CN103214480A - Pyrazolopyridines alkynylbenzene compound and medicinal composition and application - Google Patents
Pyrazolopyridines alkynylbenzene compound and medicinal composition and application Download PDFInfo
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Abstract
The invention discloses a pyrazolopyridines alkynylbenzene compound having a structural characteristic shown in a formula (I) or its pharmaceutically acceptable salt or a stereisomer or prodrug molecules, and an application of the compound and its pharmaceutically acceptable salt or the stereisomer in preparation of medicines for treating or preventing tumor. Compared with a clinical used antitumor drug (imatinib), the compound has obvious advantage for resisting the activity of a plurality of tumor-derived type and drug resistance type cells, and the compound has the characteristics of good pharmacokinetics and low toxicity. The definitions of groups in the formula are disclosed in the specification.
Description
Technical field
The invention belongs to chemical field of medicaments, relate to Pyrazolopyridine alkynes benzene-like compounds or its pharmacy acceptable salt or steric isomer and prodrugs thereof particularly, contain pharmaceutical composition and these compounds or the application of composition in the preparation medicine of this compound with formula (I) constitutional features.
Background technology
Tumour is the No.1 killer of present human health and life, and its sickness rate is only second to cardiovascular disease.And along with the influence of environmental pollution or other factors, the sickness rate of malignant tumour is fast rise trend.According to the data that World Health Organization 2003 announces, the total malignant tumor patient 1,000 ten thousand in the whole world in 2000, because of malignant tumour death person up to 6,200,000, account for 12%～25% of total death toll.Anticipate the year two thousand twenty, global annual new cases will reach 1,500 ten thousand.In recent years, though the exploitation listing of some novel target new drugs such as tyrosine protein inhibitor is arranged, but still can't satisfy growing clinical cancer patient's needs far away.The antitumor drug research and development also are still the important research direction of present medicament research and development circle.
The molecular targeted treatment of tumour is based on a kind of methods of treatment of the closely-related key molecule of tumor growth by chemistry or biological means selective killing tumour cell.The characteristics of targeted therapy are: the specificity height, and selectivity is strong, and toxic side effect is lighter; During combined utilization, it can strengthen the curative effect of traditional chemotherapy, radiotherapy, reduces postoperative recurrence.With Gleevec (STI571) is that the targeted drug of representative is that chemotherapy of tumors has been started a New Times.Neoplasm targeted therapy has obtained developing rapidly in recent years.The appearance of neoplasm targeted therapy constitutes impact to traditional administration idea and pattern, for example, and because of the little targeted drug of toxic side effect often can't reach dose-limiting toxicity and maximum tolerated dose in the I clinical trial phase; Need not during with target therapeutic agent can reach satisfactory effect with maximum tolerated dose.Neoplasm targeted therapy is the focus and the development trend of oncotherapy.
Protein tyrosine kinase (PTKs) is the phenolic hydroxyl group generation phosphorylation of a class on can the tyrosine residues of the multiple key protein of catalysis, and then the protein enzyme of the proteic function of mobilizing function system.In the intravital 520 multiple protein kinases of people nearly half be Tyrosylprotein kinase (PTKs).They have occupied crucial status in intracellular signal transduction pathway, regulating a series of physiology processes such as growth in the cell paste, differentiation, death.The protein tyrosine kinase functional disorder can cause biological intravital a series of diseases.Studies show that proto-oncogene more than half is all relevant with protein tyrosine kinase with oncogene active.The unconventionality expression of protein tyrosine kinase can cause the cell proliferation adjusting to get muddled, and then causes tumour to take place.In addition, the unconventionality expression of Tyrosylprotein kinase also with the invasion and attack and the transfer of tumour, tumor neovasculature generation, the chemotherapy resistance of tumour is closely related.Being that target spot carries out the antitumor drug research and development and becomes an international focus with the Tyrosylprotein kinase, also is the emphasis that the research of various countries drug development mechanism drops into.
So far, existing tens of kinds of protein tyrosine kinase micromolecular inhibitors and antibody enter clinical trial, the listing that has, and obtained better therapeutic effect.As: be used for the treatment of the be positive Bcr-Abl inhibitor Gleevec of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs) of Philadelphia chromosome; Be used for the treatment of the EGFR inhibitor Iressa of nonsmall-cell lung cancer and Tarceva etc.Gleevec is first appropriate design exploitation after the cause of disease of understanding cancer, and has obtained the anti-tumor medicine of remarkable effect, and its success is a milestone of cancer therapy.This significant achievement is also listed in calendar year 2001 degree ten big science and technology news by U.S.'s " science " magazine.
The immense success that obtains in clinical cancer therapy at the specificity small molecules inhibition of protein tyrosine kinase has confirmed that further protein tyrosine kinase is critical treatment target spot, and its importance in tumour takes place also is described simultaneously.Have the sudden change of conclusive evidence proof protein tyrosine kinase encoding gene to cause that tumorigenic example comprises: Bcr-Abl and chronic myelocytic leukemia (chronic myeloid leukemia, CML); C-KIT and gastrointestinal stromal tumors (GISTs) (GIST), systemic mastocytosis (systemic mastocytosis, SM); PDGFR and chronic myelomonocytic leukemia (chronic myelomonocytic leukemia), dermatofibrosarcoma protuberans (dermatofibrosarcoma protuberan), high oxyphie syndrome; Flt3 and part acute myeloblastic leukemia; B-Raf and melanoma (melanoma); RET and thyroid carcinoma etc.In addition, c-KIT and small cell lung cancer have substantial connection.
Calendar year 2001 drugs approved by FDA in order to the treatment chronic myelocytic leukemia (CML) first target therapeutic agent STI571 (Gleevec, Imatinib mesylate, Chinese name " imatinib mesylate ", Novartis Pharmaceuticals) tyrosine protein kinase inhibitor, mainly act on Bcr-Abl, cKit, PDGFR etc.The STI571 single therapy can make 98% patient CML obtain the alleviation of clinical hematology clinically, and 53% obtains cytogenetics alleviates.
Yet along with STI571 widespread use clinically, the resistance problem becomes increasingly conspicuous: the part cancer patient is to STI571 natural tolerance (primary resistance); Another part patient responds when beginning medication, but engenders acquired tolerance (secondary resistance) in the medication therapeutic process.The patient who takes for a long time easily produces tolerance.Tolerance is meant that the chronic phase patient does not fail to return to chronic phase after the STI571 treatment through occurring complete hematology reaction or acceleration period and acute transformation phase patient after the STI571 treatment.Clinically, the CML of acute transformation phase (blast-crisis), Bcr-Abl male patient ALL tolerate more general to STI571, and this two classes patient of about 70% occurred the STI571 resistance in medication in 3～6 months.And in a single day resistance appears, the state of an illness is often made progress rapidly.Acquired tolerance is considered to tumour cell for escaping a kind of defence that kills and wounds, and it is multiple that its mechanism has, and comprising: 1. target gene (Bcr-Abl, c-KIT, PDGFR) amplification; 2. mutant target gene; 3. target gene dependent/non-dependent tumour clone's formation; 4. the overexpression of the generation of α-1 acid glycoprotein and multidrug-resisting gene M DR1.But the main mechanism of generally acknowledging is target gene (Bcr-Abl, c-KIT, PDGFR) secondary mutation in expression product kinases territory (secondary mutation) at present.Studies show that with the STI571 tolerance and concern that the common point mutation site of clear and definite target gene comprises E255K, E255V, T315I and the D276G of Bcr-Abl, the D816V of c-KIT etc.The patient who carries these sudden changes is recurred easily, and prognosis is bad.There is report to point out only to have 50% transitivity gastrointestinal stromal tumors (GISTs) (GIST) patient that STI571 is reacted, reliable for effect, and this part patient carries c-KIT and faces film territory V560G sudden change.In addition, still there is 50% transitivity patient GIST that STI571 is lacked reaction.The point mutation of c-KIT tyrosine kinase domain (as D816V, T315I) then tolerates STI571 very much.Experiment in vitro shows that STI571 can not suppress to carry the propagation of D816V c-KIT and T315I mutant strain cell; The systemic mastocytosis patient who carries D816V c-KIT does not react STI571 yet.
How to overcome the important topic that the STI571 resistivity is current tumour medical science.Seek novel Tyrosylprotein kinase small molecules inhibition and be overcome the STI571 resistivity the important channel.For example, Tyrosylprotein kinase small molecules inhibition Nilotinib (AMN107), the Dasatinib (BMS-354825) of listing are effective to part (rather than all) STI571 resistivity Bcr-Abl point mutation (except that T315I) case recently.AMN107 is identical with STI571 in conjunction with the kinase whose position of Abl, also is the Abl kinases that competitiveness is attached to the disactivation configuration, but stronger than STI571 with the avidity of Abl, and drug effect is 10～50 times of the latter approximately.AMN107 has the obvious suppression effect to 15 kinds of point mutation cells except T315I, and IC50 is at 10～1000nM.Different with STI571 and AMN107, BMS-354825 combination simultaneously and suppress activation and activatory Bcr-Abl.BMS-354825 has the obvious suppression effect to 15 kinds of point mutation cells except T315I, and IC50 is at 10～125nM.But AMN107 and Dasatinib are invalid to T315I Bcr-Abl, and AMN107 and STI571 are invalid to c-KIT D816V point mutation cell.Therefore, develop novel, can effectively kill and wound STI571 resistivity c-KIT point mutation (D816V) and Bcr-Abl point mutation and carry (comprising T315I) micromolecular compound of cell and all seem very necessary and urgent in global oncotherapy scientific circles and industrial community.
In fact, present protein tyrosine kinase inhibitor series antineoplastic medicament exists the sudden change of drug-induced drug resistance gene mostly, and be faced with the clinical scope of application narrower and etc. problem.Therefore, exploitation s-generation protein tyrosine kinase inhibitor is significant to overcome existing drug resistance and to improve clinical effectiveness.
The applicant discloses a kind of heterocycle alkyne benzene-like compounds in 201010216603.7 patent application, this compounds can effectively suppress the growth of kinds of tumor cells, but, because this compounds enormous amount, still remain those skilled in the art and further investigate and can efficiently suppress kinds of tumor cells and the low compound of toxicity.
Summary of the invention
One of technical issues that need to address of the present invention provide a kind of new its pharmacy acceptable salt of Pyrazolopyridine alkynes benzene-like compounds or steric isomer, or its prodrugs, the antitumor drug (imatinib) of the more clinical use of this compounds is compared, anti-kinds of tumors derivative type and drug-resistant type cell activity with clear superiority have pharmacokinetics and the low characteristics of toxicity preferably simultaneously.
The technical scheme that solves the problems of the technologies described above is as follows:
Pyrazolopyridine alkynes benzene-like compounds or its pharmacy acceptable salt or steric isomer or its prodrugs with formula (I) constitutional features:
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
4Contain fluoroalkyl;
4) five-membered ring that contains 1-3 N atom of Qu Daiing;
R
4Certainly optional:
1)H；
2) C
1～C
4Contain fluoroalkyl;
3) five yuan or the hexa-member heterocycle containing 1-2 N atom of Qu Daiing.
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-yl) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methyl)-3-trifluoromethyl) benzamide,
N-(3-(1H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl) benzamide,
4-methyl-N-(3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl)-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl) benzamide,
N-(3-(1H-1,2, the 4-triazole-1-yl)-5-(trifluoromethyl) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl) benzamide,
4-methyl-N-(3-(3-methyl isophthalic acid H-1,2,4-triazole-1-yl)-5-(trifluoromethyl) phenyl)-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl) benzamide,
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-N-(3-(oxazole-2-yl)-5-(trifluoromethyl) phenyl) benzamide,
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-N-(4-(tetramethyleneimine-1-methylene)-3-(trifluoromethyl) phenyl) benzamide,
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-N-(4-(morphine quinoline methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
(S)-N-(4-((3-(dimethylamino) tetramethyleneimine-1-yl) methylene radical)-3-(trifluoromethyl) 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-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-N-(4-piperidines-1-methylene)-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-yl) ethynyl) benzamide,
4-ethyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
3-((1H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-4-chloro-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
4-chloro-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) 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-yl) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
3-((1H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-4-cyclopropyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
N-(the 3-tertiary butyl-5-(4-methyl isophthalic acid H-imidazoles-1-yl) 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-yl) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methyl)-3-trifluoromethyl) benzamide dimethanesulfonate,
4-chloro-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide dimethanesulfonate.
Another object of the present invention provides 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 has also related to the above-claimed cpd that utilizes effective dose can be used for the treatment of transition proliferative disease such as gastrointestinal stromal tumors (GISTs), histocyte 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.
Pyrazolopyridine alkynes benzene-like compounds and the pharmacy acceptable salt thereof that the present invention relates to, can effectively suppress the growth of kinds of tumor cells, and to Bcr-Abl, c-Kit, 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 pharmacokinetics and the low characteristics of toxicity preferably simultaneously, become the property of medicine higher.As skilled in the art to understand, related compound and the pharmacologically acceptable salts thereof of the application can be used for transition proliferative disease such as the preparation treatment mankind and other mammiferous tumour.
Embodiment
The compound that the application is related and the meta-bolites of pharmacologically acceptable salts thereof, and the prodrug that can change the structure of related compound of the application and pharmacologically acceptable salts thereof in vivo into are also contained in the application's the claim.
The present invention will be further described for following examples, but this embodiment is used to limit protection scope of the present invention.
Embodiment 1
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) 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)met?hyl)-3-(trifluoromethyl)phenyl)benzamide
Step 1.
5-bromo-2-chloro-N-methoxyl group-N-methylnicotinamide
5-bromo-2-chloro-N-methoxy-N-methylnicotinamide
5-bromo-2-chlorine apellagrin 96g (294.07mmol) is dissolved in the 1L methylene dichloride, stir and add N down, O-dimethyl hydroxylamine hydrochloride 31.45g (323.48mmol), EDC hydrochloride 62g (323.48mmol) drips triethylamine 39.2g (388.17mmol) at last, stirring is spent the night, the reaction solution washing, saturated common salt washing, organic phase anhydrous sodium sulfate drying, decompression is spin-dried for solvent, and column chromatography obtains product white solid 65g (79%).
1HNMR(400MHz，CDCl
3)，δppm?8.48(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-(5-bromo-2-chloro-phenyl-) ethyl ketone
1-(5-bromo-2-chlorophenyl)ethanone
In the three-necked bottle of 1L, compound 225g (89.75mmol) is dissolved in the 400mL anhydrous tetrahydro furan, is cooled to-40 ℃, stir and slowly drip CH down
3MgBr (3M, diethyl ether solution) 35.9mL (107.7mmol) dropwises, keep-40 ℃ 1 hour, rose to stirring at room subsequently 3 hours, the ice bath cooling adds saturated aqueous ammonium chloride down, ethyl acetate extraction, the organic phase washing, saturated common salt washing, anhydrous sodium sulfate drying, decompression is spin-dried for solvent, and the silica gel rapid column chromatography obtains light red oily matter 17.7g (84%).
1HNMR(400MHz，CDCl
3)，δppm?8.53(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
With 17.7g compound 3 (75.6mmol), 80% hydrazine hydrate 9.4g (151.3mmol), salt of wormwood 10.4g (75.6mmol) adds in the 200mL tetrahydrofuran (THF), and reflux is spent the night, and spins off most of solvent, add water, ethyl acetate extraction, organic phase washing, saturated common salt washing, anhydrous sodium sulfate drying is spin-dried for solvent and obtains light yellow solid 15.3g (95.4%).
1HNMR(400MHz，d-DMSO)，δppm?13.42(s，1H)，8.52(s，2H)，2.51(s，3H).
MS(ESI)，m/z：213(M
++H
+).
Step 4.
5-bromo-3-methyl isophthalic acid-(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
(72.17mmol) is dissolved in 100mL DMF with 15.3g compound 4, the ice bath cooling adds 60% sodium hydride 8.66g (216.51mmol) under stirring in batches, stirs 10min, drip trimethyl silicon based ethoxymethyl chlorine 20.5g (122.69mmol), dropwise and rise to stirred overnight at room temperature, add water, ethyl acetate extraction, organic phase washing three times, the saturated common salt washing, anhydrous sodium sulfate drying, silica gel column chromatography obtain light yellow look oily matter 20.8g (84%).
1HNMR(400MHz，CDCl
3)，δppm?8.55(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
methyl?4-methyl-3-((trimethylsilyl)ethynyl)benzoate
In the 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), the displacement argon gas, capping system, stirred overnight at room temperature.Filtering reacting liquid, the filtrate washing, the saturated common salt washing, the organic phase anhydrous sodium sulfate drying is spin-dried for solvent and gets red solid 267.4g (100%).
1HNMR(400MHz，CDCl
3)，δppm?8.10(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
methyl?3-ethynyl-4-methylbenzoate
In the 5L three-necked bottle, add compound 7267.4g (1087mmol), add methyl alcohol 4L again, mechanical stirring makes its dissolving, add salt of wormwood 225g (1630mmol), the 5-10min reaction finishes, and in reaction solution impouring 5L water, stirs, filtering-depositing, washing, solid vacuum-drying obtains brown solid 180g (95%).
1HNMR(400MHz，CD
3OD)，δppm?8.13(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-yl) ethynyl) methyl benzoate methyl 4-methyl-3-((3-methyl-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-pyrazolo[3,4-b] pyridin-5-yl) ethynyl) benzoate
Add compound 510g (29.24mmol), compound 85.09g, cuprous iodide 56mg (0.2924mmol) in the single neck bottle of 100mL, two (triphenylphosphine) palladium chloride 205mg (0.2924mmol), diisopropyl ethyl amine 7.54g (58.48mmol), N-Methyl pyrrolidone 30mL, the displacement argon gas, 80 ℃ of stirrings are spent the night, and add water, ethyl acetate extraction, washing, saturated common salt washing, organic phase anhydrous sodium sulfate drying, be spin-dried for solvent, column chromatography gets white solid 3.82g (54%).
1HNMR(400MHz，CDCl
3)，δppm?9.54(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-yl) 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 10 125mg (0.4591mmol) are dissolved in the 2.5mL tetrahydrofuran (THF), stir, be cooled to-20 ℃, potassium tert.-butoxide 155mg (1.378mmol) is dissolved in the 2.5mL tetrahydrofuran (THF), slowly drops in the aforementioned mixed solution, dropwise and keep-20 ℃ of 30min, rise to stirring at room 2h then, add water, ethyl acetate extraction, washing, the saturated common salt washing, anhydrous sodium sulfate drying is spin-dried for solvent, and column chromatography gets light yellow solid 204mg (65.6%).
1HNMR(400MHz，CDCl
3)，δppm?8.69(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-yl) 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)met?hyl)-3-(trifluoromethyl)phenyl)benzamide
Compound 11 204mg (0.3014mmol) are dissolved in the tetrahydrofuran solution of tetrabutyl ammonium fluoride of 5mL 1M, stir down, reflux is spent the night, add water, ethyl acetate extraction, washing, the saturated common salt washing, anhydrous sodium sulfate drying is spin-dried for solvent, and column chromatography gets light yellow solid 126mg (76.5%).
1HNMR(400MHz，d-DMSO)，δppm?13.52(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-yl)-5-(trifluoromethyl) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl) benzamide
N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-4-methyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyri?din-5-yl)ethynyl)benzamide
Synthetic method such as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm?13.49(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 isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl)-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) 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 such as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm?13.49(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, the 4-triazole-1-yl)-5-(trifluoromethyl) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) 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 such as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm?13.50(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-yl)-5-(trifluoromethyl) phenyl)-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl) benzamide
4-methyl-N-(3-(3-methyl-1H-1，2，4-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((3-methyl-1H-pyraz?olo[3，4-b]pyridin-5-yl)ethynyl)benzamide
Synthetic method such as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm?13.49(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-yl) 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-(trifluoromet?hyl)phenyl)benzamide
Synthetic method such as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm?13.49(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-yl) ethynyl)-N-(4-(tetramethyleneimine-1-methylene)-3-(trifluoromethyl) phenyl) benzamide
4-methyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-N-(4-(pyrrolidin-1-ylmethyl)-3-(tri?fluoromethyl)phenyl)benzamide
Synthetic method such as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm?13.50(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-yl) ethynyl)-N-(4-(morphine quinoline methylene radical)-3-(trifluoromethyl) phenyl) benzamide
4-methyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-N-(4-(morpholinomethyl)-3-(triflu?oromethyl)phenyl)benzamide
Synthetic method such as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm?13.49(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) tetramethyleneimine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl) benzamide
(S)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-((3-m?ethyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)benzamide
Synthetic method such as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm?13.50(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-yl) ethynyl)-N-(4-piperidines-1-methylene)-3-(trifluoromethyl) phenyl) benzamide
4-methyl-3-((3-methyl-1H-pyrazolo[3，4-b]pyridin-5-yl)ethynyl)-N-(4-(piperidin-1-ylmethyl)-3-(trif?luoromethyl)phenyl)benzamide
Synthetic method such as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm?13.49(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-y?l)methyl)-3-(trifluoromethyl)phenyl)benzamide
Step 1.
5-bromo-3-iodo-1H-pyrazolo [3,4-b] pyridine
5-bromo-3-iodo-1H-pyrazolo[3，4-b]pyridine
Compound 1 10g (50.25mmol) and N-iodo succimide 12g (53.34mmol) are dissolved in 300mL 1, in the 2-ethylene dichloride, reflux is spent the night, dilute with the 1L tetrahydrofuran (THF), saturated aqueous sodium thiosulfate is washed, washing, saturated common salt washing, the organic phase anhydrous sodium sulfate drying, the decompression revolve desolvate light yellow solid 15g (92%).
1HNMR(400MHz，d-DMSO)，δppm?14.31(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.
5-bromo-3-iodo-1-(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
(8.27mmol) is dissolved in 25mLDMF with 2.68g compound 2, the ice bath cooling 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, ethyl acetate extraction, organic phase washing three times, the saturated common salt washing, anhydrous sodium sulfate drying, silica gel column chromatography obtain light yellow oil 3.07g (82%).
1HNMR(400MHz，CDCl
3)，δppm?8.60(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.
5-bromo-3-cyclopropyl-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
With 1g compound 3 (2.2mmol), 190mg cyclopropylboronic acid (2.2mmol), 1.18g potassiumphosphate, 180mg[1,1 '-two (diphenylphosphine) ferrocene] palladium chloride methylene dichloride complex compound (0.22mmol) mixes in 10mL 1, in the 4-dioxane, the displacement argon gas, 90 ℃ are stirred 4h, add water, ethyl acetate extraction, organic phase washing three times, the saturated common salt washing, anhydrous sodium sulfate drying, silica gel column chromatography obtain white solid 580mg (71.8%).
1HNMR(400MHz，CDCl
3)，δppm?8.53(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-yl) 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
Add compound 5213mg (0.5177mmol), compound 4190mg (0.5177mmol), cuprous iodide 1mg (0.005mmol) in the single neck bottle of 10mL, two (triphenylphosphine) palladium chloride 4mg (0.005mmol), diisopropyl ethyl amine 134mg (1.0354mmol), DMF 2mL, the displacement argon gas, 80 ℃ of stirrings are spent the night, and add water, ethyl acetate extraction, washing, saturated common salt washing, organic phase anhydrous sodium sulfate drying, be spin-dried for solvent, column chromatography gets light yellow solid 196mg (54%).
1HNMR(400MHz，CDCl
3)，δppm?8.67(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-y?l)methyl)-3-(trifluoromethyl)phenyl)benzamide
Compound 6 190mg (0.2707mmol) are dissolved in the tetrahydrofuran solution of tetrabutyl ammonium fluoride of 5mL 1M, stir down, reflux is spent the night, add water, ethyl acetate extraction, washing, the saturated common salt washing, anhydrous sodium sulfate drying is spin-dried for solvent, and column chromatography gets light yellow solid 108mg (70%).
1HNMR(400MHz，d-DMSO)，δppm?13.45(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-yl) ethynyl) benzamide
4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((3-phenyl-1H-pyraz?olo[3，4-b]pyridin-5-yl)ethynyl)benzamide
Synthetic method such as embodiment 11
1HNMR(400MHz，d-DMSO)，δppm?14.12(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-yl) 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)meth?yl)-3-(trifluoromethyl)phenyl)benzamide
Step 1.3-amino-4-ethyl benzoate (3-amino-4-ethylbenzoic acid)
The 15mL nitrosonitric acid is poured in the 50mL single port bottle, be cooled to-5 ℃, add 2g to ethyl benzoate (13.3mmol) under stirring ,-5 ℃ are continued to stir 1h down, in reaction solution impouring frozen water, separate out white precipitate, suction filtration, solid is collected in washing, and vacuum-drying gets white solid 2.6g.2.6g compound 2 (13.3mmol) is dissolved in the 20mL methyl alcohol, stirs and to add 300mg 50% palladium carbon down, vacuumize, displacement hydrogen, stirred overnight at room temperature, the reaction solution diatomite filtration, reduce pressure revolve desolvate light yellow solid 2g (91%).
1HNMR(400MHz，d-DMSO)，δppm?7.23(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-iodobenzoic acid)
2g compound 3 (12.1mmol) is placed the single neck bottle of 100mL, add 28mL water, ice bath drips concentrated hydrochloric acid 8.4mL down, stir 10min, slowly splash into 2mL and contain the aqueous solution of 0.85g Sodium Nitrite (12.3mmol), ice bath splashes into the aqueous solution that 5mL contains potassiumiodide 2.05g (12.3mmol), stirred overnight at room temperature after stirring 5min down again, add water, ethyl acetate extraction, organic phase washing, saturated common salt washing, anhydrous sodium sulfate drying, silica gel column chromatography obtain white solid 2.3g (69%).
1HNMR(400MHz，d-DMSO)，δppm?13.22(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 (methyl 4-ethyl-3-iodobenzoate)
2.3g compound 4 (8.33mmol) is dissolved in the 50mL methyl alcohol, add the 0.5mL vitriol oil, reflux is spent the night, and reaction solution is cooled to room temperature, revolves most of methyl alcohol, add water, ethyl acetate extraction, organic phase washing, saturated common salt washing, anhydrous sodium sulfate drying, silica gel column chromatography get light yellow oil 2.4g (99%).
1HNMR(400MHz，CDCl
3)，δppm?8.46(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
+).
Step 4.4-ethyl-3-iodo-N-(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 the 10mL tetrahydrofuran (THF), the 10mL tetrahydrofuran solution that will be dissolved with 2.5g potassium tert.-butoxide (22.3mmol) slowly splashes in the reaction flask, reaction 10min, reaction solution drops in the frozen water, ethyl acetate extraction, organic phase washing, saturated common salt washing, anhydrous sodium sulfate drying, silica gel column chromatography obtain 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 single 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), the displacement argon gas, capping system, stirred overnight at room temperature.Filtering reacting liquid, filtrate washing, saturated common salt washing, the organic phase anhydrous sodium sulfate drying is spin-dried for solvent, adds methyl alcohol 20mL dissolving, add salt of wormwood 1.04g (7.54mmol), stirring at room 2h adds water, ethyl acetate extraction, the organic phase washing, the saturated common salt washing, anhydrous sodium sulfate drying, silica gel column chromatography get red solid 1.2g (74%).
1HNMR(400MHz，CDCl
3)，δppm?8.04(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-yl) 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
Add compound 8220mg (0.5177mmol), compound 9177mg (0.5177mmol), cuprous iodide 1mg (0.005mmol) in the single neck bottle of 10mL, two (triphenylphosphine) palladium chloride 4mg (0.005mmol), diisopropyl ethyl amine 134mg (1.0354mmol), DMF 2mL, the displacement argon gas, 80 ℃ of stirrings are spent the night, and add water, ethyl acetate extraction, washing, saturated common salt washing, organic phase anhydrous sodium sulfate drying, be spin-dried for solvent, column chromatography gets 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-yl) 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 10 230mg (0.3333mmol) are dissolved in the tetrahydrofuran solution of tetrabutyl ammonium fluoride of 5mL 1M, stir down, reflux is spent the night, add water, ethyl acetate extraction, washing, the saturated common salt washing, anhydrous sodium sulfate drying is spin-dried for solvent, and column chromatography gets light yellow solid 98mg (53%).
1HNMR(400MHz，d-DMSO)，δppm?13.49(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-yl) ethynyl)-4-chloro-N-(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 such as embodiment 13
1HNMR(400MHz，d-DMSO)，δppm?13.98(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
4-chloro-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) 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)met?hyl)-3-(trifluoromethyl)phenyl)benzamide
Synthetic method such as embodiment 13
1HNMR(400MHz，d-DMSO)，δppm?13.55(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-yl) 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-(tri?fluoromethyl)phenyl)benzamide
Synthetic method such as embodiment 13
1HNMR(400MHz，d-DMSO)，δppm?13.51(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-yl) 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 such as embodiment 13
1HNMR(400MHz，d-DMSO)，δppm?13.50(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 isophthalic acid H-imidazoles-1-yl) 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 such as embodiment 1
1HNMR(400MHz，d-DMSO)，δppm?13.50(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-yl) 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)met?hyl)-3-(trifluoromethyl)phenyl)benzamide，dimesylate
With 620mg 4-methyl-3-((3-methyl isophthalic acid H-pyrrolo-[3,4-b] pyridine-5-yl) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methyl)-3-trifluoromethyl) benzamide (1.135mmol) places 500mL single port bottle, add the 150mL dehydrated alcohol, stir and drip 220mg methylsulfonic acid (2.271mmol) down, stirred overnight at room temperature has yellow solid to separate out, and filters, filter residue is given a baby a bath on the third day after its birth inferior with ethanol, vacuum-drying gets yellow solid 70mg (84%).
1HNMR(400MHz，d-DMSO)，δppm?10.60(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
4-chloro-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) 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)met?hyl)-3-(trifluoromethyl)phenyl)benzamide，dimesylate
Synthetic method such as embodiment 19
1HNMR(400MHz，d-DMSO)，δppm?10.82(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
Heterocycle alkyne benzene-like compounds (1 * 10 with different concns
-10～1 * 10
-5M) handle K562 (chronic leukemia) respectively, Ba/F3 (carrying Bcr/Abl), Ba/F3 (carrying T315I Bcr/Abl sudden change) to the STI571 tolerance, A549 (human lung carcinoma cell), DU145 (Human Prostate Cancer Cells), HT-29 (human colon cancer cell) and HepG2 seven kinds of cells such as (human liver cancer cells), MTT or CCK8 after 72 hours, hatched again 4 hours, measure it at 570nm (CCK8,450, light absorption value 650nm) with microplate reader then.Found that, the heterocycle alkyne benzene-like compounds is handled can obviously reduce the absorption of various cells to MTT, illustrate that the heterocycle alkyne benzene-like compounds can significantly suppress the propagation of above-mentioned cell, especially suppress K562 (chronic leukemia), Ba/F3 (carrying the T315IBcr/Abl sudden change) cell to the STI571 tolerance, 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 of the growth-inhibiting effect of heterocycle alkyne benzene-like compounds to these three kinds of cells, we calculate its half-inhibition concentration (IC50, μ M) value such as table 1 description.(compound used therefor is respectively the prepared compound of embodiment 1-18, represents with Drug No. label in table 1).
More than be at the specifying of possible embodiments of the present invention, but this embodiment is not in order to limiting claim of the present invention, does not allly break away from the equivalence that skill spirit of the present invention does and implement or change, all should be contained in the claim of the present invention.
Claims (5)
1. the Pyrazolopyridine alkynes benzene-like compounds or its pharmacy acceptable salt or steric isomer or its prodrugs that have formula (I) constitutional features:
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
4Contain fluoroalkyl;
4) five-membered ring that contains 1-3 N atom of Qu Daiing;
R
4Certainly optional:
1)H；
2) C
1～C
4Contain fluoroalkyl;
3) five yuan or the hexa-member heterocycle containing 1-2 N atom of Qu Daiing.
2. Pyrazolopyridine alkynes benzene-like compounds according to claim 1 or its pharmacy acceptable salt or steric isomer 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-yl) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methyl)-3-trifluoromethyl) benzamide,
N-(3-(1H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl) benzamide,
4-methyl-N-(3-(4-methyl isophthalic acid H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl)-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl) benzamide,
N-(3-(1H-1,2, the 4-triazole-1-yl)-5-(trifluoromethyl) phenyl)-4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl) benzamide,
4-methyl-N-(3-(3-methyl isophthalic acid H-1,2,4-triazole-1-yl)-5-(trifluoromethyl) phenyl)-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl) benzamide,
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-N-(3-(oxazole-2-yl)-5-(trifluoromethyl) phenyl) benzamide,
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-N-(4-(tetramethyleneimine-1-methylene)-3-(trifluoromethyl) phenyl) benzamide,
4-methyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-N-(4-(morphine quinoline methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
(S)-N-(4-((3-(dimethylamino) tetramethyleneimine-1-yl) methylene radical)-3-(trifluoromethyl) 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-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-N-(4-piperidines-1-methylene)-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-yl) ethynyl) benzamide,
4-ethyl-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
3-((1H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-4-chloro-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
4-chloro-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) 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-yl) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
3-((1H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-4-cyclopropyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide,
N-(the 3-tertiary butyl-5-(4-methyl isophthalic acid H-imidazoles-1-yl) 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-yl) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methyl)-3-trifluoromethyl) benzamide dimethanesulfonate,
4-chloro-3-((3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl) ethynyl)-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide dimethanesulfonate.
3. medicinal compositions for the treatment of tumour, it is made up of claim 1-or 2 described Pyrazolopyridine alkynes benzene-like compounds or its pharmacy acceptable salt or steric isomer or its prodrugs and pharmaceutically acceptable carrier.
4. claim 1 or 2 described Pyrazolopyridine alkynes benzene-like compounds and pharmacy acceptable salt thereof or steric isomer or its prodrugs application in the medicine of preparation treatment or prophylaxis of tumours.
5. application according to claim 4 is characterized in that: described tumour is any in leukemia, gastrointestinal stromal tumors (GISTs), histocyte 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, the nasopharyngeal carcinoma etc.
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| CN109793733A (en) * | 2019-03-28 | 2019-05-24 | 四川大学 | 3- amino -5- alkynyl pyrazole compound is as FGFR inhibitor |
| CN113292556A (en) * | 2020-02-21 | 2021-08-24 | 苏州亚盛药业有限公司 | Preparation method and intermediate of alkynyl-containing compound |
| TWI754238B (en) * | 2020-02-21 | 2022-02-01 | 大陸商蘇州亞盛藥業有限公司 | Preparation method of alkynyl-containing compound and intermediate thereof |
| 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 |
| WO2021164045A1 (en) * | 2020-02-21 | 2021-08-26 | Ascentage Pharma (Suzhou) Co., Ltd. | A process for preparing alkynyl-containing compound and intermediate thereof |
| CN114163434A (en) * | 2020-09-10 | 2022-03-11 | 苏州亚盛药业有限公司 | Preparation method of alkynyl-containing compound and intermediate thereof |
| WO2022053014A1 (en) * | 2020-09-10 | 2022-03-17 | Ascentage Pharma (Suzhou) Co., Ltd. | Process for preparing alkynyl-containing compound and intermediate thereof |
| CN116514808A (en) * | 2020-09-10 | 2023-08-01 | 苏州亚盛药业有限公司 | Preparation method of alkynyl-containing compound and intermediate thereof |
| CN115925566A (en) * | 2022-11-10 | 2023-04-07 | 山东龙立恒医药有限公司 | Preparation method of 3-amino-4-alkylbenzoic acid |
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