CN105384738A - Heterocyclic compound as protein kinase inhibitor and preparation method and application thereof - Google Patents
Heterocyclic compound as protein kinase inhibitor and preparation method and application thereof Download PDFInfo
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- CN105384738A CN105384738A CN201510501147.3A CN201510501147A CN105384738A CN 105384738 A CN105384738 A CN 105384738A CN 201510501147 A CN201510501147 A CN 201510501147A CN 105384738 A CN105384738 A CN 105384738A
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- 0 CC*CC*C(N(*)C(C)(C)C)=* Chemical compound CC*CC*C(N(*)C(C)(C)C)=* 0.000 description 8
- MPRJESLPUOJWOZ-UHFFFAOYSA-N CC(C(C=C1CBr)=C(Nc(c(F)c2)ccc2I)N(C(C)=N)C1=N)=O Chemical compound CC(C(C=C1CBr)=C(Nc(c(F)c2)ccc2I)N(C(C)=N)C1=N)=O MPRJESLPUOJWOZ-UHFFFAOYSA-N 0.000 description 1
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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
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Abstract
The invention relates to a compound of formulas (I) and (II) and a pharmaceutically acceptable salt, prodrug and solvate thereof, wherein R1, R2, R3, A and X are as defined in the specification. The compound is a protein kinase inhibitor, particularly the protein kinase inhibitor Mek inhibitor, and can be used for treating cancers and inflammation in mammals. The invention further discloses a preparation method of the compound of formulas (I) and (II) and a medicine composition containing the compound.
Description
Technical field
The present invention relates to protein kinase (especially protein kinase Mek) inhibitor, more specifically, relate to as the Imidazopyridine of protein kinase (especially protein kinase Mek) inhibitor and pharmacy acceptable salt thereof, prodrug, solvate and the composition comprising these materials, and relate to the preparation method of described Imidazopyridine, also relate to described imidazopyridine derivatives and pharmacy acceptable salt, prodrug and the solvate purposes as protein kinase (especially protein kinase Mek) inhibitor.
Background technology
The cell signalling controlled by somatomedin and protein kinase is played an important role in the growth of cell, propagation and differentiation.In Normocellular growth, somatomedin (as PDGF or EGF etc.) activates MAP (Mitogen--activatingprotein) kinase signal transduction passage by receptor activation (as ErbB2, EGFR, PDGFR etc.).Ras/Raf/Mek/Erk signal transduction mechanism is one of most important approach of Growth of Cells.In proliferative disease, because the protein kinase producer in growth factor receptors or its downstream suddenlys change or overexpression, thus cause the growth of cell out of hand, finally cause cancer.Such as in some cancer, due to transgenation, make this signal transduction mechanism by the activation continued, thus result in the lasting generation of some somatomedins, the growth that finally result in cell loses control, thus canceration.Statistic data shows, the colorectal carcinoma of 50%, the carcinoma of the pancreas of more than 90% cause due to Ras transgenation; The malignant melanoma of more than 60% caused due to bRaf transgenation.Research shows, all finds that Ras/Raf/Mek/Erk signal transduction mechanism is activated by continuous print or excessive activation, as carcinoma of the pancreas, colorectal carcinoma, lung cancer, bladder cancer, kidney, skin carcinoma, mammary cancer etc. in kinds cancer.
Because the overactivity of this signal transduction mechanism plays vital role, so the treatment suppressing this approach to contribute to this kind of excess proliferative disease in the propagation and differentiation of cancer cells.Mek is positioned at the downstream target of Ras and Raf, in this approach, play a part key, and the substrate of Mek phosphorylation is map kinase Erk.If Mek is suppressed, then Ras/Raf/Mek/Erk signal transduction path will be closed, thus the propagation of cancer cells will be suppressed.Therefore, Mek inhibitor can the growth of anticancer, especially for the cancer that Ras or Raf overactivity causes.Meanwhile Mek also relates to the Symptom and disease of inflammation class, comprises acute and chronic inflammation.
Mek inhibitor shows certain drug effect in the pharmacodynamic experiment of nude mice.Some Mek inhibitor have entered clinical recently, and also show certain drug effect.Therefore Mek is the new target drone of potential druggability, and just because of this, increasing Mek inhibitor is being developed and is reporting out.Such as, WO98/43960; WO99/01421; WO99/01426; WO00/41505; WO00/42002; WO00/41003; WO00/41994; WO00/42022; WO00/42029; WO00/68201; WO01/68619; WO01/005390; WO02/06213; WO03/077914; WO03/077855; WO03/077914; WO05/023251; WO05/023759; WO05/051300; WO05/051301; WO05/051302; WO05/051906; WO05/000818; WO05/007616; WO05/009975; WO05/046665; WO06/134469; WO07/044084; WO07/014011; WO07/121269; WO07/121481; WO07/071951; WO07/044515; WO08/021389; WO08/076415; WO08/089459; WO08/078086; WO08/120004; WO08/124085; WO08/125820; WO09/018238; WO09/074827; WO09/013426; WO09/093008; WO09/093009; WO09/093013; WO09/153554; WO12/059041; EP1780191; US2012/0238599; WO2007/044084 etc.
Summary of the invention
One aspect of the present invention provides compound and pharmacy acceptable salt, prodrug and the solvate of formula (I) and (II)
Wherein
R
1be selected from hydrogen, halogen, cyano group, nitro, azido-, hydroxyl, C
1-C
10alkoxyl group, halo C
1-C
10alkoxyl group, sulfydryl, C
1-C
10alkylthio, halo C
1-C
10alkylthio, carboxyl ,-OC (O) H, amino, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl;
R
2be selected from hydrogen, halogen, nitro, azido-, hydroxyl, C
1-C
10alkyl, C
1-C
10alkoxyl group, halo C
1-C
10alkoxyl group, C
1-C
10alkylthio, halo C
1-C
10alkylthio, carboxyl ,-OC (O) H, amino, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl;
R
3be selected from hydrogen, C
1-C
12alkyl, C
2-C
12thiazolinyl, C
2-C
12alkynyl, C
3-C
12cycloalkyl, C
3-C
12cycloalkyl C
1-C
12alkyl, C
1-C
12alkyl C
3-C
12cycloalkyl, described alkyl, thiazolinyl, alkynyl and cycloalkyl can be selected from following group by one to three independently of one another and replace arbitrarily :-ORa ,-NRaRb ,-NRaC (O) Rb, Heterocyclylalkyl and heterocyclic aromatic base, and Heterocyclylalkyl described herein and heterocyclic aromatic base can be selected from following substituting group by one to three and replace arbitrarily: C
1-C
5alkyl ,-ORa ,-NRaRb;
X representative formula (i):
Wherein
Y is selected from O ,-ONR
8,-NR
8o ,-NR
8c (O) ,-NR
8sO
2;
Z is selected from hydrogen, C
1-C
5methene chain, described methylene radical can be replaced arbitrarily by one to three W';
R
8be selected from hydrogen, C
1-C
12alkyl ,-COR
9, described alkyl can be replaced arbitrarily by halogen ,-ORa ,-NRaRb;
R
9be selected from hydrogen, C
1-C
12alkyl, described alkyl can be replaced arbitrarily by halogen ,-ORa ,-NRaRb;
Or X representative formula (ii):
Wherein
Y
1and Y
2can be the same or different, they represent singly-bound ,-CO-,-COO-,-O-,-OCO-,-NRa-,-SO independently of one another
2-;
Z' represents C
1-C
10chain alkylene, described alkyl can be replaced arbitrarily by one to three W';
In above-mentioned formula (i) and formula (ii),
W and W' can be the same or different, and they are selected from halogen, C independently of one another
1-C
5alkyl ,-O-,-ORa ,-COORa ,-COOCORa ,-CO-halogen ,-OCORa ,-CONRaRb ,-SRa ,-SORa ,-SO
2ra ,-NRaRb ,-NRaCORb ,-NRaSO
2rb ,-SO
2nRaRb, Heterocyclylalkyl or heterocyclic aromatic base, described Heterocyclylalkyl and heterocyclic aromatic base can be selected from following substituting group by one to three and replace arbitrarily: C
1-C
5alkyl ,-ORa ,-NRaRb; Described alkyl can by hydroxyl, C
1-C
5alkoxyl group or amino replacement arbitrarily;
Above-mentioned group deoxygenation and halogen all can be interconnected to form cycloalkyl or Heterocyclylalkyl outward, and described cycloalkyl or Heterocyclylalkyl can be selected from following substituting group and replace arbitrarily :-ORa ,-NRaRb, the C replaced arbitrarily by-ORa
1-C
5alkyl;
Ra and Rb can be the same or different, and they are selected from hydrogen, C independently of one another
1-C
5alkyl, described alkyl can be selected from following substituting group by one to three and replace arbitrarily: hydroxyl, C
1-C
5alkoxyl group, amino.
As X representative formula (i), the compound of formula (I) and (II) has following structure:
As X representative formula (ii), the compound of formula (I) and (II) has with the structure of following formula (I-2):
As Y representative-O-, when W represents OH, the compound of formula (I-1) has with the structure of following formula (I-1-a):
As Y representative-NHO-, the compound of formula (I-1) has following structure:
As Y representative-NR
8during O-, the compound of formula (I-1) has with the structure of following formula (I-1-c):
Work as Y
1represent singly-bound, Y
2during representative-O-, the compound of formula (I-2) has with the structure of following formula (I-2-A):
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 route 3:
Wherein, the synthesized reference route 2 of compound 11
(D) formula (I-1-b) compound is prepared according to following route 4:
Wherein, the synthesized reference route 2 of compound 11
(E) formula (I-1-c) compound is prepared according to following route 5:
(F) formula (I-2-A) compound is prepared according to following route 6:
(G) formula (I-2-A) compound is prepared according to following route 7:
Another aspect of the present invention provides the medicinal compositions of contained (I) and (II) compound or its pharmacy acceptable salt, prodrug and solvate.
Another aspect of the invention provide formula (I) and (II) compound or its pharmacy acceptable salt, prodrug and solvate for the manufacture of the mammiferous tumour for the treatment of, acute and chronic inflammation disease, inflammatory bowel disease, tetter, diabetes, eye disease, with the disease that mammiferous blood vessel occurs or revascularization is relevant, and the purposes of medicine of the chronic pain disease of being correlated with and other disease of being modulated by Mek cascade.
Embodiment
If do not pointed out in addition, the whole disclosure of the present invention adopts following term definition:
Term " prodrug " refers to any derivative that can be converted into corresponding active pharmaceutical compounds in vivo.In one embodiment, when compound of the present invention contains hydroxyl, its prodrug can be the ester that itself and suitable acid are formed, and described acid comprises such as lactic acid, citric acid, xitix etc.
Term " pharmacy acceptable salt ", except as otherwise noted, comprise the salt of the acidic-group that can be present in the compounds of this invention (such as, but be not limited to, sylvite, sodium salt, magnesium salts, calcium salt etc.) or basic group salt (such as, but be not limited to, vitriol, hydrochloride, phosphoric acid salt, nitrate, carbonate etc.).
Term " solvate " refers in the solution, the compound molecule compound that solute molecule or ion are formed by the solvent molecule that gravitational attraction between Coulomb force, Van der Waals for, charge transfer power, hydrogen bond equimolecular is adjacent.In one embodiment, solvent is water, and namely the compounds of this invention forms hydrate.
Described alkyl, thiazolinyl, alkynyl, cycloalkyl moiety can be selected from following group optionally replace by one or more independently of one another: hydroxyl, oxo, halogen, cyano group, nitro, trifluoromethyl, azido-, amino, carboxyl, sulfydryl.
Saturated or unsaturated alkyl, such as alkyl, alkane two base or thiazolinyl, comprise and heteroatomic combination, such as alkoxyl group, can be all straight chain or with side chain respectively.
According to substituent difference, formula (I) and (II) compound can the isomer mixture form of optically active isomer or different composition exist, and are separated by usual manner if described mixture is suitable.The invention provides pure isomer and isomer mixture, and its production and use, and comprise their composition.For simplicity, be hereinafter referred to as formula (I) and (II) compound, it had both referred to pure optically active isomer, if the suitable isomer mixture also referring to different ratios.
In some embodiments of the present invention, compound and pharmacy acceptable salt, prodrug and the solvate of formula (I) and (II) are provided
Wherein
A is selected from C and N;
R
1be selected from hydrogen, halogen, cyano group, nitro, azido-, hydroxyl, C
1-C
10alkoxyl group, halo C
1-C
10alkoxyl group, sulfydryl, C
1-C
10alkylthio, halo C
1-C
10alkylthio, carboxyl ,-OC (O) H, amino, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl;
R
2be selected from hydrogen, halogen, nitro, azido-, hydroxyl, C
1-C
10alkyl, C
1-C
10alkoxyl group, halo C
1-C
10alkoxyl group, C
1-C
10alkylthio, halo C
1-C
10alkylthio, carboxyl ,-OC (O) H, amino, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl;
R
3be selected from hydrogen, C
1-C
12alkyl, C
2-C
12thiazolinyl, C
2-C
12alkynyl, C
3-C
12cycloalkyl, C
3-C
12cycloalkyl C
1-C
12alkyl, C
1-C
12alkyl C
3-C
12cycloalkyl, described alkyl, thiazolinyl, alkynyl and cycloalkyl can be selected from following group by one to three independently of one another and replace arbitrarily :-ORa ,-NRaRb ,-NRaC (O) Rb, Heterocyclylalkyl and heterocyclic aromatic base, and Heterocyclylalkyl described herein and heterocyclic aromatic base can be selected from following substituting group by one to three and replace arbitrarily: C
1-C
5alkyl ,-ORa ,-NRaRb;
X representative formula (i):
Wherein
Y is selected from O ,-ONR
8,-NR
8o ,-NR
8c (O) ,-NR
8sO
2;
Z is selected from hydrogen, C
1-C
5methene chain, described methylene radical can be replaced arbitrarily by one to three W';
R
8be selected from hydrogen, C
1-C
12alkyl ,-COR
9, described alkyl can be replaced arbitrarily by halogen ,-ORa ,-NRaRb;
R
9be selected from hydrogen, C
1-C
12alkyl, described alkyl can be replaced arbitrarily by halogen ,-ORa ,-NRaRb;
Or X representative formula (ii):
Wherein
Y
1and Y
2can be the same or different, they represent singly-bound ,-CO-,-COO-,-O-,-OCO-,-NRa-,-SO independently of one another
2-;
Z' represents C
1-C
10chain alkylene, described alkyl can be replaced arbitrarily by one to three W';
In above-mentioned formula (i) and formula (ii),
W and W' can be the same or different, and they are selected from halogen, C independently of one another
1-C
5alkyl ,-O-,-ORa ,-COORa ,-COOCORa ,-CO-halogen ,-OCORa ,-CONRaRb ,-SRa ,-SORa ,-SO
2ra ,-NRaRb ,-NRaCORb ,-NRaSO
2rb ,-SO
2nRaRb, Heterocyclylalkyl or heterocyclic aromatic base, described Heterocyclylalkyl and heterocyclic aromatic base can be selected from following substituting group by one to three and replace arbitrarily: C
1-C
5alkyl ,-ORa ,-NRaRb; Described alkyl can by hydroxyl, C
1-C
5alkoxyl group or amino replacement arbitrarily;
Above-mentioned group deoxygenation and halogen all can be interconnected to form cycloalkyl or Heterocyclylalkyl outward, and described cycloalkyl or Heterocyclylalkyl can be selected from following substituting group and replace arbitrarily :-ORa ,-NRaRb, the C replaced arbitrarily by-ORa
1-C
5alkyl;
Ra and Rb can be the same or different, and they are selected from hydrogen, C independently of one another
1-C
5alkyl, described alkyl can be selected from following substituting group by one to three and replace arbitrarily: hydroxyl, C
1-C
5alkoxyl group, amino.
Above-mentioned general formula compound (I) and (II) and following preferred formula (I) and (II) compound are preferably as follows substituting group or group:
R
1be selected from fluorine, chlorine, bromine, iodine, C
1-C
4alkoxyl group, C
1-C
4alkylthio, halo-C
1-C
4alkoxyl group, halo-C
1-C
4alkylthio, C
1-C
4alkyl, halo C
1-C
4alkyl C
2-C
4thiazolinyl, C
2-C
4alkynyl;
R
2preferred hydrogen, halogen or C
1-C
4alkyl;
R
3preferably C that is unsubstituted or that replaced by 1 to 6 hydroxyl
1-C
4alkyl, C
3-C
4cycloalkyl, C
3-C
4cycloalkyl C
1-C
4alkyl or C
1-C
4alkyl C
3-C
4cycloalkyl.
R
1be selected from bromine, iodine, C
1-C
2alkylthio, halo-C
1-C
2alkylthio, C
1-C
2alkoxyl group, halo-C
1-C
2alkoxyl group, C
1-C
2alkyl, halo C
1-C
2alkyl, C
2-C
3thiazolinyl, C
2-C
3alkynyl;
R
2more preferably hydrogen, fluorine, chlorine, bromine or C
1-C
2alkyl;
R
3more preferably C that is unsubstituted or that replaced by 1 to 3 hydroxyl
1-C
3alkyl, C
3-C
4cycloalkyl, C
3-C
4cycloalkyl C
1-C
3alkyl or C
1-C
3alkyl C
3-C
4cycloalkyl.
R
1be selected from bromine, iodine, methylthio group, trifluoromethylthio, methoxyl group, trifluoromethoxy, methyl, trifluoromethyl, vinyl, ethynyl;
R
2especially preferably fluorine, chlorine or methyl;
R
3especially preferably 2-hydroxyethyl, 3-hydroxyethyl, 2,3-dihydroxypropyls, 1-methylol-2-hydroxyethyl, 2-methyl-3-hydroxypropyl, cyclopropyl, Cvclopropvlmethvl or 1-(2,3-hydroxypropyl) cyclopropyl.
As-the Y-Z-W that X preferred formula (i) represents,
Y is-O-,-NR preferably
8o-,-NR
8c (O)-,-NR
8sO
2-;
Y is-O-,-NR more preferably
8o-,-NR
8c (O)-;
Y is-NR especially preferably
8o-,-NR
8c (O)-;
R
8preferred hydrogen, C
1-C
6alkyl ,-COR
9;
R
8more preferably hydrogen, C
1-C
3alkyl ,-COR
9;
R
8especially preferably hydrogen, methyl ,-COH ,-COCH
3,-COCH
2cH
3,-COCH (CH
3)
2,-COCH
2oH;
The preferred hydrogen of Z, C
1-C
5methene chain, described methylene radical can be replaced arbitrarily by one to three W';
Z is hydrogen ,-CH more preferably
2-,-(CH
2)
2-,-(CH
2)
3-,-CH
2(CH
3) CH
2-,-CH
2c (CH
3)
2-,-CH
2c (CH
3)
2cH
2-,-CH
2c (CH
2cH
2) CH
2-, and can be replaced arbitrarily by W';
W and W' can be the same or different, and they are preferred halogen, C independently of one another
1-C
5alkyl ,-ORa ,-COORa ,-COOCORa ,-OCORa ,-CONRaRb ,-SRa ,-SORa ,-SO
2ra ,-NRaRb ,-NRaCORb ,-NRaSO
2rb ,-SO
2nRaRb, Heterocyclylalkyl or heterocyclic aromatic base;
W and W' can be the same or different, and they are more preferably halogen, C independently of one another
1-C
3alkyl ,-ORa ,-COORa ,-COOCORa ,-OCORa ,-CONRaRb ,-SRa ,-SORa ,-SO
2ra ,-NRaRb ,-NRaCORb ,-SO
2nRaRb, Heterocyclylalkyl or heterocyclic aromatic base;
W and W' can be the same or different, and they are especially preferred hydrogen, hydroxyl, methyl ,-O (CH independently of one another
2)
2oH ,-C (O) OCH
3,-CONHCH
3,-CONHCH
2cH
3,-CONHCH (CH
3)
2,-CON (CH
3)
2,-NHCH
3,-NH (CH
2)
2oH ,-NHCOCH
3,-NHCOCH
2cH
3,-NHCOCH (CH
3)
2,-SCH
3,-SOCH
3, 1H-imidazoles-2-base, morpholine-4-base, 4-hydroxy piperidine base.
When X be formula (ii) represent substituting group time,
X is preferred
The preferred C of Z'
1-C
3chain alkylene, described alkyl can be replaced arbitrarily by one to three W';
The preferred C of W'
1-C
3alkyl ,-ORa ,-COORa ,-COOCORa ,-CO-halogen ,-OCORa ,-CONRaRb ,-SRa ,-SORa ,-SO
2ra ,-NRaRb ,-NRaCORb ,-NRaSO
2rb ,-SO
2nRaRb;
Ra and Rb can be the same or different, and they are selected from hydrogen, C independently of one another
1-C
3alkyl, described alkyl can be selected from following substituting group by one to three and replace arbitrarily: hydroxyl, C
1-C
3alkoxyl group, amino.
X more preferably
Z' is-CH more preferably
2-,-(CH
2)
2-,-(CH
2)
3-,-(CH
2)
4-, wherein hydrogen atom is all replaced arbitrarily by one to three W' arbitrarily;
W' is hydroxyl, C more preferably
1-C
2alkyl.
X is especially preferred
Each group in above-mentioned general formula (I) and (II) compound and preferred formula (I) and (II) compound can combination with one another, namely, comprise in described general formula (I) and (II) compound not preferred, and the combination between different priority other substituting group and group.Various array mode was both applicable to final product above, and was therefore also applicable to precursor and intermediate.
The present invention preferably comprises formula (I) and (II) compound of above-mentioned preferred substituents and group and combination thereof.
The present invention more preferably comprises formula (I) and (II) compound of above-mentioned more preferably substituting group and group and combination thereof.
The present invention particularly preferably comprises formula (I) and (II) compound of above-mentioned particularly preferably substituting group and group and combination thereof.
The present invention especially preferably comprises formula (I) and (II) compound of above-mentioned especially preferred substituents and group and combination thereof.
Saturated or unsaturated alkyl, such as C
1-C
10alkyl, alkane two base or thiazolinyl, comprise and heteroatomic combination, such as alkoxyl group, can be all straight chain or with side chain respectively.
Except as otherwise noted, the optional group replaced can be monosubstituted or polysubstituted, and wherein in polysubstituted situation, substituting group can be identical or different.
In some preferred embodiments, following compound can be proposed:
In a more preferred, following compound can be proposed:
synthesis
Suitable solvent conventional in organic reaction all can use in each step reaction of following preparation method of the present invention, such as, but not limited to aliphatics and aromatic, hydrocarbon (the such as pentane of optional hydrocarbon or halogenation, hexane, heptane, hexanaphthene, sherwood oil, gasoline, volatile oil, benzene, toluene, dimethylbenzene, methylene dichloride, ethylene dichloride, chloroform, tetracol phenixin, chlorobenzene and orthodichlorobenzene), aliphatics and aromatic, optional alcohols (such as methyl alcohol, ethanol, propyl alcohol, Virahol, the trimethyl carbinol, ethylene glycol etc.), ether (such as ether and dibutyl ether, glycol dimethyl ether and diglyme, tetrahydrofuran (THF) is with diox etc.), ester (such as methyl acetate or ethyl acetate etc.), nitrile (such as acetonitrile or propionitrile etc.), ketone (such as acetone, butanone etc.), acid amides (such as dimethyl formamide, N,N-DIMETHYLACETAMIDE and N-Methyl pyrrolidone etc.), and dimethyl sulfoxide (DMSO), tetramethylene sulfone and HMPA and N, N-DMPU (DMPU) etc.
purposes
Compound of the present invention can be used for treating following disease, such as: tumour (tumor), such as: vascular tumor (hemangioma), glioma (glioma), melanoma (melanoma), Kaposi ' s sarcoma (sarcoma) and ovarian cancer (ovariancancer), mammary cancer (breastcancer), lung cancer (lungcancer), carcinoma of the pancreas (pancreaticcancer), prostate cancer (prostatecancer), colorectal carcinoma (coloncancer), mammary cancer (breastcancer) and other stomach cancer etc., chronic inflammation disease (chronicinflammatorydisease), such as rheumatoid arthritis (rheumatoidarthritis), to there is (vasculogenesis) or the relevant disease of revascularization art (angiogenesis) to mammiferous blood vessel, atherosclerosis (atherosclerosis), inflammatory bowel disease (inflammatoryboweldisease), tetter, such as psoriatic (psoriasis), excema and scleroderma (sceroderma), diabetes, diabetic retinopathy (diabeticretinopathy), retinopathy of prematurity (retinopathyofprematurity), age-related macular degeneration (age-ralatedmaculardegeneration), the disease relevant to chronic pain, the disease comprising neurodynia and modulated by MEK cascade, such as post-operative pain, phantom limb pain (phantomlimbpain), burn pain (burnpain), gout (gout), trigeminal neuralgia (trigeminalneuralgia), pain (postherpeticpain) after acute hepatodynia (acuteherpetic) and liver, cusalgia (causalgia), diabetic neuropathy (diabeticneuropathy), plexusavulsion, neuroma (neuroma), vasculitis (vasculitis), crush injury (crushinjury), wound of hanging (constrictioninjury), tissue injury (tissueinjury), post-operative pain (post-surgicalpain), arthrodynia (arthritispain) or amputation (limbamputation) pain etc.
1. dosage
According to known method, those skilled in the art can consider that the factors such as age, body weight, healthy state, the disease type for the treatment of and the existence of other drug determine the dosage of patient.Generally speaking, significant quantity is 0.1 to 1000mg/kg body weight every day, preferred every day 1 to 300mg/kg body weight.For the adult of normal type, per daily dose is generally 10 to 2500 milligrams.The preparation of commercially available 100mg, 200mg, 300mg or 400mg can according to disclosed method administration.
2. preparation
Compound of the present invention, by any suitable route of administration administration, comprises systemic administration and topical.Systemic administration comprises: oral, administered parenterally, transdermal administration or rectal administration; Or inhalation.Administered parenterally represents the route of administration except administration in intestines or transdermal administration, and the administration by injection or infusion usually.Administered parenterally comprises intravenous administration, intramuscular administration and subcutaneous injection or infusion.Topical comprises and is applied to skin and eye drops, dosing eyes, intravaginal administration and intranasal administration.
Can medicinal to compound of the present invention and one or more acceptable excipient be become to be suitable for by the formulation of required route of administration to patient's administration, such as tablet, capsule, pill, lozenge, pulvis, syrup, elixir, suspension agent, solution, emulsion and sachet (sachet) etc.
Suitable medicinal acceptable vehicle changes changing according to selected concrete formulation.They comprise tackiness agent, lubricant, glidant, disintegrating agent, granulating agent, Drug coating, wetting agent, solvent, cosolvent, suspension agent, seasonings, taste masked agent, anti-caking agent, thinner, sequestrant, softening agent, viscosity modifier, antioxidant, sanitas, stablizer, tensio-active agent, emulsifying agent and buffer reagent.
Prepared by medicinal compositions of the present invention techniques and methods well known by persons skilled in the art.
synthetic example:
The synthesis of embodiment 1.5-(the fluoro-4-idodophenylamino of 2-)-N-(2-hydroxyl-oxethyl)-8-((3-oxomorpholin) methyl) imidazo [1,5-a] pyridine-6-methane amide:
The synthesis of the chloro-6-methyl of step 1:3,5-bis--2H-1,4-oxazine-2-ketone
According to EuropeanJournaloforganicChemistry; Nb, 30; (2007); P.4995-4998. title compound is prepared
lh-NMR (400MHz, DMSO-d
6) δ 2.30 (s, 3H).
The synthesis of step 2:2,6-bis-chloro-5-methylnicotinic acid ethyl ester
According to synthesis; Nb, 9; (1991); P.765-768. title compound is prepared
The synthesis of the chloro-2-of step 3:6-(the fluoro-4-idodophenylamino of 2-)-5-methylnicotinic acid ethyl ester
Fluoro-for compound 2-4-iodobenzene ammonia (12.15g, 51.26mmol) is added in reaction flask, adds anhydrous THF (50ml), under nitrogen atmosphere, after being cooled to-78 DEG C, in reaction solution, drip LiHMDS (1M, 128.5ml, 128.5mmol), after 30 minutes, compound 2 is added-78 DEG C of reactions, 6-bis-chloro-5-methylnicotinic acid ethyl ester (10g, 42.72mmol), remove dry ice after adding abundant, continue reaction 3 hours.After completion of the reaction with saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains product.(15g, yield: 81%) [M+H]
+=435.6
The synthesis of step 4:6-cyano group-2-(the fluoro-4-idodophenylamino of 2-)-5-methylnicotinic acid ethyl ester
By chloro-for compound 6-2-(the fluoro-4-idodophenylamino of 2-)-5-methylnicotinic acid ethyl ester (10.0g, 23.01mmol) add in reaction flask, add DMF (50ml), then add dicyano zinc (1.77g, 16.80mmol) and Pd (PPh
3)
4(2.66g, 2.30mmol), is heated to 100 DEG C of reactions 8 hours under nitrogen protection, and after completion of the reaction, with diluted ethyl acetate, filter, and wash organic phase with water, anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains target product.(7.6g, yield: 77%). [M+H]
+=426.2
Step 5:6-amino methyl-2-(the fluoro-4-idodophenylamino of 2-)-5-methylnicotinic acid ethyl ester
By compound 6-cyano group-2-(the fluoro-4-idodophenylamino of 2-)-5-methylnicotinic acid ethyl ester (7.0g, 16.46mmol) add in reaction flask, add methyl alcohol (80ml), then cobalt chloride (4.28g is added, 32.93mmol), stirring at room temperature is after 10 minutes, add sodium borohydride (6.23g under ice-water bath cooling in batches, 164.63mmol), add and react 15 minutes under ice-water bath complete follow-up continuing, then rise to room temperature and continue reaction 1 hour.With concentrated hydrochloric acid cancellation reaction, and stirring at room temperature 15 minutes, cross and filter white solid, and wash with methylene dichloride, concentrated organic phase, the crude product acetic acid ethyl dissolution obtained, and wash with saturated sodium carbonate solution, washing, saturated common salt is washed, anhydrous sodium sulfate drying, concentrated, obtains target product.(3.5g, yield: 49.5%). [M+H]
+=430.2 step 6:2-(synthesis of (the fluoro-4-idodophenylamino of 2-)-6-(aldehyde radical amino methyl)-5-methylnicotinic acid ethyl ester
By compound 6-amino methyl-2-(the fluoro-4-idodophenylamino of 2-)-5-methylnicotinic acid ethyl ester (3.5g, 8.15mmol) add in reaction flask, add formic acid (30ml), add diacetyl oxide (6ml) after being chilled to 0 DEG C with ice bath, at room temperature react 2 hours, dissolve with methylene dichloride after concentration of reaction solution, and wash with saturated sodium carbonate, salt is washed, anhydrous sodium sulfate drying, concentrates and obtains target product.(3.7g, yield: 99%)
The synthesis of step 7:5-(the fluoro-4-idodophenylamino of 2-)-8-Methylimidazole also [1,5-a] pyridine-6-carboxylic acid, ethyl ester
By compound 2-((the fluoro-4-idodophenylamino of 2-)-6-(aldehyde radical amino methyl)-5-methylnicotinic acid ethyl ester (3.7g, 8.09mmol) add in reaction flask, add toluene (10ml), then phosphorus oxychloride (2.48g is added, 16.18mmol), be heated to 95 DEG C of reactions 1 hour, be cooled to room temperature, the residue with Ethyl acetate obtained after concentrated dissolves, and wash with saturated sodium carbonate solution, saturated common salt is washed, organic phase anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains target product.(2.1g, yield: 59%). [M+H]
+=440.2
The synthesis of step 8:8-(brooethyl)-5-(the fluoro-4-idodophenylamino of 2-) imidazo [1,5-a] pyridine-6-carboxylic acid, ethyl ester
By compound 5-(the fluoro-4-idodophenylamino of 2-)-8-Methylimidazole also [1,5-a] pyridine-6-carboxylic acid, ethyl ester (2.10g, 4.78mmol) add in reaction flask, then tetracol phenixin (20ml) is added, NBS (0.94g, 5.26mmol) with Benzoyl Peroxide (BPO) (112mg, 0.47mmol).Be heated to 60 DEG C of reactions 4 hours, be cooled to room temperature, with saturated sodium thiosulfate solution cancellation reaction, extraction into ethyl acetate, saturated common salt is washed, anhydrous sodium sulfate drying, and concentrated, column chromatography for separation obtains product.(1.8g, yield: 72%)
The synthesis of step 9:5-(the fluoro-4-idodophenylamino of 2-)-8-((4-(methylamino)-4-oxobutoxy is amino) methyl) imidazo [1,5-a] pyridine-6-carboxylic acid, ethyl ester:
By compound 8-(brooethyl)-5-(the fluoro-4-idodophenylamino of 2-) imidazo [1,5-a] pyridine-6-carboxylic acid, ethyl ester (150mg, 0.29mmol), add in reaction flask, add acetonitrile (3ml), then salt of wormwood (60mg is added, 0.43mmol) with 4-(amino oxygen base)-N-methylbutyryl amine (58mg, 0.43mmol), 60 DEG C of reactions 4 hours, room temperature is cooled to, add and wash and be extracted with ethyl acetate, anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains product.(120mg, yield: 73%).[M+H]
+＝570.4
The synthesis of step 10:5-(the fluoro-4-idodophenylamino of 2-)-8-((4-(methylamino)-4-oxobutoxy is amino) methyl)-N-(2-(vinyl oxygen base) oxyethyl group) imidazo [1,5-a] pyridine-6-methane amide
By compound O-(2-(vinyl oxygen base) ethyl) azanol (33mg, 0.32mmol) add in reaction flask, add anhydrous THF (1ml), under nitrogen atmosphere, after being cooled to-78 DEG C, LiHMDS (1M is dripped in reaction solution, 0.63ml, 0.63mmol),-78 DEG C of reactions after 30 minutes, add compound 5-(the fluoro-4-idodophenylamino of 2-)-8-((4-(methylamino)-4-oxobutoxy is amino) methyl) imidazo [1, 5-a] pyridine-6-carboxylic acid, ethyl ester (120mg, 0.21mmol), dry ice is removed abundant after adding, continue reaction 3 hours.After completion of the reaction with saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentratedly obtains crude product and is directly used in next step.
The synthesis of step 11:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-hydroxyl-oxethyl)-8-((4-(methylamino)-4-oxo butyl oxygen is amino) methyl) imidazo [1,5-a] pyridine-6-methane amide
The crude product (120mg, 0.20mmol) arrived of previous step is added in reaction flask, adds methyl alcohol (2ml), then 1MHCl (0.4ml is added, 0.4mmol), at room temperature react 30 minutes, after completion of the reaction, add water, and be extracted with ethyl acetate, saturated common salt is washed, anhydrous sodium sulfate drying, concentrated, column chromatography for separation to product.(80mg, yield: 70%).[M+H]
+＝601.4
The synthesis of step 12:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-hydroxyl-oxethyl)-8-((3-oxo-morpholine) methyl) imidazo [1,5-a] pyridine-6-methane amide
By compound 5-(the fluoro-4-idodophenylamino of 2-)-N-(2-hydroxyl-oxethyl)-8-((4-(methylamino)-4-oxo butyl oxygen is amino) methyl) imidazo [1,5-a] pyridine-6-methane amide (80mg, 0.13mmol), add in reaction flask, add 1,2-ethylene dichloride (2ml), be added to 60 DEG C of reactions 10 hours, after TLC detection reaction, be cooled to room temperature, concentrated, column chromatography for separation obtains product.(40mg, yield: 52%).
1HNMR(400MHz,CD
3OD)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/z570(M+1)。
The synthesis of embodiment 2:N-(2,3-hydroxy propyloxy group)-5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl) imidazo [1,5-a] pyridine-6-methane amide
The synthesis of step 1:5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl) imidazo [1,5-a] pyridine-6-carboxylic acid, ethyl ester
By compound 5-(the fluoro-4-idodophenylamino of 2-)-8-((4-(methylamino)-4-oxobutoxy is amino) methyl) imidazo [1,5-a] pyridine-6-carboxylic acid, ethyl ester (500mg, 0.88mmol), add in reaction flask, add 1,2-ethylene dichloride (10ml), be heated to 60 DEG C of reactions 10 hours, after completion of the reaction, be cooled to room temperature, concentrated, column chromatography for separation obtains product.(400mg, yield: 84.6%).[M+H]
+＝539.3
Step 2:N-((2,2-dimethyl-1,3-dioxolane-4-base) methoxyl group) synthesis of-5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl) imidazo [1,5-a] pyridine-6-methane amide:
By compound O-((2, 2-dimethyl-1, 3-dioxolane-4-base) methyl) azanol (41mg, 0.28mmol) add in reaction flask, add anhydrous THF (1ml), under nitrogen atmosphere, after being cooled to-78 DEG C, LiHMDS (1M is dripped in reaction solution, 0.56ml, 0.56mmol),-78 DEG C of reactions after 30 minutes, add compound 5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl) imidazo [1, 5-a] pyridine-6-carboxylic acid, ethyl ester (100mg, 0.18mmol), dry ice is removed abundant after adding, continue reaction 3 hours.After completion of the reaction with saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentratedly obtains crude product and is directly used in next step.
The synthesis of step 3:N-(2,3-hydroxy propyloxy group)-5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl) imidazo [1,5-a] pyridine-6-methane amide:
Compound N-((2,2-dimethyl-1,3-dioxolane-4-base) methoxyl group)-5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl) imidazo [1,5-a] pyridine-6-methane amide (118mg, 0.18mmol) add in reaction flask, then ethanol (1ml) and tetrahydrofuran (THF) (1ml) is added, add 1N hydrochloric acid (0.36ml again, 0.36mmol), at room temperature react 2 hours, after completion of the reaction, concentrated, column chromatography for separation obtains compound (60mg, yield: 54%).
1HNMR(400MHz,CD
3OD)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/z600.3(M+1)
The synthesis of embodiment 3:N-(Cvclopropvlmethvl oxygen)-5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl) imidazoles [1,5-a] pyridine-6-methane amide:
By compound O-(Cvclopropvlmethvl) azanol (12mg, 0.14mmol) add in reaction flask, add anhydrous THF (1ml), under nitrogen atmosphere, after being cooled to-78 DEG C, LiHMDS (1M is dripped in reaction solution, 0.27ml, 0.27mmol), after 30 minutes, compound 5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl) imidazo [1 is added-78 DEG C of reactions, 5-a] pyridine-6-carboxylic acid, ethyl ester (50mg, 0.09mmol), remove dry ice after adding abundant, continue reaction 3 hours.After completion of the reaction with saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains product.(50mg, yield: 55%).
1HNMR(400MHz,CD
3OD)
1HNMR(400MHz,CD
3OD)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/z580.3(M+1)
The synthesis of embodiment 4:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-hydroxyl-oxethyl)-8-((3-oxo isoxazole-2-base) methyl) imidazo [1,5-a] pyridine-6-methane amide:
The synthesis of step 1:5-(the fluoro-4-idodophenylamino of 2-)-8-((3-(methylamino)-3-oxopropoxy is amino) methyl) imidazo [1,5-a] pyridine-6-carboxylic acid, ethyl ester:
By compound 8-(brooethyl)-5-(the fluoro-4-idodophenylamino of 2-) imidazo [1,5-a] pyridine-6-carboxylic acid, ethyl ester (150mg, 0.29mmol), add in reaction flask, add acetonitrile (3ml), then salt of wormwood (60mg is added, 0.43mmol) with 4-(amino oxygen base)-N-methyl propanamide (41mg, 0.43mmol), 60 DEG C of reactions 4 hours, room temperature is cooled to, add and wash and be extracted with ethyl acetate, anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains product.(120mg, yield: 73%).[M+H]
+＝556.4
The synthesis of step 2:5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxo isoxazole-2-base) methyl) imidazo [1,5-a] pyridine-6-carboxylic acid, ethyl ester:
By compound 5-(the fluoro-4-idodophenylamino of 2-)-8-((3-(methylamino)-3-oxopropoxy is amino) methyl) imidazo [1,5-a] pyridine-6-carboxylic acid, ethyl ester (120mg, 0.21mmol) add in reaction flask, add 1,2-ethylene dichloride (3ml), is heated to 60 DEG C of reactions 10 hours, 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-idodophenylamino of 2-)-8-((3-oxo isoxazole-2-base) methyl)-N-(2-(vinyloxy group) oxyethyl group) imidazo [1,5-a] pyridine-6-methane amide
By compound O-(2-(vinyl oxygen base) ethyl) azanol (26mg, 0.26mmol) add in reaction flask, add anhydrous THF (1ml), under nitrogen atmosphere, after being cooled to-78 DEG C, LiHMDS (1M is dripped in reaction solution, 0.51ml, 0.51mmol),-78 DEG C of reactions after 30 minutes, add compound 5-(the fluoro-4-idodophenylamino of 2-)-8-((4-(methylamino)-4-oxobutoxy is amino) methyl) imidazo [1, 5-a] pyridine-6-carboxylic acid, ethyl ester (90mg, 0.17mmol), dry ice is removed abundant after adding, continue reaction 3 hours.After completion of the reaction with saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentratedly obtains crude product and is directly used in next step.(100mg, yield: 100%)
Step 4:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-hydroxyl-oxethyl)-8-((3-oxo isoxazole-2-base) methyl) imidazo [1,5-a] pyridine-6-methane amide
By compound 5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxo isoxazole-2-base) methyl)-N-(2-(vinyloxy group) oxyethyl group) imidazo [1,5-a] pyridine-6-methane amide (100mg, 0.17mmol) add in reaction flask, add methyl alcohol (2ml), then 1MHCl (0.3ml is added, 0.3mmol), at room temperature react 30 minutes, add water, and be extracted with ethyl acetate, anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains product.(60mg, yield: 62%).
1HNMR(400MHz,CD
3OD)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/e556.30(M+1)
The synthesis of embodiment 5:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-hydroxyl-oxethyl)-8-((3-oxomorpholin) methyl)-[1,2,4] triazolo [4,3-a] pyridine-6-methane amide
The synthesis of step 1:2-(the fluoro-4-idodophenylamino of 2-)-6-diazanyl-5-methylnicotinic acid ethyl ester:
Chloro-for compound 6-2-(the fluoro-4-idodophenylamino of 2-)-5-methylnicotinic acid ethyl ester (5g, 11.5mmol) is added in reaction flask, adds ethanol (30ml), then hydrazine hydrate 30% (1.35g is added, 12.65mmol), 40 DEG C of reactions 4 hours are heated to, after completion of the reaction, be cooled to room temperature, concentrated, add washing, dichloromethane extraction, anhydrous sodium sulfate drying, concentrated arrives target product.(4.2g, yield: 85%).[M+H]
+＝431.2
The synthesis of step 2:2-(the fluoro-4-idodophenylamino of 2-)-6-(2 aldehyde radical diazanyl)-5-methylnicotinic acid ethyl ester:
By compound 2-(the fluoro-4-idodophenylamino of 2-)-6-diazanyl-5-methylnicotinic acid ethyl ester (4.2g, add in reaction flask, add formic acid (30ml), add diacetyl oxide (6ml) after being chilled to 0 DEG C with ice bath, at room temperature react 2 hours, dissolve with methylene dichloride after concentration of reaction solution, and wash with saturated sodium carbonate, salt is washed, anhydrous sodium sulfate drying, concentrates and obtains target product.(4.4g, yield: 98%)
The synthesis of step 3:5-(the fluoro-4-idodophenylamino of 2-)-8-methyl-[1,2,4] triazolo [4,3-a] pyridine-6-carboxylic acid, ethyl ester:
By compound 2-(the fluoro-4-idodophenylamino of 2-)-6-(2 aldehyde radical diazanyl)-5-methylnicotinic acid ethyl ester (4.4g, 9.60mmol) add in reaction flask, add toluene (10ml), then phosphorus oxychloride (2.94g is added, 19.20mmol), be heated to 95 DEG C of reactions 1 hour, be cooled to room temperature, the residue with Ethyl acetate obtained after concentrated dissolves, and wash with saturated sodium carbonate solution, saturated common salt is washed, organic phase anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains target product.(2.1g, yield: 50%). [M+H]
+=441.2
The synthesis of step 4:8-(brooethyl)-5-(the fluoro-4-idodophenylamino of 2-)-[1,2,4] triazolo [4,3-a] pyridine-3-carboxylic acid ethyl ester:
By compound 5-(the fluoro-4-idodophenylamino of 2-)-8-methyl-[1,2,4] triazolo [4,3-a] pyridine-6-carboxylic acid, ethyl ester (2.10g, 4.77mmol) add in reaction flask, then add tetracol phenixin (20ml), NBS (0.94g, 5.26mmol) with Benzoyl Peroxide (BPO) (112mg, 0.47mmol).Be heated to 60 DEG C of reactions 4 hours, be cooled to room temperature, with saturated sodium thiosulfate solution cancellation reaction, extraction into ethyl acetate, saturated common salt is washed, anhydrous sodium sulfate drying, and concentrated, column chromatography for separation obtains product.(1.8g, yield: 72.6%).[M+H]
+＝520.1
The synthesis of step 5:5-(the fluoro-4-idodophenylamino of 2-)-8-((4-(methylamino)-4-oxobutoxy is amino) methyl)-[1,2,4] triazolo [4,3-a] pyridine-6-carboxylic acid, ethyl ester:
By compound 8-(brooethyl)-5-(the fluoro-4-idodophenylamino of 2-)-[1,2,4] triazolo [4,3-a] pyridine-3-carboxylic acid ethyl ester (500mg, 0.96mmol), add in reaction flask, add acetonitrile (15ml), then add salt of wormwood (200mg, 1.44mmol) with 4-(amino oxygen base)-N-methylbutyryl amine (193mg, 1.44mmol), 60 DEG C of reactions 4 hours, room temperature is cooled to, add and wash and be extracted with ethyl acetate, anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains product.(400mg, yield: 73%).[M+H]
+＝570.4
The synthesis of step 6:5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl)-[1,2,4] triazolo [4,3-a] pyridine-6-carboxylic acid, ethyl ester:
By compound 5-(the fluoro-4-idodophenylamino of 2-)-8-((4-(methylamino)-4-oxobutoxy is amino) methyl) imidazo [1,5-a] pyridine-6-carboxylic acid, ethyl ester (400mg, 0.70mmol), add in reaction flask, add 1,2-ethylene dichloride (10ml), be heated to 60 DEG C of reactions 10 hours, after completion of the reaction, be cooled to room temperature, concentrated, column chromatography for separation obtains product.(300mg, yield: 79%).[M+H]
+＝540.3
Step 7:5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl)-N-(2-(vinyl oxygen) oxyethyl group)-[1,2,4] synthesis of triazole [4,3-a] pyridine-6-methane amide:
By compound O-(2-(vinyl oxygen base) ethyl) azanol (29mg, 0.28mmol) add in reaction flask, add anhydrous THF (1ml), under nitrogen atmosphere, after being cooled to-78 DEG C, LiHMDS (1M is dripped in reaction solution, 0.57ml, 0.57mmol),-78 DEG C of reactions after 30 minutes, add compound 5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl)-[1, 2, 4] triazolo [4, 3-a] pyridine-6-carboxylic acid, ethyl ester (100mg, 0.19mmol), dry ice is removed abundant after adding, continue reaction 3 hours.After completion of the reaction with saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentratedly obtains crude product and is directly used in next step.
The synthesis of step 8:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-hydroxyl-oxethyl)-8-((3-oxomorpholin) methyl)-[1,2,4] triazolo [4,3-a] pyridine-6-methane amide
By compound 5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl)-N-(2-(vinyl oxygen) oxyethyl group)-[1,2,4] triazole [4,3-a] pyridine-6-methane amide (100mg, 0.17mmol), add in reaction flask, add methyl alcohol alkane (2ml), then add as 1MHCl (0.34ml), room temperature reaction 1 hour, after TLC detection reaction, dilute with water, and be extracted with ethyl acetate, anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains product.(50mg, yield: 52%).
1HNMR(400MHz,CD
3OD)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/z571(M+1)。
The synthesis of embodiment 6:N-(2,3-hydroxy propyloxy group)-5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl) imidazo [1,5-a] pyridine-6-methane amide
Step 1:N-((2,2-dimethyl-1,3-dioxolane-4-ylmethoxy)-5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl)-[1,2,4] synthesis of triazolo [4,3-a] pyridine-6-methane amide:
By compound O-((2, 2-dimethyl-1, 3-dioxolane-4-base) methyl) azanol (41mg, 0.28mmol) add in reaction flask, add anhydrous THF (1ml), under nitrogen atmosphere, after being cooled to-78 DEG C, LiHMDS (1M is dripped in reaction solution, 0.56ml, 0.56mmol),-78 DEG C of reactions after 30 minutes, add compound 5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl)-[1, 2, 4] triazolo [4, 3-a] pyridine-6-carboxylic acid, ethyl ester (100mg, 0.18mmol), dry ice is removed abundant after adding, continue reaction 3 hours.After completion of the reaction with saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentratedly obtains crude product and is directly used in next step.
The synthesis of step 2:N-(2,3-hydroxy propyloxy group)-5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl) imidazo [1,5-a] pyridine-6-methane amide:
Compound N-((2,2-dimethyl-1,3-dioxolane-4-ylmethoxy)-5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl)-[1,2,4] triazolo [4,3-a] pyridine-6-methane amide (100mg, 0.16mmol) add in reaction flask, then add ethanol (1ml) and tetrahydrofuran (THF) (1ml), then add 1N hydrochloric acid (0.32ml, 0.32mmol), at room temperature react 2 hours, after completion of the reaction, concentrated, column chromatography for separation obtains compound (45mg, yield: 48%).
1HNMR(400MHz,CD
3OD)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/z601.3(M+1)
The synthesis of embodiment 7:N-(Cvclopropvlmethvl oxygen)-5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl) imidazoles [1,5-a] pyridine-6-methane amide:
By compound O-(Cvclopropvlmethvl) azanol (12mg, 0.14mmol) add in reaction flask, add anhydrous THF (1ml), under nitrogen atmosphere, after being cooled to-78 DEG C, LiHMDS (1M is dripped in reaction solution, 0.27ml, 0.27mmol), after 30 minutes, compound 5-(the fluoro-4-idodophenylamino of 2-)-8-((3-oxomorpholin) methyl) imidazo [1 is added-78 DEG C of reactions, 5-a] pyridine-6-carboxylic acid, ethyl ester (50mg, 0.09mmol), remove dry ice after adding abundant, continue reaction 3 hours.After completion of the reaction with saturated ammonium chloride cancellation reaction, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains product.(28mg, yield: 52%).
1HNMR(400MHz,CD
3OD)
1HNMR(400MHz,CD
3OD)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/z581.3(M+1)
biological examples
cytoactive is tested
1. cell: human colon carcinoma COLO205, Humanmachine tumour A375 cell, all from Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences's preclinical medicine cell centre.
2. reagent: GibcoDMEM/F12 substratum, Gibco0.25% pancreatin/EDTA cell dissociation buffer, MTT (5mg/ml), DMSO, PBS.
3. instrument: 37 DEG C, 5%CO
2incubator, TECANInfinite
tM200 series multifunctional microplate reader, Bechtop, cell counting count board.
4. test consumptive material: 96 orifice plates.
The active testing experimental procedure of human colon carcinoma COLO205 cell:
1. bed board.Digested by the cell Digestive system being in logarithmic phase, fresh culture stops, and counts, with fresh culture, cell concn is adjusted to 5*10 to cell
4individual/ml, every hole adds 200 μ L, if zeroing hole (only adding substratum) 3, the aseptic PBS in other edges fills.
2. at 37 DEG C at 5%CO
2in hatch 24 hours, allow cell be paved with at the bottom of hole about 60%.
3. administration.Medicine DMSO is dissolved, be made into 10mmol/L mother liquor, dilute with DMSO again, make 1mmol/L, 100 μm of ol/L, 10 μm of ol/L, 1mol/L, 0.1mol/L solution, during administration, get above-mentioned strength solution 1 μ L substratum and be diluted to 1mL, namely administration concentration is 10 μm of ol/L, 1 μm of ol/L, 100nmol/L, 10nmol/L, 1nmol/L, 0.1nmol/L, 0nmol/L (control group adds 1 μ LDMSO substratum and is diluted to 1ml).During administration, liquid in original hole is exhausted, adds the fresh culture containing different concns medicine, every hole 200 μ l.
● zeroing hole, only adds substratum;
● control group, containing the solvent with experimental group same volume, dilutes with perfect medium.Every hole 200 μ l;
● experimental group, the medicine substratum dissolved is diluted to 0.1,1,10,100,1000,10000nM concentration, every hole 200 μ l.
4. at 37 DEG C at 5%CO
2in hatch.
After 5.72h, every hole adds 20 μ LMTT solution (5mg/ml), continues to cultivate 4h.
6. by centrifugal for 96 orifice plate plate centrifuge, 1000 turns/5 minutes.
7. stop cultivating, carefully suck the nutrient solution in hole.
8. every hole adds 150 μ l dimethyl sulfoxide (DMSO) (DMSO), and low speed concussion 10min, after thing to be crystallized fully dissolves, in microplate reader, 490nm wavelength place surveys its light absorption value.
Shown according to the form below 2, the compounds of this invention is numbered.The IC of whole compound 1-17
50value is all less than 1000nM.
The active testing experimental procedure of Humanmachine tumour A375 cell:
1. bed board.Digested by the cell Digestive system being in logarithmic phase, fresh culture stops, and counts, with fresh culture, cell concn is adjusted to 2.5*10 to cell
4individual/ml, every hole adds 200 μ L, if zeroing hole (only adding substratum) 3, the aseptic PBS in other edges fills.
2. at 37 DEG C at 5%CO
2in hatch 36 hours, allow cell be paved with at the bottom of hole about 60%.
3. administration.Medicine DMSO is dissolved, be made into 10mmol/L mother liquor, dilute with DMSO again, make 1mmol/L, 100 μm of ol/L, 10 μm of ol/L, 1mol/L, 0.1mol/L solution, during administration, get above-mentioned strength solution 1 μ L substratum and be diluted to 1mL, namely administration concentration is 10 μm of ol/L, 1 μm of ol/L, 100nmol/L, 10nmol/L, 1nmol/L, 0.1nmol/L, 0nmol/L (control group adds 1 μ LDMSO substratum and is diluted to 1ml).During administration, liquid in original hole is exhausted, adds the fresh culture containing different concns medicine, every hole 200 μ l.
● zeroing hole, only adds substratum;
● control group, containing the solvent with experimental group same volume, dilutes with perfect medium.Every hole 200 μ l;
● experimental group, the medicine substratum dissolved is diluted to 0.1,1,10,100,1000,10000nM concentration, every hole 200 μ l.
4. at 37 DEG C at 5%CO
2in hatch.
After 5.72h, every hole adds 20 μ LMTT solution (5mg/ml), continues to cultivate 4h.
6. stop cultivating, carefully suck the nutrient solution in hole.
7. every hole adds 150 μ l dimethyl sulfoxide (DMSO) (DMSO), and low speed concussion 10min, after thing to be crystallized fully dissolves, in microplate reader, 490nm wavelength place surveys its light absorption value.
Shown according to the form below 1, the compounds of this invention is numbered.The IC of whole compound 1-7
50value is all less than 1000nM.
Table 1. test compounds
Claims (14)
1. the compound of formula (I) and (II) and pharmacy acceptable salt, prodrug and solvate
Wherein
A is selected from C and N;
R
1be selected from hydrogen, halogen, cyano group, nitro, azido-, hydroxyl, C
1-C
10alkoxyl group, halo C
1-C
10alkoxyl group, sulfydryl, C
1-C
10alkylthio, halo C
1-C
10alkylthio, carboxyl ,-OC (O) H, amino, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl;
R
2be selected from hydrogen, halogen, nitro, azido-, hydroxyl, C
1-C
10alkyl, C
1-C
10alkoxyl group, halo C
1-C
10alkoxyl group, C
1-C
10alkylthio, halo C
1-C
10alkylthio, carboxyl ,-OC (O) H, amino, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl;
R
3be selected from hydrogen, C
1-C
12alkyl, C
2-C
12thiazolinyl, C
2-C
12alkynyl, C
3-C
12cycloalkyl, C
3-C
12cycloalkyl C
1-C
12alkyl, C
1-C
12alkyl C
3-C
12cycloalkyl, described alkyl, thiazolinyl, alkynyl and cycloalkyl can be selected from following group by one to three independently of one another and replace arbitrarily :-ORa ,-NRaRb ,-NRaC (O) Rb, Heterocyclylalkyl and heterocyclic aromatic base, and Heterocyclylalkyl described herein and heterocyclic aromatic base can be selected from following substituting group by one to three and replace arbitrarily: C
1-C
5alkyl ,-ORa ,-NRaRb;
X representative formula (i):
Wherein
Y is selected from O ,-ONR
8,-NR
8o ,-NR
8c (O) ,-NR
8sO
2;
Z is selected from hydrogen, C
1-C
5methene chain, described methylene radical can be replaced arbitrarily by one to three W';
R
8be selected from hydrogen, C
1-C
12alkyl ,-COR
9, described alkyl can be replaced arbitrarily by halogen ,-ORa ,-NRaRb;
R
9be selected from hydrogen, C
1-C
12alkyl, described alkyl can be replaced arbitrarily by halogen ,-ORa ,-NRaRb;
Or X representative formula (ii):
Wherein
Y
1and Y
2can be the same or different, they represent singly-bound ,-CO-,-COO-,-O-,-OCO-,-NRa-,-SO independently of one another
2-;
Z' represents C
1-C
10chain alkylene, described alkyl can be replaced arbitrarily by one to three W';
In above-mentioned formula (i) and formula (ii),
W and W' can be the same or different, and they are selected from halogen, C independently of one another
1-C
5alkyl ,-O-,-ORa ,-COORa ,-COOCORa ,-CO-halogen ,-OCORa ,-CONRaRb ,-SRa ,-SORa ,-SO
2ra ,-NRaRb ,-NRaCORb ,-NRaSO
2rb ,-SO
2nRaRb, Heterocyclylalkyl or heterocyclic aromatic base, described Heterocyclylalkyl and heterocyclic aromatic base can be selected from following substituting group by one to three and replace arbitrarily: C
1-C
5alkyl ,-ORa ,-NRaRb; Described alkyl can by hydroxyl, C
1-C
5alkoxyl group or amino replacement arbitrarily;
Above-mentioned group deoxygenation and halogen all can be interconnected to form cycloalkyl or Heterocyclylalkyl outward, and described cycloalkyl or Heterocyclylalkyl can be selected from following substituting group and replace arbitrarily :-ORa ,-NRaRb, the C replaced arbitrarily by-ORa
1-C
5alkyl;
Ra and Rb can be the same or different, and they are selected from hydrogen, C independently of one another
1-C
5alkyl, described alkyl can be selected from following substituting group by one to three and replace arbitrarily: hydroxyl, C
1-C
5alkoxyl group, amino.
2. the compound of claim 1 and pharmacy acceptable salt, prodrug and solvate, wherein X representative formula (i):
3. the compound of claim 2 and pharmacy acceptable salt, prodrug and solvate, wherein
Y is selected from-O-,-NR
8o-,-NR
8c (O)-,-NR
8sO
2-;
Z is selected from hydrogen ,-CH
2-,-(CH
2)
2-,-(CH
2)
3-,-CH
2(CH
3) CH
2-,-CH
2c (CH
3)
2-,-CH
2c (CH
3)
2cH
2-,-CH
2c (CH
2cH
2) CH
2-;
R
8be selected from hydrogen, methyl ,-COH ,-COCH
3,-COCH
2cH
3,-COCH (CH
3)
2,-COCH
2oH;
W and W' can be the same or different, and they are selected from hydrogen, hydroxyl, methyl ,-O (CH independently of one another
2)
2oH ,-C (O) OCH
3,-CONHCH
3,-CONHCH
2cH
3,-CONHCH (CH
3)
2,-CON (CH
3)
2,-NHCH
3,-NH (CH
2)
2oH ,-NHCOCH
3,-NHCOCH
2cH
3,-NHCOCH (CH
3)
2,-SCH
3,-SOCH
3, 1H-imidazoles-2-base, morpholine-4-base, 4-hydroxy piperidine base.
4. the compound of claim 1 and pharmacy acceptable salt, prodrug and solvate, wherein X representative formula (ii):
5. the compound of claim 4 and pharmacy acceptable salt, prodrug and solvate, wherein X is selected from
Z' is selected from C
1-C
3chain alkylene, described alkyl can be replaced arbitrarily by one to three W';
W' is selected from C
1-C
3alkyl ,-ORa ,-COORa ,-COOCORa ,-CO-halogen ,-OCORa ,-CONRaRb ,-SRa ,-SORa ,-SO
2ra ,-NRaRb ,-NRaCORb ,-NRaSO
2rb ,-SO
2nRaRb;
Ra and Rb can be the same or different, and they are selected from hydrogen, C independently of one another
1-C
3alkyl, described alkyl can be selected from following substituting group by one to three and replace arbitrarily: hydroxyl, C
1-C
3alkoxyl group, amino.
6. the compound of claim 5 and pharmacy acceptable salt, prodrug and solvate, wherein X is selected from
Z' is selected from-CH
2-,-(CH
2)
2-,-(CH
2)
3-,-(CH
2)
4-, wherein hydrogen atom is all replaced arbitrarily by one to three W' arbitrarily;
W' is selected from hydroxyl, C
1-C
2alkyl.
7. the compound of claim 6 and pharmacy acceptable salt, prodrug and solvate, wherein X is selected from
8. arbitrary compound of claim 1-7 and pharmacy acceptable salt, prodrug and solvate, wherein
A is selected from C and N;
R
1be selected from fluorine, chlorine, bromine, iodine, C
1-C
4alkoxyl group, C
1-C
4alkylthio, halo-C
1-C
4alkoxyl group, halo-C
1-C
4alkylthio, C
1-C
4alkyl, halo C
1-C
4alkyl C
2-C
4thiazolinyl, C
2-C
4alkynyl;
R
2be selected from hydrogen, halogen or C
1-C
4alkyl;
R
3for C that is unsubstituted or that replaced by 1 to 6 hydroxyl
1-C
4alkyl, C
3-C
4cycloalkyl, C
3-C
4cycloalkyl C
1-C
4alkyl or C
1-C
4alkyl C
3-C
4cycloalkyl.
9. the compound of claim 8 and pharmacy acceptable salt, prodrug and solvate, wherein
R
1be selected from bromine, iodine, C
1-C
2alkylthio, halo-C
1-C
2alkylthio, C
1-C
2alkoxyl group, halo-C
1-C
2alkoxyl group, C
1-C
2alkyl, halo C
1-C
2alkyl, C
2-C
3thiazolinyl, C
2-C
3alkynyl;
R
2be selected from hydrogen, fluorine, chlorine, bromine or C
1-C
2alkyl;
R
3for C that is unsubstituted or that replaced by 1 to 3 hydroxyl
1-C
3alkyl, C
3-C
4cycloalkyl, C
3-C
4cycloalkyl C
1-C
3alkyl or C
1-C
3alkyl C
3-C
4cycloalkyl.
10. the compound of claim 9 and pharmacy acceptable salt, prodrug and solvate, wherein
R
1be selected from bromine, iodine, methylthio group, trifluoromethylthio, methoxyl group, trifluoromethoxy, methyl, trifluoromethyl, vinyl, ethynyl;
R
2be selected from fluorine, chlorine or methyl;
R
3be selected from 2-hydroxyethyl, 3-hydroxyethyl, 2,3-dihydroxypropyls, 1-methylol-2-hydroxyethyl, 2-methyl-3-hydroxypropyl, cyclopropyl, Cvclopropvlmethvl or 1-(2,3-hydroxypropyl) cyclopropyl.
Formula (I) compound of 11. claims 1, and pharmacy acceptable salt, prodrug and solvate, wherein said compound is selected from:
The preparation method of formula (I) compound of 12. claims 1, comprising:
(A) route 1
(B) route 2
(C) formula (I-1-a) compound is prepared according to following route 3:
Wherein, the synthesized reference route 2 of compound 11
(D) formula (I-1-b) compound is prepared according to following route 4:
Wherein, the synthesized reference route 2 of compound 11
(E) formula (I-1-c) compound is prepared according to following route 5:
(F) formula (I-2-A) compound is prepared according to following route 6:
(G) formula (I-2-A) compound is prepared according to following route 7:
13. 1 kinds of medicinal compositionss comprising formula (I) and (II) compound, its pharmacy acceptable salt, prodrug and/or solvate.
14. formulas (I) and (II) compound and pharmacy acceptable salt, prodrug and solvate for the manufacture of the mammiferous tumour for the treatment of, chronic inflammatory diseases, inflammatory bowel disease, tetter, diabetes, eye disease, with the disease that mammiferous blood vessel occurs or revascularization is relevant, and the purposes of medicine of the chronic pain disease of being correlated with and other disease of being modulated by Mek cascade.
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