CN105384738B - Heterocycle compound as kinases inhibitor and its production and use - Google Patents

Heterocycle compound as kinases inhibitor and its production and use Download PDF

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Publication number
CN105384738B
CN105384738B CN201510501147.3A CN201510501147A CN105384738B CN 105384738 B CN105384738 B CN 105384738B CN 201510501147 A CN201510501147 A CN 201510501147A CN 105384738 B CN105384738 B CN 105384738B
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compound
alkyl
fluoro
idodophenylaminos
methyl
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CN105384738A (en
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田红旗
黄功超
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KECHOW PHARMA Inc
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KECHOW PHARMA Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The present invention relates to formula (I) and (II) compound and its pharmaceutically acceptable salt, prodrug and solvate, wherein R1、R2、R3, A and X be defined as in the description.This kind of compound is kinases inhibitor, especially kinases inhibitor Mek inhibitor, and available for cancer and inflammation in treatment mammal.The invention also discloses the preparation method of formula (I) and (II) compound and include the pharmaceutical composition of the compound.

Description

Heterocycle compound as kinases inhibitor and its production and use
Technical field
The present invention relates to protein kinase (especially protein kinase Mek) inhibitor, more specifically, it is related to and swashs as albumen The Imidazopyridine and its pharmaceutically acceptable salt, prodrug, solvation of enzyme (especially protein kinase Mek) inhibitor Thing and the composition comprising these materials, and it is related to the preparation method of the Imidazopyridine, further relate to the miaow Azoles and pyridine derivate and its pharmaceutically acceptable salt, prodrug and solvate are used as protein kinase (especially protein kinase Mek) the purposes of inhibitor.
Background technology
The cell signalling controlled by growth factor and protein kinase is in the growth of cell, propagation and has broken up emphatically The effect wanted.In the growth of normal cell, growth factor (such as PDGF or EGF) by receptor activation (such as ErbB2, EGFR, PDGFR etc.) activation MAP (Mitogen--activating protein) kinase signal transduction passage.Ras/Raf/Mek/Erk Signal transduction mechanism is one of most important approach of cell growth.In proliferative diseases, due under growth factor receptors or its The protein kinase producer mutation of trip is over-expressed, so as to cause the growth of cell out of hand, ultimately results in cancer.Example Such as in some cancers, due to gene mutation so that the signal transduction mechanism is by lasting activation, so as to result in some growths The lasting generation of the factor, the growth for having finally resulted in cell loses control, so that canceration.Statistics shows, 50% knot Caused by intestinal cancer, more than 90% cancer of pancreas are due to Ras gene mutations；More than 60% malignant mela noma is due to bRaf Caused by gene mutation.Research shows, finds that Ras/Raf/Mek/Erk signal transduction mechanisms are continuous in kinds cancer Activation or excessive activation, such as cancer of pancreas, colon cancer, lung cancer, carcinoma of urinary bladder, kidney, cutaneum carcinoma, breast cancer.
Because the overactivity of the signal transduction mechanism has played important function in the propagation of cancer cell and differentiation, so suppression Making the approach contributes to the treatment to this kind of excess proliferative disease.Mek is located at Ras and Raf downstream target, is risen in the approach The effect of key, the substrate of Mek phosphorylations is map kinase Erk.If Mek is suppressed, Ras/Raf/Mek/Erk signals Pathway will be closed, so that the propagation of cancer cell will be suppressed.Therefore, Mek inhibitor can suppress cancer cell Increase, especially for cancer caused by Ras or Raf overactivities.At the same time Mek is directed to disease and the disease of inflammation class Shape, including acute and chronic inflammation.
Mek inhibitor shows certain drug effect in the pharmacodynamic experiment of nude mice.Some nearest Mek inhibitor are It is clinical through entering, and also show certain drug effect.Therefore Mek is the new target drone of potential druggability, just because of this, increasingly Many Mek inhibitor are being developed and report comes out.For example, WO 98/43960；WO 99/01421；WO 99/01426；WO 00/41505；WO 00/42002；WO 00/41003；WO 00/41994；WO 00/42022；WO 00/42029；WO 00/ 68201；WO 01/68619；WO 01/005390；WO 02/06213；WO 03/077914；WO 03/077855；WO 03/ 077914；WO 05/023251；WO 05/023759；WO 05/051300；WO 05/051301；WO 05/051302；WO 05/051906；WO 05/000818；WO 05/007616；WO 05/009975；WO 05/046665；WO 06/134469；WO 07/044084；WO 07/014011；WO 07/121269；WO 07/121481；WO 07/071951；WO 07/044515；WO 08/021389；WO 08/076415；WO 08/089459；WO 08/078086；WO 08/120004；WO 08/124085；WO 08/125820；WO 09/018238；WO 09/074827；WO 09/013426；WO 09/093008；WO 09/093009；WO 09/093013；WO 09/153554；WO 12/059041；EP 1780191；US 2012/0238599；WO 2007/044084 Etc..
The content of the invention
One aspect of the present invention provides the compound and its pharmaceutically acceptable salt of formula (I) and (II), prodrug and molten Agent compound
Wherein
R1Selected from hydrogen, halogen, cyano group, nitro, azido, hydroxyl, C1-C10Alkoxy, halo C1-C10Alkoxy, sulfydryl, C1-C10Alkylthio group, halo C1-C10Alkylthio group, carboxyl ,-OC (O) H, amino, C1-C10Alkyl, C2-C10Alkenyl, C2-C10Alkynyl, C3-C10Cycloalkyl；
R2Selected from hydrogen, halogen, nitro, azido, hydroxyl, C1-C10Alkyl, C1-C10Alkoxy, halo C1-C10Alkoxy, C1-C10Alkylthio group, halo C1-C10Alkylthio group, carboxyl ,-OC (O) H, amino, C2-C10Alkenyl, C2-C10Alkynyl, C3-C10Cycloalkanes Base；
R3Selected from hydrogen, C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C3-C12Cycloalkyl C1-C12Alkane Base, C1-C12Alkyl C3-C12Cycloalkyl, the alkyl, alkenyl, alkynyl and cycloalkyl can be independently of one another by one to three Arbitrarily replace selected from following group：- ORa ,-NRaRb ,-NRaC (O) Rb, Heterocyclylalkyl and heterocyclic aromatic base, it is described herein miscellaneous Cycloalkyl and heterocyclic aromatic base can arbitrarily be replaced by one to three selected from following substituent：C1-C5Alkyl ,-ORa ,- NRaRb；
X representative formula (i):
Wherein
Y is selected from O ,-ONR8、-NR8O、-NR8C(O)、-NR8SO2；
Z is selected from hydrogen, C1-C5Methene chain, the methylene can arbitrarily be replaced by one to three W'；
R8Selected from hydrogen, C1-C12Alkyl ,-COR9, the alkyl can arbitrarily replace by halogen ,-ORa ,-NRaRb；
R9Selected from hydrogen, C1-C12Alkyl, the alkyl can arbitrarily be replaced by halogen ,-ORa ,-NRaRb；
Or X representative formula (ii):
Wherein
Y1And Y2Can be the same or different, each of which independently represent singly-bound ,-CO- ,-COO- ,-O- ,-OCO- ,- NRa-、-SO2-；
Z' represents C1-C10Chain alkylene, the alkyl can arbitrarily be replaced by one to three W'；
In above-mentioned formula (i) and formula (ii),
W and W' can be the same or different, and each of which is independently selected from halogen, C1-C5Alkyl ,-O- ,-ORa ,- COORa ,-COOCORa ,-CO- halogens ,-OCORa ,-CONRaRb ,-SRa ,-SORa ,-SO2Ra、-NRaRb、-NRaCORb、- NRaSO2Rb、-SO2NRaRb, Heterocyclylalkyl or heterocyclic aromatic base, the Heterocyclylalkyl and heterocyclic aromatic base can be by one to three Arbitrarily replace selected from following substituent：C1-C5Alkyl ,-ORa ,-NRaRb；The alkyl can be by hydroxyl, C1-C5Alkoxy or Amino arbitrarily replaces；
Cycloalkyl or Heterocyclylalkyl, the cycloalkyl or heterocycle can be interconnected to form outside above-mentioned group deoxygenation and halogen Alkyl can be selected from following substituent and arbitrarily replace：- ORa ,-NRaRb, the C arbitrarily replaced by-ORa1-C5Alkyl；
Ra and Rb can be the same or different, and each of which is independently selected from hydrogen, C1-C5Alkyl, the alkyl can be by one Individual to three arbitrarily replace selected from following substituent：Hydroxyl, C1-C5Alkoxy, amino.
When X representative formula (i), formula (I) and (II) compound have following structure：
As X representative formula (ii), formula (I) and (II) compound have with following formula (I-2) structure：
As Y representative-O-, when W represents OH, the compound of formula (I-1) has with following formula (I-1-a) structure：
As Y representative-NHO-, the compound of formula (I-1) has following structure：
As Y representatives-NR8During O-, the compound of formula (I-1) has with following formula (I-1-c) structure：
Work as Y1Represent singly-bound, Y2During representative-O-, the compound of formula (I-2) has with following formula (I-2-A) structure：
Another aspect of the present invention provides the preparation method of the compound of formula (I)：
(A) route 1
(B) route 2
(C) formula (I-1-a) compound is prepared according to following routes 3：
Wherein, the synthesized reference route 2 of compound 11
(D) formula (I-1-b) compound is prepared according to following routes 4：
Wherein, the synthesized reference route 2 of compound 11
(E) formula (I-1-c) compound is prepared according to following routes 5：
(F) formula (I-2-A) compound is prepared according to following routes 6：
(G) formula (I-2-A) compound is prepared according to following routes 7：
An additional aspect of the present invention, which is provided, includes formula (I) and (II) compound or its pharmaceutically acceptable salt, prodrug With the Pharmaceutical composition of solvate.
Another aspect of the invention provides formula (I) and (II) compound or its pharmaceutically acceptable salt, prodrug and molten Agent compound is used to manufacture the tumour for the treatment of mammal, acute and chronic inflammation disease, inflammatory bowel disease, skin disease, sugar Urinate disease, eye disease, the angiogenesis to mammal or the related disease of revascularization and chronic ache correlation disease, With the purposes of the medicine of other diseases that modulation is cascaded by Mek.
Embodiment
If without it is further noted that complete disclosure of the present invention is defined using following term：
Term " prodrug " refers to that any derivative of corresponding active pharmaceutical compounds can be converted into vivo.One In individual embodiment, when the compound of the present invention contains hydroxyl, its prodrug can be the ester that it is formed with suitable acid, described Acid is included such as lactic acid, citric acid, ascorbic acid.
Term " pharmaceutically acceptable salt ", unless otherwise indicated, including the acidity that may be present in the compounds of this invention The salt (such as, but not limited to, sylvite, sodium salt, magnesium salts, calcium salt etc.) of group or the salt of basic group are (such as, but not limited to, sulphur Hydrochlorate, hydrochloride, phosphate, nitrate, carbonate etc.).
Term " solvate " refers to that in the solution solute molecule or ion pass through Coulomb force, Van der Waals for, electric charge Transmit the compound molecule compound of the adjacent solvent molecule formation of gravitational attraction between power, hydrogen bond equimolecular.In one embodiment, Solvent is water, i.e. the compounds of this invention formation hydrate.
The alkyl, alkenyl, alkynyl, cycloalkyl moiety can be appointed by one or more selected from following group independently of one another Choose generation：Hydroxyl, oxo, halogen, cyano group, nitro, trifluoromethyl, azido, amino, carboxyl, sulfydryl.
Saturation or unsaturated alkyl, such as alkyl, alkane diyl or alkenyl, including with heteroatomic combination, such as alkoxy, Can be straight chain or with side chain respectively.
According to the difference of substituent, formula (I) and (II) compound can be mixed with the isomers of optical isomer or different compositions Solvate form is present, and the mixture can be separated by conventional methods if appropriate.The invention provides pure isomer and isomery Body mixture, and its production and use, and including their compositions.For simplicity, hereinafter referred to as formula (I) and (II) compound, it had both referred to pure optical isomer, also referred to the isomer mixture of different proportion if appropriate.
In some embodiments of the present invention there is provided formula (I) and the compound and its pharmaceutically acceptable salt of (II), Prodrug and solvate
Wherein
A is selected from C and N；
R1Selected from hydrogen, halogen, cyano group, nitro, azido, hydroxyl, C1-C10Alkoxy, halo C1-C10Alkoxy, sulfydryl, C1-C10Alkylthio group, halo C1-C10Alkylthio group, carboxyl ,-OC (O) H, amino, C1-C10Alkyl, C2-C10Alkenyl, C2-C10Alkynyl, C3-C10Cycloalkyl；
R2Selected from hydrogen, halogen, nitro, azido, hydroxyl, C1-C10Alkyl, C1-C10Alkoxy, halo C1-C10Alkoxy, C1-C10Alkylthio group, halo C1-C10Alkylthio group, carboxyl ,-OC (O) H, amino, C2-C10Alkenyl, C2-C10Alkynyl, C3-C10Cycloalkanes Base；
R3Selected from hydrogen, C1-C12Alkyl, C2-C12Alkenyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C3-C12Cycloalkyl C1-C12Alkane Base, C1-C12Alkyl C3-C12Cycloalkyl, the alkyl, alkenyl, alkynyl and cycloalkyl can be independently of one another by one to three Arbitrarily replace selected from following group：- ORa ,-NRaRb ,-NRaC (O) Rb, Heterocyclylalkyl and heterocyclic aromatic base, it is described herein miscellaneous Cycloalkyl and heterocyclic aromatic base can arbitrarily be replaced by one to three selected from following substituent：C1-C5Alkyl ,-ORa ,- NRaRb；
X representative formula (i):
Wherein
Y is selected from O ,-ONR8、-NR8O、-NR8C(O)、-NR8SO2；
Z is selected from hydrogen, C1-C5Methene chain, the methylene can arbitrarily be replaced by one to three W'；
R8Selected from hydrogen, C1-C12Alkyl ,-COR9, the alkyl can arbitrarily replace by halogen ,-ORa ,-NRaRb；
R9Selected from hydrogen, C1-C12Alkyl, the alkyl can arbitrarily be replaced by halogen ,-ORa ,-NRaRb；
Or X representative formula (ii):
Wherein
Y1And Y2Can be the same or different, each of which independently represent singly-bound ,-CO- ,-COO- ,-O- ,-OCO- ,- NRa-、-SO2-；
Z' represents C1-C10Chain alkylene, the alkyl can arbitrarily be replaced by one to three W'；
In above-mentioned formula (i) and formula (ii),
W and W' can be the same or different, and each of which is independently selected from halogen, C1-C5Alkyl ,-O- ,-ORa ,- COORa ,-COOCORa ,-CO- halogens ,-OCORa ,-CONRaRb ,-SRa ,-SORa ,-SO2Ra、-NRaRb、-NRaCORb、- NRaSO2Rb、-SO2NRaRb, Heterocyclylalkyl or heterocyclic aromatic base, the Heterocyclylalkyl and heterocyclic aromatic base can be by one to three Arbitrarily replace selected from following substituent：C1-C5Alkyl ,-ORa ,-NRaRb；The alkyl can be by hydroxyl, C1-C5Alkoxy or Amino arbitrarily replaces；
Cycloalkyl or Heterocyclylalkyl, the cycloalkyl or heterocycle can be interconnected to form outside above-mentioned group deoxygenation and halogen Alkyl can be selected from following substituent and arbitrarily replace：- ORa ,-NRaRb, the C arbitrarily replaced by-ORa1-C5Alkyl；
Ra and Rb can be the same or different, and each of which is independently selected from hydrogen, C1-C5Alkyl, the alkyl can be by one Individual to three arbitrarily replace selected from following substituent：Hydroxyl, C1-C5Alkoxy, amino.
Above-mentioned general formula compound (I) and (II) and following preferred formulas (I) and (II) compound be preferably as follows substituent or Group：
R1Selected from fluorine, chlorine, bromine, iodine, C1-C4Alkoxy, C1-C4Alkylthio group, halo-C1-C4Alkoxy, halo-C1-C4Alkane Sulfenyl, C1-C4Alkyl, halo C1-C4Alkyl C2-C4Alkenyl, C2-C4Alkynyl；
R2It is preferred that hydrogen, halogen or C1-C4Alkyl；
R3It is preferred that C that is unsubstituted or being replaced by 1 to 6 hydroxyl1-C4Alkyl, C3-C4Cycloalkyl, C3-C4Cycloalkyl C1-C4 Alkyl or C1-C4Alkyl C3-C4Cycloalkyl.
R1Selected from bromine, iodine, C1-C2Alkylthio group, halo-C1-C2Alkylthio group, C1-C2Alkoxy, halo-C1-C2Alkoxy, C1-C2Alkyl, halo C1-C2Alkyl, C2-C3Alkenyl, C2-C3Alkynyl；
R2More preferably hydrogen, fluorine, chlorine, bromine or C1-C2Alkyl；
R3C that is more preferably unsubstituted or being replaced by 1 to 3 hydroxyl1-C3Alkyl, C3-C4Cycloalkyl, C3-C4Cycloalkyl C1- C3Alkyl or C1-C3Alkyl C3-C4Cycloalkyl.
R1Selected from bromine, iodine, methyl mercapto, trifluoromethylthio, methoxyl group, trifluoromethoxy, methyl, trifluoromethyl, vinyl, Acetenyl；
R2Particularly preferred fluorine, chlorine or methyl；
R3Particularly preferred 2- hydroxyethyls, 2,3- dihydroxypropyls, 1- methylol -2- hydroxyethyls, 2- methyl -3- hydroxyls Propyl group, cyclopropyl, Cvclopropvlmethvl or 1- (2,3- hydroxypropyls) cyclopropyl.
As-the Y-Z-W that X preferred formulas (i) are represented,
Y preferably-O- ,-NR8O-、-NR8C(O)-、-NR8SO2-；
Y more preferably-O- ,-NR8O-、-NR8C(O)-；
Y particularly preferably-NR8O-、-NR8C(O)-；
R8It is preferred that hydrogen, C1-C6Alkyl ,-COR9；
R8More preferably hydrogen, C1-C3Alkyl ,-COR9；
R8Particularly preferred hydrogen, methyl ,-COH ,-COCH3、-COCH2CH3、-COCH(CH3)2、-COCH2OH；
The preferred hydrogen of Z, C1-C5Methene chain, the methylene can arbitrarily be replaced by one to three W'；
Z more preferably hydrogen ,-CH2-、-(CH2)2-、-(CH2)3-、-CH2(CH3)CH2-、-CH2C(CH3)2-、-CH2C(CH3)2CH2-、-CH2C(CH2CH2)CH2-, and can arbitrarily be replaced by W'；
W and W' can be the same or different, each of which independently preferred halogen, C1-C5Alkyl ,-ORa ,-COORa ,- COOCORa、-OCORa、-CONRaRb、-SRa、-SORa、-SO2Ra、-NRaRb、-NRaCORb、-NRaSO2Rb、-SO2NRaRb、 Heterocyclylalkyl or heterocyclic aromatic base；
W and W' can be the same or different, each of which independently more preferably halogen, C1-C3Alkyl ,-ORa ,- COORa、-COOCORa、-OCORa、-CONRaRb、-SRa、-SORa、-SO2Ra、-NRaRb、-NRaCORb、-SO2It is NRaRb, miscellaneous Cycloalkyl or heterocyclic aromatic base；
W and W' can be the same or different, each of which independently particularly preferred hydrogen, hydroxyl, methyl ,-O (CH2)2OH、-C(O)OCH3、-CONHCH3、-CONHCH2CH3、-CONHCH(CH3)2、-CON(CH3)2、-NHCH3、-NH(CH2)2OH、- NHCOCH3、-NHCOCH2CH3、-NHCOCH(CH3)2、-SCH3、-SOCH3, 1H- imidazoles -2- bases, morpholine -4- bases, 4- hydroxyls Piperidyl.
When X is the substituent that formula (ii) is represented,
X is preferred
The preferred C of Z'1-C3Chain alkylene, the alkyl can arbitrarily be replaced by one to three W'；
The preferred C of W'1-C3Alkyl ,-ORa ,-COORa ,-COOCORa ,-CO- halogens ,-OCORa ,-CONRaRb ,-SRa ,- SORa、-SO2Ra、-NRaRb、-NRaCORb、-NRaSO2Rb、-SO2NRaRb；
Ra and Rb can be the same or different, and each of which is independently selected from hydrogen, C1-C3Alkyl, the alkyl can be by one Individual to three arbitrarily replace selected from following substituent：Hydroxyl, C1-C3Alkoxy, amino.
X is more preferably
Z' more preferably-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-, wherein any hydrogen atom is by one to three W' Any substitution；
W' more preferably hydroxyl, C1-C2Alkyl.
X is particularly preferred
Each group in above-mentioned logical formula (I) and (II) compound and preferred formula (I) and (II) compound can be combined with each other, That is, including not preferred in the logical formula (I) and (II) compound, and the group between the different other substituents of priority and group Close.Any of the above combination is not only suitable for final product, and is therefore also applied for precursor and intermediate.
Present invention preferably comprises the formula of above-mentioned preferred substituents and group and combinations thereof (I) and (II) compound.
The present invention more preferably includes the formula (I) and (II) compound of above-mentioned more preferably substituent and group and combinations thereof.
Formula (I) specifically preferred according to the invention comprising above-mentioned particularly preferred substituent and group and combinations thereof and (II) chemical combination Thing.
Formula (I) and (II) chemical combination of the present invention particularly preferably comprising above-mentioned particularly preferred substituent and group and combinations thereof Thing.
Saturation or unsaturated alkyl, such as C1-C10Alkyl, alkane diyl or alkenyl, including with heteroatomic combination, such as alkane Epoxide, can be straight chain or with side chain respectively.
Unless otherwise indicated, optionally substituted group can be monosubstituted or polysubstituted, wherein in polysubstituted situation Under, substituent can be with identical or different.
In some preferred embodiments, it is proposed that following compound:
In a more preferred, following compound can be proposed：
Synthesis
The suitable solvent commonly used in organic reaction can be used in each step reaction of present invention below preparation method, example Such as, but it is not limited to aliphatic and aromatic, optional hydrocarbon or the hydrocarbon of halogenation (such as pentane, hexane, heptane, hexamethylene, oil Ether, gasoline, volatile oil, benzene,toluene,xylene, dichloromethane, dichloroethanes, chloroform, carbon tetrachloride, chlorobenzene and adjacent dichloro Benzene), aliphatic and aromatic, optional alcohols (such as methanol, ethanol, propyl alcohol, isopropanol, the tert-butyl alcohol, ethylene glycol), ether (such as ether and butyl oxide, glycol dimethyl ether and diethylene glycol dimethyl ether, tetrahydrofuran He dioxane etc.), ester (such as acetic acid Methyl esters or ethyl acetate etc.), nitrile (such as acetonitrile or propionitrile), ketone (such as acetone, butanone), acid amides (such as dimethyl methyl Acid amides, dimethyl acetamide and 1-METHYLPYRROLIDONE etc.) and dimethyl sulfoxide (DMSO), tetramethylene sulfone and hexamethyl phosphinylidyne three Amine and N, N- DMPU (DMPU) etc..
Purposes
The compound of the present invention can be used for treating following disease, for example：Tumour (tumor), for example：Hemangioma (hemangioma), glioma (glioma), melanoma (melanoma), Kaposi ' s sarcomas (sarcoma) and oophoroma (ovarian cancer), breast cancer (breast cancer), lung cancer (lung cancer), cancer of pancreas (pancreatic Cancer), prostate cancer (prostate cancer), colon cancer (colon cancer), breast cancer (breast cancer) With other stomach cancers etc.；Chronic inflammation disease (chronic inflammatory disease), such as rheumatoid arthrosis Scorching (rheumatoid arthritis), the angiogenesis (vasculogenesis) with mammal or revascularization art (angiogenesis) related disease；Atherosclerosis (atherosclerosis), inflammatory bowel disease (inflammatory bowel disease)；Skin disease, such as psoriasis (psoriasis), excema and chorionitis (sceroderma), diabetes, BDR (diabetic retinopathy), retinopathy of prematurity (retinopathy of prematurity), AMD (age-ralated macular degeneration)；The disease related to chronic ache, including neuralgia and the disease that modulation is cascaded by MEK, such as it is postoperative Pain, phantom limb pain (phantom limb pain), burn pain (burn pain), gout (gout), trigeminal neuralgia Pain (postherpetic pain) after (trigeminal neuralgia), acute hepatodynia (acute herpetic) and liver, Cusalgia (causalgia), diabetic neuropathy (diabetic neuropathy), plexus avulsion, neuroma (neuroma), vasculitis (vasculitis), crush injury (crush injury), wound of hanging (constriction injury), Tissue damage (tissue injury), postoperative pain (post-surgical pain), arthralgia (arthritis pain) or Amputation (limb amputation) pain etc..
1. dosage
Those skilled in the art can according to known method and consider the age, body weight, health status, treatment disease type The dosage for patient is determined with the factor such as the presence of other drugs.In general, effective dose is daily 0.1 to 1000mg/kg Body weight, preferably daily 1 to 300mg/kg body weight.For the adult of normal type, daily dose be usually 10 to 2500 milligrams.Commercially available 100mg, 200mg, 300mg or 400mg preparation can be administered according to disclosed method.
2. preparation
The compound of the present invention can be administered by any suitable method of administration, including systemic administration and local administration. Systemic administration includes：Orally, parenteral, cutaneous penetration or rectally；Or inhalation.Parenteral represents to remove Method of administration beyond enteral administration or cutaneous penetration, and be generally administered by injecting or being transfused.Parenteral includes Intravenous administration, intramuscular administration and hypodermic injection are transfused.Local administration includes being applied to skin and eye drops, eye Administration, intravaginal administration and intranasal administration.
Can be by the compound of the present invention and one or more medicinal acceptable excipients into suitable for by required It is the formulation that patient is administered method of administration, such as tablet, capsule, pill, lozenge, pulvis, syrup, elixir, suspending agent, molten Liquor, emulsion and sachet (sachet) etc..
Suitable medicinal acceptable excipient will change and change according to selected specific formulation.They include bonding Agent, lubricant, glidant, disintegrant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, flavor enhancement, taste are covered Cover agent, anti-caking agent, diluent, chelating agent, plasticizer, viscosity modifier, antioxidant, preservative, stabilizer, surface-active Agent, emulsifying agent and buffer.
The Pharmaceutical composition of the present invention is prepared with technology well known by persons skilled in the art and method.
Synthetic example：
Embodiment 1.5- (the fluoro- 4- idodophenylaminos of 2-)-N- (2- hydroxyl-oxethyls) -8- ((3- oxomorpholins) methyl) miaow The synthesis of azoles simultaneously [1,5-a] pyridine -6- formamides：
Step 1：The synthesis of the chloro- 6- methyl -2H-1,4- oxazines -2- ketone of 3,5- bis-
According to European Journal of organic Chemistry；nb,30；(2007)；P.4995-4998. make Standby title compoundlH-NMR(400MHz,DMSO-d6)δ2.30(s,3H).
Step 2：The synthesis of the chloro- 5- methylnicotinic acids ethyl esters of 2,6- bis-
According to synthesis；nb,9；(1991)；P.765-768. title compound is prepared
Step 3：The synthesis of the chloro- 2- of 6- (the fluoro- 4- idodophenylaminos of 2-) -5- methylnicotinic acid ethyl esters
The fluoro- 4- iodobenzenes ammonia (12.15g, 51.26mmol) of compound 2- are added in reaction bulb, anhydrous THF is added (50ml), under nitrogen atmosphere, is cooled to after -78 DEG C, and LiHMDS (1M, 128.5ml, 128.5mmol) is added dropwise into reaction solution, After -78 DEG C are reacted 30 minutes, compound 2 is added, the chloro- 5- methylnicotinic acids ethyl esters (10g, 42.72mmol) of 6- bis- add recession Go dry ice abundant, continue to react 3 hours.Reaction, ethyl acetate extraction, anhydrous slufuric acid is quenched with saturated ammonium chloride after completion of the reaction Sodium is dried, and concentration, column chromatography for separation obtains product.(15g, yield：81%) [M+H]+=435.6
Step 4：The synthesis of 6- cyano group -2- (the fluoro- 4- idodophenylaminos of 2-) -5- methylnicotinic acid ethyl esters
The chloro- 2- of compound 6- (the fluoro- 4- idodophenylaminos of 2-) -5- methylnicotinic acids ethyl esters (10.0g, 23.01mmol) are added Enter in reaction bulb, add DMF (50ml), then add dicyano zinc (1.77g, 16.80mmol) and Pd (PPh3)4(2.66g, 2.30mmol), 100 DEG C of 8 hours of reaction are heated under nitrogen protection, after completion of the reaction, are diluted with ethyl acetate, are filtered, And organic phase is washed with water, anhydrous sodium sulfate drying, concentration, column chromatography for separation obtains target product.(7.6g, yield：77%) [M +H]+=426.2
Step 5:6- amino methyls -2- (the fluoro- 4- idodophenylaminos of 2-) -5- methylnicotinic acid ethyl esters
Compound 6- cyano group -2- (the fluoro- 4- idodophenylaminos of 2-) -5- methylnicotinic acids ethyl esters (7.0g, 16.46mmol) are added Enter in reaction bulb, add methanol (80ml), then add cobalt chloride (4.28g, 32.93mmol), be stirred at room temperature after 10 minutes, Sodium borohydride (6.23g, 164.63mmol) is added portionwise under ice-water bath cooling, adds and continues to react 15 points under ice-water bath after finishing Clock, is then warmed to room temperature continuation and reacts 1 hour.Reaction is quenched with concentrated hydrochloric acid, and is stirred at room temperature 15 minutes, is filtered to remove white Color solid, and washed with dichloromethane, organic phase is concentrated, obtained crude product is dissolved with ethyl acetate, and molten with saturated sodium carbonate Liquid is washed, washing, and saturated common salt washing, anhydrous sodium sulfate drying, concentration obtains target product.(3.5g, yield：49.5%) [M +H]+=430.2
Step 6：2- (the synthesis of (the fluoro- 4- idodophenylaminos of 2-) -6- (aldehyde radical amino methyl) -5- methylnicotinic acid ethyl esters
By compound 6- amino methyls -2- (the fluoro- 4- idodophenylaminos of 2-) -5- methylnicotinic acids ethyl ester (3.5g, 8.15mmol) add in reaction bulb, add formic acid (30ml), be cooled to ice bath after 0 DEG C and add acetic anhydride (6ml), at room temperature Dissolved, and washed with saturated sodium carbonate with dichloromethane after reacting 2 hours, concentration of reaction solution, salt washing, anhydrous sodium sulfate is done It is dry, it is concentrated to give target product.(3.7g, yield：99%)
Step 7：The synthesis of 5- (the fluoro- 4- idodophenylaminos of 2-) -8- methylimidazoles simultaneously [1,5-a] pyridine -6- carboxylic acid, ethyl esters
By compound 2- ((the fluoro- 4- idodophenylaminos of 2-) -6- (aldehyde radical amino methyl) -5- methylnicotinic acids ethyl ester (3.7g, 8.09mmol) add in reaction bulb, add toluene (10ml), then add POCl3 (2.48g, 16.18mmol), be heated to 95 DEG C of 1 hours of reaction, the residue with Ethyl acetate dissolving obtained after room temperature, concentration is cooled to, and it is molten with saturated sodium carbonate Liquid is washed, and saturated common salt washing, organic phase anhydrous sodium sulfate drying, concentration, column chromatography for separation obtains target product.(2.1g is received Rate：59%) [M+H]+=440.2
Step 8：8- (bromomethyl) -5- (the fluoro- 4- idodophenylaminos of 2-) imidazo [1,5-a] pyridine -6- carboxylic acid, ethyl esters Synthesis
By compound 5- (the fluoro- 4- idodophenylaminos of 2-) -8- methylimidazoles simultaneously [1,5-a] pyridine -6- carboxylic acid, ethyl esters (2.10g, 4.78mmol) is added in reaction bulb, then adds carbon tetrachloride (20ml), NBS (0.94g, 5.26mmol) and peroxide Benzoyl (BPO) (112mg, 0.47mmol).60 DEG C of 4 hours of reaction are heated to, room temperature is cooled to, uses saturated sodium thiosulfate Reaction is quenched in solution, and ethyl acetate extraction, saturated common salt washing, anhydrous sodium sulfate drying, concentration, column chromatography for separation is produced Thing.(1.8g, yield：72%)
Step 9：5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((4- (methylamino) -4- oxobutoxies amino) methyl) miaow The synthesis of azoles simultaneously [1,5-a] pyridine -6- carboxylic acid, ethyl esters：
By compound 8- (bromomethyl) -5- (the fluoro- 4- idodophenylaminos of 2-) imidazo [1,5-a] pyridine -6- carboxylic acid, ethyl esters (150mg, 0.29mmol), is added in reaction bulb, adds acetonitrile (3ml), then adds potassium carbonate (60mg, 0.43mmol) and 4- (amino epoxide)-N- methylbutyryls amine (58mg, 0.43mmol), 4 hours are reacted at 60 DEG C, are cooled to room temperature, add washing And be extracted with ethyl acetate, anhydrous sodium sulfate drying, concentrate, column chromatography for separation obtains product.(120mg, yield：73%).[M+ H]+=570.4
Step 10：5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((4- (methylamino) -4- oxobutoxies amino) methyl) - The synthesis of N- (2- (vinyl epoxide) ethyoxyl) imidazo [1,5-a] pyridine -6- formamides
Compound O- (2- (vinyl epoxide) ethyl) azanol (33mg, 0.32mmol) is added in reaction bulb, nothing is added Water THF (1ml), under nitrogen atmosphere, is cooled to after -78 DEG C, into reaction solution be added dropwise LiHMDS (1M, 0.63ml, 0.63mmol), after -78 DEG C are reacted 30 minutes, compound 5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((4- (methyl ammonia is added Base) -4- oxobutoxies amino) methyl) imidazo [1,5-a] pyridine -6- carboxylic acid, ethyl esters (120mg, 0.21mmol), after adding Remove dry ice abundant, continue to react 3 hours.Reaction, ethyl acetate extraction, anhydrous sulphur is quenched with saturated ammonium chloride after completion of the reaction Sour sodium is dried, and is concentrated to give crude product and is directly used in next step.
Step 11：5- (the fluoro- 4- idodophenylaminos of 2-)-N- (2- hydroxyl-oxethyls) -8- ((4- (methylamino) -4- oxos Butyl oxygen amino) methyl) imidazo [1,5-a] pyridine -6- formamides synthesis
The crude product (120mg, 0.20mmol) arrived of previous step is added in reaction bulb, methanol (2ml), Ran Houjia is added Enter 1M HCl (0.4ml, 0.4mmol), react at room temperature 30 minutes, after completion of the reaction, add water, and extracted with ethyl acetate Take, saturated common salt washing, anhydrous sodium sulfate drying, concentration, column chromatography for separation arrive product.(80mg, yield：70%).[M+H ]+=601.4
Step 12：5- (the fluoro- 4- idodophenylaminos of 2-)-N- (2- hydroxyl-oxethyls) -8- ((3- oxo-morpholines) methyl) The synthesis of imidazo [1,5-a] pyridine -6- formamides
By compound 5- (the fluoro- 4- idodophenylaminos of 2-)-N- (2- hydroxyl-oxethyls) -8- ((4- (methylamino) -4- oxygen For butyl oxygen amino) methyl) imidazo [1,5-a] pyridine -6- formamides (80mg, 0.13mmol), add in reaction bulb, add 1,2- dichloroethanes (2ml), adds to 60 DEG C of 10 hours of reaction, TLC is detected after completion of the reaction, is cooled to room temperature, concentrates, post Chromatography obtains product.(40mg, yield：52%).1H NMR(400MHz,CD3OD)δ8.05(s,1H),7.45(dd,1H), 7.41(dd,1H),7.28(s,1H),7.16(s,1H),6.51(m,1H),4.86(s,2H),4.04(t,2H),3.92(t, 2H),3.73(t,2H),2.53(t,2H),2.10(t,2H).m/z 570(M+1)。
Embodiment 2：N- (2,3- hydroxy propyloxy groups) -5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxomorpholins) methyl) The synthesis of imidazo [1,5-a] pyridine -6- formamides
Step 1：5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxomorpholins) methyl) imidazo [1,5-a] pyridine -6- The synthesis of carboxylic acid, ethyl ester
By compound 5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((4- (methylamino) -4- oxobutoxies amino) methyl) Imidazo [1,5-a] pyridine -6- carboxylic acid, ethyl esters (500mg, 0.88mmol), are added in reaction bulb, add 1,2- dichloroethanes (10ml), is heated to 60 DEG C of 10 hours of reaction, after completion of the reaction, is cooled to room temperature, concentrate, column chromatography for separation obtains product. (400mg, yield：84.6%).[M+H]+=539.3
Step 2：N- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -5- (the fluoro- 4- idodophenylaminos of 2-) - The synthesis of 8- ((3- oxomorpholins) methyl) imidazo [1,5-a] pyridine -6- formamides：
Compound O- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methyl) azanol (41mg, 0.28mmol) is added In reaction bulb, add anhydrous THF (1ml), under nitrogen atmosphere, be cooled to after -78 DEG C, be added dropwise into reaction solution LiHMDS (1M, 0.56ml, 0.56mmol), after -78 DEG C are reacted 30 minutes, add compound 5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxygen For morpholine) methyl) imidazo [1,5-a] pyridine -6- carboxylic acid, ethyl esters (100mg, 0.18mmol), it is abundant to remove dry ice after adding, after 3 hours of continuous reaction.Reaction, ethyl acetate extraction, anhydrous sodium sulfate drying, concentration is quenched with saturated ammonium chloride after completion of the reaction Obtain crude product and be directly used in next step.
Step 3：N- (2,3- hydroxy propyloxy groups) -5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxomorpholins) methyl) miaow The synthesis of azoles simultaneously [1,5-a] pyridine -6- formamides：
Compound N-((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -5- (fluoro- 4- iodophenyls ammonia of 2- Base) -8- ((3- oxomorpholins) methyl) imidazo [1,5-a] pyridine -6- formamides (118mg, 0.18mmol) addition reaction bulb In, ethanol (1ml) and tetrahydrofuran (1ml) are then added, 1N hydrochloric acid (0.36ml, 0.36mmol) is added, at room temperature instead 2 hours are answered, after completion of the reaction, concentration, column chromatography for separation obtains compound (60mg, yield：54%).1H NMR(400MHz, CD3OD)δ8.05(s,1H),7.43(dd,1H),7.39(dd,1H),7.28(s,1H),7.12(s,1H),6.49(m,1H), 4.84(s,2H),4.04(t,2H),3.92(t,2H),3.73(t,2H),3.67(m,1H),2.51(t,2H),2.09(t,2H) .m/z 600.3(M+1)
Embodiment 3：N- (Cvclopropvlmethvl oxygen) -5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxomorpholins) methyl) miaow The synthesis of azoles [1,5-a] pyridine -6- formamides:
Compound O- (Cvclopropvlmethvl) azanol (12mg, 0.14mmol) is added in reaction bulb, anhydrous THF is added (1ml), under nitrogen atmosphere, is cooled to after -78 DEG C, and LiHMDS (1M, 0.27ml, 0.27mmol) is added dropwise into reaction solution, - After 78 DEG C are reacted 30 minutes, compound 5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxomorpholins) methyl) imidazo is added [1,5-a] pyridine -6- carboxylic acid, ethyl esters (50mg, 0.09mmol), it is abundant to remove dry ice after adding, and continues to react 3 hours.React Reaction is quenched after finishing with saturated ammonium chloride, ethyl acetate extraction, anhydrous sodium sulfate drying, concentration, column chromatography for separation obtains product. (50mg, yield：55%).1H NMR(400MHz,CD3OD)1H NMR(400MHz,CD3OD)δ8.04(s,1H),7.45(dd, 1H),7.41(dd,1H),7.24(s,1H),7.16(s,1H),6.51(m,1H),4.86(s,2H),3.87(d,2H)3.73(t, 2H),2.53(t,2H),2.10(t,2H),0.65(m,2H),0.41(m,1H),0.35(m,2H).m/z 580.3(M+1)
Embodiment 4：5- (the fluoro- 4- idodophenylaminos of 2-)-N- (2- hydroxyl-oxethyls) -8- ((3- oxo isoxazole -2- bases) Methyl) imidazo [1,5-a] pyridine -6- formamides synthesis：
Step 1：5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- (methylamino) -3- oxopropoxies amino) methyl) miaow The synthesis of azoles simultaneously [1,5-a] pyridine -6- carboxylic acid, ethyl esters：
By compound 8- (bromomethyl) -5- (the fluoro- 4- idodophenylaminos of 2-) imidazo [1,5-a] pyridine -6- carboxylic acid, ethyl esters (150mg, 0.29mmol), is added in reaction bulb, adds acetonitrile (3ml), then adds potassium carbonate (60mg, 0.43mmol) and 4- (amino epoxide)-N- methyl propanamides (41mg, 0.43mmol), 4 hours are reacted at 60 DEG C, are cooled to room temperature, add washing And be extracted with ethyl acetate, anhydrous sodium sulfate drying, concentrate, column chromatography for separation obtains product.(120mg, yield：73%).[M+ H]+=556.4
Step 2:5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxo isoxazole -2- bases) methyl) imidazo [1,5-a] The synthesis of pyridine -6- carboxylic acid, ethyl esters：
By compound 5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- (methylamino) -3- oxopropoxies amino) methyl) Imidazo [1,5-a] pyridine -6- carboxylic acid, ethyl esters (120mg, 0.21mmol) are added in reaction bulb, add 1,2- dichloroethanes (3ml), is heated to 60 DEG C of 10 hours of reaction, after completion of the reaction, concentration of reaction solution, column chromatography for separation obtains product.(90mg, Yield：79%).[M+H]+=539.3
Step 3：5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxo isoxazole -2- bases) methyl)-N- (2- (ethylene oxies Base) ethyoxyl) imidazo [1,5-a] pyridine -6- formamides
Compound O- (2- (vinyl epoxide) ethyl) azanol (26mg, 0.26mmol) is added in reaction bulb, nothing is added Water THF (1ml), under nitrogen atmosphere, is cooled to after -78 DEG C, into reaction solution be added dropwise LiHMDS (1M, 0.51ml, 0.51mmol), after -78 DEG C are reacted 30 minutes, compound 5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((4- (methyl ammonia is added Base) -4- oxobutoxies amino) methyl) imidazo [1,5-a] pyridine -6- carboxylic acid, ethyl esters (90mg, 0.17mmol), after adding Remove dry ice abundant, continue to react 3 hours.Reaction, ethyl acetate extraction, anhydrous sulphur is quenched with saturated ammonium chloride after completion of the reaction Sour sodium is dried, and is concentrated to give crude product and is directly used in next step.(100mg, yield：100%)
Step 4：5- (the fluoro- 4- idodophenylaminos of 2-)-N- (2- hydroxyl-oxethyls) -8- ((3- oxo isoxazole -2- bases) first Base) imidazo [1,5-a] pyridine -6- formamides
By compound 5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxo isoxazole -2- bases) methyl)-N- (2- (ethene Epoxide) ethyoxyl) imidazo [1,5-a] pyridine -6- formamides (100mg, 0.17mmol) add reaction bulb in, add methanol (2ml), then adds 1M HCl (0.3ml, 0.3mmol), reacts 30 minutes at room temperature, adds water, and extracted with ethyl acetate Take, anhydrous sodium sulfate drying, concentrate, column chromatography for separation obtains product.(60mg, yield：62%).1H NMR(400MHz, CD3OD)δ8.05(s,1H),7.45(dd,1H),7.39(dd,1H),7.28(s,1H)7.13(s,1H),6.51(m,1H), 4.76(s,2H),4.36(t,2H),3.93(t,2H),3.70(t,2H),2.84(t,2H),m/e 556.30(M+1)
Embodiment 5：5- (the fluoro- 4- idodophenylaminos of 2-)-N- (2- hydroxyl-oxethyls) -8- ((3- oxomorpholins) methyl) - [1,2,4] synthesis of triazol [4,3-a] pyridine -6- formamides
Step 1：The synthesis of 2- (the fluoro- 4- idodophenylaminos of 2-) -6- diazanyl -5- methylnicotinic acid ethyl esters：
The chloro- 2- of compound 6- (the fluoro- 4- idodophenylaminos of 2-) -5- methylnicotinic acids ethyl ester (5g, 11.5mmol) is added anti- Answer in bottle, add ethanol (30ml), then add hydrazine hydrate 30% (1.35g, 12.65mmol), be heated to 40 DEG C of reactions 4 small When, after completion of the reaction, be cooled to room temperature, concentrate, add water and wash, dichloromethane extraction, anhydrous sodium sulfate drying, concentration arrive target Product.(4.2g, yield：85%).[M+H]+=431.2
Step 2：The synthesis of 2- (the fluoro- 4- idodophenylaminos of 2-) -6- (2 aldehyde radical diazanyl) -5- methylnicotinic acid ethyl esters：
By compound 2- (the fluoro- 4- idodophenylaminos of 2-) -6- diazanyl -5- methylnicotinic acids ethyl ester, (4.2g adds reaction bulb In, formic acid (30ml) is added, is cooled to ice bath after 0 DEG C and adds acetic anhydride (6ml), is reacted at room temperature 2 hours, concentration reaction Dissolved, and washed with saturated sodium carbonate with dichloromethane after liquid, salt washing, anhydrous sodium sulfate drying is concentrated to give target product. (4.4g, yield：98%)
Step 3：5- (the fluoro- 4- idodophenylaminos of 2-) -8- methyl-[1,2,4] triazol [4,3-a] pyridine -6- carboxylic acid second The synthesis of ester：
By compound 2- (the fluoro- 4- idodophenylaminos of 2-) -6- (2 aldehyde radical diazanyl) -5- methylnicotinic acids ethyl ester (4.4g, 9.60mmol) add in reaction bulb, add toluene (10ml), then add POCl3 (2.94g, 19.20mmol), be heated to 95 DEG C of 1 hours of reaction, the residue with Ethyl acetate dissolving obtained after room temperature, concentration is cooled to, and it is molten with saturated sodium carbonate Liquid is washed, and saturated common salt washing, organic phase anhydrous sodium sulfate drying, concentration, column chromatography for separation obtains target product.(2.1g is received Rate：50%) [M+H]+=441.2
Step 4:8- (bromomethyl) -5- (the fluoro- 4- idodophenylaminos of 2-)-[1,2,4] triazol [4,3-a] pyridine-3-carboxylic acid The synthesis of ethyl ester：
By compound 5- (the fluoro- 4- idodophenylaminos of 2-) -8- methyl-[1,2,4] triazol [4,3-a] pyridine -6- carboxylic acids Ethyl ester (2.10g, 4.77mmol) add reaction bulb in, then add carbon tetrachloride (20ml), NBS (0.94g, 5.26mmol) and Benzoyl peroxide (BPO) (112mg, 0.47mmol).60 DEG C of 4 hours of reaction are heated to, room temperature are cooled to, with the thio sulphur of saturation Reaction is quenched in acid sodium solution, and ethyl acetate extraction, saturated common salt washing, anhydrous sodium sulfate drying, concentration, column chromatography for separation is obtained Product.(1.8g, yield：72.6%).[M+H]+=520.1
Step 5：5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((4- (methylamino) -4- oxobutoxies amino) methyl) - [1,2,4] synthesis of triazol [4,3-a] pyridine -6- carboxylic acid, ethyl esters：
By compound 8- (bromomethyl) -5- (the fluoro- 4- idodophenylaminos of 2-)-[1,2,4] triazol [4,3-a] pyridine-carboxylic Acetoacetic ester (500mg, 0.96mmol), add reaction bulb in, add acetonitrile (15ml), then add potassium carbonate (200mg, 1.44mmol) with 4- (amino epoxide)-N- methylbutyryls amine (193mg, 1.44mmol), 4 hours are reacted at 60 DEG C, are cooled to Room temperature, adds and washes and be extracted with ethyl acetate, anhydrous sodium sulfate drying, concentrates, and column chromatography for separation obtains product.(400mg, Yield：73%).[M+H]+=570.4
Step 6：5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxomorpholins) methyl)-[1,2,4] triazol [4,3-a] The synthesis of pyridine -6- carboxylic acid, ethyl esters：
By compound 5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((4- (methylamino) -4- oxobutoxies amino) methyl) Imidazo [1,5-a] pyridine -6- carboxylic acid, ethyl esters (400mg, 0.70mmol), are added in reaction bulb, add 1,2- dichloroethanes (10ml), is heated to 60 DEG C of 10 hours of reaction, after completion of the reaction, is cooled to room temperature, concentrate, column chromatography for separation obtains product. (300mg, yield：79%).[M+H]+=540.3
Step 7：5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxomorpholins) methyl)-N- (2- (vinyl oxygen) ethoxies Base)-[1,2,4] triazole [4,3-a] pyridine -6- formamides synthesis：
Compound O- (2- (vinyl epoxide) ethyl) azanol (29mg, 0.28mmol) is added in reaction bulb, nothing is added Water THF (1ml), under nitrogen atmosphere, is cooled to after -78 DEG C, into reaction solution be added dropwise LiHMDS (1M, 0.57ml, 0.57mmol), after -78 DEG C are reacted 30 minutes, compound 5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxomorpholins) is added Methyl)-[1,2,4] triazol [4,3-a] pyridine -6- carboxylic acid, ethyl esters (100mg, 0.19mmol), it is abundant to remove dry ice after adding, after 3 hours of continuous reaction.Reaction, ethyl acetate extraction, anhydrous sodium sulfate drying, concentration is quenched with saturated ammonium chloride after completion of the reaction Obtain crude product and be directly used in next step.
Step 8：5- (the fluoro- 4- idodophenylaminos of 2-)-N- (2- hydroxyl-oxethyls) -8- ((3- oxomorpholins) methyl)-[1, 2,4] synthesis of triazol [4,3-a] pyridine -6- formamides
By compound 5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxomorpholins) methyl)-N- (2- (vinyl oxygen) second Epoxide)-[1,2,4] triazole [4,3-a] pyridine -6- formamides (100mg, 0.17mmol), add in reaction bulb, add methanol alkane (2ml), then adds such as 1M HCl (0.34ml), reacts at room temperature 1 hour, TLC is detected after completion of the reaction, is diluted with water, and It is extracted with ethyl acetate, anhydrous sodium sulfate drying, concentrates, column chromatography for separation obtains product.(50mg, yield：52%).1H NMR (400MHz,CD3OD)δ9.70(s,1H),7.45(dd,1H),7.41(dd,1H),7.16(s,1H),6.51(m,1H),4.86 (s,2H),4.04(t,2H),3.92(t,2H),3.73(t,2H),2.53(t,2H),2.10(t,2H).m/z 571(M+1)。
Embodiment 6：N- (2,3- hydroxy propyloxy groups) -5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxomorpholins) methyl) The synthesis of imidazo [1,5-a] pyridine -6- formamides
Step 1：N- ((2,2- dimethyl -1,3- dioxolane -4- ylmethoxies) -5- (the fluoro- 4- idodophenylaminos of 2-) - The synthesis of 8- ((3- oxomorpholins) methyl)-[1,2,4] triazol [4,3-a] pyridine -6- formamides：
Compound O- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methyl) azanol (41mg, 0.28mmol) is added In reaction bulb, add anhydrous THF (1ml), under nitrogen atmosphere, be cooled to after -78 DEG C, be added dropwise into reaction solution LiHMDS (1M, 0.56ml, 0.56mmol), after -78 DEG C are reacted 30 minutes, add compound 5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxygen For morpholine) methyl)-[1,2,4] triazol [4,3-a] pyridine -6- carboxylic acid, ethyl esters (100mg, 0.18mmol), removed after adding dry Ice is abundant, continues to react 3 hours.Reaction is quenched with saturated ammonium chloride after completion of the reaction, ethyl acetate extraction, anhydrous sodium sulfate is done It is dry, it is concentrated to give crude product and is directly used in next step.Step 2：N- (2,3- hydroxy propyloxy groups) -5- (fluoro- 4- iodophenyls ammonia of 2- Base) -8- ((3- oxomorpholins) methyl) imidazo [1,5-a] pyridine -6- formamides synthesis：
Compound N-((2,2- dimethyl -1,3- dioxolane -4- ylmethoxies) -5- (fluoro- 4- iodophenyls ammonia of 2- Base) -8- ((3- oxomorpholins) methyl)-[1,2,4] triazol [4,3-a] pyridine -6- formamides (100mg, 0.16mmol) plus Enter in reaction bulb, then add ethanol (1ml) and tetrahydrofuran (1ml), add 1N hydrochloric acid (0.32ml, 0.32mmol), 2 hours are reacted at room temperature, and after completion of the reaction, concentration, column chromatography for separation obtains compound (45mg, yield：48%).1H NMR (400MHz,CD3OD)δ9.63(s,1H),7.43(dd,1H),7.39(dd,1H),7.12(s,1H),6.49(m,1H),4.84 (s,2H),4.04(t,2H),3.92(t,2H),3.73(t,2H),3.67(m,1H),2.51(t,2H),2.09(t,2H).m/z 601.3(M+1)
Embodiment 7：N- (Cvclopropvlmethvl oxygen) -5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxomorpholins) methyl) miaow The synthesis of azoles [1,5-a] pyridine -6- formamides:
Compound O- (Cvclopropvlmethvl) azanol (12mg, 0.14mmol) is added in reaction bulb, anhydrous THF is added (1ml), under nitrogen atmosphere, is cooled to after -78 DEG C, and LiHMDS (1M, 0.27ml, 0.27mmol) is added dropwise into reaction solution, - After 78 DEG C are reacted 30 minutes, compound 5- (the fluoro- 4- idodophenylaminos of 2-) -8- ((3- oxomorpholins) methyl) imidazo is added [1,5-a] pyridine -6- carboxylic acid, ethyl esters (50mg, 0.09mmol), it is abundant to remove dry ice after adding, and continues to react 3 hours.React Reaction is quenched after finishing with saturated ammonium chloride, ethyl acetate extraction, anhydrous sodium sulfate drying, concentration, column chromatography for separation obtains product. (28mg, yield：52%).1H NMR(400MHz,CD3OD)1H NMR(400MHz,CD3OD)δ9.64(s,1H),7.45(dd, 1H),7.41(dd,1H),7.16(s,1H),6.51(m,1H),4.86(s,2H),3.87(d,2H)3.73(t,2H),2.53(t, 2H),2.10(t,2H),0.65(m,2H),0.41(m,1H),0.35(m,2H).m/z 581.3(M+1)
Biological examples
Cytoactive is tested
1. cell：Human colon carcinoma COLO205, Humanmachine tumour A375 cells, are all from Chinese Academy of Medical Sciences basis doctor Learn research institute's preclinical medicine cell centre.
2. reagent：Gibco DMEM/F12 culture mediums, 0.25% pancreatin of Gibco/EDTA cell dissociation buffers, MTT (5mg/ Ml), DMSO, PBS.
3. instrument：37 DEG C, 5%CO2Incubator, TECAN InfiniteTM200 series multifunctional ELIASAs, ultra-clean work Platform, cell counting count board.
4. test consumptive material：96 orifice plates.
The active testing experimental procedure of human colon carcinoma COLO205 cells：
1. bed board.Cell in exponential phase is digested with digestive juice, fresh culture is terminated, and cell is counted Number, 5*10 is adjusted to fresh culture by cell concentration4Individual/ml, adds 200 μ L per hole, if zeroing hole (only plus culture medium) 3 Individual, other edges are filled with sterile PBS.
2. at 37 DEG C in 5%CO2It is middle to be incubated 24 hours, allow cell to be paved with bottom hole 60% or so.
3. administration.Medicine DMSO is dissolved, 10mmol/L mother liquors are made into, then is diluted with DMSO, is made 1mmol/L, 100 μm of ol/L, 10 μm of ol/L, 1mol/L, 0.1mol/L solution, during administration, take the above-mentioned μ L of strength solution 1 to cultivate It is 10 μm of ol/L, 1 μm of ol/L, 100nmol/L, 10nmol/L, 1nmol/L, 0.1nmol/ that base, which is diluted to 1mL, i.e. administration concentration, L, 0nmol/L (control group, plus 1 μ L DMSO are diluted to 1ml with culture medium).During administration, liquid in original hole is exhausted, added The fresh culture of the medicine containing various concentrations, per the μ l of hole 200.
● zeroing hole, only add culture medium；
● control group, containing the solvent with experimental group same volume, diluted with complete medium.Per the μ l of hole 200；
● experimental group, the medicine dissolved is diluted to 0.1 with culture medium, 1,10,100,1000,10000nM concentration, often The μ l of hole 200.
4. at 37 DEG C in 5%CO2It is middle to be incubated.
After 5.72h, 20 μ L MTT solution (5mg/ml) are added per hole, continue to cultivate 4h.
6. 96 orifice plates are centrifuged with plate centrifuge, 1000 turns/5 minutes.
7. terminating culture, the nutrient solution in hole is carefully sucked.
8. 150 μ l dimethyl sulfoxide (DMSO)s (DMSO) are added per hole, low speed concussion 10min, after thing to be crystallized fully dissolves, in enzyme Mark and survey its light absorption value at instrument, 490nm wavelength.
The compounds of this invention is numbered shown according to the form below 2.Whole compound 1-17 IC50Value is both less than 1000nM.
The active testing experimental procedure of Humanmachine tumour A375 cells：
1. bed board.Cell in exponential phase is digested with digestive juice, fresh culture is terminated, and cell is counted Number, 2.5*10 is adjusted to fresh culture by cell concentration4Individual/ml, adds 200 μ L per hole, if zeroing hole (only plus culture medium) 3 Individual, other edges are filled with sterile PBS.
2. at 37 DEG C in 5%CO2It is middle to be incubated 36 hours, allow cell to be paved with bottom hole 60% or so.
3. administration.Medicine DMSO is dissolved, 10mmol/L mother liquors are made into, then is diluted with DMSO, is made 1mmol/L, 100 μm of ol/L, 10 μm of ol/L, 1mol/L, 0.1mol/L solution, during administration, take the above-mentioned μ L of strength solution 1 to cultivate It is 10 μm of ol/L, 1 μm of ol/L, 100nmol/L, 10nmol/L, 1nmol/L, 0.1nmol/ that base, which is diluted to 1mL, i.e. administration concentration, L, 0nmol/L (control group, plus 1 μ L DMSO are diluted to 1ml with culture medium).During administration, liquid in original hole is exhausted, added The fresh culture of the medicine containing various concentrations, per the μ l of hole 200.
● zeroing hole, only add culture medium；
● control group, containing the solvent with experimental group same volume, diluted with complete medium.Per the μ l of hole 200；
● experimental group, the medicine dissolved is diluted to 0.1 with culture medium, 1,10,100,1000,10000nM concentration, often The μ l of hole 200.
4. at 37 DEG C in 5%CO2It is middle to be incubated.
After 5.72h, 20 μ L MTT solution (5mg/ml) are added per hole, continue to cultivate 4h.
6. terminating culture, the nutrient solution in hole is carefully sucked.
7. 150 μ l dimethyl sulfoxide (DMSO)s (DMSO) are added per hole, low speed concussion 10min, after thing to be crystallized fully dissolves, in enzyme Mark and survey its light absorption value at instrument, 490nm wavelength.
The compounds of this invention is numbered shown according to the form below 2.Whole compound 1-17 IC50Value is both less than 1000nM.
The test compound of table 2.

Claims (6)

1. the compound and its pharmaceutically acceptable salt of formula (I) and (II)
Wherein
A is selected from C and N；
R1Selected from fluorine, chlorine, bromine, iodine；
R2Selected from hydrogen, halogen；
R3For C that is unsubstituted or being replaced by 1 to 3 hydroxyl1-C3Alkyl, C3-C4Cycloalkyl, C3-C4Cycloalkyl C1-C3Alkyl or C1-C3Alkyl C3-C4Cycloalkyl；
X is selected from
2. the compound and its pharmaceutically acceptable salt of claim 1, wherein
R1Selected from bromine, iodine；
R2Selected from hydrogen, fluorine, chlorine, bromine；
R3For C that is unsubstituted or being replaced by 1 to 3 hydroxyl1-C3Alkyl, C3-C4Cycloalkyl, C3-C4Cycloalkyl C1-C3Alkyl or C1-C3Alkyl C3-C4Cycloalkyl.
3. the compound and its pharmaceutically acceptable salt of claim 2, wherein
R1Selected from bromine, iodine；
R2Selected from fluorine, chlorine；
R3Selected from 2- hydroxyethyls, 2,3- dihydroxypropyls, 1- methylol -2- hydroxyethyls, 2- methyl -3- hydroxypropyls, ring third Base, Cvclopropvlmethvl or 1- (2,3- hydroxypropyls) cyclopropyl.
4. formula (I) compound of claim 1, and its pharmaceutically acceptable salt, wherein the compound is selected from：
5. a kind of formula (I) and (II) compound, its pharmaceutically acceptable salt including as described in claim any one of 1-4 Pharmaceutical composition.
6. the formula (I) and (II) compound and its pharmaceutically acceptable salt as described in claim any one of 1-4 are used to manufacture Treat the purposes of the medicine of the tumour of mammal.
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