CN108314645A - One kind has compound, preparation method and the purposes of antiproliferation - Google Patents
One kind has compound, preparation method and the purposes of antiproliferation Download PDFInfo
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- CN108314645A CN108314645A CN201710548673.4A CN201710548673A CN108314645A CN 108314645 A CN108314645 A CN 108314645A CN 201710548673 A CN201710548673 A CN 201710548673A CN 108314645 A CN108314645 A CN 108314645A
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- cancer
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- 0 *=C(c(c(Cl)n1)ccc1Cl)O Chemical compound *=C(c(c(Cl)n1)ccc1Cl)O 0.000 description 5
- SLFHRFBCGHICDW-UHFFFAOYSA-M CC(C(C(OC)=O)=C(N[Al]=C)N1C)=CC1=[U] Chemical compound CC(C(C(OC)=O)=C(N[Al]=C)N1C)=CC1=[U] SLFHRFBCGHICDW-UHFFFAOYSA-M 0.000 description 1
- BTQIMFVKWGZOGG-UHFFFAOYSA-N CN1C(Nc(ccc(I)c2)c2F)=C(C(NC(CCCC2O)C2O)O)C=CC1=O Chemical compound CN1C(Nc(ccc(I)c2)c2F)=C(C(NC(CCCC2O)C2O)O)C=CC1=O BTQIMFVKWGZOGG-UHFFFAOYSA-N 0.000 description 1
- ZHKBIQIODHDHHA-OMWUSAIZSA-N C[C@H](CCC[C@H]1NC(C(C=C2)=C(Nc(ccc(C)c3)c3F)N(C)C2=O)=O)[C@H]1O Chemical compound C[C@H](CCC[C@H]1NC(C(C=C2)=C(Nc(ccc(C)c3)c3F)N(C)C2=O)=O)[C@H]1O ZHKBIQIODHDHHA-OMWUSAIZSA-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
- C07D213/82—Amides; Imides in position 3
Abstract
The present invention relates to a kind of compound, preparation method and purposes with antiproliferation.One kind general formula disclosed by the invention has the compound or its pharmaceutically acceptable salt or its enantiomter, diastereoisomer, tautomer, solvate, polymorph or prodrug of anti-swollen cell-proliferation activity, preparation method and application pharmaceutically as shown in I, wherein the definition of each group is as noted in the discussion.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular, to one kind compound with anti-tumor activity, preparation method
And purposes.
Background technology
Mitogen-activated protein kinase (mitogen-activated protein kinase, MAPK) family is a kind of silk
Propylhomoserin/Serineprotein kinase can transduce extracellular signal to cell and core, be reacted by conservative three-stage cascade
(MAPKKK-MAPKK-MAPK) activating transcription factor adjusts gene expression.The access is present in most cells, and with it is more
Kind cell function is related, may participate in the various physiological processes such as cell movement, apoptosis, differentiation and growing multiplication.It has had determined that at present
4 MAPK signal transduction pathways：Extracellular signal-regulated kinase (ERK) signal path, c-Jun N-terminals kinases (JNK)/stress
Activated protein (SAPK) signal path, p38MAPK signal paths and the big mitogen-activated kinases of ERK5/ (BMK1) signal
Access.ERK signal paths are to study most thorough one of access, equally follow the three-level enzymatic cascade reaction of MAPKs, i.e. RAS
(upstream activat albumen) → Raf (MAPKKK) → MEK (MAPKK) → ERK (MAPK).MEK is Ras-Raf-MEK-ERK signals
The key enzyme of transduction pathway adjusts cell response, including proliferation, apoptosis, differentiation and metabolism etc., research to different growth signals
Show to find the signal path target spot excessive activation, mutation or high expression in many tumours.It therefore, can be by inhibiting MEK
Kinase activity is controlled by the extremely caused cell hyperproliferation of Ras-Raf-MEK signal paths, to reaching treatment tumour
Purpose.Tumour is clinically very universal caused by Ras-Raf-MEK abnormal signals, and is deposited in treatment of solid tumors field
Do not meeting clinical demand largely, therefore, mek inhibitor is that medical needle is extremely caused swollen to Ras-Raf-MEK signal paths
The research and development focus of tumor medicine.
Invention content
One of the technical problem to be solved in the invention is to provide a kind of novel MEK kinase inhibitors, is used to prepare swollen
Tumor medicine.
The scheme for solving above-mentioned technical problem is as follows：
A kind of such as general formula I compounds represented or its pharmaceutically acceptable salt or its enantiomter, diastereomeric are different
Structure body, tautomer, solvate, polymorph or prodrug,
In formula：R1 is selected from hydrogen, alkyl, naphthenic base, Heterocyclylalkyl；R2 is selected from naphthenic base, Heterocyclylalkyl；R3 is selected from hydrogen, halogen
Element, alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl；Ar is selected from aryl, heteroaryl；
One or more hydrogen atoms on above-mentioned any group can be replaced by deuterium, halogen respectively；Wherein, described miscellaneous
Aryl includes 1-3 hetero atoms selected from the group below：N, O or S；The heterocycle includes 1-3 hetero atoms selected from the group below：N、O
Or S.
It is a further object of the present invention to provide a kind of pharmaceutical compositions for treating tumour.Realize the technical solution of above-mentioned purpose
It is as follows：
A kind of pharmaceutical composition for treating tumour, nitrogen-containing hetero cyclics or its medicine shown in above-mentioned logical formula (I)
Acceptable salt or its enantiomter, diastereoisomer, tautomer, solvate, polymorph or prodrug on
It is formed with pharmaceutically acceptable carrier.
It is a further object of the present invention to provide a kind of purposes of above compound.Realize the technical solution of above-mentioned purpose such as
Under：
Nitrogen-containing heterocycle compound or its pharmaceutically acceptable salt or its enantiomter shown in the logical formula (I),
Diastereoisomer, tautomer, solvate, polymorph or prodrug are in preparing prevention or treatment antitumor drug
Using.
The tumour is non-small cell lung cancer, Small Cell Lung Cancer, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast cancer, prostate
Any one of cancer, liver cancer, cutaneum carcinoma, cell carcinoma, gastrointestinal stromal tumor, leukaemia, lymph cancer, nasopharyngeal carcinoma etc..
The present invention relates to the compounds with logical formula (I) structure feature, can inhibit kinds of tumor cells, especially can be high
Kill cell hyperproliferation caused by Ras-Raf-MEK abnormal proteins in effect ground.
It should be understood that, within the scope of the present invention in, the present invention above-mentioned each technical characteristic and have in below (eg embodiment)
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Specific implementation mode
The present inventor's in-depth study by long-term is prepared for a kind of compound with structure shown in Formulas I, and finds
It is with preferable MEK kinase inhibiting activities.And the compound is under extremely low concentration (can be down to≤10nmol/L), i.e., pair
MEK kinases generates specific inhibitory effect, and quite excellent to the proliferation inhibition activity of different cells, thus can be used for
Treatment and relevant disease such as tumour caused by Ras-Raf-MEK abnormal proteins.Based on above-mentioned discovery, inventor completes this hair
It is bright.
Term
Unless otherwise defined, the connotation that all scientific and technical terminologies have herein and claim theme fields technology
The normally understood connotation of personnel is identical.Unless otherwise indicated, all patents, patent application, the public material being cited in full text herein
It is integrally incorporated by reference herein.
It should be understood that above-mentioned summary and being specified as exemplary and being only used for explaining hereafter, without appointing to present subject matter
What is limited.In this application, unless otherwise expressly specified, otherwise use when odd number also includes plural number.It has to be noticed that unless in text
Separately have clear explanation, otherwise in the present specification and claims used singulative include referents plural shape
Formula.It shall yet further be noted that unless otherwise stated, "or" used, "or" indicate "and/or".In addition, term " comprising " used with
And other forms, such as it is "comprising", " containing " and " containing " and non-limiting.
It can be in bibliography (including Carey and Sundberg " ADVANCED ORGANIC CHEMISTRY 4TH
ED. " Vols. A (2000) and B (2001), Plenum Press, New York) in find standard chemistry terms determined
Justice.Unless otherwise stated, using the conventional method within the scope of art technology, such as mass spectrum, NMR, IR and UV/VIS spectrum
Method and pharmacological method.Unless proposing to be specifically defined, otherwise herein in analytical chemistry, Synthetic Organic Chemistry and drug and drug
The term used in the related description of chemistry is known in the art.It can be in chemical synthesis, chemical analysis, medicine preparation, preparation
And delivering, and to using standard technique in the treatment of patient.For example, using manufacturer to the operation instruction of kit, or
Implement to react according to the explanation of mode well known in the art or the present invention and be purified.It can usually draw according in this specification
With the description in the multiple summary and more specific document with discussion, implement above-mentioned skill according to conventional method well known in the art
Art and method.In the present specification, group and its substituent group can be selected to provide stable structural portion by those skilled in the art
Point and compound.
When the conventional chemical formulas by writing from left to right describes substituent group, which similarly includes from right to left
Write obtained equivalent substituent group in chemistry when structural formula.For example ,-CH2O- is equal to-OCH2-.
Chapter title used herein is only used for the purpose of organizational, and is not necessarily to be construed as the limit to the theme
System.All documents or literature department quoted in the application point include but not limited to patent, patent application, article, books, manipulator
Volume and paper are integrally incorporated herein by reference.
The certain chemical groups defined herein indicate carbon atom present in the group previously by symbol is simplified
Sum.For example, C1-6 alkyl refers to the alkyl as defined below with 1 to 6 carbon atom in total.Simplify the carbon in symbol
Total atom number does not include the carbon being likely to be present in the substituent group of the group.
In addition to aforementioned, when in for the description of the present application and claims, unless otherwise specified, otherwise
Following term has meaning as follows.
In this application, term " halogen " refers to fluorine, chlorine, bromine or iodine.
" hydroxyl " refers to-OH groups.
" hydroxy alkyl " refers to the alkyl as defined below replaced by hydroxyl (- OH).
" carbonyl " refers to-C (=O)-group.
" nitro " refers to-NO2。
" cyano " refers to-CN.
" amino " refers to-NH2。
" substituted amino " refers to by one or two alkyl as defined below, alkyl-carbonyl, aralkyl, heteroaryl alkane
The amino of base substitution, for example, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl alkyl amino, heteroarylalkyl amino.
" carboxyl " refers to-COOH.
In this application, the part as group or other groups (is used for example in the groups such as the alkyl of halogen substitution
In), term " alkyl " means only to be made of carbon atom and hydrogen atom, is free of unsaturated bond, has such as 1 to 12 (preferably 1
To 8, more preferably 1 to 6) carbon atom and by the rest part of singly-bound and molecule connect linear chain or branched chain hydrocarbon chain base
Group.The example of alkyl include but not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tertiary butyl,
N-pentyl, 2- methyl butyls, 2,2- dimethyl propyls, n-hexyl, heptyl, 2- methylhexyls, 3- methylhexyls, octyl, nonyl
With decyl etc..
In this application, the part as group or other groups, term " alkenyl " mean only by carbon atom and hydrogen
Atom composition contains at least one double bond, has such as 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms
And the hydrocarbon chain radical of the linear chain or branched chain connected by the rest part of singly-bound and molecule, such as, but not limited to vinyl, propylene
Base, allyl, but-1-ene base, but-2-ene base, amyl- 1- alkenyls, amyl- 1,4- dialkylenes etc..
In this application, the part as group or other groups, term " alkynyl " mean only by carbon atom and hydrogen
Atom composition, containing at least one three key and optional one or more double bonds, there are such as 2 to 14 (preferably 2 to 10
A, more preferably 2 to 6) carbon atom and the hydrocarbon chain radical of linear chain or branched chain that is connected by the rest part of singly-bound and molecule,
Such as, but not limited to acetenyl, propyl- 1- alkynyls, butyl- 1- alkynyls, amyl- 1- alkene -4- alkynyls etc..
In this application, the part as group or other groups, term " naphthenic base " mean only by carbon atom and
The non-aromatic monocyclic or multi-ring alkyl of the stabilization of hydrogen atom composition, may include condensed ring system, bridged-ring system or loop coil body
System has 3 to 15 carbon atoms, preferably has 3 to 10 carbon atoms, more preferably has 3 to 8 carbon atoms, and it is saturation
Or it is unsaturated and the connection of the rest part of singly-bound and molecule can be passed through via any suitable carbon atom.Unless another in this specification
It specializes outside, the carbon atom in naphthenic base can be aoxidized optionally.The example of naphthenic base includes but not limited to cyclopropyl, ring
Butyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cyclooctyl, 1H- indenyls, 2,3- bis-
Hydrogenated indenyl, 1,2,3,4- tetrahydro-naphthalenyls, 5,6,7,8- tetrahydro-naphthalenyls, 8,9- dihydro -7H- benzo ring heptene -6- bases, 6,
7,8,9- tetrahydrochysene -5H- benzocycloheptas alkenyl, 5,6,7,8,9,10- hexahydros-benzo ring octenyl, fluorenyl, two rings [2.2.1] heptan
Base ,-two ring of 7,7- dimethyl [2.2.1] heptyl, two rings [2.2.1] heptenyl, two rings [2.2.2] octyl, two rings [3.1.1]
Heptyl, two rings [3.2.1] octyl, two rings [2.2.2] octenyl, two rings [3.2.1] octenyl, adamantyl, octahydro -4,7-
Methylene -1H- indenyls and octahydro -2,5- methylene-pentalene base etc..
In this application, the part as group or other groups, term " heterocycle " mean by 2 to 14 carbon originals
3 yuan to 20 yuan non-aromatic cyclic groups of the stabilization of son and 1 to 6 hetero atom composition selected from nitrogen, phosphorus, oxygen and sulphur.It removes
It is in addition specialized in non-this specification, otherwise heterocycle can be the member ring systems of monocycle, bicyclic, tricyclic or more ring, can
Including condensed ring system, bridged-ring system or spiro ring system；Nitrogen, carbon or sulphur atom in its heterocycle are optionally aoxidized；Nitrogen
Atom is optionally quaternized；And heterocycle can be partially or completely to be saturated.Heterocycle can be via carbon atom or miscellaneous original
Son is simultaneously connect by singly-bound with molecule rest part.In the heterocycle comprising condensed ring, one or more rings can be hereafter institute
The aryl or heteroaryl of definition, it is non-aromatic annular atom that condition, which is with the tie point of molecule rest part,.With regard to the mesh of the present invention
For, heterocycle is preferably 4 yuan to 11 yuan nonaro-maticity lists for including 1 to 3 heteroatomic stabilization selected from nitrogen, oxygen and sulphur
Ring, bicyclic, bridged ring or spiro-cyclic groups more preferably include 4 yuan to 8 of 1 to 3 heteroatomic stabilization selected from nitrogen, oxygen and sulphur
First non-aromatic monocyclic, bicyclic, bridged ring or spiro-cyclic groups.The example of heterocycle includes but not limited to：Pyrrolidinyl, morpholinyl,
Piperazinyl, high piperazine base, piperidyl, thio-morpholinyl, 2,7- diaza-spiros [3.5] nonane -7- bases, 2- oxa- -6- azepines -
Spiral shell [3.3] heptane -6- bases, 2,5- diazas-bicyclic [2.2.1] heptane -2- bases, azetidinyl, pyranose, oxinane
Base, thiapyran base, tetrahydrofuran base, oxazinyls, dioxy cyclopenta, tetrahydro isoquinolyl, Decahydroisoquinolinpreparation base, imidazolinyl, miaow
Oxazolidinyl, quinazinyl, thiazolidinyl, isothiazole alkyl, isoxazole alkyl, indolinyl, octahydro indyl, octahydro iso-indoles
Base, pyrrolidinyl, pyrazolidinyl, phthaloyl imino etc..
In this application, the part as group or other groups, term " aryl " mean there is 6 to 18 carbon originals
The conjugated hydrocarbon member ring systems group of son (preferably with 6 to 10 carbon atoms).For purposes of the invention, aryl can be single
The member ring systems of ring, bicyclic, tricyclic or more ring, can also be condensed with naphthenic base defined above or heterocycle, and condition is virtue
Base is connected via the atom on aromatic rings by the rest part of singly-bound and molecule.The example of aryl include but not limited to phenyl,
Naphthalene, anthryl, phenanthryl, fluorenyl, 2,3- dihydro -1H- isoindolyls, 2- benzoxazolinones, 2H-1,4- benzoxazines -3
(4H)-ketone -7- bases etc..
In this application, term " aryl alkyl " refers to the alkane defined above replaced by aryl defined above
Base.
In this application, the part as group or other groups, term " heteroaryl " mean there is 1 to 15 in ring
A carbon atom (preferably with 1 to 10 carbon atom) and 1 to 6 heteroatomic 5 yuan to 16 yuan conjugate ring selected from nitrogen, oxygen and sulphur
It is group.Unless in addition being specialized in this specification, otherwise heteroaryl can be the ring body of monocycle, bicyclic, tricyclic or more ring
System, can also be condensed with naphthenic base defined above or heterocycle, and condition is that heteroaryl passes through via the atom on aromatic rings
The rest part of singly-bound and molecule connects.Nitrogen, carbon or sulphur atom in heteroaryl are optionally aoxidized；Nitrogen-atoms is optionally
It is quaternized.For purposes of the invention, heteroaryl is preferably the heteroatomic stabilization selected from nitrogen, oxygen and sulphur comprising 1 to 5
5 yuan to 12 yuan aromatic radicals, more preferably include 1 to 4 selected from nitrogen, 5 yuan to 10 of heteroatomic stabilization of oxygen and sulphur
First aromatic radical includes 1 to 3 heteroatomic 5 yuan to 6 yuan aromatic radical selected from nitrogen, oxygen and sulphur.Heteroaryl
Example include but not limited to thienyl, imidazole radicals, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyls, pyridyl group,
Pyrimidine radicals, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazoles base, indyl, furyl, pyrrole radicals, triazolyl, tetrazolium
Base, triazine radical, indolizine base, isoindolyl, indazolyl, iso indazolyl, purine radicals, quinolyl, isoquinolyl, phenodiazine naphthalene, naphthalene
Piperidinyl, quinoxalinyls, pteridyl, carbazyl, carboline base, phenanthridinyl, phenanthroline, acridinyl, phenazinyl, isothiazolyl, benzene
It is benzothiazolyl, benzothienyl, oxatriazoles base, cinnoline base, quinazolyl, thiophenyl, indolizine base, phenanthrolene base, different
Oxazolyl, phenoxazine groups, phenothiazinyl, 4,5,6,7- tetrahydro benzos [b] thienyl, naphtho- pyridyl group, [1,2,4] triazol
[4,3-b] pyridazine, [1,2,4] triazol [4,3-a] pyrazine, [1,2,4] triazol [4,3-c] pyrimidine, [1,2,4] triazol
[4,3-a] pyridine, imidazo [1,2-a] pyridine, imidazo [1,2-b] pyridazine, imidazo [1,2-a] pyrazine etc..
In this application, term " heteroaryl alkyl " refer to replaced by heteroaryl defined above it is defined above
Alkyl.
In this application, " optional " or " optionally " indicate that the event then described or situation may occur may not also
Occur, and the description occurs including the event or situation and do not occur simultaneously.For example, " aryl being optionally substituted "
Indicate that aryl is substituted or unsubstituted, and the description is simultaneously including substituted aryl and unsubstituted aryl.
Terms used herein " part ", " structure division ", " chemical part ", " group ", " chemical group " refer in molecule
Specific fragment or functional group.Chemical part is typically considered the chemical entities being embedded or attached on molecule.
" stereoisomer " refers to being made of same atoms, is bonded by identical key, but with different three-dimensional structures
Compound.The present invention will cover various stereoisomers and its mixture.
When containing alkene double bond in the compound of the present invention, unless otherwise stated, the compound of the present invention is intended to wrap
Containing E- and Z- geometric isomers.
" tautomer " refers to that proton is formed from an atom transfer of molecule to another atom of identical molecule
Isomers.All tautomeric forms of the compound of the present invention also will within the scope of the present invention.
The compound of the present invention or its pharmaceutically acceptable salt may contain one or more asymmetric carbon atoms, and therefore
Enantiomter, diastereoisomer and other stereoisomeric forms in any ratio can be generated.Each asymmetric carbon atom can be based on three-dimensional
It learns and is defined as (R)-or (S)-.The present invention is intended to include all possible isomers and its racemic modifications and optical voidness
Form.The preparation of the compound of the present invention racemic modification, diastereoisomer or enantiomter can be selected as raw material or
Intermediate.Optically active isomers can be prepared using chiral synthon or chiral reagent, or using routine techniques into
Row is split, for example, by using the methods of crystallization and chiral chromatogram.
The routine techniques of preparation/separation individual isomeric includes being synthesized by the chirality of suitable optical voidness precursor, or make
With such as chiral hplc resolution of racemic body (or racemic modification of salt or derivative), Gerald see, for example,
Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,
Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,
Annu.Rev.Anal. Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OF
PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical
Ltd.,Essex,1991,809-816； Heller,Acc.Chem.Res.1990,23,128.
In this application, term " pharmaceutically acceptable salt " includes pharmaceutically acceptable acid-addition salts and pharmaceutically may be used
The base addition salts of receiving.
" pharmaceutically acceptable acid-addition salts " be refer to retain free alkali biological effectiveness and without other side effects
, it is formed by salt with inorganic acid or organic acid.Inorganic acid salt includes but not limited to hydrochloride, hydrobromate, sulfate, nitric acid
Salt, phosphate etc.；Acylate includes but not limited to formates, acetate, 2,2- dichloroacetates, trifluoroacetate, propionic acid
Salt, caproate, caprylate, caprate, undecylenate, glycollate, gluconate, lactate, sebacate, adipic acid
Salt, glutarate, malonate, oxalates, maleate, succinate, fumarate, tartrate, citrate, palm
Hydrochlorate, stearate, oleate, cinnamate, laruate, malate, glutamate, pyroglutamate, aspartic acid
Salt, benzoate, mesylate, benzene sulfonate, tosilate, alginate, ascorbate, salicylate, 4- ammonia
Base salicylate, napadisilate etc..These salt can be prepared by method known in the art.
" pharmaceutically acceptable base addition salts " be refer to keep free acid biological effectiveness and without other side effects
, with inorganic base or organic base be formed by salt.Salt derived from inorganic base includes but not limited to sodium salt, sylvite, lithium salts, ammonium
Salt, calcium salt, magnesium salts, molysite, zinc salt, mantoquita, manganese salt, aluminium salt etc..Preferred inorganic salts are ammonium salt, sodium salt, sylvite, calcium salt and magnesium
Salt.Salt derived from organic base includes but not limited to salt below：Primary amine class, secondary amine class and tertiary amines, substituted amine, packet
Include natural substituted amine, cyclic amine and deacidite, such as ammonia, isopropylamine, trimethylamine, diethylamine, three
Ethamine, tripropyl amine (TPA), ethanol amine, diethanol amine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2- lignocaine second
Alcohol, dicyclohexyl amine, lysine, arginine, histidine, caffeine, procaine, choline, glycine betaine, ethylenediamine, gucosamine,
Methyl glucose osamine, theobromine, purine, piperazine, piperidines, N-ethylpiperidine, polyamino resin etc..Preferred organic base includes isopropyl
Amine, diethylamine, ethanol amine, trimethylamine, dicyclohexylamine, choline and caffeine.These salt can pass through method known in the art
It prepares.
" polymorph " refer to the present invention certain compounds in the solid state due to there are two or more not
The different solid crystal phases generated with molecules align.Certain compounds of the present invention may exist more than one crystal form, this hair
It is bright to be intended to include various crystal forms and its mixture.
In general, crystallization effect will produce the solvate of the compounds of this invention.Term " the solvation used in the present invention
Object " refers to the aggregation comprising one or more the compounds of this invention molecules with one or more solvent molecules.Solvent can be
Water, solvate in this case is hydrate.Alternatively, solvent can be organic solvent.Therefore, the compound of the present invention can be with
Exist with hydrate, including monohydrate, dihydrate, semihydrate, times semihydrate, trihydrate, tetrahydrate etc., with
And corresponding solvation form.The compounds of this invention can form true solvate, but in some cases, can also only protect
Indefinite water or water is stayed to add the mixture of the indefinite solvent in part.The compound of the present invention can react in a solvent or from
It Precipitation or is crystallized out in solvent.The solvate of the compounds of this invention is also contained within the scope of the present invention.
The invention also includes the prodrugs of above compound.In this application, term " prodrug " expression can be in physiological conditions
The compound of bioactive compound lower or that the present invention is converted to by solvolysis.Therefore, term " prodrug " refers to
The pharmaceutically acceptable metabolic precursor thereof of the compound of the present invention.When being given individual in need, prodrug can not have
Activity, but it is converted to the reactive compound of the present invention in vivo.Prodrug usually rapid conversion in vivo, and generate the present invention's
Parent compound, such as realized by hydrolyzing in blood.Prodrug compound usually provides in mammalian organism molten
The advantages of Xie Du, histocompatbility or sustained release.Prodrug includes known amino protecting group and carboxyl-protecting group.Specific prodrug system
Preparation Method can refer to Saulnier, M.G., et al., Bioorg.Med.Chem.Lett.1994,4,1985-1990；
Greenwald, R.B.,et al.,J.Med.Chem.2000,43,475。
In this application, " pharmaceutical composition " refers to that the compounds of this invention is used to live biology with what this field usually received
Property compound is delivered to the preparation of the medium of mammal (such as people).The medium includes pharmaceutically acceptable carrier.Drug
The purpose of composition is to promote the administration of organism, and bioactivity is played in turn conducive to the absorption of active constituent.
Terms used herein " pharmaceutically acceptable " refers to not influencing the bioactivity or property of the compounds of this invention
Substance (such as carrier or diluent), and relative nontoxic, the i.e. substance can be applied to individual without causing undesirable biological respinse
Or it is interacted with the arbitrary component for including in composition in a manner of bad.
In this application, " pharmaceutically acceptable carrier " includes but not limited to any to be permitted by relevant government administration section
Can be the acceptable adjuvant used for the mankind or domestic animal, carrier, excipient, glidant, sweetener, diluent, preservative, dye
Material/colorant, corrigent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.
" tumour " of the present invention, " cell Proliferation exception relevant disease " etc. include but not limited to leukaemia, gastro-intestinal stromal
Tumor, histiocytic lymphoma, non-small cell lung cancer, Small Cell Lung Cancer, cancer of pancreas, lung squamous cancer, adenocarcinoma of lung, breast cancer, forefront
Gland cancer, liver cancer, cutaneum carcinoma, cell carcinoma, cervical carcinoma, oophoroma, intestinal cancer, nasopharyngeal carcinoma, the cancer of the brain, osteocarcinoma, cancer of the esophagus, melanin
The diseases such as tumor, kidney, carcinoma of mouth.
Terms used herein " prevention ", " prevention " and " preventing " includes generation or the evil for so that sufferer is reduced disease or illness
The possibility of change.
The term as used herein " treatment " includes following meanings with other similar synonyms：
(i) prevent disease or illness in mammals to occur, especially when this kind of mammal be susceptible to the disease or
Illness, but when being not yet diagnosed as having suffered from the disease or illness；
(ii) inhibit disease or illness, that is, contain its development；
(iii) alleviate disease or illness, that is, the state of the disease or illness is made to subside；Or
(iv) mitigate the symptom caused by the disease or illness.
Term " effective quantity ", " therapeutically effective amount " or " pharmacy effective dose " used herein refers to taking metapedes at certain
Alleviate at least one medicament of one or more symptoms of treated disease or illness or the amount of compound in degree.Its result
Can be sign, the abatement of symptom or the cause of disease and/or alleviation or any other required variation of biosystem.For example, for controlling
" effective quantity " treated is the composition for including compound disclosed herein clinically provided needed for significant remission effect
Amount.The technology of such as dose escalation trial can be used to measure the effective quantity being suitable in any individual case.
Terms used herein " taking ", " application ", " administration " etc. are to refer to compound or composition being delivered to progress
The method in the required site of biological effect.These methods include but not limited to oral route, through intraduodenal routes, parenteral note
Penetrate (including in intravenous, subcutaneous, peritonaeum, intramuscular, intra-arterial injection or infusion), local administration and per rectum administration.This field
It can be used for the application technique of Compounds and methods for described herein known to technical staff, such as in Goodman and Gilman, The
Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's,
It is discussed in Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa
Those of.In preferred embodiments, the compound and composition being discussed herein pass through oral administration.
Term " pharmaceutical composition " used herein, " drug combination ", " applying other treatments ", " applies it at " drug combination "
Its therapeutic agent " etc. refers to the drug therapy obtained by mixing or combining more than one active constituent comprising active constituent
Fix and be not fixed combination.Term " fixed Combination " refers to being administered simultaneously to patient in the form of single entity or single dosage form
At least one compound as described herein and at least one collaboration medicament.Term " being not fixed combination " refers to the shape with corpus separatum
Formula is administered simultaneously to patient, shares or sequentially applied with variable interval time at least one compound as described herein and at least
A kind of collaboration preparation.These are also applied in cocktail therapy, such as using three or more active constituents.
It should also be appreciated by one skilled in the art that in method discussed below, midbody compound functional group may need
It to be protected by protecting group appropriate.Such functional group includes hydroxyl, amino, sulfydryl and carboxylic acid.Suitable hydroxyl protection base packet
Include trialkylsilkl or diarylalkyl-silyl (such as t-butyldimethylsilyl, tert-butyl diphenyl first
Silylation or trimethyl silyl), THP trtrahydropyranyl, benzyl etc..The protecting group of suitable amino, amidino groups and guanidine radicals includes uncle
Butoxy carbonyl, benzyloxycarbonyl group etc..Suitable sulfhydryl protected base includes-C (O)-R " (wherein R " is alkyl, aryl or aralkyl),
To methoxy-benzyl, trityl etc..Suitable carboxyl-protecting group includes alkyl, aryl or aralkyl esters.
Protecting group can be introduced and be removed according to standard technique well known by persons skilled in the art and as described herein.It protects
The use of shield base is specified in Greene, T.W. and P.G.M.Wuts, Protective Groups in Organi
Synthesis, (1999), in 4th Ed., Wiley.Protecting group can also be fluoropolymer resin.
With reference to specific embodiment, the present invention is further explained.It should be understood that, these embodiments be merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are weight percent and weight
Number.
A. aromatic amine substitution reaction universal method
Aromatic amine (1.5eq.) is dissolved in dry tetrahydrofuran, -78 DEG C is cooled to, is slowly dripped thereto under nitrogen protection
Reinforce (2.1eq.) such as alkali such as LDA solution, be added dropwise, reaction solution continues stirring 1 hour at -78 DEG C.By another substrate
The tetrahydrofuran solution of (1eq.) is slowly dropped to above-mentioned reaction solution, is added dropwise at -78 DEG C to being stirred overnight at room temperature.Use water quenching
It goes out reaction, it is 7 that 10% hydrochloric acid, which is neutralized to pH,.Ethyl acetate extracts, saturated common salt water washing, anhydrous sodium sulfate drying, filtering
Concentration, silica gel column chromatography separating purification obtain target compound.
B. ester hydrolysis universal method
By LiOHH2The THF/H of reaction substrate (1eq.) is added in O (5eq.) aqueous solution2The mixed solution of O, is stirred at room temperature
Overnight.Reaction finishes, and most of solvent is removed under reduced pressure, and 1N dilute hydrochloric acid adjusts pH to 6 or so, and ethyl acetate extraction is added, organic
It is mutually dry, it is concentrated to give target compound acid, is reacted in next step without being further purified to be directly used in.
C. amide condensed universal method
Substrate sour (1eq.) and amine (1.2eq.) are dissolved in dichloromethane, by condensing agent such as HATU etc. under ice bath cooling
Above-mentioned reaction solution is added in (1.2eq.), is stirred overnight at room temperature.Reaction solution is diluted with water, and ethyl acetate extraction, organic phase is used respectively
Dilute hydrochloric acid, saturated common salt water washing, anhydrous sodium sulfate drying are concentrated under reduced pressure, and silica gel column chromatography separating purification obtains target compound.
D, the halogenated universal method of aromatic rings
Reaction substrate (1eq.) is dissolved in anhydrous DMF, NXS or Selecflor (1eq.) is added thereto under ice bath cooling,
It is stirred at room temperature 2 hours and terminates to reaction.Reaction solution is quenched with saturated sodium thiosulfate solution, and water and ethyl acetate dilution separate
Organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying are filtered, are concentrated under reduced pressure, silica gel column chromatography separating purification
Obtain target compound.
Intermediate 1：3- Amino-cyclohexvls -- 1,2- glycol
Using cyclohexene bromine as raw material, according to described in intermediate A 125 (the 126-128 pages) in patent WO2013096744A1
Intermediate 3- Amino-cyclohexvls-rac-1,2- glycol, LC-MS (ESI+) m/z 132.1 is prepared in method.
Intermediate 2:3- aminocyclohexyl-cis-1,2- glycol
The first step：2- (hexamethylene -2- alkenyls) isoindoline -1,3- diketone
By -2 enol of hexamethylene (200mg), isoindoline -1,3- diketone (330mg) and triphenylphosphine (640mg) are dissolved in drying
Tetrahydrofuran (5mL) DEAD (430mg) is slowly added dropwise to above-mentioned solution, is stirred at room temperature under ice bath cooling, TLC monitorings are anti-
It answers.After reaction, decompression boils off most of solvent, and silica gel column chromatography purifies to obtain target compound.LC-MS(ESI+)m/z
132.1。
Second step：2- (cis-2,3- dihydroxies butylcyclohexyl) isoindoline -1,3- diketone
By 2- (hexamethylene -2- alkenyls) isoindoline -1,3- diketone (4.3g) and 4- methylmorpholine-N- oxides (6.5g)
It is suspended in acetone/water (60mL), said mixture is added in osmium tetroxide (10mg) under stirring, is stirred at room temperature 5 hours.It is saturated sulphur
Reaction, ethyl acetate extraction is quenched in sodium thiosulfate solution, and anhydrous sodium sulfate drying is concentrated under reduced pressure, and silica gel column chromatography is isolated
4.5g target compound.
Third walks：3- aminocyclohexyl-cis-1,2- glycol
Hydrazine hydrate (1g) is added to the ethyl alcohol of 2- (cis-2,3- dihydroxies butylcyclohexyl) isoindoline -1,3- diketone (5g)
In solution, reaction solution heats reaction 2 hours at 90 DEG C.After completion of the reaction, reaction solution is cooled to room temperature, and filters off insoluble matter, filtrate
Reduced pressure is directly used in reacts in next step.
Intermediate 3：Aminocyclohexyl-trans-3-1,2- glycol
Using cyclohexene bromine as raw material, using document Organic Biomolecular Chemistry, 2008, volume the 6, the 20th
Phase, 3762-3770 pages of identical method prepare synthesis and obtain aminocyclohexyl-trans-3-1,2- glycol, LC-MS
(ESI+)m/z 132.1。
Intermediate 4:
The first step：The chloro- 6- oxos -1,6- dihydropyridines -3- formic acid of 2-
2,6- dichloro-nicotinic acids (6g) are placed in 250mL round-bottomed flasks, sodium hydroxide solution (80mL) are added, mixed liquor adds
Heat to 120 DEG C react 4 hours.Reaction finishes, and is cooled to room temperature, and is acidified with the hydrochloric acid of 6N, and solid is precipitated, and filtering is dried to obtain
Target compound (4g)
Second step：The chloro- 1- methyl -6- oxos -1,6- dihydropyridines -3- formic acid esters of methyl -2-
Under nitrogen protection, sodium hydride (60%, 2g) is slowly added into chloro- 6- oxos -1, the 6- dihydropyridine -3- of 2- in batches
In DMF (50mL) solution of formic acid (4g), adds and continue stirring 40 minutes.Then, above-mentioned reaction solution is added in iodomethane (8g)
The reaction was continued 1 hour, is reacted with 2N hydrochloric acids, adjusts pH to 6-7.Reaction solution is extracted with ethyl acetate, saturated common salt washing
It washs, anhydrous sodium sulfate drying is concentrated under reduced pressure, and silica gel column chromatography separating purification obtains target compound (2g).1H NMR
(400MHz,CDCl3) δ:3.74 (s, 3H), 3.86 (s, 3H), 6.51 (d, 1H, J=9.68Hz), 7.88 (d, 1H, J=
9.68Hz).
Third walks：Aromatic amine substitution reaction universal method
Following intermediate is prepared using universal method A and universal method B the methods：
With 2,3- dihydroxy cyclo-hexylamine and intermediate 4a-4d for raw material, using universal method C, prepare synthesis obtain with
Lower embodiment：
6~embodiment of embodiment 8
The first step：Halogenating reaction
With 2- (the iodo- aniline of the fluoro- 4- of 2-) -1- methyl -6- oxo -1,6- dihydropyridine -3- carboxylate methyl esters for raw material, use
Following intermediate is prepared in universal method D：
Second step：Following intermediate is prepared with universal method B：
Third walks：Using universal method C, prepares synthesis and obtain following embodiment：
Embodiment 9：2- (the fluoro- 4- Iodoanilines of 2-) -1,5- dimethyl -6- oxo -1,6- dihydropyridine -3- carboxylic acids (cis-
2,3- dihydroxy-cyclohexyl)-amide
The first step：The chloro- 1,5- dimethyl -6- oxos -1,6- dihydropyridines -3- carboxylate methyl esters of 2-
By the chloro- 1- methyl -6- oxos -1,6- dihydroxy-pyridines -3- carboxylate methyl esters (1eq.) of the iodo- 2- of 5-, Pd (OAc) 2
(0.1eq.) mixed is in dry dioxane (2mL), after reaction solution bubbling argon, ZnMe2 (0.1eq.) is added, instead
Answering liquid, extremely the reaction was complete within 4 hours in 90 degree of heating stirrings.Stop heating, reaction solution is cooled to room temperature, and methanol is added and is quenched instead
It answers, ethyl acetate extraction, organic phase is washed with saturated ammonium chloride, and anhydrous sodium sulfate drying is filtered, is concentrated under reduced pressure, silica gel column layer
Analysis isolates and purifies to obtain target compound.1H NMR(400MHz,CDCl3)δ:(2.72 d, 3H, J=0.96Hz), 3.85 (s,
3H), 3.91 (s, 3H), 7.73 (d, 3H, J=0.96Hz)
Second step：2- (the iodo- anilino-s of the fluoro- 4- of 2-) -1,5- dimethyl -6- oxo -1,6- dihydropyridine -3- carboxylate methyl esters
Target compound is prepared using universal method A.1H NMR(400MHz,CDCl3)δ:2.13(s,3H),3.28
(s, 3H), 3.82 (s, 3H), 6.42 (m, 1H), 7.37 (d, 1H, J=8.36Hz), 7.56 (m, 1H), 7.83 (s, 1H),
9.54(s,1H).
Third walks：2- (the iodo- anilino-s of the fluoro- 4- of 2-) -1,5- dimethyl -6- oxo -1,6- dihydropyridine -3- formic acid
Target compound is prepared using universal method B.1H NMR(400MHz,d-DMSO)δ:2.01(s,3H),
3.13 (s, 3H), 6.62 (m, 1H), 7.47 (d, 1H, J=8.4Hz), 7.73 (dd, 1H, J1=10.52Hz, J2=
1.76Hz),7.82(s, 1H),9.61(s,1H).
4th step：2- (the fluoro- 4- Iodoanilines of 2-) -1,5- dimethyl -6- oxo -1,6- dihydropyridine -3- carboxylic acids (cis-2,
3- dihydroxy-cyclohexyl)-amide
Target compound, 1H NMR (400MHz, d-DMSO) δ are prepared using universal method C:1.35(m,3H),
1.61 (m, 3H), 2.05 (s, 3H), 3.21 (s, 3H), 3.85 (s, 1H), 3.95 (m, 1H), 4.29 (d, 1H, J=3.24Hz),
4.34 (d, 1H, J=6.44Hz), 6.51 (m, 1H), 7.4 (d, 1H, J=8.24Hz), 7.66 (m, 1H), 7.87 (s, 1H),
7.96 (d, 1H, J=8.08Hz), 10.39 (s, 1H) .LC-MS (ESI+) m/z 516.5.
Embodiment 10：2- (the iodo- anilino-s of the fluoro- 4- of 2-) -5- isopropenyl -1- methyl -6- oxo -1,6- dihydropyridines -
3- carboxylic acids (cis-2,3- dihydroxies butylcyclohexyl)-amide
The first step：Methyl 2- ((4- cyclopropyl -2- fluorophenyls) amino) -1- methyl -6- oxo -1,6- dihydropyridines -3-
Carboxylate
By methyl 2- ((the fluoro- 4- iodophenyls of 2-) amino) -1- methyl -6- oxo -1,6- dihydropyridine -3- carboxylates
(1eq.), cyclopropylboronic acid ester (2eq.) and powdered sodium carbonate (3eq.) mixed are in dry dioxane (5mL), reaction
Liquid is heated to 90 degree of heating stirrings overnight to the reaction was complete with Pd (dppf) Cl2 (0.1eq.) is added after bubbling argon 10min.Instead
Liquid is answered to be cooled to room temperature, ethyl acetate extraction, organic phase uses dilute hydrochloric acid, saturated common salt water washing, anhydrous sodium sulfate to dry respectively,
Filtering is concentrated under reduced pressure, and silica gel column chromatography purifies to obtain target product.LC-MS(ESI+)m/z 317.2.
Second step：2- ((4- cyclopropyl -2- fluorophenyls) amino) -1- methyl -6- oxo -1,6- dihydropyridine -3- carboxylic acids
With methyl 2- ((4- cyclopropyl -2- fluorophenyls) amino) -1- methyl -6- oxo -1,6- dihydropyridine -3- carboxylates
For raw material, target compound, LC-MS (ESI+) m/z 303.5 are prepared using universal method B.
Third walks：2- ((4- cyclopropyl -2- fluorophenyls) amino)-N- (cis-2,3- dihydroxies butylcyclohexyl) -1- methyl -6-
Oxo -1,6- dihydropyridine -3- amides
It is original with 2- ((4- cyclopropyl -2- fluorophenyls) amino) -1- methyl -6- oxo -1,6- dihydropyridine -3- carboxylic acids
Material, target compound, 1H NMR (400MHz, d-DMSO) δ are prepared using universal method C:1.32(m,12H),3.15(m,
1H), 3.42 (s, 3H), 3.47 (m, 1H), 4.09 (m, 1H), 5.53 (s, 1H), 6.51 (m, 1H), 7.39 (d, 1H, J=
8.36Hz),7.51(m,1H),7.76(s,1H)。LC-MS(ESI+)m/z 544.1。
Embodiment 11：2- (the iodo- anilino-s of the fluoro- 4- of 2-) -5- isopropenyl -1- methyl -6- oxo -1,6- dihydropyridines -
3- carboxylic acids (cis-2,3- dihydroxies butylcyclohexyl)-amide
Isopropyl acid esters is replaced with tetrabutyl ethyleneoxy tin, target is prepared using 10 identical synthetic method of embodiment
Compound,1H NMR(400MHz,d-DMSO)δ:1.41(m,6H),2.04(s,3H),3.19(s,3H),3.45(m,1H),
3.48 (m, 1H), 4.01 (s, 1H), 5.21 (m, 1H), 5.62 (m, 1H), 6.57 (m, 1H), 7.44 (d, 1H, J=8.56Hz),
7.59(m,1H),7.82(s,1H).LC-MS(ESI+)m/z 418.2。
Embodiment 12：N- (cis-2,3- dihydroxies butylcyclohexyl) -2- ((the fluoro- 4- of 2- (1- ethoxys) phenyl) amino) -1-
Methyl -6- oxo -1,6- dihydropyridine -3- amides
With embodiment 11 (20mg) for raw material, methanol is solvent (5mL), and sodium borohydride (1.2eq) is reducing agent, and room temperature is anti-
It answers and obtains within 2 hours embodiment 12, LC-MS (ESI+) m/z 420.3.
Embodiment 13：2- (the fluoro- 4- cyano-phenyl amines bases of 2-) -1- methyl -6- oxo -1,6- dihydropyridine -3- carboxylic acids
(cis-2,3- dihydroxies butylcyclohexyl)-amide
With embodiment 4 (50mg) and zinc cyanide (2eq.) for raw material, four triphenyl phosphorus palladiums (10%) are catalyst, and heating is anti-
Target compound should be obtained,1H NMR(400MHz,CDCl3)δ:1.42(m,3H),1.75(m,3H),3.43(s,3H), 4.04
(s, 1H), 4.12 (m, 2H), 6.66 (m, 1H), 7.18 (m, 2H), 7.47 (d, 1H, J=8.36Hz), 7.62 (m, 1H), 7.75
(m,2H),8.02(s,1H).LC-MS(ESI+)m/z 402.1
14 2- of embodiment (the fluoro- aniline of 4- acetenyls -2-) -1- methyl -6- oxo -1,6- dihydropyridine -3- carboxylic acids
(cis-2,3- dihydroxy-cyclohexyl)-amide
The first step：Methyl-2- (the fluoro- 4- of 2- (2- (trifluoromethyl silicon substrate) acetenyl) aniline) oxo-1-1- methyl-6-,
6- dihydropyridine -3- carboxylates
Under nitrogen protection, by methyl -2- (the fluoro- 4- iodobenzenes amidos of 2-) -1- methyl -6- oxo -1,6- dihydropyridine -3- carboxylics
Anhydrous tetrahydro furan (10mL) solution of acid esters (200mg) is added to (PPh3)2PdCl2(20mg), cuprous iodide (10mg),
In the mixture of triethylamine (100mg), trimethyl silicane ethyl-acetylene (80mg) is then added, 70 degree of heating stirrings are stayed overnight.It has reacted
Solvent is removed under reduced pressure in Quan Hou, and ethyl acetate extraction, saturated common salt water washing, column chromatographic isolation and purification obtains 170 after dry concentration
Mg target compounds.1H NMR(400MHz,CDCl3)δ:0.23(s,9H),3.21(s,3H),3.89(s,3H),6.28(d,
1H, J=9.64Hz), 6.68 (t, 1H, J=8.32Hz), 7.24 (d, 1H, J1=8.32Hz), 7.92 (m, 1Hz), 10.02 (s,
1H).
Second step：Methyl -2- (4- acetenyl -2- fluoroanilinos) -1- methyl -6- oxo -1,6- dihydropyridine -3- carboxylic acids
Ester
By methyl -2- (the fluoro- 4- of 2- (2- (trifluoromethyl silicon substrate) acetenyl) aniline) -1- methyl -6- oxo -1,6- dihydros
Pyridine -3- carboxylates (170mg) are dissolved in anhydrous tetrahydro furan (2mL), are added with stirring TBAF3H2O (280mg), room temperature is stirred
It mixes overnight.After the reaction was complete, most of solvent is removed under reduced pressure, ethyl acetate extracts, organic phase water, saturated common salt water washing,
Anhydrous sodium sulfate is dried, and filtering, column chromatographic isolation and purification obtains 110mg target compounds after reduced pressure.1H NMR
(400MHz, CDCl3)δ:3.11 (s, 1H), 3.28 (s, 3H), 3.86 (s, 3H), 6.32 (d, 1H, J=9.64Hz), 6.73
(m, 1H), 7.27 (d, 1H, J=8.4Hz), 7.88 (d, 1H, J1=9.64Hz), 10.02 (s, 1H)
Third walks：2- (4- acetenyl -2- fluoroanilinos) -1- methyl -6- oxo -1,6- dihydropyridine -3- carboxylic acids
Target compound is prepared using universal method B,1H NMR(400MHz,CD3OD)δ:3.25(s,3H),3.59
(s, 1H), 6.21 (d, 1H, J=9.52Hz), 6.89 (m, 1H), 7.27 (m, 1H), 7.35 (m, 1H), 8.09 (d, 1H, J=
9.52 Hz).
4th step：2- (the fluoro- aniline of 4- acetenyls -2-) -1- methyl -6- oxo -1,6- dihydropyridine -3- carboxylic acids (cis-
2,3- dihydroxy-cyclohexyl)-amide
Synthesis is prepared using universal method C and obtains target compound.1H NMR(400 MHz,d-DMSO)δ:1.21(m,
4H), 1.61(m,2H),3.18(s,3H),4.39(m,1H),4.2(s,1H),4.36(m,2H),5.76(s,1H),6.25(d,
1H, J=9.24 Hz), 6.78 (m, 1H), 7.27 (d, 1H, J=7.92 Hz), 7.43 (m, 1H), 7.88 (m, 1H), 8.01 (m,
1H),10.82(s,1H).LC-MS(ESI+)m/z 400.4
Embodiment 15：N- (cis-2,3- dihydroxies butylcyclohexyl) -2- ((the fluoro- 4- of 2- (1- fluoro ethyls) phenyl) amino) -1-
Methyl -6- oxo -1,6- dihydropyridine -3- amides
Embodiment 12 (50mg) is dissolved in anhydrous tetrahydro furan (2mL), DAST (1.5eq), room temperature is added under nitrogen protection
It is stirred overnight.Reaction finishes, and is concentrated under reduced pressure, and column chromatographic isolation and purification obtains target compound.LC-MS(ESI+)m/z 422.2
Embodiment 16：N- (cis-2,3- dihydroxies butylcyclohexyl) -2- ((the fluoro- 4- of 2- (2- hydroxypropyl -2- bases) phenyl) amino) -
1- methyl -6- oxo -1,6- dihydropyridine -3- amides
Embodiment 11 (200mg) is dissolved in addition methyl grignard reagent under anhydrous methylene chloride (5mL) nitrogen protection
(5eq), room temperature reaction.After reaction, ethyl acetate extracts, and organic phase uses water, saturated common salt water washing dry dense respectively
Contracting, silica gel column chromatography separating purification obtain target compound.1H NMR(400MHz,d-DMSO)δ:1.24(m,3H),1.61(m,
3H), 2.08 (s, 3H), 3.16 (s, 3H), 3.81 (s, 1H), 3.98 (m, 1H), 4.34 (d, 1H, J=3.16Hz), 4.39 (d,
1H, J=6.4Hz), 5.13 (s, 1H), 5.46 (s, 1H), 6.19 (m, 1H), 6.84 (d, 1H, J=8.68Hz), 7.27 (m,
1H), 7.42 (m, 1H), 7.96 (d, 1H, J=9.6Hz), 8.01 (m, 1H), 10.99 (s, 1H) .LC-MS (ESI+) m/z
434.2。
Embodiment 17：2- (the fluoro- 4- cumenes amidos of 2-) -1- methyl -6- oxo -1,6- dihydropyridine -3- carboxylic acids
(cis-2,3- dihydroxies butylcyclohexyl)-amide
It is dissolved in the mixed solvent (10mL/1mL) of DMF and water with embodiment 4 (100mg), copper powder (0.2eq) and first sulphur is added
Sodium alkoxide (1.2eq) is heated to 110 degree of reactions overnight.After being filtered to remove insoluble matter, ethyl acetate extraction, washing, anhydrous sodium sulfate
It is dry, it is concentrated under reduced pressure, embodiment 17 is prepared in column chromatography,1H NMR(400MHz,d-DMSO)δ:1.18 (d, 6H, J=
6.48Hz),1.30(m,6H),3.13(s,3H),3.42-3.53(m,1H),3.81(s,1H),3.98(m,1H), 4.35-
4.39 (m, 5H), 6.14 (d, 1H, J=9.6Hz), 6.76 (m, 1H), 7.01 (d, 1H, J=7.76Hz), 7.17 (m, 1H),
7.91(m,1H),8.08(m,1H),10.95(s,1H).LC-MS(ESI+)m/z 438.5。
Embodiment 18：N- (cis-4,5- dihydroxy tetrahydrochysene -2H- pyrans -3- bases) -2- ((the fluoro- 4- iodophenyls of 2-) amino) -
1- methyl -6- oxo -1,6- dihydropyridine -3- amides
With intermediate 4d (20mg) and cis-4,5- dihydroxy tetrahydrochysene -2H- pyrans -3- ammonia (1.1eq) for raw material, using logical
Synthesis, which is prepared, with method B obtains target compound.1H NMR(400MHz,CD3OD)δ:1.31(m,3H),1.56(s,3H),
1.81 (m, 3H), 3.23 (s, 3H), 3.47 (m, 1H), 3.62 (d, 1H, J=5.44Hz), 4.02 (s, 1H), 4.16 (m, 1H),
4.61 (s, 2H), 6.28 (m, 1H), 6.85 (t, 1H, J=8.48Hz), 7.21 (d, 1H, J=9.28Hz), 7.39 (m, 1H),
7.92(m,1H).LC-MS(ESI+)m/z 504.2。
Embodiment 19 and embodiment 20：N- (cis-2,3- dihydroxies butylcyclohexyl) -4- (the fluoro- 4- Iodoanilines of 2-) -1- methyl -
6- oxo -1,6- dihydropyridine -3- formamides
The first step：The chloro- 4- of 5- (the fluoro- 4- Iodoanilines of 2-) -1- methyl -6- oxo -1,6- dihydropyridine -3- formic acid
With 4,5-, bis- chloro- 1- methyl -6- oxos -1,6- dihydropyridine -3- carboxylic acids and the fluoro- 4- Iodoanilines of 2- for raw material, adopt
Target compound is prepared with universal method A,1H NMR(400MHz,d-DMSO)δ:3.57(s,3H),6.78(m,1H),
7.49 (d, 1H, J=8.2Hz), 7.62 (m, 1H), 8.51 (s, 1H), 10.03 (s, 1H)
Second step：N- (cis-2,3- dihydroxy butylcyclohexyl) -4- (the fluoro- 4- Iodoanilines of 2-) -1- methyl -6- oxos -1,6-
Dihydropyridine -3- formamides
With the chloro- 4- of 5- (the fluoro- 4- Iodoanilines of 2-) -1- methyl -6- oxo -1,6- dihydropyridine -3- formic acid for raw material, use
Target compound is prepared in universal method C,1H NMR(400MHz,d-DMSO)δ:1.33(m,3H),1.60(m,3H),
3.51 (s, 3H), 3.85 (s, 1H), 3.91 (m, 1H), 4.37 (d, 1H, J=3.2Hz), 4.54 (m, 1H), 6.72 (m, 1H),
7.43 (d, 1H, J=8.08Hz), 7.66 (m, 1H), 8.26 (s, 1H), 9.71 (s, 1H).LC-MS(ESI+)m/z 536.2
Third walks：It is prepared by SFC
By N- (cis-2,3- dihydroxy butylcyclohexyl) -4- (the fluoro- 4- Iodoanilines of 2-) -1- methyl -6- oxo -1,6- dihydro pyrroles
Pyridine -3- formamides are dissolved in methanol, using Supercritical fluid chromatography (chiralpak OD columns, methanol/CO2 ratios are from 10% to 20%) point
From embodiment 19 (peak 1, HPLC purity 99%, LC-MS (ESI+) m/z 536.3) and 20 (peak of embodiment is prepared
2, HPLC purity 99%, LC-MS (ESI+) m/z 536.2).
Intermediate 8a-8c
The first step：Following intermediate is prepared using universal method B：
Third walks：Following intermediate is prepared using universal method A：
Embodiment 21- embodiments 23
Using intermediate 8a-8d as raw material, synthesis is prepared using universal method C and obtains following embodiment compound：
Embodiment 26：The fluoro- 4- of 5- (the iodo- aniline of the fluoro- 4- of 2-) -1- methyl -6- oxo -1,6- dihydropyridine -3- carboxylic acids (2,
3- dihydroxies butylcyclohexyl)-amide
Embodiment 23 is dissolved in methanol, 26 (peak of embodiment is prepared using the similar method of the 4th step of embodiment 19
1, HPLC purity 99%, LC-MS (ESI+) m/z 520.3；Peak 2, HPLC purity 94%).
Embodiment 27 and 28：
Embodiment 5 is dissolved in methanol, using Supercritical fluid chromatography (chiralpak OD columns, methanol/CO2 ratios from 10% to
20%) embodiment 27 (peak 1, HPLC purity 98%, LC-MS (ESI+) m/z 410.2) and embodiment 28 is prepared in separation
(peak 2, HPLC purity 99%, LC-MS (ESI+) m/z 410.1).
Embodiment 29 and embodiment 30：
Embodiment 8 is dissolved in methanol, using Supercritical fluid chromatography (chiralpak OD columns, methanol/CO2 ratios from 10% to
20%) embodiment 29 (peak 1, HPLC purity 98%, LC-MS (ESI+) m/z 502.1) and embodiment 30 is prepared in separation
(peak 2, HPLC purity 99%, LC-MS (ESI+) m/z 502.3).
Embodiment 31：4- (the fluoro- 4- Iodoanilines of 2-) -1- methyl -6- oxo -1,6- dihydropyridine -3- carboxylic acid (2,3- dihydroxies
Butylcyclohexyl)-amide
The first step：The chloro- 1- methyl -6- oxos -1,6- dihydropyridines -3- carboxylic acids of 4-
With chloro- 1- methyl -6- oxos -1, the 6- dihydropyridine -3- carboxylic acid, ethyl esters of 4- for raw material, prepared using universal method B
Target compound is obtained,1H NMR(400MHz,d-DMSO)δ:3.47(s,3H),6.62(s,1H),8.56(s,1H)。
Second step：4- (the fluoro- 4- Iodoanilines of 2-) -1- methyl -6- oxo -1,6- dihydropyridine -3- carboxylic acids
With chloro- 1- methyl -6- oxos -1, the 6- dihydropyridine -3- carboxylic acids of 4- and the fluoro- 4- Iodoanilines of 2- for raw material, using logical
Target compound is prepared with method A,1H NMR(400MHz,d-DMSO)δ:3.40(s,3H),5.48(s,1H),7.32
(t, 1H, J=8.4Hz), 7.56 (d, 1H, J=8.4Hz), 7.67 (m, 1H), 8.51 (s, 1H), 9.73 (s, 1H).
Third walks：N- (cis-2,3- dihydroxies butylcyclohexyl)-4- (the fluoro- 4- iodobenzenes amidos of 2-) oxo-1-1- methyl-6-,
6- dihydropyridine -3- formamides
With 4- (the fluoro- 4- Iodoanilines of 2-) -1- methyl -6- oxo -1,6- dihydropyridine -3- carboxylic acids for raw material, use is general
Target compound is prepared in method C,1H NMR(400MHz,CD3OD)δ:1.32(m,4H),1.51(m,2H),3.45(m,
1H), 3.54 (s, 3H), 4.07 (s, 1H), 4.21 (m, 1H), 5.78 (s, 1H), 7.24 (m, 1H), 7.62 (d, 1H, J=8.4
Hz),7.62(m,1H),8.21(s,1H)。LC-MS(ESI+)m/z 502.3。
Embodiment 32 and embodiment 33
Embodiment 31 is dissolved in methanol, using Supercritical fluid chromatography (chiralpak OD columns, methanol/CO2 ratios from 10% to
20%) embodiment 32 (peak 1, HPLC purity 98%, LC-MS (ESI+) m/z 502.3) and embodiment is prepared in separation
33 (peak 2, HPLC purity 99%, LC-MS (ESI+) m/z 502.1).
Embodiment 34 and embodiment 35
Embodiment 34 (HPLC purity 98%, LC-MS (ESI+) m/ is prepared using embodiment 32 and 33 identical methods
Z 516.3) and embodiment 35 (HPLC purity 98%, LC-MS (ESI+) m/z 516.2).
Active testing example：
1, MEK kinases is tested
Using LanthaScreen Eu Kinase Binding Assay methods, on the MEK1 kinases of inactive,
The affinity of embodiment compound and enzyme is determined.Experimental procedure：1) kinases, ATP are mixed using 1 × reaction buffer
Conjunction is configured to 6 × enzyme/ATP mixed liquors, the final concentration of 0.5uM of MEK1 (inactive) final concentration of 2.5nM, ATP；2) 1 is used
Antibody MAb is configured to 6 × working solution, the final concentration of 0.5nM of MAb by × reaction buffer.By enzyme/bodies such as ATP mixed liquors and MAb
Product mixing, is made 3 × enzyme/ATP/MAb working solutions；3) 1 × reaction buffer is used to prepare 3 × Tacer working solutions；4) to 96
The test-compound, 5ul enzymes/ATP/MAb working solutions, 5ul Tacer working solutions of each concentration of 5ul, room temperature are sequentially added in orifice plate
It is detected after reaction 1h；4) 96 orifice plates 2000rpm in HERAEUS Multifuge X1R centrifuges is placed in centrifuge 1 minute, in
The enterprising line numbers of EnVisionTM according to surveying and determination, select 337nM wavelength laser be used as exciting light, measurement RFU665nM and
RFU615nM, and with RFU665nM/RFU615nMIt is analyzed as final data；5) 5.0 logarithms of Graphpad Prism are used
According to four parameter curves are carried out, corresponding IC is calculated50.IC50<100nM is used ++++indicate, 1000nM<IC50<100nM is used ++
+ indicate, IC50>1000nM is used ++ it indicates.
| Number | IC50/nM | Number | IC50/nM | Number | IC50/nM | Number | IC50/nM |
| 1 | +++ | 2 | +++ | 3 | +++ | 4 | ++++ |
| 5 | ++++ | 6 | +++ | 7 | ++++ | 8 | ++++ |
| 9 | ++++ | 10 | ++ | 11 | ++ | 12 | +++ |
| 13 | +++ | 14 | +++ | 15 | +++ | 16 | +++ |
| 17 | +++ | 18 | ++ | 19 | ++++ | 20 | ++ |
| 21 | ++ | 22 | +++ | 23 | ++++ | 24 | ++++ |
| 25 | ++ | 26 | ++++ | 27 | ++ | 28 | ++++ |
| 29 | ++++ | 30 | ++++ | 31 | ++++ | 32 | ++++ |
| 33 | ++++ | 34 | ++++ | 35 | ++++ | 36 | ++++ |
2, tumor cell proliferation inhibition activity
Embodiment compound pair is tested on COLO205 cell strains using Cell Counting Kit-8 (CCK-8) methods
The inhibitory activity of tumor cell proliferation.Experimental procedure：1) cell normally cultivated is taken, under its exponential growth state, digestion point
It according to the density of 4.4 × 104cells/mL after dissipating, is inoculated in 96 porocyte culture plates, 90 μ l is inoculated with per hole；After the completion of inoculation
Microwell plate is positioned over 37 degrees Celsius, 5% CO2Under conditions of overnight incubation；2) 10 × compound is respectively added in each hole, often
10 μ L are added in hole, wherein 2 multiple holes of each administration concentration, each compound totally 9 administration concentrations；3) compound and cell are common
After being incubated 72 hours, 10 μ l Cell Counting Kit-8 reaction solutions are added into every hole, are incubated 2-3 hour.In
The absorbance value at 450nm is measured on Flexstation 3, sets 650nm as reference wavelength；4) following equation is pressed to changing
The external inhibitory activity for closing object is calculated：Cell proliferation inhibition rate：Inhibiting rate (%)=(signal value control-signal value is given
Medicine)/signal value control × 100%, and according to the inhibiting rate of each concentration, 50% inhibition concentration, IC are calculated using LOGIT methods50。
IC50<100nM is used ++++indicate, 1000nM<IC50<100nM is used +++ it indicates, IC50>1000nM is used ++ it indicates.
| Number | IC50/nM | Number | IC50/nM | Number | IC50/nM | Number | IC50/nM |
| 1 | ++ | 2 | ++ | 3 | +++ | 4 | ++++ |
| 5 | ++++ | 6 | +++ | 7 | ++++ | 8 | ++++ |
| 9 | ++++ | 10 | ++ | 11 | +++ | 12 | +++ |
| 13 | +++ | 14 | +++ | 15 | +++ | 16 | +++ |
| 17 | +++ | 18 | ++ | 19 | +++ | 20 | +++ |
| 21 | +++ | 22 | +++ | 23 | ++++ | 24 | ++++ |
| 25 | ++ | 26 | ++++ | 27 | +++ | 28 | ++++ |
| 29 | ++++ | 30 | ++++ | 31 | ++++ | 32 | ++++ |
| 33 | ++++ | 34 | ++++ | 35 | ++++ | 36 | ++++ |
Similarly, section Example also shows higher inhibitory activity on the cell strains such as HT29：
| Embodiment is numbered | 4 | 5 | 7 | 8 | 9 | 13 | 19 |
| HT29(IC50/nM) | ++++ | ++++ | ++++ | ++++ | ++++ | +++ | +++ |
| Embodiment is numbered | 23 | 25 | 26 | 28 | 29 | 30 | 32 |
| HT29(IC50/nM) | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ | ++++ |
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To be made various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (7)
1. a kind of such as general formula I compounds represented or its pharmaceutically acceptable salt or its enantiomter, diastereo-isomerism
Body, tautomer, solvate, polymorph or prodrug,
In formula：R1 is selected from hydrogen, alkyl, naphthenic base, Heterocyclylalkyl；R2 is selected from naphthenic base, Heterocyclylalkyl；R3 is selected from hydrogen, halogen, alkane
Base, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl；Ar is selected from aryl, heteroaryl；
One or more hydrogen atoms on above-mentioned any group can be replaced by deuterium, halogen respectively；Wherein, the heteroaryl
Including 1-3 hetero atoms selected from the group below：N, O or S；The heterocycle includes 1-3 hetero atoms selected from the group below：N, O or S.
2. compound as described in claim 1, it is characterised in that；
R1 is independently selected from hydrogen, alkyl, naphthenic base or Heterocyclylalkyl, further preferably from alkyl, more preferably methyl, second
Base, cyclopropyl etc.；R2 is independently selected from naphthenic base or Heterocyclylalkyl, the naphthenic base or heterocycle that are further preferably saturated from 4-8 members
Alkyl, and there is 1-3 hydroxyl substituent on ring；R3 is independently selected from hydrogen, halogen, cyano, carbonyl, nitro, sulfuryl, alkane
Base, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, further preferably from hydrogen, alkyl, halogen and naphthenic base, more preferably hydrogen,
Fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, cyclopropyl etc.；Ar is independently selected from aryl, heteroaryl, further preferably 5-10
First aryl or heteroaryl, more preferably phenyl ring, pyridine ring etc. with 1-2 different substituents, and substituent group is preferred
For hydrogen, halogen, cyano, alkyl, naphthenic base, sulfuryl, sulfoxide group, carbonyl etc..
3. the compound as described in claim 1,2, which is characterized in that the compound has logical formula (II), (III) as follows：
4. the compound as described in claim 1,2,3, which is characterized in that the compound has the following structure：
5. a kind of the method for preparing compound of formula I, which is characterized in that the method includes the steps：
A1 reaction) is hydrolyzed under acid or base catalysis in general formula (A) compound, general formula (B) compound is prepared；With
A2) substitution reaction will be carried out under general formula (B) compound and aromatic amine compounds reaction condition existing for base catalyst,
Obtain general formula (C) compound；With
A3) by general formula (C) compound, the condition existing for condensation reagent issues with Cycloalkyl amine or Heterocyclylalkyl aminated compounds
Logical formula (I) compound is prepared in raw condensation reaction.
In various, each group is as defined above；
Preferably, the step a1), a2), a3) respectively carry out in a solvent, and the solvent is selected from the group：Water, methanol, second
Alcohol, isopropanol, ethylene glycol, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), tetrahydrofuran, toluene, dichloromethane, 1,2-, bis- chloroethenes
Alkane, acetonitrile, n,N-Dimethylformamide, n,N-dimethylacetamide, dioxane, or combinations thereof object.
Preferably, the condensation reagent is selected from the group：DCC、DIC、CDI、EDCI、HOAt、HOBt、BOP、PyBOP、HATU、
TBTU etc., or combinations thereof object.
Preferably, the inorganic base is selected from the group：Sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, the tert-butyl alcohol
Sodium, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, saleratus, sodium carbonate, sodium bicarbonate, or combinations thereof object；The organic base
It is selected from the group：Pyridine, triethylamine, n,N-diisopropylethylamine, 1,8- diazabicylos [5.4.0], 11 carbon -7- alkene (DBU),
Two silicon substrate lithium of hexamethyl, two silicon substrate sodium of hexamethyl, lutidines, or combinations thereof object.
Preferably, the acid is selected from the group：Hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid,
Trifluoromethanesulfonic acid or combinations thereof object.
6. the purposes of the compound of formula I as described in claim 1,2,3,4,5, which is characterized in that be used to prepare treatment and Ras-
The drug of Raf-MEK kinase activities or the relevant disease of expression quantity, especially tumor therapeutic agent；The tumour is independently selected
From non-small cell lung cancer, Small Cell Lung Cancer, adenocarcinoma of lung, lung squamous cancer, breast cancer, prostate cancer, liver cancer, cutaneum carcinoma, gastric cancer, intestines
Cancer, leukaemia, lymph cancer, nasopharyngeal carcinoma etc..
7. comprising such as claim 1, the pharmaceutical composition of compound of formula I composition described in 2,3,4,5,6, which is characterized in that institute
The pharmaceutical composition stated includes：
(i) a effective amount of compound of formula I or its pharmaceutically acceptable salt or its enantiomter, diastereoisomer, mutually
Tautomeric, solvate, polymorph or prodrug；With
(ii) pharmaceutically acceptable carrier.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040116479A1 (en) * | 2002-10-04 | 2004-06-17 | Fortuna Haviv | Method of inhibiting angiogenesis |
| WO2015058589A1 (en) * | 2013-10-25 | 2015-04-30 | 上海恒瑞医药有限公司 | Pyridic ketone derivatives, method of preparing same, and pharmaceutical application thereof |
| CN105267214A (en) * | 2014-07-21 | 2016-01-27 | 沈阳化工研究院有限公司 | Application of N-heteroaryl phenylamine compounds for preparation of antitumor drugs |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040116479A1 (en) * | 2002-10-04 | 2004-06-17 | Fortuna Haviv | Method of inhibiting angiogenesis |
| WO2015058589A1 (en) * | 2013-10-25 | 2015-04-30 | 上海恒瑞医药有限公司 | Pyridic ketone derivatives, method of preparing same, and pharmaceutical application thereof |
| CN105267214A (en) * | 2014-07-21 | 2016-01-27 | 沈阳化工研究院有限公司 | Application of N-heteroaryl phenylamine compounds for preparation of antitumor drugs |
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