CN104370885B - Aminopyridine analog derivative and application thereof - Google Patents
Aminopyridine analog derivative and application thereof Download PDFInfo
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- CN104370885B CN104370885B CN201410697293.3A CN201410697293A CN104370885B CN 104370885 B CN104370885 B CN 104370885B CN 201410697293 A CN201410697293 A CN 201410697293A CN 104370885 B CN104370885 B CN 104370885B
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- 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
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- 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
- C07D401/14—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 three or more hetero rings
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- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The present invention relates to aminopyridine analog derivative, and in particular to compound, its preparation method and its purposes for being used to prepare the medicine for suppressing cell hyperproliferation as shown in formula II.The invention further relates to the pharmaceutical composition comprising the compounds of this invention.The compound of the present invention can be used for treatment excess proliferative disease, such as cancer, neuropathic pain, inflammation.
Description
The application is Application No. 201110079612.0, entitled " aminopyridine analog derivative and application thereof "
The divisional application of patent application.
Technical field
The present invention relates to aminopyridine analog derivative, and in particular to compound, its preparation method as shown in formula I or formula II
And it is used for the purposes that preparation suppresses the medicine of cell hyperproliferation.
Background technology
Cancer is the disease of serious threat human health.From first cancer therapy drug forties in last century --- mustargen comes out
Since, scientist's separation and Extraction from plant goes out some natural products with potential cytotoxic activity, passes through on this basis
Structural modification obtains the compound of a variety of clear and definite antitumor activities of display, wherein vincaleukoblastinum, Etoposide, taxol etc. in succession
It is approved for clinical anticancer.However, the resource-constrained of these natural product medicaments, its molecular structure is complicated, chemistry is closed
Into difficulty, large-scale production is difficult.It is, thus, sought for small molecule, anti-tumor drug simple in construction.
The content of the invention
The present invention is intended to provide a kind of have the aminopyridine analog derivative for suppressing cell hyperproliferation activity.
One aspect of the present invention provides formula I, the compound shown in formula II, or its pharmaceutically useful salt, solvate or
N- oxides.
Wherein：
In formula II, --- optional key is represented, condition is double bond for one and only one nitrogen-atoms in ring；
R1、R2、R3、R4、R5、R7Or R8It is each independently selected from hydrogen, hydroxyl, halogen, amino, nitro, itrile group, fluoroform
Base ,-OR9、-C(O)R9、-C(O)OR9、-NR10C(O)OR9、-OC(O)R9、-NR10SO2R9、-SO2NR10R9、-NR10C(O)R9、
NR10R9、C1-C10Alkyl, C2-Cl0Alkenyl, C2-C10Alkynyl, C3-C10Cycloalkyl, C3-C10Cycloalkyl-alkyl, aryl, aryl alkane
Base, heteroaryl, heteroaryl alkyl, heterocyclic radical and cycloheteroalkylalkyl；
R6Independently selected from hydrogen, trifluoromethyl, C1-C10Alkyl, C2-Cl0Alkenyl, C2-C10Alkynyl, C3-C10Cycloalkyl, C3-
C10Cycloalkyl-alkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical and cycloheteroalkylalkyl；
W is independently selected from-OR9、-NR10OR9、-NR10SO2R9With-NR10R9；
R9、R10It is each independently selected from hydrogen, hydroxyl, halogen, trifluoromethyl, C1-C10Alkyl, C2-C10Alkenyl, C2-Cl0Alkynyl,
C3-Cl0Cycloalkyl, C3-C10Cycloalkyl-alkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical, heterocyclic radical alkane
Base；
Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moieties are optionally only by 1-5
On the spot it is selected from following substituent group：Hydroxyl, halogen, amino, nitro and trifluoromethyl；
It is preferred that compound there is the structure of formula III, IV
Wherein, each substituted radical is as defined above；
It is preferred that compound there is the structure of formula V, VI
Wherein R1、R2、R3、R4、R5、R6、W、R9、R10As defined above.
It is preferred that compound be R1、R2、R3、R4、R5、R6、R7、R8For hydrogen, halogen, nitro, itrile group, trifluoromethyl, C1-C6Alkane
Base, C3-C6Cycloalkyl, C3-C6Cycloalkyl-alkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical, heterocyclic radical alkane
Base；
It is preferred that compound be W be-OR9、-NR10OR9Or-NR10R9。
In embodiments of the invention, the compound is selected from following compound：
3,4,5- tri- fluoro- 2 [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzoic acid；
Fluoro- 2- [(the iodo- 2- pyridines of 3- methyl -5- of N- { 3- [(tert-butyI-dimethyl) siloxy] propoxyl group } -3,4,5- three
Base) amino] benzamide；
Fluoro- 2- [(the iodo- 2- pyrroles of 3- methyl -5- of N- [(2,2- methyl isophthalic acids, the base of 3 dioxolanes -4) methoxyl group] -3,4,5- three
Piperidinyl) amino] benzamide；
N- [2- (thiophene -2- bases) ethyl] -3,4,5- three fluoro- 2- [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzoyl
Amine；
The fluoro- 2- of N- (2- morpholines ethyl) -3,4,5- three [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzamide；
N- [2- (piperidin-1-yl) ethyl] -3,4,5- three fluoro- 2- [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzoyl
Amine；
The fluoro- 2- of N- benzyloxies -3,4,5- three [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzamide；
The fluoro- 2- of N- benzyloxies -3,4,5- three [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzamide；
The fluoro- 2- of N- (3- phenylpropyls) -3,4,5- three [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzamide；
Fluoro- 2- [(the chloro- 5- bromo-2-pyridyls of 3- of N- [(2,2- methyl isophthalic acids, the base of 3 dioxolanes -4) methoxyl group] -3,4,5- three
Base) amino] benzamide；
(R) fluoro- 2- [(the bromo- 2- of the chloro- 5- of 3- of-N- [(2,2- methyl isophthalic acids, the base of 3 dioxolanes -4) methoxyl group] -3,4,5- three
Pyridine radicals) amino] benzamide；
(R) [(3- methyl -5- is iodo- by the fluoro- 2- of-N- [(2,2- methyl isophthalic acids, the base of 3 dioxolanes -4) methoxyl group] -3,4,5- three
2- pyridine radicals) amino] benzamide；
The fluoro- 2- of N- (methoxyl group of ring third) -3,4,5- three [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzamide；
The fluoro- 2- of N- (3- hydroxy propyloxy groups) -3,4,5- three [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzamide；
The fluoro- 2- of N- (3- hydroxy propyloxy groups) -3,4,5- three [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzamide；
(R) the fluoro- 2- of-N- (2,3- dihydroxy propoxyl group) -3,4,5- three [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzene
Formamide；
(R) the fluoro- 2- of-N- (2,3- dihydroxy propoxyl group) -3,4,5- three [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzene first
Acid amides；
The fluoro- 2- of N- (cyclohexyl methyl) -3,4,5- three [(3- methyl -5- bromo-2-pyridyls base) amino] benzamide；
The fluoro- 2- of N- (2- morpholines ethyl) -3,4,5- three [(3- methyl -5- bromo-2-pyridyls base) amino] benzamide；
The fluoro- 2- of N- [2- (piperidin-1-yl) ethyl] -3,4,5- three [(3- methyl -5- bromo-2-pyridyls base) amino] benzoyl
Amine；
The fluoro- 2- of N- (3- phenylpropyls) -3,4,5- three [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzamide；
N- [2- (piperidin-1-yl) ethyl] -3,4,5- three fluoro- 2- [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzoyl
Amine；
5- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino] fluoro- 1H- benzimidazoles -6- formic acid of -4-；
N- [2- (thiophene -2- bases) ethyl] -5- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino] fluoro- 1H- benzimidazoles of -4- -
6- formamides；
N- [2- (piperidin-1-yl) ethyl] -5- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino] fluoro- 1H- benzimidazoles of -4- -
6- formamides.
On the other hand, the invention further relates to Formulas I, II compound or its pharmaceutically useful salt, solvate or N- oxides
Synthetic method, it includes the synthesis of following key intermediate：
1) tetrafluoro cyanophenyl is molten using dimethylbenzene as reaction with replacing PA class compound under lithium amide existence condition
Agent, reaction obtains the fluoro- 2- of intermediate 3,4,5- tri- [(substitution -2- pyridine radicals) amino] benzonitrile under the conditions of 125 DEG C；
2) 2,3,4- tri- fluorine-5-nitro benzoic acids with substitution PA class compound under LDA existence conditions ,-
Under the conditions of 70 DEG C, reaction obtains intermediate 3,4,-two fluoro- 5- nitros -2- [(substitution -2- pyridine radicals) amino] benzoic acid；
Compound of formula I synthetic schemes is as follows：
Benzoic acid using the substituted L containing leaving group is initiation material, by being reacted with methylating reagent, by carboxymethyl group
Change；Again by being reacted with ammoniacal liquor, methyl esters is converted into amide groups；In POCl3The water of an one's share of expenses for a joint undertaking is sloughed under effect, amido link is turned
Turn to cyano group；The L containing leaving group of substitution benzene first cyanogen is under alkali (such as lithium amide) effect, and leaving group is left away and substitution
Aminopyridines carry out condensation reaction；Cyan-hydrolysis is being obtained into carboxyl, carboxyl reacts with corresponding side chain, obtains formula
I；
L represents leaving group, can be halogen；
The compound synthesis scheme of formula II is as follows：
Benzoic acid using the substituted L containing leaving group, by nitration reaction, introduces nitre as initiation material on phenyl ring
Base；Under alkali (such as lithium amide) effect, the aminopyridines progress condensation reaction that leaving group is left away with substitution；
Under ammoniacal liquor effect, amino is introduced on phenyl ring；By being reacted with methylating reagent, by carboxymethyl group；Nitro is reduced to amino
After, annulation is carried out, piptonychia ester obtains carboxylic key intermediate, and carboxyl reacts with corresponding pendant moiety, obtained
The compound of formula II；
L represents leaving group, can be halogen.
The present invention also provides Formulas I, the compound of formula II or its pharmaceutically useful salt containing the present invention, solvate or N- oxidations
The pharmaceutical composition of thing and pharmaceutical acceptable carrier.
C in the present invention1-C10Alkyl, alkyl refer to the straight or branched alkyl with 1-10 carbon atom, such as first
Base, ethyl, propyl group, isopropyl, normal-butyl, sec-butyl, the tert-butyl group, amyl group, 2- amyl groups, isopentyl, neopentyl, hexyl, 2- oneself
Base, 3- hexyls, 3- methyl amyls, heptyl, octyl group etc..It is preferred that alkyl be C1-C6Alkyl.Preferred alkyl is C1-C3Alkane
Base.
C2-Cl0Alkenyl refers to the alkenyl with 2-10 carbon atom and at least one double bond, and including vinyl, third
Alkenyl, 1- butyl- 3- alkenyls, the amyl- 3- alkenyls of 1-, 1- hex- 5- alkenyls etc..More preferably there is the rudimentary alkene of 3-5 carbon atom
Base；
C2-Cl0Alkynyl refers to the alkyl with 2-10 carbon atom and at least one three key, such as including acetenyl, third
Alkynyl, butynyl, pentyne -2- bases etc..More preferably there is the alkynyl of 3-5 carbon atom；
Halogen refers to fluorine, chlorine, bromine and iodine atom；
Aryl refers to that with monocyclic (such as phenyl), polycyclic (such as xenyl) or wherein at least one ring be the multiple of armaticity
The aromatic carbocyclyl groups of fused rings (such as 1,2,3,4- tetralyls, naphthyl), it is optionally by such as halogen, low alkyl group, lower alkyl
Epoxide, trifluoromethyl, aryl, heteroaryl and hydroxyl mono-, di- or three substitutions.
Heteroaryl refers to one or more aromatics ring systems of 5,6 or 7 yuan of rings, and it includes the fusion ring system of 5-10 atom
(wherein at least one ring is armaticity), the ring system contains at least one and the most four miscellaneous originals for being selected from nitrogen, oxygen or sulphur
Son.The example of heteroaryl is pyridine radicals, imidazole radicals, pyrimidine radicals, pyrazolyl, triazolyl, pyrazinyl, tetrazole radical, furyl, thiophene
Base, isoxazolyls, thiazolyl, oxazolyls, isothiazolyl, pyrrole ring, quinoline ring, isoquinolin ring, indole ring, benzimidazole, benzene
And furan nucleus, benzothiophene ring, benzothiazole ring, pyridazine ring etc..Its optionally by such as halogen, low alkyl group, lower alkoxy,
Trifluoromethyl, aryl, heteroaryl and hydroxyl mono-, di- or three substitutions.
Carbocyclic ring, carbocylic radical, cycloalkyl, C3-C10Cycloalkyl refers to the saturated carbon ring group with 3-10 carbon atom.The ring
Alkyl can be monocyclic or polycyclic fused system, and can condense on aromatic ring.The example of these groups include cyclopropyl,
Cyclobutyl, cyclopenta and cyclohexyl.This paper cycloalkyl can be it is unsubstituted or as describe in detail, it is one or more can
Substituted position is by various substituent groups.For example, these cycloalkyl can be optionally by following substituent group：C1-C6Alkyl, C1-C6Alkane
Epoxide, itrile group, halogen, hydroxyl, amino, nitro, list (C1-C6) alkyl amino, two (C1-C6) alkyl amino, C2-C6Alkenyl, C2-
C6Alkynyl, C1-C6Haloalkyl, C1-C6Halogenated alkoxy；
Heterocycle or heterocyclic radical refer to one or more carbocyclic ring system of 5,6 or 7 yuan of rings, and it includes the thick of 4-10 atom
Cyclization system, the ring system contains the hetero atoms that at least one and most four are selected from nitrogen, oxygen or sulphur, condition be the ring of the group not
Containing two adjacent O or S atom.Fusion ring system can be heterocycle of the fusion on virtue group group.It is preferred that heterocycle include but not
It is limited to pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, thiophane, piperidyl, morpholine ring, hexamethylene ring, piperazine ring etc., it
Can be by following substituent group：C1-C6Alkyl, C1-C6Alkoxy, itrile group, halogen, hydroxyl, amino, nitro, list (C1-C6) alkane
Base amino, two (C1-C6) alkyl amino, C2-C6Alkenyl, C2-C6Alkynyl, C}-C6Haloalkyl, C1-C6Halogenated alkoxy；
Aryl alkyl refers to (as defined above) alkyl replaced by one or more (as defined above) aryl.More preferably
Aryl alkyl be aryl-Cl-C3Alkyl.Example includes benzyl, phenylethyl etc.；
Heteroaryl alkyl refers to (as defined above) alkyl replaced by (as defined above) heteroaryl.Preferred heteroaryl
Base alkyl is 5- or 6- unit's heteroaryls-C1-C3- alkyl.Example is including pyridyl-ethyl group etc.；
Cycloheteroalkylalkyl refers to (as defined above) alkyl replaced by (as defined above) heterocyclic radical.Preferred heterocycle
Base alkyl is 5- or 6- circle heterocycles bases-Cl-C3- alkyl.Example includes oxinane ylmethyl；
Cycloalkyl-alkyl refers to (as defined above) alkyl replaced by (as defined above) cycloalkyl.Preferred heterocycle
Base is 5- or 6- member cycloalkyl-Cl-C3- alkyl.Example includes Cvclopropvlmethvl；
The compounds of this invention can also be used in the form of its pharmaceutically acceptable salt or solvate.Formulas I or Formula II
The physiologically receivable salt of compound is included by pharmaceutically acceptable inorganic acid or organic acid or inorganic base or organic
The conventional salt of alkali formation and the acid-addition salts of quaternary ammonium.The more specifically example of suitable hydrochlorate includes hydrochloric acid, hydrobromic acid, sulphur
Acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, butanedioic acid, hydroxyacetic acid, formic acid, lactic acid, maleic acid, tartaric acid,
Citric acid, flutter acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, first
The salt of sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, steroic, tannic acid etc..Other acid, such as
Oxalic acid, although itself is not pharmaceutically acceptable, but can be used for preparing the salt as intermediate, to obtain of the present inventionization
Compound and its pharmaceutically acceptable salt.The more specifically example of suitable alkali salt includes sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N,
N '-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanol amine, ethylenediamine, N-METHYL-ALPHA-L-GLUCOSAMINE and procaine salt.
Some of present invention compound may use water or the crystallization of various organic solvents or recrystallization, in this case,
It is likely to form various solvates.The present invention includes the solvate of those stoichiometries, and such as hydrate is also included within low
The compound for including variable water that pressure lyophilization method is formed when preparing.
Therefore when being related to the compound of the present invention, including Formulas I or Formula II compound and its pharmaceutically acceptable salt
And solvate.
Present invention additionally comprises the prodrug of the compounds of this invention, the prodrug carries out chemistry once administration by metabolic process
Conversion, becomes active medicine afterwards.Generally, this kind of prodrug is the functional derivatives of the compounds of this invention, and it is in body
Interior easily changes into required Formulas I or Formula II compound.For example, " Design Of Prodrugs ", H Bund Saard,
Elsevier is edited, and selection is described in 1985 and the conventional method of suitable prodrug derivatives is prepared.
The present invention also includes the active metabolite of the compounds of this invention.
Another aspect of the present invention is related to pharmaceutical composition, and it contains the raceme or optical isomerism of the compounds of this invention
Body and at least one pharmaceutically acceptable carrier, it can be used for interior therapeutic and with biocompatibility.The drug regimen
Thing can be prepared into various forms according to different way of administration.Compound mentioned by the present invention can also be prepared to various
Pharmaceutically acceptable salt.
The pharmaceutical composition of the present invention includes the formula I or Formula II compound or pharmaceutically acceptable salt thereof or water of effective dose
Compound and one or more suitable pharmaceutical acceptable carrier.Here pharmaceutical carrier includes but is not limited to：Ion-exchanger, oxidation
Aluminium, aluminum stearate, lecithin, haemocyanin such as human serum albumin, buffer substance such as phosphate, glycerine, sorbic acid, sorbic acid
Potassium, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate,
Potassium hydrogen phosphate, sodium chloride, zinc salt, cabosil, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, polyethylene glycol,
Sodium carboxymethylcellulose, polyacrylate, beeswax, lanolin.
The pharmaceutical composition of the compounds of this invention can be applied with following any-mode：Orally, spraying suction, rectum is used
Medicine, nasal cavity applied medicine, cheek medication, local application, non-bowel medication, such as subcutaneous, vein is intramuscular, and intraperitoneal is intrathecal, intra-ventricle,
With intracranial injection or input in breastbone, or by a kind of explant reservoir medication.Wherein preferably orally, intraperitoneal or intravenous administration
Mode.
When oral medication, the compounds of this invention can be made into any oral acceptable dosage form, include but is not limited to
Tablet, capsule, the aqueous solution or water slurry.Wherein, the carrier that tablet is used generally comprises lactose and cornstarch, also may be used in addition
Add lubricant such as magnesium stearate.The diluent that capsule preparations are used generally comprises lactose and dried corn starch.Water slurry
Preparation is typically then to be used in mixed way active component with suitable emulsifying agent and suspending agent.If desired, above oral formulations shape
Some sweeteners, aromatic or colouring agent can be also added in formula.
When local application, particularly treat Local out dressing easy to reach and suffer from face or organ, such as eyes, skin or lower intestines
During road neurogenic disease, different topical preparations shapes the compounds of this invention can be made according to different suffer from face or organ
Formula, is described as follows:
When eye local application, the compounds of this invention can be configured to the preparation shape of a kind of micronized suspension or solution
Formula, uses carrier to be the Sterile Saline of isotonic certain pH, wherein also not adding preservative agent such as zephiran chloride alkanol can be added
Salt.For ophthalmically acceptable, compound can be also made to ointment such as petroleum jelly cream.
When topical application, the compounds of this invention can be made into appropriate ointment, lotion or cream formulation form, wherein
Active component is suspended or dissolved in one or more carriers.Carrier includes but is not limited to workable for ointment formulation：Mineral
Oil, Albolene, albolene, propane diols, polyethylene glycol oxide, PPOX, emulsifying wax and water；Lotion or creme can make
Carrier includes but is not limited to:Mineral oil, sorbitan monostearate, polysorbate60, cetyl ester wax, hexadecene
It is fragrant and mellow, 2- octyldodecanols, benzyl alcohol and water.
The compounds of this invention can be with aseptic injection preparation form medication, including aseptic injection water or oil suspension or sterile
Inject solution.Wherein, workable carrier and solvent include water, Ringer's solution and isotonic sodium chlorrde solution.In addition, sterilizing
Fixed oil also is used as solvent or suspension media, such as monoglyceride or two glyceride.
It is used to prepare the invention further relates to the compound of the present invention or its pharmaceutically useful salt, solvate or N- oxides and presses down
The purposes of the medicine of cell hyperproliferation processed.
The cell hyperproliferation includes leukaemia, spongioblastoma, lymthoma, melanoma, cancer, nerve pain
Bitterly, the disease such as inflammation.In one embodiment of the invention, the suppression cell hyperproliferation refers to that suppressing tumour cell increases
Grow.
It is anti-for preparing the invention further relates to the compound of the present invention or its pharmaceutically useful salt, solvate or N- oxides
The purposes of tumour medicine.
The beneficial effect of invention
The compound of the present invention can effectively suppress the hyper-proliferative of cell, available for hyper-proliferative in treatment mammal
Property disease, such as cancer, neuropathic pain, inflammation.
Embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.It is unreceipted specific in embodiment
Condition person, the condition advised according to normal condition or manufacturer is carried out.Agents useful for same or the unreceipted production firm person of instrument, be
Can be by the conventional products of acquisition purchased in market.
Melting point compound is determined by RY-1 types melting point apparatus, and temperature is not calibrated.1H NMR spectras are by Bruker ARX 400
Type nuclear magnetic resonance spectrometer is determined.
Fluoro- 2 [(the iodo- 2- pyridine radicals of the 3- methyl -5-) amino] benzoic acid of 1 3,4,5- of embodiment tri-
Step 1,2,3,4,5 tetra fluoro benzoic acid methyl esters
2,3,4,5- tetrafluorobenzoic aids (48.5g, 0.25mol) are dissolved in 130mL absolute methanols, trimethyl is slowly added dropwise
Chlorosilane (63mL, 0.50mol).Completion of dropping, flow back 12h.Water pump removes the trim,ethylchlorosilane of solvent and excess under reduced pressure,
Weak yellow liquid is obtained, dichloromethane 200mL is added, and is washed with 10% sodium hydrate aqueous solution, the anti-water lift layer of dichloromethane,
Merge organic layer, organic layer is stayed overnight with anhydrous sodium sulfate drying.Next day filters, and removes solvent under reduced pressure, obtains colourless liquid 2, and 3,4,
5- methyl 4-fluorobenzenes (30.52g, 97.8%),1H-NMR(400MHz,CDCl3)δppm:7.65-7.60(m,1H),3.97
(s,1H)。
Step 2,2,3,4,5- tetrafluorobenzamides
2,3,4,5- methyl 4-fluorobenzenes (29.5g, 0.147mol) and concentrated ammonia liquor (244mL, 3.24mol) are added to
In eggplant-shape bottle, system is two-phase system, as reaction is carried out, has white insoluble matter to occur, mechanical agitation is stayed overnight, and filters white
The tetrafluorobenzamide of solid 2,3,4,5- (21.2g, 74.7%),1H-NMR(400MHz,DMSO-D6)δppm:7.93(br s,
1H),7.91(br s,1H),7.63-7.61(m,1H),ESI-MS m/z:194.0[M+1]+。
Step 3,2,3,4,5- tetrafluoro cyanophenyls
2,3,4,5- tetrafluorobenzamides (5g, 0.026mol) are added in 20mL anhydrous acetonitriles, POCl3 is added
(16.6g, 0.11mol), is warming up to 70 DEG C, reacts 1.5h.Reaction solution is slowly dropped in 200mL mixture of ice and water, the mistake
Journey very exothermic, controls temperature to be not higher than 30 DEG C by controlling rate of addition, and 0.5h, acetic acid second are stirred at room temperature after completion of dropping
Ester is extracted, and organic layer is dried overnight, and next day removes solvent under reduced pressure, obtain the tetrafluoro cyanophenyl of colourless liquid 2,3,4,5- (4.21g,
92.5%).1H-NMR(400MHz,DMSO-D6)δppm:10.01(br s,1H),7.35-7.28(m,1H),19F-NMR
(400MHz,CDCl3)δppm:- 130.04.~-130.06 (m, 1H), -134.62~-134.66 (m, 1H), -143.48~-
143.60 (m, 1H), -150.60~-150.62 (m, 1H), ESI-MS m/z:176.0[M+1]+。
Step 4, the methyl -5- iodine pyridines of 2- amino -3
By the picoline of 2- amino -3 (5.5g, 0.05mol), iodine (5.1g, 0.02mol), periodic acid dihydrate
(2.28g, 0.01mol) is added in reaction bulb, sequentially adds acetic acid (30mL), water (60mL) and the concentrated sulfuric acid (0.9mL), system
Temperature rises to 25 DEG C by room temperature in heat release, system, obtains dark brown solution, is heated to 80 DEG C, reacts 4h.System natural cooling
To the Na of room temperature, thereto addition 10%2S2O4In the aqueous solution (150mL), 30min is stirred, dichloromethane extracts water layer, uses
10% sodium hydrate aqueous solution washing organic layer, organic layer is stayed overnight with anhydrous sodium sulfate drying.Next day filters, and removes under reduced pressure molten
Agent, obtains the methyl -5- iodine pyridines (10.76g, 92.0%) of faint yellow solid 2- amino -3,1H-NMR(400MHz,CDCl3)δppm:
8.11(s,1H),7.53(s,1H),4.85-4.80(br s,2H),2.01(s,3H),ESI-MSm/z:235.8[M+1]+。
Step 5, the fluoro- 2- of 3,4,5- tri- [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzonitrile
Under nitrogen protective condition, by the methyl -5- iodine pyridines (23.10g, 0.0986mol) of 2- amino -3 and lithium amide
(7.89g, 0.343mol) is added in 170mL dimethylbenzene, is heated to 100 DEG C, stirring reaction 2h.Temperature fall to room temperature, plus
Enter 2,3,4,5- tetrafluoro cyanophenyls (15g, 0.0857mol), be heated to 126 DEG C, react 3.5h.The black that course of reaction is obtained is consolidated
Body is filtered, and being sandwiched in black solid has product, is repeatedly washed on a small quantity with ethyl acetate, and use ultrasonic echography 5min.Use 1N salt
Ethyl acetate layer and reaction solution that aqueous acid washing is obtained, merge organic layer, and organic layer is stayed overnight with anhydrous sodium sulfate drying.It is secondary
Day filtering, removes solvent under reduced pressure, column chromatography obtains the fluoro- 2- of faint yellow solid 3,4,5- tri- [(the iodo- 2- pyridine radicals of 3- methyl -5-) ammonia
Base] benzonitrile (8.9g, 27%),1H-NMR(400MHz,CDCl3)δppm:8.24-8.23(m,1H),7.76-7-75(br s,
1H),7.21-7.19(m,1H),5.99(s,1H),2.31(s,3H),19F-NMR(400MHz,CDCl3)δppm:-122.29(s,
1H), -133.63~-133.72 (m, 1H), -135.71~-135.76 (m, 1H), ESI-MS m/z:390.0[M+1]+。
Step 6, the fluoro- 2- of 3,4,5- tri- [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzoic acid
3,4,5- tri- fluoro- 2- [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzonitriles (8.90g, 0.023mol) are dissolved in
Absolute ethyl alcohol：Distilled water：THF=150mL：75mL：22.5mL in the mixed solvent, addition potassium hydroxide (6.44g,
0.115mol), it is heated to reflux, reacts 30h.Remove solvent under reduced pressure, obtain grease, pH value is adjusted to 1 with 10% aqueous hydrochloric acid solution,
Ethyl acetate is extracted, and organic layer is stayed overnight with anhydrous sodium sulfate drying.Next day filters, and removes solvent under reduced pressure, obtains faint yellow solid 3,
4,5- tri- fluoro- 2- [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzoic acid (8.72g, yield 92.9%), mp 103-105 DEG C
。1H-NMR(400MHz,DMSO-D6)δppm:13.61(br s,1H),8.38(s,1H),8.11-8.09(d,1H),7.85-
7.84(d,1H),7.56-7.52(m,1H),2.49(s,3H).19F-NMR(400MHz,DMSO-D6)δppm:- 12193~-
121.99 (m, 1H), -133.82~-133.88 (m, 1H), -139.86~-139.97 (m, 1H), ESI-MS m/z:409.1[M
+1]+。
Fluoro- the 2- [(3- methyl -5- of the N- of embodiment 2 { 3- [(tert-butyI-dimethyl) siloxy] propoxyl group } -3,4,5- three
Iodo- 2- pyridine radicals) amino] benzamide
By obtained 3,4,5- tri- fluoro- 2 [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzoic acid in embodiment 1
(0.29g, 0.71mol), O- { 3 [(tert-butyI-dimethyl silicon) epoxide] propyl group } azanol (0.27g, 1.303mmol), N, N- bis-
Wopropyl ethyl amine (DIEA) (0.15mL, 0.855mmol) is dissolved in 20mL dichloromethane, adds hexafluorophosphoric acid BTA -1-
Base-epoxide tripyrrole alkyl phosphorus (PyBOP) (0.43g, 0.82mmol), is stirred at room temperature reaction 1.5h.Added into reaction system
Absolute ether 40mL, washs organic phase with water, saturated sodium-chloride water solution respectively, and organic layer is stayed overnight with anhydrous sodium sulfate drying.
Next day filters, and removes solvent under reduced pressure, column chromatography obtains white solid N- { 3- [(tert-butyI-dimethyl) siloxy] propoxyl group } -3,
4,5- tri- fluoro- 2- [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzamides (0.18g, 42.6%).1H-NMR(400MHz,
CDCl3)δppm:9.31-9.29(m,1H),8.22(s,1H),7.74-7.73(m,1H),7.67-7.66(m,1H),5.94(br
S, 1H), 4.18-4.15 (t, 2H, J=6.3Hz), 3.81-3.78 (t, 2H, J=6.3Hz), 2.30 (s, 3H), 1.97-1.91
(m, 2H), 0.89 (s, 9H), 0.088 (s, 6H),19F-NMR(400MHz,CDCl3)δppm:0.03~-0.03 (t, 1H), -
13.39~-13.45 (d, 1H), -14.71~-14.90 (m, 1H), ESI-MS m/z:596.3[M+1]+。
Fluoro- the 2- [(3- methyl -5- of the N- of embodiment 3 [(2,2- methyl isophthalic acids, the base of 3 dioxolanes -4) methoxyl group] -3,4,5- three
Iodo- 2- pyridine radicals) amino] benzamide
By obtained 3,4,5- tri- fluoro- 2 [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzoic acid in embodiment 1
(0.43g, 1.06mmol), is dissolved in anhydrous THF20mL, and system is cooled to -15 DEG C, add hexichol phosphonic chloride (0.27mL,
1.38mmol), -15 DEG C of reaction 30min.Add N-methylmorpholine (0.12mL, 1.06mmol), -15 DEG C of reaction 30min.Add
O- [(2,2- dimethyl -1,3- diketone -4- bases) methyl] azanol (0.19g, 1.27mmol), -15 DEG C of reaction 30min.Add N-
Methyl morpholine (0.18mL, 1.59mmol), recovers to room temperature, is stirred overnight at room temperature.Ethyl acetate 60mL is added in reaction solution, according to
Secondary to be washed with saturated sodium bicarbonate aqueous solution liquid, saturated sodium-chloride water solution, organic layer is stayed overnight with anhydrous sodium sulfate drying.Next day
Filtering, removes solvent under reduced pressure, column chromatography obtains faint yellow solid N- [(2,2- methyl isophthalic acids, the base of 3 dioxolanes -4) methoxyl group] -3,4,
The fluoro- 2- of 5- tri- [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzamide (0.21g, 37.1%).1H-NMR(400MHz,
CDCl3)δppm:9.70-9.68(m,1H),8.23(s,1H),7.75-7.74(m,1H),7.69-7.676(m,1H),6.00
(br s,1H),4.47-4.45(m,1H),4.18-4.13(m,2H),3.88-3.86(m,1H),3.51-3.46(m,1H),
2.30(s,3H),1.50(s,3H),1.39(s,3H),ESI-MS m/z:538.2[M+1]+。
Fluoro- 2- [(the iodo- 2- pyridine radicals of the 3- methyl -5-) ammonia of the N- of embodiment 4 [2- (thiophene -2- bases) ethyl] -3,4,5- three
Base] benzamide
By obtained 3,4,5- tri- fluoro- 2 [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzoic acid in embodiment 1
(0.23g, 0.57mol), 2- (thiophene -2- bases) ethamine (0.13g, 1.03mmol), DIEA (0.12mL, 0.68mmol) are dissolved in
In 20mL dichloromethane, add PyBOP (0.34g, 0.65mmol) and be stirred overnight at room temperature.Absolute ether is added into reaction system
40mL, washs organic phase with water, saturated sodium-chloride water solution respectively, and organic layer is stayed overnight with anhydrous sodium sulfate drying.Next day filters,
Remove solvent under reduced pressure, column chromatography obtains fluoro- the 2- [(3- methyl -5- of faint yellow solid N- [2- (thiophene -2- bases) ethyl] -3,4,5- tri-
Iodo- 2- pyridine radicals) amino] benzamide (0.21g, 72.1%).1H-NMR(400MHz,CDCl3)δppm:8.22(m,1H),
7.72(s,1H),7.71-7.68(m,1H),7.20-7.19(m,1H),6.98-6.96(m,2H),6.89-6.88(m,1H),
6.75-6.78 (m, 1H), 5.84 (br s, 1H), 3.78-3.75 (m, 2H), 3.18-3.15 (t, 2H, J=6.7Hz), ESI-MS
m/z:518.2[M+1]+。
The fluoro- 2- of the N- of embodiment 5 (2- morpholines ethyl) -3,4,5- three [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzene first
Acid amides
Method be the same as Example 4, obtains white solid N- (2- morpholines ethyl) -3,4,5- tri- fluoro- 2- [(the iodo- 2- of 3- methyl -5-
Pyridine radicals) amino] benzamide.1H-NMR(400MHz,CDCl3)δppm:8.23(m,1H),7.72(s,1H),7.71-7.68
(m,1H),7.67-7.64(m,1H),5.81(br s,1H),3.78(br s,4H),3.61(br s,2H),2.62(br s,
2H),2.54(br s,2H),2.30(s,3H),1.59(br s,2H),ESI-MS m/z:521.2[M+1]+。
Fluoro- 2- [(the iodo- 2- pyridine radicals of the 3- methyl -5-) ammonia of the N- of embodiment 6 [2- (piperidin-1-yl) ethyl] -3,4,5- three
Base] benzamide
Method be the same as Example 4, obtains white solid N- [2- (piperidin-1-yl) ethyl] -3,4,5- tri- fluoro- 2- [(3- methyl -
The iodo- 2- pyridine radicals of 5-) amino] benzamide.1H-NMR(400MHz,CDCl3)δppm:8.23(m,1H),7.72(s,1H),
7.68-7.64(m,1H),7.59(br s,1H),5.80(br s,1H),3.61-3.59(m,2H),2.63(br s,2H),
2.53 (br s, 4H), 2.30 (s, 3H), 1.66 (br s, 4H), 1.50 (br s, 2H), ESI-MS m/z:519.2[M+1]+。
Fluoro- 2- [(the chloro- 5- bromo-2-pyridyls bases of the 3-) amino] benzamides of 7 N- benzyloxies -3,4,5- of embodiment three
The chloro- 5- bromopyridines of step 1,2- amino -3-
By 2- amino -5- bromopyridines (3.0g, 17.34mmol), it is dissolved in DMF (10mL), obtains deep yellow solution.Ice bath is cold
But to 0 DEG C, NCS (2.40g, 18.03mmol), 0 DEG C of reaction 1h are added.30mL water is added into reaction system, absolute ether is used
Extraction, organic layer is stayed overnight with anhydrous sodium sulfate drying.Next day filter, remove solvent under reduced pressure, obtain black solid (2.72g,
75.6%), ESI-MS m/z:207.9[M+1]+。
Step 2, the fluoro- 2- of 3,4,5- tri- [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzonitrile
Under nitrogen protective condition, by the chloro- 5- bromopyridines (10.30g, 0.050mol) of 2- amino -3- and lithium amide (4.58g,
0.20mol) it is added in 150mL dimethylbenzene, is heated to 100 DEG C, stirring reaction 2h.Temperature fall adds 2,3,4 to room temperature,
5- tetrafluoros cyanophenyl (7.33g, 0.042mol), is heated to 126 DEG C, reacts 3.5h.Reaction solution is added to 100mL ethyl acetate
In, 10min is stirred, substantial amounts of black solid, filtering is produced.Being sandwiched in black solid has product, multiple on a small quantity with ethyl acetate
Washing, and use ultrasonic echography 5min.Obtained ethyl acetate layer and reaction solution is washed with 1N aqueous hydrochloric acid solutions, is merged organic
Layer, organic layer is dried overnight, and next day removes solvent under reduced pressure, and column chromatography obtains fluoro- 2- [(the chloro- 5- of 3- of faint yellow solid 3,4,5- tri-
Bromo-2-pyridyl base) amino] benzonitrile (4.5g, 29.6%),1H-NMR(400MHz,CDCl3)δppm:8.16-8.13(m,1H),
7.82-7.81 (m, 1H), 7.24-7.23 (m, 1H), 6.57 (br s, 1H), ESI-MS m/z:363.9[M+1]+。
Step 3, the fluoro- 2- of 3,4,5- tri- [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzoic acid
3,4,5- tri- fluoro- 2- [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzonitriles (4.50g, 12.4mmmol) are dissolved in
Absolute ethyl alcohol：Distilled water：THF=100mL：50mL：15mL in the mixed solvent, adds potassium hydroxide (3.48g), heats back
Stream, reacts 30h.Remove solvent under reduced pressure, obtain grease, adjust pH value to 1 with 10% aqueous hydrochloric acid solution, ethyl acetate extraction has
Machine layer is dried overnight, and next day removes solvent under reduced pressure, obtains the fluoro- 2- of faint yellow solid 3,4,5- tri- [(the chloro- 5- bromo-2-pyridyls bases of 3-)
Amino] benzoic acid (4.27g, 90.2%).
Step 4, the fluoro- 2- of N- benzyloxies -3,4,5- three [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzamide
By 3,4,5- tri- fluoro- 2- [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzoic acid (0.22g, 0.57mol), O- benzene first
Base azanol (0.13g, 1.03mmol), DIEA (0.12mL, 0.68mmol) are dissolved in 20mL dichloromethane, add PyBOP
(0.34g, 0.65mmol), is stirred overnight at room temperature.Absolute ether 40mL is added into reaction system, respectively with water, saturation chlorination
Sodium water solution washs organic phase, and organic layer is stayed overnight with anhydrous sodium sulfate drying.Next day filters, and removes solvent under reduced pressure, column chromatography is obtained
White solid N- benzyloxies -3,4, the fluoro- 2- of 5- tri- [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzamide (0.16g,
57.6%).1H-NMR(400MHz,CDCl3)δppm:8.98-8.96 (d, 1H, J=10.9Hz), 8.10 (s, 1H), 7.79 (s,
1H),7.70-7.68(m,1H),7.45-7.40(m,5H),6.50(s,1H),5.06(s,2H).ESI-MS m/z:488.0[M+
1]+
Embodiment 8, the fluoro- 2- of N- benzyloxies -3,4,5- three [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzamide
Method be the same as Example 4, obtains faint yellow solid N- benzyloxies -3,4, the fluoro- 2- of 5- tri- [(the iodo- 2- pyrroles of 3- methyl -5-
Piperidinyl) amino] benzamide.1H-NMR(400MHz,CDCl3)δppm:9.01-8.98 (d, 1H, J=10.2Hz), 8.22 (s,
1H),7.73(s,1H),7.67-7.66(m,1H),7.45-7.40(m,5H),5.97(s,1H),5.06(s,2H),2.29(s,
3H).ESI-MS m/z:514.2[M+1]+。
Embodiment 9, the fluoro- 2- of N- (3- phenylpropyls) -3,4,5- three [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzamide
Method be the same as Example 7, obtains faint yellow solid N- (3- phenylpropyls) -3,4,5- tri- fluoro- 2- [(the bromo- 2- pyrroles of the chloro- 5- of 3-
Piperidinyl) amino] benzamide.1H-NMR(400MHz,CDCl3)δppm:8.12-8.11(d,1H),7.79(s,1H),7.71-
7.67 (m, 1H), 7.32-7.19 (m, 5H), 6.64-6.61 (m, 1H), 6.50 (s, 1H), 3.53-3.47 (m, 2H), 2.75-
2.71 (t, 2H, J=13.2Hz), 2.00-1.96 (m, 2H), ESI-MS m/z:498.1[M-1]+。
Embodiment 10, fluoro- 2- [(the chloro- 5- of 3- of N- [(2,2- methyl isophthalic acids, the base of 3 dioxolanes -4) methoxyl group] -3,4,5- three
Bromo-2-pyridyl base) amino] benzamide
By 3,4,5- tri- fluoro- 2- [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzoic acid (0.40g, 1.06mmol), it is dissolved in
In anhydrous THF 20mL, system is cooled to -15 DEG C, adds hexichol phosphonic chloride (0.27mL, 1.38mmol), -15 DEG C of reactions
30min.Add N-methylmorpholine (0.12mL, 1.06mmol), -15 DEG C of reaction 30min.Add O- [(2,2- dimethyl -1,3-
Diketone -4- bases) methyl] azanol (0.19g, 1.27mmol), -15 DEG C of reaction 30min.Addition N-methylmorpholine (0.18mL,
1.59mmol), recover to room temperature, be stirred overnight at room temperature.Ethyl acetate 60mL is added in reaction solution, saturated sodium bicarbonate is used successively
Aqueous solution liquid, saturated sodium-chloride water solution washing, organic layer are stayed overnight with anhydrous sodium sulfate drying.Next day filters, and removes under reduced pressure molten
Agent, the white solid (0.38g, 71.1%) of column chromatography.1H-NMR(400MHz,DMSO-D6)δppm:11.90(s,1H),8.84
(s,1H),8.17-8.16(m,1H),8.12-8.11(m,1H),7.45-7.42(m,1H),4.36-4.33(m,1H),4.08-
4.06(m,1H),3.95-3.94(m,2H),3.77-3.75(m,1H),1.35(s,3H),1.29(s,3H).ESI-MS m/z:
512.2[M+1]+。
Embodiment 11, (R)-N- [(2,2- methyl isophthalic acids, the base of 3 dioxolanes -4) methoxyl group] fluoro- 2- [(3- of -3,4,5- three
Chloro- 5- bromo-2-pyridyls base) amino] benzamide
Under nitrogen protective condition, by 3,4,5- tri- fluoro- 2- [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzoic acid (0.40g,
1.06mmol) it is dissolved in anhydrous THF10mL, addition (R) O- { 3 [(tert-butyI-dimethyl silicon) epoxide] propyl group } azanol (0.16g,
1.06mmol), N-methylmorpholine (0.30mL, 2.65mmol), 0 DEG C is cooled to by above-mentioned system ice bath, is added dropwise under condition of ice bath
Hexichol phosphonic chloride (0.24mL, 1.27mmol), completion of dropping is recovered to room temperature, is stirred overnight at room temperature.Remove solvent under reduced pressure, to
Ethyl acetate 20mL, water 20mL are added in residue, is washed successively with saturated sodium bicarbonate aqueous solution, saturated sodium-chloride water solution
Organic phase, organic layer is dried overnight, and next day removes solvent under reduced pressure, column chromatography obtain faint yellow solid (R)-N- [(2,2- methyl isophthalic acids,
The base of 3 dioxolanes -4) methoxyl group] -3,4,5- tri- fluoro- 2- [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzamides (0.41g,
77.4%).1H-NMR(400MHz,DMSO-D6)δppm:11.90(s,1H),8.84(s,1H),8.17-8.16(m,1H),
8.12-8.11(m,1H),7.43-7.42(m,1H),4.36-4.33(m,1H),4.08-4.06(m,1H),3.95-3.94(m,
2H),3.77-3.75(m,1H),1.35(s,3H),1.29(s,3H),ESI-MS m/z:512.2[M+1]+。
Embodiment 12, fluoro- 2- [(the 3- first of (R)-N- [(2,2- methyl isophthalic acids, the base of 3 dioxolanes -4) methoxyl group] -3,4,5- three
The iodo- 2- pyridine radicals of base -5-) amino] benzamide
Under nitrogen protective condition, by 3,4,5- tri- fluoro- 2- [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzoic acid
(0.43g, 1.06mmol) is dissolved in anhydrous THF10mL, adds (R) O- { 3 [(tert-butyI-dimethyl silicon) epoxide] propyl group } azanol
(0.16g, 1.06mmol), N-methylmorpholine (0.30mL, 2.65mmol), 0 DEG C, condition of ice bath are cooled to by above-mentioned system ice bath
Lower dropwise addition hexichol phosphonic chloride (0.24mL, 1.27mmol), completion of dropping is recovered to room temperature, is stirred overnight at room temperature.Remove under reduced pressure molten
Agent, ethyl acetate 20mL, water 20mL are added into residue, water-soluble with saturated sodium bicarbonate aqueous solution, saturated sodium-chloride successively
Liquid washs organic phase, organic layer is dried overnight, and next day removes solvent under reduced pressure, and column chromatography obtains faint yellow solid (R)-N- [(2,2-
Methyl isophthalic acid, the base of 3 dioxolanes -4) methoxyl group] -3,4,5- three fluoro- 2- [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzoyl
Amine (0.35g, 61.8%).1H-NMR(400MHz,DMSO-D6)δppm:11.85(s,1H),8.28(s,1H),8.07-8.06
(m,1H),7.82-7.81(m,1H),7.40-7.37(m,1H),4.36-4.33(m,1H),4.08-4.06(m,1H),3.95-
3.94(m,2H),3.78-3.75(m,1H),2.26(s,3H),1.35(s,3H),1.29(s,3H),ESI-MS m/z:538.2
[M+1]+。
Embodiment 13, the fluoro- 2- of N- (methoxyl group of ring third) -3,4,5- three [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzoyl
Amine
3,4,5- tri- fluoro- 2- [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzoic acid (0.22g, 0.58mmol) are dissolved in nothing
In water THF 15mL, N-methylmorpholine (0.16mL, 1.44mmol) is added, the system is cooled to -15 DEG C of simultaneously by diphenyl
The mixed system that secondary phosphonic chloride (0.13mL, 0.69mmol) is dissolved in anhydrous THF 3mL is cooled to -15 DEG C.With peristaltic pump by hexichol
The anhydrous THF solution of base time phosphonic chloride is added in reaction system.Addition is finished, -15 DEG C of reaction 0.5h.- 15 DEG C will be cooled to
22 (0.086g, 0.069mmol) THF：DMF=1：1 solution is also added in reaction system.Addition is finished, -15 DEG C of reactions
1.5h.System returns to room temperature, is stirred overnight at room temperature.Remove solvent under reduced pressure, obtain buff grease, add ethyl acetate molten
Solution, is washed, the anhydrous sulphur of organic layer with 1M sodium bisulfates, saturated sodium bicarbonate solution, saturated sodium-chloride water solution successively
Sour sodium is dried overnight.Next day filters, and removes solvent under reduced pressure, column chromatography obtains faint yellow solid N- (methoxyl group of ring third) -3,4,5- tri-
Fluoro- 2- [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzamide (0.11g, 42.3%).1H-NMR(400MHz,DMSO-D6)δ
ppm:11.71(s,1H),9.87(s,1H),8.83(s,1H),8.16-8.08(m,1H),7.42-7.39(m,1H),3.74-
3.73(m,2H),1.08-1.04(m,1H),0.60-0.58(m,2H),0.29-0.27(m,2H),ESI-MS m/z:451.9[M
+1]+。
The fluoro- 2- of the N- of embodiment 14 (3- hydroxy propyloxy groups) -3,4,5- three [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzene
Formamide
By the fluoro- 2- of obtained N- { 3- [(tert-butyI-dimethyl) siloxy] propoxyl group } -3,4,5- three in embodiment 2
[(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzamide (0.40g, 0.67mmol) is dissolved in 5mL absolute methanol, is added
The methanol solution 0.10mL of 5M sulfuric acid, is stirred at room temperature 1h, adds the methanol solution 0.05mL of 5M sulfuric acid, 2h is stirred at room temperature.
Saturated sodium bicarbonate aqueous solution adjusts pH value to 7, adds distilled water 10mL, ethyl acetate extraction, saturated sodium-chloride water solution washing
Organic layer, organic layer is stayed overnight with anhydrous sodium sulfate drying.Next day filters, and removes solvent under reduced pressure, column chromatography obtains faint yellow solid N-
(3- hydroxy propyloxy groups) -3,4,5- tri- fluoro- 2- [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzamides (0.32g,
71.2%).1H-NMR(400MHz,DMSO-D6)δppm:11.77(s,1H),8.27(s,1H),8.06-8.05(m,1H),
7.82-7.81 (m, 1H), 7.39-7.35 (m, 1H), 4.87-4.86 (d, 1H, J=4.8Hz), 4.64-4.61 (t, 1H, J=
5.3Hz),3.99-3.96(m,1H),3.81-3.76(m,2H),3.41-3.39(m,2H),2.25(s,3H).ESI-MS m/z:
481.2[M+1]+。
The fluoro- 2- of the N- of embodiment 15 (3- hydroxy propyloxy groups) -3,4,5- three [(the chloro- 5- bromo-2-pyridyls bases of 3-) amino] benzene first
Acid amides
Method be the same as Example 14, obtaining the fluoro- 2- of white solid N- (3- hydroxy propyloxy groups) -3,4,5- tri-, [(3- methyl -5- is iodo-
2- pyridine radicals) amino] benzamide.1H-NMR(400MHz,DMSO-D6)δppm:11.82(s,1H),8.84(s,1H),8.17-
8.12(m,2H),7.44-7.41(m,1H),3.81-3.76(m,2H),3.41-3.39(m,4H)。ESI-MS m/z:454.6[M
+1]+。
The fluoro- 2- [(the iodo- 2- pyridine radicals of 3- methyl -5-) of embodiment 16 (R)-N- (2,3- dihydroxy propoxyl group) -3,4,5- three
Amino] benzamide
By the fluoro- 2- of obtained N- [(2,2- methyl isophthalic acids, the base of 3 dioxolanes -4) methoxyl group] -3,4,5- three in embodiment 3
[(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzamide (0.21g, 0.39mmol) is added to methanol (5mL) and water
The in the mixed solvent of (0.5mL), adds p-methyl benzenesulfonic acid monohydrate (0.037g, 0.196mmol), 18h is stirred at room temperature.Concentration
Reaction solution, adds water 10mL, and ethyl acetate extraction is washed with saturated sodium bicarbonate solution, saturated sodium-chloride water solution, had successively
Machine layer is stayed overnight with anhydrous sodium sulfate drying.Next day filters, and removes solvent under reduced pressure, column chromatography obtains buff granular solids (R)-N-
(2,3- dihydroxy propoxyl group) -3,4,5- tri- fluoro- 2- [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzamides (0.14g,
72.2%).1H-NMR(400MHz,DMSO-D6)δppm:8.23(s,1H),7.73(s,1H),7.64-7.60(m,1H),7.49-
7.48(m,1H),7.32-7.29(m,1H),6.28-6.26(m,1H),4,86(br s,1H),4.65(br s,1H),4.19-
4.16(m,1H),4.03-3.99(m,1H),3.72-3.70(m,2H),3.35-3.34(m,2H),2.25(s,3H),ESI-MS
m/z:498.2[M+1]+。
Fluoro- 2- [(the chloro- 5- bromo-2-pyridyls bases of the 3-) ammonia of embodiment 17 (R)-N- (2,3- dihydroxy propoxyl group) -3,4,5- three
Base] benzamide
Method be the same as Example 16, obtains fluoro- the 2- [(3- of faint yellow solid (R)-N- (2,3- dihydroxy propoxyl group) -3,4,5- tri-
Chloro- 5- bromo-2-pyridyls base) amino] benzamide.1H-NMR(400MHz,DMSO-D6)δppm:11.77(s,1H),8.28(s,
1H),8.06-8.05(m,1H),7.83-7.82(m,1H),7.38-7.36(m,1H),3.98-3.96(m,1H),3.81-3.75
(m,2H),3.45-3.36(m,2H),2.25(s,3H),ESI-MS m/z:498.1[M+1]+。
The fluoro- 2- of embodiment 18 N- (cyclohexyl methyl) -3,4,5- three [(3- methyl -5- bromo-2-pyridyls base) amino] benzene first
Acid amides
Method be the same as Example 4, obtains faint yellow solid N- (cyclohexyl methyl) -3, [(3- methyl -5- is bromo- by 4,5- tri- fluoro- 2-
2- pyridine radicals) amino] benzamide.1H-NMR(400MHz,DMSO-D6)δppm:8.56-8.53 (t, 1H, J=5.6Hz),
8.28(s,1H),7.96-7.95(m,1H),7.73-7.72(m,1H),7.33-7.31(m,1H),3.13-3.08(m,2H),
2.28(s,3H),1.74-1.50(m,8H),1.30-1.09(m,3H).ESI-MS m/z:458.1[M+1]+。
The fluoro- 2- of the N- of embodiment 19 (2- morpholines ethyl) -3,4,5- three [(3- methyl -5- bromo-2-pyridyls base) amino] benzene first
Acid amides
Method be the same as Example 4, obtaining the fluoro- 2- of faint yellow solid N- (2- morpholines ethyl) -3,4,5- tri-, [(3- methyl -5- is bromo-
2- pyridine radicals) amino] benzamide.1H-NMR(400MHz,DMSO-D6)δppm:8.42(m,1H),8.27(s,1H),7.96
(m,1H),7.72(m,1H),7.35-7.32(m,1H),3.59-3.57(m,4H),3.40-3.37(m,2H),2.49-2.42
(m,6H),2.28(s,3H),ESI-MS m/z:473.3[M+1]+。
Fluoro- 2- [(3- methyl -5- bromo-2-pyridyls base) ammonia of the N- of embodiment 20 [2- (piperidin-1-yl) ethyl] -3,4,5- three
Base] benzamide
Method be the same as Example 4, obtains fluoro- 2- [(the 3- first of faint yellow solid N- [2- (piperidin-1-yl) ethyl] -3,4,5- tri-
Base -5- bromo-2-pyridyls base) amino] benzamide.1H-NMR(400MHz,DMSO-D6)δppm:8.39(m,1H),8.27(s,
1H),7.96(m,1H),7.72(m,1H),7.34-7.33(m,1H),3.37-3.34(m,2H),2.450-2.40(m,6H),
2.28(s,3H),1.51-1.50(m,4H),1.39-1.38(m,2H),ESI-MS m/z:471.2[M+1]+。
The fluoro- 2- of the N- of embodiment 21 (3- phenylpropyls) -3,4,5- three [(the iodo- 2- pyridine radicals of 3- methyl -5-) amino] benzoyl
Amine
Method be the same as Example 4, obtains dark yellow solid N- (3- phenylpropyls) -3,4,5- tri- fluoro- 2- [(the iodo- 2- of 3- methyl -5-
Pyridine radicals) amino] benzamide.1H-NMR(400MHz,CDCl3)δppm:8.23(s,1H),7.76(s,1H),7.67-7.64
(m,1H),7.28-7.20(m,5H),6.66(br s,1H),6.17(br s,1H),3.52-3.49(m,2H),2.74-2.71
(t, 2H, J=7.6Hz), 2.29 (s, 3H), 1.99-1.96 (m, 2H).ESI-MS m/z:526.3[M+1]+。
Fluoro- 2- [(the chloro- 5- bromo-2-pyridyls bases of the 3-) ammonia of the N- of embodiment 22 [2- (piperidin-1-yl) ethyl] -3,4,5- three
Base] benzamide
Method be the same as Example 4, obtaining dark yellow solid N- [2- (piperidin-1-yl) ethyl], [(3- is chloro- by -3,4,5- tri- fluoro- 2-
5- bromo-2-pyridyls base) amino] benzamide.1H-NMR(400MHz,DMSO-D6)δppm:8.81(s,1H),8.15-8.11(s,
2H),7.39-7.36(m,1H),3.36-3.34(m,2H),2.43-2.38(m,6H),1.51-1.49(m,6H)。ESI-MS m/
z:493.1[M+1]+。
Embodiment 23,5- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino] fluoro- 1H- benzimidazoles -6- formic acid of -4-
Step 1,5- nitro -2,3,4- trifluoro-benzoic acids
It will be slowly dropped under fuming nitric aicd (37mL, 0.78mol) condition of ice bath in the concentrated sulfuric acid (200mL), other one
In individual reaction system, 2,3,4- trifluoro-benzoic acids (109.4g, 0.62mol) and concentrated sulfuric acid 330mL are added.Will under condition of ice bath
The concentrated sulfuric acid solution of fuming nitric aicd is slowly dropped in the concentrated sulfuric acid solution of reaction raw materials.Ice bath is removed, room temperature is warmed naturally to,
Stirring reaction 5h.Reaction solution is slowly dropped in 2000mL ice water solution under stirring condition, 2h is stirred at room temperature, was stood
At night, it is filtrated to get white solid 5- nitros -2,3,4- trifluoro-benzoic acids (123.7g, 90.3%), ESI-MS m/z:222.0[M+
1]+
Step 2, the fluoro- 2- of 5- nitros -3,4- two [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino]-benzoic acid
Under nitrogen protective condition, by 2- amino -3- methyl -5- iodine pyridines (10.61g, 0.045mol), 70mL is dissolved in anhydrous
In tetrahydrofuran (THF), -70 DEG C are cooled to.By the THF solution of 2M lithium diisopropylamine (LDA) drop (34mL,
0.068mol) it is added in reaction system, 1h is reacted under the conditions of -70 DEG C.5- nitro -2,3,4- trifluoro-benzenes are added dropwise into reaction system
The THF solution of formic acid (5.01g, 0.023mol), completion of dropping, -70 DEG C of reaction 1h.Naturally room temperature is warming up to, was stirred at room temperature
Night.Saturated aqueous ammonium chloride, saturated sodium-chloride water solution washing successively, ethyl acetate extracts water layer, and organic layer is dried overnight,
Column chromatography obtain the fluoro- 2- of yellow solid 5- nitros -3,4- bis- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino]-benzoic acid (4.78g,
47.8%),1H-NMR(400MHz,CDCl3)δppm:8.26-8.25(m,1H),7.76-7-75(br s,1H),7.21-7.19
(m,1H),5.99(s,1H),2.31(s,3H),ESI-MS m/z:436.0[M+1]+。
Step 3, the fluoro- 2- of 5- nitro -4- amino -3- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino]-benzoic acid
By the fluoro- 2- of 5- nitros -3,4- bis- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino]-benzoic acid (2.30g,
5.29mmol) it is added in 100mL distilled water, cools to 0 DEG C.Be added dropwise into reaction system concentrated ammonia liquor (2.21mL,
29.6mmol), 0 DEG C of reaction 1h.Clear-cutting forestland reacts 4h, filters to obtain the fluoro- 2- of yellow solid 5- nitro -4- amino -3- to room temperature
[(the iodo- 3- methyl 2- pyridine radicals of 5-) amino]-benzoic acid (1.82g, 79.5%),1H-NMR(400MHz,CDCl3)δppm:
8.26-8.25(m,1H),7.76-7-75(br s,1H),7.21-7.19(m,1H),6.27(s,2H),5.99(s,1H),2.31
(s,3H),ESI-MS m/z:433.1[M+1]+。
Step 4, the fluoro- 2- of 5- nitro -4- amino -3- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino]-methyl benzoate
By the fluoro- 2- of 5- nitro -4- amino -3- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino]-benzoic acid (1.82g,
4.21mmol) it is dissolved in 20mL absolute methanols, trim,ethylchlorosilane (1.06mL, 8.42mmol) is slowly added dropwise.Completion of dropping, is returned
Flow 12h.Water pump removes the trim,ethylchlorosilane of solvent and excess under reduced pressure, obtains weak yellow liquid, adds dichloromethane 20mL, and
Washed with 10% sodium hydrate aqueous solution, the anti-water lift layer of dichloromethane merges organic layer, organic layer anhydrous sodium sulfate drying
Overnight.Next day filters, and removes solvent under reduced pressure, obtains yellow solid 5- nitro -4- amino -3- fluoro- 2- [(the iodo- 3- methyl 2- pyridines of 5-
Base) amino]-methyl benzoate (1.84g, 97.9%),1H-NMR(400MHz,CDCl3)δppm:8.26-8.25(m,1H),
7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 6.27 (s, 2H), 5.99 (s, 1H), 3.97 (s, 3H), 2.31 (s,
3H),ESI-MS m/z:447.1[M+1]+。
Step 5,5- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino] fluoro- 1H- benzimidazoles -6- methyl formates of -4-
By the fluoro- 2- of 5- nitro -4- amino -3- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino]-methyl benzoate (1.84g,
4.12mmol), formic acid (25mL) and 20%Pd (OH)/C (1.57g, 2.95mrnol) are heated to 95 DEG C in 25mL ethanol.
After 16 hours, reactant mixture is cooled to room temperature, and add 0.5g 20%Pd (OH) 2/C and 10mL formic acid.By reaction mixing
Thing is heated to 95 DEG C.After 16 hours, reactant mixture is cooled to room temperature, and filtered by diatomite, is washed with ethanol.Decompression
Filtrate is concentrated, has solid precipitation, is filtrated to get dark yellow solid 5- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino] fluoro- 1H- of -4-
Benzimidazole -6- methyl formates (1.35g, 76.7%),1H-NMR(400MHz,CDCl3)δppm:(8.41-8.39 m, 1H),
8.19 ((s, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 6.21 (s, 1H), 5.99 (s, 1H), 3.97 (s,
3H), 2.31 (s, 3H), ESI-MS m/z:427.1[M+1]+。
Step 6,5- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino] fluoro- 1H- benzimidazoles -6- formic acid of -4-
By 5- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino] the fluoro- 1H- benzimidazoles -6- methyl formates (1.35g of -4-
3.17mmol) suspend in (30mL) in methyl alcohol, add after 20%NaOH (8mL), 16h, reactant mixture is cooled to 0 DEG C,
And 1NHCl solution is added dropwise, until pH is 2-3.Reactant mixture ethyl acetate and water are diluted, and separate each layer.Use saturation
Sodium-chloride water solution washs organic layer, and organic layer is stayed overnight with anhydrous sodium sulfate drying.Next day filters, and removes solvent, post layer under reduced pressure
Analyse dark yellow solid 5- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino] fluoro- 1H- benzimidazoles -6- formic acid of -4- (0.68g,
52.3%),1H-NMR(400MHz,CDCl3)δppm:8.41-8.39 (m, 1H), 8.19 ((s, 1H), 7.76-7-75 (br s,
1H),7.21-7.19(m,1H),6.21(s,1H),5.99(s,1H),2.31(s,3H),ESI-MS m/z:413.1[M+1]+。
Embodiment 24, N- [2- (thiophene -2- bases) ethyl] -5- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino] fluoro- 1H- of -4-
Benzimidazole -6- formamides
By obtained 35- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino] fluoro- 1H- benzimidazoles -6- of -4- in embodiment 23
Formic acid (0.23g, 0.57mol), 2- (thiophene -2- bases) ethamine (0.13g, 1.03mmol), DIEA (0.12mL, 0.68mmol) are molten
In 20mL dichloromethane, add PyBOP (0.34g, 0.65mmol) and be stirred overnight at room temperature.Anhydrous second is added into reaction system
Ether 40mL, washs organic phase with water, saturated sodium-chloride water solution respectively, and organic layer is stayed overnight with anhydrous sodium sulfate drying.Next day mistake
Filter, removes solvent under reduced pressure, column chromatography obtains faint yellow solid N- [2- (thiophene -2- bases) ethyl] -5- [(iodo- 3- methyl 2- pyridines of 5-
Base) amino] the fluoro- 1H- benzimidazoles -6- formamides of -4- (0.17g, 56.7%),1H-NMR(400MHz,CDCl3)δppm:
8.41-8.39 (m, 1H), 8.19 ((s, 1H), 7.76-7-75 (br s, 1H), 7.21-7.19 (m, 1H), 6.98-6.96 (m,
2H),6.89-6.88(m,1H),6.21(s,1H),5.99(s,1H),6.75-6.78(m,1H),3.78-3.75(m,2H),
3.18-3.15 (t, 2H, J=6.7Hz), 2.31 (s, 3H), ESI-MS m/z:522.0[M+1]+。
Embodiment 25, N- [2- (piperidin-1-yl) ethyl] -5- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino] fluoro- 1H- of -4-
Benzimidazole -6- formamides
Method be the same as Example 24, yellow solid N- [2- (piperidin-1-yl) ethyl] -5- [(iodo- 3- methyl 2- pyrroles of 5-
Piperidinyl) amino] the fluoro- 1H- benzimidazoles -6- formamides of -4-,1H-NMR(400MHz,DMSO-D6)δppm:8.41-8.39 (m,
1H), 8.19 ((s, 1H), 7.76-7-75 (brs, 1H), 6.89-6.88 (m, 1H), 6.21 (s, 1H), 5.99 (s, 1H), 6.75-
6.78(m,1H),3.36-3.34(m,2H),2.43-2.38(m,6H),2.31(s,3H),1.51-1.49(m,6H),ESI-MS
m/z:523.1[M+1]+。
Embodiment 26, active testing
Preliminary activation test has been carried out to the part of compounds in embodiment 1-25, compound has been have rated and suppresses bone in vitro
The activity of marrow leukaemia cell (K562) and Human Large Intestine Carcinoma Cells (HT-29) tumor cell proliferation.
After the growth of tumour cell of culture to certain density, attached cell is hanged with 0.25% Trypsin Induced 2-5min
Floating cell centrifugation (1000rpm/min), single cell suspension, adjustment cell concentration to corresponding density are prepared with the corresponding nutrient solution of cell
(1×105Individual/mL), it is inoculated in 96 well culture plates, 100 μ L/ holes, 37 DEG C, 5%CO280 μ L/ holes phases are first added after lower culture 24h
The full culture medium of cell is answered, the μ L/ holes of test-compound 20 of various concentrations are added, every kind of processing sets 3 repetitions, 37 DEG C, 5%
Continue to cultivate after 72h under CO2, the μ L of supernatant 100 suctioned out per hole, add 5mg/mL tetrazolium bromide (MTT) solution 10 μ L, 37 DEG C after
It is continuous to be incubated 4h, the last SDS, 37 DEG C of 5%CO that 100 μ L 10% are added per hole2Lower incubation 24h, is completely dissolved MTT crystallizations.Enzyme
Join immune detector 570nm wavelength to determine per hole absorbance.By formula：
Inhibiting rate (%)=(1-by prospect hole OD values/solvent control hole mean OD value) × 100%
Inhibiting rate is calculated, and using the logarithm of Test compound concentrations as abscissa, cell inhibitory rate average value is ordinate
Dose-effect curve is drawn, and seeks with Origin analysis softwares half Carbazole alkaloid dose value (IC50)。
Wherein the culture medium of K562 cells is 1640+10%FBS, and HT-29 culture medium is DMEM (Hg)+F12+5%
FBS。
Medicine is assigned to mother liquid concentration with DMSO (Sigma) before test, needed for being diluted to the full culture medium without the factor
Using concentration.Preliminary assessment compound for tumour cell growth inhibition effect when, from compound concentration be 3,30,300 μ
Tri- dosage groups of M, blank control group (being not added with tumour cell and test-compound, only add nutrient solution), a solvent control group (solubilization
Agent is not added with test-compound)；Further seek its half Carbazole alkaloid dose value (IC50) when, compound is selected according to primary dcreening operation result
Concentration is 1,3,10,30,100,200,300 μM of six dosage groups, blank control group (the same), solvent control group (the same).
Concrete outcome is shown in Table 1.
Inhibitory activity of the part of compounds of table 1 to K562 and HT-29
Wherein Pd198306 is positive control, and its structural formula is as follows：
Test result indicates that, compound on tumor cell of the invention has significant inhibition.
Although the embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.Root
According to disclosed all teachings, various modifications and replacement can be carried out to those details, these change the guarantor in the present invention
Within the scope of shield.The four corner of the present invention is provided by appended claims and its any equivalent.
Claims (7)
1. compound shown in formula VI, or its pharmaceutically acceptable salt,
Wherein, R4、R5、R7And R8It is each independently hydrogen, halogen, nitro, itrile group, trifluoromethyl or C1-C3Alkyl；
R6Selected from hydrogen, trifluoromethyl and C1-C3Alkyl；
W is-NR10R9；
R9For hydrogen；
R10Selected from 5-6 unit's heteroaryls-C1-C3- alkyl and 5-6 circle heterocycles bases-C1-C3- alkyl.
2. compound according to claim 1, it is selected from：
N- [2- (thiophene -2- bases) ethyl] -5- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino] fluoro- 1H- benzimidazoles -6- first of -4-
Acid amides；
N- [2- (piperidin-1-yl) ethyl] -5- [(the iodo- 3- methyl 2- pyridine radicals of 5-) amino] fluoro- 1H- benzimidazoles -6- first of -4-
Acid amides.
3. a kind of pharmaceutical composition, it includes claim 1 or 2 compound or its pharmaceutically acceptable salt, and pharmaceutically acceptable
Carrier.
4. claim 1 or 2 compound or its pharmaceutically useful salt are used for the medicine for preparing suppression cell hyperproliferation disease
Purposes.
5. the purposes of claim 4, wherein the cell hyperproliferation disease be selected from leukaemia, colorectal cancer, spongioblastoma,
Lymthoma, melanoma, neuropathic pain and inflammation.
6. claim 1 or 2 compound or its pharmaceutically useful salt are used for the purposes for preparing antineoplastic.
7. the purposes of claim 6, wherein the tumour is selected from leukaemia, colorectal cancer, spongioblastoma, lymthoma and black
Plain knurl.
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