CN104370825B - Substituted heterocyclic compound as kinase inhibitor and its preparation method and use - Google Patents

Substituted heterocyclic compound as kinase inhibitor and its preparation method and use Download PDF

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CN104370825B
CN104370825B CN201410512764.9A CN201410512764A CN104370825B CN 104370825 B CN104370825 B CN 104370825B CN 201410512764 A CN201410512764 A CN 201410512764A CN 104370825 B CN104370825 B CN 104370825B
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compound
cancer
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CN104370825A (en
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王学海
许勇
李莉娥
黄璐
乐洋
田华
盛锡军
张绪文
肖强
冯权武
夏庆丰
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Hubei Bio-Pharmaceutical Industrial Technological Institute Inc
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Ren Fu Pharmaceutical Group Stock Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/28—Cinnolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention provides a substituted heterocyclic compound as a kinase inhibitor and its preparation method and use. The substituted heterocyclic compound is a compound shown in the formula I or its medicinal salt, hydrate, solvate or prodrug, wherein R1, R2, R3 and R4 are defined in the specification. The substituted heterocyclic compound can be used as a kinase inhibitor and can be used for preparation of a drug for treating cancers.

Description

Substituted heterocyclic compound as kinase inhibitor and its production and use
Technical field
The present invention relates to field of medicaments, specifically, the present invention relates to substituted heterocyclic compound as kinase inhibitor and Preparation Method And The Use, more particularly it relates to the method for compound, prepare compound, pharmaceutical composition and change Purposes of the compound in medicine is prepared.
Background technology
At present targeted therapy is the focus in treating malignant tumor, and the exploitation of Mutiple Targets medicine is also following targeted therapy Trend.Epidermal growth factor (EGF) is widely distributed somatomedin, and it can be in cancer moderate stimulation cancer cell multiplication, resistance Disconnected apoptosis, activation invade and shift and stimulate blood vessel generation.EGF receptor (EGFR) is belonging to include the family of four kinds of associated receptors The transmembrane tyrosine kinase receptor of race, most people's epithelial cancer is with the functional activation of somatomedin and the receptor of the family Feature, so as to EGF and EGFR are the target spots for the treatment of of cancer.One of member of EGFR families be ErbB2 (also referred to neu or HER2, Epidermal growth factor-recepor-2).It is frequently found ErbB2 genes to be expanded in breast carcinoma or ovarian cancer and glioblastoma multiforme Increase.The transfection research carried out in cell model and animal model is proved the overexpression of ErbB2 causes tumorigenicity to increase, swell Tumor invasion and attack, metastatic potential increase and the sensitivity to hormone therapy agent and chemotherapeutics are sexually revised.HER2 is that breast carcinoma field is ground Study carefully the thorough target of comparison, it has already been proven that intracellular tyrosine of the tyrosine kinase inhibitor (TKI) to HER1, HER2 and HER4 There is inhibitory action in kinases area, and HER2 related HER receptor can be with direct effect HER2 receptor, so as to their work that interacts Property and follow-up malignancy of tumor growth tendency.
Therefore, current cancer treatment drugs still have much room for improvement.
The content of the invention
It is contemplated that at least solving one of above-mentioned technical problem to a certain extent or providing at a kind of useful business Industry is selected.For this purpose, it is an object of the present invention to proposing a kind of substituted heterocyclic compound as kinase inhibitor.
It is a further object to provide preparing compound or its officinal salt, hydrate, solvation shown in Formulas I The method of thing or prodrug.
It is also another object of the present invention to provide a kind of pharmaceutical composition of the compound comprising the present invention, the medicine group The compound further change comprising one or more pharmaceutically acceptable excipient and at least one present invention of therapeutically effective amount Compound or its officinal salt, hydrate, solvate or prodrug.
A further object of the present invention be to provide the present invention compound or its officinal salt, hydrate, solvate or Purposes of the prodrug in medicine is prepared.Embodiments in accordance with the present invention, the medicine can be used for as tyrosine kinase inhibitor Cancer therapy drug is prepared into, for the treatment of HER2 positive cancer patient.
The these and other objects of compound, feature and advantage are described in detail disclosed in subsequent this patent shown in of the invention Middle disclosure.
The present invention is described below in detail：
In a first aspect of the present invention, the present invention proposes a kind of compound, and the compound presses down to can serve as kinases The substituted heterocyclic compound of preparation.Embodiments in accordance with the present invention, the compound is compound shown in Formulas I or its is pharmaceutically acceptable Salt, hydrate, solvate or prodrug,
Wherein,
R1And R2It is each independently hydrogen, halogen, C1-C6Alkyl, C1-C6Haloalkyl, C1-C6Hydroxy alkyl, C1-C6Acyl Base, C3-C7Cycloalkyl, C1-C8Alkoxyl, C1-C8Alkoxyalkyl, C2-C8Alkenyl, C2-C8Alkynyl, nitrile, nitro, OR5、SR5、 NHR5、NR5R6、N(O)R5R6、(CR5R6)mNR7R8、COR5、COOR5、CONR5R6、C(O)NR5SO2R6、NR5SO2R6、C(O) NR5OR6、SO2NR5R6、(CR5R6)m- aryl, (CR5R6)m- heteroaryl or-CR5=CR6C(O)R7；Or, R1And R2Form one Individual carbon ring group, the carbon ring group contains 3-7 ring member nitrogen atoms, preferably comprises 5-6 ring member nitrogen atoms.
Embodiments in accordance with the present invention, at most 4 ring carbons in the carbon ring group be independently selected from oxygen, sulfur or The hetero atom of nitrogen replaces, and condition is that in the carbon ring group, at least one ring member nitrogen atoms are carbon atom, when the carbon ring group In containing no less than two epoxy atoms when, the epoxy atom is not adjacent to each other.
Embodiments in accordance with the present invention, the carbon ring group it is unsubstituted or by one, two or three independently of one another For halogen, hydroxyl, hydroxy alkyl, nitrile, rudimentary C1-C8Alkyl, C1-C8Alkoxyl, alkoxy carbonyl, alkyl-carbonyl, alkyl-carbonyl Amino, aminoalkyl, carboxyalkyl, trifluoromethyl, amino, (CH2)mC(O)R5R6Or O (CH2)mC(O)OR5Substituent group, M is 0～6 integer.
Embodiments in accordance with the present invention, R5And R6It is each independently hydrogen, C1-C6Alkyl, C2-C8Alkenyl, C2-C8Alkynyl, Aryl alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or heteroaryl alkyl, wherein, the aryl, heteroaryl or heteroaryl Base alkyl is unsubstituted or is each independently halogen, hydroxyl, hydroxy alkyl, nitro or acyl group by one, two or three Substituent group, or, work as R5And R6When being connected to same nitrogen-atoms, R5And R6The nitrogen-atoms being connected with it are collectively forming one 3-8 circle heterocycles A, condition is that at least one ring member nitrogen atoms are carbon atom in 3-8 circle heterocycles A.
Embodiments in accordance with the present invention, at most four ring member nitrogen atoms independently are oxygen, sulfur, S in 3-8 circle heterocycles A (O)、S(O)2Or nitrogen, when in 3-8 circle heterocycles A containing no less than two epoxy atoms, the epoxy atom not phase each other Neighbour,
Embodiments in accordance with the present invention, 3-8 circle heterocycles A are unsubstituted or each independent by one, two or three Ground is halogen, hydroxyl, hydroxy alkyl, nitrile, nitro, aryl, heteroaryl, NR7SO2R8、C(O)NR7R8、NR7C(O)R8、C(O)OR7、 C(O)NR7SO2R8、(CH2)mS(O)R7、(CH2)m- heteroaryl, O (CH2)m- heteroaryl, (CH2)mC(O)NR7R8、O(CH2)mC(O) OR7Or (CH2)SO2NR7R8Substituent group；
Embodiments in accordance with the present invention, R7And R8It is each independently hydrogen, C1-C6Alkyl, C2-C8Alkenyl, C2-C8Alkynyl, Aryl alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or heteroaryl alkyl；Or, work as R7And R8It is connected to same nitrogen former The period of the day from 11 p.m. to 1 a.m, R7And R8The nitrogen-atoms being connected with it are collectively forming 3-8 circle heterocycles B, condition be in 3-8 circle heterocycles B at least One ring member nitrogen atoms is carbon atom.
Embodiments in accordance with the present invention, at most four ring member nitrogen atoms independently are oxygen, sulfur, S in 3-8 circle heterocycles B (O)、S(O)2Or nitrogen, wherein, when in 3-8 circle heterocycles B containing no less than two epoxy atoms when, the epoxy atom that This is non-conterminous.
Embodiments in accordance with the present invention, 3-8 circle heterocycles B are unsubstituted or each independent by one, two or three Ground is halogen, hydroxyl, hydroxy alkyl, nitrile, rudimentary C1-C8Alkyl, C1-C8Alkoxyl, alkoxy carbonyl, alkyl-carbonyl, alkyl oxycarbonyl The substituent group of base amino, aminoalkyl, carboxyalkyl, trifluoromethyl or amino.
Embodiments in accordance with the present invention, R3For C1-C6Alkyl, C1-C6Haloalkyl, C1-C6Hydroxy alkyl or C3-C7Cycloalkanes Base.
Embodiments in accordance with the present invention, R4For one of following：
Wherein, R9For hydrogen, halogen, C1-C6Alkyl, C1-C6Haloalkyl, carboxyl, C1-C6Carbonylic alkoxy, C2-C7Carbonyl Alkyl, phenyl, R11-(C(R10)2)s-、R11-(C(R10)2)p-M-(C(R10)2)r-、R12R13-CH-M-(C(R10)2)r-、Het-(C (R10)2)r- or Het-W- (C (R10)2)r-；
R10For hydrogen, C1-C6Alkyl, C1-C6Haloalkyl, C1-C6Hydroxy alkyl, C2-C8Alkenyl, C2-C8Alkynyl, C3-C7 Cycloalkyl, C2-C8Carbonylic alkyl, C2-C8Carboxyalkyl, phenyl, phenyl, C optionally by one or more halogen substiuteds1-C8Alkane Epoxide, trifluoromethyl, amino, C1-C6Alkyl amino, C2-C6Dialkyl amido, nitro, itrile group, halogenated methyl, C2-C7Alkoxyl Methyl, C2-C7Carbonylic alkoxy, hydroxyl, carboxyl, phenoxy group, benzoyl, benzyl, phenyl amino, benzylamino, C2-C7Chain Alkanoyl epoxide methyl or C1-C6Alkanoylamino；
Particularly, R is worked as10For C2-C8 alkenyls or C2-C8 alkynyls when, these alkenyls or alkynyl moiety lead to oversaturated Carbon atom is connected on nitrogen or oxygen atom；
R11For-NR10R10、-OR10、-NHR10、-C(R10)3、-CHR10R10Or-CH2R10；
R12And R13Each stand alone as-(C (R10)2)rNR10R10Or-(C (R10)2)rOR10；
M is ＞ NR10,-O-, ＞ N- (C (R10)2)p-NR10R10Or ＞ N- (C (R10)2)p-OR10；
W is ＞ NR10,-O- or for key；
P is 1～4 integer；
R is 1～4 integer；
S is 1～6 integer；
Het is heterocycle, Het heterocycles be piperidines, dihydropyridine, pyrroles, nafoxidine, imidazoles, oxazoles, piperazine, furan, four Hydrogen furan, Pentamethylene oxide., pyrans, morpholine, thiomorpholine, thiazole or thiophene.
Embodiments in accordance with the present invention, the Het heterocycles are on carbon atom or nitrogen-atoms by R10Monosubstituted or two replacements, or Person is on carbon atom by-CH2OR10- replace.
Embodiments in accordance with the present invention, the Het heterocycles are on carbon atom by hydroxyl, phenyl, N (R10)2Or OR10Singly take Generation or two replacements, by monoradical-(C (R on carbon atom10)2)sOR10Or-(C (R10)2)sNR10R10Monosubstituted or two replacements, Or on saturated carbon atom Jing divalent group-O- or-O (C (R10)2)sO- is monosubstituted or two replacements.
It will be understood by those skilled in the art that according to convention used in the art, in the structural formula of the application, For describing chemical bond, the chemical bond is the point that part or substituent group are connected with core texture or framing structure.
Term " alkyl " used in the present invention includes that the straight chain and branch alkyl moieties of up to 12 carbon atoms can be contained. Moieties preferably comprise 1 to 6 carbon atoms, further preferably 1 to 4 carbon atoms.
Term " alkoxyl " used in the present invention is defined as C1-C6Alkyl-O-, wherein alkyl are as defined above.
Term " halogen " used in the present invention is fluorine, chlorine, bromine, iodine, and preferred halogen is selected from fluorine, chlorine.
Term " thiazolinyl " used in the present invention refers to the aliphatic hydrocarbyl containing a double bond and including containing 2 to 6 carbon The straight chain and branched alkenyl moieties of atom.The alkenyl part can exist with E or Z configurations, and the compounds of this invention includes two kinds of structures Type.
Term " alkynyl " used in the present invention include having at least one 3 keys containing there is the straight of 2 to 6 carbon atoms Chain and branched fraction.
Term " cycloalkyl " used in the present invention refers to the aliphatic hydrocarbyl with 3 to 12 carbon atoms and including (but not It is limited to) cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl or adamantyl.
Term " aryl " used in the present invention is defined as aromatic moiety and can be substituted or be unsubstituted.Aryl is preferred Containing 6 to 12 carbon atoms and may be selected from group below (but not limited to)：Phenyl, Alpha-Naphthyl, betanaphthyl, xenyl, anthryl, four Hydrogen naphthyl, indanyl or biphenylene.Aryl can optionally Jing selected from (but not limited to) by it is following it is basis set into group take For base is monosubstituted, two replacements, three replacements or four replacements：Alkyl, acyl group, alkoxy carbonyl group, alkoxyl, alkoxyalkyl, alkoxyl Alkoxyl, cyano group, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, trifluoro propyl, amino, alkyl amino, dialkyl group Amino, dialkyl aminoalkyl, hydroxy alkyl, alkoxyalkyl, alkylthio group ,-SO3H、-SO2NH2、-SO2NH- alkyl ,-SO2N- (alkyl)2、-CO2H、-CO2NH2、-CO2NH- alkyl ,-CO2N- (alkyl)2.The preferred substituents of aryl and heteroaryl include：Alkane Base, halogen, amino, alkyl amino, dialkyl amido, trifluoromethyl, trifluoromethoxy, aryl alkyl or alkylaryl.
Term " heteroaryl " used in the present invention is defined as heteroaromatic system (monocyclic or bicyclic), wherein heteroaryl Base portion is divided into containing 1 to 4 heteroatomic five yuan or hexatomic rings for being selected from the group that S, N and O are constituted, and including (but do not limit In)：(1) furan, thiophene, indole, azaindole, oxazoles, thiazole, isoxazoles, isothiazole, imidazoles, N- Methylimidazole .s, pyridine, Pyrimidine, pyrazine, pyrroles, N- methylpyrroles, pyrazoles, N- methylpyrazoles, 1,2,4- triazoles, 1- methyl isophthalic acids, 2,4- triazoles, 1H- tetra- Azoles, 1- methyl tetrazoliums, benzimidazole, benzofuran, quinazoline, quinoline, isoquinolin, pyrrolidinyl；(2) bicyclic aromatic is miscellaneous Ring, wherein phenyl, pyridine, pyrimidine or pyridazine ring：I () is thick with six-membered aromatic (unsaturation) heterocycle with a nitrogen-atoms Close；(ii) it is heterocyclic fused with five yuan with two nitrogen-atoms or six-membered aromatic (unsaturation)；(iii) and with a nitrogen original The 5-membered aromatic race (unsaturation) of son and an oxygen or a sulphur atom is heterocyclic fused；Or (iv) selects O, N with one Or the heteroatomic 5-membered aromatic race (unsaturation) of S is heterocyclic fused.Bicyclic heteroaryl preferably comprises 8 to 12 carbon atoms.
Term " alkylthio group " used in the present invention is defined as C1-C6Alkyl-S-.
Term " alkoxyalkyl " used in the present invention represent further that alkoxyl as defined above replaces as Alkyl defined above, preferred alkoxy portion is alkoxy methyl (such as alkoxy -C H2-)。
Term " hydroxyl " used in the present invention is defined as-OH parts.
Term " carboxyl " used in the present invention is defined as-COOH parts.
Term " hydroxy alkyl " used in the present invention is defined as HO- alkyl-moieties, and wherein moieties are by 1-6 Carbon atom is constituted.
Term " benzoyl " used in the present invention is defined as Ph-OC (O)-part.
Term " alkyl amino " used in the present invention and " dialkyl amido " are referred to one or two alkyl Part, wherein alkyl chain have 1 to 6 carbon and the group may be the same or different.
Term " alkylaminoalkyl group " used in the present invention and " dialkyl aminoalkyl " are referred to one or two The alkyl monosubstituted amino of the alkyl (identical or differ) of the nitrogen-atoms bond of the individual alkyl with junction with 1 to 6 carbon atoms And dialkylamino fragment.Dialkyl aminoalkyl part is preferably made up of and alkylaminoalkyl group part 3 to 10 carbon atoms It is preferred that being made up of 2 to 9 carbon atoms.
Term " alkoxy carbonyl group " used in the present invention is defined as-COOR, and wherein R is the alkane with 1 to 6 carbon atoms Base.
Term " carboxyalkyl " used in the present invention is defined as HOOCR- parts, and wherein R is with 1 to 6 carbon originals The alkyl of son.
Term " aminoalkyl " used in the present invention is defined as H2N- alkyl, wherein alkyl are by 1 to 5 carbon atom groups Into.
Term " alkanoylamino " used in the present invention is defined as-NH-COOR parts, and wherein R is with 1 to 6 The alkyl of carbon atom.
Term " acyl group " used in the present invention is defined as the group of formula-(C=O)-alkyl, and wherein alkyl has 1 to 6 Individual carbon atom, i.e. C2-C7 alkanoyls, are preferably but not limited to acetyl group, propiono, bytyry.
Term " substituent group " used in the present invention is used to refer to atomic radical, the official of the hydrogen-based on displacer molecule herein Can group or part.Unless expressly stated otherwise, otherwise it will be assumed any substituent group all can optionally Jing one or more be selected from Under each base substituent group：Alkyl, halogen, haloalkyl, hydroxy alkyl, nitro, amino, hydroxyl, cyano group, alkyl amino, two Alkyl amino, alkoxyl, halogenated alkoxy, alkoxyalkyl, alkyloxy-alkoxy, oxo, alkylthio group, sulfydryl, alkyl halide sulfur Base, aryl, aryloxy group, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, acyl group ,-CO2- alkyl ,-SO3H、-SO2NH2、- SO2NH- alkyl ,-SO2N- (alkyl)2、-CO2H、-CO2NH2、-CO2NH- alkyl ,-CO2N- (alkyl)2。
Term " by replacing " used in the present invention refer to hydrogen-based on molecule another atomic radical, functional group or The situation of aliquot replacement, these groups are commonly referred to as " substituent group ".
Term " yield " used in the present invention refer to reaction or method produced by compound amount, also referred to as " Amount ".Generally, this refers to the chemical combination reclaimed (such as after recrystallization or chromatographic isolation) after any adopted purification step The amount of thing.This amount represents generally with the product that reclaimed relative to the percentage rate of the amount of initial substance raw material, and generally with Molal quantity gauge.For example, if making 1.0 moles of initial substance raw material reactions and the product that reclaimed after purification rubs for 0.85 You, then the yield of product is 85.0%.Those skilled in the art of the present invention will easily understand this concept.
Term " officinal salt " used in the present invention is formed for compound shown in formula I with mineral acid or organic acid reaction Conventional nontoxic salts.For example, the conventional nontoxic salts can be by compound shown in formula I and mineral acid or organic acid reaction It is obtained, the mineral acid includes hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, amidosulfonic acid and phosphoric acid etc., and the organic acid includes Citric acid, tartaric acid, lactic acid, acetone acid, acetic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, LOMAR PWA EINECS 246-676-2, ethyl sulfonic acid, the sulphur of naphthalene two Acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propanoic acid, oxalic acid, trifluoroacetic acid, stearic acid, flutter acid, hydroxyl Malaysia Acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, para-anilinesulfonic acid, Aspirin and hydroxyl second sulphur Acid etc.；Or compound shown in formula I and propanoic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, Tartaric acid, citric acid, aspartic acid or glutamic acid form sodium salt, potassium salt, calcium salt, aluminium salt or the ammonium formed with inorganic base again after ester Salt；Or methylamine salt, ethylamine salt or the ethanolamine salt that compound shown in formula I is formed with organic base；Or chemical combination shown in formula I Thing forms right with what hydrochloric acid, hydrobromic acid, Fluohydric acid., sulphuric acid, nitric acid, phosphoric acid were formed again after ester with lysine, arginine, ornithine The inorganic acid salt answered or the corresponding acylate formed with formic acid, acetic acid, picric acid, methanesulfonic acid and ethyl sulfonic acid.
Particularly, the present invention preferably officinal salt is hydrochlorate, benzene sulfonate, tosilate or maleate.
Term " prodrug " used in the present invention represents that the compound just leads to once giving experimenter by the compound Cross metabolic process or chemical process to carry out chemical conversion, so as to obtain compound shown in Formulas I and/or its salt and/or solvation Thing.It is the model in the present invention that any compound to provide bioactive substance (i.e. compound shown in Formulas I) can in vivo be converted Enclose and the prodrug in purport.For example, the compound containing carboxyl can hydrolyzable ester on physiology, it passes through to hydrolyze in vivo Serve as prodrug to obtain compound shown in Formulas I itself.The preferred oral administration of the prodrug, this is because hydrolysis is in many situations The lower main generation under the influence of digestive enzyme.When ester itself is active or hydrolysis occurs in blood, parenteral can be used Administration.
According to a preferred embodiment of the invention, R1For hydrogen, halogen, C1-C6Alkyl, C1-C6Haloalkyl, C1-C6Acyl group or Nitrile；
R2For hydrogen, halogen, C1-C6Alkyl, OR5、NHR5、NR5R6、COR5、COOR5Or CONR5R6；
R5And R6It is each independently hydrogen, C1-C6Alkyl or aryl, wherein aryl are unsubstituted or by one, two or three It is individual to be each independently halogen, C1-C6The substituent group of acyl group；
R3For C1-C6Alkyl, preferred R3For methyl, ethyl, n-pro-pyl, isopropyl or the tert-butyl group；
R4For one of following：
Wherein,
R9For hydrogen, halogen, C1-C6Alkyl, R11-(C(R10)2)s- or Het- (C (R10)2)r-；
R10For hydrogen or C1-C6Alkyl；
R11For-NR10R10、-OR10、-NHR10、-C(R10)3、-CHR10R10Or-CH2R10；
S is 1～4 integer；
The Het heterocycles be piperidines, dihydropyridine, pyrroles, nafoxidine, imidazoles, piperazine, Pentamethylene oxide., Pentamethylene oxide., Morpholine, thiomorpholine or thiophene.
It should also be understood that the hydrate of compound shown in formula I, solvate (such as methylate, DMSO Compound) it is also within the scope of the invention.The method of solvation is well known in the art.
Embodiments in accordance with the present invention, compound shown in Formulas I of the present invention is selected from following at least one：
Inventor has found that the compound of the present invention can be used as kinase inhibitor, adjusts tyrosine kinase signal transduction.This Bright described compound is EGFR and ErbB2 (HER2) potent inhibitor of the two, and the compound of the present invention to EGFR and The inhibitory action of ErbB2 be better than existing medicine HKI-272, using the present invention compound can effectively treatment or prevention by EGFR With the cancer or tumor disease of at least one mediation in ErbB2.In addition, the compound of the present invention also shows the dissolving of raising Property and be less susceptible to from cell flow out property, so as to improve bioavailability.
In a second aspect of the present invention, the present invention proposes a kind of method for preparing foregoing compound.According to this Inventive embodiment, the method includes：Compound shown in formula a is set to be contacted with compound shown in formula b, to obtain Formulas I institute Show compound.
Wherein, R1、R2、R3、R4As defined above.
Inventor has found, can fast and effeciently prepare compound shown in Formulas I using the method for the present invention or it can medicine With salt, hydrate, solvate or prodrug, and synthetic route is short, environmental friendliness, the yield of target product and purity are higher, former Material is easy to get, operate and post processing is simple, be adapted to industrialized production.
Embodiments in accordance with the present invention, it is described to make compound shown in formula a carry out contacting further bag with compound shown in formula b Include：Under the conditions of -10 DEG C～10 DEG C, by the mixed solution of compound shown in formula b and N-Methyl pyrrolidone and chemical combination shown in formula a Thing mixes, and under room temperature condition, by resulting mixture reaction 8～16 hours.
A specific example of the invention, preparing the method for foregoing compound includes：At -10 DEG C～10 DEG C Under the conditions of, compound shown in formula a, compound shown in Deca formula b and N- crassitudes in reactant liquor are added in reaction bulb The solution of ketone (NMP) composition, adds, room temperature reaction 8～16 hours in 15～60 minutes.After TLC detection reactions completely, add suitable Amount water, pH to 10.0～11.0 is adjusted by resulting mixed solution with the sodium hydrate aqueous solution of 2.5 mol/Ls, is separated out a large amount of Solid, gained solid is carried out successively sucking filtration, washing, is dried, and obtains off-white powder, and the off-white powder solvent is tied again Brilliant purification obtains white solid product, as foregoing compound (compound i.e. of the invention).
In an embodiment of the present invention, compound of the invention can be：Compound or pharmaceutically acceptable salt thereof shown in Formulas I, hydration Thing, solvate or prodrug.
In a third aspect of the present invention, the present invention provides a kind of pharmaceutical composition, embodiments in accordance with the present invention, the medicine Compositions include foregoing compound.Embodiments in accordance with the present invention, described pharmaceutical composition may further include Pharmaceutically acceptable excipient.The Pharmaceutical composition can also further include the conventional additives such as odorant agent, flavouring agent.
Embodiments in accordance with the present invention, based on the gross mass of pharmaceutical composition, pharmaceutical composition provided by the present invention is excellent Select containing the foregoing compound that weight ratio is 1%～95% as active ingredient, it is further preferred that foregoingization Compound accounts for the 20%～40% of pharmaceutical composition gross weight as active component, remainder be pharmaceutically acceptable carrier, At least one in excipient and conventional additives.
Embodiments in accordance with the present invention, pharmaceutical composition provided by the present invention can take various forms, including but do not limit In tablet, capsule, injection, injection powder pin, powder, syrup, solution shape, suspension and aerosol etc., it is possible to be present in In suitable solid or the carrier of liquid or diluent and in the suitable disinfector for injecting or instiling.
The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to the customary preparation methods of pharmaceutical field.The present invention's Compound and pharmaceutical composition can be to mammal Clinical practices, including humans and animals, can by mouth, nose, skin, lung or The approach administration of gastrointestinal tract etc..No matter adopting which kind of instructions of taking, personal optimal dose should be according to specific therapeutic scheme It is fixed.It is under normal circumstances that from the beginning of low dose, gradually increasing dosage is until find optimal dosage.Way is most preferably administered Footpath is oral.
In a fourth aspect of the present invention, the present invention proposes compound or pharmaceutically acceptable salt thereof shown in formula Ι, hydrate, solvent The purposes of compound or prodrug in medicine is prepared.Embodiments in accordance with the present invention, the medicine is used as kinase inhibitor.Inventor It was found that, the compound of the present invention can be used as kinase inhibitor, adjust tyrosine kinase signal transduction.Compound of the present invention It is EGFR and ErbB2 (HER2) potent inhibitor of the two, and the compound of the present invention is excellent to the inhibitory action of EGFR and ErbB2 In existing medicine HKI-272.Using the present invention compound can effectively treatment or prevention by EGFR and ErbB2 at least one Plant the cancer or tumor disease of mediation.Therefore, compound of the present invention can be treated or pre- effectively as kinase inhibitor The cancer or tumor disease of at least one mediation in preventing by EGFR and ErbB2, the cancer or tumor are selected from leukemia, colon Cancer, renal cell carcinoma, gastro-intestinal stromal cancer, solid tumor cancer, multiple myeloma, breast carcinoma, the brain cancer, glioblastoma multiforme, cancer of pancreas, In nonsmall-cell lung cancer, non-Hodgkin lymphoma, hepatocarcinoma, thyroid carcinoma, bladder cancer, colorectal cancer, carcinoma of prostate extremely Few one kind.
Further, compound shown in preparation-obtained Formulas I of the invention is straight to human lung adenocarcinoma cell (A-549), people's knot Enteraden cancerous cell (Colo205), human breast cancer cell (MCF-7), human leukemia cell (HL-60), are respectively provided with good suppression Effect (IC50The μ g/ml of ＜ 100), wherein it is most strong to the inhibitory action of human breast cancer cell (MCF-7), as a result show, the present invention Can be used to be prepared into treatment nonsmall-cell lung cancer, colorectal cancer, breast carcinoma or leukemic antitumor drug, be particularly suited for It is prepared into the medicine for the treatment of breast carcinoma.And, for the cancer therapy drug HKI-272 of existing treatment breast carcinoma, the present invention The compound suppresses the effect of human breast cancer cell to be better than HKI-272, and the compound of the embodiment of the present invention is shown than coming That is for the more preferable external activity of Buddhist nun and curative effect.In certain embodiments of the invention, most preferably described tumor is breast carcinoma.
Compound or pharmaceutically acceptable salt thereof, hydrate, solvate shown in Formulas I as kinase inhibitor of the present invention Or prodrug, its as EGFR and/or ErbB2 inhibitor, with good clinical practice and medical usage.
The additional aspect and advantage of the present invention will be set forth in part in the description, and partly will become from the following description Obtain substantially, or recognized by the practice of the present invention.
Specific embodiment
Embodiments of the invention are described below in detail.The embodiments described below is exemplary, is only used for explaining this It is bright, and be not considered as limiting the invention.Unreceipted particular technique or condition in embodiment, according to text in the art Offer described technology or condition or carry out according to product description.Agents useful for same or the unreceipted production firm person of instrument, For can pass through city available from conventional products.
Embodiment 1：The preparation of compound shown in Formulas I -1
Under the conditions of -10 DEG C～0 DEG C, compound 15.5g (0.105 mole) shown in formula a-1 is added in reaction bulb, to anti- Answer the solution of compound 21.7g shown in Deca formula b-1 (0.1 mole) in liquid and 120 milliliters of N-Methyl pyrrolidone compositions, 15 points Add in clock, room temperature reaction 16 hours.TLC detection reactions are complete, add suitable quantity of water, and the sodium hydroxide with 2.5 mol/Ls is water-soluble Liquid adjusts pH10.0～11.0, separates out a large amount of solids, and sucking filtration, washing is dried, and obtains off-white powder, is tied again with acetonitrile-THF solvents Brilliant purification obtains white solid product, compound 28.7g as shown in Formulas I -1, yield 63.0%.
Embodiment 2：The preparation of compound shown in Formulas I -13
Under the conditions of 0 DEG C～10 DEG C, compound 19.8g (0.105 mole) shown in formula a-13 is added in reaction bulb, to anti- Answer the solution of compound 36.1g shown in Deca formula b-13 (0.1 mole) in liquid and 200 milliliters of N-Methyl pyrrolidone compositions, 60 Add in minute, room temperature reaction 8 hours.TLC detection reactions are complete, suitable quantity of water added, with the sodium hydroxide water of 2.5 mol/Ls Solution adjusts pH10.0～11.0, separates out a large amount of solids, and sucking filtration, washing is dried, and off-white powder is obtained, with acetonitrile-THF solvent weights Crystallization purifying obtains white solid product, compound 35.7g as shown in Formulas I -13, yield 55.8%.
Embodiment 3：The preparation of compound shown in Formulas I -29
Under the conditions of -5 DEG C～5 DEG C, compound 9.3g (0.105 mole) shown in formula a-29 is added in reaction bulb, to anti- Answer the solution of compound 26.1g shown in Deca formula b-29 (0.1 mole) in liquid and 150 milliliters of N-Methyl pyrrolidone compositions, 30 Add in minute, room temperature reaction 12 hours.TLC detection reactions are complete, suitable quantity of water added, with the sodium hydroxide water of 2.5 mol/Ls Solution adjusts pH10.0～11.0, separates out a large amount of solids, and sucking filtration, washing is dried, and off-white powder is obtained, with acetonitrile-THF solvent weights Crystallization purifying obtains white solid product, compound 29.3g as shown in Formulas I -29, yield 66.5%.
Embodiment 4：The preparation of compound shown in Formulas I -34
Under the conditions of -5 DEG C～5 DEG C, compound 19.9g (0.105 mole) shown in formula a-34 is added in reaction bulb, to anti- Answer the solution of compound 36.7g shown in Deca formula b-34 (0.1 mole) in liquid and 150 milliliters of N-Methyl pyrrolidone compositions, 30 Add in minute, room temperature reaction 12 hours.TLC detection reactions are complete, suitable quantity of water added, with the sodium hydroxide water of 2.5 mol/Ls Solution adjusts pH10.0～11.0, separates out a large amount of solids, and sucking filtration, washing is dried, and off-white powder is obtained, with acetonitrile-THF solvent weights Crystallization purifying obtains white solid product, compound 33.7g as shown in Formulas I -34, yield 52.0%.
Embodiment 5：The preparation of compound shown in Formulas I -38
Under the conditions of 0 DEG C～10 DEG C, compound 16.8g (0.105 mole) shown in formula a-38 is added in reaction bulb, to anti- Answer the solution of compound 22.5g shown in Deca formula b-38 (0.1 mole) in liquid and 180 milliliters of N-Methyl pyrrolidone compositions, 45 Add in minute, room temperature reaction 10 hours.TLC detection reactions are complete, suitable quantity of water added, with the sodium hydroxide water of 2.5 mol/Ls Solution adjusts pH10.0～11.0, separates out a large amount of solids, and sucking filtration, washing is dried, and off-white powder is obtained, with acetonitrile-THF solvent weights Crystallization purifying obtains white solid product, compound 28.9g as shown in Formulas I -38, yield 60.6%.
Embodiment 6：The preparation of compound shown in Formulas I -42
Under the conditions of -10 DEG C～0 DEG C, compound 21.0g (0.105 mole) shown in formula a-42 is added in reaction bulb, to The solution of compound 36.1g shown in Deca formula b-42 (0.1 mole) and 120 milliliters of N-Methyl pyrrolidone compositions in reactant liquor, Add in 30 minutes, room temperature reaction 12 hours.TLC detection reactions are complete, suitable quantity of water added, with the sodium hydroxide of 2.5 mol/Ls Aqueous solution adjusts pH10.0～11.0, separates out a large amount of solids, and sucking filtration, washing is dried, and off-white powder is obtained, with acetonitrile-THF solvents Recrystallization purifying obtains white solid product, compound 49.3g as shown in Formulas I -42, yield 75.8%.
Embodiment 7：The preparation of compound shown in Formulas I -53
Under the conditions of -5 DEG C～5 DEG C, compound 22.9g (0.105 mole) shown in formula a-53 is added in reaction bulb, to anti- Answer the solution of compound 41.9g shown in Deca formula b-53 (0.1 mole) in liquid and 150 milliliters of N-Methyl pyrrolidone compositions, 30 Add in minute, room temperature reaction 12 hours.TLC detection reactions are complete, suitable quantity of water added, with the sodium hydroxide water of 2.5 mol/Ls Solution adjusts pH10.0～11.0, separates out a large amount of solids, and sucking filtration, washing is dried, and off-white powder is obtained, with acetonitrile-THF solvent weights Crystallization purifying obtains white solid product, compound 50.3g as shown in Formulas I -53, yield 69.2%.
Embodiment 8：The preparation of compound shown in Formulas I -66
Under the conditions of -5 DEG C～5 DEG C, compound 20.8g (0.105 mole) shown in formula a-66 is added in reaction bulb, to anti- Answer the solution of compound 36.7g shown in Deca formula b-66 (0.1 mole) in liquid and 150 milliliters of N-Methyl pyrrolidone compositions, 30 Add in minute, room temperature reaction 12 hours.TLC detection reactions are complete, suitable quantity of water added, with the sodium hydroxide water of 2.5 mol/Ls Solution adjusts pH10.0～11.0, separates out a large amount of solids, and sucking filtration, washing is dried, and off-white powder is obtained, with acetonitrile-THF solvent weights Crystallization purifying obtains white solid product, compound 51.5g as shown in Formulas I -66, yield 78.4%.
Embodiment 9：The preparation of compound shown in Formulas I -67
Under the conditions of -5 DEG C～5 DEG C, compound 21.1g (0.105 mole) shown in formula a-67 is added in reaction bulb, to anti- Answer the solution of compound 40.5g shown in Deca formula b-67 (0.1 mole) in liquid and 150 milliliters of N-Methyl pyrrolidone compositions, 30 Add in minute, room temperature reaction 12 hours.TLC detection reactions are complete, suitable quantity of water added, with the sodium hydroxide water of 2.5 mol/Ls Solution adjusts pH10.0～11.0, separates out a large amount of solids, and sucking filtration, washing is dried, and off-white powder is obtained, with acetonitrile-THF solvent weights Crystallization purifying obtains white solid product, compound 43.2g as shown in Formulas I -67, yield 62.1%.
Embodiments in accordance with the present invention, compound shown in formula Ι or its officinal salt, hydrate, solvate or front The method of medicine includes：Compound shown in formula a is set to be contacted with compound shown in formula b, to obtain chemical combination shown in Formulas I Thing.
Wherein, R1、R2、R3、R4As defined above.
In the same manner,
Compound shown in compound to Formulas I -12 shown in Formulas I -2,
Compound shown in compound to Formulas I -28 shown in Formulas I -14,
Compound shown in compound to Formulas I -33 shown in Formulas I -30,
Compound shown in compound to Formulas I -37 shown in Formulas I -35,
Compound shown in compound to Formulas I -41 shown in Formulas I -39,
Compound shown in compound to Formulas I -52 shown in Formulas I -43,
Compound shown in compound to Formulas I -65 shown in Formulas I -54,
The preparation method of compound shown in compound to Formulas I -72 shown in Formulas I -68 is with shown in formula I-29 in embodiment 3 The method of compound.
Compound and compound shown in formula a are initiation material, compound shown in formula b and chemical combination shown in formula a wherein shown in formula b The molar ratio of thing is 1：1.05.The particular compound for finally giving is shown in the preferred chemical combination described in description of the invention Thing, product yield data are shown in Table 1.
Table 1：
Compound number Product yield Compound number Product yield Compound number Product yield
I-1 63.0% I-25 78.0% I-49 72.5%
I-2 70.6% I-26 82.6% I-50 81.8%
I-3 62.0% I-27 64.0% I-51 42.0%
I-4 55.4% I-28 52.4% I-52 78.6%
I-5 68.6% I-29 66.5% I-53 69.2%
I-6 70.4% I-30 60.6% I-54 60.4%
I-7 67.7% I-31 77.1% I-55 72.6%
I-8 72.0% I-32 62.5% I-56 69.0%
I-9 43.4% I-33 83.0% I-57 83.4%
I-10 41.3% I-34 52.0% I-58 81.2%
I-11 35.0% I-35 66.3% I-59 44.5%
I-12 56.9% I-36 70.0% I-60 76.9%
I-13 55.8% I-37 71.1% I-61 71.8%
I-14 70.5% I-38 60.6% I-62 80.9%
I-15 78.3% I-39 68.0% I-63 48.4%
I-16 61.2% I-40 50.7% I-64 61.8%
I-17 75.1% I-41 65.9% I-65 85.0%
I-18 72.0% I-42 75.8% I-66 78.4%
I-19 59.6% I-43 69.7% I-67 62.0%
I-20 68.5% I-44 78.6% I-68 52.1%
I-21 62.1% I-45 82.5% I-69 71.1%
I-22 79.0% I-46 66.8% I-70 70.0%
I-23 63.8% I-47 63.7% I-71 46.8%
I-24 76.0% I-48 70.8% I-72 55.4%
Embodiment 10：Kinase assays
Reagent and operation：
Basic reaction buffer：20mM 4- hydroxyethyl piperazine ethanesulfonic acid (Hepes, pH 7.5), 10mM MgCl2, 1mM second Glycol double (2- amino-ethyl ethers) tetraacethyl (EGTA), 0.02% Brij-35 (Brij35), 0.02mg/ml cattle Serum albumin (BSA), 0.1mM Na3VO4, 2mM dithiothreitol, DTTs (DTT), 1% dimethyl sulfoxide (DMSO).
Prepare the substrate specified in the basic reaction buffer of fresh preparation；
Any desired cofactor is added in above-mentioned substrate solution；
The kinases specified is added in the substrate solution and is gently blended；
The compound being dissolved in DMSO is added in the kinase reaction mixture；
Add in the reactant mixture33P-ATP (specific activity is 0.01 μ Ci/ μ l final volumes) is with initiation reaction.End reaction Volume is 5 μ l；
At room temperature kinase reaction thing is incubated into 120min；
By on reactant point sample to P81 ion exchange papers (Whatman#3698-915)；
Filter paper is fully washed with 0.1% phosphoric acid；
(become oblique using the S type dose responses in Prism programs (GraphPad Software, Inc., La Jolla, CA) Rate) Algorithm Analysis IC50Generate data.
Kinases information：
EGFR-Genbank accession number #NP_005219.2.Restructuring catalytic domain, aminoacid 668-1210, GST labellings, purification From insect cell.Activated in Vitro is carried out by autophosphorylation.Final concentration=4nM in measure.Substrate：pEY.Peptide sequence：It is poly- Glu-Tyr, ratio is 4：1.Final concentration=0.2mg.mL in measure.Add as cofactor in the reactant mixture 2mM MnCl2。
ErbB2/HER2-Genbank accession number #X03363.Restructuring catalytic domain, aminoacid 679-1255, GST labellings are pure Change from insect cell.Final concentration=50nM in measure.Substrate：pEY.Peptide sequence：Poly- Glu-Tyr, ratio is 4：1.In measure Final concentration=0.2mg.mL.The 2mM MnCl as cofactor are added in the reactant mixture2。
Biological assessment
Test compound shown in compound～Formulas I -72 shown in preparation-obtained Formulas I -1 of the invention.
First with from 3 times of 10 dosage IC being serially diluted of 10 μM of beginnings50Pattern (10-dose IC50Mode) this is tested Compound described in Ming Dynasty style I-1.As a result show that the compound of Formulas I -1 is EGFR and ErbB2 (HER2) potent inhibitor of the two, and formula I-1 compounds are to the inhibitory action of EGFR and ErbB2 better than existing medicine HKI-272 (note：HKI-272 is U.S. puma A kind of novel drugs for treating breast carcinoma of biotechnology companies research and development, are currently in the clinical research of III phase).
Similarly, it has been found that compound pair shown in compound～Formulas I -72 shown in preparation-obtained Formulas I -2 of the invention EGFR and ErbB2 determines the activity (IC for being respectively provided with 2 μM of ＜50), and compound pair shown in compound～Formulas I -72 shown in Formulas I -2 The inhibitory action of EGFR and ErbB2 is better than HKI-272, and compound shown in Formulas I of the present invention has higher than HKI-272 EGFR and HER2 inhibitory activity.
Kinases Compound (IC described in Formulas I -150) HKI-272 (IC50)
EGFR 1.30 2.95
ErbB2 0.89 2.26
Preparation-obtained compound of the invention is tested in human tumor cell line growth measurement.For example, inventor has found The compound of Formulas I -1 prepared according to embodiment 1 is in 3 times of 10 dosage IC being serially diluted from 10 μM of beginnings50The bar of pattern Suppress the growth of several solid tumor cell systems, the solid tumor cell system such as A431 (it is reported that overexpression EGFR) under part； NCI-H1975 (it is reported that expression EGFR mutant L858R/T790M)；NCI-H 1650 is (it is reported that expression EGFR mutants E746-A750)；BT-474 (it is reported that overexpression ErbB2)；And SKBR3 and A549 are (it is reported that overexpression EGFR and ErbB2 The two).The IC of compound described in Formulas I -150It is as follows：
Exemplary cells system Compound described in Formulas I -1 (IC50)
A431 ＜ 1mM
NCI-H1975 ＜ 10mM
NCI-H1650 ＜ 10mM
BT-474 ＜ 1mM
SKBR3 ＜ 1mM
A549 ＜ 1mM
Similarly, inventor is found through experiments, compound shown in preparation-obtained Formulas I -2 of the invention～institute of Formulas I -72 Show that compound is respectively provided with to solid tumor cell system such as A431, NCI-H1975, NCI-H1650, BT-474, SKBR3 and A549 Activity (IC described in compound described in Formulas I -150)。
The anti tumor activity in vitro test of embodiment 11, compound of the present invention
(1) material
Cell strain：Human lung adenocarcinoma cell (A-549), people's Colon and rectum gland cancer cell (Colo205), human breast cancer cell (MCF-7), human leukemia cell (HL-60).
Reagent：MTT, Amresco company；DMEM, DMEM/F12 culture medium, Gibco companies；Calf serum, Lanzhou Min Hai It is biological；Trypsin, Amresco companies.
Instrument：Superclean bench, Suzhou Decontamination Equipment Plant；CO2 incubators, Thermo companies, model：HERA Cell150；Inverted microscope, Carl Zeiss companies, model：Axiovert200；Enzyme-linked immunosorbent assay instrument, TECAN companies, Model：Sunrise；Centrifuge, Kerdro companies, model：Heraeus.
(2) method
Cell culture：Cell is seeded in containing 10% calf serum, 100IU/ml penicillin G sodium salts and 100ug/ml sulfate chains In DMEM the or DMEM/F12 complete culture solutions of mycin, put 37 DEG C, 100% relative humidity, in the incubator containing 5%CO2, pass on It is standby after 3 times.
MTT colorimetric determinations：Take the logarithm the cell of trophophase, (suspension cell need not Jing after 0.25% trypsinization Digestion), in being suspended in the culture fluid containing 10% calf serum, single cell suspension is gently blown and beaten into glass dropper, under microscope With blood cell counts plate numeration living cells.(cell concentration is 3～6 × 10 to the every μ l of hole inoculating cell suspension 90 of 96 well culture plates4 Individual/mL), after putting incubator 24h, per hole 10 μ l medicinal liquids are added.In addition, each concentration sets negative control (isoconcentration DMSO) and blank Background (is not added with cell), and each group is all provided with 6 multiple holes.48h is continuously cultivated again, and the MTT solution of 10 μ l5mg/mL is then added per hole, Continue to cultivate after 4h, carefully suck supernatant.100 μ l DMSO are added per hole, micro oscillator is put and is shaken 5min so as to crystallize CL, in microplate reader 492nm Single wavelength colorimetric, determines OD values, and result of the test is shown in Table 1.
Suppression ratio (%)=[(experimental group OD averages-blank group OD average)/(matched group OD averages-blank group OD is equal for 1- Value)] × 100%.Bliss methods calculate test-compound IC50Value.
(3) result, is shown in Table 2.
As a result show：Compound shown in compound～Formulas I -72 is to people's lung gland shown in the preparation-obtained Formulas I -1 of the present invention Cancerous cell (A-549), people's Colon and rectum gland cancer cell (Colo205), human breast cancer cell (MCF-7), human leukemia cell (HL- 60), it is respectively provided with good inhibitory action (IC50The μ g/ml of ＜ 100), wherein the inhibitory action to human breast cancer cell (MCF-7) It is most strong, as a result show, the present invention can be used to be prepared into the medicine for the treatment of antitumor/anticancer, be particularly suited for being prepared into treatment breast The medicine of adenocarcinoma.And, for the cancer therapy drug HKI-272 of existing treatment breast carcinoma, compound suppression of the present invention The effect of human breast cancer cell processed is better than HKI-272.
The IC that table 2. grows to cultured cell in vitro50(μg/ml)
Embodiment 12：For the capsule of oral administration
Composition % w/w
Active component 40.0%
Lactose 40.0%
Microcrystalline Cellulose 19.5%
Magnesium stearate 0.5%
Composition in upper table is mixed, and active component (compound of the present invention) distribution in capsule, is prepared into altogether 1000 grams of powder, into capsule, the active component of every capsule is 400mg for fill.
Embodiment 13：Tablet for oral administration
Composition % w/w
Active component 20.0%
Lactose 75.5%
Croscarmellose Sodium 3.0%
Polyvinylpyrrolidone 1.0%
Magnesium stearate 0.5%
Composition in upper table is mixed, and using solvent such as alcohol granulation.Then preparation is dried, 1000 is prepared into altogether Gram powder, and be formed as tablet with suitable tablet machine, the active component (compound of the present invention) per piece is 200mg.
Embodiment 14：For the capsule of oral administration
Composition % w/w
Active component 30.0%
Lactose 45.0%
Microcrystalline Cellulose 24.5%
Magnesium stearate 0.5%
Composition in upper table is mixed, and active component (compound of the present invention) distribution in capsule, is prepared into altogether 1000 grams of powder, into capsule, the active component of every capsule is 300mg for fill.
Embodiment 15：For the injection of drug administration by injection
Composition % w/w
Active component 0.25 gram
Sodium Chloride In right amount with isotonic
During active component (compound of the present invention) is dissolved in into partial syringe water.Then q.s is added under agitation Sodium Chloride so that solution is isotonic.The solution is supplied into weight with remaining water for injection, with 0.45 mum membrane filter mistake Filter, and aseptically pack, obtain injection.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means to combine specific features, structure, material or feature that the embodiment or example are described In being contained at least one embodiment of the present invention or example.In this manual, the schematic representation of above-mentioned term is differed Surely identical embodiment or example are referred to.And, the specific features of description, structure, material or feature can be any Combine in an appropriate manner in one or more embodiments or example.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art is in the principle and objective without departing from the present invention In the case of above-described embodiment can be changed within the scope of the invention, change, replace and modification.

Claims (12)

1. a kind of compound, it is characterised in that the compound is the pharmaceutically acceptable of compound shown in Formulas I or compound shown in Formulas I Salt,
Wherein, compound shown in the Formulas I is one of following：
2. a kind of method for preparing compound described in claim 1, it is characterised in that include：
Compound shown in formula a is set to be contacted with compound shown in formula b, to obtain compound shown in Formulas I,
Wherein, R1、R2、R3、R4As defined in claim 1.
3. method according to claim 2, it is characterised in that described to make compound shown in formula a enter with compound shown in formula b Row contact is further included：
Under the conditions of -10 DEG C～10 DEG C, will change shown in the mixed solution of compound shown in formula b and N-Methyl pyrrolidone and formula a Compound mixes, and under room temperature condition, by resulting mixture reaction 8～16 hours.
4. a kind of pharmaceutical composition, it is characterised in that include：
Compound described in claim 1；And
Pharmaceutically acceptable excipient.
5. pharmaceutical composition according to claim 4, it is characterised in that the gross mass based on described pharmaceutical composition, power Profit requires that the mass percent of the compound described in 1 is 1%～95%.
6. pharmaceutical composition according to claim 5, it is characterised in that the gross mass based on described pharmaceutical composition, power Profit requires that the mass percent of the compound described in 1 is 20%～40%.
7. pharmaceutical composition according to claim 4, it is characterised in that described pharmaceutical composition in selected from tablet, capsule, At least one form in injection, injection powder pin, powder, syrup, solution shape, suspension and aerosol.
8. purposes of the compound described in claim 1 in medicine is prepared, it is characterised in that the medicine is used as kinase inhibition Agent.
9. purposes according to claim 8, it is characterised in that the medicine is used as at least one of EGFR and ErbB2 Inhibitor.
10. purposes according to claim 8, it is characterised in that the medicine be used to treating or prevent by selected from EGFR and The cancer or tumor of at least one of ErbB2 mediations.
11. purposes according to claim 10, it is characterised in that the cancer or tumor be selected from leukemia, colon cancer, Renal cell carcinoma, gastro-intestinal stromal cancer, multiple myeloma, breast carcinoma, the brain cancer, glioblastoma multiforme, cancer of pancreas, non-small cell lung At least one in cancer, non-Hodgkin lymphoma, hepatocarcinoma, thyroid carcinoma, bladder cancer, colorectal cancer, carcinoma of prostate.
12. purposes according to claim 10 or 11, it is characterised in that the cancer or tumor are selected from non-small cell lung At least one in cancer, colorectal cancer, breast carcinoma or leukemia.
CN201410512764.9A 2014-09-29 2014-09-29 Substituted heterocyclic compound as kinase inhibitor and its preparation method and use Expired - Fee Related CN104370825B (en)

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