CN105130984B - A kind of Imidazopyridine compound and the application in PI3K inhibitor is prepared - Google Patents
A kind of Imidazopyridine compound and the application in PI3K inhibitor is prepared Download PDFInfo
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- CN105130984B CN105130984B CN201510612734.XA CN201510612734A CN105130984B CN 105130984 B CN105130984 B CN 105130984B CN 201510612734 A CN201510612734 A CN 201510612734A CN 105130984 B CN105130984 B CN 105130984B
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- WAPRRNHOYOMQNG-NSHDSACASA-N C[C@@H](c(c(-c1ccccn1)c[n]12)cc1ncc2F)Nc(ncnc1N)c1C#N Chemical compound C[C@@H](c(c(-c1ccccn1)c[n]12)cc1ncc2F)Nc(ncnc1N)c1C#N WAPRRNHOYOMQNG-NSHDSACASA-N 0.000 description 1
- DKKHBFSACTUEJU-LBPRGKRZSA-N C[C@@H](c1cc2ncc[n]2cc1-c1ccccn1)Nc(ncnc1N)c1C#N Chemical compound C[C@@H](c1cc2ncc[n]2cc1-c1ccccn1)Nc(ncnc1N)c1C#N DKKHBFSACTUEJU-LBPRGKRZSA-N 0.000 description 1
- RLKHFSNWQCZBDC-UHFFFAOYSA-N O=S(c1ccccc1)(N(F)S(c1ccccc1)(=O)=O)=O Chemical compound O=S(c1ccccc1)(N(F)S(c1ccccc1)(=O)=O)=O RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention belongs to drug world, and in particular to a kind of Imidazopyridine compound and the application in PI3K inhibitor is prepared.The Imidazopyridine compound is compound of formula I or its pharmaceutically acceptable salt, and the mixture of the solvated compoundses of described compound of formula I or its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer or its arbitrary proportion, including racemic mixture；Such compound can suppress the activity of PI3K, can apply to prepare suitable for the treatment disease related to PI3K activity, including (such as) inflammatory disease, immune base disease, cancer and Other diseases.
Description
Technical field
The invention belongs to drug world, and in particular to a kind of Imidazopyridine compound with prepare PI3K inhibitor in
Application.
Background technology
PI3K is a fat kinase families.According to its function and sequence homology, PI3K be divided into three types (I, II and
III), wherein it be the most comprehensively I types PI3K to understand.Based on signal path and the difference of regulatory protein, I types PI3K can enter again
One step is divided into IA types and IB types.IA types PI3K include PI3K α, PI3K β and PI3K δ, and they are present with heterodimer, each
Heterodimer adjusts subunit by a catalytic subunit (p110 α, p110 β or p110 δ) and one and constitutes, and its signal transduction is usual
Mediated by receptor TYR kinases (RTK).And IB type PI3K γ signals by g protein coupled receptor mediate, and by can from it is different
In the p110 γ catalytic domains composition for adjusting subunit contact of IA hypotypes.P13K is including Cycle Regulation, is breeding, survives, withering
Play an important role in the regulation of multiple cell processes such as dying and migrating, be the diseases such as cancer, diabetes and immune inflammation point
The important component part of handset reason.
PI3K gene mutation and amplification frequently occur in cancer and PTEN lack in cancer etc. all point out PI3K and
Tumorigenic substantial connection.As PI3K is located at the key signal location of multiple signal of interest Signal Transduction Pathways, it has also become anti-
The novel targets of cancer drug research and development.Main P13K isoforms in cancer are I types P13K.After IA types P13K are activated by RTK or Ras
Expedite the emergence of into phosphatidylinositols -3,4,5- triphosphoric acids
(phosphatidylinosnol-3,4,5-triphosphate, PIP3), so as to as intracellular second message,second messenger
Activation downstream targets Akt, play important regulating and controlling effect to tumor cell development, propagation, survival and growth.
PI3K γ are mainly expressed in immunity-associated cell with PI3K δ the two hypotypes, and participate in inflammatory response process,
The regulating and controlling effect of key is played in acquired immunity and inherent immunity system each.P13K δ are swashed in B cell maturation, T cell
Play an important role in living, neutrophil migration, and participate in macrophage, dendritic cell and NK T- cells etc. itself
The activation of the related leukocyte of immunological diseases.The B cell signal transduction of P13K δ Mutant Mices has specified defect, and which causes B
Antibody response after cell development obstacle and antigenic stimulus is reduced.P13K γ participate in the regulation and control of chemotactic factor signal transduction, its work
Property to t cell activation with break up it is most important.Additionally, P13K γ adjust the generation of ROS in neutrophil cell, and adjust huge
Phagocyte and the migration of neutrophil cell, its disappearance can cause macrophage and neutrophil cell raising towards inflammation site
Collection obstacle and T cell activation obstacle.Based on PI3K and the substantial connection of inflammation and autoimmune disease, PI3K has become order
The novel targets of the anti-inflammatory drug research and development that people attractes attention.
The content of the invention
In order to overcome the deficiencies in the prior art and shortcoming, the primary and foremost purpose of the present invention is to provide a kind of imidazopyridine
Compound.
Another object of the present invention is to provide the preparation method of above-mentioned Imidazopyridine compound.
It is still another object of the present invention to provide above-mentioned Imidazopyridine compound answering in PI3K inhibitor is prepared
With.
The purpose of the present invention is achieved through the following technical solutions：
A kind of Imidazopyridine compound, is compound of formula I or its pharmaceutically acceptable salt, and described Formulas I
The solvated compoundses of compound or its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer or its
The mixture of arbitrary proportion, including racemic mixture；
Wherein, Ar is substituted or unsubstituted aryl or heterocyclic base, and described substituted aryl or heterocyclic base can be appointed
Meaning ground is replaced independently selected from following substituent group by one or more：Halogen, hydroxyl and cyano group；
R1For-H, halogen, hydroxyl, cyano group or C2～C6Alkynyl；
R2For-H or C1～C6Alkyl；
Described aryl refers to the carbocyclic ring hydrocarbon containing 6～14 ring carbon atoms being made up of a ring or multiple condensed ring
Base, wherein at least one ring are aromatic rings, for example phenyl；
Described heteroaryl refers to the monocyclic aromatic hydrocarbon group with 6 annular atoms, such as pyridine radicals；
Described halogen or halo refer to fluorine, chlorine, bromine or iodine；
Described hydroxyl refers to-OH groups；
Described cyano group refers to-CN groups；
Described C2～C6Alkynyl refers to the alkynyl with 2～6 carbon atoms, and the example of alkynyl includes but is not limited to acetylene
Base, 2-propynyl and 2-butyne base；
Described C1～C6Alkyl refers to the alkyl with 1～6 carbon atom, the example of alkyl including but not limited to methyl,
Ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl and the tert-butyl group；
The described Imidazopyridine compound preferably compound with structure shown in A, B or C：
Or its pharmaceutically acceptable salt, and the described compound with structure shown in A, B or C or its pharmaceutically may be used
The mixture of the solvated compoundses of the salt of acceptance, enantiomer, diastereomer, tautomer or its arbitrary proportion,
Including racemic mixture；
The preparation method of described Imidazopyridine compound, comprises the steps of：
(1) in the presence of catalyst p-methyl benzenesulfonic acid, the bromo- iso methyl nicotinates of 2- amino -5- and 2,5- acetyl butyryl react,
Obtain the bromo- 2- of 5- (2,5- dimethyl pyrrole -1- bases)-iso methyl nicotinate；
(2) in the presence of catalyst tetrakis triphenylphosphine palladium, the bromo- 2- of 5- (2,5- dimethyl pyrazoles obtained in step (1)
Cough up -1- bases)-iso methyl nicotinate and Ar-B (OH)2Suzuki reactions are carried out, product 1 is obtained；
(3) in the basic conditions, product 1 obtained in step (2) is hydrolyzed reaction, obtains product 2；
(4) in the presence of condensing agent EDCI, obtained in step (3), product 2 and N, O- dimethyl hydroxylamine hydrochloride are carried out
Condensation reaction, is obtained product 3；
(5) product 3 obtained in step (4) and grignard reagent R2MgBr reacts, and obtains product 4；
(6) in the presence of catalyst tetraethyl titanate, product 4 and (R)-t-butyl sulfonamide obtained in step (5)
Catalyzing and condensing reaction is carried out, product 5 is obtained；
(7) in the presence of reducing agent L- 3-sec-butyl lithium borohydrides, obtained in step (6), product 5 carries out reduction reaction,
Obtain product 6；
(8) product 6 obtained in step (7) and oxammonium hydrochloride. and triethylamine react, obtain product 7；
(9) in the basic conditions, obtained in step (8), product 7 carries out cyclization with 2-Chloro-1-ethanal, obtains product 8；
(10) in acid condition, product 8 obtained in step (9) takes off terf-butylsulfinyl, obtains product 9；
(11) in the presence of DIPEA, product 9 obtained in step (10) is reacted with the chloro- pyridine -5- cyano group of 4- amino -6-,
Prepared product 10, as R1For the Imidazopyridine compound of-H；
(12) product 10 obtained in step (11) with contain halogen, hydroxyl, cyano group or C2～C6The compound of alkynyl is carried out instead
Should, obtain compound 11, as R1For halogen, hydroxyl, cyano group or C2～C6The Imidazopyridine compound of alkynyl；
The synthetic route of described Imidazopyridine compound is as follows：
Application of the described Imidazopyridine compound in PI3K inhibitor is prepared；
Application of the described Imidazopyridine compound in the medicine of disease for the treatment of PI3K mediations is prepared；
Preferably, described Imidazopyridine compound is preparing treating cancer, diabetes and/or immune inflammation medicine
In application；
Described medicine can contain one or more pharmaceutically acceptable carrier, excipient or diluent；
Described medicine includes various clinical pharmaceutical dosage form, such as tablet, injection, liposome nano granule, controlled release agent etc.；
A kind of PI3K inhibitor, comprising above-mentioned Imidazopyridine compound；
A kind of medicine of the disease for treating PI3K mediations, comprising above-mentioned Imidazopyridine compound；
The compound of the present invention has selectivity to PI3K δ, selective depressant of the compound for PI3K δ；Described
" selective depressant of PI3K δ ", it is intended that compound combine or suppress PI3K δ hypotypes affinity or efficiency compared to PI3K its
Its hypotype (i.e. PI3K α, PI3K β or PI3K γ) is larger.The compound of the present invention can be at least about 400 to the selectivity of PI3K δ
Again, at least about 800 times or at least about 1000 times.
The present invention is had the following advantages relative to prior art and effect：
Compound in the present invention can suppress the activity of PI3K, can apply to prepare be applied to and treat active with PI3K
Related disease, including (such as) inflammatory disease, immune base disease, cancer and Other diseases.
Specific embodiment
With reference to embodiment, the present invention is described in further detail, but embodiments of the present invention not limited to this.
Embodiment 1
Compound A：(S) -4- amino -6-【1- (the chloro- 6- the machine-imidazos of 3-【1,2-a】Pyridin-7-yl)-ethyl ammonia】-
Pyrimidine -5- cyano group, synthetic route are as follows：
(1) the bromo- 2- of 5- (2,5- dimethyl pyrrole -1- bases)-iso methyl nicotinate
The bromo- iso methyl nicotinates of 2- amino -5- (10 grams, 43.2 mMs) and 2,5- acetyl butyryl (5.4 grams, 47.5 mMs)
It is dissolved in 100 milliliters of toluene (Toluene), after adding p-methyl benzenesulfonic acid (TsOH, 93 milligrams, 0.43 mM), uses water knockout drum
Backflow is overnight.After being cooled to room temperature, concentration is dry, and residue is added to the water, and is stirred at room temperature 15 minutes, is filtrated to get brown solid mark
Topic product (12.05 grams).Yield：90.22%, MS (m/z)=311.0 [M+H]+312.1[M+2H]+。
(2) 2- (2,5- Dimethyl-pyrrol -1- bases) -5- phenyl-iso methyl nicotinate
Take step (1) products therefrom (12.05 grams, 38.98 mMs), (7.13 grams, 58.46 mMs) dissolvings of phenylboric acid
In 100 milliliters of dioxane (Dioxane) and 5 milliliters of water mixed solvents, four (triphenylphosphines) under nitrogen protective condition, are added
Palladium (0.45 gram, 0.39 mM) and potassium carbonate (10.77 grams, 77.96 mMs), 100 DEG C of reactions overnight, after concentration pass through post
Chromatography obtains brown solid title product (8.4 grams), yield：70.35%, MS (m/z)=307.1 [M+H]+。
(3) 2- (2,5- Dimethyl-pyrrol -1- bases) -5- phenyl-.gamma.-pyridinecarboxylic acid
Take step (2) products therefrom (8.4 grams, 27.42 mMs) and be dissolved in 40 ml methanols (MeOH) and 10 milliliters of water
In, add sodium hydroxide (3.29 grams, 82.25 mMs), room temperature reaction 4 hours.Reactant liquor dilute with water, with 3 mol/L salt
To acidity, after filtration, gained solid is title product (6.2 grams) to acid for adjusting pH.Yield：77.35%, MS (m/z)=293.1
[M+H]+。
(4) 2- (2,5- Dimethyl-pyrrol -1- bases)-N- methoxy-. N-methyl -5- phenyl-pyridin Methanamides
Take step (3) products therefrom (6.2 grams, 21.21 mMs), and N, O- dimethyl hydroxylamine hydrochloride (3.1 grams, 31.81
MM) and EDCI (4.88 grams, 25.45 mMs) be dissolved in dichloromethane (DCM), under zero degree add triethylamine (Et3N,
8.58 grams, 84.84 mMs), room temperature reaction overnight, obtains brown oil (5.8 grams) by column chromatography for separation after concentration, receives
Rate：81.57%, MS (m/z)=336.1 [M+H]+。
(5)1-【2- (2,5- Dimethyl-pyrrol -1- bases) -5- phenyl-pyridin -4- bases】Ethyl ketone
Take step (4) products therefrom (5.8 grams, 17.29 mMs) to be dissolved in 40 milliliters of dry tetrahydrofurans (THF), 0
Methyl-magnesium-bromide (MeMgBr, 12.68 milliliters, 38.04 mMs) is added at DEG C.Room temperature reaction 3 hours, saturated ammonium chloride is water-soluble
Liquid is extracted with ethyl acetate after being quenched, organic faciess saturated common salt water washing, is concentrated, column chromatography for separation after anhydrous sodium sulfate drying
Obtain brown solid title product (3.0 grams), yield：59.76%, MS (m/z)=291.1 [M+H]+。
(6) (R) -2- methyl-propans -2- sulfinic acid { 1-【2- (2,5- Dimethyl-pyrrol -1- bases) -5- phenyl-pyridins -
4- bases】Sub- second class }-amide
Take step (5) products therefrom (3.0 grams, 10.33 mMs) and (R)-t-butyl sulfonamide (1.5 grams, 12.39
MM) be dissolved in 20 milliliters of dry tetrahydrofurans (THF), add tetraethyl titanate (Ti (OEt)4).Back flow reaction overnight,
Reactant liquor is cooled to room temperature, during diluted ethyl acetate is fallen back, filters, and after concentration is dry, column chromatography for separation obtains yellow oil
Title product (3.5 grams), yield：86.10%, MS (m/z)=394.2 [M+H]+。
(7)(R)-{(S)-1-【2- (2,5- Dimethyl-pyrrol -1- bases) -5- phenyl-pyridin -4- bases】- ethyl } -2- first
Base propane -2- sulfenamides
Take step (6) products therefrom (3.5 grams, 8.89 mMs) to be dissolved in 30 milliliters of dry tetrahydrofurans (THF) ,-
78 DEG C add L- 3-sec-butyl lithium borohydrides (L-selectride, 17.78 mMs), and -78 DEG C are reacted 2 hours, saturation chlorination
Aqueous ammonium is quenched, ethyl acetate extraction, and with after saturated common salt water washing, anhydrous sodium sulfate drying passes through after concentration organic faciess
Column chromatography for separation obtains yellow oil title product (3.0 grams), yield：85.22%, MS (m/z)=396.2 [M+H]+。
(8)(R)-【(S) -1- (2- amino-5-phenyls-pyridin-4-yl)-ethyl】- 2- methylpropane -2- sulfenamides
Take (7.91 grams, the 75.8 mMs) dissolvings of step (7) products therefrom (3.0 grams, 7.58 mMs) and oxammonium hydrochloride.
In 20 milliliters of ethanol (EtOH) and 20 milliliters of water, triethylamine (Et is added3N, 7.67 grams, 75.8 mMs), back flow reaction mistake
At night, room temperature is cooled to, during diluted ethyl acetate is fallen back, is concentrated after organic phase separation, column chromatography for separation obtains yellow oily
Thing title product (1.1 grams), yield：45.7%, ee%=99.5%, MS (m/z)=318.1 [M+H]+。
(9)(R)-【(S) (6- phenyl imidazoles are simultaneously for -1-【1,2-a】Pyridin-7-yl)-ethyl】- 2- methylpropanes -2- Asias sulphur
Amide
Take step (8) products therefrom (1.1 grams, 3.46 mMs) and 2-Chloro-1-ethanal (3.4 grams, 17.33 mMs) is dissolved in
In 20 milliliters of ethanol (EtOH), sodium bicarbonate (2.32 grams, 27.68 mMs), back flow reaction is added overnight, to concentrate, column chromatography
Isolated title product (0.85 gram), yield：72.03%, MS (m/z)=342.2 [M+H]+。
(10) (S) -1- (6- phenyl imidazoles simultaneously [1,2-a] pyridin-7-yl)-ethylamine
Take step (9) products therefrom (0.85 gram, 2.49 mMs) and be dissolved in 10 milliliters of ethyl acetate (EA) and 5 milliliters of first
In alcohol (MeOH) mixed solution, 5 milliliters of 4M HCl ethyl acetate solutions, room temperature reaction 1 hour are added to be concentrated to give title Lycoperdon polymorphum Vitt
Title product (0.8 gram), yield：100%, MS (m/z)=238.1 [M+H]+。
(11) (S) -4- amino -6- [1- (6- phenyl imidazoles simultaneously [1,2-a] pyridin-7-yl)-ethyl ammonia]-pyrimidine -5- cyanogen
Base
Take step (10) products therefrom (80 milligrams, 0.29 mM) and the chloro- pyridine -5- cyano group of 4- amino -6- (67 millis
Gram, 0.43 mM) it is dissolved in n-butyl alcohol (n-BuOH), addition diisopropylethylamine (DIPEA, 112 milligrams, 0.87 mmoles
You), overnight, after reactant liquor is cooled to room temperature, column chromatography for separation obtains white solid title product (64 milligrams) for 120 DEG C of reactions, receives
Rate：62.13%, MS (m/z)=356.1 [M+H]+.。
(12) (S) -4- amino -6- [1- (3- chloro-6-phenyls-imidazo [1,2-a] pyridin-7-yl)-ethyl ammonia]-phonetic
Pyridine -5- cyano group
Take step (11) products therefrom (64 milligrams, 0.18 mM) to be dissolved in 5 milliliters of chloroforms, add N- chloros fourth two
Acid imide (NCS, 24 milligrams, 0.18 mM), overnight, after concentration, column chromatography for separation obtains white solid title product to back flow reaction
Thing (47 milligrams), yield：66.98%, MS (m/z)=390.1 [M+H]+；1H NMR(400MHz,cdcl3)δ8.03(s,1H),
7.91(s,1H),7.63(s,1H),7.55(s,1H),7.51-7.49(m,2H),7.47-7.45(m,1H),7.43-7.41(m,
1H), 5.43-5.36 (m, 2H), 5.29 (s, 2H), 1.36 (d, J=6.5,3H).
Embodiment 2
Compound B：(S) -4- amino -6- [1- (chloro- 6- pyridines -2- imidazos [1,2-a] pyridine -7- of 3-)-ethamine] is phonetic
Pyridine -5- cyano group, synthetic route are as follows：
(1) (S) -4- amino -6- [1- (- 6- pyridine -2- imidazos [1,2-a] pyridine -7-)-ethamine] pyrimidine -5- cyano group
By (S) -1- (6- pyridine -2- imidazos [1,2-a] pyridine -7-) ethylamine hydrochloride, (purchase is from Suzhou haze cloud medicine
Science and Technology Ltd.) (100 milligrams, 0.36 mM) and the chloro- 5- cyanopyrimidines of 4- amino -6- (85 milligrams, 0.55 mM)
It is added in n-butyl alcohol (n-BuOH, 5 milliliters), adds diisopropylethylamine (DIPEA, 93 milligrams, 0.72 mM), heat back
Stream reaction is overnight.After reaction terminates, room temperature is cooled to, removes solvent under reduced pressure, residue obtains white solid by column chromatography for separation
Body product (100 milligrams), yield：71.07%；MS (m/z)=357.1 [M+H]+。
(2) (S) -4- amino -6- [1- (chloro- 6- pyridines -2- imidazos [1,2-a] pyridine -7- of 3-)-ethamine] pyrimidine -5-
Cyano group
By (S) -4- amino -6- [1- (- 6- pyridine -2- imidazos [1,2-a] pyridine -7-)-ethamine] pyrimidine -5- cyano group
(100 milligrams, 0.28 mM) and N- chlorosuccinimides (NCS, 38 milligrams, 0.28 mM) are added to chloroform (5 millis
Rise) in, back flow reaction 2 hours.After reaction terminates, room temperature is cooled to, removes solvent under reduced pressure, residue passes through column chromatography for separation,
Obtain white solid product title product (75 milligrams), yield：68.53%；MS (m/z)=391.1 [M+H]+.1H NMR
(400MHz, cdcl3) δ 8.90-8.88 (m, 1H), 8.52 (d, J=8.0,1H), 8.14 (s, 1H), 8.07 (d, J=0.5,
1H),7.92-7.88(m,1H),7.73(s,1H),7.63-7.61(m,1H),7.59(s,1H),7.43-7.40(m,1H),
5.82-5.75 (m, 1H), 5.27 (s, 2H), 1.19 (d, J=7.1,3H).
Embodiment 3
Compound C：(S) -4- amino -5- [1- (the fluoro- 6- pyridines -2- bases of 3--imidazo [1,2-a] pyridin-7-yl)-second
Base ammonia]-pyrimidine -5- cyano group, synthetic route is as follows：
By (S) -4- amino -6- [1- (6- pyridines -2- bases-imidazo [1,2-a] pyridine -7-)-second ammonia]-pyrimidine -5- cyanogen
Base (30 milligrams, 0.08 mM, prepared by embodiment 2) is dissolved in 5 milliliters of chloroforms, the double benzsulfamides of addition N- fluoro (NCS,
27 milligrams, 0.08 mM), overnight, after concentration, column chromatography for separation obtains white solid product (10 milligrams) to back flow reaction, receives
Rate：31.73%, MS (m/z)=375.1 [M+H]+；1H NMR(400MHz,cdcl3) δ 8.87 (dd, J=4.9,0.9,1H),
8.50 (d, J=7.3,1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.89-7.85 (m, 1H), 7.63 (d, J=1.5,1H),
7.58 (d, J=7.8,1H), 7.44-7.38 (m, 1H), 7.21 (d, J=7.1,1H), 5.77-5.71 (m, 1H), 5.36 (s,
2H), 1.17 (d, J=7.1,3H).
The enzyme assay of embodiment 4PI3K
PI3K kinase activity biochemical analysises are carried out using the ADP-Glo technologies of Promega companies.ADP-Glo kinase assay
Test kit and PI3K beta kinases are purchased from Promega companies, and PI3K α, PI3K δ, PI3K γ kinases are purchased from Millipore companies.It is all
Experiment is completed in 384 orifice plates at room temperature.Kinase Mix is diluted with kinase buffer liquid, and kinase buffer liquid includes
50mM HEPES (pH 7.5), 3mM MgCl2, 100mM NaCl, 1mM EGTA, 0.03%CHAPS and 2mM DTT.ATP/ bottoms
Thing mixture contains 5 μM of PIP2/PS and 25 μM of ATP.Testing compound (A, B and C) 100%DMSO dissolves, and uses ddH2O
It is diluted to final concentration.2 μ L are diluted into testing compound and 4 μ L ATP/ substrate mixtures are added in each hole of 384 hole analysis plates.Instead
When should start, 4 μ L Kinase Mix are added per hole.Reaction final volume is 10 μ L, and PIP2/PS is final concentration of 2 μM, PI3K α, PI3K
β, PI3K δ and PI3K γ kinases final concentration respectively 0.2,0.6,0.25 and 0.4nM, corresponding ATP final concentrations respectively 40,
40th, 40 and 25 μM.1h is incubated after the kinases ADP-Glo reagents that 10 μ L are added per hole, 20 μ L kinase assay agent is then added per hole,
With the luminous reading of Envision microplate reader detection after incubation 30min, suppression ratio of the compound to kinases is calculated, and it is soft with XLFIT5
Part calculates IC50(50% inhibition concentration) value.The compound of measure is listed in table 1 to the suppression data of PI3K kinase activities.As a result
Show the selective depressant that listed compound is PI3K δ, its IC to PI3K δ50With to PI3K other hypotypes (i.e. PI3K α,
PI3K β or PI3K γ) to compare at least low 400 times, such compound can be active with PI3K for treatment as PI3K inhibitor
Related disease, including (such as) inflammatory disease, immune base disease, cancer and Other diseases.
1 testing compound of table is analyzed to the histamine result of PI3K kinase activities
Above-described embodiment is the present invention preferably embodiment, but embodiments of the present invention not by above-described embodiment
Limit, other any spirit without departing from the present invention and the change, modification, replacement made under principle, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.
Claims (6)
1. a kind of Imidazopyridine compound, it is characterised in that for compound of formula I or its pharmaceutically acceptable salt, Yi Jisuo
The mixture of compound of formula I, enantiomer, diastereomer, tautomer or its arbitrary proportion stated, including disappearing outward
Rotation mixture；
Wherein, Ar is phenyl or pyridine radicals；
R1For halogen；
R2For C1～C6Alkyl.
2. Imidazopyridine compound according to claim 1, it is characterised in that：
Described C1～C6Alkyl is methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or the tert-butyl group.
3. Imidazopyridine compound according to claim 1, it is characterised in that：
Described Imidazopyridine compound is the compound with structure shown in A, B or C：
Or its pharmaceutically acceptable salt, and it is the described compound with structure shown in A, B or C, enantiomer, non-right
Reflect the mixture of isomer, tautomer or its arbitrary proportion, including racemic mixture.
4. application of the Imidazopyridine compound described in any one of claims 1 to 3 in PI3K inhibitor is prepared.
5. the Imidazopyridine compound described in any one of claims 1 to 3 is preparing the medicine of the disease that treatment PI3K is mediated
Application in thing.
6. Imidazopyridine compound according to claim 5 is in the medicine of disease for the treatment of PI3K mediations is prepared
Using, it is characterised in that：
Described medicine can contain one or more pharmaceutically acceptable carrier, excipient or diluent.
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| CN101528748A (en) * | 2006-10-30 | 2009-09-09 | 诺瓦提斯公司 | Imidazopyridazines as PI3K lipid kinase inhibitors |
| WO2010007099A1 (en) * | 2008-07-15 | 2010-01-21 | Cellzome Limited | 2-aminoimidazo[1,2-b]pyridazine derivatives as pi3k inhibitors |
| WO2012116237A2 (en) * | 2011-02-23 | 2012-08-30 | Intellikine, Llc | Heterocyclic compounds and uses thereof |
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| CN101528748A (en) * | 2006-10-30 | 2009-09-09 | 诺瓦提斯公司 | Imidazopyridazines as PI3K lipid kinase inhibitors |
| WO2010007099A1 (en) * | 2008-07-15 | 2010-01-21 | Cellzome Limited | 2-aminoimidazo[1,2-b]pyridazine derivatives as pi3k inhibitors |
| WO2012116237A2 (en) * | 2011-02-23 | 2012-08-30 | Intellikine, Llc | Heterocyclic compounds and uses thereof |
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Effective date of registration: 20220901 Address after: Building 1, No. 296, Xigang Road, Tianzihu Town, Anji County, Huzhou City, Zhejiang Province 313000 (self-declaration) Patentee after: Best Beauty Biotechnology (Zhejiang) Co.,Ltd. Address before: Room B2, Floor 12, Building 3, Building 2, Dachong Business Center, at the intersection of Shennan Avenue and Tonggu Road, Yuehai Street, Nanshan District, Shenzhen, Guangdong Province, 518035 Patentee before: QIANWAN PHARMACEUTICAL TECHNOLOGY (SHENZHEN) Co.,Ltd. |