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CN109879878A - A kind of deuterated Imidazopyrazine spleen tyrosine kinase (Syk) inhibitor - Google Patents

A kind of deuterated Imidazopyrazine spleen tyrosine kinase (Syk) inhibitor Download PDF

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CN109879878A
CN109879878A CN201711277743.3A CN201711277743A CN109879878A CN 109879878 A CN109879878 A CN 109879878A CN 201711277743 A CN201711277743 A CN 201711277743A CN 109879878 A CN109879878 A CN 109879878A
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compound
deuterated
pharmaceutical composition
salt
syk
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李爽
朱允涛
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Abstract

The invention discloses imidazopyrazines or its officinal salt and preparation method thereof deuterated as shown in formula (I).Such deuterated imidazopyrazines is a kind of spleen tyrosine kinase (Syk) kinase activity inhibitor, can apply to treat or prevent the associated various diseases kinase mediated by Syk.

Description

A kind of deuterated Imidazopyrazine spleen tyrosine kinase (Syk) inhibitor
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of deuterated imidazopyrazines or its is pharmaceutically acceptable The purposes of salt and preparation method thereof and its such compound as Syk kinase activity inhibitor in terms for the treatment of disease.
Background technique
The maximum family of mankind's enzyme, protein kinase include to substantially exceed 500 protein.Spleen tyrosine kinase (Syk) is A member in the Syk family of tyrosine kinase is the development of early stage B cell and mature B cell activation, signal transduction and existence Regulator.
Syk is a kind of non-receptor tyrosine kinase, is present in various kinds of cell, the various kinds of cell include B cell, Macrophage, monocyte, mast cell, eosinocyte, basicyte, neutrophil(e) cell, Dendritic Cells, T are thin Born of the same parents, natural killer cells, blood platelet and osteoclast.Syk has expression in many tumour cells, and occurs with tumour, hair It opens up related with many signals of transfer.Syk inhibitor is in addition to that can be used to treat the immunitys disease such as asthma, rheumatic arthritis Disease can also be used to the certain types of cancer that treatment includes B cell lymphoma and leukaemia.
GS-9973 is the inhibitor of Syk kinase activity, is currently in the clinical II phase and studies.Structure is as follows:
Deuterated modification is to improve a kind of very potential new drug development technology of pharmacokinetic properties.In the method, Try by the way that one or more hydrogen atom D-atoms are replaced to slow down the drug metabolism of CYP mediation or be reduced undesirable Metabolin generation.Deuterium be it is safe and stable, do not have radioactive isotope, compared with hydrogen, deuterium and carbon can be formed more Strong key.In some cases, as a result the increased bond strength formed by deuterium can may be used with the ADME property of positive influence drug It can significantly extend drug metabolism to recycle, the interaction between the generation and drug of reduction toxic metabolite, improve safety And obtain more preferably curative effect.In the prior art, deuterated GS-9973 class compound has not been reported.
Summary of the invention
The purpose of the present invention is aiming at the shortcomings in the prior art, provide a kind of deuterated imidazopyrazines or Its officinal salt.
The second aspect of the invention provides deuterated imidazopyrazines or its officinal salt described in one kind Preparation method.
The third aspect of the invention, provides a kind of pharmaceutical composition, and described pharmaceutical composition includes described in first aspect Deuterated imidazopyrazines or its officinal salt.
The fourth aspect of the present invention, the present invention provides the pharmaceutical compositions as described in the third aspect to treat or prevent By the purposes in terms of Syk kinase mediated disease.
In order to achieve the above object, the present invention provides a kind of deuterated imidazopyrazines or its is pharmaceutically acceptable Salt, shown in chemical structure such as formula (I):
It is characterized in that, wherein:
R1-R19 is independently represented each other H or D；
Preferably, deuterium is greater than natural deuterium isotopic content (0.015%) in the deuterium isotopic content of deuterium the position of substitution, compared with It is greater than 30%, even more preferably greater than 50%, even more preferably greater than 75%, even more preferably greater than 95%, even more preferably greater than 98% goodly.
It is highly preferred that the deuterated imidazopyrazines are selected from:
Wherein, the officinal salt includes but is not limited to alkali metal salt, such as sodium salt, sylvite, lithium salts；Alkaline-earth metal Salt, such as calcium salt, magnesium salts；Other metal salts, such as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt；Inorganic base salts, such as ammonium Salt；Organic alkali salt, such as t-octyl amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine alkyl ester salt, second two Amine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexyl amine salt, N, N- dibenzyl ethylenediamine salt, Chloroprocanine salt, procaine salt, diethanolamine salt, N- benzyl-phenethyl amine salt, piperazine salt, tetramethyl amine salt, three (methylol) aminomethane salt；Halogen acid salt, such as hydrofluoride, hydrochloride, hydrobromate, hydriodate；Inorganic acid salt, Such as nitrate, perchlorate, sulfate, phosphate；Rudimentary alkyl sulfonate, such as mesylate, fluoroform sulphonate, second sulphur Hydrochlorate etc.；Arylsulphonate, such as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt；Acylate, such as acetate, malate, fumaric acid Salt, succinate, citrate, tartrate, oxalates, maleate etc.；Amino-acid salt, such as glycinate, trimethyl Glycinate, arginine salt, ornithine salt, glutamate, aspartate.
To realize above-mentioned second purpose, the present invention provides a kind of deuterated imidazopyrazines or its can medicine With the preparation method of salt, comprising the following steps:
Specifically includes the following steps:
Step 1: compound A is dissolved in organic solvent, and B is added, and base reagent, under nitrogen protection, heating react To target product compound C.
Step 2: compound C and D are dissolved in organic solvent, water are added, base reagent and palladium catalyst are in nitrogen protection Under, heating reaction obtains target product compound E.
Wherein, X1 and X2 represents halogen, preferably chlorine and bromine；Y represents boric acid or borate.
Preferably, the organic solvent is n,N-Dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, toluene, N- Methyl pyrrolidone, dioxane.
Preferably, the base reagent is K2CO3, Na2CO3, Cs2CO3, K3PO4, triethylamine, n,N-diisopropylethylamine.
In the third aspect of the present invention, a kind of pharmaceutical composition is provided, described pharmaceutical composition includes first aspect The deuterated imidazopyrazines or its officinal salt；The officinal salt includes its crystal form, can pharmaceutically connect Salt, prodrug, hydrate or the solvate received；
In a preferred example, described pharmaceutical composition further includes at least one pharmaceutically acceptable carrier；
In another preferred example, the pharmaceutical composition is injection, wafer, tablet, pill, powder or granule.
In another preferred example, described pharmaceutical composition further includes at least one other anti-tumor drug, described Other anti-tumor drug.
Preferably, the anti-tumor drug includes but is not limited to: taxol, vincaleukoblastinum, vincristine, mostly because of him Match, cis-platinum, carboplatin, cyclophosphamide, Carmustine, Dacarbazine, dactinomycin D, daunorubicin, bleomycin, podophyllotoxin Class, urine fluoropyrimidine, methotrexate (MTX), cytarabine, camptothecin, tamoxifen, Raloxifene, receptor or non-receptor tyrosine Kinases.
To realize above-mentioned 4th purpose, the present invention provides one kind comprising the deuterated Imidazopyrazines compound or The composition of its officinal salt is in treatment or prevention by the purposes in terms of Syk kinase mediated disease.
Specifically, for treat and prevent by the kinase mediated disease of Syk may include it is inflammatory, allergia, itself exempt from Epidemic disease disease and cancer, for example, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS) (ARDS), ulcer Property colitis, Crohn disease, bronchitis, dermatitis, allergic rhinitis, psoriasis, chorionitis, leather fiber crops fully recover from an illness, rheumatoid joint Inflammation, idiopathic thrombocytopenic purpura (ITP), multiple sclerosis, cancer, HIV, lupus, B cell lymphoma, leukaemia, Allergic disorder, POLYCYSTIC KIDNEY DISEASE, breast cancer, melanoma, colorectal cancer, cancer of pancreas, gastric cancer, hepatocellular carcinoma, lymph are made Blood system tumor.
The invention has the advantages that having synthesized a kind of deuterated imidazopyrazines, such compound is to Syk kinases Selective inhibitory activity is preferable, is not less than even better than reference material GS-9973.Imidazopyrazines tool after deuterated There is better stability, becomes difficult the metabolism of compound, first pass effect is caused to reduce, in this case, It can change dosage and form durative action preparation, applicability can also be improved in the form of durative action preparation.Change after deuterated simultaneously Closing object also has the effects that reduce toxic side effect, increases medicine stability, heighten the effect of a treatment, extend drug biological half-life.
Specific embodiment
The following further describes the technical solution of the present invention with reference to embodiments.But this should not be interpreted as this hair The range of bright above-mentioned theme is only limitted to following embodiment.All technologies realized based on above content of the present invention belong to this hair Bright range.
Embodiment one
The synthesis of compound D1
Step 1: compound 1 (2mmol) and 2 (2mmol) are dissolved in DMF, are added potassium carbonate (4mmol), 60 degree of items 5 hours are reacted under part, during fully reacting is fallen back, solid are precipitated and filters to obtain compound 3.
Step 2: compound 3 (2mmol) is dissolved in methanol, is added raney nickel (10wt%), under hydrogen atmosphere also Original, filtering, filtrate obtain compound 4 after being spin-dried for.
Step 3: compound 4 (2mmol) and compound 5 (2mmol) are dissolved in DMF, are added DIEA (4mmol), 120 It degree lower reaction 3 hours, pours into ice water and solid is precipitated, filter to obtain compound 6.
Step 4: compound 6 (1mmol) and compound 7 (1mmol) are dissolved in dioxane, and sodium carbonate is added (2mmol), water, two triphenylphosphine palladium of dichloro (0.1eq) react 3.5 hours under the conditions of 135 degree of microwave, are poured into water, use second Acetoacetic ester extraction, saturated sodium-chloride are washed twice, and the dry back spin dry chromatography of anhydrous sodium sulfate obtains compound D1.
1H NMR(300MHz,DMSO-d6)δ13.17(s,1H),9.50(s,1H),8.66(s,1H), 8.19(s,1H), 8.09 (s, 1H), 8.03 (d, J=8.7Hz, 2H), 7.99 (d, J=0.9Hz, 1H), 7.84 (d, J=8.7Hz, 1H), 7.72 (dd, J=8.7,0.9Hz, 1H), 7.63 (d, J=0.9Hz, 1H), 7.00 (d, J=8.7Hz, 2H), 3.77 (s, 4H)
Embodiment two
The synthesis of compound D2
Step 1: compound 8 (2mmol) and 2 (2mmol) are dissolved in DMF, are added potassium carbonate (4mmol), 60 degree of items 5 hours are reacted under part, during fully reacting is fallen back, solid are precipitated and filters to obtain compound 9.
Step 2: compound 9 (2mmol) is dissolved in methanol, is added raney nickel (10wt%), under hydrogen atmosphere also Original, filtering, filtrate obtain compound 10 after being spin-dried for.
Step 3: compound 10 (2mmol) and compound 5 (2mmol) are dissolved in DMF, are added DIEA (4mmol), Reaction 3 hours, pour into ice water and solid are precipitated, filter to obtain compound 11 under 120 degree.
Step 4: compound 11 (1mmol) and compound 7 (1mmol) are dissolved in dioxane, and sodium carbonate is added (2mmol), water, two triphenylphosphine palladium of dichloro (0.1eq), 135 degree of microwave are reacted 3.5 hours down, are poured into water, with acetic acid second Ester extraction, saturated sodium-chloride are washed twice, and the dry back spin dry chromatography of anhydrous sodium sulfate obtains compound D2.
1H NMR(300MHz,DMSO-d6)δ13.17(s,1H),9.50(s,1H),8.66(s,1H), 8.19(s,1H), 8.09 (s, 1H), 8.03 (d, J=8.7Hz, 2H), 7.99 (d, J=0.9Hz, 1H), 7.84 (d, J=8.7Hz, 1H), 7.72 (dd, J=8.7,0.9Hz, 1H), 7.63 (d, J=0.9Hz, 1H), 7.00 (d, J=8.7Hz, 2H)
Embodiment three
The synthesis of compound D3
Step 1: compound 12 (2mmol) and 2 (2mmol) are dissolved in DMF, are added potassium carbonate (4mmol), 60 degree of items 5 hours are reacted under part, during fully reacting is fallen back, solid are precipitated and filters to obtain compound 13.
Step 2: compound 13 (2mmol) is dissolved in methanol, is added raney nickel (10wt%), under hydrogen atmosphere also Original, filtering, filtrate obtain compound 14 after being spin-dried for.
Step 3: compound 14 (2mmol) and compound 5 (2mmol) are dissolved in DMF, are added DIEA (4mmol), Reaction 3 hours, pour into ice water and solid are precipitated, filter to obtain compound 15 under 120 degree.
Step 4: compound 15 (1mmol) and compound 7 (1mmol) are dissolved in dioxane, and sodium carbonate is added (2mmol), water, two triphenylphosphine palladium of dichloro (0.1eq), 135 degree of microwave are reacted 3.5 hours down, are poured into water, with acetic acid second Ester extraction, saturated sodium-chloride are washed twice, and the dry back spin dry chromatography of anhydrous sodium sulfate obtains compound D3.
1H NMR(300MHz,DMSO-d6)δ13.17(s,1H),9.50(s,1H),8.66(s,1H), 8.19(s,1H), 8.09 (s, 1H), 8.03 (d, J=8.7Hz, 2H), 7.99 (d, J=0.9Hz, 1H), 7.84 (d, J=8.7Hz, 1H), 7.72 (dd, J=8.7,0.9Hz, 1H), 7.63 (d, J=0.9Hz, 1H), 7.00 (d, J=8.7Hz, 2H), 3.11 (s, 4H)
Example IV
The synthesis of compound D4
Step 1: compound 6 (1mmol) and compound 16 (1mmol) are dissolved in dioxane, and sodium carbonate is added (2mmol), water, two triphenylphosphine palladium of dichloro (0.1eq), 135 degree of microwave are reacted 3.5 hours down, are poured into water, with acetic acid second Ester extraction, saturated sodium-chloride are washed twice, and the dry back spin dry chromatography of anhydrous sodium sulfate obtains compound D4.
1H NMR(300MHz,DMSO-d6)δ13.17(s,1H),8.66(s,1H),8.19(s,1H), 8.09(s,1H), 8.03 (d, J=8.7Hz, 2H), 7.99 (d, J=0.9Hz, 1H), 7.84 (d, J=8.7Hz, 1H), 7.72 (dd, J=8.7, 0.9Hz, 1H), 7.63 (d, J=0.9Hz, 1H), 7.00 (d, J=8.7Hz, 2H), 3.77 (s, 4H)
Embodiment five
The synthesis of compound D5
Step 1: compound 17 (2mmol) and 18 (2mmol) are dissolved in DMF, are added potassium carbonate (4mmol), 60 degree Under the conditions of react 5 hours, during fully reacting is fallen back, solid is precipitated and filters to obtain compound 19.
Step 2: compound 19 (2mmol) is dissolved in methanol, is added raney nickel (10wt%), under hydrogen atmosphere also Original, filtering, filtrate obtain compound 20 after being spin-dried for.
Step 3: compound 20 (2mmol) and compound 5 (2mmol) are dissolved in DMF, are added DIEA (4mmol), Reaction 3 hours, pour into ice water and solid are precipitated, filter to obtain compound 21 under 120 degree.
Step 4: compound 21 (1mmol) and compound 7 (1mmol) are dissolved in dioxane, and sodium carbonate is added (2mmol), water, two triphenylphosphine palladium of dichloro (0.1eq), 135 degree of microwave are reacted 3.5 hours down, are poured into water, with acetic acid second Ester extraction, saturated sodium-chloride are washed twice, and the dry back spin dry chromatography of anhydrous sodium sulfate obtains compound D5.
Step 1: compound 17 (2mmol) and 18 (2mmol) are dissolved in DMF, are added potassium carbonate (4mmol), 60 degree Under the conditions of react 5 hours, during fully reacting is fallen back, solid is precipitated and filters to obtain compound 19.
Step 2: compound 19 (2mmol) is dissolved in methanol, is added raney nickel (10wt%), under hydrogen atmosphere also Original, filtering, filtrate obtain compound 20 after being spin-dried for.
Step 3: compound 20 (2mmol) and compound 5 (2mmol) are dissolved in DMF, are added DIEA (4mmol), Reaction 3 hours, pour into ice water and solid are precipitated, filter to obtain compound 21 under 120 degree.
Step 4: compound 21 (1mmol) and compound 7 (1mmol) are dissolved in dioxane, and sodium carbonate is added (2mmol), water, two triphenylphosphine palladium of dichloro (0.1eq), 135 degree of microwave are reacted 3.5 hours down, are poured into water, with acetic acid second Ester extraction, saturated sodium-chloride are washed twice, and the dry back spin dry chromatography of anhydrous sodium sulfate obtains compound D5.
1H NMR(300MHz,DMSO-d6)δ13.17(s,1H),9.50(s,1H),8.66(s,1H), 8.19(s,1H), 8.09 (s, 1H), 7.99 (d, J=0.9Hz, 1H), 7.84 (d, J=8.7Hz, 1H), 7.72 (dd, J=8.7,0.9Hz, 1H), 7.63 (d, J=0.9Hz, 1H), 3.77 (t, J=4.6Hz, 4H), 3.11 (t, J=4.6Hz, 4H)
Embodiment six
The synthesis of the mesylate of compound D1
Step 1: compound D1 (2mmol) is dissolved in isopropanol, is added methanesulfonic acid (2.2mmol), is stirred at room temperature, Be precipitated solid filter D1 dimethanesulfonate.
Embodiment seven
The external zymetology inhibitory activity of the compounds of this invention
Syk albumen is measured using Caliper mobility shifting detection technique (Caliper mobility shift assay) Kinase activity.It is diluted after compound is dissolved with DMSO with kinase buffer, 5 times of reactions that 5 μ L are added in 384 orifice plates are dense eventually The compound (10%DMSO) of degree.It is incubated at room temperature 10 minutes after 2.5 times of enzyme (Syk) solution of 10 μ L are added, adds 10 2.5 times of substrates (Peptide FAM-P22 and ATP) solution of μ L.It is incubated for 30 minutes under 28 degree, afterwards plus 25 μ L terminate liquids terminate instead It answers.Reading and converting rate data on Caliper EZ Reader II (Caliper Life Sciences).Conversion At inhibiting rate data (% inhibiting rate=(max- conversion ratio)/(max-min) * 100).Wherein max refers to the conversion of DMSO control Rate, min refer to the conversion ratio of no enzyme activity control.Using compound concentration and inhibiting rate as transverse and longitudinal coordinate, curve is drawn, XL is used Fit excel add-in version4.3.1 software matched curve simultaneously calculates IC50。
The external zymetology inhibitory activity of 1 the compounds of this invention of table
Compound number Syk zymetology inhibitory activity IC50(nm)
GS-9973 8.1
D1 7.9
D2 8.2
D3 8.1
Embodiment eight
External people's liver microsome enzyme stability experiment
(1) experimental procedure
Test-compound (will be shown in Table) under the following conditions with people's hepatomicrosome carries out total incubation, is added into incubation tube Test-compound makees liquid, and wink is from being placed in 37 DEG C of water-baths after mixing.Then the working solution that NADPH is added starts reaction.0, 5,10,20,40,60min takes out part Incubating Solution and is transferred in acetonitrile containging interior traget and terminates reaction.After albumen precipitation, 3, 700rpm is centrifuged 10min, takes supernatant.Test-compound in supernatant is analyzed by LC-MS/MS method.According to test-compound Removing half-life period in incubation system calculates in external in clearance rate.Midazolam is incubated in parallel as positive control.It incubates The condition of educating is summarized as follows table (content of incubation system organic solvent is no more than 1%), parallel to be incubated for 2 parts:
(2) data are analyzed
The ratio between analyte/internal standard peak area (Aanalyte/AIS) will be obtained by instrument, remaining percentage (% Control it) is calculated by the ratio between non-zero time point sample and Aanalyte/AIS in zero moment sample.By Ln (%Control) It maps to incubation time and carries out linear fit.Test-compound removes constant (k, min-1), remove half-life period (T1/2, min) And external inherent clearance rate (CLint, μ L min-1 mg-1Proteins it) is calculated by following equation.
K=-slope
T1/2=0.693/k
CLint=k/Cprotein
Cprotein(mg mL-1) refer to microsomal protein matter concentration in incubation system.
(2) data are analyzed
The ratio between analyte/internal standard peak area (Aanalyte/AIS) will be obtained by instrument, remaining percentage (% Control it) is calculated by the ratio between non-zero time point sample and Aanalyte/AIS in zero moment sample.By Ln (%Control) It maps to incubation time and carries out linear fit.Test-compound removes constant (k, min-1), remove half-life period (T1/2, min) And external inherent clearance rate (CLint, μ L min-1 mg-1Proteins it) is calculated by following equation.
K=-slope
T1/2=0.693/k
CLint=k/Cprotein
Cprotein (mg mL-1) refers to the microsomal protein matter concentration in incubation system.
From the result of embodiment seven can be seen that it is deuterated after imidazopyrazines D1, D2 and D3 to Syk swash Enzymatic activity has good inhibiting effect, and compound D2 is even better than reference material GS-997 to the inhibiting effect of Syk kinase activity. Embodiment eight the experimental results showed that, it is deuterated after the removing constant k of imidazopyrazines D1 and D2 and external inherent Clearance rate is respectively less than reference substance GS-9973, and the removing half-life period of compound D1 and D2 are then higher than reference substance GS-9973.These realities It tests statistics indicate that the imidazopyrazines after deuterated not only have good inhibiting effect to Syk kinase activity, but also right The stability of external people's hepatomicrosome enzyme is substantially better than GS-9973, it is deuterated after imidazopyrazines have it is wide Market prospects.
It is discussed in detail although the contents of the present invention have passed through above preferred embodiment, but it should be appreciated that above-mentioned Description be not considered as limitation of the present invention.After those skilled in the art have read above content, for the present invention A variety of modifications and substitutions all will be apparent.Therefore, protection scope of the present invention should be limited by the attached claims It is fixed.

Claims (6)

1. a kind of imidazopyrazines or its officinal salt deuterated as shown in formula (I),
It is characterized in that, wherein:
R1-R19 is independently represented each other H or D.
2. a kind of preparation method of imidazopyrazines or its officinal salt deuterated as shown in formula (I), feature exist In shown in the following route of the method (1):
Specifically includes the following steps:
Step 1: compound A is dissolved in organic solvent, and B is added, and base reagent, under nitrogen protection, heating reaction obtain target Product Compound C.
Step 2: compound C and D are dissolved in organic solvent, and water, base reagent is added, and catalyst heats under nitrogen protection Reaction obtains target product compound E.
3. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition contains miaow deuterated as described in claim 1 Azoles and pyrazine compounds or its officinal salt.
4. pharmaceutical composition according to claim 3, which is characterized in that the pharmaceutical composition includes at least one medicine Acceptable carrier on.
5. pharmaceutical composition according to claim 3 or 4, which is characterized in that described pharmaceutical composition includes at least one Other anti-tumor drug.
6. a kind of pharmaceutical composition as claimed in claim 5 is kinase mediated by spleen tyrosine kinase (Syk) in treatment or prevention Disease in terms of purposes.
CN201711277743.3A 2017-12-06 2017-12-06 A kind of deuterated Imidazopyrazine spleen tyrosine kinase (Syk) inhibitor Pending CN109879878A (en)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
CN102307474A (en) * 2008-12-08 2012-01-04 吉利德康涅狄格股份有限公司 Imidazopyrazine SYK inhibitors
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Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102307474A (en) * 2008-12-08 2012-01-04 吉利德康涅狄格股份有限公司 Imidazopyrazine SYK inhibitors
WO2017089892A1 (en) * 2015-11-25 2017-06-01 Astrazeneca Ab Deuterated isoxazole derivatives and their use as metabotropic glutamate receptor potentiators

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SRINI RAMANATHAN, ET AL.: "Pharmacokinetics, Pharmacodynamics, and Safety of Entospletinib, a Novel pSYK Inhibitor, Following Single and Multiple Oral Dosing in Healthy Volunteers", 《CLINICAL DRUG INVESTIGATION》 *
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