CN103319456B

CN103319456B - Dihydropyridine compounds, and compositions, preparation methods and applications thereof

Info

Publication number: CN103319456B
Application number: CN201210081677.3A
Authority: CN
Inventors: 程建军; 秦继红; 叶斌
Original assignee: SHANGHAI HUILUN TECHNOLOGY Co Ltd
Current assignee: Shanghai Huilun Jiangsu Pharmaceutical Co ltd; Shanghai Huilun Pharmaceutical Co ltd
Priority date: 2012-03-23
Filing date: 2012-03-23
Publication date: 2015-05-13
Anticipated expiration: 2032-03-23
Also published as: CN103319456A

Abstract

Dihydropyridine compounds are disclosed, and are compounds represented by the following general formula (I), wherein R<1> is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; R<2> is selected from hydrogen, alkyl, substituted alkyl or a heterocycle formed by R<2> and R<3>; and R<3> is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or a heterocycle formed by R<3> and R<2>. The invention also discloses preparation methods for the compounds represented by the general formula (I), and pharmaceutical compositions and applications of the compounds.

Description

Dihydropyridine compounds, its composition, preparation method and purposes

Technical field

The present invention relates to a kind of dihydropyridine compounds, its preparation method, containing they pharmaceutical compositions as activeconstituents, and the purposes of its cancer of being correlated with in order to the treatment disease, particularly c-Met relevant to Tyrosylprotein kinase c-Met as medicine.

Background of invention

Cancer is the number one killer threatening whole world human life's health.Although the progress of medical science makes the mankind have much new means for the treatment of cancer, cancer is still considered to still unsolved difficult medical problem at present.Cause the cause of disease of cancer a lot, in recent years, the development of the subject such as molecular weight tumor, molecular pharmacology makes the essence of tumour progressively illustrate, and people recognize that the essence of cell carcinogenesis is that intracellular signal transduction pathway is lacked of proper care the cell infinite multiplication caused gradually.As participating in the of paramount importance member of cell signaling, protein tyrosine kinase (protein tyrosine kinases, PTKs are called for short Tyrosylprotein kinase) is modal growth factor receptors, with the generation of tumour with develop closely related.The hyperactivity of Tyrosylprotein kinase, causes its downstream signaling pathway to activate, thus cause cell transformation, propagation, to anti-apoptotic, promote cell survival, finally lead oncogenic formation.Therefore, the Development Trend of antitumor drug starts to turn to medicine for improper signal conduction in cell from traditional cell toxicity medicament in recent years, and there have related drugs to be applied to successively to be clinical.Compared with traditional cell toxicant series antineoplastic medicament, this kind of therapeutic effects of molecular targeted agents is strong, toxic side effect is little, becomes the focus of current antineoplastic medicine research and development gradually.

Tyrosylprotein kinase divides receptor type tyrosine kinase and non-receptor tyrosine kinase two kinds, receptor type tyrosine kinase has EGF-R ELISA (EGFR) family, vascular endothelial growth factor receptor (VEGFR) family, platelet derived growth factor receptor (PDGFR) family, fibroblast growth factor acceptor (FGFR) family etc., nonreceptor tyrosine kinase is Src kinase families, Jak such as, FAK etc., comprise again multiple hypotype in each kinase families.

Hepatic growth factor receptor c-Met is one (Park et al., Proc.Natl.Acad.Sci.USA 84:6379-83,1987 of receptor type tyrosine kinase; Bottaro et al., Science 2S 1:802-4,1991), be made up of together with extracellular domain, transmembrane segment and cytoplasmic tyrosine kinase territory the outside alpha subunit of high glycosylation and β subunit.Its endogenic ligand is pHGF (hepatocyte growth factor, HGF) (Nature, 327:239-242 (1987); J.Cell Biol., 111:2097-2108 (1990)), ligand binding induction c-Met dimerization, generate the activated receptor of autophosphorylation, promote the signal transduction in downstream, in tumour cell, mediate multiple response, comprise the increment of epithelial cell and endotheliocyte, stimulate epithelial cell movement, cell survival and morphologic change and promotion intrusion etc.In addition, HGF regulates vasculogenesis, for tumour growth and spread extremely important.C-Met and the process LAN of part in kinds of tumors (comprising thyroid carcinoma, ovarian cancer, carcinoma of the pancreas etc.) thereof also illustrate that the effect in its evolution in these tumours.At present, c-Met is as the action target spot of antitumor drug, and its advantage is progressively illustrated (Nature ReviewsCancer, 2012,12,89-103).

In the primary tumor played a key effect at c-Met receptor activation and secondary tumors transfer, the biological substance (ribozyme, antibody and sense-rna) of target HGF or c-Met can the generation of Tumor suppression, and the selectivity micromolecular inhibitor of target c-Met is also predicted has treatment potentiality.Optionally c-Met micromolecular inhibitor is all contained, Preparation Method And The Use in the patents such as WO2009091374, WO2009149836, WO2011003604, WO2011042367, WO2011042368, CN200910247948.6, CN201010175273.1.

Dihydropyridine compounds as tyrosine kinase inhibitor involved in the present invention, as tyrosine kinase inhibitor, particularly c-Met inhibitor, was never in the news.

Summary of the invention

One of technical problem to be solved by this invention is to provide a kind of dihydropyridine compounds.

Two of technical problem to be solved by this invention is to provide the preparation method of above-mentioned dihydropyridine compounds.

Three of technical problem to be solved by this invention is to provide the composition containing above-mentioned dihydropyridine compounds.

Four of technical problem to be solved by this invention is to provide the purposes of above-mentioned dihydropyridine compounds.

As the dihydropyridine compounds of first aspect present invention, for having the compound of following general formula (I):

Wherein,

R ¹be selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;

R ²be selected from hydrogen, alkyl, substituted alkyl; Or, R ²with R ³form heterocycle;

R ³be selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; Or, R ³with R ²form heterocycle.

More specifically, general formula of the present invention (I) compound is preferably from the compound as shown in the formula (I-1) to (I-15):

The dihydropyridine compounds of described general formula (I) is any one in enantiomer, diastereomer, conformer, or arbitrarily both, three or four mixture.

The dihydropyridine compounds of described general formula (I) comprises described compound pharmacy acceptable derivates.

The dihydropyridine compounds of general formula of the present invention (I) can exist as a pharmaceutically acceptable salt form.

Pharmacy acceptable salt of the present invention is hydrochloride, hydrobromate, vitriol, phosphoric acid salt, acetate, trifluoroacetate, mesylate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate, the malate of general formula (I) compound.

As the preparation method of general formula (I) dihydropyridine compounds of second aspect present invention, carry out (wherein R by method as described below ₁, R ₂, R ₃definition as mentioned above; " PG " (protecting groups) is amido protecting group; such as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl etc.): with pimelinketone-4-ethyl formate (1) for raw material; at N; intermediate (2) is converted under the effect of dinethylformamide dimethylacetal (DMF-DMA); this intermediate and hydrazine reaction, cyclisation is pyrazole compound (3).Ester group in intermediate (3) is reduced with reductive agent (as lithium aluminium hydride, sodium borohydride etc.), obtains intermediate (4).Then by the amido of intermediate (4) pyrazoles with suitable protecting group (such as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl etc.) protect to obtain intermediate (II); again by its alcoholic extract hydroxyl group with suitable condition (as Dess-Martin oxidation; Swern is oxidized) oxidation, obtain aldehydes intermediate (III).Intermediate (III) and cyano group ketone compounds (A) condensation; obtain intermediate (IV); again with raw material (B) condensation of amido alkene nitrile, then deprotection base under suitable condition, obtains compound (I).

route 1:

? route 1in, R ₁, R ₂, R ₃definition as previously mentioned; Especially, R in amido alkene nitrile raw material (B) ₂with R ₃combination preferably from following (B-1) to structure (B-3) Suo Shi:

As R in general formula (I) ₁with R ₃identical (replacing with Ra) and R ₂during for hydrogen, the compound described by it is also by method preparation (the wherein R shown in following route 2 ₁, R ₂, R ₃definition as mentioned above; " PG " (protectinggroups) is amido protecting group; such as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl etc.): with pimelinketone-4-ethyl formate (1) for raw material; at N; intermediate (2) is converted under the effect of dinethylformamide dimethylacetal (DMF-DMA); this intermediate and hydrazine reaction, cyclisation is pyrazole compound (3).Ester group in intermediate (3) is reduced with reductive agent (as lithium aluminium hydride, sodium borohydride etc.), obtains intermediate (4).Then by the amido of intermediate (4) pyrazoles with suitable protecting group (such as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl etc.) protect to obtain intermediate (II); again by its alcoholic extract hydroxyl group with suitable condition (as Dess-Martin oxidation; Swern is oxidized) oxidation, obtain aldehydes intermediate (III).Amino alkene nitrile raw material (C) condensation of this intermediate (III) and 2 equivalents, then deprotection base under suitable condition, obtain compound (I).

route 2:

Above-mentioned protecting group is amido protecting group.Described amido protecting group be tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl.

The described base of deprotection under suitable condition refers to: adopt the organic solution of hydrogenchloride or trifluoracetic acid/methylene dichloride to remove tertbutyloxycarbonyl; The method of catalytic hydrogenation is adopted to remove carbobenzoxy-(Cbz); Or adopt trifluoracetic acid to remove methoxy-benzyl.

As the composition containing dihydropyridine compounds of third aspect present invention, wherein said pharmaceutical composition comprises dihydropyridine compounds and the acceptable vehicle of pharmacy of the general formula (I) for the treatment of significant quantity.

As a kind of pharmaceutical composition of third aspect present invention, wherein said pharmaceutical composition comprises pharmacy acceptable derivates and the acceptable vehicle of pharmacy of the dihydropyridine compounds of the general formula (I) for the treatment of significant quantity.

As a kind of pharmaceutical composition of third aspect present invention, wherein said pharmaceutical composition comprises pharmacy acceptable salt and the acceptable vehicle of pharmacy of the dihydropyridine compounds of the general formula (I) for the treatment of significant quantity.

Described pharmaceutical composition makes tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis, granule, syrup, emulsion, ointment, ointment, suppository, injection.

As the application of fourth aspect present invention, be wherein that the dihydropyridine compounds of general formula (I) is preparing the application in Function protein kinase catalytic activity goods.

As the application of fourth aspect present invention, be wherein that the pharmacy acceptable derivates of the dihydropyridine compounds of general formula (I) is preparing the application in Function protein kinase catalytic activity goods.

As the application of fourth aspect present invention, be wherein that the application in Function protein kinase catalytic activity goods prepared by the pharmaceutically useful salt of the dihydropyridine compounds of general formula (I).

As the application of fourth aspect present invention, be wherein that pharmaceutical composition treats the application in the medicine of the disease relevant with protein kinase in preparation.

Described protein kinase is c-Met receptor tyrosine kinase.

Described cancer is selected from cancer of the stomach, lung cancer, thyroid carcinoma, colorectal carcinoma, kidney, liver cancer, ovarian cancer, mammary cancer, prostate cancer, bladder cancer, head and neck cancer, carcinoma of the pancreas, carcinoma of gallbladder, osteosarcoma, rhabdosarcoma, MFH/ fibrosarcoma, glioblastoma/astrocytoma, melanoma or mesothelioma.

The research of signal transduction pathway that the dihydropyridine compounds of general formula (I) involved in the present invention also can be used for the research of biology or pharmacology phenomenon, Tyrosylprotein kinase participates in and the comparative evaluation for new tyrosine kinase inhibitor.

Embodiment

The invention provides the dihydropyridine compounds shown in general formula defined above (I), prepare the method for these compounds, use the pharmaceutical composition of these compounds and use the method for these compounds.

Listed is below definition to the various terms for describing the compounds of this invention.These definition are applied to the term (unless separately having restriction on other occasions) used in each place of specification sheets, and no matter these terms are used alone or as the part of more macoradical.

Unless otherwise defined, the term " alkyl " (be used alone or as the part of another group) that the application uses refers to the univalent perssad comprising 1 to 12 carbon atom that alkane derives.Preferred alkyl has 1 to 6 carbon atom.Alkyl is the optional straight chain, side chain or the cyclic saturated hydrocarbon base that replace.Exemplary alkyl comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, isohexyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2,4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl etc.The substituting group of " substituted alkyl " is selected from following group: alkyl, halogen (as fluorine, chlorine, bromine, iodine), alkoxyl group, amino/amido, haloalkyl (as trichloromethyl, trifluoromethyl), aryl, aryloxy, alkylthio, hydroxyl, cyano group, nitro, carboxyl, alkoxy carbonyl, alkyl-carbonyl oxygen base, carbamyl, urea or sulfydryl.

Term " aryl " that the application uses (be used alone or as the part of another group) refers to monocyclic aromatic ring or polycyclic aromatic ring, the phenyl of such as phenyl, replacement etc. and the group such as naphthyl, the phenanthryl etc. that condense.Thus, aryl comprises the ring that at least one has at least 6 atoms, comprise five such rings (wherein comprising 22 atoms at the most) at the most, and between adjacent carbon atom or suitable heteroatoms, there is (conjugation) double bond alternately.Preferred aryl comprises 6 to 14 carbon atoms in ring." substituted aryl " can optionally replace one or more group, and described group includes but not limited to halogen (such as fluorine, chlorine, bromine), alkyl (such as methyl, ethyl, propyl group), substituted alkyl (as trifluoromethyl), cycloalkyl, alkoxyl group (such as methoxy or ethoxy), hydroxyl, carboxyl, amine formyl (-C (=O) NR ' R "), alkoxy carbonyl (-CO ₂r), amino/amido, nitro, cyano group, thiazolinyl oxygen base, aryl, heteroaryl, alkylsulfonyl (-SO ₂r) etc., wherein, R, R ', R " are described alkyl.

Term " heteroaryl " that the application uses (be used alone or as the part of another group) refers to replace and unsubstituted aromatics 5 or 6 yuan of monocyclic groups, 9 or 10 yuan of bicyclic radicals and 11 to 14 yuan of three cyclic group, and these groups have at least one heteroatoms (O, S or N) at least one ring.The each ring comprising heteroatomic heteroaryl can comprise one or two Sauerstoffatoms or sulphur atom and/or one to four nitrogen-atoms, condition is that in each ring, heteroatomic sum is four or less, and each ring has at least one carbon atom, the ring condensed forming above-mentioned bicyclic radicals and three cyclic groups only can comprise carbon atom, and can be saturated or fractional saturation.Nitrogen-atoms and sulphur atom can be oxidations, and nitrogen-atoms can be quaternary ammoniated.The heteroaryl of dicyclo or three rings must comprise the ring of at least one Wholly aromatic, but other ring condensed or multiple ring can be aromatics or non-aromatic.Heteroaryl can connect at any available nitrogen-atoms of any ring or carbon atom place." substituted heteroaryl " ring system can comprise zero, one, two or three and be selected from following substituting group: the alkyl of halogen, alkyl, replacement, thiazolinyl, block base, aryl, nitro, cyano group, hydroxyl, alkoxyl group, alkylthio ,-CO ₂h ,-C (=O) H ,-CO ₂the cycloalkyl of-alkyl ,-C (=O) alkyl, phenyl, benzyl, phenylethyl, phenyl oxygen base, thiophenyl, cycloalkyl, replacement, Heterocyclylalkyl, heteroaryl ,-NR ' R " ,-C (=O) NR ' R " ,-CO ₂nR ' R " ,-C (=O) NR ' R " ,-NR ' CO ₂r " ,-NR ' C (=O) R " ,-SO ₂nR ' R " and-NR ' SO ₂r ", wherein R ' and R " independently is selected from hydrogen, alkyl, the alkyl of replacement and cycloalkyl separately, or R ' and R " together with formation Heterocyclylalkyl or heteroaryl ring.

The example of bicyclic heteroaryl comprises pyrryl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, di azoly, isoxazolyl, thiazolyl, thiadiazolyl group, isothiazolyl, furyl, thienyl, oxadiazoles base, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl etc.

The example of bicyclic heteroaryl comprises indyl, benzothiazolyl, benzodioxole base, benzoxazolyl, benzothienyl, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, benzimidazolyl-, benzopyranyl, indolizine base, benzofuryl, chromone base, tonka bean camphor base, benzofuryl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridyl etc.

The example of tricyclic heteroaryl comprises carbazyl, benzindole base, phenanthroline base, acridyl, phenanthridinyl etc.

The heteroatoms that a carbon atom in term " heterocycle " that the application uses (be used alone or as the part of another group) finger ring is selected from O, S or N replaces and 3 extra carbon atoms cycloalkyl (non-aromatic) that can be replaced by described heteroatoms at the most.Term " heterocyclic radical " that the application uses (be used alone or as the part of another group) refers to comprise the stable undersaturated monocyclic ring system of saturated or part of 5 to 7 annular atomses (carbon atom and be selected from other atom of nitrogen, sulphur and/or oxygen).Heterocycle can be 5,6 or 7 yuan of monocycles, and comprises the heteroatoms that, two or three is selected from nitrogen, oxygen and/or sulphur.Heterocycle can be optional replacement; this means that heterocycle can have one or more to be independently selected from following group in one or more commutable ring position replacement: alkyl, Heterocyclylalkyl, heteroaryl, alkoxyl group, nitro, monoalkyl amido, dialkyl amino, cyano group, halogen, haloalkyl, alkyloyl, ammonia/amino-carbonyl, monoalkyl amino-carbonyl, dialkyl amino carbonyl, alkylamidoalkyl, alkoxyalkyl, alkoxy carbonyl, alkyl-carbonyl oxygen base and aryl, described aryl optionally replaces halogen, alkyl and alkoxyl group.The example of these Heterocyclylalkyls includes but not limited to: piperidines, morpholine, high morpholine, piperazine, parathiazan, tetramethyleneimine and azetidine.

Term " alkoxyl group " that the application uses (be used alone or as the part of another group) refers to the alkyl preferably with 1 to 6 carbon atom connected by Sauerstoffatom, and such as-OR, wherein R is described alkyl.

Term " amino " that the application uses (be used alone or as the part of another group) refers to-NH ₂." amido " can optionally replace have one or two substituting groups (-NR ' R "); wherein R ' and R " can be identical or different, such as alkyl, aryl, arylalkyl, thiazolinyl, alkynyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl, alkyl, hetercycloalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, antelope base alkyl, alkoxyalkyl, alkylthio, carbonyl or carboxyl.These substituting groups can replace any one in the alkyl or aryl substituting group had listed by carboxylic acid or the application further.In some embodiments, there are carboxyl or carbonyl amino replacement, forms N-acyl group or N-carbamyl deriveding group.

Term " haloalkyl " that the application uses (be used alone or as the part of another group) refers to the halogen atom connected by alkyl, such as-CF ₃.

Term " acyl group " that the application uses (be used alone or as the part of another group) refers to the alkyl that connected by carbonyl or-C (=O) R, and wherein R is described alkyl.

Ask in this used term " alkoxy carbonyl " (be used alone or as the part of another group) to refer to-C (=O) OR, wherein R is described alkyl.

The term " arylalkyl " that the application uses or " aralkyl " (be used alone or as the part of another group) refer to the aromatic ring (such as benzyl) connected by alkyl described above.

Term " aminoalkyl group " that the application uses (be used alone or as the part of another group) refers to the amino (-NR ' R ") connected by alkyl.

Term " aryl-alkyl amino " that the application uses (be used alone or as the part of another group) refers to the aryl connected by alkyl, and described alkyl is connected by amino.

Term " heteroatoms " refers to independent O, S or N of selecting.It should be noted, the ungratified any heteroatom of valency is all considered to be connected with hydrogen atom, thus meets valency.

Term " halogen " refers to independent fluorine, chlorine, the bromine or iodine selected.

The term " cycloalkyl " (part being used alone or rolling into a ball as another tomb) that the application uses refers to 3 to 9 carbon atoms, is preferably the hydrocarbon ring of the completely saturated or fractional saturation of 3 to 7 carbon atoms.In addition, cycloalkyl can be replace." cycloalkyl of replacement " refer to have once, two or three be selected from following substituent ring: the alkyl of halogen, alkyl, replacement (wherein substituting group as above alkyl substituent define), thiazolinyl, alkynyl, nitro, cyano group, oxo (=O), hydroxyl, alkoxyl group, alkylthio ,-CO ₂h ,-C (=O) H ,-CO ₂-alkyl ,-C (=O) alkyl, ketone group ,=N-OH ,=N-O-alkyl, aryl, heteroaryl, five or hexa-atomic ketal (namely 1,3-dioxane or 1,3-bis-uh alkane) ,-NR ' R " ,-C (=O) NR ' R " ,-CO ₂nR ' R " ,-C (=O) NR ' R " ,-NR ' CO ₂r " ,-NR ' C (=O) R " ,-SO ₂nR ' R " and-NR ' SO ₂respective in R ", wherein R ' and R " is independently selected from hydrogen, alkyl, the alkyl of replacement and cycloalkyl, or R ' and R ", form Heterocyclylalkyl or heteroaryl ring together.

Term " anticarcinogen " comprises the medicine known arbitrarily that can be used for Therapeutic cancer, comprising: (1) cytotoxic drug: chlormethine series pharmaceuticals, as melphalan, endoxan; Platinum coordination complex, such as cis-platinum, carboplatin and oxaliplatin; (2) anti-metabolism antitumour drug: 5 FU 5 fluorouracil, capecitabine, methotrexate, Calciumlevofolinate, Raltitrexed, purine antagonist (such as 6-thioguanine and Ismipur); (3) hormones: the female alcohol of 17 alpha-acetylenes, stilboestrol, testosterone, prednisone, Fluoxymesterone, dromostanolone propionate, testolactone, Magace, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, Chlortrianisoestrol, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, toremifene; (4) tyrosine kinase inhibitor: EGFR inhibitor, comprises Gefitinib (Gefitinib), Erlotinib (Erlotinib), Cetuximab (Cetuximab), Trastuzumab (Herceptin) etc.; VEGF inhibitor, such as VEGF antibody (Avastin (Avastin)) and micromolecular inhibitor such as Sunitinib, Vandetanib, Cediranib; Bcr-Abl inhibitor is as imatinib (Imatinib), Dasatinib (Dasatinib); Src inhibitor, MEK kinase inhibitor, mapk kinase inhibitor, PI3K kinase inhibitor, c-Met inhibitor, ALK inhibitor etc.; (5) act on the medicine of tubulin, such as vinca medicine, taxanes medicine, epothilones medicine are as ipsapirone (Ixabepilone) etc.; (6) topoisomerase I inhibitor, as topotecan, irinotecan; (7) histon deacetylase (HDAC) (HDAC) inhibitor is as Vorinostat (Vorinostat); (8) proteasome inhibitor is as Velcade (Bortezomib); (9) anticarcinogen of other classifications is as aurora kinase (aurorakinase) inhibitor, biological response modifier, growth inhibitor, glu famine antagonist, angiogenesis inhibitor and anti-vascular medicine, matrix metallo-proteinase inhibitor etc.

" Mammals " comprises the mankind and domestic animal, as cat, dog, pig, ox, sheep, goat, horse, rabbit etc.Preferably, for the purposes of the present invention, described Mammals is the mankind.

" optional () " or " optional () " represents that the environment event that describes subsequently may presence or absence, and described description comprises the situation that described event or environment occur and situation about not occurring.Such as, " aryl be optionally substituted " represents that described aryl may be substituted or not be substituted and described description comprises the aryl of replacement and unsubstituted aryl.

When " pharmacy acceptable derivates " represents to recipient's administration, directly or indirectly can provide salt or other derivatives of the salt of any nontoxic salt of the active metabolite of compound of the present invention or its inhibition or resistates, ester, ester, acid amides, acid amides.

" the acceptable vehicle of pharmacy " includes but not limited to be ratified as any assistant agent that can be used for the mankind or domestic animal, carrier, vehicle, glidant, sweeting agent, dispersion agent, thinner, sanitas, suspending agent, stablizer, dyestuff/tinting material, odorant, tensio-active agent, wetting agent, isotonic agent, solvent or emulsifying agent by state food and Drug Administration.

" pharmacologically acceptable salts " comprises acid salt and base addition salt.

" the acceptable acid salt of pharmacy " refers to such salt, and they remain biological effect and the character of free alkali, can not produce adverse consequences in biology or other, and is such as but not limited to hydrochloric acid with mineral acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc., and organic acid is such as but not limited to following acid: formic acid, acetic acid, trifluoroacetic acid, methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, tosic acid, 2,2-dichloro acetic acid, hexanodioic acid, Lalgine, xitix, aspartic acid, phenylformic acid, paraacetaminobenzoic acid, dextrocamphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, sad, carbonic acid, styracin, citric acid, cyclohexane sulfamic acid, dodecyl sulphate, ethane-1,2-disulfonic acid, fumaric acid, tetrahydroxyadipic acid, gentisinic acid, glucoheptonic acid, glyconic acid, glucuronic acid, L-glutamic acid, pentanedioic acid, 2-oxo-pentanedioic acid, Phosphoric acid glycerol esters, oxyacetic acid, urobenzoic acid, isopropylformic acid, lactic acid, lactobionic acid, lauric acid, toxilic acid, oxysuccinic acid, propanedioic acid, amygdalic acid, glactaric acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, vitamin B13, oxalic acid, palm fibre eleostearic acid, pamoic acid, propionic acid, Pyrrolidonecarboxylic acid, pyruvic acid, Whitfield's ointment, 4-ASA, sebacic acid, stearic acid, fumaric acid, succsinic acid, tartrate, thiocyanic acid, the formation such as undecylenic acid.

" the acceptable base addition salt of pharmacy " refers to such salt, and they remain biological effect and the character of free acid, can not be improper in biology or other.These salt obtain by mineral alkali or organic bases being added on free acid.The salt being derived from mineral alkali includes but not limited to sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminium salt etc.Preferred inorganic salt are ammonium, sodium, potassium, calcium and magnesium salts.The salt being derived from organic bases includes but not limited to the salt of following substances: primary amine, secondary amine and tertiary amine, the amine replaced, comprise naturally occurring replacement amine, cyclammonium and deacidite, as ammonia, methylamine, dimethylamine, Trimethylamine 99, diethylamine, triethylamine, tripropyl amine, Isopropylamine, diethanolamine, thanomin, DMAE, 2-diethylaminoethanol, dicyclohexyl amine, Methionin, arginine, Histidine, caffeine, PROCAINE HCL, PHARMA GRADE, Hai Baming (hydrabamine), choline, trimethyl-glycine, Benethamine diacetale, quadrol, glycosamine, methylglucosamine, Theobromine, trolamine, Trometamol, purine, piperidines, piperazine, N-ethylpiperidine, versamid 900 etc.Preferred organic bases is Isopropylamine, diethylamine, thanomin, triethylamine, dicyclohexyl amine, choline and caffeine.

" pharmaceutical composition " refer to compound of the present invention with biologically active cpds is delivered to Mammals as the medium of the usual acceptance in the mankind the preparation that forms.Such medium comprises all pharmaceutically acceptable carrier, thinner or vehicle to this.

" treatment significant quantity " refers to when to (the preferred mankind) during Mammals administration, be enough to the relative disease of Mammals (the preferred mankind) or illness realize as hereafter the amount of the compound of the present invention for the treatment of that defines.The amount forming the compound of the present invention of " treatment significant quantity " can according to the activity of such as applied particular compound; The metabolic stability of described compound and effect duration; Age of patient, body weight, holistic health, sex and diet; Mode of administration and time; Discharge rate; Drug combination; The seriousness of specific illness or illness; And experience the individuality for the treatment of and change, but it can be determined according to himself knowledge and the disclosure routinely by those of ordinary skill in the art.

" treat " or " treatment " for containing the Mammals to having relative disease or illness during this paper, the relative disease of the preferred mankind or the treatment of illness, and comprise:

Disease or illness is there is, especially when such Mammals is ill but when also not diagnosing out ill in (i) prevention Mammals;

(ii) suppress disease or illness, namely stop it to develop;

(iii) alleviate disease or illness, namely cause disease or illness to disappear;

(iv) stable disease or illness.

During for this paper, term " disease " and " illness " can be exchanged and to be used or can be different, reason is that specified disease or illness may not have known inducement (thus also not working out the cause of disease), therefore also disease is not considered to and only as improper situation or syndrome, wherein clinician have identified concrete syndrome more or less.

The compounds of this invention shown in this article and their structure also represent and comprise all isomer (such as enantiomer, diastereomer, rotamerism or conformational isomerism) form, they can according to amino acid whose absolute stereochemical being defined as to (R)-/(S)-or (D)-/(L)-or (R, R)-/(R, S)-/(S, S)-.The present invention represents and comprises all these possible isomer, and their racemic, enantiomorph enrichment and optional pure form.Optically-active (+) and (-), (R)-and (S)-and (R, R)-/(R, S)-/(S, S)-or (D)-chiral synthesize, chiral separation can be used to prepare with (L)-isomer, or routine techniques can be used to split such as but not limited to using the high performance liquid phase (HPLC) of chiral column.When compound as herein described comprises thiazolinyl double bond or other geometry asymmetric centers, except as otherwise noted, described compound comprises E and Z geometrical isomer.Equally, all tautomeric forms are also comprised.

" steric isomer " refers to be made up of with identical chemical bonding identical atom but to have the compound of different three-dimensional structure, and they are not interchangeable.The present invention is contained various steric isomer and composition thereof and is comprised " enantiomer " and " diastereomer ", and enantiomer refers to two kinds of steric isomers of the mirror image that its molecule each other can not be overlapping; Diastereomer refers to that molecule has two or more chiral centre, and intermolecular be the steric isomer of non-mirror.

" tautomer " refers to that proton moves to another position of same a part from an atom of molecule from original position.The present invention includes the tautomer of any described compound.

In addition, except as otherwise noted, compound of the present invention also comprises the compound that structure difference is only to exist one or more isotopic enrichment atoms.Such as, there is structure of the present invention, except replacing hydrogen with " deuterium " or " tritium ", or using ¹⁸f-fluorine mark ( ¹⁸f isotropic substance) replace fluorine, or use ¹¹c-, ¹³c-, or ¹⁴the carbon of C-enrichment ( ¹¹c-, ¹³c-, or ¹⁴c-carbon markings; ¹¹c-, ¹³c-, or ¹⁴c-isotropic substance) replace the compound of carbon atom to be in scope of the present invention.Such compound can be used as biological example measure in analysis tool or probe, or can the diagnostic imaging in vivo tracer agent of disease be used as, or as the tracer agent of pharmacodynamics, pharmacokinetics or acceptor research.

The present invention also provides following methods: (simultaneously or successively) needs the patient of this treatment by (I) compound of general formula as defined above and other anticancer agents of at least one for the treatment of significant quantity being given, and treats proliferative disease (such as cancer) via regulating c-Met kinases.In preferred embodiments, proliferative disease is cancer.

Particularly, general formula (I) compound can be used for treating kinds cancer, is most specifically those cancers depending on c-Met activation.C-Met activation regulates by gene amplification, sudden change (various mutations) and/or HGF stimulation, and wherein HGF is provided by tumour (autocrine) or host's (paracrine) tissue.Usually, compound of the present invention can be used for the treatment of following cancer:

(A) solid tumor, comprises cancer of the stomach, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer), colorectal carcinoma, kidney, liver cancer, mammary cancer, ovarian cancer, cervical cancer, esophagus cancer, carcinoma of gallbladder, bladder cancer, carcinoma of the pancreas, thyroid carcinoma, prostate cancer and skin carcinoma (comprising squamous cell carcinoma);

(B) hematopoetic tumor of lymphoid, comprise acute lymphoblastic leukemia (ALL), acute lymphoblastic leukemia, B cell lymphoma, t cell lymphoma, Hodgkin lymphoma, non-Hodgkin′s woods bar knurl, hairy cell lymphoma and Burkitt lymphoma (Burkett ' s lymphoma);

(C) hematopoetic tumor of myeloid lineage, comprises acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia;

(D) tumour of mesenchyme origin, comprises fibrosarcoma and rhabdosarcoma;

(E) tumour of maincenter and peripheral nervous system, comprises astrocytoma, neuroblastoma, neurospongioma and schwannoma;

(F) other tumour, comprises melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xeroderma pitmentosum, keratoacanthoma, follicular carcinoma of thyroid and Kaposi sarcoma.

General formula (I) compound also can be used for treating any lysis being characterized as abnormal cell proliferation, the restenosis such as, occurred after benign prostatic hyperplasia, neurofibromatosis, atherosclerosis, pulmonary fibrosis, sacroiliitis, psoriasis, glomerulonephritis, angioplasty or vascular surgery, inflammatory bowel, graft-rejection, endotoxin shock and fungi infestation.

The level of the adjustable cell RNA of general formula (I) compound and DNA synthesis.Therefore, these materials can be used for the treatment of virus infection (including but not limited to HIV, human papillomavirus, simplexvirus, poxvirus, Epstein-Barr virus, sindbis alphavirus and adenovirus).

General formula (I) compound can be used for the chemoprophylaxis of cancer.Chemoprophylaxis is defined through and blocks initial mutagenesis event or by blocking the progress of pre-malignant cells damaged and carry out the development of anti-invasion cancer or Tumor suppression recurring.

General formula (I) compound can be used for Tumor suppression vasculogenesis and transfer.

Compound of the present invention also can combinationally use with known anticarcinogen (include but not limited to mention in above-mentioned " anticarcinogen " those) or anticancer therapy (such as radiotherapy) (together with give or successively give).

In method hereinafter described, the functional group of midbody compound may need the protecting group by being suitable for protect.Such functional group comprises hydroxyl, amino (comprising the NH functional group of heteroaryl) and carboxylic acid.For hydroxyl be applicable to protecting group comprise TMS, t-butyldimethylsilyi, tert-butyldiphenylsilanyl, THP trtrahydropyranyl, benzyl, to methoxy-benzyl etc.Suitable protecting groups for amino comprises tertbutyloxycarbonyl, carbobenzoxy-(Cbz), ethanoyl, trifluoroacetyl group, benzoyl etc.Suitable protecting groups for carboxylic acid comprises alkyl, aryl or alkyl aryl.Suitable protecting groups for the heteroaryl such as NH functional group of such as indoles or indazole ring comprise tertbutyloxycarbonyl, carbobenzoxy-(Cbz), ethanoyl, benzoyl, to methoxy-benzyl, 2-trimethylsilyl-ethoxy methyl etc.

Protecting group can (also can with reference to pertinent literature as Greene T.W. according to method known to those skilled in the art; Protective Groups in Organic Synthesis; 1999, the 3rd edition, Wiley) and standard technique as herein described is added or removal.Described protecting group also can be that fluoropolymer resin is as Wang resin, Rink resin or 2-chlorine trityl chloride resin.

Meanwhile, although the protected derivative of some the compounds of this invention itself may not have pharmacological activity, they can be administered to Mammals, and then metabolism has the compounds of this invention of pharmacological activity with formation in vivo.Therefore such derivative is described to " prodrug ".All prodrugs of the compounds of this invention include within the scope of the invention.

The dihydropyridine compounds of some general formula of the present invention (I), is prepared by following method.(wherein R ₁, R ₂, R ₃definition as mentioned above; " PG " (protecting groups) is amido protecting group; such as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl etc.): with pimelinketone-4-ethyl formate (1) for raw material; at N; intermediate (2) is converted under the effect of dinethylformamide dimethylacetal (DMF-DMA); this intermediate and hydrazine reaction, cyclisation is pyrazole compound (3).Ester group in intermediate (3) is reduced with reductive agent (as lithium aluminium hydride, sodium borohydride etc.), obtains intermediate (4).Then by the amido of intermediate (4) pyrazoles with suitable protecting group (such as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl etc.) protect to obtain intermediate (II); again by its alcoholic extract hydroxyl group with suitable condition (as Dess-Martin oxidation; Swern is oxidized) oxidation, obtain aldehydes intermediate (III).Intermediate (III) and cyano group ketone compounds (A) condensation; obtain intermediate (IV); again with raw material (B) condensation of amido alkene nitrile, then deprotection base under suitable condition, obtains compound (I).

route 1:

route 2:

Wherein, following is conventional abbreviation:

DMF:N, dinethylformamide;

DMSO: dimethyl sulfoxide (DMSO);

CDCl ₃: deuterochloroform;

¹h NMR: proton nmr spectra;

MS: mass spectrum;

S: unimodal

D: bimodal

T: triplet

Dd: doublet of doublet

Br: broad peak

M: multiplet

DEG C: degree Celsius

Mol: mole

TLC: tlc

Those skilled in the art can use suitable raw material, adopt similar method, prepare in reaction scheme above with no specific disclosure of other compounds of the present invention.

By with suitable inorganic or organic bases or acid treatment, can by according to preparing all the compounds of this invention existed with free alkali or sour form above and change into their pharmacologically acceptable salts.The salt of the compound prepared above can change into their free alkali or sour form by standard technique.

Compound of the present invention is all comprises its all crystal formations, amorphous forms, dehydrate, hydrate, solvate and salt more.In addition, all compounds of the present invention comprising ester group and amide group can change into corresponding acid by method known to those skilled in the art or by method described herein.Equally, the compounds of this invention comprising hydroxy-acid group can be converted into corresponding ester and acid amides by method known to those skilled in the art.Other that also can pass through that method known to those skilled in the art (such as hydrogenation, alkylation, with acyl chloride reaction etc.) carries out on molecule replace and replace.

Prepare cyclodextrin inclusion compound of the present invention, can the compound of the general formula (I) defined in summary of the invention be above dissolved in the acceptable solvent of pharmacology such as (but being not limited to) alcohol (preferred alcohol), ketone (such as acetone) or ether (such as ether), and at 20 DEG C to 80 DEG C and alpha-cylodextrin, beta-cyclodextrin or γ-cyclodextrin, the aqueous solution of preferred beta-cyclodextrin; Or can by the acid of the compound of general formula (I) that defines in summary of the invention above with the aqueous solution form of its salt (such as sodium or sylvite) and cyclodextrin blended, then with equivalent acid (such as HCl or H ₂sO ₄) solution blending, to provide corresponding cyclodextrin inclusion compound.

Now or after the cooling period, corresponding cyclodextrin inclusion compound crystal can crystallization.Or when general formula (I) compound be oily and crystallization time, by room temperature for a long time stir (such as 1 is little of 14 days), add the aqueous solution process of cyclodextrin, also can be converted into corresponding cyclodextrin inclusion compound.Then by filtering and drying, inclusion compound can be separated into solid or crystal.

For cyclodextrin of the present invention commercially available (such as from Aldrich Chemical Co.), or adopt known method preparation by those skilled in the art.See people such as such as Croft, A.P., " Synthesis of Chemically ModifiedCyclodextrins ", Tetrahedron 1983,39,9,1417-1474.Suitable cyclodextrin comprises all kinds preparing inclusion compound with the compound of institute's column (I) above.

By selecting appropriate cyclodextrin and water, the inclusion compound of repeatably active substance content can be obtained according to stoichiometric composition.Inclusion compound can use for dry water suction form or the moisture but form more do not absorbed water.The Typical mole ratios of the compound of cyclodextrin and general formula (I) is 2: 1 (cyclodextrin: compound).

Comprising general formula (I) compound as the pharmaceutical composition of activeconstituents can be suitable for oral form, such as, be tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis or granule, syrup etc.The composition that can orally use can be prepared according to any means for the preparation of pharmaceutical composition known in the art, and these compositions can comprise the material that one or more is selected from sweeting agent, seasonings, tinting material and sanitas, to provide pharmaceutical elegant and agreeable to the taste preparation.

Tablet comprises activeconstituents, and is mixed with the nontoxic pharmaceutically acceptable vehicle or carrier that are suitable for preparing tablet.These vehicle or carrier can be inert diluent, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, such as Celluloasun Microcrystallisatum, carmethose, W-Gum or alginic acid; Tackiness agent, such as starch, gelatin, polyvinylpyrrolidone or gum arabic; And lubricant, such as Magnesium Stearate, stearic acid or talcum powder.Tablet can be non-dressing, or carrys out dressing by known technology, thus covers and make us unhappy drug tastes, or postpones disintegration and absorption in the gastrointestinal tract, provides lasting effect thus within the longer period.Such as, water miscible taste can be used to cover material (such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose) or time lag material (such as ethyl cellulose, cellulose acetate butyrate).

Capsule comprises hard-gelatin capsules, Gelseal.Hard-gelatin capsules is mixed with inert solid diluent such as calcium carbonate, calcium phosphate or kaolin by activeconstituents; Gelseal is mixed with water-soluble carrier (such as polyoxyethylene glycol) or oily medium (such as peanut oil, whiteruss or sweet oil) by activeconstituents.

Aqueous suspension comprises active substance and is suitable for preparing the vehicle of aqueous suspension.These vehicle are suspending agent, such as Xylo-Mucine, methylcellulose gum, hydroxypropyl methyl-cellulose, sodiun alginate, polyvinylpyrrolidone and gum arabic; Dispersion agent or wetting agent, the condensation product (such as polyethylene sorbitan monoleate) of partial ester that can be the condensation product (such as polyoxyethylene stearic acid ester) of naturally occurring phosphatide (such as Yelkin TTS) or oxyalkylene and lipid acid or the condensation product (such as 17 oxygen ethene hexadecanols (heptadecaethylene-oxycetanol)) of ethylene oxide and long chain aliphatic alcohol or ethylene oxide and the condensation product (such as polyoxyethylene 80 sorbitan monooleate) of partial ester derived from lipid acid and hexitol or ethylene oxide and derive from lipid acid and the liquor-saturated mixture of hexitol.Aqueous suspension also can comprise one or more sanitass (such as ethyl p-hydroxybenzoate or n-propyl), one or more tinting material, one or more seasonings and one or more sweeting agent (such as sucrose, asccharin or aspartame).

Oil suspensions is prepared by being suspended in by activeconstituents in vegetables oil (such as peanut oil, sweet oil, sesame oil or cocounut oil) or mineral oil (such as whiteruss).Oil suspensions can comprise thickening material, such as beeswax, paraffinum durum or hexadecanol.Sweeting agent (such as above listed those) and seasonings can be added, thus agreeable to the taste oral preparations is provided.These compositions come anticorrosion by adding antioxidant (such as Butylated Hydroxyanisole or alpha-tocopherol).

Dispersible pulvis and granule comprise activeconstituents, and are mixed with dispersion agent or wetting agent, suspending agent and one or more sanitas.The example of suitable dispersion agent or wetting agent and suspending agent mentioned for above those.Also other vehicle can be comprised, such as sweeting agent, seasonings and tinting material.These compositions come anticorrosion by adding antioxidant (such as xitix).Dispersible pulvis and granule prepare aqueous suspension by adding water.

Syrup can be prepared with sweeting agent (such as glycerine, propylene glycol, sorbyl alcohol or sucrose).These preparations also can comprise negative catalyst, sanitas, seasonings, tinting material and antioxidant.

Pharmaceutical composition of the present invention also can be the form of oil-in-water emulsion.Oil phase can be vegetables oil (such as sweet oil or peanut oil) or mineral oil (such as whiteruss) or their mixture.Suitable emulsifying agent can be naturally occurring phosphatide (such as soybean lecithin), condensation product (such as Polysorbate 80) from the derivative ester of lipid acid and hexitol mixture or partial ester (such as dehydrated sorbitol mono-fatty acid ester) and described partial ester and ethylene oxide.Emulsion also can comprise sweeting agent, seasonings, sanitas and antioxidant.

Pharmaceutical composition can be the form of the sterile injectable aqueous solution.Spendablely accept carrier and solvent has water, Ringer's solution (Ringer ' s solution), isotonic sodium chloride solution and glucose solution.

Sterile injectable preparation also can be sterile injectable water oil-packaging type micro-emulsion, wherein by solubilize active ingredients in oil phase.Such as, first by solubilize active ingredients in the mixture of soybean oil and Yelkin TTS.Then, obtained oil solution to be imported in the mixture of water and glycerine and to process, thus forming micro emulsion.

Injectable solution or micro emulsion import in the blood flow of patient by local bolus injection, or give described solution or micro emulsion in some way, thus maintain the circulation composition of constant the compounds of this invention.In order to maintain this constant concentration, the continuous intravenous administration set such as infusion pump can be used.

Pharmaceutical composition can be for intramuscular or the sterile injectable water-based of subcutaneous administration or the form of oil-based suspension.This suspension can use above those the suitable dispersion agents that mention or wetting agent and suspending agent to configure according to known technology.Sterile injectable preparation also can be sterile injectable solution or the suspension of nontoxic pharmaceutically acceptable diluent or solvent, the solution of such as 1,3 butylene glycol.In addition, sterile, fixed oils can be easily used as solvent or suspension medium.In order to this object, fixed oil gentle arbitrarily all can use, and comprises direactive glyceride or two glyceryl ester of synthesis.In addition, lipid acid (such as oleic acid) can use preparing in injection.

General formula (I) compound also can give by the form of the suppository for rectal administration.These compositions are prepared by hybrid medicine and suitable nonirritant excipient, and described vehicle is solid at normal temperature but is liquid in rectal temperature, therefore melts in the rectum, thus release medicine.These materials comprise theobroma oil, glycogelatin, hydrogenated vegetable oil, the mixture of polyoxyethylene glycol of different molecular weight and the fatty acid ester of polyoxyethylene glycol.

With regard to local uses, can to prepare and use comprises the ointment of general formula (I) compound, ointment, jelly, solution or suspensoid etc.

Compound of the present invention uses suitable nasal carrier and doser to give with intranasal form by local, or use those skilled in the art the form of well-known transdermal skin patches given by cutaneous routes.Compound of the present invention also can give by the form of the suppository using all matrix as described below: the mixture of the polyoxyethylene glycol of theobroma oil, glycogelatin, hydrogenated vegetable oil, different molecular weight and the fatty vinegar of polyoxyethylene glycol.

When being administered in human subject body by compound of the present invention, every per daily dose is generally determined by the doctor of prescription, and described dosage usually with the symptom of age of patient, body weight, sex and reaction and patient severity and change.Usually, the effective per daily dose of the patient for 70kg is about 0.001mg/kg to 100mg/kg, is preferably 0.01mg/kg to 50mg/kg, is more preferably 1mg/kg to 25mg/kg.

If be mixed with fixed dosage, so these combined prods are used in the compounds of this invention in dosage range described above and other medical active agent treatment in the dosage range of its approval.When combination preparation is improper, general formula (I) compound also successively can give with known anticarcinogen or cytotoxicity medicine.The present invention is not by the restriction of order of administration; General formula (I) compound can give before or after giving known anticarcinogen (multiple anticarcinogen) or cytotoxicity medicine (various kinds of cell toxicity medicine).

Compound of the present invention is the inhibitor of the disease of c-Met mediation or the illness of c-Met mediation.Term " disease of c-Met mediation " and " illness of c-Met mediation " represent the effective any morbid state of known c-Met tool or other adverse conditions.Term " c-Met mediation disease " and " illness that c-Met mediates " also represent those diseases by being eased with c-Met inhibitor for treating or illness.These diseases and illness include but not limited to cancer and other proliferative disorder.

Therefore, described compound can be used for treating such as Mammals, the following disease especially in the mankind or illness: cancer of the stomach, lung cancer, esophagus cancer, carcinoma of the pancreas, kidney, colorectal carcinoma, thyroid carcinoma, the cancer of the brain, mammary cancer, prostate cancer and other solid tumor cancers; Atherosclerosis; Adjustment blood vessel occurs; Thrombosis and pulmonary fibrosis.

The research of signal transduction pathway that compound involved in the present invention also can be used for the research of biology or pharmacology phenomenon, Tyrosylprotein kinase participates in and the comparative evaluation for new tyrosine kinase inhibitor.

Compound involved by the application, including, but not limited to the structure type given by above-mentioned route 1 and route 2, knows the personnel of art technology by suitable starting raw material, and method like application class obtains.

Embodiment

The following concrete synthesis preparation example (for the preparation of compound of the present invention) that provides and Biological examples (for proving the compounds of this invention purposes) put into practice the present invention to help, and they should not be considered to limit the scope of the invention.

Synthesis preparation example 1:2,6-dimethyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-base)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethoxy nitrile

Step 1:

Joined by pimelinketone-4-ethyl formate (20g, 0.12mol) in DMF dimethylacetal (DMF-DMA) (20mL), 100 DEG C of stirrings are spent the night.Concentrating under reduced pressure, resistates is directly used in next step.MS：[M+1]＝226；

Step 2:

Step 1 gained resistates is dissolved in ethanol (50mL), and then add hydrazine hydrate (8.25g, 0.16mmol, 99%), room temperature reaction stirs 4 hours, concentrated, obtains product (12.5g, 54%) with purification by silica gel column chromatography.MS：[M+1]＝195；

Step 3:

Under nitrogen protection, 4,5,6; 7-tetrahydrochysene-1H-indazole-5-ethyl formate (2g, 10.3mmol) is dissolved in anhydrous THF (50mL), is cooled to 0 DEG C; portion-wise with caution adds lithium aluminum hydride (586mg, 15.45mmol), stirring at room temperature 5 hours.Drip water (0.6mL) cancellation reaction, leave standstill a moment, filter, filtrate is with anhydrous sodium sulfate drying, concentrating under reduced pressure, resistates purification by silica gel column chromatography, obtains (4,5,6,7-tetrahydrochysene-1H-indazole-5-base) methyl alcohol (0.43g, 27%), white solid.

Step 4:

Under nitrogen protection, 4,5,6,7-tetrahydrochysene-1H-indazole-5-methyl alcohol (620mg, 4.07mmol) is dissolved in methylene dichloride (50mL), adds Dess-Martin oxygenant (3.46g, 8.14mmol), stirring at room temperature 5 hours.Remove solvent under reduced pressure, add ethyl acetate in resistates, stir, filter, filtrate concentrates to obtain 4,5,6,7-tetrahydrochysene-1H-indazole-5-formaldehyde crude products (370mg, 60% thick yield).

Step 5:

4,5,6,7-tetrahydrochysene-1H-indazole-5-formaldehyde (320mg, 2.13mmol) and 3-aminochlotononitlile (385mg, 4.69mmol) are dissolved in Glacial acetic acid (10mL) jointly, are heated to 95 DEG C, stir 15 minutes.Remove acetic acid under reduced pressure, resistates prepares TLC, and (methylene dichloride: methyl alcohol=10: 1) purifying, obtains 2,6-dimethyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-base)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethoxy nitrile (19mg, 3%) is white solid.ESI-MS：280[M+H]； ¹HNMR(300MHz，DMSO)δ9.51(s，1H)，7.30(s，1H)，2.49-2.74(m，1H)，2.26-2.36(m，2H)，2.03(s，1H)，1.82-1.97(m，2H)，1.52-1.72(m，3H)。

Synthesis preparation example 2:2-ethyl-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-base)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethoxy nitrile

Step 1:

Under nitrogen protection, anhydrous tetrahydro furan (125mL) is placed in three-necked bottle, is cooled to-70 DEG C; add n-Butyl Lithium (hexane solution of 2.5M, 16mL, 40mmol); stir and drip anhydrous acetonitrile (1.44g, 35mmol) again a moment.Finish stirring 3 minutes, drip ethyl propionate (2.55g, 25mmol), during dropping, keep temperature of reaction system to be no more than-66 DEG C.Complete reaction solution is warming up to-45 DEG C and stirs 2 hours.Drip 1N hydrochloric acid (60mL) cancellation, reaction solution concentrates, and resistates is with extracted with diethyl ether, and extraction liquid merges, dry, concentrated, and residual oil thing 3-oxopentanenitrile (2.224g, 92% thick yield) is directly used in next step reaction. ¹HNMR(300MHz，CDCl ₃)1.1(t，3H)，2.62(q，2H)，3.48(s，2H)。

Step 2:

(4,5,6,7-tetrahydrochysene-1H-indazole-5-base) methyl alcohol (5.1g, 34mmol) be dissolved in anhydrous tetrahydro furan (100mL), add triethylamine (3.4g, 34mmol) and DMAP (0.41g, 3.4mmol), stir and add (Boc) a moment ₂o (7.2g, 34mmol), stirred overnight at room temperature.Add water in system, extraction into ethyl acetate, extraction liquid merges, dry, and concentrated, purification by silica gel column chromatography obtains 5-(methylol)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (6.0g, 72%).MS：[M+1]＝253。

Step 3:

5-(methylol)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (3.0g, 11.9mmol) is dissolved in dry methylene dichloride (50mL), adds Dess-Martin oxygenant (10.5g, 24mmol), stirring at room temperature 2 hours.Concentration of reaction solution, resistates adds acetic acid ethyl dissolution, and with saturated sodium bicarbonate aqueous solution washing, dry, concentrated, purification by silica gel column chromatography obtains 5-formyl radical-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (1.8g, 61%).MS：[M+1]＝251。

Step 4:

5-formyl radical-4; 5; 6; 7-tetrahydrochysene-1H-indazole-1-t-butyl formate (768mg, 3.072mmol) and 3-oxopentanenitrile (597mg, 6.144mmol) are dissolved in methylene dichloride (30mL) jointly; add acetic acid (28mg; 0.461mmol) with piperidines (26mg, 0.307mmol), reflux stirred night under nitrogen protection.Reaction solution is cooled to room temperature, add dehydrated alcohol (30mL), stir after ten minutes and filter, filtrate is concentrated dry, resistates column chromatography obtains 5-(2-cyano group-3-oxygen amyl group-1-alkene-1-base)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (291mg, 29%).LC-MS(ESI+)330[M+1] ⁺。

Step 5:

By 5-(2-cyano group-3-oxygen amyl group-1-alkene-1-base)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (120mg, 0.364mmol) with 3-aminochlotononitlile (66mg, 0.801mmol) be jointly dissolved in Glacial acetic acid (10mL), be heated to 100 stirring 1 hour.Be cooled to room temperature, reaction solution concentrating under reduced pressure is done, preparation TLC purifying (methylene dichloride: methyl alcohol=20: 1) obtain 2-ethyl-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-base)-1,4-dihydropyridine-3,5-dimethoxy nitrile (53mg, 49%).MS(ESI+)：294[M+1]； ¹H NMR(300MHz，DMSO-d ₆)δ12.23(br，1H)，9.44(br，1H)，7.73(s，1H)，2.71(d，1H，J＝7.7Hz)，2.26-2.37(m，4H)，2.04(s，3H)，1.84-1.96(m，2H)，1.51-1.64(m，3H)，1.11(t，3H，J＝9.0Hz)。

Synthesis preparation example 3:

Step 1:

Under nitrogen protection, dry tetrahydrofuran (100mL) is placed in three-necked bottle, is cooled to-70 DEG C, adds n-Butyl Lithium (hexane solution of 2.5M, 12.8mL, 32mmol).Drip anhydrous acetonitrile (1.15g, 28mmol), stir and drip 3 Methylbutanoic acid ethyl ester (2.6g, 20mmol) after 3 minutes, during dropping, keep temperature of reaction system to be no more than-66 DEG C.Finish and be warming up to-45 DEG C of stirrings 2 hours.Drip 1N hydrochloric acid (40mL) cancellation, reaction solution concentrates, and adds extracted with diethyl ether in resistates, and extraction liquid merges, dry, and concentrated, resistates oily matter is the own nitrile crude product of 5-methyl-3-oxygen (2.26g, 90% thick yield). ¹H NMR(300MHz，CDCl ₃)0.93(d，6H，J＝6.9Hz)，2.15(m，1H)，2.46(d，2H，J＝6.6Hz)，3.44(s，2H)。

Step 2:

5-formyl radical-4; 5; 6; 7-tetrahydrochysene-1H-indazole-1-t-butyl formate (1g, 3.995mmol) and the own nitrile (750mg, 5.993mmol) of 5-methyl-3-oxygen are dissolved in methylene dichloride (40mL) jointly; add Glacial acetic acid (276mg; 4.594mmol) with piperidines (340mg, 3.995mmol), reflux stirred night under nitrogen protection.Reaction solution is cooled to room temperature, add dehydrated alcohol (40mL), stir after ten minutes and filter, filtrate is concentrated dry, resistates column chromatography obtains 5-(2-cyano group-5-methyl-3-oxygen hexyl-1-alkene-1-base)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (284mg, 20%).MS(ESI+)：358[M+1] ⁺。

Step 3:

By 5-(2-cyano group-5-methyl-3-oxygen hexyl-1-alkene-1-base)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (150mg, 0.42mmol) with 3-aminochlotononitlile (76mg, 0.923mmol) be dissolved in Glacial acetic acid (10mL), be heated to 100 DEG C and stir 1 hour.Be cooled to room temperature, concentrating under reduced pressure, (methylene dichloride: methyl alcohol=20: 1), obtains 2-isobutyl--6-methyl-4-(4 to preparation TLC purifying, 5,6,7-tetrahydrochysene-1H-indazole-5-base)-1,4-dihydropyridine-3,5-dimethoxy nitrile (40mg, 30%).MS(ESI+)：322[M+1] ⁺； ¹HNMR(300MHz，DMSO-d ₆)δ9.41(br，1H)，7.28(s，1H)，2.67-2.74(m，1H)，2.13-2.49(m，4H)，2.04(s，3H)，1.85-2.02(m，2H)，1.51-1.69(m，2H)，1.21(d，1H，J＝4.8Hz)，0.91(d，6H，J＝4.8Hz)。

Synthesis preparation example 4:

Step 1:

Under nitrogen protection, anhydrous tetrahydro furan (100mL) is placed in three-necked bottle, is cooled to-74 DEG C, adds n-Butyl Lithium (hexane solution of 2.5M, 16mL, 40mmol).Stir and drip anhydrous acetonitrile (1.437g, 35mmol) a moment, finish stirring and drip 4,4,4-trifluoroacetic acid ethyl ester (4.253g, 25mmol) in 3 minutes, in process, keep temperature of reaction system to be no more than-69 DEG C.Finish and be warming up to-45 DEG C of stirrings 2 hours, drip 1N hydrochloric acid (50mL) cancellation.Reaction solution concentrates, and adds extracted with diethyl ether in resistates, and extraction liquid merges, dry, and concentrated, residual oil thing thing is the own nitrile crude product of 6,6,6-tri-fluoro-3-oxo (3.91g, 95% thick yield), is directly used in next step reaction. ¹H NMR(300MHz，CDCl ₃)2.43-2.55(m，2H)，2.89(t，2H，J＝7.5Hz)，3.55(s，2H).

Step 2:

5-formyl radical-4; 5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (500mg; 2mmol) He 6; the own nitrile (660mg, 4mmol) of 6,6-tri-fluoro-3-oxo is dissolved in methylene dichloride (30mL) jointly; add Glacial acetic acid (138mg; 2.3mmol) with piperidines (170mg, 2mmol), reflux stirred night under nitrogen protection.Reaction solution is cooled to room temperature, add dehydrated alcohol (30mL), stir after ten minutes and filter, filtrate is concentrated dry, and resistates column chromatography obtains 5-(2-cyano group-6,6, the fluoro-3-oxo-hexyl of 6-tri--1-alkene-1-base)-4,5,6,7-tetrahydrochysene-1H-indazole-t-butyl formate (180mg, 23%).MS(ESI+)：398[M+1] ⁺.

Step 3:

5-(2-cyano group-6,6, the fluoro-3-oxo-hexyl of 6-tri--1-alkene-1-base)-4,5,6,7-tetrahydrochysene-1H-indazole-t-butyl formate (180mg, 0.453mmol) and 3-aminochlotononitlile (82mg, 0.997mmol) be jointly dissolved in Glacial acetic acid (8mL), be heated to 100 DEG C and stir 1 hour.Be cooled to room temperature, reaction solution is concentrated dry, resistates prepares TLC purifying (methylene dichloride: methyl alcohol=20: 1) obtain 2-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-base)-6-(3,3,3-trifluoro propyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethoxy nitrile (46mg, 28%).MS(ESI+)：362[M+1] ⁺； ¹H NMR(300MHz，DMSO-d ₆)δ9.56(br，1H)，7.27(s，1H)，2.53-2.75(m，6H)，2.24-2.34(m，2H)，2.05(s，3H)，1.84-1.91(m，2H)，1.52-1.70(m，2H)。

Synthesis preparation example 5:2-(2-methoxy ethyl)-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-base)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethoxy nitrile

Step 1:

Anhydrous tetrahydro furan (350ml) is cooled in-78 DEG C, adds n-BuLi (31mL, 77mmol), drips acetonitrile (2.9g, 70mmol), finish stirring 1 hour after stirring several minutes.Then drip 3-methoxy methyl propionate (5.9g, 50mmol), finish, temperature is increased to-45 DEG C, stirs 2 hours.Drip 2N hydrochloric acid (160mL) cancellation, reaction solution slowly rises to room temperature, with extracted with diethyl ether, combining extraction liquid, concentrates to obtain 5-methoxyl group-3-oxopentanenitrile (3.5g, 55%).

Step 2:

4,5,6,7-tetrahydrochysene-1H-indazole-5-formaldehyde (350mg, 2.3mmol) is dissolved in methylene dichloride (5mL), adds 5-methoxyl group-3-oxopentanenitrile (292mg, 2.3mmol), piperidines (11mg, 0.13mmol), acetic acid (99mg, 1.643mmol) and 4A molecular sieve, finish and be heated to return stirring and spend the night.Reaction solution is cooled, is concentrated into dry 5-methoxyl group-3-oxo-2-((4,5,6,7-tetrahydrochysene-1H-indazole-5-base) methene) valeronitrile crude product (700mg), is directly used in next step.MS：[M+1]＝262。

Step 3:

Upper step gained 5-methoxyl group-3-oxo-2-((4,5,6,7-tetrahydrochysene-1H-indazole-5-base) methene) valeronitrile (700mg, meter 2.3mmol) and 3-aminochlotononitlile (222mg, 2.7mmol) be jointly dissolved in Glacial acetic acid (20mL), be heated to 100 DEG C and stir 1 hour.Be cooled to room temperature, reaction solution is concentrated dry, resistates column chromatography purification (methylene dichloride: methyl alcohol=20: 1) obtain crude product, then through preparation TLC purifying, obtain 2-(2-methoxy ethyl)-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-base)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethoxy nitrile (56mg, 7.5%).MS(ESI+)：324[M+1] ⁺； ¹H NMR(300MHz，DMSO-d ₆)δ9.46(br，1H)，7.25(s，1H)，3.39-3.32(m，2H)，3.30(s，3H)，2.75-2.53(m，4H)，2.34-2.24(m，2H)，2.14(s，3H)，2.01-1.94(m，2H)，1.62-1.45(m，2H)。

Synthesis preparation example 6:2-(4-fluorophenyl)-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-base)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethoxy nitrile

Step 1:

5-formyl radical-4; 5; 6; 7-tetrahydrochysene-1H-indazole-1-t-butyl formate (500mg, 2.0mmol), 3-(4-fluorophenyl)-3-oxypropionitrile (326mg, 2.0mmol) are dissolved in methylene dichloride (15mL); add acetic acid (18mg; 0.3mmol) with piperidines (17mg, 0.2mmol), reflux stirred night under nitrogen protection.Reaction solution is cooled to room temperature, add methylene dichloride (30mL) dilute reaction solution, filter, filtrate is concentrated does to obtain 5-(2-cyano group-3-(4-fluorophenyl)-3-oxo third-1-alkene-1-base)-4,5,6,7-tetrahydrochysene-1H-indazole-1-carboxylic acid tert-butyl ester, is directly used in next step.

Step 2:

5-(2-cyano group-3-(4-fluorophenyl)-3-oxo third-1-alkene-1-base)-4, 5, 6, 7-tetrahydrochysene-1H-indazole-1-t-butyl formate (790mg, 2.0mmol) with 3-aminochlotononitlile (170mg, 2.0mmol) be dissolved in acetic acid (15mL), be heated to 100 DEG C stir 1 hour, be cooled to room temperature, reaction solution is concentrated dry, preparation TLC purifying (methylene dichloride: methyl alcohol=20: 1) obtain 2-(4-fluorophenyl)-6-methyl-4-(4, 5, 6, 7-tetrahydrochysene-1H-indazole-5-base)-1, 4-dihydropyridine-3, 5-dimethoxy nitrile (100mg, 14%).MS：[M+1]＝260； ¹H NMR(300MHz，DMSO-d ₆)δ12.25(s，1H)，9.82(s，1H)，7.64-7.62(m，2H)，7.40-7.32(m，3H)，3.41(br，1H)，2.75-2.42(m，4H)，2.12(s，3H)，2.05-1.95(m，1H)，1.85-1.63(m，2H)。

Synthesis preparation example 7:2-(4-p-methoxy-phenyl)-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-base)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethoxy nitrile

Step 1:

Methyl p-methoxybenzoate (2.0g, 12mmol) is dissolved in dry toluene (50mL), is cooled to 0 DEG C, adds sodium hydrogen (1.2g, 30mmol).Stir and add acetonitrile (1.23g, 30mmol) after 10 minutes, be slowly warming up to 110 DEG C, stirring is spent the night.After being cooled to room temperature, filter, collect after filter residue toluene wash and dry, obtain 1-cyano group-2-(4-p-methoxy-phenyl)-2-oxypropionitrile sodium salt (2.2g, 93%).

Step 2:

5-formyl radical-4; 5; 6; 7-tetrahydrochysene-1H-indazole-1-t-butyl formate (600mg, 2.40mmol), 1-cyano group-2-(4-p-methoxy-phenyl)-2-oxypropionitrile sodium salt (510mg, 2.88mmol) are dissolved in methylene dichloride (50mL); add acetic acid (173mg; 2.88mmol) with in piperidines (245mg, 2.88mmol), reflux stirred night under nitrogen protection.Reaction solution is cooled to room temperature, add methylene dichloride (30mL) dilute reaction solution, filter, filtrate is concentrated dry, resistates column chromatography (sherwood oil: ethyl acetate=7: 1) obtain 5-(2-cyano group-3-(4-p-methoxy-phenyl)-3-oxo third-1-alkene-1-base)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (550mg, 62%).

Step 3:

5-(2-cyano group-3-(4-p-methoxy-phenyl)-3-oxo third-1-alkene-1-base)-4; 5; 6; 7-tetrahydrochysene-1H-indazole-1-t-butyl formate (200mg; 0.49mmol) with 3-aminochlotononitlile (96mg; 0.98mmol) be dissolved in acetic acid (20mL), be heated to 100 DEG C under nitrogen protection and stir 1 hour.Be cooled to room temperature, reaction solution is concentrated dry, preparation TLC purifying (methylene dichloride: methyl alcohol=20: 1) obtain 2-(4-p-methoxy-phenyl)-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-base)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethoxy nitrile (40mg, 17%).MS(ESI+)：372[M+1]+； ¹H NMR(300MHz，CDCl ₃)δ9.74(s，1H)，8.30(s，1H)，7.52-7.49(m，2H)，7.32(s，1H)，7.06-7.04(m，2H)，3.80(s，3H)，3.36(br，1H)，2.74-2.58(m，4H)，2.12(s，3H)，1.98-1.95(m，1H)，1.80-1.61(m，2H)。

Synthesis preparation example 8:2-(pyridin-4-yl)-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-base)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethoxy nitrile

Step 1:

Iso methyl nicotinate (1.0g, 7.30mmol) is dissolved in toluene (30mL), is cooled to 0 DEG C, carefully adds after sodium hydrogen (60%, 0.58g, 14.6mmol) stirs 10 minutes.In above-mentioned solution, add acetonitrile (1.50g, 36.5mmol), be slowly warming up to 80 DEG C, stir 4 hours.After being cooled to room temperature, filtering, after filter residue toluene wash, collect filter residue, dry 1-cyano group-2-oxo-2-(pyridin-4-yl) ethane sodium salt (1.2g, 98%)

Step 2:

Under nitrogen protection; 5-formyl radical-4; 5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (600mg; 2.40mmol) with 1-cyano group-2-oxo-2-(pyridin-4-yl) ethane sodium salt (421mg; 2.88mmol) be dissolved in methylene dichloride (50mL), add acetic acid (173mg, 2.88mmol) and piperidines (245mg; 2.88mmol), return stirring spends the night.Reaction solution is cooled to room temperature, add methylene dichloride (30mL) dilute reaction solution, filter, filtrate is concentrated dry, and resistates column chromatography (DCM: MEOH=100: 1) obtains compound 5-(2-cyano group-3-oxo-3-(pyridin-4-yl) third-1-alkene-1-base)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (500mg, 72% purity, 55% yield).MS(ESI+)：379[M+1]+。

Step 3:

5-(2-cyano group-3-oxo-3-(pyridin-4-yl) third-1-alkene-1-base)-4; 5; 6; 7-tetrahydrochysene-1H-indazole-1-t-butyl formate (500mg; 1.32mmol) with 3-aminochlotononitlile (163mg; 1.98mmol) be dissolved in Glacial acetic acid (20mL), be heated to 100 DEG C under nitrogen protection and stir 1 hour.Be cooled to room temperature, by concentrated for reaction solution dry, resistates prepares TLC (methylene dichloride: methyl alcohol=20: 1) separation and purification, obtain compound 2-(pyridin-4-yl)-6-methyl-4-(4,5,6,7-tetrahydrochysene-1H-indazole-5-base)-1,4-dihydropyridine-3,5-dimethoxy nitrile (15mg, 3.3%).MS(ESI+)：343[M+1]+；1H NMR(300MHz，DMSO-d ₆)δ12.29(br，1H)，9.40(s，1H)，8.30(s，1H)，8.74-8.73(m，2H)，7.62-7.58(m，2H)，7.30(s，1H)，3.48(s，1H)，2.78-2.72(m，2H)，2.66-2.64(m，2H)，2.12(s，3H)，2.00-1.96(m，1H)，1.82-1.80(m，1H)，1.69-1.65(m，1H)。

Synthesis preparation example 9:6-methyl-8-(4,5,6,7-tetrahydrochysene-1H-indazole-5-base)-2,3,4,8-tetrahydrochysene-1H-quinolizine-7,9-dimethoxy nitriles

Step 1:

Piperidines 2-ketone (4.96g, 50mmol) is dissolved in methylene dichloride (200mL), adds MeOTf (10.2g, 62mmol), finishes stirring at room temperature 18 hours.In reaction solution, add powdered sodium carbonate (20g) and water (8mL), stir 10 minutes, filter, filtrate anhydrous sodium sulfate drying, concentrated, resistates 6-methoxyl group-2,3,4,5-tetrahydropyridine (4.525g, 81%) is directly used in the next step.MS：[M+1]＝114。

Step 2:

Upper step gained 6-methoxyl group-2,3,4,5-tetrahydropyridine (4.525g, 40mmol) is dissolved in anhydrous tetrahydro furan (150mL), adds 2-t-butylcyanoacetate (5.98g, 42.3mmol), be heated to 70 DEG C of return stirrings spend the night.Reaction solution concentrates, resistates column chromatography (sherwood oil: ethyl acetate=10: 1) obtain 2-cyano group-2-(piperidines-2-thiazolinyl) tert.-butyl acetate (3.2g, 36%).MS：[M+1]＝223。

Step 3:

2-cyano group-2-(piperidines-2-thiazolinyl) tert.-butyl acetate (444mg, 2.0mmol) be dissolved in 6M hydrochloric acid (5mL), be heated to 100 DEG C stir 15 minutes, be chilled to room temperature, concentrating under reduced pressure is done, and resistates 2-(piperidines-2-thiazolinyl) acetonitrile is directly used in the next step.

Step 4:

By compound 5-(2-cyano group-3-oxo but-1-ene-1-base)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (630mg, 2.0mmol) with upper step gained 2-(piperidines-2-thiazolinyl) acetonitrile (244mg, 2.0mmol) be dissolved in acetic acid (5mL), be heated to 100 DEG C and stir 1 hour.Be cooled to room temperature, reaction solution is concentrated dry, and resistates purification by silica gel column chromatography obtains 6-methyl-8-(4,5,6,7-tetrahydrochysene-1H-indazole-5-base)-2,3,4,8-tetrahydrochysene-1H-quinolizine-7,9-dimethoxy nitriles (150mg, 24%).MS：[M+1]＝319； ¹H NMR(300MHz，CDCl ₃)δ7.42(s，1H)，3.62-3.55(m，1H)，3.46-3.42(m，1H)，3.27-3.23(m，1H)，2.93-2.59(m，5H)，2.40-2.23(m，1H)，2.26(s，3H)，2.03-1.69(m，7H)。

With reference to the method for synthesis preparation example 9, respectively with the " 5-(2-cyano group-5-methyl-3-oxygen hexyl-1-alkene-1-base)-4; 5; 6 in " 5-(2-cyano group-3-oxygen amyl group-1-alkene-1-base)-4; 5; 6; 7-tetrahydrochysene-1H-indazole-1-t-butyl formate " in preparation example 2 and preparation example 3,7-tetrahydrochysene-1H-indazole-1-t-butyl formate " replacement " 5-(2-cyano group-3-oxo but-1-ene-1-base)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate ", the compound (I-10) in following table and (I-11) can be obtained respectively:

Synthesis preparation example 12:6-methyl-8-(4,5,6,7-tetrahydrochysene-1H-indazole-5-base)-1,3,4,8-tetrahydropyridines also [2,1-c] [Isosorbide-5-Nitrae] oxazines-7,9-dimethoxy nitrile

Step 1:

Compound morpholine-3-ketone (303mg, 3mmol) is dissolved in methylene dichloride (20mL), adds MeOTf (610mg, 3.72mmol), stirring at room temperature 18 hours.Add powdered sodium carbonate (5g), water (1mL), stir after 30 minutes and filter.Filtrate is with anhydrous sodium sulfate drying, and concentrate to obtain 5-methoxyl group-3,6-dihydro-2H-1,4-oxazines crude product (261mg, 75%) is oily matter.

Step 2:

Compound 5-methoxyl group-3,6-dihydro-2H-1,4-oxazines (261mg, 2.27mmol) and 2-t-butylcyanoacetate (461mg, 2.81mmol) are dissolved in anhydrous tetrahydro furan (10mL), and return stirring spends the night.Be cooled to room temperature, concentrating under reduced pressure, resistates column chromatography (sherwood oil: ethyl acetate=10: 1) obtaining 2-cyano group-2-(morpholine-3-thiazolinyl) tert.-butyl acetate (106mg, 21%), is white solid.

Step 3:

2-cyano group-2-(morpholine-3-thiazolinyl) tert.-butyl acetate (163mg, 0.73mmol) is added in 6N hydrochloric acid (5mL), is heated to 100 DEG C and stirs 15 minutes.Be chilled to room temperature, remove solvent under reduced pressure, resistates is 2-(morpholine-3-thiazolinyl) acetonitrile crude product, is directly used in next step.

Step 4:

By 5-(2-cyano group-3-oxo but-1-ene-1-base)-4,5,6,7-tetrahydrochysene-1H-indazole-1-t-butyl formate (230mg, 0.73mmol) with upper step gained compound 2-(morpholine-3-thiazolinyl) acetonitrile crude product (90mg, 0.73mmol) be dissolved in acetic acid (5mL), be heated to 100 DEG C and stir 1 hour.Be cooled to room temperature, by concentrated for reaction solution dry, prepare plate TLC purifying (100% ethyl acetate is launched) and obtain 6-methyl-8-(4,5,6,7-tetrahydrochysene-1H-indazole-5-base)-1,3,4,8-tetrahydropyridine is [2,1-c] [Isosorbide-5-Nitrae] oxazines-7 also, 9-dimethoxy nitrile (25mg, 11%).MS：[M+1]＝322； ¹H NMR(300MHz，CDCl ₃)δ7.36(s，1H)，6.61(br，1H)，4.65(dd，J＝55.5Hz，15.9Hz，2H)，4.06-4.22(m，1H)，3.88-3.83(m，1H)，3.65-3.61(m，1H)3.48-3.44(m，1H)，3.33-3.30(m，1H)，2.92-2.83(m，1H)，2.70-2.62(m，2H)，2.48-2.39(m，1H)，2.29(s，3H)，2.05-1.82(m，2H)，1.79-1.63(m，1H)。

Copy the method for synthesis preparation example 12, with " the 5-(2-cyano group-3-oxygen amyl group-1-alkene-1-base)-4 in preparation example 2, 5, 6, 7-tetrahydrochysene-1H-indazole-1-t-butyl formate ", " 5-(2-cyano group-5-methyl-3-oxygen hexyl-1-alkene-1-base)-4 in preparation example 3, 5, 6, 7-tetrahydrochysene-1H-indazole-1-t-butyl formate " and preparation example 4 in " 5-(2-cyano group-6, 6, the fluoro-3-oxo-hexyl of 6-tri--1-alkene-1-base)-4, 5, 6, 7-tetrahydrochysene-1H-indazole-t-butyl formate " replace intermediate " 5-(2-cyano group-3-oxo but-1-ene-1-base)-4, 5, 6, 7-tetrahydrochysene-1H-indazole-1-t-butyl formate ", the compound (I-13) in following table can be obtained respectively, and (I-15) (I-14):

Bioassay embodiment 1: compound is to the In-vitro Inhibitory Effect of c-Met enzyme

Utilize the method for Mobility Shift Assay, measure compound in vitro to the restraining effect of c-Met enzyme.

Experimental technique

1. prepare kinase buffer liquid and the stop buffer of 1.25x

1.1 containing MnCl ₂1.25 times of kinase buffer liquid

62.5mM HEPES，pH 7.5

0.001875％Brij-35

12.5mM MgCl2

2.5mMDTT

1.2 containing MnCl ₂1.25 times of kinase buffer liquid

62.5mM HEPES，pH 7.5

0.001875％Brij-35

12.5mM MgCl2

12.5mM MnCl2

2.5mM DTT

1.3 stop buffer

100mMHEPES，pH 7.5

0.015％Brij-35

0.2％Coating Reagent#3

50mMEDTA

2. compound solution preparation

2.1 diluted chemical compound

In EP pipe, add the 50mM compound of 20 μ L, add the 100%DMSO of 80 μ L, be made into the 10mM compound of 100 μ L.In another EP pipe, add the 10mM compound of 30 μ L, add the 100%DMSO of 70 μ L, be made into the 3mM compound of 100 μ L.

96 orifice plates add in second hole the 3mM compound of 100%DMSO and 5uL of 95 μ L, and other holes add the 100%DMSO of 60 μ L.From the 2nd hole, get 30 μ L compounds adds in the 3rd hole, down does 3 times of dilutions successively, dilutes 10 concentration altogether.Compound concentration range is 150uM to 7.6nM.

2.2 transferase 45s times compound is to Sptting plate

Get 10 μ L from each hole of above-mentioned 96 orifice plates to another block 96 orifice plate, add 90 μ L ultrapure waters.Therefore being the compound be dissolved in 10%DMSO in the second hole to 11-holes, is 10%DMSO in the first hole and the 12 hole.

5 μ L are taken out to one piece of 384 hole Sptting plate from above-mentioned 96 orifice plates.Therefore, the 5 times of compounds just having the 10%DMSO of 5 μ L to dissolve in 384 hole Sptting plates and the 10%DMSO of 5 μ L.The EDTA of 5 μ L 250mM is added in negative control hole.

3. kinase reaction

3.1 preparations, 2.5 times of enzyme solution

Kinases is added 1.25 times of kinase buffer liquid, form 2.5 times of enzyme solution.

The substrate solution of 3.2 preparations 2.5 times

The polypeptide mark FAM and ATP add 1.25 times of kinase buffer liquid, form 2.5 times of substrate solutions.

Enzyme solution is added in 3.3 to 384 orifice plates

5 times of compounds that in 384 hole Sptting plates, the 10%DMSO of existing 5 μ L dissolves.

2.5 times of enzyme solution of 10 μ L are added in 384 hole Sptting plates.

Incubated at room temperature 10 minutes.

Substrate solution is added in 3.4 to 384 orifice plates

2.5 times of substrate solutions of 10 μ L are added in 384 hole Sptting plates.

3.5 kinase reactions and termination

1 hour is hatched at 28 DEG C.Add 25 μ L stop buffer termination reactions.

4.Caliper reading of data

Caliper upper reading and converting rate data.

5. inhibiting rate calculates

Conversion data is copied from Caliper.Conversion is become inhibiting rate data.Wherein max refers to that the transformation efficiency that DMSO contrasts, min refer to the transformation efficiency without enzyme contrast alive.

Inhibiting rate=(max-conversion)/(max-min) × 100

Bioassay embodiment 1: experimental result

Remarks: "+" represents 100nM < IC ₅₀< 1uM; " ++ " represents 10nM < IC ₅₀< 100nM; " +++ " represents IC ₅₀< 10nM.

Bioassay embodiment 2: the restraining effect that compound is bred stomach cancer cell MKN-45

Experimental technique

1. cell cultures

This tests cell used is MKN-45 cell, is incubated in the RPMI1640 substratum containing 10% foetal calf serum.Cell cultures is containing in the substratum of following ingredients: RPMI1640 substratum, the foetal calf serum of 10% (v/v), 100U/mL penicillin, 100 μ g/mL Streptomycin sulphates.Cell cultures is in 37 DEG C of 5%CO ₂nitrogen peroxide incubator in, the ratio of going down to posterity is 1: 2 ~ 1: 6.

2. compound preparation and dilution

Be pressed powder when compound receives, according to the quality that client provides, the DMSO preparation adding respective amount claims the storing solution of 10mM, then becomes 9 concentration initial concentrations with DMSO gradient dilution.In order to obtain the IC of compound ₅₀, we have selected 9 tests final concentration (25000,8333,2778,926,309,103,34,11and 1.8nM) and test.Be diluted to final concentration with substratum, the ultimate density of DMSO is 0.25%.

3. experimental procedure

3.1 cultivate MKN-45 cells and are inoculated in 96 or 384 orifice plates and test.

3.2 add test-compound in about 24 hours after cell inoculation, and each compound is by tested 9 concentration (3 times of gradient dilutions), and each some test two is hole again.

3.3 cells at 37 DEG C, 5%CO ₂cultivate 5 days.

3.4 by the growing state of the detection method test cell of Celltiter Glo.

4. data analysis

Testing data is analyzed by XLFit software, draws half-inhibition concentration.

Bioassay embodiment 2: experimental result

Remarks: "+" represents 500nM < IC50 < 5uM; " ++ " represents 100nM < IC50 < 500nM; " +++ " represents IC50 < 100nM.

Claims

1. dihydropyridine compounds, for having the compound of following general formula (I):

Wherein, R ₁be selected from C1 ~ C3 alkyl, isobutyl-, the ethyl that trifluoromethyl replaces, the ethyl of methoxy substitution, the phenyl of fluorine or methoxy substitution, or pyridyl;

R ₂be selected from hydrogen or R ₂with R ₃form piperidines, morpholine ring;

R ₃be selected from methyl or R ₃with R ₂form piperidines, morpholine ring.

2. dihydropyridine compounds as claimed in claim 1, its formula of (I) compound is selected from the compound as shown in the formula (I-1) to (I-15):

3. dihydropyridine compounds as claimed in claim 1, the compound of its formula of (I) is any one in enantiomer, diastereomer, conformer, or arbitrarily both, three or four mixture.

4. prepare the method for dihydropyridine compounds according to claim 1 for one kind, it is characterized in that, the compound of described general formula (I) is prepared from by the following method: with pimelinketone-4-ethyl formate (1) for raw material, at N, intermediate (2) is converted under the effect of dinethylformamide dimethylacetal (DMF-DMA), this intermediate (2) and hydrazine reaction, cyclisation is pyrazole compound (3); Ester group in pyrazole compound (3) is reduced with reductive agent, obtains intermediate (4); Then the amido of intermediate (4) pyrazoles is protected to obtain intermediate (II) with suitable protecting group PG, then by the alcoholic extract hydroxyl group of intermediate (II) with the oxidation of suitable condition, obtain aldehydes intermediate (III); Aldehydes intermediate (III) and cyano group ketone compounds (A) condensation, obtain intermediate (IV), intermediate (IV) again with 1 equivalent amido alkene nitrile raw material (B) condensation, then deprotection base under suitable condition, obtains the compound (I) of general formula (I); Concrete route is as follows:

5. method as claimed in claim 4, it is characterized in that, described reductive agent is lithium aluminium hydride, sodium borohydride.

6. method as claimed in claim 4, is characterized in that, described suitable protecting group PG be tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl.

7. method as claimed in claim 4, is characterized in that, described suitable condition is oxidized to Dess-Martin oxidation, Swern oxidation.

8. method as claimed in claim 6, it is characterized in that, the described base of deprotection under suitable condition refers to: adopt the organic solution of hydrogenchloride or trifluoracetic acid/methylene dichloride to remove tertbutyloxycarbonyl; The method of catalytic hydrogenation is adopted to remove carbobenzoxy-(Cbz); Or adopt trifluoracetic acid to remove methoxy-benzyl.

9. prepare a method for dihydropyridine compounds according to claim 1, it is characterized in that, R in the compound of general formula (I) ₁with R ₃identical and R ₂during for hydrogen, the compound of its general formula (I) is compound (Ia); Compound (Ia) is prepared by following methods: with pimelinketone-4-ethyl formate (1) for raw material, at N, intermediate (2) is converted under the effect of dinethylformamide dimethylacetal (DMF-DMA), this intermediate (2) and hydrazine reaction, cyclisation is pyrazole compound (3); Ester group in pyrazole compound (3) is reduced with reductive agent, obtains intermediate (4); Then the amido of intermediate (4) pyrazoles is protected to obtain intermediate (II) with suitable protecting group PG; Again the alcoholic extract hydroxyl group of intermediate (II) is oxidized with suitable condition, obtains aldehydes intermediate (III); Amino alkene nitrile raw material (C) condensation of this aldehydes intermediate (III) and 2 equivalents, then deprotection base under suitable condition, obtain compound (Ia); Concrete route is as follows:

Wherein R ₁and R ₃replace with Ra.

10. method as claimed in claim 9, it is characterized in that, described reductive agent is lithium aluminium hydride, sodium borohydride.

11. methods as claimed in claim 10, is characterized in that, described protecting group PG be tertbutyloxycarbonyl, carbobenzoxy-(Cbz), to methoxy-benzyl.

12. methods as claimed in claim 9, is characterized in that, described suitable condition is oxidized to Dess-Martin oxidation, Swern oxidation.

13. methods as claimed in claim 11, is characterized in that, the described base of deprotection under suitable condition refers to: adopt the organic solution of hydrogenchloride or trifluoracetic acid/methylene dichloride to remove tertbutyloxycarbonyl; The method of catalytic hydrogenation is adopted to remove carbobenzoxy-(Cbz); Or adopt trifluoracetic acid to remove methoxy-benzyl.

14. containing the pharmaceutical composition of dihydropyridine compounds, and wherein said pharmaceutical composition comprises compound and the acceptable vehicle of pharmacy of the general formula according to claim 1 (I) for the treatment of significant quantity.

15. pharmaceutical compositions as claimed in claim 14, its pharmaceutical composition makes tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis, granule, syrup, emulsion, ointment, ointment, suppository or injection.

16. 1 kinds of pharmaceutical compositions, wherein said pharmaceutical composition comprises pharmacy acceptable salt and the acceptable vehicle of pharmacy of the dihydropyridine compounds of the general formula according to claim 1 (I) for the treatment of significant quantity.

17. pharmaceutical compositions as claimed in claim 16, its pharmaceutical composition makes tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis, granule, syrup, emulsion, ointment, ointment, suppository or injection.

The application of 18. 1 kinds of dihydropyridine compounds according to claim 1 is wherein that the compound of general formula (I) is preparing the application in Function protein kinase catalytic activity goods; Described protein kinase is c-Met receptor tyrosine kinase.

The application in Function protein kinase catalytic activity goods prepared by the pharmaceutically useful salt of the compound of the general formula (I) described in 19. 1 kinds of claims 1; Described protein kinase is c-Met receptor tyrosine kinase.

The application of 20. 1 kinds of dihydropyridine compounds according to claim 1 is wherein the application of compound in the medicine preparing the treatment disease relevant with protein kinase of general formula (I); Described protein kinase is c-Met receptor tyrosine kinase.

21. apply as claimed in claim 20, and the wherein said disease relevant with protein kinase is cancer.

22. apply as claimed in claim 21, and wherein said cancer is selected from cancer of the stomach, lung cancer, thyroid carcinoma, colorectal carcinoma, kidney, liver cancer, ovarian cancer, mammary cancer, prostate cancer, bladder cancer, head and neck cancer, carcinoma of the pancreas, carcinoma of gallbladder, osteosarcoma, rhabdosarcoma, MFH/ fibrosarcoma, glioblastoma/astrocytoma, melanoma or mesothelioma.

The application in the medicine of the disease relevant with protein kinase treated by the pharmaceutically useful salt of the compound of the general formula (I) described in 23. 1 kinds of claims 1 in preparation; Described protein kinase is c-Met receptor tyrosine kinase.

24. apply as claimed in claim 23, and the wherein said disease relevant with protein kinase is cancer.

25. apply as claimed in claim 24, and wherein said cancer is selected from cancer of the stomach, lung cancer, thyroid carcinoma, colorectal carcinoma, kidney, liver cancer, ovarian cancer, mammary cancer, prostate cancer, bladder cancer, head and neck cancer, carcinoma of the pancreas, carcinoma of gallbladder, osteosarcoma, rhabdosarcoma, MFH/ fibrosarcoma, glioblastoma/astrocytoma, melanoma or mesothelioma.