CN105646467B - A kind of anticancer compound Aomei replaces Buddhist nun and its synthetic method - Google Patents
A kind of anticancer compound Aomei replaces Buddhist nun and its synthetic method Download PDFInfo
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- 0 CC(C)(C)OC(N/C1=C/C=C(/C(*CC=C2)C2S2)\C2=C/C=C1)=O Chemical compound CC(C)(C)OC(N/C1=C/C=C(/C(*CC=C2)C2S2)\C2=C/C=C1)=O 0.000 description 2
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Abstract
The present invention provides a kind of anticancer compound Aomeis to replace Buddhist nun and its synthesis technology, the Aomei entitled for Buddhist nun's chemistry:(4 (4 chlorothiophene, 2 base) N (6 (2 (ethylamino-) pyridine, 4 base) hexichol [b, d] 2 base of thiophene) 1 amine of phthalazinyl), for its structural formula as shown in following formula I, synthesis technology is as follows:
Description
Technical field
The present invention relates to a kind of anticancer compound Aomeis to replace Buddhist nun and its synthetic method, belongs to medicament research and development and synthetic technology neck
Domain.
Background technology
Aurora families are a kind of protein serine/threonines, mammal have Aurora-A, Aurora-B,
Aurora-C three types.Aurora A inhibitor is the frontier of tumor cells targeted therapy.3 members of Aurora families
Function be to participate in adjusting centerbody, micro-pipe function, ensure that being precisely separated for chromosome detach with effective endochylema, they are usual
It all peaks in the G/M phases, adjusts G2/M in the cell cycle and convert, be the key factor being in progress the adjusting M phases.Wherein
Aurora-A and Aurora-B and tumour are closely related.First, Aurora-A is located in 20q13, and Aurora-B is located in
17p13, all in transposition, missing or the active chromosome segment of amplification, it is meant that they have natural unstability;Secondly,
The two chromosomal regions in breast cancer and colorectal cancer tumor tissues and breast cancer, oophoroma, colon cancer, prostate cancer,
Generally existing expands in neuroblastoma and Cervical cancer cell strain;Again, when the high expression of transfection in Ratl, NIH3T3 cell
Aurora-A can make the cell transformation at tumour cell, this Zhai transfectional cell, which is injected into visual tumors in nude mouse, to be formed.
Aurora A leads oncogenic mechanism, and to be unable to Accurate classification related for chromosome and chromatin with during mitosis, such as
Aurora A passes through p53 genes, BRCAl genes, PTEN/PDK/AKT signal paths, Aurora gene polymorphics in breast cancer
Property, the factor interactions such as estrogen participate in breast cancer tumour and are formed.
In the prior art, it by inhibiting aurora kinases to reach the existing research of compound of antitumous effect, but also deposits
It is such as poor to the inhibition of kinases, selective low in some defects.
Invention content
Goal of the invention:The present invention provides a kind of anticancer compound Aomeis to replace Buddhist nun and its synthetic method.
Technical solution:To achieve the above object, a kind of anticancer compound Aomei of present invention offer replaces Buddhist nun, chemistry entitled:(4-
(4- chlorothiophene -2- bases)-N- (6- (2- (ethylamino-) pyrimidine-4-yl) hexichol [b, d] thiophene -2- bases)-phthalazinyl -1- amine), knot
Structure formula is as shown in following formula I:
The present invention also provides the synthetic methods that the anticancer compound Aomei replaces Buddhist nun, by formula (1) compound as starting
Formula (I) compound, i.e., the described anticancer compound is finally made through following series reaction in raw material:
Preferably, compound (2) is made with carbon dioxide addition after dehydrogenation in the compound (1), reaction equation is as follows
It is shown:
Its reaction condition is:Reaction dissolvent be selected from anhydrous tetrahydro furan, anhydrous ether, anhydrous methylene chloride, dry toluene,
Anhydrous acetonitrile, the one or several kinds in anhydrous tertbutyl ether and anhydrous 2- methyltetrahydrofurans, wherein preferred solvent are anhydrous
Tetrahydrofuran;Reaction temperature is -78~25 DEG C, and wherein preferable temperature is -20~-30 DEG C;Alkali used in reaction is selected from just
Butyl lithium, tert-butyl lithium, s-butyl lithium, sodium hydride, the one or several kinds in hydrofining and lithium diisopropylamine, wherein excellent
It is tert-butyl lithium and s-butyl lithium to select alkali.
As another preferred embodiment, compound (3), reaction is made in the compound (2) after chlorination and addition substitution reaction
Formula is as follows:
Its reaction condition is:Reaction dissolvent is selected from anhydrous DMA, and anhydrous DMSO, dry toluene, anhydrous methylene chloride is anhydrous
Methyl tertiary butyl ether(MTBE), the one or several kinds in anhydrous tetrahydro furan and anhydrous 2- methyltetrahydrofurans, wherein preferred solvent are
Anhydrous tetrahydro furan;Reaction temperature is 0~80 DEG C, and wherein preferable temperature is 0-25 DEG C;Metallic catalyst used in reaction
Selected from stannous chloride, dichloride copper, the one or several kinds in dibrominated copper and cuprous bromide, wherein preferred catalyst is dichloro
Change copper;Compound (2) and the molar ratio of catalyst are 100:1~10.
As another preferred embodiment, compound (4), the following institute of reaction equation is made through a step substitution reaction in the compound (3)
Show:
Its reaction condition is:Reaction dissolvent is selected from dichloromethane, methyl tertiary butyl ether(MTBE), toluene, chloroform, tetrahydrofuran and 2-
One or several kinds in methyltetrahydrofuran, wherein preferred solvent are tetrahydrofuran and dichloromethane;Reaction temperature be 25~
120 DEG C, wherein preferable temperature is 80~90 DEG C;Alkali used in reaction is selected from triethylamine (NEt3), diisopropylethylamine
(DIPEA), n,N-Dimethylaniline, DABCO and 1, one kind in 11 carbon -7- alkene (DBU) of 8- diazabicylos [5.4.0] or
Person is several, wherein it is preferred that alkali is triethylamine;Compound (3) and the molar ratio of N,N-dimethylformamide dimethylacetal are 1:1
~1:2, wherein preferred molar ratio is 1:1.05.
As another preferred embodiment, compound is made through ring closure reaction with N- ethyl hydrochloric acid guanidine hydrochlorides in the compound (4)
(5), reaction equation is as follows:
Its reaction condition is:Reaction dissolvent is selected from anhydrous DMSO, anhydrous DMF, anhydrous DMA, anhydrous acetonitrile, anhydrous tetrahydrochysene furan
It mutters, absolute methanol, absolute ethyl alcohol, the one or several kinds in anhydrous isopropyl alcohol and anhydrous 2- methyltetrahydrofurans, wherein it is preferred that
Solvent is absolute methanol;Reaction temperature is 25~100 DEG C, and wherein preferable temperature is 45~55 DEG C;Alkali choosing used in reaction
From sodium methoxide, sodium ethoxide, sodium tert-butoxide, the one or several kinds in potassium tert-butoxide and sodium hydrogen, wherein it is preferred that alkali is sodium methoxide;Change
The molar ratio for closing object (4) and N- ethyl guanidine hydrochlorides is 1:1~1:2, wherein preferred molar ratio is 1:1.05.
As another preferred embodiment, compound (6) is made through deprotection reaction in the compound (5), reaction equation is as follows:
Its reaction condition is:Reaction dissolvent is selected from methanol, ethyl alcohol, isopropanol, tetrahydrofuran, normal propyl alcohol, n-butanol and 2-
One or several kinds in butanol, wherein preferred solvent are tetrahydrofuran;Reaction temperature is 0~40 DEG C, and wherein preferable temperature is
20~30 DEG C.
As another preferred embodiment, the compound (6) and compound (7), which are substituted reaction, is made described anticancer compound Austria
U.S. replaces Buddhist nun, reaction equation as follows:
Its reaction condition is:Reaction dissolvent is selected from absolute methanol, and absolute ethyl alcohol, anhydrous isopropyl alcohol, anhydrous DMF is anhydrous
One or several kinds in DMSO and anhydrous acetonitrile, wherein preferred solvent are anhydrous DMSO;Reaction temperature is 25~120 DEG C,
Middle preferable temperature is 90~100 DEG C;The molar ratio of compound (6) and compound (7) is 1:1~1:2, wherein preferred molar ratio is
1:1.05;Alkali used in reaction is selected from potassium carbonate, saleratus, sodium carbonate, sodium bicarbonate, lithium carbonate, LiHMDS,
NaHMDS, KHMDS, cesium carbonate, tertiary butyl sodium alkoxide, tertiary butyl potassium alcoholate, triethylamine, diisopropylethylamine, n,N-Dimethylaniline
With the one or several kinds in 1,8- diazabicylos [5.4.0], 11 carbon -7- alkene (DBU), wherein it is preferred that alkali be cesium carbonate.
The compounds of this invention Aomei is a kind of Novel ATP competitiveness small molecule aurora kinase inhibitors for Buddhist nun.In HeLa
In cell, Aomei inhibits aurora-A and-B autophosphorylations for Buddhist nun, and inhibits group on a kind of proximal end substrate Ser of aurora-B
The phosphorylation of albumen H3.Main cell responsing reaction of the tumour cell to Aomei for Buddhist nun's treatment makes cell division stop, without prolonging
Long mitosis deadtime, this eventually results in cell death.Aomei replaces Buddhist nun (about 2-4nM) under low nanomolar concentration, suppression
Make 23 tumor cell lines proliferation, including resistance to antimitotic drug cell line and other resistance to aurora kinase inhibitors (AZD1152,
MK-0457 etc.) cell line.In addition, Aomei is drug resistant to AZD1152 containing aurora-B mutant (W221L) for Buddhist nun
HCT116 variant cell lines are active.
Aomei is a kind of effective, highly selective pan-Aurora kinases inhibitor for Buddhist nun, acts on Aurora
A/B/C, IC50Respectively 4nM/2nM/1nM (similar similar marketed products are 8-10nM), acts on Aurora A and is compared to be used for
P 38 alpha, Tyk2, JNK2,20 times of Met and Tie2 high selectivities or more.
Advantageous effect:The compounds of this invention is a kind of effective, high selectivity pan-Aurora kinase inhibitors, is made
Reach anticancer effect for Aurora A to effectively inhibit the growth of tumour cell;In addition, the compounds of this invention synthesizes
Method is simple and practicable, at low cost, high income, good product quality, is suitble to big industrialized production.
Specific implementation mode
For ease of understanding, the present invention will be described in detail by specific embodiment below.It needs to particularly point out
, specific example is merely to explanation, it is clear that those skilled in the art can be according to illustrating, the present invention's herein
Various amendments are made to the present invention in range.
Embodiment 1
The preparation of compound (2)
Under nitrogen protection, 1.5kg (5mol) compound (1) is added into 50L reaction kettles under the conditions of -20 DEG C in 15L
In anhydrous tetrahydro furan, 352g (5.5mol) s-butyl lithium is slowly added dropwise.It is dry that 264g (6mol) is slowly added to after stirring half an hour
Ice, after the completion of TLC monitoring reactions, it is 6.8 that reaction solution is neutralized to pH with 5% dilute hydrochloric acid, and filtering, filter cake is washed with 5L tetrahydrofurans
It washs, merging filtrate and cleaning solution, is concentrated to give compound (3) crude product, crude product obtains compound (3) highly finished product through re-crystallizing in ethyl acetate
1.65kg (4.8mol), yield 96%.HPLC detects purity:99.2%.
1H NMR(400MHz,DMSO-d6) δ 12.62 (b, 1H), 9.88 (s, 1H), 8.79 (dd, J=14.9,3.0Hz,
1H), 8.20 (dd, J=14.9,3.0Hz, 1H), 8.07 (d, J=3.0Hz, 1H), 7.72 (dt, J=14.7,7.4Hz, 2H),
7.48 (dd, J=14.9,3.0Hz, 1H), 1.49 (s, 9H)
ESI+[M+H]+=344.
The preparation of compound (3)
Under nitrogen protection, 1.5kg (4.4mol) compound (2) and three is added into 50L reaction kettles at ambient temperature
Phenylphosphine 1.4kg (5.3mol) is slowly added to N- chlorosuccinimides (NCS) 708g (5.3mol) in the anhydrous tetrahydrochysene furans of 15L
In muttering, control temperature is less than 30 DEG C.After the completion of TLC monitoring reactions, filtering, filtrate is cooled to 0 DEG C or so, and dichloride copper is added
7.5g (0.044mol) is slowly added to methyl grignard reagent (methyl-magnesium-bromide) 536g (4.5L) (4.5mol, 1M THF solution),
It controls temperature and is not higher than 5 DEG C, after the completion of TLC monitoring reactions, it is 6.8 that reaction solution is neutralized to pH with 5% dilute hydrochloric acid, filtering, filter cake
It is washed with 5L tetrahydrofurans, merging filtrate and cleaning solution, is concentrated to give compound (3) crude product, crude product is through ethyl acetate/normal heptane
(1/3) compound (3) highly finished product 1.36kg (3.97mol), yield 90.2% are recrystallized to obtain.HPLC detects purity:95.9%.
1H NMR(400MHz,DMSO-d6) δ 9.88 (s, 1H), 8.64 (dd, J=14.8,3.1Hz, 1H), 8.07 (d, J=
3.0Hz, 1H), 7.73 (dd, J=15.0,2.3Hz, 2H), 7.62 (t, J=14.9Hz, 1H), 7.48 (dd, J=14.9,
3.0Hz,1H),2.83(s,3H),1.49(s,9H).
ESI+[M+H]+=342.
The preparation of compound (4)
1.3kg (3.8mol) compound (3) and triethylamine 395g is added into 50L reaction kettles at ambient temperature
(3.9mol) is in 15L tetrahydrofurans.It is slowly added to n,N-dimethylacetamide dimethylacetal 531g (3.99mol), is heated up
It is concentrated to give compound (4) crude product, which is directly used in the next step after the completion of TLC monitoring reactions to reflux.
ESI+[M+H]+=397.
The preparation of compound (6)
Under nitrogen protection, above-mentioned gained compound (4) crude product is added into 50L reaction kettles at ambient temperature
(3.8mol) and 1.44kg (3.99mol) N- ethyl hydrochloric acid guanidine hydrochlorides are in 20L absolute methanols.It is slowly added to sodium methoxide 430g
(8mol) is warming up to 50 DEG C, (generates compound (5) completely) after the completion of TLC monitoring reactions, be slowly added to methanol hydrochloride solution
After the completion of 2kg (20%), TLC monitoring reaction, the mashing of 10L tetrahydrofurans, filtering, filter cake 2L are poured into concentration in concentrate
Tetrahydrofuran wash, filter cake through 40 DEG C be dried in vacuo compound (6) highly finished product (hydrochloride) 1.2kg (3.4mol), yield are
89% (three step total recoverys).HPLC detects purity:99.3%.
1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.26(s,1H),7.92(s,1H),7.70(s,1H),
7.48 (s, 1H), 7.20 (d, J=20.0Hz, 2H), 7.01 (s, 1H), 6.63 (s, 1H), 4.26 (s, 2H), 3.47 (s, 2H),
1.19(s,3H).
ESI+[M+H]+=321.
Aomei replaces the preparation of Buddhist nun
1.2kg (3.4mol) compound (6) hydrochloride and 1.0kg is added into 20L reaction kettles at ambient temperature
(3.6mol) compound (7) is in the anhydrous DMSO of 6L.It is slowly added to cesium carbonate 2.4kg (7.2mol) under stirring, is warming up to 95 DEG C,
After the completion of TLC monitoring reactions, it is down to room temperature, 6L pure water is added, is filtered after stirring and crystallizing 2h, filter cake is washed with water, and 50 DEG C true
It is empty dry that Aomei replaces Buddhist nun 1.75kg (3.1mol), yield 91%.HPLC detects purity:99.8%.
1H NMR(400MHz,DMSO-d6) δ 8.82 (s, 1H), 8.55 (dd, J=15.0,3.1Hz, 1H), 8.34 (dd, J
=11.2,6.9Hz, 1H), 8.26 (d, J=15.0Hz, 1H), 8.17 (dd, J=11.0,6.9Hz, 1H), 7.92 (dd, J=
15.0,3.1Hz, 1H), 7.81 (dd, J=11.1,6.9Hz, 2H), 7.70 (t, J=14.9Hz, 1H), 7.63-7.54 (m,
3H), 7.18 (d, J=15.0Hz, 1H), 7.12 (d, J=3.1Hz, 1H), 7.06-6.96 (m, 2H), 3.47 (q, J=
12.5Hz, 2H), 1.19 (t, J=12.6Hz, 3H)
ESI+[M+H]+=566.
Embodiment 2:Inhibiting effect of the compounds of this invention to aurora kinases
Aurora A HTRF experiments
In the presence of the polypeptide PLK of the biotinylation of ATP phosphorylations, start the Aurora-A-TPX2- of Aurora-A
HTRF is tested.Experiment is added detection reagent extraction and goes out after about carrying out 120 minutes, 120 minutes.These detection reagents are swashed by diluting
It enzyme and chelates heavy metal ion with EDTA and stops reacting.It is stood overnight after adding detection reagent so that detection reagent reaches flat
Weighing apparatus.
Aurora-A-HTRF experiments have used 1uL Aomeis for 100% DMSO solution of Buddhist nun, the ATP and biology of 20uL
The acylated PLK of element, the Aurora-A-TPX2-KGDGST kinases of 20uL.Buffer conditions are:HEPES (the 4- ethoxys of 60mM
Piperazine ethanesulfonic acid) pH 7.5, the sodium-chloride water solution of 25mM, the MgCl aqueous solutions of 10mM, the DTT (dithiothreitol (DTT)) of 2mM,
0.05% BSA (bovine serum albumin(BSA)).
The experiment detection reagent extraction of 160uL is gone out, and detection reagent composition is:The Tris (trishydroxymethylaminomethane) of 50mM
The sodium-chloride water solution of pH 7.5,100mM, the EDTA solution of 3mM, 0.05% BSA solution and 0.1% soil temperature 20.
Breadboard Rubystar efficient time resolved fluorometric detector reading numerical values.Eu-anti-PLK swashs at 320nm
Hair, then radiates energy, above-mentioned energy excitation SA-APC, SA-APC radianies at 655nm at 615nm.Ratio
SA-APK (655nm)/Eu-anti-PLK (615nm) is the numerical value of substrate phosphorylation.
Measurement result shows that the compounds of this invention acts on Aurora-A, Aurora-B and Aurora-C, IC50Respectively
For 4nM, 2nM and 1nM.
Embodiment 3:High selectivity of the compounds of this invention to aurora kinases
It selects containing Aurora A, p 38 alpha, Tyk2, JNK2, Met or Tie2 to be cultivated, this hair is then added
Bright gained compound is detected.
Measurement result shows, the compounds of this invention acts on Aurora A and is compared to be used for p 38 alpha, Tyk2, JNK2, Met and
Tie2 is selectively 28 times, 35 times, 24 times, 38 times and 35 times high respectively.
Claims (8)
1. a kind of anticancer compound Aomei replaces Buddhist nun, chemistry entitled:(((2- (ethylamino-) is phonetic by 6- by 4- (4- chlorothiophene -2- bases)-N-
Pyridine -4- bases) hexichol [b, d] thiophene -2- bases)-phthalazinyl -1- amine), structural formula is as shown in following formula I:
2. anticancer compound Aomei described in claim 1 replaces the synthetic method of Buddhist nun, which is characterized in that by formula (1) compound conduct
Formula (I) compound, i.e., the described anticancer compound is finally made through following series reaction in starting material:
3. synthetic method according to claim 2, which is characterized in that the compound (1) after dehydrogenation with carbon dioxide
Compound (2) is made in addition, and reaction equation is as follows:
Its reaction condition is:Reaction dissolvent is selected from anhydrous tetrahydro furan, and anhydrous ether, anhydrous methylene chloride, dry toluene is anhydrous
Acetonitrile, the one or several kinds in anhydrous tertbutyl ether and anhydrous 2- methyltetrahydrofurans;Reaction temperature is -78~25 DEG C;Instead
Alkali used in answering is selected from n-BuLi, tert-butyl lithium, s-butyl lithium, sodium hydride, in hydrofining and lithium diisopropylamine
One or several kinds.
4. synthetic method according to claim 2, which is characterized in that the compound (2) replaces anti-through chlorination and addition
Compound (3) should be made afterwards, reaction equation is as follows:
Its reaction condition is:Reaction dissolvent is selected from anhydrous DMA, anhydrous DMSO, dry toluene, anhydrous methylene chloride, anhydrous methyl
Tertbutyl ether, the one or several kinds in anhydrous tetrahydro furan and anhydrous 2- methyltetrahydrofurans;Reaction temperature is 0~80 DEG C;
Metallic catalyst used in reaction is selected from stannous chloride, dichloride copper, one kind in dibrominated copper and cuprous bromide or
It is several;Compound (2) and the molar ratio of catalyst are 100:1~10.
5. synthetic method according to claim 2, which is characterized in that the compound (3) is made through a step substitution reaction
Compound (4), reaction equation is as follows:
Its reaction condition is:Reaction dissolvent is selected from dichloromethane, methyl tertiary butyl ether(MTBE), toluene, chloroform, tetrahydrofuran and 2- methyl
One or several kinds in tetrahydrofuran;Reaction temperature is 25~120 DEG C;Alkali used in reaction is selected from triethylamine
(NEt3), diisopropylethylamine (DIPEA), n,N-Dimethylaniline, DABCO and 1,11 carbon of 8- diazabicylos [5.4.0]-
One or several kinds in 7- alkene (DBU);Compound (3) and the molar ratio of N,N-dimethylformamide dimethylacetal are 1:1
~1:2.
6. synthetic method according to claim 2, which is characterized in that the compound (4) is with N- ethyls guanidine hydrochloride through closing
Compound (5) is made in ring reaction, and reaction equation is as follows:
Its reaction condition is:Reaction dissolvent be selected from anhydrous DMSO, anhydrous DMF, anhydrous DMA, anhydrous acetonitrile, anhydrous tetrahydro furan,
Absolute methanol, absolute ethyl alcohol, the one or several kinds in anhydrous isopropyl alcohol and anhydrous 2- methyltetrahydrofurans;Reaction temperature is 25
~100 DEG C;Alkali used in reaction is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and one kind in sodium hydrogen or
It is several;Compound (4) and the molar ratio of N- ethyl guanidine hydrochlorides are 1:1~1:2.
7. synthetic method according to claim 2, which is characterized in that the compound (5) is through deprotection reaction obtainedization
Object (6) is closed, reaction equation is as follows:
Its reaction condition is:Reaction dissolvent is selected from methanol, ethyl alcohol, isopropanol, tetrahydrofuran, normal propyl alcohol, n-butanol and 2- butanol
In one or several kinds;Reaction temperature is 0~40 DEG C.
8. synthetic method according to claim 2, which is characterized in that the compound (6) and compound (7) are substituted instead
The anticancer compound Aomei, which should be made, replaces Buddhist nun, reaction equation as follows:
Its reaction condition is:Reaction dissolvent be selected from absolute methanol, absolute ethyl alcohol, anhydrous isopropyl alcohol, anhydrous DMF, anhydrous DMSO and
One or several kinds in anhydrous acetonitrile;Reaction temperature is 25~120 DEG C;The molar ratio of compound (6) and compound (7) is 1:
1~1:2;Alkali used in reaction is selected from potassium carbonate, saleratus, sodium carbonate, sodium bicarbonate, lithium carbonate, LiHMDS,
NaHMDS, KHMDS, cesium carbonate, tertiary butyl sodium alkoxide, tertiary butyl potassium alcoholate, triethylamine, diisopropylethylamine, n,N-Dimethylaniline
With the one or several kinds in 11 carbon -7- alkene (DBU) of 1,8- diazabicylos [5.4.0].
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WO2003024935A2 (en) * | 2001-09-19 | 2003-03-27 | Pharmacia Corporation | Substituted pyrazolyl compounds for the treatment of inflammation |
WO2008124083A2 (en) * | 2007-04-05 | 2008-10-16 | Amgen Inc. | Aurora kinase modulators and method of use |
CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
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WO2003024935A2 (en) * | 2001-09-19 | 2003-03-27 | Pharmacia Corporation | Substituted pyrazolyl compounds for the treatment of inflammation |
WO2008124083A2 (en) * | 2007-04-05 | 2008-10-16 | Amgen Inc. | Aurora kinase modulators and method of use |
CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
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