 3.11mmol) is dissolved in ethyl acetate (4mL), then adds the ethyl acetate solution of hydrogen chloride in reactant liquor (4M, 10mL), after mixture is stirred at room temperature reaction 1 day, concentrating under reduced pressure, gained residue is dissolved in water (30mL), mixed Compound EtOAc/PE (1/1 (v/v), 20mL × 2) extracts, and aqueous phase adds sodium bicarbonate powder and regulated to pH=8.5, and Extracting with dichloromethane (20mL × 2), the organic facies saturated aqueous common salt (30mL) of merging is washed, and is dried with anhydrous sodium sulfate, subtracts It is white solid (566mg, 65%) that pressure is concentrated to give title compound.

MS(ESI,pos.ion)m/z:280.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.28-8.26 (d, J=8.0Hz, 1H), 7.79-7.71 (m, 2H), 7.660-7.45(m,4H),7.29-7.26(m,2H),3.44(m,1H),1.82-1.75(m,1H),1.57-1.46(m,1H), 0.81-0.78 (t, J=7.4Hz, 3H).

Step 5) (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) third Base)-3-phenylquinazoline-4 (3H)-one

By compound (S)-2-(1-aminopropyl)-3-phenylquinazoline-4 (3H)-one (51.0mg, 0.183mmol), 6- Chloro-5-(5-methyl isophthalic acid, 3,4-diazole-2-bases) pyrimidine-4-amine (41.7mg, 0.197mmol), DIPEA (45.4mg, 0.351mmol) mixture with n-butyl alcohol (2mL) is heated to 125 DEG C and is stirred overnight, and is then cooled to room temperature, concentrating under reduced pressure, It is white solid that gained residue obtains title compound through silica gel column chromatography (DCM/MeOH (v/v)=200/3) purification (43mg, 52%).

MS(ESI,pos.ion)m/z:455.0[M+H]；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.40 (d, J=7.6Hz, 1H), 8.28-8.27 (d, J=7.6Hz, 1H), 8.00 (s, 1H), 7.77-7.73 (t, J=7.2Hz, 1H), 7.69-7.67 (d, J=8.0Hz, 1H), 7.607.54 (m, 3H),7.49-7.42(m,2H),7.34-7.32(m,1H),5.19-5.14(m,1H),2.72(s,3H),1.95-1.90(m, 1H),1.83-1.77(m,1H),0.87-0.83(m,3H)。

Embodiment 8 (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-3-cyclopropyl quinazoline-4 (3H)-one

Step 1) (S)-(1-(N-cyclopropyl-2-nitrobenzamide base)-1-oxopropan-2-base) the tertiary fourth of carbamic acid Ester

Compound N-cyclopropyl-2-nitrobenzamide (1.91g, 9.26mmol) is dissolved in toluene (20mL), so After at room temperature condition, in the reactant liquor of stirring, disposably add SOCl₂(4.1g, 41.0mmol), heats the mixture to 120 DEG C and be stirred overnight, be concentrated under reduced pressure to give light brown grease, this grease be dissolved in dry dichloromethane (40mL) Obtain yellow solution；

By compound (S)-2-((tertbutyloxycarbonyl) amino) propanoic acid (1.85g, 9.78mmol) and DIPEA (2.6g, 20.0mmol) it is dissolved in dry dichloromethane (20mL), then at 0 DEG C, in solution, is slowly added to above-mentioned gained yellow Solution, mixture is stirred overnight at ambient temperature, washes with water (40mL) and saturated aqueous common salt (40mL) successively, organic facies nothing Water Na₂SO₄It is dried, concentrating under reduced pressure.Gained residue obtains title through silica gel column chromatography (PE/EtOAc (v/v)=10/1) purification Compound is yellow solid (2.72g, 81%).

MS(ESI,pos.ion)m/z:278.2[M-Boc+2H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.18 (d, J=8.2Hz, 1H), 7.69 (t, J=7.4Hz, 1H), 7.56 (t, J=7.5Hz, 1H), 7.32 (dd, J=7.6,0.9Hz, 1H), 5.32-5.11 (m, 1H), 5.00 (d, J=7.8Hz, 1H), 2.83 (s, 1H), 1.40 (s, 9H), 1.37 (d, J=7.0Hz, 3H), 1.10 (d, J=6.7Hz, 2H), 0.91 (dd, J= 9.0,5.4Hz,2H)。

Step 2) (S)-(1-(3-cyclopropyl-4-oxo-3,4-dihydroquinazoline-2-base) ethyl) t-butyl carbamate

By compound (S)-(1-(N-cyclopropyl-2-nitrobenzamide base)-1-oxopropan-2-base) carbamic acid uncle Butyl ester (2.72g, 7.21mmol) is dissolved in acetic acid (10mL), then disposably adds zinc powder in the reactant liquor of stirring (1.89g, 28.9mmol), mixture is at 35 DEG C of stirring reactions 16 hours, then sucking filtration, and by filtrate reduced in volume, gained remains It is faint yellow solid (1.2g, 50%) that thing obtains title compound through silica gel column chromatography (PE/EtOAc (v/v)=8/1) purification.

MS(ESI,pos.ion)m/z:330.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.16 (dd, J=7.9,1.0Hz, 1H), 7.66-7.62 (m, 1H), 7.56 (d, J=8.0Hz, 1H), 7.37 (t, J=7.5Hz, 1H), 5.80 (d, J=8.4Hz, 1H), 5.61 (t, 1H), 2.95 (m, J=10.9,3.6Hz, 1H), 1.46 (d, J=6.7Hz, 3H), 1.41 (s, 9H), 1.35 (d, 2H), 1.04 (dd, J= 9.7,4.3Hz, 1H), 0.89 (dd, J=10.0,4.2Hz, 1H).

Step 3) (S)-2-(1-amino-ethyl)-3-cyclopropyl quinazoline-4 (3H)-one

By compound (S)-(1-(3-cyclopropyl-4-oxo-3,4-dihydroquinazoline-2-base) ethyl) tertiary fourth of carbamic acid Ester (1.2g, 3.6mmol) is dissolved in ethyl acetate (3.0mL), disposably adds the most at ambient temperature in reactant liquor The ethyl acetate solution (4M, 3mL) of HCl, mixture stirred overnight at room temperature, gained float is dissolved in water (60mL), aqueous phase Extract by ethyl acetate (40mL × 2), and addition powdered sodium carbonate is neutralized to pH=8 in aqueous phase, then uses acetic acid second Ester (50mL × 3) extracts, and the organic facies saturated aqueous common salt (100mL) of merging is washed, and is dried with anhydrous sodium sulfate, and concentrating under reduced pressure obtains It is faint yellow solid (270mg, 25%) to title compound.

MS(ESI,pos.ion)m/z:230.15[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.20 (d, J=7.9Hz, 1H), 7.69 (t, J=11.1,4.1Hz, 1H), 7.60 (d, J=8.0Hz, 1H), 7.40 (t, J=7.5Hz, 1H), 4.78 (d, J=5.4Hz, 1H), 3.06-2.66 (m, 1H), 1.45 (d, J=6.5Hz, 3H), 1.41-1.25 (m, 2H), 1.00-0.82 (m, 2H).

Step 4) (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) second Base)-3-cyclopropyl quinazoline-4 (3H)-one

By compound (S)-2-(1-amino-ethyl)-3-cyclopropyl quinazoline-4 (3H)-one (153mg, 0.667mmol), The chloro-5-of 6-(5-methyl isophthalic acid, 3,4-diazole-2-bases) pyrimidine-4-amine (155.6mg, 0.733mmol), DIPEA (236.0mg, 1.402mmol) mixture with n-BuOH (5mL) is heated to backflow and stirs reaction 11 hours, is then cooled to room temperature, decompression Concentrating, it is white solid that gained residue obtains title compound through silica gel column chromatography (DCM/MeOH (v/v)=100/1) purification (30mg, 11%).

MS(ESI,pos.ion)m/z:405.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.61 (d, J=7.2Hz, 1H), 8.23 (t, J=7.9Hz, 1H), 8.15 (s, 1H), 7.71 (t, J=7.6Hz, 1H), 7.61 (d, J=8.0Hz, 1H), 7.44 (t, J=7.5Hz, 1H), 6.34 (p, J=6.7Hz, 1H), 3.20-2.92 (m, 1H), 2.74 (s, 3H), 1.64 (d, J=6.6Hz, 6H), 1.49-1.38 (m, 4H),1.13-1.03(m,1H),1.03-0.90(m,1H)。

Embodiment 9 (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-3-phenylquinazoline-4 (3H)-one

Step 1) 2-amino-N-phenylbenzamide

Compound 2-nitro-N-phenylbenzamide (1.0g, 4.1mmol) is dissolved in oxolane (10mL), so Backward reactant liquor adds Pd/C (150mg, 10%) and water (3mL) solution of HCOOK (2.5g, 30mmol), mixture is added Heat is to 50 DEG C and be stirred overnight, and then with suction filtered through kieselguhr, filtrate water (10mL) is washed, and aqueous phase is with ethyl acetate (20mL × 2) Extraction, the organic facies anhydrous sodium sulfate of merging is dried, be concentrated under reduced pressure to give title compound be beige solid (840mg, 96%).

MS(ESI,pos.ion)m/z:213.1[M+H]⁺。

Step 2) (S)-(1-oxo-1-((2-(phenylcarbamoyl) phenyl) amino) propane-2-base) carbamic acid The tert-butyl ester

By compound 2-amino-N-phenylbenzamide (840mg, 3.96mmol), (2S)-2-(t-butoxycarbonyl amino) Propanoic acid (786mg, 4.15mmol) and DIPEA (2mL, 10mmol) are dissolved in dichloromethane (20mL), then at-10 DEG C, to Being dividedly in some parts HATU (1.81g, 4.76mmol) in reactant liquor, mixture stirs 1 hour at-10 DEG C, then moves to room temperature, heating To 45 DEG C and be stirred overnight, more successively with water (50mL × 2), saturated NaHCO₃Aqueous solution (50mL × 2) is washed, and organic facies is with anhydrous Sodium sulfate is dried, concentrating under reduced pressure, and gained residue obtains titled through silica gel column chromatography (PE/EtOAc (v/v)=5/1) purification Compound is yellow solid (1.3g, 86%).

MS(ESI,neg.ion)m/z:282.9[M-Boc+H]⁺；

¹H NMR(600MHz,DMSO-d₆) δ (ppm): 8.51 (d, J=8.3Hz, 1H), 7.86 (d, J=7.6Hz, 1H), 7.75 (d, J=7.9Hz, 2H), 7.56 (dd, J=11.7,4.2Hz, 2H), 7.36 (t, J=7.9Hz, 2H), 7.23 (t, J= 7.6Hz, 1H), 7.14 (t, J=7.4Hz, 1H), 4.00 (m, 1H), 1.31 (s, 9H), 1.29 (d, J=7.3Hz, 3H).

Step 3) (S)-(1-(4-oxo-3-phenyl-3,4-dihydroquinazoline-2-base) ethyl) t-butyl carbamate

By compound (S)-(1-oxo-1-((2-(phenylcarbamoyl) phenyl) amino) propane-2-base) amino first Tert-butyl acrylate (1.3g, 3.4mmol), DIPEA (1.0mL, 6.80mmol) and DMAP (410mg, 3.35mmol) are dissolved in CH₃CN (11mL) in, in reactant liquor, then add BSA (7.0g, 34mmol), heat the mixture to 80 DEG C and to stir reaction 5 little Time, it being then cooled to room temperature, add ethyl acetate (150mL) dilution, gained mixture is molten with water (100mL × 3) and HCl/water again Liquid (1M, 100mL × 2) wash, separatory, organic facies anhydrous sodium sulfate is dried, and being concentrated under reduced pressure to give title compound is that Lycoperdon polymorphum Vitt is solid Body (1.15g, 93%).

MS(ESI,pos.ion)m/z:366.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.30 (d, J=7.8Hz, 1H), 7.83-7.73 (m, 2H), 7.56 (m, 4H), 7.41 (d, J=7.2Hz, 1H), 7.34-7.27 (m, 2H), 4.63-4.50 (m, 1H), 1.44 (s, 9H), 1.29 (d, J= 6.7Hz,3H)。

Step 4) (S)-2-(1-amino-ethyl)-3-phenylquinazoline-4 (3H)-one

By compound (S)-(1-(4-oxo-3-phenyl-3,4-dihydroquinazoline-2-base) ethyl) t-butyl carbamate (1.15g, 3.15mmol) is dissolved in ethyl acetate (10mL), then adds the ethyl acetate solution of HCl in reactant liquor (4M, 5mL), mixture stirred overnight at room temperature, then sucking filtration, filter cake is dissolved in 15mL saturated sodium bicarbonate aqueous solution, institute Obtaining mixture ethyl acetate (20mL × 3) to extract, the organic facies anhydrous sodium sulfate of merging is dried, and is concentrated under reduced pressure to give title Compound is khaki solid (580mg, 69.5%).

MS(ESI,pos.ion)m/z:266.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.12 (dd, J=7.9,1.1Hz, 1H), 7.90-7.83 (m, 1H), 7.73 (d, J=8.0Hz, 1H), 7.63-7.44 (m, 6H), 3.45 (q, J=6.6Hz, 1H), 1.90 (s, 2H), 1.17 (d, J= 6.6Hz,3H)。

Step 5) (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) second Base)-3-phenylquinazoline-4 (3H)-one

By compound (S)-2-(1-amino-ethyl)-3-phenylquinazoline-4 (3H)-one (100mg, 0.38mmol) and 6- Chloro-5-(5-methyl isophthalic acid, 3,4-diazole-2-bases) pyrimidine-4-amine (83mg, 0.39mmol) is suspended in n-BuOH (4mL), so Adding DIPEA (0.1mL, 0.5mmol) in backward reactant liquor, mixture is stirred overnight at 120 DEG C, then concentrating under reduced pressure, gained Residue through silica gel column chromatography (PE/EtOAc (v/v)=1/5) purification obtain title compound be white solid (83mg, 49%).

MS(ESI,pos.ion)m/z:441.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.53 (d, J=6.9Hz, 1H), 8.29 (d, J=7.8Hz, 1H), 8.02 (s, 1H), 7.77 (dd, J=11.7,4.8Hz, 1H), 7.71 (d, J=8.0Hz, 1H), 7.63-7.52 (m, 3H), 7.49 (m, 1H), 7.42 (d, J=7.2Hz, 1H), 7.37-7.32 (m, 1H), 5.20 (m, 1H), 2.74 (s, 3H), 1.46 (d, J= 6.6Hz,3H)。

Embodiment 10 (S)-2-(1-((6-amino-5-(3-ethyl-1,2,4-diazole-5-base) pyrimidine-4-yl) amino) Propyl group)-5-chloro-3-phenylquinazoline-4 (3H)-one

By compound (S)-2-(1-aminopropyl)-5-chloro-3-phenylquinazoline-4 (3H)-one (50.3mg, 0.16mmol) it is suspended in the chloro-5-of 6-(3-ethyl-1,2,4-diazole-5-base) pyrimidine-4-amine (37.8mg, 0.17mmol) In n-BuOH (4mL), in reactant liquor, then add DIPEA (35.1mg, 0.27mmol), gained mixture is heated to backflow And stirring reaction 3 hours, concentrating under reduced pressure, gained residue obtains through silica gel column chromatography (MeOH/DCM (v/v)=1/100) purification Title compound is white solid (24.3mg, 30.1%).

MS(ESI,pos.ion)m/z:503.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.76(s,1H),8.04(s,1H),7.60(m,5H),7.48(s, 2H), 7.34 (d, J=4.6Hz, 2H), 5.12 (s, 1H), 3.51 (s, 1H), 2.90 (d, J=7.0Hz, 2H), 2.04 (s, 1H), 1.94(s,1H),1.80(m,1H),1.45(m,5H)。

Embodiment 11 (S)-2-(1-((6-amino-5-(3-ethyl-1,2,4-diazole-5-base) pyrimidine-4-yl) amino) Ethyl)-5-chloro-3-phenylquinazoline-4 (3H)-one

By compound (S)-2-(1-amino-ethyl)-5-chloro-3-phenylquinazoline-4 (3H)-one (55mg, 0.18mmol) Be dissolved in n-butyl alcohol (1mL), then in reactant liquor add the chloro-5-of 6-(3-ethyl-1,2,4-diazole-5-bases) pyrimidine- 4-amine (45mg, 0.2mmol) and DIPEA (0.06mL, 0.37mmol), mixture is stirred overnight at 110 DEG C, and concentrating under reduced pressure is residual Thing is stayed to be dispersed in CH₂Cl₂(50mL) and water (5mL) in, aqueous phase CH₂Cl₂(50mL) extraction, the saturated food of the organic facies of merging Saline (5mL) is washed, and is dried with anhydrous sodium sulfate, concentrating under reduced pressure, and gained residue is through silica gel column chromatography (MeOH/CH₂Cl₂(v/v) =1/20) purification obtains title compound is yellow solid (70mg, 78%).

MS(ESI,pos.ion)m/z:489.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.80 (d, J=6.5Hz, 1H), 8.05 (s, 1H), 7.71-7.53 (m, 5H), 7.52-7.44 (m, 2H), 7.36 (d, J=9.2Hz, 1H), 5.17 (p, J=6.8Hz, 1H), 2.91 (q, J=7.6Hz, 2H), 1.48 (d, J=6.7Hz, 3H), 1.45 (t, J=7.6Hz, 3H).

Embodiment 12 (S)-2-(1-((6-amino-5-(3-isopropyl-1,2,4-diazole-5-base) pyrimidine-4-yl) ammonia Base) ethyl)-5-chloro-3-phenylquinazoline-4 (3H)-one

By compound (S)-2-(1-amino-ethyl)-5-chloro-3-phenylquinazoline-4 (3H)-one (50.6mg, 0.17mmol), the chloro-5-of 6-(3-isopropyl-1,2,4-diazole-5-bases) pyrimidine-4-amine (42.2mg, 0.17mmol), DIPEA The mixture of (49mg, 0.38mmol) and n-BuOH (1mL) is heated to backflow and stirs reaction 15 hours, is subsequently cooled to room Temperature, concentrating under reduced pressure, gained residue obtains title compound through silica gel column chromatography (DCM/MeOH (v/v)=100/1) purification is Faint yellow solid (43mg, 51%).

MS(ESI.pos.ion)m/z:502.8[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.77(s,1H),8.03(s,1H),7.62-7.34(m,8H),5.84 (s,2H),5.15(m,1H),3.22(m,1H),1.44-1.41(m,9H)。

Embodiment 13 (S)-2-(1-((6-amino-5-(3-ethyl-1,2,4-diazole-5-bases) pyrimidine-4-yl) amino) Propyl group)-5-fluoro-3-phenylquinazoline-4 (3H)-one

By compound (S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazoline-4 (3H)-one (50.4mg, 0.17mmol), the chloro-5-of 6-(3-ethyl-1,2,4-diazole-5-bases) pyrimidine-4-amine (40.2mg, 0.17mmol), DIPEA The mixture of (44.8mg, 0.34mmol) and n-butyl alcohol (1mL) is heated to 120 DEG C and stirs reaction 2.5 hours, is subsequently cooled to Room temperature, concentrating under reduced pressure, it is that rice white is solid that residue obtains title compound through preparation TLC (PE/EtOAc (v/v)=3/7) purification Body (40mg, 48%).

MS(ESI,pos.ion)m/z:486.9[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 9.08-9.07 (d, J=7.0Hz, 1H), 7.98 (s, 1H), 7.88- 7.82 (m, 1H), 7.61-7.48 (m, 6H), 7.33-7.28 (dd, J=8.0,10.4Hz, 1H), 4.96-4.91 (m, 1H), 2.89-2.84 (q, J=7.2Hz, 2H), 1.93-1.88 (m, 1H), 1.68-1.63 (m, 1H), 1.36-1.32 (t, J= 7.6Hz, 3H), 0.78-0.74 (t, J=7.6Hz, 3H).

Embodiment 14 (S)-2-(1-((6-amino-5-(2-isopropyl-2H-tetrazolium-5-base) pyrimidine-4-yl) amino) second Base)-5-chloro-3-cyclopropyl quinazoline-4 (3H)-one

Step 1) 2-isopropyl-2H-tetrazolium

Compound tetrazolium (1.75g, 25.0mmol) is dissolved in sulphuric acid (18mL), is then added dropwise in reactant liquor Propane-2-alcohol (2.3mL, 30mmol), dropping in 10 minutes is complete, holding temperature 20～25 DEG C, and then stirring reaction 1 hour, inclines Pouring in frozen water (100mL), gained mixture dichloromethane (35mL × 3) extracts, the organic facies anhydrous sodium sulfate of merging Being dried, being concentrated under reduced pressure to give crude product is yellow oil (1.87g, 67%).

MS(ESI,pos.ion)m/z:113.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.45 (s, 1H), 5.08 (hept, J=6.7Hz, 1H), 1.63 (d, J =6.7Hz, 6H).

Step 2) 2-isopropyl-5-(tributyl tinbase)-2H-tetrazolium

Compound 2-isopropyl-2H-tetrazolium (1.67g, 14.9mmol) is dissolved in anhydrous tetrahydro furan (40mL, 100% Mass fraction) in, then at-78 DEG C, add in reactant liquor n-BuLi hexane solution (2.4mol/L, 7.5mL, 18mmol), dropping in 45 minutes is complete, is added dropwise over tributyltin chloride (5.3mL, 20mmol) the most again, and mixture is at-60 DEG C It is stirred overnight, is subsequently adding saturated NH₄Cl aqueous solution cancellation is reacted, and gained mixture ethyl acetate (35mL × 3) extracts, and closes And organic facies saturated aqueous common salt (10mL) wash, be dried with anhydrous sodium sulfate, concentrating under reduced pressure, gained residue is through silica gel column layer It is colorless oil (4.84g, 81.0%) that analysis (EtOAc/PE (v/v)=1/50) purification obtains title compound.

MS(ESI,pos.ion)m/z:403.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 5.06 (hept, J=6.7Hz, 1H), 1.64-1.50 (m, 12H), 1.38-1.25 (m, 7H), 1.21-1.13 (m, 5H), 0.83 (t, J=7.4Hz, 9H).

Step 3) 5-(2-isopropyl-2H-tetrazolium-5-base)-4,6-dimethoxypyridin

By bromo-for compound 5-4,6-dimethoxypyridin (3.5g, 16mmol), 2-isopropyl-5-(tributyl tinbase)- 2H-tetrazolium (7.9g, 20mmol), Pd (dppf) Cl₂·CH₂Cl₂(1.3g, 1.6mmol) and N,N-dimethylformamide (80mL) Mixture be heated under nitrogen protection 125 DEG C and stir reaction 24 hours, be then cooled to room temperature, concentrating under reduced pressure, gained Residue through silica gel column chromatography (EtOAc/PE (v/v)=1/4) purification obtain title compound be white solid (2.36g, 59%).

MS(ESI,pos.ion)m/z:251.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.52(s,1H),5.96-4.70(m,1H),3.98(s,6H),1.72 (d, J=6.7Hz, 6H).

Step 4) the chloro-5-of 4,6-bis-(2-isopropyl-2H-tetrazolium-5-base) pyrimidine

5-(2-isopropyl tetrazolium-5-base)-4,6-dimethoxypyridin (2.36g, 9.43mmol) is dissolved in hydrochloric acid In the mixture of (12mol/L, 15mL, 180mmol) and acetic acid (15mL), it is little that gained solution is heated to refluxing and stir reaction 6 Time, it is then cooled to room temperature, is concentrated under reduced pressure to give 5-(2-isopropyl tetrazolium-5-base) pyrimidine-4,6-glycol (2.1g, 9.5mmol, 100%) it is white solid；

The white solid obtained is dissolved in phosphorus oxychloride (25mL), gained mixture is heated to 120 DEG C and stirs Reacting 12 hours, be then cooled to room temperature, concentrating under reduced pressure, residue joins in frozen water (30mL), gained mixture CH₂Cl₂ (30mL × 3) extract, and the organic facies anhydrous sodium sulfate of merging is dried, and being concentrated under reduced pressure to give title compound is yellow solid (2.4g, 98%).

Step 5) the chloro-5-of 6-(2-isopropyl-2H-tetrazolium-5-base) pyrimidine-4-amine

Chloro-for compound 4,6-bis-5-(2-isopropyl tetrazolium-5-base) pyrimidine (2.4g, 9.3mmol) is dissolved in the third of ammonia In the solution of alkane-2-alcohol (7M, 40mL, 280mmol), gained solution is stirred at room temperature reaction 12 hours, then concentrating under reduced pressure, gained It is white solid (1.16g, 52%) that residue obtains title compound through silica gel column chromatography (EtOAC/PE (v/v)=2/5).

MS(ESI,pos.ion)m/z:240.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.37 (s, 1H), 5.18 (hept, J=6.7Hz, 1H), 1.74 (d, J =6.7Hz, 6H).

Step 6) (S)-2-(1-((6-amino-5-(2-isopropyl-2H-tetrazolium-5-base) pyrimidine-4-yl) amino) second Base)-5-chloro-3-cyclopropyl quinazoline-4 (3H)-one

By compound (S)-2-(1-amino-ethyl)-5-chloro-3-cyclopropyl quinazoline-4 (3H)-one (100.5mg, 0.3811mmol), DIPEA (102.6mg, 0.7939mmol) and the chloro-5-of 6-(2-isopropyl tetrazolium-5-base) pyrimidine-4-amine (91.6mg, 0.382mmol) is dissolved in n-BuOH (4mL), and gained solution is heated to backflow and is stirred overnight, and then reduces pressure dense Contracting, it is white solid (140mg, 78%) that residue obtains title compound through preparation TLC purification.

MS(ESI,pos.ion)m/z:467.3[M+H]⁺；

¹H NMR(600MHz,CDCl₃) δ (ppm): 9.12 (d, J=7.5Hz, 1H), 8.15 (s, 1H), 7.55-7.49 (m, 2H), 7.40 (dd, J=5.6,3.4Hz, 1H), 6.41-6.34 (m, 1H), 5.19 (dt, J=13.4,6.7Hz, 1H), 3.48 (s, 1H), 3.11 (ddd, J=11.1,7.1,4.2Hz, 1H), 2.04 (d, J=6.7Hz, 1H), 1.76 (t, J=6.7Hz, 6H), 1.66 (d, J=6.7Hz, 3H), 1.46-1.39 (m, 2H), 1.19-1.12 (m, 1H), 0.95-0.88 (m, 1H).

Embodiment 15 (S)-2-(1-((6-amino-5-(2-isopropyl-2H-tetrazolium-5-base) pyrimidine-4-yl) amino) second Base)-5-fluoro-3-phenylquinazoline-4 (3H)-one

By compound (S)-2-(1-amino-ethyl)-5-fluoro-3-phenylquinazoline-4 (3H)-one (50mg, 0.18mmol) 5-chloro-with 6-(2-isopropyl-2H-tetrazolium-5-base) pyrimidine-4-amine (43mg, 0.18mmol) is dissolved in n-BuOH (5mL), Then adding DIPEA (0.1mL, 0.5mmol) in reactant liquor, mixture is stirred overnight at 120 DEG C, is then cooled to room temperature, Sucking filtration, the mixed solvent of filter cake use water/ethanol (10/1 (v/v), 2mL) is washed, and is vacuum dried and obtains title compound for white admittedly Body (25mg, 29.1%).

MS(ESI,pos.ion)m/z:487.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.94-8.93 (d, J=6.9Hz, 1H), 7.97 (s, 1H), 7.87- 7.82 (m, 1H), 7.61-7.55 (m, 5H), 7.51-7.49 (d, J=8.2Hz, 3H), 7.33-7.28 (dd, J=10.8, 8.3Hz, 1H), 5.29 (m, 1H), 4.97-4.94 (m, 1H), 1.70-1.69 (d, J=6.6Hz, 6H), 1.41-1.39 (d, J= 6.6Hz,3H)。

Embodiment 16 (S)-2-(1-((6-amino-5-(5-isopropyl-1,3,4-diazole-2-base) pyrimidine-4-yl) ammonia Base) ethyl)-5-chloro-3-phenylquinazoline-4 (3H)-one

Step 1) 2-isobutyryl hydrazine t-butyl formate

At 0 DEG C, to compound N-amino-carbamic acid tert-butyl ester (1.24g, 9.38mmol) and triethylamine (1.80g, 18.0mmol) mixture in dichloromethane (10mL) adds 2-methyl-prop acyl chlorides (1mL, 9.48mmol), then move to Room temperature is also stirred overnight, and adds water (30mL) and dichloromethane (30mL) cancellation reaction, and aqueous phase dichloromethane (20mL) extracts, The organic facies saturated aqueous common salt (15mL) merged is washed, and is dried with anhydrous sodium sulfate, concentrating under reduced pressure, and gained residue is through silicagel column It is white solid (645mg, 34%) that chromatography (PE/EtOAc (v/v)=2/1) purification obtains title compound.

MS(ESI,pos.ion)m/z:147(M+1-56)；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.30(br s,1H),6.51(br s,1H),2.45-2.38(tt,J =6.8,6.8Hz, 1H), 1.47 (s, 9H), 1.20-1.18 (d, J=6.8Hz, 6H).

Step 2) isobutyryl hydrazine hydrochloride

Compound 2-isobutyryl hydrazine t-butyl formate (645mg, 3.19mmol) is dissolved in ethyl acetate (4mL), Then in reactant liquor, add the ethyl acetate solution (4M, 10mL) of hydrogen chloride at 17 DEG C, mixture is warming up to 30 DEG C and stirs Mixing reaction 4 hours, the crude product being concentrated under reduced pressure to give title compound is white solid (442mg, 100%), without further Purification is directly used in next step reaction.

MS(ESI,pos.ion)m/z:103.0[M+H]⁺。

Step 3) 4,6-bis-chloro-N'-isobutyryl pyrimidine-5-carbohydrazide

By compound 4,6-dichloro pyrimidine-5-formic acid (590.0mg, 3.05mmol) and N,N-dimethylformamide (50.0mg, 0.68mmol) is dissolved in oxolane (3mL), is heated to backflow and stirs reaction 1.5 hours, being subsequently cooled to room Temperature, concentrating under reduced pressure, residue is dissolved in dichloromethane (4mL), 0 DEG C, gained solution is joined isobutyryl hydrazine hydrochloride (442mg, 3.19mmol) and the triethylamine (1mL) solution in dichloromethane (12mL), gained mixture is stirred at 0 DEG C At night, then it is concentrated under reduced pressure to give faint yellow solid at 30 DEG C, in this solid, adds water (3mL), ethyl acetate (4mL) and oil The mixed solvent of ether (6mL), gained mixture is stirred at room temperature 1 hour, then sucking filtration, and obtaining title compound is faint yellow solid (980mg, 115%).

MS(ESI,pos.ion)m/z:277.0[M+H]⁺。

Step 4) 4-amino-6-chloro-N'-isobutyryl pyrimidine-5-carbohydrazide

Chloro-for compound 4,6-bis-N'-isobutyryl pyrimidine-5-carbohydrazide (980mg, 3.5365mmol) is suspended in isopropyl In alcohol (10mL), in reactant liquor, then it is passed through ammonia bubbling, gained mixture is heated in tube sealing 50 DEG C and stirred At night, being then cooled to room temperature, add normal hexane (10mL), gained mixture is stirred at room temperature 2 hours, and sucking filtration obtains title compound Thing is faint yellow solid (600mg, 66%).

MS(ESI,pos.ion)m/z:258.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.27 (s, 1H), 7.51 (br s, 4H), 2.54-2.47 (q, J= 6.8Hz, 1H), 1.08-1.06 (d, J=6.8Hz, 6H).

Step 5) the chloro-5-of 6-(5-isopropyl-1,3,4-diazole-2-base) pyrimidine-4-amine

By compound 4-amino-6-chloro-N'-isobutyryl pyrimidine-5-carbohydrazide (600mg, 2.32mmol) and pyridine (408mg, 5.12mmol) suspends again in dichloromethane (20mL), then-10 DEG C, adds trifluoromethanesulfanhydride anhydride in reactant liquor (1mL, 5.92mmol), gained solution stirs 1 hour at this temperature, the most progressively rises to 0 DEG C and is stirred overnight, being subsequently adding Saturated NaHCO₃Aqueous solution (20mL) cancellation is reacted, and aqueous phase dichloromethane (20mL) extracts, the saturated food of the organic facies of merging Saline (20mL) is washed, concentrating under reduced pressure, and gained residue obtains title through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purification Compound is faint yellow solid (15mg, 3%).

MS(ESI,pos.ion)m/z:240.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.68(br s,1H),8.38(s,1H),6.05(br s,1H),3.32 (dt, J=14.0,7.2Hz, 1H), 1.48 (d, J=6.8Hz, 6H).

Step 6) (S)-2-(1-((6-amino-5-(5-isopropyl-1,3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-5-chloro-3-phenylquinazoline-4 (3H)-one

By compound (S)-2-(1-amino-ethyl)-5-chloro-3-phenylquinazoline-4 (3H)-one (19.1mg, 0.06mmol), DIPEA (20.1mg, 0.15mmol) and the chloro-5-of 6-(5-isopropyl-1,3,4-diazole-2-bases) pyrimidine-4- The amine (13mg, 0.05mmol) mixture in n-butyl alcohol (1mL) is heated to 120 DEG C and stirs reaction 5 hours, is subsequently cooled to Room temperature, concentrating under reduced pressure, gained residue obtains title compound through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purification is Beige solid (19mg, 59%).

MS(ESI,pos.ion)m/z:502.8[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.65-8.63 (d, J=6.8Hz, 1H), 7.96 (s, 1H), 7.80- 7.76 (dd, J=8.0,8.0Hz, 1H), 7.61-7.75 (m, 7H), 7.24 (br s, 2H), 4.88-4.83 (dt, J=6.4, 6.4Hz,1H),3.40-3.29(m,1H),1.39-1.36(m,9H)。

Embodiment 17 (S)-2-(1-((6-amino-5-(5-ethyl-1,3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-5-chloro-3-phenylquinazoline-4 (3H)-one

Step 1) propanoic acid hydrazine

Compound ethyl propionate (10g, 97.9mmol) is suspended in the anhydrous EtOH of 25mL, then adds in reactant liquor Hydrazine hydrate (4.5mL, 93.0mmol, 80%), mixture, 90 DEG C of back flow reaction 8 hours, is then cooled to room temperature, concentrating under reduced pressure Obtaining title compound is white solid (4.37g, 54%).

MS(ESI,pos.ion)m/z:89.2[M+H]⁺。

Step 2) 4,6-dichloro pyrimidine-5-phosgene

Add in the mixture of compound 4,6-dichloro pyrimidine-5-formic acid (2.0g, 10.0mmol) and 10mL oxolane Enter N,N-dimethylformamide (0.1mL, 1.0mmol) and SOCl₂(1.2mL, 16mmol), is heated to 80 DEG C by gained mixture And stir reaction 7 hours, being concentrated under reduced pressure to give title compound is yellow oil (2.12g, 97%), without being further purified It is directly used in next step reaction.

Step 3) 4,6-bis-chloro-N'-propiono pyrimidine-5-carbohydrazide

At 0 DEG C, to stirring propanoic acid hydrazine (1.0g, 11.0mmol) and triethylamine (3mL, 21.0mmol) at dichloromethane (6mL) mixture is slowly added to the dichloromethane (15mL) of 4,6-dichloro pyrimidine-5-phosgene (2.12g, 10.0mmol) Solution, mixture continues stirring 2 hours, then concentrating under reduced pressure in this temperature, adds PE/EtOAc/H in residue₂O(9mL/ Mixed solvent 10mL/10mL), is stirred at room temperature 3 hours, then sucking filtration, obtain title compound be yellow solid (1.48g, 54%).

MS(ESI,pos.ion)m/z:263.0[M+H]⁺。

Step 4) 4-amino-6-chloro-N'-propiono pyrimidine-5-carbohydrazide

4,6-bis-chloro-N'-propiono pyrimidine-5-carbohydrazide (1.48g, 5.63mmol) and NH is added in tube sealing₃Different Propanol solution (30mL, 3.0M), mixture is stirred overnight at 90 DEG C, is then cooled to room temperature, and sucking filtration obtains title compound and is Yellow solid (1.1g, 81.0%).

MS(ESI,pos.ion)m/z:244.2[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm)8.28(s,1H),7.87(s,2H),7.47(s,2H),2.23(q,J =7.6Hz, 2H), 1.06 (t, J=7.6Hz, 3H).

Step 5) the chloro-5-of 6-(5-ethyl-1,3,4-diazole-2-base) pyrimidine-4-amine

Compound 4-amino-6-chloro-N'-propiono pyrimidine-5-carbohydrazide (500mg, 2.05mmol) is suspended in 20mL In toluene, then adding burgess reagent (978mg, 4.10mmol) in reactant liquor, mixture is little 110 DEG C of stirring reactions 2 Time, it being then cooled to room temperature, concentrating under reduced pressure, residue is dissolved in ethyl acetate/water (15mL/5mL) mixed solvent, and aqueous phase is used Ethyl acetate (10mL) extracts, and the organic facies saturated aqueous common salt (10mL) of merging is washed, and is dried with anhydrous sodium sulfate, concentrating under reduced pressure, It is faint yellow solid that gained residue obtains title compound through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purification (60mg, 13.0%).

MS(ESI,pos.ion)m/z:226.0[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆) δ (ppm): 8.38 (s, 1H), 7.76 (s, 2H), 2.95 (q, J=7.5Hz, 2H), 1.33 (t, J=7.6Hz, 3H).

Step 6) (S)-2-(1-((6-amino-5-(5-ethyl-1,3,4-diazole-2-base) pyrimidine-4-yl) amino) second Base)-5-chloro-3-phenylquinazoline-4 (3H)-one

By chloro-for compound 6-5-(5-ethyl-1,3,4-diazole-2-base) pyrimidine-4-amine (30mg, 0.13mmol) and (S)-2-(1-amino-ethyl)-5-chloro-3-phenylquinazoline-4 (3H)-one (39.0mg, 0.13mmol) is suspended in n-BuOH (5mL) in, then adding DIPEA (0.1mL) in reactant liquor, mixture is stirred overnight at 120 DEG C, is then cooled to room temperature, Concentrating under reduced pressure, it is faint yellow solid that residue obtains title compound through preparative TLC (DCM/MeOH (v/v)=20/1) purification (33.1mg, 53%).

MS(ESI,pos.ion)m/z:489.8[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.49 (d, J=7.0Hz, 1H), 8.02 (s, 1H), 7.60 (d, J= 4.3Hz, 2H), 7.55 (m, 3H), 7.47 (dd, J=8.8,4.5Hz, 2H), 7.33 (d, J=9.1Hz, 1H), 6.40 (s, 2H), 5.14 (m, 1H), 3.09-3.00 (m, 2H), 1.51 (d, J=7.6Hz, 3H), 1.49-1.44 (t, J=4.28Hz, 3H).

Embodiment 18 (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-2-cyclopropyl-8-fluorine isoquinolin-1 (2H)-one

Step 1) N-cyclopropyl-2-fluoro-6-methyl benzamide

Under room temperature condition, fluoro-for compound 2-6-ar-Toluic acid (4.0g, 25.95mmol) is suspended in toluene (26mL) In, in reactant liquor, then add SOCl₂(7.5mL, 103.80mmol), mixture is stirred overnight at 90 DEG C, is subsequently cooled to Room temperature, concentrating under reduced pressure, residue is dissolved in 30mL oxolane, at 0 DEG C, in gained solution, is added dropwise over triethylamine (10.85mL, 77.85mmol) and cyclopropylamine (1.89mL, 27.25mmol), gained mixture is stirred at room temperature reaction 5 hours, Then concentrating under reduced pressure, residue is dispersed in water (200mL) and ethyl acetate (200mL), and organic facies uses unsaturated carbonate hydrogen successively Sodium water solution (200mL) and saturated aqueous common salt (200mL) are washed, and are dried with anhydrous sodium sulfate, are concentrated under reduced pressure to give title compound For beige solid (4.25g, 85%).

¹H NMR(400MHz,CDCl₃) δ (ppm): 7.23-7.17 (ddd, J=8.0,8.0,6.0Hz, 1H), 6.97- 6.95 (d, J=7.6Hz, 1H), 6.89-6.85 (dd, J=8.8,8.8Hz, 1H), 6.00 (br s, 1H), 2.92-2.85 (m, 1H),2.36(s,3H),0.88-0.83(m,2H),0.62-0.58(m,2H)。

Step 2) (S)-3-(1-amino-ethyl)-2-cyclopropyl-8-fluorine isoquinolin-1 (2H)-one

Compound N-cyclopropyl-2-fluoro-6-methyl benzamide (3.00g, 15.53mmol) is dissolved in oxolane (22mL), in, under then-30 DEG C and nitrogen are protected, in reactant liquor, n-BuLi (16.2mL, 38.82mmol), institute it are added dropwise over Obtain deep yellow solution and continue stirring 30 minutes in this temperature；

By compound (S)-(1-(methoxyl group (methyl) amino)-1-oxopropan-2-base) t-butyl carbamate (5.41g, 23.29mmol) is dissolved in oxolane (110mL), under then-30 DEG C and nitrogen are protected, in reactant liquor dropwise Adding the tetrahydrofuran solution (2M, 12.8mL, 25.6mmol) of i-PrMgCl, dropping in 30 minutes is complete, and gained mixture is-30 DEG C continue stirring 30 minutes, then gained solution is added dropwise in above-mentioned gained deep yellow solution, is warming up to-15 DEG C and continues Stirring reaction 2 hours, adds water (5mL) cancellation reaction, at 0 DEG C, adds concentrated hydrochloric acid aqueous solution and adjusted in gained mixture Joint is to pH=1, concentrating under reduced pressure, and residue is dissolved in the methanol of 45mL, is subsequently adding 22mL concentrated hydrochloric acid aqueous solution, and gained mixes Thing, after 80 DEG C of stirrings 1 hour, is cooled to room temperature, concentrating under reduced pressure, and residue is dissolved in dichloromethane (40mL) and methanol (20mL), in mixed solvent, in solution, add sodium bicarbonate powder alkalized to pH=8.5, be stirred at room temperature 4 hours, subtract Pressure concentrates, and it is yellow jelly that residue obtains title compound through silica gel column chromatography (DCM/MeOH (v/v)=10/1) purification (4.5g, 80%).MS(ESI,pos.ion)m/z:247.0[M+H]；

¹H NMR(400MHz,CDCl₃) δ (ppm): 7.53-7.48 (ddd, J=8.0,8.0,4.8Hz, 1H), 7.22 (d, J =8.0Hz, 1H), 7.06-7.01 (ddd, J=0.8,8.0,11.6Hz, 1H), 6.63-6.62 (d, J=2.0Hz, 1H), 4.82 (q, J=6.4Hz, 1H), 2.95-2.92 (m, 1H), 1.46-1.45 (d, J=6.4Hz, 3H), 1.34-1.25 (m, 2H), 0.95-0.82(m,2H)。

Step 3) (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) second Base)-2-cyclopropyl-8-fluorine isoquinolin-1 (2H)-one

By compound (S)-3-(1-amino-ethyl)-2-cyclopropyl-8-fluorine isoquinolin-1 (2H)-one (51.5mg, 0.209mmol), the chloro-5-of 6-(5-methyl isophthalic acid, 3,4-diazole-2-bases) pyrimidine-4-amine (47.1mg, 0.223mmol) and The DIPEA (52.6mg, 0.407mmol) mixture in n-butyl alcohol (2mL), 125 DEG C of back flow reaction 20 hours, then cools down To room temperature, concentrating under reduced pressure, residue obtains crude product, crude product through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purification Obtaining title compound through preparative TLC (pure ethyl acetate) purification again is faint yellow solid (53mg, 60%).

MS(ESI,pos.ion)m/z:421.9[M+H]；

¹H NMR(600MHz,CDCl₃) δ (ppm): 8.71-8.70 (d, J=6.6Hz, 1H), 8.11 (s, 1H), 7.45- 7.42 (m, 1H), 7.10-7.09 (d, J=8.4Hz, 1H), 7.01-6.98 (dd, J=10.8,8.4Hz, 1H), 6.43 (s, 1H), 6.15-6.11 (dddd, J=6.0,6.0,6.0,6.0Hz, 1H), 6.04 (br s, 2H), 3.00-2.99 (m, 1H), 2.68 (s, 3H), 1.65-1.63 (d, J=6.6Hz, 3H), 1.43-1.40 (m, 1H), 1.39-1.34 (m, 1H), 1.31-1.27 (m,1H),0.94-0.90(m,1H)。

Embodiment 19 (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Propyl group)-2-cyclopropyl-8-fluorine isoquinolin-1 (2H)-one

By compound (S)-3-(1-aminopropyl)-2-cyclopropyl-8-fluorine isoquinolin-1 (2H)-one (47.7mg, 0.183mmol), the chloro-5-of 6-(5-methyl isophthalic acid, 3,4-diazole-2-bases) pyrimidine-4-amine (44.8mg, 0.212mmol) and DIPEA (51.9mg, 0.402mmol), is subsequently cooled to 120 DEG C of back flow reaction 12 hours at the mixture of n-butyl alcohol (2mL) Room temperature, concentrating under reduced pressure, residue obtains crude product through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purification, and crude product is again Obtaining title compound through preparative TLC (pure ethyl acetate) purification is beige solid (11mg, 14%).

MS(ESI,pos.ion)m/z:435.9[M+H]⁺；

¹H NMR(600MHz,CDCl₃) δ (ppm): 8.82-8.81 (d, J=7.2Hz, 1H), 8.10 (s, 1H), 7.45- 7.41 (ddd, J=8.4,8.4,4.8Hz, 1H), 7.09-7.07 (d, J=7.8Hz, 1H), 7.00-6.97 (dd, J=11.4, 7.8Hz,1H),6.36(s,1H),6.02-5.99(m,3H),3.02-2.98(m,1H),2.69(s,3H),2.07-2.00(m, 1H),1.88-1.80(m,1H),1.52-1.47(m,1H),1.41-1.36(m,1H),1.33-1.27(m,1H),1.12-1.10 (t, J=7.2Hz, 3H), 0.94-0.90 (m, 1H).

Embodiment 20 (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Propyl group)-8-methyl-2-phenyl isoquinolin quinoline-1 (2H)-one

By compound (S)-3-(1-aminopropyl)-8-methyl-2-phenyl isoquinolin quinoline-1 (2H)-one (50.3mg, 0.172mmol), the chloro-5-of 6-(5-methyl isophthalic acid, 3,4-diazole-2-bases) pyrimidine-4-amine (40.6mg, 0.192mmol) and three second The amine (87.1mg, 0.816mmol) mixture in n-butyl alcohol (2.5ml) is heated to backflow and stirs reaction 18 hours, then Being cooled to room temperature, concentrating under reduced pressure, residue obtains title compound through silica gel column chromatography (DCM/MeOH (v/v)=50/1) purification For faint yellow solid (60mg, 75%).

MS(ESI,pos.ion)m/z:468.3[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ 8.34 (d, J=6.7Hz, 1H), 7.97 (s, 1H), 7.59-7.44 (m, 5H), 7.40 (dd, J=7.2,4.7Hz, 2H), 7.20 (d, J=7.2Hz, 2H), 6.55 (s, 1H), 4.56 (dd, J=10.9, 8.5Hz, 1H), 2.72 (s, 3H), 2.59 (s, 3H), 1.84-1.79 (m, 1H), 1.66-1.61 (m, 1H), 0.74 (t, J= 7.2Hz,3H)。

Embodiment 21 (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-8-methyl-2-phenyl isoquinolin quinoline-1 (2H)-one

Step 1) 2,6-dimethyl-N-phenyl Benzoylamide

Under room temperature, to compound 2,6-mesitylenic acid (1.99g, 13.3mmol), DMF Adding oxalyl chloride (2.25mL) in the mixture of (103mg, 1.409mmol) and dichloromethane (15mL), mixture stirs in room temperature Mixing reaction 4 hours, then concentrating under reduced pressure, residue is dissolved in Isosorbide-5-Nitrae-dioxane (4mL), at 0 DEG C, is added by gained solution To aniline (1.28g, 13.7mmol), sodium bicarbonate (2.80g, 175mmol), Isosorbide-5-Nitrae-dioxane (11mL) and water (7mL) In mixture, then move to stirred overnight at room temperature, mixture is poured in water (100mL), gained mixture ethyl acetate (50mL × 2) extract, and the organic facies concentrating under reduced pressure that will merge, residue is through silica gel column chromatography (PE/EtOAc (v/v)=10/1) It is beige solid (740mg, 25%) that purification obtains title compound.

MS(ESI,pos.ion)m/z:226.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 7.63-7.61 (d, J=8.0Hz, 2H), 7.39-7.36 (dd, J= 8.0,8.0Hz, 2H), 7.36 (brs, 1H), 7.23-7.13 (m, 2H), 7.08-7.06 (d, J=7.6Hz, 2H), 2.40 (s, 6H)。

Step 2) (S)-3-(1-amino-ethyl)-8-methyl-2-phenyl isoquinolin quinoline-1 (2H)-one

Compound 2,6-dimethyl-N-phenyl Benzoylamide (730mg, 3.24mmol) is dissolved in 25mL oxolane In, then at-30 DEG C, in reactant liquor, adding n-BuLi (2.4mol/L, 4mL), gained solution stirs 30 points in this temperature Clock；

By compound (S)-(1-(methoxyl group (methyl) amino)-1-oxopropan-2-base) t-butyl carbamate (1.14g, 4.91mmol) is dissolved in 15mL oxolane, then-30 DEG C of tetrahydrofuran solutions adding i-PrMgCl (2M, 3mL), mixture, after this temperature stirs 30 minutes, joins in above-mentioned gained solution, and the mixture obtained stirs 1 at-15 DEG C Hour, adding 20mL saturated aqueous ammonium chloride cancellation reaction, separatory, organic facies 20mL saturated common salt is washed, concentrating under reduced pressure, Residue is dissolved in the methanol of 10mL, in gained solution, adds 5mL aqueous hydrochloric acid solution (36%), heat the mixture to 90 DEG C and stir reaction 2 hours, be then cooled to room temperature, concentrating under reduced pressure, residue be dissolved in 20mL ethyl acetate and 35mL In the mixed solvent of water, the aqueous phase mixed extractant solvent of PE/EtOAc (5mL/5mL), add sodium bicarbonate powder and alkalize extremely PH=8.5, sucking filtration, it is faint yellow solid (329mg, 36% liang of step that filter cake obtains title compound for 4 hours 60 DEG C of vacuum drying Productivity).MS(ESI,pos.ion)m/z:279.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.56-7.52(m,2H),7.50-7.44(m,2H),7.38-7.36 (d, J=8.0Hz, 1H), 7.29-7.26 (m, 2H), 7.21-7.19 (d, J=7.2Hz, 1H), 6.68 (s, 1H), 3.70-3.65 (q, J=6.4Hz, 1H), 2.86 (s, 3H), 1.27-1.25 (d, J=6.4Hz, 3H).

Step 3) (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) second Base)-8-methyl-2-phenyl isoquinolin quinoline-1 (2H)-one

By compound (S)-3-(1-amino-ethyl)-8-methyl-2-phenyl isoquinolin quinoline-1 (2H)-one (55.0mg, 0.198mmol), the chloro-5-of 6-(5-methyl isophthalic acid, 3,4-diazole-2-bases) pyrimidine-4-amine (42.0mg, 0.198mmol), DIPEA The mixture of (47.4mg, 0.367mmol) and n-butyl alcohol (2mL), 125 DEG C of back flow reaction 13 hours, is then cooled to room temperature, Concentrating under reduced pressure, it is faint yellow solid that residue obtains title compound through silica gel column chromatography (PE/EtOAc (v/v)=1/4) purification (57mg, 64%).

MS(ESI,pos.ion)m/z:454.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.57-8.55 (d, J=6.4Hz, 1H), 7.99 (s, 1H), 7.53- 7.48 (m, 1H), 7.46-7.38 (m, 4H), 7.32-7.27 (m, 2H), 7.19-7.17 (d, J=7.6Hz, 1H), 6.53 (s, 1H), 5.96 (br s, 2H), 5.03-4.96 (dq, J=6.8,6.8Hz, 1H), 2.85 (s, 3H), 2.67 (s, 3H), 1.46- 1.44 (d, J=6.8Hz, 3H).

Embodiment 22 (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Propyl group)-8-fluoro-2-phenyl isoquinolin quinoline-1 (2H)-one

By compound (S)-3-(1-aminopropyl)-8-fluoro-2-phenyl isoquinolin quinoline-1 (2H)-one (150mg, 0.51mmol) 5-chloro-with 6-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-amine (108mg, 0.51mmol) is suspended in n-butyl alcohol (6mL) In, in reactant liquor, then adding DIPEA (0.3mL, 1.72mmol), gained mixture is stirred overnight at 120 DEG C, then reduces pressure Concentrating, it is beige solid that residue obtains title compound through silica gel column chromatography (PE/EtOAc (v/v)=1/5) purification (62mg, 25.7%).

MS(ESI,pos.ion)m/z:472.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.76 (d, J=6.6Hz, 1H), 8.05 (s, 1H), 7.57-7.43 (m, 5H), 7.33-7.31 (d, J=7.6Hz, 1H), 7.19-7.17 (d, J=7.9Hz, 1H), 7.05-7.01 (dd, J=11.3, 8.1Hz,1H),6.47(s,1H),6.05(s,2H),4.84-4.79(m,1H),2.68(s,3H),1.84(m,2H),0.84(t, J=7.4Hz, 3H).

Embodiment 23 (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-8-fluoro-2-phenyl isoquinolin quinoline-1 (2H)-one

Step 1) (S)-(4-(3-fluoro-2-(phenylcarbamoyl) phenyl)-3-oxo-butanes-2-base) carbamic acid uncle Butyl ester

Fluoro-for compound 2-6-Methyl-N-phenyl-Benzoylamide (2.0g, 8.7mmol) is dissolved in anhydrous tetrahydro furan (20mL), in, in reactant liquor, then it is added dropwise over n-BuLi (hexane solution of 9.2mL, 22.1mmol, 2.4M), within 30 minutes, drips Adding complete, mixture obtains red tan solution (i-1) for 35 minutes-30 DEG C of stirrings, this solution is the most purified be directly used in following Reaction；

By compound (1-(methoxyl group (methyl) amino)-1-oxopropan-2-base) t-butyl carbamate (3.04g, 13.1mmol) it is suspended in anhydrous tetrahydro furan (25mL), then at-30 DEG C, in the reactant liquor of stirring, is added dropwise over i- PrMgCl (tetrahydrofuran solution of 2.0M, 7.2mL, 14.4mmol), dropping in 30 minutes is complete, and gained mixture stirs in this temperature Mix 35 minutes and obtain yellow solution (i-2)；

At-30 DEG C, in the red tan solution (i-1) obtained, it is added dropwise over the yellow solution (i-2) obtained, mixture Stirring 3.5 hours at-15 DEG C, be subsequently adding water (50mL) cancellation reaction, mixture is dispersed in saturated aqueous ammonium chloride (100mL) With in the mixed solvent of ethyl acetate (100mL), aqueous phase ethyl acetate (100mL × 2) extracts, and the organic facies of merging is used successively Saturated aqueous ammonium chloride (100mL) and saturated aqueous common salt (100mL) are washed, and are dried with anhydrous sodium sulfate, are concentrated under reduced pressure to give mark Topic compound is faint yellow solid, is directly used in the next step without further purification.

Step 2) (S)-3-(1-amino-ethyl)-8-fluoro-2-phenyl isoquinolin quinoline-1 (2H)-one

By compound (S)-4-(3-fluoro-2-(phenylcarbamoyl) phenyl)-3-oxo-butanes-2-base) carbamic acid The tert-butyl ester (4.0g, 10mmol) is dissolved in methanol (20mL), then adds concentrated hydrochloric acid (20mL) in reactant liquor, by mixture Being heated to 95 DEG C and be stirred overnight, being then cooled to room temperature, concentrating under reduced pressure, residue is dispersed in PE/EtOAc (50mL/25mL) With in the mixed solvent of water (20mL), aqueous phase adds sodium bicarbonate powder alkalization, then extracts with dichloromethane (100mL × 3), closes And organic facies saturated aqueous common salt (150mL) wash, concentrating under reduced pressure, residue through silica gel column chromatography (DCM/MeOH (v/v)= 50/1) purification obtains title compound is beige solid (1.8g, 64%).

MS(ESI,pos.ion)m/z:283.1[M+H]⁺。

Step 3) (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) second Base)-8-fluoro-2-phenyl isoquinolin quinoline-1 (2H)-one

By compound (S)-3-(1-amino-ethyl)-8-fluoro-2-phenyl isoquinolin quinoline-1 (2H)-one (100mg, 0.35mmol) 5-chloro-with 6-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-amine (75mg, 0.35mmol) is suspended in n-butyl alcohol (5mL) In, in reactant liquor, then adding DIPEA (0.3mL, 1.72mmol), mixture, 125 DEG C of stirring reactions 5 hours, then subtracts Pressure concentrates, and it is beige solid that residue obtains title compound through silica gel column chromatography (PE/EtOAc (v/v)=1/5) purification (62mg, 38.2%).

MS(ESI,pos.ion)m/z:458.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.64 (d, J=6.5Hz, 1H), 8.01 (s, 1H), 7.55-7.47 (m, 3H), 7.44-7.40 (m, 2H), 7.32-7.30 (d, J=7.4Hz, 1H), 7.21-7.20 (d, J=7.9Hz, 1H), 7.06- 7.01 (dd, J=11.3,8.1Hz, 1H), 6.55-6.54 (d, J=1.6Hz, 1H), 5.99 (s, 2H), 5.02-4.95 (m, 1H), 2.67 (s, 3H), 1.45-1.44 (d, J=6.8Hz, 3H).

Embodiment 24 (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-2-cyclopropyl-8-methylisoquinolinium-1 (2H)-one

Step 1) N-cyclopropyl-2,6-dimethyl benzamide

By compound 2,6-mesitylenic acid (2.06g, 13.7mmol) is dissolved in dichloromethane (10mL), then room Temperature condition, adds oxalyl chloride (2.3mL, 27mmol) in reactant liquor, and 45 DEG C of stirrings are reacted 5 hours, are then cooled to room temperature, subtract Pressure concentrates, and is dissolved in by residue in dichloromethane (20mL), at ambient temperature, adds triethylamine in gained solution (5.5mL, 40mmol) and cyclopropylamine (1mL, 14.4mmol), mixture is stirred at room temperature overnight, the most successively with water (100mL × 2), saturated sodium bicarbonate aqueous solution (100mL × 2) and saturated aqueous common salt (100mL) are washed, separatory, organic facies anhydrous slufuric acid Sodium is dried, concentrating under reduced pressure, and it is white that residue obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=1/4) purification Color solid (1.35g, 52%).

MS(ESI,pos.ion)m/z:190.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.30 (s, 1H), 7.19-7.09 (m, 1H), 7.02 (d, J= 7.5Hz,2H),2.81(m,1H),2.18(s,6H),0.72-0.61(m,2H),0.52-0.43(m,2H)。

Step 2) (S)-3-(1-amino-ethyl)-2-cyclopropyl-8-methylisoquinolinium-1 (2H)-one

Compound N-cyclopropyl-2,6-dimethyl benzamide (1.2g, 6.3mmol) is dissolved in oxolane (10mL) In, then under-30 DEG C and nitrogen are protected, in reactant liquor, it is added dropwise over n-BuLi (2.4M, 6.6mL, 15.84mmol), 0.5 Hour dropping complete, the pale yellow solution obtained stirs at this temperature 2 hours and obtains solution A；

By compound (S)-(1-(methoxyl group (methyl) amino)-1-oxopropan-2-base) t-butyl carbamate (2.20g, 9.48mmol) is dissolved in oxolane (15mL), then under-30 DEG C and nitrogen are protected, in reactant liquor dropwise Adding the tetrahydrofuran solution (2M, 5.2mL, 10.4mmol) of i-PrMgCl, dropping in 0.5 hour is complete, and the solution obtained is-30 DEG C stirring obtains solution B in 2 hours；

At-30 DEG C, being added dropwise over solution B in solution A, dropping in 0.5 hour is complete, and the solution obtained is-15 DEG C of stirrings React 2.5 hours, add 40mL shrend and go out reaction, gained mixture is dispersed in ethyl acetate (100mL) and saturated ammonium chloride In aqueous solution (100mL), aqueous phase ethyl acetate (100mL × 2) extracts, and the organic facies of merging is successively with the saturated chlorination of 100mL Aqueous ammonium and the washing of 100mL saturated common salt, be concentrated under reduced pressure to give faint yellow solid, be dissolved in by solid in methanol (20mL), Under room temperature, in the solution obtained, add concentrated hydrochloric acid (20mL), 95 DEG C of stirring reactions 3 hours, be then cooled to room temperature, decompression Concentrating, residue PE/EtOAc (50mL/25mL) extracts, and aqueous phase adds powdered sodium carbonate and regulated to pH=8.5, then Extracting with dichloromethane (100mL × 3), the organic facies of merging 100mL saturated common salt is washed, and concentrating under reduced pressure, residue is through silicon It is pale yellow oil (1g, 65%) that plastic column chromatography (EtOAc/PE (v/v)=4/1) purification obtains title compound.MS(ESI, pos.ion)m/z:243.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.24 (s, 1H), 7.24 (d, J=9.4Hz, 4H), 2.90-2.72 (m,1H),2.31(s,3H),0.67(m,2H),0.54-0.49(m,2H)。

Step 3) (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) second Base)-2-cyclopropyl-8-methylisoquinolinium-1 (2H)-one

By compound (S)-3-(1-amino-ethyl)-2-cyclopropyl-8-methylisoquinolinium-1 (2H)-one (100mg, 0.3592mmol), the chloro-5-of 6-(5-methyl isophthalic acid, 3,4-diazole-2-bases) pyrimidine-4-amine (83.9mg, 0.396mmol), The mixture of DIPEA (0.12mL, 0.73mmol) and n-butyl alcohol (4mL) is heated to 125 DEG C and stirs reaction 4 hours, the coldest But to room temperature, concentrating under reduced pressure, residue obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=2/1) purification is White solid (97.4mg, 64.9%).

MS(ESI,pos.ion)m/z:417.9[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 7.44 (d, J=7.5Hz, 1H), 7.34 (d, J=7.8Hz, 1H), 7.14 (d, J=7.2Hz, 1H), 6.66 (s, 1H), 4.60 (dd, J=6.5Hz, J=6.5Hz, 1H), 2.93 (m, 1H), 2.75 (s, 3H), 1.32 (d, J=6.5Hz, 3H), 1.16 (dd, J=6.7,2.6Hz, 2H), 0.82-0.72 (m, 1H), 0.70-0.60 (m,1H)。

Embodiment 25 (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Propyl group)-2-cyclopropyl isoquinolin-1 (2H)-one

Step 1) N-cyclopropyl-2-methyl benzamide

Compound 2-ar-Toluic acid (3.04g, 22.3mmol) is dissolved in dichloromethane (20mL), then in room temperature Under, in reactant liquor, adding oxalyl chloride (3.7mL, 44mmol), mixture, 45 DEG C of stirring reactions 5.5 hours, is subsequently cooled to Room temperature, concentrating under reduced pressure, residue is dissolved in dichloromethane (20mL), then in room temperature, in gained solution, adds three second Amine (9.3mL, 66mmol) and cyclopropylamine (1.6mL, 23mmol), mixture is stirred at room temperature reaction 3 hours, uses water the most successively (100mL × 2), saturated sodium bicarbonate aqueous solution (100mL × 2) and saturated aqueous common salt (100mL) are washed, separatory, organic facies nothing Aqueous sodium persulfate is dried, concentrating under reduced pressure, and residue obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=1/4) purification Thing is white solid (1.77g, 45.1%).

MS(ESI,pos.ion)m/z:176.1[M+H]⁺；

Step 2) (S)-3-(1-aminopropyl)-2-cyclopropyl isoquinolin-1 (2H)-one

Compound N-cyclopropyl-2-methyl benzamide (808.2mg, 4.612mmol) is dissolved in oxolane (10mL), in, then under-30 DEG C and nitrogen are protected, in reactant liquor, n-BuLi (2.4M, 4.8mL, 12mmol) it is added dropwise over, Dropping in 0.5 hour is complete, and the yellow solution obtained stirs 1 hour at this temperature, obtains solution A；

By compound (S)-(1-(methoxyl group (methyl) amino)-1-oxo-butanes-2-base) t-butyl carbamate (1.688g, 6.853mmol) is dissolved in oxolane (15mL), then under-30 DEG C and nitrogen are protected, in reactant liquor by Being added dropwise to the tetrahydrofuran solution (2M, 3.8mL, 7.6mmol) of i-PrMgCl, dropping in 0.5 hour is complete, and gained solution is-30 DEG C stirring 1 hour, obtain solution B；

At-30 DEG C, being added dropwise over solution B in solution A, dropping in 0.5 hour is complete, and gained solution is anti--15 DEG C of stirrings Answer 3.5 hours, add 40mL shrend and go out reaction, then mixture is dispersed in 100mL ethyl acetate and 100mL saturated ammonium chloride In aqueous solution, aqueous phase ethyl acetate (100mL × 2) extracts, and the organic facies of merging uses 100mL saturated aqueous ammonium chloride successively Wash with 100mL saturated common salt, be concentrated under reduced pressure to give light yellow oil, this grease be dissolved in 20mL methanol, room temperature Under the conditions of, in gained solution, adding 20mL concentrated hydrochloric acid, gained solution at 95 DEG C overnight, is then cooled to room temperature, concentrating under reduced pressure, Residue with Ethyl acetate (100mL × 2) extracts, and after aqueous phase addition powdered sodium carbonate is basified to pH=8.5, uses dichloromethane Alkane (100mL × 3) extracts, and the organic facies of merging 100mL saturated common salt is washed, and being concentrated under reduced pressure to give title compound is yellow Grease (837mg, 74.9%).

MS(ESI,pos.ion)m/z:243.05[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.11 (d, J=8.0Hz, 1H), 7.68-7.59 (m, 1H), 7.54 (d, J=7.7Hz, 1H), 7.45-7.34 (m, 1H), 6.73 (s, 1H), 4.42 (dd, J=7.4,5.4Hz, 1H), 2.96 (m, 1H), 1.80-1.66 (m, 1H), 1.53 (m, 1H), 1.22-1.10 (m, 2H), 0.93 (t, J=7.4Hz, 3H), 0.89-0.84 (m,1H),0.73-0.63(m,1H)。

Step 3) (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) third Base)-2-cyclopropyl isoquinolin-1 (2H)-one

By compound (S)-3-(1-aminopropyl)-2-cyclopropyl isoquinolin-1 (2H)-one (110mg, 0.45mmol), 6- Chloro-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-amine (131.7mg, 0.62mmol) and DIPEA (0.14mL, 0.85mmol) mixture in n-butyl alcohol (4mL) is heated to 125 DEG C and stirs reaction 10 hours, is then cooled to room temperature, subtracts Pressure concentrates, and it is white solid that residue obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=2/1) purification (110.1mg, 58.9%).

MS(ESI,pos.ion)m/z:417.9[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.48 (d, J=6.9Hz, 1H), 8.12 (d, J=7.9Hz, 1H), 8.01 (s, 1H), 7.60 (t, J=7.1Hz, 1H), 7.49 (d, J=7.8Hz, 1H), 7.41 (t, J=7.5Hz, 1H), 7.25 (s,2H),6.51(s,1H),5.88(m,1H),3.07(m,1H),2.61(s,3H),2.09-2.01(m,1H),1.85-1.74 (m, 1H), 1.26 (m, 2H), 1.05 (t, J=7.3Hz, 3H), 0.82 (m, 1H), 0.80 (m, 1H).

Embodiment 26 (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-bases) pyrimidine-4-yl) amino) Propyl group)-2-phenyl isoquinolin quinoline-1 (2H)-one

Step 1) 2-Methyl-N-phenyl Benzoylamide

Compound 2-ar-Toluic acid (3.3g, 24mmol) is dissolved in dichloromethane (30mL) and DMF (0.2mL, In 3mmol), the most at ambient temperature, being added dropwise over oxalyl chloride (5.5mL, 64mmol) in reactant liquor, mixture is in room temperature Stirring reaction 3 hours, then concentrating under reduced pressure, residue is dissolved in dichloromethane (40mL), gained solution stirs one at 0 DEG C Meeting, is then sequentially added into triethylamine (10mL, 70mmol) and aniline (2.02g, 21.7mmol), mixture room temperature in reactant liquor Being stirred overnight, the most successively with water (100mL), saturated sodium bicarbonate aqueous solution (100mL) and saturated aqueous common salt (100mL) are washed, Separatory, organic facies anhydrous sodium sulfate is dried, concentrating under reduced pressure, and residue is through silica gel column chromatography (PE/EtOAc (v/v)=10/1) It is yellow solid (1.61g, 31.7%) that purification obtains title compound.

MS(ESI,pos.ion)m/z:212.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 7.64 (d, J=7.4Hz, 2H), 7.58 (s, 1H), 7.49 (d, J= 7.4Hz, 1H), 7.38 (t, J=7.8Hz, 3H), 7.31-7.23 (m, 2H), 7.18 (t, J=7.4Hz, 1H), 2.52 (s, 3H).

Step 2) (S)-3-(1-aminopropyl)-2-phenyl isoquinolin quinoline-1 (2H)-one

Compound 2-Methyl-N-phenyl Benzoylamide (1.605g, 7.596mmol) is dissolved in oxolane (15mL) In, then under-30 DEG C and nitrogen are protected, in reactant liquor, it is added dropwise over n-BuLi (2.4M, 7.9mL, 19mmol), 0.5 is little Time drip complete, gained yellow solution this temperature stir 1.5 hours, obtain solution A；

By compound (S)-(1-(methoxyl group (methyl) amino)-1-oxo-butanes-2-base) t-butyl carbamate (2.81g, 11.39mmol) is dissolved in oxolane (20mL), then under-30 DEG C and nitrogen are protected, in reactant liquor by Being added dropwise to the tetrahydrofuran solution (2M, 6.2mL, 12mmol) of i-PrMgCl, dropping in 0.5 hour is complete, and mixture stirs at-30 DEG C Mix 1.5 hours, obtain solution B；

At-30 DEG C, being added dropwise over B in solution A, dropping in 0.5 hour is complete, and gained solution stirs reaction 3.5 at-15 DEG C Hour, adding 40mL shrend and go out reaction, mixture is dispersed in 100mL ethyl acetate and 100mL saturated aqueous ammonium chloride, water Extracting by ethyl acetate (100mL × 2) mutually, the organic facies of merging is saturated with 100mL saturated aqueous ammonium chloride and 100mL successively Sal is washed, and is concentrated under reduced pressure to give yellow oil.This grease is dissolved in 20mL methanol, under room temperature condition, molten to gained Adding 20mL concentrated hydrochloric acid in liquid, mixture is stirred overnight at 95 DEG C, is then cooled to room temperature, concentrating under reduced pressure, is dissolved by residue In 100mL water, gained mixture ethyl acetate (100mL × 2) extracts, and aqueous phase adds powdered sodium carbonate and alkalizes to pH= 8.5, then extract with dichloromethane (100mL × 3), the organic facies of merging 100mL saturated common salt is washed, and is concentrated under reduced pressure to give Title compound is faint yellow solid (1.73g, 81.75%).

MS(ESI,pos.ion)m/z:279.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.15 (d, J=8.0Hz, 1H), 7.78-7.70 (m, 1H), 7.67 (d, J=7.6Hz, 1H), 7.55 (t, J=7.5Hz, 2H), 7.52-7.41 (m, 2H), 7.36 (d, J=7.6Hz, 1H), 7.33- 7.21 (m, 1H), 6.87 (s, 1H), 3.20 (dd, J=7.4,4.9Hz, 1H), 1.67-1.50 (m, 1H), 1.40-1.27 (m, 1H), 0.66 (t, J=7.3Hz, 3H).

Step 3) (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) third Base)-2-phenyl isoquinolin quinoline-1 (2H)-one

By compound (S)-3-(1-aminopropyl)-2-phenyl isoquinolin quinoline-1 (2H)-one (107.6mg, 0.3865mmol), The chloro-5-of 6-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-amine (114.3mg, 0.54mmol) and DIPEA (0.12mL, 0.73mmol) mixture in n-butyl alcohol (4mL) is heated to 125 DEG C and stirs reaction 16 hours, is then cooled to room temperature, subtracts Pressure concentrates, and it is white solid that residue obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=2/1) purification (104.3mg, 59.5%).

MS(ESI,pos.ion)m/z:453.9[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.37 (d, J=6.7Hz, 1H), 8.15 (d, J=7.8Hz, 1H), 7.98 (s, 1H), 7.70 (t, J=7.6Hz, 1H), 7.62 (d, J=7.8Hz, 1H), 7.57 (t, J=7.0Hz, 1H), 7.49 (m, 4H), 7.43 (d, J=8.0Hz, 1H), 7.22 (s, 2H), 6.65 (s, 1H), 4.60 (m, 1H), 2.60 (s, 3H), 1.69- 1.59 (m, 1H), 1.42 (m, 1H), 0.75 (t, J=7.3Hz, 3H).

Embodiment 27 (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-2-phenyl isoquinolin quinoline-1 (2H)-one

Step 1) (S)-(3-oxo-4-(2-(phenylcarbamoyl) phenyl) butane-2-base) t-butyl carbamate

Compound 2-Methyl-N-phenyl Benzoylamide (1.6g, 7.6mmol) is dissolved in dry oxolane (15mL) In, then at-30 DEG C, in the reactant liquor of stirring, it is added dropwise over n-BuLi (hexane solution of 2.4M, 8mL), within 30 minutes, drips Adding complete, gained mixture obtains red tan solution A in 35 minutes-30 DEG C of stirrings, is directly used in lower step without being further purified Reaction；

By compound (S)-(1-(methoxyl group (methyl) amino)-1-oxopropan-2-base) t-butyl carbamate (2.65g, 11.4mmol) is dissolved in dry oxolane (20mL), then at-30 DEG C, is added dropwise over i-in reactant liquor PrMgCl (tetrahydrofuran solution of 2.0M, 6.3mL), dropping in 30 minutes is complete, and mixture obtains in the stirring of this temperature for 35 minutes Yellow solution B；

At-30 DEG C, being added dropwise over flaxen solution B in solution A, mixture ,-15 DEG C of stirring reactions 4 hours, adds Entering saturated aqueous ammonium chloride (100mL) cancellation reaction, then extract by ethyl acetate (100mLx 3), the organic facies of merging is successively Wash with saturated aqueous ammonium chloride (100mL) and saturated aqueous common salt (100mL), be then dried with anhydrous sodium sulfate, concentrating under reduced pressure Obtain faint yellow solid (2.9g, 100%), be directly used in the next step without being further purified.

Step 2) (S)-3-(1-amino-ethyl)-2-phenyl isoquinolin quinoline-1 (2H)-one

By compound (S)-(3-oxo-4-(2-(phenylcarbamoyl) phenyl) butane-2-base) tertiary fourth of carbamic acid Ester (2.9g, 7.6mmol) is dissolved in methanol (20mL), then adds concentrated hydrochloric acid (20mL) in reactant liquor, and mixture is 95 DEG C being stirred overnight, be then cooled to room temperature, concentrating under reduced pressure, residue is dispersed in PE/EtOAc (50mL/25mL) and water (20mL) Mixed solvent in, aqueous phase add powdered sodium carbonate alkalize to pH=8, then with dichloromethane (100mL × 3) extraction, conjunction And organic facies saturated aqueous common salt (150mL) wash, being concentrated under reduced pressure to give title compound is yellow solid (1.32g, 66%).

MS(ESI,pos.ion)m/z:265.0[M+H]⁺。

Step 3) (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) second Base)-2-phenyl isoquinolin quinoline-1 (2H)-one

By compound (S)-3-(1-amino-ethyl)-2-phenyl isoquinolin quinoline-1 (2H)-one (100mg, 0.38mmol) and 6- Chloro-5-(5-methyl isophthalic acid, 3,4-diazole-2-bases) pyrimidine-4-amine (80mg, 0.38mmol) is suspended in n-butyl alcohol (4mL), so Adding DIPEA (0.1mL, 0.6mmol) in backward reactant liquor, mixture is stirred overnight at 120 DEG C, is then cooled to room temperature, subtracts Pressure concentrates, and through silica gel column chromatography, (it is beige solid that PE/EtOAc (v/v=1/5) purification obtains title compound to residue (48mg, 28.8%).

MS(ESI,pos.ion)m/z:440.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.64-8.62 (d, J=6.6Hz, 1H), 8.39 (d, J=8.0Hz, 1H), 8.02 (s, 1H), 7.64 (t, J=7.1Hz, 1H), 7.57-7.52 (m, 1H), 7.51-7.47 (m, 2H), 7.47-7.41 (m, 3H), 7.35 (d, J=7.8Hz, 1H), 6.64 (s, 1H), 6.02 (s, 2H), 5.07 (m, 1H), 2.69 (s, 3H), 1.49 (d, J=6.8Hz, 3H).

Embodiment 28 (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-2-cyclopropyl isoquinolin-1 (2H)-one

Step 1) (S)-(4-(2-(cyclopropylcarbamoyl) phenyl)-3-oxo-butanes-2-base) the tertiary fourth of carbamic acid Ester

Compound N-cyclopropyl-2-methyl benzamide (820mg, 4.68mmol) is suspended in dry oxolane (10mL) in, then at-30 DEG C, in reactant liquor, n-BuLi (hexane solution of 2.4M, 5mL), dropping in 30 minutes it are added dropwise over Complete, mixture obtains red tan solution A in 35 minutes-30 DEG C of stirrings, and this solution is directly used in next without being further purified Step reaction；

By compound (S)-(1-(methoxyl group (methyl) amino)-1-oxopropan-2-base) t-butyl carbamate (1.63g, 7.02mmol) is dissolved in dry oxolane (15mL), then at-30 DEG C, is added dropwise over i-in reactant liquor PrMgCl (tetrahydrofuran solution of 4mL, 2.0M), dropping in 30 minutes is complete, and mixture obtains light in 35 minutes in the stirring of this temperature Yellow solution B；

At-30 DEG C, being added dropwise over solution B in the solution A obtained, mixture was-15 DEG C of stirring reactions 4 hours, then Add saturated aqueous ammonium chloride (100mL) cancellation reaction, the mixture ethyl acetate (100mL × 3) obtained extraction, merge Organic facies wash with saturated aqueous ammonium chloride (100mL) and saturated aqueous common salt (100mL) successively, then with anhydrous sodium sulfate do Dry, being concentrated under reduced pressure to give title compound is faint yellow solid (1.6g, 99%), and this product, without being further purified, is directly used In the next step.

MS(ESI,pos.ion)m/z:247.2[M-Boc+2H]⁺。

Step 2) (S)-3-(1-amino-ethyl)-2-cyclopropyl isoquinolin-1 (2H)-one

By compound (S)-(4-(2-(cyclopropylcarbamoyl) phenyl)-3-oxo-butanes-2-base) carbamic acid uncle Butyl ester (1.6g, 4.6mmol) is dissolved in methanol (15mL), then adds concentrated hydrochloric acid (15mL) in reactant liquor, and mixture exists 95 DEG C are stirred overnight, are then cooled to room temperature, concentrating under reduced pressure, and residue is dispersed in PE/EtOAc (50mL/25mL) and water (20mL), in mixed solvent, aqueous phase adds powdered sodium carbonate and is alkalized to pH=8, then extracts with dichloromethane (100mL × 3) Taking, the organic facies saturated aqueous common salt (150mL) of merging is washed, and being concentrated under reduced pressure to give title compound is yellow oil (832mg, 79%).

MS(ESI,pos.ion)m/z:229.1[M+H]⁺。

Step 3) (S)-3-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) second Base)-2-cyclopropyl isoquinolin-1 (2H)-one

By compound (S)-3-(1-amino-ethyl)-2-cyclopropyl isoquinolin-1 (2H)-one (100mg, 0.44mmol) and The chloro-5-of 6-(5-methyl isophthalic acid, 3,4-diazole-2-bases) pyrimidine-4-amine (93mg, 0.44mmol) is suspended in n-butyl alcohol (4mL), Then adding DIPEA (0.1mL, 0.6mmol) in reactant, mixture is stirred overnight at 120 DEG C, is then cooled to room temperature, Concentrating under reduced pressure, it is yellow solid that residue obtains title compound through silica gel column chromatography (PE/EtOAc (v/v)=1/5) purification (83mg, 47%).

MS(ESI,pos.ion)m/z:404.9[M+H]⁺；

1H NMR(400MHz,CDCl₃) δ (ppm): 8.69-8.68 (d, J=6.9Hz, 1H), 8.33-8.31 (d, J= 7.9Hz, 1H), 8.11 (s, 1H), 7.56-7.52 (t, J=7.5Hz, 1H), 7.41-7.26 (m, 2H), 6.50 (s, 1H), 6.22-6.15 (m, 3H), 3.07-3.01 (m, 1H), 2.67 (s, 3H), 1.66-1.65 (d, J=6.8Hz, 3H), 1.34-1.27 (m,2H),1.19-1.07(m,1H),0.99-0.90(m,1H)。

Embodiment 29 (S)-3-(1-((6-amino-5-(3-ethyl-1,2,4-diazole-5-base) pyrimidine-4-yl) amino) Ethyl)-8-chloro-2-phenyl isoquinolin quinoline-1 (2H)-one

By compound (S)-3-(1-amino-ethyl)-8-chloro-2-phenyl isoquinolin quinoline-1 (2H)-one (51.3mg, 0.172mmol), the chloro-5-of 6-(3-ethyl-1,2,4-diazole-5-bases) pyrimidine-4-amine (46.3mg, 0.205mmol) and The DIPEA (29.9mg, 0.231mmol) float (2.0mL) in propanol is heated to 100 DEG C and stirs reaction 5 hours, will be mixed Compound concentrating under reduced pressure, residue successively analyse (DCM/MeOH (v/v)=100/1) purification to obtain title compound being yellowish through silica gel Color solid (54mg, 65%).

MS(ESI,pos.ion)m/z:487.8[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.32 (d, J=5.8Hz, 1H), 8.02 (s, 1H), 7.55-7.39 (m, 6H), 7.33 (t, J=8.4Hz, 2H), 6.51 (s, 1H), 5.10-4.83 (m, 1H), 2.85 (q, J=7.5Hz, 2H), 1.44 (d, J=6.7Hz, 3H), 1.38 (t, J=7.5Hz, 3H).

Embodiment 30 (S)-3-(1-((6-amino-5-(3-ethyl-1,2,4-diazole-5-base) pyrimidine-4-yl) amino) Ethyl)-8-chloro-2-cyclopropyl isoquinolin-1 (2H)-one

By chloro-for compound 6-5-(3-ethyl-1,2,4-diazole-5-base) pyrimidine-4-amine (41.0mg, 0.194mmol) It is dissolved in n-butyl alcohol (2mL), in reactant liquor, is then initially charged (S)-3-(1-amino-ethyl)-8-chloro-2-cyclopropyl isoquinoline Quinoline-1 (2H)-one (50.0mg, 0.190mmol), then it is added dropwise over DIPEA (0.05mL, 0.25mmol), gained mixture exists 100 DEG C of stirrings are reacted 4 hours, are then cooled to room temperature, concentrating under reduced pressure, are dissolved in by residue in methanol (1mL), then to institute Obtain and solution is added dropwise over dichloromethane addition recrystallization, sucking filtration, filtrate reduced in volume is obtained yellow solid, solid is dissolved In dichloromethane, it is white solid (28.2mg, 33.8%) that gained solution obtains title compound through HPTLC purification.

MS(ESI,pos.ion)m/z:451.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.53 (d, J=4.0Hz, 1H), 8.15 (s, 1H), 7.40 (t, J= 4.0Hz, 2H), 7.38-7.37 (dd, J=8.0,4.0Hz, 1H), 6.40 (s, 1H), 6.18-6.11 (m, 1H), 3.05-2.99 (m, 1H), 2.85 (q, J=8.0Hz, 2H), 1.65 (d, J=8.0Hz, 3H), 1.43-1.28 (m, 7H), 0.96-0.91 (m, 2H)。

Embodiment 31 (S)-3-(1-((6-amino-5-(5-ethyl-1,2,4-diazole-3-base) pyrimidine-4-yl) amino) Propyl group)-8-chloro-2-phenyl isoquinolin quinoline-1 (2H)-one

By compound (S)-3-(1-aminopropyl)-8-chloro-2-phenyl isoquinolin quinoline-1 (2H)-one (50.5mg, 0.16mmol), the chloro-5-of 6-(5-ethyl-1,2,4-diazole-3-bases) pyrimidine-4-amine (37.4mg, 0.16mmol) and DIPEA (40.4mg, 0.31mmol) mixture in n-butyl alcohol (1mL) is heated to backflow and stirs reaction 18 hours, is subsequently cooled to Room temperature, concentrating under reduced pressure, it is light that residue obtains title compound through silica gel column chromatography (DCM/MeOH (v/v)=100/1) purification Yellow solid (32mg, 40%).

MS(ESI.pos.ion)m/z:501.8[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):8.53(s,1H),8.07(s,1H),7.55-7.32(m,8H),6.42 (s, 1H), 4.80 (m, 1H), 2.87-2.85 (q, J=6.4Hz, 2H), 1.84 (m, 1H), 1.66 (m, 1H), 1.40-1.37 (m, 3H),0.88-0.84(m,3H)。

Embodiment 32 (S)-3-(1-((6-amino-5-(2-isopropyl-2H-tetrazolium-5-base) pyrimidine-4-yl) amino) second Base)-8-fluoro-2-phenyl isoquinolin quinoline-1 (2H)-one

By chloro-for compound 6-5-(2-isopropyl tetrazolium-5-base) pyrimidine-4-amine (30.7mg, 0.128mmol), (S)-3- (1-amino-ethyl)-8-fluoro-2-phenyl isoquinolin quinoline-1 (2H)-one (47mg, 0.1665mmol) and DIPEA (35mg, 0.27081mmol) mixture in n-butyl alcohol (3mL) is heated to 110 DEG C and stirs reaction 20 hours, is subsequently cooled to room Temperature, concentrating under reduced pressure, it is solid for white that residue obtains title compound through silica gel column chromatography (EtOAc/PE (v/v)=2/5) purification Body (37mg, 56.9%).

MS(ESI.pos.ion)m/z:486.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.63 (d, J=5.7Hz, 1H), 8.02 (s, 1H), 7.71 (s, 1H), 7.58-7.46 (d, J=4.5Hz, 4H), 7.43 (s, 2H), 7.33 (d, J=7.3Hz, 1H), 7.19 (d, J=7.8Hz, 1H), 7.10-6.96 (m, 1H), 6.57 (s, 1H), 5.23-5.09 (m, 1H), 5.05-4.94 (m, 1H), 1.74 (d, J=6.2Hz, 6H), 1.25 (d, J=7.1Hz, 3H).

Embodiment 33 (S)-3-(1-((6-amino-5-(2-isopropyl-2H-tetrazolium-5-base) pyrimidine-4-yl) amino) second Base)-8-chloro-2-cyclopropyl isoquinolin-1 (2H)-one

By chloro-for compound 6-5-(2-isopropyl tetrazolium-5-base) pyrimidine-4-amine (100mg, 0.41726mmol), (S)-3- (1-amino-ethyl)-8-chloro-2-cyclopropyl isoquinolin-1 (2H)-one (112mg, 0.4263mmol) and DIPEA (0.15mL, 0.91mmol) mixture in n-butyl alcohol (5mL) was 110 DEG C of stirring reactions 20 hours, is then cooled to room temperature, reduces pressure dense Contracting, residue through silica gel column chromatography (EtOAc/PE (v/v)=2/5) purification obtain title compound be white solid (182mg, 93.62%).

MS(ESI.pos.ion)m/z:466.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.70 (d, J=6.7Hz, 1H), 8.15 (s, 1H), 7.41-7.34 (m, 2H), 7.26-7.21 (m, 1H), 6.45 (s, 1H), 6.17 (p, J=6.7Hz, 1H), 5.19 (hept, J=6.7Hz, 1H), 3.06-2.98 (m, 1H), 1.77 (d, J=6.7Hz, 3H), 1.75 (d, J=6.7Hz, 3H), 1.67 (d, J=6.8Hz, 3H), 1.50-1.30(m,4H)。

Embodiment 34 (S)-3-(1-((6-amino-5-(5-ethyl-1,3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-8-chloro-2-cyclopropyl isoquinolin-1 (2H)-one

By chloro-for compound 6-5-(5-ethyl-1,3,4-diazole-2-base) pyrimidine-4-amine (30mg, 0.13mmol) and (S)-3-(1-amino-ethyl)-8-chloro-2-cyclopropyl isoquinolin-1 (2H)-one (34.0mg, 0.13mmol) is suspended in the positive fourth of 5mL In alcohol, in reactant liquor, then add DIPEA (0.1mL), heat the mixture to 120 DEG C and be stirred overnight, being subsequently cooled to Room temperature, concentrating under reduced pressure, it is yellowish that residue obtains title compound through preparative TLC (DCM/MeOH (v/v)=20/1) purification Color solid (31.0mg, 53%).

MS(ESI,pos.ion)m/z:452.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.71 (d, J=6.6Hz, 1H), 8.11 (s, 1H), 7.37 (dd, J= 6.8,3.6Hz, 2H), 7.22 (dd, J=5.9,3.2Hz, 1H), 6.40 (s, 1H), 6.18-6.09 (m, 1H), 6.03 (s, 2H), 3.05-2.97 (q, J=7.2Hz, 2H), 1.64 (d, J=6.8Hz, 3H), 1.47 (t, J=7.6Hz, 3H), 1.44-1.35 (m, 2H),1.35-1.23(m,3H)。

Embodiment 35 (S)-2-(1-((6-amino-5-(5-(amino methyl)-1,3,4-diazole-2-base) pyrimidine-4- Base) amino) ethyl)-5-chloro-3-phenylquinazoline-4 (3H)-one

Step 1) (2-diazanyl-2-oxoethyl) t-butyl carbamate

By compound 2-methyl aminoacetate hydrochlorate (28.1g, 224mmol) and sodium bicarbonate (36.4g, 433mmol) It is suspended in acetonitrile (400mL), then under 0 DEG C and nitrogen are protected, in the reactant liquor of stirring, adds Bis(tert-butoxycarbonyl)oxide (45mL,200mmol).Mixture is stirred at room temperature 21 hours, then concentrating under reduced pressure.Residue adds H₂O (40mL) dilutes, and obtains Mixture with DCM (50mL × 3) extract.The organic facies merged saturated common salt washes (50mL), is dried with anhydrous sodium sulfate, It is concentrated under reduced pressure to give white solid and is directly used in next step reaction.

White solid is dissolved in ethanol (100mL), the most at room temperature, in solution, adds hydrazine hydrate (27mL), To mixture be stirred at room temperature 24 hours, then concentrating under reduced pressure, residue add H₂O (50mL) dilutes, and the mixture obtained is used DCM (100mL × 3) extracts, and the organic facies of merging saturated common salt washes (60mL), is dried with anhydrous sodium sulfate, concentrating under reduced pressure Obtain white solid, be directly used in next step reaction (31g, 73%) without being further purified.

MS(ESI,pos.ion)m/z:90.3[M-Boc+2H]⁺。

Step 2) (2-(2-(4,6-dichloro pyrimidine-5-carbonyl) diazanyl)-2-oxoethyl) t-butyl carbamate

Under room temperature condition, to the 4 of stirring, 6-dichloro pyrimidine-5-formic acid (9.01g, 46.7mmol) and N, N-dimethyl methyl Oxolane (30mL) solution of amide (0.33g, 4.5mmol) disposably adds SOCl₂(8.20g,68.9mmol).Reaction Mixture, 45 DEG C of stirring reactions 3 hours, is then concentrated under reduced pressure to give yellow oil and is directly used in next step reaction.

Yellow oil is dissolved in DCM (20mL) and obtains yellow suspension thing, then at 0-2 DEG C, by this yellow suspension thing by Be added dropwise to (2-diazanyl-2-oxoethyl) t-butyl carbamate (8.45g, 44.7mmol) and triethylamine (9.0g, In DCM (40mL) solution 65mmol), reactant mixture ,-2 DEG C of stirring reactions 4 hours, adds petroleum ether (40mL), gained Reactant mixture continues stirring 30 minutes, the float sucking filtration that will obtain, and filter cake DCM/PE (v/v=3/2,15mL × 2) washes Wash title compound is white solid (14.1g, 92%).

MS(ESI,neg.ion)m/z:362.2[M-H]^-；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 11.05 (d, J=66.1Hz, 1H), 10.43 (d, J=24.2Hz, 1H), 9.02 (s, 1H), 7.04 (t, J=6.0Hz, 1H), 3.65 (t, J=10.9Hz, 2H), 1.38 (s, 9H).

Step 3) (2-(2-(4-amino-6-chloropyrimide-5-carbonyl) diazanyl)-2-oxoethyl) t-butyl carbamate

By compound (2-(2-(4,6-dichloro pyrimidine-5-carbonyl) diazanyl)-2-oxoethyl) t-butyl carbamate (1.03g, 2.83mmol) is dissolved in isopropanol (2mL), then add in reactant liquor ammonia aqueous isopropanol (2.0M, 15.0mL), mixture was 35 DEG C of stirring reactions 24 hours, and then concentrating under reduced pressure, residue is through silica gel column chromatography purification (DCM/ MeOH (v/v)=100/1-20/1) title compound be white solid (840mg, 84%).

MS(ESI,pos.ion)m/z:345.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):10.50(s,1H),10.36(s,1H),8.28(s,1H),7.84(s, 1H), 7.30 (s, 1H), 7.13 (t, J=6.0Hz, 1H), 3.68 (d, J=6.1Hz, 2H), 1.39 (s, 9H).

Step 4) ((5-(4-amino-6-chloropyrimide-5-base)-1,3,4-diazole-2-base) methyl) tertiary fourth of carbamic acid Ester

By compound (2-(2-(4-amino-6-chloropyrimide-5-carbonyl) diazanyl)-2-oxoethyl) t-butyl carbamate (820g, 2.4mmol) is dissolved in acetonitrile, then adds triphenylphosphine (812mg, 3.1mmol) and triethylamine in reactant liquor (0.50mL, 3.6mmol), mixture room temperature condition stirring reaction 20 minutes, the most disposably adds four under nitrogen protection Chlorination carbon (0.35mL, 3.6mmol), gained reactant mixture is heated to 50 DEG C and continues stirring reaction 2 hours, concentrating under reduced pressure, Residue through silica gel column chromatography purification (DCM/MeOH (v/v)=100/1) title compound be white solid (880mg, 88%).

MS(ESI,pos.ion)m/z:327.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.38 (s, 1H), 8.28 (s, 1H), 7.75 (s, 1H), 7.63 (t, J= 5.8Hz, 1H), 4.45 (d, J=5.8Hz, 2H), 1.39 (s, 9H).

Step 5) 5-(5-(amino methyl)-1,3,4-diazole-2-base)-6-chloropyrimide-4-amine

By compound ((5-(4-amino-6-chloropyrimide-5-base)-1,3,4-diazole-2-base) methyl) carbamic acid uncle Butyl ester (680mg, 2.1mmol) is dissolved in ethyl acetate (2mL), then adds the ethyl acetate solution of hydrogen chloride in reactant liquor (2.0M, 15.0mL), mixture is stirred overnight at 35 DEG C, and the float obtained is dissolved in water (20mL), separatory, aqueous phase DCM (10mL × 3) extract, and be subsequently adding powdered sodium carbonate and aqueous phase is neutralized to pH=9, then extract with DCM (15mL × 3), merging Organic facies saturated common salt washes (20mL), is dried with anhydrous sodium sulfate, and it is faint yellow solid that concentrating under reduced pressure obtains title compound (210mg, 21%).

MS(ESI,pos.ion)m/z:227.2[M+H]⁺；

¹H NMR(400MHz,CDCl3)δ(ppm):8.37(s,1H),8.24(s,1H),7.72(s,1H),3.97(s, 2H),2.16(s,2H)。

Step 6) (S)-2-(1-((6-amino-5-(5-(amino methyl)-1,3,4-diazole-2-base) pyrimidine-4-yl) Amino) ethyl)-5-chloro-3-phenylquinazoline-4 (3H)-one

By compound (S)-2-(1-amino-ethyl)-5-chloro-3-phenylquinazoline-4 (3H)-one (60.4mg, 0.201mmol), 5-(5-(amino methyl)-1,3,4-diazole-2-bases)-6-chloropyrimide-4-amine (51.3mg, 0.266mmol) It is heated to 120 DEG C with the DIPEA (44.2mg, 0.342mmol) mixture in propanol (2.5mL) and stirs reaction 6.5 hours, By mixture concentrating under reduced pressure, residue obtains title compound through silica gel column chromatography purification (DCM/MeOH (v/v)=50/1-20/1) Thing is faint yellow solid (50mg, 50.7%).

MS(ESI,pos.ion)m/z:490.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.56 (s, 1H), 8.02 (s, 1H), 7.60 (d, J=20.3Hz, 5H), 7.47 (s, 2H), 7.40-7.31 (m, 1H), 6.63 (d, J=8.5Hz, 2H), 4.29 (s, 2H), 3.75-3.60 (m, 1H), 3.11 (d, J=7.6Hz, 1H), 2.00 (s, 2H), 1.45 (s, 3H).

Embodiment 36 (S)-2-(1-((6-amino-5-(3-methyl isophthalic acid, 2,4-diazole-5-bases) pyrimidine-4-yl) amino) Ethyl)-6-fluoro-3-phenylquinazoline-4 (3H)-one

Step 1) 5-fluoro-2-nitro-N-phenylbenzamide

Fluoro-for compound 5-2-nitrophenoxy acid (10.0g, 54.0mmol) is dissolved in THF (108mL), then to reactant liquor Middle addition DMF (0.5mL) and SOCl₂(5.88mL, 81.1mmol), mixture, 60 DEG C of stirring reactions 5 hours, is subsequently cooled to 0 DEG C, add triethylamine (18.8mL, 140.0mmol) and aniline (6.4mL, 70.0mmol).Gained mixture is at this temperature Continuing to be stirred overnight, be subsequently adding water (300mL) dilution, gained mixture ethyl acetate (200mL × 2) extracts, merging Organic facies is washed with aqueous hydrochloric acid solution (1.0M, 100mL × 2) and aqueous sodium carbonate (100mL × 2) successively, then uses anhydrous sulfur Acid sodium is dried, and concentrating under reduced pressure, residue obtains title compound through silica gel column chromatography purification (PE/EtOAc (v/v)=5/1) and is Yellow solid (12.0g, 85.3%).

MS(ESI,pos.ion)m/z:261.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 10.69 (s, 1H), 8.28 (dd, J=9.1,4.8Hz, 1H), 7.76 (dd, J=8.4,2.8Hz, 1H), 7.70-7.58 (m, 3H), 7.38 (t, J=7.9Hz, 2H), 7.14 (t, J=7.4Hz, 1H).

Step 2) 2-amino-5-fluorine-N-phenylbenzamaide

To compound 5-fluoro-2-nitro-N-phenylbenzamide (5.0g, 19.2mmol) at the mixture of ethanol (60mL) Middle addition Fe powder (5.4g, 95.0mmol) and HCOONH₄Water (12.0mL) solution of (4.9g, 78.0mmol), adds mixture Heat is to 90 DEG C and is stirred overnight, and is subsequently cooled to 50 DEG C, and with suction filtered through kieselguhr, by filtrate reduced in volume, residue is through silicagel column It is pale pink solid (3.0g, 68.0%) that chromatography purification (PE/EtOAc (v/v)=6/1) obtains title compound.

MS(ESI,pos.ion)m/z:231.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 10.02 (s, 1H), 7.71-7.69 (d, J=7.7Hz, 2H), 7.51-7.48 (dd, J=10.1,2.9Hz, 1H), 7.36-7.32 (t, J=7.9Hz, 2H), 7.14-7.08 (m, 2H), 6.79- 6.77 (dd, J=9.0,5.0Hz, 1H), 6.21 (s, 2H).

Step 3) (S)-(1-((4-fluoro-2-(phenylcarbamoyl) phenyl) amino)-1-oxo acrylate-2-yl) amino first Tert-butyl acrylate

At 0 DEG C, to 2-amino-5-fluorine-N-phenylbenzamaide (1.0g, 4.35mmol), (2S)-2-(tertiary fourth of stirring Oxygen carbonylamino) propanoic acid (987mg, 5.22mmol) and DCM (8mL) mixture in add DIPEA (1.5mL, 8.6mmol) and HATU (1.99g, 5.23mmol), mixture is stirred overnight at 45 DEG C, is subsequently adding water (30mL), gained mixture acetic acid second Ester (50mL × 2) extract, will merge organic facies concentrating under reduced pressure, residue through silica gel column chromatography purification (PE/EtOAc (v/v)= 5/1) obtaining title compound is off-white color solid (1.6g, 92.0%).MS(ESI,neg.ion)m/z:400.2[M-H]^-；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 11.08 (s, 1H), 10.49 (s, 1H), 8.47 (dd, J=9.1, 5.3Hz, 1H), 7.73 (d, J=7.7Hz, 3H), 7.52 (d, J=6.5Hz, 1H), 7.44 (td, J=8.8,3.0Hz, 1H), 7.36 (t, J=7.9Hz, 2H), 7.15 (t, J=7.4Hz, 1H), 4.08-3.93 (m, 1H), 1.30 (s, 9H), 1.28-1.27 (d, J=4.0Hz, 3H).

Step 4) (S)-(1-(6-fluorin-4-oxygen generation-3-phenyl-3,4-dihydroquinazoline-2-base) ethyl) carbamic acid uncle Butyl ester

By compound (S)-(1-((4-fluoro-2-(phenylcarbamoyl) phenyl) amino)-1-oxo acrylate-2-yl) amino T-butyl formate (501mg, 1.25mmol) is dissolved in acetonitrile (5mL), be then sequentially added in reactant liquor DIPEA (0.45mL, 2.60mmol), DMAP (153mg, 1.25mmol) and BSA (1.0mL, 4.1mmol), heat the mixture to 80 DEG C and stirred At night, being then cooled to room temperature, add ethyl acetate (50mL) dilution, the mixture saturated aqueous common salt (30mL × 2) obtained is washed, Being dried with anhydrous sodium sulfate, concentrating under reduced pressure, residue obtains titled through silica gel column chromatography purification (PE/EtOAc (v/v)=8/1) Compound is brown oil (490mg, 102%).

MS(ESI,pos.ion)m/z:384.2[M+H]⁺。

Step 5) (S)-2-(1-amino-ethyl)-6-fluoro-3-phenylquinazoline-4 (3H)-one

By compound (S)-(1-(6-fluorin-4-oxygen generation-3-phenyl-3,4-dihydroquinazoline-2-base) ethyl) carbamic acid The tert-butyl ester (490mg, 1.278mmol, mass fraction 100%) is dissolved in ethyl acetate (3mL), then adds dense in reactant liquor Hydrochloric acid (2mL, 22mmol), mixture, room temperature condition stirring reaction 1.5 hours, is subsequently adding ethyl acetate (10mL) dilution, The mixture obtained adds aqueous sodium carbonate and neutralizes, then extracts by ethyl acetate (10mL × 2), and the organic facies of merging is with anhydrous Sodium sulfate is dried, and it is light brown grease (360mg, 99.4%) that concentrating under reduced pressure obtains title compound.

Step 6) (S)-2-(1-((6-amino-5-(3-methyl isophthalic acid, 2,4-diazole-5-base) pyrimidine-4-yl) amino) second Base)-6-fluoro-3-phenylquinazoline-4 (3H)-one

To compound (S)-2-(1-amino-ethyl)-6-fluoro-3-phenylquinazoline-4 (3H)-one (50.0mg, 0.18mmol), the chloro-5-of 6-(3-methyl isophthalic acid, 2,4-diazole-5-base) pyrimidine-4-amine (41.0mg, 0.19mmol) and the tert-butyl alcohol (1.5mL) mixture adds DIPEA (0.07mL, 0.4mmol), and mixture, 110 DEG C of stirring reactions 5 hours, then reduces pressure Concentrating, it is off-white color solid that residue obtains title compound through combiflash companion (PE/EtOAc (v/v)=2/1) purification (59mg, 72.9%).

MS(ESI,pos.ion)m/z:459.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃) δ (ppm): 8.84 (d, J=6.4Hz, 1H), 8.05 (s, 1H), 7.93 (dd, J= 8.3,2.7Hz, 1H), 7.77 (dd, J=8.9,4.8Hz, 1H), 7.67-7.56 (m, 3H), 7.52 (td, J=8.6,2.8Hz, 1H), 7.46 (d, J=7.5Hz, 1H), 7.37 (d, J=6.6Hz, 1H), 5.84 (s, 2H), 5.24-5.16 (m, 1H), 2.55 (s, 3H), 1.49 (d, J=6.7Hz, 3H).

Embodiment 37 (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-6-fluoro-3-phenylquinazoline-4 (3H)-one

To compound (S)-2-(1-amino-ethyl)-6-fluoro-3-phenylquinazoline-4 (3H)-one (50.0mg, 0.18mmol), the chloro-5-of 6-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-amine (41.0mg, 0.19mmol) and n-butyl alcohol (1.5mL) adding DIPEA (0.07mL, 0.4mmol) in mixture, mixture is stirred overnight at 120 DEG C, then reduces pressure dense Contracting, it is faint yellow solid that residue obtains title compound through quick preparative scale chromatography purification (PE/EtOAc (v/v)=1/1) (69mg, 85.2%).

MS(ESI,pos.ion)m/z:459.2[M+H]⁺；

¹H NMR(600MHz,CDCl₃) δ (ppm): 8.59 (d, J=6.7Hz, 1H), 8.03 (s, 1H), 7.93 (dd, J= 8.2,2.6Hz, 1H), 7.74 (dd, J=8.9,4.7Hz, 1H), 7.60 (m, 3H), 7.51 (td, J=8.5,2.7Hz, 1H), 7.46 (d, J=7.3Hz, 1H), 7.36 (d, J=7.4Hz, 1H), 5.24-5.14 (m, 1H), 2.74 (s, 3H), 1.49 (d, J= 6.6Hz,3H)。

Embodiment 38 (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) Ethyl)-3-cyclopropyl-6-Fluquinconazole quinoline-4 (3H)-one

Step 1) N-cyclopropyl-5-fluoro-2-nitrobenzamide

By fluoro-for compound 5-2-nitrobenzoic acid (5.0g, 27.0mmol) and SOCl₂(13mL) mixture is heated to 80 DEG C and stir reaction 5.0 hours, be then cooled to room temperature and concentrating under reduced pressure, residue is dissolved in DCM (20mL), then 0 DEG C, gained solution is joined triethylamine (7.5mL, 54.0mmol), cyclopropylamine (2.3mL, 32.0mmol) and DCM (10mL) In mixture, after adding, mixture continues this temperature stirring reaction 5.5 hours, and then concentrating under reduced pressure, residue is dissolved in water (30mL) with in ethyl acetate (100mL), separatory, aqueous phase ethyl acetate (50mL) extracts, and the organic facies of merging uses salt successively Aqueous acid (1.0M, 100mL × 2) and saturated aqueous sodium carbonate (100mL × 2) are washed, and are dried with anhydrous sodium sulfate, reduce pressure dense Contract title compound is faint yellow solid (4.26g, 70.3%).

MS(ESI,pos.ion)m/z:225.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.69 (d, J=2.8Hz, 1H), 8.17 (dd, J=8.9,4.8Hz, 1H),7.58-7.47(m,2H),2.77(m,1H),0.76-0.67(m,2H),0.57-0.49(m,2H)。

Step 2) (S)-(1-(N-cyclopropyl-5-fluoro-2-nitrobenzamide base)-1-oxo acrylate-2-yl) carbamic acid The tert-butyl ester

To compound N-cyclopropyl-5-fluoro-2-nitrobenzamide (4.2g, 18.7mmol) and the mixing of toluene (25mL) Thing adds SOCl₂(7mL, 96.5mmol), mixture was 120 DEG C of stirring reactions 10 hours, and then concentrating under reduced pressure, by residue It is dissolved in DCM (20mL), at 0 DEG C, above-mentioned gained solution is joined (2S)-2-(t-butoxycarbonyl amino) propanoic acid of stirring In the mixture of (3.55g, 18.8mmol), DIPEA (6.5mL, 37mmol) and DCM (10mL), after dripping, mixture is moved To room temperature, and continuing to be stirred overnight, be subsequently adding DCM (30mL) dilution, gained mixture water (100mL × 2) is washed, separatory, Organic facies anhydrous sodium sulfate is dried, concentrating under reduced pressure, and residue obtains through silica gel column chromatography purification (PE/EtOAc (v/v)=10/1) Title compound is yellow oil (4.15g, 56.0%).

MS(ESI,neg.ion)m/z:296.2[M-99]^-；

¹H NMR(400MHz,CDCl₃) δ (ppm): 8.23 (dd, J=9.1,4.7Hz, 1H), 7.25-7.17 (m, 1H), 6.99 (dd, J=7.7,2.6Hz, 1H), 5.26-5.19 (m, 1H), 4.98-4.97 (d, J=7.3Hz, 1H), 2.88-2.87 (m, 1H), 1.42 (s, 9H), 1.38-1.37 (d, J=7.0Hz, 3H), 1.19-1.16 (m, 2H), 1.04-1.02 (m, 1H), 0.96-0.86(m,1H)。

Step 3) (S)-(1-(3-cyclopropyl-6-fluorin-4-oxygen generation-3,4-dihydroquinazoline-2-base) ethyl) carbamic acid The tert-butyl ester

By compound (S)-(1-(N-cyclopropyl-5-fluoro-2-nitrobenzamide base-1-oxo acrylate-2-yl) carbamic acid The tert-butyl ester (4.15g, 10.5mmol) is dissolved in acetic acid (20mL), then in reactant liquor add zinc powder (2.78g, 42.5mmol), mixture is stirred overnight at 35 DEG C, sucking filtration, and by filtrate reduced in volume, residue is through silica gel column chromatography purification (PE/ EtOAc (v/v)=10/1) title compound be light brown grease (1.14g, 31.3%).

MS(ESI,pos.ion)m/z:348.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 7.74 (d, J=8.7Hz, 1H), 7.67-7.62 (m, 2H), 7.32 (d, J=7.4Hz, 1H), 5.43-5.33 (m, 1H), 3.08-2.99 (m, 1H), 1.41 (d, J=6.7Hz, 3H), 1.37 (s, 9H),1.23(m,2H),1.07-0.97(m,1H),0.94-0.86(m,1H)。

Step 4) (S)-2-(1-amino-ethyl)-3-cyclopropyl-6-Fluquinconazole quinoline-4 (3H)-one

By compound (S)-(1-(3-cyclopropyl-6-fluorin-4-oxygen generation-3,4-dihydroquinazoline-2-base) ethyl) amino first Tert-butyl acrylate (1.10g, 3.17mmol) is dissolved in ethyl acetate (5mL), then adds concentrated hydrochloric acid in reactant liquor (3.0mL), mixture is stirred at room temperature reaction 1.5 hours, adds ethyl acetate (20mL) dilution, and gained mixture adds carbonic acid Sodium powder is regulated to pH=8, and aqueous phase ethyl acetate (30mL) extracts, and organic facies anhydrous sodium sulfate is dried, and reduces pressure dense Contract title compound is brown oil (584mg, 74.6%).

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 7.73 (dd, J=8.8,2.6Hz, 1H), 7.70-7.60 (m, 2H), 4.66 (m, H), 3.09 (m, 1H), 1.36 (d, J=6.6Hz, 3H), 1.22 (m, 2H), 0.99-0.89 (m, 1H), 0.88-0.78 (m,1H)。

Step 5) (S)-2-(1-((6-amino-5-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-yl) amino) second Base)-3-cyclopropyl-6-Fluquinconazole quinoline-4 (3H)-one

To compound (S)-2-(1-amino-ethyl)-3-cyclopropyl-6-Fluquinconazole quinoline-4 (3H)-one (50mg, 0.20mmol), the chloro-5-of 6-(5-methyl isophthalic acid, 3,4-diazole-2-base) pyrimidine-4-amine (47.0mg, 0.22mmol) and n-butyl alcohol (1.5mL) adding DIPEA (0.07mL, 0.4mmol) in mixture, mixture is stirred overnight at 120 DEG C, then reduces pressure dense Contracting, residue through silica gel column chromatography purification (PE/EtOAc (v/v)=3/1) title compound be faint yellow solid (57mg, 66.7%).

MS(ESI,pos.ion)m/z:423.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm): 8.87 (d, J=7.1Hz, 1H), 8.06 (s, 1H), 7.76 (dd, J =8.6,2.7Hz, 1H), 7.72-7.60 (m, 2H), 7.29 (s, 2H), 6.15 (m, 1H), 3.24-3.18 (m, 1H), 2.62 (s, 3H), 1.59 (d, J=6.6Hz, 3H), 1.32-1.25 (m, 2H), 1.18-1.08 (m, 1H), 0.95-0.92 (m, 1H).

Embodiment 39 (S)-2-(1-((6-amino-5-(3-methyl isophthalic acid, 2,4-diazole-5-base) pyrimidine-4-yl) amino) Ethyl)-3-cyclopropyl-6-Fluquinconazole quinoline-4 (3H)-one

By compound (S)-2-(1-amino-ethyl)-3-cyclopropyl-6-Fluquinconazole quinoline-4 (3H)-one (50mg, 0.20mmol), the chloro-5-of 6-(3-methyl isophthalic acid, 2,4-diazole-5-base) pyrimidine-4-amine (47.0mg, 0.22mmol) and n-butyl alcohol (1.5mL) adding DIPEA (0.07mL, 0.4mmol) in mixture, mixture is in 110 DEG C of stirring reactions 2.0 hours, decompression Concentrate, residue through silica gel column chromatography purification (PE/EtOAc (v/v)=1/1) title compound be faint yellow solid (60mg, 70.2%).

MS(ESI,pos.ion)m/z:423.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm): 9.07 (d, J=7.0Hz, 1H), 8.18 (s, 1H), 7.88 (dd, J= 8.5,2.9Hz, 1H), 7.69 (dd, J=8.9,4.8Hz, 1H), 7.45 (m, 1H), 6.39-6.28 (m, 1H), 3.13 (m, 1H), 2.55 (s, 3H), 1.68 (d, J=6.6Hz, 3H), 1.52-1.41 (m, 2H), 1.17-1.09 (m, 1H), 1.05-0.95 (m, 1H)。

Biologic test

The LC/MS/MS system analyzed includes Agilent 1200 series vacuum degassing furnace, binary syringe pump, and orifice plate is certainly Dynamic sampler, post calorstat, tri-grades of level Four bar mass spectrographs of Agilent G6430 in charged spray ionization (ESI) source.Quantitative analysis Carry out under MRM pattern, MRM conversion parameter as in Table A:

Table A

Many reaction detection scan	490.2→383.1
		Fragmentation voltage	230V
Capillary voltage	55V
		Dryer temperature	350℃
Nebulizer	40psi
		Exsiccator flow velocity	10L/min

Analyze and use Agilent XDB-C18,2.1 × 30mm, 3.5 μM post, inject 5 μ L sample.Analysis condition: flowing phase It is aqueous formic acid (A) and the formic acid methanol solution (B) of 0.1% of 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

Additionally, also have Agilent 6330 series LC/MS/MS spectrogrph for analyze, note equipped with G1312A binary Penetrate pump, G1367A automatic sampler and G1314C UV detector；LC/MS/MS spectrogrph uses ESI radioactive source.Use titer Each analyte is carried out suitable cation models treated and MRM conversion carries out optimal analysis.Use during analyzing Capcell MP-C18 post, specification is: 100 × 4.6mm I.D., 5 μMs (Phenomenex, Torrance, California, USA).Flowing is 5mM ammonium acetate mutually, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 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 sample.

Embodiment A: compound stability in people and rat liver microsomes

People or rat liver microsomes are placed in polypropylen tubes and hatch, and guide it to replicate.Typically hatch mixed liquor Including people or rat liver microsomes (0.5mg protein/mL), target compound (5 μMs) and the NADPH that cumulative volume is 200 μ L (1.0mM) kaliumphosphate buffer (PBS, 100mM, pH value is 7.4), by compound dissolution in DMSO, and uses PBS that it is dilute Release so that it is the concentration of final DMSO solution is 0.05%.And the water-bath communicated with air at 37 DEG C is hatched, incubate in advance Educate and 3 minutes backward mixed liquors add albumen and starts reaction.At different time points (0,5,10,15,30 and 60min), add Enter same volume ice-cold acetonitrile and terminate reaction.Sample preserves until carrying out LC/MS/MS analysis at-80 DEG C.

Compound concentration in people or rat liver microsomes mixtures incubated is that the method by LC/MS/MS measures 's.The range of linearity of concentration range is determined by each test-compound.

Parallel hatch test and use the microsome of degeneration as negative control, hatch at 37 DEG C, react when different Between point (0,15 and 60min) terminate.

Dextromethorphan (70 μ Μ), as positive control, is hatched at 37 DEG C, react different time point (0,5,10, 15,30 and 60min) terminate.Each assay method all includes the positive and negative control sample, to ensure that microsome hatches body The integrity of system.Additionally, the stability data that compound of the present invention is in people or rat liver microsomes also can be by following examination Test and obtain.People or rat liver microsomes are placed in polypropylen tubes and hatch, and guide it to replicate.Typical mixtures incubated bag Including people or rat liver microsomes (ultimate density: 0.5mg albumen/mL), compound (ultimate density: 1.5 μMs) and cumulative volume are 30 μ The K-buffer solution (containing 1.0mM EDTA, 100mM, pH 7.4) of L.By compound dissolution in DMSO, and use K-buffer solution Dilution, the ultimate density making DMSO is 0.2%.After preincubate 10 minutes, add 15 μ L NADPH (ultimate density: 2mM) and carry out Enzymatic reaction, whole test is carried out in the incubation tube of 37 DEG C.At different time points (0,15,30 and 60 minute), add 135 μ L acetonitrile (containing IS) terminates reaction.It is centrifuged 10 minutes with 4000rpm, removes albumen, collect the supernatant, divide with LC-MS/MS Analysis.

In above-mentioned test, ketanserin (1 μM) is selected as positive control, hatches at 37 DEG C, and reaction is in the different time Point (0,15,30 and 60 minute) terminates.Each assay method all includes positive control sample, to ensure that microsome hatches body The integrity of system.

Data analysis

Each is reacted, compound concentration (as a percentage) in people or rat liver microsomes are hatched is pressed The plotted as percentage of Relative Zero time point, infers internal CLint CL 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)。

Table 1 embodiment of the present invention stability data in people and rat liver microsomes

Table 1 result shows, the compounds of this invention half-life in the hepatomicrosome of people and rat is more reasonable.

Embodiment B: the Pharmacokinetic Evaluation after the compounds of this invention is injected and be administered orally to mice, rat, dog and monkey

The compounds of this invention pharmacokinetic in mice, rat, dog or monkey body is commented by the present invention Estimate.The compounds of this invention with aqueous solution or the aqueous solution of 2%HPMC+1% tween 80, the saline solution of 5%DMSO+5%, 4% MC or capsule form are administered.For intravenous administration, animal gives the dosage of 1 or 2mg/kg.For oral dose (p.o.), rat and mice are 5 or 10mg/kg, and dog and monkey are 10mg/kg.It is 0.25 at time point, 0.5,1.0,2.0, Within 3.0,4.0,6.0,8.0,12 and 24 hours, take blood (0.3mL), and 3,000 or 4, be centrifuged 10 minutes under 000rpm.Collect blood Slurry solution, and preserve at-20 DEG C or-70 DEG C until carrying out above-mentioned LC/MS/MS and analyzing.

Table 2 embodiment of the present invention pharmacokinetic data in rat body

Table 2 result shows, the compounds of this invention is preferable at rat body absorption, and the half-life is reasonable.

Embodiment C: Kinase activity assays

The compounds of this invention can be evaluated by following test as the activity of PI3K and mTOR inhibitors of kinases 's.

The general description of kinase assay

Kinase assay by detection mix γ-³³The myelin basic protein (MBP) of P-ATP completes.Prepare 20 μ g/ MBP (Sigma #M-1891) trishydroxymethylaminomethane buffer salt solution (TBS of mL；50mM Tris pH 8.0,138mM NaCl, 2.7mM KCl), it is coated white 384 orifice plates (Greiner) of high associativity, every hole 60 μ L.4 DEG C, hatch 24 hours.Afterwards Plate is washed 3 times with 100 μ L TBS.Kinase reaction is at kinase buffer liquid (the 5mM Hepes pH 7.6,15mM that cumulative volume is 34 μ L NaCl, 0.01% bovine serum albumin (Sigma#I-5506), 10mM MgCl₂, 1mM DTT, 0.02%TritonX-100) in Carry out.By compound dissolution in DMSO, adding in each hole, the ultimate density of DMSO is 1%.Each data determination twice, often The mensuration of individual compound at least carries out twice test.Such as, the ultimate density of enzyme is 10nM or 20nM.Addition does not has markd ATP (10 μMs) and γ-³³ATP (every hole 2 × 10 of P labelling⁶Cpm, 3000Ci/mmole) start reaction.Reaction is at room temperature shaken Swing and carry out 1 hour.384 orifice plates with 7 × PBS, be subsequently adding the scintillation solution of every hole 50 μ L.Use Wallac Trilux Enumerator testing result.To those of ordinary skill in the art, this is only the one in numerous detection method, other 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, pressing down Make compound concentration during 50% enzymatic activity.The extension rate utilizing 1/2log makes the curve comprising 10 concentration point, estimation IC₅₀Value (such as, make a typical curve by following compound concentration: 10 μMs, 3 μMs, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM and 0 μM).

PI3 kinase whose ordinary test scheme

PI3K (p110 α/p85 α) (h) [cold test]

PI3K (p110 α/p85 α) (h) is containing 10 μMs of phosphoric acid acyl inositol-4,5-diphosphonic acid and MgATP, (concentration is according to need Ask and determine) buffer solution in hatch.After adding ATP solution, start reaction.After incubated at room temperature 30 minutes, add wherein Enter the stop buffer containing EDTA and biotin phosphatidylinositols-3,4,5-triphosphoric acid and terminate reaction.Finally, detection buffering is added Liquid, including the anti-GST monoclonal antibody of europium labelling, the GRP1PH domain of GST labelling and streptavidin-allophycocyanin.Orifice plate time Between reading under resolved fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal is by equation HTRF=10000 × (Em665nm/ Em620nm) determine.

PI3K (p110 β/p85 α) (h) [cold test]

PI3K (p110 β/p85 α) (h) is containing 10 μMs of phosphoric acid acyl inositol-4,5-diphosphonic acid and MgATP, (concentration is according to need Ask and determine) buffer solution in hatch.After adding ATP solution, start reaction.After incubated at room temperature 30 minutes, add wherein Enter the stop buffer containing EDTA and biotin phosphatidylinositols-3,4,5-triphosphoric acid and terminate reaction.Finally, detection buffering is added Liquid, including the anti-GST monoclonal antibody of europium labelling, the GRP1PH domain of GST labelling and streptavidin-allophycocyanin.Orifice plate time Between reading under resolved fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal is by equation HTRF=10000 × (Em665nm/ Em620nm) determine.

PI3K (p110 δ/p85 α) (h) [cold test]

PI3K (p110 δ/p85 α) (h) is containing 10 μMs of phosphoric acid acyl inositol-4,5-diphosphonic acid and MgATP, (concentration is according to need Ask and determine) buffer solution in hatch.After adding ATP solution, start reaction.After incubated at room temperature 30 minutes, add wherein Enter the stop buffer containing EDTA and biotin phosphatidylinositols-3,4,5-triphosphoric acid and terminate reaction.Finally, detection buffering is added Liquid, including the anti-GST monoclonal antibody of europium labelling, the GRP1PH domain of GST labelling and streptavidin-allophycocyanin.Orifice plate time Between reading under resolved fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal is by equation HTRF=10000 × (Em665nm/ Em620nm) determine.

PI3K (p120 γ) (h) [cold test]

PI3K (p120 γ) (h) is containing 10 μMs of phosphoric acid acyl inositol-4,5-diphosphonic acid and MgATP, (concentration is the most true Buffer solution calmly) is hatched.After adding ATP solution, start reaction.After incubated at room temperature 30 minutes, it is added thereto to contain The stop buffer having EDTA and biotin phosphatidylinositols-3,4,5-triphosphoric acid terminates reaction.Finally, add detection buffer, Including the anti-GST monoclonal antibody of europium labelling, the GRP1PH domain of GST labelling and streptavidin-allophycocyanin.Orifice plate divided in the time Distinguishing reading under fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal is by equation HTRF=10000 × (Em665nm/ Em620nm) determine.

mTOR(h)

MTOR (h) is the HEPES of 7.0,1mM EDTA at 50mM pH value, 0.01% polysorbas20,2mg/mL substrate, 3mM chlorine Change manganese and [γ-³³P-ATP] (specific activity about 500cpm/pmol, concentration determines according to demand) hatch under conditions of existing. Reaction is started after adding MnATP mixture.After incubated at room temperature 40 minutes, it is added thereto to 3% phosphoric acid solution and terminates reaction. Be mottled being distributed on P30 filter by 10 μ L reactant liquors, and cleaned 3 times in 5 minutes with 75mM phosphoric acid, and be dried and Put at once before scinticounting in methanol solution and preserve.

Kinase assay in the present invention by Millipore company of Britain complete (Millipore UK Ltd, Dundee Technology Park,Dundee DD2 1SW,UK)。

The kinase activity data of table 3 embodiment of the present invention

Table 3 result shows, the compounds of this invention has good inhibitory activity to PI3K δ.

The kinase inhibiting activity of the compounds of this invention can also pass through KINOMEscan^TMTest, it is mainly based upon quantitatively Measure the test of sample and the part fixing, active site guides and kinases competitive binding ability.It is complete that this is tested Become and need to combine following three elements: the kinases of DNA-labelling, fixing part and testing sample.Testing sample and fixed ligands The kinase whose ability of competitive binding can be determined by the amount measuring the PCR in DNA marker.

For great majority are tested, the T7 phage strain of kinases-labelling is the large intestine bar that origin comes from BL21 bacterial strain Bacterium host prepare.The most first escherichia coli are cultivated exponential phase, then infected by T7 phage, and by it In 32 DEG C of hatchings until cracking, lysate is centrifugal, sucking filtration under concussion continuously, remove cell debris.Remaining at HEK-293 And then the kinases of intracellular generation carrys out labelling with DNA, for the detection of qPCR.It is coated with the magnetic bead of Streptavidin with biological After the smaller ligand of elementization at room temperature reacts 30 minutes, generate the affine resin for kinase assay.The magnetic bead being coordinated Blocked, with blocking buffer (SEABLOCK by the biotin of excess^TM(Pierce), 1%BSA, 0.05% tween 20,1mM DTT) washing removes free part, to reduce non-specific binding.Association reaction is all by kinases, the affinity that has been coordinated Magnetic bead and testing sample 1 × combine buffer (20%SEABLOCK^TM, 0.17 × PBS, 0.05% tween 20,6mM DTT) complete in.Responded and all carried out in 96 orifice plates of the polystyrene that final volume is 0.135mL.The orifice plate of test is equal Hatch 1 hour in room temperature condition under continuously concussion, the magnetic bead of affinity all with lavation buffer solution (1 × PBS, 0.05% tween- 20) washing, (0.5 μM of non-biotinylated affinity is joined for 1 × PBS, 0.05% tween 20 to be then resuspended to elution buffer Body) in, and hatch 30 minutes in room temperature condition under concussion continuously.Kinase concentration in eluent is measured by qPCR.

Kinase assay in the present invention is by the KINOMEscan of DiscoveRx company^TMAnalysis Service completes (42501 Albrae St.Fremont,CA 94538,USA)。

In the description of this specification, reference term " embodiment ", " some embodiments ", " example ", " specifically show Example " or the description of " some examples " etc. means to combine this embodiment or example describes specific features, structure, material or spy Point is contained at least one embodiment or the 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.And, the specific features of description, structure, material or feature can be in office One or more embodiments or example combine in an appropriate manner.Additionally, in the case of the most conflicting, the skill of this area The feature of the different embodiments described in this specification or example and different embodiment or example can be tied by art personnel Close and combination.

Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is example Property, it is impossible to being interpreted as limitation of the present invention, those of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, revises, replaces and modification.

Claims

1. a compound, it is compound or its stereoisomer of one of, tautomer, nitrogen oxides, Solvate, metabolite, pharmaceutically acceptable salt or its prodrug:

2. a pharmaceutical composition, it comprises the arbitrary compound described in claim 1.

Pharmaceutical composition the most according to claim 2, comprises further: pharmaceutically acceptable carrier, excipient, dilution Agent, adjuvant or combinations thereof.

4., according to the pharmaceutical composition described in Claims 2 or 3, comprise one or more therapeutic agents further.

5. the arbitrary compound described in claim 1 or the pharmaceutical composition described in any one of claim 2-4 are preparing medicine In purposes, wherein said medicine is used for protecting, process, treat or alleviate PI3-kinases exception relevant disease.

Purposes the most according to claim 5, wherein said PI3-kinases exception relevant disease is respiratory tract disease, virus sense Dye, non-viral respiratory tract infection, anaphylactic disease, autoimmune disease, inflammatory diseases, cardiovascular disease, malignant hematologic disease, Neurodegenerative diseases, pancreatitis, multiple organ failure, MOF, nephropathy, platelet aggregation, cancer, motility of sperm, transplant rejection, transplant Thing repels, injury of lung or pain.

Purposes the most according to claim 5, wherein said PI3-kinase-associated conditions is asthma, chronic obstructive pulmonary disease (COPD), viral respiratory tract infection, viral respiratory disease deteriorates, aspergillosis, leishmaniasis, allergic rhinitis, allergy Atopic dermatitis, rheumatic arthritis, multiple sclerosis, inflammatory bowel, thrombosis, atherosclerosis, malignant hematologic disease, neural Degenerative disease, pancreatitis, multiple organ failure, MOF, nephropathy, platelet aggregation, cancer, motility of sperm is abnormal, and transplant rejection is transplanted Thing repels, injury of lung, the pain relevant to rheumatoid arthritis or osteoarthritis, backache, systemic inflammatorome pain, god after liver Dysmenorrhoea, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia or central pain.

8. the arbitrary compound described in claim 1 or the pharmaceutical composition described in any one of claim 2-4 are preparing medicine In purposes, described medicine is used for suppressing PI3-kinase activity.

Purposes the most according to claim 8, comprises further and makes the arbitrary compound described in claim 1 or claim Pharmaceutical composition described in any one of 2-4 contacts with biological sample.

Purposes the most according to claim 8, wherein said PI3-kinases is PI3K δ.