CN107793417A - Pyrrolo- [2,3 d] pyrimidines and its salt, and preparation method and pharmaceutical usage - Google Patents

Pyrrolo- [2,3 d] pyrimidines and its salt, and preparation method and pharmaceutical usage Download PDF

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CN107793417A
CN107793417A CN201610801094.1A CN201610801094A CN107793417A CN 107793417 A CN107793417 A CN 107793417A CN 201610801094 A CN201610801094 A CN 201610801094A CN 107793417 A CN107793417 A CN 107793417A
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compound
follows
pyrrolo
pyrimidines
acid
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CN107793417B (en
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张倩
黄健
谈寒
谈寒一
刘星
龚超超
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Fudan University
Chinese National Human Genome Center at Shanghai
Shanghai Human Genome Research Center
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Fudan University
Shanghai Human Genome Research Center
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The invention belongs to organic chemistry and pharmaceutical synthesis field, it is related to a kind of pyrrolo- [2,3 d] pyrimidine compound and its salt, such compound and its salt have significant inhibitory action to focal adhesion kinase, available for the medicine for preparing treatment focal adhesion kinase relevant disease, can be especially useful for preparing the medicine for treating the high expression related neoplasms of focal adhesion kinase.

Description

Pyrrolo- [2,3-d] pyrimidines and its salt, and preparation method and pharmaceutical usage
Technical field
The invention belongs to organic chemistry and pharmaceutical synthesis field, is related to a kind of pyrrolo- [2,3-d] pyrimidine compound and its salt, Such compound and its salt have significant inhibitory action to focal adhesion kinase, and focal adhesion kinase correlation disease is treated available for preparing The medicine of disease, it can be especially useful for preparing the medicine of the high expression related neoplasms for the treatment of focal adhesion kinase.
Background technology
It is a kind of non-receptor type junket ammonia prior art discloses focal adhesion kinase (Focal adhesion kinase, FAK) Acid kinase, central role is play in the cell-signaling pathways of mediated by integrin.Activation be present and swash with non-in studies have shown that FAK Two kinds of conformations living, in the presence of integrin, conformation changes the FAK in unactivated state so that tyrosine residue Autophosphorylation occurs for Y397, and FAK is changed into state of activation, and the FAK after activation combines to form compound with Src family proteins, altogether The complicated signal path in coactivation downstream, adjust cell stick, migrate, breeding, breaking up and organism in angiogenesis. There are some researches show FAK has significantly high expression, including liver cancer, colon cancer, lung cancer, breast cancer, thyroid gland in kinds of tumor cells Cancer, prostate cancer, cervix cancer, mouth epithelial cells cancer and oophoroma etc..Meanwhile the increasing increased with activity of FAK expression By force with the transfer of tumour and poor prognosis into positive correlation.Therefore, FAK is considered as a potential target spot of oncotherapy.
At present, coming into the Fak inhibitor of clinical research mainly has the PF-562271 of Pfizer, Poniard pharmacy The Defactinib (structural formula See Figure) of the PND-1186 and Verastem companies of company, its key structural feature is that have Trifluoromethyl pyrimidine ring parent nucleus.The main patent related to this kind of compound has WO2008129380 and WO2010141406 etc., But so far there are no, and Fak inhibitor class medicine goes through that listing is used for clinical therapy of tumor.
Based on above-mentioned technical background, present inventor intends providing structure novel pyrrolo- [2,3-d] miazines Compound and its salt, and preparation method and pharmaceutical usage, to meet the needs of clinical cancer therapy.
The content of the invention
It is an object of the present invention to：A kind of compound with pyrrolo- [2,3-d] pyrimidine parent nucleus skeleton is provided, should Class compound has the function that to suppress focal adhesion kinase (FAK)；
It is another object of the present invention to：The pyrrolo- [2,3-d] preparation method of pyrimidines is provided；
Another object of the present invention is：Described pyrrolo- [2,3-d] pyrimidines are provided pharmaceutically may be used The salt of receiving；
Another object of the present invention is：The pyrrolo- [2,3-d] pyrimidines are provided and its pharmaceutically may be used The pharmaceutical usage of the salt of receiving, available for the medicine for preparing treatment focal adhesion kinase relevant disease, particularly prepare treatment and stick together The medicine of the high expression related neoplasms of spot kinases, relates generally to liver cancer, colon cancer, lung cancer, breast cancer etc..
The above-mentioned purpose of the present invention is achieved through the following technical solutions：
Pyrrolo- [2,3-d] pyrimidines of the structure as shown in formula (I) are provided,
Wherein, L is 0 or 1；
R1、R2、R3、R4And R5It can be substituent that is identical or differing, be respectively selected from-H ,-OCH3、-NO2、-CN、- F、-Cl、-(CH2)mCH3、-(CH2)mOH、-(CH2)mNH2、-(CH2)mNHCOCH3、-(CH2)mNHCO(CH2)m-, morpholine -4- bases, Piperidin-1-yl, piperidin-4-yl, piperazine -1- bases, 1- methyl piperidine -4- bases or 4- methyl piperazine bases, m be 0-3 integer, phase Adjacent group, i.e. R1With R2、R2With R3、R3With R4、R4With R5Between can by one five yuan or hexa-atomic lactam nucleus connect；
X and Y can be atom that is identical or differing, selected from C atoms or N atoms；
R6、R7、R8、R9And R10It can be substituent that is identical or differing, be respectively selected from-H ,-(CH2)nCH3、-O(CH2)nCH3、-NH(CH2)nCH3、-N(CH3)SO2(CH2)nCH3、-NHSO2(CH2)nCH3、-NHCO(CH2)nCH3、-CONH(CH2)nCH3 Or-SO2(CH2)nCH3, n is 0-2 integer；
R11Selected from-H ,-CN ,-OH ,-Cl ,-F ,-CH3、-CH2CH3Or-OCH3Deng.
In compound shown in the above-mentioned formula (I) of the present invention, further preferred compound includes：
Compound 1, structure is as follows：
Compound 2, structure is as follows：
Compound 3, structure is as follows：
Compound 4, structure is as follows：
Compound 5, structure is as follows：
Compound 6, structure is as follows：
Compound 7, structure is as follows：
Compound 8, structure is as follows：
Compound 9, structure is as follows：
Compound 10, structure is as follows：
Compound 11, structure is as follows：
Compound 12, structure is as follows：
Compound 13, structure is as follows：
Compound 14, structure is as follows：
Compound 15, structure is as follows：
Compound 16, structure is as follows：
Compound 17, structure is as follows：
Compound 18, structure is as follows：
Compound 19, structure is as follows：
Compound 20, structure is as follows：
Compound 21, structure is as follows：
Compound 22, structure is as follows：
The preparation method of formula (I) described compound involved in the present invention, as shown in formula (II), passes through two step key reactions Complete：
The introducing of 4 substituted-aminos of the first step is that compound B preparation is obtained by following two methods：Method 1, raw material A in appropriate solvent, under the catalysis of alkaline reagent, is obtained with 1-1.5 times of equivalent amine reagent by nucleophilic substitution；Or side Method 2, raw material A and 1-1.5 times of equivalent amine reagent are in appropriate solvent, anti-by being coupled under the catalysis of palladium reagent and phosphorus part It should obtain；
Wherein, raw material A is selected from purchase or homemade 5-R11- 2,4- dichloro pyrrolo- [2,3-d] pyrimidine, wherein substituent R11Can be-H ,-CN ,-OH ,-Cl ,-F ,-CH3、-CH2CH3Or-OCH3Deng；
Arylamine or substituted arylmethylamine of the amine reagent for substitution, wherein, X and Y can be C atoms or N atoms； R6、R7、R8、R9And R10It can be substituent that is identical or differing, can be-H ,-(CH2)nCH3、-O(CH2)nCH3、-NH (CH2)nCH3、-N(CH3)SO2(CH2)nCH3、-NHSO2(CH2)nCH3、-NHCO(CH2)nCH3、-CONH(CH2)nCH3Or-SO2 (CH2)nCH3, n is 0-2 integer；
Solvent is selected from ethanol, isopropanol, n-butanol, the tert-butyl alcohol, tetrahydrofuran, dioxane, or N, N- dimethyl methyl Acid amides etc.；
Alkaline reagent is selected from pyridine, triethylamine, DIPEA, potassium carbonate, cesium carbonate etc.；
Palladium reagent is selected from palladium, palladium bichloride, three (dibenzalacetone) two palladium, tetrakis triphenylphosphine palladium etc.；
Phosphorus-containing ligand is selected from Ph3P, Xantphos, Xphos, BINAP etc..
The introducing of 2 substituted anilinics of second step is that the preparation of compound shown in Formulas I is obtained by following two methods：Side Method 1, above-mentioned first step reaction product are compound B with 1-1.5 times of equivalent substituted aniline reagent in appropriate solvent, are tried in alkalescence Under the catalysis of agent, obtained by nucleophilic substitution；Or method 2, compound B exist with 1-1.5 times of equivalent substituted aniline reagent In appropriate solvent, under palladium reagent and phosphorus-containing ligand catalysis, obtained by coupling reaction；
Wherein, in substituted aniline reagent, R1、R2、R3、R4And R5It can be substituent that is identical or differing, select respectively From-H ,-OCH3、-NO2、-CN、-F、-Cl、-(CH2)mCH3、-(CH2)mOH、-(CH2)mNH2、-(CH2)mNHCOCH3、-(CH2)mNHCO(CH2)m-, morpholine -4- bases, piperidin-1-yl, piperidin-4-yl, piperazine -1- bases, 1- methyl piperidine -4- bases or 4- methyl Piperazinyl, m be 0-3 integer, adjacent group, i.e. R1With R2、R2With R3、R3With R4、R4With R5Between can be by one five yuan or hexa-atomic Lactam nucleus connection；
Solvent is selected from ethanol, isopropanol, n-butanol, the tert-butyl alcohol, tetrahydrofuran, dioxane, or N, N- dimethyl methyl Acid amides etc.；
Alkaline reagent is selected from pyridine, triethylamine, DIPEA, potassium carbonate, cesium carbonate etc.；
Palladium reagent is selected from palladium, palladium bichloride, three (dibenzalacetone) two palladium, tetrakis triphenylphosphine palladium etc.；
Phosphorus-containing ligand is selected from Ph3P, Xantphos, Xphos, BINAP etc..
The present invention also provides pyrrolo- [2,3-d] pyrimidines described in formula (I) pharmaceutically acceptable salt, institute The salt stated is the addition salts that the azolopyrimidines are formed with acid, and described acid can be but not limited to hydrochloric acid, hydrogen Bromic acid, sulfuric acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid or p-methyl benzenesulfonic acid.
Described various acid and each compound of the present invention can be used to be raw material for the addition salts of the invention described above compound, Acid-addition salts are prepared with reference to existing method.
The azolopyrimidines provided by the invention and its addition salts formed with acid, can be according to different reasons Change the preparation that property is used for the medicine of different dosage forms.
The invention provides formula (I) compound and its all kinds of salt to focal adhesion kinase (FAK) inhibitory activity, can use In the medicine for preparing treatment focal adhesion kinase relevant disease, the high medicine for expressing tumour for the treatment of focal adhesion kinase is particularly prepared, Relate generally to liver cancer, colon cancer, lung cancer, breast cancer etc..
Embodiment
Embodiment 1：
(1) 98mg (0.456mmol) N- [3- (amino methyl) pyridine -2- bases]-N- methylmethanesulfonamides, 85mg (0.456mmol) 2,4- dichloros pyrrolo- [2,3-d] pyrimidine and 0.156mL (0.912mmol) N, N- diisopropylethylamine are dissolved in 4mL ethanol, outer bath return stirring.Stop reaction after reacting 1h, solvent is removed in rotation, and gained crude product is washed, obtained successively with water, ether White solid 77mg, yield 46.1%.m.p.218-211℃.1H-NMR (DMSO-d6,400MHz) δ=3.14 (s, 3H), 3.26 (s, 3H), 4.74 (d, J=5.40Hz, 2H), 6.59 (s, 1H), 7.12 (s, 1H), 7.41 (dd, J=7.72Hz, J= 4.72Hz, 1H), 7.82 (d, J=7.64Hz, 1H), 8.43 (d, J=4.64Hz), 8.47 (s, 1H), 11.75 (s, 1H) ppm.ESI-MS m/z367.1[M+H]+.
(2) solid, 32mg (0.22mmol) 5- amino indole -2- ketone and 75mg obtained by 80mg (0.22mmol) step (1) (0.44mmol) p-methyl benzenesulfonic acid is dissolved in 1.5mL n-butanols, 150 DEG C of reaction 3h of microwave.Solvent, residue are removed in rotation after reaction terminates Column chromatography for separation is directly carried out, eluant, eluent polarity is dichloromethane：Methanol=30:1, get white solid 27mg, yield 25.7%.m.p.172-176℃.1H-NMR (DMSO-d6,400MHz) δ=3.16 (s, 3H), 3.18 (s, 3H), 3.31 (s, 2H), 4.79 (d, J=5.80Hz, 2H), 6.41 (s, 1H), 6.54 (d, J=8.36Hz, 1H), 6.76 (t, J=2.36Hz, 1H), 7.38-7.41 (m, 2H), 7.61 (s, 1H), 7.72 (s, 1H), 7.82 (d, J=6.80Hz, 1H), 8.39 (s, 1H), 8.41 (dd, J=4.76Hz, J=1.64Hz, 1H), 10.09 (s, 1H), 10.99 (s, 1H) ppm.ESI-MS m/z 478.8 [M +H]+.。
Embodiment 2：
(1) bis- chloro- 5- methylpyrroles of 60mg (0.299mmol) 2,4- simultaneously [2,3-d] pyrimidine, 77mg (0.358mmol) N- [3- (amino methyl) pyridine -2- bases]-N- methylmethanesulfonamides and 0.100mL (0.585mmol) N, N- diisopropylethylamine are molten In 4mL ethanol, outer bath return stirring.Stop after reaction 40h, now there are a large amount of solids to separate out in reaction solution.Reaction solution is transferred to Ice bath stirs 30min, is filtrated to get faint yellow solid 75mg, yield 66.0%.1H-NMR (DMSO-d6,400MHz) δ=2.38 (s, 3H), 3.12 (s, 3H), 3.28 (s, 3H), 4.70 (s, 2H), 6.68 (s, 1H), 7.38 (m, 2H), 7.85 (d, J= 6.36Hz, 1H), 8.40 (d, J=2.96Hz, 1H), 11.43 (s, 1H) ppm.ESI-MS m/z381.1 [M+H]+.
(2) solid obtained by 150mg (0.396mmol) step (1), 58mg (0.395mmol) 5- amino indole -2- ketone, 163.5mg (1.185mmol) potassium carbonate, 36mg (0.0395mmol) Pd2(dba)3And 38mg (0.0790mmol) Xphos is dissolved in The 6mL tert-butyl alcohols, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 2h, water is added into reaction solution and is carried out with ethyl acetate Extraction, column chromatography after organic phase is dried, eluant, eluent polarity, dichloromethane：Methanol=20:1, get Light brown solid 78mg, receive Rate 40.0%.m.p.166-172℃.1H-NMR (DMSO-d6,400MHz) δ=2.31 (s, 3H), 3.17 (s, 6H), 3.28 (s, 2H), 4.80 (d, J=5.44Hz, 2H), 6.51 (m, 2H), 6.72 (brs, 1H), 7.33 (d, J=8.36Hz, 1H), 7.38 (dd, J=7.64Hz, J=4.72Hz, 1H), 7.55 (s, 1H), 7.85 (d, J=7.08Hz, 1H), 8.33 (s, 1H), 8.40 (d, J=3.20Hz, 1H), 10.08 (s, 1H), 10.67 (s, 1H) ppm.ESI-MS m/z493.2 [M+H]+.。
Embodiment 3：
(1) bis- chloro- 5- cyanopyrroles of 200mg (0.943mmol) 2,4- simultaneously [2,3-d] pyrimidine, 243mg (1.132mmol) N- [3- (amino methyl) pyridine -2- bases]-N- methylmethanesulfonamides and 0.322mL (1.886mmol) N, N- diisopropylethylamine It is dissolved in 8mL ethanol, outer bath return stirring.Stop after reaction 16h, there are a large amount of solids to separate out in reaction solution.Reaction solution is transferred to ice Bath stirring 30min, is filtrated to get faint yellow solid 220mg, yield 60.0%.m.p.>250℃.1H-NMR(DMSO-d6, 400MHz) δ=3.12 (s, 3H), 3.28 (s, 3H), 4.79 (d, J=5.24Hz, 2H), 7.40 (dd, J=7.64Hz, J= 4.54Hz, 1H), 7.70 (t, J=5.84Hz, 1H), 7.86 (d, J=6.16Hz, 1H), 8.20 (s, 1H), 8.43 (d, J= 2.92Hz,1H),12.92(s,1H)ppm.ESI-MS m/z392.1[M+H]+.
(2) solid obtained by 50mg (0.128mmol) step (1), 19mg (0.128mmol) 5- amino indole -2- ketone and 66mg (0.384mmol) p-methyl benzenesulfonic acid is dissolved in 2mL n-butanols, outer 130 DEG C of stirrings of bath.Stop after reaction 14h, reaction solution rotation Sample column chromatography is directly mixed after dry, eluant, eluent polarity is dichloromethane：Methanol=20:1, get pale solid 6mg, yield 9.3%.m.p.>250℃.1H-NMR (DMSO-d6,400MHz) δ=3.17 (s, 3H), 3.18 (s, 3H), 3.31 (s, 2H), 4.85 (d, J=5.60Hz, 2H), 6.58 (d, J=8.56Hz, 1H), 6.84 (brs, 1H), 7.35 (d, J=8.24Hz, 1H), 7.41 (dd, J=7.64Hz, J=4.84,1H), 7.55 (s, 1H), 7.84-7.88 (m, 2H), 8.44 (d, J=2.92Hz, 1H),8.75(s,1H),10.15(s,1H),12.15(s,1H)ppm.ESI-MS m/z504.2[M+H]+.。
Embodiment 4：
(1) 280mg (1.27mmol) 2,4,5- trichlorines pyrrolo- [2,3-d] pyrimidine, 327mg (1.52mmol) N- [3- (ammonia Ylmethyl) pyridine -2- bases]-N- methylmethanesulfonamides and 0.433mL (2.534mmol) N, N- diisopropylethylamine be dissolved in 8mL second Alcohol, outer bath return stirring.Stop after reaction 11h, there are a large amount of solids to separate out in reaction solution, reaction solution is filtered after letting cool, obtained white Color solid 335mg, filtrate mix column chromatography after sample, and eluant, eluent polarity is dichloromethane：Methanol=75:1, obtain white solid 55mg, altogether 390mg, yield 65.9%.m.p.234-238℃.1H-NMR (DMSO-d6,400MHz) δ=3.11 (s, 3H), 3.27 (s, 3H), 4.75 (d, J=5.12Hz, 2H), 7.34 (d, J=2.52Hz, 1H), 7.39 (dd, J=7.72Hz, J= 4.72Hz, 1H), 7.68 (t, J=5.84Hz, 1H), 7.83 (d, J=7.44Hz, 1H), 8.41 (d, J=2.84Hz, 1H), 12.12(s,1H)ppm.ESI-MS m/z401.0[M+H]+.
(2) solid obtained by 100mg (0.250mmol) step (1), 37mg (0.250mmol) 5- amino indole -2- ketone, 104mg (0.750mmol) potassium carbonate, 11.5mg (0.0125mmol) Pd2(dba)3And 11.9mg (0.0250mmol) Xphos is molten The Argon gas shielded in the 4mL tert-butyl alcohols, microwave tube, 100 DEG C of reactions of microwave.Stop after reaction 2h, add water and extract with ethyl acetate Take, separate organic phase, column chromatography after drying, eluant, eluent polarity is dichloromethane：Methanol=30:1, red solid 21mg is obtained, Yield 16.4%.m.p.164-169℃.1H-NMR (DMSO-d6,400MHz) δ=3.16 (s, 3H), 3.18 (s, 3H), 3.33 (s, 2H), 4.84 (d, J=4.76Hz, 2H), 6.56 (d, J=8.32Hz, 1H), 6.94 (s, 2H), 7.35 (d, J=8.00Hz, 1H), 7.40 (s, 1H), 7.57 (s, 1H), 7.85 (d, J=7.28Hz, 1H), 8.42 (s, 1H), 8.57 (s, 1H), 10.12 (s, 1H),11.31(s,1H)ppm.ESI-MS m/z513.1[M+H]+.。
Embodiment 5：
(1) 113mg (0.527mmol) N- [3- (amino methyl) pyridine -2- bases]-N- methylmethanesulfonamides, 90mg Solid and 0.15mL (0.878mmol) N, N- bis- are different obtained by the chloro- fluoro- pyrrolo-es of 5- [2,3-d] pyrimidines of (0.459mmol) 2,4- bis- Propylethylamine is dissolved in 8mL ethanol, outer bath return stirring.Stop after reaction 6h, column chromatography is directly carried out after reaction solution is spin-dried for, is washed De- agent polarity is dichloromethane：Methanol=75:1, assign to white solid 80mg, yield 45.4%.m.p.243-246℃.1H- NMR (DMSO-d6,400MHz) δ=3.10 (s, 3H), 3.27 (s, 3H), 4.69 (s, 2H), 7.10 (s, 1H), 7.38 (dd, J= 7.72Hz, J=4.68Hz, 1H), 7.83 (d, J=6.52Hz, 1H), 8.09 (brs, 1H), 8.41 (d, J=2.92Hz, 1H), 11.64(s,1H)ppm.ESI-MS m/z385.1[M+H]+.
(2) solid obtained by 50mg (0.130mmol) step (1), 19.3mg (0.130mmol) 5- amino indole -2- ketone, 54mg (0.391mmol) potassium carbonate, 6mg (0.0065mmol) Pd2(dba)3And 6.2mg (0.013mmol) Xphos is dissolved in uncle 3mL Butanol, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 12h, water added into reaction solution and is extracted with ethyl acetate, Column chromatography after organic phase is dried, eluant, eluent polarity is dichloromethane：Methanol=30:1, obtain faint yellow solid 20mg, yield 31.0%.m.p.165-168℃.1H-NMR (DMSO-d6,400MHz) δ=3.16 (s, 3H), 3.17 (s, 3H), 3.31 (s.2H), 4.79 (d, J=5.56Hz, 2H), 6.54 (d, J=8.36Hz, 1H), 6.68 (s, 1H), 7.23 (brs, 1H), 7.34 (d, J=7.72Hz, 1H), 7.39 (dd, J=7.60Hz, J=4.60Hz, 1H), 7.56 (s, 1H), 7.82 (d, J=7.76Hz, 1H), 8.41 (d, J=3.00Hz, 1H), 8.51 (s, 1H), 10.11 (s, 1H), 10.79 (1H) ppm.ESI-MS m/z497.1 [M+H]+.。
Embodiment 6：
Solid, 36mg (0.390mmol) aniline, 81mg obtained by the step (1) of 75mg (0.195mmol) embodiment 5 (0.585mmol) potassium carbonate, 9mg (0.00975mmol) Pd2(dba)3And 9.3mg (0.0195mmol) Xphos is dissolved in the tertiary fourths of 4mL Alcohol, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 15h, water is added into reaction solution and is extracted with ethyl acetate, is had Machine mutually dries rear pillar chromatography, and eluant, eluent polarity is dichloromethane：Methanol=150:1, obtain faint yellow solid 29mg.Yield 33.7%.m.p.209-213℃.1H-NMR (DMSO-d6,400MHz) δ=3.18 (s, 3H), 3.20 (s, 3H), 4.83 (d, J =5.28Hz, 2H), 6.74 (s, 1H), 6.78 (t, J=7.24Hz, 1H), 7.09 (t, J=7.48Hz, 2H), 7.31 (brs, 1H), 7.41 (t, J=4.76Hz, 1H), 7.62 (d, J=7.72Hz, 2H), 7.85 (d, J=7.28Hz, 1H), 8.43 (s, 1H),8.70(s,1H),10.88(s,1H)ppm.ESI-MS m/z441.9[M+H]+.。
Embodiment 7：
Solid, 32.6mg (0.293mmol) para-fluoroaniline, 81mg obtained by the step (1) of 75mg (0.195mmol) embodiment 5 (0.585mmol) potassium carbonate, 9mg (0.00975mmol) Pd2(dba)3And 9.3mg (0.0195mmol) Xphos is dissolved in the tertiary fourths of 4mL Alcohol, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 15h, water is added into reaction solution and is extracted with ethyl acetate, is had Machine mutually dries rear pillar chromatography, and eluant, eluent polarity is dichloromethane：Methanol=150:1, obtain orange solids 25mg.Yield 27.9%.m.p.197-200℃.1H-NMR (DMSO-d6,400MHz) δ=3.19 (s, 3H), 3.20 (s, 3H), 4.82 (s, 2H), 6.74 (s, 1H), 6.93 (m, 2H), 7.30 (brs, 1H), 7.41 (brs, 1H), 7.63 (m, 2H), 7.84 (d, J= 7.32Hz,1H),8.44(s,1H),8.76(s,1H),10.88(s,1H)ppm.ESI-MS m/z459.8[M+H]+.。
Embodiment 8：
Solid obtained by the step (1) of 75mg (0.195mmol) embodiment 5, the chloro- 4- fluoroanilines of 43mg (0.293mmol) 3-, 81mg (0.585mmol) potassium carbonate, 9mg (0.00975mmol) Pd2(dba)3And 9.3mg (0.0195mmol) Xphos is dissolved in 4mL The tert-butyl alcohol, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 15h, water is added into reaction solution and is extracted with ethyl acetate Take, column chromatography after organic phase is dried, eluant, eluent polarity is dichloromethane：Methanol=125:1, obtain gray solid 30mg.Yield 31.2%.m.p.213-218℃.1H-NMR (DMSO-d6,400MHz) δ=3.15 (s, 3H), 3.18 (s, 3H), 4.81 (d, J =5.40Hz, 2H), 6.75 (s, 1H), 7.12 (t, J=9.16Hz, 1H), 7.32 (brs, 1H), 7.39 (dd, J=7.72Hz, J =4.68Hz, 1H), 7.55 (brs, 1H), 7.83 (d, J=7.84Hz, 1H), 7.99 (d, J=5.12Hz, 1H), 8.41 (s, 1H),8.95(s,1H),10.97(s,1H)ppm.ESI-MS m/z493.8[M+H]+.。
Embodiment 9：
Solid, 45mg (0.293mmol) 3,4- dimethoxy benzenes obtained by the step (1) of 75mg (0.195mmol) embodiment 5 Amine, 81mg (0.585mmol) potassium carbonate, 9mg (0.00975mmol) Pd2(dba)3And 9.3mg (0.0195mmol) Xphos is dissolved in The 4mL tert-butyl alcohols, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 15h, water is added into reaction solution and is carried out with ethyl acetate Extraction, column chromatography after organic phase is dried, eluant, eluent polarity is dichloromethane：Methanol=100:1, obtain yellow solid 27mg.Receive Rate 27.6%.m.p.115-118℃.1H-NMR (DMSO-d6,400MHz) δ=3.14 (s, 3H), 3.18 (s, 3H), 3.64 (s, 3H), 3.65 (s, 3H), 4.80 (d, J=5.76Hz, 2H), 6.67-6.69 (m, 2H), 7.13 (d, J=8.28Hz, 1H), 7.21 (brs, 1H), 7.37-7.39 (m, 2H), 7.84 (d, J=7.08Hz, 1H), 8.40 (d, J=3.04Hz, 1H), 8.45 (s, 1H),10.79(s,1H)ppm.ESI-MS m/z501.9[M+H]+.。
Embodiment 10：
Solid, 54mg (0.293mmol) 3,4,5- trimethoxy-benzenes obtained by the step (1) of 75mg (0.195mmol) embodiment 5 Amine, 81mg (0.585mmol) potassium carbonate, 9mg (0.00975mmol) Pd2(dba)3And 9.3mg (0.0195mmol) Xphos is dissolved in The 4mL tert-butyl alcohols, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 16h, water is added into reaction solution and is carried out with ethyl acetate Extraction, column chromatography after organic phase is dried, eluant, eluent polarity is dichloromethane：Methanol=100:1, obtain yellow solid 44mg.Receive Rate 42.5%.m.p.247-249℃.1H-NMR (DMSO-d6,400MHz) δ=3.16 (s, 3H), 3.21 (s, 3H), 3.58 (s, 3H), 3.68 (s, 6H), 4.85 (d, J=5.84Hz, 2H), 6.75 (s, 1H), 7.18 (s, 2H), 7.24 (m, 1H), 7.41 (dd, J=7.56Hz, J=4.64Hz, 1H), 7.90 (d, J=7.28Hz, 1H), 8.42 (d, J=3.04Hz, 1H), 8.57 (s, 1H), 10.85(s,1H)ppm.ESI-MS m/z531.8[M+H]+.。
Embodiment 11：
Solid, 40mg (0.293mmol) 2- methyl -3- methoxyl groups obtained by the step (1) of 75mg (0.195mmol) embodiment 5 Aniline, 81mg (0.585mmol) potassium carbonate, 9mg (0.00975mmol) Pd2(dba)3And 9.3mg (0.0195mmol) Xphos is molten In the 4mL tert-butyl alcohols, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 12h, water is added into reaction solution and is entered with ethyl acetate Row extraction, column chromatography after organic phase is dried, eluant, eluent polarity is dichloromethane：Methanol=100:1, obtain yellow solid 27mg. Yield 28.5%.m.p.107-112℃.1H-NMR (DMSO-d6,400MHz) δ=1.97 (s, 3H), 3.12 (s, 3H), 3.15 (s, 3H), 3.75 (s, 3H), 4.72 (d, J=5.12Hz, 2H), 6,63-6.65 (m, 2H), 6.93 (t, J=7.72Hz, 1H), 7.05 (d, J=7.84Hz, 1H), 7.23 (brs, 1H), 7.39 (t, J=5.08Hz, 1H), 7.70 (s, 1H), 7.80 (d, J= 7.24Hz,1H),8.42(s,1H),10.77(s,1H)ppm.ESI-MS m/z485.9[M+H]+.。
Embodiment 12：
Solid obtained by the step (1) of 75mg (0.195mmol) embodiment 5,44mg (0.293mmol) 3- acetylaminoanilines, 81mg (0.585mmol) potassium carbonate, 9mg (0.00975mmol) Pd2(dba)3And 9.3mg (0.0195mmol) Xphos is dissolved in 4mL The tert-butyl alcohol, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 14h, water is added into reaction solution and is extracted with ethyl acetate Take, column chromatography after organic phase is dried, eluant, eluent polarity is dichloromethane：Methanol=30:1, obtain yellow solid 33mg.Yield 34.0%.m.p.138-143℃.1H-NMR (DMSO-d6,400MHz) δ=2.00 (s, 3H), 3.17 (s, 3H), 3.19 (s, 3H), 4.83 (d, J=4.72Hz, 2H), 6.72 (s, 1H), 6.98 (t, J=8.08Hz, 1H), 7.05 (d, J=7.52Hz, 1H), 7.26 (brs, 1H), 7.39 (dd, J=7.60Hz, J=4.76Hz, 1H), 7.45 (d, J=7.44Hz, 1H), 7.64 (s, 1H), 7.86 (d, J=7.48Hz, 1H), 8.41 (s, 1H), 8.70 (s, 1H), 9.74 (s, 1H), 10.84 (s, 1H) ppm.ESI- MS m/z498.8[M+H]+.。
Embodiment 13：
Solid, 115mg (0.700mmol) 3- acetylamino methyls obtained by the step (1) of 75mg (0.195mmol) embodiment 5 Aniline, 81mg (0.585mmol) potassium carbonate, 9mg (0.00975mmol) Pd2(dba)3And 9.3mg (0.0195mmol) Xphos is molten In the 4mL tert-butyl alcohols, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 14h, water is added into reaction solution and is entered with ethyl acetate Row extraction, column chromatography after organic phase is dried, eluant, eluent polarity is dichloromethane：Methanol=20:1, obtain orange solids 30mg.Receive Rate 30.0%.m.p.119-122℃.1H-NMR (DMSO-d6,400MHz) δ=1.85 (s, 3H), 3.18 (s, 3H), 3.20 (s, 3H), 4.12 (d, J=5.52Hz, 1H), 4.83 (d, J=5.52Hz, 2H), 6.69 (d, J=7.28Hz, 1H), 6.74 (s, 1H), 7.03 (t, J=7.72Hz, 1H), 7.27 (brs, 1H), 7.39-7.42 (m, 2H), 7.67 (d, J=8.36Hz, 1H), 7.86 (d, J=7.28Hz, 1H), 8.23 (brs, 1H), 8.42 (s, 1H), 8.71 (s, 1H), 10.86 (s, 1H) ppm.ESI-MS m/z512.8[M+H]+.。
Embodiment 14：
Solid, 56mg (0.293mmol) 4- (4- methyl piperazines) benzene obtained by the step (1) of 75mg (0.195mmol) embodiment 5 Amine, 81mg (0.585mmol) potassium carbonate, 9mg (0.00975mmol) Pd2(dba)3And 9.3mg (0.0195mmol) Xphos is dissolved in The 4mL tert-butyl alcohols, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 15h, water is added into reaction solution and is carried out with ethyl acetate Extraction, column chromatography after organic phase is dried, eluant, eluent polarity is dichloromethane：Methanol=15:1, obtain rose solid 12mg.Receive Rate 11.4%.m.p.188-192℃.1H-NMR (DMSO-d6,400MHz) δ=2.24 (s, 3H), 2.50 (s, 4H), 3.00 (s, 4H), 3.17 (s, 3H), 3.19 (s, 3H), 4.80 (d, J=5.08Hz, 2H), 6.68 (s, 1H), 6.72 (d, J=8.52Hz, 2H), 7.22 (brs, 1H), 7.42-7.45 (m, 3H), 7.84 (d, J=7.64Hz, 1H), 8.41 (s, 2H), 10.78 (s, 1H) ppm.ESI-MS m/z539.9[M+H]+.。
Embodiment 15：
Solid, 52mg (0.293mmol) 4- morpholines aniline, 81mg obtained by the step (1) of 75mg (0.195mmol) embodiment 5 (0.585mmol) potassium carbonate, 9mg (0.00975mmol) Pd2(dba)3And 9.3mg (0.0195mmol) Xphos is dissolved in the tertiary fourths of 4mL Alcohol, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 14h, water is added into reaction solution and is extracted with ethyl acetate, is had Machine mutually dries rear pillar chromatography, and eluant, eluent polarity is dichloromethane：Methanol=50:1, obtain salmon coloured solid 25mg.Yield 24.4%. m.p.155-158℃.1H-NMR (DMSO-d6,400MHz) δ=2.97 (m, 4H), 3.18 (s, 3H), 3.19 (s, 3H), 3.72 (m, 4H), 4.80 (d, J=5.52Hz, 2H), 6.68 (s, 1H), 6.73 (d, J=8.96Hz, 2H), 7.23 (brs, 1H), 7.39-7.42 (m, 1H), 7.46 (d, J=8.72Hz, 2H), 7.84 (d, J=6.84Hz, 1H), 8.43 (s, 2H), 10.78 (s, 1H)ppm.ESI-MS m/z526.8[M+H]+.
Embodiment 16：
Solid, 81mg (0.391mmol) 2- methoxyl group 4- morpholine benzene obtained by the step (1) of 75mg (0.195mmol) embodiment 5 Amine, 81mg (0.585mmol) potassium carbonate, 9mg (0.00975mmol) Pd2(dba)3And 9.3mg (0.0195mmol) Xphos is dissolved in The 4mL tert-butyl alcohols, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 14h, water is added into reaction solution and is carried out with ethyl acetate Extraction, column chromatography after organic phase is dried, eluant, eluent polarity is dichloromethane：Methanol=50:1, obtain Light brown solid 20mg.Receive Rate 18.4%.m.p.138-141℃.1H-NMR (DMSO-d6,400MHz) δ=3.03 (s, 4H), 3.16 (s, 3H), 3.26 (s, 3H), 3.73 (s, 4H), 3.80 (s, 3H), 4.74 (d, J=4.72Hz, 2H), 6.34 (d, J=7.20Hz, 1H), 6.60 (s, 1H), 6.71 (s, 1H), 7.03 (s, 1H), 7.40 (m, 2H), 7.85 (d, J=7.28Hz, 1H), 8.00 (d, J=8.72Hz, 1H),8.42(s,1H),10.87(s,1H)ppm.ESI-MS m/z556.8[M+H]+.。
Embodiment 17：
Solid, 35mg (0.293mmol) 3- cyano-anilines, 81mg obtained by the step (1) of 75mg (0.195mmol) embodiment 5 (0.585mmol) potassium carbonate, 9mg (0.00975mmol) Pd2(dba)3And 9.3mg (0.0195mmol) Xphos is dissolved in the tertiary fourths of 4mL Alcohol, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 14h, water is added into reaction solution and is extracted with ethyl acetate, is had Machine mutually dries rear pillar chromatography, and eluant, eluent polarity is dichloromethane：Methanol=100:1, obtain Light brown solid 30mg.Yield 33.0%.m.p.>250℃.1H-NMR (DMSO-d6,400MHz) δ=3.18 (s, 3H), 3.22 (s, 3H), 4.85 (d, J= 5.68Hz, 3H), 6.81 (s, 1H), 7.23 (d, J=7.68Hz, 1H), 7.31 (t, J=7.92Hz, 2H), 7.40-7.43 (m, 2H), 7.86 (d, J=7.72Hz, 1H), 7.92 (d, J=7,96Hz, 1H), 8.24 (s, 1H), 8.44 (s, 1H), 9.16 (s, 1H),11.07(s,1H)ppm.ESI-MS m/z466.8[M+H]+.。
Embodiment 18：
(1) solid, the tertiary fourth oxygen acylamino-s of 87mg (0.39mmol) 3- obtained by the step (1) of 75mg (0.195mmol) embodiment 5 Methylaniline, 81mg (0.585mmol) potassium carbonate, 9mg (0.00975mmol) Pd2(dba)3And 9.3mg (0.0195mmol) Xphos is dissolved in the 4mL tert-butyl alcohols, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 15h, water and second are added into reaction solution Acetoacetic ester is extracted, and column chromatography after organic phase is dried, eluant, eluent polarity is dichloromethane：Methanol=80:1, obtain faint yellow Solid 51mg.Yield 45.9%.m.p.110-113℃.1H-NMR (DMSO-d6,400MHz) δ=1.36 (s, 9H), 3.15 (s, 3H), 3.18 (s, 3H), 3.98 (d, J=5.52Hz, 2H), 4.81 (d, J=5.60Hz, 2H), 6.67 (d, J=7.28Hz, 1H), 6.71 (s, 1H), 7.01 (t, J=7.72Hz, 1H), 7.25 (m, 2H), 7.36-7.40 (m, 2H), 7.62 (d, J= 7.80Hz, 1H), 7.84 (d, J=6.48Hz, 1H), 8.40 (d, J=3.04Hz, 1H), 8.69 (s, 1H), 10.84 (s, 1H) ppm.ESI-MS m/z570.8[M+H]+.
(2) solid obtained by 145mg (0.254mmol) step (1) is dissolved in 7mL dichloromethane, adds 0.39mL (5.10mmol) trifluoroacetic acid, is stirred at room temperature.Stop after reaction 5h, rotation go after solvent to add saturated sodium carbonate solution adjust pH to 8, add ethyl acetate extraction.Organic phase carries out preparing plate separation, and solvent polarity is dichloromethane：Methanol=10:1, point Obtain faint yellow solid 30mg, yield 25.1%.m.p.178-183℃.1H-NMR (DMSO-d6,400MHz) δ=3.11 (s, 3H), 3.14 (s, 3H), 3.78 (s, 2H), 4.80 (d, J=5.84Hz, 2H), 7.00 (d, J=6.64Hz, 1H), 7.15-7.23 (m, 4H), 7.40 (dd, J=7.80Hz, J=4.76Hz, 1H), 7.57-7.64 (m, 3H), 7.73 (d, J=7.00Hz, 1H), 7.93 (s, 1H), 8.41 (d, J=2.8Hz, 1H), 9.51 (s, 1H) ppm.ESI-MS m/z470.9 [M+H]+.。
Embodiment 19：
(1) chloro- 5- fluorine pyrrolo- [2,3-d] pyrimidines of 655mg (3.20mmol) 2,4- bis-, 577mg (3.84mmol) N- first Base -2- aminobenzamides and 1.1mL (6.40mmol) DIPEA are dissolved in 30mL ethanol, and outer bath backflow is stirred Mix.Stop after reaction 40h, filtered after being stirred overnight at room temperature, obtain white solid 546mg, yield 53.5%.m.p.>250℃ .1H-NMR (DMSO-d6,400MHz) δ=2.76 (d, J=4.32Hz, 3H), 7.11 (t, J=7.40Hz, 1H), 7.26 (s, 1H), 7.52 (t, J=7.56Hz, 1H), 7.72 (d, J=7.40Hz, 1H), 8.68 (d, J=8.48Hz, 1H), 8.75 (s, 1H),11.89(s,1H),11.94(s,1H)ppm.ESI-MS m/z319.9[M+H]+.
(2) solid obtained by 150mg (0.470mmol) step (1), 84mg (0.564mmol) 5- amino indole -2- ketone, 195mg (1.41mmol) potassium carbonate, 22mg (0.0235mmol) Pd2(dba)3And 22mg (0.047mmol) Xphos is dissolved in uncle 6mL Butanol, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 15h, reaction solution is spin-dried for rear column chromatography, and eluant, eluent polarity is dichloro Methane：Methanol=20:1, get faint yellow solid 27mg, yield 13.3%.m.p.>250℃.1H-NMR(DMSO-d6, 400MHz) δ=2.75 (d, J=3.6Hz, 3H), 3.38 (s, 2H), 6.66 (d, J=8.20Hz, 1H), 6.78 (s, 1H), 7.03 (t, J=7.16Hz, 1H), 7.39-7.41 (m, 2H), 7.66 (d, J=8.00Hz, 1H), 7.70 (s, 1H), 8.64 (s, 1H), 8.84 (s, 1H), 8.90 (d, J=8.20Hz, 1H), 10.17 (s, 1H), 10.97 (s, 1H), 11.36 (s, 1H) .ESI-MS m/ z431.9[M+H]+.。
Embodiment 20：
Solid, 147mg (0.70mmol) 2- methoxyl groups -4- obtained by the step (1) of 150mg (0.470mmol) embodiment 19 Quinoline aniline, 195mg (1.41mmol) potassium carbonate, 22mg (0.0235mmol) Pd2(dba)3And 22mg (0.047mmol) Xphos is molten In the 6mL tert-butyl alcohols, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 15h, reaction solution is spin-dried for rear column chromatography, eluant, eluent pole Property is dichloromethane：Methanol=50:1, get Light brown solid 40mg, yield 17.3%.m.p.>250℃.1H-NMR(DMSO- D6,400MHz) δ=2.78 (d, J=4.44Hz, 3H), 3.08 (brs, 4H), 3.74 (brs, 4H), 3.79 (s, 3H), 6.47 (d, J=8.72Hz, 1H), 6.63 (s, 1H), 6.79 (s, 1H), 7.03 (t, J=7.04Hz, 1H), 7.40 (t, J=7.48Hz, 1H), 7.51 (s, 1H), 7.68 (d, J=6.72Hz, 1H), 7.79 (d, J=8.76Hz, 1H), 8.67 (s, 1H), 8.83 (d, J =8.12Hz, 1H), 10.98 (s, 1H), 11.39 (s, 1H) ppm.ESI-MS m/z491.9 [M+H]+.。
Embodiment 21：
Solid, 150mg (0.91mmol) 3- acetylamino methyls obtained by the step (1) of 150mg (0.470mmol) embodiment 19 Aniline, 195mg (1.41mmol) potassium carbonate, 22mg (0.0235mmol) Pd2(dba)3And 22mg (0.047mmol) Xphos is dissolved in The 6mL tert-butyl alcohols, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 15h, reaction solution is spin-dried for rear column chromatography, eluant, eluent polarity For dichloromethane：Methanol=30:1, get white solid 53mg, yield 25.2%.m.p.>250℃.1H-NMR(DMSO-d6, 400MHz) δ=1.88 (s, 3H), 2.81 (d, J=4.40Hz, 3H), 4.21 (d, J=5.64Hz, 2H), 6.80 (d, J= 7.32Hz, 1H), 6.88 (s, 1H), 7.09 (t, J=7.24Hz, 1H), 7.21 (t, J=7.84Hz, 1H), 7.50 (t, J= 7.32Hz, 1H), 7.55 (s, 1H), 7.73 (d, J=6.92Hz, 1H), 7.83 (d, J=8.36Hz, 1H), 8.31 (s, 1H), 8.71 (d, J=4.20Hz, 1H), 9.03 (d, J=8.56Hz, 1H), 9.10 (s, 1H), 11.10 (s, 1H), 11.50 (s, 1H) ppm.ESI-MS m/z447.9[M+H]+.。
Embodiment 22：
Solid, 78mg (0.517mmol) 3- acetyl amino phenyls obtained by the step (1) of 110mg (0.345mmol) embodiment 19 Amine, 143mg (1.04mmol) potassium carbonate, 16mg (0.0173mmol) Pd2(dba)3And 16mg (0.0345mmol) Xphos is dissolved in The 6mL tert-butyl alcohols, nitrogen protection, outer 100 DEG C of stirrings of bath.Stop after reaction 15h, reaction solution is spin-dried for rear column chromatography, eluant, eluent polarity For dichloromethane：Methanol=30:1, get white solid 41mg, yield 27.4%.m.p.>250℃.1H-NMR(DMSO-d6, 400MHz) δ=2.01 (s, 3H), 2.78 (d, J=4.36Hz, 3H), 6.84 (s, 1H), 7.03-7.16 (m, 3H), 7.42 (t, J =8.24Hz, 1H), 7.60 (d, J=7.92Hz, 1H), 7.69 (d, J=7.88Hz, 1H), 7.77 (s, 1H), 8.67 (d, J= 4.16Hz, 1H), 9.05 (d, J=8.64Hz, 1H), 9.07 (s, 1H), 9.80 (s, 1H), 11.05 (s, 1H), 11.49 (s, 1H) ppm.ESI-MS m/z433.9[M+H]+.。
The focal adhesion kinase of embodiment 23 (FAK) inhibitory activity is tested
Experimental method：40mM Tris(pH 7.4)、10nM MgCl2、0.1mg/mL BSA、1mM DTT、10μM ATP、 240ng FAK, 0.2mg/mL Poly (Glu, Tyr) and concentration to be measured compound group are into 50 μ L reaction system, compound Concentration gradient for 0.1nM, 0.33nM, 1nM, 3.3nM, 10nM, 33nM, 100nM, 333nM, 1 μM.Reaction system is at 30 DEG C After reacting 120min, 50 μ L Kinase-Glo Plus detection agents, 30 DEG C of reactions 10min, MD- are added into system Luminous, collection data, according to formula enzymatic activity % are detected under SpectraMax M5 multi-function microplate reader Luminecesce patterns ={ (LuWithout enzyme—LuDosing)/(LuWithout enzyme—LuThere is enzyme without medicine) * 100% enzymatic activity under each concentration is calculated, then use Graphpad Prism5 software processings, fitting obtain IC50Value.
Experimental result shows that the compound and its all kinds of salt have remarkable inhibiting activity (such as to focal adhesion kinase (FAK) Shown in table 1).
Table 1
Embodiment 24：Growth of tumour cell Inhibition test
Experimental method：Using the DMEM culture mediums that with the addition of 10% calf serum (FBS), satisfy in 37 DEG C, 5% carbon dioxide Cellar culture is carried out to tumour cell with the sterile culture case of humidity.After experiment starts, growth period cell of taking the logarithm, use 0.25% pancreatin digests, and after centrifugation plus culture medium adjustment cell concentration is 50000/mL, is inoculated with afterwards into 96 well culture plates, often The μ L cell suspensions of hole 100, overnight incubation in incubator, make cell attachment.Afterwards, the medicine to be measured of various concentrations is added into hole Thing, concentration gradient are 100 μM, 50 μM, 20 μM, 10 μM, 1 μM and 0.1 μM, each 4 multiple holes of concentration, while set not dosing Negative control.Cell after dosing is placed in 37 DEG C, cultivated in the incubator of 5% carbon dioxide saturated humidity.After 48h, to every hole 10 μ L 5mg/mL of middle addition MTT solution, continue to cultivate 4h.After abundant reaction generation formazan crystal, nutrient solution is sucked, often Hole adds 150 μ L DMSO Rong Xie formazans.After abundant mix, the absorbance OD values at the every hole 490nM wavelength of ELIASA test, According to formula cell proliferation inhibition rate %=[(ODIt is negative-ODAdministration)/(ODIt is negative-ODZeroing)] * 100% calculate each concentration increment suppress Rate, then obtain IC with Graphpad Prism5 software processings, fitting50Value.
Experimental result shows that the compound on tumor cell growth significantly inhibits (as shown in table 2).
Table 2

Claims (11)

  1. Pyrrolo- [2,3-d] pyrimidines of formula 1. (I) structure,
    Wherein, L is 0 or 1；
    R1、R2、R3、R4And R5It is substituent that is identical or differing, is respectively selected from-H ,-OCH3、-NO2、-CN、-F、-Cl、- (CH2)mCH3、-(CH2)mOH、-(CH2)mNH2、-(CH2)mNHCOCH3、-(CH2)mNHCO(CH2)m-, morpholine -4- bases, piperidines -1- Base, piperidin-4-yl, piperazine -1- bases, 1- methyl piperidine -4- bases or 4- methyl piperazine bases, m be 0-3 integer, adjacent group, That is R1With R2、R2With R3、R3With R4、R4With R5Between by one five yuan or hexa-atomic lactam nucleus connect；
    X and Y is atom that is identical or differing, selected from C atoms or N atoms；
    R6、R7、R8、R9And R10It is substituent that is identical or differing, is respectively selected from-H ,-(CH2)nCH3、-O(CH2)nCH3、-NH (CH2)nCH3、-N(CH3)SO2(CH2)nCH3、-NHSO2(CH2)nCH3、-NHCO(CH2)nCH3、-CONH(CH2)nCH3Or-SO2 (CH2)nCH3, n is 0-2 integer；
    R11Selected from-H ,-CN ,-OH ,-Cl ,-F ,-CH3、-CH2CH3Or-OCH3。
  2. 2. pyrrolo- [2,3-d] pyrimidines as described in claim 1, it is characterised in that
    L is 0 or 1；
    R1、R2、R3、R4And R5It is substituent that is identical or differing, is respectively selected from-H ,-OCH3、-F、-Cl、-(CH2)mNH2、- (CH2)mNHCOCH3、-(CH2)mNHCO(CH2)m-, morpholine -4- bases, piperidin-1-yl, piperidin-4-yl, piperazine -1- bases, 1- methyl Piperidin-4-yl or 4- methyl piperazine bases, m be 0-3 integer, adjacent group, i.e. R1With R2、R2With R3、R3With R4、R4With R5It Between by one five yuan or hexa-atomic lactam nucleus connect；
    X and Y is atom that is identical or differing, selected from C atoms or N atoms；
    R6、R7、R8、R9And R10It is substituent that is identical or differing, is respectively selected from-H ,-NH (CH2)nCH3、-N(CH3)SO2 (CH2)nCH3、-NHSO2(CH2)nCH3、-NHCO(CH2)nCH3、-CONH(CH2)nCH3Or-SO2(CH2)nCH3, n is the whole of 0-2 Number；
    R11Selected from-H ,-Cl ,-F or-CH3。
  3. 3. pyrrolo- [2,3-d] pyrimidines as described in claim 1, it is characterised in that described compound is：
    Compound 1, structure is as follows：
    Compound 2, structure is as follows：
    Compound 3, structure is as follows：
    Compound 4, structure is as follows：
    Compound 5, structure is as follows：
    Compound 6, structure is as follows：
    Compound 7, structure is as follows：
    Compound 8, structure is as follows：
    Compound 9, structure is as follows：
    Compound 10, structure is as follows：
    Compound 11, structure is as follows：
    Compound 12, structure is as follows：
    Compound 13, structure is as follows：
    Compound 14, structure is as follows：
    Compound 15, structure is as follows：
    Compound 16, structure is as follows：
    Compound 17, structure is as follows：
    Compound 18, structure is as follows：
    Compound 19, structure is as follows：
    Compound 20, structure is as follows：
    Compound 21, structure is as follows：
    Compound 22, structure is as follows：
  4. 4. the preparation method of pyrrolo- [2,3-d] pyrimidines described in claim 1, it is characterised in that press
    Completed shown in formula (II) by two step key reactions：
    The first step, the introducings of 4 substituted-aminos are that compound B preparation is obtained by following methods：(1), raw material A and 1-1.5 Times equivalent amine reagent under the catalysis of alkaline reagent, is obtained in appropriate solvent by nucleophilic substitution；Or (2), raw material A With 1-1.5 times of equivalent amine reagent in appropriate solvent, under the catalysis of palladium reagent and phosphorus part, obtained by coupling reaction；
    Second step, the introducings of 2 substituted anilinics are that the preparation of compound shown in Formulas I is obtained by following methods：(1) it is, above-mentioned First step reaction product is compound B with 1-1.5 times of equivalent substituted aniline reagent in appropriate solvent, in the catalysis of alkaline reagent Under, obtained by nucleophilic substitution；Or (2), compound B and 1-1.5 times of equivalent substituted aniline reagent in appropriate solvent, Under palladium reagent and phosphorus-containing ligand catalysis, obtained by coupling reaction.
  5. 5. the method as described in claim 4, it is characterised in that in the described first step,
    Raw material A is selected from 5-R11- 2,4- dichloro pyrrolo- [2,3-d] pyrimidine, wherein substituent R11Be-H ,-CN ,-OH ,-Cl ,-F ,- CH3、-CH2CH3Or-OCH3；
    Arylamine or substituted arylmethylamine of the amine reagent for substitution, wherein, X and Y are C atoms or N atoms；R6、R7、R8、R9 And R10It is substituent that is identical or differing, selected from-H ,-(CH2)nCH3、-O(CH2)nCH3、-NH(CH2)nCH3、-N(CH3)SO2 (CH2)nCH3、-NHSO2(CH2)nCH3、-NHCO(CH2)nCH3、-CONH(CH2)nCH3Or-SO2(CH2)nCH3, n is the whole of 0-2 Number；
    Solvent is selected from ethanol, isopropanol, n-butanol, the tert-butyl alcohol, tetrahydrofuran, dioxane, or DMF；
    Alkaline reagent is selected from pyridine, triethylamine, DIPEA, potassium carbonate or cesium carbonate；
    Palladium reagent is selected from palladium, palladium bichloride, three (dibenzalacetone) two palladium or tetrakis triphenylphosphine palladium；Phosphorus-containing ligand is selected from Ph3P, Xantphos, Xphos or BINAP.
  6. 6. the method as described in claim 4, it is characterised in that in described second step,
    In substituted aniline reagent, R1、R2、R3、R4And R5It is substituent that is identical or differing, is respectively selected from-H ,-OCH3、- NO2、-CN、-F、-Cl、-(CH2)mCH3、-(CH2)mOH、-(CH2)mNH2、-(CH2)mNHCOCH3、-(CH2)mNHCO(CH2)m-、 Morpholine -4- bases, piperidin-1-yl, piperidin-4-yl, piperazine -1- bases, 1- methyl piperidine -4- bases or 4- methyl piperazine bases, m 0- 3 integer, adjacent group, i.e. R1With R2、R2With R3、R3With R4、R4With R5Between by one five yuan or hexa-atomic lactam nucleus connect Connect；
    Solvent is selected from ethanol, isopropanol, n-butanol, the tert-butyl alcohol, tetrahydrofuran, dioxane, or DMF；
    Alkaline reagent is selected from pyridine, triethylamine, DIPEA, potassium carbonate or cesium carbonate；
    Palladium reagent is selected from palladium, palladium bichloride, three (dibenzalacetone) two palladium or tetrakis triphenylphosphine palladium；Phosphorus-containing ligand is selected from Ph3P, Xantphos, Xphos or BINAP.
  7. 7. according to pyrrolo- [2,3-d] pyrimidines of formula (I) structure described in claim 1, it is characterised in that also wrap Pharmaceutically acceptable salt, described salt are the pyrrolo-es to pyrrolo- [2, the 3-d] pyrimidines for including described in formula (I) The addition salts that pyrimidines are formed with acid, described acid is hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, lactic acid, third Ketone acid, acetic acid, maleic acid, methanesulfonic acid or p-methyl benzenesulfonic acid.
  8. 8. according to formula (I) structure described in claim 1 or claim 7 pyrrolo- [2,3-d] pyrimidines and its Salt, it is characterised in that pyrrolo- [2, the 3-d] pyrimidines and its salt are used for different doses according to different physicochemical properties The medicine preparation of type.
  9. 9. pyrrolo- [2,3-d] pyrimidines and its salt of formula (I) structure described in claim 1 or claim 7 exist The purposes in medicine for preparing treatment focal adhesion kinase relevant disease, wherein, the pyrrolo- of described formula (I) structure [2, 3-d] pyrimidines and its salt is to focal adhesion kinase (FAK) remarkable inhibiting activity.
  10. 10. the purposes as described in claim 9, it is characterised in that the focal adhesion kinase relevant disease is to focal adhesion kinase Height expression tumour.
  11. 11. the purposes as described in claim 10, it is characterised in that described tumour is liver cancer, colon cancer, lung cancer or mammary gland Cancer.
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