CN105111151B - Aminopyridine derivative as PPAR- gamma modulators - Google Patents

Aminopyridine derivative as PPAR- gamma modulators Download PDF

Info

Publication number
CN105111151B
CN105111151B CN201510184572.4A CN201510184572A CN105111151B CN 105111151 B CN105111151 B CN 105111151B CN 201510184572 A CN201510184572 A CN 201510184572A CN 105111151 B CN105111151 B CN 105111151B
Authority
CN
China
Prior art keywords
bases
amino
ketone
chlorine pyrimidine
anilino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201510184572.4A
Other languages
Chinese (zh)
Other versions
CN105111151A (en
Inventor
周立宏
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chengdu Univeristy of Technology
Original Assignee
Chengdu Univeristy of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chengdu Univeristy of Technology filed Critical Chengdu Univeristy of Technology
Priority to CN201510184572.4A priority Critical patent/CN105111151B/en
Publication of CN105111151A publication Critical patent/CN105111151A/en
Application granted granted Critical
Publication of CN105111151B publication Critical patent/CN105111151B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to 2 shown in formula I, 4 diamino, 6 chloropyrimidone derivative and/or their officinal salt and preparation method thereof, it includes inflammation (including rheumatoid arthritis), atherosclerosis, I types or type-2 diabetes mellitus, diabetic complication, obesity, hyperlipidemia, impaired glucose tolerance, cerebral ischemia, parkinsonism, insulin resistance and osteoporosis, and the pharmaceutical composition containing the compound that they, which can be used for treating and/or prevent the relevant diseases of peroxisome proliferator-activated receptor subtype PPAR γ,.Wherein, to R1And R2The restriction of two substituent groups is such as just described in text.

Description

Aminopyridine derivative as PPAR- gamma modulators
Technical field
The invention belongs to medicinal chemistry arts, and in particular to described in claim a kind of aminopyridine derivative and Its physiologically acceptable salt, their preparation and they treating and/or preventing and inflammation (including rheumatoid joint It is scorching), atherosclerosis, I type or type II diabetes, diabetic complication, obesity, hyperlipidemia, impaired glucose tolerance, brain lack Purposes in blood, parkinsonism, insulin resistance and the relevant disease of osteoporosis.
Technical background
Peroxisome proliferator-activated receptor (peroxisome proliferator-activatived Receptors, abbreviation PPAR) be a kind of ligand activation transcription factor, belong to nuclear hormone receptor superfamily, including PPAR- α, Tri- kinds of phenotypes of PPAR- β/δ and PPAR- γ, wherein the most deep with the research of PPAR- γ.The activation of PPAR is to adjusting internal pole Extensive metabolic process has irreplaceable role.
Peroxidase (peroxisome) is a kind of internal subcellular structure, and function includes removing molecular oxygen and hydrogen mistake Oxide, and it is related with sugar, fat, cholesterol, the synthesis of cholic acid and fatty acid oxidation.A series of natural or artificial synthesized fat Fat acids chemical substance can stimulate the proliferation of peroxidase, referred to as peroxisome proliferator (peroxisome proliferation).Peroxisome proliferator can activate its receptor, to cause a series of biological action, so This receptoroid is called peroxisome proliferator-activated receptor (PPAR).A variety of biologies are generated after people's vivo activation PPAR Act on, and such as adjusts the metabolism of lipid, improves the sensibility of insulin, and antitumor action protects neuron, inhibits inflammatory reaction Deng.The effect of these associated signal paths and relevant cell factor is specified, relevant disease mechanism and prevention can further be carried For strong foundation and intervention.
One, the structure of PPAR
About the structure of PPAR, Marx N et al. are in (2004,94 (9) Circ.Res.:Report, PPAR in 1168-1178) It is a kind of transcription factor of ligand activation, belongs to nuclear hormone receptor superfamily, participates in the gene regulation in a variety of metabolic processes. PPAR has 3 kinds of subtype alphas, beta, gamma, gene to be located on the 22nd, 6 and No. 3 chromosome of the mankind.The structure of PPAR includes 4 work( It can area：The areas NDuan A/B are the transcription activating areas for not depending on ligand, and the plot structure difference of each hypotype is apparent, its serine is residual Base can inhibit the activity of receptor after by blocking effect of mitogen activated protein kinases (MAPK) phosphorylation；The areas C have the conservative of height, wherein 70 or so amino acid sequences constitute the combined areas DNA (DBD), are used for and the PPAR response elements (PPRE) on target gene In conjunction with；The areas D are also known as hinge area (hinge domain), and DBD is connected with ligand binding domain；The areas CDuan E/F are ligand bindings Area (LBD), the difference of the region amino acid sequence make the PPAR of each hypotype generate affinity to different ligands respectively, i.e., with the bodily form At dimer.
The ligand of PPAR in structure there are one common ground, containing carboxy functional group and hydrophobic region (MarxN, Duez H, Fruchart JC, et al.Circ.Res., 2004,94 (9):1168-1178).The ligand of PPAR is divided into synthesis and matches Body and native ligand.Synthetic ligands are mainly some drugs.Native ligand is mainly derived from the metabolite of diet and body, such as Linoleic acid, arachidonic acid and its derivative leukotriene B4 (LTB4), 8 (S) hydroxyeicosatetraenoic acids [8 (S) HETE], 15- Dehydrogenation prostaglandin J2 (15-d-PGJ2).Human ppar α has 468 amino acid residues, PPAR- β to have 441 amino acid residual Base, PPAR- γ have 479 amino acid residues.The structure of PPAR3 kind hypotypes has 60%~80% homology, but they match Body and target gene have apparent difference.The ligand of PPAR- α includes leukotriene B4 and fibrate lipid-lowering medicine, mainly adjusts lipid Metabolism.The ligand of PPAR- β is polyunsaturated fatty acids, prostaglandin and retinoic acid etc..Kuenzli S et al. exist Br.J.Dermatol.(2003,149(2):Expression and skin of the report PPAR- β on Human keratinocytes in 229-236) Skin disease is related.The ligand of PPAR- γ is the thiophenes such as Rosiglitazone (rosiglitazone), Pioglitazone (pigoglitazone) Oxazolidinedione class compound and 15- dehydrogenation prostaglandin J2 adjust the metabolism of glycogen and fat.
Two, with the relevant diseases of PPAR
(1) PPAR and inflammation
PPAR- γ can play the work for inhibiting inflammatory reaction by the generation of Competitive assays inflammatory signals access and inflammatory mediator With relevant inflammatory signals access includes mainly four kinds, is JAK-STAT, NF- κ B, nuclear factor of activated T cells respectively (nuclear factor of activated T cell, NFAT) and AP-1.
JAK-STAT signal transduction pathways activate after starting from JAK-2 phosphorylations, the JAK-2 reactivation JAK-1 of activation, then Under the action of JAK-1, STATl and STAT2 are activated respectively, the former formed after homodimer must with cooperate with activation factor CREB binding proteins (CBP) or p300 could play its biological activity after combining in nucleus.As PPAR- γ and ligand knot After merging activation, combined amount limited collaboration activation factor CBP and p300 are recruited in the competition of PPAR- γ-RXR heterodimers, are made It cooperates with activation factor quantity to reduce at what can be combined with STATl, to inhibit the activation of STATl, and has blocked STAT phases The pro-inflammatory cytokine (IL-6, IL-1, TNF-α) of pass generation (Li M, et a1.Mol Cell Biol, 2000,20: 4699).In inflammatory reaction, INF- γ and PPA- γ coherent signals are closely related.It has been reported that, can induce simultaneously after IFN-γ stimulation Activate JAK/STAT accesses, make TNF-α, IL-1 β generation increase (Li Q, et al.Nat Rev Immunol, 2002,2: 725).In rat macrophage and people's DLDl cells, IFN-γ etc. is increased by the STATl and STAT3 of activation JAK2 and downstream Strong Inducible nitric oxide synthase (iNOS) expresses and aggravates inflammatory reaction.In above-mentioned reaction, iNOS can under endotoxin stimulation Inducing cell be overexpressed NO, the latter can coup injury cell DNA, fracture is brought it about, so that Apoptosis (Bohrer H, et a1.J Clin Invest,1997,100:972).And PPAR- γ have blocked the rush of IFN-γ by inhibiting JAK-STAT approach Inflammation effect.
NF- κ B have two subunits of p50 and p65.In resting cell, NF- κ B with inhibit protein monomer I κ B α and I κ B β with Inactive combining form be present in cytoplasm (Ghosh S, et a1.Annu Rev Immunol, 1998,16:225).In inflammation In reaction, two serine residues (α, β) of proinflammatory inflammation factor and I κ B combine so that I κ B α/βs ubiquitinations are simultaneously degraded, and cause P50/p65 dimers are dissociated with I κ B α/βs.The dimer of dissociation again with cooperate with activation factor p300 and CBP combine after in core with The specific κ B sequences of DNA combine, and on the one hand can induce other inflammatory mediator gene expressions, while can also increase COX-2 works With.COX-2 can promote arachidonic acid to PGH in inflammatory reaction2Conversion, and PGH2PGE can be generated again2, transmitting inflammation Medium generation (Straus DS, et al.Proc Natl Acad Sci USA, 2000,97:4844).PPAR- γ can be straight It connects and is combined with the subunit p65/p50 of NF- κ B, protein-protein interaction occurs, form Transcription inhibition compound, reduce NF- κ B and DNA binding activity inhibit NF- κ B DNA synthesis, to inhibit it to express (Chung SW, et al.J Biol Chem,2000,275:32681).PPAR- γ can also be inhibited by cooperateing with activation factor p300 and CBP with competitive binding The transcription of NF- κ B.In the model of rat colonitis, using PPAR- gamma agonist Rosiglitazones, it is observed that rat tissue Middle COX-2, PGE2, the inflammatory mediators expression such as TNF-α substantially reduces, it was confirmed that above-mentioned saying (Sanchez-Hidalgo M, et a1.Biochem Pharmacol,2005,69:1733)。
NFAT is mainly in T cell and other immunocytes, such as B cell, NK cells, mast cell surface expression. NFAT exists in cytoplasm with inactive phosphorylation state, by activation such as calcineurins (calcineurin) After factor activator, dephosphorylation and activate and be indexed into nucleus, play a role.Straus DS et al. discoveries, PPAR- γ inhibits the gene expression of IL-2 in the inflammatory reaction that T cell mediates by influencing NFAT approach.PPAR- γ can be by matching Body suppresses DNA combinations and the transcriptional activity of NFAT, suppresses NFAT regulatory T-cell IL-2 promoters.Lead between PPAR- γ and NFAT The activation for crossing protein-protein interaction to inhibit T cell in inflammation, and IL-2 promoters are lowered, to play suppression Inflammation processed effect (Proc Natl Acad Sci USA, 2000,97:4844).
AP-1 is a kind of nuclear factor.Typical AP-1 compounds are made of c-Jun and c-Fos Liang Ge subunits, are led to Leucine is crossed to be combined with DNA.In inflammatory reaction, AP-1 has the conjunction of the apoptosis, adhesion factor and inflammatory factor of inducing cell At etc. functions (Straus DS, et al.Proc Natl Acad Sci USA, 2000,97:4844).PPAR- γ by with AP-1 competitive bindings cooperate with activation factor CBP and p300, play the inhibiting effect to AP-1 signal transduction pathways, this mechanism with The approach that PPAR- γ influence JAK-STAT is similar.(2) PPAR and metabolic syndrome
Diabetes are to cause metabolic disorder characterized by chronic hyperglycemia by Different types of etiopathogenises, mainly due to insulin secretion Or the defect or the two of effect exist simultaneously and cause.Insulin resistance is the key link of metabolic syndrome, PPAR- γ Sensibility of the peripheral tissues to insulin is mainly increased to the adjusting of glycometabolism, so as to improve insulin resistance.PPAR- γ work( It impaired can lead to serious insulin resistance, and the PPAR- gamma agonist Thiazolidinediones synthesized include Qu Gelie Ketone (troglitazone), Rosiglitazone, Pioglitazone can be effectively improved the insulin sensitivity and drop of diabetes B patient Hypoglycemia (Demg T, Shan S, Li PP, et al.Endocrinology, 2006,147 (2):875-884).PPAR- γ increase The mechanism for adding insulin sensitivity may be：Phosphatidylinositol3 3 kinase (PI3K) is that target cell mediating glucose enters into the cell Key lipid kinase, adjust subunit and catalytic subunit by one and form, P13K is a kind of lipid kinase, is adjusted by one sub- Base and catalytic subunit composition.It adjusts subunit to be combined with insulin receptor substrate (IRS), by IRS activated cell films in conjunction with after The phosphorylation of phosphatidylinositols (PI).When quiescent condition, adjusts subunit and play inhibiting effect with catalytic subunit, in insulin stimulating Under, IRS is combined with subunit is adjusted, and inhibiting effect releases, i.e. activating catalytic subunit.After P13K activation, PI, phosphorus can be promoted respectively Acyl Inositol Monophosphate (PIP) and phosphatidylinositol diphosphate (PIP2) phosphorylation generate PIP, PIP2 or PIP3.These product quilts Insulin and other growth factors second messenger are considered, wherein mostly important with PIP3.PPAR- γ are in PI3K signal paths It can promote PI3K gene expressions, enhance the sensibility of insulin, can also enhance glucose transporter 4 (GluT4) gene expression, Promote the intake to glucose；PPAR- γ activation can accelerate triglycerides in the decomposition of peripheral tissues, increase it at fatty group Synthesis in knitting, the generation of glucagon suppression.
Perilipin (perilipin) can reduce triglyceride hydrolysis, in the storage and metabolism for adjusting lipid It plays an important role.Thiazolidinediones (TZD) drug can obviously reduce fatty caused by TNF-α as PPAR- gamma agonists It decomposes, perilipin caused by TNF-α can also obviously be prevented to reduce.Further study showed that perilipin gene promoters Subregion includes functional PPAR- gamma reactions element, and PPAR- gamma agonists can obviously increase perilipin gene tables It reaches, to regulate and control the decomposition of fat.Also it was reported that PPAR- γ regulating lipid metabolisms are due in liver cell and PECTORAL LIMB SKELETON In, PPAR- gamma agonists have raised the gene expression of hormone-sensitive lipase (HSL).Its mechanism may be：PPAR- γ are opened Sub-area includes two GC boxes, and the transcriptional activity that PPAR- γ are mediated is realized by the promoter of its nearside.It is endogenic PPAR- γ enhancing transcription factor SP 1 and promoter combine, activated transcription activity, to make HSL gene expressions up-regulation (Demg T, Shan S, Li PP, et al.Endocrinology, 2006,147 (2):875-884).In addition, PPAR- alfa agonists can reduce Triglycerides in blood increases high low density lipoprotein, the former is to increase fat by controlling the transcriptional regulatory of several genes It absorbs, activation and metabolism, the latter are by promoting liver apolipoprotein A-I (apoA- I) and Apolipoprotein A-II (apoA- II) Generation mediate.
(3) PPAR and atherosclerosis
Atherosclerosis is one and is gathered by arterial blood tube wall atheromatous plaque progressive, is a kind of chronic inflammation of blood vessel Reaction, it is related with c reactive protein, fibrinogen, TNF-α and IL-6 increases, eventually lead to the pathology of focal obstruction of artery Process.The former relates generally to 3 pathologic processes, i.e. the differentiation, inflammatory reaction of foam cells (foam cell) and cell increases It grows.In lesion early stage, usually there is the aggregation of Monocytes/Macrophages and T cell, and progressive stage, is visible rich in lipid monokaryon/macrophage The foam cells of cell origin increases and vascular smooth muscle cells (VSMC) migration proliferation, cell debris accumulation, so that athero- Plaque fibrous cap generates.Thus it can be induced and the relevant local inflammation reaction (Desvergne of atherosclerosis in endarterium B,et al.Endocr Rev,1999,20:649).It has recently been found that the visible PPAR- in the mankind and the damage of mouse atheromatous plaque γ is obviously expressed, prompt PPAR- γ play an important role in atherosis (Tontonoz P, et al.Cell, 1998,93: 241).Inhibit the formation of atherosclerosis after PPAR- α activation by different mechanisms：(1) improve the reaction of early stage vascular wall Property, prevent deposition and infiltration of the lipid in vascular wall.(2) expression for reducing endothelial cell surface adhesion molecule, it is thin to reduce inflammation Intracellular cytokine, to mitigate the adhesion and aggregation reaction of leucocyte.(3) later stage of atherosclerosis plaque forming, PPAR- alfa agonists make patch Stability reinforce, prevent from falling off, it is unexpected to reduce cardiovascular and cerebrovascular.(4) disorders of lipid metabolism is corrected, the shape of atheromatous plaque is prevented At.
Oneself knows that inflammatory reaction plays an important role in atherosclerosis occurrence and development.In above-mentioned pathological change, PPAR- γ inhibits inflammatory reaction by the inhibiting effect to transcription factor, mitigates the pathology damage of atherosclerosis.Including PPAR- γ inhibits synthesizing by the human vascular endothelial Endothelin receptor A of thrombin induction by the signal path for inhibiting AP-1 to mediate (Delerive P,et al.Circ Res,1999,85:394)；Also TNF-α can be inhibited to lure by influencing NF- κ B signal approach The expression for the endothelial cell vascular cell adhesion molecule-1 (VCAM-1) led, and then adjust suppression monocyte in early stage atheromatous plaque At block formation aggregation (Marx N, et a1.Circulation, 1999,99:3125)；And inhibit adhesion molecule ICAM-1, E- Selectin etc., can inhibit inflammatory cell recruitment and infiltration (Verrier E, et a1.Circ RPJ, 2004,94:1515). In short, in the chronic inflammation processes of atherosclerosis, PPAR- γ can lower the expression of adhesion molecule, and it is thin to reduce inflammation Born of the same parents assemble.On the one hand the release of inflammatory mediator can be reduced；On the other hand Monocytes/Macrophages can be inhibited to foam cells Conversion.
Endothelin is a kind of endothelin detached from endothelial cell, can induce the hyperplasia of smooth muscle cell.Artery The release of interior Endothelin increases, the formation of meeting induction of vascular spasm and atheromatous plaque.(WY14643, PPAR- α match Pirinixic Acid Body) and Rosiglitazone can inhibit Endothelin secretion and oxidized low density lipoprotein (OX-LDL) induction protein kinase C, Reduce the formation of atherosclerosis.In addition, 15- dehydrogenation prostaglandin J2 or Ciglitazone (ciglitazone) can enhance NO From the release of pulmonary artery and aorta, protection vascular wall (Calnek DS, Mazzella L, Roser S, Arterioscler Thromb.Vasc.Biol., 2003,23 (1):52-57).
(4) PPAR and tumour
The relationship of PPAR and tumour has received universal concern, PPAR- γ can adjust the proliferation of cell in tissue, differentiation and Apoptosis：(1) ppar gamma receptor agonist can lead to G1 phase cell cycle arrests, inhibit cell Proliferation.FarroW et al. is in pancreas It is found in the research of cancer, PTEN can be raised after activation PPAR- γ, to inhibit the phosphorylation of Akt in PI-3K signal pathways, So that the pancreatic tumor cell period is still in G0/G1Phase (Farrow B, et a1.Biochem Biophys Res Commun, 2003,301:50).In the research of liver cancer cells, researcher has found that PPAR- γ can be by raising p21Cipl/Waf1Or p27kipCome inhibit cell proliferation (Koga H, et a1.Hepatology, 2001,33:1087).p21Cipl/Waf1Or p27kip It can inhibit the activity of cyclin-DK compounds, and the process of cell cycle is adjusted in the compound.Jung Researchs are waited to point out, p21Cipl/Waf1Or p27kipAt least partly take part in suppression of the Ciglitazone to C-4II plants of cell growths of cervical carcinoma System (Jung TI, et a1.Gynecol Oncol, 2005,97:365).Thiazolidinediones may act on cyclin Deopendent protein kinase (CDK) inhibiting factor, such as P18, P21.Research finds that PPAR- gamma agonists can make in P18 and P21 expression It adjusts, these factors can reduce into retina mother by reducing the formation of cyclin (cyclin) and CDK complexs The phosphorylation of retinoblastoma protein (Rb albumen) promotes tumour cell G1 phase growth retardations, the proliferation week of final suppression of cell Phase, to reach antitumor proliferation effect.(2) PPAR- gamma agonists can be with inducing cell apoptosis.Hairs of the PPAR- γ in tumour By the apoptosis of inducing cell in hair tonic exhibition, the regulation and control of cell cycle are participated in play a role.The study found that c6 glioma cells Under the effect of PPAR- gamma agonists, preceding apoptotic protein Bax and Bad up-regulated expressions lead to the release of cromoci, cause a system The activation for arranging the caspase families factor, finally causes the apoptosis of tumour cell.(3) PPAR- gamma agonists can also be by inhibiting swollen The formation of tumor new vessels and generate antitumor action.PPAR- γ can such as press down cancer base after being activated by target gene downstream Because of (PTEN), proto-oncogene (c-myc), p27, COX-2 and matrix metallo-proteinase 9 (MMP9) etc., realize that its inhibits cell life Long, inducing cell apoptosis, and the biological functions such as induction tumor cell differentiation and inhibition Tumor angiogenesis.Correlative study refers to Go out, the PPAR- γ of activation can be by inhibiting platelet derived growth factor, insulin-induced minichromosome to maintain albumen (insulin induced minichromosome maintenance protein) and E2F signals, with this to cell week The duplication of phase and DNA play inhibiting effect (Bruemmer D, et a1.Eur J Pharmacol, 2003,466:225).(4) PPAR- gamma agonists can inhibit cancer metastasis.LiuH et al. (Liu H, Zang C, Fenner MH, et al.Breast Cancer Res.Treat.,2003,79(1):It 63-74) reports, matrix metalloproteinase (MMP) especially gelatinase (gelatinase) expression increase forms related to tumour.The activation of PPAR- γ can inhibit Gelatinase B, and can prevent huge Phagocyte and myocyte's migration, prompt PPAR- γ ligands that may play the role of inhibiting Nasopharyngeal neoplasms.PPAR- γ ligands Tissue inhibition MMP-1 (TIMP-1) can be raised, so that the Gelatinolytic of gelatinase is acted on and declines, prevent cancer cell from shifting. Also there are the expression of PPAR- γ, troglitazone and Rosiglitazone to can inhibit melanocytoma in melanocytoma and its transfer stove The Proliferation, Differentiation of cell can be used to treat melanocytoma (Mossner R, Schulz U, Kruger U, et al.JInvest.Dermatol.,2002,119(3):576-582)。
(5) PPAR and cerebral ischemia
Shimazu etc. is research shows that the activation of PPAR- γ can increase copper-zinc superoxide dismutase (Cu/Zn-SOD), clearly Except free radical (Shimazu T, Inoue I, Araki N, et al.Stroke, 2005,36 (2):353-359).PPAR- γ's Activation can protect neure damage in cerebral ischemia re-pouring.In addition, the damaging action of inflammatory reaction is by people after cerebral ischemia Concern.Dendritic Cells is a kind of important antigen presenting cell, and the inflammation after cerebral ischemia is participated in by release cell factor Disease is damaged.PPAR- gamma agonists Ciglitazone can mitigate the expression of the Dendritic Cells of OX-LDL inductions, inhibit Dendritic Cells Endocytosis, reduce the immune response that is caused of Dendritic Cells, reduce inflammatory reaction (Luo Y, Liang after cerebral ischemia C,Xu C,et al.J Cardiovasc Pharmacol,2004,44(3):381-385).Due to PPAR and cerebral ischemia reperfusion Note damage is closely related, can find Neuroprotective Agents by target spot of PPAR.
(6) PPAR and Parkinson's disease
DehmerT et al. is in (2004,88 (2) J Neurochem:The study found that PPAR- γ are in pa gold in 494-501) There is expression in the nigrostriatum of gloomy disease patient.In the pa gold that MPTP (1- methyl 4-phenyls -1,2,3,6- tetrahydropyridines) is induced In gloomy disease model, nitric oxide synthase type (iNOS) catalysis generates NO, and dopamine neuronal is adjusted as a kind of important medium The death of first cell.Pioglitazone can protect the loss and catechu of dopamine neuronal cell in the corpus straitum that MPTP is induced The loss of phenol amine.Oral Pioglitazone can protect the activity of the tyrosine hydroxylase of substantia nigra neuron, can reduce nigrostriatum The activity of compact part microglia reduces the activity of glial fibrillary acid protein.In addition, Pioglitazone can reduce NO mediations Cellular damage.Its mechanism may be due to inhibit NF- κ B subunit p65 be transferred in the core of spongiocyte and dopamine neuron, To play cytoprotection.
(7) PPAR and skin disease
Studies have shown that PPAR- β play decisive role during epidermal wound heals.PPAR- β are to adjusting skin Growth and Differentiation and the scytitis reaction of epidermal cell have important role.PPAR- β and psoriasis, atopic dermatitis, acne and The healing of skin related (Kuenzli S, Saurat JH.Br.J.Dermatol., 2003,149 (2):229-236).Tan NS Et al. in (2003,4 (8) Am.J.Clin.Dermatol.:Report in 523-530), under the stimulation of the factors such as skin injury, Damage location generates inflammatory factor, on the one hand these inflammatory factors activate PPAR- β, on the other hand can be used as apoptotic signal Cause the apoptosis of horn cell.PPAR- β can delay TNF-α as a kind of important transcription factor, the inflammation such as IFN-γ because Son adjusts cell adapted stress situation in the generation of damage location, far from apoptotic signal caused by inflammatory factor.
Early stage skin trauma, PPAR- β make trauma skin edge have the sufficient amount of great-hearted cutin of tool thin Born of the same parents.The repairing phase in wound later stage, PPAR- β make the keratinocyte differentiation at trauma skin edge shift, form new epidermis, promote Into the healing of skin wound.Its mechanism may be PPAR- β up-regulation integral protein associated kinases and 3- phosphoinositides dependent kinase- 1.Both kinase activators cascade reaction of AKT, the activation of AKT cause cutin formed albumen increase (Tan NS, Michalik L,Desvergne B,et al.Am.J.Clin.Dermatol.2003,4(8):523-530).Wahli W etc. People is in Eur.J.Biochem. (2003,270 (Suppl1):16) report, PPAR- β also stimulate the activity and MMP-9 of NF- κ B in Generation, adjust the transfer of keratinocyte.
Conclusion
PPAR is current one of research hotspot, many studies have shown that PPAR is related with a variety of diseases, for the related disease for the treatment of Disease provides target spot (Konopleva M, Andreeff M.Curr.Opin.Hematol., 2002,9 (4):294-302).But It is not thorough enough due to studying at present it, and have been reported that display PPAR can inhibit the function of mitochondrial complex I, make its application It is restricted.With molecular biology and pharmacological development, PPAR is bound to provide new approach for treatment disease.
Summary of the invention
The present invention describes type I compound and/or their officinal salt
Wherein, R1Selected from trifluoromethyl, (C1-C10) linear or branched alkyl group, (C2-C10) linear chain or branched chain alkenyl, (C2- C10) linear chain or branched chain alkynyl, 3-12 members alicyclic group, phenyl, other (C5-C10) aryl, (C5-C10) heteroaryl or (C3- C7) heterocycle, wherein the heteroaryl or heterocycle have the hetero atom of at most 3 O, S or N, and (C1-C10) linear chain or branched chain Alkyl, (C2-C10) linear chain or branched chain alkenyl, (C2-C10) linear chain or branched chain alkynyl, 3-12 members alicyclic group, phenyl, other (C5-C10) aryl, (C5-C10) heteroaryl or (C3-C7) heterocycle is respectively independent and is arbitrarily replaced by most 3 substituent groups, institute It states substituent group and is selected from-OR ' ,-CF3、-OCF3、-SR′、-S(O)R′、-SO2R′、-SCF3, halogen ,-CN ,-COOR ' ,-COR- ,-O (CH2)2N(R′)2、-OCH2N(R′)2、-CON(R′)2、-(CH2)2OR′、-CH2OR′、-CH2CN, the phenyl arbitrarily replaced or benzene Oxygroup ,-N (R ')2、-NHR′、-C(O)OR′、-NR′C(O)R′、-(CH2)2N(R′)2Or-CH2N(R′)2；
R2Selected from at least one, (the C of at most 3 substituent groups1-C6) linear or branched alkyl group, 3-12 member alicyclic groups Group, phenyl, other (C5-C10) aryl, (C5-C10) heteroaryl or (C3-C7) heterocycle, wherein the heteroaryl or heterocycle tool There are the hetero atom of at most 3 O, S or N；(the C1-C6) at least one of linear or branched alkyl group institute band, at most 3 substituent group choosings From-OR ' ,-CF3、-OCF3、-SR′、-S(O)R′、-SO2R′、-SCF3, halogen ,-CN ,-COOR ' ,-COR- ,-O (CH2)2N (R′)2、-OCH2N(R′)2、-CON(R′)2、-(CH2)2OR′、-CH2OR′、-CH2CN, the phenyl arbitrarily replaced or phenoxy group ,-N (R′)2、-NHR′、-C(O)OR′、-NR′C(O)R′、-(CH2)2N(R′)2Or-CH2N(R′)2；The 3-12 members alicyclic group, Phenyl, other (C5-C10) aryl, (C5-C10) heteroaryl or (C3-C7) heterocycle is respectively independent and is arbitrarily replaced by most 3 Base replaces, and the substituent group is selected from-OR ' ,-CF3、-OCF3、-SR′、-S(O)R′、-SO2R′、-SCF3, halogen ,-CN ,- COOR′、-COR-、-O(CH2)2N(R′)2、-OCH2N(R′)2、-CON(R′)2、-(CH2)2OR′、-CH2OR′、-CH2It is CN, arbitrary Substituted phenyl or phenoxy group ,-N (R ')2、-NHR′、-C(O)OR′、-NR′C(O)R′、-(CH2)2N(R′)2Or-CH2N(R′)2。
The group that R ' is independently selected from hydrogen or arbitrarily replaces, the group are selected from (C1-C8) aliphatic group, have The independent 3-8 members saturations selected from nitrogen, oxygen or sulfur heteroatom of 0-3, fractional saturation or undersaturated monocycle or with 0-5 completely It is a independent selected from nitrogen, the 8-12 members saturation of oxygen meeting sulfur heteroatom, fractional saturation or complete undersaturated bicyclic ring system, or twice The R ' of appearance atoms connected to them are formed together with 0-4 independent optionally taking selected from nitrogen, oxygen or sulfur heteroatom 3-12 members saturation, fractional saturation or the complete undersaturated monocycle or bicyclic in generation.
Preferably, for type I compound, wherein R1For (C2-C10) linear chain or branched chain alkenyl, (C2-C10) linear chain or branched chain Alkynyl can respectively arbitrarily be replaced independently and by most 3 substituent groups, and the substituent group is selected from-OR ' ,-CF3、-OCF3、- SR′、-S(O)R′、-SO2R′、-SCF3, halogen ,-CN ,-COOR ' ,-COR- ,-O (CH2)2N(R′)2、-OCH2N(R′)2、-CON (R′)2、-(CH2)2OR′、-CH2OR′、-CH2CN, the phenyl arbitrarily replaced or phenoxy group ,-N (R ')2、-NHR′、-C(O)OR′、- NR′C(O)R′、-(CH2)2N(R′)2Or-CH2N(R′)2；R2Selected from at least one, (the C of at most 3 substituent groups1-C6) straight chain Or branched alkyl, phenyl, (the C1-C6) at least one of linear or branched alkyl group institute band, at most 3 substituent groups are selected from and arbitrarily take The phenyl or phenoxy group in generation；The phenyl is replaced by most 3 substituent groups, and the substituent group is selected from-OR ' ,-CF3、-OCF3、- SR′、-S(O)R′、-SO2R′、-SCF3, halogen ,-CN ,-COOR ' ,-COR- ,-O (CH2)2N(R′)2、-OCH2N(R′)2、-CON (R′)2、-(CH2)2OR′、-CH2OR′、-CH2CN, the phenyl arbitrarily replaced or phenoxy group ,-N (R ')2、-NHR′、-C(O)OR′、- NR′C(O)R′、-(CH2)2N(R′)2Or-CH2N(R′)2；The group that R ' is independently selected from hydrogen or arbitrarily replaces, the group Selected from (C1-C8) aliphatic group, be saturated with the independent 3-8 members selected from nitrogen, oxygen or sulfur heteroatom of 0-3, fractional saturation or Complete undersaturated monocycle is saturated, fractional saturation or complete with the 0-5 independent 8-12 members selected from nitrogen, oxygen meeting sulfur heteroatom Complete undersaturated bicyclic ring system, or the R ' atoms connected to them occurred twice are formed together with 0-4 independent choosings From the 3-12 members saturation of nitrogen, oxygen or sulfur heteroatom optionally replaced, fractional saturation or undersaturated monocycle or bicyclic completely.
Preferably, for type I compound, wherein R1For (C2-C10) linear chain or branched chain alkynyl, it can be respectively independent and arbitrary Replaced by most 3 substituent groups, the substituent group is selected from-OR ' ,-CF3、-OCF3、-SR′、-S(O)R′、-SO2R′、-SCF3, halogen Element ,-CN ,-COOR ' ,-COR- ,-O (CH2)2N(R′)2、-OCH2N(R′)2、-CON(R′)2、-(CH2)2OR′、-CH2OR′、- CH2CN, the phenyl arbitrarily replaced or phenoxy group ,-N (R ')2、-NHR′、-C(O)OR′、-NR′C(O)R′、-(CH2)2N(R′)2Or- CH2N(R′)2；R2Selected from at least one, (the C of at most 3 substituent groups1-C6) linear or branched alkyl group, phenyl, (the C1- C6) at least one of linear or branched alkyl group institute band, at most 3 substituent groups are selected from arbitrary substituted phenyl；The phenyl is by most 3 substituent group substitutions, the substituent group are selected from arbitrary substituted phenyl or phenoxy group；R ' is independently selected from hydrogen or arbitrarily takes The group in generation, the group are selected from (C1-C8) aliphatic group, with the independent 3-8 selected from nitrogen, oxygen or sulfur heteroatom of 0-3 Member saturation, fractional saturation or completely undersaturated monocycle or with 0-5 it is independent selected from nitrogen, oxygen can sulfur heteroatom 8-12 members Saturation, fractional saturation or complete undersaturated bicyclic ring system, or the R ' atoms connected to them occurred twice are formed together With 0-4 independent the 3-12 members saturation optionally replaced, fractional saturation or complete unsaturations selected from nitrogen, oxygen or sulfur heteroatom Monocycle or bicyclic.
For R1For substituent group, representational example is following (only by taking straight chain alkynes or alkene as an example),
And
Asterisk (*) indicates that the key is connected with carbonylic carbon atom in figure.
For R2For substituent group, representational example is as follows,
Asterisk (*) indicates that the key is connected with 4 bit amino nitrogen-atoms of pyrimidine ring in figure.
For with the above representational R1And R2The corresponding type I compound of substituent group, we devise as follows Synthetic route.
Synthetic route one：
Synthetic route two：
G (referring to group) in said synthesis route in compound molecule formula, which is represented, arbitrarily meets preceding claims restriction The substituent group of condition.
According to synthetic route one, R can be synthesized1Change for alkynes and triple carbon-carbon bonds and the preferred formula I that carbonyl carbon is connected directly Close object.Because being related to introducing R1And R2The sequencing of substituent group is different and is divided into two kinds of strategies.The first strategy is, with 2- ammonia Base -4,6- dihydroxy-pyrimidine (II) is raw material, is reacted with phosphorus oxychloride, n,N-Dimethylformamide (DMF) and generates amino -4 2-, (bibliography has Wainwright P, et al.Synlett to 6- dichloro pyrimidine -5- formaldehyde (III)；nb.13；(2011)； P.1900-1904 or Baraldi PG, et al.Bioorganic and Medicinal Chemistry, vol.11； nb.19；(2003)；P.4161-4169 etc.).2- amino -4,6- dichloro pyrimidine -5- formaldehyde (III) and R2Substituted amine (IV) exists Suitable inorganic base (such as sodium hydrogen, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide or potassium tert-butoxide etc.) or organic base (ratio Such as triethylamine, diisopropyl ethyl amine, pyridine) in the presence of can react generation and have been introduced into R2The pyrimidine -5-formaldehyde of substituent group (V) (there are many bibliography of structure proximate, are not listed one by one herein).Substituted end position alkynes (VI) first with n-BuLi or Person's Grignard Reagent or the reaction of other organometallic reagent generate corresponding alkynyl metal salt, then again with have been introduced into R2Substitution Addition reaction occurs for the pyrimidine -5-formaldehyde (V) of base, you can generates the propargyl alcohol derivative (VII) of 5 substitutions of pyrimidine.Finally, sharp With the well-known oxidant of organic synthesis field, such as manganese dioxide, Dess-Martin oxidants, Jones reagents, PCC The hydroxyl of third, alkynes can be oxidized to ketone, you can obtain required pyrimidine acetylenic ketone derivative (VIII) by (pyridinium chloro-chromate) etc.. Second of strategy is first not introduce R2Substituted amine (IV), but allow 2-amino-4,6-dichloropyrimidine -5- formaldehyde (III) first with Substituted end position alkynes (VI) reacts, and generates pyrimidine propargyl alcohol derivative (Ⅸ), is then re-introduced into R2Substituted amine (IV) generates Introduce R2The pyrimidine alkynol (Ⅹ) of substituent group.Next, deriving likewise, oxidation reaction occurs again and generates required pyrimidine acetylenic ketone Object (VIII).Under normal circumstances, why first pyrimidine propargyl alcohol derivative (Ⅸ) is not oxidized to again draw after pyrimidine acetylenic ketone derivative Enter R2Substituted amine (IV) is to generate cyclic side products or other by-products because acetylenic ketone structure is easy to happen side reaction with amine Object.It is that R is depended entirely on using the first strategy or second of strategy1And R2Whether two substituent groups mutually will produce before Interference, so that unnecessary side reaction occurs even can hamper the introducing of another substituent group completely.If R1And R2Two The introducing of a substituent group will not be interfered to other side, then two kinds of strategies can be optional.Certainly, compound point is not being influenced Group is had been introduced into son or even if is influenced under the premise of still capable of finally restoring, if R1Or R2According to molecule structure in substituent group It builds and needs also to need further to chemically react, or take off protecting group, or form new covalent bond and introduce new group, etc., So pyrimidine acetylenic ketone derivative (VIII) is not just final required compound, also to continue to chemically react.
According to synthetic route two, R can be synthesized1The change of preferred formula I being connected directly with carbonyl carbon for alkene and carbon-carbon double bond Close object.Likewise, because being related to introducing R1And R2The sequencing of substituent group is different and is divided into two kinds of strategies.Two kinds of strategies all with 1- (2- amino -4,6- dichloro pyrimidine -5- bases) ethyl ketone (Ⅻ) this key intermediate is starting material.1- (2- amino -4,6- two Chlorine pyrimidine -5- bases) ethyl ketone (Ⅻ) synthesis, can with 2-amino-4,6-dichloropyrimidine -5- formaldehyde (III) be raw material, elder generation and first Addition reaction occurs for base Grignard Reagent, obtains 1- (2-amino-4,6-dichloropyrimidine -5- bases) ethyl alcohol (Ⅺ), then hydroxyl is aoxidized At ketone, you can obtain 1- (2-amino-4,6-dichloropyrimidine -5- bases) ethyl ketone (Ⅻ) (bibliography has WO2005/28434, (2005), (A2) or WO2014/96423, (2014), (A1) etc.).The first strategy is 1- (2-amino-4,6-dichloropyrimidine- 5- yls) ethyl ketone (Ⅻ) with substitution aldehyde (Ⅹ III) occurs under alkaline condition aldol reaction generation pyrimidine ketenes derivative (Ⅹ IV) (approximate bibliography has Rana NK, et al.Journal of Organic Chemistry；vol.75； nb.6；(2010)；P.2089-2091 or Chong J, et al.Journal of the American Chemical Society；vol.122；nb.8；(2000)；P.1822-1823 etc.) substitution reaction, then occurs again and introduces R2Substituted amine (IV), it obtains required having been introduced into R2The pyrimidine ketenes derivative (Ⅹ V) of substituent group.Second of strategy is, with the first strategy Reaction sequence on the contrary, first carry out substitution reaction introduce R2Substituted amine (IV), generation have been introduced into R2The pyrimidine ethyl ketone of substituent group spreads out Biological (Ⅹ VI) then occur aldol reaction and generate pyrimidine ketenes derivative (Ⅹ V) again.Likewise, selection uses first Kind strategy or second of strategy, depend on R1And R2Whether two substituent groups mutually will produce interference before.Similarly, if R1 Or R2It needs also to need further to chemically react according to molecule construction in substituent group, then pyrimidine ketenes derivative (Ⅹ V) is just It is not final required compound, also continues to chemically react.Especially, it should be noted that although in preferred R1Substituent group In representational example, double bond is all drawn as anti-configuration, this is because what most drug was all made of is anti-configuration isomers, But in the double bond in building pyrimidine ketenes derivative Ⅹ IV or Ⅹ V, it is possible to while obtaining Cis formulas and trans- mixing Object, the reason of being based only on steric hindrance or control reaction condition make the product generated based on transisomer, anti- When should post-process, unwanted Cis formulas product is removed.
R of the said synthesis route just for two kinds of preferable cases (alkene and alkynes)1Substituent group and different R2Substituent group Mutually arrange in pairs or groups and design.Other R for the type I compound for meeting claim1Substituent group, synthetic method will be made certainly Transformation, this is basic common sense well-known to those skilled in the art.
The invention further relates to as drug (or medicament) type I compound and/or its officinal salt prepare prevent and/or Treat the purposes in the drug of following disease, i.e. inflammation (including rheumatoid arthritis), atherosclerosis, I type or II type Diabetes, diabetic complication, obesity, hyperlipidemia, impaired glucose tolerance, cerebral ischemia, parkinsonism, insulin resistance with And osteoporosis.
The invention further relates to pharmaceutical preparation (or pharmaceutical composition), containing a effective amount of at least one type I compound and/ Or the excipient and carrier of its officinal salt, physiology tolerance, and also have other additives and/or other activity in due course Ingredient.Drug can be administered orally, such as with pill, tablet (including sustained release and controlled release), spraying piece (lacquered Tablets), coating tablet, pulvis, granule, hard and Perle, solution, syrup, emulsion, suspension, aerosol mixing The form of object, lipid or polymer microballoon or nanosphere or capsule.But using can also be carried out with following parenteral route：Through Rectally, such as with suppository form；Or parenteral, such as through intravenous, intramuscular or subcutaneously to inject solution or infusion Solution, micro-capsule, implant or the form for being implanted into stick；Or percutaneous, part or ophthalmic administration, such as with ointment, cream, breast Agent, ointment, impregnated pads, solution, gel, polymeric chip, spray, lotion, tincture or suspended form；Or with other approach Administration, such as with aerosol or form of nasal sprays.
The pharmaceutical preparation of the present invention is prepared in a manner of known per se and be known to those skilled in the art, in addition to formula Outside I compound and/or their officinal salt and/or their prodrug, using pharmaceutical inertia or there is certain drug activity Inorganic and/or organic carrier substances and/or additive.For pill, pulvis, granule, tablet, coating tablet and glutoid glue For the preparation of capsule, it may use such as lactose, cornstarch or derivatives thereof, talcum, stearic acid or its salt.Soft gelatin glue The carrier mass of capsule and suppository has such as fat, wax, semisolid and liquid polyol, natural or fixed oil.It is suitable for preparing Solution for example injects solution or the carrier mass of emulsion or syrup and has such as water, brine, alcohol, glycerine, polyalcohol (including poly- Ethylene glycol), sucrose, inverted sugar, glucose, vegetable oil etc..Suitable for micro-capsule, implant or the carrier mass for being implanted into stick, example Such as the copolymer of oxyacetic acid and lactic acid.Pharmaceutical preparation usually contains about 0.001% to about 90% weight, and preferably 0.01% to 10% The type I compound of weight and/or their officinal salt and/or their prodrug.I chemical combination of active constituent formula in pharmaceutical preparation Object and/or the amount of their officinal salt and/or their prodrug are typically about 0.5mg to about 1000mg, and preferably from about 1mg is to about 500mg。
Other than the active constituent of formula I and/or their officinal salt and carrier mass, pharmaceutical preparation can contain one kind Or multiple additives, as filler, disintegrant, adhesive, lubricant, wetting agent (moisture adjuster), stabilizer, emulsifier, It is preservative, screening agent, sweetener, colorant, corrigent, aromatic, thickener, diluent, buffer substance (pH adjusting agent), molten Agent, solubilizer, the reagent for obtaining depot effect, salt (osmotic pressure regulator), coating agent or the antioxidant for changing osmotic pressure.It Can also contain two or more type I compounds and/or their officinal salt.Contain two or more in pharmaceutical composition It, can be according to the specific overall pharmacological property of pharmaceutical preparation to the selection of individual compound when kind type I compound.For example, effect Duration shorter height potent compound can be combined with the lower long-acting compound of effect.Certainly, people in the art Member by the optional additives in careful selection pharmaceutical composition to be added so that the intrinsic advantageous feature of the present invention not by or it is real It is not adversely affected by the estimated substance that is added in matter.Permitted flexibility makes for substituent group selection in type I compound Numerous controls can be carried out to the biology and physicochemical properties of compound, thus, it is possible to select required compound.In addition, removing Outside at least one type I compound and/or its officinal salt, pharmaceutical preparation can also contain one or more other therapeutic or pre- The active constituent of anti-property.
When using type I compound, dosage can change, agent in grace period and according to conventional with known to doctor Amount should be suitable for the individual instances of each example.Dosage depends on particular compound, the property of treated disease such as applied Matter and severity, method of application and scheme or whether that is treated be acute or chronic disease or prevented.Suitable Dosage can utilize clinical method known to medical domain to establish.In general, result needed for being obtained in the adult for weighing about 75kg Daily dose be about 0.01mg/kg to about 100mg/kg, preferably from about 0.1mg/kg to about 50mg/kg, especially about 0.1mg/kg extremely About 10mg/kg (in each case with mg/kg batheroom scales).Especially in the case of application relatively large amount, daily dose can divide If for stem portion, such as the application of 2,3 or 4 parts.In general, according to individual behavior, it may be necessary to described in deviateing upward or downward Daily dose.
In addition, type I compound can be used as preparing among other compounds, the especially synthesis of other drugs active constituent Body can for example be obtained by introducing substituent group or modification functional group by compound of formula I.
In most cases, the reaction mixture of the final compound containing formula I or intermediate is post-processed, such as It is necessary to can be purified product by conventional method well known by persons skilled in the art fruit.For example, synthesized compound can profit It is such as crystallized with well known method, all kinds of chromatographies (including liquid chromatogram, gas-chromatography) or reversed-phased high performace liquid chromatographic (RP- HPLC) or it is based on such as compound molecule size, whether with charge or with hydrophily or hydrophobicity build-in attribute etc. Other separation methods purified.Similar, it is well known to analyze and identify method such as amino acid sequence analysis, NMR, IR and mass spectrum Method (MS, including high resolution mass spectrum) can be used for characterizing compound of the present invention.
Therefore, following embodiment is the part of the present invention, is not intended to limit the present invention for illustrating.
It should be intended that, the active modification of the various embodiments of the non-substantial effect present invention is included in disclosed herein The scope of the invention in.
Specific implementation mode
Embodiment 1：1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (piperidines -1- Base) -2- hexin -1- ketone preparation
The first step：N- (3- (4- Fonnylphenyls) phenyl) urea (compound number 1)
In the case where being bubbled deoxygenation through prior nitrogen and continuing logical nitrogen protection, by Anhydrous potassium carbonate (27.6g, 0.2mol), acetic acid Palladium (0.90g, 4.0mmol) andMolecular sieve (2.0g is activated through Muffle furnace high-temperature roasting in advance) is sequentially added to bromobenzene first (18.0g, 0.1mol can refer to document Journal of for aldehyde (18.5g, 0.1mol) and urea groups phenyl boric acid American Chemical Society；vol.81；(1959)；P.3017 synthesized) tetrahydrofuran (150mL) and water In (40mL) mixed solution.Oil bath heating is to flowing back under nitrogen protection, and insulation reaction about 6 hours.Ethyl acetate is added (300mL) stirs half an hour, is filtered to remove insoluble matter, gained mixed solution is washed with saturated salt solution (200mL*2).Point Liquid, organic phase are dried over anhydrous sodium sulfate, and filtering removes solvent under reduced pressure, residue purify through silica gel column chromatography (gradient elution, Eluent is petroleum ether:Ethyl acetate=5:1 to 1:1) 19.7g faint yellow solids, as N- (3- (4- Fonnylphenyls) benzene are obtained Base) urea, yield 82.0%.MS:M/z=241.1 (M+H+)。
Second step：N- (3- (4- hydroxymethyl phenyls) phenyl) urea (compound number 2)
N- (3- (4- Fonnylphenyls) phenyl) urea (19.0g, 79.1mmol) is dissolved in methanol (100mL), ice-water bath Cooling, careful is added portionwise sodium borohydride (1.5g, 39.7mmol).After adding sodium borohydride, half an hour is stirred, ice is removed Water-bath allows reaction solution to be warmed to room temperature naturally, and the reaction was continued about 3-5 hours, and TLC monitors (petroleum ether:Ethyl acetate=1:1) until The reaction was complete.The dilute hydrochloric acid solution of 2M is slowly added dropwise, until pH value, is 2-3.Revolving removes most of methanol, in residue Ethyl acetate (200mL) is added, gained mixed solution is washed with saturated salt solution (100mL*2).Liquid separation, organic phase is through anhydrous sulphur The drying of sour sodium, filtering remove solvent under reduced pressure, obtain 18.0g off-white powders, as N- (3- (4- hydroxymethyl phenyls) phenyl) urea, Yield 93.9%.MS:M/z=243.1 (M+H+)。
Third walks：N- (3- (4- 2-bromomethylphenyls) phenyl) urea (compound number 3)
Under ice-water bath, chloroform (50mL) solution of phosphorus tribromide (19.5g, 72.2mol) is slowly added dropwise into N- (3- (4- hydroxymethyl phenyls) phenyl) urea (17.5g, 72.2mmol) chloroform (200mL) solution in.Control was dripped off at about 30 minutes. The reaction was continued under ice-water bath, and TLC monitors (petroleum ether:Ethyl acetate=1:1) it until the reaction is complete, about needs 1 hour.Ice is added Reaction is quenched in aqueous mixtures (100g).Liquid separation, water phase are extracted with dichloromethane (100mL*1), and liquid separation merges organic phase, through nothing After aqueous sodium persulfate drying, filtering removes solvent under reduced pressure, obtains 21.6g yellow foamy solids, as N- (3- (4- bromomethyl benzene Base) phenyl) urea, yield 98.1%.MS:M/z=305.0,307.0 (M+H+)。
4th step：N- (4- (3- Ureidophenyls) benzyl) phthalimide (compound number 4)
N- (3- (4- 2-bromomethylphenyls) phenyl) urea is added in potassium phthalimide (12.1g, 65.5mmol) In n,N-Dimethylformamide (200mL) solution of (20.0g, 65.5mmol).It reacts at room temperature about 10-15 hours, TLC monitoring (petroleum ether:Ethyl acetate=2:1) until the reaction is complete.Water (300mL) is added, there are a large amount of solids to be precipitated.Filtering, vacuum are dry It is dry, obtain 22.4g off-white powders, as N- (4- (3- Ureidophenyls) benzyl) phthalimide, yield 92.1%.MS: M/z=372.1 (M+H+)。
5th step：N- (3- (4- aminomethyls phenyl) phenyl) urea (compound number 5)
N- (4- (3- Ureidophenyls) benzyl) phthalyl is added in hydrazine hydrate (55% aqueous solution, 49.0g, 0.5mol) In ethyl alcohol (200mL) solution of imines (20.0g, 53.9mmol).By reaction solution oil bath heating to 40 DEG C and react about 5-6 it is small When, TLC monitors (dichloromethane:Methanol=8:1) until the reaction is complete.It is filtered to remove insoluble matter, removes solvent, residue under reduced pressure It is dissolved with dichloromethane (300mL), refilters primary, removing insoluble matter.(100mL*2) dichloromethane solution is washed with water.Have After machine is mutually dried over anhydrous sodium sulfate, filtering removes solvent under reduced pressure, obtains 11.2g off-white powders, as N- (3- (4- aminomethyls Phenyl) phenyl) urea, yield 86.1%.MS:M/z=242.1 (M+H+)。
6th step：2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5-formaldehyde (compound number 6)
In ethyl alcohol (100mL) solution of N- (3- (4- aminomethyls phenyl) phenyl) urea (10.0g, 41.4mmol), successively Triethylamine (21.2g, 0.21mol) and 2-amino-4,6-dichloropyrimidine -5- formaldehyde (8.0g, 41.4mmol) is added.By reaction solution With oil bath heating to flowing back and reacting about 6-7 hours, TLC monitors (dichloromethane:Methanol=10:1) until the reaction is complete.Decompression Solvent is evaporated off, water (200mL) is added, is beaten, filtering, filter cake ethyl alcohol recrystallization is simultaneously dried in vacuo, and obtains 14.4g pale yellow colored solids Body, as 2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5-formaldehydes, yield 88.4%.MS:M/z= 397.2(M+H+)。
7th step：1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (piperidines -1- Base) -2- hexin -1- alcohol (compound number 7)
Under nitrogen protection, by 1- (4- pentynyls) piperidines, (19.1g, 126.0mmol can refer to document Cui Li, et al.Chemical Communications,2010,vol.46,#19p.3351–3353；Meier Galina,et Al.Bioorganic and Medicinal Chemistry, 2002, vol.10, #8p.2535-2542 or WO2014/ 81645A1,2014 are synthesized) anhydrous tetrahydro furan (100mL) solution be cooled to -78 DEG C with liquid nitrogen ethanol bath, slowly drip N-BuLi (2.5M hexane solutions, 50.4mL, 126.0mmol) solution, control is added to be dripped off at about 1 hour.Keep -78 DEG C and Under nitrogen protection, then be added dropwise 2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5-formaldehyde (12.5g, Anhydrous tetrahydro furan (100mL) solution 31.5mmol).Drop finishes, and reaction system of leaving is warmed to room temperature and reacts overnight, TLC prisons Control (dichloromethane:Methanol=10:1) until the reaction is complete.Water (50mL) is added dropwise, reaction is quenched, adds ethyl acetate (200mL).Gained mixed solution is washed with saturated salt solution (100mL*3).Liquid separation, organic phase are dried over anhydrous sodium sulfate, mistake Filter removes solvent under reduced pressure, and through silica gel column chromatography purifying, (gradient elution, eluent are dichloromethane to residue:Methanol=20:1 to 10:1) 11.8g faint yellow solids, as 1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases)-are obtained 6- (piperidin-1-yl) -2- hexin -1- alcohol, yield 68.3%.MS:M/z=548.3 (M+H+)。
8th step：1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (piperidines -1- Base) -2- hexin -1- ketone (compound number 8)
1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group)-are added in activated manganese dioxide (6.3g, 72.8mmol) 6- chlorine pyrimidine -5- bases) -6- (piperidin-1-yl) -2- hexin -1- alcohol (10.0g, 18.2mmol) dichloromethane (100mL) solution In.It reacts 24 hours at room temperature.It is filtered to remove insoluble matter, removes solvent under reduced pressure, residue through silica gel column chromatography purifying (wash by gradient De-, eluent is dichloromethane:Methanol=30:1 to 15:1) 7.8g faint yellow solids, as 1- (2- amino -4- (4- (3- are obtained Ureidophenyl) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (piperidin-1-yl) -2- hexin -1- ketone, yield 78.6%.MS:M/z= 546.2(M+H+)。
1H NMR(300MHz,DMSO-d6)δ:10.02(s,2H),9.83(s,2H),7.90-7.88(m,1H),7.75- 7.73(m,1H),7.44-7.40(m,2H),7.33-7.27(m,4H),4.67(s,2H),3.92(s,2H),2.65-2.61(m, 2H),2.34-2.28(m,4H),1.99-1.92(m,2H),1.66-1.54(m,8H).
Embodiment 2：1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups - The preparation of valerylene -1- ketone
The first step：(compound number is 2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5-formaldehyde 9)
Under nitrogen protection, by 4- (4- methoxyphenyls) aniline, (11.4g, 57.3mmol can refer to document Razler TM et al.Journal of Organic Chemistry；vol.74；nb.3；(2009)；P.1381 it -1384 is synthesized) Anhydrous tetrahydro furan (120mL) solution cooled down with ice-water bath, be carefully added into batches sodium hydrogen (60% mineral oil powder, 4.6g, 114.6mmol).It finishes, continues to be stirred to react about half an hour, add 2-amino-4,6-dichloropyrimidine -5- formaldehyde (10.0g, 52.1mmol).Ice-water bath is removed, reaction system is made to react at ambient temperature about 8-10 hours, TLC monitors (oil Ether:Ethyl acetate=2:1) until the reaction is complete.Water (20mL) is slowly added dropwise, reaction is quenched.Add ethyl acetate (200mL). Gained mixed solution is washed with saturated salt solution (100mL*3).Liquid separation, organic phase are dried over anhydrous sodium sulfate, and filtering, decompression is steamed Except solvent, residue is through recrystallization (petroleum ether:Ethyl acetate=5:1) it and is dried in vacuo, obtains 15.3g faint yellow solids, as 2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5-formaldehydes, yield 82.7%.MS:M/z=355.1 (M+ H+)。
Second step：1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups - Valerylene -1- alcohol (compound number 10)
Under nitrogen protection, by 4- methoxyl group -1- butine, (10.6g, 126.0mmol can refer to document JacksonW, et al.Australian Journal of Chemistry；vol.41；nb.2；(1988)；P.251-261 synthesized) nothing Water tetrahydrofuran (100mL) solution is cooled to -78 DEG C with liquid nitrogen ethanol bath, be slowly added dropwise n-BuLi (2.5M hexane solutions, 50.4mL, 126.0mmol) solution, it controls and was dripped off at about 1 hour.It keeps under -78 DEG C and nitrogen protection, then 2- amino -4- is added dropwise The anhydrous tetrahydro furan (100mL) of (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5-formaldehyde (11.2g, 31.5mmol) Solution.Drop finishes, and reaction system of leaving is warmed to room temperature and reacts overnight, and TLC monitors (dichloromethane:Methanol=10:1) until reaction Completely.Water (50mL) is added dropwise, reaction is quenched, adds ethyl acetate (200mL).Gained mixed solution saturated salt solution (100mL*3) is washed.Liquid separation, organic phase are dried over anhydrous sodium sulfate, and filtering removes solvent under reduced pressure, residue is through silica gel column layer (gradient elution, eluent are dichloromethane for analysis purifying:Methanol=30:1 to 15:1) 10.9g faint yellow solids, as 1- (2- are obtained Amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups-valerylene -1- alcohol, yield 78.7%.MS:M/z=439.2 (M+H+)。
Third walks：1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups - Valerylene -1- ketone (compound number 11)
1- (2- amino -4- (4- (4- methoxyphenyls) aniline is added in activated manganese dioxide (6.3g, 72.8mmol) Base) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups-valerylene -1- alcohol (8.0g, 18.2mmol) dichloromethane (100mL) solution In.It reacts 24 hours at room temperature.It is filtered to remove insoluble matter, removes solvent under reduced pressure, residue through silica gel column chromatography purifying (wash by gradient De-, eluent is dichloromethane:Methanol=40:1 to 20:1) 6.9g yellow solids, 1- (2- amino -4- (4- (4- methoxyl groups are obtained Phenyl) anilino-) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups-valerylene -1- ketone, yield 86.8%.MS:M/z=437.1 (M+H+)。
1H NMR(300MHz,DMSO-d6)δ:9.97(s,1H),7.52-7.48(m,2H),7.39-7.35(m,2H), 7.01-6.96(m,2H),6.64-6.59(m,2H),4.73(s,2H),3.91(s,3H),3.65-3.60(m,2H),3.32(s, 3H),2.33-2.28(m,2H).
Embodiment 3：(E) -1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- first The preparation of oxygroup -2- hexene -1- ketone
The first step：(E) -1- (2- amino -4,6- dichloro pyrimidine -5- bases) -6- methoxyl group -2- hexene -1- ketone (compile by compound Number for 12)
By 1- (2-amino-4,6-dichloropyrimidine -5- bases) ethyl ketone, (10.0g, 48.5mmol can refer to document WO2005/ 28434, (2005), (A2) or WO2014/96423, (2014), (A1) is synthesized) anhydrous tetrahydro furan (100mL) solution Be cooled to -78 DEG C with liquid nitrogen ethanol bath, be slowly added dropwise lithium diisopropylamine (LDA, 2.0M hexane solution, 24.3mL, 48.5mmol) solution, control are dripped off in about half an hour.It keeps under -78 DEG C and nitrogen protection, then 4- methoxyl group -1- fourths is added dropwise (5.0g, 48.5mmol can refer to document WO2009/7814 to aldehyde, (2009), (A1), Borbas K, et al.Organic Letters；vol.10；nb.10；(2008)；Or Chau ST, et al.Organic Letters p.1931-1934； vol.13；nb.4；(2011)；P.756-759 synthesized) anhydrous tetrahydro furan (30mL) solution.Drop finishes, reactant of leaving It is that nature is warmed to room temperature, overnight, TLC monitors (petroleum ether for reaction:Ethyl acetate=1:1) until the reaction is complete.It is slowly added dropwise full Reaction is quenched with aqueous ammonium chloride solution (20mL).Add ethyl acetate (200mL).Gained mixed solution saturated salt solution (100mL*3) is washed.Liquid separation, organic phase are dried over anhydrous sodium sulfate, and filtering removes solvent under reduced pressure, residue is through silica gel column layer (gradient elution, eluent are petroleum ether for analysis purifying:Ethyl acetate=5:1 to 2:1) 8.7g off-white powders, are obtained, as (E)- 1- (2-amino-4,6-dichloropyrimidine -5- bases) -6- methoxyl group -2- hexene -1- ketone, yield 61.9%.MS:M/z=290.0 (M+ H+)。
Second step：(E) -1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- methoxies Base -2- hexene -1- ketone (compound number 13)
Under nitrogen protection, by 4- (4- methoxyphenyls) aniline, (5.7g, 28.8mmol can refer to document Razler TM et al.Journal of Organic Chemistry；vol.74；nb.3；(2009)；P.1381-1384 synthesized) Anhydrous tetrahydro furan (60mL) solution is cooled down with ice-water bath, be carefully added into batches sodium hydrogen (60% mineral oil powder, 2.3g, 57.6mmol).It finishes, continues to be stirred to react about half an hour, add (E) -1- (2-amino-4,6-dichloropyrimidine -5- bases) - 6- methoxyl group -2- hexene -1- ketone (7.6g, 26.2mmol).Ice-water bath is removed, reaction system is made to react about 8- at ambient temperature 10 hours, TLC monitored (petroleum ether:Ethyl acetate=2:1) until the reaction is complete.Water (10mL) is slowly added dropwise, reaction is quenched.Again Ethyl acetate (100mL) is added.Gained mixed solution is washed with saturated salt solution (50mL*3).Liquid separation, organic phase is through anhydrous sulphur Sour sodium drying, filtering remove solvent under reduced pressure, residue is through recrystallization (petroleum ether:Ethyl acetate=5:1) it and is dried in vacuo, obtains 9.6g faint yellow solids, as (E) -1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- Methoxyl group -2- hexene -1- ketone, yield 80.9%.MS:M/z=453.2 (M+H+)。
1H NMR(300MHz,DMSO-d6)δ:9.95(s,1H),7.50-7.46(m,2H),7.41-7.37(m,2H), 7.05-6.99(m,2H),6.89-6.85(m,1H),6.66-6.61(m,2H),6.21(d,1H),4.73(s,2H),3.91(s, 3H),3.62-3.57(m,2H),3.32(s,3H),2.11-2.06(m,2H),1.72-1.67(m,2H).
The type I compound for meeting two kinds of preferable cases of claims (alkene and alkynes) may be used and above-mentioned implementation The approximate synthetic method of example obtains, and only need to change different starting materials.Representational compound is as follows：
14.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- butine -1- Ketone
15.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- methoxyl group -2- butine - 1- ketone
16.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- hydroxyls-valerylene -1- Ketone
17.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups-valerylene - 1- ketone
18.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- amino -2- butine -1- Ketone
19.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- methylamino -2- butine - 1- ketone
20.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- dimethylamino -2- fourths Alkynes -1- ketone
21.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- amino-valerylene -1- Ketone
22.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- methylaminos-valerylene - 1- ketone
23.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- dimethylaminos -2- penta Alkynes -1- ketone
24.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- hydroxyl -2- hexins -1- Ketone
25.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- methoxyl group -2- hexins - 1- ketone
26.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- amino -2- hexins -1- Ketone
27.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- methylamino -2- hexins - 1- ketone
28.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- dimethylaminos -2- oneself Alkynes -1- ketone
29.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- (pyrans -2- bases) -2- Butine -1- ketone
30.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- (pyrans -2- bases) -2- Pentyne -1- ketone
31.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (pyrans -2- bases) -2- Hexin -1- ketone
32.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- (pyrroles -1- bases) -2- Butine -1- ketone
33.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- (pyrroles -1- bases) -2- Pentyne -1- ketone
34.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (pyrroles -1- bases) -2- Hexin -1- ketone
35.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- (piperidin-1-yl) -2- Butine -1- ketone
36.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- (piperidin-1-yl) -2- Pentyne -1- ketone
37.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- (piperazine -1- bases) -2- Butine -1- ketone
38.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- (piperazine -1- bases) -2- Pentyne -1- ketone
39.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (piperazine -1- bases) -2- Hexin -1- ketone
40.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- butine -1- Ketone
41.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- methoxyl group -2- butine - 1- ketone
42.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- hydroxyls-valerylene -1- Ketone
43.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups-valerylene - 1- ketone
44.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- amino -2- butine -1- Ketone
45.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- methylamino -2- butine - 1- ketone
46.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- dimethylamino -2- fourths Alkynes -1- ketone
47.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- amino-valerylene -1- Ketone
48.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- methylaminos-valerylene - 1- ketone
49.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- dimethylaminos -2- penta Alkynes -1- ketone
50.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- hydroxyl -2- hexins -1- Ketone
51.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- methoxyl group -2- hexins - 1- ketone
52.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- amino -2- hexins -1- Ketone
53.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- methylamino -2- hexins - 1- ketone
54.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- dimethylaminos -2- oneself Alkynes -1- ketone
55.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- (pyrans -2- bases) -2- Butine -1- ketone
56.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- (pyrans -2- bases) -2- Pentyne -1- ketone
57.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (pyrans -2- bases) -2- Hexin -1- ketone
58.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- (pyrroles -1- bases) -2- Butine -1- ketone
59.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- (pyrroles -1- bases) -2- Pentyne -1- ketone
60.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (pyrroles -1- bases) -2- Hexin -1- ketone
61.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- (piperidin-1-yl) -2- Butine -1- ketone
62.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- (piperidin-1-yl) -2- Pentyne -1- ketone
63.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (piperidin-1-yl) -2- Hexin -1- ketone
64.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- (piperazine -1- bases) -2- Butine -1- ketone
65.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- (piperazine -1- bases) -2- Pentyne -1- ketone
66.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (piperazine -1- bases) -2- Hexin -1- ketone
67.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- butine - 1- ketone
68.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- methoxyl group -2- fourths Alkynes -1- ketone
69.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- hydroxyls-valerylene - 1- ketone
70.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups -2- penta Alkynes -1- ketone
71.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- amino -2- butine - 1- ketone
72.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- methylamino -2- fourths Alkynes -1- ketone
73.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- dimethylaminos -2- Butine -1- ketone
74.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- amino-valerylene - 1- ketone
75.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- methylaminos -2- penta Alkynes -1- ketone
76.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- dimethylaminos -2- Pentyne -1- ketone
77.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- hydroxyl -2- hexins - 1- ketone
78.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- methoxyl groups -2- oneself Alkynes -1- ketone
79.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- amino -2- hexins - 1- ketone
80.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- methylaminos -2- oneself Alkynes -1- ketone
81.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- dimethylaminos -2- Hexin -1- ketone
82.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- (pyrans -2- bases) - 2- butine -1- ketone
83.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- (pyrans -2- bases) - Valerylene -1- ketone
84.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (pyrans -2- bases) - 2- hexin -1- ketone
85.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- (pyrroles -1- bases) - 2- butine -1- ketone
86.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- (pyrroles -1- bases) - Valerylene -1- ketone
87.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (pyrroles -1- bases) - 2- hexin -1- ketone
88.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- (piperidin-1-yl) - 2- butine -1- ketone
89.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- (piperidin-1-yl) - Valerylene -1- ketone
90.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (piperidin-1-yl) - 2- hexin -1- ketone
91.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- (piperazine -1- bases) - 2- butine -1- ketone
92.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- (piperazine -1- bases) - Valerylene -1- ketone
93.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (piperazine -1- bases) - 2- hexin -1- ketone
94.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- fourths Alkynes -1- ketone
95.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- methoxyl groups -2- Butine -1- ketone
96.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- hydroxyls -2- penta Alkynes -1- ketone
97.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups -2- Pentyne -1- ketone
98.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- amino -2- fourths Alkynes -1- ketone
99.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- methylaminos -2- Butine -1- ketone
100.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- dimethylaminos - 2- butine -1- ketone
101.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- amino -2- penta Alkynes -1- ketone
102.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- methylaminos -2- Pentyne -1- ketone
103.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- dimethylaminos - Valerylene -1- ketone
104.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- hydroxyls -2- oneself Alkynes -1- ketone
105.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- methoxyl groups -2- Hexin -1- ketone
106.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- amino -2- oneself Alkynes -1- ketone
107.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- methylaminos -2- Hexin -1- ketone
108.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- dimethylaminos - 2- hexin -1- ketone
109.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- (pyrans -2- Base) -2- butine -1- ketone
110.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- (pyrans -2- Base)-valerylene -1- ketone
111.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (pyrans -2- Base) -2- hexin -1- ketone
112.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- (pyrroles -1- Base) -2- butine -1- ketone
113.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- (pyrroles -1- Base)-valerylene -1- ketone
114.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (pyrroles -1- Base) -2- hexin -1- ketone
115.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- (piperidines -1- Base) -2- butine -1- ketone
116.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- (piperidines -1- Base)-valerylene -1- ketone
117.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (piperidines -1- Base) -2- hexin -1- ketone
118.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- (piperazine -1- Base) -2- butine -1- ketone
119.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- (piperazine -1- Base)-valerylene -1- ketone
120.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- (piperazine -1- Base) -2- hexin -1- ketone
121.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- butine -1- ketone
122.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -4- methoxyl group -2- butine -1- ketone
123.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -5- hydroxyls-valerylene -1- ketone
124.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups-valerylene -1- ketone
125.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -4- amino -2- butine -1- ketone
126.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -4- methylamino -2- butine -1- ketone
127.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -4- dimethylamino -2- butine -1- ketone
128.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -5- amino-valerylene -1- ketone
129.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -5- methylaminos-valerylene -1- ketone
130.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -5- dimethylaminos-valerylene -1- ketone
131.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -6- hydroxyl -2- hexin -1- ketone
132.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -6- methoxyl group -2- hexin -1- ketone
133.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -6- amino -2- hexin -1- ketone
134.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -6- methylamino -2- hexin -1- ketone
135.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -6- dimethylamino -2- hexin -1- ketone
136.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -4- (pyrans -2- bases) -2- butine -1- Ketone
137.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -5- (pyrans -2- bases)-valerylene -1- Ketone
138.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -6- (pyrans -2- bases) -2- hexins -1- Ketone
139.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -4- (pyrroles -1- bases) -2- butine -1- Ketone
140.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -5- (pyrroles -1- bases)-valerylene -1- Ketone
141.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -6- (pyrroles -1- bases) -2- hexins -1- Ketone
142.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -4- (piperidin-1-yl) -2- butine -1- Ketone
143.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -5- (piperidin-1-yl)-valerylene -1- Ketone
144.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -6- (piperidin-1-yl) -2- hexins -1- Ketone
145.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -4- (piperazine -1- bases) -2- butine -1- Ketone
146.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -5- (piperazine -1- bases)-valerylene -1- Ketone
147.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -6- (piperazine -1- bases) -2- hexins -1- Ketone
148.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- butine - 1- ketone
149.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- methoxyl group -2- fourths Alkynes -1- ketone
150.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- hydroxyls-valerylene - 1- ketone
151.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups -2- penta Alkynes -1- ketone
152.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- amino -2- butine - 1- ketone
153.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- methylamino -2- fourths Alkynes -1- ketone
154.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- dimethylamino -2- fourths Alkynes -1- ketone
155.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- amino-valerylene - 1- ketone
156.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- methylaminos -2- penta Alkynes -1- ketone
157.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- dimethylaminos -2- penta Alkynes -1- ketone
158.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- hydroxyl -2- hexins - 1- ketone
159.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- methoxyl groups -2- oneself Alkynes -1- ketone
160.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- amino -2- hexins - 1- ketone
161.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- methylaminos -2- oneself Alkynes -1- ketone
162.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- dimethylaminos -2- oneself Alkynes -1- ketone
163.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- (pyrans -2- bases) - 2- butine -1- ketone
164.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- (pyrans -2- bases) - Valerylene -1- ketone
165.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- (pyrans -2- bases) - 2- hexin -1- ketone
166.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- (pyrroles -1- bases) - 2- butine -1- ketone
167.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- (pyrroles -1- bases) - Valerylene -1- ketone
168.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- (pyrroles -1- bases) - 2- hexin -1- ketone
169.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- (piperidin-1-yl) - 2- butine -1- ketone
170.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- (piperidin-1-yl) - Valerylene -1- ketone
171.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- (piperidin-1-yl) - 2- hexin -1- ketone
172.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- (piperazine -1- bases) - 2- butine -1- ketone
173.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- (piperazine -1- bases) - Valerylene -1- ketone
174.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- (piperazine -1- bases) - 2- hexin -1- ketone
175.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- fourths Alkynes -1- ketone
176.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- methoxyl group -2- fourths Alkynes -1- ketone
177.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- hydroxyls -2- penta Alkynes -1- ketone
178.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups -2- penta Alkynes -1- ketone
179.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- amino -2- fourths Alkynes -1- ketone
180.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- methylamino -2- fourths Alkynes -1- ketone
181.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- dimethylaminos -2- Butine -1- ketone
182.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- amino -2- penta Alkynes -1- ketone
183.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- methylaminos -2- penta Alkynes -1- ketone
184.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- dimethylaminos -2- Pentyne -1- ketone
185.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- hydroxyls -2- oneself Alkynes -1- ketone
186.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- methoxyl groups -2- oneself Alkynes -1- ketone
187.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- amino -2- oneself Alkynes -1- ketone
188.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- methylaminos -2- oneself Alkynes -1- ketone
189.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- dimethylaminos -2- Hexin -1- ketone
190.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- (pyrans -2- Base) -2- butine -1- ketone
191.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- (pyrans -2- Base)-valerylene -1- ketone
192.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- (pyrans -2- Base) -2- hexin -1- ketone
193.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- (pyrroles -1- Base) -2- butine -1- ketone
194.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- (pyrroles -1- Base)-valerylene -1- ketone
195.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- (pyrroles -1- Base) -2- hexin -1- ketone
196.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- (piperidines -1- Base) -2- butine -1- ketone
197.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- (piperidines -1- Base)-valerylene -1- ketone
198.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- (piperidines -1- Base) -2- hexin -1- ketone
199.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- (piperazine -1- Base) -2- butine -1- ketone
200.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- (piperazine -1- Base)-valerylene -1- ketone
201.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- (piperazine -1- Base) -2- hexin -1- ketone
202.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- fourths Alkynes -1- ketone
203.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- methoxyl groups -2- Butine -1- ketone
204.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- hydroxyls -2- penta Alkynes -1- ketone
205.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups -2- Pentyne -1- ketone
206.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- amino -2- fourths Alkynes -1- ketone
207.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- methylaminos -2- Butine -1- ketone
208.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- dimethylaminos - 2- butine -1- ketone
209.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- amino -2- penta Alkynes -1- ketone
210.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- methylaminos -2- Pentyne -1- ketone
211.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- dimethylaminos - Valerylene -1- ketone
212.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- hydroxyls -2- oneself Alkynes -1- ketone
105.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- methoxyl groups -2- Hexin -1- ketone
213.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- amino -2- oneself Alkynes -1- ketone 214.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- methylaminos -2- Hexin -1- ketone
215.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- dimethylaminos - 2- hexin -1- ketone
216.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- (pyrans -2- Base) -2- butine -1- ketone
217.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- (pyrans -2- Base)-valerylene -1- ketone
218.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- (pyrans -2- Base) -2- hexin -1- ketone
219.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- (pyrroles -1- Base) -2- butine -1- ketone
220.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- (pyrroles -1- Base)-valerylene -1- ketone
221.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- (pyrroles -1- Base) -2- hexin -1- ketone
222.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- (piperidines -1- Base) -2- butine -1- ketone
223.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- (piperidines -1- Base)-valerylene -1- ketone
224.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- (piperidines -1- Base) -2- hexin -1- ketone
225 1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- (piperazine -1- Base) -2- butine -1- ketone
226 1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- (piperazine -1- Base)-valerylene -1- ketone
227.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- (piperazine -1- Base) -2- hexin -1- ketone
228.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- butine -1- ketone
229.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -4- methoxyl group -2- butine -1- ketone
230.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -5- hydroxyls-valerylene -1- ketone
231.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups-valerylene -1- ketone
232.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -4- amino -2- butine -1- ketone
233.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -4- methylamino -2- butine -1- ketone
234.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -4- dimethylamino -2- butine -1- ketone
235 1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -5- amino-valerylene -1- ketone
236.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -5- methylaminos-valerylene -1- ketone
237.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -5- dimethylaminos-valerylene -1- ketone
238.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -6- hydroxyl -2- hexin -1- ketone
239.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -6- methoxyl group -2- hexin -1- ketone
240.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -6- amino -2- hexin -1- ketone
241.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -6- methylamino -2- hexin -1- ketone
242.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -6- dimethylamino -2- hexin -1- ketone
243.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -4- (pyrans -2- bases) -2- butine -1- Ketone
244 1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -5- (pyrans -2- bases)-valerylene -1- Ketone
245.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -6- (pyrans -2- bases) -2- hexins -1- Ketone
246.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -4- (pyrroles -1- bases) -2- butine -1- Ketone
247.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -5- (pyrroles -1- bases)-valerylene -1- Ketone
248.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -6- (pyrroles -1- bases) -2- hexins -1- Ketone
249.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -4- (piperidin-1-yl) -2- butine -1- Ketone
250.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -5- (piperidin-1-yl)-valerylene -1- Ketone
251.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -6- (piperidin-1-yl) -2- hexins -1- Ketone
252.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -4- (piperazine -1- bases) -2- butine -1- Ketone
253.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -5- (piperazine -1- bases)-valerylene -1- Ketone
254.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -6- (piperazine -1- bases) -2- hexins -1- Ketone
255.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- butylene - 1- ketone
256.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- butylene - 1- ketone
257.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- fourths Alkene -1- ketone
258.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- fourths Alkene -1- ketone
259.1- (2- amino-4- (4- phenylbenzylamines base)-6- chlorine pyrimidine-5- bases)-4- hydroxyl-2- butene-1 -one
260.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- butylene - 1- ketone
261.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- butylene Alkynes -1- ketone
262.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- fourths Alkene -1- ketone
263.1- (2- amino-4- (4- phenylanilines base)-6- chlorine pyrimidine-5- bases)-4- hydroxyl-2- butene-1 -one
264.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- methoxyl group -2- fourths Alkene -1- ketone
265.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- methoxyl group -2- fourths Alkene -1- ketone
266.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- methoxyl group -2- fourths Alkene -1- ketone
267.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -4- methoxyl groups -2- Butene-1 -one
268.1- (2- amino-4- (4- phenylbenzylamines base)-6- chlorine pyrimidine-5- bases)-4- methoxyl group-2- butene-1 -one
269.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- methoxyl group -2- fourths Alkene -1- ketone
270.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- methoxyl group -2- fourths Eneyne -1- ketone
271.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- methoxyl groups -2- Butene-1 -one
272.1- (2- amino-4- (4- phenylanilines base)-6- chlorine pyrimidine-5- bases)-4- methoxyl group-2- butene-1 -one
273.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- hydroxyl -2- amylenes - 1- ketone
274.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- hydroxyl -2- amylenes - 1- ketone
275.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- hydroxyls -2- penta Alkene -1- ketone
276.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- hydroxyls -2- penta Alkene -1- ketone
277.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -5- hydroxyl -2- amylene -1- ketone
278.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- hydroxyl -2- amylenes - 1- ketone
279.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- hydroxyls -2- penta Alkene -1- ketone
280.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- hydroxyls -2- penta Alkene -1- ketone
281.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -5- hydroxyl -2- amylene -1- ketone
282.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups -2- penta Alkene -1- ketone
283.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups -2- penta Alkene -1- ketone
284.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups -2- penta Alkene -1- ketone
285.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups -2- Amylene -1- ketone
286.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -5- methoxyl group -2- amylene -1- ketone
287.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups -2- penta Alkene -1- ketone
288.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups -2- penta Alkene -1- ketone
289.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups -2- Amylene -1- ketone
290.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -5- methoxyl group -2- amylene -1- ketone
291.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- hydroxyl -2- hexenes - 1- ketone
292.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- hydroxyl -2- hexenes - 1- ketone
293.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- hydroxyls -2- oneself Alkene -1- ketone
294.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- hydroxyls -2- oneself Alkene -1- ketone
295.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -6- hydroxyl -2- hexene -1- ketone
296.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- hydroxyl -2- hexenes - 1- ketone
297.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- hydroxyls -2- oneself Alkene -1- ketone
298.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- hydroxyls -2- oneself Alkene -1- ketone
299.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -6- hydroxyl -2- hexene -1- ketone
300.1- (2- amino -4- (4- (3- Ureidophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- methoxyl groups -2- oneself Alkene -1- ketone
301.1- (2- amino -4- (4- (3- aminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- methoxyl groups -2- oneself Alkene -1- ketone
302.1- (2- amino -4- (4- (3- Methylaminophenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- methoxyl groups -2- oneself Alkene -1- ketone
303.1- (2- amino -4- (4- (3- dimethylamino phenyls) benzamido group) -6- chlorine pyrimidine -5- bases) -6- methoxyl groups -2- Hexene -1- ketone
304.1- (2- amino -4- (4- phenylbenzylamines base) -6- chlorine pyrimidine -5- bases) -6- methoxyl group -2- hexene -1- ketone
305.1- (2- amino -4- (4- (3- aminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- methoxyl groups -2- oneself Alkene -1- ketone
306.1- (2- amino -4- (4- (3- Methylaminophenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- methoxyl groups -2- oneself Alkene -1- ketone
307.1- (2- amino -4- (4- (3- dimethylamino phenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- methoxyl groups -2- Hexene -1- ketone
308.1- (2- amino -4- (4- phenylanilines base) -6- chlorine pyrimidine -5- bases) -6- methoxyl group -2- hexene -1- ketone
309.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- fourths Alkynes -1- ketone
310.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- methoxyl group -2- fourths Alkynes -1- ketone
311.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- hydroxyls -2- penta Alkynes -1- ketone
312.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups -2- penta Alkynes -1- ketone
313.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- amino -2- fourths Alkynes -1- ketone
314.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- methylamino -2- fourths Alkynes -1- ketone
315.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- dimethylaminos -2- Butine -1- ketone
316.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- amino -2- penta Alkynes -1- ketone
317.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- methylaminos -2- penta Alkynes -1- ketone
318.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- dimethylaminos -2- Pentyne -1- ketone
319.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- hydroxyls -2- oneself Alkynes -1- ketone
320.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- methoxyl groups -2- oneself Alkynes -1- ketone
321.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- amino -2- oneself Alkynes -1- ketone
322.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- methylaminos -2- oneself Alkynes -1- ketone
323.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- dimethylaminos -2- Hexin -1- ketone
324.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- (pyrans -2- Base) -2- butine -1- ketone
325.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- (pyrans -2- Base)-valerylene -1- ketone
326.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- (pyrans -2- Base) -2- hexin -1- ketone
327.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- (pyrroles -1- Base) -2- butine -1- ketone
328.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- (pyrroles -1- Base)-valerylene -1- ketone
329.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- (pyrroles -1- Base) -2- hexin -1- ketone
330.1- (2- amino -4- (4-4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- (piperidin-1-yl) - 2- butine -1- ketone
331.1- (2- amino -4- (4-4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- (piperidin-1-yl) - Valerylene -1- ketone
332.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- (piperidines -1- Base) -2- hexin -1- ketone
333.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- (piperazine -1- Base) -2- butine -1- ketone
334.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- (piperazine -1- Base)-valerylene -1- ketone
335.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- (piperazine -1- Base) -2- hexin -1- ketone
336.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- hydroxyl -2- fourths Alkene -1- ketone
337.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -4- methoxyl group -2- fourths Alkene -1- ketone
338.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- hydroxyls -2- penta Alkene -1- ketone
339.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -5- methoxyl groups -2- penta Alkene -1- ketone
340.1- (2- amino -4- (4- (4- methoxyphenyls) anilino-) -6- chlorine pyrimidine -5- bases) -6- hydroxyls -2- oneself Alkene -1- ketone
Meet the different R of claim1Substituent group and different R2Substituent group is arbitrarily arranged in pairs or groups, so that it may more to be accorded with Other type I compounds of claim are closed, this is basic common sense well-known to those skilled in the art, numerous to list herein.
Determination of activity
By routine experiment as described below, illustrate type I compound and/or their the officinal salt conduct of the present invention Purposes of the PPAR- gamma modulators in PPAR- γ relevant diseases.
Embodiment：PPAR- γ transactivation assays
The activation of ppar gamma receptor is made using agonist (activator) in Human cervical cancer cell lines (Hela cell lines) With causing gene expression, luciferase that can shine in the presence of substrate.In the presence of reference agonist, by quantitative described The fluorescence that generates after cell culture weighs the adjustment effect to ppar gamma receptor.Agonist is replaced with knowing from experience from its site. Active measure is carried out by measuring the light quantitatively generated.It is this affine to ppar gamma receptor by measuring testing molecule The method of power make it possible determine the compounds of this invention adjusting activity.Since the numerical value can be according to the Basal activity of the receptor It is fluctuated with expression, therefore is referred to as apparent Kd (KdApp is indicated with nM).
It is a kind of cross curve for drawing test products to reference agonist using 96- orifice plates, i.e., to determine the constant Untested compound is configured to 10 concentration to be in line plus concentration 0, and 7 concentration of reference agonist are added into 0 row of concentration Cheng Yilie.This indicates 88 measurement points for a kind of product and a kind of receptor.Remaining 8 holes are compareed for repeatability.Every In a hole, cell is made to be contacted with certain density test products and certain density reference agonist, 5- (4- (2- (methyl (pyrroles Pyridine -2- bases) amino) ethyoxyl) benzyl) thiazolidine is used as the reference agonists of PPAR γ receptors.Used HeLa cell lines are turning for the stabilization comprising plasmid ERE- β Glob-Luc-SV-Neo (indicator) and PPAR γ Gal-hPPAR Dye.Luciferase is as transfection agents.In 100 μ l without in phenol red DMEM media, with the standard of 10000 cells/wells by this A little cell inoculations are supplemented in 96- orifice plates and with 10% degreasing calf serum, then plate in 37 DEG C and 7%CO2Under the conditions of train It supports 18 hours.With the amount addition sample to be tested in 5 holes μ l/ and with reference to the various dilutions of ligand, and then plate similarly 37 DEG C and 7%CO2Under the conditions of cultivate 20 hours.Culture medium is removed by overturning, then by 100 μ l 1:The mixing of 1PBS/ fluoresceins Object is added in each hole.After ten minutes, using fluorescence reader (Microbeta Wallac, Perkin Elmer) to plate into Row counts quantitative.The AC under the various concentration of sample to be tested with reference to ligand can be determined using these cross curves50Value (observation Concentration when to 50% activation).Meet the straight line of Schild equations by drawing, is based on these AC50Value calculates Schild returns (" Quantitation in Receptor Pharmacology ", Terry P.Kenakin, Receptors And Channels, 2001,7,371-385), you can obtain KdApp values (being indicated with nM).
The compatibility and functional activity data of some representative compounds of the invention are as shown in the table.
Compound number PPAR γ receptor affinities PPAR γ Receptor Functional Activities
Reference agonist ++ Partial agonist
8 +++ Partial agonist
11 ++ Partial agonist
13 + Antagonist
16 ++ Partial agonist
27 ++ Partial agonist
32 + Partial agonist
36 + Partial agonist
51 + Partial agonist
63 ++ Partial agonist
68 + Partial agonist
80 ++ Partial agonist
91 + Partial agonist
108 + Partial agonist
117 + Partial agonist
122 ++ Partial agonist
174 + Partial agonist
196 + Partial agonist
252 + Partial agonist
266 + Antagonist
301 + Antagonist
322 + Antagonist
Annotation：" +++ " represents KdApp ＜ 1000nM；" ++ " represents 1000≤KdApp ＜ 3000；"+" represent KdApp >= 3000。
Test result data show compatibility of the compounds of this invention to PPAR γ.

Claims (5)

1. type I compound and/or their officinal salt
Wherein, R1It is selected from
Asterisk (*) indicates that the key is connected with carbonylic carbon atom in figure；
R2It is selected from
Asterisk (*) indicates that the key is connected with 4 bit amino nitrogen-atoms of pyrimidine ring in figure.
2. the purposes of at least one type I compound and/or its officinal salt in medicine preparation described in claim 1.
3. at least one type I compound and/or its officinal salt described in claim 1 are in the case where preparing prevention and/or treatment Purposes in the drug of row disease：It is inflammation, atherosclerosis, I type or type II diabetes, diabetic complication, obesity, high in fat Mass formed by blood stasis, impaired glucose tolerance, cerebral ischemia, parkinsonism, insulin resistance and osteoporosis.
4. the purposes in claim 3, wherein the inflammation refers to rheumatoid arthritis.
5. drug, it includes described in the claim 1 of therapeutically effective amount at least one type I compound and/or its is pharmaceutically acceptable The excipient and carrier that salt, physiology are resistant to, and also have other additives and/or other active components in due course.
CN201510184572.4A 2015-04-17 2015-04-17 Aminopyridine derivative as PPAR- gamma modulators Expired - Fee Related CN105111151B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510184572.4A CN105111151B (en) 2015-04-17 2015-04-17 Aminopyridine derivative as PPAR- gamma modulators

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510184572.4A CN105111151B (en) 2015-04-17 2015-04-17 Aminopyridine derivative as PPAR- gamma modulators

Publications (2)

Publication Number Publication Date
CN105111151A CN105111151A (en) 2015-12-02
CN105111151B true CN105111151B (en) 2018-09-28

Family

ID=54659306

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510184572.4A Expired - Fee Related CN105111151B (en) 2015-04-17 2015-04-17 Aminopyridine derivative as PPAR- gamma modulators

Country Status (1)

Country Link
CN (1) CN105111151B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111018834B (en) * 2018-10-10 2022-07-15 成都理工大学 Aminopyrimidine butenone derivatives as PPAR-gamma modulators
EP3870579B1 (en) 2018-10-22 2024-10-02 Alumis Inc. Tyk2 inhibitors and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101484441A (en) * 2006-07-06 2009-07-15 艾尼纳制药公司 Modulators of metabolism and the treatment of disorders related thereto
CN101925584A (en) * 2007-11-22 2010-12-22 阿斯利康(瑞典)有限公司 Be used for the treatment of asthma, COPD, allergic rhinitis, anaphylaxis conjunctivitis, atopic dermatitis, cancer, hepatitis B, hepatitis C, HIV, HPV, infectation of bacteria and dermopathic pyrimidine derivatives
CN102786517A (en) * 2011-05-18 2012-11-21 中国医学科学院药物研究所 Pyrimidine thiazole amine derivative having GK (glucokinase) and PPAR (peroxidase proliferator-activated receptor) dual agonist activities
CN103025331A (en) * 2010-04-23 2013-04-03 赛特凯恩蒂克公司 Certain amino-pyrimidines, compositions thereof, and methods for their use

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10212235A (en) * 1997-01-29 1998-08-11 Nippon Shoji Kk Antitumor medicine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101484441A (en) * 2006-07-06 2009-07-15 艾尼纳制药公司 Modulators of metabolism and the treatment of disorders related thereto
CN101925584A (en) * 2007-11-22 2010-12-22 阿斯利康(瑞典)有限公司 Be used for the treatment of asthma, COPD, allergic rhinitis, anaphylaxis conjunctivitis, atopic dermatitis, cancer, hepatitis B, hepatitis C, HIV, HPV, infectation of bacteria and dermopathic pyrimidine derivatives
CN103025331A (en) * 2010-04-23 2013-04-03 赛特凯恩蒂克公司 Certain amino-pyrimidines, compositions thereof, and methods for their use
CN102786517A (en) * 2011-05-18 2012-11-21 中国医学科学院药物研究所 Pyrimidine thiazole amine derivative having GK (glucokinase) and PPAR (peroxidase proliferator-activated receptor) dual agonist activities

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PPAR的结构及其与疾病的关系;刘晓海;《国外医学药学分册》;20070630;第34卷(第3期);200-203 *

Also Published As

Publication number Publication date
CN105111151A (en) 2015-12-02

Similar Documents

Publication Publication Date Title
CN101616915B (en) Composition and methods for modulating a kinase cascade
WO2002053547A1 (en) Alkanoic acid derivatives, process for their production and use thereof
TW202214587A (en) Cyclopropyl dihydroquinoline sulfonamide compounds
WO2010126002A1 (en) Pharmaceutical product containing heterocyclic sulfonamide compound
EP3083622B1 (en) Maleimide derivatives as modulators of wnt pathway
US20120165339A1 (en) Cyclopropane derivatives
CN109776512A (en) A kind of N- substituted imidazole formate ester derivative and application thereof
CN114667289A (en) Heteroaryl plasma kallikrein inhibitors
CN105111151B (en) Aminopyridine derivative as PPAR- gamma modulators
KR101676889B1 (en) Phenylimidazole compounds
CN108947879A (en) PRMT I type inhibitor and its preparation method and application
CN102451178A (en) Application of dihydrofuran-2-ketone compounds in preparing medicament for resisting diabetes mellitus and glucose and lipid metabolism
CN107108656B (en) N- substitution -3,5- disubstituted benzenes Carbox amide and its preparation method and application
TW201024286A (en) Novel compounds
CN109666027A (en) GPR40 agonist compound of a kind of amide structure and application thereof
AU2019208634B2 (en) Dihydroindolizinone derivative
CN104592217B (en) 3 (1,3,4 oxadiazolyl) 5 phenoxypyridines analog derivative and preparation method and application
CN109456274A (en) Benzimidazoles derivative, preparation method and its purposes as drug
CN104860919B (en) Benzimidizole derivatives containing piperidines and its production and use
KR101812626B1 (en) (phenoxy)alkoxy-1H-indole derivatives or pharmaceutically acceptable salts thereof, preparation method therof and pharmaceutical composition for use in preventing or treating PPARα, PPARγ and PPARδ related diseases containing the same as an active ingredient
CN107162913A (en) The new deuterated phenylpropionic acid derivative of one class, its preparation method and its purposes as medicine
KR101749102B1 (en) 3-(3-phenoxyphenoxy)propoxy-1H-indole derivatives or pharmaceutically acceptable salts thereof, preparation method therof and pharmaceutical composition for use in preventing or treating PPARα, PPARγ and PPARδ related diseases containing the same as an active ingredient
JP2005320250A (en) Bislactone derivative and use thereof as medicinal composition
CN111018834B (en) Aminopyrimidine butenone derivatives as PPAR-gamma modulators
CN109206375A (en) A kind of 5 cyclosubstituted 2,4- diaminopyrimidines with benzene glycinol class formation, its preparation and purposes

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20180928