CN104774188B - Benzo-heterocycle or benzo hetero-aromatic ring analog derivative, preparation method and its application in medicine - Google Patents

Benzo-heterocycle or benzo hetero-aromatic ring analog derivative, preparation method and its application in medicine Download PDF

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CN104774188B
CN104774188B CN201410799059.1A CN201410799059A CN104774188B CN 104774188 B CN104774188 B CN 104774188B CN 201410799059 A CN201410799059 A CN 201410799059A CN 104774188 B CN104774188 B CN 104774188B
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fluoro
amino
compound
cancer
iodophenyl
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CN104774188A (en
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陆标
黄崧
张民生
吕贺军
孙飘扬
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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    • A61K31/4164—1,3-Diazoles
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Abstract

The present invention relates to benzo-heterocycle or benzo hetero-aromatic ring analog derivative, preparation method and its applications in medicine.Specifically, the present invention relates to benzo-heterocycle shown in a kind of logical formula (I) or benzo hetero-aromatic ring analog derivatives and its officinal salt, preparation method and they as mek inhibitor especially as the purposes of cancer therapeutic agent, definition is the same as that in the specification for each substituent group in formula of (I).Compound provided by the invention has good activity, and shows the effect of excellent anti-tumour cell proliferative.

Description

Benzo-heterocycle or benzo hetero-aromatic ring analog derivative, preparation method and its in medicine On application
Technical field
The present invention relates to a kind of novel benzo-heterocycle or benzo hetero-aromatic ring analog derivatives and its officinal salt, its preparation side The purposes of method and pharmaceutical composition containing the derivative as well as mek inhibitor especially as cancer therapeutic agent.
Background technique
The generation of the exception and tumour of MAPKs kinase pathways is closely related, since it leads to uncontrolled cellular proliferation and differentiation Retardance, it has also become the preferred target of tumour medicine exploitation.
Serine/threonine mitogen-activated protein kinase (MAPKs, also referred to as extracellular signal-regulated kinase, ERKs) is by junket ammonia Acid kinase receptor (such as EGF receptor) and/or the relevant cytokine receptor activation of G-protein heterotrimer, can be with a variety of by not The intracellular signal interaction evoked with second messenger, phosphorylation and adjust various enzymes and transcription factor activity (such as NF- κ B, Rsk 90, phospholipase A2, c-Myc, CREB, Ets-1, AP-1 and c-jun etc.).Participate in it is normal and abnormal cell growth In MAPK approach, Ras/Raf/MEK/Erk kinase pathways are that study the most clearly be also one of most important approach.More than ten years Before, scientist has found that protein kinase family Erks has proliferation, and subsequent research identifies the upstream kinases of Erk quickly MEK family then finds that Raf can activate MEKs, upstream Ras to belong to G-protein, and the GTP of activation is in conjunction with Ras, indirect activation Raf.There are Ras gene mutations for about 30% malignant tumor patient, and in cancer of pancreas, Ras gene mutation rate reaches as high as 90%.Mutation rate of the B-Raf in melanoma is up to 50%-70%, up to 35% in oophoroma, reaches in thyroid cancer 30%, up to 10% in colon cancer.MEKs can also be independent of the kinases of Raf, and MEK kinases (also referred to as MEKK) is activated.
MEKs is also referred to as map kinase (MAPKK or Erk kinases), belongs to dual-specificity kinase, phosphorylatable MAPK (p44MAPK (Erk 1) and p42MAPK(Erk 2)) serine/threonine residue and tyrosine residue (Erk1 phosphorylation site be T202 and Y204, Erk2 phosphorylation site be T183 and Y185), MEK family include five kinds of genes: MEK1, MEK2, MEK3, MEK4 and MEK5.The end N- of MEKs is negative control region, and the catalytic domain at the end C- has with Erks ining conjunction with and activate the function of Erks, and experiment is sent out Existing, the control region for knocking out MEK1 will lead to the inhibition of MEK1 and Erk intrinsic activity.
The molecular weight of MEK1 is about 44kDa, contains 393 amino acid altogether, is mainly expressed in adult tissue especially brain tissue In, micro MEK1 expression also can be detected during embryonic development.MEK1 is touched by the phosphorylation in the site S218 and S222 Its activity is sent out, research is found in NIH3T3 cell, changes the two residues into aspartic acid or glutamic acid, and activity increases, The formation of colony also increases.The intrinsic activity of MEK1 promotes aging and the p53 and p16 of cell in primitive cell cultureINK4aTable It reaches, and in immortality cell and p53 or p16INK4aIn the cell of missing, the effect of MEK1 is exactly the opposite.The molecular weight of MEK2 is about 45kDa has 79% sequence similarity with MEK1, its activity is triggered by the phosphorylation in the site S222 and S226.MEK1 With MEK2 to different MAPK hypotypes, the phosphorylation catalytic activity of Erk1 and Erk2 is different.MEK3, MEK4 and MEK5 do not pass through work Its effect is played for Erks.
For MAPK signal path, have at present multiple specificity inhibit the active compounds of Raf and MEK be in it is clinical and The listing stage.Wherein sorafenib (Bay 43-9006) was listed in 2006, belonged to nonspecific serine/threonine and tyrosine Kinase inhibitor, action target spot include Raf, MEK, VEGFR2/3, Flt-3, PDGFR, c-Kit etc..B-Raf specificity inhibits Agent such as dabrafenib (GSK2118436) and vemurafenib (PLX4032) shows good clinical effectiveness, but duration It is impermanent, meanwhile, clinical research discovery receives the patient that PLX4032 is effectively treated, and symptom largely recurs, and prompts B- The long-term treatment of Raf inhibitor will lead to patient and generate acquired resistance, no longer sensitive to B-Raf inhibitor.Suffer to overcome Mek inhibitor and B-Raf inhibitor are clinically often combined by the drug resistance of person.Specificity inhibits MEK1/2 inhibitor Trametinib (GSK-1120212) is developed by GSK company, has been listed, other MEK1/2 inhibitor Selumetinib (AZD-6244), Pimasertib hydrochloride (AS-703026), TAK-733 etc. have entered clinical experimental stage, but These mek inhibitors have no the interaction data for announcing itself and Erk1 or Erk2.
Disclose the patent application of a series of mek inhibitor at present, including WO2007096259, WO2010003022 and WO2012162293 etc..
In order to achieve the purpose that better oncotherapy effect, the market demand is better met, it is therefore desirable to be able to develop The inhibitor for MAPKs signal path of the high-efficiency low-toxicity of a new generation, especially MEK target spot inhibitor.The present invention will provide A kind of new structural mek inhibitor, and the compound for being found to have this class formation has good activity, and shows excellent Anti-tumour cell proliferative effect.
Summary of the invention
The purpose of the present invention is to provide logical formula (I) compound represented or its tautomer, mesomer, racemics Or mixtures thereof body, enantiomter, diastereoisomer form or its officinal salt:
Wherein:
For singly-bound or double bond；
P is selected from O, CR6Or-CR6R7-；
R1Selected from hydrogen atom, halogen, cyano, nitro, alkyl or halogenated alkyl；
R2、R3Or R4It is each independently selected from hydrogen atom, alkyl, halogen, cyano, nitro or halogenated alkyl；
R5Selected from heterocycle, heteroaryl ,-NHS (O)mR8、-C(O)NR9R10、-C(O)R11、-C(O)NHNR9R10、-C(O) NHNHC(O)R9、-C(O)NHNHC(O)NR9R10、-NHC(O)R9、-NHC(O)OR9、-NHC(O)NR9R10、-NHC(O)NR9OR10 Or-OC (O) R9, wherein the heterocycle or heteroaryl each independently optionally further by one or more selected from halogen, Cyano, nitro, alkyl, halogenated alkyl, hydroxyalkyl, naphthenic base, heterocycle, aryl, heteroaryl ,-OR9、-C(O)OR9、-OC(O) R9、-NHS(O)mR9、-C(O)R9、-NHC(O)R9、-NHC(O)OR9、-NR9R10、-OC(O)NR9R10Or-C (O) NR9R10Substitution Replaced base；
R6Or R7It is each independently selected from hydrogen atom or alkyl, wherein the alkyl is optionally further one or more Substituent group selected from alkyl, halogen, hydroxyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl, carboxylic acid group or carboxylate It is replaced；
R8Selected from naphthenic base, wherein the naphthenic base is further replaced alkyl, the alkyl optionally further by Replaced substituent group of the one or more selected from hydroxyl, halogen or alkoxy；
R9Or R10Be each independently selected from hydrogen atom, alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl or Heteroaryl, wherein alkyl, alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl or the heteroaryl is appointed each independently Choosing further by one or more selected from alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, ethyleneoxy, naphthenic base, heterocycle, Aryl, heteroaryl, carboxylic acid group or carboxylate substituent group replaced；
Alternatively, R9Or R105~8 circle heterocyclic ring bases are formed together with the nitrogen-atoms being connected, wherein the heterocycle includes There is one or more N, O or S (O)mHetero atom, and the heterocycle is optionally further selected from alkyl, halogen by one or more Element, hydroxyl, alkoxy, hydroxyalkyl, naphthenic base, heterocycle, aryl, heteroaryl, carboxylic acid group or carboxylate substituent group taken Generation；
R11Selected from hydrogen atom, alkoxy, alkenyl, alkynyl, naphthenic base, heterocycle, aryl or heteroaryl, wherein the alkane Oxygroup, alkenyl, alkynyl, naphthenic base, aryl or heteroaryl are optionally further selected from alkyl, halogen by one or more each independently Element, hydroxyl, hydroxyalkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl, carboxylic acid group or carboxylate substituent group taken Generation；
M is 0,1 or 2；And
N is 0 or 1.
In a preferred embodiment of the present invention, a kind of logical formula (I) compound represented or its tautomer, interior Or mixtures thereof raceme, racemic modification, enantiomter, diastereoisomer form or its officinal salt, are general formula (II) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer or its Form of mixtures or its officinal salt:
Wherein:P, R1~R3And R5Definition as described in logical formula (I).
In a preferred embodiment of the present invention, a kind of logical formula (I) compound represented or its tautomer, interior Or mixtures thereof raceme, racemic modification, enantiomter, diastereoisomer form or its officinal salt, are general formula (III) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer or its Form of mixtures or its officinal salt:
Wherein: R1~R3And R5Definition as described in logical formula (I).
In a preferred embodiment of the present invention, a kind of logical formula (I) compound represented or its tautomer, interior Or mixtures thereof raceme, racemic modification, enantiomter, diastereoisomer form or its officinal salt, are general formula (IV) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer or its Form of mixtures or its officinal salt:
Wherein:N, P, R1~R3And R11Definition as described in logical formula (I).
In a preferred embodiment of the present invention, a kind of logical formula (I) compound represented or its tautomer, interior Or mixtures thereof raceme, racemic modification, enantiomter, diastereoisomer form or its officinal salt, are general formula (V) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer or it is mixed Solvate form or its officinal salt:
Wherein: R1~R3And R11Definition as described in logical formula (I).
In a preferred embodiment of the present invention, a kind of logical formula (I) compound represented or its tautomer, interior Or mixtures thereof raceme, racemic modification, enantiomter, diastereoisomer form or its officinal salt, wherein R1It is selected from Halogen, preferably F or Cl.
In a preferred embodiment of the present invention, a kind of logical formula (I) compound represented or its tautomer, interior Or mixtures thereof raceme, racemic modification, enantiomter, diastereoisomer form or its officinal salt, wherein R2Or R3 Selected from halogen, R2Preferably Br or I, R3Preferably F or Cl.
In a preferred embodiment of the present invention, a kind of logical formula (I) compound represented or its tautomer, interior Or mixtures thereof raceme, racemic modification, enantiomter, diastereoisomer form or its officinal salt, wherein R4It is selected from Hydrogen atom.
In a preferred embodiment of the present invention, a kind of logical formula (I) compound represented or its tautomer, interior Or mixtures thereof raceme, racemic modification, enantiomter, diastereoisomer form or its officinal salt, wherein R5It is selected from Heteroaryl, wherein the heteroaryl is optionally further by halogen, cyano, nitro, alkyl, halogenated alkyl, hydroxyalkyl, cycloalkanes Base, heterocycle, aryl, heteroaryl ,-OR9、-C(O)OR9、-OC(O)R9、-NHS(O)mR9、-C(O)R9、-NHC(O)R9、-NHC (O)OR9、-NR9R10、-OC(O)NR9R10Or-C (O) NR9R10Substituent group replaced, preferably-NR9R10, wherein m, R9~R10 Definition as described in logical formula (I).
In a preferred embodiment of the present invention, a kind of logical formula (I) compound represented or its tautomer, interior Or mixtures thereof raceme, racemic modification, enantiomter, diastereoisomer form or its officinal salt, wherein R5For-C (O)NR9R10, wherein R9~R10Definition as described in logical formula (I).
In a preferred embodiment of the present invention, a kind of logical formula (I) compound represented or its tautomer, interior Or mixtures thereof raceme, racemic modification, enantiomter, diastereoisomer form or its officinal salt, wherein R9It is selected from Hydrogen atom；R10Selected from alkoxy, wherein the alkoxy is optionally further replaced one or two hydroxyls or naphthenic base.
The typical compound of the present invention includes, but are not limited to:
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer shape Formula or its officinal salt.
The present invention also provides a kind of general formula (IA) compound represented or its tautomer, mesomer, racemic modification, Or mixtures thereof enantiomter, diastereoisomer form or its officinal salt:
Wherein:
PG is selected from-NR9R10、-C(O)Rd,-OH or-S (O)m Rd；
RdSelected from hydroxyl or halogen；And
M, n, P, R1~R4, R9And R10Definition as described in logical formula (I).
The typical compound of general formula (IA) of the present invention includes, but are not limited to:
Or or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer shape Formula or its officinal salt.
Logical formula (I) compound represented or its tautomer, mesomer, racemic are prepared the present invention also provides a kind of The method of or mixtures thereof body, enantiomter, diastereoisomer form or its officinal salt, this method comprises:
General formula (IA) compound and formula compound G or its reactant salt, optionally further slough protecting group, hydroxylating or cyclization Reaction obtains logical formula (I) compound；
Wherein:
PG is selected from-NR9R10、-C(O)Rd, hydroxyl or-S (O)m Rd；
Compound G is selected from heterocyclic compound, heteroaromatic ring compounds, carboxylic acid halides, sulfonic acid halide, hydrazine, amine or alcohol compound；
RdSelected from hydroxyl or halogen；
Preferably, when PG is selected from-NR9R10Or when hydroxyl, compound G is selected from carboxylic acid halides, sulfonic acid halide；
When PG is selected from-C (O) RdOr-S (O)m RdWhen, compound G be selected from heterocyclic compound, heteroaromatic ring compounds, hydrazine, Amine or alcohol compound；
M, n, P, R1~R5, R9And R10Definition as described in logical formula (I)；
The protecting group of hydroxyl is preferably isopropyl subunit or vinyl；
The protecting group of amino is preferably tert-butoxycarbonyl；
The reagent of bishydroxy is preferably osmium tetroxide.
The present invention also provides a kind of general formula (IIA) compound represented or its tautomer, mesomer, racemics Or mixtures thereof body, enantiomter, diastereoisomer form or its officinal salt:
Wherein:
PG is selected from-NR9R10、-C(O)Rd, hydroxyl or-S (O)m Rd；
RdSelected from hydroxyl or halogen；
AndM, R1~R3, R9And R10Definition as described in logical formula (I).
The present invention also provides a kind of logical formula (II) compound represented or its tautomer, mesomer, racemic modification, The synthetic method of or mixtures thereof enantiomter, diastereoisomer form or its officinal salt, this method comprises:
General formula (IIA) compound and compound G or its reactant salt, optionally further slough protecting group, hydroxylating or cyclization Reaction obtains logical formula (II) compound；
Wherein:
PG is selected from-NR9R10、-C(O)Rd, hydroxyl or-S (O)m Rd；
Compound G is selected from heterocyclic compound, heteroaromatic ring compounds, carboxylic acid halides, sulfonic acid halide, hydrazine, amine or alcohol compound；
RdSelected from hydroxyl or halogen；
Preferably, when PG is selected from-NR9R10Or when hydroxyl, compound G is selected from carboxylic acid halides, sulfonic acid halide；
When PG is selected from-C (O) RdOr-S (O)m RdWhen, compound G be selected from heterocyclic compound, heteroaromatic ring compounds, hydrazine, Amine or alcohol compound；
M, P, R1~R3, R5And R9~R10Definition as described in logical formula (I)；
The protecting group of hydroxyl is preferably isopropyl subunit or vinyl；
The protecting group of amino is preferably tert-butoxycarbonyl；
The reagent of bishydroxy is preferably osmium tetroxide.
The present invention also provides a kind of general formula (IIIA) compound represented or its tautomer, mesomer, racemics Or mixtures thereof body, enantiomter, diastereoisomer form or its officinal salt:
Wherein:
PG is selected from-NR9R10、-C(O)Rd, hydroxyl or-S (O)m Rd；
RdSelected from hydroxyl or halogen；And
M, R1~R3, R9And R10Definition as described in logical formula (I).
The present invention also provides a kind of logical formula (III) compound represented or its tautomer, mesomer, racemics The synthetic method of or mixtures thereof body, enantiomter, diastereoisomer form or its officinal salt, this method comprises:
General formula (IIIA) compound and compound G or its reactant salt, optionally further slough protecting group, hydroxylating or cyclization Reaction obtains logical formula (III) compound；
Wherein:
PG is selected from-NR9R10、-C(O)Rd, hydroxyl or-S (O)m Rd；
Compound G includes but is not limited to heterocyclic compound, heteroaromatic ring compounds, carboxylic acid halides, sulfonic acid halide, hydrazine, amine or alcohol Class compound；
RdSelected from hydroxyl or halogen；
Preferably, when PG is selected from-NR9R10Or when hydroxyl, compound G is selected from carboxylic acid halides, sulfonic acid halide；
When PG is selected from-C (O) RdOr-S (O)m RdWhen, compound G be selected from heterocyclic compound, heteroaromatic ring compounds, hydrazine, Amine or alcohol compound；
M, R1~R3, R5And R9~R10Definition as described in logical formula (I)；
The protecting group of hydroxyl is preferably isopropyl subunit or vinyl；
The protecting group of amino is preferably tert-butoxycarbonyl；
The reagent of bishydroxy is preferably osmium tetroxide.
The present invention also provides a kind of general formula (IVA) compound represented or its tautomer, mesomer, racemics Or mixtures thereof body, enantiomter, diastereoisomer form or its officinal salt:
Wherein:N, P, R1~R3And R11Definition as described in the appended claim 1.
It prepares logical formula (IV) compound represented or its tautomer the present invention also provides a kind of, mesomer, outside disappear Or mixtures thereof body, enantiomter, diastereoisomer form or the method for its officinal salt are revolved, this method comprises:
General formula (IVA) compound and compound G or its reactant salt, optionally further slough protecting group, hydroxylating or cyclization Reaction obtains logical formula (IV) compound；
Wherein:
Compound G is preferably heterocyclic compound, heteroaromatic ring compounds, hydrazine, amine or alcohol compound；
RdSelected from hydroxyl or halogen；
N, P, R1~R3And R11Definition as described in logical formula (I)；
The protecting group of hydroxyl is preferably isopropyl subunit or vinyl；
The protecting group of amino is preferably tert-butoxycarbonyl；
The reagent of bishydroxy is preferably osmium tetroxide.
The present invention also provides a kind of general formula (VA) compound represented or its tautomer, mesomer, racemic modification, Or mixtures thereof enantiomter, diastereoisomer form or its officinal salt:
Wherein: R1~R3Definition as described in logical formula (I)；And
RdSelected from hydroxyl or halogen.
Logical formula (V) compound represented or its tautomer, mesomer, racemic are prepared the present invention also provides a kind of The method of or mixtures thereof body, enantiomter, diastereoisomer form or its officinal salt, this method comprises:
It is anti-optionally further to slough protecting group, hydroxylating or cyclization for general formula (VA) compound and compound G or its reactant salt It answers, obtains logical formula (V) compound；
Wherein:
Compound G is preferably heterocyclic compound, heteroaromatic ring compounds, hydrazine, amine or alcohol compound；
RdSelected from hydroxyl or halogen；
R1~R3And R11Definition as described in logical formula (I)；
The protecting group of hydroxyl is preferably isopropyl subunit or vinyl；
The protecting group of amino is preferably tert-butoxycarbonyl；
The reagent of bishydroxy is preferably osmium tetroxide.
The invention further relates to a kind of pharmaceutical composition, the present invention containing therapeutically effective amount is led to shown in formula (I) Or mixtures thereof compound or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form, Or its officinal salt and one or more pharmaceutically acceptable carriers, diluent or excipient.
The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, Or mixtures thereof enantiomter, diastereoisomer form or its officinal salt, or prepared comprising its pharmaceutical composition Inhibit the purposes in the drug of MEK.
The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, Or mixtures thereof enantiomter, diastereoisomer form or its officinal salt, or prepared comprising its pharmaceutical composition Treat the use in the drug of inflammatory conditions, autoimmune disease, cardiovascular disorder, proliferative diseases or the illness of impression injury On the way, wherein the proliferative diseases can be cancer (defined below).
The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, Or mixtures thereof enantiomter, diastereoisomer form or its officinal salt, or prepared comprising its pharmaceutical composition Purposes in the drug for the treatment of cancer, wherein the cancer be selected from melanoma, brain tumor (with pernicious astroglia and The glioma etc. of Oligodendroglioma ingredient), the cancer of the esophagus, gastric cancer, liver cancer, cancer of pancreas, colorectal cancer (colon Cancer, carcinoma of the rectum etc.), lung cancer (non-small cell lung cancer, Small Cell Lung Cancer, primary or metastatic carcinoma squamosum etc.), kidney, breast cancer, Oophoroma, prostate cancer, cutaneum carcinoma, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testis Tumour, uterine cancer (cervix cancer, carcinoma of endometrium etc.), H/N tumors (cancer of maxilla, laryngocarcinoma, pharynx cancer, tongue cancer, cancer in mouth Deng), Huppert's disease, malignant lymphoma (reticulosarcoma, lymphosarcoma, Hodgkin lymphoma etc.), genuine erythrocyte (acute myeloblastic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, chronic lymphatic are thin for increase disease, leukaemia Born of the same parents' leukaemia etc.), thyroid tumors, tumor of ureter, tumor of bladder, gallbladder cancer, cholangiocarcinoma, chorioepithelioma or paediatrics it is swollen Tumor is (especially because of familial sarcoma, Willms sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testis cancer, neuroblastoma, view Nethike embrane blastoma, hepatoblastoma, nephroblastoma etc.) etc..
The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, Or mixtures thereof enantiomter, diastereoisomer form or its officinal salt, or prepared comprising its pharmaceutical composition Purposes in the drug for the treatment of cancer, wherein the cancer is preferably colorectal cancer or lung cancer.
The invention further relates to logical formula (I) compound represented or its tautomer, mesomer, racemic modification, Or mixtures thereof enantiomter, diastereoisomer form or its officinal salt, or prepared comprising its pharmaceutical composition Purposes in the drug for the treatment of cancer, wherein the drug further with another or a variety of anti-cancer agent in conjunction applications, institute It states anticancer agent and is selected from alkylating agent (cyclophosphamide, ifosfamide, melphalan, busulfan, Nimustine, Ranimustine, Dacca bar Piperazine, Temozolomide, mustine hydrochlcride, dibromannitol etc.), platinum complexing agent (cis-platinum, carboplatin, oxaliplatin etc.), metabolic antagonist (methotrexate (MTX), 5 FU 5 fluorouracil, Tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed etc.), plant alkaloid (vincristine, vincaleukoblastinum, eldisine, Etoposide, docetaxel, taxol, Irinotecan, vinorelbine, rice support anthracene Quinone, vinflunine, topotecan etc.), hormone anticancer agent (Leuprorelin, Goserelin, Exemestane, Letrozole, Ah Nagqu Azoles, dutasteride etc.), antibody drug (trastuzumab, handkerchief trastuzumab, Rituximab, Cetuximab, Victibix, shellfish Cut down monoclonal antibody etc.), VEGFR or EGFR inhibitor (Sutent, Sorafenib, Imatinib, Gefitinib, Erlotinib, all morals His Buddhist nun, pazopanib, Lapatinib etc.), mTOR inhibitors (everolimus, sirolimus, Zuo Tamosi etc.), PI3K kinases suppression Preparation (BKM-120, XL-147, BEZ-235 etc.), B-Raf inhibitor (Wei Luofeini, GSK-2118436 etc.) or AKT inhibitor (piperazine Li Fuxin, MK-2206 etc.) etc..
The invention further relates to a kind of active methods of inhibition MEK comprising gives the general formula of required bacterium (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer or it is mixed Solvate form or its officinal salt, or the pharmaceutical composition comprising it.
In other words, inflammatory conditions, autoimmune disease, cardiovascular disorder, proliferative disease are treated the present invention relates to a kind of Disease or impression injury illness method comprising give required bacterium logical formula (I) compound represented or Or mixtures thereof its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form or its can medicine With salt, or comprising its pharmaceutical composition, wherein the proliferative diseases can be cancer (defined below).
The invention further relates to a kind of methods for the treatment of cancer comprising gives the general formula of required bacterium (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer or it is mixed Solvate form or its officinal salt, or comprising its pharmaceutical composition, wherein the cancer is selected from melanoma, brain tumor (has Pernicious astroglia and the glioma of Oligodendroglioma ingredient etc.), the cancer of the esophagus, gastric cancer, liver cancer, pancreas Gland cancer, colorectal cancer (colon and rectum carcinoma etc.), lung cancer (non-small cell lung cancer, Small Cell Lung Cancer, primary or metastatic squama Shape cancer etc.), kidney, breast cancer, oophoroma, prostate cancer, cutaneum carcinoma, neuroblastoma, sarcoma, osteochondroma, osteoma, bone Sarcoma, seminoma, orchioncus, uterine cancer (cervix cancer, carcinoma of endometrium etc.), H/N tumors (cancer of maxilla, larynx Cancer, pharynx cancer, tongue cancer, cancer etc. in mouth), Huppert's disease, malignant lymphoma (reticulosarcoma, lymphosarcoma, Huo Qijin leaching Bar tumor etc.), polycythemia vera, (acute myeloblastic leukemia, chronic myelocytic leukemia, acute lymphoblastic are thin for leukaemia Born of the same parents' leukaemia, chronic lymphocytic leukemia etc.), thyroid tumors, tumor of ureter, tumor of bladder, gallbladder cancer, cholangiocarcinoma, Chorioepithelioma or pediatric tumors are (especially because of familial sarcoma, Willms sarcoma, rhabdomyosarcoma, angiosarcoma, embryo's testis Ball cancer, neuroblastoma, retinoblastoma, hepatoblastoma, nephroblastoma etc.) etc..
The invention further relates to a kind of methods for the treatment of cancer comprising gives the logical formula (I) of required bacterium Or mixtures thereof compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereo-isomerism Form or its officinal salt, or include its pharmaceutical composition and another or a variety of anticancer agents, the anticancer agent choosing From alkylating agent, (cyclophosphamide, melphalan, busulfan, Nimustine, Ranimustine, Dacarbazine, replaces not azoles at ifosfamide Amine, mustine hydrochlcride, dibromannitol etc.), platinum complexing agent (cis-platinum, carboplatin, oxaliplatin etc.), metabolic antagonist (methotrexate (MTX), 5 FU 5 fluorouracil, Tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed etc.), plant alkaloid (vincristine, Vincaleukoblastinum, eldisine, Etoposide, docetaxel, taxol, Irinotecan, vinorelbine, mitoxantrone, vinflunine, Topotecan etc.), hormone anticancer agent (Leuprorelin, Goserelin, Exemestane, Letrozole, Anastrozole, dutasteride Deng), antibody drug (trastuzumab, handkerchief trastuzumab, Rituximab, Cetuximab, Victibix, bevacizumab etc.), VEGFR or EGFR inhibitor (Sutent, Sorafenib, Imatinib, Gefitinib, Erlotinib, Vande Thani, pa azoles Pa Ni, Lapatinib etc.), mTOR inhibitors (everolimus, sirolimus, Zuo Tamosi etc.), PI3K kinase inhibitor (BKM- 120, XL-147, BEZ-235 etc.), (piperazine founds good fortune for B-Raf inhibitor (Wei Luofeini, GSK-2118436 etc.) or AKT inhibitor Newly, MK-2206 etc.) etc..
The invention further relates to as inhibit the active drug of MEK logical formula (I) compound represented or its tautomer, Or mixtures thereof mesomer, racemic modification, enantiomter, diastereoisomer form or its officinal salt, or include it Pharmaceutical composition.
The invention further relates to as treatment inflammatory conditions, autoimmune disease, cardiovascular disorder, proliferative diseases or sense The logical formula (I) compound represented of the drug for the illness being hurt or its tautomer, mesomer, racemic modification, mapping Or mixtures thereof isomers, diastereoisomer form or its officinal salt, or comprising its pharmaceutical composition, wherein described Proliferative diseases can be cancer (defined below).
The invention further relates to the logical formula (I) compound represented of the drug as treating cancer or its tautomerisms Or mixtures thereof body, mesomer, racemic modification, enantiomter, diastereoisomer form or its officinal salt, or packet Containing its pharmaceutical composition, wherein the cancer is selected from melanoma, brain tumor (with pernicious astroglia and few prominent mind Glioma etc. through spongiocytoma ingredient), the cancer of the esophagus, gastric cancer, liver cancer, cancer of pancreas, colorectal cancer it is (colon cancer, straight Intestinal cancer etc.), lung cancer (non-small cell lung cancer, Small Cell Lung Cancer, primary or metastatic carcinoma squamosum etc.), kidney, breast cancer, ovary Cancer, prostate cancer, cutaneum carcinoma, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testis are swollen Tumor, uterine cancer (cervix cancer, carcinoma of endometrium etc.), H/N tumors (cancer of maxilla, laryngocarcinoma, pharynx cancer, tongue cancer, cancer etc. in mouth), Huppert's disease, malignant lymphoma (reticulosarcoma, lymphosarcoma, Hodgkin lymphoma etc.), polycythemia vera (acute myeloblastic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic are white for disease, leukaemia Blood disease etc.), thyroid tumors, tumor of ureter, tumor of bladder, gallbladder cancer, cholangiocarcinoma, chorioepithelioma or pediatric tumors (especially because of familial sarcoma, Willms sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testis cancer, neuroblastoma, view Film blastoma, hepatoblastoma, nephroblastoma etc.) etc..
The invention further relates to the logical formula (I) compound represented of the drug as treating cancer or its tautomers, interior Or mixtures thereof raceme, racemic modification, enantiomter, diastereoisomer form or its officinal salt, or comprising its Pharmaceutical composition and another or a variety of anticancer agents, the anticancer agent be selected from alkylating agent (cyclophosphamide, ifosfamide, Melphalan, busulfan, Nimustine, Ranimustine, Dacarbazine, Temozolomide, mustine hydrochlcride, dibromannitol etc.), platinum network Mixture (cis-platinum, carboplatin, oxaliplatin etc.), metabolic antagonist (methotrexate (MTX), 5 FU 5 fluorouracil, Tegafur, gemcitabine, card Train his shore, fulvestrant, pemetrexed etc.), plant alkaloid it is (vincristine, vincaleukoblastinum, eldisine, Etoposide, mostly western His match, taxol, Irinotecan, vinorelbine, mitoxantrone, vinflunine, topotecan etc.), (bright third is auspicious for hormone anticancer agent Woods, Goserelin, Exemestane, Letrozole, Anastrozole, dutasteride etc.), (the appropriate pearl of trastuzumab, pa is single for antibody drug Anti-, Rituximab, Cetuximab, Victibix, bevacizumab etc.), VEGFR or EGFR inhibitor (Sutent, Suo La Non- Buddhist nun, Imatinib, Gefitinib, Erlotinib, Vande Thani, pazopanib, Lapatinib etc.), mTOR inhibitors are (according to dimension Mo Si, sirolimus, Zuo Tamosi etc.), PI3K kinase inhibitor (BKM-120, XL-147, BEZ-235 etc.), B-Raf inhibit Agent (Wei Luofeini, GSK-2118436 etc.) or AKT inhibitor (piperazine Li Fuxin, MK-2206 etc.) etc..
Pharmaceutical composition containing active constituent, which can be, is suitable for oral form, such as tablet, dragee, pastille, water Or oil suspension, dispersible powder or particle, lotion, hard or soft capsule or syrup or elixir.It can be any according to this field Know that the method for preparing Pharmaceutical composition prepares Orally administered composition, such composition can containing it is one or more it is selected from the following at Point: sweetener, corrigent, colorant and preservative, to provide pleasing and palatable pharmaceutical formulation.Tablet contain active constituent and The suitable nontoxic pharmaceutical excipient for preparing tablet for mixing.These excipient can be inert excipient, such as carbon Sour calcium, sodium carbonate, lactose, calcium phosphate or sodium phosphate；Granulating agent and disintegrating agent, such as microcrystalline cellulose, cross-linked carboxymethyl fiber Plain sodium, cornstarch or alginic acid；Adhesive, such as starch, gelatin, polyvinylpyrrolidone or Arabic gum and lubricant, example Such as magnesium stearate, stearic acid or talcum powder.These tablets can not be coated or can be by covering the taste of drug or in gastrointestinal tract Middle delay disintegration and absorption, thus the known technology for providing slow releasing function in a long time is coated.For example, water can be used Dissolubility taste masked substance, such as hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or extend time substance such as ethyl fibre Dimension element, acetylbutyrylcellulose.
Also available wherein active constituent mixes hard bright with inert solid diluent such as calcium carbonate, calcium phosphate or kaolin Glue capsule or in which active constituent and water-solubility carrier such as polyethylene glycol or oily solvent such as peanut oil, atoleine or olive The Perle of olive oil mixing provides oral preparation.
Water slurry contains active material and the suitable excipient for preparing water slurry for mixing.Such excipient is Suspending agent, such as sodium carboxy methyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, mosanom, polyvinylpyrrolidone And Arabic gum；Dispersing agent or wetting agent can be the contracting of naturally-produced phosphatide such as lecithin or alkylene oxide and fatty acid Close the condensation product of product such as Myrj 45 or ethylene oxide and long-chain fatty alcohol, such as 17 carbon ethylidene Oxygroup cetanol (heptadecaethyleneoxy cetanol) or ethylene oxide and the portion as derived from fatty acid and hexitol The condensation product of ester, such as polyoxyethylene sorbitol monoleate or ethylene oxide is divided to spread out with by fatty acid and hexitan The condensation product of raw partial ester, such as polyethylene oxide Sorbitan Monooleate.Aqueous suspension can also containing a kind of or Determination of Preservatives such as ethylparaben or nipalgin n-propyl, one or more colorants, one or more corrigents and one Kind or a variety of sweeteners, such as sucrose, saccharin or aspartame.
Oil suspension can by making active constituent be suspended in vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or It is formulated in mineral oil such as atoleine.Oil suspension can contain thickener, such as beeswax, hard paraffin or cetanol.It can Above-mentioned sweetener and corrigent is added, to provide palatable preparation.It can be by the way that antioxidant such as Butylated Hydroxyanisole or α-be added Give birth to these compositions of phenol preservation.
It can make to be suitable for preparing that water is suspended dispersible powder also and particle provides active constituent and is used for by the way that water is added Mixed dispersing agent or wetting agent, suspending agent or one or more preservatives.Suitable dispersing agent or wetting agent and suspending agent can Illustrate above-mentioned example.Other excipient such as sweetener, corrigent and colorant can also be added.By the way that antioxidant example is added As ascorbic acid saves these compositions.
Pharmaceutical composition of the invention is also possible to the form of oil in water emulsion.Oil mutually can be vegetable oil such as olive oil Or or mixtures thereof peanut oil or mineral oil such as atoleine.Suitable emulsifier can be naturally-produced phosphatide, such as Soybean lecithin and the ester as derived from fatty acid and hexitan or partial ester such as sorbitan monooleate and the partial ester and ring The condensation product of oxidative ethane, such as polyoxyethylene sorbitol monoleate.Emulsion can also contain sweetener, corrigent, prevent Rotten agent and antioxidant.Syrup and elixir can be prepared with Sweetening agents such as glycerol, propylene glycol, sorbierite or sucrose.Such preparation Moderator, preservative, colorant and antioxidant can be contained.
Pharmaceutical composition can be sterile injectable aqueous form.Can have in the acceptable solvent and solvent used Water, ringer's solution and isotonic sodium chlorrde solution.Aseptic injection preparation can be the aseptic injection that wherein active constituent is dissolved in oily phase Oil-in-water microemulsion.Such as active constituent is dissolved in the mixture of soybean oil and lecithin.Then water and sweet is added in oil solution Processing forms micro emulsion in the mixture of oil.Can be by a large amount of injections in part, it will be in injection or the blood flow of micro emulsion injection patient.Or Person preferably gives solution and micro emulsion in the way of it can keep the compounds of this invention constant circulating concentration.To keep this constant dense Degree, can be used continuous intravenous delivery device.The example of this device is Deltec CADD-PLUS.TM.5400 type vein note Penetrate pump.
Pharmaceutical composition can be for intramuscular and the aseptic injection water of subcutaneous administration or the form of oil suspension.It can be by Know technology, the dispersing agent or wetting agent and suspending agent for being suitable for those described above prepare the suspension.Aseptic injection preparation can also be with It is the aseptic injectable solution or suspension prepared in the acceptable diluent of nontoxic parenteral or solvent, such as 1,3-BDO The solution of middle preparation.Furthermore, it is convenient to use sterile fixed oil as solvent or suspension media.For this purpose, usable include Any reconciliation fixing oil including synthetic glycerine list or diester.In addition, fatty acid such as oleic acid can also prepare injection.
The compounds of this invention can be given by the suppository form for rectally.It can be by by drug and at normal temperatures For solid but in the rectum it is liquid, thus can dissolves and discharge the suitable nonirritant excipient mixing of drug in the rectum To prepare these pharmaceutical compositions.Substance of this kind includes the poly- second of cocoa butter, glycerin gelatine, hydrogenated vegetable oil, various molecular weight The mixture of the aliphatic ester of two pure and mild polyethylene glycol.
Well-known to those skilled in the art, the dosage of drug depends on many factors, including but and it is non-limiting with Lower factor: the activity of specific compound used, the age of patient, the weight of patient, the health status of patient, patient row by, Diet, administration time, administration mode, the rate of excretion, combination of drug of patient etc.；In addition, optimal therapeutic modality is such as controlled The type of the mode for the treatment of, the consumption per day of general formula compound (I) or pharmaceutical salt can be verified according to traditional therapeutic scheme.
Detailed description of the invention
Unless stated to the contrary, otherwise following that there are following meanings with term in the specification and in the claims.
" alkyl " refers to the aliphatic hydrocarbon groups of saturation, straight chain and branched group including 1 to 20 carbon atom.It preferably comprises The alkyl of 1 to 10 carbon atom, the alkyl of further preferably 1 to 6 carbon atom, the alkane of most preferably 1 to 4 carbon atom Base, most preferably methyl.Non-limiting embodiment include methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, Sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl Butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- Dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- Methyl amyl, 2,3- dimethylbutyl, n-heptyl, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2, 3- dimethyl amyl group, 2,4- dimethyl amyl group, 2,2- dimethyl amyl group, 3,3- dimethyl amyl group, 2- ethylpentyl, 3- ethyl penta Base, n-octyl, 2,3- dimethylhexanyl, 2,4- dimethylhexanyl, 2,5- dimethylhexanyl, 2,2- dimethylhexanyl, 3,3- bis- Methylhexyl, 4,4- dimethylhexanyl, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- methyl -2- ethylpentyl, 2- Methyl -3- ethylpentyl, n-nonyl, 2- methyl -2- ethylhexyl, 2- methyl -3- ethylhexyl, 2,2- diethyl amyl group, just Decyl, 3,3- diethylhexyl, 2,2- diethylhexyl and its various branched isomers etc..More preferably contain 1 to 6 The low alkyl group of carbon atom, non-limiting embodiment include methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary fourth Base, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- first Base butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1, 2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2,3- dimethylbutyl etc..Alkyl can be substituted or unsubstituted, and when substituted, substituent group can be with It is substituted on any workable tie point, preferably one or more following groups, independently selected from alkyl, alkenyl, alkynes Base, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, heterocycle, aryl, heteroaryl, Cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, amino, halogenated alkyl, hydroxyalkyl, carboxylic acid group, carboxylic Perester radical ,-OR11、-C(O)OR11、-OC(O)R11、-NHS(O)mR11、-C(O)R11、-NHC(O)R11、-NHC(O)OR11、- NR9R10、-OC(O)NR9R10Or-C (O) NR9R10。
Term " alkenyl " refers to the alkane as defined above by being at least made of two carbon atoms and at least one carbon-to-carbon double bond Base, such as vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- cyclobutenyl etc..It is preferred that C2-10Alkenyl, more preferable C2-6Alkenyl, Most preferably C2-4Alkenyl.Alkenyl can be it is substituted or non-substituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, Cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo Base, amino, halogenated alkyl, hydroxyalkyl, carboxylic acid group, carboxylate ,-OR11、-C(O)OR11、-OC(O)R11、-NHS(O)mR11、-C (O)R11、-NHC(O)R11、-NHC(O)OR11、-NR9R10、-OC(O)NR9R10Or-C (O) NR9R10。
Term " alkynyl " refers to the alkane as defined above being at least made of two carbon atoms and at least one carbon-carbon triple bond Base, such as acetenyl, 1- propinyl, 2-propynyl, 1-, 2- or 3- butynyl etc..It is preferred that C2-10Alkynyl, more preferable C2-6Alkynyl, Most preferably C2-4Alkynyl.Alkynyl can be it is substituted or non-substituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, Cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo Base, amino, halogenated alkyl, hydroxyalkyl, carboxylic acid group, carboxylate ,-OR11、-C(O)OR11、-OC(O)R11、-NHS(O)mR11、-C (O)R11、-NHC(O)R11、-NHC(O)OR11、-NR9R10、-OC(O)NR9R10Or-C (O) NR9R10。
" naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, 3 to 12 carbon atoms are preferably included, more preferable cycloalkyl ring includes 3 to 10 carbon atoms, and most preferably cycloalkyl ring includes 3 to 6 A carbon atom, most preferably cyclopropyl.The non-limiting embodiment of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, ring penta Alkenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc., preferably cyclopropyl, cyclohexene Base.Polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring.Naphthenic base can be optionally it is substituted or unsubstituted, when When being substituted, substituent group is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane sulphur Base, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, heterocycle, aryl, heteroaryl, cycloalkyloxy, heterocycle Alkoxy, cycloalkylthio, heterocycle alkylthio group, oxo base, amino, halogenated alkyl, hydroxyalkyl, carboxylic acid group, carboxylate ,-OR11、- C(O)OR11、-OC(O)R11、-NHS(O)mR11、-C(O)R11、-NHC(O)R11、-NHC(O)OR11、-NR9R10、-OC(O)NR9R10 Or-C (O) NR9R10。
" heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 annular atoms, Wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), but do not include-O-O- ,- The loop section of O-S- or-S-S-, remaining annular atom are carbon.3 to 12 annular atoms are preferably included, wherein 1~4 is hetero atom, More preferable heterocyclic ring includes 3 to 10 annular atoms, and more preferable heterocyclic ring includes 5 to 6 annular atoms.Monocyclic heterocycles base it is non- Restricted embodiment includes pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, high piperazine base, pyranose, tetrahydro Furyl, oxazolyl, isoxazolyl etc..Multiring heterocyclic includes the heterocycle of loop coil, condensed ring and bridged ring.Heterocycle, which can be, appoints Select substituted or unsubstituted, when substituted, substituent group is preferably one or more following groups, independently selected from alkyl, Alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, heterocycle, aryl, Heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, amino, halogenated alkyl, hydroxyalkyl, carboxylic Acidic group, carboxylate ,-OR11、-C(O)OR11、-OC(O)R11、-NHS(O)mR11、-C(O)R11、-NHC(O)R11、-NHC(O) OR11、-NR9R10、-OC(O)NR9R10Or-C (O) NR9R10。
" aryl " refers to that 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle are (namely shared to adjoin The ring of carbon atom pair) group, preferably 6 to 10 yuan of aryl, more preferable phenyl and naphthalene, most preferably phenyl.The aryl rings It can condense on heteroaryl, heterocycle or cycloalkyl ring, wherein being aryl rings, non-limit with the ring that precursor structure links together Property embodiment processed includes:
Aryl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, Independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkanes Base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-OR11、-C(O) OR11、-OC(O)R11、-NHS(O)mR11、-C(O)R11、-NHC(O)R11、-NHC(O)OR11、-NR9R10、-OC(O)NR9R10Or-C (O)NR9R10。
" heteroaryl " refers to that with 1 to 4 hetero atom, as annular atom, remaining annular atom is 5 to 14 yuan of aryl of carbon, into One step includes 1 to 4 heteroatomic, and wherein hetero atom is selected from one or more oxygen, sulphur or nitrogen.Preferably 5 to 10 yuan of heteroaryl Base, more preferably 5 yuan to 6 yuan of heteroaryl, even more preferably furyl, thienyl, pyridyl group, pyrrole radicals, N- alkyl pyrroles Base, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical, oxadiazoles base etc..The heteroaryl ring can condense in aryl, heterocycle or On cycloalkyl ring, wherein the ring to link together with precursor structure is heteroaryl ring, non-limiting embodiment includes:
Heteroaryl can be it is optionally substituted or unsubstituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyanogen Base, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-OR11、- C(O)OR11、-OC(O)R11、-NHS(O)mR11、-C(O)R11、-NHC(O)R11、-NHC(O)OR11、-NR9R10、-OC(O)NR9R10 Or-C (O) NR9R10。
" alkoxy " refers to-O- (alkyl) and-O- (unsubstituted naphthenic base), and wherein alkyl, naphthenic base are as defined above institute It states.Non-limiting embodiment include methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, Cyclohexyloxy etc..Alkoxy can be optionally it is substituted or unsubstituted, when substituted, substituent group be preferably one or more Following group, independently selected from for alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitre Base, cyano, naphthenic base, heterocycle, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, ammonia Base, halogenated alkyl, hydroxyalkyl, carboxylic acid group, carboxylate ,-OR11、-C(O)OR11、-OC(O)R11、-NHS(O)mR11、-C(O) R11、-NHC(O)R11、-NHC(O)OR11、-NR9R10、-OC(O)NR9R10Or-C (O) NR9R10。
" halogenated alkyl " refers to that alkyl is replaced by one or more halogens, and wherein alkyl is as defined above.
" hydroxyl " refers to-OH group.
" hydroxyalkyl " refers to the alkyl being optionally substituted by a hydroxyl group, and wherein alkyl is as defined above.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" amino " refers to-NH2。
" cyano " refers to-CN.
" nitro " refers to-NO2。
" oxo base " refers to=O.
" carboxylic acid group " refers to-C (O) OH.
" carboxylate " refers to-C (O) O (alkyl) or (naphthenic base), and wherein alkyl, naphthenic base are as defined above.
" hydroxyl protection base " refers in organic synthesis, the molecule containing 2 or multiple functional groups, to make hydroxyl from reaction Destruction, commonly use certain reagent and first protected, to slough protecting group again after the reaction was completed.Hydroxyl protection base includes but is not limited to Methyl, ethyl, isopropyl subunit, tert-butyl diphenyl silicon substrate, tert-butyl, benzyl, acetyl group, benzoyl or vinyl.
" amino protecting group " refers in organic synthesis, the molecule containing 2 or multiple functional groups, to make amino from reaction Destruction, commonly use certain reagent and first protected, to slough protecting group again after the reaction was completed.Amino protecting group includes but is not limited to Tertbutyloxycarbonyl, benzyloxycarbonyl group, formoxyl or trifluoroacetyl group.
" heterocyclic compound " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon comprising 3 to 20 annular atoms, Middle one or more annular atom is selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), but do not include-O-O- ,-O- The loop section of S- or-S-S-, remaining annular atom are carbon.3 to 12 annular atoms are preferably included, wherein 1~4 is hetero atom, more It is preferred that heterocyclic ring includes 3 to 10 annular atoms, more preferable heterocyclic compound includes 5 to 6 annular atoms.Monocyclic heterocyclic compound Non-limiting embodiment include pyrrolidines, piperidines, piperazine, morpholine, thiomorpholine, homopiperazine, pyrans, tetrahydrofuran etc..It is more Ring heterocycle includes the heterocycle of loop coil, condensed ring and bridged ring.Heterocyclic compound can be optionally it is substituted or unsubstituted, work as quilt When substitution, substituent group is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, Alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, heterocycle, aryl, heteroaryl, cycloalkyloxy, heterocycle alcoxyl Base, cycloalkylthio, heterocycle alkylthio group, oxo base, amino, halogenated alkyl, hydroxyalkyl, carboxylic acid group, carboxylate ,-OR11、-C(O) OR11、-OC(O)R11、-NHS(O)mR11、-C(O)R11、-NHC(O)R11、-NHC(O)OR11、-NR9R10、-OC(O)NR9R10Or-C (O)NR9R10。
" heteroaromatic ring compounds " refer to that with 1 to 4 hetero atom, as annular atom, remaining annular atom is 5 to 14 yuan of carbon Aromatic ring, further include 1 to 4 it is heteroatomic, wherein hetero atom is selected from one or more oxygen, sulphur or nitrogen.Preferably 5 to 10 yuan Hetero-aromatic ring, it is more preferably 5 yuan to 6 yuan of hetero-aromatic ring, even more preferably furans, thiophene, pyridine, pyrroles, N- alkyl pyrroles, phonetic Pyridine, pyrazine, imidazoles, tetrazolium etc..
" carboxylic acid halides " refers to the compound containing-C (O)-halogen group；
" sulfonic acid halide " refers to containing-S (O)2The compound of the group of halogen；
" hydrazine " refers to R9-NHNH-R10Structure compound；
" amine " refers to R9-NH-R10Structure compound；
" alcohols " refers to the compound after the hydrogen atom in alkane molecule is optionally substituted by a hydroxyl group, preferably R9The compound of-OH, alkane Hydrocarbon can be optionally substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, independently Selected from alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, heterocycle, Aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, amino, halogenated alkyl, hydroxyl alkane Base, carboxylic acid group, carboxylate ,-OR11、-C(O)OR11、-OC(O)R11、-NHS(O)mR11、-C(O)R11、-NHC(O)R11、-NHC (O)OR11、-NR9R10、-OC(O)NR9R10Or-C (O) NR9R10。
" optional " or " optionally " mean event or environment described later can with but need not occur, which includes The event or environment generation or not spot occasion.For example, meaning that alkyl can be with " optionally by alkyl-substituted heterocyclic group " But necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom Replaced independently of one another by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, this Field technical staff, which can determine in the case where not paying excessive make great efforts and (pass through experiment or theoretical), may or impossible take Generation.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key Fixed.
" pharmaceutical composition " indicate containing one or more compounds described herein or its physiologically/pharmaceutical salt or The mixture and other components such as physiology/pharmaceutical carrier and excipient of pro-drug and other chemical constituents.Medicine The purpose of compositions is the administration promoted to organism, plays bioactivity in turn conducive to the absorption of active constituent.
M, R9~R11Definition as described in logical formula (I).
Synthetic method of the invention
In order to complete synthesis purpose of the invention, the present invention uses following synthetic technology scheme:
It is a kind of to prepare logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomerism The method of or mixtures thereof body, diastereoisomer form or its officinal salt, this method comprises:
General formula (IA) compound and formula compound G or its reactant salt, optionally further slough protecting group, hydroxylating or cyclization Reaction obtains logical formula (I) compound；
Wherein:
PG is selected from-NR9R10、-C(O)Rd,-OH or-S (O)m Rd；
Compound G is selected from heterocyclic compound, heteroaromatic ring compounds, carboxylic acid halides, sulfonic acid halide, hydrazine, amine or alcohol compound；
RdSelected from hydroxyl or halogen；
Preferably, when PG is selected from-NR9R10Or when-OH, compound G is selected from carboxylic acid halides, sulfonic acid halide；
When PG is selected from-C (O) RdOr-S (O)m RdWhen, compound G be selected from heterocyclic compound, heteroaromatic ring compounds, hydrazine, Amine or alcohol compound；
M, n, P, R1~R5And R9~R10Definition as described in logical formula (I)；
The protecting group of hydroxyl is preferably isopropyl subunit or vinyl；
The protecting group of amino is preferably tert-butoxycarbonyl；
The reagent of bishydroxy is preferably osmium tetroxide.
It is a kind of to prepare logical formula (II) compound represented or its tautomer, mesomer, racemic modification, enantiomerism The method of or mixtures thereof body, diastereoisomer form or its officinal salt, this method comprises:
General formula (IIA) compound and compound G or its reactant salt, optionally further hydrolysis, hydroxylating or annulation, obtain To logical formula (II) compound；
Wherein:
PG is selected from-NR9R10、-C(O)Rd,-OH or-S (O)m Rd；
Compound G is selected from heterocyclic compound, heteroaromatic ring compounds, carboxylic acid halides, sulfonic acid halide, hydrazine, amine or alcohol compound；
RdSelected from hydroxyl or halogen；
Preferably, when PG is selected from-NR9R10Or when-OH, compound G is selected from carboxylic acid halides, sulfonic acid halide；
When PG is selected from-C (O) RdOr-S (O)m RdWhen, compound G be selected from heterocyclic compound, heteroaromatic ring compounds, hydrazine, Amine or alcohol compound；
M, P, R1~R3, R5And R9~R10Definition as described in logical formula (I)；
The protecting group of hydroxyl is preferably isopropyl subunit or vinyl；
The protecting group of amino is preferably tert-butoxycarbonyl；
The reagent of bishydroxy is preferably osmium tetroxide.
It is a kind of that prepare logical formula (III) compound represented or its tautomer, mesomer, racemic modification, mapping different The method of or mixtures thereof structure body, diastereoisomer form or its officinal salt, this method comprises:
General formula (IIIA) compound and compound G or its reactant salt, optionally further hydrolysis, hydroxylating or annulation, Obtain logical formula (III) compound；
Wherein:
PG is selected from-NR9R10、-C(O)Rd,-OH or-S (O)m Rd；
Compound G includes but is not limited to heterocyclic compound, heteroaromatic ring compounds, carboxylic acid halides, sulfonic acid halide, hydrazine, amine or alcohol Class compound；
RdSelected from hydroxyl or halogen；
Preferably, when PG is selected from-NR9R10Or when-OH, compound G is selected from carboxylic acid halides, sulfonic acid halide；
When PG is selected from-C (O) RdOr-S (O)m RdWhen, compound G be selected from heterocyclic compound, heteroaromatic ring compounds, hydrazine, Amine or alcohol compound；
M, R1~R3, R5And R9~R10Definition as described in logical formula (I)；
The protecting group of hydroxyl is preferably isopropyl subunit or vinyl；
The protecting group of amino is preferably tert-butoxycarbonyl；
The reagent of bishydroxy is preferably osmium tetroxide.
It is a kind of to prepare logical formula (IV) compound represented or its tautomer, mesomer, racemic modification, enantiomerism The method of or mixtures thereof body, diastereoisomer form or its officinal salt, this method comprises:
General formula (IVa) compound carries out oxidation reaction, obtains general formula (IVb) compound；General formula (IVb) compound and substitution Aniline reaction, obtain general formula (IVA) compound；General formula (IVA) compound and compound G or its reactant salt, optionally further Protecting group, hydroxylating or annulation are sloughed, logical formula (IV) compound is obtained；
Wherein:
Compound G is selected from heterocyclic compound, heteroaromatic ring compounds, hydrazine, amine or alcohol compound；
RdSelected from hydroxyl or halogen；
X is selected from halogen；
N, P, R1~R3And R11Definition as described in logical formula (I)；
The protecting group of hydroxyl is preferably isopropyl subunit or vinyl；
The protecting group of amino is preferably tert-butoxycarbonyl；
The reagent of bishydroxy is preferably osmium tetroxide.
Specifically, a kind of logical formula (V) compound represented or its tautomer, mesomer, racemic modification, right of preparing Or mixtures thereof isomers, diastereoisomer form or the method for its officinal salt are reflected, this method comprises:
General formula (Va) compound and bromo- 1, the 1- diethoxyethane of 2- heat reaction under alkaline condition, obtain general formula (Vb) compound；General formula (Vb) compound is reacted with polyphosphoric acids, obtains general formula (Vc) compound；General formula (Vc) compound carries out Catalytic hydrogenation obtains general formula (Vd) compound；Titanium tetrachloride and 1,1- is added under condition of ice bath in general formula (Vd) compound Dichlormethyl ether reaction, obtains general formula (Ve) compound；General formula (Ve) compound and iso-amylene, sodium dihydrogen phosphate and sodium chlorite are anti- It answers, obtains general formula (Vf) compound；General formula (Vf) compound reacts under alkaline condition with substituted aniline, obtains general formula (Vg) Compound；General formula (Vg) compound and 2, chloro- 5, the 6- dicyanoquinone of 3- bis-, obtains general formula (VA) compound；General formula (VA) is changed Close object and compound G or its salt carry out condensation reaction under the conditions of condensation reagent, optionally further slough protecting group, hydroxylating or Annulation obtains logical formula (V) compound；
Wherein:
Compound G is selected from heterocyclic compound, heteroaromatic ring compounds, hydrazine, amine or alcohol compound；
RdSelected from hydroxyl or halogen；
X is selected from halogen；
R1~R3And R11Definition as described in logical formula (I)；
The protecting group of hydroxyl is preferably isopropyl subunit or vinyl；
The protecting group of amino is preferably tert-butoxycarbonyl；
The reagent of bishydroxy is preferably osmium tetroxide.
The reagent of alkaline condition includes organic base and inorganic base, and the organic bases include but is not limited to N, and N- bis- is different Propylethylamine, triethylamine, lithium amide, n-BuLi or potassium tert-butoxide, the inorganic base include but is not limited to cesium carbonate, carbon Sour potassium, sodium carbonate, sodium bicarbonate, sodium dihydrogen phosphate, saleratus or sodium hydride, preferably potassium carbonate.
Catalyst includes but is not limited to 10% palladium carbon, palladium chloride, palladium acetate or tris(dibenzylideneacetone) dipalladium.
Condensation reagent includes but is not limited to N, N- dicyclohexylcarbodiimide, N, two Asia of N- diisopropyl carbon, O- benzo three Nitrogen azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester (TBTU) etc., preferably O- benzotriazole-N, N, N', N'- tetramethyl Urea tetrafluoro boric acid ester (TBTU), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU) are excellent It is selected as 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU).
Solvent for use includes but is not limited to: ethyl acetate, methylene chloride, toluene, tetrahydrofuran, dimethyl sulfoxide, N, N- The mixed solvent of dimethylformamide, the tert-butyl alcohol and water or above-mentioned solvent.
Specific embodiment
The present invention is further described with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.
Test method without specific conditions in the embodiment of the present invention, usually according to normal condition, or according to raw material or Condition proposed by commodity manufacturer.The reagent in specific source is not specified, for the conventional reagent of market purchase.
Embodiment
The structure of compound is by nuclear magnetic resonance (NMR) or/and mass spectrum (MS) come what is determined.NMR is displaced (δ) with 10-6 (ppm) unit provides.The measurement of NMR is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometer, and measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), inside it is designated as tetramethylsilane (TMS).
The measurement of MS is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: Finnigan LCQ advantage MAX)。
The measurement of HPLC uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150 × 4.6mm chromatography Column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150 × 4.6mm chromatographic column).
Kinases average inhibition and IC50The measurement of value is with NovoStar microplate reader (German BMG company).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and thin-layered chromatography (TLC) makes The specification that silica gel plate uses is 0.15mm~0.2mm, thin-layer chromatography isolate and purify product use specification be 0.9mm~ 1.0mm。
Column chromatography is generally carrier using 200~300 mesh silica gel of Yantai Huanghai Sea silica gel.
Known starting material of the invention can be used or be synthesized according to methods known in the art, or can purchase certainly ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, splendid remote chemical science and technology (Accela ChemBio Inc), up to the companies such as auspicious chemicals.
Without specified otherwise in embodiment, reaction can be carried out under argon atmospher or nitrogen atmosphere.
Argon atmospher or nitrogen atmosphere refer to that reaction flask connects the argon gas or nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.
Pressure hydration reaction uses Parr 3916EKX type hydrogenation instrument and clear indigo plant QL-500 type hydrogen generator or HC2-SS Type hydrogenates instrument.
Hydrogenation usually vacuumizes, and is filled with hydrogen, operates 3 times repeatedly.
Microwave reaction uses 908860 type microwave reactor of CEM Discover-S.
Without specified otherwise in embodiment, solution refers to aqueous solution.
Without specified otherwise in embodiment, it is 20 DEG C~30 DEG C that the temperature of reaction, which is room temperature,.
The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), reacts the system of used solvent Have: A: methylene chloride and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone, The volume ratio of solvent is different according to the polarity of compound and is adjusted.
The system of eluant, eluent and the solvent system of thin-layered chromatography for the column chromatography that purifying compound uses include: A: two Chloromethanes and methanol system, B: n-hexane and ethyl acetate system, C: methylene chloride and acetone system, D: n-hexane and dichloromethane The volume ratio of alkane system, solvent is different according to the polarity of compound and is adjusted, and a small amount of triethylamine and vinegar can also be added The alkalinity such as acid or acid reagent are adjusted.
Embodiment 1
(R)-N- (2,3- dihydroxy propoxyl group) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) benzofuran -5- formyl Amine
The first step
1- (2,2- diethoxy ethyoxyl) -2,3- difluorobenzene
2,3- difluorophenol 1a (50g, 0.39mol) is dissolved in 400mL dimethyl sulfoxide, bromo- 1, the 1- bis- of 2- is added Ethoxyethane (79.50g, 0.40mol) and potassium carbonate (79.60g, 0.58mol), are heated to 95 DEG C, are stirred to react 16 hours. Reaction solution is cooled to room temperature, 1L ethyl acetate, filtering, filtrate water (750mL × 2) washing, the anhydrous sulphur of organic phase is added Sour sodium dries, filters, filtrate decompression concentration, obtain title product 1- (2,2- diethoxy ethyoxyl) -2,3- difluorobenzene 1b (80g, Colorless oil), yield: 84.4%.
Second step
6,7- difluorobenzo-fur
1- (2,2- diethoxy ethyoxyl) -2,3- difluorobenzene 1b (80g, 0.33mol) is dissolved in 800mL toluene, It is added polyphosphoric acids (154g, 0.46mol), is heated to 100 DEG C, is stirred to react 6 hours.Reaction solution is cooled to room temperature, is poured into In 1L water, layering, water phase is extracted with ethyl acetate (500mL × 3), merges organic phase, molten with saturated sodium-chloride (750mL × 1) Liquid washing, is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, purify with silica gel column chromatography with eluant, eluent system B obtained by Residue obtains title product 6,7- difluorobenzo-fur 1c (8.90g, colorless oil), yield 17.8%.
Third step
The fluoro- 2,3- Dihydrobenzofuranes of 6,7- bis-
6,7- difluorobenzo-fur 1c (8.60g, 55.80mmol) is dissolved in 100mL ethyl acetate, 10% palladium is added Carbon (1g), hydrogen are replaced three times, under nitrogen atmosphere, are stirred to react 16 hours.Reaction solution is filtered by diatomite, filtrate decompression is dense Contracting, obtains title product 6, fluoro- 2, the 3- Dihydrobenzofuranes 1d (6.90g, colorless oil) of 7- bis-, yield 79.3%.
4th step
The fluoro- 2,3- Dihydrobenzofuranes -5- formaldehyde of 6,7- bis-
Fluoro- 2, the 3- Dihydrobenzofuranes 1d (6.90g, 44.20mmol) of 6,7- bis- is dissolved in 100mL methylene chloride, Ice-water bath is cooled to 0 DEG C, is added titanium tetrachloride (13.40g, 70.40mmol), stirs 5 minutes, 1,1- dichlormethyl ether is slowly added dropwise (7.60g, 66.30mmol), is added dropwise, and is warmed to room temperature stirring 12 hours.100mL ice water is added, layering, organic phase is with anhydrous Sodium sulphate dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, marked Inscribe product 6, fluoro- 2, the 3- Dihydrobenzofuranes -5- formaldehyde 1e (6.80g, light yellow solid) of 7- bis-, yield 83.6%.
5th step
The fluoro- 2,3- Dihydrobenzofuranes -5- carboxylic acid of 6,7- bis-
Fluoro- 2, the 3- Dihydrobenzofuranes -5- formaldehyde 1e (6.50g, 35.30mmol) of 6,7- bis- is dissolved in the tertiary fourth of 300mL In the mixed solution of alcohol and water (V/V=3:1), sequentially add iso-amylene (22g, 0.32mol), sodium dihydrogen phosphate (24.80g, 0.16mol) with sodium chlorite (6.40g, 70.60mmol), it is stirred to react 16 hours.200mL water is added, uses ethyl acetate (250mL × 2) extraction, merges organic phase, is dried, filtered with anhydrous sodium sulfate, and filtrate decompression concentration obtains title product 6,7- Two fluoro- 2,3- Dihydrobenzofuranes -5- carboxylic acid 1f (7g, white solid), yield 99.1%.
6th step
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid
By fluoro- 2, the 3- Dihydrobenzofuranes -5- carboxylic acid 1f (7g, 35mmol) of 6,7- bis-, the fluoro- 4- Iodoaniline of 2- (9.10g, 38.50mmol), lithium amide (3.25g, 0.14mol) and 50mL tetrahydrofuran are added in reaction flask, and 95 DEG C of microwave are reacted 75 points Clock.Reaction solution is cooled to room temperature, is poured into 300mL water, 4M salt acid for adjusting pH < 7 are added dropwise, is extracted with ethyl acetate (250mL × 3) It takes, merges organic phase, dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system D Purifying gained residue, obtains the fluoro- 6- of title product 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic Sour 1g (8g, brown solid), yield 54.8%.
7th step
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzofuran -5- carboxylic acid
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid 1g (310mg, It 0.74mmol) is dissolved in 30mL toluene, chloro- 5, the 6- dicyanoquinone (253mg, 1.11mmol) of 2,3- bis- is added, is heated to It 105 DEG C, is stirred to react 2 hours.Reaction solution is cooled to room temperature, 60mL water is added, is extracted with ethyl acetate (50mL × 3), is closed And organic phase, dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, purify with thin-layered chromatography with solvent system B obtained by Residue, obtaining the fluoro- 6- of title product 7- ((the fluoro- 4- iodophenyl of 2-) amino), (80mg, brown are solid by benzofuran -5- carboxylic acid 1h Body), yield: 25.9%.
MS m/z(ESI):415.8[M+1]
8th step
(R)-N- ((2,2- dimethyl -1,3- dioxole -4- base) methoxyl group) the fluoro- 6- of -7- ((the fluoro- 4- iodine of 2- Phenyl) amino) benzofuran -5- formamide
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzofuran -5- carboxylic acid 1h (40mg, 0.10mmol) is dissolved in In 10mL n,N-Dimethylformamide, it is added (R)-O- ((2,2- dimethyl -1,3- dioxole -4- base) methyl) Azanol 1i (16mg, 0.11mmol, using well known method " Tetrahedron Letters, 2006,47 (43), 7607- 7609 " are prepared), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (55mg, 0.14mmol) with n,N-diisopropylethylamine (40mg, 0.30mmol), it is stirred to react 2 hours.20mL water is added, with acetic acid second Ester (20mL × 1) extraction, organic phase washed with water (20mL × 1) and saturated sodium chloride solution (20mL × 2) washing, anhydrous slufuric acid Sodium dries, filters, filtrate decompression concentration, with thin-layered chromatography with solvent system B purify obtained by residue, obtain title product (R)-N- ((2,2- dimethyl -1,3- dioxole -4- base) methoxyl group) the fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) ammonia Base) benzofuran -5- formamide 1j (30mg, yellow solid), yield: 60.0%.
MS m/z(ESI):544.9[M+1]
9th step
(R)-N- (2,3- dihydroxy propoxyl group) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) benzofuran -5- formyl Amine
By (R)-N- ((2,2- dimethyl -1,3- dioxole -4- base) methoxyl group) the fluoro- 6- of -7- ((the fluoro- 4- of 2- Iodophenyl) amino) benzofuran -5- formamide 1j (30mg, 0.06mmol) is dissolved in 5mL methanol, 1mL1M hydrochloric acid is added, It is stirred to react 3 hours.Be added 20mL water, with ethyl acetate (20mL × 1) extract, organic phase washed with water (20mL × 1) and satisfy It is washed with sodium chloride solution (20mL × 1), anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with thin-layered chromatography to be unfolded Agent system B purifying gained residue, obtains title product (R)-N- (2,3- dihydroxy propoxyl group) the fluoro- 6- of -7- ((fluoro- 4- iodine of 2- Phenyl) amino) benzofuran -5- formamide 1 (8mg, white solid), yield: 28.6%.
MS m/z(ESI):505.2[M+1]
1H NMR(400MHz,CD3OD)δ7.97(s,1H),7.90(d,1H),7.42(dd,1H),7.27(dd,1H), 7.00-6.99(m,1H),6.47-6.43(m,1H),4.03-3.98(m,2H),3.86-3.83(m,2H),3.58-3.52(m, 2H)。
Embodiment 2
N- ((1,3- dihydroxypropane -2- base) oxygroup) the fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) benzofuran -5- Formamide
The first step
N- ((2,2- dimethyl -1,3- dioxanes -5- base) oxygroup) the fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo Furans -5- formamide
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzofuran -5- carboxylic acid 1h (62mg, 0.15mmol) is dissolved in In 2mL n,N-Dimethylformamide, addition O- (2,2- dimethyl -1,3- dioxanes -5- base) azanol 2a (33mg, 0.22mmol is prepared using well known method " patent WO2003062191A1 "), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (85mg, 0.22mmol) and n,N-diisopropylethylamine (58mg, 0.45mmol), are stirred Mix reaction 16 hours.40mL water is added, is extracted with ethyl acetate (35mL × 2), merges organic phase, it is dry with anhydrous sodium sulfate, Filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system B purify obtained by residue, obtain title product N- ((2, 2- dimethyl -1,3- dioxanes -5- base) oxygroup) the fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) benzofuran -5- formamide 2b (28mg, brown oil), yield: 34.3%.
MS m/z(ESI):545.1[M+1]
Second step
N- ((1,3- dihydroxypropane -2- base) oxygroup) the fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) benzofuran -5- Formamide
By N- ((2,2- dimethyl -1,3- dioxanes -5- base) oxygroup) the fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) benzene And furans -5- formamide 2b (28mg, 0.05mmol) is dissolved in 5mL methanol, and 1mL 1M hydrochloric acid is added, is stirred to react 4 hours. Reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, obtain title product N- ((1,3- Dihydroxypropane -2- base) oxygroup) the fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) benzofuran -5- formamide 2 (6mg, it is pale yellow Color solid), yield 23.1%.
MS m/z(ESI):505.3[M+1]
1H NMR(400MHz,DMSO-d6)δ7.94(d,1H),7.74(s,1H),7.45-7.42(m,1H),7.29(d, 1H),7.02(t,1H),6.47-6.43(m,1H),3.84(t,1H),3.66(d,4H)
Embodiment 3
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- hydroxyl-oxethyl) benzofuran -5- formamide
The first step
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- (ethyleneoxy) ethyoxyl) benzofuran -5- formamide
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzofuran -5- carboxylic acid 1h (32mg, 0.08mmol) is dissolved in In 2mL n,N-Dimethylformamide, addition O- (2- (ethyleneoxy) ethyl) azanol (it is scientific and technological to be purchased from splendid remote chemistry, 9mg, 0.09mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (44mg, 0.12mmol) and N,N-diisopropylethylamine (30mg, 0.23mmol) is stirred to react 4 hours.30mL water is added, with ethyl acetate (30mL × 2) Extraction merges organic phase, is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purifying gained residue, obtains the fluoro- 6- of title product 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- (ethyleneoxy) ethoxy Base) benzofuran -5- formamide 3a (20mg, off-white powder), yield: 51.9%.
MS m/z(ESI):501.0[M+1]
Second step
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- hydroxyl-oxethyl) benzofuran -5- formamide
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- (ethyleneoxy) ethyoxyl) benzofuran -5- formyl Amine 3a (20mg, 0.04mmol) is dissolved in 2mL methanol, and 1mL 1M hydrochloric acid is added, is stirred to react 3 hours.Reaction solution is depressurized Concentration, with thin-layered chromatography with solvent system A purify obtained by residue, obtain the fluoro- 6- of title product 7- ((the fluoro- 4- iodobenzene of 2- Base) amino)-N- (2- hydroxyl-oxethyl) benzofuran -5- formamide 3 (6mg, off-white powder), yield 31.6%.
MS m/z(ESI):475.2[M+1]
1H NMR(400MHz,CD3OD)δ7.83(d,1H),7.68(s,1H),7.37(dd,1H),7.25(d,1H),6.93 (t,1H),6.46-6.40(m,1H),3.94(t,2H),3.69(t,2H)
Embodiment 4
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (3- hydroxy propyloxy group) benzofuran -5- formamide
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzofuran -5- carboxylic acid 1h (62mg, 0.15mmol) is dissolved in In 2mL n,N-Dimethylformamide, 3- (amino oxygroup) propane -1- alcohol hydrochloride 4a (33mg, 0.22mmol, using public affairs is added The method " patent WO2011020861A1 " known is prepared), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea Hexafluorophosphoric acid ester (85mg, 0.23mmol) and n,N-diisopropylethylamine (58mg, 0.45mmol), are stirred to react 4 hours.It is added 25mL water is extracted with ethyl acetate (30mL × 2), is merged organic phase, is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, With thin-layered chromatography with solvent system A purify gained residue, obtain the fluoro- 6- of title product 7- ((the fluoro- 4- iodophenyl of 2-) ammonia Base)-N- (3- hydroxy propyloxy group) benzofuran -5- formamide 4 (18mg, white solid), yield: 24.7%.
MS m/z(ESI):488.9[M+1]
1H NMR(400MHz,CD3OD)δ7.90-7.88(m,2H),7.45-7.40(m,1H),7.30-7.28(m,1H), 7.00-6.98(m,1H),6.50-6.45(m,1H),3.97(t,1H),3.69(t,1H),3.33-3.31(m,4H),1.86- 1.83(m,1H),1.63-1.59(m,1H)。
Embodiment 5
(S)-N- (2,3- dihydroxy propoxyl group) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) benzofuran -5- formyl Amine
The first step
(S)-N- ((2,2- dimethyl -1,3- dioxole -4- base) methoxyl group) the fluoro- 6- of -7- ((the fluoro- 4- iodine of 2- Phenyl) amino) benzofuran -5- formamide
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzofuran -5- carboxylic acid 1h (42mg, 0.10mmol) is dissolved in In 2mL n,N-Dimethylformamide, (S)-O- ((2,2- dimethyl -1,3- dioxole -4- base) methyl) hydroxyl is added Amine 5a (18mg, 0.12mmol are prepared using well known method " patent WO2003062189A1 "), 2- (7- azo benzo Triazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (57mg, 0.15mmol) and n,N-diisopropylethylamine (39mg, 0.30mmol), it is stirred to react 16 hours.30mL water is added, is extracted with ethyl acetate (30mL × 2), merges organic phase, use is anhydrous Sodium sulphate dries, filters, filtrate decompression concentration, with thin-layered chromatography with solvent system B purify obtained by residue, obtain title Product (S)-N- ((2,2- dimethyl -1,3- dioxole -4- base) methoxyl group) the fluoro- 6- of -7- ((fluoro- 4- iodobenzene of 2- Base) amino) benzofuran -5- formamide 5b (23mg, colorless oil), yield: 42.3%.
MS m/z(ESI):545.1[M+1]
Second step
(S)-N- (2,3- dihydroxy propoxyl group) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) benzofuran -5- formyl Amine
By (S)-N- ((2,2- dimethyl -1,3- dioxole -4- base) methoxyl group) the fluoro- 6- of -7- ((the fluoro- 4- of 2- Iodophenyl) amino) benzofuran -5- formamide 5b (23mg, 0.04mmol) is dissolved in 5mL methanol, 1mL 1M hydrochloric acid is added, It is stirred to react 3 hours.Reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, marked Inscribe product (S)-N- (2,3- dihydroxy propoxyl group) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) benzofuran -5- formamide 5 (3mg, white solid), yield: 14.3%.
MS m/z(ESI):504.8[M+1]
1H NMR(400MHz,CD3OD)δ7.97(s,1H),7.90(d,1H),7.42(dd,1H),7.27(dd,1H), 7.00-6.99(m,1H),6.47-6.43(m,1H),4.03-3.98(m,2H),3.86-3.83(m,2H),3.58-3.52(m, 2H)。
Embodiment 6
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- ((1- hydroxy-2-methyl propane -2- base) oxygroup) benzo furan It mutters -5- formamide
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzofuran -5- carboxylic acid 1h (42mg, 0.10mmol) is dissolved in In 2mL n,N-Dimethylformamide, addition 2- (amino oxygroup) -2- methylpropane -1- alcohol hydrochloride 6a (21mg, 0.15mmol is prepared using well known method " patent US20120238599A1 "), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (57mg, 0.15mmol) and n,N-diisopropylethylamine (39mg, 0.30mmol), are stirred Mix reaction 6 hours.30mL water is added, is extracted with ethyl acetate (30mL × 2), merges organic phase, mistake dry with anhydrous sodium sulfate Filter, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by residue, obtain the fluoro- 6- of title product 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- ((1- hydroxy-2-methyl propane -2- base) oxygroup) benzofuran -5- formamide 6 (15mg, off-white powder), yield: 29.5%.
MS m/z(ESI):503.0[M+1]
1H NMR(400MHz,CDCl3)δ9.42(s,1H),7.97(s,1H),7.75(s,1H),7.42(d,1H),6.90- 6.89(m,1H),6.83(s,1H),6.40-6.36(m,1H),4.56-4.54(m,1H),3.30-3.28(m,2H),1.20(s, 6H)。
Embodiment 7
6- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- hydroxyl-oxethyl) -2,3- Dihydrobenzofuranes -5- formamide
The first step
The fluoro- 2,3- Dihydrobenzofuranes -5- carboxylic acid of 6-
By fluoro- 2, the 3- Dihydrobenzofuranes -5- formaldehyde 7a of 6- (300mg, 1.81mmol, using well known method at 0 DEG C " patent WO2012019430A1 " is prepared) it is dissolved in the mixed solution of the 24mL tert-butyl alcohol and water (V/V=3:1), it is added Iso-amylene (1.14g, 16.27mmol) and sodium dihydrogen phosphate (1.27g, 8.15mmol), be added portionwise sodium chlorite (0.41g, 3.62mmol), it is warmed to room temperature and is stirred to react 4 hours.20mL water is added, is extracted with ethyl acetate (150mL × 1), organic phase is used Saturated sodium chloride solution (100mL × 1) washing, anhydrous sodium sulfate dry, filter, and filtrate decompression concentration obtains title product 6- Fluoro- 2,3- Dihydrobenzofuranes -5- carboxylic acid 7b (300mg, yellow solid), yield 91.2%.
Second step
6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid
By fluoro- 2, the 3- Dihydrobenzofuranes -5- carboxylic acid 7b (100mg, 0.55mmol) of 6-, the fluoro- 4- Iodoaniline of 2- (156mg, 0.66mmol), bis- (trimethyl silicon substrate) lithium amides (459mg, 2.75mmol) and 2mL tetrahydrofuran are added in reaction flask, microwave 120 DEG C are reacted 1 hour.Reaction solution is cooled to room temperature, is poured into 30mL ice water, it is 1 that 1M salt acid for adjusting pH, which is added dropwise, with acetic acid second Ester (50mL × 3) extraction, merge organic phase, dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, with thin-layered chromatography with Solvent system B purifying gained residue, obtains title product 6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- dihydrobenzo furan It mutters -5- carboxylic acid 7c (20mg, brown oil), yield 9.1%.
MS m/z(ESI):400.0[M+1]
Third step
6- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- (ethyleneoxy) ethyoxyl) -2,3- Dihydrobenzofuranes -5- first Amide
6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid 7c (20mg, 0.05mmol) is molten I-hydroxybenzotriazole (10mg, 0.08mmol) and 1- (3- dimethylamino-propyl)-is added in 2mL methylene chloride in solution at 0 DEG C 3- ethyl-carbodiimide hydrochloride (14mg, 0.08mmol) is warmed to room temperature and is stirred to react 2 hours.2mL O- (2- (ethylene is added Oxygroup) ethyl) azanol (12mg, 0.12mmol) and n,N-diisopropylethylamine (14mg, 0.12mmol) dichloromethane solution, It is stirred to react 36 hours.Reaction solution is concentrated under reduced pressure, 2mL n,N-Dimethylformamide and O- (2- (ethyleneoxy) second is added Base) azanol (6mg, 0.06mmol), it is stirred to react 48 hours.5mL saturated sodium chloride solution and 20mL ethyl acetate is added, point Layer, organic phase dries, filters with anhydrous sodium sulfate, filtrate decompression concentration, purify with thin-layered chromatography with solvent system B obtained by Residue obtains title product 6- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- (ethyleneoxy) ethyoxyl) -2,3- dihydrobenzene And furans -5- formamide 7d (5mg, white solid), yield: 20.6%.
MS m/z(ESI):483.1[M-1]
4th step
6- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- hydroxyl-oxethyl) -2,3- Dihydrobenzofuranes -5- formamide
By 6- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- (ethyleneoxy) ethyoxyl) -2,3- Dihydrobenzofuranes -5- Formamide 7d (5mg, 0.01mmol) is dissolved in 1mL ethyl alcohol, and 0.1mL 1M hydrochloric acid is added at 0 DEG C, is warmed to room temperature and is stirred to react 2 Hour.It is 7 that saturated sodium bicarbonate solution is added at 0 DEG C and adjusts pH, is extracted with ethyl acetate (20mL × 3), merges organic phase, used Anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with thin-layered chromatography with solvent system B purify obtained by residue, obtain Title product 6- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- hydroxyl-oxethyl) -2,3- Dihydrobenzofuranes -5- formamide 7 (3mg, white solid), yield 57.1%.
MS m/z(ESI):459.3[M+1]
1H NMR(400MHz,CDCl3)δ9.23(s,1H),8.64(s,1H),7.47-7.44(m,1H),7.40-7.37 (m,1H),7.12-7.07(m,1H),6.56(s,1H),4.61(t,2H),4.06-4.04(m,2H),3.78-3.76(m,2H), 3.65-3.64(m,1H),3.15(t,2H).
Embodiment 8
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- hydroxyl-oxethyl) -2,3- Dihydrobenzofuranes -5- formyl Amine
The first step
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- (ethyleneoxy) ethyoxyl) -2,3- Dihydrobenzofuranes - 5- formamide
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid 1g (42mg, It 0.10mmol) is dissolved in 3mL n,N-Dimethylformamide, addition O- (2- (ethyleneoxy) ethyl) azanol (13mg, 0.12mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (57mg, 0.15mmol) and N,N-diisopropylethylamine (33mg, 0.25mmol) is stirred to react 5 hours.30mL water is added, with ethyl acetate (30mL × 2) Extraction merges organic phase, is washed with saturated sodium chloride solution (40mL × 1), anhydrous sodium sulfate dries, filters, and filtrate decompression is dense Contracting, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain the fluoro- 6- of title product 7- ((the fluoro- 4- iodobenzene of 2- Base) amino)-N- (2- (ethyleneoxy) ethyoxyl) -2,3- Dihydrobenzofuranes -5- formamide 8a (45mg, brown solid), it produces Rate: 89.0%.
MS m/z(ESI):501.0[M-1]
Second step
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- hydroxyl-oxethyl) -2,3- Dihydrobenzofuranes -5- formyl Amine
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- (ethyleneoxy) ethyoxyl) -2,3- dihydrobenzo furan - 5- formamide the 8a (45mg, 0.09mmol) that mutters is dissolved in 3mL methanol, and 1mL 1M hydrochloric acid is added, is stirred to react 3 hours.Reaction Liquid be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain fluoro- the 6- ((2- of title product 7- Fluoro- 4- iodophenyl) amino)-N- (2- hydroxyl-oxethyl) -2,3- Dihydrobenzofuranes -5- formamide 8 (30mg, white solid), Yield 70.3%.
MS m/z(ESI):477.2[M+1]
1H NMR(400MHz,CDCl3)δ7.48(s,1H),7.42(d,1H),7.28(s,1H),6.46-6.43(m,1H), 4.79(t,2H),3.97-3.94(m,2H),3.78-3.70(m,2H),3.31(t,2H)。
Embodiment 9
The chloro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- hydroxyl-oxethyl) -2,3- Dihydrobenzofuranes -5- formyl Amine
The first step
The fluoro- 2,3- Dihydrobenzofuranes -5- carboxylic acid of the chloro- 6- of 7-
Fluoro- 2, the 3- Dihydrobenzofuranes -5- carboxylic acid 7b (346mg, 1.90mmol) of 6- is dissolved in 7mL N, N- dimethyl In formamide, it is added N- chlorosuccinimide (355mg, 2.66mmol), is warming up to 60 DEG C and is stirred to react 16 hours.It is added 120mL ethyl acetate is washed with saturated sodium chloride solution (100mL × 2), and anhydrous sodium sulfate dries, filters, and filtrate decompression is dense Contracting, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain fluoro- 2, the 3- dihydrobenzene of the chloro- 6- of title product 7- And furans -5- carboxylic acid 9a (30mg, yellow solid), yield 7.3%.
Second step
The chloro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid
By fluoro- 2, the 3- Dihydrobenzofuranes -5- carboxylic acid 9a (30mg, 0.14mmol) of the chloro- 6- of 7-, the fluoro- 4- Iodoaniline of 2- (39mg, 0.17mmol), lithium amide (14mg, 0.55mmol) and 4mL tetrahydrofuran are added in reaction flask, 100 DEG C of microwave reactions 1 Hour.Reaction solution is cooled to room temperature, 30mL water is added, 1M salt acid for adjusting pH < 7 are added dropwise, is extracted with ethyl acetate (30mL × 3) It takes, merges organic phase, dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B Purifying gained residue, obtains the chloro- 6- of title product 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic Sour 9b (18mg, brown solid), yield 30.0%.
Third step
The chloro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- (ethyleneoxy) ethyoxyl) -2,3- Dihydrobenzofuranes - 5- formamide
By the chloro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid 9b (18mg, It 0.04mmol) is dissolved in 2mL n,N-Dimethylformamide, addition O- (2- (ethyleneoxy) ethyl) azanol (5mg, 0.05mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (23mg, 0.06mmol) and N,N-diisopropylethylamine (16mg, 0.12mmol) is stirred to react 3 hours.30mL water is added, with ethyl acetate (30mL × 2) Extraction merges organic phase, is washed with saturated sodium chloride solution (40mL × 1), anhydrous sodium sulfate dries, filters, and filtrate decompression is dense Contracting, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain the chloro- 6- of title product 7- ((the fluoro- 4- iodobenzene of 2- Base) amino)-N- (2- (ethyleneoxy) ethyoxyl) -2,3- Dihydrobenzofuranes -5- formamide 9c (8mg, brown solid), it produces Rate: 37.2%.
4th step
The chloro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- hydroxyl-oxethyl) -2,3- Dihydrobenzofuranes -5- formyl Amine
By the chloro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- (ethyleneoxy) ethyoxyl) -2,3- dihydrobenzo furan - 5- formamide the 9c (8mg, 0.02mmol) that mutters is dissolved in 2mL methanol, and 1mL 1M hydrochloric acid is added, is stirred to react 3 hours.It will be anti- Answer liquid to be concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, obtain chloro- the 6- ((2- of title product 7- Fluoro- 4- iodophenyl) amino)-N- (2- hydroxyl-oxethyl) -2,3- Dihydrobenzofuranes -5- formamide 9 (4mg, brown solid), Yield 51.3%.
MS m/z(ESI):493.4[M+1]
1H NMR(400MHz,CDCl3)δ10.12(br,1H),7.82(s,1H),7.43(d,1H),6.42-6.40(m, 1H),6.28-6.24(m,1H),4.80(t,2H),3.86-3.84(m,2H),3.61-3.59(m,2H),3.37(t,2H)。
Embodiment 10
(S)-N- (2,3- dihydroxypropyl) -6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- first Amide
6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid 7c (40mg, 0.10mmol) is molten (S) -3- amino -1,2-PD (11mg, 0.12mmol), 2- (7- azo is added in 3mL n,N-Dimethylformamide in solution Benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (57mg, 0.15mmol) and n,N-diisopropylethylamine (32mg, 0.25mmol) is stirred to react 3 hours.30mL water is added, is extracted with ethyl acetate (30mL × 2), merges organic phase, Washed with saturated sodium chloride solution (25mL × 1), anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with thin-layered chromatography with Solvent system A purifying gained residue, obtains title product (S)-N- (2,3- dihydroxypropyl) -6- ((fluoro- 4- iodobenzene of 2- Base) amino) -2,3- Dihydrobenzofuranes -5- formamide 10 (25mg, pale red solid), yield: 52.8%.
MS m/z(ESI):471.0[M-1]
1H NMR(400MHz,CDCl3)δ9.59(s,1H),7.44(dd,1H),7.36(dd,1H),7.33(s,1H), 7.12(t,1H),6.61(s,1H),6.55-6.52(m,1H),4.58(t,2H),3.89-3.87(m,1H),3.68-3.53(m, 4H),3.15(t,2H)
Embodiment 11
(R)-N- (2,3- dihydroxypropyl) -6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- first Amide
6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid 7c (40mg, 0.10mmol) is molten (R) -3- amino -1,2-PD (11mg, 0.12mmol), 2- (7- azo is added in 3mL n,N-Dimethylformamide in solution Benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (57mg, 0.15mmol) and n,N-diisopropylethylamine (32mg, 0.25mmol) is stirred to react 4 hours.30mL water is added, is extracted with ethyl acetate (25mL × 2), merges organic phase, Washed with saturated sodium chloride solution (25mL × 1), anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with thin-layered chromatography with Solvent system A purifying gained residue, obtains title product (R)-N- (2,3- dihydroxypropyl) -6- ((fluoro- 4- iodobenzene of 2- Base) amino) -2,3- Dihydrobenzofuranes -5- formamide 11 (15mg, Tan solid), yield: 31.7%.
MS m/z(ESI):473.3[M+1]
1H NMR(400MHz,CDCl3)δ9.59(s,1H),7.43(dd,1H),7.37(dd,1H),7.33(s,1H), 7.12(t,1H),6.61(s,1H),6.57-6.54(m,1H),4.61(t,2H),3.90-3.85(m,1H),3.65-3.56(m, 4H),3.14(t,2H)。
Embodiment 12
(S) the fluoro- 6- of-N- (2,3- dihydroxypropyl) -7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes - 5- formamide
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid 1g (42mg, 0.10mmol) It is dissolved in 3mL n,N-Dimethylformamide, (S) -3- amino -1,2-PD (11mg, 0.12mmol) is added, (7- is even by 2- Nitrogen benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (57mg, 0.15mmol) and n,N-diisopropylethylamine (33mg, 0.25mmol) is stirred to react 3 hours.30mL water is added, is extracted with ethyl acetate (30mL × 2), merges organic phase, It is washed with saturated sodium chloride solution (25mL × 1), anhydrous sodium sulfate dries, filters, and silica gel column chromatography is used in filtrate decompression concentration Gained residue is purified with eluant, eluent system A, obtaining the fluoro- 6- of title product (S)-N- (2,3- dihydroxypropyl) -7-, ((2- is fluoro- 4- iodophenyl) amino) -2,3- Dihydrobenzofuranes -5- formamide 12 (30mg, white solid), yield: 60.8%.
MS m/z(ESI):491.2[M+1]
1H NMR(400MHz,CDCl3)δ9.59(s,1H),7.43(dd,1H),7.37(dd,1H),7.33(s,1H), 7.12(t,1H),6.61(s,1H),6.57-6.54(m,1H),4.61(t,2H),3.90-3.85(m,1H),3.65-3.56(m, 4H),3.14(t,2H)。
Embodiment 13
(R)-N- (2,3- dihydroxy propoxyl group) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- dihydrobenzo furan It mutters -5- formamide
The first step
(R)-N- ((2,2- dimethyl -1,3- dioxole -4- base) methoxyl group) the fluoro- 6- of -7- ((the fluoro- 4- iodine of 2- Phenyl) amino) -2,3- Dihydrobenzofuranes -5- formamide
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid 1g (17mg, It 0.04mmol) is dissolved in 1mL n,N-Dimethylformamide, (R)-O- ((2,2- dimethyl -1,3- Dloxoles is added Alkene -4- base) methyl) azanol 1i (8mg, 0.05mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetra- are added at 0 DEG C Methylurea hexafluorophosphoric acid ester (23mg, 0.06mmol) and n,N-diisopropylethylamine (13mg, 0.10mmol), are warmed to room temperature stirring Reaction 2 hours.30mL water is added, is extracted with ethyl acetate (25mL × 2), merges organic phase, with saturated sodium chloride solution (30mL × 1) wash, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with thin-layered chromatography with solvent system B purify obtained by it is residual Excess obtains title product (R)-N- ((2,2- dimethyl -1,3- dioxole -4- base) methoxyl group) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- formamide 13a (10mg, white solid), yield: 45.4%.
MS m/z(ESI):547.1[M+1]
Second step
(R)-N- (2,3- dihydroxy propoxyl group) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- dihydrobenzo furan It mutters -5- formamide
By (R)-N- ((2,2- dimethyl -1,3- dioxole -4- base) methoxyl group) the fluoro- 6- of -7- ((the fluoro- 4- of 2- Iodophenyl) amino) -2,3- Dihydrobenzofuranes -5- formamide 13a (10mg, 0.02mmol) is dissolved in 2mL ethyl alcohol, it is added 2mL 1M hydrochloric acid is stirred to react 2 hours.Reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained it is residual Excess obtains title product (R)-N- (2,3- dihydroxy propoxyl group) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- bis- Hydrogen benzofuran -5- formamide 13 (3mg, brown solid), yield: 32.4%.
MS m/z(ESI):507.2[M+1]
1H NMR(400MHz,CD3OD)δ7.43(dd,1H),7.33-7.32(m,1H),7.30(s,1H),6.53-6.47 (m,1H),4.77(t,2H),3.98-3.96(m,1H),3.88-3.84(m,2H),3.59-3.56(m,2H),3.36(m,1H), 3.36(t,2H)。
Embodiment 14
(S)-N- (2,3- dihydroxy propoxyl group) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- dihydrobenzo furan It mutters -5- formamide
The first step
(S)-N- ((2,2- dimethyl -1,3- dioxole -4- base) methoxyl group) the fluoro- 6- of -7- ((the fluoro- 4- iodine of 2- Phenyl) amino) -2,3- Dihydrobenzofuranes -5- formamide
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid 1g (40mg, It 0.10mmol) is dissolved in 1mL n,N-Dimethylformamide, (S)-O- ((2,2- dimethyl -1,3- Dloxoles is added Alkene -4- base) methyl) azanol 5a (17mg, 0.12mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetra- are added at 0 DEG C Methylurea hexafluorophosphoric acid ester (55mg, 0.14mmol) and n,N-diisopropylethylamine (31mg, 0.24mmol), are warmed to room temperature stirring Reaction 4 hours.30mL water is added, is extracted with ethyl acetate (30mL × 1), merges organic phase, mistake dry with anhydrous sodium sulfate Filter, filtrate decompression concentration, with thin-layered chromatography with solvent system B purify obtained by residue, obtain title product (S)-N- ((2,2- dimethyl -1,3- dioxole -4- base) methoxyl group) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) -2, 3- Dihydrobenzofuranes -5- formamide 14a (35mg, white solid), yield: 67.3%.
MS m/z(ESI):546.9[M+1]
Second step
(S)-N- (2,3- dihydroxy propoxyl group) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- dihydrobenzo furan It mutters -5- formamide
By (S)-N- ((2,2- dimethyl -1,3- dioxole -4- base) methoxyl group) the fluoro- 6- of -7- ((the fluoro- 4- of 2- Iodophenyl) amino) -2,3- Dihydrobenzofuranes -5- formamide 14a (35mg, 0.06mmol) is dissolved in 2mL ethyl alcohol, it is added 1mL 1M hydrochloric acid is stirred to react 2 hours.Reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained it is residual Excess obtains title product (S)-N- (2,3- dihydroxy propoxyl group) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- bis- Hydrogen benzofuran -5- formamide 14 (13mg, light yellow solid), yield: 40.6%.MS m/z(ESI):507.2[M+1]
1H NMR(400MHz,CDCl3)δ7.48(s,1H),7.42(dd,1H),7.28-7.26(m,1H),7.18(s, 1H),6.40-6.40(m,1H),4.78(t,2H),3.92-3.85(m,3H),3.73-3.71(m,2H),3.69-3.59(m, 1H),3.28(t,2H)。
Embodiment 15
N- ((1,3- dihydroxypropane -2- base) oxygroup) the fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- dihydrobenzene And furans -5- formamide
The first step
N- ((2,2- dimethyl -1,3- dioxanes -5- base) oxygroup) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) -2, 3- Dihydrobenzofuranes -5- formamide
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid 1g (42mg, It 0.10mmol) is dissolved in 2mL n,N-Dimethylformamide, O- (2,2- dimethyl -1,3- dioxanes -5- base) azanol is added 2a (16mg, 0.11mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (57mg, 0.15mmol) with n,N-diisopropylethylamine (39mg, 0.30mmol), it is stirred to react 3 hours.30mL water is added, with acetic acid second Ester (30mL × 2) extraction, merge organic phase, dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, with thin-layered chromatography with Solvent system B purifying gained residue, obtains title product N- ((2,2- dimethyl -1,3- dioxanes -5- base) oxygroup) -7- Fluoro- 6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- formamide 15a (19mg, off-white powder) is produced Rate: 34.5%.
MS m/z(ESI):544.9[M-1]
Second step
N- ((1,3- dihydroxypropane -2- base) oxygroup) the fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- dihydrobenzene And furans -5- formamide
By N- ((2,2- dimethyl -1,3- dioxanes -5- base) oxygroup) the fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) - 2,3- Dihydrobenzofuranes -5- formamide 15a (19mg, 0.03mmol) are dissolved in 2mL methanol, and 1mL 1M hydrochloric acid is added, stirs Mix reaction 4 hours.Reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, obtain title Product N- ((1,3- dihydroxypropane -2- base) oxygroup) the fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- dihydrobenzo furan It mutters -5- formamide 15 (4mg, brown solid), yield 23.5%.
1H NMR(400MHz,CDCl3)δ7.50(d,1H),7.44-7.38(m,1H),7.29-7.26(m,1H),6.43- 6.38(m,1H),4.78(t,2H),3.89-3.82(m,1H),3.70-3.64(m,4H),3.30(t,2H)。
Embodiment 16
The fluoro- 6- of N- (cyclopropyl methoxyl group) -7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- formamide
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid 1g (42mg, It 0.10mmol) is dissolved in 2mL n,N-Dimethylformamide, addition O- (cyclopropyl methyl) azanol 16a (26mg, 0.30mmol, Be prepared using well known method " patent WO2012074999A1 "), 2- (7- azo benzotriazole)-N, N, N', N'- tetra- Methylurea hexafluorophosphoric acid ester (57mg, 0.15mmol) and n,N-diisopropylethylamine (39mg, 0.30mmol), it is small to be stirred to react 4 When.30mL water is added, is extracted with ethyl acetate (30mL × 2), merges organic phase, is dried, filtered with anhydrous sodium sulfate, filtrate subtracts Pressure concentration, with thin-layered chromatography with solvent system B purify obtained by residue, obtain title product N- (cyclopropyl methoxyl group) -7- Fluoro- 6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- formamide 16 (13mg, light tan solid), yield: 26.5%.
MS m/z(ESI):487.3[M+1]
1H NMR(400MHz,CDCl3)δ9.06(s,1H),7.56(s,1H),7.40-7.37(m,2H),6.48-6.44 (m,1H),4.77(t,2H),3.73(d,2H),2.89(t,2H),1.12-1.09(m,1H),0.58-0.55(m,2H),0.30- 0.27(m,2H)。
Embodiment 17
(R)-(the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- base) (the different evil of 4- hydroxyl Azoles -2- base) ketone
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid 1g (42mg, It 0.10mmol) is dissolved in 2mL n,N-Dimethylformamide, addition (R)-isoxazole -4- alcohol hydrochloride 17a (15mg, 0.12mmol, using well known method " Tetrahedron Letters, 2006,47 (43), 7635-7639 " are prepared), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (57mg, 0.15mmol) and N, N- diisopropyl Base ethamine (39mg, 0.30mmol) is stirred to react 4 hours.30mL water is added, is extracted, is associated with ethyl acetate (30mL × 2) Machine phase, is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, with silica gel column chromatography with remaining obtained by eluant, eluent system B Object obtains title product (R)-(the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- base) (4- hydroxyl Base isoxazole -2- base) ketone 17 (10mg, brown solid), yield: 20.4%.
MS m/z(ESI):489.2[M+1]
1H NMR(400MHz,CD3OD)δ7.38(d,1H),7.29-7.26(m,2H),6.50-6.45(m,1H),4.78- 4.71(m,3H),3.95-3.88(m,3H),3.69(d,1H),3.30(t,2H)。
Embodiment 18
(S)-(the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- base) (the different evil of 4- hydroxyl Azoles -2- base) ketone
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid 1g (42mg, It 0.10mmol) is dissolved in 2mL n,N-Dimethylformamide, addition (S)-isoxazole -4- alcohol hydrochloride 18a (15mg, 0.12mmol, using well known method " Tetrahedron Letters, 2006,47 (43), 7635-7639 " are prepared), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (57mg, 0.15mmol) and N, N- diisopropyl Base ethamine (39mg, 0.30mmol) is stirred to react 6 hours.35mL water is added, is extracted, is associated with ethyl acetate (30mL × 2) Machine phase, is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, with thin-layered chromatography with residue obtained by solvent system A, Obtaining title product (S)-(the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- base), (4- hydroxyl is different Oxazole -2- base) ketone 18 (19mg, off-white powder), yield: 38.8%.
MS m/z(ESI):489.3[M+1]
1H NMR(400MHz,CD3OD)δ7.38(d,1H),7.29-7.25(m,2H),6.50-6.45(m,1H),4.77- 4.71(m,3H),3.95-3.87(m,3H),3.69(d,1H),3.29(t,2H)。
Embodiment 19
1- (2,3- dihydroxypropyl)-N- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes - 5- yl) cyclopropane -1- sulfanilamide (SN)
The first step
The fluoro- 5- nitro -2,3- Dihydrobenzofuranes of 6,7- bis-
Fluoro- 2, the 3- Dihydrobenzofuranes 1d (350mg, 2.24mmol) of 6,7- bis- is dissolved in the 5mL concentrated sulfuric acid at 0 DEG C, It is added sodium nitrate (200mg, 2.35mmol), stirs 1 hour.Be added 20mL ice water and 20mL ethyl acetate, layering, organic phase according to Secondary to be washed with water (20mL × 2) and saturated sodium chloride solution (20mL × 2), anhydrous sodium sulfate dries, filters, and filtrate decompression is dense Contracting, obtains title product 6, fluoro- 5- nitro -2, the 3- Dihydrobenzofuranes 19a (450mg, red solid) of 7- bis-, yield 100%.
Second step
The fluoro- N- of 7- (the fluoro- 4- iodophenyl of 2-) -5- nitro -2,3- Dihydrobenzofuranes -6- amine
By fluoro- 5- nitro -2, the 3- Dihydrobenzofuranes 19a (450mg, 2.24mmol) of 6,7- bis- and the fluoro- 4- Iodoaniline of 2- (640mg, 2.70mmol) is dissolved in 5mL dimethyl sulfoxide, is added cesium carbonate (1.10g, 3.38mmol), 90 DEG C are stirred to react 2 hours.30mL water and 30mL ethyl acetate, layering, organic phase washed with water (20mL × 1) and saturated sodium chloride solution is added (20mL × 2) washing, anhydrous sodium sulfate dry, filter, and filtrate decompression concentration, obtaining the fluoro- N- of crude title product 7-, (2- is fluoro- 4- iodophenyl) -5- nitro -2,3- Dihydrobenzofuranes -6- amine 19b (0.94g, yellow solid), directly progress next step reaction.
Third step
The fluoro- N of 7-6(the fluoro- 4- iodophenyl of 2-) -2,3- Dihydrobenzofuranes -5,6- diamines
By the fluoro- N- of 7- (the fluoro- 4- iodophenyl of 2-) -5- nitro -2,3- Dihydrobenzofuranes -6- amine 19b (0.94g, It 2.25mmol) is dissolved in 5mL ether with stannous chloride dihydrate (1.52g, 6.75mmol), addition 2mL concentrated hydrochloric acid, 60 DEG C Stirring 2 hours.Reaction solution is cooled to room temperature, it is 7 that 1M sodium hydroxide solution, which is added dropwise, and adjusts pH, and 30mL water and 30mL acetic acid is added Ethyl ester, layering, organic phase washed with water (30mL × 1) and saturated sodium chloride solution (30mL × 2) washing, anhydrous sodium sulfate are dry It is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 7- Fluoro- N6(the fluoro- 4- iodophenyl of 2-) -2,3- Dihydrobenzofuranes -5,6- diamines 19c (0.30g, white powder), yield 34.5%.
MS m/z(ESI):389.0[M+1]
4th step
1- allyl-N- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- base) cyclopropyl Alkane -1- sulfanilamide (SN)
By the fluoro- N of 7-6(the fluoro- 4- iodophenyl of 2-) -2,3- Dihydrobenzofuranes -5,6- diamines 19c (75mg, 0.19mmol) With 1- allyl cyclopropane -1- sulfonic acid chloride 19d (75mg, 0.42mmol, using well known method " patent US20120136030A1 " is prepared) it is dissolved in 2mL pyridine, it is added 4-dimethylaminopyridine (2mg, 0.02mmol), stirs Mix reaction 16 hours.Reaction solution is poured into 20mL ice water, is extracted with ethyl acetate (20mL × 1), organic phase anhydrous slufuric acid Sodium dries, filters, filtrate decompression concentration, with thin-layered chromatography with solvent system B purify obtained by residue, obtain title product 1- allyl-N- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- base) cyclopropane -1- sulfanilamide (SN) 19e (60mg, yellow oil), yield: 58.3%.
5th step
1- (2,3- dihydroxypropyl)-N- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes - 5- yl) cyclopropane -1- sulfanilamide (SN)
By 1- allyl-N- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- base) cyclopropyl Alkane -1- sulfanilamide (SN) 19e (30mg, 0.06mmol) is dissolved in 2mL tetrahydrofuran, and 40 μ L, 4% osmium tetroxide solution is added dropwise, and is added 4- methyl morpholine nitrogen oxides (7mg, 0.06mmol) is stirred to react 16 hours.20mL saturated sodium chloride solution is added, uses acetic acid Ethyl ester (60mL × 1) extraction, organic phase are dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, with thin-layered chromatography to be unfolded Agent system B purifying gained residue, obtains title product 1- (2,3- dihydroxypropyl)-N- (the fluoro- 6- of 7- ((fluoro- 4- iodobenzene of 2- Base) amino) -2,3- Dihydrobenzofuranes -5- base) cyclopropane -1- sulfanilamide (SN) 19 (10mg, brown solid), yield: 31.3%.
MS m/z(ESI):567.3[M+1]
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.40-7.38(m,1H),7.25-7.23(m,1H),6.26- 6.23(m,1H),6.04(s,1H),4.72(t,2H),3.92-3.90(m,1H),3.57-3.54(m,1H),3.44-3.41(m, 1H),3.30(t,2H),2.10-2.05(m,2H),0.91-0.84(m,4H)。
Embodiment 20
5- (6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- base) -1,3,4- oxadiazoles -2- amine
The first step
2- (6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carbonyl) tert-butyl carbazate
6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid 7c (100mg, 0.25mmol) is molten Tert-butyl carbazate (70mg, 0.53mmol) and 1H- benzotriazole -1- is added in 2mL n,N-Dimethylformamide in solution Base oxygen tripyrrole alkyl hexafluorophosphate (195mg, 0.38mmol) is stirred to react 2 hours.20mL water and 20mL acetic acid second is added Ester, layering, organic phase washed with water (20mL × 1) and saturated sodium chloride solution (20mL × 2) washing, anhydrous sodium sulfate is dry, Filtering, filtrate decompression concentration, obtains title product 2- (6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- Carbonyl) tert-butyl carbazate 20a (80mg, yellow oil), yield: 66.7%.
MS m/z(ESI):512.0[M-1]
Second step
6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carbohydrazide
By 2- (6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carbonyl) tert-butyl carbazate 20a (80mg, 0.16mmol) is dissolved in 5mL methylene chloride, and 1mL trifluoroacetic acid is added, is stirred to react 3 hours.20mL is added Water and 20mL ethyl acetate, layering, organic phase washed with water (20mL × 1) and saturated sodium chloride solution (20mL × 2) washing, nothing Aqueous sodium persulfate dries, filters, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by residue, marked Product 6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carbohydrazide 20b (30mg, black solid) is inscribed, is produced Rate 45.4%.
MS m/z(ESI):414.0[M+1]
Third step
5- (6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- base) -1,3,4- oxadiazoles -2- amine
By 6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carbohydrazide 20b (30mg, 0.07mmol) It is dissolved in 5mL dioxane, sequentially adds bromine cyanogen (10mg, 0.09mmol), sodium bicarbonate (7mg, 0.08mmol) and 5mL Water, 60 DEG C are stirred to react 1 hour.Be added 10mL water and 10mL ethyl acetate, layering, organic phase washed with water (20mL × 1) and Saturated sodium chloride solution (20mL × 2) washing, anhydrous sodium sulfate dry, filter, filtrate decompression concentration, with thin-layered chromatography to open up Agent system A purifying gained residue is opened, title product 5- (6- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- dihydrobenzo furan is obtained Mutter -5- base) -1,3,4- oxadiazoles -2- amine 20 (15mg, white solid), yield 47.2%.
MS m/z(ESI):439.0[M+1]
1H NMR(400MHz,CDCl3)δ9.16(s,1H),7.52(s,1H),7.48(d,1H),7.41(d,1H),7.21 (t,1H),6.58(s,1H),4.97(s,2H),4.62(t,2H),3.20-3.16(m,2H)。
Embodiment 21
5- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- base) -1,3,4- oxadiazoles - 2- amine
The first step
2- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carbonyl) tertiary fourth of carbazic acid Ester
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carboxylic acid 1g (150mg, It 0.36mmol) is dissolved in 3mL n,N-Dimethylformamide, tert-butyl carbazate (57mg, 0.43mmol), 2- (7- is added Azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (205mg, 0.54mmol) and N, N- diisopropyl second Amine (139mg, 1.08mmol) is stirred to react 3 hours.40mL ethyl acetate is added, is washed with saturated sodium chloride solution (40mL × 1) Wash, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify gained remnants Object obtains title product 2- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carbonyl) diazanyl first Tert-butyl acrylate 21a (168mg, brown solid), yield: 87.9%.
MS m/z(ESI):529.9[M-1]
Second step
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carbohydrazide
By 2- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carbonyl) carbazic acid uncle Butyl ester 21a (168mg, 0.32mmol) is dissolved in 5mL methanol, and 1mL is added and is saturated methanol hydrochloride solution, is stirred at room temperature 2 hours, Stop reaction.Reaction solution is concentrated under reduced pressure, the fluoro- 6- of crude product 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- dihydrobenzo furan is obtained It mutters -5- carbohydrazide 21b (140mg, white solid), is directly used in and reacts in next step.
Third step
5- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- base) -1,3,4- oxadiazoles - 2- amine
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carbohydrazide 21b (140mg, 0.32mmol) be dissolved in the mixed solution of 8mL dioxane and water (V/V=1:1), sequentially add bromine cyanogen (37mg, 0.36mmol) with sodium bicarbonate (7mg, 0.36mmol), 60 DEG C are stirred to react 1 hour.40mL water is added, uses ethyl acetate (40mL × 2) extraction, merge organic phase, dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, with silica gel column chromatography with Eluant, eluent system B purifying gained residue, obtains title product 5- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- bis- Hydrogen benzofuran -5- base) -1,3,4- oxadiazoles -2- amine 21 (60mg, white solid), yield 40.5%.
MS m/z(ESI):457.1[M+1]
Embodiment 22
((5- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- coumaran -5- base) -1,3,4- dislikes two to 2- Azoles -2- base) amino) ethyl alcohol
The first step
5- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- coumaran -5- base) -1,3,4- oxadiazoles -2 (3H) -one
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- Dihydrobenzofuranes -5- carbohydrazide 21b (120mg, It 0.26mmol) is dissolved in 5mL n,N-Dimethylformamide, N, N'- carbonyl dimidazoles (243mg, 1.50mmol) and N, N- is added Reaction 16 hours is stirred at room temperature in diisopropylethylamine (483mg, 3.75mmol).Be added 30mL water, with ethyl acetate (30mL × 2), dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify gained remnants Object obtains title product 5- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- coumaran -5- base) -1,3,4- (3H) -one of oxadiazoles -2 22a (120mg, yellow-brown solid), yield: 35.1%.
MS m/z(ESI):455.9[M-1]
Second step
2- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- coumaran -5- carbonyl)-N- (2- ethoxy) Semicarbazides
5- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- coumaran -5- base) -1,3,4- is disliked two (3H) the -one 22a of azoles -2 (120mg, 0.26mmol) and 2 hydroxy ethylamine (48mg, 0.78mmol) are dissolved in 10mL ethyl alcohol, heating It is stirred to react 16 hours to 100 DEG C, stops reaction.Reaction solution is concentrated under reduced pressure, crude title product 2- (the fluoro- 6- of 7- is obtained ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- coumaran -5- carbonyl)-N- (2- ethoxy) semicarbazides 22b (129mg, palm fibre Brown solid), it is directly used in and reacts in next step.
MS m/z(ESI):519.1[M+1]
Third step
((5- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- coumaran -5- base) -1,3,4- dislikes two to 2- Azoles -2- base) amino) ethyl alcohol
By crude material 2- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- coumaran -5- carbonyl)-N- (2- ethoxy) semicarbazides 22b (129mg, 0.25mmol) is dissolved in 30mL methylene chloride, sequentially adds triphenylphosphine It is anti-to be heated to reflux for (98mg, 0.37mmol), triethylamine (51mg, 0.50mmol) and carbon tetrachloride (154mg, 1.00mmol) It answers 6 hours, stops reaction.Reaction solution is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, obtain To title product 2-, ((5- (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) -2,3- coumaran -5- base) -1,3,4- is disliked Diazole -2- base) amino) ethyl alcohol 22 (13mg, brown-red solid), yield 10.0%.
MS m/z(ESI):501.2[M+1]
1H NMR(400MHz,CD3OD)δ7.96(s,1H),7.45(s,1H),7.40(d,1H),7.30(d,1H),6.58- 6.55(m,1H),4.75(t,2H),3.72(t,2H),3.41(t,2H),3.32(t,2H)。
Embodiment 23
6- ((the bromo- 2- chlorphenyl of 4-) amino)-N- (2- hydroxyl-oxethyl) -2,3- Dihydrobenzofuranes -5- formamide
The first step
6- ((the bromo- 2- chlorphenyl of 4-) amino) -2,3- coumaran -5- carboxylic acid
By fluoro- 2, the 3- Dihydrobenzofuranes -5- carboxylic acid 7b (50mg, 0.27mmol) of 6-, the bromo- 2- chloroaniline of 4- (68mg, 0.33mmol), lithium amide (34mg, 1.38mmol) is added in reaction flask, and nitrogen is replaced three times, and 1mL tetrahydrofuran, microwave is added 80 DEG C are reacted 1 hour.Reaction solution is cooled to room temperature, is poured into 40mL ice water, it is 1~2 that 1M salt acid for adjusting pH, which is added dropwise, uses acetic acid Ethyl ester (40mL × 3) extraction, merges organic phase, is dried, filtered with anhydrous sodium sulfate, and thin-layered chromatography is used in filtrate decompression concentration Gained residue is purified with solvent system B, obtains title product 6- ((the bromo- 2- chlorphenyl of 4-) amino) -2,3- benzo dihydro Furans -5- carboxylic acid 23a (20mg, yellow solid), yield 19.8%.
MS m/z(ESI):367.9[M+1]
Second step
6- ((the bromo- 2- chlorphenyl of 4-) amino)-N- (2- (ethyleneoxy) ethyoxyl) -2,3- coumaran -5- first Amide
By 6- ((the bromo- 2- chlorphenyl of 4-) amino) -2,3- coumaran -5- carboxylic acid 23a (20mg, 0.05mmol), I-hydroxybenzotriazole (11mg, 0.08mmol), 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (16mg, It 0.08mmol) is dissolved in 1mL n,N-Dimethylformamide, is stirred 20 minutes at 0 DEG C, O- (2- (ethyleneoxy) second is added Base) azanol (11mg, 0.11mmol), triethylamine (13mg, 0.13mmol), it is warmed to room temperature, is stirred to react 12 hours naturally, stop Reaction.3mL saturated sodium chloride solution is added, is extracted with ethyl acetate (10mL × 3), merges organic phase, it is dry with anhydrous sodium sulfate Dry, filtering, filtrate decompression concentration obtains crude title product 6- ((the bromo- 2- chlorphenyl of 4-) amino)-N- (2- (ethyleneoxy) Ethyoxyl) -2,3- coumaran -5- formamide 23b (19mg, yellow solid), it is directly used in and reacts in next step.
MS m/z(ESI):451.0[M-1]
Third step
6- ((the bromo- 2- chlorphenyl of 4-) amino)-N- (2- hydroxyl-oxethyl) -2,3- Dihydrobenzofuranes -5- formamide
By 6- ((the bromo- 2- chlorphenyl of 4-) amino)-N- (2- (ethyleneoxy) ethyoxyl) -2,3- coumaran -5- Formamide 23b (19mg, 0.04mmol) is dissolved in 1mL ethyl alcohol, and 0.2mL1M hydrochloric acid is added at 0 DEG C, is warmed to room temperature, stirs naturally Mix reaction 2 hours.2mL saturated sodium bicarbonate is added at 0 DEG C, is extracted with ethyl acetate (20mL × 3), merges organic phase, with nothing Aqueous sodium persulfate dries, filters, filtrate decompression concentration, with thin-layered chromatography with solvent system B purify obtained by residue, marked Inscribe product 6- ((the bromo- 2- chlorphenyl of 4-) amino)-N- (2- hydroxyl-oxethyl) -2,3- Dihydrobenzofuranes -5- formamide 23 (5mg, white solid), yield 29.6%.MS m/z(ESI):427.1[M+1]
1H NMR(400MHz,CDCl3)δ9.31(s,1H),8.72(s,1H),7.56(s,1H),7.30(d,1H),7.26 (s,1H),6.65(s,1H),4.62(t,3H),4.06-4.04(m,2H),3.78-3.77(m,2H),3.15(t,3H)。
Embodiment 24
The fluoro- 7- of 8- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- hydroxyl-oxethyl) benzodihydropyran -6- formamide
The first step
7,8- difluoro benzodihydropyran -6- formaldehyde
By 7,8- difluoro benzodihydropyran 24a (190mg, 1.12mmol, using well known method " patent WO2009068152 " is prepared) it is dissolved in 10mL methylene chloride, ice-water bath is cooled to 0 DEG C, and titanium tetrachloride is added (338mg, 1.79mmol) is stirred 5 minutes, 1,1- dichlormethyl ether (192mg, 1.67mmol) is slowly added dropwise, is added dropwise, rises to It is stirred at room temperature 12 hours.20mL ice water quenching reaction is added, is extracted with methylene chloride (25mL × 2), organic phase is collected, with saturation Sodium chloride solution (30mL × 1) washing, is dried, filtered with anhydrous sodium sulfate, and filtrate decompression concentration obtains crude title product 7, 8- difluoro benzodihydropyran -6- formaldehyde 24b (230mg, yellow oil) is directly used in and reacts in next step.
Second step
7,8- difluoro benzodihydropyran -6- carboxylic acid
By crude product 7,8- difluoro benzodihydropyran -6- formaldehyde 24b (230mg, 1.12mmol) is dissolved in the 12mL tert-butyl alcohol In the mixed solution of water (V/V=3:1), sequentially add iso-amylene (705mg, 10.08mmol), sodium dihydrogen phosphate (786mg, 5.04mmol) with sodium chlorite (202mg, 2.24mmol), it is stirred to react 4 hours.30mL water is added, with ethyl acetate (25mL × 2) it extracts, merges organic phase, washed, dried, filtered with anhydrous sodium sulfate, filtrate with saturated sodium chloride solution (30mL × 1) It is concentrated under reduced pressure, obtains title product 7,8- difluoro benzodihydropyran -6- carboxylic acid 24c (220mg, yellow solid), yield 88.7%.
Third step
The fluoro- 7- of 8- ((the fluoro- 4- iodophenyl of 2-) amino) benzodihydropyran -6- carboxylic acid
By the fluoro- 4- Iodoaniline of 7,8- difluoro benzodihydropyran -6- carboxylic acid 24c (220mg, 1.03mmol), 2- (268mg, 1.13mmol), lithium amide (64mg, 2.56mmol) and 4mL tetrahydrofuran are added in reaction flask, and 90 DEG C of microwave are reacted 80 minutes. Reaction solution is cooled to room temperature, 50mL ethyl acetate is added, solution successively uses 1M hydrochloric acid (20mL × 1), saturated sodium chloride solution (40mL × 1) washing, is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B Purifying gained residue, obtains the fluoro- 7- of title product 8- ((the fluoro- 4- iodophenyl of 2-) amino) benzodihydropyran -6- carboxylic acid 24d (250mg, brown solid), yield 58.0%.
MS m/z(ESI):430.0[M-1]
4th step
The fluoro- 7- of 8- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- (ethyleneoxy) ethyoxyl) benzodihydropyran -6- first Amide
By the fluoro- 7- of 8- ((the fluoro- 4- iodophenyl of 2-) amino) benzodihydropyran -6- carboxylic acid 24d (50mg, 0.116mmol) It is dissolved in 2mL n,N-Dimethylformamide with O- (2- (ethyleneoxy) ethyl) azanol (14mg, 0.14mmol), adds at 0 DEG C Enter n,N-diisopropylethylamine (37mg, 0.29mmol) and 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea six Fluorophosphoric acid ester (66mg, 0.17mmol) is warmed to room temperature and is stirred to react 12 hours.30mL water is added, with ethyl acetate (25mL × 2) Extraction merges organic phase, is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, with thin-layered chromatography with solvent system B Purifying gained residue, obtains the fluoro- 7- of title product 8- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- (ethyleneoxy) ethoxy Base) benzodihydropyran -6- formamide 24e (35mg, white solid), yield: 58.3%.
MS m/z(ESI):515.1[M-1]
5th step
The fluoro- 7- of 8- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- hydroxyl-oxethyl) benzodihydropyran -6- formamide
By the fluoro- 7- of 8- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- (ethyleneoxy) ethyoxyl) benzodihydropyran -6- Formamide 24e (35mg, 0.07mmol) is dissolved in 2mL methanol, and 1mL 1M hydrochloric acid is added, is stirred to react 4 hours.Reaction solution subtracts Pressure concentration, with thin-layered chromatography with solvent system A purify obtained by residue, obtain the fluoro- 7- of title product 8- ((the fluoro- 4- iodine of 2- Phenyl) amino)-N- (2- hydroxyl-oxethyl) benzodihydropyran -6- formamide 24 (10mg, white solid), yield 30.3%.
MS m/z(ESI):491.2[M+1]
1H NMR(400MHz,CDCl3)δ9.72(brs,1H),7.42-7.39(m,2H),7.26-7.24(s,1H),6.86 (br,1H),6.41-6.36(m,1H),4.37-4.31(m,2H),3.93-3.91(m,2H),3.67-3.65(m,2H),2.83- 2.81(m,2H),2.08-2.04(m,2H)。
Embodiment 25
(R)-N- (2,3- dihydroxy propoxyl group) fluoro- 7- of -8- ((the fluoro- 4- iodophenyl of 2-) amino) benzodihydropyran -6- Formamide
The first step
(R)-N- ((2,2- dimethyl -1,3- dioxole -4- base) methoxyl group) the fluoro- 7- of -8- ((the fluoro- 4- iodine of 2- Phenyl) amino) benzodihydropyran -6- formamide
By the fluoro- 7- of 8- ((the fluoro- 4- iodophenyl of 2-) amino) benzodihydropyran -6- carboxylic acid 24d (50mg, 0.12mmol) and (R)-O- ((2,2- dimethyl -1,3- dioxole -4- base) methyl) azanol 1i (16mg, 0.11mmol) is dissolved in In 3mL n,N-Dimethylformamide, n,N-diisopropylethylamine (37mg, 0.29mmol), 2- (three nitrogen of 7- azo benzo is added Azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (66mg, 0.17mmol) is stirred to react 12 hours.20mL water is added, uses Ethyl acetate (30mL × 2) extraction, is dried, filtered with anhydrous sodium sulfate, and filtrate decompression concentration obtains crude title product (R)- N- ((2,2- dimethyl -1,3- dioxole -4- base) methoxyl group) the fluoro- 7- of -8- ((the fluoro- 4- iodophenyl of 2-) amino) benzene And dihydropyran -6- formamide 25a (45mg, brown oil), it is directly used in and reacts in next step.
MS m/z(ESI):561.1[M+1]
Second step
(R)-N- (2,3- dihydroxy propoxyl group) fluoro- 7- of -8- ((the fluoro- 4- iodophenyl of 2-) amino) benzodihydropyran -6- Formamide
By crude product (R)-N- ((2,2- dimethyl -1,3- dioxole -4- base) methoxyl group) fluoro- the 7- ((2- of -8- Fluoro- 4- iodophenyl) amino) benzodihydropyran -6- formamide 25a (30mg, 0.06mmol) is dissolved in 3mL methanol, it is added 2mL 1M hydrochloric acid is stirred to react 4 hours.Reaction solution be concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained remnants Object obtains title product (R)-N- (2,3- dihydroxy propoxyl group) fluoro- 7- of -8- ((the fluoro- 4- iodophenyl of 2-) amino) benzo dihydro Pyrans -6- formamide 25 (8mg, white solid), yield: 28.6%.
MS m/z(ESI):521.2[M+1]
1H NMR(400MHz,CDCl3)δ9.87(br,1H),7.45-7.41(m,2H),7.27-7.26(m,1H),6.71 (brs,1H),6.36-6.41(m,1H),4.34-4.31(m,2H),3.89-3.68(m,5H),3.59-3.65(m,1H),3.53 (m,1H),2.86-2.83(m,2H),2.09-2.06(m,2H)。
Embodiment 26
(R) two between-N- (2,3- dihydroxy propoxyl group) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] Oxole -5- formamide
The first step
4,5- difluoro benzo [d] [1,3] dioxole
Successively by 3,4- bis- fluoro- 1,2- benzenediol 26a (900mg, 6.16mmol, using well known method " FEMS Microbiology Letters, 1999,181 (1), 73-82 " are prepared), methylene bromide (1.60g, 9.24mmol) and carbon Sour caesium (3.01g, 9.24mmol) is dissolved in 10mL n,N-Dimethylformamide, is heated to 110 DEG C, is stirred to react 2 hours. Reaction solution is cooled to room temperature, 50mL ethyl acetate, filtering, filtrate water (50mL × 1) washing, water phase ethyl acetate is added (50mL × 1) extraction, merge organic phase, dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, with silica gel column chromatography with Eluant, eluent system B purifying gained residue, obtains title product 4,5- difluoro benzo [d] [1,3] dioxole 26b (280mg, light yellow oil), yield: 28.7%.
Second step
6,7- difluoro benzo [d] [1,3] dioxole -5- formaldehyde
4,5- difluoro benzo [d] [1,3] dioxole 26b (280mg, 1.77mmol) is dissolved in 10mL dichloro In methane, titanium tetrachloride (535mg, 2.83mmol) is added at 0 DEG C, stirs 5 minutes, addition 1,1- dichlormethyl ether (305mg, 2.65mmol), it is warmed to room temperature and is stirred to react 12 hours.30g ice water quenching reaction is added, is extracted with methylene chloride (30mL × 2), Merge organic phase, dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration is purified with silica gel column chromatography with eluant, eluent system B Gained residue, obtains title product 6, and 7- difluoro benzo [d] [1,3] dioxole -5- formaldehyde 26c (140mg, it is white Color solid), yield: 42.5%.
Third step
6,7- difluoro benzo [d] [1,3] dioxole -5- carboxylic acid
6,7- difluoro benzo [d] [1,3] dioxole -5- formaldehyde 26c (140mg, 0.75mmol) is dissolved in The in the mixed solvent of the 5mL tert-butyl alcohol and water (V/V=3:1) sequentially adds 2- methyl-2-butene (472mg, 6.75mmol), phosphorus Acid dihydride sodium (526mg, 3.38mmol) and sodium chlorite (135mg, 1.50mmol), are stirred to react 4 hours.20mL water is added, 1M hydrochloric acid solution is added dropwise and adjusts pH < 7, is extracted with ethyl acetate (30mL × 2), merges organic phase, mistake dry with anhydrous sodium sulfate Filter, filtrate decompression distillation, obtains title product 6,7- difluoro benzo [d] [1,3] dioxole -5- carboxylic acid 26d (150mg, white solid), yield 98.6%.
4th step
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- carboxylic acid
6,7- difluoro benzo [d] [1,3] dioxole -5- carboxylic acid 26d (150mg, 0.25mmol), 2- is fluoro- 4- Iodoaniline (64mg, 0.27mmol) and lithium amide (16mg, 0.62mmol) are added in reaction flask, and 6mL tetrahydrofuran, nitrogen is added Gas is replaced three times, and 90 DEG C of microwave are reacted 75 minutes.LC-MS display reaction does not carry out, adds lithium amide (16mg, 0.62mmol), 100 DEG C of microwave are reacted 1.5 hours.Reaction solution is cooled to room temperature, 30mL water is added, 1M salt acid for adjusting pH < 7 are added dropwise, use acetic acid Ethyl ester (30mL × 3) extraction, merges organic phase, is dried, filtered with anhydrous sodium sulfate, and silica gel column chromatography is used in filtrate decompression concentration Method purifies gained residue with eluant, eluent system B, obtains the fluoro- 6- of title product 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- carboxylic acid 26e (61mg, brown solid), yield 19.6%.
5th step
(R)-N- ((2,2- dimethyl -1,3- dioxolane -4- base) methoxyl group) the fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) Amino) benzo [d] [1,3] dioxole -5- formamide
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- carboxylic acid 26e (30mg, 0.07mmol) and (R)-O- ((2,2- dimethyl -1,3- dioxole -4- base) methyl) azanol 1i (12mg, It 0.08mmol) is dissolved in 2mL n,N-Dimethylformamide, n,N-diisopropylethylamine (28mg, 0.22mmol) and 2- is added (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (41mg, 0.11mmol) are stirred to react 4 hours. 30mL water is added, is extracted with ethyl acetate (30mL × 2), merges organic phase, is dried, filtered with anhydrous sodium sulfate, filtrate decompression Concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product (R)-N- ((2,2- diformazans Base -1,3- dioxolane -4- base) methoxyl group) dioxa between the fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] Cyclopentene -5- formamide 26f (45mg, brown oil), yield: 51.2%.
MS m/z(ESI):549.0[M+1]
6th step
(R) two between-N- (2,3- dihydroxy propoxyl group) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] Oxole -5- formamide
By (R)-N- ((2,2- dimethyl -1,3- dioxolane -4- base) methoxyl group) the fluoro- 6- of -7- ((the fluoro- 4- iodobenzene of 2- Base) amino) benzo [d] [1,3] dioxole -5- formamide 26f (20mg, 0.04mmol) is dissolved in 2mL methanol, 1mL 1M hydrochloric acid is added, is stirred to react 3 hours.Reaction solution is concentrated under reduced pressure, and purifies institute with silica gel column chromatography with eluant, eluent system A Residue, obtain crude product 30mg, with thin-layered chromatography with solvent system A purify obtained by crude product, obtain title product (R)- N- (2,3- dihydroxy propoxyl group) fluoro- 6- of -7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole - 5- formamide 26 (4mg, brown solid), yield: 22.2%.
MS m/z(ESI):509.0[M+1]
1H NMR(400MHz,CD3OD)δ7.40(d,1H),7.28(d,1H),6.96(s,1H),6.43-6.38(m,1H), 6.14(s,2H),3.92-3.90(m,1H),3.83-3.79(m,2H),3.57-3.53(m,2H)。
Embodiment 27
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- hydroxyl-oxethyl) benzo [d] [1,3] Dloxole Alkene -5- formamide
The first step
Dioxy between the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- (ethyleneoxy) ethyoxyl) benzo [d] [1,3] Heterocyclic pentene -5- formamide
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- carboxylic acid 26e (100mg, 0.24mmol), O- (2- (ethyleneoxy) ethyl) azanol (26mg, 0.26mmol), 2- (three nitrogen of 7- azo benzo Azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (140mg, 0.36mmol) is dissolved in 5mL n,N-Dimethylformamide, It is added n,N-diisopropylethylamine (93mg, 0.72mmol), reaction 3 hours is stirred at room temperature.20mL water is added, uses ethyl acetate (20mL × 1) extraction, organic phase washed with water (20mL × 1) and saturated sodium chloride solution (20mL × 2) washing, use anhydrous slufuric acid Sodium dries, filters, filtrate decompression concentration, with thin-layered chromatography with solvent system B purify obtained by residue, obtain title product The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- (ethyleneoxy) ethyoxyl) benzo [d] [1,3] Dloxole Alkene -5- formamide 27a (80mg, black solid), yield: 66.7%.
MS m/z(ESI):502.9[M-1]
Second step
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- hydroxyl-oxethyl) benzo [d] [1,3] Dloxole Alkene -5- formamide
It will be two between the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- (ethyleneoxy) ethyoxyl) benzo [d] [1,3] Oxole -5- formamide 27a (80mg, 0.07mmol) is dissolved in 10mL methanol, and 5mL 1M hydrochloric acid is added, is stirred to react 3 hours.20mL water, filtering are added in reaction solution, filter cake water (20mL × 1), ethyl acetate (20mL × 2) wash, and dry, obtain To dioxane between the fluoro- 6- of title product 7- ((the fluoro- 4- iodophenyl of 2-) amino)-N- (2- hydroxyl-oxethyl) benzo [d] [1,3] Amylene -5- formamide 27 (25mg, white solid), yield 78.1%.MS m/z(ESI):479.2[M+1]
1H NMR(400MHz,CD3OD)δ11.7(s,1H),8.21(s,1H),7.53-7.50(m,1H),7.30-7.28 (m,1H),7.03(s,1H),6.42-6.40(m,1H),6.21(s,2H),4.71(t,1H),3.80(t,2H),3.53-3.51 (m,2H)。
Embodiment 28
(R)-(the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- base) (2- (methylol) pyrrolidin-1-yl) ketone
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- carboxylic acid 26e (50mg, 0.12mmol), D- prolinol (13mg, 0.13mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethyl Urea hexafluorophosphoric acid ester (70mg, 0.18mmol) and n,N-diisopropylethylamine (46mg, 0.36mmol) are dissolved in 10mL N, N- bis- In methylformamide, it is stirred to react 3 hours.20mL water is added, is extracted with ethyl acetate (20mL × 1), organic phase washed with water The washing of (20mL × 1) and saturated sodium chloride solution (20mL × 2), is dried, filtered with anhydrous sodium sulfate, and filtrate decompression concentration is used Thin-layered chromatography purifies gained residue with solvent system B, obtains title product (R)-(the fluoro- 6- of 7- ((the fluoro- 4- iodobenzene of 2- Base) amino) benzo [d] [1,3] dioxole -5- base) (2- (methylol) pyrrolidin-1-yl) ketone 28 (10mg, it is black Color solid), yield: 16.7%.
MS m/z(ESI):503.2[M+1]
1H NMR(400MHz,CDCl3)δ7.37-7.35(m,1H),7.27-7.25(m,1H),6.70(s,1H),6.49- 6.45(m,1H),6.33(brs,1H),6.10(s,2H),4.22-4.15(m,2H),3.72-3.69(m,1H),3.53-3.51 (m,1H),3.49-3.38(m,2H),2.25-2.06(m,2H),1.82-1.78(m,2H)。
Embodiment 29
(R)-(the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- base) (4- Hydroxyl isoxazole -2- base) ketone
The first step
(R)-(the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- base) (4- Hydroxyl isoxazole -2- base) ketone
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- carboxylic acid 26e (50mg, 0.12mmol), (R)-isoxazole -4- alcohol hydrochloride 17a (17mg, 0.13mmol), 2- (7- azo benzotriazole) - N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (70mg, 0.18mmol), n,N-diisopropylethylamine (50mg, 0.36mmol) are molten Reaction 3 hours is stirred at room temperature in 10mL n,N-Dimethylformamide in solution.20mL water is added, with ethyl acetate (20mL × 1) Extraction, organic phase water (20mL × 1), saturated sodium chloride solution (20mL × 2) are washed, are dried, filtered with anhydrous sodium sulfate, are filtered Liquid be concentrated under reduced pressure, with thin-layered chromatography with solvent system B purify obtained by residue, obtain title product (R)-(the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- base) (4- hydroxyl isoxazole -2- base) ketone 29 (20mg, pink solids), yield: 33.3%.
MS m/z(ESI):491.2[M+1]
1H NMR(400MHz,DMSO-d6)δ7.55(s,1H),7.48-7.45(m,1H),7.27-7.25(m,1H), 6.37-6.35(m,1H),6.21(s,2H),5.58(d,1H),4.61(brs,1H),3.81-3.73(m,3H),3.46(d, 1H)。
Embodiment 30
(the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- base) (4- methyl Piperazine -1- base) ketone
The first step
(the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- base) (4- methyl Piperazine -1- base) ketone
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- carboxylic acid 26e (100mg, 0.24mmol), N methyl piperazine (26mg, 0.26mmol) are dissolved in 10mL n,N-Dimethylformamide, are added 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (140mg, 0.36mmol) and N, N- diisopropyl Base ethamine (93mg, 0.72mmol) is stirred to react 3 hours.20mL water is added, is extracted with ethyl acetate (20mL × 1), organic phase It is successively washed, is dried, filtered with anhydrous sodium sulfate, filtrate decompression with water (20mL × 1) and saturated sodium chloride solution (20mL × 2) Concentration, with thin-layered chromatography with solvent system B purify obtained by residue, obtain title product (the fluoro- 6- of 7- ((the fluoro- 4- iodine of 2- Phenyl) amino) benzo [d] [1,3] dioxole -5- base) (4- methylpiperazine-1-yl) ketone 30 (10mg, pink Solid), yield: 8.3%.
MS m/z(ESI):500.2[M-1]
1H NMR(400MHz,CDCl3)δ7.37-7.34(m,1H),7.25-7.22(m,1H),6.61(s,1H),6.44- 6.39(m,1H),6.10(s,2H),6.03-5.97(m,1H),3.62-3.34(m,8H),2.23(s,3H)。
Embodiment 31
(the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- base) (5- methyl - 1H- imidazoles -2- base) ketone
The first step
The fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- acyl chlorides
By the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- carboxylic acid 26e (50mg, 0.12mmol) is dissolved in 3mL toluene, and thionyl chloride (19mg, 0.14mmol) and 1 drop N, N- dimethyl formyl is added dropwise Amine is warming up to 60 DEG C, reacts 2 hours.Vacuum distillation, obtains the fluoro- 6- of crude title product 7- ((the fluoro- 4- iodophenyl of 2-) amino) Benzo [d] [1,3] dioxole -5- acyl chlorides 31a (55mg, black solid) is directly used in next step.
Second step
(the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- base) (5- methyl - 1- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -1H- imidazoles -2- base) ketone
By 5- methyl-1-((2- (trimethyl silicon substrate) ethyoxyl) methyl)-1H- imidazoles 31b, (25mg, 0.12mmol are used Well known method " Journal of Organic Chemistry, 1986,51 (10), 1891-4 " are prepared) it is dissolved in 2mL tetra- In hydrogen furans, n-BuLi (0.1mL, 0.15mmol) is added dropwise at -78 DEG C, is stirred to react 20 minutes, it is fluoro- that 1mL crude product 7- is added 6- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- acyl chlorides 31a's (55mg, 0.12mmol) Tetrahydrofuran solution is warmed to room temperature, and is stirred 20 minutes.5mL water quenching reaction is added, is extracted with ethyl acetate (20mL × 3), closes And organic phase, dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, purify with thin-layered chromatography with solvent system B obtained by Residue obtains title product (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- Base) (5- methyl-1-((2- (trimethyl silicon substrate) ethyoxyl) methyl)-1H- imidazoles-2- base) ketone 31c (5mg, yellow oily Object), yield: 7.2%.
MS m/z(ESI):614.2[M+1]
Third step
(the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- base) (5- methyl - 1H- imidazoles -2- base) ketone
By (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) amino) benzo [d] [1,3] dioxole -5- base) (5- first Base -1- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -1H- imidazoles -2- base) ketone 31c (5mg, 0.01mmol) is dissolved in 2mL In ethyl alcohol, 2mL 4M hydrochloric acid is added, is heated to 60 DEG C, is stirred to react 3 hours.5mL water is added in reaction solution, sodium bicarbonate is added dropwise It is 9~10 that solution, which adjusts pH, is extracted with ethyl acetate (20mL × 3), is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, With thin-layered chromatography with solvent system B purify gained residue, obtain title product (the fluoro- 6- of 7- ((the fluoro- 4- iodophenyl of 2-) Amino) benzo [d] [1,3] dioxole -5- base) (5- methyl-1 H- imidazoles -2- base) (1.2mg, yellow are solid for ketone 31 Body), yield 30.7%.
MS m/z(ESI):484.0[M+1]
Test case:
Biological assessment
The measurement of test case 1, the compounds of this invention to MEK kinase activity
External MEK kinase activity is tested by the following method.
The MEK kinases that this experiment uses: MEK 1 (Recombinant Human Protein, Invitrogen, article No. PV3093)。
Use kit: Z'-LYTETMKinase Assay Kit-Ser/Thr 03Peptide (Invitrogen, goods Number PV3176).
In vitro cell experiment as described below can measure test-compound to the proliferation inhibition activity of MEK kinases, testization It closes object and dimethyl sulfoxide is dissolved according to concentration needed for testing, be made into compound DMSO solution, concentration are as follows: 100 μM, 50 μM, 25 μ M、12.5μM、6.25μM、3.125μM、1.5625μM、0.78125μM、0.390625μM、0.1953125μM、0.09765625μ M and 0.048828125 μM.It prepares 1 × Buffer A (Invitrogen, article No. PV3189)；ATP is diluted with 1 × Buffer A 400 μM of ATP solution are obtained, by appropriate Z'-LYTETMSer/Thr 03Peptide (Invitrogen, article No. PV3200), MEK Kinases (MEK1) enzyme is mixed with 1 × Buffer A；Appropriate Z'-LYTETMSer/Thr 03phosphoPeptide substrate It is stand-by that (Invitrogen, article No. PV3215) and 1 × Buffer A are made into mixed liquor, test compound DMSO solution with 1 × delay Fliud flushing is configured to the compound solution of 4%DMSO, in reacting hole plus 2.5 μ L test compound DMSO solution with 1 × Buffer A, 2.5 400 μM of μ L ATP solution and 5 μ L enzymes and Substrate cocktail become 10 μ L reaction systems, and 37 DEG C are incubated for 4 hours Afterwards, mixed liquor is prepared according to Reagent A:Buffer B=1:1024,5 μ L Reagent A is added in reacting hole The mixed liquor of (Invitrogen, article No. PV3295) and Buffer B (Invitrogen, article No. P3127), 25 DEG C of incubation 60min Afterwards, fluorescence, excitation wavelength: 400nm, launch wavelength: 445nm and 520nm are read using NovoStar microplate reader.
The activity of the compounds of this invention: the biochemical inhibitory activity of the MEK kinases (MEK 1) of the compounds of this invention passes through above Test is measured, the IC measured50Value is shown in Table 1.
Inhibitory activity of 1 the compounds of this invention of table to MEK kinases (MEK 1)
Embodiment number Mek1
1 1.01
2 3.48
3 1.74
4 29.76
5 5.66
6 7.62
7 62.82
8 5.67
9 21.47
13 6.96
14 6.01
15 11.65
16 83.69
26 13.86
27 82.86
Conclusion: the compounds of this invention significantly inhibits 1 kinase activity of MEK.
Test case 2, the compounds of this invention measure the Proliferation Ability of MEK2 kinases
External MEK2 kinase activity is tested by the following method.
The MEK kinases that this experiment uses:
MAP2K2 (MEK2) Recombinant Human Protein (Invitrogen, Catalog No.PV3615)
MAPK1 (ERK2) Recombinant Human Protein (Invitrogen, Catalog No.PV3314)
The kit that this experiment uses: Z'-LYTETM Kinase Assay Kit-Ser/Thr 03Peptide (Invitrogen, article No. PV3176).
In vitro cell experiment as described below can measure test-compound to the proliferation inhibition activity of MEK kinases, testization It closes object and dimethyl sulfoxide is dissolved according to concentration needed for testing, be made into compound DMSO solution, concentration are as follows: 100 μM, 50 μM, 25 μ M、12.5μM、6.25μM、3.125μM、1.5625μM、0.78125μM、0.390625μM、0.1953125μM、0.09765625μ M and 0.048828125 μM.It prepares 1 × Buffer A (Invitrogen, article No. PV3189)；ATP is diluted with 1 × Buffer A 400 μM of ATP solution are obtained, by appropriate Z'-LYTETMSer/Thr 03Peptide (Invitrogen, article No. PV3200), MEK Kinases (MEK2) enzyme, (ERK2) enzyme are mixed with 1 × Buffer A；Appropriate Z'-LYTETM Ser/Thr 03phosphoPeptide It is stand-by that substrate (Invitrogen, article No. PV3215) and 1 × Buffer A are made into mixed liquor, and test compound DMSO solution is with 1 × buffer at 4%DMSO compound solution, in reacting hole plus 2.5 μ L 4%DMSO compound dilution buffer it is molten Liquid, 2.5 400 μM of μ L ATP solution and 5 μ L enzymes and Substrate cocktail become 10 μ L reaction systems, after 25 DEG C are incubated for 1.5 hours, Mixed liquor is prepared according to Reagent A:Buffer B=1:1024,5 μ L Reagent A are added in reacting hole The mixed liquor of (Invitrogen, article No. PV3295) and Buffer B (Invitrogen, article No. P3127), 25 DEG C of incubation 60min Afterwards, fluorescence, excitation wavelength: 400nm, launch wavelength: 445nm and 520nm are read using NovoStar microplate reader.
The biochemical inhibitory activity of the MEK kinases (MEK 2) of the compounds of this invention is measured by above test, is measured IC50Value is shown in Table 2.
Inhibitory activity of 2 the compounds of this invention of table to MEK kinases (MEK 2)
Embodiment IC50/(nM)
1 93.20
2 218.1
3 135.1
8 403.9
26 555.4
Conclusion: the compounds of this invention significantly inhibits 2 kinase activity of MEK.
Test case 3, the compounds of this invention measure the Proliferation Ability of Colo205
The cell strain source that this experiment uses: Colo205 (Chinese Academy of Sciences's cell bank, article No. TCHu102).
Cell assay in vitro as described below can measure test-compound to the Proliferation Ability of human colon cancer cell cell strain Activity, activity can use IC50Value indicates.The general approach of such test is as follows: cell strain to be measured (being purchased from the Chinese Academy of Sciences first Cell bank) it is seeded on 96 well culture plates with 4000 cells of suitable cell concentration/mL medium, then by cell in carbon dioxide Cultivated for 37 DEG C in insulating box, allow they grow to overnight, replace medium to added with a series of concentration degree of passing (10000nM, 1000nM, 100nM, 10nM, 1nM, 0.1nM) test-compound solution culture medium, culture plate is placed back in into incubator, even 72 hours of continuous culture.After 72 hours, can with CCK8 (cell calculate kit 8 (Cell Counting Kit-8), article No.: CK04, be purchased from colleague chemistry) method carry out test compound for inhibit cell-proliferation activity.IC50Value can by it is a series of not With under concentration, test-compound calculates the inhibition numerical value of cell.
The compounds of this invention bioactivity from the above analysis gained, calculate resulting IC50Value such as the following table 3:
Proliferation inhibition activity of 3 the compounds of this invention of table to Colo205 cell
Embodiment number Colo205
1 0.20
2 4.72
3 1.52
4 76.48
5 6.24
6 12.03
8 9.93
9 38.35
13 7.17
14 90.10
15 14.33
26 99.06
Conclusion: preferred compound of the present invention has apparent proliferation inhibition activity to Colo205 cell.
Test case 4, the compounds of this invention measure the Proliferation Ability of HCT116 cell
It is thin to Non-small cell lung carcinoma cell, human colon carcinoma that cell assay in vitro as described below can measure test-compound The proliferation inhibition activity of born of the same parents, activity can use IC50Value indicates.
The cell strain that this experiment uses: HCT116 (Chinese Academy of Sciences's cell bank, article No. TCHu 99)
The general approach of such test is as follows: first connecing cell strain to be measured with 1000 cells/wells of suitable cell concentration Kind in 384 porocyte culture plates, cell is then placed on 37 DEG C, is cultivated in 5% carbon dioxide incubator, them is allowed to grow to Overnight, replace medium to added with a series of concentration gradients (1000nM, 250nM, 62.50nM, 15.63nM, 3.91nM, 0.98nM, 0.24nM, 0.06nM, 0.015nM, 0.004nM) test-compound solution culture medium, culture plate is placed back in Incubator continuously cultivates 72 hours.After 72 hours, CCK8 (cell calculating (the Cell Counting Kit- of kit 8 can be used 8), article No.: CK04, be purchased from colleague chemistry) method carry out test compound inhibit cell-proliferation activity.IC50Value can pass through a system Under column various concentration, test-compound calculates the inhibition numerical value of cell.
The compounds of this invention bioactivity from the above analysis gained, calculate resulting IC50Value such as the following table 4:
Proliferation inhibition activity of 4 the compounds of this invention of table to HCT116 cell
Embodiment IC50/(nM)
1 1
2 12.38
8 106.50
Conclusion: preferred compound of the present invention has apparent proliferation inhibition activity to HCT116 cell.
Test case 5, the compounds of this invention measure the Proliferation Ability of Non-small cell lung carcinoma cell A549
Cell assay in vitro as described below can measure test-compound to the proliferation of Non-small cell lung carcinoma cell A549 Inhibitory activity, activity can use IC50Value indicates.
Cell strain: A549 (Chinese Academy of Sciences's cell bank, article No. TCHu150)
Use kit: cell calculates kit Cell Counting Kit-8, and (CCK8, article No.: CK04 is purchased from colleague Chemistry)
The general approach of such test is as follows: first connecing cell strain to be measured with 1000 cells/wells of suitable cell concentration Kind in 384 porocyte culture plates, cell is then placed on 37 DEG C, is cultivated in 5% carbon dioxide incubator, them is allowed to grow to Overnight, replace medium to added with a series of concentration gradients (1000nM, 250nM, 62.50nM, 15.63nM, 3.91nM, 0.98nM, 0.24nM, 0.06nM, 0.015nM, 0.004nM) test-compound solution culture medium, culture plate is placed back in Incubator continuously cultivates 72 hours.After 72 hours, CCK8 (cell calculating (the Cell Counting Kit- of kit 8 can be used 8), article No.: CK04, be purchased from colleague chemistry) method carry out test compound inhibit cell-proliferation activity.IC50Value can pass through a system Under column various concentration, test-compound calculates the inhibition numerical value of cell.
The compounds of this invention bioactivity from the above analysis gained, calculate resulting IC50Value such as the following table 4:
Proliferation inhibition activity of 5 the compounds of this invention of table to A549 cell
Embodiment IC50/(nM)
1 184.10
2 47.24
8 486.6
Conclusion: preferred compound of the present invention has apparent proliferation inhibition activity to A549 cell.
Pharmacokinetic Evaluation
The pharmacokinetics test of test case 6,3 compound of the embodiment of the present invention 1, embodiment 2 and embodiment
1, it makes a summary
Using SD rat as animal subject, rat oral gavage is determined using LC/MS/MS method and gives embodiment 1,2 and of embodiment Drug concentration after 3 compound of embodiment in different moments blood plasma.It is dynamic in rat intracorporal medicine generation to study the compound of the present invention Mechanical behavior evaluates its characteristics of pharmacokinetics.
2, testing program
2.1 test drug
Embodiment 1, embodiment 2 and embodiment 3
2.2 experimental animal
Healthy adult SD rat 12, it is divided into 3 groups, every group 4, half male and half female is dynamic purchased from the western Poole-Bi Kai experiment in Shanghai Object Co., Ltd, animal productiong licensing number: SCXK (Shanghai) 2008-0016.
2.3 drugs are prepared
Appropriate amount of sample is weighed, 40 μ L Tween 80s are added, 0.5%CMC-Na is added, 1mg/mL suspension is made in ultrasound.
2.4 administration
SD rat 12, it is divided into 3 groups, every group 4, half male and half female distinguishes gastric infusion after one night of fasting, dosage is 10mg/kg, administered volume 10mL/kg.
3, it operates
It is taken a blood sample 0.1mL by eye socket within 0.5,1,2,4,6,8,11,24 hour before administration and after administration, is placed in heparinised tubes In, 3500rpm is centrifuged 10 minutes, separated plasma, is saved in -20 DEG C.It feeds within 2 hours after administration.
With the untested compound content in rat plasma after LC/MS/MS method measurement gastric infusion.The linear model of analysis method It encloses for 1.00-2000ng/mL, lower limit of quantitation 1.00ng/mL；Plasma sample is analyzed after protein precipitation pre-processes.
4, pharmacokinetic parameter result
The pharmacokinetic parameter of the compounds of this invention such as the following table 6:
Conclusion: in the medicine generation of the compounds of this invention, absorbs well, has apparent medicine for assimilation effect.

Claims (17)

1. a kind of logical formula (I) compound represented or its officinal salt:
Wherein:
For singly-bound or double bond；
P is selected from O, CR6Or-CR6R7-；
R1、R2、R3Or R4It is each independently selected from hydrogen atom or halogen；
R5For-C (O) NR9R10；
R6Or R7It is each independently selected from hydrogen atom；
R9For hydrogen atom；
R10For C1-6Alkoxy, wherein the C1-6Alkoxy is optionally further selected from hydroxyl or C by one or more3-6Cycloalkanes Replaced the substituent group of base；
N is 0.
2. logical formula (I) compound represented according to claim 1 or its officinal salt, to change shown in logical formula (II) Close object or its officinal salt:
Wherein:P, R1~R3And R5Definition as described in the appended claim 1.
3. logical formula (I) compound represented according to claim 1 or its officinal salt, wherein R1For halogen.
4. logical formula (I) compound represented according to claim 1 or its officinal salt, wherein R2Or R3For halogen.
5. logical formula (I) compound represented according to claim 1 or its officinal salt, wherein R4For hydrogen atom.
6. logical formula (I) compound represented according to claim 1 or its officinal salt, wherein R9For hydrogen atom；R10For C1-6Alkoxy, wherein the C1-6Alkoxy is optionally further replaced by one or two hydroxyls or by a C3-6Cycloalkanes Replaced base.
7. compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from:
8. a kind of general formula (IA) compound represented or its officinal salt:
Wherein:
PG is-C (O) Rd；
RdSelected from hydroxyl or halogen；And
N, P, R1~R4Definition as described in the appended claim 1.
9. general formula (IA) compound represented according to claim 8 or its officinal salt, wherein the compound is selected from:
10. a kind of method for preparing compound or pharmaceutically acceptable salt thereof according to claim 1, this method comprises:
General formula (IA) compound and compound G or its reactant salt obtain logical formula (I) compound；
Wherein:
PG is-C (O) Rd, compound G is aminated compounds；
RdSelected from hydroxyl；And
N, P, R1~R5Definition as described in the appended claim 1.
11. a kind of pharmaceutical composition, described pharmaceutical composition contains any one institute according to claim 1~7 of therapeutically effective amount The compound or pharmaceutically acceptable salt thereof stated and one or more pharmaceutically acceptable carriers.
12. described in any item compound or pharmaceutically acceptable salt thereofs or according to claim 11 according to claim 1~7 Purposes of the pharmaceutical composition in the drug that preparation inhibits MEK.
13. purposes according to claim 12, to treat inflammatory conditions, autoimmune disease, cardiovascular disease in preparation Disease, proliferative diseases drug in purposes.
14. purposes according to claim 12 is the purposes in the drug of preparation treating cancer, wherein the cancer Selected from melanoma, brain tumor, the cancer of the esophagus, gastric cancer, liver cancer, cancer of pancreas, colorectal cancer, lung cancer, kidney, breast cancer, oophoroma, Prostate cancer, cutaneum carcinoma, neuroblastoma, sarcoma, osteoma, orchioncus, uterine cancer, H/N tumors, Huppert's disease, Malignant lymphoma, leukaemia, thyroid tumors, tumor of ureter, tumor of bladder, gallbladder cancer, cholangiocarcinoma, chorioepithelioma or Pediatric tumors.
15. purposes according to claim 12 is the purposes in the drug of preparation treating cancer, wherein the cancer Selected from osteosarcoma or seminoma.
16. purposes according to claim 12 is the purposes in the drug of preparation treating cancer, wherein the cancer Selected from osteochondroma, colorectal cancer or lung cancer.
17. purposes according to claim 14, wherein the drug further joins with another or a variety of anticancer agents Close application.
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CN1333754A (en) * 1999-01-13 2002-01-30 沃尼尔·朗伯公司 Benzoheterocycles and their use as MEK inhibitors
CN1358094A (en) * 1999-07-16 2002-07-10 沃尼尔·朗伯公司 Method for treating chronic pain using MEK inhibitors

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CN1333754A (en) * 1999-01-13 2002-01-30 沃尼尔·朗伯公司 Benzoheterocycles and their use as MEK inhibitors
CN1358094A (en) * 1999-07-16 2002-07-10 沃尼尔·朗伯公司 Method for treating chronic pain using MEK inhibitors

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