CN104447727B - Substituted amino-metadiazine compound and its application method and purposes - Google Patents

Substituted amino-metadiazine compound and its application method and purposes Download PDF

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CN104447727B
CN104447727B CN201410441263.6A CN201410441263A CN104447727B CN 104447727 B CN104447727 B CN 104447727B CN 201410441263 A CN201410441263 A CN 201410441263A CN 104447727 B CN104447727 B CN 104447727B
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alkylidene
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CN104447727A (en
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习宁
王亮
王婷瑾
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Guangdong HEC Pharmaceutical
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Add And Open Up Scientific Co
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

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

Description

Substituted amino-metadiazine compound and its application method and purposes
Invention field
The invention belongs to drug field, and in particular to a kind of noval chemical compound as kinase activity inhibitor, prepare them Method, the pharmaceutical composition comprising the compound and the compound and its pharmaceutical composition treating a variety of different diseases Application in disease.More specifically, compound of the present invention can be used as phosphoinositide 3-kinase family (PI3- Kinases, PI3Ks, such as PI3K δ, PI3K α, PI3K β and PI3K γ) activity or function inhibitor.
Background of invention
Phosphoinositide 3-kinase (PI3- kinases or PI3Ks), as a family of lipid kinase, many cells into Journey, such as the survival of cell, important adjustment effect is played in breeding and differentiation.As receptor tyrosine kinase (RTKs) and G Major influence factors in the conduction of protein-coupled receptor (GPCRs) downstream, by producing phosphatide, PI3Ks will come from all kinds of growths The signal transduction of factor and the factor to intracellular, activation Ser-ine-threonine protein kinase AKT (also referred to as protein kinase B (PKB)) and Other downstream passages.Tumor suppressor gene or PTEN (homologous phosphatase-tensin) are most important in PI3K signal paths Reverse conditioning agent (" Small-molecule inhibitors of the PI3K signaling network. " Future Med.Chem.,2011,3,5,549-565)。
Up to the present, the PI3Ks of 8 kinds of mammals has been identified, based on gene order, structure, adapter molecule, table Reach, the difference of activation mechanism and substrate can be divided into three classes (I, II and III).Wherein, again can be according to letter according to I classes PI3Ks Number path and regulatory protein are divided into two class of IA and IB.IA classes PI3Ks (PI3K α, PI3K β and PI3K δ) is by catalytic subunit P110 (being p110 α, p110 β and p110 δ respectively) and regulator subunit p85 (such as：P85 α, p85 β, p55 δ, p55 α and p50 α) The heterodimeric nanocrystal composition of composition.P110 subunits with catalytic activity using ATP phosphorylations phosphatidylinositols (PI, PtdIns), PI4P and PI (4,5) P2.The response of these signals is transmitted typically by receptor tyrosine kinase (RTKs).IB classes PI3K γ signal be by g protein coupled receptor (GPCRs) transmit, be made of catalytic subunit p110 γ, with p110 γ Relevant adjusting subunit is different from IA class hypotypes.
With the function of effector enzyme and adjust the relevant signal path in phosphatide be I classes PI3Ks (e.g., PI3K δ, PI3Kdelta after) being activated, second messenger is generated on membrane phospholipid.I classes PI3Ks using membrane phospholipid PI (4,5) P2 be converted into as PI (3,4,5) P3 of second messenger.PI and PI (4) P is also the substrate of PI3K, they can also be phosphorylated and convert respectively For PI3P and PI (3,4) P2.In addition, these phosphoinositides can also pass through the catalysis of 5'- specificity and 3'- specificity phosphatases Effect changes into other phosphoinositides.In this way, active two kinds direct or indirect of the generation of PI3K enzymes signal transduction in the cell In approach as second messenger 3'- phosphoinositides hypotype (Nature Reviews Molecular Cell Biology, 2010,11,329)。
The expression way of PI3K α and PI3K two kinds of hypotypes of β is generally existing, but mainly found in leucocyte The expression way of both hypotypes of PI3K δ and PI3K γ can be more confined from.PI3K δ and PI3K γ relatively limited expression way, Except showing that the accumulative data to mice study also can show that the two hypotypes in adaptability and innate immune system Important function (J.Med.Chem., 2012,55,20,8559-8581).
In B and T cell, PI3Ks plays an important roll, the family by the Tec families of activator protein tyrosine kinase Race includes proleulzin-induction type T- cell kinases in Bruton ' s tyrosine kinase (BTK) and T cell in B cell (ITK).Once PI3K is activated, BTK or ITK transpositions to plasma membrane, they are then by Src tyrosine phosphorylations there.The ITK of activation 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 Interior calcium level improves and can activate the protein kinase C diglyceride (DAG) in the T cell of activation.
PI3K δ kinases, which completely knocks in (knock-in) mouse, can also survive, and their phenotype is limited to immune signal The defects of conduction (Okkenhaug et al., Science, 2002,297, p.1031-4).These transgenic mices provide The understanding in depth of functions of the PI3K δ in B- cells and T- cellular signal transductions.Especially, PI3K δ for CD28 PI (3, 4,5) it is required that P3, which forms downstream and/or φt cell receptor (TCR) signal,.The important function in the PI3K signal transductions downstream of TCR It is the activation to Akt, it makes the anti-apoptotic factor and a variety of different transcription factor phosphoric acid produced for cell factor Change.As a result, the T cell with inactive PI3K δ lacks in terms of breeding with Th1 and Th2 cytokine secretions.T cell is led to Crossing the activation of CD28 reduces value and duration of the TCR by the threshold value of antigenic activation and increase breeder reaction.These effects are all It is to be situated between in the transcription for include IL2 (an important t cell growth factor) by many genes to PI3K δ-dependence increase Lead.
Therefore, the expection of PI3K inhibitor via it in adjusting and breathing problem, such as asthma, COPD and cystic fibrosis Effect in inflammatory reaction cell-mediated associated T- provides treatment benefit.Can additionally, there are the therapy for having T- cells guiding There is provided save Corticosteroids (corticosteroid sparing) characteristic instruction (Lancet, 1992,339, p.324- 8) it, is prompted to merge either as independent (standalone) or with suction or oral glucocorticosteroid, it is possible to provide Useful therapy in breathing problem.PI3K inhibitor also can be with other routine treatments, such as long acting beta-2-agonists (LABA) one Rise and be used for asthma.
In vascular system, PI3K δ are expressed by endothelial cell, and by adjusting these cells in being responded with TNF α Pre- attachment (neutrophil) state participate in neutrophil migration (trafficking) (Blood, 2004,103,9, p.3448).TNF αs of the PI3K δ in endothelial cell can be proved by the pharmacology inhibitory action of Akt phosphorylation and PDK1 activity The effect of the signal transduction of induction.In addition, PI3K δ are related to vascular permeability and air flue tissue edema by VEGF paths (Allergy Clin.Immunol.,2006,118,2,p.403).These observations show that PI3K δ suppress extra in asthma Benefit, the benefit are reduced and realized by merging leucocyte spilling associated with asthma and vascular permeability.In addition, PI3K δ are active Mast cell function for both in vitro and in vivo be need (Nature, 2004,431, p.1007；J.Immunol., 2008,180,4, p.2538), also prompting PI3K to suppress should be to allergic reaction indication, such as asthma, allergic rhinitis and spy Answer atopic dermatitis that there is treatment benefit.
PI3K δ offer in B cell proliferation, antibody-secreting, B- cellular antigens and the conduction of IL-4 receptor signals, B cell antigen Effect in function also obtain it is definite (J.Immunol., 2007,178,4, p.2328-35；Blood,2006,107,2,p.642- 50), and it is shown in autoimmune disease, such as the effect in rheumatic arthritis or systemic loupus erythematosus.Therefore, PI3K inhibitor also has a better effect above-mentioned indication tool.
The pharmacological inhibitory action of PI3K δ suppresses agar glycosyl of the neutrophil cell to ICAM coatings of fMLP- dependences The chemotaxis (Sadhu etc., J.Immunol., 2003,170,5, p.2647-54) of the deflection system of matter integrin-dependence. The suppression of PI3K δ adjusts neutrophil activation, adhesion and migration, without influence neutrophil cell mediation to golden yellow Staphylococcic phagocytosis and bactericidal activity (Sadhu etc., Biochem.Biophys.Res.Commun, 2003,308,4, p.764-9).In short, the data shows that PI3K δ suppress to suppress to defend required neutrophilia to congenital immunity comprehensively Granulocyte function.Effects of the PI3K δ in neutrophil cell is provided including treatment of tissue remodeling (such as COPD and rheumatic pass Section is scorching) inflammation disease more room.
PI3K γ have been determined as the medium of the adjusting of G β-γ-dependence of JNK activity, and G β-γ are heterotrimers The subunit (J.Biol.Chem., 1998,273,5, p.2505-8) of G-protein (heterotrimeric G proteins).Most Closely, (Laffargue etc., Immunity, 2002,16,3, p.441-51) has been described PI3K γ and passes through a variety of G (i)-coupling Acceptor transfer (relays) inflammatory signals (inflammatory signals), and it is to mast cell function and white Stimulant in cell and immunology context is important, and the stimulant includes such as cell factor, chemotactic factor (CF), gland Glycosides, antibody, integrin, agglutination factor, growth factor, virus or hormone (Immunity, 2002,16,3, p.441-51； J.Cell Sci., 2001,114 (Pt 16), p.2903-10 with Curr.Opinion Cell Biol., 2002,14,2, p.203-13)。
It has been best understood by now, the imbalance of oncogene and tumor suppressor gene, such as given birth to by increased cell Long and propagation or increase cell survival promote malignant tumour to be formed.Now it is also known that road, the signal mediated by PI3K families pass Guiding path plays an important roll in multiple cell processes including breeding and surviving, and the imbalance of these paths is various Human cancer and Other diseases the origin cause of formation (Annual Rev.Cell Dev.Biol., 2001,17, p.615-675 and J.Cell Science,2003,116,15,p.3037-3040)。
In addition, also there is good evidence to show that I class PI3K enzymes also directly or indirectly facilitate various human cancers Tumour (Vivanco and Sawyers, Nature Reviews Cancer, 2002,2,7, p.489-501) occurs.For example, The suppression of PI3K δ is disorderly for hematologic, such as acute myelogenous leukemia have preferable therapeutic effect (Oncogene, 2006,25,50,p.6648-59).In addition, activated mutant and a variety of different other tumours in p110 α (PIK3CA genes), Such as colon cancer, breast cancer and lung cancer be associated (Science, 2004,304,5670, p.554；Nature Reviews Cancer,2009,9,551)。
Also result of study shows, PI3K is related to the central sensitization (central in painful inflammatory disease Determining sensitization) (J.of Neuroscience, 2008,28,16, p.4261-4270).
Various retrovirus and DNA base activated viral PI3K paths, as host between pre- anti-virus infection period The mode of cell death and finally explore be used for its duplication host cell synthesis mechanism (Virology, 2006,344,1, p.131-8；And Nat.Rev.Microbiol., 2008,6,4, p.265-75).Therefore, PI3K inhibitor is except more definite molten Outside knurl (oncolytic) and anti-inflammation indication, can also have ntiviral characteristic.These antivirus actions cause in virus The inflammation of induction prospect interesting in deteriorating.For example, common cold ERC group virus (HRV) causes the respiratory tract sense more than 50% Dye, but the complication of these infection can have more meaning in some crowds.This is especially in breathing problem, such as asthma or slow It is especially such in the case of property obstructive lung disease (COPD).The rhinovirus infection of epithelial cell cause PI3K rely on cell because Sub and chemokine secretion (J.Biol.Chem., 2005,280,44, p.36952).The inflammatory reaction during infection with breathing disease The deterioration of shape is related.Therefore, PI3K inhibitor can inhibit the immune response of (dampen) other benign virus amplification.It is most of HRV bacterial strains infect bronchial epithelial cell by initial combination to ICAM-1 acceptors.Then, endocytosis is further passed through HRV-ICAM-1 compounds are included into intracellular (internalised) and to have shown that this measure has PI3K activity required (J.Immunol.,2008,180,2,p.870-880).Therefore, PI3K inhibitor also can be by suppressing cell entry host cell And prevent virus infection.
PI3K inhibitor can be used for reducing other types of respiratory infections, including fungal infection aspergillosis (Mucosal Immunol.,2010,3,2,p.193-205).In addition, the mouse that PI3K δ lack is to by the very large Li Shiman of protozoon parasite Protozoon (Leishmania.major) infected with stronger resistance (J.Immunol., 2009,183,3, p.1921- 1933).In view of the effect to virus infection, these reports prompting PI3K inhibitor can be used for treating various infection.
Research shows, PI3K suppress can also to promote regulatory T cells differentiation (Sauer etc., Proc.Natl.Acad.Sci.USA, 2008,105,22, p.7797-7802), prompt PI3K inhibitor can in autoimmunity or In allergic reaction indication, by inducing to the immunological tolerance of autoantigen or allergic reaction original and for therapeutic purposes.Closely Phase, the insensitive association (Am.J.Respir.Crit.Care of glucocorticoid that PI3K δ hypotypes have also been induced with smoking Med.,2009,179,7,p.542-548).This researches show that COPD patient, its differently to glucocorticosteroid response not It is good, benefit can be obtained from the combination of PI3K inhibitor and glucocorticosteroid.
PI3K also has been directed to other breathing problems, such as idiopathic pulmonary fibrosis (IPF).IPF is fibre modification disease Disease, with progressive decreased lung function and caused by respiratory failure, the death rate increases.In IPF, Circulating fibrocyte (circulating fibrocytes) is oriented to lung via Chemokine receptor CXCR4.Signal transductions of the PI3K for CXCR4 It is both required (Int.J.Biochem.and Cell Biol., 2009,41, p.1708-1718) with expression.Therefore, By reducing CXCR4 expression and blocking its effector functions, PI3K inhibitor can inhibit fibrocyte and raise to lung and thus Fibrotic processes, a kind of disease of height less than foot therapy demand are slowed down based on IPF.
3 Κ β of PI3K α and Ρ Ι are in homeostasis and drug inhibition with the relevant molecular target of cancer is maintained Play the role of indispensable (Maira etc., Expert Opin.Ther.Targets, 2008,12,223).
Signal transductions and molecular growth path-dependent (Nature, 2006,441,366) of the PI3K α also with insulin.ΡΙ3 The selective inhibitory of Κ δ hypotypes is expected to be avoided that some potential side effects, such as hyperglycaemia and metabolism or growth failure.
Some groups have been developed for the alternative cpd to PI3K γ, its effect is for autoimmune disease Immunodepressant (Nature Reviews, 2006,5,903-918).It is worth noting that, AS 605240 is had been demonstrated in class It is effective (Nature Medicine, 2005,11,936-943) in the mouse model of rheumatic arthritis, and in system It can postpone the breaking-out (Nature Medicine, 2005,11,933-935) of disease in the model of property lupus erythematosus.
PI3K δ-selective depressant has been described recently.Most selective compound includes quinolinone purine inhibitors (PIK39 and IC87114), IC87114 suppresses PI3K δ on high nanomolar range (three digits), and has to PI3K δ and be more than 100 times of selectivity, has PI3K β 52 times of selectivity, but lacks selectivity (about 8 times) to PI3K γ.It is to experiment Any protein kinase do not show active (Cell, 2006,125,733-747).Use PI3K δ-alternative cpd or heredity Gene control mouse (PI3K δD910A) prove, in addition to playing a crucial role in B and t cell activation, PI3K δ are also related in part to Neutrophil migration and the breathing of sensitization neutrophil, and cause the part of the mast cell threshing of antigen-IgE mediations Block (Blood, 2005,106,1432-1440；Nature,2002,431,1007-1011).Therefore, PI3K δ are as very much What the important medium of critical inflammatory reaction occurred, the inflammatory reaction, which it is known that, participates in abnormal inflammatory disease, includes but not limited to Autoimmune disease and allergy.In order to support the viewpoint, generated not from the experiment using Genetic tools and medicament Disconnected increased 1) PI3K δ verifications data.Therefore, using PI3K δ alternative cpd IC87114 and PI3K δD910AMouse, Ali etc. Verified PI3K δ's people (Nature, 2002,431,1007-1011) play a crucial role in the mouse model of anaphylactia. In the case of there is no function δ, passive cutaneous anaphylaxis (PCA) substantially reduces, and can be attributed to antigen-IgE and lure The mast cells activation led and the reduction of threshing.In addition, the mouse mould of the asthma in the airway inflammation induced using ovalbumin In type, with IC87114 suppress δ have been demonstrated to significantly improve inflammation (FASEB, 2006,20:455-465).Difference group used In the same model of quick airway inflammation, using these data of compound in PI3K δD910AIt is mutually authenticated in mutant mice (Eur.J.Immunol.,2007,37,416-424)。
Need to be provided as the new PI3K inhibitor of good drug candidate.Specifically, preferable compound should be with PI3K acceptors effectively combine, while hardly show compatibility to other acceptors, and show the function as activator Activity.The compound should be fully absorbed by intestines and stomach, metabolic stability and have good pharmacokinetic property.When targeting maincenter During acceptor in nervous system, they can freely pass through blood-brain barrier, and ought selectively target in peripheral neverous system Acceptor when, they would not pass through blood-brain barrier.They should be non-toxic and show few side effect.In addition, the ideal Drug candidate should exist with stabilization, non-hygroscopic and the physical form easily prepared.The compounds of this invention shows specific water The selectivity of the flat PI3K α for different paralogous (paralogs), beta, gamma and δ.Particularly, specified level is shown The selectivity for 3 Κ δ of Ρ Ι.
The compounds of this invention all has treatment potential to a series of illnesss being widely present, particularly to autoimmune Disease, diseases associated with inflammation, anaphylactia, disease relevant with immune system or infection, airway disorders, such as asthma and chronic resistance Plug property tuberculosis (COPD), graft-rejection, tumour, such as hematopoietic system cancer or solid tumor.
The invention further relates to the treatment method that other one or more pharmaceutical active compounds are used alone or in combination, this is controlled Treatment method includes the treatment of following disease or obstacle, breathing problem, including asthma, Chronic Obstructive Pulmonary Disease (COPD) and spy Hair property pulmonary fibrosis (IPF)；Virus infection, including viral respiratory infection and viral respiratory disease deteriorate, and such as roar Asthma and COPD；Non-viral respiratory tract infection, including aspergillosis and leishmaniasis；Anaphylactia, including allergic rhinitis and spy Answer atopic dermatitis；Autoimmune disease, including rheumatoid arthritis and multiple sclerosis；Inflammatory disease, including inflammatory Enteropathy；Angiocardiopathy, including thrombosis and atherosclerosis (Future Med.Chem., 2013,5,4,479-492； Biochemical Society Transactions,2004,32,378)；Malignant hematologic disease；Nerve degenerative diseases；Pancreas It is scorching；Multiple organ failure；Nephrosis；Platelet aggregation；Cancer；Sperm motility；Graft rejection；Graft rejection；Injury of lungs；And pain Bitterly, including with neuralgia, sugar after rheumatoid arthritis or the relevant pain of osteoarthritis, backache, systemic inflammatorome pain, liver Urinate characteristic of disease neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia and central pain；Malignant hematologic disease, including Acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), the white blood of chronic myelognous Sick (CML), T cell acute lymphoblastic leukemia (T-ALL), B cell acute lymphoblastic leukemia (B-ALL), Fei Huoqi Golden lymthoma (NHL), B cell lymphoma, solid tumor (e.g., breast cancer).
Abstract of invention
The invention discloses a kind of noval chemical compound can be used as kinase activity inhibitor, can particularly be used as PI3- kinase activities Inhibitor.Compound as PI3- kinase inhibitors can be used for treatment kinases exception relevant disease, particularly PI3- kinases Abnormal relevant disease, such as treating and preventing the disease by PI3- kinases mechanisms mediates.It is it should be noted that described herein Kinases includes kinase activity and/or abnormal expression extremely.Such disease includes at least one of：Breathing problem, including Asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF)；Virus infection, including viral respiratory infection Deteriorate with viral respiratory disease, such as asthma and COPD；Non-viral respiratory tract infection, including aspergillosis and leishmaniasis； Allergic diseases, including allergic rhinitis and atopical dermatitis；Autoimmune disease, including rheumatoid arthritis And multiple sclerosis；Inflammatory disease, including inflammatory bowel disease；Angiocardiopathy, including thrombosis and atherosclerosis；Pernicious blood Liquid disease；Nerve degenerative diseases；Pancreatitis；Multiple organ failure；Nephrosis；Platelet aggregation；Cancer；Sperm motility；Graft rejection； Graft rejection；Injury of lungs；And pain, including it is scorching with rheumatoid arthritis or the relevant pain of osteoarthritis, backache, whole body Neuralgia, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia and maincenter after disease property pain, liver Property pain.
In some embodiments, the compounds of this invention is shown exceedes other kinases to the selectivity of PI3- kinases.
In other embodiments, the compounds of this invention can be effective inhibitor of PI3K δ.
In other embodiments, the compounds of this invention is shown exceedes other PI3- kinases to the selectivity of PI3K δ Type.
On the one hand, the present invention relates to a kind of compound, it is chemical combination shown in the compound of structure shown in formula (I) or formula (I) The stereoisomer of thing, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug：
Wherein：Each X, Y, R3And R4With definition as described in the present invention.
In some embodiments, X C3-7Heterocyclic radical, C3-7Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Aryl- C1-4Alkylidene, 5-10 former molecular heteroaryl or (5-10 former molecular heteroaryl)-C1-4Alkylidene, wherein described X is optionally by 1,2,3,4 or 5 R1Group is substituted；
Y is
Wherein described Y is optionally by 1,2,3,4 or 5 R2Group is substituted；
Each R1And R2It independently is H, F, Cl, Br, CN, NO2, oxo (=O) ,-C (=O) Ra,-C (=O) ORa,-C (=O) NRaRb,-OC (=O) NRaRb,-OC (=O) ORa,-N (Rc) C (=O) NRaRb,-N (Rc) C (=O) ORa,-N (Rc) C (=O) Ra,-S (=O)2NRaRb,-S (=O)2Ra,-N (Rc) S (=O)2Ra,-N (Rc)-(C1-4Alkylidene)-S (=O)2Ra, RbRaNC (= O)-C1-4Alkylidene, RbRaNC (=O) N (Rc)-C1-4Alkylidene, RaOC (=O) N (Rc)-C1-4Alkylidene, RbRaNC (=O) O- C1-4Alkylidene, RbRaNS (=O)2-C1-4Alkylidene, RaS (=O)2N(Rc)-C1-4Alkylidene, ORa, NRaRb, RaO-C1-4Alkylene Base, RbRaN-C1-4Alkylidene, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkyl, C3-8Cycloalkyl-C1-4Alkylidene, C3-7It is miscellaneous Ring group, C3-7Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5-10 former molecular heteroaryl or (5-10 former molecular heteroaryl)-C1-4Alkylidene, wherein each C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkanes Base, C3-8Cycloalkyl-C1-4Alkylidene, C3-7Heterocyclic radical, C3-7Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylene Base, 5-10 former molecular heteroaryl and (5-10 former molecular heteroaryl)-C1-4Alkylidene it is independently unsubstituted or Substituted by 1,2,3 or 4 substituent, the substituent is independently selected from F, Cl, Br, CN, ORa, NRaRb, C1-6Alkyl, RaO- C1-4Alkylidene or RbRaN-C1-4Alkylidene；
Each R3And R4It independently is H, F, CN ,-C (=O) Ra,-C (=O) ORa,-C (=O) NRaRb, RbRaNC (=O)-C1-4 Alkylidene, RbRaNC (=O) N (Rc)-C1-4Alkylidene, RaOC (=O) N (Rc)-C1-4Alkylidene, RbRaNC (=O) O-C1-4Alkylene Base, RbRaNS (=O)2-C1-4Alkylidene, RbS (=O)2N(Rc)-C1-4Alkylidene, RaO-C1-4Alkylidene, RbRaN-C1-4Alkylene Base, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkyl, C3-8Cycloalkyl-C1-4Alkylidene, C3-7Heterocyclic radical, C3-7Heterocyclic radical- C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5-10 former molecular heteroaryl or (5-10 atom composition Heteroaryl)-C1-4Alkylidene, wherein each C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkyl, C3-8Cycloalkyl-C1-4 Alkylidene, C3-7Heterocyclic radical, C3-7Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5-10 atom group Into heteroaryl and (5-10 original molecular heteroaryl)-C1-4Alkylidene is independently unsubstituted or is taken by 1,2,3 or 4 Substituted for base, the substituent is independently selected from F, Cl, Br, CN, ORa, NRaRb, C1-6Alkyl, RaO-C1-4Alkylidene or RbRaN-C1-4Alkylidene；Or R3, R4Together with the carbon atom being connected with them, 3-8 substituted or non-substituted atom is formed The carbocyclic ring or heterocycle of composition；With
Each Ra, RbAnd RcIt independently is H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-4It is sub- Alkyl, C3-6Heterocyclic radical, C3-6Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5-10 atom composition Heteroaryl or (5-10 former molecular heteroaryl)-C1-4Alkylidene, wherein each C1-6Alkyl, C2-6Alkenyl, C2-6Alkynes Base, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocyclic radical, C3-6Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Virtue Base-C1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 former molecular heteroaryl)-C1-4Alkylidene is independently Unsubstituted or substituted by 1,2,3 or 4 substituent, the substituent is independently selected from F, Cl, CN, N3, OH, NH2, C1-6Alkane Base, C1-6Haloalkyl, C1-6Alkoxy or C1-6Alkyl amino；Or Ra, RbTogether with the nitrogen-atoms being connected with them, substitution is formed Or non-substituted 3-8 former molecular heterocycle.
In other embodiments, X C3-7Heterocyclic radical or 5-10 former molecular heteroaryl, wherein the X appoints Selection of land is by 1,2,3 or 4 R1Group is substituted.
In other embodiments, each R1And R2It independently is H, F, Cl, CN, oxo (=O) ,-C (=O) ORa,-C (=O) NRaRb,-N (Rc) C (=O) NRaRb,-N (Rc) C (=O) ORa,-N (Rc) C (=O) Ra,-S (=O)2NRaRb,-N (Rc)S (=O)2Ra,-N (Rc)-(C1-4Alkylidene)-S (=O)2Ra, RbRaNC (=O)-C1-4Alkylidene, RbRaNC (=O) N (Rc)-C1-4 Alkylidene, RbRaNS (=O)2-C1-4Alkylidene, RaS (=O)2N(Rc)-C1-4Alkylidene, ORa, NRaRb, RaO-C1-4Alkylidene, RbRaN-C1-4Alkylidene, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkyl, C3-8Cycloalkyl-C1-4Alkylidene, C3-7Heterocycle Base, C3-7Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5-10 former molecular heteroaryl or (5- 10 molecular heteroaryls of original)-C1-4Alkylidene, wherein each C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkyl, C3-8Cycloalkyl-C1-4Alkylidene, C3-7Heterocyclic radical, C3-7Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 former molecular heteroaryl)-C1-4Alkylidene it is independently unsubstituted or by 1,2,3 or 4 substituent is substituted, and the substituent is independently selected from F, Cl, CN, ORa, NRaRb, C1-3Alkyl, RaO-C1-4It is sub- Alkyl or RbRaN-C1-4Alkylidene.
In other embodiments, each R3And R4It independently is H, F, CN ,-C (=O) NRaRb, RbRaNC (=O)- C1-2Alkylidene, RbRaNC (=O) N (Rc)-C1-2Alkylidene, RaOC (=O) N (Rc)-C1-2Alkylidene, RbRaNC (=O) O-C1-2 Alkylidene, RbRaNS (=O)2-C1-2Alkylidene, RbS (=O)2N(Rc)-C1-2Alkylidene, RaO-C1-2Alkylidene, RbRaN-C1-2It is sub- Alkyl, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-2Alkylidene, C3-5Heterocyclic radical, C3-5Heterocycle Base-C1-2Alkylidene, phenyl, phenyl-C1-2Alkylidene, the molecular heteroaryl of 5 originals or (5 molecular heteroaryls of original)- C1-2Alkylidene, wherein each C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-2Alkylidene, C3-5 Heterocyclic radical, C3-5Heterocyclic radical-C1-2Alkylidene, phenyl, phenyl-C1-2Alkylidene, 5 molecular heteroaryls of original and (5 atoms The heteroaryl of composition)-C1-2Alkylidene is independently unsubstituted or is substituted by 1,2,3 or 4 substituent, and the substituent is only On the spot it is selected from F, Cl, Br, CN, ORa, NRaRb, C1-6Alkyl, RaO-C1-4Alkylidene or RbRaN-C1-4Alkylidene；Or R3, R4With with The carbon atom that they are connected together, forms the former molecular carbocyclic ring of substituted or non-substituted 3-8 or heterocycle.
In other embodiments, each Ra, RbAnd RcIt independently is H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-6 Cycloalkyl, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocyclic radical, C3-6Heterocyclic radical-C1-4Alkylidene or 5-10 original are molecular miscellaneous Aryl, wherein each C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocycle Base, C3-6Heterocyclic radical-C1-4The former molecular heteroaryl of alkylidene and 5-10 is independently unsubstituted or is taken by 1,2,3 or 4 Substituted for base, the substituent is independently selected from F, CN, N3, OH, NH2, C1-3Alkyl, C1-3Haloalkyl, C1-4Alkoxy or C1-4Alkyl amino.
In other embodiments, X is
Wherein described X is optionally by 1,2 or 3 R1Group is substituted.
In other embodiments, Y is
Wherein described Y is optionally by 1,2 or 3 R2Group is substituted.
In other embodiments, each R3And R4It independently is H, F, CN, C1-3Alkyl, C3-6Cycloalkyl, C3-5Heterocycle Base or C3-5Heterocyclic radical-C1-2Alkylidene, wherein each C1-3Alkyl, C3-6Cycloalkyl, C3-5Heterocyclic radical and C3-5Heterocyclic radical-C1-2 Alkylidene is independently unsubstituted or is substituted by 1,2,3 or 4 substituent, the substituent independently selected from F, Cl, Br, CN, ORa, NRaRb, C1-6Alkyl, RaO-C1-4Alkylidene or RbRaN-C1-4Alkylidene；Or R3, R4The carbon atom being connected with them Together, the former molecular carbocyclic ring of substituted or non-substituted 3-8 or heterocycle are formed.
In other embodiments, each R1And R2It independently is H, F, Cl, CN, oxo (=O) ,-C (=O) ORa,-C (=O) NRaRb,-N (Rc) C (=O) NRaRb,-N (Rc) C (=O) ORa,-N (Rc) C (=O) Ra,-N (Rc)-(C1-2Alkylidene)-S (=O)2Ra, RbRaNC (=O)-C1-2Alkylidene, RbRaNC (=O) N (Rc)-C1-2Alkylidene, RaS (=O)2N(Rc)-C1-2Alkylene Base, ORa, NRaRb, RaO-C1-2Alkylidene, RbRaN-C1-2Alkylidene, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-2Alkylidene, C3-5Heterocyclic radical, C3-5Heterocyclic radical-C1-2Alkylidene, phenyl, phenyl-C1-2Alkylidene, 5-6 former Molecular heteroaryl and (5-6 former molecular heteroaryl)-C1-2Alkylidene, wherein each C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-2Alkylidene, C3-5Heterocyclic radical, C3-5Heterocyclic radical-C1-2Alkylidene, phenyl, benzene Base-C1-2Alkylidene, 5-6 former molecular heteroaryl and (5-6 former molecular heteroaryl)-C1-2Alkylidene is independently not It is substituted or is substituted by 1,2,3 or 4 substituent, the substituent is independently selected from F, Cl, CN, ORa, NRaRbOr C1-3Alkane Base.
On the one hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the above-claimed cpd of the present invention. In some embodiments, described pharmaceutical composition further includes pharmaceutically acceptable carrier, excipient, and diluent is auxiliary Agent, medium, or combinations thereof.In some embodiments, pharmaceutical composition provided by the invention further includes one kind Or a variety of therapeutic agents.In other embodiments, pharmaceutical composition can be liquid, and solid is semi-solid, gel or spraying Formulation.
On the other hand, the purposes the present invention provides above-claimed cpd or aforementioned pharmaceutical compositions in medicine preparation, its Described in medicine be used for protect, handle, treat or mitigate patient's PI3- kinases exception relevant diseases.
In some embodiments, PI3- kinases of the present invention is PI3K δ kinases.
In other embodiments, PI3- kinases exception relevant disease of the present invention is breathing problem, disease Poison infection, non-viral respiratory tract infection, anaphylactia, autoimmune disease, inflammatory disease, angiocardiopathy, pernicious blood Liquid disease, nerve degenerative diseases, pancreatitis, multiple organ failure, nephrosis, platelet aggregation, cancer, sperm motility, graft rejection, Graft rejection, injury of lungs and pain.
In other embodiments, PI3- kinases exception relevant disease of the present invention is asthma, chronic obstruction Property tuberculosis (COPD), viral respiratory infection, viral respiratory disease deteriorate, aspergillosis, leishmaniasis, allergia nose Inflammation, allergic dermatitis, rheumatic arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematologic Disease, nerve degenerative diseases, pancreatitis, multiple organ failure, nephrosis, platelet aggregation, cancer, sperm motility, graft rejection, is moved Plant repels, injury of lungs, and rheumatoid arthritis or the relevant pain of osteoarthritis, backache, systemic inflammatorome pain, after liver Neuralgia, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia and central pain.
On the other hand, the purposes the present invention provides above-claimed cpd or aforementioned pharmaceutical compositions in medicine preparation, institute State medicine and be used for the kinases of inhibition of phosphatidylinositol3-3 (PI3- kinases) activity, including：Make PI3- kinases and a effective amount of present invention Disclosed above-claimed cpd or aforementioned pharmaceutical compositions contact；In some embodiments, contact procedure can further comprise The cell of contact expression PI3- kinases；In the other embodiment of this method, inhibitory action occurs enduring one kind or more In the object of type PI3- kinases exception relevant diseases.One or more type PI3- kinases exception phases according to the present invention Related disorders include autoimmune disease, rheumatic arthritis, respiratory disease, allergic reaction and various types of cancers At least one of.
In some embodiments, method of the present invention includes applying therapeutic agent to study subject.
In other embodiments, the extremely relevant disease of PI3- kinases is selected from rheumatic arthritis, rigid spine Inflammation, osteoarthritis, psoriatic arthritis, psoriasis, at least one of diseases associated with inflammation and autoimmune disease；Other realities Apply in scheme, the extremely relevant disease of PI3- kinases is selected from angiocardiopathy, atherosclerosis, hypertension, deep vein thrombosis Formed, apoplexy, miocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolysis disease, Acute arterial ischeamia, peripheral blood At least one of bolt obstruction and coronary artery disease.In other embodiments, the extremely relevant disease of PI3- kinases is selected from cancer Disease, colon cancer, glioblastoma, carcinoma of endometrium, liver cancer, lung cancer, melanoma, kidney, thyroid cancer, lymthoma, lymph Proliferative disorder, Small Cell Lung Cancer, prognosis of squamous cell lung cancer, glioma, breast cancer, prostate cancer, oophoroma, cervical carcinoma and white blood At least one of disease.In other embodiments, the extremely relevant disease of PI3- kinases is selected from type ii diabetes；At other In embodiment, the extremely relevant disease of PI3- kinases is selected from breathing problem, bronchitis, asthma and chronic obstructive pulmonary disease At least one of；In other embodiments, study subject is people.
On the other hand, the present invention relates to the treatment method of PI3- kinase mediated diseases, the treatment method includes the use of this The step of invention compound or pharmaceutical composition are administered.
On the other hand, the present invention relates to rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, The treatment of psoriasis, diseases associated with inflammation or autoimmune disease, the treatment include the use of the compounds of this invention or medicine group The step of compound is administered.
On the other hand, the present invention relates to including asthma, Chronic Obstructive Pulmonary Disease (COPD) and idiopathic pulmonary fibrosis (IPF) treatment of breathing problem, the step that the treatment includes the use of the compounds of this invention or pharmaceutical composition is administered such as Suddenly.
On the other hand, the present invention relates to inflammatory bowel disease, inflammatory ocular disease, inflammation or unstable bladder disease, The skin disease of inflammatory component, chronic inflammation, systemic loupus erythematosus (SLE), myasthenia gravis, acute diseminated encephalomyelitis, Idiopathic blood platelet reduction property purpura, multiple sclerosis, Sjogren syndrome and autoimmune hemolytic anemia, mistake The treatment of quick property and pleoergy disease, the step that the treatment includes the use of the compounds of this invention or pharmaceutical composition is administered Suddenly.
On the other hand, it is involved in the present invention to be mediated by PI3- kinase activities, swash dependent on PI3- kinase activities or with PI3- The activity of the treatment, especially PI3K δ of the relevant cancer of enzymatic activity, the treatment include any of above and following embodiment party of administration The step of compound of case.
On the other hand, the present invention relates to the treatment method selected from following cancer：Acute myelogenous leukemia, spinal cord development are different Normal syndrome, myeloproliferative disease, chronic myelogenous leukemia, T cell acute lymphoblastic leukemia, B cell acute lymphoblastic are thin Born of the same parents' leukaemia, non-Hodgkin lymphoma, B cell lymphoma, solid tumor and breast cancer, the treatment method include the use of the present invention The step of compound or pharmaceutical composition are administered.
On the other hand, the present invention relates to the compounds of this invention as the application in terms of medicine.
On the other hand, the present invention relates to the compounds of this invention to prepare the medicine side for the treatment of PI3- kinases exception relevant diseases The application in face.
On the other hand, the present invention relates to the compounds of this invention prepare treat rheumatoid arthritis, ankylosing spondylitis, Osteoarthritis, psoriatic arthritis, psoriasis, diseases associated with inflammation, including asthma, Chronic Obstructive Pulmonary Disease (COPD) and special hair Property pulmonary fibrosis (IPF) etc. breathing problem, the application of medicine in terms of autoimmune disease and cancer.
Unless otherwise mentioned, the present invention includes the stereoisomer of all the compounds of this invention, geometric isomer, mutually variation Structure body, solvate, hydrate, metabolite, salt and pharmaceutically acceptable prodrug.
In some embodiments, the salt refers to pharmaceutically acceptable salt.Term " pharmaceutically acceptable " refers to Material or composition must be with other components comprising preparation and/or with the mammals of its treatment chemically and/or toxicology It is upper compatible.
The compound of the present invention further includes the form of its salt, which is not necessarily pharmaceutically acceptable salt, but can be with It is used to prepare and/or purifies the compound of the present invention and/or the intermediate of the enantiomer for separating the compounds of this invention.
The compounds of this invention including its salt can also be obtained with its hydrate forms, or be crystallized including other for it Solvent.The compounds of this invention can form the solvate with acceptable solvent (including water) inherently or by designing； Therefore, present invention additionally comprises its solvated and unsolvated form.
On the other hand, the present invention provides the preparation of compound shown in formula (I), separation and the method purified.The present inventionization Compound may include the form of several asymmetric centers or its usual described raceme mixture.The present invention is also into one Step includes racemic mixture, partial racemic compound and isolated enantiomer and diastereomer.
The compounds of this invention can be with one in possible isomers, rotational isomer, atropisomer, dynamic isomer Kind form or the form of its mixture exist, and the present invention can further include isomers, the rotational isomeric of the compounds of this invention Body, atropisomer, the mixture of dynamic isomer, or isomers, rotational isomer, atropisomer, dynamic isomer Part mixes or the separated isomers opened, rotational isomer, atropisomer, dynamic isomer.
On the other hand, compound of the present invention includes the use of chemical combination defined in the present invention of various isotope marks Thing, for example, wherein there are radio isotope, such as3H,14C and18Those compounds of F, or wherein there are the same position of on-radiation Element, such as2H and13The compound of C.
On the other hand, the method for preparation, separation and the purifying of the compound included the present invention relates to formula (I).
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
The present invention will in detail list the document corresponding to the content of definite materialization, and embodiment is all accompanied by structure The diagram of formula and chemical formula.The present invention, which has, expectedly covers all choices, variation and coordinate, these may be as right Existing invention field is included in defined in it is required that like that.Those skilled in the art will identify it is many similar or equivalent to This described method and material, these can be applied in the practice of the present invention.The present invention is limited to absolutely not method and material Description.There is many documents and similar material to distinguish or contradict with the present patent application, 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, technical and scientific term used in the present invention and the technical field of the invention technical staff It is conventional understand that there is identical implication, unless otherwise noted, all patents public affairs cited in full content are disclosed in the present invention Open publication and be integrally incorporated the present invention by reference.
The present invention will apply defined below unless other aspects show.Purpose according to the present invention, chemical element is according to member Plain periodic table, CAS versions and chemicals handbook, 75,thEd, 1994 define.In addition, organic chemistry General Principle is shown in “Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999, and“March's Advanced Organic Chemistry”,by Michael B.Smith and Jerry March, John Wiley&Sons,New York:2007, therefore all contents of the invention have all merged bibliography.
Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.It is tested right As also referring to primate (such as people), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc..Some In embodiment, the study subject is primate.In other other embodiments, the study subject is people.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.
Present invention additionally comprises the compounds of this invention of isotope marks, its except for the following fact with it is of the present invention those Compound phase is same：One or more atoms are different from the original of natural common atomic quality or mass number by atomic mass or mass number Filial generation is replaced.The Exemplary isotopes that can be also introduced into the compounds of this invention include the same position of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine Element, such as2H,3H,13C,14C,15N,16O,17O,31P,32P,36S,18F and37Cl。
The compounds of this invention and the compound comprising other of aforementioned isotopes and/or other atoms isotope Pharmaceutically acceptable salt is included within the scope of the present invention.The compounds of this invention of isotope marks, such as the same position of radioactivity Element, such as3H and14C, which is incorporated into the compounds of this invention, can be used for medicine and/or substrate tissue distributional analysis.Due to it is easily prepared with And detection, tritium generation, i.e.3H, and carbon-14, i.e.,14C, isotope are particularly preferred.In addition, with weight isotope, such as deuterium, i.e.,2H Substitution, it is possible to provide some are derived from the advantage in the treatment of the metabolic stability of bigger, such as increased Half-life in vivo or reduction Volume requirements.Therefore, it is probably preferable in some cases.
The Stereochemical definitions and convention that the present invention uses are generally according to S.P.Parker, Ed, McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons, Inc.,New York,1994.The compounds of this invention can contain asymmetric center or chiral centre, therefore with different three-dimensional different Configuration formula exists.It is expected that all stereoisomeric forms in any ratio of the compounds of this invention, include but not limited to diastereo-isomerism Body, enantiomter and atropisomer (atropisomer) and their mixture such as racemic mixture, are also contained in this Within invention scope.Many organic compounds exist with optical active forms, i.e., they, which have, sends out the plane of linearly polarized light Raw rotating ability.When describing compound with optical activation, represented using prefix D and L or R and S with regard in molecule The absolute configuration of molecule for chiral centre (or multiple chiral centers).Prefix d and l or (+) and (-) are to be used for appointed compound The caused rotating symbol of linearly polarized light, wherein (-) or l represent that compound is left-handed.Prefix is (+) or the compound of d is Dextrorotation.For given chemical constitution, in addition to these stereoisomers each other mirror image, these stereoisomers are identical 's.Specific stereoisomer is alternatively referred to as enantiomter, and the mixture of the isomers is commonly referred to as enantiomerism The mixture of body.The 50 of enantiomter:50 mixtures are known as racemic mixture or racemic modification, when in chemical reaction or side When there is no stereoselectivity or stereospecificity in method, the racemic mixture or racemic modification may occur in which.
According to the selection of raw material and method, the compounds of this invention can be with one in possible isomers or theirs is mixed The form of compound exists, such as pure optical isomer, or as isomer mixture, it is such as different as racemic and non-corresponding Structure body mixture, this depends on the quantity of asymmetric carbon atom.Chiral synthesis can be used in (R)-or (S)-isomers of optical activity Prepared by son or chiral agents, or split using routine techniques.If this compound contains a double bond, substituent may be E or Z Configuration；If containing dibasic cycloalkyl in this compound, the substituent of cycloalkyl may be cis or trans (cis- or Trans-) configuration.
The compounds of this invention can contain asymmetric center or chiral centre, therefore be deposited with different stereoisomer forms .It is expected that all stereoisomer forms of the compounds of this invention, include but not limited to diastereoisomer, mapping Isomers and atropisomer (atropisomer) and geometry (or conformation) isomers and their mixture, as racemic is mixed Compound, within the scope of the present invention.
Unless otherwise noted, the structure that describes of the present invention be also represented by including this structure all isomers (e.g., enantiomer, Diastereomer atropisomer (atropisomer) and geometry (or conformation)) form；For example, the R and S structures of each asymmetric center Type, (Z) and (E) double bond isomer, and (Z) and (E) rotamer.Therefore, the single spatial chemistry of the compounds of this invention Isomers and mixture of enantiomers, non-enantiomer mixture and geometric isomer (or rotamer) mixture are in this hair Within the scope of bright.
Term " dynamic isomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of dynamic isomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include by proton transfer the mutual inversion of phases that carries out, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the restructuring of some bonding electrons come The mutual inversion of phases carried out.The instantiation of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyls are mutual The change of tautomeric.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the change of pyridine -4- alcohol and pyridine -4 (1H) -one dynamic isomer.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.
" nitrogen oxides " used in the present invention refers to when compound contains several amine functional groups, can be by 1 or more than 1 Nitrogen-atoms aoxidize to form N- oxides.The particular example of N- oxides is the N- oxides or nitrogen heterocyclic ring nitrogen-atoms of tertiary amine N- oxides.Available oxidant example, as hydrogen peroxide or peracid (such as peroxycarboxylic acid) handle corresponding amine and form N- oxides (referring to Advanced Organic Chemistry, Wiley Interscience, the 4th edition, Jerry March, pages). Especially, N- oxides can be prepared (Syn.Comm.1977,7,509-514) with the method for L.W.Deady, wherein for example lazy Property solvent, such as dichloromethane in, react amine compounds and m- chlorine benzylhydroperoxide (MCPBA).
" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention are formed Thing.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.
" metabolite " refers to specific compound or its salt in vivo by the obtained product of metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology well-known in the art Adopt as stating and experimentally characterized.Such product can be by, by aoxidizing, being reduced, water to drug compound The methods of solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc., obtains.Correspondingly, the present invention includes compound Metabolite, including compound and the mammal of the present invention are come into full contact with into metabolite caused by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:It is 1-19. described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates, resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphurs Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that appropriate alkali obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any The quaternary ammonium salt that the compound of the group of included N is formed.Water-soluble or oil-soluble or dispersion product can be turned into by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
Term " prodrug " used in the present invention, represents a compound and is converted into compound shown in formula (I) in vivo. Such conversion is hydrolyzed or influenced in blood or tissue through enzymatic conversion for precursor structure in blood by pro-drug.This hair Bright pro-drug compounds can be ester, and ester can be as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, you can be acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.Completely begged on pro-drug By may be referred to documents below：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
The shape that any asymmetric atom (for example, carbon etc.) of the compounds of this invention can be enriched with racemic or enantiomer Formula exists, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom (R)- Or there is at least 50% enantiomeric excess in terms of (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, extremely Few 80% enantiomeric excess, at least at least 90% enantiomeric excess, 95% enantiomeric excess, or at least 99% enantiomeric excess. If it would be possible, substituent on the atom with unsaturated double-bond can by cis-(Z)-or trans-(E)-in the form of deposit .
Therefore, as described in the present invention, compound of the invention can be with possible isomers, rotational isomeric The form of a kind of form or its mixture in body, atropisomer, dynamic isomer exists, for example, substantially pure geometry (cis or trans) isomers, diastereoisomer, optical isomer (enantiomer), racemic modification or its form of mixtures.
Any isomer mixture of gained can be separated into according to the physical chemical differences of component pure or substantially pure Geometry or optical isomer, diastereoisomer, racemic modification, such as separated by chromatography and/or fractional crystallization.
The racemic modification of any gained end-product or intermediate can be passed through into those skilled in the art with known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Thing can also be separated by chiral chromatogram, e.g., use the high pressure liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can prepare (e.g., Jacques, et al., Enantiomers, Racemates and by asymmetric syntheses Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；and Wilen, S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed., Univ.of Notre Dame Press,Notre Dame,IN 1972)。
As described in the invention, compound of the invention can optionally be substituted by one or more substituents, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can exchange use to " optionally substituting " this term with " substituted or non-substituted ".Term is " optionally Ground ", " optional " or " optional " refer to the then described event or situation can with but may not occur, and the description is including wherein There is a situation where the event or situation, and wherein there is a situation where the event or situation.In general, term " optionally " Whether it is located at before term " substituted ", all represents to give one or more of structure hydrogen atom by specific substituent institute Substitution.Unless otherwise indicated, an optional substituted radical can be substituted in each commutable position of group.When More than one position can be substituted by one or more substituents selected from specific group in given structural formula, then substitution Base can substitute in each position identical or differently.The wherein described substituent can be, but be not limited to, D, F, Cl, Br, CN, N3, OH, NH2, NO2, oxo (=O) ,-C (=O) Ra,-C (=O) ORa,-C (=O) NRaRb,-OC (=O) NRaRb,-OC (=O) ORa,-N (Rc) C (=O) NRaRb,-N (Rc) C (=O) ORa,-N (Rc) C (=O) Ra,-S (=O)2NRaRb,-S (=O)2Ra,-N (Rc) S (=O)2Ra,-N (Rc)-(C1-4Alkylidene)-S (=O)2Ra, RbRaNC (=O)-C1-4Alkylidene, RbRaNC (= O)N(Rc)-C1-4Alkylidene, RaOC (=O) N (Rc)-C1-4Alkylidene, RbRaNC (=O) O-C1-4Alkylidene, RbRaNS (=O)2- C1-4Alkylidene, RaS (=O)2N(Rc)-C1-4Alkylidene, ORa, NRaRb, RaO-C1-4Alkylidene, RbRaN-C1-4Alkylidene, C1-6Alkane Base, C1-6Haloalkyl, C1-6Alkoxy, C1-6Alkyl amino, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkyl, C3-8Cycloalkyl-C1-4 Alkylidene, C3-7Heterocyclic radical, C3-7Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, includes 1,2,3 or 4 A heteroatomic 5-10 former molecular heteroaryl for being independently selected from O, S and N or (5-10 former molecular heteroaryl)- C1-4Alkylidene, wherein, the Ra, RbAnd RcWith defining as described herein.
In addition, it is necessary to explanation, unless otherwise explicitly point out, used describing mode in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can exchange, and should all be interpreted broadly, it both may be used To refer in different groups, do not influence mutually, can also represent in phase between expressed specific option between same-sign In same group, do not influenced mutually between expressed specific option between same-sign.
In each several part of this specification, the substituent that the present invention discloses compound is disclosed according to radical species or scope.It is special Do not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.For example, term “C1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each several part of the present invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.If for example, the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then is represented respectively it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.
Terminology used in the present invention " alkyl " or " alkyl group ", represent saturated straight chain or side chain containing 1-20 carbon atom Monovalence hydrocarbon atomic group.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom, and some of them are implemented Example is that alkyl group contains 1-10 carbon atom, and other embodiment is that alkyl group contains 1-8 carbon atom, in addition one A little embodiments are that alkyl group contains 1-6 carbon atom, and other embodiment is that alkyl group contains 1-4 carbon atom, Other embodiment is that alkyl group contains 1-3 carbon atom.
The example of alkyl group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n- Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,- CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl groups (- CH (CH3)CH2CH2CH3), 3- amyl groups (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl isophthalic acids-butyl (- CH2CH2CH(CH3)2), 2- first Base -1- butyl (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3) CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyl groups (- C (CH3)2CH2CH2CH3), 3- first Base -2- amyl groups (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyl groups (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- penta Base (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl groups (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc., wherein described Alkyl group can be independently unsubstituted or be substituted by one or more substituents described in the invention.
Term " alkyl " used in the present invention and its prefix " alkane ", the saturated carbon chains all comprising straight chain and side chain.
Term " alkylidene " represents to remove two obtained saturations of hydrogen atom from the saturated hydrocarbyl of straight or branched Bivalent hydrocarbon radical group.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom, and other embodiment is, sub- Alkyl group contains 1-6 carbon atom, and other embodiment is that alkylidene group contains 1-4 carbon atom, and other is real Applying example is, alkylidene group contains 1-2 carbon atom.Such example includes methylene (- CH2-), ethylidene (- CH2CH2-), Isopropylidene (- CH (CH3)CH2-) etc., wherein the alkylidene group can be independently unsubstituted or one or more Substituent described in the invention is substituted.
Term " alkenyl " represents 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or 2-4 carbon original The monovalent hydrocarbon of the straight or branched of son, wherein at least one position is undersaturated condition, i.e., a C-C is sp2Double bond, wherein The group of alkenyl can be independently unsubstituted or be substituted by one or more substituents described in the invention, including base There are the positioning of negation " just " or " E " " Z " in group, wherein specific example includes, but is not limited to, vinyl (- CH=CH2), alkene Propyl group (- CH2CH=CH2) etc..
Term " alkynyl " represents 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or 2-4 carbon atom Straight or branched monovalent hydrocarbon, wherein at least one position is undersaturated condition, i.e., a C-C is tri- keys of sp, wherein alkynes Base group can be independently unsubstituted or be substituted by one or more substituents described in the invention, specific example bag Include, but be not limited to, acetenyl (- C ≡ CH), propargyl (- CH2C ≡ CH), 1- propinyls (- C ≡ C-CH3) etc..
Term " alkoxy " represents that alkyl group is connected by oxygen atom with molecule remainder, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-20 carbon atom, some of real Applying example is, alkoxy base contains 1-10 carbon atom, and other embodiment is that alkoxy base contains 1-8 carbon atom, Other embodiment is that alkoxy base contains 1-6 carbon atom, and other embodiment is that alkoxy base contains 1-4 A carbon atom, other embodiment are that alkoxy base contains 1-3 carbon atom.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH3)3), 1- amoxys (n- amoxys ,-OCH2CH2CH2CH2CH3), 2- amoxys (- OCH (CH3) CH2CH2CH3), 3- amoxys (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- fourths Epoxide (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (- OCH2CH(CH3)CH2CH3), etc., wherein the alkoxy base can be independently unsubstituted or by this one or more hair Bright described substituent is substituted.
Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represent alkyl, and alkenyl or alkoxy base are by one A or multiple halogen atoms are substituted, and such example includes, but is not limited to, trifluoromethyl, trifluoromethoxy etc..
Term " carbocyclic ring ", " carbocylic radical " or " annular aliphatic " refer to have one or more tie points be connected to molecule its Remaining part point, non-aromatic, saturation or part are undersaturated, contain 3-12 carbon atom, or 3-10 carbon atom, or 3-8 Carbon atom, or monocyclic, the bicyclic and three-ring system of 3-6 carbon atom.Bicyclic system includes that spiral shell is bicyclic and condensed-bicyclic.Suitably Carbon ring group includes, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of carbon ring group further comprises, but never It is limited to, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyls, 1- cyclopenta -2- alkenyls, 1- cyclopenta -3- alkenyls, ring Hexyl, 1- cyclohexyl -1- alkenyls, 1- cyclohexyl -2- alkenyls, 1- cyclohexyl -3- alkenyls, cyclohexadienyl, suberyl, ring are pungent Base, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..
Term " cycloalkyl " refers to the remainder for having one or more tie points to be connected to molecule, saturation, containing 3-12 Monocyclic, the bicyclic or three-ring system of a carbon atom.Some of embodiments are the member ring systems containing 3-10 carbon atom；Other Embodiment is the member ring systems containing 3-8 carbon atom；Other embodiment is the member ring systems containing 3-6 carbon atom；Other Embodiment is the member ring systems containing 5-6 carbon atom；And the group of naphthene base can be independently unsubstituted or by one or more A substituent described in the invention is substituted.
Term " cycloalkyl alkylidene " represents that alkyl group can be substituted by one or more groups of naphthene base, wherein alkane Base and group of naphthene base have implication as described in the present invention.Some of embodiments are, cycloalkyl alkylidene group refer to " compared with Rudimentary cycloalkyl alkylidene " group, i.e. group of naphthene base are connected to C1-6Alkyl group on.Other embodiment is ring Alkyl group is connected to C1-4Alkyl group on.Other embodiment is that group of naphthene base is connected to C1-3Alkyl group On.Other embodiment is that group of naphthene base is connected to C1-2Alkyl group on.Such example includes, but and unlimited In, cyclopropylethyl, cyclopentyl-methyl, cyclohexyl methyl etc..The cycloalkyl alkylidene group can not taken independently In generation, is substituted by one or more substituents described in the invention.
Term " heterocycle ", " heterocyclic radical " or " heterocycle " are used interchangeably here, bicyclic all referring to monocyclic, or tricyclic System, one or more atoms are replaced by hetero atom individually optionally in its middle ring, ring can be it is fully saturated or comprising One or more degrees of unsaturation, but be definitely not the fragrant same clan, there is the remainder that one or more tie points are connected to molecule. Its bicyclic system includes that spiral shell is bicyclic and condensed-bicyclic, and one of ring can be monocyclic carbocyclic ring or single heterocycle.One of them or Multiple ring hydrogen atoms are substituted by one or more substituents described in the invention individually optionally.Some of them are implemented Example is " heterocycle ", " heterocyclic radical " or " heterocycle " group be 4-8 original it is molecular it is monocyclic (3-7 carbon atom and selected from N, O, The 1-3 hetero atom of P, S, are optionally substituted to obtain picture S=O, SO in this S or P by one or more oxygen atoms2, PO, PO2's Group)；Other embodiment is " heterocycle ", and " heterocyclic radical " or " heterocycle " group is 4-7 former molecular monocyclic (3-6 A carbon atom and selected from N, O, P, the 1-3 hetero atom of S, optionally substitutes to obtain in this S or P by one or more oxygen atoms As S=O, SO2, PO, PO2Group)；Other embodiment is " heterocycle ", and " heterocyclic radical " or " heterocycle " group is 3-7 Former molecular monocyclic (2-6 carbon atom and selected from N, O, P, the 1-3 hetero atom of S, in this S or P optionally by one or more A oxygen atom substitutes to obtain as S=O, SO2, PO, PO2Group)；Other embodiment is " heterocycle ", " heterocyclic radical " or " heterocycle " group is 4-6 former molecular monocyclic (3-5 carbon atom and selected from N, O, P, the 1-3 hetero atom of S, in this S Or P optionally substitutes to obtain as S=O, SO by one or more oxygen atoms2, PO, PO2Group)；Other embodiment " heterocycle ", " heterocyclic radical " or " heterocycle " group be 3-6 it is former it is molecular it is monocyclic (2-5 carbon atom and selected from N, O, P, The 1-3 hetero atom of S, is optionally substituted to obtain picture S=O, SO in this S or P by one or more oxygen atoms2, PO, PO2Base Group, when it is described be 3 originals molecular ring when, only one of which hetero atom), or 7-10 former molecular bicyclic (4-9 is a Carbon atom and selected from N, O, P, the 1-3 hetero atom of S, optionally substitutes to obtain picture in this S or P by one or more oxygen atoms S=O, SO2, PO, PO2Group).
Heterocyclic radical can be carbon-based or hetero atom base." heterocyclic radical " equally also includes heterocyclic group and saturation or part insatiable hunger With ring or heterocyclic fused formed group.The example of heterocycle includes, but is not limited to, pyrrolidinyl, tetrahydrofuran base, dihydro Furyl, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, Thioxane base, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, glycidyl, Azacycloheptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, 4,5- dihydros are disliked Oxazolyl, 2- pyrrolinyls, 3- pyrrolinyls, indolinyl, 2H- pyranoses, 4H- pyranoses, dioxane hexyl, 1,3- bis- Oxygen amyl group, pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2, 3,4- tetrahydro isoquinolyls.The example of heterocyclic group further includes, two carbon atoms on 1,1- dioxidothiomorpholinyl, and its middle ring Substituted by oxygen atom such as hybar X base.
Term " heterocycloalkylene " represents that alkyl group can be substituted by one or more heterocyclyl groups, wherein alkane Base and heterocyclyl groups have implication as described in the present invention.Some of embodiments are, heterocycloalkylene group refer to " compared with Rudimentary heterocycloalkylene " group, i.e. heterocyclyl groups are connected to C1-6Alkyl group on.Other embodiment is, miscellaneous Cyclic groups are connected to C1-4Alkyl group on.Other embodiment is that heterocyclyl groups are connected to C1-2Alkyl group On.Such example includes, but is not limited to, 2- pyrrolidines ethyls, 3- azetidine methyl etc..The heterocyclic radical alkylene Base group can be independently unsubstituted or be substituted by one or more substituents described in the invention.
Term " n former molecular ", wherein n is integer, the number of ring member nitrogen atoms in molecule is typically described, described The number of ring member nitrogen atoms is n in molecule.For example, piperidyl is 6 molecular Heterocyclylalkyls of original, and 1,2,3,4- tetralyl It is the molecular carbocylic radical group of 10 originals.
Term " hetero atom " refers to O, S, N, P and Si, including the form of N, S and any oxidation state of P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N is (as in 3,4- dihydro-2 h-pyrrole bases N), NH (as the NH in pyrrolidinyl) or NR (NR in the pyrrolidinyl substituted as N-).
Term " halogen " refers to F, Cl, Br or I.
Term " N3" represent a nitrine structure.This group can be connected with other groups, for example, can be with a first Base is connected to form triazonmethane (MeN3), or it is connected to form phenylazide (PhN with a phenyl3)。
Term " aryl " can be used alone or the big portion as " aralkyl ", " aralkoxy " or " aryloxy alkyl " Point, expression contains 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom is monocyclic, bicyclic, and the carbocyclic ring of tricyclic System, wherein, at least one member ring systems are aromatic, and each of which member ring systems include 3-7 former molecular ring, and have One or more attachment points are connected with the remainder of molecule.Term " aryl " can be exchanged with term " aromatic rings " and used, such as Aromatic rings can include phenyl, naphthyl and anthryl.The aromatic yl group can be independently unsubstituted or by one or more sheet Described substituent is invented to be substituted.
Term " aryl alkylene " represent alkyl group can be substituted by one or more aromatic yl groups, wherein alkyl and Aromatic yl group has implication as described in the present invention, and some of embodiments are that arylalkylene groups refer to the " virtue of lower level Base alkylidene " group, i.e. aromatic yl group are connected to C1-6Alkyl group on.Other embodiment is arylalkylene groups Refer to contain C1-4Alkyl " benzene alkylene ".Other embodiment is that arylalkylene groups refer to that aromatic yl group is connected to C1-2Alkyl group on.Wherein instantiation includes benzyl, diphenyl methyl, phenethyl etc..The arylalkylene groups Can be independently unsubstituted or be substituted by one or more substituents described in the invention.
Term " heteroaryl " can be used alone or as most of " heteroaryl alkyl " or " heteroarylalkoxy ", Expression contains 5-14 annular atom, or 5-12 annular atom, or 5-10 annular atom, or 5-6 annular atom is monocyclic, bicyclic, And three-ring system, wherein at least one member ring systems are aromatic, and at least one member ring systems include one or more hetero atoms, Each of which member ring systems include 5-7 former molecular ring, and have one or more attachment points to be connected with molecule remainder. Term " heteroaryl " can exchange use with term " hetero-aromatic ring " or " heteroaromatics ".In some embodiments, heteroaryl Base is comprising 1,2,3 or 4 former molecular heteroaryl of be independently selected from O, S and N heteroatomic 5-12.In other implementations In scheme, heteroaryl is comprising 1,2,3 or 4 former molecular heteroaryl of be independently selected from O, S and N heteroatomic 5-10. In other embodiments, heteroaryl is to include 1,2,3 or 4 heteroatomic 5-6 atom group for being independently selected from O, S and N Into heteroaryl.In other embodiments, heteroaryl is to be independently selected from heteroatomic the 5 of O, S and N comprising 1,2,3 or 4 A molecular heteroaryl of original.
Other embodiment is, heteroaryl includes following monocyclic, but it is monocyclic to be not limited to these：2- furyls, 3- Furyl, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyls, 2- oxazolyls, 4- oxazolyls, 5- oxazolyls, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridine radicals, 4- pyrroles Piperidinyl, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, pyridazinyl (such as 3- pyridazinyls), 2- thiazolyls, 4- thiazolyls, 5- thiazoles Base, tetrazole radical (such as 5H- tetrazole radicals and 2H- tetrazole radicals), triazolyl (such as 2- triazolyls, 5- triazolyls, 4H-1,2,4- triazolyls, 1H-1,2,4- triazolyls and 1,2,3-triazoles base), 2- thienyls, 3- thienyls, pyrazolyl (e.g., 2- pyrazolyls and 3- pyrazoles Base), isothiazolyl, 1,2,3- oxadiazolyl, 1,2,5- oxadiazolyl, 1,2,4- oxadiazolyl, 1,3,4- oxadiazolyl, 1,2, 3- thio biphosphole bases, 1,3,4- thio biphosphole base, 1,2,5- thio biphosphole base, pyrazinyl, 1,3,5-triazines base；Also include following It is bicyclic, but it is bicyclic to be not limited to these：Benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- indoles Base), purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinolyls), and (such as 1- isoquinolyls, 3- are different for isoquinolyl Quinolyl or 4- isoquinolyls).The heteroaryl groups are optionally taken by one or more substituents described in the invention Generation.
Term " heteroarylalkylenyl " represents that alkyl group can be substituted by one or more heteroaryl groups, wherein alkane Base and heteroaryl groups have implication as described in the present invention, and some of embodiments are, heteroarylalkylenyl group refer to " compared with Rudimentary heteroarylalkylenyl " group, i.e. heteroaryl groups are connected to C1-6Alkyl group on.Other embodiment is, miscellaneous Aromatic yl group is connected to C1-4Alkyl group on.Other embodiment is that heteroaryl groups are connected to C1-2Alkyl group On.Wherein instantiation includes 2- picolyls, 3- furylethyls etc..The heteroarylalkylenyl group can independently not It is substituted or is substituted by one or more substituents described in the invention.
No matter term " carboxyl ", be single use or be used in conjunction with other terms, such as " carboxyalkyl ", expression-CO2H；Term No matter " carbonyl ", be single use or be used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", represents-(C=O)-.
Term " alkyl amino " includes " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino group independently Ground is substituted by one or two alkyl group.Some of embodiments are that alkyl amino is one or two C1-6Alkyl connects The alkylamino group of lower level on to nitrogen-atoms.Other embodiment is that alkyl amino is C1-3Lower level alkyl Amino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but not It is limited to, N- methylaminos, N- ethylaminos, N, N- dimethylaminos, N, N- lignocaines etc..
Term " fragrant amino " represents that amino group is substituted by one or two aromatic yl group, and such example includes, but It is not limited to N- phenylaminos.Some of embodiments are that the aromatic ring in fragrant amino can be further substituted.
Term " aminoalkyl " includes the C substituted by one or more amino1-10Straight or branched alkyl group.Wherein Some embodiments are that aminoalkyl is the C substituted by one or more amino groups1-6" aminoalkyl of lower level ", so Example include, but is not limited to, aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.
As described in the invention, the member ring systems formed in substituent one key connection of picture to the ring at center are (such as formula a and formula Shown in b-1, b-2 and b-3) represent substituent any commutable position on ring and can substitute.For example, formula a is represented on B rings Any possible substituted position, as shown in formula b-1, b-2 and b-3：
Used term is " undersaturated " in the present invention represents in group containing one or more degrees of unsaturation.
Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded from otherwise Content.
As described herein, term " pharmaceutically acceptable carrier " includes any solvent, decentralized medium, coating agents, Surfactant, antioxidant, preservative (such as antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizing agent, bonding Agent, excipient, dispersant, lubricant, sweetener, flavor enhancement, colouring agent, or its composition, these carriers are all affiliated technologies Known (such as Remington's Pharmaceutical Sciences, the 18th Ed.Mack of field technology personnel Printing Company, described in 1990, pp.1289-1329).Except any conventional carrier feelings incompatible with active ingredient Outside condition, cover its purposes in treatment or pharmaceutical composition.
" therapeutically effective amount " of term the compounds of this invention refers to that the biology or medicinal response, example of study subject will be triggered Such as reduce or suppress enzyme or protein active or improve symptom, relax symptom, slow down or delay progression of disease or prevention disease The amount of used the compounds of this invention.It is applied in some non-limiting embodiments, term " therapeutically effective amount " refers to work as The used amount to the effective the compounds of this invention of the following during study subject：(1) at least partly relax, suppress, prevention And/or improve (i) by disease PI3K imbalance mediations or that (ii) is related with PI3K activity or (iii) is characterized by PI3K activity Trouble or conditions or diseases；Or (2) mitigate or suppress PI3K activity.In other non-limiting embodiments, " treatment has term Effect amount " refers to when being applied to cell or tissue or non-cellular biological material or medium, at least partly mitigates illness or suppression The amount of the effective the compounds of this invention of PI3K；Or mitigate illness at least to a certain extent or suppress the activity of PI3K.Term " therapeutically effective amount ", can also be in the same manner using taking office except for illustrating the content of the embodiments above on PI3K What his relevant protein/polypeptide/enzyme.
Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (slow down or prevent mitigate disease or the development of its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stable body Parameter) or above-mentioned two aspects adjusting disease or illness.In other embodiments, " treatment " refers to prevention or delay disease or disease Breaking-out, generation or the deterioration of disease.
When term " blocking group " or " PG " refer to a substituent with other reacted with functional groups, commonly used to hinder It is disconnected or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected with amino group to block Or the feature of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyls (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent of base is used for blocking or protecting the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl Blocking group " refers to that the substituent of carboxyl is used for blocking or protect the feature of carboxyl, general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group refers to document：T W.Greene,Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.
The description of the compound of the present invention
The invention discloses a new class of compound, can be used as kinase activity inhibitor, can particularly be used as PI3- kinases The inhibitor of activity.Compound as PI3- kinase inhibitors can be used for treatment abnormal with kinases, and particularly PI3- kinases is different Normal relevant disease, such as treating and preventing the disease by PI3- kinases mechanisms mediates.Such disease include it is following at least One of：Breathing problem, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF)；Virus infection, Deteriorate including viral respiratory infection and viral respiratory disease, such as asthma and COPD；Non-viral respiratory tract infection, bag Include aspergillosis and leishmaniasis；Allergic diseases, including allergic rhinitis and atopical dermatitis；Autoimmune disease Disease, including rheumatoid arthritis and multiple sclerosis；Inflammatory disease, including inflammatory bowel disease；Angiocardiopathy, including thrombosis And atherosclerosis；Malignant hematologic disease；Nerve degenerative diseases；Pancreatitis；Multiple organ failure；Nephrosis；Platelet aggregation；Cancer Disease；Sperm motility；Graft rejection；Graft rejection；Injury of lungs；And pain, including with rheumatoid arthritis or osteoarthritis Neuralgia, diabetic neuropathy, neuro-inflammatory pain after relevant pain, backache, systemic inflammatorome pain, liver (wound), trigeminal neuralgia and central pain.
In some embodiments, the compounds of this invention, which can be shown, swashs the selectivity of PI3- kinases more than other types 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 be shown exceedes other types to the selectivity of PI3K δ PI3- kinases.
On the one hand, the present invention relates to a kind of compound, it is chemical combination shown in the compound of structure shown in formula (I) or formula (I) The stereoisomer of thing, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug：
Wherein：Each X, Y, R3And R4With definition as described in the present invention.
In some embodiments, X C3-7Heterocyclic radical, C3-7Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Aryl- C1-4Alkylidene, 5-10 former molecular heteroaryl or (5-10 former molecular heteroaryl)-C1-4Alkylidene, wherein described X is optionally by 1,2,3,4 or 5 R1Group is substituted；
Y is
Wherein described Y is optionally by 1,2,3,4 or 5 R2Group is substituted；
Each R1And R2It independently is H, F, Cl, Br, CN, NO2, oxo (=O) ,-C (=O) Ra,-C (=O) ORa,-C (=O) NRaRb,-OC (=O) NRaRb,-OC (=O) ORa,-N (Rc) C (=O) NRaRb,-N (Rc) C (=O) ORa,-N (Rc) C (=O) Ra,-S (=O)2NRaRb,-S (=O)2Ra,-N (Rc) S (=O)2Ra,-N (Rc)-(C1-4Alkylidene)-S (=O)2Ra, RbRaNC (= O)-C1-4Alkylidene, RbRaNC (=O) N (Rc)-C1-4Alkylidene, RaOC (=O) N (Rc)-C1-4Alkylidene, RbRaNC (=O) O- C1-4Alkylidene, RbRaNS (=O)2-C1-4Alkylidene, RaS (=O)2N(Rc)-C1-4Alkylidene, ORa, NRaRb, RaO-C1-4Alkylene Base, RbRaN-C1-4Alkylidene, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkyl, C3-8Cycloalkyl-C1-4Alkylidene, C3-7It is miscellaneous Ring group, C3-7Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5-10 former molecular heteroaryl or (5-10 former molecular heteroaryl)-C1-4Alkylidene, wherein each C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkanes Base, C3-8Cycloalkyl-C1-4Alkylidene, C3-7Heterocyclic radical, C3-7Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylene Base, 5-10 former molecular heteroaryl and (5-10 former molecular heteroaryl)-C1-4Alkylidene it is independently unsubstituted or Substituted by 1,2,3 or 4 substituent, the substituent is independently selected from F, Cl, Br, CN, ORa, NRaRb, C1-6Alkyl, RaO- C1-4Alkylidene or RbRaN-C1-4Alkylidene；
Each R3And R4It independently is H, F, CN ,-C (=O) Ra,-C (=O) ORa,-C (=O) NRaRb, RbRaNC (=O)-C1-4 Alkylidene, RbRaNC (=O) N (Rc)-C1-4Alkylidene, RaOC (=O) N (Rc)-C1-4Alkylidene, RbRaNC (=O) O-C1-4Alkylene Base, RbRaNS (=O)2-C1-4Alkylidene, RbS (=O)2N(Rc)-C1-4Alkylidene, RaO-C1-4Alkylidene, RbRaN-C1-4Alkylene Base, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkyl, C3-8Cycloalkyl-C1-4Alkylidene, C3-7Heterocyclic radical, C3-7Heterocyclic radical- C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5-10 former molecular heteroaryl or (5-10 atom composition Heteroaryl)-C1-4Alkylidene, wherein each C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkyl, C3-8Cycloalkyl-C1-4 Alkylidene, C3-7Heterocyclic radical, C3-7Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5-10 atom group Into heteroaryl and (5-10 original molecular heteroaryl)-C1-4Alkylidene is independently unsubstituted or is taken by 1,2,3 or 4 Substituted for base, the substituent is independently selected from F, Cl, Br, CN, ORa, NRaRb, C1-6Alkyl, RaO-C1-4Alkylidene or RbRaN-C1-4Alkylidene；Or R3, R4Together with the carbon atom being connected with them, 3-8 substituted or non-substituted atom is formed The carbocyclic ring or heterocycle of composition；With
Each Ra, RbAnd RcIt independently is H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-4It is sub- Alkyl, C3-6Heterocyclic radical, C3-6Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5-10 atom composition Heteroaryl or (5-10 former molecular heteroaryl)-C1-4Alkylidene, wherein each C1-6Alkyl, C2-6Alkenyl, C2-6Alkynes Base, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocyclic radical, C3-6Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Virtue Base-C1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 former molecular heteroaryl)-C1-4Alkylidene is independently Unsubstituted or substituted by 1,2,3 or 4 substituent, the substituent is independently selected from F, Cl, CN, N3, OH, NH2, C1-6Alkane Base, C1-6Haloalkyl, C1-6Alkoxy or C1-6Alkyl amino；Or Ra, RbTogether with the nitrogen-atoms being connected with them, substitution is formed Or non-substituted 3-8 former molecular heterocycle.
In other embodiments, X C3-7Heterocyclic radical or 5-10 former molecular heteroaryl, wherein the X appoints Selection of land is by 1,2,3 or 4 R1Group is substituted.
In other embodiments, each R1And R2It independently is H, F, Cl, CN, oxo (=O) ,-C (=O) ORa,-C (=O) NRaRb,-N (Rc) C (=O) NRaRb,-N (Rc) C (=O) ORa,-N (Rc) C (=O) Ra,-S (=O)2NRaRb,-N (Rc)S (=O)2Ra,-N (Rc)-(C1-4Alkylidene)-S (=O)2Ra, RbRaNC (=O)-C1-4Alkylidene, RbRaNC (=O) N (Rc)-C1-4 Alkylidene, RbRaNS (=O)2-C1-4Alkylidene, RaS (=O)2N(Rc)-C1-4Alkylidene, ORa, NRaRb, RaO-C1-4Alkylidene, RbRaN-C1-4Alkylidene, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkyl, C3-8Cycloalkyl-C1-4Alkylidene, C3-7Heterocycle Base, C3-7Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5-10 former molecular heteroaryl or (5- 10 molecular heteroaryls of original)-C1-4Alkylidene, wherein each C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-8Cycloalkyl, C3-8Cycloalkyl-C1-4Alkylidene, C3-7Heterocyclic radical, C3-7Heterocyclic radical-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 former molecular heteroaryl)-C1-4Alkylidene it is independently unsubstituted or by 1,2,3 or 4 substituent is substituted, and the substituent is independently selected from F, Cl, CN, ORa, NRaRb, C1-3Alkyl, RaO-C1-4It is sub- Alkyl or RbRaN-C1-4Alkylidene.
In other embodiments, each R3And R4It independently is H, F, CN ,-C (=O) NRaRb, RbRaNC (=O)- C1-2Alkylidene, RbRaNC (=O) N (Rc)-C1-2Alkylidene, RaOC (=O) N (Rc)-C1-2Alkylidene, RbRaNC (=O) O-C1-2 Alkylidene, RbRaNS (=O)2-C1-2Alkylidene, RbS (=O)2N(Rc)-C1-2Alkylidene, RaO-C1-2Alkylidene, RbRaN-C1-2It is sub- Alkyl, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-2Alkylidene, C3-5Heterocyclic radical, C3-5Heterocycle Base-C1-2Alkylidene, phenyl, phenyl-C1-2Alkylidene, the molecular heteroaryl of 5 originals or (5 molecular heteroaryls of original)- C1-2Alkylidene, wherein each C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-2Alkylidene, C3-5 Heterocyclic radical, C3-5Heterocyclic radical-C1-2Alkylidene, phenyl, phenyl-C1-2Alkylidene, 5 molecular heteroaryls of original and (5 atoms The heteroaryl of composition)-C1-2Alkylidene is independently unsubstituted or is substituted by 1,2,3 or 4 substituent, and the substituent is only On the spot it is selected from F, Cl, Br, CN, ORa, NRaRb, C1-6Alkyl, RaO-C1-4Alkylidene or RbRaN-C1-4Alkylidene；Or R3, R4With with The carbon atom that they are connected together, forms the former molecular carbocyclic ring of substituted or non-substituted 3-8 or heterocycle.
In other embodiments, each Ra, RbAnd RcIt independently is H, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-6 Cycloalkyl, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocyclic radical, C3-6Heterocyclic radical-C1-4Alkylidene or 5-10 original are molecular miscellaneous Aryl, wherein each C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-4Alkylidene, C3-6Heterocycle Base, C3-6Heterocyclic radical-C1-4The former molecular heteroaryl of alkylidene and 5-10 is independently unsubstituted or is taken by 1,2,3 or 4 Substituted for base, the substituent is independently selected from F, CN, N3, OH, NH2, C1-3Alkyl, C1-3Haloalkyl, C1-4Alkoxy or C1-4Alkyl amino.
In other embodiments, X is
Wherein described X is optionally by 1,2 or 3 R1Group is substituted.
In other embodiments, Y is
Wherein described Y is optionally by 1,2 or 3 R2Group is substituted.
In other embodiments, each R3And R4It independently is H, F, CN, C1-3Alkyl, C3-6Cycloalkyl, C3-5Heterocycle Base or C3-5Heterocyclic radical-C1-2Alkylidene, wherein each C1-3Alkyl, C3-6Cycloalkyl, C3-5Heterocyclic radical and C3-5Heterocyclic radical-C1-2 Alkylidene is independently unsubstituted or is substituted by 1,2,3 or 4 substituent, the substituent independently selected from F, Cl, Br, CN, ORa, NRaRb, C1-6Alkyl, RaO-C1-4Alkylidene or RbRaN-C1-4Alkylidene；Or R3, R4The carbon atom being connected with them Together, the former molecular carbocyclic ring of substituted or non-substituted 3-8 or heterocycle are formed.
In other embodiments, each R1And R2It independently is H, F, Cl, CN, oxo (=O) ,-C (=O) ORa,-C (=O) NRaRb,-N (Rc) C (=O) NRaRb,-N (Rc) C (=O) ORa,-N (Rc) C (=O) Ra,-N (Rc)-(C1-2Alkylidene)-S (=O)2Ra, RbRaNC (=O)-C1-2Alkylidene, RbRaNC (=O) N (Rc)-C1-2Alkylidene, RaS (=O)2N(Rc)-C1-2Alkylene Base, ORa, NRaRb, RaO-C1-2Alkylidene, RbRaN-C1-2Alkylidene, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-2Alkylidene, C3-5Heterocyclic radical, C3-5Heterocyclic radical-C1-2Alkylidene, phenyl, phenyl-C1-2Alkylidene, 5-6 former Molecular heteroaryl and (5-6 former molecular heteroaryl)-C1-2Alkylidene, wherein each C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-2Alkylidene, C3-5Heterocyclic radical, C3-5Heterocyclic radical-C1-2Alkylidene, phenyl, benzene Base-C1-2Alkylidene, 5-6 former molecular heteroaryl and (5-6 former molecular heteroaryl)-C1-2Alkylidene is independently not It is substituted or is substituted by 1,2,3 or 4 substituent, the substituent is independently selected from F, Cl, CN, ORa, NRaRbOr C1-3Alkane Base.
In other embodiments, the present invention relates to the compound of one of or its stereoisomer, Geometric isomer, dynamic isomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug, But it is not limited to these compounds：
On the other hand, the purposes the present invention provides above-claimed cpd in medicine preparation, wherein the medicine is used to press down Phosphatidylinositol 3-kinase (PI3- kinases) processed, including：PI3- kinases is set to be connect with a effective amount of compound disclosed in this invention Touch；In some embodiments, contact procedure can further comprise the cell of contact expression PI3- kinases；Other the one of this method In a little embodiments, inhibitory action occurs in the object for enduring one or more type PI3- kinases exception relevant diseases.This The involved one or more extremely relevant diseases of type PI3- kinases of invention include autoimmune disease, rheumatism joint Inflammation, respiratory disease, allergic reaction and various types of cancers.
In some embodiments, method of the present invention includes applying therapeutic agent to object.
In other embodiments, disease kinase mediated PI3- is selected from rheumatic arthritis, ankylosing spondylitis, bone Arthritis, psoriatic arthritis, psoriasis, diseases associated with inflammation and autoimmune disease；In other embodiments, PI3- swashs The disease of enzyme mediation is selected from angiocardiopathy, atherosclerosis, hypertension, Deep vain thrombosis, apoplexy, miocardial infarction, Unstable angina, thromboembolism, pulmonary embolism, thrombolysis disease, Acute arterial ischeamia, peripheral thrombus obstruction and coronary artery disease Disease.In other embodiments, disease kinase mediated PI3- is selected from cancer, colon cancer, glioblastoma, carcinoma of endometrium, Liver cancer, lung cancer, melanoma, kidney, thyroid cancer, lymthoma, lymphoproliferative disorder, Small Cell Lung Cancer, squamous cell lung Cancer, glioma, breast cancer, prostate cancer, oophoroma, cervical carcinoma and leukaemia.In other embodiments, PI3- kinases is situated between The disease led is selected from type ii diabetes；In other embodiments, disease kinase mediated PI3- is selected from breathing problem, branch Tracheitis, asthma and chronic obstructive pulmonary disease；In other embodiments, study subject is people.
On the other hand, the present invention relates to the treatment of PI3- kinase mediated diseases, the treatment to include any of above reality of administration The step of applying the compound of scheme.
On the other hand, the present invention relates to rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, The treatment of psoriasis, diseases associated with inflammation or autoimmune disease, the treatment include the change of any of above embodiment is administered The step of compound.
On the other hand, the present invention relates to including asthma, Chronic Obstructive Pulmonary Disease (COPD) and idiopathic pulmonary fibrosis (IPF) treatment of breathing problem, the treatment includes the compound of any of above embodiment the is administered the step of such as.
On the other hand, the present invention relates to inflammatory bowel disease, inflammatory ocular disease, inflammation or unstable bladder disease, The skin disease of inflammatory component, chronic inflammation, systemic loupus erythematosus (SLE), myasthenia gravis, acute diseminated encephalomyelitis, Idiopathic blood platelet reduction property purpura, multiple sclerosis, Sjogren syndrome and autoimmune hemolytic anemia, mistake The step for the treatment of of quick property and pleoergy, the treatment includes the compound of any of above and following embodiment is administered.
On the other hand, it is involved in the present invention to be mediated by PI3- kinase activities, swash dependent on PI3- kinase activities or with PI3- The activity of the treatment, especially PI3K δ of the relevant cancer of enzymatic activity, the treatment include any of above and following embodiment party of administration The step of compound of case.
On the other hand, the present invention relates to the treatment selected from following cancer：Acute myelogenous leukemia, spinal cord development are extremely comprehensive Simulator sickness, myeloproliferative disease, chronic myelogenous leukemia, T cell acute lymphoblastic leukemia, B cell acute lymphoblastic are white Blood disease, non-Hodgkin lymphoma, B cell lymphoma, solid tumor and breast cancer, the treatment include any of above and following reality of administration The step of applying the compound of scheme.
On the other hand, the compound the present invention relates to any of above embodiment is as the application in terms of medicine.
On the other hand, the present invention relates to any of above embodiment compound PI3- kinase mediated diseases curative The application of thing manufacture view.
On the other hand, the compound the present invention relates to any of above embodiment is preparing treatment rheumatoid arthritis, Ankylosing spondylitis, osteoarthritis, psoriatic arthritis, psoriasis, diseases associated with inflammation, including asthma, Chronic Obstructive Pulmonary Disease Disease breathing problem, autoimmune disease and the cancer such as (COPD) and idiopathic pulmonary fibrosis (IPF).
Unless otherwise stated, the present invention relates to the stereoisomer of all the compounds of this invention, geometric isomer, mutually variation Structure body, solvate, hydrate, metabolite, salt and pharmaceutically acceptable prodrug.
In some embodiments, the salt refers to pharmaceutically acceptable salt.Term " pharmaceutically acceptable " refers to Material or composition must be with other components comprising preparation and/or with the mammals of its treatment chemically and/or toxicology It is upper compatible.
The compound of the present invention further includes other salt of such compound, which is not necessarily pharmaceutically acceptable Salt, and may be used as being used to prepare and/or purify the compound of the present invention and/or the compound for separating the present invention The intermediate of enantiomer.
Pharmaceutically useful acid-addition salts can be formed with inorganic acid and organic acid, such as acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Thing/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.
The inorganic acid of salt can be obtained by its derivative to be included such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.
The organic acid of salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, butanedioic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..
Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.
The inorganic base that can obtain salt by its derivative includes, such as the metal of the I races of ammonium salt and periodic table to XII races. In some embodiments, which is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.
The organic base of salt can be obtained by its derivative includes primary amine, secondary amine and tertiary amine, the amine of substitution including naturally occurring Substituted amine, cyclic amine, deacidite etc..Some organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.
The officinal salt of the present invention can be synthesized with conventional chemical processes by parent compound, alkalescence or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate etc.) reaction, or by counting the free alkali form of these compounds and chemistry The suitable acid of amount amount is reacted to be prepared.Such reaction usually carries out in water or organic solvent or the mixture of the two.One As, in appropriate cases, it is necessary to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.In example As " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts：Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the suitable salt of other can be found in.
Moreover, the compounds of this invention including its salt can also be obtained with its hydrate forms, or it is used for it including other The solvent of crystallization.The compounds of this invention can form the solvation with acceptable solvent (including water) inherently or by designing Thing；Therefore, the invention is intended to including solvated and unsolvated form.
The compounds of this invention might have several asymmetric centers or the usually shape of described raceme mixture Formula.The present invention further includes racemic mixture, the mixture of partial racemization and isolated enantiomer and non-right Reflect body.
The compound of the present invention can be with possible isomers, rotational isomer, atropisomer, dynamic isomer A kind of form or the form of its mixture exist, and the present invention can further include isomers, rotational isomer, resistance turn isomery The mixture of body, dynamic isomer, or the part mixes of isomers, rotational isomer, atropisomer, dynamic isomer Or isomers, rotational isomer, atropisomer, the dynamic isomer separated.
Any structural formula that the present invention provides is also intended to the form and isotope mark for representing that these compounds are not labeled The form of note.The structure that the general formula that there is the compound of isotope marks the present invention to provide is described, except one or more atoms Replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention include Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, the isotope of fluorine and chlorine, such as2H,3H,11C,13C,14C,15N,18F,31P,32P,36S,37Cl and125I。
On the other hand, compound of the present invention includes the compound defined in the present invention of various isotope marks, For example, wherein there are radio isotope, such as3H,14C and18Those compounds of F, or wherein there are non radioactive isotope, Such as2H and13C.The compound of such isotope marks can be used for metabolism research (to use14C), Reaction kinetics research (use example Such as2H or3H), detection or imaging technique, are surveyed such as positron emission tomography (PET) or including medicine or substrate tissue distribution Fixed single photon emission computed tomography (SPECT), or available in the radiotherapy of patient.18The compound pair of F marks It is especially desirable for PET or SPECT researchs.Formula (I) compound of isotope marks can pass through those skilled in the art Known routine techniques or embodiment in the present invention and preparation process are described is substituted using suitable isotope labeling reagent Originally prepared by used unmarked reagent.
In addition, higher isotope particularly deuterium is (i.e.,2H or D) substitution some treatment advantages can be provided, these advantages are Brought by metabolic stability higher.For example, Half-life in vivo increase or reduction of volume requirements or therapeutic index obtain improving band Come.It should be appreciated that the deuterium in this context is seen as the substituent of formula (I) compound.Isotope enrichment factor can be used To define the concentration of such higher isotope particularly deuterium.Term " isotope enrichment factor " used in the present invention refers to meaning Determine the ratio between the isotope abundance of isotope and natural abundance.If the substituent of the compounds of this invention is designated as deuterium, The compound has at least 3500 (at each specified D-atoms 52.5% deuterium incorporation), at least for each D-atom specified 4000 (60% deuterium incorporations), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% deuterium incorporations), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporations), at least 6466.7 The isotope enrichment of (97% deuterium incorporation), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuterium incorporations) The factor.The pharmaceutically useful solvate of the present invention includes such as D that wherein recrystallisation solvent can be isotope substitution2O, acetone-d6、 Or DMSO-d6Those solvates.
The composition of the compound of the present invention, preparation and administration
On the one hand, the compound shown in formula (I), the change listed by the present invention are included the characteristics of pharmaceutical composition of the invention Compound, or the compound of embodiment 1-24, and pharmaceutically acceptable carrier, assistant agent or excipient.In the composition of the present invention The amount of compound can effectively, detectably suppress biological sample or the protein kinase of patient's body.
The compound of the present invention exists in a free form or in the form of suitable, pharmaceutically acceptable derivates.Pharmacy Upper acceptable derivates include, but is not limited to, pharmaceutically acceptable prodrug, salt, ester, esters salt, can directly or Be grounded other any adducts or derivative for being administered according to needs of patient, the present invention in terms of other described compounds or Their metabolite or residue.
As described in the invention, pharmaceutical composition of the present invention or pharmaceutically acceptable composition further wrap Containing pharmaceutically acceptable carrier, assistant agent or excipient, applied as of the invention, including be suitable for distinctive target formulation , any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickener, emulsifying agent, Preservative, solid binder or lubricant, etc..As described in documents below：Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams& Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology, Eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, document above disclose Content is incorporated in of the invention for reference with its full text.Literature cited, which describes, herein is used to prepare pharmaceutically acceptable combination Preparation method known to the different carriers and composition of thing.Except the conventional carrier matchmaker incompatible with the compound of the present invention It is situated between, such as bad biological effect can be produced or harmful phase occurs with any other component in pharmaceutically acceptable composition Interaction, other any conventional carrier mediums and their purposes are also the scope that the present invention is considered.
The pharmaceutical composition of the present invention can prepare and be packaged as form in bulk, wherein can extract out safely, effectively agent Compound or its pharmaceutically acceptable salt shown in the formula (I) of amount, can be administered to a patient in the form of powder or syrup.Or Person, pharmaceutical composition of the present invention can be prepared or be packaged in unit dosage forms, wherein, each unit dosage forms are containing shown in formula (I) Compound or its pharmaceutically acceptable salt.When being prepared into unit dosage forms, pharmaceutical composition of the invention usually contains 0.5mg To the compound or its pharmaceutically acceptable salt shown in the formula (I) of 1g or 1mg to 700mg or 5mg to 100mg.
The pharmaceutical composition of the present invention is typically containing the compound or its pharmaceutically acceptable salt shown in formula (I).
Term " pharmaceutically acceptable excipient " in the present invention refers to and gives pharmaceutical composition shape or compatibility Pharmaceutically acceptable material, composition or carrier.In mixing, every kind of excipient must be with other in pharmaceutical composition Component is compatible, so that the effect of avoiding when giving patient, substantially reducing the compounds of this invention or its pharmaceutically acceptable salt And cause the interaction of pharmaceutically unacceptable composition.In addition, every kind of excipient must all have sufficiently high purity So that it is pharmaceutically acceptable.Compound or its pharmaceutically acceptable salt shown in formula (I) and pharmaceutically acceptable Excipient or assistant agent, are usually formulated as being suitable for giving the formulation with patient by required method of administration.For example, suitable for The formulation of lower method of administration：(1) be administered orally, as tablet, capsule, caplet agent, pill, containing tablet, pulvis, syrup, elixir, Supensoid agent, solution, emulsion, sachet and sachet；(2) parenteral, as sterile solution agent, supensoid agent and for redissolution Pulvis；(3) percutaneous dosing, such as transdermal patch；(4) rectally, such as suppository；(5) inhalation, as aerosol, solution and Dry powder doses；(6) local administration, such as cream, ointment, washing lotion, solution, paste, spray, foaming agent and gelling agent.
Suitable pharmaceutically acceptable excipient will be different regarding selected specific formulation.In addition, them can be directed in group The specific function played in compound selects suitable pharmaceutically acceptable excipient.For example, it can help to give birth to according to them Produce the ability of equal one dosage type low temperature and select some pharmaceutically acceptable excipient.Them can be directed to when giving patient, contributed to The compounds of this invention or its pharmaceutically acceptable salt are carried or transported from an organ of human body or partly to the another of human body A organ or partial ability select some pharmaceutically acceptable excipient.Them, which can be directed to, strengthens the energy of patient compliance Power selects some pharmaceutically acceptable excipient.
Suitable pharmaceutically acceptable excipient includes following kind of excipient：Diluent, filler, adhesive, Disintegrant, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweetener, rectify Taste agent, odor mask, colouring agent, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilization Agent, surfactant and buffer.It would be recognized by those skilled in the art that some pharmaceutically acceptable excipient can play it is more In a kind of function, and alternative function can be played, this is depended in the formulation, and there are what in the presence of how much excipient and preparation Kind other compositions.
Those skilled in the art grasp the knowledge and technology of this area so that they can be selected for the appropriate of the present invention Amount, suitable, pharmaceutically acceptable excipient.In addition, those skilled in the art be able to can pharmaceutically connect from many descriptions The place for the excipient received obtains resource, and available for the suitable pharmaceutically acceptable excipient of selection.Such as： Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
Pharmaceutical composition of the present invention is prepared using technique well known by persons skilled in the art and method.Commonly used in the art Certain methods refer to：Remington's Pharmaceutical Sciences(Mack Publishing Company).
On the other hand, prepared the present invention relates to one kind comprising the compound shown in a formula (I) or its is pharmaceutically acceptable Salt and one or more pharmaceutically acceptable excipient containing blending ingredients pharmaceutical composition method.It is this to include The pharmaceutical composition of compound or its pharmaceutically acceptable salt shown in one formula (I) can be made under room temperature, condition of normal pressure It is standby to obtain.
In some embodiments, the compound shown in formula (I) or its pharmaceutically acceptable salt be prepared to take orally to The formulation of medicine.In other embodiments, the compound shown in formula (I) or its pharmaceutically acceptable salt are prepared to suck The formulation of administration.In other embodiments, the compound shown in formula (I) or its pharmaceutically acceptable salt are prepared to fit In the formulation of nasal-cavity administration.
On the one hand, the present invention relates to solid oral administrations formulation, such as：Tablet or capsule, it includes safely, effectively Compound or its pharmaceutically acceptable salt, diluent or filler shown in the formula (I) of dosage.Suitable diluent and filling Agent includes：(e.g., cornstarch, potato starch and pregel form sediment for lactose, sucrose, glucose, mannitol, D-sorbite, starch Powder), calcium sulfate, calcium monohydrogen phosphate.Oral dosage form can also further include adhesive.Suitable adhesive includes starch (e.g., cornstarch, potato starch and pregelatinized starch), gelatin, Arabic gum, sodium alginate, alginic acid, tragacanth, melon That glue, povidone, cellulose and their derivative (e.g., microcrystalline cellulose).Oral dosage form can also include disintegrant. Suitable disintegrant, includes crospovidone, sodium starch glycolate, cross-linked carboxymethyl cellulose, alginic acid, carboxymethyl cellulose Plain sodium.Oral solid dosage formulation, can also include lubricant.Suitable lubricant includes magnesium stearate, calcium stearate, tristearin Acid and talcum powder.
If appropriate, microencapsulation can be carried out to the dosage unit preparations of oral administration.By the way that particulate matter is coated Or be embedded in polymer, wax etc., it can extend or control the release of the pharmaceutical composition.
Compound or its pharmaceutically acceptable salt shown in formula (I) can also be with the solubilities as target medicine carrier Polymer is coupled.Suitable polymer includes：Polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide- Cascophen, polyhydroxyethylaspart or the polyoxyethylene poly-D-lysine substituted by palmitic acid residues.In addition, Compound or its pharmaceutically acceptable salt shown in formula (I) can also with a series of achievable controlled release drug administrations, can biology drop The polymer of solution is combined.Such as：Polylactic acid, polycaprolactone, multi-hydroxybutyrate, polyorthoester, polyacetals, poly- dihydropyran, The crosslinking of polybutylcyanoacrylate and hydrogel or amphiphilic block copolymer.
On the other hand, the present invention relates to liquid oral form of administration.Liquid oral dosage form, such as：Solution, syrup, Elixir, can be made in a unit, in such a given metering containing the compounds of this invention of scheduled volume or its Pharmaceutically acceptable salt.Syrup is that the compounds of this invention or its pharmaceutically acceptable salt are dissolved in suitably seasoned water It is made in solution, and elixir is made by using nontoxic alcoholic vehicle.Supensoid agent is by the compounds of this invention or its pharmacy Upper acceptable salt, which is suspended in non-toxic carrier, to be made.Can also add solubilizer and emulsifying agent such as ethoxylated isostearyl alcohol and Polyoxyethylene sorbitol ether, preservative, flavor enhancement such as peppermint oil, natural sweetener or saccharin or other artificial sweetening agents etc..
On the other hand, the present invention relates to it is a kind of can to patient carry out inhalation formulation, as dry powder doses, aerosol, Supensoid agent or liquid composite.In some embodiments, the present invention relates to can to patient carry out inhalation formulation, such as Dry powder doses.In other embodiments, the present invention relates to carry out inhalation in aerosol to patient.Pass through suction Mode contain the compounds of this invention or its pharmaceutically acceptable salt of fine powder form to the dry powder composite of pulmonary administration With one or more pharmaceutically acceptable excipient of fine powder form.To those skilled in the art, it is particularly suitable The pharmaceutically acceptable excipient used in dry powder doses includes, lactose, starch, mannitol, monose, disaccharides or polysaccharide.Point Dissipating good powder can be obtained by way of micronized and grinding.In general, size reduces (such as micronized) chemical combination The size of thing is by D50Value limits, about 1 to 10 microns (for example, being measured with laser diffractometry).
The dry powder can be administered to a patient by the inhalator (RDPI) of reservoir dry powder, which, which has, is suitable for storage Deposit (non-dosing) drug reservoir of multiple dry powder forms.RDPI generally include to measure from storage each drug dose to The equipment of medicine position.For example, the measuring equipment can include jigger, it can be moved to the second place from first position, At first position, jigger can be full of the medicine from storage, and in the second place, the drug dose measured can be by patient Suction.
Alternatively, the dry powder can be stored in capsule (e.g., gelatin or plasthetics), cartridge case or blister pack So that multidose dry powder inhaler (MDPI) uses in (blister packs).MDPI is inhalator, and wherein medicine is comprised in Containing (or carry) multiple limiting doses (or part thereof) in the multiple-unit container of medicine.When the dry powder is with blister pack In the presence of form, it includes multiple bubble-caps (blister) containing dry powder form medicament.Typically, the bubble-cap is with rule side Formula arranges, to facilitate from wherein discharging medicine.For example, the bubble-cap can usually be arranged in collar plate shape bubble-cap in a circular manner In packaging, or the bubble-cap can be elongated, such as including strip or banding.Each capsule, cartridge case or bubble-cap can be such as The compounds of this invention or its pharmaceutically acceptable salt containing 20 μ g-10mg.
Aerosol can be promoted by by the compounds of this invention or its pharmaceutically acceptable salt, being suspended or dissolved in liquefaction Prepared in agent.Suitable propellant includes halogenated hydrocarbons, hydro carbons and other liquefied gases.Representational propellant includes： Arcton 11 (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1- Difluoroethanes (HFA-152a), dichloromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, perfluorinated butane, perflenapent, butane, iso-butane and pentane.Comprising the compounds of this invention or its The aerosol of pharmaceutically acceptable salt is administered to a patient typically via quantitative pressure inhalator (MDI).These devices are these Known to field technology personnel.
Aerosol can excipient pharmaceutically acceptable containing other, being typically used together with MDI such as surface work Property agent, lubricant, cosolvent and other excipient, to improve the physical stability of preparation, improve valve performance, improve dissolving Degree improves taste.
Therefore, the present invention provides the medicinal aerosol as another aspect of the present invention, it includes chemical combination of the present invention Thing or its pharmaceutically acceptable salt and fluorocarbon, hydrogeneous chlorofluorocarbons are as propellant, optional and surfactant And/or cosolvent is combined.
According to another aspect of the present invention, the present invention provides a kind of medicinal aerosol, propellant to be selected from 1,1,1,2- tetra- Fluoroethane, 1,1,1,2,3,3,3- seven fluorine n-propane and their mixture.
The preparation of the present invention can also add suitable buffer buffering.
For sucking or being blown into the capsule and cartridge case of administration, such as gelatina, can be configured to containing the powder suitable for suction The preparation of mixture, the mixture of powders include the compounds of this invention or its pharmaceutically acceptable salt and suitable mealiness base Matter, such as lactose or starch.Each capsule and cartridge case usually contain the compounds of this invention of 20 μ g-10mg or its is pharmaceutically acceptable Salt.In addition, capsule or cartridge case can comprise only the compounds of this invention or its pharmaceutically acceptable salt and be free of other figurations Agent such as lactose.
The ratio of reactive compound of the present invention or its pharmaceutically acceptable salt in topical composition depends on institute The specific formulation prepared, ratio usually used is in the range of the weight ratio of 0.001-10%.Typically for most of doses Suitable proportion used in type is from 0.005%~1%, such as is in the range of 0.01%-0.5% in some embodiments. But ratio used in the powder in inhalant and insufflation is in the range of 0.1%-5%.
It is the unit metered dose of aerosol or " penetrating " dosage is contained 20 μ g- that the preferable dosage of aerosol, which is formulated, 10mg, the preferably approximately salt of the compounds of this invention of 20 μ g-500 μ g or its pharmaceutical acceptable.Administration can be one day one It is secondary or one day for several times, such as 2,3,4 or 8 times, administration every time is such as 1,2 or 3 unit dose.The total daily dose of aerosol is in 100 μ G-10mg, preferably in the range of 200 μ g-2000 μ g.Capsule or cartridge case are to suck or be blown into day total agent of administration release Amount and metered dose are usually twice in the dosage of aerosol.
In suspension aerosol, the granule size of particle (such as particulate) should meet with aerosol form inhalation Afterwards, whole medicines can enter lung；Therefore, particle diameter should be less than 100 microns, and preferably particle diameter is less than 20 microns, especially Be particle diameter at 1-10 microns, such as 1-5 microns, preferably particle diameter is in the range of 2-3 microns.
The formulation of the present invention can by appropriate containers by medicine and the compounds of this invention or its is pharmaceutically acceptable Salt be dispersed or dissolved in propellant and prepare, such as aided in using sonication or high-shear mixer.This was prepared Journey will carry out in the environment of control air humidity.
The chemistry of aerosol of the present invention, physical stability and acceptability pharmaceutically can be by those skilled in the art Measured using techniques well known.For example, compound, after long-term storage, stability can be analyzed by HPLC and measured. Physical stability data can be obtained by other conventional analysis test methods, for example, being commented by leak test, valve for medicine Fixed (opening the weight averagely discharged every time), dose reproducibility evaluation (opening the active principle discharged every time) and spray Distributional analysis.
The stability of the suspension aerosol of the present invention can be measured by routine techniques, for example, by measuring floccules Degree distribution, using back-illuminated light scattering apparatus or by measuring particle size distribution, by colliding step by step (cascade impaction) Or " binary collision " (twin impinger) assay." binary collision " determination method of the present invention refers to that " use device A exists In pressurizing vessel measure eject medicament precipitation ", this definition is shown in British Pharmacopoeia 1988, the A204-207 pages, annex XVII C.This technology can calculate the inhalable particle part in aerosol.One kind is used to calculate inhalable particle Method be this is using above-mentioned " binary collision " by " fine grained classification " method, open every time from collision cell collective low to Active ingredient amount, be expressed as opening the percentage of the active ingredient total amount ejected every time.
Term " metered dose inhaler " or MDI refer to a combination, include a tank, the protection cap covered in tank, a He Gai Formula metering valve on son.MDI systems include suitable transfer device.Suitable transfer device includes, and such as a valve drives Device, a cylindric or coniform passage, patient can be delivered to by this passage medicine from filling tank by metering valve Nose or face in, such as blow gun actuator.
MDI tanks generally comprise a container that can bear propellant vapour pressure, e.g., plastics or plastic-faced vial Preferably metal can, for example, aluminium pot, or aluminium alloy can, it can be by anodization, varnish application and/or plastics Coating, (for example, introducing bibliography patent WO 96/32099 herein, which part or all inner surfaces are coated with one Or multiple fluorocarbon polymers and one or more non-fluorocarbon polymers), container metering jam pot cover mouth.Lid can be by super The mode that sound wave welding, screw are fixed or crimped is fixed on tank.MDI (dose inhaler) shown in this article can pass through this area Known method is made (referenced patent WO96/32099).Preferably, it is furnished with lid on cartridge case, wherein, medication dosing valve is positioned at lid On son, the lid is crimped on cartridge case.
In some embodiments of the present invention, one layer of fluoropolymer is coated by the metallic interior surface of tank, more preferably, Coating is the mixture of fluoropolymer and non-fluorinated polymer.In other embodiments of the present invention, the metallic interior surface of tank Copolymer mixture coated with polytetrafluoroethylene (PTFE) and polyethersulfone resin.In other embodiments, table in the whole metal of tank Face is each coated with the copolymer mixture of polytetrafluoroethylene (PTFE) and polyethersulfone resin.The design of metering valve is intended to open every time and can all provide The formulation of metering, and contain a packing ring for preventing propellant from being leaked at valve.Packing ring can include any suitable bullet Property material, such as low density polyethylene (LDPE), chlorobutyl, brombutyl, ethylene propylene diene rubber, the butadiene-acrylonitrile of black or white Rubber, butyl rubber and neoprene.Suitable valve can be from purchase obtains at manufacturer known to aerosol industry, such as Valois, French (such as DF10, DF30, DF60), Bespak pic, Britain such as (BK300, BK357) and 3M-TM Neotechnic Ltd, Britain (such as Spraymiser).
In various embodiments, metered dose inhaler can also be used for being incorporated in other structures, such as, but not limited to, be used for Storage, the external packing box comprising metered dose inhaler, specifically may be referred to United States Patent (USP) US 6, and 119,853,6,179,118,6, 315,112,6,352,152,6,390,291, and 6,679,374, and the relevant patent of batching counter also has but is not limited to, United States Patent (USP) US 6,360,739 and 6,431,168.
Medicinal aerosol can be used to manufacture conventional batch production method well known to those skilled in the art and equipment to carry out The large-scale production of wound packages medicine.Thus, for example in a kind of method for producing suspension aerosol in batches, metering valve is crimped on Empty cylinder is formed on one aluminium pot.Granulated drug is fitted into filling container, and suitable excipient and liquefied propellant are passed through Filling container pressurization is filled with manufacture container.Drug suspension is mixed before filling machine circulation is entered, by aliquot Drug suspension be filled with by metering valve in cylinder.In the embodiment of other batch production Liquid Aerosols, it will measure Valve, which is crimped on an aluminium pot, forms empty cylinder.The medicine of dissolving is fitted into filling container, and by suitable excipient and liquefied Propellant is filled with manufacture container by filling container pressurization.
In process of production, the liquid preparation per equal portions is added in the container of opening at temperature cold enough, with true Protect preparation will not evaporation loss, after powder charge again by metering valve crimping to the container.
In general, in the producing by batch of medicine, the cylinder of each filling is examined, is weighed, stamps lot number, before release test It is fitted into disk and stores.Suspension and solution containing the compounds of this invention or its pharmaceutically acceptable salt can also pass through spraying Device administers to a patient.Solvent or suspension for atomization are all pharmaceutically acceptable liquid, such as water, salting liquid, alcohol or two First alcohol, such as ethanol, isopropanol, glycerine, propane diols, polyethylene glycol or their mixture.In salting liquid salt used be to There is no or has the salt of seldom pharmacological activity after medicine.Organic salt, such as alkali metal salt or ammonium halide salt, such as sodium chloride, potassium chloride Or organic salt, such as potassium, sodium and ammonium salt and organic acids such as ascorbic acid, citric acid, acetic acid, tartaric acid may be used to this mesh 's.
Other pharmaceutically acceptable excipient can also be used in suspension or solution.The compounds of this invention or its pharmaceutically The stability of acceptable salt, can be by adding inorganic acid such as hydrochloric acid, nitric acid, sulfuric acid and/or phosphoric acid；Organic acid such as Vitamin C Acid, citric acid, acetic acid, tartaric acid etc., complexometric reagent such as EDTA or citric acid and its salt, or antioxidant such as vitamin E and anti- Bad hematic acid.In the formulation, above excipient can be used alone or together can pharmaceutically be connect with stablizing the compounds of this invention or its The salt received.Preservative such as benzalkonium chloride, benzoic acid and its salt can also be added in preparation.Especially, surface-active can be added Agent is used for the physical stability for improving suspending agent.Surfactant such as, lecithin, dioctyl sulfo-succinic acid disodium, oleic acid and Sorbitan ester.
Another aspect of the present invention is related to the formulation of intranasal administration.
The formulation of intranasal administration includes giving the pressurized aerosol formulation and aqueous solution preparation of nose by force (forcing) pump.It is non-pressurised And gain a special interest suitable for the preparation of intranasal administration.For this purpose, suitable preparation is to be used as diluent or load using water Body.The conventional excipients that the liquid dosage form of preparation lung or intranasal administration uses have buffer, tension regulator etc..Aqueous solution system Agent can also be by Neulized inhalation to intranasal administration.The compounds of this invention or its pharmaceutically acceptable salt can be configured to using stream The liquid preparation of body distributor transmission administration, fluid distributor contains a distribution nozzle and aperture, when the power that user applies When being applied to the pump configuration of fluid distributor, the liquid preparation of dosing is distributed by distributing nozzle or dispensing aperture.This Kind fluid distributor is generally provided with accommodating the storage tank of multiple dosing liquid preparations, and dosage can pass through the action point of continuously pump Match somebody with somebody.Configurable distribution nozzle or aperture to be inserted into user nostril, for by liquid preparation spray distribution into nasal cavity.It is foregoing to carry And fluid distributor be the type illustrated in patent WO05/044354, entire contents are incorporated in the present invention by quoting.Should Distributor has the housing for accommodating fluid discharging apparatus, and fluid discharging apparatus, which includes, to be installed on the container for accommodating liquid preparation Force (forcing) pump.Housing have it is at least one can finger manipulation side lever, which can move inward relative to housing, with cam band Container in dynamic housing is upward, so that cause pump pressure to contract pumps out pump rod by the preparation of dosing by the nose nozzle of housing (stem).Especially preferred fluid distributor is the general type illustrated in Figure 30-40 of patent WO05/044354.
It is suitable for the pharmaceutical composition of intranasal administration, carrier therein is solid, including particle diameter is for example at 20-500 microns Corase meal；It can be administered in such a way, powder fills in a reservoir, holds close to nasal cavity, quick by nasal passage Suction.Suitable composition, aqueous solution or oil solution comprising the compounds of this invention or its pharmaceutically acceptable salt, wherein carrying Body is liquid, is administered using nasal spray or is administered as nasal drop.
It is adapted to the pharmaceutical composition of percutaneous dosing can be used with separated patch form, for close with the epidermis of patient Contact one section of longer time.For example, the discharge active component from patch can be penetrated into by ion, its common description is shown in Pharmaceutical Research,3(6),318(1986)。
Ointment, emulsion, suspension, washing lotion, pulvis, molten can also be configured to suitable for the pharmaceutical composition of local administration Liquid, paste, gelling agent, spray, aerosol or finish.Ointment, emulsion and gelling agent can use water or oleaginous base plus conjunction Suitable thickener and/or gelling agent are prepared.Matrix such as atoleine, for example poly- second of vegetable oil such as peanut oil, castor oil or solvent Glycol.Thickener and gelling agent will make choice according to the property of matrix, include paraffin, aluminum stearate, hexadecanol and octadecyl alcolol Mixture, polyethylene glycol, lanolin, beeswax, the derivative and/or glycerin monostearate of carbopol and cellulose, and/ Or nonionic emulsifier.
Lotion can use water or oleaginous base to prepare, and typically contain one or more emulsifying agents, stabilizer, disperse Agent, suspending agent or thickener.
External powder agent needs to add suitable powdered substrate, such as talcum powder, lactose or starch when preparing.Dropping liquid is matched somebody with somebody System generally uses water or non-aqueous base, additionally containing one or more dispersing agents, chaotropic agent, suspending agent or preservative.
The preparation of local application can daily to affected part in single or divided doses, use impermeable plastic wound dressing in skin affected part.Even Continuous, long-term administration can be realized by pasting drug-reservoir.
The pharmaceutical composition for treating eye or other outside organizations such as face, skin can be with local application's cream and breast The form application of agent.When being configured to ointment, the compounds of this invention or its pharmaceutically acceptable salt can use paraffin or can be with The miscible ointment bases of water.In addition, the compounds of this invention or its pharmaceutically acceptable salt can use oil-in-water or Water-In-Oil Substrate preparation into emulsion.
Pharmaceutical composition for parenteral includes water and non-aqueous sterile injection liquid, its can contain antioxidant, Buffer solution, bacteriostatic agent and solute, it causes the preparation and the isotonic and aqueous and anhydrous nothing of the blood of specified recipient Bacterium suspension can contain suspending agent and thickener.The composition can be such as close in unit dose or multi-dose container Store, and can be stored in lyophilized (freeze-drying) condition in the ampoule and medicine bottle of envelope, it only needs immediately to add before use Enter sterile liquid carrier, such as water for injection.Extemporaneous injection solutions and suspension can be by sterile powder, granula and tablet systems It is standby.
The compound and pharmaceutical composition of the present invention can be with one or more other therapeutic agents use in conjunction, the treatment Agent is selected from antiinflammatory, anticholinergic drug (particularly M1/M2/M3Receptor antagonist), β2- 3 adrenergic receptor agonists, anti-sense Stain, such as antibiotic or antivirotic or antihistamine.The present invention further provides a kind of composition, and it includes a kind of formula (I) Shown compound or its pharmaceutically acceptable salt and one or more other active therapeutic agents, the active therapeutic agent are selected from Anti-inflammatory agent, such as steroidal anti-inflammatory drugs, non-steroid anti-inflammatory drug, anticholinergic drug, β2- 3 adrenergic receptor agonists, anti-sense Stain such as antivirotic or antiseptic, or antihistamine.Another aspect of the present invention is related to some compositions, and it includes formula (I) Shown compound or its pharmaceutically acceptable salt, and β2- 3 adrenergic receptor agonists, anticholinergic drug and/or PDE-4 Inhibitor and/or antihistamine.
In some embodiments, the present invention includes a kind of safe to use, a effective amount of the compounds of this invention or its pharmacy Upper acceptable salt and one or more active therapeutic agents, the method for the disease of the disorderly mediation for the treatment of PI3K kinase activities.
Some specific compounds of the present invention have PI3K δ the selectivity better than other PI3K.Therefore, it is of the invention another On the one hand a kind of pharmaceutical composition is provided, it includes the compound or its medicine that act on shown in the formula (I) of PI3K δ of selectivity Receivable salt and other PI3K are acted on, the compound or its pharmaceutical acceptable as shown in the formula (I) of PI3K γ Salt.
On the other hand, the present invention also includes composition, and it includes one or two kinds of other therapeutic agents.
To those skilled in the art, situations below is clear, i.e.,：In appropriate circumstances, other therapeutic agents Can be the form such as alkali metal salt, ammonium salt of salt, or the salt as sour addition, or the form of prodrug, or the form of ester Such as lower alkyl esters, or the form of solvate for example optimizes activity and/stability and/or physical characteristic, as dissolubility, The hydrate of therapeutic component.Following situation is equally clear, i.e., in appropriate circumstances, active therapeutic ingredient is with optics Pure form application.
In some embodiments, the present invention provides a kind of product, it includes the chemical combination shown in formula (I) as combination preparation Thing and at least one other therapeutic agents, contained component are used to treat at the same time, respectively or successively.In other embodiments In, what is treated is disease or illness extremely relevant with PI3K.Product as combination preparation includes composition, the combination Thing contains the compound and other therapeutic agents shown in the formula (I) of the present invention in identical pharmaceutical composition, or containing independent Formula (I) of the present invention shown in compound and other therapeutic agents, such as in the form of medicine box.
In some embodiments, the present invention provides a kind of pharmaceutical composition, and it includes the compound shown in formula (I) and its His therapeutic agent.Optionally, described pharmaceutical composition can also include above-described pharmaceutically acceptable carrier.
In some embodiments, present invention additionally comprises a kind of medicine box, it contains two or more single drug regimens Thing, wherein at least one composition contain the compound shown in formula (I) of the present invention.In other embodiments, medicine box includes For storing the different utensils of the various pharmaceutical compositions, such as container, separated bottle or separated paper tinsel bag respectively. Such example is blister package.Commonly used in package troche, capsule etc..
The medicine box of the present invention, available for different formulations, such as orally and parenterally formulation, for difference Spacing of doses applies single composition, or is stepped up single composition for another kind relatively.In order to increase compliance, The medicine box of the present invention usually all contains operation instruction.
In the therapeutic alliance of the present invention, the compounds of this invention and other therapeutic agents can be by identical or different factories Family prepares or prepares.Moreover, the compounds of this invention and other therapeutic agents can be collectively incorporated into a therapeutic combination：(i) exist Before combination product is issued to doctor (such as medicine box containing the compounds of this invention and other therapeutic agents) (ii) Before administration is faced, (iii) is carried out by doctor oneself (or in the case where doctor instructs) and is carried out by patient oneself, such as is being applied successively During the compounds of this invention and other treatment.
Correspondingly, it is abnormal in treatment PI3K the present invention provides compound shown in formula (I) or its pharmaceutically acceptable salt Purposes in relevant disease or illness, medicine therein are prepared for being co-administered with other therapeutic agents.The present invention also carries The purposes of the other therapeutic agents of the extremely relevant diseases for the treatment of PI3K or illness is supplied, wherein the medicine and formula (I) compound is co-administered.
It is used for the use for treating the extremely relevant diseases of PI3K or illness present invention also offers the compound shown in formula (I) On the way, the compound wherein shown in formula (I) and other therapeutic agents are prepared to the preparation for combined administration.Present invention also offers Other therapeutic agents are used for the purposes for treating the extremely relevant diseases of PI3K or illness, wherein the other therapeutic agents and the present invention Compound shown in formula (I) is prepared to the preparation for combined administration.
Present invention also offers purposes of formula (I) compound in the extremely relevant diseases for the treatment of PI3K or illness, wherein Patient previously with other therapeutic agents treated by (such as interior when 24 is small).Present invention also offers other therapeutic agents to exist The purposes in the extremely relevant diseases of PI3K and illness is treated, wherein previously (such as interior when 24 is small) uses formula (I) to patient Shown compound is treated.Compound shown in formula (I) as unique active component or with other assistant agents or medicine It is used cooperatively, wherein assistant agent or medicine such as immunodepressant, immunomodulator or other antiinflammatories, same for treating or preventing Kind or the acute or chronic rejection of heterograft or the medicine of inflammation or autoimmune disease, or chemotherapeutant, such as Malignant cell antiproliferative.For example, the compound shown in formula (I) of the present invention is applied jointly with neural pherylarsin oxide With for example, cyclosporin A or FK506；MTOR inhibitors, such as rapamycin, 40-O- (2- ethoxys)-rapamycin, CCI779, ABT578, AP23573, TAFA-93 etc., biolimus-7 or biolimus-9, ascosin, has immunosupress The ABT-281 of activity, ASM981, cortin, endoxan, azathioprene, methotrexate, leflunomide, imidazoles are stood Guest, mycophenolic acid or its salt, mycophenolate, 15-deoxyspergualine or immunosuppressive homologues, analog or derivative Thing, pkc inhibitor etc., as described in patent WO 02/38561or WO 03/82859, embodiment compound 56 or 70, or JAK3 kinase inhibitors, such as：N- benzyl -3- benzals -1,4- dihydroxy-cyanoacetamide-alpha-cyanos-(3,4- dihydroxy) - N- benzyls cinnamamide (tyrphostin AG 490), prodigiosin 25-C (PNU156804), 4- (4 '-hydroxy benzenes Base)-amido-6,7-dimethoxy quinazoline (WHI-P131), [4- (the bromo- 4- hydroxy phenyls of 3-)-amino -6,7- dimethoxy Quinazoline] (WHI-P154), 4- (the bromo- 4'- hydroxy phenyls of 3', 5'- bis-)-amido-6,7-dimethoxy quinazoline WHI-P97, KRX-211,3- { (3R, 4R) -4- methyl -3- [methyl-(7H- pyrrolo-es [2,3-d] pyrimidine-4-yl)-amino]-piperidines -1- Base } -3- oxo-propionitriles, the form presence of free form or pharmaceutically acceptable salt, such as list citric acid (also referred to as CP-690, 550), or the compound in patent WO 04/052359 or WO 05/066156, immunodepressant monoclonal antibody, leucocyte by The monoclonal antibody of body, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or their ligand, and other immunomodulatory compounds, have CTLA4 extracellular domains or its mutant at least The restructuring binding molecule of a part, for example, the CTLA4lg (such as referred to as ATCC 68629) that be connected with non-CTLA4 protein sequences or Its variation (for example, LEA29Y) or other adhesion molecule inhibitors such as LFA-1 antagonists ICAM-1 or -3 antagonists, VCAM-4 are short of money Anti-agent or VLA-4 antagonists or antihistamine, or pectoral, bronchodilator, angiotensin receptor blocker or anti-sense Stain.
Compound shown in formula (I) of the present invention and other immunodepressant/immunomodulators, antiinflammatory, chemotherapeutant Or anti-infective co-administration, wherein immunodepressant/immunomodulator, antiinflammatory, chemotherapeutant or anti-infective are common The dosage of medication depends on the type of drug combination, is steroid compound or calcineurin inhibitors, and be used for The specific medicine for the treatment of and treatment etc..
In one embodiment, the present invention includes containing formula (I) compound or its pharmaceutically acceptable salt, and β2- kidney The combination of upper parathyrine receptor stimulating agent.
β2The example of-adrenoceptor agonists includes salmeterol (salmeterol), and (it can be racemic chemical combination Thing or single enantiomter, such as R- enantiomters), salbutamol (salbutamol) (its can be racemic compound or Single enantiomter, such as R- enantiomters), (it can be racemic compound or single to Formoterol (formoterol) Diastereoisomer, such as R, R- diastereoisomers), salmefamol (salmefamol), fenoterol (fenoterol), card Mo Teluo (carmoterol), Yi Tanteluo (etanterol), naminterol (naminterol), Clenbuterol (clenbuterol), pirbuterol (pirbuterol), Flerobuterol (flerbuterol), Reproterol (reproterol), bambuterol (bambuterol), datro (indacaterol), Terbutaline (terbutaline) And their salt, such as the xinafoate (1- hydroxy-2-naphthoic acids salt) of salmeterol, the sulfate of salbutamol or free The fumarate of alkali or Formoterol.In some embodiments, long-acting beta2- adrenoceptor agonists, for example, carrying For effective bronchiectasis up to 12 when small or the longer time compound, be preferable.
β2- adrenoceptor agonists can be with the form of pharmaceutically acceptable sour forming salt.It is described pharmaceutically The acid of receiving is selected from sulfuric acid, hydrochloric acid, fumaric acid, carbonaphthoic acid (such as 1- or 3- hydroxy-2-naphthoic acids), cinnamic acid, the meat of substitution Cinnamic acid, triphenylacetic acid, sulfamic acid, p-aminobenzene sulfonic acid, 3- (1- naphthyls) acrylic acid, benzoic acid, 4- methoxy benzoic acids, 2- or 4-HBA, 4- chlorobenzoic acids and 4- Phenylbenzoic acids.
Suitable antiinflammatory includes corticosteroid.Available for formula (I) compound or its pharmaceutically acceptable salt group The suitable corticosteroid closed is those oral and suction corticosteroids, and its has the prodrug of anti-inflammatory activity.Example Including methylprednisolone, prednisolone (prednisolone), dexamethasone (dexamethasone), fluticasone propionate (fluticasone propionate), -17 α of -16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-[(4- methyl-1,3-thiazoles - 5- carbonyls) epoxide] -3- oxo-androst-Isosorbide-5-Nitrae-diene -17 β-thiocarboxylic acid S- fluorine methyl esters, 6 α, 9 α-two fluoro- 17 α-[(2- furans Mutter carbonyl) epoxide]-16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of-11 beta-hydroxy-thiocarboxylic acid S- fluorine methyl esters (furancarboxylic acids Fluticasone), 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-- 17 α of methyl-3- oxos-propionyloxy-androsta-Isosorbide-5-Nitrae-β of diene-17- Thiocarboxylic acid S- (2- oXo-tetrahydro furans -3S- bases) ester, 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--17 α of methyl -3- oxos - (2,2,3,3- tetramethyls cyclopropyl carbonyl) epoxide--17 β of androstane -1,4- diene-thiocarboxylic acid S- cyano methyl esters and 6 α, 9 α-two Fluoro- -17 α of -16 Alpha-Methyl of 11 beta-hydroxy--17 β of (1- ethyls cyclopropyl carbonyl) epoxide -3- oxo-androst -1,4- diene-thio Carboxylic acid S- methyl fluoride esters, beclomethasone ester (such as 17- propionic esters or 17,21- dipropionic acid fat), budesonide (budesonide), Flunisolide (flunisolide), Mometasone ester (such as momestasone furoate), Triamcinolone acetonide (triamcinolone Acetonide), sieve fluoronaphthalene moral (rofleponide), ([[(R)-cyclohexyl is sub- by 16 α, 17- for ciclesonide (ciclesonide) Methyl] double (epoxides)] -11 β, 21- dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene -3,20- diketone), butixocort propionate (butixocort Propionate), RPR-106541 and ST-126.Preferable corticosteroid includes fluticasone propionate (fluticasone Propionate), 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha-methyl-17-alpha-[(4- methyl isophthalic acids, 3- thiazole -5- carbonyls) epoxide] - 3- oxo-androst-Isosorbide-5-Nitrae-diene -17 β-thiocarboxylic acid S- methyl fluoride esters, fluoro- 17 α of 6 α, 9 α-two-[(2- furanylcarbonyls) oxygen Base]-16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of-11 beta-hydroxy-thiocarboxylic acid S- methyl fluoride esters, 6 α, 9 α-two are fluoro- - 17 α of -16 Alpha-Methyl -3- oxos of 11 beta-hydroxy-(2,2,3,3- tetramethyls cyclopropyl carbonyl) epoxide-androstane -1,4- diene -17 - 17 α of β-thiocarboxylic acid S- cyano methyl esters and -16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-(1- methylcyclopropyl groups carbonyl) oxygen - 17 β of base -3- oxo-androst -1,4- diene-thiocarboxylic acid S- fluorine methyl esters.In some embodiments, corticosteroid is 6 α, - 16-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of fluoro- 17 α of 9 α-two-[(2- furanylcarbonyls) epoxide]-11 beta-hydroxy-sulphur For carboxylic acid S- methyl fluoride esters.
Transcription inhibition is swashed with selectivity (compared with transcriptional activation), available for therapeutic alliance with glucocorticoid Moving the nonsteroidal compound of activity includes those compounds covereding in following patent：WO03/082827、WO98/ 54159、WO04/005229、WO04/009017、WO04/018429、WO03/104195、WO03/082787、WO03/ 082280、WO03/059899、WO03/101932、WO02/02565、WO01/16128、WO00/66590、WO03/086294、 WO04/026248, WO03/061651 and WO03/08277.More nonsteroidal compounds are in WO2006/000401, WO2006/ It is included in 000398 and WO2006/015870.
The example of antiinflammatory includes nonsteroidal anti-inflammatory drug (NSAID's).
The example of NSAID's includes nasmil, sodium nedocromil (nedocromil sodium), phosphodiesterase (PDE) inhibitor (such as theophylline, PDE4 inhibitor, or mixed type PDE3/PDE4 inhibitor), leukotriene antagonist, leukotriene close Into inhibitor (such as montelukast), iNOS inhibitor, trypsase and elastatinal, Beta 2 integrin antagonist With adenosine receptor agonist or antagonist (e.g., adenosine 2a receptor stimulating agents), (such as chemokine receptors is short of money for cytokine antagonist Anti-agent, including CCR3 antagonists), cytokine synthesis inhibitor, or 5-LO inhibitor.Wherein, iNOS (inductivities one Nitric oxide synthase) inhibitor is preferably administered orally.The example of iNOS inhibitor includes those in WO93/13055, WO98/ 30537th, the compound disclosed in WO02/50021, WO95/34534 and WO99/62875.CCR3 inhibitor include those Compound disclosed in WO02/26722.
In one embodiment, offer formula (I) compound of the present invention is in the group with phosphodiesterase 4 (PDE4) inhibitor Application in conjunction, the especially application in the case where being suitable for sucking preparation.PDE4 specificity for this aspect of the present invention Inhibitor can be known suppression PDE4 enzymes or be found any compound as PDE4 inhibitor, they are only PDE4 Inhibitor, is not to suppress other members in PDE families, such as the compound of PDE3 and PDE5.Compound include cis -4- cyano group - 4- (3- cyclopentyloxy -4- methoxyphenyls) hexamethylene -1- carboxylic acids, 2- carbomethoxy -4- cyano group -4- (3- cyclo propyl methoxies - 4- difluoro-methoxies phenyl) hexamethylene -1- ketone and cis-[4- cyano group -4- (3- cyclo propyl methoxy -4- difluoromethoxy phenyls Base) hexamethylene -1- alcohol]；Also cis -4- cyano group -4- [3- (ring propoxyl group) -4- methoxyphenyls] hexamethylene -1- carboxylic acids are included (also referred to as Xi Luosi) and its salt, ester, prodrug or physical form, its in 09 month 1996 No. 03 United States Patent (USP) US 5 authorized, Disclosed in 552,438, this patent and its disclosed compound are by quoting and being integrally incorporated in the present invention.
The example of anticholinergic is compounds that those are used as muscarinic receptor antagonist, particularly those as M1 or M3 receptor antagonists, M1/M3Or M2/M3Receptor dual antagonist or M1/M2/M3The compound of the general antagonist of acceptor.Inhalation Example compound include ipratropium (for example, as bromide, CAS 22254-24-6,For Trade name is sold), oxygen support ammonium (for example, as bromide, CAS 30286-75-0) and tiotropium (for example, as bromide, CAS 136310-93-5,Sold for trade name)；Be also interested in also have Revatropate (for example, As hydrobromate, CAS 262586-79-8) and LAS-34273 disclosed in WO01/04118.What is be administered orally is instantiating Compound includes pirenzepine (CAS 28797-61-7), darifenacin (CAS133099-04-4, or its hydrobromate CAS 133099-07-7, sells by trade name of Enablex), oxybutynin (CAS 5633-20-5, Sold for trade name), terodiline (CAS 15793-40-5), Tolterodine (CAS 124937-51-5, or its tartrate CAS 124937-52-6,Sold for trade name), Austria is for ammonium (for example, as bromide, CAS26095- 59-0, withSold for trade name), trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478- 37-1, or its succinate CAS 242478-38-2, i.e. compound YM-905,Sold for trade name Sell).
In some embodiments, the present invention provides one kind to include formula (I) compound or its pharmaceutically acceptable salt, with The combination of H1 antagonists.The example of H1 antagonists includes, but not limited to Amlexanox (amelexanox), this western imidazoles (astemizole), azatadine (azatadine), azelastine (azelastine), Acrivastine (acrivastine), Brompheniramine (brompheniramine), cetirizine (cetirizine), levocetirizine (levocetirizine), second Fluorine profit piperazine (efletirizine), chloropheniramine (chlorpheniramine), clemastine (clemastine), marezine (cyclizine), Carebastine (carebastine), cyproheptadine (cyproheptadine), carbinoxamine (carbinoxamine), descarboethoxyloratadine (descarboethoxyloratadine), doxylamine (doxylamine), diformazan indenes (dimethindene), Ebastine (ebastine), epinastine (epinastine), second Fluorine profit piperazine (efletirizine), fexofenadine (fexofenadine), hydroxyzine (hydroxyzine), Ketotifen (ketotifen), Loratadine (loratadine), levocabastine (levocabastine), Mizolastine (mizolastine), mequitazine (mequitazine), Mianserin (mianserin), the primary sting of promise (noberastine), meclizine (meclizine), Tecastemizole (norastemizole), olopatadine (olopatadine), piperacetazine (picumast), it is more special than Lamine (pyrilamine), phenergan (promethazine) Fei Nading (terfenadine), Tripelennamine (tripelennamine), temelastine (temelastine), nedeltran (trimeprazine) and triprolidine (triprolidine), preferred cetirizine (cetirizine), levocetirizine (levocetirizine), Efletirizine (efletirizine) and fexofenadine (fexofenadine).At another In embodiment, the present invention provides one kind to include formula (I) compound or its pharmaceutically acceptable salt, with H3 antagonists (and/ Or inverse agonist) combination.The example of H3 antagonists includes those disclosed in WO2004/035556 and WO2006/045416 Compound.Available for the present invention compound combination other histamine receptor antagonists include H4 receptor antagonists (and/or Inverse agonist), such as in Jablonowski et al., J.Med.Chem.46:Chemical combination disclosed in 3957-3960 (2003) Thing.
Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with The combination of PDE-4 inhibitor.
Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with β2- The combination of adrenoceptor agonists.
Therefore, on the other hand, the present invention, which provides one kind, includes the compound or its pharmaceutically acceptable salt of formula (I), with The combination of corticosteroid.
Therefore, on the other hand, the present invention provides one kind to include the compound or its pharmaceutically acceptable salt of formula (I), With the combination of nonsteroidal GR activators.
Therefore, on the other hand, the present invention provides one kind to include the compound or its pharmaceutically acceptable salt of formula (I), With the combination of anticholinergic drug.
Therefore, on the other hand, the present invention provides one kind to include the compound or its pharmaceutically acceptable salt of formula (I), With antihistaminic combination.
Therefore, on the other hand, the present invention provides one kind to include the compound or its pharmaceutically acceptable salt of formula (I), With PDE4 inhibitor and β2The combination of-adrenoceptor agonists.
Therefore, on the other hand, the present invention provides one kind to include the compound or its pharmaceutically acceptable salt of formula (I), With the combination of anticholinergic drug and PDE-4 inhibitor.
Combination of the above can easily be prepared into pharmaceutical composition to use, therefore, including defined above group Close and represent another aspect of the present invention with the pharmaceutical composition of pharmaceutically acceptable diluent or carrier.
Single compounds of these combinations can give with alone or in combination pharmaceutical dosage form order of administration or at the same time Medicine.In some embodiments, single compound component is administered simultaneously with the pharmaceutical dosage form of combination.Known treatment agent Suitable dosage be easy to be understood by the person skilled in the art.
Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with it The pharmaceutical composition of his therapeutically active agent combination.
Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with The pharmaceutical composition of PDE4 inhibitor combination.
Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with β 2- The pharmaceutical composition of adrenoceptor agonists combination.
Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with skin The pharmaceutical composition of matter steroid combination.
Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, and non- The pharmaceutical composition of steroid GR agonist combinations.
Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with resisting The pharmaceutical composition of cholinergic agent combination.
Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with resisting The pharmaceutical composition of histamine drug combination.
Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with PDE4 inhibitor and the pharmaceutical composition of beta-2-adrenoreceptor agonists combination.
Therefore, on the other hand, the present invention, which provides one kind, includes formula (I) compound or its pharmaceutically acceptable salt, with resisting Cholinergic agent and the pharmaceutical composition of PDE4 inhibitor combination.
Formula (I) compound can also be advantageously utilised in the combination with other compounds, or and other therapeutic agents, it is especially anti- In the combination of multiplication agent.Such antiproliferative includes, but not limited to aromatase inhibitor；Antiestrogenic；Topoisomerase I Inhibitor；Topoisomerase II inhibitors；Microtubule active agent；Alkylating agent；Histon deacetylase (HDAC) inhibitor；Inducing cell point The compound of change process；Cyclooxygenase-2 inhibitors；MMP inhibitor；MTOR inhibitors；Antitumor antimetabolite；Platinum compounds；Target To/reduce the compound of albumen or lipid kinase activity and the compound of other anti-angiogenesis；Targeting, reduce or suppress albumen Or the compound of lipid phosphate esterase active；Gonadorelin excitomotor；Antiandrogen；Methionine aminopeptidase inhibitor；Double phosphines Hydrochlorate；Biological response modifiers；Antiproliferation antibodies；Heparanase inhibitors；The carcinogenic hypotype inhibitor of Ras；Telomerase suppresses Agent；Proteasome inhibitor；Treat the medicament of neoplastic hematologic disorder；Targeting, the compound for reducing or suppressing Flt-3 activity；Hsp90 presses down Preparation；TemozolomideAnd Calciumlevofolinate.
Term used herein " aromatase inhibitor ", refers to the compound inhibited estrogen production, that is, it is male to suppress substrate Alkene diketone and testosterone change into the compound of oestrone and estradiol respectively.The term includes, but are not limited to：Steroid, especially It is atamestane (atamestane), Exemestane (exemestane) and formestane (formestane)；And particularly Non-steroids, especially aminoglutethimide (aminoglutethimide), Rogletimide (roglethimide), pyrrole Rumi Special (pyridoglutethimide), Trilostane (trilostane), Testolactone (testolactone), ketoconazole (ketoconazole), fluorine chlorazol (vorozole), Fadrozole (fadrozole), Anastrozole (anastrozole) and come it is bent Azoles (letrozole).Exemestane can be with commercially available, if trade mark is the form administration of Arnold new (AROMASIN).Formestane (formestane) can be with commercially available, if trade mark is the form administration of Lentaron (LENTARON).Fadrozole (fadrozole) Can be with commercially available, the form if trade mark is AFEMA is administered.Anastrozole (anastrozole) can be with commercially available, such as trade mark It is administered for the form of Arimidex (ARIMIDEX).Letrozole (letrozole) can be with commercially available, if trade mark is fluon (FEMARA) or FEMAR form administration.Aminoglutethimide (aminoglutethimide) can be with commercially available, if trade mark is Austria The form administration of U.S. fixed (ORIMETEN).The present invention include aromatase inhibitor chemotherapeutic combination be particularly useful for the treatment of hormone by The tumour that body is positive, such as tumor of breast.
Term used herein " antiestrogenic ", refers to the compound in Estrogen Receptor antagonising oestrogen effectiveness. The term includes, but not limited to tamoxifen (tamoxifen), fulvestrant (fulvestrant), Raloxifene (raloxifene) and raloxifene hydrochloride (raloxifene hydrochloride).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 or commercially available with United States Patent (USP) US 4, the formulation disclosed in 659,516, as trade mark is The form administration of FASLODEX.Combination of the present invention including antiestrogenic chemotherapeutic is particularly useful for the treatment of estrogen receptor and is positive Tumour, such as tumor of breast.
Term used herein " antiandrogen " refers to any material that can suppress male sex hormone biological action, it is wrapped Include, but be not limited to, Bicalutamide (bicalutamide, trade name CASODEX), its formulation can according to United States Patent (USP) US 4, 636,505 prepare.
Term used herein " Gonadorelin excitomotor " includes, but not limited to abarelix (abarelix), Ge She Rayleigh (goserelin) and goserelin acetate.Goserelin is disclosed in United States Patent (USP) US 4,100,274, can be with city Sell, if trade mark is the form administration of Zoladex (ZOLADEX).Abarelix (abarelix) can be according to United States Patent (USP) US Method disclosed in 5,843,901 prepares formulation.
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- nitros Camptothecine (9-nitrocamptothecin) and macromolecular camptothecin conjugated compound PNU-166148 are (in WO 99/17804 Compound A1).Irinotecan can be with commercially available, if trade mark is the form administration of Cape Extension (CAMPTOSAR).Topotecan can With with commercially available, as trade mark is and the form administration of U.S. new (HYCAMTIN).
Term used herein " Topoisomerase II inhibitors " includes, but are not limited to anthracycline compound, such as how soft ratio Star (doxorubicin), its Lipidosome, the triumphant Lay of trade name (CAELYX)；Daunomycin (daunorubicin)；Table It is soft than star (epirubicin)；Idarubicin (idarubicin)；The not soft pyrrole star (nemorubicin) of naphthalene；Anthraquinones rice support anthracene Quinone (mitoxantrone) and Losoxantrone (losoxantrone)；Podophillotoxines etoposide (etoposide) and for Buddhist nun Moor glycosides (teniposide).Etoposide can be with commercially available, if trade mark is the form administration of Etopophos (ETOPOPHOS).Replace Buddhist nun moors glycosides can be with commercially available, and the form if trade mark is VM 26-BRISTOL is administered.Doxorubicin can be with commercially available, such as business It is designated as the form administration of adriamycin (ADRIBLASTIN) or adriamycin (ADRIAMYCIN).Epirubicin can be with city Sell, if trade mark is the form administration of Pharmorubicin RD (PHARMORUBICIN).Idarubicin can be with commercially available, as trade mark does good Only it is administered up to the form of (ZAVEDOS).Mitoxantrone can be with commercially available, such as the form that trade mark is can destroy tumors (NOVANTRON) Administration.
Term " microtubule active agent " refers to microtubule stabilizer, microwave destabiliser and microtubule polymerization inhibitor.It includes, but not It is limited to taxanes, such as taxol (paclitaxel) and Docetaxel (docetaxel)；Vinca alkaloids, such as Changchun Alkali (vinblastine), especially vinblastine sulfate, especially vincristine, vincristine sulphate and vinorelbine (vinorelbine)；discodermolides；Colchicin；And Epothilones and its derivative, such as epothilone B or D Or derivatives thereof.Taxol can be with commercially available, if trade mark is the form administration of taxol (TAXOL).Docetaxel can be with It is commercially available, if trade mark is that safe Supreme Being is plain (TAXOTERE).Vinblastine sulfate can be with commercially available, if trade mark is VINBLASTIN R.P. form administration.Vincristine sulphate can be with commercially available, and the form if trade mark is FARMISTIN is administered. Discodermolide can be obtained according to the method disclosed in United States Patent (USP) US 5,010,099.It is additionally included in WO 98/ 10121st, United States Patent (USP) US 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653,98/22461 and of WO Epothilones analog derivative disclosed in WO 00/31247, particularly preferred ebomycin A and/or B.
Term used herein " alkylating agent " includes, but not limited to endoxan (cyclophosphamide), different ring phosphorus Acid amides (ifosfamide), melphalan (melphalan) or Nitrosourea (nitrosourea, such as BCNU or carmustine).Ring phosphinylidyne Amine can be with commercially available, if trade mark is the form administration of cyclophosphamide (CYCLOSTIN).Ifosfamide can be with commercially available, such as Trade mark is administered for the form of Holoxan (HOLOXAN).
Term " histon deacetylase (HDAC) inhibitor " or " hdac inhibitor " refer to inhibition of histone deacetylase, and Compound with antiproliferative activity.It is included in the compound disclosed in WO 02/22577, especially N- hydroxyls -3- [4- [[(2- ethoxys) [2- (1H- indol-3-yls) ethyl]-amino] methyl] phenyl] -2E-2- acrylamides, N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- bases)-ethyl]-amino] methyl] phenyl] -2E-2- acrylamides and its it can pharmaceutically connect The salt received.Especially include Vorinostat (SAHA).
Term " antitumor antimetabolite " includes, but not limited to 5-fluor-uracil (5-fluorouracil) or 5-FU； Capecitabine (capecitabine)；Gemcitabine (gemcitabine)；DNA demethylation reagents, such as U-18496 (5- ) and Decitabine (decitabine) azacytidine；Methotrexate (MTX) (methotrexate) and Edatrexate (edatrexate)；And antifol, such as pemetrexed (pemetrexed).Capecitabine can be with commercially available, such as business It is designated as the form administration of Xeloda (XELODA).Gemcitabine can be with commercially available, such as the form that trade mark is gemzar (GEMZAR) Administration.This term further includes monoclonal antibody Herceptin (trastuzumab), can be with commercially available, if trade mark is He Sai The form administration in spit of fland (HERCEPTIN).
Term used herein " platinum compounds " includes, but are not limited to carboplatin (carboplatin), cDDP (cis- Platin), cis-platinum (cisplatinum) and oxaliplatin (oxaliplatin).Carboplatin can be with commercially available, as trade mark isForm administration.Oxaliplatin can be with commercially available, and the form if trade mark is Le Satin (ELOXATIN) is given Medicine.
Term used herein " the change of targeting/reduction albumen or lipid kinase activity or albumen or lipid phosphatase activity Compound, or the compound of other anti-angiogenesis " include, but not limited to protein tyrosine kinase and/or serine and/or Threonine inhibitor, or lipid kinase inhibitors, such as
A) target, reduce or suppress the compound of platelet derived growth factor receptor (PDGFR) activity；Targeting, reduce Or suppress the compound of PDGFR activity, especially suppressing the compound of pdgf receptor includes N- phenyl-2-pyrimidine-amine derivatives, Such as Imatinib (imatinib), SU101, SU6668, GFB-111 etc.；
B) targeting, reduction or the compound for suppressing fibroblast growth factor acceptor (FGFR) activity；
C) targeting, reduction or the compound for suppressing insulin-like growth factor receptor -1 (IGF-1R) activity；Targeting, reduce Or suppress the compound of IGF-1R activity, especially suppressing the compound of IGF-1 receptor actives includes those in patent WO 02/ Compound disclosed in 092599；
D) targeting, reduction or the compound for suppressing Trk receptor tyrosine kinase family actives；
E) targeting, reduction or the compound for suppressing Axl Receptor Tyrosine Kinase family active；
F) targeting, reduction or the compound for suppressing c-Met receptor actives；
G) targeting, reduction or the compound for suppressing Kit/SCFR receptor tyrosine kinase activities；
H) targeting, reduction or the chemical combination for suppressing C-kit receptor tyrosine kinases (part in PDGFR families) activity Thing；Targeting, the compound for reducing or suppressing C-kit receptor tyrosine kinase family actives, especially suppress the change of c-Kit acceptors Compound, including Imatinib (imatinib) etc.；
I) target, reduce or suppress c-Abl families and their gene fusion products, such as the change of BCR-Abl kinase activities Compound；Targeting, the compound for reducing or suppressing c-Abl family members and their Gene Fusion things include N- phenyl -2- pyrimidines - Amine derivative, such as Imatinib, PD180970, AG957, NSC 680410, the PD173955 from ParkeDavis
J) target, Raf family members in reduction or suppression protein kinase C (PKC) and serine/threonine kinases, MEK, SRC, JAK, FAK, PDK and Ras/MAPK family member, Pl (3) kinase families member, or Pl (3) kinases associated kinase family into 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 Further 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, such as in WO 00/09495 those disclosed；FTIs；PD184352；A kind of or QAN697 (P13K suppressions Preparation)；
K) targeting, reduction or the compound for suppressing protein tyrosine kinase inhibitor activity；Targeting, reduce or suppress The compound of protein tyrosine kinase inhibitor activity includes Gleevec (GLEEVEC) or tyrosine phosphorylation presses down Preparation；Preferred low molecular weight (the Mr of tyrphostin<1500) compound, or its pharmaceutically acceptable salt, especially Compound selected from the third two eyeball class of two eyeball class of benzyl allyl or S- aryl sheet or Double bottom thing quinolines, is further selected from tyrosine phosphorus Acidification inhibitors A23/RG-50810, AG 99, tyrphostin AG 213, tyrphostin AG 1748, tyrphostin AG 490, tyrphostin B44, tyrphostin B44 (+) Enantiomer, tyrphostin AG 555, AG 494, tyrphostin AG 556, AG957 and Adaphostin (4- { [(2,5- dihydroxy phenyls) methyl] amino }-benzoic acid Buddha's warrior attendant alkyl ester, NSC 680410, adaphostin)；With
I) target, reduce or suppress receptor tyrosine kinase epidermal growth factor receptor family (EGFR, ErbB2, The equal or heterodimer of ErbB3, ErbB4) activity compound；Targeting, reduce or suppress Epidermal Growth Factor Receptor Family Compound refer in particular to suppress EGF receptor family member (such as EGF receptor, ErbB2, ErbB3, ErbB4, or can with EGF or The material that EGF associated ligands combine) compound, albumen or antibody, is particularly summarized in the following documents or it is specific openly Compound, albumen or monoclonal antibody：WO 97/02266 (such as embodiment 39), EP 0564409, WO 99/03854, EP 0520722、EP 0566226、EP 0787722、EP 0837063、US5,747,498、WO 98/10767、WO 97/30034、 WO 97/49688 and WO 97/38983, WO 96/30347 (such as CP 358774), (such as compound ZD of WO 96/33980 1839), WO 95/03283 (such as compound ZM105180), Herceptin (Trastuzumab), Cetuximab, Iressa, special sieve It is triumphant, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, E7.6.3, and the 7H- pyrrolo-es being disclosed in WO 03/013541-[2,3-d] pyrimidine derivatives.
In addition, anti-angiogenic compounds include having other active mechanisms (for example, with albumen or lipid kinase suppressing not It is related) compound, such as Thalidomide (THALOMID) and TNP-470.
Targeting, reduction or the compound of suppression albumen or lipid kinase activity are the inhibitor of phosphatase -1, and phosphatase 2A presses down Preparation, PTEN inhibitor or CDC25 inhibitor, such as okadaic acid or derivatives thereof.
The compound of Cell differentiation inducing activity process is vitamin A acid, α-, γ-or Delta-Tocopherol, α-, γ-or δ-fertility triolefin Phenol.
Term used herein " cyclooxygenase-2 inhibitors " includes, but not limited to Cox-2 inhibitor, and 5- is alkyl-substituted 2- fragrant aminos phenylacetic acid and its derivative, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, is examined with cutting down Former times, or 5- alkyl -2- fragrant amino phenylacetic acids, such as 5- methyl -2- (the chloro- 6'- fluoroanilinos of 2'-) phenylacetic acids or Lu meter Kao former times
Term used herein " diphosphonate " includes, but not limited to Etidronic Acid, Clodronate, Tiludronic Acid, pa rice phosphine Acid, alendronic acid, ibandronic acid, Risedronic Acid and zoledronic acid.Etidronic Acid can with commercially available, as trade name Supreme Being sieve how (DIDRONEL) form administration.Clodronate can be with commercially available, as the form of trade name Bonefos (BONEFOS) is administered.Replace Shandong phosphonic acids can be with commercially available, as the form of trade name SKELID is administered；Pamidronic acid (Pamidronic acid) can be with It is commercially available, such as trade name Aredia (AREDIATM) form administration；Alendronic acid can be with commercially available, such as trade name good fortune The form administration of kind U.S. (FOSAMAX)；Ibandronic acid can be with commercially available, such as the shape of trade name Bang Luoli (BONDRANAT) Formula is administered；Risedronic Acid can be with commercially available, as the form of trade name ANTU good (ACTONEL) is administered；Zoledronic acid can be with With commercially available, such as the form administration in trade name pool safe (ZOMETA).
Term " mTOR inhibitors " refers to suppress mammal rapamycin (mTOR) target protein have antiproliferative activity Compound, such as sirolimus (sirolimus,), everolimus (CerticanTM), CCI-779 and ABT578.
Term used herein " heparanase inhibitors " refers to, targets, reduces or suppress acetylsulfuric acid depolymerized heparin Compound.This term includes, but unlimited PI-88.
Term used herein " biological response modifiers " refers to lymphokine or interferon, such as interferon gamma.
Term used herein " the carcinogenic hypotypes of Ras (such as H-Ras, K-Ras or N-Ras) inhibitor " refers to target, reduces Or suppress the compound of Ras carcinogenic activities, such as " farnesyl transferase inhibitor ", such as L-744832, DK8G557 or R115777(Zarnestra)。
Term used herein " telomerase inhibitor " refers to the compound targeted, lowered or inhibited telomerase activity.Target Refer in particular to suppress the compound of telornerase receptor, such as telomere mycin to, the compound that reduces or suppress telomerase activation.
Term used herein " methionine aminopeptidase inhibitor " refers to target, reduce or suppress methionine aminopeptidase activity Compound.Targeting, the compound for reducing or suppressing methionine aminopeptidase activity include bengamide or derivatives thereof.
Term used herein " proteasome inhibitor " refers to target, reduces or the chemical combination of protease inhibition body activity Thing.The compound of targeting, reduction or protease inhibition body activity includes PS-341 and MLN 341.
Term used herein " Matrix Metalloproteinase Inhibitors " or " MMP inhibitor " include, but not limited to glue Former albumen peptides and non-peptide inhibitor, tetracycline derivant, such as hydroxamic acid peptide inhibitor Batimastat (batimastat) With its equivalent homologue Marimastat (marimastat, BB-2516) of oral bio, prinomastat (prinomastat, AG3340), Mei Tasita (metastat, NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996。
Term used herein " reagent for being used for treating neoplastic hematologic disorder " includes, but not limited to FMS- sample tyrosine kinase Inhibitor.Targeting, the compound for reducing or suppressing FMS- samples tyrosine kinase receptor (Flt-3R) activity；Interferon, 1-b-D- Arabinofuranosyl adenin cytimidine (ara-c) and bisulfan；With ALK inhibitor, such as targeting, reduce or suppress anaplastic lymphoma kinase Compound.
Targeting, reduce or suppress FMS- samples tyrosine kinase receptor (Flt-3R) compound especially suppress Flt-3 by The compound of body kinase families member, albumen or antibody, such as PKC412, midostaurin (midostaurin), staurosporin Derivative, SU11248 and MLN518.
Term used herein " HSP90 inhibitor " includes, but are not limited to target, reduce or suppress the endogenous of HSP90 The compound of atpase activity；The chemical combination degraded by ubiquitin protein body enzymatic pathway, targeted, reduce or suppress HSP90 client proteins Thing.Targeting, the compound for the Endogenous ATP enzymatic activity for reducing or suppressing HSP90 refer in particular to suppress the Endogenous ATP of HSP90 The compound of enzymatic activity, albumen or antibody, for example, 17- allyl aminos, 17-AAG (17AAG), its The relevant compound of his geldanamycin, red shell rhzomorph and hdac inhibitor.
Term used herein " antiproliferation antibodies " includes, but not limited to Herceptin (HerceptinTM), toltrazuril Monoclonal antibody-DM1, Tarceva (TarcevaTM), bevacizumab (AvastinTM), RituximabPR064553 (anti-CD40) and 2C4 antibody.Antibody means complete monoclonal antibody, polyclonal antibody, by the complete antibody of at least two The multi-specificity antibody and antibody fragment (as long as they have desired bioactivity) of formation.For the white blood of acute myeloid sample For the treatment of sick (AML), the leukemia therapy of formula (I) compound and standard can be used in combination, especially with for AML The therapy for the treatment of is used in combination.Specifically, can by formula (I) compound and such as farnesyl tranfering enzyme inhibitor and/or its He be used for AML treatment medicine for example daunorubicin, adriamycin, Ara-C, VP-16, Teniposide, mitoxantrone, idarubicin, Carboplatin and PKC412 administering drug combinations.
Formula (I) compound can also be advantageously utilised in the combination with other compounds or with the combination of other therapeutic agents, Especially other anti-malarial agents.Such anti-malarial agents include, but are not limited to chloroguanide (proguanil), Chlorproguanil (chlorproguanil), trimethoprim (trimethoprim), chloroquine (chloroquine), Mefloquine (mefloquine), Lumefantrine (lumefantrine), Atovaquone (atovaquone), pyrimethamine-sulfanilamide (SN) (pyrimethamine- Sulfadoxine), pyrimethamine-chlorobenzene (pyrimethamine-dapsone), halofantrine (halofantrine), quinine (quinine), quinindium (quinidine), amodiaquine (amodiaquine), amopyroquine (amopyroquine), sulfanilamide (SN) Class medicine, qinghaosu, Arteflene (arteflene), Artemether, Artesunate, primaquine, sucks NO, L-arginine, dipropyl Alkene triamine NONO esters (NO donor), Rosiglitazone (PPARy activators), activated carbon, hematopoietin, levamisol, And Malaridine.
Formula (I) compound can also be advantageously used in the combination with other compounds or the combination of other therapeutic agents, example Such as treat the other therapeutic agents of leishmaniasis, trypanosomiasis, toxoplasmosis and cerebral cysticercosis.Such medicament includes, but are not limited to Nivaquin, atovaquone-proguanil, Artemether-lumenfantrine, quinine sulfate, Artesunate, quinine, fortimicin (doxycycline), clindamycin (clindamycin), meglumine antimony (meglumine antimoniate), gluconic acid Antimony sodium (sodium stibogluconate), Miltefosine (miltefosine), ketoconazole (ketoconazole), pentamidine (pentamidine), amphotericin B (AmB), AmB liposomes, paromomycin (paromomycine), Eflornithine (eflornithine), nifurtimox (nifurtimox), suramin (suramin), melarsoprol (melarsoprol), sprinkle Ni Songlong (prednisolone), benzimidazole, sulphadiazine, pyrimethamine, abactrim, radonil, Ah Miramycin (azitromycin), Atovaquone, dexamethasone, praziquantel, albendazole (albendazole), beta-lactam, Fluoroquinolones medicine, macrolides medicine, aminoglycoside medicine, sulphadiazine and pyrimethamine.
The structure of active ingredient and its preparation can be from classic " The determined by code name, common name or trade name Merck Index (Merck index) " current edition (such as M.J.O ' Neil et al. compile ' The MerckIndex ', the 13rd Version, Merck Research Laboratories, 2001) or from database (such as Patents International (examples Such as IMS World Publications)) in know.
Compound that is above-described, being used with formula (I) compound combination, can be pressed by those skilled in the art Prepare and be administered according to above-mentioned method recorded in the literature.Formula (I) compound can also be combined with therapeutic process, improve curative effect.Example Such as, hormone therapy or special radiotherapy are given.Formula (I) compound is used especially as radiosensitizer, it is especially useful in right The weak oncotherapy of those radiotherapeutic responses.
" combination " represents the medicine box of the fixed Combination in single dose unit form or the part for combined administration, its Middle formula (I) compound and combined partner can be applied in same time individual application or respectively at a certain time interval With, particularly make combined partner show cooperation, for example act synergistically.Term " co-administration " as used in the present invention or " group Single individual (such as the patient) for being applied to selected COMBINATION OF THE INVENTION and needing it to be administered in combination is included in conjunction administration " etc., and wraps Wherein material is included without going through identical route of administration or the therapeutic scheme being administered simultaneously.Term " medicine group as used in the present invention Close product " represent to mix or combine obtained product by more than one active ingredients, and both included the fixation of active ingredient Combination also includes non-fixed combinations.Term " fixed Combination " represent active ingredient as shown in formula (I) compound and COMBINATION OF THE INVENTION with Single entities or the form of dosage are administered simultaneously in patient.Term " non-fixed combinations " represents active ingredient such as formula (I) shownization Compound and COMBINATION OF THE INVENTION are successively applied to patient with limiting at the same time, jointly or without special time as corpus separatum, wherein should It is applied in the treatment level of significance that patient's body provides two kinds of compounds.The latter applies also for cocktail therapy, such as using 3 Kind or more kind active ingredient.
The purposes of the compounds of this invention and pharmaceutical composition
The compounds of this invention is the inhibitor of kinase activity, particularly the inhibitor of PI3- kinase activities.For PI3- kinases The compound of inhibitor can be used for treating wherein potential pathology (at least part of) and be attributed to improperly PI3- kinase activities Disorder, such as asthma and chronic obstructive pulmonary disease (COPD)." improperly PI3- kinase activities " refers to and in specific patient In desired normal PI3- kinase activities have any PI3- kinase activities of deviation.Improperly PI3- kinases can be taken, for example, living Property abnormal increase, or the distortion of PI3- kinases or control not normal form.Improperly activity can be due to for these, such as causes not When or not controlled make the overexpression of protein kinase being activated or mutation.Therefore, on the other hand, the present invention relates to treatment institute State disorderly or disease method.
Such disorderly or disease includes, but is not restricted to, respiratory disease, including asthma, chronic obstructive Tuberculosis and idiopathic pulmonary fibrosis (IPF)；Virus infection, including viral respiratory infection and viral respiratory disease are disliked Change, such as asthma and COPD；Non-viral respiratory tract infection, including aspergillosis and leishmaniasis；Anaphylactia, including allergy Property rhinitis and atopic dermatitis；Autoimmune disease, including rheumatoid arthritis and multiple sclerosis；Diseases associated with inflammation, Including inflammatory bowel disease；Angiocardiopathy, including thrombosis and atherosclerosis；Malignant hematologic disease；Nerve degenerative diseases； Pancreatitis；Multiple organ failure；Kidney trouble；Platelet aggregation；Cancer；Sperm motility；Graft rejection；Graft rejection； Injury of lungs；And pain, including with rheumatoid arthritis or the relevant pain of osteoarthritis, backache, systemic inflammatorome pain, Neuralgia, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia and central pain after liver. In one embodiment, such disorder includes, respiratory disease, including asthma and chronic obstructive pulmonary disease (COPD)；Anaphylaxis Disease, including allergic rhinitis and atopic dermatitis；Autoimmune disease, including rheumatoid arthritis and multiple hard Change；Diseases associated with inflammation, including inflammatory bowel disease；Angiocardiopathy, including thrombosis and atherosclerosis；Malignant hematologic disease； Nerve degenerative diseases；Pancreatitis；Multiple organ failure；Kidney trouble；Platelet aggregation；Cancer；Sperm motility；Transplanting row Reprimand；Graft rejection；Injury of lungs；And pain, including with rheumatoid arthritis or the relevant pain of osteoarthritis, backache, Neuralgia, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia after systemic inflammatorome pain, liver And central pain.
The treatment method of the present invention include giving patient in need with compound shown in safety and a effective amount of formula (I) or Its pharmaceutically acceptable salt.Each embodiment of the present invention is included by giving patient in need with safety and a effective amount of Compound or its pharmaceutically acceptable salt shown in formula (I), any disorderly or disease method that the treatment present invention mentions.
Compound shown in formula (I) can be given to study subject or its is pharmaceutically acceptable by any suitable method of administration Salt, including both Formulations for systemic administration and local administration.Formulations for systemic administration include orals administration, parenteral administration, cutaneous penetration and directly Enteral administration.Parenteral refer to except enteral or it is transdermal in addition to method of administration, typically inject or infuse.Parenteral administration Including intravenous, intramuscular and hypodermic injection or infusion.Local administration includes being applied to skin, and intraocular, ear, vagina Interior, suction and intranasal administration.Suction refers to being administered to the intrapulmonary of patient, is sucked whether through oral cavity suction or nasal cavity. In certain embodiments, compound or its pharmaceutically acceptable salt shown in formula (I) can be administered orally.In other embodiments In, can compound or its pharmaceutically acceptable salt shown in administration by inhalation formula (I).In further embodiments, can be through intranasal Give compound shown in formula (I) or its pharmaceutically acceptable salt.
It can once give or give formula (I) compound or its pharmaceutically acceptable salt according to a dosage regimen, in institute State in dosage regimen, it is specified that period in give some dosage at various time intervals.For example, can give 1 time daily, 2 times, 3 times or 4 dosage.In certain embodiments, 1 dosage is given once daily.In further embodiments, 2 dosage are given once daily. Dosage can be given until reaching required therapeutic effect or indefinitely maintaining desired therapeutic effect.Chemical combination shown in formula (I) The suitable dosage regimen of thing or its pharmaceutically acceptable salt depends on the pharmacokinetic property of the compound, such as inhales Receipts, distribution and half-life period, it can be determined by professional technician.In addition, suitable dosage regimen, including scheme it is lasting when Between, for formula (I) compound or its pharmaceutically acceptable salt, depending on the disorder treated or disease, receiving The disorder for the treatment of or the severity of disease, the age of patients receiving treatment and physical condition, the medical history, same of patient under consideration When the property of therapy, the effect of expected treatment and some factors in the knowledge and technical skill of professional technician.Specialty Technical staff is also understood that according to reaction of the individual patient to dosage regimen or as time passage individual patient needs to change When, in order to be sufficiently accurate it may be desired to adjust suitable dosage regimen.
The present invention compound can with one or more other drugs at the same time, before or after be administered.The change of the present invention Compound can be administered alone by identical or different method of administration, or together be given in same pharmaceutical composition with other drugs Medicine.
The pharmaceutical composition of the present invention or combination can be about 1-1000mg active ingredients for the individual of about 50-70kg, Or the unit dose of about 1-500mg or about 1-250mg or about 1-150mg or the active ingredient of about 0.5-100mg or about 1-50mg Amount.The treatment effective dose of compound, pharmaceutical composition or its combination depends on species, weight, age and the individual disease of individual Disease, disorder or disease or severity to be treated.The doctor of this area common skill, clinician or animal doctor can be easily Determine the effective dose of each active ingredient for preventing, treating or suppressing disorderly or progression of disease.Dosage cited above is special Property used favourable mammal, such as mouse, rat, dog, monkey or isolated organ, tissue and its sample external and Confirmed in vivo studies.The compound of the present invention can use in vitro as a solution, such as aqueous solution, also can be in suspension Or the vein that the form of aqueous solution enterally, parenterally and preferably passes through uses in vivo.A effective amount of scope of interior therapeutic depends on giving The approach of medicine, between about 0.01-500mg/kg, or about between 1-100mg/kg.
In addition, compound shown in formula (I) can be administered with pro-drug.Term used in the present invention, chemistry " prodrug " of the compound of formula (I) is its feature for the compound for finally discharging chemical formula (I) when delivering medicine to patient in vivo Derivative.During with the compound of prodrug administration chemistry formula (I), those skilled in the art can implement one kind in following manner and with On：(a) the internal onset time of compound is changed；(b) the internal acting duration of compound is changed；(c) compound is changed Internal conveying or distribution；(d) the internal solubility of compound is changed；And (e) overcomes the side effect or its that compound faced His difficult point.The typical functional derivatives of prodrug are used to prepare, comprising in vivo chemically or the mode of enzyme cracks The variation of compound.Comprising preparing these variations of phosphate, acid amides, ester, monothioester, carbonate and carbaminate to ability It is well-known for field technique personnel.
On the one hand, the present invention provides PI3- kinases exception relevant diseases or the treatment method of disorder.The treatment method Including by giving patient in need with safety and a effective amount of formula (I) compound or its pharmaceutically acceptable salt, treatment Any disorderly or disease method that the present invention mentions.
In some embodiments, PI3- kinases exception relevant disease or disorder include：Breathing problem, such as asthma, slowly Property obstructive lung disease (COPD) and idiopathic pulmonary fibrosis (IPF) etc.；Virus infection, including viral respiratory infection and virus Property breathing problem deteriorate, such as asthma and COPD；Non-viral respiratory tract infection, including aspergillosis and leishmaniasis；Allergy is anti- Answering property disease, including allergic rhinitis and atopical dermatitis；Autoimmune disease, including rheumatoid arthritis and multiple Property hardening；Inflammatory disease, including inflammatory bowel disease；Angiocardiopathy, including thrombosis and atherosclerosis；Malignant hematologic disease； Nerve degenerative diseases；Pancreatitis；Multiple organ failure；Nephrosis；Platelet aggregation；Cancer；Sperm motility；Graft rejection；Transplanting Thing repels；Injury of lungs；And pain, including with rheumatoid arthritis or the relevant pain of osteoarthritis, backache, systemic inflammatorome Neuralgia, diabetic neuropathy, neuro-inflammatory pain (wound), trigeminal neuralgia and central pain after pain, liver Bitterly.
The compounds of this invention can be used for treatment to have the function of disease or the sense of one or more immune systems of B cell Dye, for example, antibody tormation, antibody present, cell factor generation or lymphoid organ formed abnormal or worthless illness, disease or The method of illness, the illness, disease or illness include rheumatoid arthritis, pemphigus vulgaris, essential thrombocytopenia and subtract Few property purpura, systemic loupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren syndrome, Autoimmune hemolytic are poor Blood, ANCA associated vasculitis, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic auto-immune nettle rash, Allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), Goodpasture's syndrome, AMR (antibody-mediated transplanting Repel), B cell mediation super acute, acute and chronic graft rejection and hematopoiesis source cancer, include but not limited to multiple bone Myeloma；Acute myeloid leukaemia；Chronic myelogenous leukemia；Lymphocytic leukemia；Myeloid leukemia；Non-Hodgkin's lymph Knurl；Lymthoma；Polycythemia vera；Primary thrombocytosis；Myelofibrosis with metaplasia outside marrow；With watt Er Dengsitelun diseases.
The present invention includes one or more functions such as superoxides release for the treatment of wherein neutrophil cell, is excited born of the same parents Spit or migration is abnormal or the method for worthless illness, disease or illness, the illness, disease or illness include rheumatoid Property arthritis, sepsis, lung or respiratory disorder are such as asthma, inflammatory skin diseases such as psoriasis.
The present invention includes one or more functions such as migration for the treatment of wherein basophilic granulocyte and mast cell Or allergen-IgE- mediations threshing is abnormal or the method for worthless illness, disease or illness, the illness, disease or disease Disease include anaphylactia (atopic dermatitis, contact dermatitis, allergic rhinitis) and other illnesss such as COPD, asthma or Pulmonary emphysema.
The present invention includes one or more functions such as cell factor generation or cell-mediated thin for the treatment of wherein T cell Cellular toxicity is abnormal or the method for worthless illness, disease or illness, the illness, disease or illness include rheumatoid and close Save the cancer in acute or chronic repulsion or the hematopoiesis source of inflammation, multiple sclerosis, cell tissue or organ graft.
In addition, the present invention includes the method for the treatment of neurodegenerative disease, angiocardiopathy and platelet aggregation.
In addition, the present invention includes treatment skin disease such as porphyria cutanea tarda, polymorphous light eruption (polymorphous light eruption), dermatomyositis, urticaria solaris, oral lichen planus, panniculitis, chorionitis, The method of urticarial vasculitis.
In addition, the present invention includes the method for the treatment of chronic inflammatory disease such as sarcoidosis, granuloma annulare.
In other embodiments, illness or disorder are selected from (as PI3K is mediated)：Polycythemia vera, primary Piastrenemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS (acute respiratory distress syndrome), Loew Le are comprehensive Simulator sickness, eosinophilic pneumonia, parasite (particularly metazoa) infect (including increased tropical eosinophils), bronchus Pulmonary aspergilosis, nodular polyarteritis (including Qiu-this syndrome), eosinophilic granuloma, the influence as caused by drug response The disorder related with acidophic cell of air flue, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, blister Rash sample dermatitis, chorionitis, leucoderma, allergic vasculitis, nettle rash, bullous pemphigoid, lupus erythematosus, pemphigus (pemphisus), posterior bullous epidermis release, (such as hemolytic anemia, aplastic are poor for autoimmune hematological disease Blood, pure red cell anaemia and essential thrombocytopenia are reduced), systemic loupus erythematosus, polychondritis, chorionitis, Wegener Granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, steven-Johnson syndrome, idiopathic sprue, itself Immunity inflammatory bowel disease (such as ulcerative colitis and Crohn disease), endocrine ophthalmopathy, Graves disease, sarcoidosis, lung Steep inflammation, chronic anaphylaxis pneumonia, multiple sclerosis, primary biliary cirrhosis, (front and rear) uveitis, interstitial lung Fibrosis, psoriatic arthritis, glomerulonephritis, angiocardiopathy, atherosclerosis, hypertension, deep vein thrombosis shape Into, it is apoplexy, miocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolysis disease, Acute arterial ischeamia, outer All thrombotic occlusions and coronary artery disease, reperfusion injury, retinopathy, such as diabetic retinopathy or hyperbaric oxygen draw The retinopathy risen, and illness, such as glaucoma characterized by raising intraocular pressure or aqueous humor secretion.
In some embodiments, pain is shown as by PI3- kinases exception associated disorders.
In another embodiment, the compounds of this invention can be used for treatment to be selected from following illness or illness：Primary Cutaneous B cell lymphoma, immunity bubble disease (immunobullous disease), pemphigus vulgaris, fallen leaves property day Blister sore, Brazilian pemphigus (Fogoselvagem), tumour formed sign pemphigus (paraneoplastic pemphigus), Bullous pemphigoid, mucosal pemphigus, acquired epidermolysis bullosa, chronic graft versus host disease, dermatomyositis, Systemic loupus erythematosus, vasculitis, polyangitis, low complement courage and uprightness urticarial vasculitis (hypocomplementemic Urticarial vasculitis), anti-neutrophil cell cytoplasmic antibody associated vasculitis, cryoglobulinemia, Schnitzler syndromes, macroglobulinemia Waldenstron, angioedema, hickie, systemic loupus erythematosus, special hair Property thrombocytopenic purpura, multiple sclerosis, cold coagulation disease, autoimmune hemolytic anemia, anti-neutrophil cell Cytoplasmic antibody associated vasculitis, graft versus host disease(GVH disease), cryoglobulinemia and Thrombotic Thrombocytopenic reduce disease.
In other embodiments, the present invention can be used for treating, prevent or alleviating autoimmunity disease and inflammatory disease Disease, particularly teiology includes the inflammatory condition of autoimmune component, such as arthritis (such as rheumatoid arthritis, slowly Property into fertility arthritis (arthritis chronic progrediente) and arthritis deformans) and rheumatic disease, bag Include the inflammatory condition and rheumatic disease for involving bone lesion；Inflammatory pain, spondyloarthropathy (including ankylosing spondylitis, Lai Te That syndrome, adjuvant arthritis, psoriatic arthritis and enteropathic arthritis (enterophathics arthritis)), Hypersensitivity (including air flue hypersensitivity and skin hypersensitivity) and allergy.The specific autoimmune disease of antibody of the present invention can be used Disease includes autoimmune hematological illness (including such as hemolytic anemia, alpastic anemia, pure red cell anaemia and spy Hair property thrombopenia), Acquired hemophilia A, cold coagulation disease, cryoglobulinemia, thrombotic thrombocytopenic it is purple Purplish or white patches on the skin, Sjogren syndrome, systemic loupus erythematosus, inflammatory muscular disorders, polychondritis, scleroderma, anti-neutrophil cell kytoplasm Antibody associated vasculitis, the neuropathy of IgM mediations, opsoclonia-myoclonic syndrome, wegener granulomatosis, musculus cutaneus Inflammation, chronic active hepatitis, myasthenia gravis, psoriasis, Si-about syndrome, pemphigus vulgaris, pemphigus foliaceus, spy (including for example ulcerative colitis, regional enteritis and intestines easily swash are comprehensive for hair property sprue, autoimmune inflammatory enteropathy Simulator sickness), endocrine ophthalmocace change, Graves disease, sarcoidosis, multiple sclerosis, neuromyelitis optica, primary biliary liver it is hard Change, juvenile-onset diabetes (type i diabetes), uveitis (anterior uveitis, intermediate uveitis and posterior uveitis and complete Uveitis), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulus Ephritis (with without nephrotic syndrome, such as including idiopathic nephrotic syndrome or minute nephropathy), tumour, skin With cornea inflammatory disease, myositis, bone graft relaxation, metabolic disorder such as atherosclerosis, diabetes and dyslipidemia (dislipidemia)。
In some embodiments, the present invention provides the therapeutical uses of compound shown in formula (I), other embodiments In, the treatment is used for the treatment with the relevant disease of PI3K inhibitory action.In other embodiments, can treat Disease is selected from above-mentioned list of diseases, including autoimmune disease, diseases associated with inflammation, anaphylactia, airway disorders (e.g., heavy breathing Asthma and COPD), graft rejection；Antibody tormation, antibody present, cell factor generates or lymphoid organ formation is abnormal or can not The conditions or diseases taken, including rheumatoid arthritis, pemphigus vulgaris, Idiopathic Thrombocytopenic Purpura, systematicness Lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren syndrome, autoimmune hemolytic anemia, ANCA associated vessels Inflammation, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic auto-immune nettle rash, allergy (idiopathic skin Inflammation, contact dermatitis, allergic rhinitis), Goodpasture's syndrome, AMR (antibody-mediated graft rejection), B cell mediation Super acute, acute and chronic graft rejection and hematopoiesis source cancer, include but not limited to Huppert's disease；Leukaemia；It is acute Myelogenous leukemia；Chronic myelogenous leukemia；Lymphocytic leukemia；Myeloid leukemia；Non-Hodgkin lymphoma；Lymthoma； Polycythemia vera；Primary thrombocytosis；Myelofibrosis with metaplasia outside marrow；With Walden Si Telun Disease.Wherein described conditions or diseases are selected from rheumatoid arthritis (RA), pemphigus vulgaris (PV), essential thrombocytopenia and reduce Property purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune hemolytic anemia (AIHA), acquired blood friend Sick A types (AHA), systemic loupus erythematosus (SLE), multiple sclerosis (MS), myasthenia gravis (MG), Sjogren syndrome (SS), ANCA associated vasculitis, cryoglobulinemia, chronic auto-immune nettle rash (CAU), (atopic dermatitis, connect allergy Touch property dermatitis, allergic rhinitis), Goodpasture's syndrome, graft rejection and make haematogenous cancer；Equally it can treat and exempt from Epidemic disease relevant disease of science or infection, such as severe malaria, cerebral malaria, trypanosomiasis, leishmaniasis, toxoplasmosis and cerebral cysticercosis Disease.
Therefore, in some more particular embodiments, the compound the present invention relates to any of above embodiment is in PI3K The application of disease mediated medicine manufacture view；In other embodiments, the medicine is that treatment suppresses with PI3K Act on the medicine of relevant disease；In other embodiments, the disease that can be treated is selected from above-mentioned list of diseases, including Autoimmune disease, diseases associated with inflammation, anaphylactia, airway disorders (e.g., asthma and COPD), graft rejection；Antibody tormation, It is abnormal or worthless conditions or diseases that antibody, which presents, cell factor generation or lymphoid organ are formed, including rheumatoid Arthritis, pemphigus vulgaris, Idiopathic Thrombocytopenic Purpura, systemic loupus erythematosus, multiple sclerosis, severe flesh without Power, Sjogren syndrome, autoimmune hemolytic anemia, ANCA associated vasculitis, cryoglobulinemia, Thrombotic Thrombocytopenic Reduction property purpura, chronic auto-immune nettle rash, allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), Gourde(G) Super acute, the acute and chronic graft rejection and make that Paasche mound syndrome, AMR (antibody-mediated graft rejection), B cell mediate Blood source cancer, includes but not limited to Huppert's disease；Leukaemia；Acute myeloid leukaemia；Chronic myelogenous leukemia；Lymph is thin Born of the same parents' property leukaemia；Myeloid leukemia；Non-Hodgkin lymphoma；Lymthoma；Polycythemia vera；Idiopathic thrombocythemia Disease；Myelofibrosis with metaplasia outside marrow；And Waldenstrom.Wherein described conditions or diseases 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 loupus erythematosus (SLE), It is multiple sclerosis (MS), myasthenia gravis (MG), Sjogren syndrome (SS), ANCA associated vasculitis, cryoglobulinemia, slow Property autoimmune urticaria (CAU), allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), Goodpasture are comprehensive Simulator sickness, graft rejection and make haematogenous cancer；Disease relevant with immunopathology or infection can be equally treated, such as serious malaria Disease, cerebral malaria, trypanosomiasis, leishmaniasis, toxoplasmosis and cerebral cysticercosis.
General building-up process
For the description present invention, embodiment is listed below.But it is to be understood that the present invention is not limited to these Examples, simply The method that the practice present invention is provided.
Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent such as formula (I).Following reaction scheme and embodiment are used to this is further illustrated The content of invention.
The professional of fields will be recognized that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and the other methods for being used to prepare the compound of the present invention are considered as the model in the present invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention Completed by method of modifying, such as appropriate protection interference group, by using other known reagent except described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified during use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Teng Long chemical reagent Co., Ltd, and Haiyang Chemical Plant, Qingdao's purchase It can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by metallic sodium reflux.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.
Reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects below Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.The survey of nuclear magnetic resonance spectroscopy Strip part is：Under room temperature, the nuclear magnetic resonance spectrometer of Brooker (Bruker) 400MHz or 600MHz, with CDC13、DMSO-d6、CD3OD Or acetone-d6For solvent (in units of ppm), reference standard is used as by the use of TMS (0ppm) or chloroform (7.26ppm).It is more when occurring When weight peak, following abbreviation will be used：S (singlet, unimodal), d (doublet, bimodal), t (triplet, it is triple Peak), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), Dt (doublet of triplets, double triplets).Coupling constant, is represented with J, and unit is hertz (Hz).
The test condition of Algorithm (MS) data is：Agilent 6120Quadrupole HPLC-MS (pillars Model：Zorbax SB-C18,2.1 × 30mm, 3.5 μm, 6min, flow velocity 0.6mL/min, mobile phase：5%-95% (contains The CH of 0.1% formic acid3CN) (H of 0.1% formic acid is being contained2O the ratio in)), detected in 210nm/254nm with UV, use electron spray Ionization pattern (ESI).
The characteristic manner of compound purity is：1260 preparative high performance liquid chromatographies of Agilent (Pre-HPLC) or 250 preparative high performance liquid chromatographies of Calesep Pump (Pre-HPLC) (pillar model：NOVASEP, 50/80mm, DAC), 210nm/254nm is detected with UV.
The use of brief word below is through the present invention：
ATP atriphos
AcOH,HAc,HOAc,CH3COOH acetic acid, acetic acid
AcOK,CH3COOK potassium acetates
AIBN azodiisobutyronitriles
AlCl3Aluminium chloride
BBr3Boron tribromide
Bu4NF tetrabutyl ammonium fluorides
Burgess reagent (Burgess Reagent) N- (triethyl ammonium sulphonyl) methyl carbamate
2,2'- pairs-(diphenyl phosphine) -1,1'- dinaphthalenes of BINAP
BPO peroxidating (two) benzoyl
BSA bovine serum albumin(BSA)s
BOC, Boc tert-butoxycarbonyl
N-BuOH n-butanols
N-BuLi n-BuLis
(n-Bu)3SnCl tri-n-butyltin chlorides
Ca(SO3CF3)2Trifluoromethyl calcium sulfate
Cs2CO3Cesium carbonate
CCl4Carbon tetrachloride
CHCl3Chloroform
CH2I2Diiodomethane
CH3CHO acetaldehyde
CH3MgBr methyl-magnesium-bromides
CDCl3Deuterochloroform
CH2Cl2, DCM dichloromethane
CH3CN, MeCN acetonitrile
CH3SO2Cl, MsCl methylsufonyl chloride
Cu copper
CuI cuprous iodides
DCC N, N'- dicyclohexylcarbodiimides
11 carbon -7- alkene of DBU 1,8- diazabicylos [5.4.0]
The bromo- 5,5- Dimethyl Hydan of DBDMH 1,3- bis-
D2Deuterium
DIBAL diisobutyl aluminium hydrides
DIAD diisopropyl azodiformates
DIEA, DIPEA, iPr2Net N, N- diisopropylethylamine
DEAD diethyl azodiformates
DMF n,N-Dimethylformamide, dimethylformamide
DMAP 4-dimethylaminopyridine
DMSO dimethyl sulfoxide (DMSO)s
DMFDMA N,N-dimethylformamide dimethylacetals
DMP (Dess-Martin periodinane) Dai Si-Martin's oxidant
DPPA diphenyl phosphate azides
DTT dithiothreitol
EDC, EDCI 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides
EDTA ethylenediamine tetra-acetic acids
EtOAc, EA ethyl acetate
Et3N, TEA triethylamine
Et2O ether
EtOH ethanol
EtMgBr ethylmagnesium bromides
FBS hyclones
G grams
HATU 2- (7- azos benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters
HBr hydrobromic acids
HBTU O- benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphates
HCl hydrochloric acid
HOAT N- hydroxyl -7- azepine benzotriazole
HOBt I-hydroxybenzotriazole hydrates
H2Hydrogen
When h is small
H2O water
H2O2Hydrogen peroxide
H3PO4Phosphoric acid
H2SO4Sulfuric acid
HNO3Nitric acid
HCOOK potassium formates
HMDS hmds
HPLC high pressure liquid chromatographies or high performance liquid chromatography
I2Iodine
I-PrMgBr isopropyl magnesium bromides
I-PrMgCl isopropylmagnesium chlorides
Fe iron
Two silicon substrate base lithium of LiHMDS hexamethyls
LDA lithium diisopropyl amidos
MBP myelin alkaline proteins
MCPBA metachloroperbenzoic acids
MgSO4Magnesium sulfate
Mg ATP adenosine triphosphate magnesium
MeOH,CH3OH methanol
MeI,CH3I iodomethane
MOPS 3- (N- morpholinoes) propane sulfonic acid
ML, ml milliliters
Min minutes
N2Nitrogen
NH3Ammonia
NMP 1-methyl-2-pyrrolidinones
NaHCO3Sodium acid carbonate
NaBH4Sodium borohydride
NaBH3CN sodium cyanoborohydrides
NaOtBu sodium tert-butoxides
NaOMe,CH3ONa sodium methoxides
NaOH sodium hydroxides
NaClO2Sodium chlorite
NaCl sodium chloride
NaH2PO4Sodium dihydrogen phosphate
NaH sodium hydrides
NaI sodium iodides
Na2SO4Sodium sulphate
NBS N- bromo-succinimides
NIS N- N-iodosuccinimides
NCS N- chlorosuccinimides
NEt3Triethylamine
Nonidet promises are lotion
NH3Ammonia
NH4Cl sal-ammoniacs
NH2OH azanols
Pd/C palladiums/carbon
Pd2(dba)3Three (dibenzalacetone) two palladium
Pd(OAc)2Palladium
Pd(OH)2Palladium dydroxide
Pd(PPh3)4Tetrakis triphenylphosphine palladium
Pd(PPh3)2Cl2Double (triphenylphosphine) palladium chlorides
Pd(dppf)Cl21,1 '-two (diphenylphosphino) ferrocene palladium chlorides
Pd(dppf)Cl2·CH2Cl2[double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex
P(t-Bu)3Three (tert-butyl group) phosphines
PE petroleum ethers (60-90 DEG C)
PBS phosphate buffered saline (PBS)s
POCl3Phosphorus oxychloride
PPA polyphosphoric acids
PhI(OAc)2Iodobenzene diacetate
K2CO3Potassium carbonate
KOH potassium hydroxide
RT, rt, r.t. room temperature
Rt retention times
SOCl2Thionyl chloride
SO2Cl2Sulfonic acid chloride
T-BuOK potassium tert-butoxides
TBTU O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid esters
THF tetrahydrofurans
TFA trifluoroacetic acids
TBAI tetrabutylammonium iodides
TBS trimethylolaminomethane buffered salines
TEAC bis- (tetraethyl ammonium) carbonate
TLC thin-layer chromatographys
Tris trishydroxymethylaminomethanes
TsCl paratoluensulfonyl chlorides
X-Phos 2- dicyclohexyl phosphorus -2', 4', 6'- tri isopropyl biphenyls
Zn zinc
μ L microlitre
Synthetic schemes 1-4 lists the experimental procedure for preparing compound disclosed in the present invention.Wherein, each X, R2, R3And R4Tool There is definition as described in the present invention.
Synthetic schemes 1
Targeted kinase inhibitor(10)It can be prepared by the method described in synthetic schemes 1.First, benzoic acid Derivative(1)And SOCl2In nonpolar solvent (e.g., toluene), react generate acid chloride intermediate at a reflux temperature, in acyl chlorides Mesosome is again and amino-compound(2)Reaction generation compound(3).Compound(4)And compound(5)Contract in alkaline conditions Close reaction generation compound(6).Compound(6)Under nitrogen protection with compound(7)React generation mixture A, meanwhile, Compound(3)Generation mixture B is reacted with highly basic (such as n-BuLi) under nitrogen protection, then, mixture A and mixture B is sent out The product of raw reaction obtains intermediate with acid treatment again(8).Intermediate(8)Finally in alkaline conditions with compound(9)Occur Condensation reaction generates targeted kinase inhibitor(10)。
Synthetic schemes 2
Targeted kinase inhibitor(21)It can be prepared by the method described in synthetic schemes 2.First, compound(11)In CH2I2, CuI and compound(12)In the presence of occur iodide reaction generation compound(13).Compound(13)Exist in alkali Lower and tributyltin chloride, which reacts, generates compound(14).Compound(14)In the presence of Pd catalyst with compound(15) Generation coupling reaction generates compound(17).Compound(17)Flow back in acid condition, the methoxyl group above it is changed into Hydroxyl, generates compound(18).Compound(18)Flow back again in the presence of phosphorus oxychloride, the hydroxyl above it changed into chlorine, Generate compound(19).Compound(19)The compound of reaction generation mono amino substitution under ammonia atmosphere(20).Compound(20)Finally and intermediate(8)React generation targeted kinase inhibitor in alkaline conditions(21)。
Synthetic schemes 3
Targeted kinase inhibitor(25)It can be prepared by the method described in synthetic schemes 3.First, compound(22)In two methoxyl groups in chlorinating agent POCl3Or SOCl2In the presence of change into chlorine, generate compound(23).Next, change Compound(23)The reaction generation compound under ammonia atmosphere(24).Finally, compound(24)With compound(8)In alkaline condition Under, the reaction generation targeted kinase inhibitor in solvent, n-butanol(25)。
Synthetic schemes 4
Targeted kinase inhibitor(35)It can be prepared by the method described in synthetic schemes 4.Compound(26) With SO2Cl2Generation chloride compounds are reacted with AIBN(27), compound(27)Generation amide compound is reacted in ammonia atmosphere(28).Compound(28)The chlorine above compound is changed into methoxyl group with sodium methoxide reaction, generates compound(29).Compound(29)Again and compound(30)Reaction generation compound(31).Compound(31)It is cyclized in alkaline conditions with hydroxylamine hydrochloride Reaction generation compound(32).Compound(32)In methoxyl group in chlorinating agent POCl3Under the action of change into chlorine, generate chemical combination Thing(34).Compound(34)First and a chlorine in compound is changed into amino by ammonia reaction, generates compound(34).Chemical combination Thing(34)Finally in alkaline conditions with compound(8)Reaction, generates targeted kinase inhibitor(35)。
Embodiment
Following embodiments are used to illustrate the present invention, but are not limited to the scope of the present invention.
Embodiment 1 (S) -3- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Propyl group) -1 (2H) -one of -2- cyclopropyl -8- fluorine isoquinolin
The fluoro- 6- methyl benzamides of step 1) N- cyclopropyl -2-
The fluoro- 6- methyl benzoic acids (4.0g, 25.95mmol) of 2- are suspended in toluene (26mL), then at room temperature, to SOCl is added in reaction solution2(7.5mL, 103.80mmol), reaction solution are stirred overnight at 90 DEG C, are subsequently cooled to room temperature, and It is concentrated under reduced pressure.Residue is dissolved in THF (30mL) solution of triethylamine (10.85mL, 77.85mmol), at 0 DEG C, to Cyclopropylamine (1.89mL, 27.25mmol) is added dropwise in obtained solution, then mixture is warmed to room temperature and stirs reaction 5 Hour, it is concentrated under reduced pressure, residue is dissolved in H2In O (200mL) and EtOAc (200mL), the organic phase that liquid separation obtains is used successively Saturation NaHCO3Aqueous solution (200mL) and saline solution (200mL) washing, use anhydrous Na2SO4It is dry, it is concentrated under reduced pressure to give titled Compound is white 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)-(1- (methoxyl group (methyl) amino) -1- oxo-butanes -2- bases) t-butyl carbamate
By compound (S) -2- ((tertbutyloxycarbonyl) amino) butyric acid (36.00g, 177.13mmol), N, O- dimethylhydroxylamines Hydrochloride (20.73g, 212.56mmol), DMAP (21.64g, 177.13mmol) and triethylamine (96.89mL, 690.82mmol) It is dissolved in DCM (370mL), then at -5 DEG C, EDCI (40.75g, 212.56mmol) is added dropwise into reaction solution.Institute Obtain mixture to be stirred at room temperature overnight, then use water (200mL × 2), saturation NaHCO successively3Aqueous solution (200mL) and salt Water (200mL) washs, and the organic phase that liquid separation is obtained is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/EtOAc (v/v) =4/1) purify, it is colorless oil (37.16g, 85%) to obtain title compound.
1H NMR(400MHz,CDCl3)δ(ppm):5.17-5.16 (d, J=7.6Hz, 1H), 4.62 (m, 1H), 3.76 (s, 3H), 3.20 (s, 3H), 1.79-1.70 (m, 1H), 1.61-1.50 (m, 1H), 1.43 (s, 9H), 0.95-0.91 (t, J= 7.5Hz,3H)。
- 1 (2H) -one of step 3) (S) -3- (1- aminopropyls) -2- cyclopropyl -8- fluorine isoquinolin
The fluoro- 6- methyl benzamides (3.00g, 15.53mmol) of compound N-cyclopropyl -2- are dissolved in THF (22mL) In, then under -30 DEG C and nitrogen protection, n-BuLi (15.5mL, 38.82mmol) is added dropwise into reaction solution, obtains Yellow solution is directly used in after being stirred 30 minutes at -30 DEG C to react in next step.
By compound (S)-(1- (methoxyl group (methyl) amino) -1- oxo-butanes -2- bases) t-butyl carbamate (5.74g, 23.29mmol) is dissolved in THF (110mL), and then under -30 DEG C and nitrogen protection, i- is added dropwise thereto PrMgBr (25.6mL, 25.6mmol), after reaction solution stirs 30 minutes at -30 DEG C, then is added dropwise above obtained Solution, after adding, by gained mixture be warming up to -15 DEG C and stir reaction 2 it is small when, then with the H of 5mL2Reaction is quenched in O, Then at 0 DEG C, then with concentrated hydrochloric acid mixture is adjusted to pH=1, gained mixture is concentrated under reduced pressure.The residue that will be obtained Be dissolved in MeOH (45mL) and concentrated hydrochloric acid (22mL), resulting solution stirred at 80 DEG C 1 it is small when after, be cooled to room temperature, and subtract Pressure concentration.Obtained residue is dissolved in DCM (40mL) and added with NaHCO3The MeOH (20mL) of (100mg, 1.20mmol) is molten In liquid, mixture be stirred at room temperature 4 it is small when after, filter, filtrate decompression is concentrated, residue is through silica gel column chromatography (DCM/ MeOH (v/v)=10/1) purifying, it is faint yellow solid (3.08g, 76%) to obtain title compound.
MS(ESI,pos.ion)m/z:261.0[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.53-7.50 (ddd, J=8.4,8.4,4.8Hz, 1H), 7.35- 7.34 (d, J=7.9Hz, 1H), 7.18 (s, 1H), 7.07-7.04 (dd, J=11.2,8.2Hz, 1H), 5.22-5.20 (m, 1H),3.08(m,1H),2.39-3.32(m,1H),2.21-2.15(m,1H),2.08-2.02(m,1H),1.34-1.29(m, 1H), 1.22-1.17 (m, 1H), 1.04-1.01 (t, J=7.8Hz, 3H), 0.66-0.62 (m, 1H).
Step 4) (S) -3- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) third Base) -1 (2H) -one of -2- cyclopropyl -8- fluorine isoquinolin
By -1 (2H) -one of compound (S) -3- (1- aminopropyls) -2- cyclopropyl -8- fluorine isoquinolin (35mg, 0.13mmol), the chloro- 5- of 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (28mg, 0.13mmol), DIPEA The mixture of (52mg, 0.40mmol) and n-BuOH (1mL) be heated to 130 DEG C and stir reaction 24 it is small when, be subsequently cooled to room Temperature, then be concentrated under reduced pressure, gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=50/1), obtains title compound For white solid (23mg, 40%).
MS(ESI,pos.ion)m/z:436.0[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.60-8.59 (d, J=5.4Hz, 1H), 8.11 (s, 1H), 7.45 (ddd, J=7.8,7.8,4.8Hz, 1H), 7.10-7.09 (d, J=7.8Hz, 1H), 7.01-6.98 (dd, J=10.8, 87.8Hz, 1H), 6.33 (s, 1H), 6.01-5.98 (ddd, J=7.8,7.8,4.2Hz, 1H), 3.01-2.97 (m, 1H), 2.51 (s,3H),2.07-2.02(m,1H),1.86-1.79(m,1H),1.50-1.47(m,1H),1.42-1.37(m,1H),1.31- 1.27 (m, 1H), 1.12-1.10 (t, J=7.4Hz, 3H), 0.94-0.89 (m, 1H).
Embodiment 2 (S) -3- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Propyl group) -1 (2H) -one of -8- methyl -2- phenyl isoquinolins quinoline
Step 1) 2,6- dimethyl-N-phenyl benzamides
By compound 2,6- methyl benzoic acids (5.0g, 33.29mmol) are suspended in toluene (100mL), then in room temperature Under, dichloride sulfoxide (12.08mL, 166.47mmol) is added into reaction solution, reaction solution is refluxed overnight, and is subsequently cooled to room Temperature, and be concentrated under reduced pressure, residue is dissolved in dichloromethane (50mL), resulting solution is directly used in reacts in next step.
Triethylamine (6.73g, 66.54mmol) and aniline (3.10g, 33.27mmol) are dissolved in dichloromethane (50mL) In, then at 0 DEG C, solution obtained above is added dropwise into reaction solution, then adds water (100mL).Liquid separation obtains Organic phase washed with water (100mL × 2) and saline solution (50mL) washing, dried, be concentrated under reduced pressure with anhydrous sodium sulfate.Gained is residual Stay thing through silica gel column chromatography (PE/EtOAc (v/v)=6/1) purify, obtain title compound for faint yellow solid (4.9g, 65.4%).
MS(ESI,pos.ion)m/z:226.3[M+H]+；
1H NMR(600MHz,DMSO-d6)δ(ppm):10.37 (s, 1H), 7.74 (d, J=7.6Hz, 2H), 7.34 (t, J =7.9Hz, 2H), 7.24 (t, J=7.6Hz, 1H), 7.17-7.01 (m, 3H), 2.28 (s, 6H)；
13C NMR(151MHz,DMSO-d6)δ(ppm):168.36(s),139.56(s),138.94(s),134.13(s), 129.20(s),128.86(s),127.73(s),124.06(s),120.03(s),19.33(s)。
- 1 (2H) -one of step 2) (S) -3- (1- aminopropyls) -8- methyl -2- phenyl isoquinolins quinoline
2,6- Methyl-N-phenyls benzamide (3.00g, 13.32mmol) is dissolved in tetrahydrofuran (50mL) ,- Under 30 DEG C and nitrogen protection, the hexane solution (2.4M, 13.87mL, 33.29mmol) of n-BuLi is added dropwise thereto, secretly Yellow mixture stirs 30 minutes at -30 DEG C, and resulting solution is used to react in next step.
By compound (S)-(1- (methoxyl group (methyl) amino) -1- oxo-butanes -2- bases) t-butyl carbamate (4.92g, 19.97mmol) is dissolved in tetrahydrofuran (50mL), then under -30 DEG C and nitrogen protection, is added dropwise thereto Enter the tetrahydrofuran solution (2M, 10.99mL, 21.97mmol) of i-PrMgCl, gained mixture continues stirring 30 at -30 DEG C Minute, then at such a temperature, the solution for reacting obtain above is added dropwise.The mixture is when -15 DEG C of stirrings 3 are small, then uses Reaction is quenched in water (10mL), at 0 DEG C, is adjusted to pH=1-2 with concentrated hydrochloric acid, and gained mixture is concentrated under reduced pressure.Concentration Residue is dissolved in methanol (50mL), then adds concentrated hydrochloric acid (25mL).Gained mixture be heated to reflux 3 it is small when, then cool down To room temperature, and it is concentrated under reduced pressure and removes methanol, gained residue is diluted with water (25mL), then is extracted with ethyl acetate (50mL × 2). Separated organic phase is adjusted to pH=7-8 with saturated sodium bicarbonate aqueous solution, then is extracted with ethyl acetate (100mL × 3).Merge Organic phase is washed with saline solution (100mL), is dried, is concentrated under reduced pressure with anhydrous sodium sulfate, and gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/1) is purified, and it is faint yellow solid (2.5g, 64.2%) to obtain title compound.
MS(ESI,pos.ion)m/z:293.2[M+H]+；
1H NMR(600MHz,DMSO-d6)δ(ppm):7.59-7.51(m,3H),7.51-7.44(m,2H),7.33(d,J =7.6Hz, 1H), 7.28 (d, J=6.8Hz, 1H), 7.21 (d, J=7.2Hz, 1H), 6.77 (s, 1H), 3.14 (dd, J= 7.2,5.1Hz, 1H), 2.73 (s, 3H), 1.62-1.52 (m, 1H), 1.35-1.27 (m, 1H), 0.66 (t, J=7.3Hz, 3H)；
13C NMR(151MHz,DMSO-d6)δ(ppm):163.51(s),149.74(s),141.12(s),139.20(d,J =1.4Hz), 132.41 (s), 130.26 (s), 129.70 (s), 129.45 (d, J=16.2Hz), 128.59 (s), 124.91 (s),123.02(s),102.42(s),53.19(s),30.51(s),23.90(s),11.24(s)。
Step 3) (S) -3- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) third Base) -1 (2H) -one of -8- methyl -2- phenyl isoquinolins quinoline
By the chloro- 5- of compound 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (31mg, 0.147mmol) and (S) -1 (2H) -one (52mg, 0.178mmol) of -3- (1- aminopropyls) -8- methyl -2- phenyl isoquinolins quinoline is suspended in n-butanol In (2mL), then into reaction solution add DIPEA (38mg, 0.293mmol), reaction mixture be heated to reflux 22 it is small when, be used in combination Thin-layered chromatography (PE/EtOAc, v/v, 1/3) monitoring reaction, after having reacted, reaction solution is cooled to room temperature, then is concentrated under reduced pressure, Residue is diluted in ethyl acetate (15mL), and gained residue is washed with water (15mL) and saturated salt solution (10mL) respectively, The organic phase that liquid separation obtains is dried with anhydrous sodium sulfate, is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/EtOAc (v/ V)=2/1) purify, it is pale solid (50mg, 73.0%) to obtain title compound.MS(ESI,pos,ion)m/z:468.3 [M+H]+；HPLC：99.2%；
1H NMR(400MHz,CDCl3)δ(ppm):8.43 (d, J=6.5Hz, 1H), 8.06 (s, 1H), 7.59-7.51 (m, 3H), 7.50-7.44 (m, 2H), 7.34 (d, J=7.7Hz, 1H), 7.30 (d, J=8.7Hz, 1H), 7.21 (d, J=7.3Hz, 1H), 6.47 (s, 1H), 4.86 (td, J=8.2,4.5Hz, 1H), 2.88 (s, 3H), 2.52 (s, 3H), 1.94-1.81 (m, 1H), 1.78-1.63 (m, 2H), 0.89 (t, J=7.4Hz, 3H).
Embodiment 3 (S) -3- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Propyl group) chloro- 2- phenyl isoquinolins quinoline -1 (2H) -one of -8-
The chloro- 6- Methyl-N-phenyls benzamides of step 1) 2-
The chloro- 6- methyl benzoic acids (6.00g, 35.17mmol) of compound 2- are dissolved in toluene (40mL), then in room Under temperature, SOCl is added thereto2(10.21mL,140.69mmol).Reaction solution stirred at 110 DEG C 5 it is small when after, be cooled to room Temperature, then be concentrated under reduced pressure.Concentrated residues thing is dissolved in DCM (50mL), at 0 DEG C, adds NEt3(14.71mL, 105.51mmol) and aniline (2.95g, 31.65mmol).Resulting solution is stirred at room temperature overnight, then successively with 200mL's H2O, the saturation NaHCO of 200mL3The saturated common salt water washing of aqueous solution and 200mL.Organic phase is concentrated under reduced pressure, gained residue Purified through silica gel column chromatography (PE/EtOAc (v/v)=4/1), it is white solid (7.4g, 86%) to obtain title compound
MS(ESI,pos.ion)m/z:246.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.63-7.61 (d, J=8.0Hz, 2H), 7.45 (br.s, 1H), 7.39-7.35 (t, J=8.0Hz, 2H), 7.25-7.13 (m, 4H), 2.42 (s, 3H).
Chloro- 2- phenyl isoquinolins quinoline -1 (2H) -one of step 2) (S) -3- (1- aminopropyls) -8-
The chloro- 6- Methyl-N-phenyls benzamides (1.50g, 6.10mmol) of compound 2- are dissolved in THF (10mL), Then under -30 DEG C and nitrogen protection, the THF solution (2.5M, 6.10mL, 15.26mmol) of n-BuLi is added dropwise thereto, Time for adding is 30 minutes, and gained dark yellow reaction solution is directly used in and reacts in next step after the temperature continues stirring 30 minutes.
By compound (1- (methoxyl group (methyl) amino) -1- oxo-butanes -2- bases) t-butyl carbamate (2.26g, 9.16mmol) be dissolved in THF (15mL), then -30 DEG C and nitrogen protection under, be added dropwise thereto i-PrMgCl (2M, 5.04mL, 10.08mmol), time for adding be 30 minutes, gained reaction solution continue at -30 DEG C stirring 30 minutes, then - At 30 DEG C, be added dropwise system obtained above, resulting solution stirred at -15 DEG C 2 it is small when, then the H with 50mL2O is quenched instead Should, gained mixture is extracted with ethyl acetate (100mL × 2), and the organic phase of merging uses the saturation NH of 100mL successively4Cl is water-soluble The saturated common salt water washing of liquid and 100mL, then be concentrated under reduced pressure, pale yellow oil is obtained, the grease is not purified, directly uses Reacted in next step.
At room temperature, pale yellow oil derived above is dissolved in the MeOH of 20mL, and adds 15mL thereto Concentrated hydrochloric acid, resulting solution is stirred overnight at 95 DEG C, is cooled to room temperature, and is concentrated under reduced pressure and removes solvent.Gained residue With the mixed extractant solvent of PE/EtOAc (50mL/25mL), water mutually uses NaHCO3Powder is adjusted to pH=8.5, then with DCM (80mL × 3) extract, the saturated common salt water washing of the organic phase 100mL of merging, then be concentrated under reduced pressure.Gained residue is through silica gel column layer (DCM/MeOH (v/v)=20/1) purifying is analysed, it is pale yellow oil (1.2g, 63%) to obtain title compound.
MS(ESI,pos.ion)m/z:313.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm)：7.53-7.39(m,6H),7.25-7.23(m,2H),6.62(s,1H), 3.42-3.38 (dd, J=7.2,5.2Hz, 0H), 1.74-1.64 (m, 1H), 1.51 (m, 1H), 0.80-0.76 (t, J= 7.2Hz,1H)。
Step 3) (S) -3- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) third Base) chloro- 2- phenyl isoquinolins quinoline -1 (2H) -one of -8-
By chloro- 2- phenyl isoquinolins quinoline -1 (2H) -one (44mg, 0.14mmol) of compound (S) -3- (1- aminopropyls) -8-, The chloro- 5- of 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (30mg, 0.14mmol) and DIPEA (55mg, 0.42mmol) be suspended in n-BuOH (1mL), mixture be heated to 125 DEG C reaction 16 it is small when, be subsequently cooled to room temperature, then It is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=200/4), and it is light to obtain title compound Yellow solid (43mg, 62%).
MS(ESI,pos.ion)m/z:488.0[M+H]+；HPLC：98%；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.53 (d, J=6.4Hz, 1H), 8.02 (s, 1H), 7.58-7.42 (m,8H),6.65(s,1H),4.56-4.51(m,1H),2.44(s,3H),1.86-1.79(m,1H),1.69-1.61(m,1H), 0.78-0.74 (t, J=7.2Hz, 3H).
Embodiment 4 (S) -3- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) Ethyl) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-
The chloro- N- cyclopropyl -6- methyl benzamides of step 12-
The chloro- 6- methyl benzoic acids (4.0g, 23.45mmol) of 2- are suspended in toluene (30mL), then at room temperature, to Wherein add SOCl2(8.0mL, 106.54mmol), reaction solution are stirred overnight at 90 DEG C, are subsequently cooled to room temperature, then depressurize Concentration.Gained residue is dissolved in the DCM of 30mL, and then at 0 DEG C, NEt is added dropwise into obtained solution3 (13.00mL, 93.79mmol) and cyclopropylamine (1.80mL, 25.79mmol), resulting solution is stirred at room temperature overnight, Ran Houyong Reaction is quenched in the saturated salt solution of 50mL, and organic phase uses 100mL saturations NaHCO successively3Aqueous solution and 100mL saturated salt solutions Wash, use anhydrous Na2SO4It is dry, it is concentrated under reduced pressure.Gained residue purifies (PE/EtOAc (v/v)=1/1) through silica gel column chromatography and obtains It is white solid (4.5g, 90%) to title compound.
1H NMR(600MHz,CDCl3)δ(ppm):7.16-7.15(m,2H),7.06-7.05(m,1H),5.93(br.s, 1H),2.90-2.87(m,1H),2.31(s,3H),0.87-0.84(m,2H),0.64-0.61(m,2H)。
Step 2 (S) -2- ((tertbutyloxycarbonyl) amino) propionic acid
Compound (S) -2- alanines (10.00g, 112.24mmol) are suspended in H2In O (56mL), then at 0 DEG C Under, NaOH (6.73g, 168.36mmol) is added into reaction solution, then the THF and (Boc) of 56mL are added with funnel2O (31.85g, 145.91mmol), resulting solution be stirred at room temperature 17 it is small when, then with petroleum ether (100mL × 2) extract, water PH=1 mutually is adjusted to 4M HCl/water solution, is then extracted again with EtOAc (100mL × 4), organic phase the satisfying with 100mL of merging And brine It, dried with anhydrous sodium sulfate, and be concentrated under reduced pressure, obtain title compound for colorless oil (21.2g, 100%), the oily compound is without being further purified, for reacting in next step.
1H NMR(600MHz,CDCl3)δ(ppm):9.95 (br.s, 1H), 5.19-5.18 (d, J=5.5Hz, 1H), 4.32-4.31 (m, 1H), 1.41 (s, 9H), 1.41-1.39 (d, J=7.8Hz, 3H).
Step 3 (S)-(1- (methoxyl group (methyl) amino) -1- oxopropan -2- bases) t-butyl carbamate
By compound (S) -2- ((tertbutyloxycarbonyl) amino) propionic acid (22.00g, 116.27mmol), N, O- dimethylhydroxylamines Hydrochloride (12.35g, 127.90mmol) and HOAT (18.99g, 139.53mmol) are suspended in DCM (232mL), then 0 At DEG C, NEt is added thereto3(64.8mL, 465.09mmol), is cooled to -10 DEG C, then be added dropwise EDCI (26.75g, 139.53mmol), after adding, gained mixture reacted at -10 DEG C 1 it is small when after, after 2 days are then stirred at room temperature again, With the H of 200mL2Reaction is quenched in O.Organic phase uses the saturation NaHCO of 200mL successively3Aqueous solution and the washing of the saturated common salt of 200mL Wash, then use anhydrous Na2SO4It is dry, and be concentrated under reduced pressure.Gained residue is pure through silica gel column chromatography (PE/EtOAc (v/v)=4/1) Change, it is white solid (7.4g, 86%) to obtain title compound.
MS(ESI,pos.ion)m/z:177.0[M-C4H8+H]+, 133.0 [M-Boc+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):5.24 (d, J=5.4Hz, 1H), 4.68 (m, 1H), 3.76 (s, 3H), 3.20 (s, 3H), 1.43 (s, 9H), 1.31-1.30 (d, J=6.6Hz, 3H).
Chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of step 4) (S) -3- (1- amino-ethyls) -8-
The chloro- N- cyclopropyl -6- methyl benzamides (1.50g, 7.15mmol) of compound 2- are dissolved in THF (10mL) In, then under -30 DEG C and nitrogen protection, n-BuLi (2.5M, 7.15mL, 17.87mmol) is added dropwise thereto, gained is dark After yellow reaction liquid continues stirring 30 minutes at such a temperature, it is directly used in and reacts in next step.
By compound (S)-(1- (methoxyl group (methyl) amino) -1- oxopropan -2- bases) t-butyl carbamate (2.49g, 10.73mmol) is dissolved in THF (15mL), and then under -30 DEG C and nitrogen protection, i- is added dropwise thereto PrMgCl (2M, 5.90mL, 11.80mmol), after 30 minutes are added dropwise, after being stirred 30 minutes at -30 DEG C, in the temperature Under, mixture is added dropwise in reaction solution obtained above.Resulting solution stirred at -15 DEG C 3 it is small when, then use 40mL H2Reaction is quenched in O, adds the saturation NH of the EtOAc and 60mL of 60mL4Cl aqueous solutions.Water is mutually extracted with EtOAc (100mL × 2) Take, the organic phase of merging uses the saturation NH of 100mL respectively4The saturated common salt water washing of Cl aqueous solutions and 100mL, then be concentrated under reduced pressure Pale yellow oil is obtained, the grease is not purified, is directly used in and reacts in next step.
At room temperature, grease will be obtained above to be dissolved in the MeOH of 15mL, and adds the concentrated hydrochloric acid of 15mL thereto, Resulting solution is stirred overnight at 95 DEG C, is subsequently cooled to room temperature, and is concentrated under reduced pressure and is removed organic solvent, residue PE/ EtOAc (50mL/25mL) mixed extractant solvent, water mutually use NaHCO3Powder is adjusted to pH=8.5, then is extracted with DCM (100mL × 3) Take, the saturated common salt water washing of the organic phase 100mL of merging, and be concentrated under reduced pressure.Residue is through silica gel column chromatography (DCM/MeOH (v/v)=20/1) purify, it is faint yellow solid (1.67g, 89%) to obtain title compound.
MS(ESI,pos.ion)m/z:263.0[M+H]+；
1H NMR(600MHz,DMSO-d6)δ(ppm):7.53-7.50 (t, J=7.8Hz, 1H), 7.48-7.46 (dd, J= 7.8,1.0Hz, 1H), 7.38-7.37 (dd, J=7.8,1.2Hz, 1H), 6.72 (s, 1H), 4.61-4.57 (q, J=6.6Hz, 1H), 2.97 (m, 1H), 1.31-1.30 (d, J=6.6Hz, 3H), 1.18-1.16 (m, 2H), 0.78-0.75 (m, 1H), 0.65- 0.62(m,1H)。
Step 5) (S) -3- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) second Base) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-
By chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of compound (S) -3- (1- amino-ethyls) -8- (39mg, 0.148mmol), the chloro- 5- of 6- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine -4- amine (30mg, 0.142mmol), DIPEA The mixture of (55mg, 0.42mmol) and n-BuOH (1mL) be heated to 130 DEG C and stir reaction 24 it is small when, be subsequently cooled to room Temperature, and be concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=100/1), obtains title compound For faint yellow solid (35mg, 56%).
MS(ESI,pos.ion)m/z:438.0[M+H]+；HPLC:98%；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.41 (d, J=4.4Hz, 1H), 8.02 (s, 1H), 7.48-7.40 (m,3H),7.28(s,2H),6.54(s,1H),5.95(m,1H),3.02(m,1H),2.60(s,3H),1.59(s,3H),1.22 (m,4H)。
Embodiment 5 (S) -3- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) Propyl group) chloro- 2- phenyl isoquinolins quinoline -1 (2H) -one of -8-
Chloro- 2- phenyl isoquinolins quinoline -1 (2H) -one of (S) -3- (1- aminopropyls) -8- (46mg, 0.147mmol), 6- is chloro- 5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine -4- amine (30mg, 0.142mmol) and DIPEA (55mg, 0.42mmol) are outstanding Float in n-BuOH (1.5mL), reaction mixture stirred at 125 DEG C 16 it is small when, be subsequently cooled to room temperature, and be concentrated under reduced pressure, Gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=50/1), obtains crude product, the crude product is through thin-layer chromatography Method is further purified, and it is faint yellow solid (39mg, 56%) to obtain title compound.
MS(ESI,pos.ion)m/z:488.0[M+H]+；HPLC:97%；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.35(s,1H),8.00(s,1H),7.55-7.24(m,8H), 6.62(s,1H),4.52(m,1H),2.60(s,3H),1.82(m,1H),1.63(m,1H),0.74(m,3H)。
Embodiment 6 (S) -3- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) Propyl group) -1 (2H) -one of -2- cyclopropyl -8- methylisoquinoliniums
Step 1) N- cyclopropyl -2,6- dimethyl benzamides
By compound 2,6- mesitylenic acids (4.0g, 26.64mmol) are suspended in toluene (30mL), then in room temperature Under, SOCl is added thereto2(8.0mL, 106.54mmol), reaction solution are stirred overnight at 90 DEG C, are subsequently cooled to room temperature, and It is concentrated under reduced pressure.Gained residue is dissolved in the DCM of 30mL, and at 0 DEG C, NEt is added into resulting solution3(14.85mL, 106.54mmol), then it is added dropwise cyclopropylamine (2.03mL, 29.30mmol).Resulting solution be stirred at room temperature 2 it is small when after, add Reaction is quenched in the saturated salt solution for entering 50mL.Liquid separation, organic phase use the saturation NaHCO of 100mL successively3Aqueous solution and 100mL's Saturated common salt water washing, then dried with anhydrous sodium sulfate, it is concentrated under reduced pressure, concentrated residues thing is through silica gel column chromatography (PE/EtOAc (v/ V)=4/1) purify, it is white solid (4.0g, 80%) to obtain title compound.
1H NMR(400MHz,CDCl3)δ(ppm):7.14-7.10 (dd, J=7.6,7.6Hz, 1H), 6.99-6.97 (d, J =7.6Hz, 2H), 5.81 (br.s, 1H), 3.92-2.86 (m, 1H), 2.28 (s, 6H), 0.88-0.84 (m, 2H), 0.60- 0.56(m,2H)。
- 1 (2H) -one of step 2) (S) -3- (1- aminopropyls) -2- cyclopropyl -8- methylisoquinoliniums
Compound N-cyclopropyl -2,6- dimethyl benzamides (2.00g, 10.57mmol) are dissolved in THF (20mL) In, then under -30 DEG C and nitrogen protection, n-BuLi (10.57mL, 26.42mmol) is added dropwise thereto, is added dropwise within 30 minutes Finish, after obtained dark yellow solution continues stirring 30 minutes at such a temperature, be directly used in and react in next step.
By compound (S)-(1- (methoxyl group (methyl) amino) -1- oxo-butanes -2- bases) t-butyl carbamate (3.90g, 15.85mmol) is dissolved in THF (20mL), and then under -30 DEG C and nitrogen protection, i- is added dropwise thereto PrMgBr (1M, 17.44mL, 17.44mmol), is added dropwise for 30 minutes, and reaction mixture continues stirring 30 minutes in this temperature, Then secondary mixture is added dropwise in system obtained above at such a temperature.It is small that resulting solution stirs 3 at -15 DEG C When, then the H with 50mL2Reaction is quenched in O, and gained mixture is extracted with EtOAc (100mL × 2), and the organic phase of merging is used successively The saturation NH of 100mL4The saturated common salt water washing of Cl aqueous solutions and 100mL, then be concentrated under reduced pressure, the grease of yellow is obtained, should Not purified be directly used in of grease is reacted in next step.
The yellow oil that upper step obtains is dissolved in the MeOH of 20mL, then at room temperature, adds 20mL thereto Concentrated hydrochloric acid.Reaction solution stirred at 80 DEG C 1 it is small when, be subsequently cooled to room temperature, then be concentrated under reduced pressure.Residue PE/EtOAc The mixed extractant solvent of (50mL/25mL), water mutually use NaHCO3Powder alkalizes to pH=8.5, then is extracted with DCM (100mL × 3) Take.The saturated common salt water washing of the organic phase of merging 100mL, then be concentrated under reduced pressure, gained residue is through silica gel column chromatography (DCM/ MeOH (v/v)=10/1) purifying, it is yellow oil (1.7g, 62%) to obtain title compound.
MS(ESI,pos.ion)m/z:257.0[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.40-7.37 (dd, J=7.8,7.2Hz, 1H), 7.25-7.23 (d, J =7.8Hz, 1H), 7.14-7.13 (d, J=7.2Hz, 1H), 6.48 (s, 1H), 4.55-4.53 (dd, J=7.2,5.4Hz, 1H), 2.91-2.87 (m, 1H), 2.87 (s, 3H), 1.85-1.78 (m, 1H), 1.33-1.22 (m, 3H), 0.99 (t, J= 7.4Hz,3H),0.85-0.76(m,2H)。
Step 3) (S) -3- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) third Base) -1 (2H) -one of -2- cyclopropyl -8- methyl isoquinolines oxazoline
By -1 (2H) -one of compound (S) -3- (1- aminopropyls) -2- cyclopropyl -8- methylisoquinoliniums (38mg, 0.148mmol), the chloro- 5- of 6- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine -4- amine (30mg, 0.142mmol), DIPEA The mixture of (55mg, 0.42mmol) and n-BuOH (1.5mL) be heated to 130 DEG C and stir reaction 16 it is small when, be subsequently cooled to Room temperature, then be concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=50/1), obtains crude product, slightly Product is further purified through thin-layered chromatography, and it is faint yellow solid (39mg, 63.6%) to obtain title compound.
MS(ESI,pos.ion)m/z:432.0[M+H]+；HPLC:94%；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.47(s,1H),8.01(s,1H),7.39-7.14(m,3H), 6.38(s,1H),5.84(m,1H),2.98(m,1H),2.74(s,3H),2.60(s,3H),2.02(m,1H),1.78(m,1H), 1.22(m,4H),1.04(m,3H)。
Embodiment 7 (S) -3- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Propyl group) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-
The chloro- N- cyclopropyl -6- methyl benzamides of step 1) 2-
The chloro- 6- methyl benzoic acids (4.0g, 23.45mmol) of compound 2- are suspended in toluene (30mL), then in room Under temperature, SOCl is added thereto2(8.0mL, 106.54mmol), reaction solution are stirred overnight at 90 DEG C, are subsequently cooled to room temperature, It is concentrated under reduced pressure again.Gained residue is dissolved in the DCM of 30mL, at 0 DEG C, adds NEt thereto3(13.00mL, 93.79mmol), then it is added dropwise cyclopropylamine (1.80mL, 25.79mmol).Resulting solution is stirred at room temperature overnight, Ran Houyong Reaction is quenched in the saturated salt solution of 50mL, and the organic phase that liquid separation obtains uses the saturation NaHCO of 100mL successively3Aqueous solution and 100mL Saturated common salt water washing, then dried, be concentrated under reduced pressure with anhydrous sodium sulfate.Residue is through silica gel column chromatography (PE/EtOAc (v/v) =1/1) purify, it is white solid (4.5g, 90%) to obtain title compound.
1H NMR(600MHz,CDCl3)δ(ppm):7.16-7.15(m,2H),7.06-7.05(m,1H),5.93(br.s, 1H),2.90-2.87(m,1H),2.31(s,3H),0.87-0.84(m,2H),0.64-0.61(m,2H)。
Chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of step 2) (S) -3- (1- aminopropyls) -8-
The chloro- N- cyclopropyl -6- methyl benzamides (2.00g, 9.54mmol) of compound 2- are dissolved in THF (20mL) In, then under -30 DEG C and nitrogen protection, n-BuLi (10.50mL, 25.75mmol) is added dropwise thereto, is added dropwise within 30 minutes Finish, gained dark yellow solution continues stirring 30 minutes at such a temperature, which is directly used in reacts in next step.
By compound (S)-(1- (methoxyl group (methyl) amino) -1- oxo-butanes -2- bases) t-butyl carbamate (3.99g, 16.22mmol) is dissolved in THF (20mL), and under -30 DEG C and nitrogen protection, i-PrMgBr is added dropwise thereto (2M,9.54mL,19.08mmol).Reaction solution continue at -30 DEG C stirring 30 minutes, then at such a temperature, reaction solution by It is added dropwise in system obtained above.Resulting solution stirred at -15 DEG C 3 it is small when after, with the H of 50mL2Reaction is quenched in O, mixes Compound is extracted with EtOAc (100mL × 2), and the organic phase of merging uses the saturation NH of 100mL successively4The food of Cl aqueous solutions and 100mL Salt water washing, then be concentrated under reduced pressure, yellow oil is obtained, the grease is not purified, is directly used in and reacts in next step.
Grease obtained above is dissolved in the MeOH of 20mL, and at room temperature, adds the dense HCl of 20mL thereto In, resulting solution stirred at 80 DEG C 1 it is small when, be subsequently cooled to room temperature, then be concentrated under reduced pressure, gained residue PE/EtOAc (50mL/25mL) is extracted, and water mutually uses NaHCO3Alkalization is extracted to pH=8.5, then with DCM (100mL × 3).The organic phase of merging With the brine It of 100mL, and it is concentrated under reduced pressure, gained residue is pure through silica gel column chromatography (DCM/MeOH (v/v)=20/1) Change, it is pale yellow oil (2.5g, 95%) to obtain title compound.
MS(ESI,pos.ion)m/z:277.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.38-7.35 (m, 2H), 7.29-7.27 (dd, J=6.8,2.4Hz, 1H), 6.50 (s, 1H), 4.56-4.53 (dd, J=7.2,5.2Hz, 1H), 2.92-2.86 (m, 1H), 1.86-1.75 (m, 1H), 1.34-1.29 (m, 1H), 1.28-1.23 (m, 2H), 1.02-0.96 (t, J=7.6Hz, 3H), 0.86-0.80 (m, 2H).
Step 3) (S) -3- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) third Base) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-
By chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of compound (S) -3- (1- aminopropanes) -8- (47mg, 0.17mmol), the chloro- 5- of 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (30mg, 0.14mmol), DIPEA The mixture of (55mg, 0.42mmol) and n-BuOH (1mL) be heated to 130 DEG C and stir reaction 24 it is small when, be subsequently cooled to room Temperature, is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=100/1), and obtaining title compound is Faint yellow solid (46mg, 72%).
MS(ESI,pos.ion)m/z:452.0[M+H]+；HPLC:96%；
1H NMR(600MHz,CDCl3)δ(ppm):8.59-8.58 (d, J=5.4Hz, 1H), 8.11 (s, 1H), 7.38- 7.34 (m, 2H), 7.22-7.21 (dd, J=6.6,2.4Hz, 1H), 6.30 (s, 1H), 6.00-5.97 (td, J=7.8, 4.8Hz,1H),3.02-2.98(m,1H),2.50(s,3H),2.08-2.01(m,1H),1.86-1.79(m,1H),1.51- 1.47 (m, 1H), 1.42-1.37 (m, 1H), 1.33-1.28 (m, 1H), 1.12-1.09 (t, J=7.8Hz, 3H), 0.90-0.86 (m,1H)。
Embodiment 8 (S) -3- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Ethyl) chloro- 2- phenyl isoquinolins quinoline -1 (2H) -one of -8-
The chloro- 6- Methyl-N-phenyls benzamides of step 1) 2-
The chloro- 6- methyl benzoic acids (6.00g, 35.17mmol) of compound 2- are dissolved in toluene (40mL), then in room Under temperature, SOCl is added thereto2(10.21mL, 140.69mmol), reaction solution stirred at 110 DEG C 5 it is small when, be subsequently cooled to Room temperature, is concentrated under reduced pressure.Gained residue is dissolved in DCM (50mL), and at 0 DEG C, NEt is added into resulting solution3 (14.71mL, 105.51mmol) and aniline (2.95g, 31.65mmol).Gained mixture is stirred at room temperature overnight, Ran Houyi The secondary H with 200mL2O, the saturation NaHCO of 200mL3The saturated common salt water washing of aqueous solution and 200mL.Liquid separation is obtained organic Mutually it is concentrated under reduced pressure, gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=4/1), and it is white to obtain title compound Color solid (7.4g, 86%).
MS(ESI,pos.ion)m/z:246.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.63-7.61 (d, J=8.0Hz, 2H), 7.45 (br.s, 1H), 7.39-7.35 (t, J=8.0Hz, 2H), 7.25-7.13 (m, 4H), 2.42 (s, 3H).
Chloro- 2- phenyl isoquinolins quinoline -1 (2H) -one of step 2) (S) -3- (1- aminopropyls) -8-
The chloro- 6- Methyl-N-phenyls benzamides (2.00g, 8.14mmol) of compound 2- are dissolved in THF (15mL), Then under -30 DEG C and nitrogen protection, n-BuLi (8.14mL, 20.35mmol) is added dropwise thereto, time for adding is more than 30 Minute, after gained dark yellow solution continues stirring 30 minutes at such a temperature, which is used to react in next step.
By compound (S)-(1- (methoxyl group (methyl) amino) -1- oxopropan -2- bases) t-butyl carbamate (2.84g, 12.21mmol) is dissolved in THF (20mL), and then under -30 DEG C and nitrogen protection, i- is added dropwise thereto PrMgCl (2M, 6.72mL, 13.43mmol), gained reaction solution are stirred 30 minutes at -30 DEG C, then incited somebody to action at such a temperature To mixture be added dropwise in system obtained above.Resulting solution stirred at -15 DEG C 3 it is small when after, with the H of 40mL2O Reaction is quenched, and adds the saturation NH of the EtOAc and 100mL of 100mL4Cl aqueous solutions.Isolated water mutually uses EtOAc (100mL × 2) extract, and the organic phase of merging uses the saturation NH of 100mL successively4Cl aqueous solutions and the washing of the saturated common salt of 100mL Wash, then be concentrated under reduced pressure, obtain yellow oil, which is directly used in and reacts in next step without being further purified.
At room temperature, yellow oil obtained above is dissolved in the MeOH of 15mL, and adds 15mL's thereto Concentrated hydrochloric acid, resulting solution stirred at 95 DEG C 14 it is small when, be subsequently cooled to room temperature, then be concentrated under reduced pressure and remove, gained residue PE/ EtOAc (50mL/25mL) is extracted, and water mutually uses NaHCO3Powder is adjusted to pH=8.5, then is extracted with DCM (100mL × 3), merging The brine It of organic phase 100mL, then be concentrated under reduced pressure, gained residue through silica gel column chromatography (DCM/MeOH (v/v)= 10/1) purify, it is faint yellow solid (2.0g, 78.6%) to obtain title compound.
MS(ESI,pos.ion)m/z:299.0[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.54-7.41(m,6H),7.27-7.26(m,2H),6.71(s,1H), 3.72-3.69 (q, J=6.6Hz, 1H), 1.25-1.24 (d, J=6.6Hz, 3H).
Step 3) (S) -3- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) second Base) chloro- 2- phenyl isoquinolins quinoline -1 (2H) -one of -8-
By chloro- 2- phenyl isoquinolins quinoline -1 (2H) -one (42mg, 0.13mmol) of compound (S) -3- (1- aminopropyls) -8-, The chloro- 5- of 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (25mg, 0.12mmol), DIPEA (46mg, 0.35mmol) and n-BuOH (1mL) mixture be warming up to 125 DEG C and stir reaction 7 it is small when, be subsequently cooled to room temperature, then subtract Pressure concentration.Gained residue is purified through silica gel column chromatography (DCM/MeOH (v/v)=50/1), and it is solid for white to obtain title compound Body (17mg, 30%).
MS(ESI,pos.ion)m/z:474.0[M+H]+；HPLC:98%；
1H NMR(600MHz,CDCl3)δ(ppm):8.29-8.28 (d, J=5.4Hz, 1H), 8.03 (s, 1H), 7.54- 7.43 (m, 6H), 7.38-7.36 (dd, J=7.2,1.2Hz, 1H), 7.34-7.33 (d, J=7.2Hz, 1H), 6.53 (s, 1H), 5.00-4.98 (m, 1H), 2.50 (s, 3H), 1.47 (d, J=6.8Hz, 3H).
Embodiment 9 (S) -3- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) Ethyl) chloro- 2- phenyl isoquinolins quinoline -1 (2H) -one of -8-
Chloro- 2- phenyl isoquinolins quinoline -1 (2H) -one of (S) -3- (1- aminopropyls) -8- (50mg, 0.16mmol) and 6- is chloro- 5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine -4- amine (45mg, 0.21mmol) is suspended in n-BuOH (5mL), then Add DIPEA (45mg, 0.35mmol) thereto, gained mixture be heated to reflux 16 it is small when, and with thin-layered chromatography (PE/ EtOAc, v/v, 1/2) monitoring reaction, after having reacted, mixture is cooled to room temperature, then be concentrated under reduced pressure, gained residue is through silicon Plastic column chromatography (PE/EtOAc (v/v)=1/2) purifies, and it is white solid (65mg, 86%) to obtain title compound.
MS(ESI,pos,ion):474.1[M+H]+；HPLC:99.3%；
1H NMR(600MHz,CDCl3)δ(ppm):8.88 (d, J=6.6Hz, 1H), 8.02 (s, 1H), 7.60-7.11 (m, 7H), 6.56 (s, 1H), 6.45 (s, 2H), 5.03 (dd, J=13.4,6.7Hz, 1H), 4.14 (q, J=7.1Hz, 1H), 2.69 (s, 3H), 1.49 (d, J=6.8Hz, 3H).
Embodiment 10 (S) -3- (1- ((6- amino -5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine-4-yl) amino) Propyl group) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-
By chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of (S) -3- (1- aminopropyls) -8- (80mg, 0.29mmol) and 6- Chloro- 5- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) pyrimidine -4- amine (60mg, 0.28mmol) is suspended in n-BuOH (5mL), so Add DIPEA (90mg, 0.58mmol) thereto afterwards, gained mixture be heated to reflux 24 it is small when, and with thin-layered chromatography (PE/ EtOAc, v/v, 1/2) monitoring reaction.Mixture is cooled to room temperature, and is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (PE/ EtOAc (v/v)=1/2) purifying, it is white solid (51mg, 39%) to obtain title compound.
MS(ESI,pos,ion):452.2[M+H]+；HPLC:96.8%；
1H NMR(600MHz,CDCl3)δ(ppm):8.83 (d, J=7.0Hz, 1H), 8.13 (d, J=11.5Hz, 1H), 7.37 (dd, J=6.8,3.6Hz, 2H), 7.22 (dd, J=5.9,3.2Hz, 1H), 6.35 (s, 1H), 6.14 (s, 2H), 6.01 (td, J=8.5,4.1Hz, 1H), 3.13 (m, 1H), 2.69 (d, J=10.6Hz, 3H), 1.87 (m, 1H), 1.52 (m, 1H), 1.45 (m, 1H), 1.32 (m, 1H), 1.13 (t, J=7.4Hz, 3H) .0.91 (m, 2H).
Embodiment 11 (S) -3- (1- ((6- amino -5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) Ethyl) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-
By chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of (S) -3- (1- amino-ethyls) -8- (80mg, 0.30mmol) and 6- Chloro- 5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine -4- amine (60mg, 0.28mmol) is suspended in n-BuOH (5mL), so Add DIPEA (90mg, 0.58mmol) thereto afterwards, gained mixture be heated to reflux 24 it is small when, and with thin-layered chromatography (PE/ EtOAc, v/v, 1/2) monitoring reaction, mixture is cooled to room temperature, is concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/ EtOAc (v/v)=1/2) purifying, it is white solid (42mg, 35%) to obtain title compound.
MS(ESI,pos,ion):438.1[M+H]+；HPLC:96.3%；
1H NMR(400MHz,CDCl3)δ(ppm):8.35 (d, J=6.5Hz, 1H), 8.12 (s, 1H), 7.51-7.33 (m, 2H),7.25(m,1H),6.42(s,1H),6.20-6.07(m,1H),3.01(s,1H),2.73(s,3H),1.65(m,3H), 1.44(m,2H),0.91(m 2H)。
Embodiment 12 (S) -3- (1- ((6- amino -5- (2- methyl -2H- tetrazole -5- bases) pyrimidine-4-yl) amino) second Base) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-
The iodo- 2- methyl -2H- tetrazoles of step 1) 5-
By 2- methyl -2H- tetrazole -5- amine (15.0g, 153mmol), CH2I2(62mL, 765mmol) and CuI (29.0g, 153mmol) it is suspended in THF (160mL), and adds amyl nitrite (62mL, 549mmol) thereto.Reaction mixture Be heated to reflux 1 it is small when, be subsequently cooled to room temperature, and be concentrated under reduced pressure, gained residue is diluted with EtOAc (150mL), separated to have Machine is mutually washed with ammonium hydroxide (20mL, 25% aqueous solution) and saline solution (10mL) successively, anhydrous sodium sulfate drying, and decompression is dense Contracting.Gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=20/1), and it is white solid to obtain title compound (24.2g, 76%).
MS(ESI,pos.ion.)m/z:211.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):4.42(s,3H)。
Step 2) 2- methyl -5- (tributyl tin) -2H- tetrazoles
The iodo- 2- methyl -2H- tetrazoles (3.0g, 14.3mmol) of 5- are dissolved in dry THF (70mL), then - Under 78 DEG C and nitrogen protection, the hexane solution (2.5M, 7.15mL, 17.9mmol) of n-BuLi is slowly added into reaction solution, Mixture stirs 30 minutes at -78 DEG C, is then slowly added into tributyltin chloride (4.3mL, 15.7mmol), reaction mixture Continue at -78 DEG C stirring 30 minutes after, be warmed to room temperature, stirring 2 it is small when after, add 5%NH4Cl aqueous solutions (30mL) are quenched instead Should, gained mixture is extracted with EtOAc (30mL × 3), organic phase washed with water (2mL) and saline solution (2mL) washing of merging, To be dried, be concentrated under reduced pressure with anhydrous sodium sulfate again, gained residue is purified through silica gel column chromatography (PE/EtOAc (v/v)=20/1), It is colourless liquid (3.6g, 68%) to obtain title compound.
MS(ESI,pos.ion.)m/z:375.1[M+H]+。
Step 3) 4,6- dimethoxys -5- (2- methyl -2H- tetrazole -5- bases) pyrimidine
By compound 2- methyl -5- (tributyl tin) -2H- tetrazoles (1.85g, 4.96mmol), bromo- 4, the 6- dimethoxies of 5- Yl pyrimidines (543mg, 2.48mmol) and [double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex (204mg, 0.25mmol) is suspended in dry DMF (10mL), and mixture is heated to 120 DEG C, and stirs under nitrogen protection React 24 it is small when, be subsequently cooled to room temperature, then be concentrated under reduced pressure, gained residue through silica gel column chromatography (PE/EtOAc (v/v)= 10/1) purify, it is white solid (300mg, 55%) to obtain title compound.
MS(ESI,pos.ion.)m/z:223.2[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.55(s,1H),4.45(s,3H),4.00(s,6H)。
Step 4) 5- (2- methyl -2H- tetrazole -5- bases) pyrimidine -4,6- glycol
4,6- dimethoxys -5- (2- methyl -2H- tetrazole -5- bases) pyrimidine (65mg, 0.29mmol) is dissolved in acetic acid In (1mL), then thereto add concentrated hydrochloric acid (12M, 1mL), reaction solution be heated to reflux 4 it is small when, be subsequently cooled to room temperature, depressurize Concentration, it is white solid (53mg, 95%) to obtain title compound.
MS(ESI,pos.ion.)m/z:195.1[M+H]+。
Bis- chloro- 5- of step 5) 4,6- (2- methyl -2H- tetrazole -5- bases) pyrimidine
Compound 5- (2- methyl -2H- tetrazole -5- bases) glycol of pyrimidine -4,6 (53mg, 0.27mmol) is dissolved in POCl3In (2mL), then thereto add DMF (0.3mL), be heated to reflux 5 it is small when after, unnecessary POCl is removed under reduced pressure3.To institute Obtain and 2g frozen water is added in residue, mixture is extracted with EtOAc (5mL × 3), and the organic phase of merging is washed with water (1mL), then is used Anhydrous sodium sulfate is dried, and is concentrated under reduced pressure, it is brown syrup shape thing (57mg, 91%) to obtain title compound, and the syrup is not It is purified, it is directly used in and reacts in next step.
MS(ESI,pos.ion.)m/z:231.0[M+H]+。
The chloro- 5- of step 6) 6- (2- methyl -2H- tetrazole -5- bases) pyrimidine -4- amine
Bis- chloro- 5- of compound 4,6- (2- methyl -2H- tetrazole -5- bases) pyrimidine (65mg, 0.28mmol) is dissolved in In THF (3mL), ammonia is then persistently filled with into reaction solution and is stirred overnight, is then concentrated under reduced pressure, residue is dissolved in In EtOAc (5mL), gained mixture uses H successively2O (1mL) and saline solution (1mL) washing, isolated organic phase is with anhydrous Sodium sulphate is dried, and is concentrated under reduced pressure.Gained residue is purified through silica gel column chromatography (n-hexane/ethyl acetate (v/v)=2/1), is obtained It is white solid (34mg, 56%) to title compound.
MS(ESI,pos.ion.)m/z:212.1[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.40(s,1H),4.51(s,3H)。
Step 7) (S) -3- (1- ((6- amino -5- (2- methyl -2H- tetrazole -5- bases) pyrimidine-4-yl) amino) second Base) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-
By the chloro- 5- of compound 6- (2- methyl -2H- tetrazole -5- bases) pyrimidine -4- amine (60mg, 0.284mmol) and (S) - Chloro- 2- cyclopropyl isoquinolin -1 (2H) -one (78.3mg, 0.298mmol) of 3- (1- amino-ethyls) -8- are dissolved in the n- of 5mL In BuOH, then thereto add DIPEA (0.2mL, 0.568mmol), mixture stir at 120 DEG C react 36 it is small when after, Be cooled to room temperature, then be concentrated under reduced pressure, residue is dissolved in EtOAc (20mL), gained mixture successively with water (15mL) and Saline solution (15mL) washs, and isolated organic phase is dried with anhydrous sodium sulfate, is concentrated under reduced pressure, and gained residue is through silicagel column (PE/EtOAc (v/v)=3/1) purifying is chromatographed, it is white solid (66mg, 53%) to obtain title compound.
MS(ESI,pos.ion)m/z:438.1[M+H]+；
1HNMR(400MHz,CDCl3)δ(ppm):8.57 (d, J=6.8Hz, 1H), 8.15 (s, 1H), 7.42-7.34 (m, 2H), 7.23 (dd, J=6.5,2.6Hz, 1H), 6.44 (s, 1H), 6.22-6.12 (m, 1H), 4.50 (s, 3H), 3.55 (s, 2H), 3.06-2.97 (m, 1H), 1.68 (d, J=6.8Hz, 3H), 1.51-1.39 (m, 2H), 0.97-0.89 (m, 2H).
Embodiment 13 (S) -3- (1- ((6- amino -5- (2- methyl -2H- tetrazole -5- bases) pyrimidine-4-yl) amino) third Base) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-
By the chloro- 5- of compound 6- (2- methyl -2H- tetrazole -5- bases) pyrimidine -4- amine (60mg, 0.284mmol) and (S) - Chloro- 2- cyclopropyl isoquinolin -1 (2H) -one (82.5mg, 0.298mmol) of 3- (1- aminopropyls) -8- are suspended in the n- of 5mL In BuOH, then thereto add DIPEA (0.2mL, 0.568mmol), mixture stir at 120 DEG C 36 it is small when after, cool down To room temperature, then it is concentrated under reduced pressure, residue is dissolved in EtOAc (20mL), gained mixture uses water (15mL) and salt successively Water (15mL) washs, and organic phase is dried with anhydrous sodium sulfate, is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=20/1) purify, it is white solid (32mg, 24.9%) to obtain title compound.
MS(ESI,pos.ion)m/z:452.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.66 (d, J=7.3Hz, 1H), 8.14 (s, 1H), 7.43-7.32 (m, 2H), 7.20 (dd, J=6.8,2.2Hz, 1H), 6.37 (s, 1H), 6.05 (d, J=8.0Hz, 1H), 4.52 (s, 3H), 3.65- 3.42 (m, 2H), 3.04 (s, 1H), 2.07 (s, 2H), 1.42 (dd, J=13.2,7.1Hz, 2H), 1.15 (t, J=7.4Hz, 2H), 0.90 (t, J=6.7Hz, 3H).
Embodiment 14 (S) -3- (4- amino -6- ((1- (chloro- 2- cyclopropyl -1- oxos -1,2- dihydro-isoquinolines -3- of 8- Base) propyl group) amino) pyrimidine -5- bases) -1- methyl isophthalic acid H-1,2,4- triazole -5- butyl formates
Step 1) 3- (4,6- dichloro pyrimidine -5- bases) -1- methyl isophthalic acid H-1,2,4- triazole -5- Ethyl formates
By compound 3- (4,6- dimethoxypyridin -5- bases) -1- methyl isophthalic acid H-1,2,4- triazole -5- Ethyl formates (500mg, 1.70mmol) is dissolved in toluene (25mL), then adds POCl thereto3(2mL, 17.0mmol) and DMF (4mL).Mixture stirred at 120 DEG C reaction 48 it is small when after, be cooled to room temperature, be concentrated under reduced pressure, gained residue is through silicagel column (PE/EtOAc (v/v)=10/1) purifying is chromatographed, it is pale yellow oil (375mg, 73%) to obtain title compound.
MS(ESI,pos,ion):303.1[M+H]+。
Step 2) 3- (4- amino -6- chlorine pyrimidine -5- bases) -1- methyl isophthalic acid H-1,2,4- triazole -5- Ethyl formates
By compound 3- (4,6- dichloro pyrimidine -5- bases) -1- methyl isophthalic acid H-1,2,4- triazole -5- Ethyl formates (375mg, 1.24mmol) is dissolved in dry THF (20mL), and ammonia is filled with into reaction solution, is then stirred at room temperature anti- Answer 5 it is small when, and with thin-layered chromatography (EtOAc) monitor react, mixture is filtered, and with ethyl acetate (10mL) rinse filter Cake, for filtrate through being concentrated under reduced pressure, it is white solid (320mg, 91.2%) to obtain title compound.
MS(ESI,pos,ion):283.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.35 (s, 1H), 4.53 (q, J=7.1Hz, 2H), 4.36 (s, 3H), 1.69 (s, 2H), 1.49 (t, J=7.1Hz, 3H).
Step 3) (S) -3- (4- amino -6- ((1- (the chloro- 2- cyclopropyl -1- oxos -1,2- dihydro-isoquinolines -3- bases of 8-) Propyl group) amino) pyrimidine -5- bases) -1- methyl isophthalic acid H-1,2,4- triazole -5- butyl formates
By compound 3- (4- amino -6- chlorine pyrimidine -5- bases) -1- methyl isophthalic acid H-1,2,4- triazole -5- Ethyl formates Chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of (60mg, 0.212mmol) and (S) -3- (1- aminopropyls) -8- (61.4mg, 0.222mmol) it is dissolved in the n-BuOH of 5mL, then adds DIPEA (0.2mL, 0.424mmol) thereto.Mixture is close It is enclosed in tube sealing, when 160 DEG C of stirring reactions 24 are small, is then concentrated under reduced pressure, gained residue is dissolved in EtOAc (15mL), And washed successively with water (15mL) and saline solution (15mL), organic phase is concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=3/1) is purified, and it is white solid (34mg, 29%) to obtain title compound.
MS(ESI,pos.ion)m/z:551.2[M+H]+；HPLC:95.6%；
1H NMR(400MHz,CDCl3)δ(ppm):9.32 (d, J=6.8Hz, 1H), 8.08 (s, 1H), 7.35 (q, J= 7.3Hz, 2H), 7.20 (dd, J=7.0,2.1Hz, 1H), 6.38 (s, 1H), 6.01 (m, 1H), 4.47-4.40 (m, 2H), 4.36 (s, 3H), 3.03 (m, 1H), 2.13-2.00 (m, 2H), 1.91-1.80 (m, 1H), 1.77 (dd, J=14.7,6.8Hz, 3H), 1.63 (m, 1H), 1.53-1.38 (m, 3H), 1.38-1.32 (m, 1H), 1.14 (t, J=7.4Hz, 3H), 0.95 (t, J= 7.4Hz,3H),0.93-0.84(m,1H)。
Embodiment 15 (S) -3- (1- ((6- amino -5- (2- methyl -2H- tetrazole -5- bases) pyrimidine-4-yl) amino) second Base) chloro- 2- phenyl isoquinolins quinoline -1 (2H) -one of -8-
By the chloro- 5- of compound 6- (2- methyl -2H- tetrazole -5- bases) pyrimidine -4- amine (30mg, 0.142mmol) and (S) - Chloro- 2- phenyl isoquinolins quinoline -1 (2H) -one (44mg, 0.149mmol) of 3- (1- amino-ethyls) -8- are suspended in n-BuOH (3mL), Then add DIPEA (37mg, 0.284mmol) thereto, reaction mixture be heated to reflux 42 it is small when, and use thin-layered chromatography (PE/EtOAc, v/v, 1/3) monitoring reaction, mixture is cooled to room temperature, then is concentrated under reduced pressure, gained residue EtOAc (15mL) dilutes, and mixture is washed with water (15mL) and saline solution (10mL) respectively, and organic phase is dried with anhydrous sodium sulfate, then is subtracted Pressure concentration, gained residue are purified through preparative thin layer chromatography (PE/EtOAc (v/v)=1/4), and it is light to obtain title compound Yellow solid (35mg, 52.1%).
MS(ESI,pos,ion):474.1[M+H]+；HPLC:91.4%；
1H NMR(400MHz,CDCl3)δ(ppm):8.79 (d, J=6.8Hz, 1H), 8.01 (s, 1H), 7.56-7.32 (m, 8H), 6.58 (s, 1H), 5.11 (d, J=6.9Hz, 1H), 4.52 (s, 3H), 1.53 (d, J=6.8Hz, 3H).
Embodiment 16 (S) -3- (1- ((6- amino -5- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine-4-yl) ammonia Base) ethyl) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-
By the chloro- 5- of compound 6- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine -4- amine (31mg, 0.147mmol) Chloro- 2- cyclopropyl isoquinolin -1 (2H) -one (41mg, 0.155mmol) of (S) -3- (1- amino-ethyls) -8- are suspended in n-BuOH In (3mL), then add DIPEA (38mg, 0.294mmol) thereto, reaction mixture be heated to reflux 20 it is small when, and using thin Layer chromatography (CH2Cl2/ MeOH, v/v, 25/1) reaction is monitored, postcooling that the reaction was complete is concentrated under reduced pressure to room temperature, adds EtOAc (15mL) dilutes residue, and gained mixture is washed with water (15mL) and saline solution (10mL) successively, and liquid separation, obtains Organic phase is dried with anhydrous sodium sulfate, is concentrated under reduced pressure, and gained residue is through silica gel column chromatography (DCM/MeOH (v/v)=200/3) It is faint yellow solid (32mg, 51.4%) that purifying, which obtains title compound,.
MS(ESI,pos,ion):437.2[M+H]+；HPLC:94.9%；
1H NMR(400MHz,CDCl3)δ(ppm):9.59 (d, J=6.9Hz, 1H), 8.18 (s, 1H), 8.11 (s, 1H), 7.44-7.36 (m, 2H), 7.25 (dd, J=6.5,2.5Hz, 1H), 6.43 (s, 1H), 6.20-6.09 (m, 1H), 4.06 (s, 3H), 2.98 (dt, J=6.8,5.7Hz, 1H), 1.68 (d, J=6.7Hz, 3H), 1.34-1.30 (m, 2H), 0.96-0.86 (m, 2H)。
Embodiment 17 (S) -3- (1- ((6- amino -5- (5- (methoxy) -1- methyl isophthalic acid H-1,2,4- triazoles -3- Base) pyrimidine-4-yl) amino) propyl group) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-
By the chloro- 5- of compound 6- (5- (methoxy) -1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine -4- amine Chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of (25mg, 0.098mmol) and (S) -3- (1- aminopropyls) -8- (40mg, 0.145mmol) it is suspended in n-BuOH (3mL), then adds DIPEA (25mg, 0.196mmol), gained mixture thereto Be heated to reflux 16 it is small when, and with thin-layered chromatography (CH2Cl2/ MeOH, v/v, 25/1) monitoring reaction, react, mixture is cold But to room temperature, and it is concentrated under reduced pressure, adds EtOAc (15mL) dilution residues, gained mixture uses water (15mL) and salt successively Water (10mL) washs, and organic phase is dried with anhydrous sodium sulfate, then is concentrated under reduced pressure, and residue is through preparative thin layer chromatography (CH2Cl2/ MeOH (v/v)=25/1) purifying, it is light pink solid (19mg, 39.1%) to obtain title compound.
MS(ESI,pos,ion):495.2[M+H]+；HPLC:93.7%；
1H NMR(400MHz,CDCl3)δ(ppm):9.26 (d, J=6.6Hz, 1H), 8.06 (s, 1H), 7.42-7.32 (m, 2H), 7.20 (dd, J=6.7,2.3Hz, 1H), 6.38 (s, 1H), 5.99 (td, J=7.5,4.5Hz, 1H), 4.71 (s, 2H), 4.04(s,3H),3.48(s,3H),3.09-2.95(m,1H),2.06-2.00(m,1H),1.65-1.56(m,1H),1.36- 1.32 (m, 2H), 1.13 (t, J=7.3Hz, 3H), 0.90-0.82 (m, 2H).
Embodiment 18 (S) -3- (1- ((6- amino -5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) Propyl group) fluoro- 2- phenyl isoquinolins quinoline -1 (2H) -one of -8-
The fluoro- 6- Methyl-N-phenyls benzamides of step 1) 2-
The fluoro- 6- methyl benzoic acids (7.7g, 50.0mmol) of compound 2- are suspended in toluene (50mL), then thereto Add SOCl2(23.8g, 200mmol), mixture be heated to reflux 12 it is small when after, be concentrated under reduced pressure, and residue is dissolved in drying THF (30mL) in, 0 DEG C and nitrogen protection under, aniline (4.7g, 50mmol) and Et are added dropwise into obtained solution3N THF (30mL) solution of (15.2g, 150mmol), mixture is warmed to room temperature, and stir reaction 5 it is small when, filter, filtrate is subtracted Pressure is concentrated to give brown solid, which is washed with ether (10mL × 3), and title compound is obtained after vacuum drying as white Solid (10.7g, 93%).
MS(ESI,pos.ion)m/z:230.1[M+H]+；
1H NMR(600MHz,CDCl3)δ(pm):7.65 (d, J=7.9Hz, 2H), 7.59 (br.s, 1H), 7.40 (t, J= 7.8Hz, 2H), 7.34-7.30 (m, 1H), 7.19 (t, J=7.4Hz, 1H), 7.07 (d, J=7.6Hz, 1H), 6.99 (t, J= 8.9Hz,1H),2.49(s,3H)。
Fluoro- 2- phenyl isoquinolins quinoline -1 (2H) -one of step 2) (S) -3- (1- aminopropyls) -8-
The fluoro- 6- Methyl-N-phenyls benzamides (2.3g, 10.0mmol) of compound 2- are dissolved in dry THF In (40mL), then under -30 ° and nitrogen protection, the tetrahydrofuran solution of n-BuLi is added dropwise thereto while stirring (25mmol, 2.5M), after 10 minutes are added dropwise, mixture continues stirring 30 minutes at -30 DEG C, and resulting solution is directly used in React in next step.
By compound (S)-(1- (methoxyl group (methyl) amino) -1- oxo-butanes -2- bases) t-butyl carbamate (3.7g, 15mmol) is dissolved in dry THF (40mL), then under -30 DEG C and nitrogen protection, is added dropwise thereto different The tetrahydrofuran solution (16.5mmol, 2.0M) of propyl group magnesium chloride, is added dropwise, mixture stirs 30 at -30 DEG C for 10 minutes Minute, then at such a temperature, then it is added dropwise into mixture and solution is obtained above.Gained mixture stirs 4 at -15 DEG C After hour, reaction is quenched with water (20mL), gained mixture is adjusted to pH=1-3 with concentrated hydrochloric acid, then is concentrated under reduced pressure.Residue is molten Solution in MeOH (40mL) and concentrated hydrochloric acid (20mL), gained mixture be heated to reflux 2 it is small when, then be concentrated under reduced pressure remove it is most Methanol, residue with Ethyl acetate (100mL) extraction after concentration, water mutually first use saturation NaHCO3Aqueous solution is adjusted to pH=7-8, Extracted again with ethyl acetate (100mL × 3), the organic phase of merging is dried with anhydrous sodium sulfate, is concentrated under reduced pressure, gained residue warp It is faint yellow solid (2.32g, 78%) that silica gel column chromatography (ethyl acetate) purifying, which obtains title compound,.
MS(ESI,pos.ion)m/z:297.2[M+H]+；
1H NMR(600MHz,DMSO-d6)δ(ppm):7.70 (td, J=8.0,4.9Hz, 1H), 7.58-7.53 (m, 2H), 7.50 (d, J=7.4Hz, 1H), 7.47 (d, J=7.9Hz, 1H), 7.36 (dd, J=7.2,1.6Hz, 1H), 7.31 (dd, J= 5.4,4.2Hz, 1H), 7.17 (dd, J=11.5,8.1Hz, 1H), 6.87 (d, J=1.6Hz, 1H), 3.16 (dd, J=7.6, 4.8Hz, 1H), 1.81 (br.s, 2H), 1.61-1.53 (m, 1H), 1.30 (tt, J=14.7,7.3Hz, 1H), 0.65 (t, J= 7.3Hz,3H)；
13C NMR(151MHz,DMSO-d6)δ(ppm):163.0,161.3,159.82,159.79,151.5,140.3, 138.4,134.4,134.3,130.2,129.8,129.6,129.4,128.8,122.6,122.5,113.53,113.47, 113.0,112.9,101.59,101.58,53.3,30.5,11.2。
Step 3) (S) -3- (1- ((6- amino -5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) third Base) fluoro- 2- phenyl isoquinolins quinoline -1 (2H) -one of -8-
By the chloro- 5- of compound 6- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine -4- amine (23.0mg, 0.11mmol), (S) fluoro- 2- phenyl isoquinolins quinoline -1 (2H) -one (39.0mg, 0.13mmol) of -3- (1- aminopropyls) -8-, N, N- diisopropyl second The mixture of amine (42.6mg, 0.33mmol) and n-butanol (2.0mL) is sealed in tube sealing, and when 150 DEG C of reactions 12 are small, so After be concentrated under reduced pressure, gained residue through silica gel column chromatography (PE/EtOAc (v/v)=1/2) purify, it is white to obtain title compound Color solid (47mg, 91%).
MS(ESI,pos.ion)m/z:472.2[M+H]+；HPLC:99.61%；
1H NMR(600MHz,CDCl3)δ(ppm):8.32 (d, J=6.3Hz, 1H), 8.06 (s, 1H), 7.90 (br.s, 1H), 7.62 (d, J=7.3Hz, 1H), 7.57-7.50 (m, 3H), 7.49-7.45 (m, 1H), 7.38-7.33 (m, 1H), 7.21 (d, J=8.0Hz, 1H), 7.05 (dd, J=11.2,8.1Hz, 1H), 6.48 (s, 1H), 5.56 (br.s, 1H), 4.85-4.79 (m, 1H), 2.74 (s, 3H), 1.85 (ddt, J=14.7,11.4,7.4Hz, 1H), 1.67 (dq, J=22.3,7.4Hz, 1H), 0.87 (t, J=7.4Hz, 3H)；
13C NMR(151MHz,CDCl3)δ(ppm):174.3,166.0,163.6,161.8,161.3,160.83, 160.79,159.7,158.5,147.1,139.7,137.5,133.33,133.25,129.43,129.36,129.1,128.7, 121.7,121.6,114.4,114.3,113.1,112.0,101.63,101.60,82.6,53.3,28.3,12.4,10.7。
Embodiment 19 (S) -3- (1- ((6- amino -5- (isoxazole -3-bases) pyrimidine-4-yl) amino) propyl group) the fluoro- 2- of -8- Phenyl isoquinolin quinoline -1 (2H) -one
By the chloro- 5- (isoxazole -3-bases of compound 6-) pyrimidine -4- amine (49.1mg, 0.25mmol), (S) -3- (1- amino Propyl group) fluoro- 2- phenyl isoquinolins quinoline -1 (2H) -one (88.9mg, 0.30mmol) of -8-, n,N-diisopropylethylamine (96.9mg, 0.75mmol) be suspended in n-butanol (2.0mL), mixture is sealed in tube sealing, and at 150 DEG C reaction 6 it is small when, reacted Afterwards, reaction mixture is concentrated under reduced pressure, gained residue is purified through silica gel column chromatography (EtOAc), and it is white to obtain title compound Color solid (15mg, 13%).
MS(ESI,pos.ion)m/z:457.2[M+H]+；HPLC:96.41%；
1H NMR(600MHz,CDCl3)δ(ppm):8.60(s,1H),8.05(s,1H),7.60-7.43(m,5H),7.31 (d, J=7.8Hz, 1H), 7.25 (s, 1H), 7.24 (d, J=8.0Hz, 1H), 7.06 (dd, J=11.1,8.2Hz, 1H), 6.85 (d, J=1.1Hz, 1H), 6.48 (d, J=1.2Hz, 1H), 5.58 (br.s, 2H), 4.77 (dd, J=11.5,7.7Hz, 1H), 1.87-1.79 (m, 1H), 1.62 (dq, J=22.3,7.3Hz, 1H), 0.83 (t, J=7.3Hz, 3H).
Embodiment 20 (S) -3- (1- ((6- amino -5- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine-4-yl) ammonia Base) propyl group) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-
By chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of compound (S) -3- (1- aminopropyls) -8- (55.4mg, 0.2mmol) and the chloro- 5- of 6- (1- methyl isophthalic acid H-1,2,4- triazole -3- bases) pyrimidine -4- amine (42mg, 0.2mmol) is suspended in n- In BuOH (2mL), DIPEA (51.7mg, 0.4mmol) is then added thereto.Reaction mixture be heated to reflux 24 it is small when after, it is cold But to room temperature, then it is concentrated under reduced pressure.Residue is dissolved in EtOAc (10mL), gained mixture successively with water (10mL × 2) and Saline solution (10mL) washs, organic phase anhydrous Na2SO4It is dry, it is concentrated under reduced pressure.Gained residue is through silica gel column chromatography (CH2Cl2/ MeOH (v/v)=100/2) to obtain title compound be white solid (26.7mg, 29.6%) for purifying.
MS(ESI,pos,ion)m/z:451.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.17(s,1H),8.08(s,1H),7.35(m,2H),7.20(dd,J =6.8,2.2Hz, 1H), 6.38 (s, 1H), 5.99 (td, J=7.7,4.1Hz, 1H), 4.05 (s, 3H), 3.02 (ddd, J= 11.0,7.1,4.2Hz, 1H), 1.83 (m, 1H), 1.60 (m, 1H), 1.33 (m, 2H), 1.13 (t, J=7.4Hz, 3H), 0.93 (m,2H)。
Embodiment 21 (S) -3- (1- ((6- amino -5- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine-4-yl) amino) Propyl group) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-
By chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of compound (S) -3- (1- aminopropyls) -8- (55.4mg, 0.2mmol) and the chloro- 5- of 6- (5- methyl isophthalic acids, 2,4- oxadiazole -3- bases) pyrimidine -4- amine (42.3mg, 0.2mmol) is suspended in n- In BuOH (2mL), DIPEA (51.7mg, 0.4mmol) is then added thereto.Reaction mixture is refluxed overnight, is then cooled down To room temperature, it is concentrated under reduced pressure.Residue is dissolved in EtOAc (10mL), gained mixture uses water (10mL × 2) and salt successively Water (10mL) washs, and liquid separation, obtained organic phase is dried with anhydrous sodium sulfate, is then concentrated under reduced pressure.Residue is through silica gel column layer Analyse (CH2Cl2/ MeOH (v/v)=80/1) to obtain title compound be faint yellow solid (43mg, 47.6%) for purifying.
MS(ESI,pos,ion)m/z:452.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.42 (d, J=6.8Hz, 1H), 8.10 (s, 1H), 7.37 (m, 2H), 7.23 (dd, J=6.3,2.9Hz, 1H), 6.35 (s, 1H), 6.00 (td, J=7.9,4.2Hz, 1H), 3.02 (ddd, J= 11.0,7.2,4.1Hz,1H),2.75(s,3H),2.06(m,2H),1.84(m,2H),1.57(m,1H),1.40(m,1H), 1.13 (t, J=7.4Hz, 3H).
Embodiment 22 (S) -3- (1- ((6- amino -5- (3- ethyl -1,2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Propyl group) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-
By chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of compound (S) -3- (1- aminopropyls) -8- (70mg, 0.252mmol) it is suspended in the chloro- 5- of 6- (3- ethyl -1,2,4- oxadiazole -5- bases) pyrimidine -4- amine (55mg, 0.243mmol) In n-BuOH (4mL), then thereto add DIPEA (75mg, 0.580mmol), gained mixture be heated to reflux 12 it is small when, and Monitored and reacted with thin-layered chromatography (PE/EtOAc, v/v, 1/1), after having reacted, mixture is cooled to room temperature, then depressurizes dense Contracting, gained residue are purified through silica gel column chromatography (PE/EtOAc (v/v)=2/1), and it is white solid to obtain title compound (62mg, 55%).
MS(ESI,pos,ion)m/z:466.2[M+H]+；HPLC:98.9%；
1H NMR(400MHz,CDCl3)δ(ppm):8.71 (d, J=5.6Hz, 1H), 8.14 (s, 1H), 7.40-7.36 (m, 2H), 7.26-7.23 (m, 1H), 6.34 (s, 1H), 6.05-6.00 (m, 1H), 3.03 (m, 1H), 2.90 (q, J=7.4Hz, 2H), 2.06 (s, 2H), 1.85-1.81 (m, 1H), 1.51-1.48 (m, 1H), 1.42 (t, J=7.4Hz, 3H), 1.38 (m, 2H), 1.13 (t, J=7.1Hz, 3H), 0.96-0.88 (m, 2H).
Embodiment 23 (S) -3- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Ethyl) the chloro- 2- of -8- (3- fluorophenyls) isoquinolin -1 (2H) -one
The chloro- N- of step 1) 2- (3- fluorophenyls) -6- methyl benzamides
The chloro- 6- methyl benzoic acids (2.0g, 11.72mmol) of compound 2- are suspended in toluene (20mL), then in room Under the conditions of temperature, SOCl is added into reaction solution2(3.4mL, 46.90mmol), reaction solution is heated to flowing back, and stirs reaction 6 Hour, room temperature is subsequently cooled to, is concentrated under reduced pressure, dichloromethane (20mL) is added and dissolves residue, at 0 DEG C, to resulting solution It is middle first to add triethylamine (3.4mL, 24.66mmol), then 3- fluoroanilines (1.3g g, 11.74mmol) are added dropwise, mixture exists Room temperature condition is stirred overnight, and is then washed successively with saturated sodium bicarbonate aqueous solution (25mL) and saline solution (20mL), liquid separation, obtains Organic phase dried with anhydrous sodium sulfate, be concentrated under reduced pressure, gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=10/1) It is pink solid (2.55g, 82.3%) that purifying, which obtains title compound,.
1H NMR(400MHz,DMSO-d6)δ(ppm):10.79 (s, 1H), 7.69 (dt, J=11.6,2.2Hz, 1H), 7.44 (ddd, J=7.5,4.5,2.9Hz, 1H), 7.41-7.35 (m, 3H), 7.34-7.28 (m, 1H), 7.00-6.93 (m, 1H),2.32(s,3H)。
Step 2) (S) -3- (1- amino-ethyls) -8- chloro- 2- (3- fluorophenyls) isoquinolin -1 (2H) -one
The chloro- N- of compound 2- (3- fluorophenyls) -6- methyl benzamides (2.5g, 9.48mmol) are dissolved in THF In (30mL), then -30 DEG C and nitrogen protection under, be added dropwise into reaction solution n-BuLi hexane solution (2.4M, 9.88mL, 23.70mmol), stir 30 minutes at this temperature, obtain reaction solution 1.
By compound (S)-(1- (methoxyl group (methyl) amino) -1- oxopropan -2- bases) t-butyl carbamate (3.3g, 14.22mmol) is dissolved in THF (30mL), then under -30 DEG C and nitrogen protection, is added dropwise into this solution The THF solution (2M, 7.11mL, 14.22mmol) of i-PrMgCl, stirs 30 minutes, obtains reaction solution 2 at this temperature.
At -30 DEG C, reaction solution 1 is added dropwise in reaction solution 2, rise to -15 DEG C and continue stirring reaction 4 it is small when, Ran Houjia Enter water (20mL) and reaction is quenched, at 0 DEG C, its pH is adjusted to 1-2 by addition concentrated hydrochloric acid into obtained mixture, is concentrated under reduced pressure, will Residue is dissolved in MeOH (50mL), and concentrated hydrochloric acid aqueous solution (30mL) is then added into this solution, and obtained mixture adds Heat to flow back, and continue stirring reaction 1.5 it is small when, be subsequently cooled to room temperature, be concentrated under reduced pressure, add water (40mL) dilution residual Thing, adds solid sodium carbonate and obtained mixture is neutralized to pH=7-8, extracted with ethyl acetate (100mL × 2), merging Organic phase is washed with saline solution (100mL), is dried, is concentrated under reduced pressure with anhydrous sodium sulfate, and gained residue is purified through silica gel column chromatography It is orange/yellow solid (2.5g, 64.2%) that (DCM/MeOH (v/v)=100/1), which obtains title compound,.
MS(ESI,pos.ion)m/z:317.2[M+H]+。
Step 3) (S) -3- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) second Base) the chloro- 2- of -8- (3- fluorophenyls) isoquinolin -1 (2H) -one
To the chloro- 5- of compound 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (50mg, 0.236mmol) and (S) in the mixture of -3- (1- amino-ethyls) -8- chloro- 2- (3- fluorophenyls) isoquinolin -1 (2H) -one (85mg, 0.268mmol) Add DIPEA (61mg, 0.473mmol), be then heated to reflux, and stir reaction 4 it is small when, reaction pass through TLC monitoring (PE/ EtOAc,v/v,1/3).Reaction solution is cooled to room temperature, is concentrated under reduced pressure, adds dichloromethane (20mL) dilution, obtained mixing Thing is washed with water (15mL) and saline solution (10mL), and liquid separation, obtained organic phase is dried with anhydrous sodium sulfate, is concentrated under reduced pressure, gained It is faint yellow solid that residue preparative thin-layer chromatography method (PE/EtOAc (v/v)=1/3) purifying, which obtains title compound, (51mg, 43.9%).
MS(ESI,pos,ion):492.2[M+H]+；HPLC:96.9%；
1H NMR(600MHz,CDCl3) δ (ppm) 8.30 (d, J=5.6Hz, 1H), 8.06 (d, J=11.9Hz, 1H), 7.57-7.44(m,3H),7.45-7.35(m,2H),7.33-7.29(m,1H),7.28-7.25(m,1H),7.19-7.08(m, 2H), 6.55 (s, 1H), 5.07-4.91 (m, 1H), 2.51 (d, J=1.5Hz, 3H), 1.49 (dd, J=6.7,5.4Hz, 3H).
Embodiment 24 (S) -3- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) Ethyl) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-
Step 1) 4,6- dichloro pyrimidine -5- formyl chlorides
By compound 4,6- dichloro pyrimidine -5- formaldehyde (10g, 56.50mmol) is dissolved in carbon tetrachloride (100mL), so Sulfonic acid chloride (11.44g, 84.75mmol) and azodiisobutyronitrile (0.464g, 2.83mmol) are sequentially added in backward reaction solution. After mixture is when 80 DEG C of stirring reactions 4.5 are small, it is cooled to room temperature, filters, filtrate decompression is concentrated, gained residue depressurizes again Dry, it is yellow jelly (12.22g, 100%) to obtain title compound.
Step 2) 4,6- dichloro pyrimidine -5- formamides
By compound 4,6- dichloro pyrimidine -5- formyl chlorides (36g, 170mmol) are dissolved in THF (200mL), then react Liquid is stirred in ammonia atmosphere in room temperature condition to react, and reacts by thin-layer chromatography monitoring until disappearance of starting material, is then depressurized dense Contracting, gained residue is dispersed in ethyl acetate (300mL) and water (100mL), liquid separation, water mutually use ethyl acetate (100mL × 2) extract, the organic phase of merging is washed with saline solution (100mL), dried with anhydrous sodium sulfate, be concentrated under reduced pressure to give title compound For yellow solid (27.2g, 83.2%).
MS(ESI,pos.ion)m/z:191.9[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.85(s,1H),6.23(br.s,1H),5.96(br.s,1H)。
Step 3) 4,6- dimethoxypyridin -5- formamides
By compound 4,6- dichloro pyrimidine -5- formamides (24.6g, 128mmol) are dissolved in methanol (200mL), then Methanol (100mL) solution of sodium methoxide (15.2g, 282mmol) is added into reaction solution, it is small that reaction 4.5 is stirred at room temperature in mixture Shi Hou, is concentrated under reduced pressure, gained residue through silica gel column chromatography purify to obtain title compound for faint yellow solid (18.3g, 71.1%).
MS(ESI,pos.ion)m/z:184.1[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):8.47(s,1H),6.30(br s,1H),5.98(br.s,1H),4.07 (s,6H)。
Step 4) N- (1- (dimethylamino) ethylidene) -4,6- dimethoxypyridin -5- formamides
By compound 4,6- dimethoxypyridin -5- formamides (5.0g, 27.3mmol) and 1,1- dimethoxys-N, N- bis- Methyl ethyl-amine (15mL) mixture be heated to 110 DEG C and continue stirring reaction 1 it is small when, react and (EtOAc) monitored by thin-layer chromatography, After having reacted, reaction mixture is concentrated under reduced pressure, obtain the crude product of title compound for Tan solid (6.89g, 100%), without being further purified, it is directly used in and reacts in next step.
Step 5) 5- (4,6- dimethoxypyridin -5- bases) -3- methyl isophthalic acids, 2,4- oxadiazoles
By the thick production of N- obtained above (1- (dimethylamino) ethylidene) -4,6- dimethoxypyridin -5- formamides Thing is dissolved in Isosorbide-5-Nitrae-dioxane (50mL), and hydroxylamine hydrochloride (2.0g, 28.7mmol), hydrogen are then sequentially added into reaction solution The mixture of aqueous solution of sodium oxide (5M, 6mL), water (14mL) and acetic acid (50mL), heats the mixture to 110 DEG C and continues to stir Mix reaction 1 it is small when, be subsequently cooled to room temperature, add water (150mL) dilution, obtained mixture is with ethyl acetate (150mL × 3) Extraction, the organic phase of merging are washed with saline solution (100mL), are dried, be concentrated under reduced pressure with anhydrous sodium sulfate, gained residue is through silica gel It is pale solid (5.14g, step 4 and step 5 that column chromatography (PE/EtOAc (v/v)=10/1) purifying, which obtains title compound, Gross production rate for 84.7%).
MS(ESI,pos.ion)m/z:223.1[M+H]+。
Step 6) 5- (4,6- dichloro pyrimidine -5- bases) -3- methyl isophthalic acids, 2,4- oxadiazoles
By compound 5- (4,6- dimethoxypyridin -5- bases) -3- methyl isophthalic acids, 2,4- oxadiazoles (5.14g, 23.1mmol) It is suspended in dry toluene (100mL), then the POCl into reaction solution3(21mL, 231mmol) and DMF (10mL), by mixture Be heated to flowing back and continue stirring reaction 24 it is small when, then mixture supernatant liquor is separated, is concentrated under reduced pressure, obtains one It is yellow slurry to divide crude product；Lower floor's solid is dispersed in water (150mL), obtained mixture ethyl acetate (150mL) is extracted, and obtained organic phase is washed with saline solution (50mL), is then concentrated under reduced pressure, and obtains another part crude product；By two Part crude product merges, and it is white powder (4.76g, 89.1%) to purify to obtain title compound through silica gel column chromatography.
MS(ESI,pos,ion):231.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.98(s,1H),2.60(s,3H)；
13C NMR(101MHz,CDCl3)δ(ppm):168.70(s),168.16(s),161.87(s),159.61(s), 120.81(s),11.68(s)。
The chloro- 5- of step 7) 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine
By compound 5- (4,6- dichloro pyrimidine -5- bases) -3- methyl isophthalic acids, 2,4- oxadiazoles (4.76g, 20.6mmol) dissolving In THF (100mL), then under ammonia atmosphere, when stirring reaction 1 is small, and pass through thin-layer chromatography (PE/EtOAc, v/v, 4/ 1) monitoring reaction, filters, and filter cake is rinsed with ethyl acetate (20mL), and it is white cotton that filtrate decompression is concentrated to give title compound Flower-shaped solid (4.22g, 96.8%).
MS(ESI,pos,ion):212.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm)：8.81(br.s,1H),8.43(s,1H),6.16(br.s,1H),2.54 (s,3H),1.63(s,1H)。
Step 8) (S) -3- (1- ((6- amino -5- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine-4-yl) amino) second Base) chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of -8-
By chloro- 2- cyclopropyl isoquinolin -1 (2H) -one of compound (S) -3- (1- amino-ethyls) -8- (30mg, 0.114mmol), the chloro- 5- of 6- (3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) pyrimidine -4- amine (24mg, 0.114mmol), DIPEA The mixture of (29mg, 0.228mmol) and n-BuOH (1mL) are heated to 125 DEG C, and continue stirring reaction 4 it is small when, then cool down To room temperature, be concentrated under reduced pressure, gained residue through silica gel column chromatography purify to obtain title compound for pale solid (24mg, 48%).
MS(ESI,Pos.ion)m/z:438.0[M+H]+；HPLC:99%；
1H NMR(400MHz,CDCl3)δ(ppm):8.45(s,1H),8.12(s,1H),7.38(m,3H),6.40(s, 1H), 6.08 (m, 1H), 3.00 (m, 1H), 2.49 (s, 3H), 1.64-1.63 (d, J=4.0Hz, 3H), 1.39 (m, 2H), 1.31 (m,1H),0.88(m,1H)。
Biologic test
The LC/MS/MS systems of analysis include the serial vacuum degassing furnaces of Agilent 1200, and binary syringe pump, orifice plate is certainly Dynamic sampler, column insulating box, charged spray ionize the Agilent G6430 three-level level Four bar mass spectrographs in (ESI) source.Quantitative analysis Carried out under MRM patterns, the parameter of MRM conversions is as in Table A：
Table A
More reaction detection scannings 490.2→383.1
Fragmentation voltage 230V
Capillary voltage 55V
Dryer temperature 350℃
Atomizer 40psi
Drier flow velocity 10L/min
Analysis uses the Agilent μM columns of XDB-C18,2.1 × 30mm, 3.5, injects 5 μ L samples.Analysis condition：Mobile phase For 0.1% aqueous formic acid (A) and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient such as table Shown in B：
Table B
Time The gradient of Mobile phase B
0.5min 5%
1.0min 95%
2.2min 95%
2.3min 5%
5.0min Stop
In addition, also having the series LC/MS/MS spectrometers of Agilent 6330 for analysis, noted equipped with G1312A binary Penetrate pump, G1367A automatic samplers and G1314C UV detectors；LC/MS/MS spectrometers use ESI radioactive sources.Use titer Suitable cation model treatment and MRM conversion is carried out to each analyte and carries out optimal analysis.Use during analysis Capcell MP-C18 columns, specification are：100 × 4.6mm I.D., 5 μM (Phenomenex, Torrance, California, USA).Mobile phase is 5mM ammonium acetates, 0.1% methanol aqueous solution (A)：5mM ammonium acetates, 0.1% methanol acetonitrile solution (B) (70: 30, v/v)；Flow velocity is 0.6mL/min；Column temperature is maintained at room temperature；Inject 20 μ L samples.
Embodiment A：Stability of the compound in people and rat liver microsomes
People or rat liver microsomes are placed in polypropylen tubes and are incubated, and guides its duplication.It is typical to be incubated mixed liquor Including people or rat liver microsomes (0.5mg protein/mL), target compound (5 μM) and the NADPH that cumulative volume is 200 μ L (1.0mM) kaliumphosphate buffer (PBS, 100mM, pH value 7.4), compound is dissolved in DMSO, and using PBS that its is dilute Release, the concentration for making its final DMSO solution is 0.05%.And be incubated in the water-bath communicated at 37 DEG C with air, incubate in advance Educate and albumen is added in 3 minutes backward mixed liquors and starts to react.At different time points (0,5,10,15,30 and 60min), add Enter same volume ice-cold acetonitrile and terminate reaction.Sample is preserved at -80 DEG C until carrying out LC/MS/MS analyses.
Concentration of the compound in people or rat liver microsomes mixtures incubated is measured by the method for LC/MS/MS 's.The range of linearity of concentration range is come definite by each test-compound.
It is parallel to be incubated experiment and use the microsome being denatured to hatch at 37 DEG C as negative control, react when different Between point (0,15 and 60min) terminate.
Dextromethorphan (70 μ Μ) is used as positive control, hatches at 37 DEG C, react different time point (0,5,10, 15,30 and 60min) terminate.All include positive and negative control sample in each assay method, to ensure that microsome hatches body The integrality of system.In addition, stability data of the compound of the present invention in people or rat liver microsomes also can be by following examination Test to obtain.People or rat liver microsomes are placed in polypropylen tubes and are incubated, and guides its duplication.Typical mixtures incubated bag Include people or rat liver microsomes (ultimate density：0.5mg albumen/mL), compound (ultimate density：1.5 μM) and cumulative volume be 30 μ The K- buffer solutions (EDTA containing 1.0mM, 100mM, pH 7.4) of L.Compound is dissolved in DMSO, and with K- buffer solutions Dilution, the ultimate density for making DMSO are 0.2%.Preincubate after ten minutes, adds 15 μ LNADPH (ultimate densities：2mM) carry out enzyme Promote reaction, whole experiment carries out in 37 DEG C of incubation tube.At different time points (0,15,30 and 60 minute), 135 μ L are added Acetonitrile (containing IS) terminates reaction.Centrifuged 10 minutes with 4000rpm, except deproteinized, collect supernatant liquor, analyzed with LC-MS/MS.
In above-mentioned experiment, ketanserin (1 μM) is selected as positive control, hatches at 37 DEG C, reacts in the different time Point terminates for (0,15,30 and 60 minute).All include positive control sample in each assay method, to ensure that microsome hatches body The integrality of system.
Data analysis
For each reaction, concentration of the compound in people or rat liver microsomes are incubated is pressed (as a percentage) With respect to the plotted as percentage of zero time point, internal liver clearance rate CL is inferred with thisint(ref.:Naritomi Y, Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition 2001,29:1316-1324)。
Stability data of 1 embodiment of the present invention of table in people and rat liver microsomes
1 the results show of table：The compounds of this invention has more rational half-life period in the hepatomicrosome of people and rat.
Embodiment B：The Pharmacokinetic Evaluation after the compounds of this invention is injected and taken orally to mouse, rat, dog and monkey
The present invention comments pharmacokinetic of the compounds of this invention in mouse, rat, dog or monkey body Estimate.The compounds of this invention is with aqueous solution or the aqueous solution of 2%HPMC+1% Tween-80s, the saline solution of 5%DMSO+5%, and 4% MC or capsule form are administered.It is administered for intravenous injection, animal gives the dosage of 1 or 2mg/kg.For oral dose (p.o.), rat and mouse are 5 or 10mg/kg, and dog and monkey are 10mg/kg.It is 0.25,0.5,1.0,2.0 at time point, 3.0,4.0,6.0,8.0,12 and 24 take blood (0.3mL) when small, and are centrifuged 10 minutes under 3,000 or 4,000rpm.Collect blood Solution is starched, and is preserved at -20 DEG C or -70 DEG C until carrying out above-mentioned LC/MS/MS analyses.
Pharmacokinetic data of 2 embodiment of the present invention of table in rat body
2 the results show of table：The compounds of this invention is preferable in rat body absorption, and half-life period is more reasonable.
Embodiment C：Kinase activity assays
The compounds of this invention can be evaluated as the activity of PI3K and mTOR kinase inhibitors by following experiments 's.
The general description of kinase assay
Kinase assay by detect incorporation γ-33The myelin basic protein (MBP) of P-ATP is come what is completed.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), white 384 orifice plate (Greiner) of high associativity is coated with, per 60 μ L of hole.4 DEG C, when incubation 24 is small.Afterwards With 100 μ L TBS board-washings 3 times.Kinase reaction is in kinase buffer liquid (the 5mM Hepes pH 7.6,15mM that cumulative volume is 34 μ L NaCl, 0.01% bovine serum albumin(BSA) (Sigma#I-5506), 10mM MgCl2, 1mM DTT, 0.02%TritonX-100) in Carry out.Compound is dissolved in DMSO, is added in each hole, the ultimate density of DMSO is 1%.Each twice of data determination, often The measure of a compound is at least tested twice.For example the ultimate density of enzyme is 10nM or 20nM.Addition does not have markd ATP (10 μM) and γ-33The ATP of P marks is (per hole 2 × 106Cpm, 3000Ci/mmole) start to react.Reaction is shaken at room temperature Swing and carry out 1 hour.384 orifice plates with 7 × PBS cleaning, then add the scintillation solution per 50 μ L of hole.With Wallac Trilux Counter testing result.To those of ordinary skill in the art, this is only one kind in numerous detection methods, others side Method also may be used.
The IC that above-mentioned test method can be inhibited50And/or inhibition constant Ki。IC50It is defined as under test conditions, suppression Make compound concentration during 50% enzymatic activity.The curve for including 10 concentration points is made using the extension rate of 1/2log, is estimated IC50Value by following compound concentration (for example, make a typical curve：10μM,3μM,1μM,0.3μM,0.1μM,0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM and 0 μM).
The ordinary test scheme of PI3- kinases
PI3K (p110 α/p85 α) (h) [cold test]
PI3K (p110 α/p85 α) (h) is containing 10 μM of phosphoric acid acyl inositol -4,5- diphosphonic acid and MgATP, (concentration is according to need Ask definite) buffer solution in be incubated.After adding ATP solution, start to react.After being incubated 30 minutes at room temperature, add thereto Enter the terminate liquid containing EDTA and biotin phosphatidylinositols -3,4,5- triphosphoric acids to terminate reaction.Finally, detection buffering is added Liquid, includes the anti-GST monoclonal antibodies of europium mark, the GRP1PH domains and streptavidin-allophycocyanin of GST marks.Orifice plate when Between reading under resolved fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal 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 μM of phosphoric acid acyl inositol -4,5- diphosphonic acid and MgATP, (concentration is according to need Ask definite) buffer solution in be incubated.After adding ATP solution, start to react.After being incubated 30 minutes at room temperature, add thereto Enter the terminate liquid containing EDTA and biotin phosphatidylinositols -3,4,5- triphosphoric acids to terminate reaction.Finally, detection buffering is added Liquid, includes the anti-GST monoclonal antibodies of europium mark, the GRP1PH domains and streptavidin-allophycocyanin of GST marks.Orifice plate when Between reading under resolved fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal 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 μM of phosphoric acid acyl inositol -4,5- diphosphonic acid and MgATP, (concentration is according to need Ask definite) buffer solution in be incubated.After adding ATP solution, start to react.After being incubated 30 minutes at room temperature, add thereto Enter the terminate liquid containing EDTA and biotin phosphatidylinositols -3,4,5- triphosphoric acids to terminate reaction.Finally, detection buffering is added Liquid, includes the anti-GST monoclonal antibodies of europium mark, the GRP1PH domains and streptavidin-allophycocyanin of GST marks.Orifice plate when Between reading under resolved fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal is by equation HTRF=10000 × (Em665nm/ Em620nm) determine.
PI3K (p120 γ) (h) [cold test]
PI3K (p120 γ) (h) is containing 10 μM of phosphoric acid acyl inositol -4,5- diphosphonic acid and MgATP, (concentration is true according to demand It is incubated in buffer solution calmly).After adding ATP solution, start to react.After being incubated 30 minutes at room temperature, add contain thereto There is the terminate liquid of EDTA and biotin phosphatidylinositols -3,4,5- triphosphoric acids to terminate reaction.Finally, detection buffer solution is added, Include the anti-GST monoclonal antibodies of europium mark, the GRP1PH domains and streptavidin-allophycocyanin of GST marks.Orifice plate is in the time point Distinguish reading under fluorescence mode, homogeneous phase time discrimination fluorescence (HTRF) signal is by equation HTRF=10000 × (Em665nm/ Em620nm) determine.
mTOR(h)
MTOR (h) is in the HEPES that 50mM pH value is 7.0,1mM EDTA, 0.01% polysorbas20,2mg/mL substrates, 3mM chlorine Change manganese and [γ-33P-ATP] it is incubated under the conditions of (specific activity about 500cpm/pmol, concentration determine according to demand) is existing. Start to react after adding MnATP mixtures.After being incubated 40 minutes at room temperature, 3% phosphoric acid solution is added thereto and terminates reaction. 10 μ L reaction solutions are distributed on P30 filters in mottled, and are cleaned in 5 minutes 3 times with 75mM phosphoric acid, and dry and It is put into methanol solution and preserves at once before scinticounting.
Kinase assay in the present invention be by Millipore companies of Britain come complete (Millipore UK Ltd, Dundee Technology Park,Dundee DD21SW,UK)。
The kinase inhibition data of 3 embodiment of the present invention of table
NT：Represent that sample is not tested
3 the results show of table：The compounds of this invention has good selectivity to the different subtype in PI3- kinase families.
The kinase inhibiting activity of the compounds of this invention can also pass through KINOMEscanTMTest, it is mainly based upon quantitative The ligand and the experiment of kinases competitive binding ability that determination sample and fixed, active site are oriented to.This is tested complete Into needing to combine following three elements：Kinases, the ligand and sample to be tested of fixation of DNA- marks.Sample to be tested and fixed ligands The ability of competitive binding kinases can be determined by measuring the amount of the PCR in DNA marker.
For most of experiments, the T7 phage strains of kinases-mark are the large intestine bars that origin comes from BL21 bacterial strains Bacterium host is prepared.First Escherichia coli are cultivated to exponential phase, are then infected with T7 bacteriophages, and by its Lysate is centrifuged, is filtered, removes cell fragment until cracking in 32 DEG C of hatchings under continuous concussion.It is remaining in HEK-293 And then the kinases produced into the cell is marked with DNA, the detection for qPCR.It is coated with the magnetic bead and biology of Streptavidin After the smaller ligand of elementization reacts 30 minutes at room temperature, affine resin of the generation for kinase assay.The magnetic bead being coordinated Blocked by excessive biotin, with blocking buffer (SEABLOCKTM(Pierce), 1%BSA, 0.05% Tween-20,1mM DTT) washing removes free ligand, to reduce non-specific binding.Association reaction is all by kinases, the compatibility being coordinated Magnetic bead and sample to be tested in 1 × combination buffer (20%SEABLOCKTM, 0.17 × PBS, 0.05% Tween-20,6mM DTT completed in).All reactions carry out in 96 orifice plates of the polystyrene that final volume is 0.135mL.The orifice plate of experiment is equal Under continuous concussion when room temperature condition hatching 1 is small, the magnetic bead of compatibility with lavation buffer solution (1 × PBS, 0.05% tween- 20) wash, being then resuspended to elution buffer, (1 × PBS, 0.05% Tween-20,0.5 μM of non-biotinylated compatibility are matched somebody with somebody Body) in, and hatch 30 minutes in room temperature condition under continuous concussion.Kinase concentration in eluent is measured by qPCR.
Kinase assay in the present invention is by the KINOMEscan of DiscoveRx companiesTMAnalysis Service is completed (42501Albrae St.Fremont,CA 94538,USA)。
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or the spy for combining the embodiment or example description Point is contained at least one embodiment of the present invention or example.In the present specification, schematic expression of the above terms is not It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be in office Combined in an appropriate manner in one or more embodiments or example.In addition, without conflicting with each other, the skill of this area Art personnel can be tied the different embodiments or example described in this specification and different embodiments or exemplary feature Close and combine.
Although the embodiment of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is impossible to limitation of the present invention is interpreted as, those of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changes, replacing and modification.

Claims (13)

1. a kind of compound, it is pharmaceutically acceptable for compound shown in the compound of structure shown in formula (I) or formula (I) Salt,
Wherein X is
Wherein described X is optionally by 1,2 or 3 R1Group is substituted；
Y is
R1It independently is H, F, Cl, CN ,-C (=O) ORa, RaO-C1-2Alkylidene, C1-4Alkyl, C3-6Cycloalkyl, C3-6Cycloalkyl- C1-2Alkylidene, wherein each C1-4Alkyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-2Alkylidene is independently unsubstituted or by 1, 2,3 or 4 substituents are substituted, and the substituent is independently selected from F, Cl, CN, ORa, NRaRbOr C1-3Alkyl；
Each R3And R4It independently is H, F, CN or C1-3The wherein described C of alkyl1-3Alkyl is unsubstituted or by 1,2,3 or 4 substituent Substituted, the substituent is independently selected from F, Cl, Br or CN；
Each Ra, RbIt independently is H or C1-6Alkyl, wherein the C1-6Alkyl is unsubstituted or is taken by 1,2,3 or 4 substituent In generation, the substituent is independently selected from F, CN, N3, OH or NH2。
2. a kind of compound, has the structure of one of：
3. a kind of pharmaceutical composition, it includes claim 1-2 any one of them compounds.
4. pharmaceutical composition according to claim 3, further includes：Pharmaceutically acceptable carrier, excipient, dilution Agent, assistant agent, medium, or combinations thereof.
5. the pharmaceutical composition according to claim 3 or 4, further includes one or more therapeutic agents.
6. any one of any one of the claim 1-2 compounds or claim 3-5 described pharmaceutical composition is preparing medicine In purposes, the medicine be used for protect, handle, treat or mitigate PI3- kinases exception relevant diseases.
7. purposes according to claim 6, wherein the PI3- kinases exception relevant disease is breathing problem, virus sense Dye, anaphylactia, autoimmune disease, inflammatory disease, angiocardiopathy, nerve degenerative diseases, pancreatitis, multiple organ Exhaustion, nephrosis, platelet aggregation, cancer, graft rejection, injury of lungs or pain.
8. purposes according to claim 7, wherein the breathing problem is non-viral respiratory tract infection.
9. purposes according to claim 7, wherein the angiocardiopathy is malignant hematologic disease.
10. purposes according to claim 7, wherein the graft rejection is graft rejection.
11. purposes according to claim 6, wherein the PI3- kinases exception relevant disease is asthma, chronic obstructive Tuberculosis, viral respiratory infection, viral respiratory disease deteriorate, aspergillosis, leishmaniasis, allergic rhinitis, anaphylaxis Dermatitis, rheumatic arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, malignant hematologic disease, nerve move back Row disease, pancreatitis, multiple organ failure, nephrosis, platelet aggregation, cancer, graft rejection, injury of lungs, is closed with rheumatoid Section is scorching or the relevant pain of osteoarthritis, backache, systemic inflammatorome pain, neuralgia after liver, diabetic neuropathy, inflammation Nerve pain, trigeminal neuralgia or central pain.
12. purposes according to claim 11, wherein the graft rejection is graft rejection.
13. prepared by claim 1-2 any one of them compound or claim 3-5 any one of them pharmaceutical composition Purposes in medicine, wherein the medicine is used to suppress PI3- kinase activities.
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