CN103214480B - Pyrazolopyridine alkynes benzene-like compounds and medicinal compositions thereof and application - Google Patents
Pyrazolopyridine alkynes benzene-like compounds and medicinal compositions thereof and application Download PDFInfo
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- FVJMYXDLWAEIKP-UHFFFAOYSA-N CC(c(cc(cc1)Br)c1Cl)=O Chemical compound CC(c(cc(cc1)Br)c1Cl)=O FVJMYXDLWAEIKP-UHFFFAOYSA-N 0.000 description 1
- 0 Cc(c1c2)n[n](*)c1ncc2C#Cc1cc(C(OC)=O)ccc1C Chemical compound Cc(c1c2)n[n](*)c1ncc2C#Cc1cc(C(OC)=O)ccc1C 0.000 description 1
Abstract
The invention discloses one and have the Pyrazolopyridine alkynes benzene-like compounds of formula (I) constitutional features or its pharmacy acceptable salt or steric isomer or its prodrugs, the application in the medicine of preparation treatment or prophylaxis of tumours of this compound and pharmacy acceptable salt thereof or steric isomer.This compounds is compared compared with the antitumor drug (imatinib) of Clinical practice, has the anti-kinds of tumors derivative type of clear superiority and the activity of drug-resistant type cell, has good pharmacokinetics and the low feature of toxicity simultaneously.In formula, each group definition refers to specification sheets.
Description
Technical field
The invention belongs to chemical medicine, relate to the Pyrazolopyridine alkynes benzene-like compounds or its pharmacy acceptable salt or steric isomer and prodrugs thereof with formula (I) constitutional features particularly, the pharmaceutical composition containing this compound is preparing the application in medicine with these compounds or composition.
Background technology
Tumour is the number one killer of current human health and life, and its sickness rate is only second to cardiovascular disease.And along with the impact of environmental pollution or other factors, the sickness rate of malignant tumour is quick ascendant trend.According to the data that the World Health Organization announces for 2003, the total malignant tumor patient 1,000 ten thousand in the whole world in 2000, because mortality of malignant tumors person is up to 6,200,000, accounts for 12% ~ 25% of total death toll.Anticipate the year two thousand twenty, the annual new cases in the whole world will reach 1,500 ten thousand.In recent years, though the exploitation listing of the target new drugs such as the tyrosine protein inhibitor having some novel, but still the sick human needs of growing clinical cancer cannot be met far away.Antitumor drug research and development are also still the important research direction of current medicament research and development circle.
Tumor cells targeted therapy is a kind of methods for the treatment of based on passing through chemistry or biological means selective killing tumour cell to the closely-related key molecule of tumor growth.The feature of targeted therapy is: specificity is high, and selectivity is strong, and toxic side effect is lighter; During combined utilization, it can strengthen the curative effect of classic chemotherapy, radiotherapy, reduces postoperative recurrence.The targeted drug being representative with Gleevec (STI571) is that chemotherapy of tumors has started a New Times.Neoplasm targeted therapy obtains in recent years and develops rapidly.The appearance of neoplasm targeted therapy has been formed convenient administration idea and pattern to be impacted, such as, because the little targeted drug of toxic side effect often cannot reach dose-limiting toxicity and maximum tolerated dose in I clinical trial phase; With during target therapeutic agent without the need to can satisfactory effect be reached with maximum tolerated dose.Neoplasm targeted therapy is focus and the development trend of oncotherapy.
Protein tyrosine kinase (PTKs) is that a class can phenolic hydroxyl group generation phosphorylation on the tyrosine residues of the multiple key protein of catalysis, and then the protease system of the function of mobilizing function albumen.In 520 multiple protein kinases in human body, nearly half is Tyrosylprotein kinase (PTKs).They occupy very consequence in intracellular signal transduction pathway, regulate a series of physiology processes such as cell growth in vivo, differentiation, death.Protein tyrosine kinase functional disorder can cause a series of diseases in organism.Research shows, proto-oncogene more than half is all relevant to protein tyrosine kinase with the activation of oncogene.The unconventionality expression of protein tyrosine kinase can cause cell proliferation adjustment to get muddled, and then causes tumour to occur.In addition, the unconventionality expression of Tyrosylprotein kinase also with the Infiltration and metastasis of tumour, tumor neovasculature generation, the chemotherapy resistance of tumour is closely related.With Tyrosylprotein kinase be target spot carry out antitumor drug research and development become an international focus, drug development mechanism of Ye Shi various countries research drop into emphasis.
So far, existing tens of kinds of protein tyrosine kinase micromolecular inhibitors and antibody enter clinical trial, the listing had, and achieve good result for the treatment of.As: be used for the treatment of Philadelphia chromosome and be positive the Bcr-Abl inhibitor Gleevec of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs); Be used for the treatment of the EGFR inhibitor Iressa and Tarceva etc. of nonsmall-cell lung cancer.Gleevec is first appropriate design exploitation after the cause of disease understanding cancer, and achieves the anti-tumor medicine of remarkable effect, and its success is a milestone of cancer therapy.This significant achievement is also listed in the large science and technology news of calendar year 2001 degree ten by the U.S.'s " science " magazine.
The immense success obtained in clinical cancer therapy for the specific small molecule inhibition of protein tyrosine kinase further demonstrate that protein tyrosine kinase is critical therapy target, and its importance in tumour occurs also is described simultaneously.The sudden change of protein tyrosine kinase encoding gene causes tumorigenic example to comprise to have conclusive evidence to prove: Bcr-Abl and chronic myelocytic leukemia (chronicmyeloidleukemia, CML); C-KIT and gastrointestinal stromal tumors (GISTs) (GIST), systemic mastocytosis (systemicmastocytosis, SM); PDGFR and chronic myelomonocytic leukemia (chronicmyelomonocyticleukemia), dermatofibrosarcoma protuberans (dermatofibrosarcomaprotuberan), hypereosinophilic syndrome; Flt3 and part of Acute myelocytic leukemia; B-Raf and melanoma (melanoma); RET and thyroid carcinoma etc.In addition, c-KIT and small cell lung cancer have substantial connection.
First target therapeutic agent STI571 (Gleevec in order to treat chronic myelocytic leukemia (CML) of calendar year 2001 U.S. FDA approval, Imatinibmesylate, Chinese name " imatinib mesylate ", NovartisPharmaceuticals) tyrosine protein kinase inhibitor, mainly act on Bcr-Abl, cKit, PDGFR etc.STI571 single therapy can make patient CML of 98% obtain the alleviation of clinical hematology clinically, and 53% obtains cytogenetics alleviates.
But along with STI571 widespread use clinically, resistance problems becomes increasingly conspicuous: part cancer patient is to STI571 natural tolerance (primaryresistance); Another part patient responds when starting medication, but in medication therapeutic process, engender acquired tolerance (secondaryresistance).The patient of long-term taking easily produces tolerance.Tolerance refers to that chronic phase patient does not occur that after STI571 treatment the reaction of complete hematology or acceleration period and acute transformation phase patient fail to return to chronic phase after STI571 treatment.Clinically, patient ALL of CML, Bcr-Abl positive of acute transformation phase (blast-crisis) is comparatively general to STI571 tolerance, and this two classes patient of about 70% occurs STI571 resistance in medication for 3 ~ 6 months.And once there is resistance, the state of an illness is often in progress rapidly.It is escape the one defence killed and wounded that acquired tolerance is considered to tumour cell, and its mechanism has multiple, comprising: 1. target gene (Bcr-Abl, c-KIT, PDGFR) amplification; 2. mutant target gene; 3. the formation of target gene dependent/non-dependent tumor colonies; 4. the generation of α-1 acid glycoprotein and the overexpression of multidrug-resisting gene M DR1.But the main mechanism of generally acknowledging at present is the secondary mutation (secondarymutation) in target gene (Bcr-Abl, c-KIT, PDGFR) expression product kinases territory.Research shows that the common point mutation site of the target gene clear and definite with STI571 Tolerance comprises E255K, E255V, T315I and D276G of Bcr-Abl, the D816V etc. of c-KIT.The patient carrying these sudden changes is easily recurred, and prognosis is bad.Report is had to point out that transitivity gastrointestinal stromal tumors (GISTs) (GIST) patient only having 50% reacts STI571, reliable for effect, and this part patient carries c-KIT and faces film territory V560G and suddenly change.In addition, transitivity patient GIST of 50% is still had to lack reaction to STI571.The point mutation (as D816V, T315I) of c-KIT tyrosine kinase domain then tolerates STI571 very much.Experiment in vitro shows that STI571 can not suppress to carry the propagation of D816Vc-KIT and T315I Mutant Cells; The systemic mastocytosis patient carrying D816Vc-KIT does not also react STI571.
How to overcome the important topic that STI571 resistivity is current medical oncology.Find novel Tyrosylprotein kinase small molecules inhibition be overcome STI571 resistivity important channel.Such as, Tyrosylprotein kinase small molecules inhibition Nilotinib (AMN107) gone on the market recently, Dasatinib (BMS-354825) are effective to part (instead of whole) STI571 resistivity Bcr-Abl point mutation (except T315I) case.AMN107 is identical with STI571 in conjunction with the kinase whose position of Abl, is also the Abl kinases of competitive binding to disactivation configuration, but stronger than STI571 with the avidity of Abl, and drug effect is about 10 ~ 50 times of the latter.AMN107 has obvious restraining effect to kind of the point mutation cell of 15 except T315I, and IC50 is at 10 ~ 1000nM.Different from STI571 and AMN107, the Bcr-Abl that BMS-354825 can combine simultaneously and suppress not activate and activated.BMS-354825 has obvious restraining effect to kind of the point mutation cell of 15 except T315I, and IC50 is at 10 ~ 125nM.But AMN107 and Dasatinib is invalid to T315IBcr-Abl, and AMN107 and STI571 is invalid to c-KITD816V point mutation cell.Therefore, develop novel, effectively can kill and wound the micromolecular compound that STI571 resistivity c-KIT point mutation (D816V) and Bcr-Abl point mutation carry (comprising T315I) cell and all seem very necessary and urgent in global oncotherapy scientific circles and industrial community.
In fact, current protein tyrosine kinase inhibitor series antineoplastic medicament mostly also exist drug-induced drug resistance gene sudden change, and be faced with the clinical scope of application narrower and etc. problem.Therefore, exploitation s-generation protein tyrosine kinase inhibitor, to overcome existing drug resistance and to improve clinical effectiveness, is significant.
Applicant discloses a kind of heterocycle alkyne benzene-like compounds in the patent application of 201010216603.7, this compounds effectively can suppress the growth of kinds of tumor cells, but, because such compound amounts is huge, and efficiently can suppress kinds of tumor cells and the low compound of toxicity still needs those skilled in the art furthers investigate.
Summary of the invention
One of technical issues that need to address of the present invention are to provide a kind of new its pharmacy acceptable salt of Pyrazolopyridine alkynes benzene-like compounds or steric isomer, or its prodrugs, this compounds is compared compared with the antitumor drug (imatinib) of Clinical practice, there is the anti-kinds of tumors derivative type of clear superiority and the activity of drug-resistant type cell, there is good pharmacokinetics and the low feature of toxicity simultaneously.
The technical scheme solved the problems of the technologies described above is as follows:
There is the Pyrazolopyridine alkynes benzene-like compounds of formula (I) constitutional features or its pharmacy acceptable salt or steric isomer or its prodrugs:
R
1certainly optional:
1)H；
2) C
1~ C
6alkyl;
3) C
3~ C
6cycloalkyl;
4) phenyl
R
2certainly optional:
1)H；
2) halogen;
3) C
1~ C
5alkyl;
4) C
3~ C
6cycloalkyl;
R
3, R
5certainly optional:
1)H；
2) C
1~ C
4alkyl;
3) C
1~ C
4containing fluoroalkyl;
4) five-membered ring containing 1-3 atom N replaced;
R
4certainly optional:
1)H；
2) C
1~ C
4containing fluoroalkyl;
3) five yuan or the hexa-member heterocycle containing 1-2 the atom N that replace.
Preferably, described heterocycle alkyne benzene-like compounds is selected from following compound:
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methyl)-3-trifluoromethyl) benzamide,
N-(3-(1H-imidazoles-1-base)-5-(trifluoromethyl) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) benzamide,
4-methyl-N-(3-(4-methyl-1 H-imidazole-1-group)-5-(trifluoromethyl) phenyl)-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) benzamide,
N-(3-(1H-1,2,4-triazole-1-yl)-5-(trifluoromethyl) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) benzamide,
4-methyl-N-(3-(3-methyl isophthalic acid H-1,2,4-triazole-1-base)-5-(trifluoromethyl) phenyl)-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) benzamide,
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(3-(oxazole-2-base)-5-(trifluoromethyl) phenyl) benzamide,
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-(pyrrolidin-1-yl methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-(morpholine methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
(S)-N-(4-((3-(dimethylamino) pyrrolidin-1-yl) methylene radical)-3-(trifluoromethyl) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) benzamide,
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-piperidin-1-yl methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
3-((3-cyclopropyl-1H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-trifluoromethyl) benzamide,
4-methyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl)-3-((3-phenyl-1H-pyrazoles [3,4-b] pyridine-5-base) ethynyl) benzamide,
4-ethyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
3-((1H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) the chloro-N-of-4-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
The chloro-3-of 4-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
3-((-1H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-4-cyclopropyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
N-(the 3-tertiary butyl-5-(4-methyl-1 H-imidazole-1-group) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl) benzamide,
4-methyl-3-((3-methyl isophthalic acid H-pyrrolo-[3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methyl)-3-trifluoromethyl) benzamide dimethanesulfonate,
The chloro-3-of 4-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide dimethanesulfonate.
Another object of the present invention is to provide the application of above-claimed cpd.
Above-mentionedly state the application in the medicine of preparation treatment or prophylaxis of tumours of compound and pharmacy acceptable salt thereof or steric isomer or its prodrugs.
The application also relate to and utilizes the above-claimed cpd of effective dose to may be used for the transition proliferative disease such as treatment gastrointestinal stromal tumors (GISTs), histiocytic lymphatic cancer, nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, skin carcinoma, cell carcinoma, prostate cancer, nasopharyngeal carcinoma, leukemia.
The Pyrazolopyridine alkynes benzene-like compounds that the present invention relates to and pharmacy acceptable salt thereof, effectively can suppress the growth of kinds of tumor cells, and to Bcr-Abl, c-Kit, the protease-producing restraining effect such as PDGF, can be used for preparing antitumor drug, and can overcome the resistance that existing medicine (Gleevec) brings out, have good pharmacokinetics and the low feature of toxicity, druggability is higher simultaneously.As understood by those skilled in the art, the compound involved by the application and pharmacologically acceptable salts thereof can be used for transition proliferative disease such as preparation the treatment mankind and other mammiferous tumour etc.
Embodiment
Compound involved by the application and the meta-bolites of pharmacologically acceptable salts thereof, and the prodrug of the structure of the compound that can change in vivo involved by the application and pharmacologically acceptable salts thereof, be also contained in the claim of the application.
The present invention will be further described for following examples, but this embodiment is not for limiting the scope of the invention.
Embodiment 1
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methyl)-3-trifluoromethyl) benzamide
4-methyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
Step 1.
The bromo-2-of 5-chloro-N-methoxy-. N-methyl niacinamide
5-bromo-2-chloro-N-methoxy-N-methylnicotinamide
Bromo-for 5-2-chlorine apellagrin 96g (294.07mmol) is dissolved in 1L methylene dichloride, N is added under stirring, O-dimethyl hydroxylamine hydrochloride 31.45g (323.48mmol), EDC hydrochloride 62g (323.48mmol), finally drip triethylamine 39.2g (388.17mmol), stirring is spent the night, reaction solution is washed, and saturated common salt is washed, organic phase anhydrous sodium sulfate drying, decompression is spin-dried for solvent, and column chromatography obtains product as white solid 65g (79%).
1HNMR(400MHz，CDCl
3)，δppm8.48(d，J＝2.0Hz，1H)，7.79(s，1H)，3.51(s，3H)，3.37(s，3H).MS(ESI)，m/z：279(M
+).
Step 2.
1-(the bromo-2-chloro-phenyl-of 5-) ethyl ketone
1-(5-bromo-2-chlorophenyl)ethanone
In the three-necked bottle of 1L, compound 225g (89.75mmol) is dissolved in 400mL anhydrous tetrahydro furan, is cooled to-40 DEG C, under stirring, slowly drips CH
3mgBr (3M, diethyl ether solution) 35.9mL (107.7mmol), dropwises, maintain-40 DEG C 1 hour, rise to stirring at room temperature subsequently 3 hours, under ice bath cooling, add saturated aqueous ammonium chloride, extraction into ethyl acetate, organic phase is washed, and saturated common salt is washed, anhydrous sodium sulfate drying, decompression is spin-dried for solvent, and silica gel rapid column chromatography obtains light-red oil 17.7g (84%).
1HNMR(400MHz，CDCl
3)，δppm8.53(d，J＝2.0Hz，1H)，8.00(d，J＝2.0Hz，1H)，2.69(s，3H).MS(ESI)，m/z：234(M
++H
+).
Step 3.
5-bromo-3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine
5-bromo-3-methyl-1H-pyrazolo[3，4-b]pyridine
By 17.7g compound 3 (75.6mmol), 80% hydrazine hydrate 9.4g (151.3mmol), salt of wormwood 10.4g (75.6mmol) adds in 200mL tetrahydrofuran (THF), and heated overnight at reflux spins off most of solvent, add water, extraction into ethyl acetate, organic phase is washed, and saturated common salt is washed, anhydrous sodium sulfate drying, is spin-dried for solvent and obtains light yellow solid 15.3g (95.4%).
1HNMR(400MHz，d-DMSO)，δppm13.42(s，1H)，8.52(s，2H)，2.51(s，3H).
MS(ESI)，m/z：213(M
++H
+).
Step 4.
The bromo-3-methyl isophthalic acid of 5--(2-trimethyl silicane ethoxy methylene)-1H-pyrazolo [3,4-b] pyridine
5-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3，4-b]pyridine
15.3g compound 4 (72.17mmol) is dissolved in 100mLDMF, ice bath cools, add 60% sodium hydride 8.66g (216.51mmol) under stirring in batches, stir 10min, drip trimethyl silicon based ethoxymethyl chlorine 20.5g (122.69mmol), dropwise and rise to stirred overnight at room temperature, add water, extraction into ethyl acetate, organic phase washes three times, saturated common salt is washed, and anhydrous sodium sulfate drying, silica gel column chromatography obtains light yellow look oily matter 20.8g (84%).
1HNMR(400MHz，CDCl
3)，δppm8.55(d，J＝2.0Hz，1H)，8.12(d，J＝2.0Hz，1H)，5.76(s，2H)，3.62(t，J＝8.4Hz，2H)，2.55(s，3H)，0.93(t，J＝8.4Hz，2H)，-0.05(s，9H).
MS(ESI)，m/z：343(M
++H
+).
Step 5.
4-methyl-3-((trimethyl silicon based) ethynyl) methyl benzoate
methyl4-methyl-3-((trimethylsilyl)ethynyl)benzoate
In 5L three-necked bottle, add compound 6300g (1087mmol), cuprous iodide 2.06g (10.87mmol), two (triphenylphosphine) palladium chloride 7.63g (10.87mmol), ethyl acetate 4L, triethylamine 329.3g (3260mmol), trimethylsilyl acetylene 159.8g (1630mmol), displacement argon gas, capping system, stirred overnight at room temperature.Filtering reacting liquid, filtrate is washed, and saturated common salt is washed, and organic phase anhydrous sodium sulfate drying, is spin-dried for solvent and obtains red solid 267.4g (100%).
1HNMR(400MHz，CDCl
3)，δppm8.10(d，J＝1.6Hz，1H)，7.86(dd，J＝8.0，2.0Hz，1H)，7.26(d，J＝8.0Hz，1H)，3.89(s，3H)，2.48(s，3H)，0.19(s，9H).
MS(ESI)，m/z：247(M
++H
+).
Step 6.
3-ethynyl-methyl 4 methylbenzoate
methyl3-ethynyl-4-methylbenzoate
In 5L three-necked bottle, add compound 7267.4g (1087mmol), then add methyl alcohol 4L, mechanical stirring makes it dissolve, add salt of wormwood 225g (1630mmol), 5-10min reaction is complete, by reaction solution impouring 5L water, stirs, filtering-depositing, washing, solid vacuum-drying, obtains brown solid 180g (95%).
1HNMR(400MHz，CD
3OD)，δppm8.13(s，1H)，7.90(d，J＝8.0Hz，1H)，7.27(d，J＝8.0Hz，1H)，3.90(s，3H)，3.34(s，1H)，2.50(s，3H).
MS(ESI)，m/z：175(M
++H
+).
Step 7.
4-methyl-3-((3-methyl isophthalic acid-(2-trimethyl silicane ethoxy methylene)-1H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) methyl benzoate methyl4-methyl-3-((3-methyl-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-pyrazolo [3,4-b] pyridin-5-yl) ethynyl) benzoate
Compound 510g (29.24mmol) is added in the mono-neck bottle of 100mL, compound 85.09g, cuprous iodide 56mg (0.2924mmol), two (triphenylphosphine) palladium chloride 205mg (0.2924mmol), diisopropyl ethyl amine 7.54g (58.48mmol), N-Methyl pyrrolidone 30mL, displacement argon gas, 80 DEG C of stirrings are spent the night, and add water, extraction into ethyl acetate, washing, saturated common salt is washed, organic phase anhydrous sodium sulfate drying, be spin-dried for solvent, column chromatography obtains white solid 3.82g (54%).
1HNMR(400MHz，CDCl
3)，δppm9.54(d，J＝2.0Hz，1H)，8.20(d，J＝2.0Hz，1H)，8.18(d，J＝1.6Hz，1H)，7.92(m，1H)，7.31(m，1H)，5.80(s，1H)，3.93(s，3H)，3.64(t，J＝8.4Hz，2H)，2.60(s，6H)，0.95(m，2H)，-0.05(s，9H).
MS(ESI)，m/z：436(M
++H
+).
Step 8.
4-methyl-3-((3-methyl isophthalic acid-(2-trimethyl silicane ethoxy methylene)-1H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-trifluoromethyl) benzamide
4-methyl-3-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3，4-b]pyridin-5-yl)ethyny
l)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
Compound 9200mg (0.4591mmol) and compound 10125mg (0.4591mmol) is dissolved in 2.5mL tetrahydrofuran (THF), stir, be cooled to-20 DEG C, potassium tert.-butoxide 155mg (1.378mmol) is dissolved in 2.5mL tetrahydrofuran (THF), slowly drop in aforementioned mixed solution, dropwise and maintain-20 DEG C of 30min, then stirring at room temperature 2h is risen to, add water, extraction into ethyl acetate, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is spin-dried for solvent, and column chromatography obtains light yellow solid 204mg (65.6%).
1HNMR(400MHz，CDCl
3)，δppm8.69(d，J＝2.0Hz，1H)，8.16(d，J＝2.0Hz，1H)，8.02(d，J＝1.6Hz，1H)，7.98(s，1H)，7.90(m，1H)，7.85(d，J＝2.0Hz，1H)，7.79(s，1H)，7.77(s，1H)，7.39(d，J＝8.0Hz，2H)，5.80(s，2H)，3.66(m，4H)，2.61(s，3H)，2.58(s，3H)，2.44(br，4H)，2.31(s，3H)，0.93(m，2H)，-0.05(s，9H).
MS(ESI)，m/z：677(M
++H
+).
Step 9.
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methyl)-3-trifluoromethyl) benzamide
4-methyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
Compound 11204mg (0.3014mmol) is dissolved in the tetrahydrofuran solution of the tetrabutyl ammonium fluoride of 5mL1M, under stirring, heated overnight at reflux, add water, extraction into ethyl acetate, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is spin-dried for solvent, and column chromatography obtains light yellow solid 126mg (76.5%).
1HNMR(400MHz，d-DMSO)，δppm13.52(s，1H)，10.57(s，1H)，8.69(d，J＝2.0Hz，1H)，8.22(d，J＝2.0Hz，1H)，8.18(d，J＝2.0Hz，1H)，8.07(d，J＝8.8Hz，1H)，7.93(d，J＝7.6Hz，1H)，7.70(m，2H)，7.52(d，J＝8.0Hz，1H)，3.56(m，2H)，2.59(s，3H)，2.51(s，3H)，2.33(brs，8H)，2.15(m，3H).
MS(ESI)，m/z：547(M
++H
+).
Embodiment 2
N-(3-(1H-imidazoles-1-base)-5-(trifluoromethyl) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) benzamide
N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-4-methyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)benzamide
Synthetic method is as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm13.49(s，1H)，10.75(s，1H)，8.69(d，J＝2.0Hz，1H)，8.52(d，J＝2.0Hz，1H)，8.34(s，2H)，8.22(s，2H)，7.95(d，J＝8.0Hz，1H)，7.79(s，2H)，7.56(d，J＝8.0Hz，1H)，7.17(s，1H)，2.60(s，3H)，2.53(s，3H).
MS(ESI)，m/z：501(M
++H
+).
Embodiment 3
4-methyl-N-(3-(4-methyl-1 H-imidazole-1-group)-5-(trifluoromethyl) phenyl)-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) benzamide
4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)benzamide
Synthetic method is as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm13.49(s，1H)，10.72(s，1H)，8.70(d，J＝1.6Hz，1H)，8.52(d，J＝1.6Hz，1H)，8.30(s，1H)，8.21(s，2H)，8.17(s，2H)，7.95(m，2H)，7.74(s，2H)，7.56(d，J＝8.0Hz，1H)，7.49(s，2H)，2.60(s，3H)，2.54(s，3H)，2.19(s，3H).
MS(ESI)，m/z：515(M
++H
+).
Embodiment 4
N-(3-(1H-1,2,4-triazole-1-yl)-5-(trifluoromethyl) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) benzamide
N-(3-(1H-1，2，4-triazol-1-yl)-5-(trifluoromethyl)phenyl)-4-methyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)benzamide
Synthetic method is as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm13.50(s，1H)，10.83(s，1H)，9.47(s，1H)，8.70(m，2H)，8.52(d，J＝1.6Hz，1H)，8.32(s，2H)，8.30(s，1H)，8.24(d，J＝1.6Hz，1H)，8.04(s，1H)，7.97(m，2H)，7.55(d，J＝8.0Hz，1H)，2.60(s，3H)，2.54(s，3H).
MS(ESI)，m/z：502(M
++H
+).
Embodiment 5
4-methyl-N-(3-(3-methyl isophthalic acid H-1,2,4-triazole-1-base)-5-(trifluoromethyl) phenyl)-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) benzamide
4-methyl-N-(3-(3-methyl-1H-1，2，4-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)benzamide
Synthetic method is as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm13.49(s，1H)，10.79(s，1H)，9.32(s，1H)，8.69(m，2H)，8.52(d，J＝1.6Hz，1H)，8.39(s，1H)，8.35(s，1H)，7.97(m，2H)，7.55(d，J＝8.0Hz，1H)，2.60(s，3H)，2.54(s，3H).
MS(ESI)，m/z：516(M
++H
+).
Embodiment 6
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(3-(oxazole 2-yl)-5-(trifluoromethyl) phenyl) benzamide
4-methyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-N-(3-(oxazol-2-yl)-5-(trifluoromethyl)phenyl)benzamide
Synthetic method is as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm13.49(s，1H)，10.77(s，1H)，8.80(s，1H)，8.69(d，J＝1.6Hz，1H)，8.51(d，J＝2.0Hz，1H)，8.41(s，2H)，8.32(s，1H)，8.23(d，J＝1.6Hz，1H)，7.95(m，2H)，7.54(d，J＝8.0Hz，1H)，7.47(s，1H)，2.60(s，3H)，2.53(s，3H).MS(ESI)，m/z：502(M
++H
+).
Embodiment 7
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-(pyrrolidin-1-yl methylene radical)-3-(trifluoromethyl) phenyl) benzamide
4-methyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-N-(4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)phenyl)benzamide
Synthetic method is as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm13.50(s，1H)，10.67(s，1H)，8.69(d，J＝1.6Hz，1H)，8.52(d，J＝1.6Hz，1H)，8.29(s，1H)，8.20(d，J＝1.6Hz，1H)，8.15(s，1H)，7.95(m，1H)，7.54(d，J＝8.0Hz，1H)，3.15(m，2H)，2.60(s，3H)，2.56(s，3H)，1.85(brs，4H)，1.56(m，2H)，1.32(m，2H).
MS(ESI)，m/z：518(M
++H
+).
Embodiment 8
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-(morpholine methylene radical)-3-(trifluoromethyl) phenyl) benzamide
4-methyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-N-(4-(morpholinomethyl)-3-(trifluoromethyl)phenyl)benzamide
Synthetic method is as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm13.49(s，1H)，10.54(s，1H)，8.69(d，J＝2.0Hz，1H)，8.52(d，J＝2.0Hz，1H)，8.22(d，J＝2.0Hz，1H)，8.18(d，J＝2.0Hz，1H)，8.08(d，J＝8.0Hz，1H)，7.92(dd，J＝8.0，2.0Hz，1H)，7.74(d，J＝8.8Hz，1H)，7.53(d，J＝8.4Hz，1H)，3.60(s，3H)，3.58(s，3H)，2.59(s，2H)，2.54(m，4H)，2.39(s，4H).MS(ESI)，m/z：534(M
++H
+).
Embodiment 9
(S)-N-(4-((3-(dimethylamino) pyrrolidin-1-yl) methylene radical)-3-(trifluoromethyl) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) benzamide
(S)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)benzamide
Synthetic method is as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm13.50(s，1H)，10.54(s，1H)，8.69(d，J＝1.6Hz，1H)，8.52(d，J＝2.0Hz，1H)，8.20(m，1H)，8.07(d，J＝7.6Hz，1H)，7.92(d，J＝8.0Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.53(d，J＝8.0Hz，1H)，3.67(m，2H)，2.69(m，3H)，2.59(s，3H)，2.53(s，3H)，2.33(m，1H)，1.89(m，1H)，1.63(m，1H).
MS(ESI)，m/z：561(M
++H
+).
Embodiment 10
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-piperidin-1-yl methylene radical)-3-(trifluoromethyl) phenyl) benzamide
4-methyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-N-(4-(piperidin-1-ylmethyl)-3-(trifluoromethyl)phenyl)benzamide
Synthetic method is as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm13.49(s，1H)，10.57(s，1H)，8.69(d，J＝2.0Hz，1H)，8.52(d，J＝1.6Hz，1H)，8.23(s，1H)，8.18(s，2H)，8.09(d，J＝8.0Hz，1H)，7.93(m，1H)，7.74(m，1H)，7.63(m，1H)，7.53(d，J＝8.4Hz，1H)，3.17(s，2H)，2.59(s，3H)，2.54(s，3H)，2.45(brs，4H)，1.55(brs，4H)，1.43(brs，2H).MS(ESI)，m/z：532(M
++H
+).
Embodiment 11
3-((3-cyclopropyl-1H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-trifluoromethyl) benzamide
3-((3-cyclopropyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
Step 1.
The bromo-3-of 5-iodo-1H-pyrazolo [3,4-b] pyridine
5-bromo-3-iodo-1H-pyrazolo[3，4-b]pyridine
Compound 110g (50.25mmol) and N-N-iodosuccinimide 12g (53.34mmol) is dissolved in 300mL1, in 2-ethylene dichloride, heated overnight at reflux, dilute with 1L tetrahydrofuran (THF), saturated aqueous sodium thiosulfate is washed, washing, and saturated common salt is washed, organic phase anhydrous sodium sulfate drying, decompression is revolved desolventizing and is obtained light yellow solid 15g (92%).
1HNMR(400MHz，d-DMSO)，δppm14.31(s，1H)，8.63(d，J＝2.0Hz，1H)，8.18(d，J＝1.6Hz，1H).MS(ESI)，m/z：325(M
++H
+).
Step 2.
The iodo-1-of the bromo-3-of 5-(2-trimethyl silicane ethoxy methylene)-1H-pyrazolo [3,4-b] pyridine
5-bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3，4-b]pyridine
2.68g compound 2 (8.27mmol) is dissolved in 25mLDMF, ice bath cools, and adds 60% sodium hydride 1g (24.8mmol) under stirring in batches, stirs 10min, drip trimethyl silicon based ethoxymethyl chlorine 2.33g (14mmol), dropwise and rise to stirred overnight at room temperature, add water, extraction into ethyl acetate, organic phase washes three times, saturated common salt is washed, and anhydrous sodium sulfate drying, silica gel column chromatography obtains light yellow oil 3.07g (82%).
1HNMR(400MHz，CDCl
3)，δppm8.60(d，J＝2.0Hz，1H)，7.96(d，J＝1.6Hz，1H)，5.81(s，2H)，3.65(m，2H)，0.92(m，2H)，-0.05(s，9H).
MS(ESI)，m/z：455(M
++H
+).
Step 3.
The bromo-3-cyclopropyl of 5--1-(2-trimethyl silicane ethoxy methylene)-1H-pyrazolo [3,4-b] pyridine
5-bromo-3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3，4-b]pyridine
By 1g compound 3 (2.2mmol), 190mg cyclopropylboronic acid (2.2mmol), 1.18g potassiumphosphate, 180mg [1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (0.22mmol) is mixed in 10mL1, in 4-dioxane, displacement argon gas, 90 DEG C are stirred 4h, add water, extraction into ethyl acetate, organic phase washes three times, saturated common salt is washed, and anhydrous sodium sulfate drying, silica gel column chromatography obtains white solid 580mg (71.8%).
1HNMR(400MHz，CDCl
3)，δppm8.53(d，J＝2.0Hz，1H)，8.17(d，J＝2.0Hz，1H)，5.73(s，2H)，3.60(m，2H)，2.15(m，1H)，1.07(m，4H)，0.91(m，2H)，-0.04(s，9H).
MS(ESI)，m/z：369(M
++H
+).
Step 4.
3-((3-cyclopropyl-1-(2-trimethyl silicane ethoxy methylene)-1H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide
3-((3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
Compound 5213mg (0.5177mmol) is added in the mono-neck bottle of 10mL, compound 4190mg (0.5177mmol), cuprous iodide 1mg (0.005mmol), two (triphenylphosphine) palladium chloride 4mg (0.005mmol), diisopropyl ethyl amine 134mg (1.0354mmol), DMF2mL, displacement argon gas, 80 DEG C of stirrings are spent the night, and add water, extraction into ethyl acetate, washing, saturated common salt is washed, organic phase anhydrous sodium sulfate drying, be spin-dried for solvent, column chromatography obtains light yellow solid 196mg (54%).
1HNMR(400MHz，CDCl
3)，δppm8.67(d，J＝2.0Hz，1H)，8.21(d，J＝2.0Hz，1H)，8.02(d，J＝2.0Hz，1H)，7.95(s，1H)，7.91(d，J＝2.0Hz，1H)，7.89(d，J＝2.0Hz，1H)，7.86(d，J＝2.0Hz，1H)，7.78(dd，J＝8.0，2.0Hz，1H)，7.39(d，J＝8.0Hz，1H)，5.77(s，2H)，3.64(m，4H)，2.62(s，3H)，2.58(brs，8H)，2.31(s，3H)，2.21(m，1H)，1.12(m，4H)，0.94(s，2H)，-0.04(s，9H).
MS(ESI)，m/z：703(M
++H
+).
Step 5.
3-((3-cyclopropyl-1H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-trifluoromethyl) benzamide
3-((3-cyclopropyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
Compound 6190mg (0.2707mmol) is dissolved in the tetrahydrofuran solution of the tetrabutyl ammonium fluoride of 5mL1M, under stirring, heated overnight at reflux, add water, extraction into ethyl acetate, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is spin-dried for solvent, and column chromatography obtains light yellow solid 108mg (70%).
1HNMR(400MHz，d-DMSO)，δppm13.45(s，1H)，10.54(s，1H)，8.68(d，J＝1.6Hz，1H)，8.55(d，J＝1.6Hz，1H)，8.22(s，1H)，8.19(s，1H)，8.07(d，J＝8.8Hz，1H)，7.91(d，J＝8.0Hz，1H)，7.70(m，1H)，7.53(d，J＝8.0Hz，1H)，3.57(m，2H)，2.60(m，3H)，2.36(m，8H)，2.19(s，3H)，1.67(m，1H)，1.33(m，4H).
MS(ESI)，m/z：573(M
++H
+).
Embodiment 12
4-methyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl)-3-((3-phenyl-1H-pyrazoles [3,4-b] pyridine-5-base) ethynyl) benzamide
4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((3-phenyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)benzamide
Synthetic method is as embodiment 11
1HNMR(400MHz，d-DMSO)，δppm14.12(s，1H)，10.55(s，1H)，8.84(d，J＝2.0Hz，1H)，8.79(d，J＝2.0Hz，1H)，8.21(s，2H)，8.19(m，3H)，7.93(d，J＝8.0Hz，1H)，7.71(d，J＝8.0Hz，1H)，7.55(m，3H)，7.45(d，J＝8.0Hz，1H)，3.57(m，2H)，2.67(m，3H)，2.40(m，8H)，2.17(s，3H).
MS(ESI)，m/z：609(M
++H
+).
Embodiment 13
4-ethyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide
4-ethyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
Step 1.3-amino-4-ethyl benzoate (3-amino-4-ethylbenzoicacid)
15mL nitrosonitric acid is poured in 50mL single port bottle, be cooled to-5 DEG C, under stirring, add 2g p-ethylbenzoic acid (13.3mmol), continue at-5 DEG C to stir 1h, by in reaction solution impouring frozen water, separate out white precipitate, suction filtration, washing, collect solid, vacuum-drying obtains white solid 2.6g.2.6g compound 2 (13.3mmol) is dissolved in 20mL methyl alcohol, adds 300mg50% palladium carbon under stirring, vacuumize, replacing hydrogen, stirred overnight at room temperature, reaction solution diatomite filtration, decompression is revolved desolventizing and is obtained light yellow solid 2g (91%).
1HNMR(400MHz，d-DMSO)，δppm7.23(s，1H)，7.10(dd，J＝8.0，1.6Hz，1H)，7.00(d，J＝8.0Hz，1H)，2.47(m，2H)，1.13(m，3H).
MS(ESI)，m/z：166(M
++H
+).
Step 2.4-ethyl-3-iodo-benzoic acid (4-ethyl-3-iodobenzoicacid)
2g compound 3 (12.1mmol) is placed in the mono-neck bottle of 100mL, add 28mL water, concentrated hydrochloric acid 8.4mL is dripped under ice bath, stir 10min, slow instillation 2mL contains the aqueous solution of 0.85g Sodium Nitrite (12.3mmol), the aqueous solution of 5mL containing potassiumiodide 2.05g (12.3mmol) is instilled again after stirring 5min under ice bath, stirred overnight at room temperature, add water, extraction into ethyl acetate, organic phase is washed, and saturated common salt is washed, anhydrous sodium sulfate drying, silica gel column chromatography obtains white solid 2.3g (69%).
1HNMR(400MHz，d-DMSO)，δppm13.22(s，1H)，8.30(d，J＝1.6Hz，1H)，7.88(dd，J＝8.0，1.6Hz，1H)，7.42(d，J＝8.0Hz，1H)，2.70(m，2H)，1.18(m，3H).
MS(ESI)，m/z：277(M
++H
+).
Step 3.4-ethyl-3-iodo-benzoic acid methyl esters (methyl4-ethyl-3-iodobenzoate)
2.3g compound 4 (8.33mmol) is dissolved in 50mL methyl alcohol, add the 0.5mL vitriol oil, heated overnight at reflux, reaction solution is cooled to room temperature, revolves most of methyl alcohol, add water, extraction into ethyl acetate, organic phase is washed, and saturated common salt is washed, anhydrous sodium sulfate drying, silica gel column chromatography give light yellow oil 2.4g (99%).
1HNMR(400MHz，CDCl
3)，δppm8.46(d，J＝2.0Hz，1H)，7.93(dd，J＝8.0，1.6Hz，1H)，7.28(d，J＝8.0Hz，1H)，3.90(s，1H)，2.77(m，2H)，1.23(m，3H).
MS(ESI)，m/z：291(M
++H
+).
The iodo-N-of step 4.4-ethyl-3-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide
(4-ethyl-3-iodo-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide)
1.1g compound 5 (3.79mmol) and 1g compound 6 (3.79mmol) are dissolved in 10mL tetrahydrofuran (THF), the 10mL tetrahydrofuran solution being dissolved with 2.5g potassium tert.-butoxide (22.3mmol) is slowly instilled in reaction flask, reaction 10min, reaction solution drops in frozen water, extraction into ethyl acetate, organic phase is washed, and saturated common salt is washed, anhydrous sodium sulfate drying, silica gel column chromatography obtains light yellow solid 2g (99%).
MS(ESI)，m/z：532(M
++H
+).
Step 5.4-ethyl-3-ethynyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide
(4-ethyl-3-ethynyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide)
In the mono-neck bottle of 50mL, add compound 72g (3.77mmol), cuprous iodide 7mg (0.0377mmol), two (triphenylphosphine) palladium chloride 26mg (0.0377mmol), acetonitrile 20mL, diisopropylethylamine 1.95g (15.08mmol), trimethylsilyl acetylene 740mg (7.54mmol), displacement argon gas, capping system, stirred overnight at room temperature.Filtering reacting liquid, filtrate is washed, and saturated common salt is washed, organic phase anhydrous sodium sulfate drying, is spin-dried for solvent, adds methyl alcohol 20mL and dissolves, add salt of wormwood 1.04g (7.54mmol), stirring at room temperature 2h, adds water, extraction into ethyl acetate, organic phase is washed, saturated common salt is washed, and anhydrous sodium sulfate drying, silica gel column chromatography obtains red solid 1.2g (74%).
1HNMR(400MHz，CDCl
3)，δppm8.04(d，J＝2.0Hz，1H)，7.93(d，J＝2.0Hz，1H)，7.79(m，4H)，7.33(d，J＝8.0Hz，1H)，3.62(s，2H)，3.31(s，1H)，2.88(m，2H)，2.45(brs，8H)，2.29(s，3H)，1.90(s，1H)，1.26(m，3H).
MS(ESI)，m/z：430(M
++H
+).
Step 6.4-ethyl-3-((3-methyl isophthalic acid-(the trimethyl silicon based ethoxy methylene of 2-)-1H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide
4-ethyl-3-((3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
Compound 8220mg (0.5177mmol) is added in the mono-neck bottle of 10mL, compound 9177mg (0.5177mmol), cuprous iodide 1mg (0.005mmol), two (triphenylphosphine) palladium chloride 4mg (0.005mmol), diisopropyl ethyl amine 134mg (1.0354mmol), DMF2mL, displacement argon gas, 80 DEG C of stirrings are spent the night, and add water, extraction into ethyl acetate, washing, saturated common salt is washed, organic phase anhydrous sodium sulfate drying, be spin-dried for solvent, column chromatography obtains light yellow solid 230mg (64.4%).MS(ESI)，m/z：691(M
++H
+).
Step 7.4-ethyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide
4-ethyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
Compound 10230mg (0.3333mmol) is dissolved in the tetrahydrofuran solution of the tetrabutyl ammonium fluoride of 5mL1M, under stirring, heated overnight at reflux, add water, extraction into ethyl acetate, washing, saturated common salt is washed, anhydrous sodium sulfate drying, is spin-dried for solvent, and column chromatography obtains light yellow solid 98mg (53%).
1HNMR(400MHz，d-DMSO)，δppm13.49(s，1H)，10.54(s，1H)，8.68(d，J＝1.6Hz，1H)，8.51(d，J＝1.6Hz，1H)，8.21(s，1H)，8.18(s，1H)，8.06(d，J＝8.4Hz，1H)，7.95(d，J＝8.0Hz，1H)7.71(d，J＝8.0Hz，1H)，7.53(d，J＝8.4Hz，1H)，3.57(s，2H)，2.96(m，2H)，2.54(s，3H)，2.35(brs，8H)，2.16(s，3H)，1.31(t，J＝8.0Hz，1H).
MS(ESI)，m/z：561(M
++H
+).
Embodiment 14
3-((1H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) the chloro-N-of-4-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide
3-((1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-4-chloro-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
Synthetic method is as embodiment 13
1HNMR(400MHz，d-DMSO)，δppm13.98(s，1H)，10.66(s，1H)，8.73(d，J＝2.0Hz，1H)，8.54(d，J＝2.0Hz，1H)，8.33(d，J＝2.0Hz，1H)，8.24(s，1H)，8.19(d，J＝1.6Hz，1H)，8.02(m，2H)，7.80(d，J＝7.6Hz，1H)，7.71(d，J＝8.8Hz，1H)，3.57(m，2H)，3.17(s，3H)，2.40(brs，8H)，2.18(s，3H).MS(ESI)，m/z：554(M
++H
+).
Embodiment 15
The chloro-3-of 4-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide
4-chloro-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
Synthetic method is as embodiment 13
1HNMR(400MHz，d-DMSO)，δppm13.55(s，1H)，10.66(s，1H)，8.69(d，J＝2.0Hz，1H)，8.54(d，J＝1.6Hz，1H)，8.32(d，J＝1.6Hz，1H)，8.20(s，2H)，8.02(m，2H)，7.81(d，J＝8.8Hz，1H)，7.72(d，J＝8.4Hz，1H)，3.58(s，2H)，2.54(s，3H)，2.41(s，8H)，2.21(s，3H).
MS(ESI)，m/z：568(M
++H
+).
Embodiment 16
3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide
3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
Synthetic method is as embodiment 13
1HNMR(400MHz，d-DMSO)，δppm13.51(s，1H)，10.70(s，1H)，8.68(d，J＝1.6Hz，1H)，8.51(d，J＝1.6Hz，1H)，8.25(s，1H)，8.22(s，1H)，8.13(d，J＝8.0Hz，1H)，8.03(d，J＝8.0Hz，1H)7.81(d，J＝8.0Hz，1H)，7.68(m，2H)，3.66(s，2H)，3.10(brs，8H)，2.69(s，3H)，2.53(s，3H).
MS(ESI)，m/z：533(M
++H
+).
Embodiment 17
3-((-1H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-4-cyclopropyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide
3-((1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-4-cyclopropyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
Synthetic method is as embodiment 13
1HNMR(400MHz，d-DMSO)，δppm13.50(s，1H)，10.55(s，1H)，8.74(d，J＝2.0Hz，1H)，8.53(d，J＝2.0Hz，1H)，8.21(m，3H)，8.06(dd，J＝8.4，1.6Hz，1H)，8.01(dd，J＝8.0，1.6Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.09(d，J＝8.4Hz，1H)，3.56(m，2H)，2.33(brs，8H)，2.15(s，3H)，1.55(m，1H)，1.30(m，4H).MS(ESI)，m/z：559(M
++H
+).
Embodiment 18
N-(the 3-tertiary butyl-5-(4-methyl-1 H-imidazole-1-group) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl) benzamide
N-(3-tert-butyl-5-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)benzamide
Synthetic method is as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm13.50(s，1H)，10.41(s，1H)，8.70(s，1H)，8.52(s，1H)，8.20(s，1H)，8.06(s，1H)，7.92(m，2H)，7.74(s，1H)，7.52(m，1H)，7.38(s，1H)，7.30(s，1H)，2.60(s，3H)，2.54(s，3H)，2.18(s，3H)，1.34(s，9H).
MS(ESI)，m/z：503(M
++H
+).
Embodiment 19
4-methyl-3-((3-methyl isophthalic acid H-pyrrolo-[3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methyl)-3-trifluoromethyl) benzamide dimethanesulfonate
4-methyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide，dimesylate
By 620mg4-methyl-3-((3-methyl isophthalic acid H-pyrrolo-[3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methyl)-3-trifluoromethyl) benzamide (1.135mmol) is placed in 500mL single port bottle, add 150mL dehydrated alcohol, stir lower dropping 220mg methylsulfonic acid (2.271mmol), stirred overnight at room temperature, yellow solid is had to separate out, filter, filter residue ethanol washes three times, and vacuum-drying obtains yellow solid 70mg (84%).
1HNMR(400MHz，d-DMSO)，δppm10.60(s，1H)，8.74(d，J＝2.0Hz，1H)，8.69(d，J＝2.0Hz，1H)，8.52(d，J＝2.0Hz，1H)，8.25(d，J＝2.0Hz，1H)，8.23(s，2H)，8.19(d，J＝1.6Hz，1H)，8.15(d，J＝8.4Hz，1H)，7.93(dd，J＝8.0，2.0Hz，1H)，7.75(d，J＝8.4Hz，1H)，7.54(d，J＝8.4Hz，1H)，3.83(s，2H)，3.44(br，4H)，3.08(br，4H)，2.83(s，3H)，2.60(s，2H)，2.54(s，3H)，2.36(s，6H).
MS(ESI)，m/z：.547，643
Embodiment 20
The chloro-3-of 4-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide dimethanesulfonate
4-chloro-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide，dimesylate
Synthetic method is as embodiment 19
1HNMR(400MHz，d-DMSO)，δppm10.82(s，1H)，8.70(d，J＝2.0Hz，1H)，8.54(d，J＝2.0Hz，1H)，8.34(d，J＝2.0Hz，1H)，8.31(s，1H)，8.20(d，J＝8.4Hz，1H)，8.02(dd，J＝8.4，2.0Hz，1H)，7.87(d，J＝8.4Hz，1H)，7.82(d，J＝8.4Hz，1H)，4.23(s，2H)，3.62(br，2H)，3.40(br，4H)，3.05(br，4H)，2.87(s，3H)，2.54(s，3H)，2.45(s，6H).
MS(ESI)，m/z：.568，664
Embodiment 21
With the heterocycle alkyne benzene-like compounds (1 × 10 of different concns
-10~ 1 × 10
-5m) K562 (chronic leukemia) is processed respectively, Ba/F3 (carrying Bcr/Abl), Ba/F3 (carries T315IBcr/Abl sudden change, to STI571 tolerance), A549 (human lung carcinoma cell), DU145 (Human Prostate Cancer Cells), seven kinds of cells such as HT-29 (human colon cancer cell) and HepG2 (human liver cancer cell), MTT or CCK8 after 72 hours, hatch 4 hours again, then its light absorption value at 570nm (CCK8,450,650nm) is measured by microplate reader.Found that, the process of heterocycle alkyne benzene-like compounds obviously can reduce the absorption of various cell to MTT, illustrate that heterocycle alkyne benzene-like compounds significantly can suppress the propagation of above-mentioned cell, especially K562 (chronic leukemia) is suppressed, Ba/F3 (carries T315IBcr/Abl sudden change, to STI571 tolerance) cell, A549 (human lung carcinoma cell), DU145 (Human Prostate Cancer Cells), the increment of HT-29 (human colon cancer cell) and HepG2 (human liver cancer cell), inhibiting rate becomes positive correlation with drug level.According to the growth-inhibiting effect of heterocycle alkyne benzene-like compounds to these three kinds of cells, we calculate its half-inhibition concentration (IC50, μM) value described by table 1.(compound used therefor is respectively the compound prepared by embodiment 1-18, represents in Table 1 with DrugNo. label).
Be more than illustrating for possible embodiments of the present invention, but this embodiment be not used to limit the scope of the claims of the present invention, allly do not depart from the equivalence that skill of the present invention spirit does and implement or change, all should be contained in the scope of the claims of the present invention.
Claims (4)
1. Pyrazolopyridine alkynes benzene-like compounds or its pharmacy acceptable salt, is characterized in that, described Pyrazolopyridine alkynes benzene-like compounds is selected from following compound:
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methyl)-3-trifluoromethyl) benzamide,
N-(3-(1H-imidazoles-1-base)-5-(trifluoromethyl) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) benzamide,
4-methyl-N-(3-(4-methyl-1 H-imidazole-1-group)-5-(trifluoromethyl) phenyl)-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) benzamide,
N-(3-(1H-1,2,4-triazole-1-base)-5-(trifluoromethyl) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) benzamide,
4-methyl-N-(3-(3-methyl isophthalic acid H-1,2,4-triazole-1-base)-5-(trifluoromethyl) phenyl)-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) benzamide,
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(3-(oxazole-2-base)-5-(trifluoromethyl) phenyl) benzamide,
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-(pyrrolidin-1-yl methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-(morpholine methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
(S)-N-(4-((3-(dimethylamino) pyrrolidin-1-yl) methylene radical)-3-(trifluoromethyl) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) benzamide,
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-piperidin-1-yl methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
3-((3-cyclopropyl-1H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-trifluoromethyl) benzamide,
4-ethyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
The chloro-3-of 4-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
N-(the 3-tertiary butyl-5-(4-methyl-1 H-imidazole-1-group) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl) benzamide,
4-methyl-3-((3-methyl isophthalic acid H-pyrrolo-[3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methyl)-3-trifluoromethyl) benzamide dimethanesulfonate,
The chloro-3-of 4-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-base) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide dimethanesulfonate.
2. treat a medicinal compositions for tumour, it is made up of Pyrazolopyridine alkynes benzene-like compounds according to claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
3. Pyrazolopyridine alkynes benzene-like compounds described in claim 1 and the application of pharmacy acceptable salt in the medicine preparing treatment or prophylaxis of tumours thereof.
4. application according to claim 3, is characterized in that: described tumour is any one in leukemia, gastrointestinal stromal tumors (GISTs), histiocytic lymphatic cancer, nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, skin carcinoma, cell carcinoma, nasopharyngeal carcinoma.
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| CN110016015B (en) * | 2013-12-24 | 2021-06-25 | 昂康塔睿迪斯股份有限公司 | Benzamide and nicotinamide compounds and methods of use thereof |
| CN105198881B (en) * | 2015-09-23 | 2017-12-15 | 上海泰坦科技股份有限公司 | The synthesis technique of 5 bromine 3 methyl 1H pyrazolos [3,4 B] pyridine |
| CN108473476B (en) * | 2016-10-13 | 2021-02-19 | 深圳市塔吉瑞生物医药有限公司 | Alkynyl heterocyclic compounds for inhibiting protein kinase activity |
| CN109793733B (en) * | 2019-03-28 | 2021-11-12 | 四川大学 | 3-amino-5-alkynyl pyrazole compounds as FGFR inhibitors |
| CN113292556B (en) * | 2020-02-21 | 2022-08-23 | 苏州亚盛药业有限公司 | Preparation method and intermediate of alkynyl-containing compound |
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