CN105111151A - Aminopyrimidine derivative used as PPAR-gamma regulator - Google Patents

Aminopyrimidine derivative used as PPAR-gamma regulator Download PDF

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CN105111151A
CN105111151A CN201510184572.4A CN201510184572A CN105111151A CN 105111151 A CN105111151 A CN 105111151A CN 201510184572 A CN201510184572 A CN 201510184572A CN 105111151 A CN105111151 A CN 105111151A
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amino
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chloropyrimide
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CN105111151B (en
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周立宏
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Chengdu Univeristy of Technology
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    • 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

Abstract

The invention relates to an aminopyrimidine derivative used as a PPAR-gamma regulator, specifically to a 2,4-diamino-6-chloropyrimidone derivative as shown in a formula I which is described in the specification, and/or medicinal salts thereof, a preparation method thereof, and application of the derivatives and/or medicinal salts thereof in treatment and/or prevention of disease related to peroxidase proliferator-activated acceptor subtype PPAR-gamma, e.g., inflammations (including rheumatoid arthritis), atherosclerosis, diabetes type I or II, diabetic complications, obesity, hyperlipidemia, impaired glucose tolerance, cerebral ischemia, Parkinson's disease, insulin resistance and osteoporosis. The invention also relates to a pharmaceutical composition containing the derivative. In the formula I, two substituents, i.e., R1 and R2 are defined in the specification.

Description

As the aminopyridine derivative of PPAR-gamma modulators
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of aminopyridine derivative described in claim and physiologically acceptable salt thereof, their preparation and they treating and/or preventing the purposes in the disease relevant to inflammation (comprising rheumatoid arthritis), atherosclerosis, I type or type II diabetes, diabetic complication, obesity, hyperlipidaemia, impaired glucose tolerance, cerebral ischemia, parkinsonism, insulin resistant and osteoporosis.
Technical background
Peroxisome proliferator-activated receptor (peroxisomeproliferator-activativedreceptors, be called for short PPAR) be the transcription factor of a class ligand activation, belong to nuclear hormone receptor superfamily, comprise PPAR-α, PPAR-β/δ and PPAR-γ tri-kinds phenotype, wherein deep with the research of PPAR-γ.The activation of PPAR has irreplaceable effect to metabolic process a very wide range of in control agent.
Peroxidase (peroxisome) is a kind of subcellular structure in body, and its function comprises removes molecular oxygen and hydroperoxide, and relevant with the synthesis of sugar, fat, cholesterol, cholic acid and Fatty Acid Oxidation.A series of fatty acid chemical substance that is natural or synthetic can stimulate the propagation of peroxidase, is called peroxisome proliferator (peroxisomeproliferation).Peroxisome proliferator can activate its acceptor, thus causes a series of biological action, so this receptoroid is called peroxisome proliferator-activated receptor (PPAR).After people's vivo activation PPAR, producing various biological effect, as regulated the metabolism of lipid, improving the susceptibility of Regular Insulin, antitumor action, neuroprotective unit, inflammation-inhibiting reaction etc.Specify the effect of these associated signal paths and relevant cell factor, power foundation and intervention can be further provided with to relative disease mechanism and control.
One, the structure of PPAR
About the structure of PPAR, the people such as MarxN are report in Circ.Res. (2004,94 (9): 1168-1178), and PPAR is a kind of transcription factor of ligand activation, belong to nuclear hormone receptor superfamily, participate in the gene regulating in multiple metabolic process.PPAR has 3 kinds of subtype alphas, beta, gamma, and its gene lays respectively at the mankind the 22nd, on 6 and No. 3 karyomit(e)s.The structure of PPAR comprises 4 functional zone: N Duan A/B district is the transcription activating district not relying on part, this plot structure difference of each hypotype is obvious, and its serine residue is by the activity that can suppress acceptor after blocking effect of mitogen activated protein kinases (MAPK) phosphorylation; C district has the conservative property of height, and wherein the aminoacid sequence of about 70 constitutes DNA land (DBD), for combining with the PPAR response element (PPRE) on target gene; D district is also called hinge area (hingedomain), is connected by DBD with ligand binding domain; C Duan E/F district is ligand binding domain (LBD), and the difference of this region amino acid sequence makes the PPAR of each hypotype produce avidity to different ligands respectively, namely forms dimer with part.
The part of PPAR structurally has a common ground, containing carboxy functional group and a hydrophobic region (MarxN, DuezH, FruchartJC, etal.Circ.Res., 2004,94 (9): 1168-1178).The part of PPAR is divided into synthetic ligands and native ligand.Synthetic ligands is some medicines mainly.Native ligand is mainly derived from the meta-bolites of diet and body, as linolic acid, arachidonic acid and derivative leukotriene B4 (LTB4) thereof, 8 (S) hydroxyeicosatetraenoic acid [8 (S) HETE], 15-dehydrogenation prostaglandin(PG) J2 (15-d-PGJ2).Human ppar α has 468 amino-acid residues, and PPAR-β has 441 amino-acid residues, and PPAR-γ has 479 amino-acid residues.The structure of PPAR3 kind hypotype has the homology of 60% ~ 80%, but their part and target gene have obvious difference.The part of PPAR-α comprises leukotriene B4 and fibrate lipid-lowering medicine, the main metabolism regulating lipid.The part of PPAR-β is polyunsaturated fatty acids, prostaglandin(PG) and vitamin A acid etc.The people such as KuenzliS report PPAR-β expression on Human keratinocytes in Br.J.Dermatol. (2003,149 (2): 229-236) is relevant to dermatosis.The part of PPAR-γ is thiazolidine dione compounds and the 15-dehydrogenation prostaglandin(PG) J2 such as rosiglitazone (rosiglitazone), pioglitazone (pigoglitazone), regulates the metabolism of glycogen and fat.
Two, relevant to PPAR disease
(1) PPAR and inflammation
PPAR-γ plays the effect of inflammation-inhibiting reaction by the generation of Competitive assays inflammatory signals path and inflammatory mediator, relevant inflammatory signals path mainly comprises four kinds, JAK-STAT, NF-κ B, nuclear factor of activated T cells (nuclearfactorofactivatedTcell, NFAT) and AP-1 respectively.
JAK-STAT signal transduction pathway activates after starting from JAK-2 phosphorylation, the JAK-2 reactivation JAK-1 activated, then under the effect of JAK-1, STATl and STAT2 is activated respectively, could nucleus in play its biologic activity after must being combined after the former forms homodimer with collaborative activation factor CREB associated proteins (CBP) or p300.After PPAR-γ and ligand binding also activate, the competition of PPAR-γ-RXR heterodimer, recruitment are in conjunction with a limited number of collaborative activation factor CBP and p300, the collaborative activation factor quantity that can be combined with STATl is caused to reduce, thus inhibit the activation of STATl, and STAT relevant pro-inflammatory cytokine (IL-6, IL-1 are blocked, TNF-α) generation (LiM, eta1.MolCellBiol, 2000,20:4699).In inflammatory reaction, INF-γ and PPA-γ coherent signal closely related.Have report, IFN-γ can induce after stimulating and activate JAK/STAT path, TNF-α, IL-1 β is produced and increases (LiQ, etal.NatRevImmunol, 2002,2:725).In rat macrophage and people DLDl cell, IFN-γ etc., by activating STATl and STAT3 of JAK2 and downstream, strengthen Inducible nitric oxide synthase (iNOS) and express and exacerbate inflammation reaction.In above-mentioned reaction, iNOS can inducing cell process LAN NO under intracellular toxin stimulates, and the latter can coup injury cell DNA, makes it rupture, so that apoptosis (BohrerH, eta1.JClinInvest, 1997,100:972).And PPAR-γ is by suppressing JAK-STAT approach, block the proinflammatory effect of IFN-γ.
NF-κ B has p50 and p65 two subunits.In resting cell, NF-κ B and arrestin monomer I κ B α and I κ B β is present in tenuigenin (GhoshS, eta1.AnnuRevImmunol, 1998,16:225) with non-activity combining form.In inflammatory reaction, proinflammatory inflammation factor and I κ B two serine residues (α, β) combine, and make I κ B α/β ubiquitination and are degraded, and cause p50/p65 dimer and I κ B α/β is dissociated.After the dimer dissociated is combined with collaborative activation factor p300 and CBP again, in core, κ B sequence specific with DNA is combined, and can induce other inflammatory mediator genetic expression on the one hand, can also increase COX-2 effect simultaneously.COX-2 can impel arachidonic acid to PGH in inflammatory reaction 2transform, and PGH 2pGE can be generated again 2, the generation (StrausDS, etal.ProcNatlAcadSciUSA, 2000,97:4844) of transmitting inflammation medium.PPAR-γ can directly be combined with the subunit p65/p50 of NF-κ B, there is protein-protein interaction, form Transcription inhibition mixture, reduce NF-κ B and DNA binding activity, suppress NF-κ BDNA synthesis, thus suppress it to express (ChungSW, etal.JBiolChem, 2000,275:32681).PPAR-γ can also suppress transcribing of NF-κ B by working in coordination with activation factor p300 and CBP with competition binding.In the model of rat colonitis, application PPAR-gamma agonist rosiglitazone, can observe COX-2, PGE in rat tissue 2, the inflammatory mediator such as TNF-α expresses and significantly reduces, and confirms above-mentioned saying (Sanchez-HidalgoM, eta1.BiochemPharmacol, 2005,69:1733).
NFAT mainly at T cell and other immunocytes, as surface expressions such as B cell, NK cell, mastocyte.NFAT exists with the phosphorylation state of non-activity in tenuigenin, is subject to after the incitant such as calcineurin (calcineurin) activates, dephosphorylation and activate and be indexed in nucleus, plays a role.The people such as StrausDS finds, suppresses the genetic expression of IL-2 in the inflammatory reaction that PPAR-γ mediates in T cell by affecting NFAT approach.PPAR-γ prevents the DNA of NFAT to combine and transcriptional activity by part, prevents NFAT regulatory T-cell IL-2 promotor.Carry out the activation of suppressor T cell in inflammation by protein-protein interaction between PPAR-γ and NFAT, and lower IL-2 promotor, thus play the effect (ProcNatlAcadSciUSA, 2000,97:4844) of inflammation-inhibiting.
AP-1 is a kind of nuclear factor.Typical AP-1 mixture is made up of c-Jun and c-Fos Liang Ge subunit, is combined with DNA by leucine.In inflammatory reaction, AP-1 has the functions (StrausDS, etal.ProcNatlAcadSciUSA, 2000,97:4844) such as the synthesis of the apoptosis of inducing cell, adhesion factor and inflammatory factor.PPAR-γ, by working in coordination with activation factor CBP and p300 with AP-1 competition binding, plays the restraining effect to AP-1 signal transduction pathway, and the approach that this mechanism and PPAR-γ affect JAK-STAT is similar.(2) PPAR and metabolism syndrome
Diabetes are that to be caused by Different types of etiopathogenises with chronic hyperglycemia be the metabolism disorder of feature, and mainly due to the defect of insulin secretion or effect, or both exist simultaneously and cause.Insulin resistant is the key link of metabolism syndrome, and PPAR-γ mainly increases the susceptibility of peripheral tissues to Regular Insulin to glycometabolic adjustment, thus improves insulin resistant.The impaired meeting of PPAR-γ function causes serious insulin resistant, and the PPAR-gamma agonist Thiazolidinediones of synthesis comprises troglitazone (troglitazone), rosiglitazone, pioglitazone effectively can improve the insulin sensitivity of diabetes B patient and reduce blood sugar (DemgT, ShanS, LiPP, etal.Endocrinology, 2006,147 (2): 875-884).The mechanism that PPAR-γ increases insulin sensitivity may be: phosphatidylinositol3 3 kinase (PI3K) is that target cell mediating glucose enters intracellular key lipid kinase, subunit and catalytic subunit is regulated to form by one, P13K is a kind of lipid kinase, regulates subunit and catalytic subunit to form by one.Regulate subunit to combine with IRS (IRS), in conjunction with after by the phosphorylation of phosphatidylinositols (PI) on IRS activated cell film.During quiescent condition, regulate subunit and catalytic subunit to play restraining effect, under insulin stimulating, IRS is combined with adjustment subunit, and its restraining effect is removed, i.e. activating catalytic subunit.After P13K activates, PI, phosphatidylinositols-phosphoric acid (PIP) and phosphatidylinositol diphosphate (PIP2) phosphorylation can be impelled respectively to generate PIP, PIP2 or PIP3.These products are considered to Regular Insulin and other somatomedins second messenger, wherein important with PIP3.PPAR-γ can promote PI3K genetic expression in PI3K signal path, strengthens the susceptibility of Regular Insulin, also can strengthen glucose transporter 4 (GluT4) genetic expression, promote the picked-up to glucose; PPAR-γ activation can accelerate the decomposition of triglyceride level in peripheral tissues, increases its synthesis in fatty tissue, the generation of glucagon suppression.
Perilipin (perilipin) can reduce triglyceride hydrolysis, plays an important role in the storage regulating lipid and metabolism.Thiazolidinediones (TZD) medicine obviously can reduce as PPAR-gamma agonist the steatolysis that TNF-α causes, and the perilipin that also can obviously stop TNF-α to cause reduces.Further research shows, perilipin gene promoter region includes functional PPAR-gamma reaction element, and PPAR-gamma agonist can obviously increase perilipin genetic expression, thus the decomposition of regulation and control fat.Also it was reported that PPAR-γ regulating lipid metabolism is that PPAR-gamma agonist has raised the genetic expression of hormone-sensitive lipase (HSL) due in liver cell and PECTORAL LIMB SKELETON.Its mechanism may be: PPAR-γ promoter region comprises two GC boxes, and the transcriptional activity that PPAR-γ mediates is realized by the promotor of its nearside.Endogenic PPAR-γ strengthens transcription factor SP 1 and promotor combines, and activated transcription is active, thus makes HSL genetic expression raise (DemgT, ShanS, LiPP, etal.Endocrinology, 2006,147 (2): 875-884).In addition, PPAR-alfa agonists can reduce triglyceride level in blood, increase high low density lipoprotein, the former is that the transcriptional regulatory by controlling several genes increases fatty absorption, activation and metabolism, and the latter is by promoting that the generation of liver apolipoprotein A-I (apoA-I) and Apolipoprotein A-II (apoA-II) mediates.
(3) PPAR and atherosclerosis
Atherosclerosis is one and is gathered by arterial blood tube wall atheromatous plaque Progressive symmetric erythrokeratodermia, is a kind of chronic inflammatory reaction of blood vessel, increases relevant, finally cause the pathologic process of focal obstruction of artery with c reactive protein, Fibrinogen, TNF-α and IL-6.The former relates generally to 3 pathologic processes, i.e. the differentiation of foam cell (foamcell), inflammatory reaction and cell proliferation.Early stage in pathology, usually have the gathering of Monocytes/Macrophages and T cell, and the foam cell that progressive stage is rich in lipid Monocytes/Macrophages source as seen increases, and vascular smooth muscle cell (VSMC) migration propagation, cell debris is piled up, so that atheromatous plaque fibrous cap generates.Local inflammation reaction (DesvergneB, etal.EndocrRev, 1999,20:649) relevant to atherosclerosis can be brought out thus at endarterium.Recent discovery, in the mankind and the damage of mouse atheromatous plaque, visible PPAR-γ obviously expresses, and prompting PPAR-γ plays an important role (TontonozP, etal.Cell, 1998,93:241) in atherosis.PPAR-α suppresses atherosclerotic formation by different mechanisms after activating: (1) improves the reactivity of early stage vessel wall, prevents lipid in the deposition of vessel wall and infiltration.(2) reduce the expression of endothelial cell surface adhesion molecule, reduce inflammatory cytokine, thus alleviate the reaction of leukocytic adhesion and aggregation.(3) later stage of atherosclerosis plaque forming, PPAR-alfa agonists makes the stability of patch strengthen, and prevents from coming off, and reduces cordis and cerebral accident.(4) correct lipid metabolism disorders, prevent the formation of atheromatous plaque.
Oneself knows that inflammatory reaction plays an important role in atherosclerosis develops.In above-mentioned pathological change, PPAR-γ, by carrying out inflammation-inhibiting reaction to the restraining effect of transcription factor, alleviates atherosclerotic pathology damage.Comprising PPAR-γ by suppressing the signal path of AP-1 mediation, suppressing by the synthesis of the human vascular endothelial Endothelin receptor A of thrombin induction (DeleriveP, etal.CircRes, 1999,85:394); Also by affecting NF-κ B signal pathway, suppress the expression of the endotheliocyte VCAM-1 (VCAM-1) of TNF-α induction, and then tune presses down monocyte in the gathering (MarxN of early stage atherosclerotic plaque forming position, eta1.Circulation, 1999,99:3125); And suppress adhesion molecule ICAM-1, E-Selectin etc., can the raising and infiltrate (VerrierE, eta1.CircRPJ, 2004,94:1515) of inflammation-inhibiting cell.In a word, in atherosclerotic chronic inflammation processes, PPAR-γ can lower the expression of adhesion molecule, reduces inflammatory cell and assembles.The release of inflammatory mediator can be reduced on the one hand; Monocytes/Macrophages can be suppressed to the conversion of foam cell on the other hand.
Endothelin is a kind of endothelin be separated from endotheliocyte, can induce the hyperplasia of smooth muscle cell.The release of intra-arterial endothelin increases, the formation of meeting induction of vascular spasm and atheromatous plaque.The protein kinase C that Wyeth 14643 (WY14643, PPAR-alpha ligands) and rosiglitazone can suppress the secretion of endothelin and oxidized low density lipoprotein (OX-LDL) to be induced, reduces atherosclerotic formation.In addition; 15-dehydrogenation prostaglandin(PG) J2 or ciglitazone (ciglitazone) can strengthen NO from pulmonary artery and aortal release; protection vessel wall (CalnekDS; MazzellaL; RoserS; ArteriosclerThromb.Vasc.Biol., 2003,23 (1): 52-57).
(4) PPAR and tumour
The relation of PPAR and tumour has received general concern, and PPAR-γ can regulate propagation, the differentiation and apoptosis of cell in tissue: (1) ppar gamma receptor agonist can cause G1 phase cell cycle arrest, antiproliferative effect.The people such as FarroW find in the research of carcinoma of the pancreas, can raise PTEN after activating PPAR-γ, thus suppress the phosphorylation of Akt in PI-3K signal pathway, make the pancreatic tumor cell cycle be still in G 0/ G 1phase (FarrowB, eta1.BiochemBiophysResCommun, 2003,301:50).In the research of liver cancer cell, researchist finds that PPAR-γ can by raising p21 cipl/Waf1or p27 kipcarry out the propagation (KogaH, eta1.Hepatology, 2001,33:1087) of T suppression cell.P21 cipl/Waf1or p27 kipcan the activity of T suppression cell cycle regulating protein-DK mixture, and the process of this mixture adjustable cell cycle.The research such as Jung is pointed out, p21 cipl/Waf1or p27 kiptake part in the suppression (JungTI, eta1.GynecolOncol, 2005,97:365) of ciglitazone to cervical cancer C-4II strain Growth of Cells at least partly.Thiazolidinediones can act on Cyclin dependent kinase (CDK) supressor, as P18, P21.Research finds that PPAR-gamma agonist can make P18 and P21 up-regulated, these factors can be lowered into the phosphorylation of Retinoblastoma Protein (Rb albumen) by reducing cyclin (cyclin) and the formation of CDK complex body, impel tumour cell G1 phase cessation of growth cessation, the proliferating cycle of final suppression of cell, thus reach antitumor multiplication effect.(2) PPAR-gamma agonist can cell death inducing.PPAR-γ is by the apoptosis of inducing cell in the developing of tumour, and the regulation and control participating in the cell cycle play a role.Research finds, c6 glioma cell is under the effect of PPAR-gamma agonist, and front apoptotic protein Bax and Bad up-regulated, cause the release of cytochrome C, causes the activation of a series of caspase families factor, finally causes the apoptosis of tumour cell.(3) PPAR-gamma agonist also produces antitumor action by the formation of Tumor suppression new vessel.By its downstream goal gene after PPAR-γ is activated, as cancer suppressor gene (PTEN), proto-oncogene (c-myc), p27, COX-2 and matrix metallo-proteinase 9 (MMP9) etc., realize its cell growth inhibiting, cell death inducing, and the biological function such as inducing tumor cell differentiation and Tumor suppression vascularization.Correlative study is pointed out, the PPAR-γ activated can by suppressing platelet derived growth factor, insulin-induced minichromosome maintains albumen (insulininducedminichromosomemaintenanceprotein) and E2F signal, restraining effect (BruemmerD is played with this cell cycle and copying of DNA, eta1.EurJPharmacol, 2003,466:225).(4) PPAR-gamma agonist can anticancer transfer.The people such as LiuH (LiuH, ZangC, FennerMH, etal.BreastCancerRes.Treat., 2003,79 (1): 63-74) report, the expression increase of matrix metalloproteinase (MMP) especially gelatinase (gelatinase) is formed relevant to tumour.The activation of PPAR-γ can suppress Gelatinase B, and can stop scavenger cell and myocyte's migration, the effect that prompting PPAR-γ part may have inhibition tumor cell to shift.PPAR-γ part also can raise organizes inhibition MMP-1 (TIMP-1), the Gelatinolytic effect of gelatinase is declined, prevents cancer cells from shifting.Melanocytoma and metastasis thereof also have the expression of PPAR-γ, troglitazone and rosiglitazone can suppress the proliferation and differentiation of melanophore oncocyte, can be used to treatment melanocytoma (MossnerR, SchulzU, KrugerU, etal.JInvest.Dermatol., 2002,119 (3): 576-582).
(5) PPAR and cerebral ischemia
The research such as Shimazu shows that the activation of PPAR-γ can increase copper-zinc superoxide dismutase (Cu/Zn-SOD), scavenging free radicals (ShimazuT, InoueI, ArakiN, etal.Stroke, 2005,36 (2): 353-359).The activation of PPAR-γ can protect neuronal damage in cerebral ischemia re-pouring.In addition, after cerebral ischemia, the damaging action of inflammatory reaction has received the concern of people.Dendritic cell is a kind of important antigen presenting cell, participates in the inflammation damnification after cerebral ischemia by the release cells factor.PPAR-gamma agonist ciglitazone can alleviate the expression of the dendritic cell of OX-LDL induction, suppress the endocytosis of dendritic cell, reduce the immune response that dendritic cell causes, reduce the inflammatory reaction (LuoY after cerebral ischemia, LiangC, XuC, etal.JCardiovascPharmacol, 2004,44 (3): 381-385).Due to PPAR and cerebral ischemia re-pouring injured closely related, can PPAR be that target spot finds Neuroprotective Agents.
(6) PPAR and Parkinson's disease
The people such as DehmerT research in JNeurochem (2004,88 (2): 494-501) finds, PPAR-γ has expression in the nigrostriatum of patients with Parkinson disease.In the Parkinson disease model that MPTP (1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine) induces, nitric oxide synthase type (iNOS) catalysis produces NO, regulates the death of dopamine neuronal cell as a kind of important medium.The loss of dopamine neuronal cell and the loss of catecholamine in the striatum that pioglitazone can protect MPTP to induce.Oral pioglitazone can protect the activity of the tyrosine hydroxylase of substantia nigra neuron, can reduce the activity of nigrostriatum compact part microglia, reduces the activity of glial fibrillary acidic protein.In addition, pioglitazone can reduce the cell injury of NO mediation.Its mechanism may be owing to suppressing NF-κ B subunit p65 to proceed in the core of spongiocyte and dopamine neuron, thus plays cytoprotection.
(7) PPAR and dermatosis
Research shows, plays decisive role in the process that PPAR-β heals in epidermal wound.PPAR-β has important effect to regulating the Growth and Differentiation of skin epidermal cells and skin inflammation reaction.PPAR-β relevant with the healing of psoriatic, atopic dermatitis, acne and skin (KuenzliS, SauratJH.Br.J.Dermatol., 2003,149 (2): 229-236).The people such as TanNS are at Am.J.Clin.Dermatol. (2003,4 (8): 523-530) report in, under the stimulation of the factors such as skin injury, damage location produces inflammatory factor, these inflammatory factors make PPAR-β activate on the one hand, can cause the apoptosis of keratinocyte on the other hand as apoptotic signal.PPAR-β, as a kind of important transcription factor, can delay TNF-α, and the inflammatory factors such as IFN-γ, in the generation of damage location, regulate cell adapted stress situation, away from the apoptotic signal that inflammatory factor causes.
Early stage at skin wound, PPAR-β makes trauma skin edge have the great-hearted keratinocyte of the tool of sufficient amount.The repairing phase in wound later stage, PPAR-β makes the keratinocyte differentiation at trauma skin edge shift, and forms new epidermis, promotes the healing of skin wound.Its mechanism may be that PPAR-β raises integral protein associated kinase and 3-phosphoinositide dependent kinase-1.These two kinds of kinase activators cascade reaction of AKT, the activation of AKT causes cutin to form the increase (TanNS, MichalikL, DesvergneB, etal.Am.J.Clin.Dermatol.2003,4 (8): 523-530) of albumen.At Eur.J.Biochem., (2003,270 (Suppl1): report 16), PPAR-β also stimulates the activity of NF-κ B and the generation of MMP-9 to the people such as WahliW, regulates the transfer of keratinocyte.
Conclusion
PPAR is one of current study hotspot, and much research shows that PPAR is relevant with various diseases, for treatment relative disease provides target spot (KonoplevaM, AndreeffM.Curr.Opin.Hematol., 2002,9 (4): 294-302).But due to thorough not to its research at present, and there is report display PPAR can suppress the function of mitochondrial complex I, its application is restricted.Along with molecular biology and pharmacological development, PPAR is bound to as disease therapy provides new approach.
Summary of the invention
The invention describes type I compound, and/or their pharmacologically acceptable salt
Wherein, R 1be selected from trifluoromethyl, (C 1-C 10) straight or branched alkyl, (C 2-C 10) straight or branched thiazolinyl, (C 2-C 10) straight or branched alkynyl, 3-12 unit alicyclic group, phenyl, other (C 5-C 10) aryl, (C 5-C 10) heteroaryl or (C 3-C 7) heterocyclic radical, wherein said heteroaryl or heterocyclic radical have the heteroatoms of 3 O, S or N at the most, and (C 1-C 10) straight or branched alkyl, (C 2-C 10) straight or branched thiazolinyl, (C 2-C 10) straight or branched alkynyl, 3-12 unit alicyclic group, phenyl, other (C 5-C 10) aryl, (C 5-C 10) heteroaryl or (C 3-C 7) heterocyclic radical separately independent sum replaced by 3 substituting groups at the most arbitrarily, described substituting group is selected from-OR ' ,-CF 3,-OCF 3,-SR ' ,-S (O) R ' ,-SO 2r ' ,-SCF 3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH 2) 2n (R ') 2,-OCH 2n (R ') 2,-CON (R ') 2,-(CH 2) 2oR ' ,-CH 2oR ' ,-CH 2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ') 2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH 2) 2n (R ') 2or-CH 2n (R ') 2;
R 2be selected from at least 1, an at the most 3 substituent (C 1-C 6) straight or branched alkyl, 3-12 unit alicyclic group, phenyl, other (C 5-C 10) aryl, (C 5-C 10) heteroaryl or (C 3-C 7) heterocyclic radical, wherein said heteroaryl or heterocyclic radical have the heteroatoms of 3 O, S or N at the most; Described (C 1-C 6) straight or branched alkyl with at least 1, at the most 3 substituting groups be selected from-OR ' ,-CF 3,-OCF 3,-SR ' ,-S (O) R ' ,-SO 2r ' ,-SCF 3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH 2) 2n (R ') 2,-OCH 2n (R ') 2,-CON (R ') 2,-(CH 2) 2oR ' ,-CH 2oR ' ,-CH 2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ') 2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH 2) 2n (R ') 2or-CH 2n (R ') 2; Described 3-12 first alicyclic group, phenyl, other (C 5-C 10) aryl, (C 5-C 10) heteroaryl or (C 3-C 7) heterocyclic radical separately independent sum replaced by 3 substituting groups at the most arbitrarily, described substituting group is selected from-OR ' ,-CF 3,-OCF 3,-SR ' ,-S (O) R ' ,-SO 2r ' ,-SCF 3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH 2) 2n (R ') 2,-OCH 2n (R ') 2,-CON (R ') 2,-(CH 2) 2oR ' ,-CH 2oR ' ,-CH 2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ') 2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH 2) 2n (R ') 2or-CH 2n (R ') 2.
The group that R ' is independently selected from hydrogen separately or replaces arbitrarily, described group is selected from (C 1-C 8) aliphatic group, have that 0-3 to be independently selected from that the 3-8 unit of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or have that 0-5 is independently selected from nitrogen, oxygen can saturated, the fractional saturation of the 8-12 unit of sulfur heteroatom or complete undersaturated bicyclic ring system, or formed together with the atom that connects with them of the R ' of twice appearance have that 0-4 3-12 unit being independently selected from the optional replacement of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or dicyclo.
Preferably, for type I compound, wherein R 1for (C 2-C 10) straight or branched thiazolinyl, (C 2-C 10) straight or branched alkynyl, can be replaced by 3 substituting groups at the most arbitrarily by independent sum separately, described substituting group is selected from-OR ' ,-CF 3,-OCF 3,-SR ' ,-S (O) R ' ,-SO 2r ' ,-SCF 3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH 2) 2n (R ') 2,-OCH 2n (R ') 2,-CON (R ') 2,-(CH 2) 2oR ' ,-CH 2oR ' ,-CH 2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ') 2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH 2) 2n (R ') 2or-CH 2n (R ') 2; R 2be selected from at least 1, an at the most 3 substituent (C 1-C 6) straight or branched alkyl, phenyl, described (C 1-C 6) straight or branched alkyl with at least 1, at the most 3 substituting groups be selected from the phenyl or phenoxy group that replace arbitrarily; Described phenyl is replaced by 3 substituting groups at the most, and described substituting group is selected from-OR ' ,-CF 3,-OCF 3,-SR ' ,-S (O) R ' ,-SO 2r ' ,-SCF 3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH 2) 2n (R ') 2,-OCH 2n (R ') 2,-CON (R ') 2,-(CH 2) 2oR ' ,-CH 2oR ' ,-CH 2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ') 2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH 2) 2n (R ') 2or-CH 2n (R ') 2; The group that R ' is independently selected from hydrogen separately or replaces arbitrarily, described group is selected from (C 1-C 8) aliphatic group, have that 0-3 to be independently selected from that the 3-8 unit of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or have that 0-5 is independently selected from nitrogen, oxygen can saturated, the fractional saturation of the 8-12 unit of sulfur heteroatom or complete undersaturated bicyclic ring system, or formed together with the atom that connects with them of the R ' of twice appearance have that 0-4 3-12 unit being independently selected from the optional replacement of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or dicyclo.
Preferably, for type I compound, wherein R 1for (C 2-C 10) straight or branched alkynyl, can be replaced by 3 substituting groups at the most arbitrarily by independent sum separately, described substituting group is selected from-OR ' ,-CF 3,-OCF 3,-SR ' ,-S (O) R ' ,-SO 2r ' ,-SCF 3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH 2) 2n (R ') 2,-OCH 2n (R ') 2,-CON (R ') 2,-(CH 2) 2oR ' ,-CH 2oR ' ,-CH 2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ') 2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH 2) 2n (R ') 2or-CH 2n (R ') 2; R 2be selected from at least 1, an at the most 3 substituent (C 1-C 6) straight or branched alkyl, phenyl, described (C 1-C 6) straight or branched alkyl with at least 1, at the most 3 substituting groups be selected from the phenyl replaced arbitrarily; Described phenyl is replaced by 3 substituting groups at the most, and described substituting group is selected from the phenyl or phenoxy group that replace arbitrarily; The group that R ' is independently selected from hydrogen separately or replaces arbitrarily, described group is selected from (C 1-C 8) aliphatic group, have that 0-3 to be independently selected from that the 3-8 unit of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or have that 0-5 is independently selected from nitrogen, oxygen can saturated, the fractional saturation of the 8-12 unit of sulfur heteroatom or complete undersaturated bicyclic ring system, or formed together with the atom that connects with them of the R ' of twice appearance have that 0-4 3-12 unit being independently selected from the optional replacement of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or dicyclo.
For R 1substituting group, representational example following (only for straight chain alkynes or alkene),
And
In figure, asterisk (*) represents that this key is connected with carbonylic carbon atom.
For R 2substituting group, representational example is as follows,
In figure, asterisk (*) represents that this key is connected with pyrimidine ring 4 bit amino nitrogen-atoms.
For with above representational R 1and R 2the type I compound that substituting group is corresponding, we devise synthetic route as follows.
Synthetic route one:
Synthetic route two:
G (referring to group) representative in said synthesis route in compound molecule formula meets arbitrarily the substituted radical of aforementioned claim qualifications.
According to synthetic route one, R can be synthesized 1for alkynes and the preferred type I compound that is directly connected of carbon carbon triple bond and carbonyl carbon.R is introduced because relating to 1and R 2substituent sequencing is different and be divided into two kinds of strategies.The first strategy is, with 2-amino-4,6-dihydroxy-pyrimidine (II) is raw material, with phosphorus oxychloride, N, dinethylformamide (DMF) reaction generates 2-amino-4, (reference has WainwrightP to 6-dichloro pyrimidine-5-formaldehyde (III), etal.Synlett; Nb.13; (2011); P.1900 – 1904 or BaraldiPG, etal.BioorganicandMedicinalChemistry, vol.11; Nb.19; (2003); P.4161 – 4169 etc.).ADCP-5-formaldehyde (III) and R 2the amine (IV) replaced can react generation when suitable mineral alkali (such as sodium hydrogen, potassium hydroxide, sodium hydroxide, sodium methylate, sodium ethylate or potassium tert.-butoxide etc.) or organic bases (such as triethylamine, diisopropyl ethyl amine, pyridine etc.) exist and introduce R 2substituent pyrimidine-5-formaldehyde (V) (reference of structure proximate is a lot, does not enumerate herein).End position alkynes (VI) replaced first is reacted to n-Butyl Lithium or Grignard reagent or other organometallic reagent and is generated corresponding alkynyl metal-salt, and then with introduce R 2there is addition reaction in substituent pyrimidine-5-formaldehyde (V), can generate the propargyl alcohol derivative (VII) that pyrimidine 5 replaces.Finally, utilize the well-known oxygenant in organic synthesis field, such as Manganse Dioxide, Dess-Martin oxygenant, Jones reagent, PCC (pyridinium chloro-chromate) etc., the hydroxyl oxygen of third, alkynes can be changed into ketone, required pyrimidine acetylenic ketone derivative (VIII) can be obtained.The second strategy is, does not first introduce R 2the amine (IV) replaced, but allow ADCP-5-formaldehyde (III) first react with end position alkynes (VI) replaced, generate pyrimidine propargyl alcohol derivative (Ⅸ), and then introduce R 2the amine (IV) replaced, generates and introduces R 2substituent pyrimidine alkynol (Ⅹ).Next, same, then there is the pyrimidine acetylenic ketone derivative (VIII) needed for oxidizing reaction generation.Generally, why first pyrimidine propargyl alcohol derivative (Ⅸ) is not oxidized to pyrimidine acetylenic ketone derivative after introduce R again 2the amine (IV) replaced, is because acetylenic ketone structure and amine easily side reaction occur, generates cyclic side products or other by products.Be adopt the first strategy or the second strategy, depend on R completely 1and R 2whether two substituting groups can produce interference mutually before, to such an extent as to unnecessary side reaction occur or even can hamper another substituent introducing completely.If R 1and R 2two substituent introducings can not cause interference to the other side, and so two kinds of strategies just can be optional.Certainly, though do not affect in compound molecule introduced group or impact but under the prerequisite finally can restored, if R 1or R 2need also to need further chemical reaction to occur according to molecule construction in substituting group; or take off protecting group, or form new covalent linkage and introduce new group, etc.; so pyrimidine acetylenic ketone derivative (VIII) is not just final required compound, also will continue chemical reaction occurs.
According to synthetic route two, R can be synthesized 1for alkene and the preferred type I compound that is directly connected of carbon-carbon double bond and carbonyl carbon.Same, introduce R because relating to 1and R 2substituent sequencing is different and be divided into two kinds of strategies.Two kinds of strategies all with 1-(ADCP-5-base) ethyl ketone (Ⅻ) this key intermediate for starting material.1-(2-amino-4,6-dichloro pyrimidine-5-base) synthesis of ethyl ketone (Ⅻ), can with 2-amino-4,6-dichloro pyrimidine-5-formaldehyde (III) is raw material, first with methyl Grignard generation addition reaction, obtain 1-(2-amino-4,6-dichloro pyrimidine-5-base) ethanol (Ⅺ), again hydroxyl oxygen is changed into ketone, (reference has WO2005/28434 to ethyl ketone (Ⅻ) can to obtain 1-(ADCP-5-base), (2005), (A2) or WO2014/96423, (2014), (A1) etc.).The first strategy is, 1-(2-amino-4,6-dichloro pyrimidine-5-base) ethyl ketone (Ⅻ) with replace aldehyde (Ⅹ III) occurs in the basic conditions aldol reaction generate pyrimidine ketenes derivative (Ⅹ IV) (be similar to reference have RanaNK, etal.JournalofOrganicChemistry; Vol.75; Nb.6; (2010); P.2089 – 2091 or ChongJ, etal.JournaloftheAmericanChemicalSociety; Vol.122; Nb.8; (2000); P.1822 – 1823 etc.), and then there is substitution reaction introducing R 2the amine (IV) replaced, obtains the required R of introducing 2substituent pyrimidine ketenes derivative (Ⅹ V).The second strategy is, the reaction sequence with the first strategy is contrary, first carries out substitution reaction and introduces R 2the amine (IV) replaced, generates and introduces R 2substituent pyrimidine ethanone derivatives (Ⅹ VI), and then there is aldol reaction generation pyrimidine ketenes derivative (Ⅹ V).Same, select to adopt the first strategy or the second strategy, depend on R 1and R 2whether two substituting groups can produce interference mutually before.In like manner, if R 1or R 2need also to need further chemical reaction to occur according to molecule construction in substituting group, so pyrimidine ketenes derivative (Ⅹ V) is not just final required compound, also will continue chemical reaction occurs.Especially, it should be noted that, although at preferred R 1in the representational example of substituting group, double bond is all drawn as transconfiguration, this is because most medicine all adopts is transconfiguration isomer, but when building the double bond in pyrimidine ketenes derivative Ⅹ IV or Ⅹ V, likely obtain Cis formula and trans mixture simultaneously, just make the product generated based on trans-isomer(ide) based on sterically hindered reason or control reaction conditions, when processing after the reaction, by unwanted Cis formula product removing.
Said synthesis route is just for the R of two kinds of preferable case (alkene and alkynes) 1substituting group and different R 2substituting group is arranged in pairs or groups mutually and is designed.For other R of type I compound meeting claim 1substituting group, synthetic method will make conversion certainly, and this is basic general knowledge well-known to those skilled in the art.
The invention still further relates to and preparing the purposes prevented and/or treated in the medicine of following disease, i.e. inflammation (comprising rheumatoid arthritis), atherosclerosis, I type or type II diabetes, diabetic complication, obesity, hyperlipidaemia, impaired glucose tolerance, cerebral ischemia, parkinsonism, insulin resistant and osteoporosis as the type I compound of medicine (or medicament) and/or its pharmacologically acceptable salt.
The invention still further relates to pharmaceutical preparation (or pharmaceutical composition), it contains at least one type I compound of significant quantity and/or its pharmacologically acceptable salt, the vehicle of physiology tolerance and carrier, and also has other additives and/or other activeconstituentss in due course.Medicine can be Orally administered, such as, with the form of pill, tablet (comprise slowly-releasing and controlled release), spraying sheet (lacqueredtablets), coating tablet, pulvis, granule, hard and soft gelatin capsule, solution, syrup, emulsion, suspensoid, aerosol mixtures, lipid or polymer microballoon or nanometer ball or capsule.But, use and also can carry out with following parenteral route: per rectum administration, such as, with suppository form; Or parenteral admin, such as, through intravenously, intramuscular or subcutaneous with injection solution or infusion solution, micro-capsule, implant or the form implanting rod; Or through skin, local or dosing eyes, such as, with ointment, ointment, emulsion, ointment, impregnated pads, solution, gel, polymeric chip, sprays, lotion, tincture or suspended form; Or with other administrations, such as, with aerosol or form of nasal sprays.
Pharmaceutical preparation of the present invention with itself known and the mode be familiar with by those skilled in the art prepare, except type I compound and/or their pharmacologically acceptable salt and/or their prodrug, use pharmaceutically useful inertia or have the inorganic of certain drug activity and/or organic carrier substances and/or additive.For the preparation of pill, pulvis, granule, tablet, coating tablet and hard gelatin capsule, such as lactose, W-Gum or derivatives thereof, talcum, stearic acid or its salt etc. may be used.The carrier substance of soft gelatin capsule and suppository has such as fat, wax, semisolid and liquid polyol, natural or sclerosis wet goods.The carrier substance being suitable for preparing solution, such as injection solution or emulsion or syrup has such as water, salt solution, alcohol, glycerine, polyvalent alcohol (comprising polyoxyethylene glycol), sucrose, Nulomoline, glucose, plant wet goods.Be suitable for micro-capsule, implant or implant excellent carrier substance, the multipolymer of such as hydroxyethanoic acid and lactic acid.Pharmaceutical preparation usually containing 0.001% to about 90% weight of having an appointment, the preferably type I compound of 0.01% to 10% weight and/or their pharmacologically acceptable salt and/or their prodrug.Activeconstituents type I compound in pharmaceutical preparation and/or the amount of their pharmacologically acceptable salt and/or their prodrug are generally about 0.5mg to about 1000mg, preferably about 1mg to about 500mg.
Except the activeconstituents of formula I and/or their pharmacologically acceptable salt and carrier substance, pharmaceutical preparation can contain one or more additives, as the reagent of weighting agent, disintegrating agent, tackiness agent, lubricant, wetting agent (moisture adjuster), stablizer, emulsifying agent, sanitas, sequestering agent, sweeting agent, tinting material, correctives, perfume compound, thickening material, thinner, buffer substance (pH adjusting agent), solvent, solubilizing agent, acquisition depot effect, the salt (osmotic pressure regulator) changing osmotic pressure, Drug coating or antioxidant.They also can contain two or more type I compound and/or their pharmacologically acceptable salt.When pharmaceutical composition contains two or more type I compound, can according to the specific overall pharmacological property of pharmaceutical preparation to the selection of individual compound.Such as, the height potent compound that acting duration is shorter can combine by the long-acting compound lower with effect.Certainly, those skilled in the art, by the optional additives in pharmaceutical composition to be added for careful selection, are not subject to the advantageous feature making the present invention intrinsic or in fact add the disadvantageous effect of material by expectation.With regard to substituting group in type I compound is selected, the handiness that allows makes it possible to carry out numerous control to the biology of compound and physicochemical property, can select required compound thus.In addition, except at least one type I compound and/or its pharmacologically acceptable salt, pharmaceutical preparation also can contain one or more other treatments or preventative activeconstituents.
When using type I compound, dosage can in grace period and conveniently with doctor known and change, dosage should be suitable for the individual instances of often kind example.Dosage depends on the character of such as applied particular compound, institute's disease therapy and severity, method of application and scheme or what treat is acute or chronic disease or whether prevent.The clinical method that the dosage be applicable to can utilize medical field known is set up.Generally speaking, the per daily dose obtaining results needed in the adult of heavily about 75kg is about 0.01mg/kg to about 100mg/kg, preferably about 0.1mg/kg to about 50mg/kg, special about 0.1mg/kg to about 10mg/kg (in each case with mg/kg batheroom scale).Special in using relatively a large amount of, per daily dose can be divided into some parts, and such as 2,3 or 4 parts are used.Usually, according to individual behavior, may be necessary to depart from described per daily dose up or down.
In addition, type I compound can be used as preparing other compounds, particularly the synthetic intermediate of other drug activeconstituents, and it such as can be obtained by introducing substituting group or modifying functional group by formula I.
In most of the cases, aftertreatment is carried out to the reaction mixture of the finalization compound containing formula I or intermediate, if necessary, can by product by ordinary method purifying well known by persons skilled in the art.Such as, synthesized compound can utilize the method known as crystallization, all kinds of chromatogram (comprising liquid chromatography, gas-chromatography etc.) or reversed-phased high performace liquid chromatographic (RP-HPLC) or based on such as compound molecule size, whether carry out purifying with electric charge or other separation methods with wetting ability or hydrophobicity build-in attribute etc.Similar, the Analysis and Identification method known such as amino acid sequence analysis, NMR, IR and mass spectroscopy (MS comprises high resolution mass spectrum) can be used for characterizing the compound that the present invention relates to.
Therefore, following examples are parts of the present invention, unrestricted the present invention for illustrating.
Should indicate, the modification of non-substantial effect the present invention various embodiment activity is included in the scope of the invention disclosed herein.
Embodiment
The preparation of embodiment 1:1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-6-(piperidin-1-yl)-2-hexin-1-ketone
The first step: N-(3-(4-Fonnylphenyl) phenyl) urea (compound number is 1)
Through prior nitrogen bubble deoxygenation and under continuing the protection of logical nitrogen, by Anhydrous potassium carbonate (27.6g, 0.2mol), palladium (0.90g, 4.0mmol) and molecular sieve (2.0g, in advance through retort furnace high-temperature roasting activation) add p-bromobenzaldehyde (18.5g successively, 0.1mol) and a urea groups phenylo boric acid (18.0g, 0.1mol, can reference JournaloftheAmericanChemicalSociety; Vol.81; (1959); P.3017 synthesized) tetrahydrofuran (THF) (150mL) and water (40mL) mixing solutions in.Under nitrogen protection, oil bath is heated to backflow, and insulation reaction about 6 hours.Add ethyl acetate (300mL), stir half hour, cross and filter insolubles, gained mixing solutions saturated aqueous common salt (200mL*2) washs.Separatory; organic phase is through anhydrous sodium sulfate drying; filter; remove solvent under reduced pressure; residuum is through purification by silica gel column chromatography (gradient elution; elutriant is sherwood oil: ethyl acetate=5:1 to 1:1) obtain 19.7g faint yellow solid, be N-(3-(4-Fonnylphenyl) phenyl) urea, yield 82.0%.MS:m/z＝241.1(M+H +)。
Second step: N-(3-(4-hydroxymethyl phenyl) phenyl) urea (compound number is 2)
Be dissolved in methyl alcohol (100mL) by N-(3-(4-Fonnylphenyl) phenyl) urea (19.0g, 79.1mmol), ice-water bath cools, and careful adds sodium borohydride (1.5g, 39.7mmol) in batches.After adding sodium borohydride, stir half hour, remove ice-water bath, allow reaction solution naturally rise to room temperature, continue to react about 3-5 hour, TLC and monitor (sherwood oil: ethyl acetate=1:1) until react completely.Slowly dripping the dilute hydrochloric acid solution of 2M, until pH value, is 2-3.Revolve and steam the most of methyl alcohol of removing, in residuum, add ethyl acetate (200mL), gained mixing solutions saturated aqueous common salt (100mL*2) washs.Separatory, organic phase, through anhydrous sodium sulfate drying, is filtered, is removed solvent under reduced pressure, obtain 18.0g off-white color solid, be N-(3-(4-hydroxymethyl phenyl) phenyl) urea, yield 93.9%.MS:m/z＝243.1(M+H +)。
3rd step: N-(3-(4-2-bromomethylphenyl) phenyl) urea (compound number is 3)
Under ice-water bath, by phosphorus tribromide (19.5g, chloroform (50mL) solution 72.2mol) is slowly added dropwise in chloroform (200mL) solution of N-(3-(4-hydroxymethyl phenyl) phenyl) urea (17.5g, 72.2mmol).Control to drip off at about 30 minutes.Continue reaction under ice-water bath, TLC monitoring (sherwood oil: ethyl acetate=1:1), until react completely, approximately needs 1 hour.Add mixture of ice and water (100g) cancellation reaction.Separatory, aqueous phase methylene dichloride (100mL*1) extraction, separatory, merges organic phase, after anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, obtain 21.6g yellow foamy solid, be N-(3-(4-2-bromomethylphenyl) phenyl) urea, yield 98.1%.MS:m/z＝305.0、307.0(M+H +)。
4th step: N-(4-(3-Ureidophenyl) benzyl) phthalic imidine (compound number is 4)
Potassium phthalimide (12.1g, 65.5mmol) is added in DMF (200mL) solution of N-(3-(4-2-bromomethylphenyl) phenyl) urea (20.0g, 65.5mmol).React about 10-15 hour, TLC under room temperature and monitor (sherwood oil: ethyl acetate=2:1) until react completely.Add water (300mL), have a large amount of solid to separate out.Filter, vacuum-drying, obtains 22.4g off-white color solid, is N-(4-(3-Ureidophenyl) benzyl) phthalic imidine, yield 92.1%.MS:m/z＝372.1(M+H +)。
5th step: N-(3-(4-aminomethyl phenyl) phenyl) urea (compound number is 5)
Hydrazine hydrate (55% aqueous solution, 49.0g, 0.5mol) is added in ethanol (200mL) solution of N-(4-(3-Ureidophenyl) benzyl) phthalic imidine (20.0g, 53.9mmol).Reaction solution oil bath is heated to 40 DEG C and reacts about 5-6 hour, TLC monitor (methylene dichloride: methyl alcohol=8:1) until react completely.Cross and filter insolubles, remove solvent under reduced pressure, residuum methylene dichloride (300mL) dissolves, and refilters once, removing insolubles.Wash (100mL*2) dichloromethane solution with water.Organic phase, after anhydrous sodium sulfate drying, is filtered, is removed solvent under reduced pressure, obtain 11.2g off-white color solid, be N-(3-(4-aminomethyl phenyl) phenyl) urea, yield 86.1%.MS:m/z＝242.1(M+H +)。
6th step: 2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-formaldehyde (compound number is 6)
At N-(3-(4-aminomethyl phenyl) phenyl) urea (10.0g, in ethanol (100mL) solution 41.4mmol), successively add triethylamine (21.2g, 0.21mol) with 2-amino-4,6-dichloro pyrimidine-5-formaldehyde (8.0g, 41.4mmol).Reaction solution oil bath is heated to reflux and reacts about 6-7 hour, TLC and monitor (methylene dichloride: methyl alcohol=10:1) until react completely.Remove solvent under reduced pressure, add water (200mL), making beating, filter, filter cake ethyl alcohol recrystallization vacuum-drying, obtain 14.4g faint yellow solid, be 2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-formaldehyde, yield 88.4%.MS:m/z＝397.2(M+H +)。
7th step: 1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-6-(piperidin-1-yl)-2-hexin-1-alcohol (compound number is 7)
Under nitrogen protection, by 1-(4-pentynyl) piperidines, (19.1g, 126.0mmol, can reference CuiLi, etal.ChemicalCommunications, 2010, vol.46, #19p.3351 – 3353; MeierGalina, etal.BioorganicandMedicinalChemistry, 2002, vol.10, #8p.2535-2542 or WO2014/81645A1,2014 are synthesized) anhydrous tetrahydro furan (100mL) solution liquid nitrogen ethanol bath be cooled to-78 DEG C, slow dropping n-Butyl Lithium (2.5M hexane solution, 50.4mL, 126.0mmol) solution, control to drip off at about 1 hour.Under keeping-78 DEG C and nitrogen protection, then drip anhydrous tetrahydro furan (100mL) solution of 2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-formaldehyde (12.5g, 31.5mmol).Drip and finish, reaction system of leaving rises to room temperature and reaction is spent the night, and TLC monitoring (methylene dichloride: methyl alcohol=10:1) is until react completely.Drip water (50mL) cancellation reaction, then add ethyl acetate (200mL).Gained mixing solutions saturated aqueous common salt (100mL*3) washs.Separatory, organic phase is through anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, residuum is through purification by silica gel column chromatography (gradient elution, elutriant is methylene dichloride: methyl alcohol=20:1 to 10:1) obtain 11.8g faint yellow solid, be 1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-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-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-6-(piperidin-1-yl)-2-hexin-1-ketone (compound number is 8)
By activated manganese dioxide (6.3g, 72.8mmol) add in methylene dichloride (100mL) solution of 1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-6-(piperidin-1-yl)-2-hexin-1-alcohol (10.0g, 18.2mmol).React 24 hours under room temperature.Cross and filter insolubles, remove solvent under reduced pressure, residuum is through purification by silica gel column chromatography (gradient elution, elutriant is methylene dichloride: methyl alcohol=30:1 to 15:1) obtain 7.8g faint yellow solid, be 1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-6-(piperidin-1-yl)-2-hexin-1-ketone, yield 78.6%.MS:m/z＝546.2(M+H +)。
1HNMR(300MHz,DMSO-d 6)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).
The preparation of embodiment 2:1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-methoxyl group-valerylene-1-ketone
The first step: 2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-formaldehyde (compound number is 9)
Under nitrogen protection, by 4-(4-p-methoxy-phenyl) aniline, (11.4g, 57.3mmol, can reference RazlerTMetal.JournalofOrganicChemistry; Vol.74; Nb.3; (2009); P.1381 – 1384 is synthesized) anhydrous tetrahydro furan (120mL) solution ice-water bath lower the temperature, carefully add sodium hydrogen (60% mineral oil powder, 4.6g, 114.6mmol) in batches.Finish, continue stirring reaction and be about half hour, then add ADCP-5-formaldehyde (10.0g, 52.1mmol).Remove ice-water bath, make reaction system react about 8-10 hour, TLC at ambient temperature and monitor (sherwood oil: ethyl acetate=2:1) until react completely.Slow dropping water (20mL) cancellation reaction.Add ethyl acetate (200mL) again.Gained mixing solutions saturated aqueous common salt (100mL*3) washs.Separatory, organic phase is through anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, residuum is through recrystallization (sherwood oil: ethyl acetate=5:1) and vacuum-drying, obtain 15.3g faint yellow solid, be 2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-formaldehyde, yield 82.7%.MS:m/z＝355.1(M+H +)。
Second step: 1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-methoxyl group-valerylene-1-alcohol (compound number is 10)
Under nitrogen protection, by 4-methoxyl group-ethyl acetylene, (10.6g, 126.0mmol, can reference JacksonW, etal.AustralianJournalofChemistry; Vol.41; Nb.2; (1988); P.251-261 synthesized) anhydrous tetrahydro furan (100mL) solution liquid nitrogen ethanol bath be cooled to-78 DEG C, slow dropping n-Butyl Lithium (2.5M hexane solution, 50.4mL, 126.0mmol) solution, control to drip off at about 1 hour.Under keeping-78 DEG C and nitrogen protection, then drip anhydrous tetrahydro furan (100mL) solution of 2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-formaldehyde (11.2g, 31.5mmol).Drip and finish, reaction system of leaving rises to room temperature and reaction is spent the night, and TLC monitoring (methylene dichloride: methyl alcohol=10:1) is until react completely.Drip water (50mL) cancellation reaction, then add ethyl acetate (200mL).Gained mixing solutions saturated aqueous common salt (100mL*3) washs.Separatory, organic phase is through anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, residuum is through purification by silica gel column chromatography (gradient elution, elutriant is methylene dichloride: methyl alcohol=30:1 to 15:1) obtain 10.9g faint yellow solid, be 1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-methoxyl group-valerylene-1-alcohol, yield 78.7%.MS:m/z＝439.2(M+H +)。
3rd step: 1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-methoxyl group-valerylene-1-ketone (compound number is 11)
By activated manganese dioxide (6.3g, 72.8mmol) add in methylene dichloride (100mL) solution of 1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-methoxyl group-valerylene-1-alcohol (8.0g, 18.2mmol).React 24 hours under room temperature.Cross and filter insolubles, remove solvent under reduced pressure, residuum is through purification by silica gel column chromatography (gradient elution, elutriant is methylene dichloride: methyl alcohol=40:1 to 20:1) obtain 6.9g yellow solid, 1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-methoxyl group-valerylene-1-ketone, yield 86.8%.MS:m/z＝437.1(M+H +)。
1HNMR(300MHz,DMSO-d 6)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) preparation of-1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexene-1-ketone
The first step: (E)-1-(ADCP-5-base)-6-methoxyl group-2-hexene-1-ketone (compound number is 12)
By 1-(2-amino-4,6-dichloro pyrimidine-5-base) ethyl ketone (10.0g, 48.5mmol, can reference WO2005/28434, (2005), or WO2014/96423 (A2), (2014), (A1) synthesized) anhydrous tetrahydro furan (100mL) solution liquid nitrogen ethanol bath be cooled to-78 DEG C, slow dropping lithium diisopropylamine (LDA, 2.0M hexane solution, 24.3mL, 48.5mmol) solution, controls about half hour drips off.Under keeping-78 DEG C and nitrogen protection, then (5.0g, 48.5mmol, can reference WO2009/7814, (2009), (A1), BorbasK, etal.OrganicLetters to drip 4-methoxyl group-1-butyraldehyde; Vol.10; Nb.10; (2008); Or ChauST, etal.OrganicLetters p.1931-1934; Vol.13; Nb.4; (2011); P.756-759 synthesized) anhydrous tetrahydro furan (30mL) solution.Drip and finish, reaction system of leaving rises to room temperature naturally, and reaction is spent the night, and TLC monitoring (sherwood oil: ethyl acetate=1:1) is until react completely.Slow dropping saturated aqueous ammonium chloride (20mL) cancellation reaction.Add ethyl acetate (200mL) again.Gained mixing solutions saturated aqueous common salt (100mL*3) washs.Separatory, organic phase is through anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, residuum is through purification by silica gel column chromatography (gradient elution, elutriant is sherwood oil: ethyl acetate=5:1 to 2:1), obtain 8.7g off-white color solid, be (E)-1-(ADCP-5-base)-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-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexene-1-ketone (compound number is 13)
Under nitrogen protection, by 4-(4-p-methoxy-phenyl) aniline, (5.7g, 28.8mmol, can reference RazlerTMetal.JournalofOrganicChemistry; Vol.74; Nb.3; (2009); P.1381 – 1384 is synthesized) anhydrous tetrahydro furan (60mL) solution ice-water bath lower the temperature, carefully add sodium hydrogen (60% mineral oil powder, 2.3g, 57.6mmol) in batches.Finish, continue stirring reaction and be about half hour, then add (E)-1-(ADCP-5-base)-6-methoxyl group-2-hexene-1-ketone (7.6g, 26.2mmol).Remove ice-water bath, make reaction system react about 8-10 hour, TLC at ambient temperature and monitor (sherwood oil: ethyl acetate=2:1) until react completely.Slow dropping water (10mL) cancellation reaction.Add ethyl acetate (100mL) again.Gained mixing solutions saturated aqueous common salt (50mL*3) washs.Separatory, organic phase is through anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, residuum is through recrystallization (sherwood oil: ethyl acetate=5:1) and vacuum-drying, obtain 9.6g faint yellow solid, be (E)-1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexene-1-ketone, yield 80.9%.MS:m/z＝453.2(M+H +)。
1HNMR(300MHz,DMSO-d 6)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 meeting claims two kinds of preferable case (alkene and alkynes) all can adopt the synthetic method approximate with above-described embodiment to obtain, and only need change different starting materials.Representational compound is as follows:
14.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-4-hydroxyl-2-butyne-1-ketone
15.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-4-methoxyl group-2-butyne-1-ketone
16.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-5-hydroxyl-valerylene-1-ketone
17.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-5-methoxyl group-valerylene-1-ketone
18.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-4-amino-2-butyne-1-ketone
19.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-4-methylamino--2-butyne-1-ketone
20.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-4-dimethylamino-2-butyne-1-ketone
21.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-5-amino-valerylene-1-ketone
22.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-5-methylamino--valerylene-1-ketone
23.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-5-dimethylamino-valerylene-1-ketone
24.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexin-1-ketone
25.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexin-1-ketone
26.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-6-amino-2-hexin-1-ketone
27.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-6-methylamino--2-hexin-1-ketone
28.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-6-dimethylamino-2-hexin-1-ketone
29.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-4-(pyrans-2-base)-2-butyne-1-ketone
30.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-5-(pyrans-2-base)-valerylene-1-ketone
31.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-6-(pyrans-2-base)-2-hexin-1-ketone
32.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-4-(pyrroles-1-base)-2-butyne-1-ketone
33.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-5-(pyrroles-1-base)-valerylene-1-ketone
34.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-6-(pyrroles-1-base)-2-hexin-1-ketone
35.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-4-(piperidin-1-yl)-2-butyne-1-ketone
36.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-5-(piperidin-1-yl)-valerylene-1-ketone
37.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-4-(piperazine-1-base)-2-butyne-1-ketone
38.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-5-(piperazine-1-base)-valerylene-1-ketone
39.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-6-(piperazine-1-base)-2-hexin-1-ketone
40.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-hydroxyl-2-butyne-1-ketone
41.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-methoxyl group-2-butyne-1-ketone
42.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-hydroxyl-valerylene-1-ketone
43.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-methoxyl group-valerylene-1-ketone
44.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-amino-2-butyne-1-ketone
45.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-methylamino--2-butyne-1-ketone
46.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-dimethylamino-2-butyne-1-ketone
47.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-amino-valerylene-1-ketone
48.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-methylamino--valerylene-1-ketone
49.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-dimethylamino-valerylene-1-ketone
50.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexin-1-ketone
51.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexin-1-ketone
52.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-amino-2-hexin-1-ketone
53.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-methylamino--2-hexin-1-ketone
54.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-dimethylamino-2-hexin-1-ketone
55.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-(pyrans-2-base)-2-butyne-1-ketone
56.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-(pyrans-2-base)-valerylene-1-ketone
57.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-(pyrans-2-base)-2-hexin-1-ketone
58.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-(pyrroles-1-base)-2-butyne-1-ketone
59.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-(pyrroles-1-base)-valerylene-1-ketone
60.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-(pyrroles-1-base)-2-hexin-1-ketone
61.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-(piperidin-1-yl)-2-butyne-1-ketone
62.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-(piperidin-1-yl)-valerylene-1-ketone
63.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-(piperidin-1-yl)-2-hexin-1-ketone
64.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-(piperazine-1-base)-2-butyne-1-ketone
65.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-(piperazine-1-base)-valerylene-1-ketone
66.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-(piperazine-1-base)-2-hexin-1-ketone
67.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-hydroxyl-2-butyne-1-ketone
68.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-methoxyl group-2-butyne-1-ketone
69.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-hydroxyl-valerylene-1-ketone
70.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-methoxyl group-valerylene-1-ketone
71.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-amino-2-butyne-1-ketone
72.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-methylamino--2-butyne-1-ketone
73.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-dimethylamino-2-butyne-1-ketone
74.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-amino-valerylene-1-ketone
75.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-methylamino--valerylene-1-ketone
76.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-dimethylamino-valerylene-1-ketone
77.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexin-1-ketone
78.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexin-1-ketone
79.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-amino-2-hexin-1-ketone
80.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-methylamino--2-hexin-1-ketone
81.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-dimethylamino-2-hexin-1-ketone
82.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-(pyrans-2-base)-2-butyne-1-ketone
83.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-(pyrans-2-base)-valerylene-1-ketone
84.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-(pyrans-2-base)-2-hexin-1-ketone
85.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-(pyrroles-1-base)-2-butyne-1-ketone
86.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-(pyrroles-1-base)-valerylene-1-ketone
87.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-(pyrroles-1-base)-2-hexin-1-ketone
88.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-(piperidin-1-yl)-2-butyne-1-ketone
89.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-(piperidin-1-yl)-valerylene-1-ketone
90.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-(piperidin-1-yl)-2-hexin-1-ketone
91.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-(piperazine-1-base)-2-butyne-1-ketone
92.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-(piperazine-1-base)-valerylene-1-ketone
93.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-(piperazine-1-base)-2-hexin-1-ketone
94.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-4-hydroxyl-2-butyne-1-ketone
95.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-4-methoxyl group-2-butyne-1-ketone
96.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-5-hydroxyl-valerylene-1-ketone
97.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-5-methoxyl group-valerylene-1-ketone
98.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-4-amino-2-butyne-1-ketone
99.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-4-methylamino--2-butyne-1-ketone
100.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-4-dimethylamino-2-butyne-1-ketone
101.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-5-amino-valerylene-1-ketone
102.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-5-methylamino--valerylene-1-ketone
103.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-5-dimethylamino-valerylene-1-ketone
104.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexin-1-ketone
105.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexin-1-ketone
106.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-6-amino-2-hexin-1-ketone
107.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-6-methylamino--2-hexin-1-ketone
108.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-6-dimethylamino-2-hexin-1-ketone
109.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-4-(pyrans-2-base)-2-butyne-1-ketone
110.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-5-(pyrans-2-base)-valerylene-1-ketone
111.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-6-(pyrans-2-base)-2-hexin-1-ketone
112.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-4-(pyrroles-1-base)-2-butyne-1-ketone
113.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-5-(pyrroles-1-base)-valerylene-1-ketone
114.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-6-(pyrroles-1-base)-2-hexin-1-ketone
115.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-4-(piperidin-1-yl)-2-butyne-1-ketone
116.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-5-(piperidin-1-yl)-valerylene-1-ketone
117.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-6-(piperidin-1-yl)-2-hexin-1-ketone
118.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-4-(piperazine-1-base)-2-butyne-1-ketone
119.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-5-(piperazine-1-base)-valerylene-1-ketone
120.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-6-(piperazine-1-base)-2-hexin-1-ketone
121.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-4-hydroxyl-2-butyne-1-ketone
122.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-4-methoxyl group-2-butyne-1-ketone
123.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-5-hydroxyl-valerylene-1-ketone
124.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-5-methoxyl group-valerylene-1-ketone
125.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-4-amino-2-butyne-1-ketone
126.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-4-methylamino--2-butyne-1-ketone
127.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-4-dimethylamino-2-butyne-1-ketone
128.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-5-amino-valerylene-1-ketone
129.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-5-methylamino--valerylene-1-ketone
130.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-5-dimethylamino-valerylene-1-ketone
131.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexin-1-ketone
132.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexin-1-ketone
133.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-6-amino-2-hexin-1-ketone
134.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-6-methylamino--2-hexin-1-ketone
135.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-6-dimethylamino-2-hexin-1-ketone
136.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-4-(pyrans-2-base)-2-butyne-1-ketone
137.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-5-(pyrans-2-base)-valerylene-1-ketone
138.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-6-(pyrans-2-base)-2-hexin-1-ketone
139.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-4-(pyrroles-1-base)-2-butyne-1-ketone
140.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-5-(pyrroles-1-base)-valerylene-1-ketone
141.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-6-(pyrroles-1-base)-2-hexin-1-ketone
142.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-4-(piperidin-1-yl)-2-butyne-1-ketone
143.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-5-(piperidin-1-yl)-valerylene-1-ketone
144.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-6-(piperidin-1-yl)-2-hexin-1-ketone
145.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-4-(piperazine-1-base)-2-butyne-1-ketone
146.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-5-(piperazine-1-base)-valerylene-1-ketone
147.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-6-(piperazine-1-base)-2-hexin-1-ketone
148.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-4-hydroxyl-2-butyne-1-ketone
149.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-4-methoxyl group-2-butyne-1-ketone
150.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-5-hydroxyl-valerylene-1-ketone
151.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-5-methoxyl group-valerylene-1-ketone
152.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-4-amino-2-butyne-1-ketone
153.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-4-methylamino--2-butyne-1-ketone
154.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-4-dimethylamino-2-butyne-1-ketone
155.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-5-amino-valerylene-1-ketone
156.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-5-methylamino--valerylene-1-ketone
157.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-5-dimethylamino-valerylene-1-ketone
158.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexin-1-ketone
159.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexin-1-ketone
160.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-6-amino-2-hexin-1-ketone
161.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-6-methylamino--2-hexin-1-ketone
162.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-6-dimethylamino-2-hexin-1-ketone
163.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-4-(pyrans-2-base)-2-butyne-1-ketone
164.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-5-(pyrans-2-base)-valerylene-1-ketone
165.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-6-(pyrans-2-base)-2-hexin-1-ketone
166.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-4-(pyrroles-1-base)-2-butyne-1-ketone
167.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-5-(pyrroles-1-base)-valerylene-1-ketone
168.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-6-(pyrroles-1-base)-2-hexin-1-ketone
169.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-4-(piperidin-1-yl)-2-butyne-1-ketone
170.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-5-(piperidin-1-yl)-valerylene-1-ketone
171.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-6-(piperidin-1-yl)-2-hexin-1-ketone
172.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-4-(piperazine-1-base)-2-butyne-1-ketone
173.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-5-(piperazine-1-base)-valerylene-1-ketone
174.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-6-(piperazine-1-base)-2-hexin-1-ketone
175.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-4-hydroxyl-2-butyne-1-ketone
176.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-4-methoxyl group-2-butyne-1-ketone
177.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-5-hydroxyl-valerylene-1-ketone
178.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-5-methoxyl group-valerylene-1-ketone
179.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-4-amino-2-butyne-1-ketone
180.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-4-methylamino--2-butyne-1-ketone
181.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-4-dimethylamino-2-butyne-1-ketone
182.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-5-amino-valerylene-1-ketone
183.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-5-methylamino--valerylene-1-ketone
184.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-5-dimethylamino-valerylene-1-ketone
185.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexin-1-ketone
186.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexin-1-ketone
187.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-6-amino-2-hexin-1-ketone
188.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-6-methylamino--2-hexin-1-ketone
189.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-6-dimethylamino-2-hexin-1-ketone
190.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-4-(pyrans-2-base)-2-butyne-1-ketone
191.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-5-(pyrans-2-base)-valerylene-1-ketone
192.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-6-(pyrans-2-base)-2-hexin-1-ketone
193.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-4-(pyrroles-1-base)-2-butyne-1-ketone
194.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-5-(pyrroles-1-base)-valerylene-1-ketone
195.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-6-(pyrroles-1-base)-2-hexin-1-ketone
196.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-4-(piperidin-1-yl)-2-butyne-1-ketone
197.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-5-(piperidin-1-yl)-valerylene-1-ketone
198.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-6-(piperidin-1-yl)-2-hexin-1-ketone
199.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-4-(piperazine-1-base)-2-butyne-1-ketone
200.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-5-(piperazine-1-base)-valerylene-1-ketone
201.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-6-(piperazine-1-base)-2-hexin-1-ketone
202.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-4-hydroxyl-2-butyne-1-ketone
203.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-4-methoxyl group-2-butyne-1-ketone
204.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-5-hydroxyl-valerylene-1-ketone
205.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-5-methoxyl group-valerylene-1-ketone
206.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-4-amino-2-butyne-1-ketone
207.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-4-methylamino--2-butyne-1-ketone
208.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-4-dimethylamino-2-butyne-1-ketone
209.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-5-amino-valerylene-1-ketone
210.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-5-methylamino--valerylene-1-ketone
211.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-5-dimethylamino-valerylene-1-ketone
212.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexin-1-ketone
105.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexin-1-ketone
213.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-6-amino-2-hexin-1-ketone
214.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-6-methylamino--2-hexin-1-ketone
215.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-6-dimethylamino-2-hexin-1-ketone
216.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-4-(pyrans-2-base)-2-butyne-1-ketone
217.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-5-(pyrans-2-base)-valerylene-1-ketone
218.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-6-(pyrans-2-base)-2-hexin-1-ketone
219.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-4-(pyrroles-1-base)-2-butyne-1-ketone
220.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-5-(pyrroles-1-base)-valerylene-1-ketone
221.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-6-(pyrroles-1-base)-2-hexin-1-ketone
222.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-4-(piperidin-1-yl)-2-butyne-1-ketone
223.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-5-(piperidin-1-yl)-valerylene-1-ketone
224.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-6-(piperidin-1-yl)-2-hexin-1-ketone
2251-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-4-(piperazine-1-base)-2-butyne-1-ketone
2261-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-5-(piperazine-1-base)-valerylene-1-ketone
227.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-6-(piperazine-1-base)-2-hexin-1-ketone
228.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-4-hydroxyl-2-butyne-1-ketone
229.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-4-methoxyl group-2-butyne-1-ketone
230.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-5-hydroxyl-valerylene-1-ketone
231.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-5-methoxyl group-valerylene-1-ketone
232.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-4-amino-2-butyne-1-ketone
233.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-4-methylamino--2-butyne-1-ketone
234.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-4-dimethylamino-2-butyne-1-ketone
2351-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-5-amino-valerylene-1-ketone
236.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-5-methylamino--valerylene-1-ketone
237.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-5-dimethylamino-valerylene-1-ketone
238.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexin-1-ketone
239.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexin-1-ketone
240.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-6-amino-2-hexin-1-ketone
241.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-6-methylamino--2-hexin-1-ketone
242.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-6-dimethylamino-2-hexin-1-ketone
243.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-4-(pyrans-2-base)-2-butyne-1-ketone
2441-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-5-(pyrans-2-base)-valerylene-1-ketone
245.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-6-(pyrans-2-base)-2-hexin-1-ketone
246.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-4-(pyrroles-1-base)-2-butyne-1-ketone
247.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-5-(pyrroles-1-base)-valerylene-1-ketone
248.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-6-(pyrroles-1-base)-2-hexin-1-ketone
249.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-4-(piperidin-1-yl)-2-butyne-1-ketone
250.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-5-(piperidin-1-yl)-valerylene-1-ketone
251.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-6-(piperidin-1-yl)-2-hexin-1-ketone
252.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-4-(piperazine-1-base)-2-butyne-1-ketone
253.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-5-(piperazine-1-base)-valerylene-1-ketone
254.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-6-(piperazine-1-base)-2-hexin-1-ketone
255.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-4-hydroxyl-2-butylene-1-ketone
256.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-hydroxyl-2-butylene-1-ketone
257.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-hydroxyl-2-butylene-1-ketone
258.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-4-hydroxyl-2-butylene-1-ketone
259.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-4-hydroxyl-2-butylene-1-ketone
260.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-4-hydroxyl-2-butylene-1-ketone
261.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-4-hydroxyl-crotonylene-1-ketone
262.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-4-hydroxyl-2-butylene-1-ketone
263.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-4-hydroxyl-2-butylene-1-ketone
264.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-4-methoxyl group-2-butylene-1-ketone
265.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-methoxyl group-2-butylene-1-ketone
266.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-4-methoxyl group-2-butylene-1-ketone
267.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-4-methoxyl group-2-butylene-1-ketone
268.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-4-methoxyl group-2-butylene-1-ketone
269.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-4-methoxyl group-2-butylene-1-ketone
270.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-4-methoxyl group-crotonylene-1-ketone
271.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-4-methoxyl group-2-butylene-1-ketone
272.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-4-methoxyl group-2-butylene-1-ketone
273.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-5-hydroxyl-2-amylene-1-ketone
274.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-hydroxyl-2-amylene-1-ketone
275.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-hydroxyl-2-amylene-1-ketone
276.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-5-hydroxyl-2-amylene-1-ketone
277.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-5-hydroxyl-2-amylene-1-ketone
278.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-5-hydroxyl-2-amylene-1-ketone
279.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-5-hydroxyl-2-amylene-1-ketone
280.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-5-hydroxyl-2-amylene-1-ketone
281.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-5-hydroxyl-2-amylene-1-ketone
282.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-5-methoxyl group-2-amylene-1-ketone
283.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-methoxyl group-2-amylene-1-ketone
284.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-5-methoxyl group-2-amylene-1-ketone
285.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-5-methoxyl group-2-amylene-1-ketone
286.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-5-methoxyl group-2-amylene-1-ketone
287.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-5-methoxyl group-2-amylene-1-ketone
288.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-5-methoxyl group-2-amylene-1-ketone
289.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-5-methoxyl group-2-amylene-1-ketone
290.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-5-methoxyl group-2-amylene-1-ketone
291.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexene-1-ketone
292.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexene-1-ketone
293.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexene-1-ketone
294.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexene-1-ketone
295.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexene-1-ketone
296.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexene-1-ketone
297.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexene-1-ketone
298.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexene-1-ketone
299.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexene-1-ketone
300.1-(2-amino-4-(4-(3-Ureidophenyl) benzamido group)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexene-1-ketone
301.1-(2-amino-4-(4-(3-aminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexene-1-ketone
302.1-(2-amino-4-(4-(3-Methylaminophenyl) benzamido group)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexene-1-ketone
303.1-(2-amino-4-(4-(3-dimethylamino phenyl) benzamido group)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexene-1-ketone
304.1-(2-amino-4-(4-phenylbenzylamine base)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexene-1-ketone
305.1-(2-amino-4-(4-(3-aminophenyl) anilino)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexene-1-ketone
306.1-(2-amino-4-(4-(3-Methylaminophenyl) anilino)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexene-1-ketone
307.1-(2-amino-4-(4-(3-dimethylamino phenyl) anilino)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexene-1-ketone
308.1-(2-amino-4-(4-phenylaniline base)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexene-1-ketone
309.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-4-hydroxyl-2-butyne-1-ketone
310.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-4-methoxyl group-2-butyne-1-ketone
311.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-hydroxyl-valerylene-1-ketone
312.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-methoxyl group-valerylene-1-ketone
313.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-4-amino-2-butyne-1-ketone
314.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-4-methylamino--2-butyne-1-ketone
315.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-4-dimethylamino-2-butyne-1-ketone
316.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-amino-valerylene-1-ketone
317.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-methylamino--valerylene-1-ketone
318.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-dimethylamino-valerylene-1-ketone
319.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexin-1-ketone
320.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-6-methoxyl group-2-hexin-1-ketone
321.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-6-amino-2-hexin-1-ketone
322.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-6-methylamino--2-hexin-1-ketone
323.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-6-dimethylamino-2-hexin-1-ketone
324.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-4-(pyrans-2-base)-2-butyne-1-ketone
325.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-(pyrans-2-base)-valerylene-1-ketone
326.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-6-(pyrans-2-base)-2-hexin-1-ketone
327.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-4-(pyrroles-1-base)-2-butyne-1-ketone
328.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-(pyrroles-1-base)-valerylene-1-ketone
329.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-6-(pyrroles-1-base)-2-hexin-1-ketone
330.1-(2-amino-4-(4-4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-4-(piperidin-1-yl)-2-butyne-1-ketone
331.1-(2-amino-4-(4-4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-(piperidin-1-yl)-valerylene-1-ketone
332.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-6-(piperidin-1-yl)-2-hexin-1-ketone
333.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-4-(piperazine-1-base)-2-butyne-1-ketone
334.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-(piperazine-1-base)-valerylene-1-ketone
335.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-6-(piperazine-1-base)-2-hexin-1-ketone
336.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-4-hydroxyl-2-butylene-1-ketone
337.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-4-methoxyl group-2-butylene-1-ketone
338.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-hydroxyl-2-amylene-1-ketone
339.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-5-methoxyl group-2-amylene-1-ketone
340.1-(2-amino-4-(4-(4-p-methoxy-phenyl) anilino)-6-chloropyrimide-5-base)-6-hydroxyl-2-hexene-1-ketone
Meet the different R of claim 1substituting group and different R 2substituting group is arranged in pairs or groups arbitrarily, just can obtain other type I compound of more multiple coincidence claim, and this is basic general knowledge well-known to those skilled in the art, does not enumerate at this.
Determination of activity
By the normal experiment of the following stated, illustrate that type I compound of the present invention and/or their pharmacologically acceptable salt are as the purposes of PPAR-gamma modulators in PPAR-γ relative disease.
Embodiment: PPAR-γ transactivation assay
In Human cervical cancer cell lines (Hela clone), utilize agonist (activator) activation to ppar gamma receptor to cause genetic expression, luciferase can be luminous under substrate exists.Under the existence of reference agonist, weigh the regulating effect to ppar gamma receptor by the quantitative fluorescence produced after described cell cultures.Part can replace agonist from its site.Active mensuration is undertaken by measuring the light quantitatively produced.Thisly the adjustment activity determining the compounds of this invention is made to become possibility by measuring the method for testing molecule to ppar gamma receptor avidity.Because this numerical value can fluctuate according to the Basal activity of described acceptor and expression, be therefore referred to as apparent Kd (KdApp represents with nM).
In order to determine this constant, being utilize 96-orifice plate to draw test products to a kind of cross curve of reference agonist, being mixed with 10 concentration by testing compound and adding that concentration 0 is in line, and add concentration 0 with reference to 7 concentration of agonist and form a line.This represents 88 measurement point for a kind of product and a kind of acceptor.8 remaining holes are used for repeatability contrast.In each hole, cell is contacted with certain density reference agonist with certain density test products, 5-(4-(2-(methyl (pyridine-2-base) is amino) oxyethyl group) benzyl) thiazolidine-2,4-diketone is used as the reference agonist of PPAR γ acceptor.HeLa clone used is the stable transfectant comprising plasmid ERE-β Glob-Luc-SV-Neo (indicator) and PPAR γ Gal-hPPAR.Luciferase is as transfection agents.At 100 μ l containing in phenol red DMEM medium, these cells to be seeded in 96-orifice plate with the standard of 10000 cells/well and to supplement with 10% degreasing calf serum, then plate at 37 DEG C and 7%CO 2cultivate 18 hours under condition.Add testing sample with the amount in 5 μ l/ holes and with reference to the various dilutions of part, and then same for plate at 37 DEG C and 7%CO 2cultivate 20 hours under condition.By upset removing substratum, then the mixture of 100 μ l1:1PBS/ fluoresceins is joined in each hole.After 10 minutes, fluorescence reader (MicrobetaWallac, PerkinElmer) is used to carry out counting quantitatively to plate.Utilize these cross curves can determine the AC of reference part under the various concentration of testing sample 50value (observing concentration during 50% activation).By drawing the straight line meeting Schild equation, based on these AC 50value calculates Schild and returns (" QuantitationinReceptorPharmacology ", TerryP.Kenakin, ReceptorsandChannels, 2001,7,371-385), can obtain KdApp value (representing with nM).
Affinity and the functional activity data of some representative compound of the present invention are as shown in the table.
Compound number PPAR γ receptor affinity PPAR γ Receptor Functional Activity
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; "+" represents KdApp >=3000.
The test-results data presentation affinity of the compounds of this invention to PPAR γ.

Claims (6)

1. type I compound, and/or their pharmacologically acceptable salt
Wherein, R 1be selected from trifluoromethyl, (C 1-C 10) straight or branched alkyl, (C 2-C 10) straight or branched thiazolinyl, (C 2-C 10) straight or branched alkynyl, 3-12 unit alicyclic group, phenyl, other (C 5-C 10) aryl, (C 5-C 10) heteroaryl or (C 3-C 7) heterocyclic radical, wherein said heteroaryl or heterocyclic radical have the heteroatoms of 3 O, S or N at the most, and (C 1-C 10) straight or branched alkyl, (C 2-C 10) straight or branched thiazolinyl, (C 2-C 10) straight or branched alkynyl, 3-12 unit alicyclic group, phenyl, other (C 5-C 10) aryl, (C 5-C 10) heteroaryl or (C 3-C 7) heterocyclic radical separately independent sum replaced by 3 substituting groups at the most arbitrarily, described substituting group is selected from-OR ' ,-CF 3,-OCF 3,-SR ' ,-S (O) R ' ,-SO 2r ' ,-SCF 3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH 2) 2n (R ') 2,-OCH 2n (R ') 2,-CON (R ') 2,-(CH 2) 2oR ' ,-CH 2oR ' ,-CH 2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ') 2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH 2) 2n (R ') 2or-CH 2n (R ') 2;
R 2be selected from at least 1, an at the most 3 substituent (C 1-C 6) straight or branched alkyl, 3-12 unit alicyclic group, phenyl, other (C 5-C 10) aryl, (C 5-C 10) heteroaryl or (C 3-C 7) heterocyclic radical, wherein said heteroaryl or heterocyclic radical have the heteroatoms of 3 O, S or N at the most; Described (C 1-C 6) straight or branched alkyl with at least 1, at the most 3 substituting groups be selected from-OR ' ,-CF 3,-OCF 3,-SR ' ,-S (O) R ' ,-SO 2r ' ,-SCF 3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH 2) 2n (R ') 2,-OCH 2n (R ') 2,-CON (R ') 2,-(CH 2) 2oR ' ,-CH 2oR ' ,-CH 2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ') 2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH 2) 2n (R ') 2or-CH 2n (R ') 2; Described 3-12 first alicyclic group, phenyl, other (C 5-C 10) aryl, (C 5-C 10) heteroaryl or (C 3-C 7) heterocyclic radical separately independent sum replaced by 3 substituting groups at the most arbitrarily, described substituting group is selected from-OR ' ,-CF 3,-OCF 3,-SR ' ,-S (O) R ' ,-SO 2r ' ,-SCF 3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH 2) 2n (R ') 2,-OCH 2n (R ') 2,-CON (R ') 2,-(CH 2) 2oR ' ,-CH 2oR ' ,-CH 2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ') 2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH 2) 2n (R ') 2or-CH 2n (R ') 2.
The group that R ' is independently selected from hydrogen separately or replaces arbitrarily, described group is selected from (C 1-C 8) aliphatic group, have that 0-3 to be independently selected from that the 3-8 unit of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or have that 0-5 is independently selected from nitrogen, oxygen can saturated, the fractional saturation of the 8-12 unit of sulfur heteroatom or complete undersaturated bicyclic ring system, or formed together with the atom that connects with them of the R ' of twice appearance have that 0-4 3-12 unit being independently selected from the optional replacement of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or dicyclo.
2. according to the type I compound of claim 1, wherein R 1for (C 2-C 10) straight or branched thiazolinyl, (C 2-C 10) straight or branched alkynyl, can be replaced by 3 substituting groups at the most arbitrarily by independent sum separately, described substituting group is selected from-OR ' ,-CF 3,-OCF 3,-SR ' ,-S (O) R ' ,-SO 2r ' ,-SCF 3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH 2) 2n (R ') 2,-OCH 2n (R ') 2,-CON (R ') 2,-(CH 2) 2oR ' ,-CH 2oR ' ,-CH 2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ') 2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH 2) 2n (R ') 2or-CH 2n (R ') 2;
R 2be selected from at least 1, an at the most 3 substituent (C 1-C 6) straight or branched alkyl, phenyl, described (C 1-C 6) straight or branched alkyl with at least 1, at the most 3 substituting groups be selected from the phenyl or phenoxy group that replace arbitrarily; Described phenyl is replaced by 3 substituting groups at the most, and described substituting group is selected from-OR ' ,-CF 3,-OCF 3,-SR ' ,-S (O) R ' ,-SO 2r ' ,-SCF 3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH 2) 2n (R ') 2,-OCH 2n (R ') 2,-CON (R ') 2,-(CH 2) 2oR ' ,-CH 2oR ' ,-CH 2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ') 2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH 2) 2n (R ') 2or-CH 2n (R ') 2.
The group that R ' is independently selected from hydrogen separately or replaces arbitrarily, described group is selected from (C 1-C 8) aliphatic group, have that 0-3 to be independently selected from that the 3-8 unit of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or have that 0-5 is independently selected from nitrogen, oxygen can saturated, the fractional saturation of the 8-12 unit of sulfur heteroatom or complete undersaturated bicyclic ring system, or formed together with the atom that connects with them of the R ' of twice appearance have that 0-4 3-12 unit being independently selected from the optional replacement of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or dicyclo.
3. according to the type I compound of claim 1, wherein R 1for (C 2-C 10) straight or branched alkynyl, can be replaced by 3 substituting groups at the most arbitrarily by independent sum separately, described substituting group is selected from-OR ' ,-CF 3,-OCF 3,-SR ' ,-S (O) R ' ,-SO 2r ' ,-SCF 3, halogen ,-CN ,-COOR ' ,-COR-,-O (CH 2) 2n (R ') 2,-OCH 2n (R ') 2,-CON (R ') 2,-(CH 2) 2oR ' ,-CH 2oR ' ,-CH 2cN, the phenyl replaced arbitrarily or phenoxy group ,-N (R ') 2,-NHR ' ,-C (O) OR ' ,-NR ' C (O) R ' ,-(CH 2) 2n (R ') 2or-CH 2n (R ') 2;
R 2be selected from at least 1, an at the most 3 substituent (C 1-C 6) straight or branched alkyl, phenyl, described (C 1-C 6) straight or branched alkyl with at least 1, at the most 3 substituting groups be selected from the phenyl replaced arbitrarily; Described phenyl is replaced by 3 substituting groups at the most, and described substituting group is selected from the phenyl or phenoxy group that replace arbitrarily.
The group that R ' is independently selected from hydrogen separately or replaces arbitrarily, described group is selected from (C 1-C 8) aliphatic group, have that 0-3 to be independently selected from that the 3-8 unit of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or have that 0-5 is independently selected from nitrogen, oxygen can saturated, the fractional saturation of the 8-12 unit of sulfur heteroatom or complete undersaturated bicyclic ring system, or formed together with the atom that connects with them of the R ' of twice appearance have that 0-4 3-12 unit being independently selected from the optional replacement of nitrogen, oxygen or sulfur heteroatom is saturated, fractional saturation or complete undersaturated monocycle or dicyclo.
4. at least one type I compound in claim 1-3 described in any one and/or its pharmacologically acceptable salt are preparing the purposes in medicine.
5. at least one type I compound in claim 1-3 described in any one and/or its pharmacologically acceptable salt are preparing the purposes prevented and/or treated in the medicine of following disease: inflammation (comprising rheumatoid arthritis), atherosclerosis, I type or type II diabetes, diabetic complication, obesity, hyperlipidaemia, impaired glucose tolerance, cerebral ischemia, parkinsonism, insulin resistant and osteoporosis.
6. medicine, it comprises at least one type I compound described in any one in the claim 1-3 for the treatment of significant quantity and/or its pharmacologically acceptable salt, the vehicle of physiology tolerance and carrier, and also has other additives and/or other activeconstituentss in due course.
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