CN105315293A - Heterocyclic compounds serving as protein kinase inhibitors and preparation method for heterocyclic compounds and use of heterocyclic compounds - Google Patents
Heterocyclic compounds serving as protein kinase inhibitors and preparation method for heterocyclic compounds and use of heterocyclic compounds Download PDFInfo
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- CN105315293A CN105315293A CN201410368274.6A CN201410368274A CN105315293A CN 105315293 A CN105315293 A CN 105315293A CN 201410368274 A CN201410368274 A CN 201410368274A CN 105315293 A CN105315293 A CN 105315293A
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Abstract
The invention relates to compounds represented by formulae (I) and (II) as well as pharmaceutically acceptable salts and pro-drugs thereof, wherein R1, R2, R3, R4, R5, R6, X, Y, Z and W are as defined in the description. The compounds are protein kinase inhibitors, particularly protein kinase Mek inhibitors, and can be used for treating cancers and inflammation of mammals. The invention further discloses a method for treating diseases such as cancers and inflammation of mammals by using the compounds as well as pharmaceutical compositions comprising the compounds. The invention relates to a preparation process of benzoheterocyclic compounds. The invention mainly relates to preparation of compounds capable of becoming drugs, for example, pyridinoheterocyclic derivatives and the like.
Description
Technical field
The present invention relates to protein kinase (especially protein kinase Mek) inhibitor, more specifically, relate to as the Benzoheterocyclic compounds of protein kinase (especially protein kinase Mek) inhibitor and prodrug thereof, solvate and the composition comprising these materials, and relate to the preparation method of described Benzoheterocyclic compounds, also relate to the purposes of described Benzheterocyclic derivatives 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 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 inflammatory diseases and symptom, 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; 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 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
represent
or
X and W represents N, O, S or CR independently
5;
Y is N or CR
6;
Z is selected from C or N
And
R
1, R
2and R
3be selected from hydrogen, halogen, nitro, azido-,-OR independently of one another
7,-C (O) R
7,-C (O) OR
7,-NR
8c (O) OR
10,-OC (O) R
7,-NR
8sO
2r
10,-SO
2nR
7r
8,-NR
8c (O) R
7,-C (O) NR
7r
8,-NR
9c (O) NR
7r
8,-NR
9c (NCN) NR
7r
8,-NR
7r
8, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkyl C
1-C
10alkyl ,-S (O)
j(C
1-C
10alkyl) ,-S (O)
j(CR
8r
9)
m, C
6-C
14aryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl, heteroaryl C
1-C
10alkyl, heterocyclic radical, heterocyclic radical C
1-C
10alkyl ,-O (CR
8r
9)
m-C
6-C
14aryl ,-NR
8(CR
8r
9)
m-C
6-C
14aryl ,-O (CR
8r
9)
m-heteroaryl ,-NR
8(CR
8r
9)
m-heteroaryl ,-O (CR
8r
9)
m-heterocyclic radical ,-NR
8(CR
8r
9)
m-heterocyclic radical;
Wherein said C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
6-C
14aryl, heteroaryl and heterocyclyl moieties can be selected from following group optionally replace by one or more independently of one another: oxo, halogen, cyano group, nitro, trifluoromethyl, azido-,-OR
7,-C (O) R
7,-C (O) OR
7,-NR
8c (O) OR
10,-OC (O) R
7,-NR
8sO
2r
10,-SO
2nR
7r
8,-NR
8c (O) R
7,-C (O) NR
7r
8,-NR
9c (O) NR
7r
8,-NR
9c (NCN) NR
7r
8,-NR
7r
8, C
6-C
14aryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl, heteroaryl C
1-C
10alkyl, heterocyclic radical, heterocyclic radical C
1-C
10alkyl;
R
4be selected from heteroaryl, heterocyclic radical ,-C (O) OR
7,-C (O) NR
7r
8,-C (O) NR
8oR
7,-C (O) R
8oR
7,-C (O) (C
3-C
10cycloalkyl) ,-C (O) (C
1-C
10alkyl) ,-C (O) (C
6-C
14aryl) ,-C (O) (heteroaryl) and-C (O) (heterocyclic radical);
These groups can be selected from following group optionally replace by one or more independently of one another :-NR
7r
8,-OR
7, C
1-C
10alkyl, C
2-C
10thiazolinyl and C
2-C
10alkynyl, each in them is optionally selected from-NR by 1 or 2
7r
8with-OR
7in group replace;
R
5be selected from hydrogen, halogen, C
1-C
6alkyl, C
3-C
6cycloalkyl, C
2-C
6thiazolinyl, C
5-C
6cycloalkenyl group, C
2-C
6alkynyl; Wherein, each alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group or alkynyl group are optionally independently selected from halogen, hydroxyl, amino, alkylamino, dialkyl amido, heterocyclic radical, C
1-C
4alkyl, C
1-C
41-3 substituting group of alkoxyl group, cyano group, cyano methyl, trifluoromethyl, difluoro-methoxy and phenyl replaces, and one or two ring carbon atom of described group of naphthene base is optionally by independently O, S or N replace;
R
6be selected from hydrogen, halogen, C
1-C
10alkyl, C
1-C
10alkoxyl group, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkyloxy, C
3-C
10cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, heterocyclic radical and cycloheteroalkylalkyl, wherein, each alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical are not substituted or are independently selected from halogen, hydroxyl, C
1-C
4alkyl, C
1-C
41-3 substituting group of alkoxyl group, cyano group, trifluoromethyl or difluoromethyl;
R
7, R
8and R
9be selected from hydrogen, C independently of one another
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkyl C
1-C
10alkyl, C
6-C
14aryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl, heteroaryl C
1-C
10alkyl, heterocyclic radical and heterocyclic radical C
1-C
10alkyl;
Wherein said C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
6-C
14aryl, heteroaryl and heterocyclyl moieties can be selected from following group optionally replace by one or more independently of one another: hydroxyl, oxo, halogen, cyano group, nitro, trifluoromethyl, azido-,-NR ' SO
2r " " ,-SO
2nR ' R " ,-C (O) R ' ,-C (O) OR ' ,-OC (O) R ' ,-NR ' C (O) R " " ,-NR ' C (O) R " ,-C (O) NR ' R " ,-SR ' ,-S (O) R " " ,-SO
2r " " ,-NR ' R " ,-NR ' C (O) NR " R " ' ,-NR ' C (NCN) NR " R " ' ,-OR ', C
6-C
14aryl, heteroaryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl C
1-C
10alkyl, heterocyclic radical and heterocyclic radical C
1-C
10alkyl;
Or
R
7and R
83-10 unit's heteroaryl or heterocycle is formed together with the atom that they connect;
These groups can be selected from following group optionally replace by one or more independently of one another: halogen, cyano group, nitro, trifluoromethyl, azido-,-NR ' SO
2r " " ,-SO
2nR ' R " ,-C (O) R ' ,-C (O) OR ' ,-OC (O) R ' ,-NR ' C (O) R " " ,-NR ' C (O) R " ,-C (O) NR ' R " ,-SR ' ,-S (O) R " " ,-SO
2r " " ,-NR ' R " ,-NR ' C (O) NR " R " ' ,-NR ' C (NCN) NR " R " ' ,-OR ', C
6-C
14aryl, heteroaryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl C
1-C
10alkyl, heterocyclic radical and heterocyclic radical C
1-C
10alkyl;
Or
R
8and R
93-10 unit's heteroaryl or heterocycle is formed together with the atom that they connect;
These groups can be selected from following group optionally replace by one or more independently of one another: halogen, cyano group, nitro, trifluoromethyl, azido-,-NR ' SO
2r " " ,-SO
2nR ' R " ,-C (O) R ' ,-C (O) OR ' ,-OC (O) R ' ,-NR ' C (O) R " " ,-NR ' C (O) R " ,-C (O) NR ' R " ,-SR ' ,-S (O) R " " ,-SO
2r " " ,-NR ' R " ,-NR ' C (O) NR " R " ' ,-NR ' C (NCN) NR " R " ' ,-OR ', C
6-C
14aryl, heteroaryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl C
1-C
10alkyl, heterocyclic radical and heterocyclic radical C
1-C
10alkyl;
R
10be selected from hydrogen, C
1-C
10alkyl, C
3-C
10cycloalkyl, C
6-C
14aryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl, heteroaryl C
1-C
10alkyl, heterocyclic radical, heterocyclic radical C
1-C
10alkyl;
Wherein said C
1-C
10alkyl, C
3-C
10cycloalkyl, C
6-C
14aryl, heteroaryl and heterocyclyl moieties can be selected from following group optionally replace by one or more independently of one another: oxo, halogen, cyano group, nitro, trifluoromethyl, azido-,-NR ' SO
2r " " ,-SO
2nR ' R " ,-C (O) R ' ,-C (O) OR ' ,-OC (O) R ' ,-NR ' C (O) R " " ,-NR ' C (O) R " ,-C (O) NR ' R " ,-SR ' ,-S (O) R " " ,-SO
2r " " ,-NR ' R " ,-NR ' C (O) NR " R " ' ,-NR ' C (NCN) NR " R " ' ,-OR ', C
6-C
14aryl, heteroaryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl C
1-C
10alkyl, heterocyclic radical and heterocyclic radical C
1-C
10alkyl;
R ', R " and R " ' independently selected from hydrogen, C
1-C
10alkyl, C
2-C
6thiazolinyl, C
6-C
14aryl and C
6-C
14aryl C
1-C
10alkyl;
R " " be selected from C
1-C
10alkyl, C
2-C
6thiazolinyl, C
6-C
14aryl and C
6-C
14aryl C
1-C
10alkyl;
Or
R ', R ", R " ' or R " " in any two atoms that can connect with them together with form 3-10 unit heteroaryl or heterocycle;
These groups can be selected from following group optionally replace by one or more independently of one another: halogen, cyano group, nitro, trifluoromethyl, difluoro-methoxy, trifluoromethoxy, azido-, C
6-C
14aryl, heteroaryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl C
1-C
10alkyl, heterocyclic radical and heterocyclic radical C
1-C
10alkyl;
M is 0,1,2,3,4 or 5; And
J is 0,1 or 2.
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.
When Y and Z is carbon, formula (I) and (II) compound have following general formula:
When W is CR
5, Y is CR
6time the invention provides some preferred compounds of following formula,
Wherein X is O or S; And R
1, R
2, R
3, R
4, R
5, R
6, as above definition;
On the other hand, the invention provides some preferred compounds of formula I and II, wherein Y is CR
6, and R
6for H, halogen, C
1-C
6a heatable brick bed base, C
3-C
6cycloalkyl, C
2-C
6thiazolinyl, C
5-C
6cycloalkenyl group or C
2-C
6alkynyl; Wherein, each alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group or fast base group be optionally independently selected from halogen, entered base, amino, alkylamino, dialkyl amido, heterocyclic radical, C
1-C
4alkyl, C
1-C
41-3 substituting group of alkoxyl group, amino, amino methyl, trifluoromethyl, difluoro-methoxy and phenyl replaces, and described C
3-C
6one or two ring carbon atom of ring a heatable brick bed base group is optionally by independently O, N or S replace; Or its pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug.
On the other hand, the invention provides some preferred compounds of above-mentioned general formula, or its pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, wherein
R
1and R
2more preferably hydrogen, halogen or C is selected from independently of one another
1-C
4alkyl.
R
1and R
2particularly preferably be selected from hydrogen, fluorine, chlorine, bromine or C independently of one another
1-C
2alkyl.
R
1and R
2especially preferably hydrogen, fluorine, chlorine or methyl is represented independently of one another.
R
3be preferably selected from hydrogen, halogen, C
1-C
6alkoxyl group, C
1-C
6alkyl, halo-C
1-C
6alkyl, C
1-C
6alkylthio, halo-C
1-C
6alkoxyl group, halo-C
1-C
6alkylthio.
R
3be more preferably fluorine, chlorine, bromine, iodine, C
1-C
4alkyl, halo-C
1-C
4alkyl, C
1-C
4alkoxyl group, C
1-C
4alkylthio, halo-C
1-C
4alkoxyl group, halo-C
1-C
4alkylthio.
R
3be particularly preferably 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.
R
3especially bromine, iodine, methyl, methoxyl group, methylthio group, trifluoromethyl, trifluoromethoxy, trifluoromethylthio is preferably.
R
4be preferably-C (O) NR
8oR
7,-C (O) NR
8r
7or-NHSO
2r
7,
R
7and R
8preferably be selected from hydrogen, C independently of one another
1-C
6alkyl, C
3-C
6cycloalkyl, C
3-C
6cycloalkyl C
1-C
6alkyl, C
1-C
6alkyl C
3-C
6cycloalkyl;
Wherein said C
1-C
6alkyl, C
3-C
6cycloalkyl, C
3-C
6cycloalkyl C
1-C
6alkyl, C
1-C
6alkyl C
3-C
6cycloalkyl can be selected from following group optionally replace by one or more independently of one another: hydroxyl, sulfydryl.
R
4be more preferably-C (O) NR
8oR
7,-C (O) NR
8r
7or-NHSO
2r
7;
R
7the C being more preferably unsubstituted or being 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
8be more preferably hydrogen or C
1-C
4alkyl.
R
4be particularly preferably-C (O) NR
8oR
7or-NHSO
2r
7;
R
7the C being particularly preferably unsubstituted or being 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
8be particularly preferably hydrogen.
R
4especially-C (O) NHOR is preferably
7or-NHSO
2r
7;
R
7especially 2-hydroxyethyl, 2,3-dihydroxypropyls, 1-methylol-2-hydroxyethyl, 2-methyl-3-hydroxypropyl, cyclopropyl, Cvclopropvlmethvl or 1-(2,3-hydroxypropyl) cyclopropyl is preferably.
In some specific embodiments, provide the compound with following formula, wherein X and W as defined above, R
1, R
3, R
4, the implication had in following table:
R
1and R
3represented by following table:
| R 1 | R 3 | R 1 | R 3 | R 1 | R 3 |
| F | Br | F | Br | F | Br |
| F | I | F | I | F | I |
| F | SMe | F | SMe | F | SMe |
| F | OCF 3 | F | OCF 3 | F | OCF 3 |
| F | CF 3 | F | CF 3 | F | CF 3 |
| Cl | Br | Cl | Br | Cl | Br |
| Cl | I | Cl | I | Cl | I |
| Cl | SMe | Cl | SMe | Cl | SMe |
[0065]
| Cl | OCF 3 | Cl | OCF 3 | Cl | OCF 3 |
| Cl | CF 3 | Cl | CF 3 | Cl | CF 3 |
| Me | Br | Me | Br | Me | Br |
| Me | I | Me | I | Me | I |
| Me | SMe | Me | SMe | Me | SMe |
| Me | OCF 3 | Me | OCF 3 | Me | OCF 3 |
| Me | CF 3 | Me | CF 3 | Me | CF 3 |
R
4following group can be selected from:
On the other hand, the invention provides compound or its pharmacy acceptable salt, solvate, polymorphic form, vinegar, tautomer or prodrug that following formula represents.
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) 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
Those skilled in the art will determine the dosage of patient according to known method, and consider the factors such as age, body weight, healthy state, the disease type for the treatment of and the existence of other drug.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.The preparation of commercially available 100mg, 200mg, 300mg or 400mg can according to disclosed method administration.
2. preparation
The binding substances of available multiple Mek inhibitor or Mek inhibitor and other medicinal reagent is made suitable preparation and is used for the treatment of above-mentioned disease.Described medicinal reagent comprises, such as weighting agent, carrier, tackifier, tinting material, additive, stablizer, synergistic agent, slow control agent etc.
Suitable dosage form comprises, such as solution, emulsion, water base and oil-based suspension, pulvis, powder agent, paste, soluble powder, granule, outstanding newborn enriching agent, capsule, tablet, potus, Haust, pill, suppository etc.
Suitable administering mode comprises, such as: carry out administration in intestines by forms such as tablet, capsule, potus, Haust, granule, paste, pills; By such as injecting (intramuscular, subcutaneous, intravenously, intraperitoneal etc.), implanting and carry out administered parenterally; Pass through nasal administration; Pass through, such as, soak or bathing, spraying, sprinkle and water and carry out percutaneous drug delivery etc. with the form such as drop, cleaning.
On the other hand, the invention provides the preparation method of above-claimed cpd:
Embodiment
If do not pointed out in addition, adopt following term definition in full herein:
Term " halogen " represents fluorine, chlorine, bromine and iodine.
Term " C
1-C
10alkyl " represent the straight chain or branched saturated hydrocarbyl that contain 1 to 10 carbon atom; such as; but be not limited to, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, positive decyl etc.
Term " C
2-C
10thiazolinyl " represent the alkyl containing 2 to 10 carbon atoms and at least 1 double bond, such as, but not limited to, vinyl, 1-propenyl, 2-propenyl, 1-methyl ethylene, 1-butylene base, crotyl, 3-butenyl, 1-methyl-1-propylene base, 2-methyl-1-propylene base, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl isophthalic acid-butenyl, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, 4-methyl-1-pentene base, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-crotyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butylene base, 1,2-dimethyl-crotyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butylene base, 1,3-dimethyl-crotyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butylene base, 2,3-dimethyl-crotyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butylene base, 3,3-dimethyl-crotyl, 1-ethyl-1-butylene base, 1-ethyl-crotyl, 1-ethyl-3-butenyl, 2-ethyl-1-butylene base, 2-ethyl-crotyl, 2-ethyl-3-butenyl, 1,1,2-trimethylammonium-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-Ethyl-2-Methyl-1-propenyl and 1-Ethyl-2-Methyl-2-propenyl etc.
Term " C
2-C
10alkynyl " represent the alkyl containing 2 to 10 carbon atoms and at least 1 triple bond, such as, but not limited to, ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-methyl-2-butyne base, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl isophthalic acid-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-methyl-valerylene base, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentene alkynyl, 3-methyl-4-pentynyl, 4-methyl-1-pentene alkynyl, 4-methyl-valerylene base, 1,1-dimethyl-2-butyne base, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-ethyl acetylene base, 1-ethyl-2-butyne base, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl etc.
Term " C
3-C
10cycloalkyl " represent containing 3 to 10 carbon monocycle, stable hydrocarbon group, such as, but not limited to, cyclopropyl, cyclopentyl and cyclohexyl;
Term " C
6-C
14aryl " represent containing the monocycle of 6 to 14 carbon atoms or the aromatic hydrocarbon group of many rings, such as, but not limited to, phenyl, naphthyl, anthryl etc.
Term " C
3-C
10cycloalkyl C
1-C
10alkyl " represent by C
3-C
10the C of cycloalkyl substituted
1-C
10moieties, such as, but not limited to, Cvclopropvlmethvl.
Term " C
6-C
14aryl C
1-C
10alkyl " represent by one or more C
6-C
14the C that aryl moiety replaces
1-C
10moieties, such as, but not limited to, benzyl, styroyl etc.
Term " heterocyclic radical " represents monocycle or the bicyclic groups of 3 yuan to 10 yuan, described group can be completely saturated, fractional saturation or completely undersaturated or be fragrance, and can be mixed with by least one or more identical or different atom being selected from nitrogen, sulphur or oxygen, but wherein two Sauerstoffatoms can not direct neighbor and ring has a carbon atom at least.Such as, but be not limited to, heteroatomic 3 to 15 yuan of saturated or undersaturated heterocycles of part of oxygen, nitrogen and sulphur are selected from: the heterocycle of single, double or three rings, wherein except carbon ring member, containing 1 to 3 nitrogen-atoms and/or 1 oxygen or sulphur atom or 1 or 2 oxygen and/or sulphur atom containing 1 to 4, if containing multiple Sauerstoffatom in ring, they directly do not adjoin, such as (but being not limited to) Oxyranyle, '-aziridino, 2-tetrahydrofuran base, 3-tetrahydrofuran base, 2-tetrahydro-thienyl, 3-tetra--hydrogen thienyl, 2-pyrrolidyl, 3-pyrrolidyl, 3-isoxazole alkyl, 4-isoxazole alkyl, 5-isoxazole alkyl, 3-isothiazole alkyl, 4-isothiazole alkyl, 5-isothiazole alkyl, 3-pyrazolidyl, 4-pyrazolidyl, 5-pyrazolidyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidyl, 4-thiazolidyl, 5-thiazolidyl, 2-imidazolidyl, 4-imidazolidyl, 1,2,4-oxadiazole alkane-3-base, 1,2,4-oxadiazole alkane-5-base, 1,2,4-thiadiazolidine-3-base, 1,2,4-thiadiazolidine-5-base, 1,2,4-triazolidine-3-base, 1,3,4-oxadiazole alkane-2-base, 1,3,4-thiadiazolidine-2-base, 1,3,4-triazolidine-2-base, 2,3 dihydro furan-2-base, 2,3 dihydro furan-3-base, 2,4-dihydrofuran-2-base, 2,4-dihydrofuran-3-base, 2,3-dihydro-thiophene-2-base, 2,3-dihydro-thiophene-3-base, 2,4-dihydro-thiophene-2-base, 2,4-dihydro-thiophene-3-base, 2-pyrroline-2-base, 2-pyrroline-3-base, 3-pyrroline-2-base, 3-pyrroline-3-base, 2-isoxazoline-3-base, 3-isoxazoline-3-base, 4-isoxazoline-3-base, 2-isoxazoline-4-base, 3-isoxazoline-4-base, 4-isoxazoline-4-base, 2-isoxazoline-5-base, 3-isoxazoline-5-base, 4-isoxazoline-5-base, 2-isothiazoline-3-base, 3-isothiazoline-3-base, 4-isothiazoline-3-base, 2-isothiazoline-4-base, 3-isothiazoline-4-base, 4-isothiazoline-4-base, 2-isothiazoline-5-base, 3-isothiazoline-5-base, 4-isothiazoline-5-base, 2,3-pyrazoline-1-base, 2,3-pyrazoline-2-base, 2,3-pyrazoline-3-base, 2,3-pyrazoline-4-base, 2,3-pyrazoline-5-base, 3,4-pyrazoline-1-base, 3,4-pyrazoline-3-base, 3,4-pyrazoline-4-base, 3,4-pyrazoline-5-base, 4,5-pyrazoline-1-base, 4,5-pyrazoline-3-base, 4,5-pyrazoline-4-base, 4,5-pyrazoline-5-base, 2,3-dihydro-oxazole-2-base, 2,3-dihydro-oxazole-3-base, 2,3-dihydro-oxazole-4-base, 2,3-dihydro-oxazole-5-base, 3,4-dihydro-oxazole-2-base, 3,4-dihydro-oxazole-3-base, 3,4-dihydro-oxazole-4-base, 3,4-dihydro-oxazole-5-base, 3,4-dihydro-oxazole-2-base, 3,4-dihydro-oxazole-3-base, 3,4-dihydro-oxazole-4-base, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1,3-diox-5-base, 2-THP trtrahydropyranyl, 4-THP trtrahydropyranyl, 2-tetrahydro-thienyl, 3-hexahydro-pyridazine base, 4-six-hydrogen pyridazinyl, 2-six-hydrogen pyrimidyl, 4-hexahydropyrimidine base, 5-hexahydropyrimidine base, 2-piperazinyl, 1,3,5-Hexahydrotriazine-2-base and 1,2,4-Hexahydrotriazine-3-base.
Term " heteroaryl " represents the substituted radical with the heterocyclic radical definition being only limited to aromatic heterocyclic ring systems.Such as, but not limited to, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrryl, 3-pyrryl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazole-Ji, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 1,2,4-oxadiazole-3-base, 1,2,4-oxadiazole-5-base, 1,2,4-thiadiazoles-3-base, 1,2,4-thiadiazoles-5-base, 1,2,4-triazole-3-base, 1,3,4-oxadiazole-2-base, 1,3,4-thiadiazoles-2-base and 1,3,4-triazole-2-base, 1-pyrryl, 1-pyrazolyl, 1,2,4-triazol-1-yl, 1-imidazolyl, 1,2,3-triazoles-1-base and 1,3,4-triazol-1-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyrazinyl, 1,3,5-triazines-2-base, 1,2,4-triazine-3-base and 1,2,4,5-tetrazine-3-base, indoles-1-base, indoles-2-base, indol-3-yl, indoles-4-base, indoles-5-base, indoles-6-base, indoles-7-base, benzoglyoxaline-1-base, benzimidazolyl-2 radicals-Ji, benzoglyoxaline-4-base, benzoglyoxaline-5-base, indazole-1-base, indazole-3-base, indazole-4-base, indazole-5-base, indazole-6-base, indazole-7-base, indazole-2-base, 1-cumarone-2-base, 1-cumarone-3-base, 1-cumarone-4-base, 1-cumarone-5-base, 1-cumarone-6-base, 1-cumarone-7-base, 1-thionaphthene-2-base, 1-thionaphthene-3-base, 1-thionaphthene-4-base, 1-thionaphthene-5-base, 1-thionaphthene-6-base, 1-thionaphthene-7-base, 1,3-benzothiazole-2-base, 1,3-benzothiazole-4-base, 1,3-benzothiazole-5-base, 1,3-benzothiazol-6-yl, 1,3-benzothiazole-7-base, 1,3-benzoxazole-2-base, 1,3-benzoxazole-4-base, 1,3-benzoxazole-5-base, 1,3-benzoxazole-6-base and 1,3-benzoxazole-7-base, quinoline-2-base, quinoline-3-base, quinolyl-4, quinoline-5-base, quinoline-6-base, quinoline-7-base, quinoline-8-yl, isoquinolyl-1, isoquinoline 99.9-3-base, isoquinoline 99.9-4-base, isoquinoline 99.9-5-base, isoquinoline 99.9-6-base, isoquinoline 99.9-7-base, and isoquinoline 99.9-8-base.
Term " heterocyclic radical C
1-C
10alkyl " represent the C replaced by heterocyclyl moieties
1-C
10moieties, such as, but not limited to, tetrahydropyrans ylmethyl etc.
Term " heteroaryl C
1-C
10alkyl " represent the C replaced by heteroaryl moieties
1-C
10moieties, Li as, but be not limited to ， oxazolyl methyl, pyridyl-ethyl group etc.
Term " prodrug " refers to the compound transforming in organism and just have pharmacological action, itself does not have biological activity or activity very low.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 attract adjacent solvent molecule to be formed by power between Coulomb force, Van der Waals for, charge transfer power, hydrogen bond equimolecular consumingly.When solvent is water, be called hydrate.
Term " polymorphic form " or " polymorph " refer to the compounds of this invention existed with different form crystal lattices.
Term " ester " refers to by oxygen acid group and the derivative entering the compounds of this invention that base group derives, and both can there is oxygen acid group and also can exist into base group in the compounds of this invention.
Term " tautomer " refers to the isomer being easy to by the migration of such as hydrogen atom or proton shifting be obtained by the compounds of this invention change.
The synthesis of synthetic example 1:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-hydroxyl-oxethyl) furo [3,2-c] imidazo [1,5-a] pyridine-6-acid amides
The synthesis of step 1:2-(2-methoxyl group-2-oxoethyl) furans-3-carboxylate methyl ester
2-monochloroacetaldehyde (67.6g, 345mmol, 1.2eq..40%) is added to containing in the anhydrous pyridine stirred solution (100mI) of 3-oxoglutarate (50g, 287mmoI) under ice bath.Mixture is spent the night 50 DEG C of stirrings.After decompression removing pyridine, add ethyl acetate, wash organic phase with water, anhydrous sodium sulfate drying, concentrated, by Silica hydrogel flash column chromatography residue, obtain object product (productive rate: 61%).
1HNMR(400MHz,CDCl
3)δ7.34(d,J＝2.0Hz,1H),6.70(d,J＝2.0Hz,1H),4.09(s,2H),3.83(s,3H),3.73(s,3H)。
The synthesis of step 2:6-(the fluoro-4-idodophenylamino of 2-)-4-oxo-4,5-dihydrofuran [3,2-c] pyridine-7-carboxylic acid methyl esters
Add NaH (1.11g, 27.75mmol1.1eq..60%) to containing in anhydrous THF (50mI) stirred solution of furans diester (5.0g, 25.23mmol1.0eq) at 0 DEG C in batches.Then, utilize dropping funnel in 1 hour, slowly add the fluoro-N-of 2-(iminomethylene)-4-Iodoaniline (7.27g, 27.75mmol1.1eq.), mixture is at room temperature stirred spend the night subsequently.After adding water and acetic acid ethyl ester, collect the white precipitate of new formation and wash by ethyl acetate, vacuum-drying, obtains object product (6.0g, productive rate: 56%).1HNMR(400MHz,DMSO-D6)δ9.16(s,1H),8.10(s,1H),7.91(d,J＝2.0Hz,1H),7.65-7.68(dd,J＝1.8&10.6Hz,1H),7.37-7.39(dd,J＝1.0&8.2Hz,1H),6.98-6.99(d,J＝2.0Hz,1H),6.64-6.68(t,J＝8.8Hz,1H),3.69(s,3H).
The synthesis of the chloro-6-of step 3:4-(the fluoro-4-idodophenylamino of 2-) furo [3,2-c] pyridine-7-methyl-formiate
By compound 6-(the fluoro-4-idodophenylamino of 2-)-4-oxo-4,5-dihydrofuran [3,2-c] pyridine-7-carboxylic acid methyl esters (5.5g, 12.85mmol) adds in reaction flask, adds phosphorus oxychloride (10ml), be heated to 70 DEG C of reactions 4 hours, remove unnecessary phosphorus oxychloride after completion of the reaction, with saturated sodium bicarbonate solution cancellation reaction solution, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentrated arrives target product.(5.0g yield: 87%)
1hNMR (400MHz, DMSO-D
6) δ 9.17 (s, 1H), 7.95 (d, J=2.0Hz, 1H), 7.66-7.69 (dd, J=1.8 & 10.6Hz, 1H), 7.38-7.40 (dd, J=1.0 & 8.2Hz, 1H), 6.99-7.01 (d, J=2.0Hz, 1H), 6.67-6.69 (t, J=8.8Hz, 1H), 3.89 (s, 3H).
Step 4:4-cyano group-6-(the fluoro-4-idodophenylamino of 2-) furo [3,2-c] pyridine-7-methyl-formiate
By compound 4-chloro-6-(the fluoro-4-idodophenylamino of 2-) furo [3,2-c] pyridine-7-methyl-formiate (4.0g, 8.96mmol) add in reaction flask, add DMF (20ml), then dicyano zinc (0.77g, 6.54mmol) and Pd (PPh is added
3)
4(1.03g, 0.90mmol), 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.(3.1g, yield: 79%).
1HNMR(400MHz,DMSO-D
6)δ9.15(s,1H),7.93(d,J＝2.0Hz,1H),7.67-7.63(dd,J＝1.8&10.6Hz,1H),7.39-7.37(dd,J＝1.0&8.2Hz,1H),7.01-6.99(d,J＝2.0Hz,1H),6.68-6.65(t,J＝8.8Hz,1H),3.88(s,3H).
The synthesis of step 5:4-(amino methyl)-6-(the fluoro-4-idodophenylamino of 2-) furo [3,2-c] pyridine-7-methyl-formiate
By compound 4-cyano group-6-(the fluoro-4-idodophenylamino of 2-) furo [3,2-c] pyridine-7-methyl-formiate (3.0g, 6.86mmol) add in reaction flask, add methyl alcohol (50ml), then cobalt chloride (1.78g is added, 13.72mmol), stirring at room temperature is after 10 minutes, add sodium borohydride (2.6g under ice-water bath cooling in batches, 68.6mmol), 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.(1.5g, yield: 50%). [M+H]
+=442.2
The synthesis of step 6:6-(the fluoro-4-idodophenylamino of 2-)-4-(carboxaldehyde radicals amino methyl) furo [3,2-c] pyridine-7-methyl-formiate
By compound 4-(amino methyl)-6-(the fluoro-4-idodophenylamino of 2-) furo [3,2-c] pyridine-7-methyl-formiate (1.5g, 3.4mmol) add in reaction flask, add formic acid (20ml), after being chilled to 0 DEG C with ice bath, add diacetyl oxide (4ml), 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.(1.6g, yield: 100%)
The synthesis of step 7:5-(the fluoro-4-idodophenylamino of 2-) furo [3,2-c] imidazo [1,5-a] pyridine-6-methyl-formiate
By compound 6-(the fluoro-4-idodophenylamino of 2-)-4-(carboxaldehyde radicals amino methyl) furo [3,2-c] pyridine-7-methyl-formiate (1.6g, 3.4mmol) add in reaction flask, add toluene (10ml), then phosphorus oxychloride (1.01g is added, 6.82mmol), 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 washes with saturated sodium carbonate solution, saturated common salt is washed, organic phase anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains target product.(0.6g, yield: 39%) [M+H]
+=452.2
The synthesis of step 8:5-(the fluoro-4-idodophenylamino of 2-) furo [3,2-c] imidazo [1,5-a] pyridine-6-formic acid
By compound 5-(the fluoro-4-idodophenylamino of 2-) furo [3,2-c] imidazo [1,5-a] pyridine-6-methyl-formiate (600mg, 1.33mmol) add in reaction flask, add IMS (6ml), then add NaOH (1M, 2.7ml, 2.7mmol), be heated to 65 DEG C of reactions 2 hours, concentrated removing IMS, adjust PH to about 5 with the hydrochloric acid of 1M, separate out solid, filter, vacuum-drying obtains target product.(580mg, yield: 100%) [M+H]
+=438.2
The synthesis of step 9:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-(vinyloxy group) oxyethyl group) furo [3,2-c] imidazo [1,5-a] pyridine-6-methane amide
By compound 5-(the fluoro-4-idodophenylamino of 2-) furo [3, 2-c] imidazo [1, 5-a] pyridine-6-formic acid (580mg, 1.33mmol) add in reaction flask, add DMF (2ml), then HOBt (0.27g is added, 2.00mmol) with EDCI (0.38g, 2.00mmol), at room temperature stirring reaction is after 30 minutes, add O-(2-(vinyloxy group) ethyl) azanol (206mg, 2.00mmol), at room temperature react after 3 hours, add water, and be extracted with ethyl acetate, organic phases washed with water, anhydrous sodium sulfate drying, concentrated obtain target product and be directly used in next step.
The synthesis of step 10:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-hydroxyl-oxethyl) furo [3,2-c] imidazo [1,5-a] pyridine-6-methane amide
Compound (690mg, 1.33mmol) obtained in the previous step is added in reaction flask, adds methyl alcohol (10ml), then add 2NHCl (1ml, 2mmol), at room temperature react after 30 minutes, concentrated, add water and ethyl acetate, be separated organic phase, organic phase saturated common salt is washed, anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains target compound (500mg, yield: 76%)
1hNMR (400MHz, CDCl
3) δ 10.82 (s, 1H), 9.84 (s, 1H), 7.93 (s, 1H), 7.58-7.48 (m, 2H), 7.47-7.28 (m, 1H), 7.26 (s, 1H), 7.02 (s, 1H), 6.56 (t, J=8.8Hz, 1H), 4.12-4.06 (m, 3H), 3.79-3.76 (m, 2H); MS (ES+): m/z497.2 [MH
+]
Embodiment 2:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-hydroxyl-oxethyl)-9-methyl furan also [3,2-c] imidazo [1,5-a] pyridine-6-methane amide
The synthesis of step 1:2-(2-oxyethyl group-2-oxoethyl)-4-methyl furan-3-carboxylic acid, ethyl ester
According to J.Am.Chem.Soc, 1985,107,2196-2198.. prepares title compound.
1H-NMR(400MHz,CDCl
3)δ7.13(s,1H),4.28(q,J＝7.2Hz,2H),4.18(q,J＝6.8Hz,2H),4.01(s,2H),2.17(s,3H),1.34(t,J＝6.8Hz,3H),1.26(t,J＝7.2Hz,3H).
The synthesis of step 2:6-(the fluoro-4-idodophenylamino of 2-)-3-methyl-4-oxo-4,5-dihydrofuran also [3,2-c] pyridine-7-carboxylic acid ethyl ester
To containing 2-(2-oxyethyl group-2-oxoethyl)-4-methyl furan-3-carboxylic acid, ethyl ester (6.0g at 0 DEG C, add NaH (1.1g, 27.47mmol1.1eq..60%) in anhydrous THF (50mI) stirred solution 24.97mmol1.0eq) in batches.Then, utilize dropping funnel slowly to add the fluoro-N-of 2-(iminomethylene)-4-Iodoaniline (7.2g, 27.47mmol1.1eq.) in 1 hour, mixture is at room temperature stirred spend the night subsequently.After adding water and acetic acid ethyl ester, collect the white precipitate of new formation and wash by ethyl acetate, vacuum-drying, obtains object product (7.0g, productive rate: 61%).[M+H]
+＝457.2
The synthesis of the chloro-6-of step 3:4-(the fluoro-4-idodophenylamino of 2-)-3-methyl furan also [3,2-c] pyridine-7-carboxylic acid ethyl ester
By compound 6-(the fluoro-4-idodophenylamino of 2-)-3-methyl-4-oxo-4,5-dihydrofuran also [3,2-c] pyridine-7-carboxylic acid ethyl ester (7.0g, 15.34mmol) add in reaction flask, add phosphorus oxychloride (15ml), be heated to 70 DEG C of reactions 4 hours, remove unnecessary phosphorus oxychloride after completion of the reaction, with saturated sodium bicarbonate solution cancellation reaction solution, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentrated arrives target product. (6.5g yield: 89%). [M+H]
+=475.6
The synthesis of step 4:4-cyano group-6-(the fluoro-4-idodophenylamino of 2-)-3-methyl furan also [3,2-c] pyridine-7-carboxylic acid ethyl ester
By compound 4-chloro-6-(the fluoro-4-idodophenylamino of 2-)-3-methyl furan also [3,2-c] pyridine-7-carboxylic acid ethyl ester (6.5g, 13.69mmol) add in reaction flask, add DMF (30ml), then dicyano zinc (1.05g, 10.00mmol) and Pd (PPh is added
3)
4(1.58g, 1.37mmol), 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.(5.0g, yield: 78%). [M+H]
+=466.2
The synthesis of step 5:4-(amino methyl)-6-(the fluoro-4-idodophenylamino of 2-)-3-methyl furan also [3,2-c] pyridine-7-carboxylic acid ethyl ester
By compound 4-cyano group-6-(the fluoro-4-idodophenylamino of 2-)-3-methyl furan also [3,2-c] pyridine-7-carboxylic acid ethyl ester (5.0g, 10.75mmol) add in reaction flask, add methyl alcohol (50ml), then cobalt chloride (2.79g is added, 21.50mmol), stirring at room temperature is after 10 minutes, add sodium borohydride (4.07g under ice-water bath cooling in batches, 107.48mmol), 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.(2.5g, yield: 49%). [M+H]
+=470.2
The synthesis of step 6:6-(the fluoro-4-idodophenylamino of 2-)-4-(carboxaldehyde radicals amino methyl)-3-methyl furan also [3,2-c] pyridine-7-carboxylic acid ethyl ester
By compound 4-(amino methyl)-6-(the fluoro-4-idodophenylamino of 2-)-3-methyl furan also [3,2-c] pyridine-7-carboxylic acid ethyl ester (2.5g, 5.33mmol) add in reaction flask, add formic acid (30ml), diacetyl oxide (6ml) is added 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.(2.6g, yield: 98%)
The synthesis of step 7:5-(the fluoro-4-idodophenylamino of 2-)-9-methyl furan also [3,2-c] imidazo [1,5-a] pyridine-6-carboxylic acid, ethyl ester
By compound 6-(the fluoro-4-idodophenylamino of 2-)-4-(carboxaldehyde radicals amino methyl)-3-methyl furan also [3,2-c] pyridine-7-carboxylic acid ethyl ester (2.6g, 5.38mmol) add in reaction flask, add toluene (10ml), then phosphorus oxychloride (1.65g is added, 10.76mmol), 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 washes with saturated sodium carbonate solution, saturated common salt is washed, organic phase anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains target product.(1.2g, yield: 48%). [M+H]
+=466.2
The synthesis of step 8:5-(the fluoro-4-idodophenylamino of 2-)-9-methyl furan also [3,2-c] imidazo [1,5-a] pyridine-6-carboxylic acid
By compound 5-(the fluoro-4-idodophenylamino of 2-)-9-methyl furan also [3,2-c] imidazo [1,5-a] pyridine-6-carboxylic acid, ethyl ester (1.2g, 2.5mmol) add in reaction flask, add IMS (6ml), then add NaOH (1M, 5.0ml, 5.0mmol), be heated to 65 DEG C of reactions 2 hours, concentrated removing IMS, adjust PH to about 5 with the hydrochloric acid of 1M, separate out solid, filter, vacuum-drying obtains target product.(1.13g, yield: 100%). [M+H]
+=452.2
The synthesis of step 9:5-(the fluoro-4-idodophenylamino of 2-)-9-methyl-N-(2-(vinyloxy group) oxyethyl group) furo [3,2-c] imidazo [1,5-a] pyridine-6-methane amide
By compound 5-(the fluoro-4-idodophenylamino of 2-) furo [3, 2-c] imidazo [1, 5-a] pyridine-6-formic acid (100mg, 0.22mmol) add in reaction flask, add DMF (1ml), then HOBt (45mg is added, 0.33mmol) with EDCI (63mg, 0.33mmol), at room temperature stirring reaction is after 30 minutes, add O-(2-(vinyloxy group) ethyl) azanol (34mg, 0.33mmol), at room temperature react after 3 hours, add water, and be extracted with ethyl acetate, organic phases washed with water, anhydrous sodium sulfate drying, concentrated obtain target product and be directly used in next step
The synthesis of step 10:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-hydroxyl-oxethyl)-9-methyl furan also [3,2-c] imidazo [1,5-a] pyridine-6-methane amide
By obtained in the previous step
Compound (118mg, 0.22mmol) obtained in the previous step is added in reaction flask, adds methyl alcohol (2ml), then add 2NHCl (0.3ml, 0.6mmol), at room temperature react after 30 minutes, concentrated, add water and ethyl acetate, be separated organic phase, organic phase saturated common salt is washed, anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains target compound (70mg, yield: 62%)
1hNMR (400MHz, CDCl3) δ 10.78 (s, 1H), 9.86 (s, 1H), 8.05 (s, 1H) 7.47-7.49 (dd, J=1.6 & 9.6Hz, 1H), (7.37-7.39 d, J=8.4Hz, 1H), 7.37 (s, 1H), 7.28 (s, 1H), (6.51-6.55 t, J=8.4Hz, 1H), 4.08-4.10 (m, 2H), 3.74-3.78 (m, 2H), 2.37 (s, 3H) MS (ES+): m/z511.2 [MH
+]
Embodiment 3:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-hydroxyl-oxethyl) imidazo [1,5-a] thieno-[3,2-c] pyridine-6-methane amide
The synthesis of step 1:2-(2-methoxyl group-2-oxoethyl) thiophene-3-carboxylate methyl ester
Title compound is prepared according to WO2005087779.1HNMR(400MHz,DMSO-D6)。δ7.46(d,J＝5.6Hz,1H),7.36(d,J＝5.6Hz,1H),4.21(s,2H),3.73(s,3H),3.61(s,3H)。
The synthesis of step 2:6-(the fluoro-4-idodophenylamino of 2-)-4-oxo-4,5-dihydro-thiophene also [3,2-c] pyridine-7-carboxylic acid methyl esters
To containing 2-(2-methoxyl group-2-oxoethyl) thiophene-3-carboxylate methyl ester (5.0g at 0 DEG C, add NaH (1.03g, 25.67mmol1.1eq..60%) in anhydrous THF (50mI) stirred solution 23.34mmol1.0eq) in batches.Then, utilize dropping funnel slowly to add the fluoro-N-of 2-(iminomethylene)-4-Iodoaniline (6.73g, 25.67mmol1.1eq.) in 1 hour, mixture is at room temperature stirred spend the night subsequently.After adding water and acetic acid ethyl ester, collect the white precipitate of new formation and wash by ethyl acetate, vacuum-drying, obtains object product (6.2g, productive rate: 60%) [M+H] +=445.2
The synthesis of the chloro-6-of step 3:4-(the fluoro-4-idodophenylamino of 2-) thieno-[3,2-c] pyridine-7-methyl-formiate
By compound 6-(the fluoro-4-idodophenylamino of 2-)-4-oxo-4,5-dihydro-thiophene also [3,2-c] pyridine-7-carboxylic acid methyl esters (6.2g, 13.96mmol) adds in reaction flask, adds phosphorus oxychloride (18ml), be heated to 70 DEG C of reactions 4 hours, remove unnecessary phosphorus oxychloride after completion of the reaction, with saturated sodium bicarbonate solution cancellation reaction solution, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentrated arrives target product.(6.4g, yield: 99%). [M+H] +=463.7
The synthesis of step 4:4-cyano group-6-(the fluoro-4-idodophenylamino of 2-) thieno-[3,2-c] pyridine-7-carboxylic acid methyl esters
By compound 4-chloro-6-(the fluoro-4-idodophenylamino of 2-) thieno-[3; 2-c] pyridine-7-methyl-formiate (6.4g; 13.83mmol) add in reaction flask; add DMF (30ml); then dicyano zinc (1.06g is added; 10.10mmol) with Pd (PPh3) 4 (1.6g; 1.38mmol), 100 DEG C of reactions 8 hours are heated under nitrogen protection, 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.(4.8g, yield: 76%). [M+H] +=454.2
The synthesis of step 5:4-(amino methyl)-6-(the fluoro-4-idodophenylamino of 2-) thieno-[3,2-c] pyridine-7-methyl-formiate
By compound 4-cyano group-6-(the fluoro-4-idodophenylamino of 2-) thieno-[3,2-c] pyridine-7-carboxylic acid methyl esters (4.8g, 10.59mmol) add in reaction flask, add methyl alcohol (50ml), then cobalt chloride (2.75g is added, 21.18mmol), stirring at room temperature is after 10 minutes, add sodium borohydride (4.01g under ice-water bath cooling in batches, 105.91mmol), 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.(2.3g, yield: 47%). [M+H]
+=458.2
The synthesis of step 6:6-(the fluoro-4-idodophenylamino of 2-)-4-(carboxaldehyde radicals amino methyl) thieno-[3,2-c] pyridine-7-methyl-formiate
By compound 4-(amino methyl)-6-(the fluoro-4-idodophenylamino of 2-) thieno-[3,2-c] pyridine-7-methyl-formiate (2.3g, 5.03mmol) add in reaction flask, add formic acid (30ml), after being chilled to 0 DEG C with ice bath, add diacetyl oxide (6ml), 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.(2.4g, yield: 98%)
The synthesis of step 7:5-(the fluoro-4-idodophenylamino of 2-) imidazo [1,5-a] thieno-[3,2-c] pyridine-6-methyl-formiate
By compound 6-(the fluoro-4-idodophenylamino of 2-)-4-(carboxaldehyde radicals amino methyl) thieno-[3,2-c] pyridine-7-methyl-formiate (2.4g, 4.95mmol) add in reaction flask, add toluene (10ml), then phosphorus oxychloride (1.53g is added, 9.89mmol), 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 washes with saturated sodium carbonate solution, saturated common salt is washed, organic phase anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains target product.(1.15g, yield: 50%) [M+H]
+=468.2
The synthesis of step 8:5-(the fluoro-4-idodophenylamino of 2-) imidazo [1,5-a] thieno-[3,2-c] pyridine-6-formic acid
By compound 5-(the fluoro-4-idodophenylamino of 2-) imidazo [1,5-a] thieno-[3,2-c] pyridine-6-methyl-formiate (1.15g, 2.46mmol) add in reaction flask, add IMS (6ml), then add NaOH (1M, 5.0ml, 5.0mmol), be heated to 65 DEG C of reactions 2 hours, concentrated removing IMS, adjust PH to about 5 with the hydrochloric acid of 1M, separate out solid, filter, vacuum-drying obtains target product.(1.1g, yield: 99%) [M+H]
+=454.2
The synthesis of step 9:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-(vinyloxy group) oxyethyl group) imidazo [1,5-a] thieno-[3,2-c] pyridine-6-methane amide
By compound 5-(the fluoro-4-idodophenylamino of 2-) imidazo [1, 5-a] thieno-[3, 2-c] pyridine-6-formic acid (100mg, 0.22mmol) add in reaction flask, add DMF (1ml), then HOBt (45mg is added, 0.33mmol) with EDCI (63mg, 0.33mmol), at room temperature stirring reaction is after 30 minutes, add O-(2-(vinyloxy group) ethyl) azanol (34mg, 0.33mmol), at room temperature react after 3 hours, add water, and be extracted with ethyl acetate, organic phases washed with water, anhydrous sodium sulfate drying, concentrated obtain target product and be directly used in next step
The synthesis of step 10:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-hydroxyl-oxethyl) imidazo [1,5-a] thieno-[3,2-c] pyridine-6-methane amide
By compound (118mg obtained in the previous step, 0.22mmol) add in reaction flask, add methyl alcohol (2ml), then 2NHCl (0.3ml is added, 0.6mmol), at room temperature react after 30 minutes, concentrated, add water and ethyl acetate, be separated organic phase, organic phase saturated common salt is washed, anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains target compound (70mg, yield: 62%) 1HNMR (400MHz, DMSO-D6) 011.31 (s, 1H), 8.30 (s, 1H), 8.03 (s, 1H), 7.62-7.63 (d, J=5.6Hz, 2H), 7.56-7.59 (d, J=10.4Hz, 1H), 7.49-7.50 (d, J=5.2Hz, 1H), 7.30-7.32 (d, J=8.4Hz, 1H), 7.26 (s, 1H), 6.49-6.53 (t, J=8.8Hz), 4.68 (s, 1H), 3.60 (m, 2H), 3.43 (m, 2H), MS (ES+): m/z513.3 [MH+]
Embodiment 4:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-hydroxyl-oxethyl) imidazo [1,5-a] thiazole also [4,5-c] pyridine-4-methane amide
The synthesis of step 1:5-(2-methoxyl group-2-oxoethyl) thiazole-4-carboxylic acid's methyl esters
According to Bioorganic & MedicinalChemistryLetters, 2008,18 (6), 2206-2210.. prepare title compound.1HNMR(400MHz,CDCl3):δ8.75(s,1H),4.38(s,2H),3.96(s,3H),3.78(s,3H)。
The synthesis of step 2:6-(the fluoro-4-idodophenylamino of 2-2-)-4-oxo-4,5-thiazoline also [4,5-c] pyridine-7-carboxylic acid methyl esters
To containing 5-(2-methoxyl group-2-oxoethyl) thiazole-4-carboxylic acid's methyl esters (5.0g at 0 DEG C, add NaH (1.02g, 25.55mmol1.1eq..60%) in anhydrous THF (50mI) stirred solution 23.23mmol1.0eq) in batches.Then, utilize dropping funnel slowly to add the fluoro-N-of 2-(iminomethylene)-4-Iodoaniline (6.70g, 25.55mmol1.1eq.) in 1 hour, mixture is at room temperature stirred spend the night subsequently.After adding water and acetic acid ethyl ester, collect the new white precipitate formed also with ethyl acetate washing, vacuum-drying, obtain object product (6.0g, productive rate: 58%). [M+H]
+=446.2
The synthesis of the chloro-6-of step 3:4-(the fluoro-4-idodophenylamino of 2-) thiazole also [4,5-c] pyridine-7-carboxylic acid methyl esters
By compound 6-(the fluoro-4-idodophenylamino of 2-)-4-oxo-4,5-thiazoline also [3,2-c] pyridine-7-carboxylic acid methyl esters (6.0g, 13.48mmol) adds in reaction flask, adds phosphorus oxychloride (18ml), be heated to 70 DEG C of reactions 4 hours, remove unnecessary phosphorus oxychloride after completion of the reaction, with saturated sodium bicarbonate solution cancellation reaction solution, extraction into ethyl acetate, anhydrous sodium sulfate drying, concentrated arrives target product.(6.2g, yield: 99%).[M+H]
+＝464.7
The synthesis of step 4:4-cyano group-6-(the fluoro-4-idodophenylamino of 2-) thiazole also [4,5-c] pyridine-7-carboxylic acid methyl esters
By compound 4-chloro-6-(the fluoro-4-idodophenylamino of 2-) thiazole also [4; 5-c] pyridine-7-carboxylic acid methyl esters (6.2g; 13.37mmol) add in reaction flask; add DMF (30ml); then dicyano zinc (1.03g is added; 9.76mmol) with Pd (PPh3) 4 (1.55g; 1.34mmol), 100 DEG C of reactions 8 hours are heated under nitrogen protection, 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.(4.5g, yield: 74%). [M+H]
+=455.2
The synthesis of step 5:4-(amino methyl)-6-(the fluoro-4-idodophenylamino of 2-) thiazole also [4,5-c] pyridine-7-carboxylic acid methyl esters
By compound 4-cyano group-6-(the fluoro-4-idodophenylamino of 2-) thiazole also [4,5-c] pyridine-7-carboxylic acid methyl esters (4.5g, 9.91mmol) add in reaction flask, add methyl alcohol (50ml), then cobalt chloride (2.57g is added, 19.81mmol), stirring at room temperature is after 10 minutes, add sodium borohydride (3.75g under ice-water bath cooling in batches, 99.07mmol), 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.(2.3g, yield: 51%). [M+H]
+=458.2
The synthesis of step 6:6-(the fluoro-4-idodophenylamino of 2-)-4-(carboxaldehyde radicals amino methyl) thiazole also [4,5-c] pyridine-7-carboxylic acid methyl esters
By compound 4-(amino methyl)-6-(the fluoro-4-idodophenylamino of 2-) thiophene [3,2-c] pyridine-7-methyl-formiate (2.3g, 5.03mmol) add in reaction flask, add formic acid (30ml), after being chilled to 0 DEG C with ice bath, add diacetyl oxide (6ml), 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.(2.4g, yield: 98%)
The synthesis of step 7:5-(the fluoro-4-idodophenylamino of 2-) imidazo [1,5-a] thiazole also [4,5-c] Pyridine-4-carboxylic acid methyl esters
By compound 6-(the fluoro-4-idodophenylamino of 2-)-4-(carboxaldehyde radicals amino methyl) thiazole also [4,5-c] pyridine-7-carboxylic acid methyl esters (2.4g, 4.94mmol) add in reaction flask, add toluene (10ml), then phosphorus oxychloride (1.51g is added, 9.87mmol), 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 washes with saturated sodium carbonate solution, saturated common salt is washed, organic phase anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains target product.(1.1g, yield: 47%) [M+H]
+=469.2
The synthesis of step 8:5-(the fluoro-4-idodophenylamino of 2-) imidazo [1,5-a] thiazole also [4,5-c] Pyridine-4-carboxylic acid
By compound 5-(the fluoro-4-idodophenylamino of 2-) imidazo [1,5-a] thiazole also [4,5-c] Pyridine-4-carboxylic acid methyl esters (1.1g, 2.35mmol) add in reaction flask, add IMS (6ml), then add NaOH (1M, 5.0ml, 5.0mmol), be heated to 65 DEG C of reactions 2 hours, concentrated removing IMS, adjust PH to about 5 with the hydrochloric acid of 1M, separate out solid, filter, vacuum-drying obtains target product.(1.0g, yield: 99%) [M+H] +=455.2
The synthesis of step 9:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-(vinyloxy group) oxyethyl group) imidazo [1,5-a] thiazole also [4,5-c] pyridine-4-methane amide:
By compound 5-(the fluoro-4-idodophenylamino of 2-) imidazo [1, 5-a] thiophene [3, 2-c] pyridine-6-formic acid (100mg, 0.22mmol) add in reaction flask, add DMF (1ml), then HOBt (45mg is added, 0.33mmol) with EDCI (63mg, 0.33mmol), at room temperature stirring reaction is after 30 minutes, add O-(2-(vinyloxy group) ethyl) azanol (34mg, 0.33mmol), at room temperature react after 3 hours, add water, and be extracted with ethyl acetate, organic phases washed with water, anhydrous sodium sulfate drying, concentrated obtain target product and be directly used in next step.
The synthesis of step 10:5-(the fluoro-4-idodophenylamino of 2-)-N-(2-hydroxyl-oxethyl) imidazo [1,5-a] thiazole also [4,5-c] pyridine-4-methane amide
By compound (118mg obtained in the previous step, 0.22mmol) add in reaction flask, add methyl alcohol (2ml), then 2NHCl (0.3ml is added, 0.6mmol), at room temperature react after 30 minutes, concentrated, add water and ethyl acetate, be separated organic phase, organic phase saturated common salt is washed, anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains target compound (75mg, yield: 67%) 1HNMR (400MHz, CD30D) δ 9.05 (s, 1H), 8.10 (s, 1H), 8.04 (s, 1H), 7.53-7.56 (dd, J=1.8 & 10.6Hz, 1H), 7.38-7.40 (d, J=8.4Hz, 1H), 7.28 (s, 1H), 6.61 (s, 1H), 3.59-3.71 (m, 4H), MS (ES+): m/z514.3 [MH+].
Claims (10)
1. the compound of formula (I) and (II), and pharmacy acceptable salt, prodrug and solvate
Wherein
represent
or
X and W represents N, O, S or CR independently
5;
Y is N or CR
6;
Z is selected from C or N
And
R
1, R
2and R
3be selected from hydrogen, halogen, nitro, azido-,-OR independently of one another
7,-C (O) R
7,-C (O) OR
7,-NR
8c (O) OR
10,-OC (O) R
7,-NR
8sO
2r
10,-SO
2nR
7r
8,-NR
8c (O) R
7,-C (O) NR
7r
8,-NR
9c (O) NR
7r
8,-NR
9c (NCN) NR
7r
8,-NR
7r
8, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkyl C
1-C
10alkyl ,-S (O)
j(C
1-C
10alkyl) ,-S (O)
j(CR
8r
9)
m, C
6-C
14aryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl, heteroaryl C
1-C
10alkyl, heterocyclic radical, heterocyclic radical C
1-C
10alkyl ,-O (CR
8r
9)
m-C
6-C
14aryl ,-NR
8(CR
8r
9)
m-C
6-C
14aryl ,-O (CR
8r
9)
m-heteroaryl ,-NR
8(CR
8r
9)
m-heteroaryl ,-O (CR
8r
9)
m-heterocyclic radical ,-NR
8(CR
8r
9)
m-heterocyclic radical;
Wherein said C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
6-C
14aryl, heteroaryl and heterocyclyl moieties can be selected from following group optionally replace by one or more independently of one another: oxo, halogen, cyano group, nitro, trifluoromethyl, azido-,-OR
7,-C (O) R
7,-C (O) OR
7,-NR
8c (O) OR
10,-OC (O) R
7,-NR
8sO
2r
10,-SO
2nR
7r
8,-NR
8c (O) R
7,-C (O) NR
7r
8,-NR
9c (O) NR
7r
8,-NR
9c (NCN) NR
7r
8,-NR
7r
8, C
6-C
14aryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl, heteroaryl C
1-C
10alkyl, heterocyclic radical, heterocyclic radical C
1-C
10alkyl;
R
4be selected from heteroaryl, heterocyclic radical ,-C (O) OR
7,-C (O) NR
7r
8,-C (O) NR
8oR
7,-C (O) R
8oR
7,-C (O) (C
3-C
10cycloalkyl) ,-C (O) (C
1-C
10alkyl) ,-C (O) (C
6-C
14aryl) ,-C (O) (heteroaryl) and-C (O) (heterocyclic radical);
These groups can be selected from following group optionally replace by one or more independently of one another :-NR
7r
8,-OR
7, C
1-C
10alkyl, C
2-C
10thiazolinyl and C
2-C
10alkynyl, each in them is optionally selected from-NR by 1 or 2
7r
8with-OR
7in group replace;
R
5be selected from hydrogen, halogen, C
1-C
6alkyl, C
3-C
6cycloalkyl, C
2-C
6thiazolinyl, C
5-C
6cycloalkenyl group, C
2-C
6alkynyl; Wherein, each alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group or alkynyl group are optionally independently selected from halogen, hydroxyl, amino, alkylamino, dialkyl amido, heterocyclic radical, C
1-C
4alkyl, C
1-C
41-3 substituting group of alkoxyl group, cyano group, cyano methyl, trifluoromethyl, difluoro-methoxy and phenyl replaces, and one or two ring carbon atom of described group of naphthene base is optionally by independently O, S or N replace;
R
6be selected from hydrogen, halogen, C
1-C
10alkyl, C
1-C
10alkoxyl group, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkyloxy, C
3-C
10cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, heterocyclic radical and cycloheteroalkylalkyl, wherein, each alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical are not substituted or are independently selected from halogen, hydroxyl, C
1-C
4alkyl, C
1-C
41-3 substituting group of alkoxyl group, cyano group, trifluoromethyl or difluoromethyl;
R
7, R
8and R
9be selected from hydrogen, C independently of one another
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkyl C
1-C
10alkyl, C
6-C
14aryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl, heteroaryl C
1-C
10alkyl, heterocyclic radical and heterocyclic radical C
1-C
10alkyl;
Wherein said C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
6-C
14aryl, heteroaryl and heterocyclyl moieties can be selected from following group optionally replace by one or more independently of one another: hydroxyl, oxo, halogen, cyano group, nitro, trifluoromethyl, azido-,-NR ' SO
2r " " ,-SO
2nR ' R " ,-C (O) R ' ,-C (O) OR ' ,-OC (O) R ' ,-NR ' C (O) R " " ,-NR ' C (O) R " ,-C (O) NR ' R " ,-SR ' ,-S (O) R " " ,-SO
2r " " ,-NR ' R " ,-NR ' C (O) NR " R " ' ,-NR ' C (NCN) NR " R " ' ,-OR ', C
6-C
14aryl, heteroaryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl C
1-C
10alkyl, heterocyclic radical and heterocyclic radical C
1-C
10alkyl;
Or
R
7and R
83-10 unit's heteroaryl or heterocycle is formed together with the atom that they connect;
These groups can be selected from following group optionally replace by one or more independently of one another: halogen, cyano group, nitro, trifluoromethyl, azido-,-NR ' SO
2r " " ,-SO
2nR ' R " ,-C (O) R ' ,-C (O) OR ' ,-OC (O) R ' ,-NR ' C (O) R " " ,-NR ' C (O) R " ,-C (O) NR ' R " ,-SR ' ,-S (O) R " " ,-SO
2r " " ,-NR ' R " ,-NR ' C (O) NR " R " ' ,-NR ' C (NCN) NR " R " ' ,-OR ', C
6-C
14aryl, heteroaryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl C
1-C
10alkyl, heterocyclic radical and heterocyclic radical C
1-C
10alkyl;
Or
R
8and R
93-10 unit's heteroaryl or heterocycle is formed together with the atom that they connect;
These groups can be selected from following group optionally replace by one or more independently of one another: halogen, cyano group, nitro, trifluoromethyl, azido-,-NR ' SO
2r " " ,-SO
2nR ' R " ,-C (O) R ' ,-C (O) OR ' ,-OC (O) R ' ,-NR ' C (O) R " " ,-NR ' C (O) R " ,-C (O) NR ' R " ,-SR ' ,-S (O) R " " ,-SO
2r " " ,-NR ' R " ,-NR ' C (O) NR " R " ' ,-NR ' C (NCN) NR " R " ' ,-OR ', C
6-C
14aryl, heteroaryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl C
1-C
10alkyl, heterocyclic radical and heterocyclic radical C
1-C
10alkyl;
R
10be selected from hydrogen, C
1-C
10alkyl, C
3-C
10cycloalkyl, C
6-C
14aryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl, heteroaryl C
1-C
10alkyl, heterocyclic radical, heterocyclic radical C
1-C
10alkyl;
Wherein said C
1-C
10alkyl, C
3-C
10cycloalkyl, C
6-C
14aryl, heteroaryl and heterocyclyl moieties can be selected from following group optionally replace by one or more independently of one another: oxo, halogen, cyano group, nitro, trifluoromethyl, azido-,-NR ' SO
2r " " ,-SO
2nR ' R " ,-C (O) R ' ,-C (O) OR ' ,-OC (O) R ' ,-NR ' C (O) R " " ,-NR ' C (O) R " ,-C (O) NR ' R " ,-SR ' ,-S (O) R " " ,-SO
2r " " ,-NR ' R " ,-NR ' C (O) NR " R " ' ,-NR ' C (NCN) NR " R " ' ,-OR ', C
6-C
14aryl, heteroaryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl C
1-C
10alkyl, heterocyclic radical and heterocyclic radical C
1-C
10alkyl;
R ', R " and R " ' independently selected from hydrogen, C
1-C
10alkyl, C
2-C
6thiazolinyl, C
6-C
14aryl and C
6-C
14aryl C
1-C
10alkyl;
R " " be selected from C
1-C
10alkyl, C
2-C
6thiazolinyl, C
6-C
14aryl and C
6-C
14aryl C
1-C
10alkyl;
Or
R ', R ", R " ' or R " " in any two atoms that can connect with them together with form 3-10 unit heteroaryl or heterocycle;
These groups can be selected from following group optionally replace by one or more independently of one another: halogen, cyano group, nitro, trifluoromethyl, difluoro-methoxy, trifluoromethoxy, azido-, C
6-C
14aryl, heteroaryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl C
1-C
10alkyl, heterocyclic radical and heterocyclic radical C
1-C
10alkyl;
M is 0,1,2,3,4 or 5;
And J is 0,1 or 2.
2. compound as claimed in claim 1 or its pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug be wherein that in O or S, X and W, another is C one of in X and W, and Y is C.
3. the compound of formula I-1-a and II-1-a as claimed in claim 2 or its pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug,
Wherein X is O or S; And R
1, R
2, R
3, R
4, R
5, R
6, as the definition in claim 1.
4. the compound according to any one of claim 1-3 or its pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, wherein Y is CR
6, and R
6for H, halogen, C
1-C
6a heatable brick bed base, C
3-C
6cycloalkyl, C
2-C
6thiazolinyl, C
5-C
6cycloalkenyl group or C
2-C
6alkynyl; Wherein, each alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group or fast base group be optionally independently selected from halogen, entered base, amino, alkylamino, dialkyl amido, heterocyclic radical, C
1-C
4alkyl, C
1-C
41-3 substituting group of alkoxyl group, amino, amino methyl, trifluoromethyl, difluoro-methoxy and phenyl replaces, and described C
3-C
6one or two ring carbon atom of ring a heatable brick bed base group is optionally by independently O, N or S replace; Or its pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug.
5. compound as claimed in claim 4 or its pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, wherein,
R
1and R
2be selected from hydrogen, halogen or C independently of one another
1-C
6alkyl,
R
3be selected from hydrogen, halogen, C
1-C
6alkoxyl group, C
1-C
6alkylthio, halo-C
1-C
6alkoxyl group, halo-C
1-C
6alkylthio, C
1-C
6alkyl, halo C
1-C
6alkyl,
R
4for-C (O) NR
8oR
7,-C (O) NR
8r
7or-NHSO
2r
7,
R
7and R
8be selected from hydrogen, C independently of one another
1-C
6alkyl, C
3-C
6cycloalkyl, C
3-C
6cycloalkyl C
1-C
6alkyl, C
1-C
6alkyl C
3-C
6cycloalkyl,
Wherein said C
1-C
6alkyl, C
3-C
6cycloalkyl, C
3-C
6cycloalkyl C
1-C
6alkyl, C
1-C
6alkyl C
3-C
6cycloalkyl can be selected from following group optionally replace by one or more independently of one another: hydroxyl, sulfydryl.
6. the compound according to any one of claim 1-5 or its pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, wherein
R
1and R
2be selected from hydrogen, halogen or C independently of one another
1-C
4alkyl,
R
3for 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,
R
4for-C (O) NR
8oR
7,-C (O) NR
8r
7or-NHSO
2r
7,
R
7for 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
8for hydrogen or C
1-C
4alkyl.
7. the compound according to any one of claim 1-6 or its pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, wherein
R
1and R
2be selected from hydrogen, fluorine, chlorine, bromine or C independently of one another
1-C
2alkyl,
R
3for 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,
R
4for-C (O) NR
8oR
7or-NHSO
2r
7,
R
7for 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
8for hydrogen.
8. the compound according to any one of claim 1-7 or its pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, wherein
R
1and R
2represent hydrogen, fluorine, chlorine or methyl independently of one another,
R
3for bromine, iodine, methylthio group, trifluoromethylthio, methoxyl group, trifluoromethoxy, methyl, trifluoromethyl,
R
4for-C (O) NHOR
7or-NHSO
2r
7,
R
7for 2-hydroxyethyl, 2,3-dihydroxypropyls, 1-methylol-2-hydroxyethyl, 2-methyl-3-hydroxypropyl, cyclopropyl, Cvclopropvlmethvl or 1-(2,3-hydroxypropyl) cyclopropyl.
9. compound according to claim 8 or its pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, described compound is selected from:
10. pharmaceutical composition, it comprises compound according to any one of the claim 1-9 of pharmacy effective dose or its pharmacy acceptable salt, solvate, polymorphic form, ester, tautomer or prodrug, and pharmaceutically acceptable carrier; Or the application in the pharmaceutical composition for the preparation of suppression MEK enzyme of this solvate, polymorphic form, ester, tautomer or prodrug; Or formula (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 art 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; The preparation method of formula (I) and (II):
Wherein:
R
1, R
2, R
3there is above-mentioned definition, and
R
7be selected from hydrogen, C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
3-C
10cycloalkyl C
1-C
10alkyl, C
6-C
14aryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl, heteroaryl C
1-C
10alkyl, heterocyclic radical and heterocyclic radical C
1-C
10alkyl;
Wherein said C
1-C
10alkyl, C
2-C
10thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, C
6-C
14aryl, heteroaryl and heterocyclyl moieties can be selected from following group optionally replace by one or more independently of one another: hydroxyl, oxo, halogen, cyano group, nitro, trifluoromethyl, azido-,-NR ' SO
2r " " ,-SO
2nR ' R " ,-C (O) R ' ,-C (O) OR ' ,-OC (O) R ' ,-NR ' C (O) R " " ,-NR ' C (O) R " ,-C (O) NR ' R " ,-SR ' ,-S (O) R " " ,-SO
2r " " ,-NR ' R " ,-NR ' C (O) NR " R " ' ,-NR ' C (NCN) NR " R " ' ,-OR ', C
6-C
14aryl, heteroaryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl C
1-C
10alkyl, heterocyclic radical and heterocyclic radical C
1-C
10alkyl;
R ', R " and R " ' independently selected from hydrogen, C
1-C
10alkyl, C
2-C
6thiazolinyl, C
6-C
14aryl and C
6-C
14aryl C
1-C
10alkyl;
R " " be selected from C
1-C
10alkyl, C
2-C
6thiazolinyl, C
6-C
14aryl and C
6-C
14aryl C
1-C
10alkyl;
Or
R ', R ", R " ' or R " " in any two atoms that can connect with them together with form 3-10 unit heteroaryl or heterocycle;
These groups can be selected from following group optionally replace by one or more independently of one another: halogen, cyano group, nitro, trifluoromethyl, difluoro-methoxy, trifluoromethoxy, azido-, C
6-C
14aryl, heteroaryl, C
6-C
14aryl C
1-C
10alkyl, heteroaryl C
1-C
10alkyl, heterocyclic radical and heterocyclic radical C
1-C
10alkyl.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018028665A1 (en) * | 2016-08-12 | 2018-02-15 | 正大天晴药业集团股份有限公司 | Method for preparing intermediate of 6-arylaminopyridonecarboxamide compound as mek inhibitor |
| CN113717167A (en) * | 2020-05-21 | 2021-11-30 | 广州费米子科技有限责任公司 | Fused ring compound, preparation method thereof, pharmaceutical composition and application |
| WO2024165044A1 (en) * | 2023-02-10 | 2024-08-15 | 上海科州药物研发有限公司 | Polymorph as protein kinase mek inhibitor, and preparation method therefor and use thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101903387A (en) * | 2007-12-19 | 2010-12-01 | 健泰科生物技术公司 | 8-anilin0imidaz0pyridines and their use as anti-cancer and/or anti-inflammatory agents |
| CN101945870A (en) * | 2007-12-19 | 2011-01-12 | 健泰科生物技术公司 | 5-anilinoimidazopyridines and methods of use |
-
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101903387A (en) * | 2007-12-19 | 2010-12-01 | 健泰科生物技术公司 | 8-anilin0imidaz0pyridines and their use as anti-cancer and/or anti-inflammatory agents |
| CN101945870A (en) * | 2007-12-19 | 2011-01-12 | 健泰科生物技术公司 | 5-anilinoimidazopyridines and methods of use |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018028665A1 (en) * | 2016-08-12 | 2018-02-15 | 正大天晴药业集团股份有限公司 | Method for preparing intermediate of 6-arylaminopyridonecarboxamide compound as mek inhibitor |
| US10501468B2 (en) | 2016-08-12 | 2019-12-10 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd | Method for preparing intermediate of 6-arylaminopyridonecarboxamide compound as MEK inhibitor |
| CN113717167A (en) * | 2020-05-21 | 2021-11-30 | 广州费米子科技有限责任公司 | Fused ring compound, preparation method thereof, pharmaceutical composition and application |
| WO2024165044A1 (en) * | 2023-02-10 | 2024-08-15 | 上海科州药物研发有限公司 | Polymorph as protein kinase mek inhibitor, and preparation method therefor and use thereof |
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