CN103664903A - Benzoazepine compounds and preparation method and application thereof - Google Patents

Benzoazepine compounds and preparation method and application thereof Download PDF

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CN103664903A
CN103664903A CN201210324492.0A CN201210324492A CN103664903A CN 103664903 A CN103664903 A CN 103664903A CN 201210324492 A CN201210324492 A CN 201210324492A CN 103664903 A CN103664903 A CN 103664903A
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alkyl
hydrogen
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张翱
耿美玉
刘志清
丁健
艾菁
彭霞
宋子兰
张静
纪寅淳
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention relates to benzoazepine compounds shown by the general formula I or pharmaceutically acceptable salt or solvate thereof, a preparation method thereof, a pharmaceutical composition containing the compounds, and an application of the compounds in preparation of drugs for preventing or treating the diseases related to abnormal cell proliferation, morphologic change, hyperkinesia and the like related to the gradual-change lymphoma enzyme in a biological body and drugs for preventing or treating the diseases related to angiogenesis or cancerometastasis, and particularly an application in preparation of drugs for treating or preventing tumor growth and metastasis.

Description

Tall and erect compounds of benzene nitrogen and its production and use
Technical field
The present invention relates to a class has gradually changeable lymphoma enzyme (ALK) and suppresses the tall and erect compounds of active benzene nitrogen or its pharmacy acceptable salt or solvate, its preparation method, the pharmaceutical composition that comprises this compound, and these compounds in for the preparation of prevention or treatment organism to the relevant abnormal cell proliferation of gradually changeable lymphoma enzyme, the medicine of the disease that metamorphosis and hypoerkinesia etc. are relevant, and the purposes in the medicine of the disease relevant to angiogenesis or metastasis of cancer, in particular for the purposes in the medicine for the treatment of or prophylaxis of tumours growth and transfer.
Background technology
1, ALK biological function and inhibitor
Gradually changeable lymphoma enzyme (ALK) is a kind of receptor tyrosine kinase, is under the jurisdiction of insulin receptor superfamily.Be found in the earliest in gradually changeable large celllymphoma (ALCL), in the ALCL of about 60%-85%, have the expression of ALK, and ALK is single-minded normally, be expressed in neural system, in especially neonatal brain.In human body, ALK gene expression dose declines along with reaching maturity of brain, and the amount in ripe cerebral tissue is very low, expresses and has certain regionality; Other system is not especially found the expression of ALK in hemopoietic system.ALK gene lacks expression in the non-hematopoietic system cancer of the overwhelming majority and healthy tissues, and the distribution range that shows alk protein is extremely narrow.
ALK gene is positioned at karyomit(e) 2p23 site, and the mRNA of the big or small 6222bp of the transcribed generation of ALK in normal circumstances servant source, consists of 29 exons, the I type membrane-spanning protein ALK of 1620 aminoacid sequence 200KDa of coding.ALK gene, conventionally in dormant state, causes cell deterioration to develop into malignant tumour owing to occurring to merge with other genes.Yet can have much with the gene that its occurs to merge, at nonsmall-cell lung cancer (non-small cell lung cancer, NSCLC) in, be mainly to merge with EML4 gene (echinoderms microtubule-associated protein sample 4), between echinoderms microtubule-associated protein sample 4-, becoming lymphoma kinases (EML4-ALK) fusion gene is 2%～7% in the incidence of NSCLC.
Along with deepening continuously of nonsmall-cell lung cancer (NSCLC) molecular biology research, the individualized treatment based on molecular marked compound has been gone to clinical from laboratory, and in NSCLC patient's treatment, has obtained significant clinical progress late.It is also important that, except traditional histopathology classification, the difference that NSCLC can also express according to various molecular marked compounds, carry out molecular phenotype classification, and to take the driven nature gene relevant to tumorigenesis be target spot, research and develop new medicine, carry out individuation molecular targeted therapy targetedly, improve patient's prognosis.In the ideal situation, all NSCLC patients should implement treatment targetedly in the advance detection of line correlation molecular marked compound for the treatment of in the situation that fully understanding patient tumors developed by molecule feature, improve result for the treatment of.Under such background, ALK micromolecular inhibitor, the two target inhibitor of c-Met/ALK etc. become very powerful and exceedingly arrogant molecular target.
At present, the micromolecular inhibitor PF02341066(compound 1 of Pfizer company exploitation) by U.S. FDA, on August 26th, 2011, ratified listing, this is also the micromolecular inhibitor of a unique ALK who has gone on the market.But existing clinical study shows PF02341066 to occur resistance, in the body of PF02341066, bioavailability needs further to be improved simultaneously.In addition, the AF-802(compound 2 of Japan), in clinical 2 phases, the AP-26113 of the LDK-378 of Novartis, the ASP-3026 of Astellas and ARIAD is in clinical 1 phase.Also have in addition 9 compounds in the discovery stage.
Figure BDA00002097479000021
Summary of the invention
An object of the present invention is to provide the tall and erect class twin nuclei compound of a class benzene nitrogen or its pharmacy acceptable salt or solvate, described compound has the structure shown in following general formula I, and it is that a class has ALK and suppresses active compound.
Another object of the present invention is to provide the preparation method of the tall and erect compounds of the benzene nitrogen shown in above-mentioned general formula I.
The tall and erect compounds of benzene nitrogen shown in general formula I provided by the invention or its pharmacy acceptable salt or solvate are by suppressing the effect of the performance inhibition tumor cell growths such as abnormal cell proliferation, metamorphosis and hypoerkinesia that gradually changeable lymphoma enzyme is relevant.The effect that these compounds also have angiogenesis inhibiting or anticancer to shift.
Therefore, a further object of the present invention be to provide disease that the tall and erect compounds of benzene nitrogen shown in general formula I or its pharmacy acceptable salt or solvate abnormal cell proliferation, metamorphosis and the hypoerkinesia relevant to the overexpression of gradually changeable lymphoma enzyme in for the preparation of prevention or treatment organism is relevant and with the medicine of angiogenesis or the relevant disease of metastasis of cancer in purposes, especially in the purposes for the preparation of in treatment or prophylaxis of tumours growth and the medicine shifting.
Another object of the present invention is to provide and comprises the tall and erect compounds of benzene nitrogen that general formula I represents or its pharmacy acceptable salt or solvate or its mixture as the pharmaceutical composition of activeconstituents.
Another object of the present invention be to provide a kind of treat disease that abnormal cell proliferation, metamorphosis and hypoerkinesia relevant to the overexpression of gradually changeable lymphoma enzyme in organism are relevant and with the method for angiogenesis or the relevant disease of metastasis of cancer, described method comprises and comprises compound, its pharmacy acceptable salt or pharmaceutically acceptable solvate that general formula I represents or its mixture as the pharmaceutical composition of activeconstituents to patient's administering therapeutic significant quantity.
To achieve these goals, the tall and erect compounds of benzene nitrogen or its pharmacy acceptable salt or solvate that one aspect of the present invention provides following general formula I to represent,
Figure BDA00002097479000031
Wherein, R 1for the C1-C8 alkyl not replacing or phenyl replaces; Or-T-G;
Wherein T be-C (=O)-,-S (=O) 2-,-C (=O) N (R a)-,-B-C (=O)-,-B-S (=O) 2-or-B-C (=O) N (R a)-; R wherein afor hydrogen or C1-C4 alkyl; B is C1-C4 alkylidene group;
G is C1-C8 alkyl; C3-C8 cycloalkyl; C6-C10 aryl; Contain 1-3 4-8 unit heterocyclic radical that is selected from N, O and S atom; Or contain 1-3 5-8 unit heteroaryl that is selected from N, O and S atom;
R 2and R 2' be hydrogen, C1-C8 alkyl or C6-C10 aryl independently of one another;
Or, R 2and R 2' formation group
Figure BDA00002097479000032
wherein, R band R cbe hydrogen or C1-C4 alkyl independently of one another;
R 3and R 4be hydrogen, halogen, cyano group, nitro, hydroxyl, amino or C1-C8 alkyl independently of one another;
Or, R 3and R 4form C4-C8 aliphatic series ring together with the carbon atom being connected; C6-C10 aromatic ring; Contain 1-3 4-8 unit heterocycle that is selected from N, O and S atom; Or contain 1-3 5-8 unit hetero-aromatic ring that is selected from N, O and S atom;
R 5and R 6be independently of one another hydrogen, C1-C8 alkyl or
Figure BDA00002097479000033
Wherein L be-C (=O)-,-S (=O) 2-,-C (=O) N (R d)-or-S (=O) 2n(R d)-; Wherein, R dfor hydrogen or C1-C4 alkyl;
M is hydrogen or C1-C8 alkyl.
Preferably, in compound of Formula I,
Wherein, R 1for the C1-C6 alkyl not replacing or phenyl replaces; Or-T-G;
Wherein T be-C (=O)-,-S (=O) 2-,-C (=O) N (R a)-,-B-C (=O)-,-B-S (=O) 2-or-B-C (=O) N (R a)-; Wherein, R afor hydrogen or C1-C4 alkyl; B is C1-C4 alkylidene group;
G is C1-C6 alkyl; C3-C6 cycloalkyl; C6-C8 aryl; Contain 1-3 4-6 unit heterocyclic radical that is selected from N, O and S atom; Or contain 1-3 5-7 unit heteroaryl that is selected from N, O and S atom;
R 2and R 2' be hydrogen, C1-C6 alkyl or C6-C8 aryl independently of one another;
Or, R 2and R 2' formation group
Figure BDA00002097479000041
wherein, R band R cbe hydrogen or C1-C4 alkyl independently of one another;
R 3and R 4be hydrogen, halogen, cyano group, nitro, hydroxyl, amino or C1-C6 alkyl independently of one another;
Or, R 3and R 4form C4-C6 aliphatic series ring together with the carbon atom being connected; C6-C8 aromatic ring; Contain 1-3 4-6 unit heterocycle that is selected from N, O and S atom; Or contain 1-3 5-7 unit hetero-aromatic ring that is selected from N, O and S atom;
R 5and R 6be independently of one another hydrogen, C1-C6 alkyl or
Figure BDA00002097479000042
L is-C (=O)-,-S (=O) 2-,-C (=O) N (R d)-or-S (=O) 2n(R d)-; Wherein, R dfor hydrogen or C1-C4 alkyl;
M is hydrogen or C1-C6 alkyl.
More preferably, in compound of Formula I,
Wherein, R 1for the C1-C4 alkyl not replacing or phenyl replaces; Or-T-G;
Wherein T be-C (=O)-,-S (=O) 2-,-C (=O) N (R a)-,-B-C (=O)-,-B-S (=O) 2-or-B-C (=O) N (R a)-; Wherein, R afor hydrogen or C1-C2 alkyl; B is C1-C2 alkylidene group;
G is C1-C4 alkyl; C3-C6 cycloalkyl; C6-C8 aryl; Contain 1-3 4-6 unit heterocyclic radical that is selected from N, O and S atom; Or contain 1-3 5-7 unit heteroaryl that is selected from N, O and S atom;
R 2and R 2' be hydrogen, C1-C4 alkyl or C6-C8 aryl independently of one another;
Or, R 2and R 2' formation group
Figure BDA00002097479000043
wherein, R band R cbe hydrogen or C1-C4 alkyl independently of one another;
R 3and R 4be hydrogen, halogen, cyano group, nitro, hydroxyl, amino or C1-C4 alkyl independently of one another;
Or, R 3and R 4form C4-C6 aliphatic series ring together with the carbon atom being connected; C6-C8 aromatic ring; Contain 1-3 4-6 unit heterocycle that is selected from N, O and S atom; Or contain 1-3 5-7 unit hetero-aromatic ring that is selected from N, O and S atom;
R 5and R 6be independently of one another hydrogen, C1-C4 alkyl or
L is-C (=O)-,-S (=O) 2-,-C (=O) N (R d)-or-S (=O) 2n(R d)-; Wherein, R dfor hydrogen or C1-C2 alkyl;
M is hydrogen or C1-C4 alkyl.
Further preferably, in compound of Formula I,
Wherein, R 1for methyl, benzyl or-T-G;
Wherein T be-C (=O)-,-S (=O) 2-,-C (=O) N (R a)-,-B-C (=O)-,-B-S (=O) 2-or-B-C (=O) N (R a)-; Wherein, R afor hydrogen or methyl; B is methylene radical;
G is methyl, ethyl, cyclopropyl, phenyl or morpholinyl;
R 2and R 2' be hydrogen, ethyl, n-propyl, sec.-propyl or phenyl independently of one another;
Or, R 2and R 2' formation methylene radical, 1,1-ethylidene or 2,2-propylidene;
R 3and R 4be hydrogen, halogen, cyano group, nitro, hydroxyl or amino independently of one another;
Or, R 3and R 4form pyridine ring together with the carbon atom being connected;
R 5and R 6be independently of one another hydrogen or
L is-C (=O)-,-S (=O) 2-,-C (=O) N (R d)-or-S (=O) 2n(R d)-; Wherein, R dfor hydrogen or methyl; M is methyl or sec.-propyl.
Preferably, in above-mentioned general formula I, R 5and R 6in one be hydrogen, another is
Figure BDA00002097479000052
be that the compound shown in general formula I is preferably the compound shown in following general formula V:
Figure BDA00002097479000053
Wherein, R 1, R 2, R 2', R 3, R 4, L and M definition identical with the definition of the compound shown in above-mentioned general formula I.Typical compound of the present invention includes but not limited to the compound shown in table one:
Table one
Figure BDA00002097479000061
Figure BDA00002097479000071
Figure BDA00002097479000081
Another aspect of the present invention provides the preparation method of the tall and erect compounds of benzene nitrogen that general formula I represents, the tall and erect compounds of benzene nitrogen that general formula I represents can the method by coupling or replacement be obtained by compound ii and compound III.
Aniline II and pyrimidine III obtain through coupling the compound that general formula I represents under catalyzer exists;
Figure BDA00002097479000082
For example, the substituted pyrimidines III of the substituted aniline II of 1 equivalent and 1 equivalent is mixed in microwave tube, adds the cesium carbonate of 2 equivalents, the palladium of 0.25 equivalent, 4 of 0.5 equivalent, two diphenylphosphine-9 of 5-, the solvent 1 of 9-dimethyl oxa-anthracene and 3mL, 4-1 dioxane, 150 watts, 120 degree are lower to be stirred 2 hours, and reaction solution is extracted with ethyl acetate, saturated common salt washing, anhydrous sodium sulfate drying.Filtration is spin-dried for, and crosses silicagel column and obtains target product.
Or,
Aniline II and pyrimidine III are carried out substitution reaction under camphorsulfonic acid catalysis, obtain the compound that general formula I represents;
Figure BDA00002097479000083
For example, the pyrimidine III of the substituted aniline II of 1 equivalent and 1 equivalent is mixed in microwave tube, adds camphorsulfonic acid and the Virahol 3mL of 2 equivalents, 150 watts, the lower heating of 80 degree one hour, reaction solution is extracted with ethyl acetate, saturated sodium bicarbonate is washed, saturated common salt washing, anhydrous sodium sulfate drying.Filtration is spin-dried for, and crosses silicagel column and obtains target product.
Wherein, R 1, R 2, R 2', R 3, R 4, R 5and R 6definition identical with the definition in above-mentioned general formula I;
X is fluorine, chlorine, bromine or iodine.
Another aspect of the present invention also provide disease that the tall and erect compounds of benzene nitrogen shown in general formula I or its pharmacy acceptable salt or its solvate abnormal cell proliferation, metamorphosis and the hypoerkinesia relevant to the overexpression of gradually changeable lymphoma enzyme in for the preparation of prevention or treatment organism is relevant and with the medicine of angiogenesis or the relevant disease of metastasis of cancer in purposes, especially in the purposes for the preparation of in treatment or prophylaxis of tumours growth and the medicine shifting.
Another aspect of the present invention provides a kind of pharmaceutical composition, it comprises the tall and erect compounds of the benzene nitrogen shown in one or more general formula Is for the treatment of significant quantity or its pharmacy acceptable salt or solvate, and can optionally further comprise pharmaceutically acceptable carrier or vehicle.
Another aspect of the present invention provide a kind of treat disease that abnormal cell proliferation, metamorphosis and hypoerkinesia relevant to the overexpression of gradually changeable lymphoma enzyme in organism are relevant and with the method for angiogenesis or the relevant disease of metastasis of cancer, described method comprises and comprises benzene nitrogen Zhuo compounds, its pharmacy acceptable salt or pharmaceutically acceptable solvate that general formula I represents or its mixture as the pharmaceutical composition of activeconstituents to patient's administering therapeutic significant quantity.
Accompanying drawing explanation
Fig. 1 is the HPLC spectrogram of raceme S1;
Fig. 2 is the HPLC spectrogram of optical isomer S2;
Fig. 3 is the HPLC spectrogram of optical isomer S3.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.These embodiment are only for purpose of explanation, and do not limit the scope of the invention and essence.
Preparation Example
1h-NMR measures with Varian MercuryAMX300 type instrument; 2,4,5-trichloropyrimidine; isatoic anhydride, p-nitrophenyl ethanol, N-methylbenzylamine; 2,4-dichloropyridine is [3,2-d] pyrimidine also; 2-(sec.-propyl alkylsulfonyl) aniline, palladium, the chloro-1-beautiful jade second-1-of 2-ketone; the chloro-N,N-dimethylacetamide of 2-, 4; two diphenylphosphine-9 of 5-, 9-dimethyl oxa-anthracene is purchased from J & KChemica lark prestige chemical reagents corporation, and all the other reagent are produced by Chinese Medicine reagent company limited.All solvents all pass through re-distillation before use, and the anhydrous solvent using is all to obtain by standard method drying treatment; Except explanation, it is all under nitrogen protection, to carry out and TLC tracking that institute responds, and during aftertreatment, all through saturated sodium-chloride water solution, washs and anhydrous sodium sulfate drying process; The purifying of product is all used silica gel (200 ~ 300 order) column chromatography except explanation; Wherein silica gel (200 ~ 300 order) is produced by Haiyang Chemical Plant, Qingdao, and GF-254 thin-layer silicon offset plate is produced by Yantai Jiang You silica gel development corporation, Ltd..
1. compound S 1 is synthetic
Figure BDA00002097479000101
The synthesized reference document of its Raw 1-1: the synthesized reference document of WO2008080891. raw material 1-2: Bioorganic & Medicinal Chemistry Letters, 21 (2), 660-663; 2011.
Compound 1-1,1-2, palladium, part 4, two diphenylphosphine-9 of 5-, 9-dimethyl oxa-anthracene, and cesium carbonate is mixed in microwave tube, adds 2ml Isosorbide-5-Nitrae-dioxane, microwave 110 degree, 1 hour, 150 watts.Be chilled to room temperature, add ethyl acetate washing, merge organic layer, saturated sodium bicarbonate is washed, anhydrous sodium sulfate drying, and filtration is spin-dried for, upper silicagel column, methylene dichloride: methyl alcohol: ammoniacal liquor=30:1:0.1 obtains product S 1.
Compound S 1: 1h NMR (300MHz, CDCl 3) δ 11.05 (s, 1H), 8.64 (d, J=8.4Hz, 1H), 8.13 – 8.03 (m, 1H), 7.50 – 7.35 (m, 3H), 7.16 (s, 1H), 7.04 (dd, J=12.7,7.1Hz, 3H), 6.25 (s, 1H), 3.17 – 2.62 (m, 8H), 2.36 (s, 5H), 1.30 (d, J=7.2Hz, 3H).
2. compound S 2 is synthetic
Figure BDA00002097479000102
The synthesized reference document of its Raw 2-1: WO2008080891.
The same S1 of synthetic method of compound S 2.
Compound S 2: 1h NMR (300MHz, CDCl 3) δ 11.05 (s, 1H), 8.64 (d, J=8.4Hz, 1H), 8.13-8.03 (m, 1H), 7.50 – 7.35 (m, 3H), 7.16 (s, 1H), 7.04 (dd, J=12.7,7.1Hz, 3H), 6.25 (s, 1H), 3.17 – 2.62 (m, 8H), 2.36 (s, 5H), 1.30 (d, J=7.2Hz, 3H).
3. compound S 3 is synthetic
Figure BDA00002097479000111
The synthesized reference document of its Raw 3-1: WO2008080891.
The same S1 of synthetic method of compound S 3.
Compound S 3: 1h NMR (300MHz, CDCl 3) δ 11.05 (s, 1H), 8.64 (d, J=8.4Hz, 1H), 8.13 – 8.03 (m, 1H), 7.50 – 7.35 (m, 3H), 7.16 (s, 1H), 7.04 (dd, J=12.7,7.1Hz, 3H), 6.25 (s, 1H), 3.17 – 2.62 (m, 8H), 2.36 (s, 5H), 1.30 (d, J=7.2Hz, 3H).
4. compound S 4 is synthetic
The synthesized reference document of raw material 4-1: WO2009143389.
The same S1 of synthetic method of compound S 4.
Compound S 4: 1h NMR (300MHz, CDCl 3) δ 9.56 (s, 1H), 8.53 (d, J=8.4Hz, 1H), 8.11 (d, J=1.4Hz, 1H), 7.87 (d, J=7.9Hz, 1H), 7.53 (t, J=7.9Hz, 1H), 7.36 (d, J=8.1Hz, 1H), 7.23 – 7.13 (m, 2H), 7.00 (d, J=8.0Hz, 1H), 3.29-3.17 (m, 1H), 3.14-2.94 (m, 2H), 2.92-2.71 (m, 2H), 2.64 (d, J=12.2Hz, 1H), 2.34 (s, 4H), 2.24 (d, J=9.1Hz, 1H), 1.29 (d, J=6.0Hz, 6H), 1.22 (d, J=7.2Hz, 3H).
5. compound S 5 is synthetic
The synthetic same 1-2 of intermediate 5-3.
The synthetic same S1 of compound S 5.
Compound S 5: 1h NMR (300MHz, CDCl 3) δ 12.37 (s, 1H), 8.97 (d, J=7.8Hz, 1H), 8.64 (d, J=4.1Hz, 1H), 7.82 (d, J=8.4Hz, 1H), 7.59 – 7.46 (m, 4H), 7.07 (d, J=7.9Hz, 1H), 6.87 (d, J=7.9Hz, 1H), 6.52 (s, 1H), 6.47 (d, J=7.8Hz, 2H), 3.32 (ddd, J=45.7,24.5,12.4Hz, 5H), 3.05 (d, J=4.8Hz, 3H), 2.92 (d, J=11.5Hz, 2H), 2.50 (s, 3H), 1.36 (d, J=7.3Hz, 3H).
6. compound s 6 is synthetic
Figure BDA00002097479000122
The synthesized reference patent of raw material 6-1: WO8500808.
The synthetic same S1 of compound s 6.
Compound s 6: 1h NMR (300MHz, CDCl 3) δ 11.00 (s, 1H), 8.59 (d, J=8.0Hz, 1H), 8.00 (s, 1H), 7.58 (d, J=7.5Hz, 1H), 7.46 (d, J=8.2Hz, 1H), 7.33 (dd, J=16.2,8.9Hz, 4H), 7.17 (d, J=7.0Hz, 2H), 7.11 – 7.03 (m, 2H), 6.80 (s, 1H), 6.58 (s, 1H), 6.21 (s, 1H), 4.30 (s, 1H), 3.06 (s, 2H), 3.02 (d, J=4.9Hz, 3H), 2.87 (s, 4H), 2.41 (s, 3H).
7. compound S 7 is synthetic
Figure BDA00002097479000131
The synthetic same 1-2 of raw material 7-3, synthesized reference document: WO2008080891.
The synthetic same S1. of compound S 7
Compound S 7: 1h NMR (300MHz, CDCl 3) δ 11.14 (s, 1H), 8.51 (d, J=8.2Hz, 1H), 7.52 – 7.30 (m, 6H), 7.29 (d, J=7.2Hz, 1H), 7.23 (d, J=7.5Hz, 1H), 7.13 (d, J=8.2Hz, 1H), 7.04 (t, J=7.5Hz, 1H), 6.93 (s, 1H), 6.79 (s, 1H), 6.30 (s, 1H), 4.45 (d, J=8.9Hz, 1H), 3.19 (d, J=11.3Hz, 2H), 3.01 (d, J=4.8Hz, 3H), 2.99 – 2.81 (m, 3H), 2.45 (s, 4H).
8. compound S 8 is synthetic
Figure BDA00002097479000141
The synthesized reference document of raw material 8-1: WO2008080891.
Intermediate 8-2's is synthetic: raw material 8-1 is dissolved in DMF, under ice bath, slowly drips the DMF diluent of allyl group benzylamine, moves on to stirring at room 1h after dripping off, reaction solution is poured in frozen water, adds ethyl acetate extraction, merges organic phase, saturated sodium bicarbonate is washed, and saturated sodium-chloride is washed, anhydrous sodium sulfate drying.Filtration is spin-dried for to obtain 8-2.
Intermediate 8-3's is synthetic: raw material 8-2, and three (dibenzalacetone) two palladiums, Tetrafluoroboric acid tri-butyl phosphine and triethylamine are mixed in Isosorbide-5-Nitrae-dioxane, and 90 degree stir and spend the night.In cooling falling back, be extracted with ethyl acetate, after organic phase is dry, column chromatography obtains 8-3.
Intermediate 8-4's is synthetic: raw material 8-3, in DCE, adds salt of wormwood and chloroformate-1-chloro-ethyl ester, and backflow 2h filters salt of wormwood, and filtrate being spin-dried for adds methyl alcohol, continues backflow 5h, is spin-dried for the methyl alcohol extraction that adds methylene chloride, after dry pillar, obtain intermediate 8-4. 1h NMR (300MHz, CDCl 3) δ 8.13-7.97 (m, 2H), 7.25 (d, J=3.4Hz, 1H), 5.32 (s, 1H), 5.23 (s, 1H), 3.58 (s, 2H), 3.13-2.90 (m, 4H).
Intermediate 8-5's is synthetic: raw material 8-4, and the chloro-1-beautiful jade second-1-ketone of 2-and salt of wormwood are mixed in acetonitrile, are heated to 45 degree, and stirring is spent the night, ethyl acetate extraction product, column chromatography obtains intermediate 8-5. 1h NMR (300MHz, CDCl 3) δ 8.12-7.98 (m, 2H), 7.25 (d, J=2.7Hz, 1H), 5.43-5.25 (m, 2H), 3.61 (d, J=7.1Hz, 4H), 3.52 (s, 2H), 3.48 (s, 4H), 3.39 (s, 2H), 2.94 (dd, J=10.7,3.4Hz, 4H).
Intermediate 8-6's is synthetic: raw material 8-5 is dissolved in the mixed solution of second alcohol and water, adds iron powder and ammonium chloride, and reflux 1h filters, and filtrate is extracted with ethyl acetate, and after organic layer is dry, column chromatography for separation obtains intermediate 8-6. 1h NMR (300MHz, CDCl 3) δ 6.83 (d, J=7.9Hz, 1H), 6.58 (d, J=2.4Hz, 1H), 6.48 (dd, J=7.9,2.5Hz, 1H), 5.22 (d, J=1.7Hz, 1H), 5.12 – 5.07 (m, 1H), 3.67 – 3.47 (m, 11H), 3.40 (s, 2H), 3.35 (d, J=1.7Hz, 2H), 2.79 (tt, J=9.5,3.0Hz, 4H).
Synthesizing of compound S 8: raw material 1-2 and 8-6 are dissolved in Virahol, add 4A molecular sieve, camphorsulfonic acid, microwave 80 degree, 1h, 150w, adds sodium bicarbonate and ethyl acetate extraction, and after organic layer is dry, direct column chromatography obtains compound S 8.
Compound S 8: 1h NMR (300MHz, CDCl 3) δ 11.07 (s, 1H), 8.62 (d, J=8.6Hz, 1H), 8.08 (s, 1H), 7.54 – 7.28 (m, 4H), 7.09 – 6.95 (m, 3H), 6.31 (s, 1H), 5.22 (s, 1H), 5.12 (s, 1H), 3.67 – 3.46 (m, 12H), 3.02 (d, J=4.8Hz, 3H), 2.86 (s, 4H).
9. compound S 9 is synthetic
Figure BDA00002097479000151
The synthetic same 8-6. of intermediate 9-2
The synthetic same S8. of compound S 9
Compound S 9: 1h NMR (300MHz, DMSO) δ 11.62 (s, 1H), 9.44 (s, 1H), 8.73 (t, J=6.9Hz, 2H), 8.22 (s, 1H), 7.73 (d, J=7.9Hz, 1H), 7.61 (d, J=7.0Hz, 2H), 7.46 (t, J=7.8Hz, 1H), 7.11 (dd, J=11.5,8.1Hz, 2H), 5.21 (d, J=11.3Hz, 2H), 4.17 (s, 2H), 3.40 (d, J=5.8Hz, 2H), 2.89 (d, J=5.9Hz, 2H), 2.79 (d, J=4.5Hz, 3H), 2.72 (s, 3H).
10. compound S 10 is synthetic
Figure BDA00002097479000161
The synthetic same S8. of compound S 10
Compound S 10: 1h NMR (400MHz, CDCl 3) δ 9.60 (s, 1H), 8.52 (d, J=8.3Hz, 1H), 8.16 (s, 1H), 7.92 (dd, J=8.0,1.4Hz, 1H), 7.66 – 7.57 (m, 1H), 7.48 (dd, J=6.2,2.2Hz, 2H), 7.38 (s, 1H), 7.09 (d, J=8.9Hz, 1H), 5.25 (s, 2H), 4.28 (s, 2H), 3.65 – 3.57 (m, 2H), 3.30 – 3.21 (m, 1H), 3.00 – 2.94 (m, 2H), 2.58 (s, 3H), 1.32 (d, J=6.9Hz, 6H).
Synthesizing of 11. compound Ss 11
Figure BDA00002097479000162
The synthesized reference document of raw material 11-1: WO2008080891
Synthetic same 9-1, the 9-2. of intermediate 11-2,11-3
Intermediate 11-3: 1hNMR (300MHz, CDCl 3) δ 6.86 (t, J=7.3Hz, 1H), 6.56-6.37 (m, 2H), 3.55 (ddd, J=23.1,15.2,10.3Hz, 6H), 3.09-2.87 (m, 2H), 2.84-2.67 (m, 1H), 2.37 (dd, J=14.5,7.2Hz, 2H), 1.27 (dd, J=9.0,5.5Hz, 3H), 1.14 (dd, J=13.6,7.4Hz, 3H).
The synthetic same S1 of compound S 11.
Compound S 11: 1h NMR (400MHz, CDCl 3) δ 11.13 (d, J=20.9Hz, 1H), 8.64 (t, J=8.4Hz, 1H), 8.10 (s, 1H), 7.53 (d, J=6.9Hz, 1H), 7.46-7.35 (m, 2H), 7.31 (d, J=13.3Hz, 1H), 7.23 (s, 0H), 7.14 – 6.94 (m, 2H), 6.59 (s, 1H), 3.96 – 3.42 (m, 4H), 3.05 (dd, J=15.7,5.8Hz, 5H), 2.84 (dd, J=15.3,6.2Hz, 1H), 2.41 (q, J=7.4Hz, 2H), 1.33 – 1.26 (m, 2H), 1.23 (d, J=7.2Hz, 2H), 1.16 (td, J=7.4,4.6Hz, 3H).
Synthesizing of 12. compound Ss 12
The synthetic same S8. of compound S 12
Compound S 12: 1h NMR (300MHz, CDCl 3) δ 11.09 (s, 1H), 8.63 (d, J=8.4Hz, 1H), 8.06 (s, 1H), 7.48 (d, J=7.6Hz, 1H), 7.43 – 7.31 (m, 3H), 7.15 (s, 1H), 7.00 (dd, J=13.9,7.7Hz, 2H), 6.57 (d, J=4.3Hz, 1H), 3.24 (d, J=2.1Hz, 2H), 3.13 (s, 3H), 2.99 (d, J=4.7Hz, 3H), 2.95 (s, 3H), 2.92 (s, 2H), 2.66 (d, J=11.9Hz, 5H), 1.27 (d, J=7.3Hz, 3H).
Synthesizing of 13. compound Ss 13
Figure BDA00002097479000172
Intermediate 13-2: 1h NMR (300MHz, CDCl 3) δ 6.87 (d, J=7.8Hz, 1H), 6.60 (d, J=2.1Hz, 1H), 6.55 – 6.48 (m, 1H), 5.21 (d, J=16.3Hz, 2H), 3.57 (s, 2H), 3.29 (s, 2H), 2.78 (d, J=4.1Hz, 4H), 2.43 (s, 3H).
The synthetic same S8. of compound S 13
Compound S 13: 1h NMR (300MHz, CDCl 3) δ 11.06 (s, 1H), 8.62 (d, J=8.5Hz, 1H), 8.07 (s, 1H), 7.49 – 7.33 (m, 3H), 7.28 (s, 1H), 7.02 (t, J=8.2Hz, 2H), 6.36 (s, 1H), 5.18 (d, J=13.8Hz, 2H), 3.31 (s, 2H), 2.99 (d, J=4.8Hz, 3H), 2.83 (d, J=15.9Hz, 4H), 2.42 (s, 3H).
14. compound S 14 is synthetic
Figure BDA00002097479000181
The synthetic same 8-3. of intermediate 14-2
The synthetic same 8-6. of intermediate 14-3
The synthetic same S8. of compound S 14
Compound S 14: 1h NMR (300MHz, DMSO) δ 11.60 (s, 1H), 9.34 (s, 1H), 8.72 (s, 2H), 8.19 (s, 1H), 7.72 (d, J=8.0Hz, 1H), 7.46 (d, J=8.0Hz, 1H), 7.40 (s, 1H), 7.34 (d, J=7.9Hz, 1H), 7.28 (d, J=4.4Hz, 5H), 7.25-7.17 (m, 1H), 7.08 (t, J=7.5Hz, 1H), 6.96 (d, J=8.1Hz, 1H), 5.53 (d, J=7.0Hz, 1H), 3.64 (s, 2H), 3.25 (s, 2H), 2.79 (d, J=4.4Hz, 3H), 2.71 (s, 4H), 1.52 (d, J=6.9Hz, 3H).
Synthesizing of 15. compound Ss 15
Figure BDA00002097479000191
The synthetic same 12-2. of intermediate 15-3
The synthetic same S8. of compound S 15
Compound S 15: 1h NMR (300MHz, DMSO) δ 11.57 (s, 1H), 9.39 (s, 1H), 8.74 (s, 2H), 8.20 (s, 1H), 7.74 (d, J=7.9Hz, 1H), 7.48 (t, J=8.1Hz, 2H), 7.39 (s, 1H), 7.14 (t, J=7.6Hz, 1H), 7.01 (d, J=8.3Hz, 1H), 3.68 (s, 2H), 3.17 – 2.93 (m, 2H), 2.86 – 2.76 (m, 8H), 2.69 (d, J=12.4Hz, 2H), 1.63 (d, J=24.1Hz, 2H), 0.83 (s, 3H).
16. compound S 16 is synthetic
Figure BDA00002097479000192
The synthetic same S8. of compound S 16
Compound S 16: 1h NMR (300MHz, CDCl 3) δ 9.56 (s, 1H), 8.53 (d, J=8.4Hz, 1H), 8.13 (s, 1H), 7.90 (dd, J=8.0,1.5Hz, 1H), 7.59 (t, J=7.9Hz, 1H), 7.44-7.36 (m, 1H), 7.31 (s, 1H), 7.19 (d, J=1.8Hz, 1H), 7.01 (d, J=8.2Hz, 1H), 3.82 (d, J=12.5Hz, 2H), 3.22 (dt, J=20.0,9.8Hz, 3H), 3.00-2.78 (m, 2H), 2.74 (s, 4H), 1.83-1.66 (m, 2H), 1.30 (dd, J=6.8,3.4Hz, 7H), 0.88 (t, J=7.3Hz, 3H).
Synthesizing of 17. compound Ss 17
Figure BDA00002097479000201
The synthetic same S1. of compound S 17
Compound S 17: 1h NMR (300MHz, CDCl 3) δ 11.10 (d, J=10.7Hz, 1H), 8.64 (dd, J=8.2,3.9Hz, 1H), 8.09 (s, 1H), 7.55-7.37 (m, 3H), 7.23 (s, 1H), 7.15-6.95 (m, 3H), 6.53 (d, J=4.8Hz, 1H), 4.33-3.64 (m, 2H), 3.43 (d, J=13.2Hz, 1H), 3.14 (dd, J=27.2,15.4Hz, 1H), 3.01 (d, J=4.8Hz, 3H), 2.96 – 2.66 (m, 2H), 1.91 – 1.47 (m, 4H), 0.81 (qd, J=18.3,8.2Hz, 7H).
Synthesizing of 18. compound Ss 18
Figure BDA00002097479000202
The synthesized reference document of intermediate 18-1: WO2011140338.
The synthetic same 11-3. of intermediate 18-2
Intermediate 18-2: 1h NMR (300MHz, CDCl 3) δ 6.86 (d, J=8.5Hz, 1H), 6.45 (d, J=5.1Hz, 2H), 3.81 (s, 2H), 3.57 (s, 1H), 3.20 – 3.03 (m, 2H), (2.91 d, J=12.0Hz, 1H), 2.81 – 2.60 (m, 5H), 1.78 (m, 1H), 0.93 (d, 6H).
The synthetic same S8. of compound S 18
Compound S 18: 1h NMR (300MHz, DMSO) δ 11.57 (s, 1H), 9.39 (s, 1H), 8.74 (s, 2H), 8.20 (s, 1H), 7.74 (d, J=7.9Hz, 1H), 7.48 (t, J=8.1Hz, 2H), 7.39 (s, 1H), 7.14 (t, J=7.6Hz, 1H), 7.01 (d, J=8.3Hz, 1H), 3.68 (s, 2H), 3.17 – 2.93 (m, 2H), 2.86 – 2.76 (m, 7H), 2.69 (s, 3H), 0.83 (d, 6H).
Synthesizing of 19. compound Ss 19
Figure BDA00002097479000211
The synthetic same 13-2. of intermediate 19-1
Intermediate 19-1: 1h NMR (300MHz, CDCl 3) δ 6.87 (d, J=7.8Hz, 1H), 6.60 (d, J=2.1Hz, 1H), 6.55 – 6.48 (m, 1H), 5.21 (d, J=16.3Hz, 2H), 3.57 (s, 2H), 3.29 (s, 2H), 2.78 (d, J=4.1Hz, 4H), 2.43 (s, 3H), 1.80(s, 6H).
The synthetic same S8. of compound S 19
Compound S 19: 1h NMR (300MHz, CDCl 3) δ 11.06 (s, 1H), 8.62 (d, J=8.5Hz, 1H), 8.07 (s, 1H), 7.49-7.33 (m, 3H), 7.28 (s, 1H), 7.02 (t, J=8.2Hz, 2H), 6.36 (s, 1H), 5.18 (d, J=13.8Hz, 2H), 3.31 (s, 2H), 2.99 (d, J=4.8Hz, 3H), 2.83 (d, J=15.9Hz, 4H), 2.42 (s, 3H), 1.82(s, 6H).
Two, test example
1, receptor tyrosine kinase ALK molecular level activity rating
The active Inhibitory molecules level screening of receptor tyrosine kinase ALK of representative compound, method therefor:
Enzyme-linked immunosorbent assay (ELISA)
(1) the PBS(10mM sodium phosphate buffer of enzyme reaction substrate Poly (Glu, Tyr) 4:1 without potassium ion, 150mM NaCl, pH7.2-7.4) be diluted to 20 μ g/mL, 125 μ L/ hole coated elisa plates, put 37 ° of C reaction 12-16 hour.Discard liquid in hole.Wash plate, with the T-PBS(in 200 μ L/ holes, contain the PBS without potassium ion of 0.1%Tween-20) wash plate three times, each 5 minutes.Dry enzyme plate 1-2 hour in 37 ° of C baking ovens.
(2) every hole adds with reaction buffer (50mM HEPES pH 7.4,50mM MgCl 2, 0.5mM MnCl 2, 0.2mM Na 3vO 4, 1mM DTT) and the ATP solution 49 μ L of dilution, in every hole, add 1 μ L compound, add compound to be tested, then add each kinases territory recombinant protein of reaction buffer dilution for 50 μ L to start reaction, each experiment need be established without ATP control wells two holes.Put 37 ° of C shaking tables (100rpm) reaction 1 hour.Discard liquid in hole, T-PBS washes plate three times.
(3) add antibody PY99100 μ L/ hole (the T-PBS 1:500 dilution containing BSA 5mg/mL for antibody), 37 ° of C shaking tables react 0.5 hour.Discard liquid in hole, T-PBS washes plate three times.
(4) add the anti-100 μ L/ holes of sheep anti mouse two (the T-PBS 1:2000 dilution containing BSA 5mg/ml for antibody) of horseradish peroxidase-labeled, 37 ° of C shaking tables react 0.5 hour.Discard liquid in hole, T-PBS washes plate three times.
(5) add the OPD nitrite ion 100 μ L/ holes of 2mg/ml (with containing 0.03%H 2o 20.1M citric acid-sodium citrate damping fluid (pH=5.4) dilution), 25 ° of C lucifuges reaction 1-10 minute.
(6) add 2M H 2sO 450 μ L/ hole stopped reactions, with the wavelengthtunable orifice plate microplate reader VERSAmax reading that declines, wavelength is 490nm.
(7) interpretation of result
Figure BDA00002097479000221
The test result of representative compound is as shown in following table two:
Table two
Figure BDA00002097479000222
Figure BDA00002097479000231
Figure BDA00002097479000241
The test result of representative compound shows, the compound of this type is under the concentration of 10 μ M, to the inhibiting rate of ALK, all reach more than 80%, under the concentration of 1 μ M, inhibiting rate is more than 50%, the activity of some compounds and positive control quite or more excellent, are therefore very potential ALK inhibitor.
In addition, we find that part of compounds wherein has obvious inhibition activity test method the same to the ALK of anomaly (L1196M) enzyme.
Table three. compound is to receptor tyrosine kinase ALK (L1196M) enzyme inhibiting rate (%) alive
Figure BDA00002097479000242
2, compound chirality splits
Because compound at least has the chiral centre of 1 1-position mostly, we split them by chirality preparative liquid chromatography, obtain corresponding optical isomer.For example two of compound S 1 enantiomer S2 and S3 all show higher ALK enzyme inhibition activity, and wherein the activity of the specific activity S2 of S3 exceeds one times, shows that the combination of S3 and enzyme is better.
(1), preparation embodiment
Adopt HPLC method, use chiral column to chirality isomer separation, collect its respective components, rotary evaporation, except desolventizing, obtains the sterling of optical isomer.
Splitting condition:
Chiral column: CHIRALCEL OJ-H
Chiral column size: 0.46cmI.D. * 15cmL
Moving phase: MeOH/DEA=100/0.1 flow velocity: 1ml/min
Detect wavelength: UV254nm
Preparation result
1) table four: optical purity value
Figure BDA00002097479000251
2) table five: quality
Figure BDA00002097479000252
2) table six: desiccated balance process
Figure BDA00002097479000253
Wb: bottle and the weight of filling in; Ws+b: bottle and the gross weight of plug and sample; Wsample: the final weight of sample
(2), chirality HPLC spectrogram is referring to Fig. 1-3.
(3), enantiomer ALK enzyme inhibition activity:
The ALK enzyme inhibition activity of table seven: S1 and corresponding isomer S2, S3
Figure BDA00002097479000261
3, receptor tyrosine kinase ALK cell levels activity rating
(1), testing method:
KARPAS in logarithmic phase 299 cells are seeded to the 96 micro-culture plates in hole by 5000/ hole, every hole 100 μ L, after overnight incubation, the compound effects 72 hours that adds different concns (1,0.1), each concentration is established three multiple holes, and establishes the contrast of physiological saline solvent and the acellular zeroing hole of respective concentration.After effect finishes, discard nutrient solution, add 10% (w/v) trichoroacetic acid(TCA) (100 μ L/ hole) to fix 1 hour in 4 ° of C, use subsequently distilled water flushing five times, after being at room temperature dried, every hole adds SRB solution (4mg/mL, be dissolved in 1% glacial acetic acid) 100 μ L, under room temperature, hatch dyeing after 15 minutes, with 1% glacial acetic acid, rinse and wash away unconjugated SRB five times, after dry under room temperature, every hole adds 10mM Tris solution 100 μ L, and VERSMax microplate reader is measured the optical density(OD) (OD value) under 515nm wavelength.Experiment repeats twice.
(2), test result is as shown in following table eight:
Table eight
Figure BDA00002097479000262
Figure BDA00002097479000271
As can be seen from the above results, new compound not only has high reactivity at ALK enzyme level, on directly related cell KARPAS 299 cells of ALK, also performance is significantly active, active surpassing of part of compounds is positive compound PF02341066, therefore, these compounds have good antitumor research and development potentiality

Claims (9)

1. the following general formula I of a class represents the tall and erect compounds of benzene nitrogen or its pharmacy acceptable salt or solvate,
Figure FDA00002097478900011
Wherein, R 1for the C1-C8 alkyl not replacing or phenyl replaces; Or-T-G;
Wherein T be-C (=O)-,-S (=O) 2-,-C (=O) N (R a)-,-B-C (=O)-,-B-S (=O) 2-or-B-C (=O) N (R a)-; R wherein afor hydrogen or C1-C4 alkyl; B is C1-C4 alkylidene group;
G is C1-C8 alkyl; C3-C8 cycloalkyl; C6-C10 aryl; Contain 1-3 4-8 unit heterocyclic radical that is selected from N, O and S atom; Or contain 1-3 5-8 unit heteroaryl that is selected from N, O and S atom;
R 2and R 2' be hydrogen, C1-C8 alkyl or C6-C10 aryl independently of one another;
Or, R 2and R 2' formation group
Figure FDA00002097478900012
wherein, R band R cbe hydrogen or C1-C4 alkyl independently of one another;
R 3and R 4be hydrogen, halogen, cyano group, nitro, hydroxyl, amino or C1-C8 alkyl independently of one another;
Or, R 3and R 4form C4-C8 aliphatic series ring together with the carbon atom being connected; C6-C10 aromatic ring; Contain 1-3 4-8 unit heterocycle that is selected from N, O and S atom; Or contain 1-3 5-8 unit hetero-aromatic ring that is selected from N, O and S atom;
R 5and R 6be independently of one another hydrogen, C1-C8 alkyl or
Figure FDA00002097478900013
Wherein L be-C (=O)-,-S (=O) 2-,-C (=O) N (R d)-or-S (=O) 2n(R d)-; Wherein, R dfor hydrogen or C1-C4 alkyl;
M is hydrogen or C1-C8 alkyl.
2. the tall and erect compounds of benzene nitrogen according to claim 1 or its pharmacy acceptable salt or solvate, wherein, R 1for the C1-C6 alkyl not replacing or phenyl replaces; Or-T-G;
Wherein T be-C (=O)-,-S (=O) 2-,-C (=O) N (R a)-,-B-C (=O)-,-B-S (=O) 2-or-B-C (=O) N (R a)-; Wherein, R afor hydrogen or C1-C4 alkyl; B is C1-C4 alkylidene group;
G is C1-C6 alkyl; C3-C6 cycloalkyl; C6-C8 aryl; Contain 1-3 4-6 unit heterocyclic radical that is selected from N, O and S atom; Or contain 1-3 5-7 unit heteroaryl that is selected from N, O and S atom;
R 2and R 2' be hydrogen, C1-C6 alkyl or C6-C8 aryl independently of one another;
Or, R 2and R 2' formation group wherein, R band R cbe hydrogen or C1-C4 alkyl independently of one another;
R 3and R 4be hydrogen, halogen, cyano group, nitro, hydroxyl, amino or C1-C6 alkyl independently of one another;
Or, R 3and R 4form C4-C6 aliphatic series ring together with the carbon atom being connected; C6-C8 aromatic ring; Contain 1-3 4-6 unit heterocycle that is selected from N, O and S atom; Or contain 1-3 5-7 unit hetero-aromatic ring that is selected from N, O and S atom;
R 5and R 6be independently of one another hydrogen, C1-C6 alkyl or
Figure FDA00002097478900022
L is-C (=O)-,-S (=O) 2-,-C (=O) N (R d)-or-S (=O) 2n(R d)-; Wherein, R dfor hydrogen or C1-C4 alkyl;
M is hydrogen or C1-C6 alkyl.
3. the tall and erect compounds of benzene nitrogen according to claim 2 or its pharmacy acceptable salt or solvate, wherein,
R 1for the C1-C4 alkyl not replacing or phenyl replaces; Or-T-G;
Wherein T be-C (=O)-,-S (=O) 2-,-C (=O) N (R a)-,-B-C (=O)-,-B-S (=O) 2-or-B-C (=O) N (R a)-; Wherein, R afor hydrogen or C1-C2 alkyl; B is C1-C2 alkylidene group;
G is C1-C4 alkyl; C3-C6 cycloalkyl; C6-C8 aryl; Contain 1-3 4-6 unit heterocyclic radical that is selected from N, O and S atom; Or contain 1-3 5-7 unit heteroaryl that is selected from N, O and S atom;
R 2and R 2' be hydrogen, C1-C4 alkyl or C6-C8 aryl independently of one another;
Or, R 2and R 2' formation group
Figure FDA00002097478900023
wherein, R band R cbe hydrogen or C1-C4 alkyl independently of one another;
R 3and R 4be hydrogen, halogen, cyano group, nitro, hydroxyl, amino or C1-C4 alkyl independently of one another;
Or, R 3and R 4form C4-C6 aliphatic series ring together with the carbon atom being connected; C6-C8 aromatic ring; Contain 1-3 4-6 unit heterocycle that is selected from N, O and S atom; Or contain 1-3 5-7 unit hetero-aromatic ring that is selected from N, O and S atom;
R 5and R 6be independently of one another hydrogen, C1-C4 alkyl or
Figure FDA00002097478900024
L is-C (=O)-,-S (=O) 2-,-C (=O) N (R d)-or-S (=O) 2n(R d)-; Wherein, R dfor hydrogen or C1-C2 alkyl;
M is hydrogen or C1-C4 alkyl.
4. the tall and erect compounds of benzene nitrogen according to claim 3 or its pharmacy acceptable salt or solvate, wherein, R 1for methyl, benzyl or-T-G;
Wherein T be-C (=O)-,-S (=O) 2-,-C (=O) N (R a)-,-B-C (=O)-,-B-S (=O) 2-or-B-C (=O) N (R a)-; Wherein, R afor hydrogen or methyl; B is methylene radical;
G is methyl, ethyl, cyclopropyl, phenyl or morpholinyl;
R 2and R 2' be hydrogen, ethyl, n-propyl, sec.-propyl or phenyl independently of one another;
Or, R 2and R 2' formation methylene radical, 1,1-ethylidene or 2,2-propylidene;
R 3and R 4be hydrogen, halogen, cyano group, nitro, hydroxyl or amino independently of one another;
Or, R 3and R 4form pyridine ring together with the carbon atom being connected;
R 5and R 6be independently of one another hydrogen or
Figure FDA00002097478900031
L is-C (=O)-,-S (=O) 2-,-C (=O) N (R d)-or-S (=O) 2n(R d)-; Wherein, R dfor hydrogen or methyl;
M is methyl or sec.-propyl.
5. the tall and erect compounds of benzene nitrogen according to claim 1 or its pharmacy acceptable salt or solvate, wherein, one of the tall and erect compounds of described benzene nitrogen is following compounds:
Figure FDA00002097478900032
Figure FDA00002097478900041
Figure FDA00002097478900051
6. a method of preparing the tall and erect compounds of benzene nitrogen claimed in claim 1,
Aniline II and pyrimidine III obtain through coupling the compound that general formula I represents under catalyzer exists;
Or,
Aniline II and pyrimidine III are carried out substitution reaction under camphorsulfonic acid catalysis, obtain the compound that general formula I represents;
Figure FDA00002097478900061
Wherein, R 1, R 2, R 2', R 3, R 4, R 5and R 6definition identical with the definition in claim 1;
X is fluorine, chlorine, bromine or iodine.
7. the medicine of the disease that in claim 1-5, the tall and erect compounds of the benzene nitrogen described in any one or its pharmacy acceptable salt or solvate abnormal cell proliferation, metamorphosis and the hypoerkinesia relevant to gradually changeable lymphoma enzyme in for the preparation of prevention or treatment organism is relevant and with the medicine of angiogenesis or the relevant disease of metastasis of cancer in purposes.
In claim 1-5 the tall and erect compounds of the benzene nitrogen described in any one or its pharmacy acceptable salt or solvate in the purposes for the preparation of in treatment or prophylaxis of tumours growth and the medicine shifting.
9. a pharmaceutical composition, its comprise one or more treatment significant quantities according to the tall and erect compounds of benzene nitrogen described in any one in claim 1-5 or its pharmacy acceptable salt or solvate, and can optionally further comprise pharmaceutically acceptable carrier or vehicle.
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WO2018215557A1 (en) * 2017-05-23 2018-11-29 Centre National De La Recherche Scientifique Ion channel inhibitor compounds for cancer treatment

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WO2018215557A1 (en) * 2017-05-23 2018-11-29 Centre National De La Recherche Scientifique Ion channel inhibitor compounds for cancer treatment
FR3066761A1 (en) * 2017-05-23 2018-11-30 Centre National De La Recherche Scientifique NOVEL IONIC CHANNEL INHIBITOR COMPOUNDS
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