CN106349158A - c-Met small-molecule inhibitor, pharmaceutical composition containing same and pharmaceutical application of pharmaceutical composition containing same - Google Patents
c-Met small-molecule inhibitor, pharmaceutical composition containing same and pharmaceutical application of pharmaceutical composition containing same Download PDFInfo
- Publication number
- CN106349158A CN106349158A CN201610639314.5A CN201610639314A CN106349158A CN 106349158 A CN106349158 A CN 106349158A CN 201610639314 A CN201610639314 A CN 201610639314A CN 106349158 A CN106349158 A CN 106349158A
- Authority
- CN
- China
- Prior art keywords
- halo
- alkyl
- compound
- alkoxyl
- halogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 CC(C=C1O)=C=C(*)C=C1Cl Chemical compound CC(C=C1O)=C=C(*)C=C1Cl 0.000 description 1
- IGYPVZQMZZJPDD-UHFFFAOYSA-N Cc1c(C(N)O)nccc1Cl Chemical compound Cc1c(C(N)O)nccc1Cl IGYPVZQMZZJPDD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a c-Met small-molecule inhibitor, a preparation method thereof, a pharmaceutical composition containing derivatives, salts of the pharmaceutical composition and application of medicines with the pharmaceutical composition or salts thereof as active ingredients to preparation of antitumor drugs and drugs for treating diseases relevant to liver diseases. The c-Met small-molecule inhibitor is structurally shown as the general formula (I). The pharmaceutical composition is high in in-vitro tumor inhibiting activity and capable of reaching a nanomole level for c-Me kinase inhibiting activity and can be used as liver cancer treatment drugs novel in structure, thereby being high in commercial value.
Description
Technical field
The present invention relates to drug world and in particular to a kind of c-met micromolecular inhibitor, containing its pharmaceutical composition and its
Pharmaceutical applications.
Background technology
Malignant tumor is to threaten one of major disease of human health.By inference to before the year two thousand twenty, global cancer will increase newly
15000000 cancer patients, the death toll of cancer, also in the swift and violent rising in the whole world, may increase to 13,200,000.The preventing and treating of tumor becomes
Important subject for the world of medicine of various countries.
Hepatocarcinoma is one of common malignant tumor in world wide, and its M ＆ M is in ascendant trend year by year, mesh
Front become the third-largest common cancer being only second to gastric cancer and esophageal carcinoma, be mainly distributed on East Asia, Southeast Asia and Africa
Central and west regions.The treatment meanss of hepatocarcinoma mainly include operative treatment, and (liver transplantation, tumor resection and non-ablated local treatment are such as
Hepatic arterial chemoembolization), radiotherapy and chemotherapy, wherein, because hepatocarcinoma grade malignancy is high, development and change are fast, and early stage exists in liver
Disseminate and the factor such as liver function decompensation, so only a few patients can carry out the curative therapy scheme such as excision.Root
According to data statisticss, excise therapy radical cure relapse rate after 5 years for the hepatocarcinoma and be still up to 40-70%, these for hepatocarcinoma are biological
Feature, application system chemotherapeutics stop its invasion and attack and shift and suppress the systematic treating pattern of Advanced cancers evolution to be liver
One of target of cancer standardized therapeutic.
The traditional chemotherapy of hepatocellular carcinoma medicine clinically using at present have mitomycin, 5-fluorouracil, amycin and table Ah
Mycin etc., the modal defect of this kind of chemotherapeutics is that tissue selectivity is poor, widely distributed in vivo, is therefore playing the same of curative effect
When often produce serious general toxic and side effects, such as bone marrow inhibition, gastrointestinal toxicity (nausea and vomiting) and hair are thin
Cellular toxicity etc..Therefore, the searching new type anticancer medicine that curative effect is higher and toxic and side effects are little has become chemotherapy of hepatocellular carcinoma original new drug and has ground
Important Problems in studying carefully.
C-met is a prototypical member of tyrosine kinase receptor family ron subtribe, is expressed by proto-oncogene c-met, it
It is the only known hepatocyte growth factor (hgf) high-affinity receptor.Research shows, in liver cancer tissue, c-met in mrna and
The positive rate of protein level and expression are significantly higher than the other nonneoplastic tissue of cancer or normal liver tissue, and the grade malignancy with tumor
Related.Additionally, the jumping phenomenon of c-met gene also has generation in hepatocarcinoma, this also illustrates the mutation of c-met gene and hepatocarcinoma
Occurrence and development also have certain association.In recent years, to have evoked Pharmaceutical Chemist dense for the medicines resistant to liver cancer research based on c-met target spot
And it was found that some have the drug candidate of DEVELOPMENT PROSPECT, experiment is proved individually to adopt c-met to suppress thick research interest
Agent or collaborative other embolic chemotherapy are treated, and inducible hepatoma cell apoptosis suppress its drug resistance.Clinical research aspect,
Find multiple c-met micromolecular inhibitor medicines to the hepatocarcinoma patient with liver cirrhosis in the clinical research covering kinds of tumors
Liver function is not significantly damaged, and has certain safely controllable property, also tentatively presents its therapeutic effect to hepatocarcinoma simultaneously.This
A little researchs all demonstrate hgf/c-met and serve not only as one of therapy of tumor, the focus of antitumor drug exploitation in recent years,
One of target spot for the treatment of liver-cancer medicine research and development and exploitation can be become.
Goal of the invention
For the deficiencies in the prior art, it is an object of the invention to provide a kind of c-met micromolecular inhibitor and its preparation side
Method, the pharmaceutical composition containing these derivants, the salt of this compound and with this compound or its salt class as active component
Application in preparing antitumor drug and hepatopathy treating correlative diseases medicine for the medicine.
Term illustrates: term used herein " aryl " refers to that the full carbon of 5 to 12 carbon atoms is monocyclic or fused polycycle base
Group, has the pi-electron system of total conjugated.The non-limiting examples of aromatic ring have: phenyl ring, naphthalene nucleus and anthracene nucleus.Aromatic ring can be taken
Generation or unsubstituted.The substituent group of aromatic ring is selected from halogen, nitro, amino, cyano group, c1-c4Alkyl, the c of halo1-c4Alkyl, c1-
c4Alkoxyl, c1-c4Alkylamino radical, the c of halo1-c4Alkoxyl, the c of halo1-c4Alkylamino radical.
Term used herein " heterocyclic aryl " refers to the undersaturated carbocyclic ring of 5 to 12 annular atoms, wherein one or more
Carbon is by the hetero atom such as displacement such as oxygen, nitrogen, sulfur.Hetero-aromatic ring can be monocyclic or bicyclic, condensed by two rings and
Become.Specific heterocyclic aryl may is that pyridine radicals, pyrimidine radicals, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl,
Oxazolyl and imidazole radicals etc..Heterocyclic aryl can be substituted or unsubstituted.The substituent group of heterocyclic aryl can be selected from halogen, nitre
Base, amino, cyano group, c1-c4Alkyl, the c of halo1-c4Alkyl, c1-c4Alkoxyl, c1-c4Alkylamino radical, the c of halo1-c4Alcoxyl
Base, the c of halo1-c4Alkylamino radical.
Term used herein " Heterocyclylalkyl " refers to monocyclic or fused ring group, has 5 to 9 annular atoms in ring, its
In at least one or two annular atoms be selected from n, o, s (o)mThe hetero atom of (wherein m is 0 to 2 integer), remaining annular atom is
c.These rings can have one or more double bond, but these rings do not have the pi-electron system of total conjugated.Heterocyclylalkyl is permissible
It is substituted or unsubstituted.Unsubstituted Heterocyclylalkyl can be pyrrolidinyl, piperidyl, piperazinyl, morpholino base, thio
Morpholino base, homopiperazine base etc..Heterocycle can be substituted or unsubstituted.The substituent group of heterocycle be selected from halogen, nitro, amino,
Cyano group, c1-c4Alkyl, the c of halo1-c4Alkyl, c1-c4Alkoxyl, c1-c4Alkylamino radical, the c of halo1-c4Alkoxyl, halo
c1-c4Alkylamino radical.
Term used herein " cycloalkyl " refers to the saturation monocycle carbocyclic ring with 3-6 carbon atom." cycloalkyl " includes
Such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and cyclooctyl." cycloalkyl " also includes substituted cycloalkyl.Described
Cycloalkyl also can optionally be substituted by one or more substituents on any available carbon, described substituent group is selected from alcoxyl
Base, halogen and haloalkyl, such as perfluoroalkyl etc..
Term used herein " alkoxyl " refers to-o- alkyl group.The example of the present invention used " alkoxyl " include but
It is not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy and tert-butoxy." alkoxyl " also includes replacing alkane
Epoxide.Alkoxyl can optionally be optionally substituted by halogen one or many.
Term used herein " halogen " represents fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
Term used herein " alkylamino radical " refers to-n- alkyl group.The example of the present invention used " alkylamino " include but
It is not limited to first class substituted-amino, ethyl substituted-amino, n-pro-pyl substituted-amino, isopropyl substituted-amino, normal-butyl substituted-amino.
Alkylamino can optionally be replaced once or twice by methyl, ethyl, propyl group.
Term used herein " alkylamino radical " refers to-n- alkyl group, has general structure-nh (alkyl) or-n (alkane
Base) (alkyl) two grades or tertiary amine, each alkyl may be the same or different.This base comprises such as single-(c1-c8Alkyl) amido and
Two-(c1-c8Alkyl) amido, wherein each alkyl may be the same or different and can contain 1 to 8 carbon atom, and list-(c1-c6Alkane
Base) amido and two-(c1-c6Alkyl) amido and list-(c1- c4Alkyl) amido and two-(c1- c4Alkyl) amido.The present invention
The example of " alkylamino radical " used includes but is not limited to first class substituted-amino, ethyl substituted-amino, n-pro-pyl substituted-amino, isopropyl
Substituted-amino, normal-butyl substituted-amino.Alkylamino radical can optionally be replaced once or twice by methyl, ethyl, propyl group etc..
Term used herein " solvate " refers to by solute (for example: the formula (i) of the present invention～formula () chemical combination
Thing) and solvent formed varying chemical metering complex.For the purposes of the present invention, described solvent can not disturb the life of solute
Thing activity.The example of suitable solvent includes but is not limited to water, methanol, ethanol and acetic acid.The solvent preferably using is pharmacy
Acceptable solvent.Suitable pharmaceutical acceptable solvents include but is not limited to water, ethanol and acetic acid.It is highly preferred that solvent for use is
Water.
The present invention adopts the following technical scheme that:
C-met molecule inhibitor compounds provided by the present invention have formula () structure:
And its pharmaceutically acceptable salt or solvate；
Wherein: r1Selected from halogen, c1-c4Alkyl, the c of halo1-c4Alkyl, c1-c4Alkoxyl, the c of halo1-c4Alkoxyl；
r2Selected from h, c1-c4Alkyl, the c of halo1-c4Alkyl, c1-c4Alkoxyl, the c of halo1-c4Alkoxyl；
r3、r4、r5、r7And r8Selected from h, halogen, nitro, amino, cyano group, c1-c4Alkyl, the c of halo1-c4Alkyl, c1-c4
Alkoxyl, the c of halo1-c4Alkoxyl；
r6Selected from unsubstituted or replace aryl, unsubstituted or replace heterocyclic aryl, unsubstituted or replace cycloalkyl,
Unsubstituted or replace saturated heterocyclic alkyl, unsubstituted or replace unsaturated heterocycle alkyl, the aryl arbitrarily condensing, heterocycle virtue
Base, described substituted substituent group is optionally from halogen, nitro, amino, cyano group, c1-c4Alkyl, the c of halo1-c4Alkyl, c1-c4Alkane
Epoxide, c1-c4Alkylamino radical, the c of halo1-c4Alkoxyl, the c of halo1-c4Alkylamino radical；Preferably, described aryl or miscellaneous
Cyclophane base is selected from pyrroles, furan, thiophene, pyrazoles, imidazoles, thiazole, azoles, phenyl ring, pyridine, pyridazine, pyrimidine, pyrazine.
Further, currently preferred compound has formula () structure:
And its pharmaceutically acceptable salt or solvate；Wherein:
r1、r2、r7And r8As formula () structure defines；
r6Selected from the heterocyclic aryl of substituted or unsubstituted aryl, replacement, described substituted substituent group is optionally from halogen, nitre
Base, amino, cyano group, c1-c3Alkyl, the c of halo1-c3Alkyl, c1-c3Alkoxyl, c1-c3Alkylamino radical, the c of halo1-c3Alcoxyl
Base, the c of halo1-c3Alkylamino radical；Preferably, described aryl or heterocyclic aryl are selected from pyrroles, furan, thiophene, pyrazoles, miaow
Azoles, thiazole, azoles, phenyl ring, pyridine.
Further, currently preferred compound has formula (iii) structure:
And its pharmaceutically acceptable salt or solvate, wherein:
r1、r2、r7And r8As defined in claim 1；
r9And r10Selected from hydrogen, halogen, nitro, amino, cyano group, c1-c3Alkyl, the c of halo1-c3Alkyl, c1-c3Alkoxyl,
c1-c3Alkylamino radical, the c of halo1-c3Alkoxyl, the c of halo1-c3Alkylamino radical.
More specifically, the preferred compound of formula (iii) structure of the present invention is:
N- (5- chloro-2-methyl -4- (3- methyl-2-amino pyridine -4- epoxide) phenyl)-n- (3- fluorophenyl) cyclopropyl -
1,1- diformamide；
N- (5- chloro- 1- methyl isophthalic acid h- pyrazoles -2- base)-n- (the chloro- 4- of 3- (3- chloro- PA -4- epoxide) phenyl)
Cyclopropyl -1,1- diformamide；
N- (the chloro- 4- of 5- (3- chloro- 2- (dimethylamino) pyridine -4- epoxide) -2- methoxyphenyl)-n- (furan -2- base)
Cyclopropyl -1,1- diformamide；
N- (3- chloro- 2- furan -4- (3- fluoro- PA -4- epoxide) phenyl)-n- cyclohexyl ring propyl group -1,1- two
Methanamide；
And its above-claimed cpd pharmaceutically acceptable salt or solvate.
The present invention can prepare cyclopropyl two formyl of the present invention using method well-known to those skilled in the art
The salt of aminated compoundss.Described salt can be acylate, inorganic acid salt etc., described acylate include citrate,
Fumarate, oxalates, malate, lactate, camsilate, tosilate, mesylate etc.；Described is inorganic
Hydrochlorate includes halogen acid salt, sulfate, phosphate, nitrate etc..For example, with lower alkanesulfonic acid, such as methanesulfonic acid, fluoroform sulphur
Acid etc. can form mesylate, fluoroform sulphonate；Can be formed to toluene with aryl sulfonic acid, such as benzenesulfonic acid or p-methyl benzenesulfonic acid etc.
Sulfonate, benzene sulfonate；With organic carboxyl acid, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or lemon
Lemon acid etc. can form corresponding salt；Glutamate, Glu or aspartate can be formed with aminoacid, such as glutamic acid or aspartic acid.With
Mineral acid, such as halogen acids (as Fluohydric acid., hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, sulphuric acid or phosphoric acid etc. also can be formed
Corresponding salt.
Second object of the present invention is to provide a kind of pharmaceutical composition, and described pharmaceutical composition comprises at least one activity
Component and one or more pharmaceutically acceptable carrier or excipient, described active component can be the ring third of the present invention
Base dicarboxylic acid diamides, described compound pharmaceutically acceptable salt, any one in described compound solvent compound
Plant or arbitrarily multiple.
Described carrier includes the conventional thinner of pharmaceutical field, excipient, filler, binding agent, wetting agent, disintegrating agent,
Absorption enhancer, surfactant, absorption carrier, lubricant etc. is it may also be necessary to add flavouring agent, sweeting agent etc..This
Bright medicine can make tablet, powder, granule, capsule, the various ways such as oral liquid and injecting drug use, the medicine of above-mentioned each dosage form
All can prepare according to the conventional method of pharmaceutical field.
Third object of the present invention is to provide above-described various compounds, described compound to be pharmaceutically subjected to
Salt, the solvate of described compound, purposes in preparing antitumor drug for the described pharmaceutical composition, described tumor
Selected from breast carcinoma, sarcoma, pulmonary carcinoma, carcinoma of prostate, colon and rectum carcinoma, renal carcinoma, cancer of pancreas, leukemia, neuroblastoma, god
Through glioma, head cancer, neck cancer, thyroid carcinoma, hepatocarcinoma, ovarian cancer, carcinoma vulvae, cervical cancer, carcinoma of endometrium, carcinoma of testis, wing
Guang cancer, the esophageal carcinoma, gastric cancer, nasopharyngeal carcinoma, carcinoma of buccal mucosa, oral cancer, gastrointestinal stromal tumor, skin carcinoma, multiple myeloma.
Fourth object of the present invention is to provide above-described various compounds, described compound to be pharmaceutically subjected to
Salt, the solvate of described compound, described pharmaceutical composition preparation hepatopathy treating correlative diseases medicine in purposes,
Described hepatopathy relevant disease is selected from viral hepatitis, autoimmune hepatitiss, drug toxicity hepatitis, hepatopathy hepatic injury, liver function
Can exhaustion, chronic severe hepatitises, liver cirrhosis, liver abscess, fatty liver, primary hepatocarcinoma.
The present invention also provides above-described various compound, described compound pharmaceutically acceptable salt, describedization
The solvate of compound, described pharmaceutical composition, are used in combination in preparation hepatopathy treating correlative diseases medicine with other drugs
Purposes in thing, described hepatopathy relevant disease is selected from viral hepatitis, autoimmune hepatitiss, drug toxicity hepatitis, hepatopathy
Hepatic injury, liver failure, chronic severe hepatitises, liver cirrhosis, liver abscess, fatty liver, primary hepatocarcinoma.
Present invention also offers the method preparing formula () and its pharmaceutically acceptable derivant, by three of compound
Key component, the present invention is referred to as the reaction of the head () of compound, center (v) and tail () to prepare formula () chemical combination
Thing, the synthetic route of partial Formula () compound is as follows:
Every kind of formula () compound all can be conveniently by separate three kinds of constructs preparing described compound, Ran Houzai
These group subassemblys are formed formula () compound.For convenience, described three kinds of constructs are referred to as head in the present invention
(), center (v) and tail ().For convenience, when used alone, term head, center and the tail table using in the whole text
Show each construct, when being combined into now with head/center, tail/center and/or head/center/tail in the text, be also
Refer to corresponding part.
The head component (component) of the compounds of this invention is the substituted ethylene-acetic acid as representative with formula ()
Compound:
The center component (component) of the compounds of this invention is that the substituted-amino phenol that has as representative is tied with formula (v)
The compound of structure:
The tail group of the compounds of this invention is divided into the change with substituted-amino azepine ring structure with formula () as representative
Compound:
Compound head (), center (v) and tail () are combined with the synthetic route shown in following scheme:
As shown in above reaction equation, by formula center (v) and formula tail () in the presence of alkali (as potassium tert-butoxide), in non-pole
Property solvent (as dmf) in, react (at 100 DEG C) in a heated condition, the intermediate obtaining again with head () in protochloride
In the presence of sulfone, solvent (as dichloromethane), it is condensed at ambient temperature, obtain target chemical combination finally by the reaction such as Deprotection
Thing ().
The present invention also provides compound or pharmaceutically acceptable salt thereof of the present invention in preparing tyrosine kinase inhibitor
Application, the particularly application in preparation treatment cell proliferative diseases.Described cell proliferative diseases include cancer.In other words,
The c-met molecule inhibitor compounds that the present invention provides or its officinal salt individually or with other drugs are used in combination in treatment
Application in proliferative diseases (as cancer).Can be anti-swollen with what compound or pharmaceutically acceptable salt thereof provided by the present invention was used in combination
Tumor medicine include but and non-limiting at least one following species: mitotic inhibitor is (as auspicious in vinblastine, vindesine and Changchun
Guest)；Tubulin decomposing inhibitor (as Taxol)；Alkylating reagent (as cisplatin, carboplatin and cyclophosphamide)；Antimetabolite is (such as
5-fluorouracil, ftorafur, methotrexate, cytosine arabinoside and hydroxyurea)；Pluggable antibiotic (as A Leisu, mitomycin and
Bleomycin A5)；Enzyme (as asparagine enzyme)；Topoisomerase inhibitors (as relied on primary glycosides and camptothecine)；Biological respinse is adjusted
Agent (as interferon).
The compound that the present invention is obtained has preferable Vitro Tumor inhibitory activity, the inhibitory activity energy to c-met kinases
Reach nanomole rank, such as compound 2 and compound 3, during three kinds of tumor cell lines are all shown, wait until strong inhibitory activity,
Compound 1 and compound 4 are less than 5 μm to the inhibitory activity of tumor cell line hepg2, suitable with positive control Taxol activity,
Therefore, the compound involved by this patent has stronger anti-tumor activity, can be used as the novel liver cancer treatment medicine of a class formation
Thing.In sum, such compound has preferable liver disease and antitumor application thereof prospect, thus has good business valency
Value.
Specific embodiment
The exploitativeness of the present invention to be described below by embodiment, it will be understood by those of skill in the art that according to existing
There is the teaching of technology, corresponding technical characteristic is modified or replaces, still fall within the scope of protection of present invention.
The preparation of embodiment 1.1- (3- Fluorophenylamino formoxyl) cyclopropane-carboxylic acid
Compound 2-a (ethylene-malonic acid) (1.3g, 1.00mmol) is dissolved in dichloromethane (10ml), stirs under ice bath
After 10min, add triethylamine (4.15ml, 3.00mmol), be slowly added to thionyl chloride (1.43g, 1.20mmol), continue in ice
Bath is lower to stir half an hour, and slowly Deca is dissolved with the dichloromethane solution of compound 1-a (3- fluoroaniline) (1.23g, 1.0mmol)
(10ml), continue to stir half an hour under ice bath, recover 1h (whether tlc monitoring reaction complete) is stirred at room temperature.After the completion of reaction,
Recovered under reduced pressure dichloromethane, adds saturated sodium-chloride water solution (40ml), ethyl acetate extractive reaction liquid 3 in residual reactant
Secondary, merge organic faciess, anhydrous sodium sulfate drying, decompression and solvent recovery.Obtain white solid 2.09g.
Yield 94.5%；esi(m+h)+=224.16 (m+1).
The preparation of embodiment 2.1- (5- chloro- 1- methyl isophthalic acid h- pyrazoles -2- base carbamoyl) cyclopropane-carboxylic acid
With compound 1-b and compound 2-a as raw material, according to the synthesis of embodiment 1 method.Obtain target product.
Yield 81.4%；esi(m+h)+=243.54 (m+1).
The preparation of embodiment 3.1- (furan -2- base carbamoyl) cyclopropane-carboxylic acid
With compound 1-c and compound 2-a as raw material, according to the synthesis of embodiment 1 method.Obtain target product.
Yield 75.6%；esi(m+h)+=196.04 (m+1).
The preparation of embodiment 4.1- (cyclohexyl carboxyamide base) cyclopropane-carboxylic acid
With compound 1-d and compound 2-a as raw material, according to the synthesis of embodiment 1 method.Obtain target product.
Yield 83.3%；esi(m+h)+=212.04 (m+1).
The preparation of embodiment 5.4- (4- amino -2- chloro- 5- methylphenoxy) -3- picoline amide
Potassium tert-butoxide (1.76g, 1.58mmol) is added dissolved with compound 4-a (the chloro- 3 methyl 2- picolinamide formyls of 4-
Amine) (1.86g, 1.46mmol) anhydrous n, in n- dimethylformamide (10ml) solution.0.5h is stirred at room temperature, adds compound
3-a (4- amino -2- chloro- 5- methylphenol) (2.00g, 1.02mmol), argon is protected, and reactant liquor is warming up to 50 DEG C, stirring
1h, recovers (whether tlc monitoring reaction complete) is stirred at room temperature.After the completion of reaction, decompression and solvent recovery, add in residual reactant
Enter saturated sodium-chloride water solution (40ml), ethyl acetate extractive reaction liquid 3 times, merge organic faciess, anhydrous sodium sulfate drying, decompression
Recycling design.Column chromatography (petrol ether/ethyl acetate 1:1), obtains white solid 1.66g.Yield 56.0%；esi(m+h)+=
292.56(m+1).
The preparation of embodiment 6.4- (4- amino -2- chlorophenoxy) -3- chloropyridine amide
With compound 3-b and compound 4-b as raw material, according to the synthesis of embodiment 5 method.Obtain intermediate 6.
Yield 48.3%；esi(m+h)+=299.05 (m+1).
Embodiment 7.4- (4- amino -2- chloro-5-methoxyl phenoxy group) the chloro- n of -3-, the system of n- lutidines -2- amino
Standby
With compound 3-c and compound 4-c as raw material, according to the synthesis of embodiment 5 method.Obtain intermediate 7.
Yield 42.1%；esi(m+h)+=329.24 (m+1).
The preparation of embodiment 8.4- (4- amino -2- chloro- 3- fluorophenoxy) -3- fluorine picolinamide
With compound 3-d and compound 4-d as raw material, according to the synthesis of embodiment 5 method.Obtain intermediate 8.
Yield 51.6%；esi(m+h)+=300.42 (m+1).
Embodiment 9.n- (4- (2- amino -3- picoline -4- epoxide) -5- chloro-2-methyl phenyl)-n- (3- fluorophenyl)
The preparation of cyclopropyl -1,1- diformamide (compound 1)
With intermediate 5 and intermediate 1 as raw material, according to the synthesis of embodiment 1 method.Obtain intermediate 9.
Yield 83.5%；esi(m+h)+=582.14 (m+1).
Intermediate 9 (5.0g, 1.03mmol) is dissolved in ethyl acetate/water/acetonitrile (20ml, 2:2:1), under condition of ice bath
Slowly Deca iodobenzene diacetate (4.0g, 1.24mmol), recovers room temperature, stirs 1h, recycling design, adds in residual reactant
Water (30ml), ethyl acetate extractive reaction liquid 3 times, merge organic faciess saturated sodium-chloride and wash 1 time, anhydrous sodium sulfate drying, decompression
Recycling design.Silica gel column chromatography (ethyl acetate: petroleum ether=2.5:1), obtains target compound 13.98g.
Yield 86.5%；esi(m+h)+=469.54 (m+1).
Embodiment 10.n- (4- (2- amino -3- chloropyridine -4- epoxide) -3- chlorphenyl)-n- (5- chloro- 1- methyl isophthalic acid h- pyrrole
Azoles -2- base) cyclopropyl -1,1- diformamide (compound 2) preparation
With intermediate 2 and intermediate 6 as raw material, according to the synthesis of embodiment 1 method.Obtain intermediate 10.
Yield 85.8%；esi(m+h)+=503.51 (m+1).
With intermediate 10 as raw material, according to the synthesis of embodiment 9 method.Obtain compound 2.
Yield 84.7%；esi(m+h)+=485.52 (m+1).
Embodiment 11.n- (the chloro- 4- of 5- (3- chloro- 2- (dimethylamino) pyridine -4- epoxide) -2- methoxyphenyl)-n- (furan
Mutter -2- base) preparation of cyclopropyl -1,1- diformamide (compound 3)
With intermediate 3 and intermediate 7 as raw material, according to the synthesis of embodiment 1 method.Obtain compound 3.
Yield 81.2%；esi(m+h)+=503.51 (m+1).
Embodiment 12.n- (4- (2- amino -3- fluorine pyridine -4- epoxide) 3- chloro- 2- fluorophenyl)-n- cyclohexyl ring propyl group -
The preparation of 1,1- diformamide (compound 4)
With intermediate 4 and intermediate 8 as raw material, according to the synthesis of embodiment 1 method.Obtain intermediate 11.
Yield 83.6%；esi(m+h)+=493.26 (m+1).
With intermediate 12 as raw material, according to the synthesis of embodiment 9 method.Obtain compound 4.
Yield 81.5%；esi(m+h)+=465.48 (m+1).
The growth inhibition effect to c-met kinases, liver and other tumor cells for the compound that the present invention is obtained
With compound bms-777607 and paclitaxel as positive control, compound is measured to common tumor using mtt method
The vitro inhibition of cell strain (human hepatoma cell strain hepg2, human lung carcinoma cell line ebc-1, human prostate cancer cell line pc-3) is made
With (ic50), utilize the c-met kinase reagent box of commercialization simultaneously, evaluate c-met enzyme inhibition activity (ic50).
The pharmacological experimental method of the compounds of this invention anti-tumor activity is as follows with result:
It is the mensure of Vitro Tumor proliferation inhibition activity and preliminary structure activity study first, from different solid tumors
With leukemia cell line, synthesized compound is carried out with the mensure of anti tumor activity in vitro.
Experiment material
Cell strain: human hepatoma cell strain hepg2, human lung carcinoma cell line ebc-1, human prostate cancer cell line pc-3
Culture medium: hepg2:rpmi 1640+ hyclone
Ebc-1:rpmi 1640+ hyclone
Pc-3:rpmi 1640+ hyclone
Method for preparation of drug: medicine is dissolved in the storing solution making 50mm in dmso, and dilution obtains 5 by a certain percentage
Variable concentrations.
Tumor cell In vitro culture:
By selected three plants of tumor cells hepg2, ebc-1, pc-3, in 37 DEG C, 5%co2It is incubated in cell culture incubator,
(passing on after attached cell duck ' s edta digestion) is passed on when cell density grows to 70～90%,
For needed for later experiment.
Compound dimethyl sulfoxide (dmso) is dissolved, dilution, tumor cell hepg2, ebc-1, pc-3, in 96 orifice plates
Upper kind enters 4000/200 μ l/ holes, and every hole adds compound 1 μ l, and final concentration of 50 μm, 10 μm, 2 μm, 0.4 μm, 0.08 μm altogether
It is same as 37 DEG C, 5%co2It is incubated 72 hours in cell culture incubator, with dmso (1%) as blank.After 72 hours, add dense eventually
Spend the mtt for 0.25mg/ml, be placed in 37 DEG C, 5%co24 hours in cell culture incubator, blot culture fluid afterwards, every hole adds
100 μ l dmso, with enzyme linked immunological instrument at 570nm mensuration absorbance (od value), the data obtained is used for calculating ic50.
The computing formula of cell inhibitory rate is: cell inhibitory rate %=(matched group od value-medication group od value)/compared with control cells
Od value × 100%, obtains half-inhibition concentration (ic with bliss method50).
Next to that the method for testing to c-met enzyme inhibition rate for the c-met molecule inhibitor compounds:
Fluorescence polarization detects that c-met kinases uses the principle of competitive reaction: fluorescently-labeled phosphorylation tracer and
The unmarked Phosphorylated products being produced by c-met kinase reaction can be vied each other combination with anti-serine antibody.Without phosphorus at one
In the reaction liquid mixture of acidizing product, higher polarization value can be led to when a part of fluorescent tracing thing and antibodies.But
Be, include Phosphorylated products reactant liquor mix in, less tracer can be attached on antibody (fluorescent tracing thing by from
Substitute on antibody), the signal sending depolarizes.Therefore, the c-met kinases changing directly and in reaction of polarization
Activity is related.
Target compound and positive control bms-777607 dimethyl sulfoxide (dmso) are dissolved, being diluted to concentration is 50
μm.Under room temperature, take the compound sample that concentration is 50 μm and each 0.25 μ l of positive control, add 384 orifice plates, and each sample
Three parallel holes of setting, 10 μ l stk substrate 3working being then separately added into in each sample orifice plate
Solution, 5 μ l c-met working solution, 10 μ l atp working solution, slight oscillatory simultaneously shakes up
Several minutes.Start after 10 μ l atp working solution to react due to adding in hole, by this timing, room temperature reaction 1 is little
When.After one hour, it is separately added into 5 μ l stk stop mix in each sample well, 5 μ l stk antibody mix come eventually
Only react.Add after finishing, room temperature places four hours, with the polarization value of microplate reader fluorescence polarization detection sample (24
Detect in hour that its signal is all effective), the suppression ratio to enzyme for the compound is calculated by polarization value.
Experiment four groups of comparisons are set simultaneously, be respectively buffer control wells, tracer control wells,
No enzyme wells and the dimethyl sulphoxide control of blank.The data obtained is used for calculating suppression ratio.
The ic to tumor cell proliferation and c-met kinases for table 1 target compound50(μm)
As can be seen from the table, prepared compound has preferable Vitro Tumor inhibitory activity, to c-met kinases
Inhibitory activity can reach nanomole rank, such as compound 2 and compound 3, wait until during three kinds of tumor cell lines are all shown
Strong inhibitory activity, compound 1 and compound 4 are less than 5 μm to the inhibitory activity of tumor cell line hepg2, purple with positive control
Quite, therefore, the compound involved by this patent has stronger anti-tumor activity to China fir alcohol activity, can be novel as a class formation
Cancer treatment drug.In sum, such compound has preferable liver disease and antitumor application thereof prospect, thus tool is good
Commercial value.
Claims (10)
1. a kind of c-met micromolecular inhibitor it is characterised in that: described inhibitor is to have the compound of below formula ():
And its pharmaceutically acceptable salt or solvate,
Wherein:
r1Selected from halogen, c1-c4Alkyl, the c of halo1-c4Alkyl, c1-c4Alkoxyl, the c of halo1-c4Alkoxyl；
r2Selected from h, c1-c4Alkyl, the c of halo1-c4Alkyl, c1-c4Alkoxyl, the c of halo1-c4Alkoxyl；
r3、r4、r5、r7And r8Selected from h, halogen, nitro, amino, cyano group, c1-c4Alkyl, the c of halo1-c4Alkyl, c1-c4Alcoxyl
Base, the c of halo1-c4Alkoxyl；
r6Selected from unsubstituted or replace aryl, unsubstituted or replace heterocyclic aryl, unsubstituted or replace cycloalkyl, no take
Generation or the saturated heterocyclic alkyl replacing, unsubstituted or the unsaturated heterocycle alkyl replacing, the aryl arbitrarily condensing, heterocyclic aryl,
Described substituted substituent group is optionally from halogen, nitro, amino, cyano group, c1-c4Alkyl, the c of halo1-c4Alkyl, c1-c4Alcoxyl
Base, c1-c4Alkylamino radical, the c of halo1-c4Alkoxyl, the c of halo1-c4Alkylamino radical；Preferably, the substituent group of described heterocyclic aryl
Selected from halogen, nitro, amino, cyano group, c1-c4 alkyl, the c1-c4 alkyl of halo, c1-c4 alkoxyl, c1-c4 alkylamino radical, halogen
The c1-c4 alkoxyl in generation, the c1-c4 alkylamino radical of halo；Preferably, the substituent group of described aromatic ring be selected from halogen, nitro, amino,
Cyano group, c1-c4 alkyl, the c1-c4 alkyl of halo, c1-c4 alkoxyl, c1-c4 alkylamino radical, the c1-c4 alkoxyl of halo, halo
C1-c4 alkylamino radical；Preferably, the substituent group of described Heterocyclylalkyl is selected from halogen, nitro, amino, cyano group, c1-c4 alkyl, halogen
The c1-c4 alkyl in generation, c1-c4 alkoxyl, c1-c4 alkylamino radical, the c1-c4 alkoxyl of halo, the c1-c4 alkylamino radical of halo；Excellent
Choosing, the substituent group of described cycloalkyl is selected from alkoxyl, halogen and haloalkyl；Preferably, described alkoxyl can be optionally by halogen
Element replaces one or many；Preferably, described alkoxyl can optionally be replaced once or twice by methyl, ethyl, propyl group；Preferably
, described alkylamino radical can optionally be replaced once or twice by methyl, ethyl, propyl group.
2. compound according to claim 1 is it is characterised in that described compound has formula () structure:
And its pharmaceutically acceptable salt or solvate, wherein:
r1、r2、r7And r8As defined in claim 1；
r6Selected from the heterocyclic aryl of substituted or unsubstituted aryl, replacement, described substituted substituent group is optionally from halogen, nitro, ammonia
Base, cyano group, c1-c3Alkyl, the c of halo1-c3Alkyl, c1-c3Alkoxyl, c1-c3Alkylamino radical, the c of halo1-c3Alkoxyl, halo
C1-c3Alkylamino radical.
3. compound according to claim 2 is it is characterised in that described compound has formula () structure:
And its pharmaceutically acceptable salt or solvate, wherein:
r1、r2、r7And r8As defined in claim 1；
r9And r10Selected from hydrogen, halogen, nitro, amino, cyano group, c1-c3Alkyl, the c of halo1-c3Alkyl, c1-c3Alkoxyl, c1-c3
Alkylamino radical, the c of halo1-c3Alkoxyl, the c of halo1-c3Alkylamino radical.
4. compound according to claim 3 is it is characterised in that described compound is selected from:
N- (4- (2- amino -3- picoline -4- epoxide) -5- chloro-2-methyl phenyl)-n- (3- fluorophenyl) cyclopropyl -1,1-
Diformamide；
N- (4- (2- amino -3- chloropyridine -4- epoxide) -3- chlorphenyl)-n- (5- chloro- 1- methyl isophthalic acid h- pyrazoles -2- base) ring third
Base -1,1- diformamide；
N- (the chloro- 4- of 5- (3- chloro- 2- (dimethylamino) pyridine -4- epoxide) -2- methoxyphenyl)-n- (furan -2- base) ring third
Base -1,1- diformamide；
N- (4- (2- amino -3- fluorine pyridine -4- epoxide) 3- chloro- 2- fluorophenyl)-n- cyclohexyl ring propyl group -1,1- diformamide；
And its above-claimed cpd pharmaceutically acceptable salt or solvate.
5. a kind of pharmaceutical composition, described pharmaceutical composition comprises at least one active component and at least one pharmaceutically can connect
The carrier being subject to or excipient, described active component exists selected from the compound described in any one of claim 1-4, described compound
In pharmaceutically acceptable salt, described compound solvent compound any one or arbitrarily multiple.
6. the compound described in any one of claim 1-4, described compound pharmaceutically acceptable salt, described compound
Purposes in preparing antitumor drug for the pharmaceutical composition described in solvate, claim 5.
7. the compound described in any one of claim 1-4, described compound pharmaceutically acceptable salt, described compound
Purposes in preparation hepatopathy treating correlative diseases medicine for the pharmaceutical composition described in solvate, claim 5.
8. the compound described in any one of claim 1-4, described compound pharmaceutically acceptable salt, described compound
Pharmaceutical composition described in solvate, claim 5, is used in combination in preparation hepatopathy treating correlative diseases medicine with other drugs
Purposes in thing；Preferably, the described other drugs being used in combination are selected from mitotic inhibitor, tubulin decomposes suppression
Agent, alkylating reagent, antimetabolite, pluggable antibiotic, enzyme, Topoisomerase inhibitors, biological response modifier.
9. purposes according to claim 6 it is characterised in that: described tumor be selected from breast carcinoma, sarcoma, pulmonary carcinoma, prostatitis
Adenocarcinoma, colon and rectum carcinoma, renal carcinoma, cancer of pancreas, leukemia, neuroblastoma, glioma, head cancer, neck cancer, thyroid
Cancer, hepatocarcinoma, ovarian cancer, carcinoma vulvae, cervical cancer, carcinoma of endometrium, carcinoma of testis, bladder cancer, the esophageal carcinoma, gastric cancer, nasopharyngeal carcinoma, cheek
Cancer, oral cancer, gastrointestinal stromal tumor, skin carcinoma, multiple myeloma.
10. the purposes according to claim 7 or 8 it is characterised in that: described hepatopathy relevant disease be selected from viral liver
Inflammation, autoimmune hepatitiss, drug toxicity hepatitis, hepatopathy hepatic injury, liver failure, chronic severe hepatitises, liver cirrhosis, liver pus
Swollen, fatty liver, primary hepatocarcinoma.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610639314.5A CN106349158B (en) | 2016-08-03 | 2016-08-03 | C-Met small molecule inhibitor, pharmaceutical composition containing same and pharmaceutical application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610639314.5A CN106349158B (en) | 2016-08-03 | 2016-08-03 | C-Met small molecule inhibitor, pharmaceutical composition containing same and pharmaceutical application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106349158A true CN106349158A (en) | 2017-01-25 |
| CN106349158B CN106349158B (en) | 2020-02-28 |
Family
ID=57844517
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610639314.5A Active CN106349158B (en) | 2016-08-03 | 2016-08-03 | C-Met small molecule inhibitor, pharmaceutical composition containing same and pharmaceutical application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106349158B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113372267A (en) * | 2020-03-10 | 2021-09-10 | 鲁南制药集团股份有限公司 | C-Met kinase inhibitor |
| CN115381956A (en) * | 2021-05-25 | 2022-11-25 | 海创药业股份有限公司 | Pharmaceutical composition for treating cancer and application thereof |
| EP4103188A4 (en) * | 2020-02-10 | 2024-04-10 | StemSynergy Therapeutics, Inc. | Myc inhibitors and uses thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090227556A1 (en) * | 2008-01-31 | 2009-09-10 | Eisai R&D Management Co., Ltd. | Receptor tyrosine kinase inhibitors comprising pyridine and pyrimidine derivatives |
| WO2010064300A1 (en) * | 2008-12-02 | 2010-06-10 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Composition for treatment of esophageal cancer |
| CN103068384A (en) * | 2010-04-29 | 2013-04-24 | 德西费拉制药有限责任公司 | Cyclopropyl dicarboxamides and analogs exhibiting anti-cancer and anti-proliferative activites |
-
2016
- 2016-08-03 CN CN201610639314.5A patent/CN106349158B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090227556A1 (en) * | 2008-01-31 | 2009-09-10 | Eisai R&D Management Co., Ltd. | Receptor tyrosine kinase inhibitors comprising pyridine and pyrimidine derivatives |
| WO2010064300A1 (en) * | 2008-12-02 | 2010-06-10 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Composition for treatment of esophageal cancer |
| CN103068384A (en) * | 2010-04-29 | 2013-04-24 | 德西费拉制药有限责任公司 | Cyclopropyl dicarboxamides and analogs exhibiting anti-cancer and anti-proliferative activites |
Non-Patent Citations (1)
| Title |
|---|
| 孙亮: "《STN》", 3 April 2018 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4103188A4 (en) * | 2020-02-10 | 2024-04-10 | StemSynergy Therapeutics, Inc. | Myc inhibitors and uses thereof |
| CN113372267A (en) * | 2020-03-10 | 2021-09-10 | 鲁南制药集团股份有限公司 | C-Met kinase inhibitor |
| CN113372267B (en) * | 2020-03-10 | 2024-05-24 | 鲁南制药集团股份有限公司 | C-Met kinase inhibitor |
| CN115381956A (en) * | 2021-05-25 | 2022-11-25 | 海创药业股份有限公司 | Pharmaceutical composition for treating cancer and application thereof |
| CN115381956B (en) * | 2021-05-25 | 2024-01-30 | 海创药业股份有限公司 | Pharmaceutical composition for treating cancer and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106349158B (en) | 2020-02-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2904544T3 (en) | Indazole compounds as FGFR kinase inhibitors, preparation and use thereof | |
| CN102686581B (en) | Quinazoline derivant | |
| JP5719770B2 (en) | Icotinib hydrochloride, compound, crystallographic form, concomitant drug and its use | |
| CN1807413B (en) | Carbazole sulfonamide derivative and its preparation method | |
| CN108948082A (en) | A kind of diaminopyrimidine compounds and the composition comprising the compound | |
| CN105985342B (en) | As the pyrimido-pyrimidine derovatives of EGFR inhibitor and its application | |
| BRPI0608160A2 (en) | isolated antibody, host cell, method of inhibiting psma + cell growth, and use of a defucosylated anti-psma antibody | |
| CA2604284A1 (en) | Protein kinase inhibitors | |
| CN107922348A (en) | Bicyclic heterocycle amide derivatives | |
| JP2019524883A (en) | Heterocyclic compounds as FGFR inhibitors | |
| BRPI0711045A2 (en) | tetrahydropyridothienopyrimidine compounds and methods of use thereof | |
| CN104926788B (en) | Substituted piperidine analog derivative, the pharmaceutical composition containing it and its application in antitumor | |
| CN107531683A (en) | USP7 inhibitor compounds and application method | |
| WO2019223766A1 (en) | Fgfr inhibitor, preparation method therefor and pharmaceutical application thereof | |
| CN106349158A (en) | c-Met small-molecule inhibitor, pharmaceutical composition containing same and pharmaceutical application of pharmaceutical composition containing same | |
| CN105732616A (en) | Pyrrolopyridine compounds containing biaryl amide structure, preparation method and applications thereof | |
| CN108341801A (en) | Polyfluoro substitution virtue connection heterocyclic derivative, the pharmaceutical composition containing it and its application | |
| CN109721599A (en) | A kind of amino replaces nitrogenous fused ring compound and its preparation method and application | |
| CN108191837A (en) | PI3K α/mTOR bidifly enzyme inhibitors and its pharmaceutical composition and application | |
| CN106831707B (en) | Benzheterocycle analog derivative and its medical application as c-Met kinase inhibitor | |
| CN103980287B (en) | Containing the preparations and applicatio of the thienopyrimidines of chromone hydrazone structure | |
| CN108864081A (en) | Fgfr4 inhibitor and its preparation and application | |
| Dubinina et al. | Novel 5, 7-disubstituted 6-amino-5H-pyrrolo [3, 2-b] pyrazine-2, 3-dicarbonitriles, the promising protein kinase inhibitors with antiproliferative activity | |
| CN102584828B (en) | Tetramethyleneimine [3,4-d] pyrimidine derivatives, preparation method and application thereof | |
| CN106892922B (en) | As the 5,8- dihydropteridine -6,7- derovatives of EGFR inhibitor and its application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |