CN107602537A - Phthalimide derivative with jak kinase inhibitory activity - Google Patents
Phthalimide derivative with jak kinase inhibitory activity Download PDFInfo
- Publication number
- CN107602537A CN107602537A CN201711044111.2A CN201711044111A CN107602537A CN 107602537 A CN107602537 A CN 107602537A CN 201711044111 A CN201711044111 A CN 201711044111A CN 107602537 A CN107602537 A CN 107602537A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- unsubstituted
- substituted
- inhibitory activity
- kinase inhibitory
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides the compound or its pharmaceutically acceptable salt that one kind has following formula (I) expression；
Description
Technical field
The present invention relates to pharmaceutical technology field, more particularly to a kind of phthalyl with jak kinase inhibitory activity are sub-
Amine derivative.
Background technology
Phthalimide analog derivative is a kind of very important heterocyclic compound, MOLECULE DESIGN with synthesis in it is standby
Paid close attention to by people, phthalimide derivatives are in anti-inflammatory and antitumor etc. show good bioactivity.
All contain phthalimide or its analog in many drug molecules, such as immunodepressant Thalidomide, be clinically used for
Treat leprosy nodular erythema, Huppert's disease, Behcet disease, systemic loupus erythematosus (SLE), rheumatoid arthritis
(RA), ankylosing spondylitis (AS) and dermatomyositis (DM) etc..
It is such medicine phthalimide structure parent nucleus to be modified or transformed the new analog of synthesis or derivative
The basic methods of thing exploitation, such as lenalidomide are exactly to carry out transformation acquisition to Thalidomide structure phthalimide-based group
Immunodepressant of new generation.
The content of the invention
It is an object of the invention to disclose a kind of new derivative of the phthalimide with jak kinase inhibitory activity
Thing, to strengthen target-oriented drug, and improve and more preferable therapeutic effect is realized to diseases such as Huppert's disease and arthritis.
To achieve the above object, the invention provides one kind the compound or its is pharmaceutically acceptable that following formula (I) represents
Salt；
Wherein, in formula (I)：
A be selected from singly-bound-C (=O)-,-C (=O) O- ,-S (=O)2- ,-C (=O) NH- ,-NH- ,-S (=O) NH- ,-S
(=O)2NH-；
B is selected from C and N；
R is selected from H, CN, OH, NH2、Me、Et、CF3、CH2CF3、NHCH3、N(CH3)2Or halogen；
R1Selected from OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl, substituted C3-C6First cycloalkanes
Base, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6Miscellaneous alkyl, unsubstituted C3-C6Member
Cycloalkyl or unsubstituted C3-C6Circle heterocycles alkyl；
R2And R3Simultaneously or it is respectively selected from H, OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl,
Substituted C3-C6First cycloalkyl, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6It is miscellaneous
Alkyl, unsubstituted C3-C6First cycloalkyl or unsubstituted C3-C6Circle heterocycles alkyl.
Compared with prior art, the beneficial effects of the invention are as follows：Announcement of the present invention has jak kinase inhibitory activity
Phthalimide derivative, can effectively and selectively suppress JAK3 and block cytokine signaling and cell because
The gene expression of son induction, tests prove that, realizing, there is preferably treatment to imitate to diseases such as arthritis, Huppert's diseases
Fruit, and drug safety has also obtained certain raising.
Embodiment
With reference to each embodiment, the present invention is described in detail, but it should explanation, these embodiments are simultaneously
Non- limitation of the present invention, those of ordinary skill in the art are according in these embodiment institute work energy, method or structures
Equivalent transformation or replacement, belong within protection scope of the present invention.
Unless otherwise specified, the term " room temperature " in each embodiment of this specification is specially 23 DEG C；When term " h " is specially
Between measurement unit：Hour；Term " min " is specially time measurement unit：Minute；Term " ml " is specially volume unit：Milliliter；
Term " L " is specially volume unit：Rise；Term " mol/L " is specially concentration unit.Term " mmol " is specially the amount of material
Unit, i.e., mM；Term " mg " is unit of weight, i.e. milligram.
Present embodiment discloses the phthalimide derivative with jak kinase inhibitory activity, and it has
The compound or its pharmaceutically acceptable salt that following formula (I) represents；
Wherein, in formula (I)：
A be selected from singly-bound-C (=O)-,-C (=O) O- ,-S (=O)2- ,-C (=O) NH- ,-NH- ,-S (=O) NH- ,-S
(=O)2NH-；
B is selected from C and N；
R is selected from H, CN, OH, NH2、Me、Et、CF3、CH2CF3、NHCH3、N(CH3)2Or halogen；
R1Selected from OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl, substituted C3-C6First cycloalkanes
Base, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6Miscellaneous alkyl, unsubstituted C3-C6Member
Cycloalkyl or unsubstituted C3-C6Circle heterocycles alkyl；
R2And R3Simultaneously or it is respectively selected from H, OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl,
Substituted C3-C6First cycloalkyl, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6It is miscellaneous
Alkyl, unsubstituted C3-C6First cycloalkyl or unsubstituted C3-C6Circle heterocycles alkyl.
Meanwhile this specification also discloses a kind of compound of formula (I) expression or the synthesis of its pharmaceutically acceptable salt
Method.The synthetic method is that 10 steps react (i.e. step a~step j), the following institute of reaction equation involved by its synthetic route
Show：
Step a
By 3- amino-4-methylpyridine 21.63g starting materials 1, by 150mlTHF (anhydrous tetrahydro furan) and sodium tert-butoxide
23.07g is added in 500ml there-necked flasks, is stirred at room temperature 30 minutes, and 24.11g acetic anhydrides are added dropwise, 8h is reacted at room temperature after being added dropwise,
Frozen water 200ml is slowly added dropwise, extracts reaction of going out, dichloromethane extracts 3 times, each 200ml, merges organic layer solution, and to organic
Layer solution is washed to PH7 successively using frozen water and saturated sodium bicarbonate, and anhydrous sodium sulfate drying is overnight, is filtered, filtrate concentration, residual
Slag is separated using silica gel column chromatography, and the eluant, eluent used described in silica gel column chromatography separation is by ethyl acetate and petroleum ether according to 1:
1 ratio mixes, and obtains faint yellow solid 35.4g, produces intermediate 2.
Step b
8.5g intermediates 2 are dissolved in 100ml ethanol (absolute ethyl alcohol), 3.3g acetic acid and 5%Pd/C (1.7g, it is aqueous 45%)
Mixed solution in, and be added to hydriding reactor, be passed through hydrogen, 50 DEG C, under 5MPa, react 8h, naturally cool to room temperature, take out
Filter, filtrate concentration, obtains colourless oil liquid 7.8g, produces intermediate 3.
Step c
By 8.5g intermediates 3, acetonitrile 50ml and 9.5gDIEA (DIPEA) are added to 250ml there-necked flasks
In, under condition of ice bath, bromobenzyl 8.3ml is added dropwise, room temperature reaction 2h is warming up to after being added dropwise, is concentrated under reduced pressure, residue adds
90ml frozen water, PH to 3~4, ethyl acetate extraction are adjusted with 2M hydrochloric acid, water layer uses dichloromethane again after adjusting PH to 7~8 with concentrated ammonia liquor
Extraction 3 times, each 50ml, merge organic layer solution, organic layer solution is stayed overnight using anhydrous sodium sulfate drying, filter, filtrate
Concentration, obtains 9.8g pale yellow oils, produces intermediate 4.
Step d
9.4g intermediates 4 and 50ml are newly steamed into anhydrous THF and are added to 250ml there-necked flasks, is added dropwise and contains under condition of ice bath
The THF solution 50ml of 1.9g tetrahydrochysene lithium aluminiums, after being added dropwise, back flow reaction 3h, cool down, under condition of ice bath, slowly add water 60ml
Extraction is gone out, and is filtered, and filtrate concentration, is obtained pale yellow oil 8.1g, is produced intermediate 5.
Step e
4.5g intermediates 5 and the chloro- 7- nitros-phthalimide 8.4g of 2- (p-toluenesulfonyl) -4- are dissolved in
50ml n-butanols, 7.4gDIEA (DIPEA) is continuously added, magnetic agitation, is heated to back flow reaction 16h, TLC
Detection reaction is complete, and reaction solution pressurization concentration, residue is diluted with 100ml water, and aqueous phase ethyl acetate extracts 3 times, each 50ml, closes
And organic layer solution and stayed overnight using anhydrous sodium sulfate drying, filter, be concentrated under reduced pressure, residue uses silica gel column chromatography separation (PE:
EA=1：2) light yellow solid 6.2g, is obtained, produces intermediate 6.
Wherein, PE is petroleum ether, and EA is ethyl acetate.To washing used in the separation of residue silica gel column chromatography in step c
De- liquid is selected from the mixed solution of petroleum ether and ethyl acetate, and the mol ratio of eluent petrochina ether and ethyl acetate is 1:2.
Step f
Condition of ice bath, nitrogen are protected, and it (is specially anhydrous four that 3.1g intermediates 6 and THF120ml are added in 250ml there-necked flasks
Hydrogen furans), magnetic agitation, NaH about 500mg, insulation reaction 1h is added portionwise, iodomethane about 7.5g is then gradually added dropwise, be added dropwise
Finish, warm naturally to room temperature, reaction 1h, TLC detection reaction is complete, adds 10ml saturated ammonium chlorides and extracts reaction of going out, Ran Houjia
Enter frozen water 50ml, DCM/MeOH (3:1) extract 3 times, each 50ml, merge organic layer solution, and nothing is used to organic layer solution
Aqueous sodium persulfate is dried overnight, and is filtered, and intermediate 7 is obtained after filtrate concentration, and intermediate 7 is directly used in react in next step.
Step g
By 12.8g intermediates 7,50% ethanol 100ml, 3.5ml hydrochloric acid and 2g iron powders are added to hydriding reactor, room temperature reaction
8h, filter, filtrate concentration, obtain colourless oil liquid 10.0g, produce intermediate 8.
Step h
Under room temperature condition, the intermediate 8 obtained by step g is dissolved in the ethanol solution 200ml that concentration is 1mol/L, adds second
Sodium alkoxide 25.2g, insulated and stirred 16~20h, TLC detection reaction is complete, and reaction solution concentration, residue is diluted with 500ml water, layering,
Water layer is extracted 3 times with dichloromethane 100ml, merges organic layer, and anhydrous sodium sulfate drying is overnight, is filtered, filtrate concentration, residue
(DCM/MeOH=1/1~10/1, mol ratio in eluent) is separated using silica gel column chromatography, obtains the about 5.9mg of intermediate 9, is produced
Rate 8.2%.
Step i
By 2.5g intermediates 9,1.1g cyanoacetic acids, 1.8gHOBt and 50ml dichloromethane is added in 100ml three-necked bottles,
React at room temperature 12h.25ml water is added after completion of the reaction, is extracted 3 times, each 15ml with dichloromethane, merges organic layer solution, and
Organic layer solution is stayed overnight using anhydrous sodium sulfate drying, filtered, filtrate concentration, obtains 2.4g intermediates 10.
Step j
Intermediate 10 is split by hand-type post, then four monomer component isopropanols and the mixing that THF is formed are molten
Liquid recrystallizes to obtain white solid in 50 DEG C, obtains target product 11, target product 12, target product 13 and target product 14, optics
Purity is above 99.5%.
Jak1, Jak2, Jak3 kinases external activity are tested
Experiment material
Recombination human source Jak1, Jak2, Jak3 protease is purchased from life technology.LANCE Ultra
ULightTM-Jak1 (Tyr1023) peptide and LANCE Eu-w1024Anti-phosphotyrosine (PT66) are purchased from
PerkinElmer
Use multi-joint ELIASA Envision (PerkinElmer).
Experimental method
Test compound is subjected to 3 times of concentration gradient dilutions, final concentration of 10 μM are arrived 0.17nM totally 11 concentration, Mei Genong
Spend two multiple holes；Contents of the DMSO in detection is reacted is 1%.
Jak1 enzyme reactions
0.02nM Jak1 protein kinases, 50nM LANCE Ultra ULightTM- Jak1 (Tyr1023) peptide,
38 Μ m ATP, 50mM HEPES (PH 7.5), 10nM MgCl2,1mM EGTA, 2mM DTT, 0.01%BRIG-35. detection plate
For White Proxiplate 384-Plus plate (PerkinElmer), 90min is reacted at room temperature, reaction system is 10 μ l.
Jak2 enzyme reactions
0.02nM Jak2 protein kinases, 50nM LANCE Ultra ULightTM- Jak1 (Tyr1023) peptide,
38 Μ m ATP, 50mM HEPES (PH 7.5), 10nM MgCl2,1mM EGTA, 2mM DTT, 0.01%BRIG-35. detection plate
For White Proxiplate 384-Plus plate (PerkinElmer), 90min is reacted at room temperature, reaction system is 10 μ l.
Jak3 enzyme reactions
0.02nM Jak3 protein kinases, 50nM LANCE Ultra ULightTM- Jak1 (Tyr1023) peptide,
38 Μ m ATP, 50mM HEPES (PH 7.5), 10nM MgCl2,1mM EGTA, 2mM DTT, 0.01%BRIG-35. detection plate
For White Proxiplate 384-Plus plate (PerkinElmer), 90min is reacted at room temperature, reaction system is 10 μ l.
Reaction detection
Add 10 μ l detection reagents into reaction plate, wherein LANCE Eu-w1024 Anti-phosphotyrosine
(PT66) the final concentration of 10mM of final concentration of 2nM, EDTA, 60min, Envision instrument read plates are incubated at room temperature.
Data analysis
Reading is converted into by inhibiting rate (%)=(Min-Ratio)/(Max-Min) × 100% by following equation.4 ginsengs
Curve fit (the inXLFIT5 iDBS of Model 205) measures IC50 data, specifically see the table below.
| Compound | JAK1 | JAK2 | JAK3 |
| WXFQ-0125 | D | D | B |
| WXFQ-0126 | C | D | D |
| WXFQ-0127 | C | D | B |
| WXFQ-0128 | B | D | C |
| WXFQ-0129 | A | D | B |
| WXFQ-0130 | D | D | C |
| WXFQ-0131 | D | D | D |
| WXFQ-0132 | B | D | C |
A≤10nM, 10nM≤B≤100nM, 100nM≤C≤100nM, D ＞ 1000nM
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power
Profit requires rather than described above limits, it is intended that all in the implication and scope of the equivalency of claim by falling
Change is included in the present invention.
Moreover, it will be appreciated that although the present specification is described in terms of embodiments, not each embodiment is only wrapped
Containing an independent technical scheme, this narrating mode of specification is only that those skilled in the art should for clarity
Using specification as an entirety, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
It is appreciated that other embodiment.
Claims (1)
1. one kind has the compound or its pharmaceutically acceptable salt of following formula (I) expression；
Wherein, in formula (I)：
A be selected from singly-bound-C (=O)-,-C (=O) O- ,-S (=O)2- ,-C (=O) NH- ,-NH- ,-S (=O) NH- ,-S (=O)2NH-；
B is selected from C and N；
R is selected from H, CN, OH, NH2、Me、Et、CF3、CH2CF3、NHCH3、N(CH3)2Or halogen；
R1Selected from OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl, substituted C3-C6First cycloalkyl, quilt
Substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6Miscellaneous alkyl, unsubstituted C3-C6First cycloalkanes
Base or unsubstituted C3-C6Circle heterocycles alkyl；
R2And R3Simultaneously or it is respectively selected from H, OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl, taken
The C in generation3-C6First cycloalkyl, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6Miscellaneous alkyl,
Unsubstituted C3-C6First cycloalkyl or unsubstituted C3-C6Circle heterocycles alkyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711044111.2A CN107602537A (en) | 2017-10-31 | 2017-10-31 | Phthalimide derivative with jak kinase inhibitory activity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711044111.2A CN107602537A (en) | 2017-10-31 | 2017-10-31 | Phthalimide derivative with jak kinase inhibitory activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107602537A true CN107602537A (en) | 2018-01-19 |
Family
ID=61084520
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711044111.2A Pending CN107602537A (en) | 2017-10-31 | 2017-10-31 | Phthalimide derivative with jak kinase inhibitory activity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107602537A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107573364A (en) * | 2017-10-31 | 2018-01-12 | 无锡福祈制药有限公司 | A kind of jak kinase inhibitors |
| CN107602590A (en) * | 2017-10-31 | 2018-01-19 | 无锡福祈制药有限公司 | Endocyclic compound with Janus kinase inhibiting activities |
| CN107602591A (en) * | 2017-10-31 | 2018-01-19 | 无锡福祈制药有限公司 | A kind of JAK3 inhibitor |
| CN107652308A (en) * | 2017-10-31 | 2018-02-02 | 无锡福祈制药有限公司 | A kind of JAK3 inhibitor |
| CN107722006A (en) * | 2017-10-31 | 2018-02-23 | 无锡福祈制药有限公司 | A kind of thalidomide analogs |
| CN107721988A (en) * | 2017-10-31 | 2018-02-23 | 无锡福祈制药有限公司 | The ketone compounds of iso-indoles 1 with anti-inflammatory activity |
| CN107778321A (en) * | 2017-10-31 | 2018-03-09 | 无锡福祈制药有限公司 | A kind of tropsch imatinib analog |
| CN107805259A (en) * | 2017-10-31 | 2018-03-16 | 无锡福祈制药有限公司 | A kind of azolopyrimidines |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1696127A (en) * | 2005-04-18 | 2005-11-16 | 中国科学院长春应用化学研究所 | Analogue of thalidomide and preparation method |
-
2017
- 2017-10-31 CN CN201711044111.2A patent/CN107602537A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1696127A (en) * | 2005-04-18 | 2005-11-16 | 中国科学院长春应用化学研究所 | Analogue of thalidomide and preparation method |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107573364A (en) * | 2017-10-31 | 2018-01-12 | 无锡福祈制药有限公司 | A kind of jak kinase inhibitors |
| CN107602590A (en) * | 2017-10-31 | 2018-01-19 | 无锡福祈制药有限公司 | Endocyclic compound with Janus kinase inhibiting activities |
| CN107602591A (en) * | 2017-10-31 | 2018-01-19 | 无锡福祈制药有限公司 | A kind of JAK3 inhibitor |
| CN107652308A (en) * | 2017-10-31 | 2018-02-02 | 无锡福祈制药有限公司 | A kind of JAK3 inhibitor |
| CN107722006A (en) * | 2017-10-31 | 2018-02-23 | 无锡福祈制药有限公司 | A kind of thalidomide analogs |
| CN107721988A (en) * | 2017-10-31 | 2018-02-23 | 无锡福祈制药有限公司 | The ketone compounds of iso-indoles 1 with anti-inflammatory activity |
| CN107778321A (en) * | 2017-10-31 | 2018-03-09 | 无锡福祈制药有限公司 | A kind of tropsch imatinib analog |
| CN107805259A (en) * | 2017-10-31 | 2018-03-16 | 无锡福祈制药有限公司 | A kind of azolopyrimidines |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107602537A (en) | Phthalimide derivative with jak kinase inhibitory activity | |
| CN103848785B (en) | One class deuterated 3-cyano quinoline compound, its Pharmaceutical composition, preparation method and its usage | |
| CN107652308A (en) | A kind of JAK3 inhibitor | |
| CN103570725B (en) | Piperazidinoltriazole compound as well as preparation method and application thereof | |
| Nie et al. | Structure-based design and synthesis of novel macrocyclic pyrazolo [1, 5-a][1, 3, 5] triazine compounds as potent inhibitors of protein kinase CK2 and their anticancer activities | |
| Matsumoto et al. | Structure-based design, synthesis, and evaluation of imidazo [1, 2-b] pyridazine and imidazo [1, 2-a] pyridine derivatives as novel dual c-Met and VEGFR2 kinase inhibitors | |
| CA2647036C (en) | Tetrahydropyridothienopyrimidine compounds and methods of use thereof | |
| CN107602591A (en) | A kind of JAK3 inhibitor | |
| CN104341425B (en) | Deuterated acetylene-derivative, its pharmaceutical composition and application | |
| JP2016523922A (en) | Tricyclic pyrido-carboxamide derivatives as ROCK inhibitors | |
| CA2662031A1 (en) | Heteroaryl derivatives as protein kinase inhibitors | |
| AU2007249925A1 (en) | Substituted azaspiro derivatives | |
| CN108239083B (en) | Aromatic hydrocarbon receptor modulators | |
| CN107573364A (en) | A kind of jak kinase inhibitors | |
| Amer et al. | Synthesis, DFT calculation, pharmacological evaluation, and catalytic application in the synthesis of diverse pyrano [2, 3-c] pyrazole derivatives | |
| Mabkhot et al. | Substituted thieno [2, 3-b] thiophenes and related congeners: Synthesis, β-glucuronidase inhibition activity, crystal structure, and POM analyses | |
| CN107602590A (en) | Endocyclic compound with Janus kinase inhibiting activities | |
| Gouda et al. | Design, synthesis and pharmacological evaluation of novel pyrrolizine derivatives as potential anticancer agents | |
| CN107778321A (en) | A kind of tropsch imatinib analog | |
| ES2540962T3 (en) | Azaindole derivatives as inhibitors of Abl and Src protein kinases | |
| US10689361B2 (en) | Quinoline derivative and use thereof | |
| Bindi et al. | Thieno [3, 2-c] pyrazoles: A novel class of Aurora inhibitors with favorable antitumor activity | |
| Naidu et al. | Synthesis of some novel functionalized dihydropyrido [2, 3-d] pyrimidines via an one-pot three-component reaction catalysed by InCl3 | |
| Wei et al. | Design, synthesis and biological evaluation of novel spiro-pentacylamides as acetyl-CoA carboxylase inhibitors | |
| Deng et al. | Novel complex crystal structure of prolyl hydroxylase domain-containing protein 2 (PHD2): 2, 8-Diazaspiro [4.5] decan-1-ones as potent, orally bioavailable PHD2 inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180119 |