CN105906621A - Ethanol compound used as FGFR inhibitor - Google Patents
Ethanol compound used as FGFR inhibitor Download PDFInfo
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- CN105906621A CN105906621A CN201610205596.8A CN201610205596A CN105906621A CN 105906621 A CN105906621 A CN 105906621A CN 201610205596 A CN201610205596 A CN 201610205596A CN 105906621 A CN105906621 A CN 105906621A
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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 discloses an ethanol compound used as a FGFR inhibitor. The invention provides the compound as shown in a formula I which is described in the specification or a pharmaceutically acceptable salt thereof, a preparation method for the compound and application of the compound as a medicine to treatment of cancers.
Description
Technical field
The invention belongs to field of pharmacology, relate to a class (E)-2-(4-(2-(5-(1-substituent group-1HPyrazolo heteroaromatic-
3-yl) vinyl)-1H-pyrazol-1-yl) alcohol compound and its production and use.It is specifically related to such as structural formula I
One compounds and preparation method thereof and the purposes in FGFR inhibitor, above-claimed cpd has significant anti-tumor activity.
Background technology
Protein kinase is the protein that a class regulates various cell functions.This is by specific amino acids on protein substrate
Phosphorylation and substrate protein conformational change is completed.The change of conformation regulates substrate active or it combines with other
The ability that gametophyte interacts.The enzymatic activity of protein kinase refers to that kinases is toward the speed adding phosphate groups on substrate.This
Can be measured by the function of amount and time that mensuration is converted into substrate.There is the phosphorus of substrate in active sites at protein kinase
Acidifying.
Tyrosine kinase is catalyzed the Asia that the terminal phosphate of ATP is converted into the protein kinase of tyrosine residue on protein substrate
Group.These kinases causing cell proliferation, break up and the propagation of growth factor signal conduction that migrates have important function.
Fibroblast growth factor (FGF) is considered as that many physiological process are (as grown and shape during angiogenic growth
State change) important medium.Presently, there are known FGF family member Sino-German more than 25.Fibroblast growth factor acceptor
(FGFR) family includes it being a member, and it is respectively swashed by the outer ligand binding domain of born of the same parents, single membrane span district and intracellular cytoplasmic protein tyrosine
Enzyme district forms.Under FGF stimulates, there is dimerization and transphosphorylation in FGFR, and cause receptor activation.The activation foot of receptor
To recover and to activate specific downstream signal gametophyte, described downstream signal gametophyte participates in various processes such as cell and grows, carefully
Regulation (Eswarakumar, V. P. etc., the Cytokine&Growth Factor Reviews of born of the same parents' metabolism and cell survival
2005,16,139-149).For tumor cell proliferation, migrate, invade and in the critical life process such as vascularization,
FGF/FGFR signal path has manifold effect effect, the most relevant with human cancer.
In kinds of tumors such as bladder, nephrocyte and prostate etc., the expression of various FGF all has increase.FGF is also to have by force
Power ground angiogenesis factor.The activated mutant of various FGF is relevant with bladder cancer and multiple myeloma, has document to prove to be subject to simultaneously
Body prostate and bladder cancer have expression (Grose, R. etc., Cytokine&Growth Factor Reviews 2005,
16,179-186；Kwabi-Addo, B. etc., Endocrime-Related Caner 2004,11,709-24). therefore, target
Treatment to the conduction of FGFR and FGF signal can directly affect neoplastic cell nuclei tumor-blood-vessel growth, and FGF signal transducting system is
Attractive therapy target.
Summary of the invention
It is an object of the invention to (E)-2-(4-(2-(5-(1-that an open class shown in following general structural formula I is brand-new
Substituent group-1HPyrazolo heteroaromatic-3-base) vinyl)-1H-pyrazol-1-yl) alcohol compound.
Another object of the present invention is to disclose above-mentioned (E)-2-(4-(2-(5-(1-substituent group-1HPyrazolo virtue is miscellaneous
Ring-3-base) vinyl)-1H-pyrazol-1-yl) preparation method of alcohol compound.
A further object of the present invention is to disclose above-mentioned (E)-2-(4-(2-(5-(1-substituent group-1HPyrazolo virtue is miscellaneous
Ring-3-base) vinyl)-1H-pyrazol-1-yl) alcohol compound use in the antitumor drug preparing FGFR inhibitor
On the way.
The invention provides compound of formula I or its most acceptable salt.
Wherein
X represents N；
Y represents N；
B-A-(R1) a representsOrOrGroup；
As optimal way, X represents atom N, and Y represents atom N；
It is preferred that, X represents the atom N of correspondence and can be uniquely present in this compounds；X represents the atom N of correspondence
Can be uniquely present in this compounds；X, Y represent the atom N of correspondence and can simultaneously appear in this compounds.
It is preferred that, in described B-A-(R1) a, selected from racemic modification 1-(3,5-dichloropyridine-4-base) ethyoxyl,
R-1-(3,5-dichloropyridine-4-base) ethyoxyl, S-1-(3,5-dichloropyridine-4-base) ethyoxyl；
Including any of the above-described described (E)-2-(4-(2-(5-(1-substituent group-1HPyrazolo heteroaromatic-3-base) vinyl)-
1H-pyrazol-1-yl) alcohol compound preparation in homoiothermic animal produce FGFR inhibitory action with anti-tumor drug
In purposes.
As optimal way, described tumor is nonsmall-cell lung cancer.
As optimal way, described tumor is gastric cancer.
As optimal way, described tumor is multiple myeloma.
Including any of the above-described described (E)-2-(4-(2-(5-(1-substituent group-1HPyrazolo heteroaromatic-3-base) ethylene
Base)-1H-pyrazol-1-yl) alcohol compound and pharmaceutically acceptable salt, the pharmaceutical composition of hydrate.
On Chinese materia medica of the present invention, acceptable salt includes: the mineral acids such as hydrochlorate, hydrobromate, sulfate, phosphate, with
And malate, fumarate, maleate, methanesulfonic acid, p-methyl benzenesulfonic acid, formates, neck phthalate, acetate, grass
The acylates such as hydrochlorate, succinate, tartaric acid, malonic acid, lactate, mandelate, and sodium salt, potassium salt, barium salt etc..
The beneficial effects of the present invention is: the present invention provides a series of compound for FGFR inhibitor with antineoplastic
Purposes, conventional method can synthesize.Through experiment, find that its antineoplastic action is obvious.
Accompanying drawing explanation
Fig. 1 is representative (E)-2-(4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-pyrazoles
And [4,3-b] pyridin-3-yl) vinyl)-1H-pyrazol-1-yl) synthetic route of ethanol；
Fig. 2 is representative (E)-2-(4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-pyrazoles
And [4,3-d] pyrimidin-3-yl) vinyl)-1H-pyrazol-1-yl) synthetic route of ethanol；
Fig. 3 is representative (E)-2-(4-(2-(5-(1-(3,5-dichloropyridine-4-base) ethyoxyl)-1H-pyrazoles
And [3,4-c] pyridin-3-yl) vinyl)-1H-pyrazol-1-yl) synthetic route of ethanol.
Detailed description of the invention
All features disclosed in this specification, or disclosed all methods or during step, except mutually exclusive spy
Levy and/or beyond step, all can combine by any way.
Embodiment 1: the present invention (E)-2-(4-(2-(5-(1-substituent group-1HPyrazolo heteroaromatic-3-base) vinyl)-
1H-pyrazol-1-yl) compound structure representative in alcohol compound is as follows:
(E)-2-(4-(2-(5-(1-substituent group-1H pyrazolo heteroaromatic-3-base that table 1 is representative) vinyl)-1H-
Pyrazol-1-yl) alcohol compoundH
| Compound | Numbering |
| 1a | |
| 2a | |
| 3a | |
| 1b | |
| 2b | |
| 3b | |
| 1c | |
| 2c | |
| 3c |
Embodiment 2: the present invention (E)-2-(4-(2-(5-(1-substituent group-1HPyrazolo heteroaromatic-3-base) vinyl)-1H-pyrrole
Azoles-1-base) synthetic route of compound representative in alcohol compound.
Embodiment 2: the synthesis of compound 2
Concentrated sulphuric acid 110mL is cooled down at 0-1 DEG C, is slowly added to raw material 1(20g), it is cooled to 0 DEG C, being slowly added to volume ratio is
The 110mL nitric acid acid of 1:1, reacts 11h, reactant liquor EA at 50 DEG C after going to 30min is stirred at room temperature and extract after-1 DEG C of stirring,
EA layer ammonia scrubbing, concentrated gas liquor layer is poured water layer into, is separated out solid 2(18g), productivity 75%.
Embodiment 3: the synthesis of compound 3
By raw material 2(5g) add in 15mL water, drip concentrated sulphuric acid 25mL at outer temperature-5 DEG C, slow under conditions of temperature 0 ~-5 DEG C in keeping
Slowly NaNO is dripped2(2.48g/8mL) aqueous solution 20mL, goes to stir at 20 DEG C 2h, and reactant liquor is poured frozen water into, had solid to separate out,
Decompression sucking filtration obtains product 3(4.7g), productivity 56.3%.
Embodiment 4: the synthesis of compound 4
By raw material 3(150mg) and PCl5(210mg) and POCl3(180mg) back flow reaction at 100 DEG C it is placed in round-bottomed flask
2h, removes POCl under reduced pressure3After add water stirring, separate out solid, decompression sucking filtration obtains thick product, and column chromatography obtains pure product 4
(100mg), productivity 63.8%.
Embodiment 5: the synthesis of compound 5
By raw material 4(500mg) it is dissolved in toluene 15mL, add racemic modification 1-(3, the 5-dichloropyridine-4-base of 450mg) second
Alcohol stirs 0.5h, then reaction overnight at 40 DEG C at room temperature, and raw material fundamental reaction is complete, and column chromatography purification obtains pure
Product 5(600mg), productivity 63.8%.
Embodiment 6: the synthesis of compound 6
By raw material 5(1.4g) and iron powder (1g) and ammonium chloride (300mg) be placed in reaction bulb, add the mixed solvent of second alcohol and water
(10 mL/3 mL), after 80 DEG C of back flow reaction 40min, substrate reactions is complete.The intermediate 6 obtained after crude product column chromatography
(1.2g), productivity 76.4%.
Embodiment 7: the synthesis of compound 7
By raw material 6(260mg) it is dissolved in the chloroform of 5mL, add potassium acetate 140mg and acetic anhydride 486mg, stir 1h under room temperature right
After go to reflux at 80 DEG C, be cooled under room temperature to be subsequently adding amyl nitrite (836mg) and react overnight.Next day is by reactant liquor
Solvent is spin-dried for obtaining yellow solid.Add potassium carbonate stirring, by product crude product column chromatography purification, obtain the product 7 of 170mg, produce
Rate 69.2%.
Embodiment 8: the synthesis of compound 8
By raw material 7(165mg) it is dissolved in 4mL DMF, add KOH(120mg under room temperature after stirring) and iodine 328mg, reaction
After 1.5h, raw material reflects completely substantially, separates out solid, extracts with EA, merge after adding appropriate saturated sodium thiosulfate in solution
Organic facies, anhydrous sodium sulfate is dried, obtains 350mg product 8, productivity 72.4% after being spin-dried for solvent.
Embodiment 9: the synthesis of compound 9
By raw material 8(345mg) it is dissolved in 40mL DCM, stir at room temperature after adding 66.6mg TsOH and 387mg THP,
After reaction 1h, raw material fundamental reaction is complete, by crude reaction column chromatography, obtains the product 9 of 270mg, productivity 80.14%.
Embodiment 10: the synthesis of compound 10
By PEG2000 and be dissolved in 0.5M sodium hydroxide in, under room temperature stir 5min, add raw material
(400mg) and palladium 8mg, then reflux at 140 DEG C 5.5h, is subsequently adding raw material 9 (187mg) and palladium 8mg, then
The 7h. reactant liquor column chromatography that refluxes at 120 DEG C obtains product 10 (500mg), productivity 77.9%.
Embodiment 11: the synthesis of compound 1a
Raw material 10 (27mg) is dissolved in the methanol of 10mL, adds the HCl of 0.1mL.Stirring 2h under room temperature, column chromatography purification obtains
To pure product 1a (17mg), productivity 87.9%.H1-NMR(DMSO):δ13.112 (s,1H), 8.565 (s,2H),
7.973 (s,1H), 7.943 (s,1H), 7.780 (s,1H), 7.348 (d,1H,J=16.8HZ), 7.003 (s,
1H), 6.969 (d,1H,J=16.8HZ), 6.474 (q,1H), 5.007 (s,1H), 4.199 (t,2H), 1.736
(d,3H,J=6.8HZ)。
Embodiment 12: the synthesis of compound 2a, 3a
The initiation material of the synthesis of the two compound is the method according to embodiment 5, by raw material 4 respectively with R-1-(3,5-bis-
Chloropyridine-4-base) ethanol or S-1-(3,5-dichloropyridine-4-base) ethanol stirs 0.5h, at room temperature then at 40 DEG C
The chemical combination 5 that reaction overnight is i.e. available corresponding, then according to the method for embodiment 6-11 continue synthesis i.e. can get compound 2a,
3a。
Compound 2a:H1-NMR(DMSO):δ13.076 (br,1H), 8.559 (s,2H), 7.965 (s,1H),
7.745 (d,1H,J=9.0HZ), 7.772 (s,1H), 7.342 (d,1H,J=16.8HZ), 6.985 (d,1H,J=
9.0HZ),6.960 (d,1H,J=16.8HZ), 6.470 (q,1H), 5.005 (m,1H), 4.090 (m,2H), 3.781
(m,2H), 1.730 (s,3H)
Compound 3a:H1-NMR(DMSO):δ8.242 (s,2H), 8.130 (d,1H,J=9.2HZ) , 8.051 (s,1H),
7.960 (s,1H), 7.847 (s,1H), 7.782 (d,1H,J=16.4HZ), 7.064 (d,1H,J=8.8HZ),
7.022 (d,1H,J=16.4HZ), 6.489 (q,1H,J=6.4HZ), 5.744(m,1H), 4.541(m,1H) , 4.291
(s,2H), 3.978~3.372(m,6H), 2.298 (m,1H) 1.947 (m,2H), 1.717 (d,3H,J=5.6HZ)
1.725~1.384(m,12H)
Embodiment 13: the present invention (E)-2-(4-(2-(5-(1-substituent group-1HPyrazolo heteroaromatic-3-base) vinyl)-1H-pyrrole
Azoles-1-base) synthetic route of compound representative in alcohol compound.
Embodiment 14: the synthesis of compound 12
By raw material 11(6.3g) be dissolved in the concentrated sulphuric acid of 30ml, at-2 DEG C slowly at a low price nitration mixture (concentrated sulphuric acid/concentrated nitric acid=
10ml/12ml), being turning lastly at 35 DEG C react 12h, raw material reaction is complete.Reactant liquor is poured in frozen water, have substantial amounts of pale yellow
The solid of color separates out, and after filtration under diminished pressure, obtains light yellow solid 12(4g), productivity 65.2%.
Embodiment 15: the synthesis of compound 13
Raw material 12 (1eq) is dissolved in the phosphorus oxychloride of 17.54ml, under room temperature, is slowly added dropwise the N of 2.92ml, N-dimethyl benzene
Amine (1eq), then drip the DMF (0.00445eq) of 8.04ul, back flow reaction 8h at 120 DEG C, after raw material reaction is complete, subtract
Pressure steams phosphorus oxychloride, adds frozen water, adds ethyl acetate extraction, merges organic layer, washs with saturated aqueous common salt, anhydrous slufuric acid
Sodium is dried, and is spin-dried for solvent, obtains yellowish-brown grease, dry method loading, and final purification obtains yellow solid 13(1g), productivity 65%.
Embodiment 16: the synthesis of compound 14
By raw material 13(860mg) and Pd/C (180mg) be dissolved in ethyl acetate (30ml), hydrogen take a breath 3 times, in Hydrogen Vapor Pressure
Room temperature reaction under 40psi, after raw material reaction is complete, filters Pd/C, filtrate is spin-dried for, obtains yellow solid 14(500mg), productivity
65.1%。
Embodiment 17: the synthesis of compound 15
By raw material 14(2.63g), add the Pd/C of 263mg, add triethylamine 3.5ml, dehydrated alcohol 88ml, water 4ml, in
The Hydrogen Vapor Pressure reaction 8h of 20psi, the completely rear sucking filtration of raw material reaction, it is spin-dried for solvent, obtains yellow solid, dry method loading, purification
After obtain white solid 15(1.22g) productivity 74.4%.
Embodiment 18: the synthesis of compound 16
By raw material 15(83mg, 1eq) it is dissolved in the chloroform of 2ml, add potassium acetate and the acetic anhydride of 45.4mg (1.2eq)
(157.5mg, 4eq), is placed at 80 DEG C backflow 1h after stirring 1h, TLC monitoring raw material reaction is complete under room temperature, is cooled to room temperature
Rear addition amyl nitrite 311.6ul (6eq), reaction monitoring intermediate reaction the most afterwards is complete, is spin-dried for solvent and obtains yellow
Solid 16(100mg), productivity 73.7%.
Embodiment 19: the synthesis of compound 17
By raw material 16 (100mg), it is dissolved in the methanol of 5ml, adds the potassium carbonate of 333mg, under room temperature, stir 1h, raw material reaction
It is spin-dried for solvent, dry method loading purification after Wan Quan, finally obtains white solid 17 (50mg), productivity 75.1%.
Embodiment 20: the synthesis of compound 18
The racemization alcohol (3.2eq) of 905ul is added in the anhydrous THF of 30ml, adds 327mg(3.0eq) 60%NaH, activation
After 30min, adding the raw material 17 of 400mg, after backflow 12h, raw material reaction is complete, adds water and ethyl acetate extraction, merges organic
Layer, saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, is spin-dried for solvent, obtains brown oil 18 (420mg), productivity
57.3%。
Embodiment 21: the synthesis of compound 19
By raw material 18(1eq) it is dissolved in DMF, add the iodine of KOH and 1.8eq of 3eq, after 1h is stirred at room temperature, raw material reaction is complete
Entirely, being poured into by reactant liquor in saturated sodium thiosulfate, have white solid to separate out, ethyl acetate extracts, and merges organic layer, saturated food
Saline washs, and anhydrous sodium sulfate is dried, and is spin-dried for solvent and obtains yellow oil, dry method loading, obtains white solid 19 after purification.
Embodiment 22: the synthesis of compound 20
By raw material 19(1g, 1eq), p-methyl benzenesulfonic acid (0.4eq) is dissolved in DCM, adds 2-Pentamethylene oxide. (5eq) room temperature afterwards and stirs
Mix 2h, raw material reaction completely after be directly spin-dried for solvent, dry method loading purification finally obtains white solid 20 (0.8g), productivity
67.2%。
Embodiment 23: the synthesis of compound 21
By PEG2000 and be dissolved in 0.5M sodium hydroxide in, under room temperature stir 5min, add raw material
And palladium, then reflux at 140 DEG C 5.5h, is subsequently adding raw material 20 and palladium, and the 7h. that then refluxes at 120 DEG C is anti-
Liquid column chromatography is answered to obtain product 21.
Embodiment 24: the synthesis of compound 1b
Raw material 21 is dissolved in methanol, adds the reaction of concentrated hydrochloric acid stirred overnight at room temperature, after raw material reaction is complete, be spin-dried for solvent,
Ethyl acetate is obtained by extraction yellow solid, and column chromatography purification obtains compound 1b.H1-NMR(DMSO):δ13.322 (s,1H),
8.525 (s,2H), 7.924 (s,1H), 7.913 (s,1H), 7.680 (s,1H), 7.338 (d,1H,J=
16.8HZ), 7.023 (s,1H), 6.989 (d,1H,J=16.8HZ), 6.444 (q,1H), 5.677 (s,1H),
4.179 (t,2H), 1.746 (d,3H,J=6.8HZ)。
Embodiment 25: the synthesis of compound 2b, 3b
The initiation material of the synthesis of the two compound is the method according to embodiment 18, by raw material 17 respectively with R-1-(3,5-
Dichloropyridine-4-base) ethanol or S-1-(3,5-dichloropyridine-4-base) ethanol stirs 0.5h, at room temperature then in 40 DEG C
The i.e. available corresponding chemical combination 18 of lower reaction overnight, the method continuation synthesis then according to embodiment 18-24 i.e. can get chemical combination
Thing 2b, 3b.
Compound 2b:H1-NMR(DMSO):δ13.176 (br,1H), 8.529 (s,2H), 7.995 (s,1H),
7.776 (d,1H,J=9.0HZ), 7.756 (s,1H), 7.876 (d,1H,J=16.8HZ), 6.786 (d,1H,J=
9.0HZ),6.335 (d,1H,J=16.8HZ), 6.244 (q,1H), 5.545 (m,1H), 4.456 (m,2H), 3.781
(m,2H), 1.787 (s,3H)。
Compound 3b:H1-NMR(DMSO):δ8.453 (s,2H), 8.134 (d,1H,J=9.2HZ) , 8.343 (s,
1H), 7.896 (s,1H), 7.846 (s,1H), 7.432 (d,1H,J=16.4HZ), 7.045 (d,1H,J=8.8HZ),
7.031 (d,1H,J=16.4HZ), 6.453(q,1H,J=6.4HZ), 5.876(m,1H), 4.454(m,1H) , 4.564
(s,2H), 3.978~3.334(m,6H), 2.676 (m,1H) 1.943 (m,2H), 1.743 (d,3H,J=5.6HZ)
1.725~1.345(m,12H)。
Embodiment 26: the present invention (E)-2-(4-(2-(5-(1-substituent group-1HPyrazolo heteroaromatic-3-base) vinyl)-
1H-pyrazol-1-yl) synthetic route of compound representative in alcohol compound.
Embodiment 27: the synthesis of compound 23
Measure the dense H2SO4 of 150ml to add in 500ml round-bottomed flask, be placed in pre-cooling in-5 DEG C of low temperature cold baths, after 20min in batches
Add 50g raw material 22(2-amino-4 picoline), solution is gradually become yellow, viscous solution from colorless cleared solution, whole
In process keeps, temperature is less than 0 DEG C.The preparation dense H of 34ml2SO4HNO dense with 34ml3Nitration mixture pre-cooling in-5 DEG C, dripped by constant voltage
Liquid funnel is slowly added in reactant liquor, keeps temperature less than 0 DEG C, drips and finish, reaction be placed in after 20min is stirred at room temperature, turns
Moving to be slowly heated in oil bath pan and be warming up to 50 DEG C, produce a large amount of bubble, reactant liquor color gradually deepens to become brown.Treat no longer
After producing bubble, 50 DEG C are kept to continue reaction.TLC monitors reaction, and after 24h, reaction is completely, stopped reaction.Reactant liquor is slowly added
Enter in the beaker equipped with frozen water stirring, it is to avoid heat release is too fast, with NaOH solution regulation pH value to alkalescence (about 8), separate out a large amount of
Mud yellow solid, filters and washes with water solid the most neutral, go in culture dish, is dried, then at 50 DEG C of decompressions under infrared lamp
It is dried 3h, obtains yellow solid crude product 41.61g.With EA recrystallization, after heat filtering removes insoluble impurity, rotation is evaporated off a part
Again with EA recrystallization after solvent, in room temperature crystallize, after 24h, it is filtrated to get orange solids 18.54g, productivity 37.08%.
Embodiment 28: the synthesis of compound 24
Weigh raw material 2-amino-4-methyl-5-nitro pyridine 23(10g) in 250ml round-bottomed flask, add the dense H of 70ml2SO4
Stirring and dissolving, after raw material is completely dissolved, is placed in reaction bulb in-5 DEG C of low temperature cold baths, constant voltage low liquid funnel is slowly added dropwise
The NaNO being pre-configured with2(6.76g) solution, produces a large amount of bubble, it is to avoid temperature raises too fast, keeps Wen Buchao in whole process
Crossing 0 DEG C, along with reaction is carried out, gradually separate out solid in reaction bulb, drip and finish, after stirring 10min, to become orange clarification molten for reactant liquor
Liquid, 0 DEG C is continued reaction.
After TLC monitoring display 3h, reaction is completely, stopped reaction.Reactant liquor is poured in the beaker equipped with about 300ml water, analysis
Go out a large amount of yellow solid, after room temperature crystallize 3h, solid be collected by filtration and be dried under infrared lamp, obtaining yellow solid 6.72g, produce
Rate 67.2%.
Embodiment 29: the synthesis of compound 25
Weigh raw material 2-hydroxy-4-methyl-5-nitropyridine 24(3.21g) and the different hydroxyethyl of the chloro-4-of raceme 3,5-bis-
Pyridine 4g adds in 250ml round-bottomed flask, adds 150mlTHF stirring and makes solid dissolve, drip 8.26mlDIAD in reaction bulb
After, reactant liquor is become brown color turbid solution from light yellow settled solution, and after adding 10.93gPh3P, reactant liquor first becomes clarification,
Heat release, after gradually become khaki turbid solution, be stirred at room temperature reaction overnight.(18:00)
9:00, TLC display next day raw material reaction is complete, stopped reaction.After rotation is evaporated off solvent, dry method loading carries out column chromatography,
First cross out the multiple little polar impurity before product with PE/EA=300:1, then cross out product with PE/EA=100/1, finally strengthen
Whole for product mistakes are gone out by eluant polarity to PE/EA=50/1, are concentrated to give white solid 3.19g, productivity 46.83%.
Embodiment 30: the synthesis of compound 26
Weigh raw material 25(2.6g) add in 100ml round-bottomed flask, stir after adding EtOH/H2O 30ml/9ml in reaction bulb
The most completely by material dissolution, add 1.78g Fe powder and 0.42g NH4It is transferred to reaction bulb after Cl in the oil bath pan of 80 DEG C return
Stream reaction, reactant liquor is gradually become brown from faint yellow.TLC monitoring reaction is carried out, and shows that raw material reaction is complete after 1h, stops anti-
Should.With filtered on buchner funnel, with a small amount of H2O and EA washs filter cake, and merging filtrate EA extracts solution three times, merges organic layer also
Return with Brine and wash, then be dried a period of time with anhydrous sodium sulfate, concentrate solution and obtain yellow solid 2.28g.Do not cross post, directly
Cast single step reaction.
Embodiment 31: the synthesis of compound 27
Take raw material 26(2.28g) in 50ml round-bottomed flask, it is dissolved in 15mlCHCl3Solution, adds 0.91g AcOK in reaction bulb
And 2.9mlAc2After O, reaction is stirred at room temperature.
After 1h, TLC display raw material reaction is complete, after being slowly added dropwise 4.13ml (i-pen) ONO in reaction bulb, and will reaction
It is transferred in 80 DEG C of oil bath pans back flow reaction overnight.(18:30)
Completely, reactant liquor is become brown settled solution from the yellow started, and rotation is evaporated off solvent in 9:00, TLC display reaction next day
After, add 13ml MeOH and 5gK2CO3After, reaction is stirred at room temperature.15:00, TLC display reaction is complete, and stopped reaction adds
After suitable quantity of water, with EA extraction solution three times, merge organic layer returning with Brine and wash, then be dried a period of time with anhydrous sodium sulfate,
After concentrating solution, dry method loading carries out column chromatography, and eluant is crossed post by PE/EA=8/1 → PE/EA=5/1, is concentrated to give brown solid
Body 1.46g, productivity 61.76%.
Embodiment 32: the synthesis of compound 28
Weigh raw material 27(1.45g) add in 25ml round-bottomed flask, in reaction bulb, add 12ml DMF, stirring reactant liquor is palm fibre
Color settled solution, adds 0.79gKOH and 2.14g I2After, reactant liquor gradually blackening, reaction is stirred at room temperature.
TLC monitoring reaction is carried out, and after 1h, raw material reaction is complete, stopped reaction.Reactant liquor is poured into the saturated Na of 50ml2S2O3
Solution stirs after 30min, with EA extraction solution three times, merges organic layer returning with Brine and wash, then be dried with anhydrous sodium sulfate
A period of time, after concentration, obtain yellow solid 2.15g.Dry method loading carries out column chromatography, and eluant is by PE/EA=8/1 → PE/EA=
5/1 → PE/EA=2/1 crosses post, is concentrated to give faint yellow solid 1.73g, productivity 84.68%.
Embodiment 33: the synthesis of compound 29
Weigh raw material 28(1g) add in 50ml round-bottomed flask, in reaction bulb, add 30ml DCM solid is dissolved, add
Being slowly added dropwise 1.00ml 3,4-dihydropyran after 0.16g TsOH, the color of reactant liquor gradually deepens, and room temperature continues reaction.
TCL monitors reaction, and 2.5h afterproduct point concentration is relatively big, and now raw material point unreacted are complete, if but continuing anti-
Should, product point will be thin out and have the new point of a little polarity and produce and constantly thicken, therefore stopped reaction.Dry method loading post layer
Analysis, eluant is crossed post by PE/EA=10/1 → PE/EA=8/1, is concentrated to give yellow oil 0.62g, productivity 51.95%.
Embodiment 34: the synthesis of compound 30
Weigh 520mg raw material 29 and 230mgAdd in 50ml two-neck bottle, add in reaction bulb
25ml heavily steams anhydrous DMF solution stirring and is dissolved by solid, adds 227 μ l DIEA, in water pump by the sky in reaction bulb after 20min
Gas is changed to N2, 30min is stirred at room temperature, adds 23mg Pd (OAc)2And 37mg P (O-tol)3After again will reaction bulb change to
N2, reaction bulb is placed in the oil bath pan of 100 DEG C and reacts.(17:30) temperature of oil bath pan is adjusted to 80 DEG C of reactions by 21:00
Overnight.
9:00, TLC display next day raw material reaction is complete, stopped reaction.After rotation is evaporated off solvent, dry method loading carries out post layer
Analysis, eluant is by PE/EA=50/1 → PE/EA=30/1 → PE/EA=20/1 → PE/EA=10/1 → PE/EA=5/1 → PE/EA=
2/1 → PE/EA=1/1 crosses post, is concentrated to give brown oil 220mg, productivity 35.82%.
Embodiment 35: the synthesis of compound 1c
Take raw material 30 (220mg) and add in 50ml round-bottomed flask, in reaction bulb, add 15mlMeOH dissolved, under room temperature
After being slowly added dropwise the dense HCl of 1.5ml, reaction is stirred at room temperature.
TCL monitors reaction, and after 8h, raw material reaction is complete, stopped reaction.Rotation adds suitable quantity of water after solvent is evaporated off, and extracts with EA
Take solution three times, merge organic layer returning with Brine and wash, then be dried a period of time with anhydrous sodium sulfate, concentrate solution and obtain Huang
Color solid 210mg, dry method loading carries out column chromatography, and eluant is crossed post by DCM/MeOH=50/1 → DCM/MeOH=30/1, concentrates
Obtain yellow solid 90mg, productivity 56.39%.H1-NMR(DMSO):δ13.122(s,1H), 8.433 (s,2H), 7.866
(s,1H), 7.813 (s,1H), 7.660 (s,1H), 7.367 (d,1H,J=16.8HZ), 7.127 (s,1H),
6.953 (d,1H,J=16.8HZ), 6.443(q,1H), 5.662 (s,1H), 4.134 (t,2H), 1.734 (d,3H,J
=6.8HZ)。
Embodiment 36: the synthesis of compound 2c, 3c
The initiation material of the synthesis of the two compound is the method according to embodiment 29, by raw material 24 respectively with R-1-(3,5-
Dichloropyridine-4-base) ethanol or S-1-(3,5-dichloropyridine-4-base) ethanol stirs 0.5h, at room temperature then in 40 DEG C
The i.e. available corresponding chemical combination 25 of lower reaction overnight, the method continuation synthesis then according to embodiment 29-35 i.e. can get chemical combination
Thing 2c, 3c.
Compound 2c:H1-NMR(DMSO):δ13.123 (br,1H), 8.329 (s,2H), 7.934 (s,1H),
7.234 (d,1H,J=9.0HZ), 7.256 (s,1H), 7.216 (d,1H,J=16.8HZ), 6.586 (d,1H,J=
9.0HZ),6.345 (d,1H,J=16.8HZ), 6.243 (q,1H), 5.543(m,1H), 4.478 (m,2H), 3.745
(m,2H), 1.787 (s,3H)。
Compound 3c:H1-NMR(DMSO):δ8.432 (s,2H), 8.189(d,1H,J=9.2HZ) , 8.143(s,
1H), 7.832 (s,1H), 7.823 (s,1H), 7.497 (d,1H,J=16.4HZ), 7.098 (d,1H,J=8.8HZ),
7.032 (d,1H,J=16.4HZ), 6.445(q,1H,J=6.4HZ), 5.843(m,1H), 4.454(m,1H) , 4.576
(s,2H), 3.954~3.343(m,6H), 2.645 (m,1H) 1.945(m,2H), 1.765 (d,3H,J=5.6HZ)
1.723~1.345(m,12H)。
Embodiment 37: anti tumor activity in vitro is tested
Based on CellTiter-Glo cell growth inhibition test model, each compound test concentration is 10 μMs, cell and change
Compound detects after hatching 72 hours, calculates cell inhibitory effect percentage ratio.Experiment arranges negative control group (not dosing simultaneously
Only containing 0.2% DMSO) and doxorubicin hydrochloride (doxorubicin, Doxorubicin) positive controls, positive control is 8 concentration
Amount effect curve.
1. material
1.1 cell culture materials:
(1) RPMI 1640 culture medium, Cat. No. #22400-089, Lot. No. #792079(Gibco)
(2) FBS, Cat. No. #26140-079, Lot. No. #1227693(Gibco)
(3) DMSO, Cat. No. #0231-500ml, Lot. No. #2210C024 (Amresco)
(4) 0.25% Trypsin-EDTA, Cat.No. #GB25200-072, Lot. No. #862530(Gibco)
(5) PBS, Cat.No. #21300-025, Lot.No.#1434815(Gibco)
(6) 6 orifice plates, Cat.No.#3516, Lot.No.#34609010 (Corning)
(7) 50 ml centrifuge tubes, Cat. No. #430828, Lot. No. #17409032 (Corning)
(8) 384 hole detection plates, Cat. No. #3707 (Corning)
(9) 15 ml centrifuge tubes, Cat. No. #430053 (Corning)
1.2 detectable
CellTiter-Glo test kit, Cat. No. #G7571, Lot. No. #328530 (Promega) 2. test
Method:
2.1 cells are cultivated
2.1.1 cell recovery
Before experiment, superclean bench table top ultraviolet irradiates 30 min.Water-bath is preheated to 37 DEG C, by freshly prepared training
Foster base is placed in water-bath preheating.Take out frozen cell, cryopreservation tube is put in the water-bath having been warmed up solve rapidly rapidly
Freeze, and constantly shake, make the liquid in pipe melt rapidly.After about 1-2 min, frozen liquid in pipe is completely dissolved, and takes out and uses
Outer wall containing 70% cotton ball soaked in alcohol wiping cryopreservation tube.Draw cryopreservation tube inner cell, be transferred in 15 ml centrifuge tubes, be simultaneously introduced 5
Ml preheats complete medium.The 500 x g slow-speed of revolution are centrifuged 3-5 min, inhale and abandon supernatant.In centrifuge tube, add 10 ml cultivate
Liquid, cell suspension is made in soft piping and druming.By Trypan Blue cell count and after carrying out vitality test, cell suspension is added
In 10 cm culture dishs, overnight incubation in containing 37 DEG C/5% CO2 incubator.
2.1.2 cell is cultivated and is passed on
Culture medium and the ratio of passage that cell is required when cultivating cultivate description with reference to cell supplier's cell.
2.2 compound treatment
It is diluted to ultimate density (ultimate density the is 10 μMs) use of 5 times with complete medium after testing compound DMSO dissolving
In experiment.After project completes, GenScript can preserve client's sample and store liquid 3 months, can do discard processing afterwards.
2.3 CellTiter-Glo cell activity detection method
(1) inoculating cell:
Collect logarithmic (log) phase cell, adjust concentration of cell suspension, 384 orifice plates are inoculated 40 μ l cell suspension (2 × 104/mL),
Edge hole is filled with aseptic PBS.
(2) cell plates are placed on 37 ° of C/5% CO2 incubators hatch to adherent, add 10 μ l 5 x concentration to be measured
Compound.Can add compound in principle after cell attachment, the method that this research uses is to complete cell incubation to add after 6 hours
Medicine.
(3) cell is hatched at 37 ° of C/5% CO2 incubators, at 24 hours, 48 hours and 72 hours inverted microscope
Observe.
(4) plate is read:
After 72 hours, every hole adds 30 μ L every hole CellTiter-Glo reactant mixtures, is vibrated 2-3 minute by detection plate, room
Temperature hatches 10min.At Pherastar(BMG labtech) read RLU value and preserve data.
2.4 data analysis
Cell Growth inhibition% = 100% × [1-RLUSample/RLUNegative], wherein RLUSampleFor add compound well or
Positive control wells RLU value, RLUNegativeFor only containing the RLU value of DMSO.Use GraphPad Prism 6.0 software to carry out data to divide
Analysis.
Detect the growth inhibited effect when 10 μMs to tumor cell SNU-16 and KATO III of 16 compounds, each
The multiple hole of Concentration Testing 2.
Above-mentioned the results show: the activity of compound has reached higher level, (E)-2-(4-(2-(5-of the present invention
(1-substituent group-1HPyrazolo heteroaromatic-3-base) vinyl)-1H-pyrazol-1-yl) alcohol compound all has significant anti-
Tumor promotion.
The invention is not limited in aforesaid detailed description of the invention.The present invention expands to any disclose in this manual
New feature or any new combination, and the arbitrary new method that discloses or the step of process or any new combination.
Claims (10)
1. a class (the E)-2-(4-(2-(5-(1-substituent group-1 shown in general structure IHPyrazolo heteroaromatic-3-base) ethylene
Base)-1H-pyrazol-1-yl) alcohol compound or its pharmaceutically acceptable salt:
Wherein
X represents N；
Y represents N；
B-A-(R1) a representsOrOrGroup.
2. according to (the E)-2-(4-(2-(5-(1-substituent group-1 described in claim 1HPyrazolo heteroaromatic-3-base) ethylene
Base)-1H-pyrazol-1-yl) alcohol compound, it is characterised in that: X represents atom N, and Y represents atom N.
3. according to (the E)-2-(4-(2-(5-(1-substituent group-1 described in claim 1HPyrazolo heteroaromatic-3-base) ethylene
Base)-1H-pyrazol-1-yl) alcohol compound, it is characterised in that: X represents the atom N of correspondence can be uniquely present in this type of
In compound；X represents the atom N of correspondence and can be uniquely present in this compounds；X, Y represent the atom N of correspondence can be same
Time occur in this compounds.
4. according to (the E)-2-(4-(2-(5-(1-substituent group-1 described in claim 1HPyrazolo heteroaromatic-3-base) ethylene
Base)-1H-pyrazol-1-yl) alcohol compound, it is characterised in that: in described B-A-(R1) a, selected from racemic modification 1-(3,5-
Dichloropyridine-4-base) ethyoxyl, R-1-(3,5-dichloropyridine-4-base) ethyoxyl, S-1-(3,5-dichloropyridine-4-base) second
Epoxide.
5. according to (E)-2-(4-(2-(5-(1-substituent group-1 of the arbitrary described logical formula I of claim 1-4HPyrazolo virtue is miscellaneous
Ring-3-base) vinyl)-1H-pyrazol-1-yl) alcohol compound derivant or its pharmaceutically acceptable salt, hydrate, its
It is characterised by that described compound is selected from:
Or its pharmaceutically acceptable salt, hydrate.
6. (E)-2-(4-(2-(5-(1-substituent group-1 described in any one in claim 1 ~ 5HPyrazolo heteroaromatic-3-
Base) vinyl)-1H-pyrazol-1-yl) and alcohol compound preparation in homoiothermic animal produce FGFR inhibitory action with
Purposes in anti-tumor drug.
7. according to the purposes described in claim 5, it is characterised in that described tumor is nonsmall-cell lung cancer.
8. according to the purposes described in claim 5, it is characterised in that described tumor is gastric cancer.
9. according to the purposes described in claim 5, it is characterised in that described tumor is multiple myeloma.
10. a pharmaceutical composition with anti-tumor activity, it is characterised in that comprise one or more power of therapeutically effective amount
Profit requires (the E)-2-(4-(2-(5-(1-substituent group-1 in 1 ~ 5 described in any oneHPyrazolo heteroaromatic-3-base) ethylene
Base)-1H-pyrazol-1-yl) alcohol compound and pharmaceutically acceptable salt, the pharmaceutical composition of hydrate.
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Cited By (3)
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| WO2021088859A1 (en) * | 2019-11-06 | 2021-05-14 | 暨南大学 | Indazole compound, pharmaceutical composition of same, and applications thereof |
| WO2022090101A1 (en) * | 2020-10-26 | 2022-05-05 | Boehringer Ingelheim International Gmbh | Process for synthesis of 2,4-dichloro-5-aminopyrimidine |
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| CN111705099A (en) * | 2020-07-01 | 2020-09-25 | 天津药明康德新药开发有限公司 | Preparation method of (S) -1- (3, 5-dichloropyridine-4-substituted) ethanol |
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