CN103626765A - Substituted azaindole compound and salt, composition and application thereof - Google Patents

Substituted azaindole compound and salt, composition and application thereof Download PDF

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CN103626765A
CN103626765A CN201310377134.0A CN201310377134A CN103626765A CN 103626765 A CN103626765 A CN 103626765A CN 201310377134 A CN201310377134 A CN 201310377134A CN 103626765 A CN103626765 A CN 103626765A
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compound
alkylidene group
salt
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alkyl
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CN103626765B (en
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习宁
王婷瑾
唐胤
孙明明
王茜
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Guangdong HEC Pharmaceutical
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Add And Open Up Scientific Co
Guangdong HEC Pharmaceutical
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

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Abstract

The invention provides a substituted azaindole compound having a structure as represented by a formula (I) and a pharmaceutically acceptable salt and a medicinal preparation thereof. The compound is used for adjusting activity of protein kinase and adjusting intercellular or intracellular signal response. The invention further relates to a pharmaceutical composition including the compound and a method of applying the pharmaceutical composition to treatment of highly proliferative diseases of mammals, especially of mankind.

Description

The azaindole compound and salt, composition and the purposes that replace
The application requires to submit on 08 27th, 2012 the Chinese patent application that Patent Office of the People's Republic of China, application number are 201210307104.8, denomination of invention is " the azaindole compound of replacement and salt and using method " and on 04 03rd, 2013, submits the right of priority of the Chinese patent application that Patent Office of the People's Republic of China, application number are 201310116870.0, denomination of invention is " the azaindole compound of replacement and salt and using method " to, and its full content is by reference in conjunction with in this application.
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to a kind of azaindole compound and salt, composition and purposes of replacement.
Background technology
Kinases, as the extended familys in albumen, has become the main target spot of a class in drug research.Human genome order-checking confirms have 500 protein kinases of surpassing to be present in Human genome, and they are called as human kinase group.These protein kinases, based on structure, are divided into 7 families, and wherein, 388 serine/threonine kinases are divided into 5 families, comprise AGC, CAMK, CMGC, CK1 and STE; 90 Tyrosylprotein kinases are divided into 2 families, i.e. TK (Tyrosylprotein kinase) family (58) and TKL (Tyrosylprotein kinase sample) family (32); In addition, also have 40 atypia kinases that textural difference is larger.Many effective drug targets all derive from TK family, EGF-R ELISA (EGFR) for example, vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR).Recent clinical data shows, uses B-Raf inhibitor to treat because of B-Raf v600Ethe melanoma that causes of sudden change, thus melanoma is shifted in approval Wei Luofeini (vemurafenib) treatment late period.
Kinases can be by independent signal path and two kinds of approach regulation and control growth of cancer cells of synergistic signal transduction, for example, Ras/Raf/MEK/ERK mitogen activated protein kinase (MAPK) path, the cell that can mediate various growth signals is corresponding, in cancer cells, this path is usually lacked of proper care.Raf family is by serine/threonine kinases A-Raf, and B-Raf and C-Raf (Raf-1) form, and they can phosphorylation and activation MEK, but only has B-Raf in various cancers, to produce sudden change; And modal B-Raf sudden change occurs in 600 (BRAF of codon v600E) upper-L-glutamic acid replaced by α-amino-isovaleric acid.After B-Raf transgenation, by constitutive character, activate MAPK path is amplified, even without any growth signals, also can cause the growth of malignant tumour.
2002, an important research showed, in all melanoma patients, surpasses 50% and exists the activation of BRAF gene to suddenly change.Except melanoma, the BRAF of activation sudden change is also present in colorectal cancer (40% occurs mispairing rectification of defects), in 50% thyroid papillary carcinoma and 30% rudimentary serous ovarian cancer.Although other Raf substructure, as A-Raf and C-Raf, also can activate some signal path, only have B-Raf can activate MAPK path.
Melanoma is transformed by a kind of special pigment cell-melanophore.Melanoma can occur in skin (epidermis), eyes (uveal tract), or mucosal tissue (mucous membrane).Although in European descent crowd, melanoma comes the 3rd (after squamous cell carcinoma and rodent cancer) of skin cancer, and dead skin carcinoma patient is nearly all melanoma patient.Once be diffused into organ, that melanoma just becomes is quite thorny, M & M very high clinical disease all.Instantly, the melanoma patient of clinical IV phase, the average survival time rate is 6-10 month, this situation in 30 years, does not all have too large variation in the past.
Wei Luofeini (vemurafenib) (trade(brand)name
Figure BDA0000372253260000021
once used code name PLX4032) be a kind of small molecules B-Raf kinase inhibitor, be used for the treatment of the cancer of being drawn by the BRAF sudden change activating.The first indication of Wei Luofeini (vemurafenib) is melanoma (>50% exists the BRAF sudden change activating), application on other solid tumor also under study for action, as colorectal cancer (the BRAF sudden change that >10% exist to activate).Kinase assay proof Wei Luofeini (vemurafenib) and the analogue thereof of purifying can efficiently suppress B-Raf activity, and the selectivity that V600E is suddenlyd change is higher than 3 times of wild-types.
In preclinical body and in external model test, Wei Luofeini (vemurafenib) and homologue thereof can suppress B-Raf v600Ethe growth of positive melanoma cells strain.Clinical I is interim, and Advanced Colon Cancer patient uses oral capsule twice every day, and dosage is progressively increased to 600mg from 200mg.Because the releasing effect of crystal formation preparation is general, therefore, Wei Luofeini (vemurafenib) has been made into microdeposit powder in bulk (MBP) formulation, in order to improve the bioavailability of medicine.
Wei Luofeini (vemurafenib) poorly water-soluble, water solubility rate is low, and bioavailability is not high, especially during oral administration.Poor bioavailability makes patient to medicine, not reach the absorption of expection, thus dosage or the result for the treatment of of impact expection.In addition, for the low medicine of bioavailability, food can affect it and absorb, and need adjust at any time dosage, visible, and this medicine absorbs unstable, needs a very wide safe dose scope.Because this medicine must be under high dosage, just can reach efficient system or target concentration, therefore to some case impracticable, or have side effects (Testa et al., Prodrugs:bridging pharmacodynamic/pharmacokineticgaps.Curr.Opin.Chem.Biol. 2009,13,1-7).
Prodrug is the resemblance of bulk drug, after administration, through conversion or metabolism in organism, becomes activated medicament forms.Usually, prodrug, by improving the pharmacokinetics character of former medicine aspect one or more, improves result for the treatment of, it can overcome the multiple difficulty of former medicine aspect formulation and metabolism, for example, water-soluble low, poor stability, oral administration biaavailability is inadequate, and first pass effect is obviously and toxicity.
The defect of Wei Luofeini (vemurafenib) is that bioavailability is low, oral dosage is large, and (the approval dosage of MBP formulation is every day 2 times, each 960mg), but it is to melanomatous significant curative effect, become the medicine substrate receiving much concern, investigator's expectation, by synthetic Wei Luofeini (vemurafenib) analogue, improves oral administration biaavailability.Therefore,, for improving bioavailability, the prodrug that synthesizes it is necessary, especially the NH on azaindole and/or aromatic amide base is modified, and can be conducive to GI absorption.The analogue easy (reducing dosage and frequency of utilization) obtaining like this, efficient, side effect is little, in addition, also can be made into quiet injecting type or slow release formulation.
Summary of the invention
In view of this, the invention provides a kind of azaindole compound and raceme thereof of new replacement, steric isomer, geometrical isomer, tautomer, solvate, oxynitride, meta-bolites or pharmacy acceptable salt, each described compound is Wei Luofeini (vemurafenib) prodrug, inhibited to protein kinase, can be for the preparation of the medicine that prevents and treat the such proliferative disease of cancer.
Compound involved in the present invention has restraining effect to albumen junket kinase activity, particularly the restraining effect to B-Raf protein kinase.
Especially, the present invention also provides the related pharmaceutically acceptable composition of compound, and related composition can effectively prevent and treat the medicine of the such cell proliferation disorders of cancer.
On the one hand, the invention provides a kind of compound as shown in the formula (I):
Figure BDA0000372253260000041
Or its raceme, steric isomer, geometrical isomer, tautomer, solvate, oxynitride, meta-bolites or pharmacy acceptable salt, wherein:
Each X and Y are H independently ,-C (=O) R 3,-C (=O) OR 4,-C (R 1r 2) OC (=O) R 3,-C (R 1r 2) OC (=O) OR 4or-C (R 1r 2) OP (=O) (OR 4) (OR 4a), and when Y is H, X can not be H or ethanoyl;
Each R 1and R 2be H independently, D, C 1-6alkyl, C 1-6haloalkyl, C 3-6cycloalkyl ,-(C 1-4alkylidene group)-(C 3-6cycloalkyl), C 3-6heterocyclic radical or-(C 1-4alkylidene group)-(C 3-6heterocyclic radical), described each R 1and R 2be connected with carbon atom respectively, or R 1and R 2after being connected, be connected with carbon atom, or R 1, R 2and together with the carbon atom connected with them, form and replace or the individual former molecular carbocyclic ring of unsubstituted 3-8 or heterocycle;
Each R 3be H independently, D, C 1-10alkyl, C 1-10haloalkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl or-(C 1-6alkylidene group)-(5-10 former molecular heteroaryl), wherein, described each C 1-10alkyl, C 1-10haloalkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl and-(C 1-6alkylidene group)-(5-10 former molecular heteroaryl) is not substituted or optionally by 1,2,3 or 4 are independently selected from D, F, Cl, Br, I ,-OH ,-NH 2, C 1-6alkyl, C 1-6haloalkyl, C 1-6alkoxyl group and C 1-6the substituting group of alkylamino replaces;
Each R 4and R 4abe H independently, C 1-10alkyl, C 1-10haloalkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl or-(C 1-6alkylidene group)-(5-10 former molecular heteroaryl), wherein, described each C 1-10alkyl, C 1-10haloalkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl and-(C 1-6alkylidene group)-(5-10 former molecular heteroaryl) is not substituted or optionally by 1,2,3 or 4 are independently selected from D, F, Cl ,-OH ,-NH 2, oxo (=O), C 1-6alkyl, C 1-6haloalkyl, C 1-6alkoxyl group and C 1-6the substituting group of alkylamino replaces.
In some embodiments, each R 1and R 2be H, D or C independently 1-3alkyl.
In other embodiment, each R 3be C independently 1-10alkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl or-(C 1-6alkylidene group)-(C 6-10aryl), wherein, described each C 1-10alkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl and-(C 1-6alkylidene group)-(C 6-10aryl) be not substituted or optionally by 1,2,3 or 4 are independently selected from D, F, OH ,-OMe ,-NH 2,-NHMe ,-NMe 2and C 1-3the substituting group of alkyl replaces.
In some embodiments, each R 4and R 4abe H independently, C 1-10alkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical) or C 6-10aryl, wherein, described each C 1-10alkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical) and C 6-10aryl is not substituted or optionally by 1,2,3 or 4 are independently selected from D, F, OH ,-OMe ,-NH 2,-NHMe ,-NMe 2, oxo (=O) and C 1-3the substituting group of alkyl replaces.
In other embodiment, each X and Y be independently H or-C (R 1r 2) OP (=O) (OH) 2, and X and Y can not be H simultaneously.
In some embodiments, each X and Y are H independently ,-C (=O) R 3,-C (=O) OR 4,-C (R 1r 2) OC (=O) R 3,-C (R 1r 2) OC (=O) OR 4, and when Y is H, X can not be H or ethanoyl.
In other embodiment, acyl group fragment (C (=O) R 3) be the group that a-amino acid or its optical isomer form.
In some embodiments, a-amino acid is Isoleucine, leucine, Methionin, methionine(Met), phenylalanine, Threonine, tryptophane, α-amino-isovaleric acid, L-Ala, asparagine, aspartic acid, L-glutamic acid, glutamine, proline(Pro), Serine, p-tyrosine, arginine, Histidine, halfcystine, glycine, sarkosine, DMG, homoserine, norvaline, nor-leucine, ornithine, homocysteine, hyperphenylalaninemia, phenylglycocoll, o-tyrosine, m-tyrosine or oxyproline.
In other embodiment, described a-amino acid is Isoleucine, leucine, Methionin, methionine(Met), phenylalanine, Threonine, tryptophane, α-amino-isovaleric acid, L-Ala, asparagine, aspartic acid, L-glutamic acid, glutamine, proline(Pro), Serine, tyrosine, arginine or Histidine, wherein, described each amino acid whose alpha-position is all S configuration.
In some embodiments, described formula (I) compound pharmacy acceptable salt is its an alkali metal salt, alkaline earth salt, ammonium salt or N +(C 1-4alkyl) 4salt.
In other embodiment, described formula (I) compound pharmacy acceptable salt is its sodium salt, lithium salts, sylvite, calcium salt, magnesium salts, ammonium salt, quaternary ammonium salt, or their combination.
In some embodiments, described formula (I) compound pharmacy acceptable salt can be its inorganic salt, organic salt or their combination, wherein, described inorganic salt are hydrochlorides, hydrobromate, vitriol, nitrate, phosphoric acid salt or their combination, described organic salt is acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, pyruvate salt, oxalate, glycollate, salicylate, glucuronate, galacturonic hydrochlorate, Citrate trianion, tartrate, aspartate, glutaminate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate, or their combination.
On the other hand, the present invention also provides a kind of pharmaceutical composition, comprises the compounds of this invention and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle, or their combination.
In some embodiments, pharmaceutical composition of the present invention, also comprises additional treatment agent, described additional treatment agent is selected from chemotherapeutic agent, and antiproliferative is used for the treatment of atherosclerotic medicine, the medicine that is used for the treatment of pulmonary fibrosis, or their combination.
In some embodiments, described additional treatment agent is Chlorambucil (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busulfan), carmustine (carmustine), lomustine (lomustine), streptozotocin (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), Dacarbazine (dacarbazine), Temozolomide (temozolomide), Procarbazine (procarbazine), methotrexate (methotrexate), Fluracil (fluorouracil), cytosine arabinoside (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vinealeucoblastine(VLB) (vinblastine), vincristine(VCR) (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), Etoposide (etoposide), ET-743 (trabectedin), gengshengmeisu (dactinomycin), Dx (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), ametycin (mitomycin), ipsapirone (ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analogue (gonadorelin analogues), megestrol (megestrol), prednisone (prednisone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon alpha (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Ah method is for Buddhist nun (afatinib), alisertib, amuvatinib, A Pa is for Buddhist nun (apatinib), Axitinib (axitinib), Velcade (bortezomib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, Ke Zhuo is for Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), imatinib (imatinib), iniparib, lapatinibditosylate (lapatinib), lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, fork clip is for Buddhist nun (saracatinib), saridegib, Xarelto (sorafenib), Sutent (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, volasertib, alemtuzumab (alemtuzumab), rhuMAb-VEGF (bevacizumab), brentuximab vedotin, block appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), method wood monoclonal antibody (ofatumumab) difficult to understand, Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab) or their combination.
On the other hand, the present invention also provides with compound of the present invention or described pharmaceutical composition for the preparation of the purposes of protecting, process, treat or alleviate the medicine of patient's proliferative disease.
In some embodiments, proliferative disease of the present invention is cancer, glioblastoma, myeloproliferative disease, atherosclerosis or the pulmonary fibrosis of metastatic carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, mammary cancer, kidney, liver cancer, lung cancer, skin carcinoma, thyroid carcinoma, the cancer of the brain, neck cancer, prostate cancer, carcinoma of the pancreas, central nervous system (CNS).
On the other hand, the present invention also provides with compound of the present invention or pharmaceutical composition to use the compounds of this invention or pharmaceutical composition to contact with described biological sample for the preparation of suppressing or regulate the purposes of protein kinase activity, described purposes to comprise in biological sample.
Some embodiments therein, protein kinase of the present invention is B-Raf.
On the other hand, the invention provides some pharmaceutical compositions, it comprises the present invention as the compound of kinases inhibitor, or its steric isomer, geometrical isomer, tautomer, solvate, meta-bolites, or its pharmacy acceptable salt, pharmaceutically acceptable carrier, thinner, assistant agent, vehicle, or their combination.
In some embodiments, pharmaceutical composition provided by the present invention comprises the compound that can be used as the agent of B-Raf kinase signal response suppression, or its steric isomer, geometrical isomer, tautomer, solvate, meta-bolites, or its pharmacy acceptable salt, or pharmaceutically acceptable carrier, thinner, assistant agent, vehicle, or their combination.
In other embodiment, compound of the present invention is Wei Luofeini (vemurafenib) prodrug.In other embodiment, pharmaceutical composition of the present invention further also comprises additional treatment agent.
On the other hand, the present invention relates to the method for arrestin kinase activity, the method comprises the compounds of this invention or its pharmaceutical composition contacts with described kinases.In some embodiments, the present invention relates to suppress the method for B-Raf signal response, the method comprises the compounds of this invention or its pharmaceutical composition contacts with described acceptor.Other embodiment is that in cell or multicellular organisms, arrestin kinases receptors is active, particularly suppresses the activity of B-Raf signal response.According to method of the present invention, the method comprises uses the compounds of this invention or its pharmaceutical composition to carry out administration to described multicellular organisms.In some embodiments, described multicellular organisms refers to Mammals.In other embodiment, described multicellular organisms refers to the mankind.In some embodiments, the method for the invention further comprises additional treatment agent and contacts with described kinases.
On the other hand, the present invention relates to a kind of method that suppresses cell-proliferation activity, described method comprises effective therapeutic dose and the cells contacting of using the compounds of this invention or its pharmaceutical composition can suppress propagation.In some embodiments, the method for the invention further comprises additional treatment agent and cells contacting.
On the other hand, the present invention relates to a kind of method of the patient's for the treatment of cell proliferation disorders, described method comprises uses effective therapeutic dose of the compounds of this invention or its pharmaceutical composition to carry out administration to patient.In some embodiments, the method for the invention further comprises the administration of additional treatment agent.
On the other hand, the present invention relates to a kind of method that suppresses patient tumors growth, described method comprises uses effective therapeutic dose of the compounds of this invention or its pharmaceutical composition to carry out administration to patient.In some embodiments, the method for the invention further comprises the administration of additional treatment agent.
On the other hand, the present invention relates to the method for preparation, separation and the purifying of the compound that formula (I) comprises.
Content noted earlier has only been summarized some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will be done more concrete complete description below.
Embodiment
definition and general terms
The present invention will list the corresponding document of specific content of determining in detail, and embodiment is attended by the diagram of structural formula and chemical formula.The present invention has expectedly contains all choices, variant and coordinator, and these may be included in existing invention field as claim is defined.Those skilled in the art is many similar or be equal to method described herein and material by identification, and these can be applied to go in practice of the present invention.The present invention is limited to absolutely not the description of method and material.Have a lot of documents distinguish or conflict with similar material and the present patent application, comprising but be never limited to the definition of term, the usage of term, the technology of description, or the scope of controlling as the present patent application.
Unless other aspects show, the present invention by application to give a definition.
According to object of the present invention, chemical element is according to the periodic table of elements, CAS version and pharmaceutical chemicals handbook, and 75, thed, 1994 define.In addition, organic chemistry General Principle is shown in " Organic Chemistry; " Thomas Sorrell, University Science Books, Sausalito:1999, and " March ' s Advanced Organic Chemistry; " by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, therefore all contents have all merged reference.
Picture is described in the invention, and compound of the present invention can optionally be replaced by one or more substituting group, as general formula compound above, or the special example in picture embodiment the inside, and subclass, and the compounds that comprises of the present invention.Should be appreciated that " optional replacement " this term can exchange use with " replacement " this term.Generally speaking, term " replacement " or " replacement ", represent that the one or more hydrogen atoms of give in structure are replaced by concrete substituting group.Unless other aspects show, an optional substituted radical can have a substituting group to replace in each commutable position of group.Not only one or more substituting group that position can be selected from concrete group in given structural formula replaces, and substituting group can replace in each position identical or differently so.Wherein said substituting group can be, but is not limited to, deuterium, and fluorine, chlorine, bromine, iodine, oxo, alkyl, haloalkyl, hydroxyl, amino, alkoxyl group, alkylamino, ester group, carboxyl, etc.
Term " alkyl " or " alkyl group " that the present invention uses, represent saturated straight chain or side chain monovalence hydrocarbon polymer atomic group containing 1-20 carbon atom.Wherein said alkyl group can independently optionally be replaced by one or more substituting group.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom, some of them embodiment is, alkyl group contains 1-10 carbon atom, other embodiment is, alkyl group contains 1-8 carbon atom, and other embodiment is that alkyl group contains 1-6 carbon atom, other embodiment is, alkyl group contains 1-5 carbon atom, and other embodiment is that alkyl group contains 1-4 carbon atom, other embodiment is, alkyl group is containing 1-3 carbon atom, and other embodiment is that alkyl group is containing 1-2 carbon atom.
The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH 3), ethyl (Et ,-CH 2cH 3), n-propyl (n-Pr ,-CH 2cH 2cH 3), sec.-propyl (i-Pr, i-propyl ,-CH (CH 3) 2), normal-butyl (n-Bu, n-butyl ,-CH 2cH 2cH 2cH 3), isobutyl-(i-Bu, i-butyl ,-CH 2cH (CH 3) 2), sec-butyl (s-Bu, s-butyl ,-CH (CH 3) CH 2cH 3), the tertiary butyl (t-Bu, t-butyl ,-C (CH 3) 3), n-pentyl (n-pentyl ,-CH 2cH 2cH 2cH 2cH 3), 2-amyl group (CH (CH 3) CH 2cH 2cH 3), 3-amyl group (CH (CH 2cH 3) 2), 2-methyl-2-butyl (C (CH 3) 2cH 2cH 3), 3-methyl-2-butyl (CH (CH 3) CH (CH 3) 2), 3-methyl isophthalic acid-butyl (CH 2cH 2cH (CH 3) 2), 2-methyl-1-butene base (CH 2cH (CH 3) CH 2cH 3), n-hexyl (CH 2cH 2cH 2cH 2cH 2cH 3), 2-hexyl (CH (CH 3) CH 2cH 2cH 2cH 3), 3-hexyl (CH (CH 2cH 3) (CH 2cH 2cH 3)), 2-methyl-2-amyl group (C (CH 3) 2cH 2cH 2cH 3), 3-methyl-2-amyl group (CH (CH 3) CH (CH 3) CH 2cH 3), 4-methyl-2-amyl group (CH (CH 3) CH 2cH (CH 3) 2), 3-methyl-3-amyl group (C (CH 3) (CH 2cH 3) 2), 2-methyl-3-amyl group (CH (CH 2cH 3) CH (CH 3) 2), 2,3-dimethyl-2-butyl (C (CH 3) 2cH (CH 3) 2), 3,3-dimethyl-2-butyl (CH (CH 3) C (CH 3) 3), n-heptyl, n-octyl, etc.And alkyl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl group, alkylamino, ester group, carboxyl etc.
Term used in the present invention " alkyl " and its prefix " alkane ", all comprise the saturated carbon chains of straight chain and side chain.
The term " alkylidene group " that the present invention uses, represents the saturated bivalent hydrocarbon radical obtaining from two hydrogen atoms of straight or branched saturated hydrocarbon cancellation.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom, some of them embodiment is, alkylidene group contains 1-6 carbon atom, and other embodiment is that alkylidene group contains 1-4 carbon atom, other embodiment is, alkylidene group contains 1-3 carbon atom, and other embodiment is that alkylidene group contains 1-2 carbon atom.The example of alkylidene group comprises, but is not limited to methylene radical (CH 2-), ethylidene (CH 2cH 2-), ethylidine (CH (CH 3)-), inferior sec.-propyl (CH (CH 3) CH 2-) etc.Alkylidene group can be further substituted, and this substituting group is selected from, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl group, alkylamino, cycloalkyl, heterocyclic radical, aryl, heteroaryl etc.
Term " thiazolinyl " represents the monovalence alkyl of straight or branched, and wherein at least one position is undersaturated condition, and a C-C is sp 2two keys.Unless otherwise detailed instructions, thiazolinyl contains 2-12 carbon atom, and some of them embodiment is that thiazolinyl contains 2-8 carbon atom; Other embodiment is that thiazolinyl contains 2-6 carbon atom; Other embodiment is that thiazolinyl contains 2-4 carbon atom.The concrete example of thiazolinyl comprises, but is not limited to vinyl (CH=CH 2), allyl group (CH 2cH=CH 2) etc.Wherein the group of alkenyl can independently optionally be replaced by one or more substituting groups described in the invention, comprises that group has the location of negation, " just ", " E " or " Z ".
Term " alkynyl " represents the monovalence alkyl of straight or branched, and wherein at least one position is undersaturated condition, and a C-C is sp triple bond.Unless otherwise detailed instructions, alkynyl contains 2-12 carbon atom; In certain embodiments, alkynyl contains 2-8 carbon atom; In other embodiment, alkynyl contains 2-6 carbon atom; In other embodiment, alkynyl contains 2-4 carbon atom.The concrete example of alkyl includes, but are not limited to, ethynyl (C ≡ CH), propargyl (CH 2c ≡ CH) etc.Wherein hydrocarbyl group can independently optionally be replaced by one or more substituting groups described in the invention.
Term " haloalkyl ", " halogenated alkenyl " or " halogenated alkoxy " represents that alkyl, alkenyl or alkoxy base are replaced by one or more halogen atom, wherein alkenyl and alkoxyl group have implication of the present invention, such example comprises, but be not limited to, trifluoromethyl, trifluoromethoxy etc.Haloalkyl can be further substituted, and this substituting group is selected from, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl group, alkylamino etc.
Term " carbocyclic ring " or " carbocylic radical " refer to monovalence or multivalence, and non-aromatic is saturated or part is unsaturated, containing the monocycle of 3-12 carbon atom.Unless otherwise detailed instructions, carbocyclic ring contains 3-12 carbon atom, and other embodiment is that carbocyclic ring contains 3-8 carbon atom.Suitable cyclic aliphatic group comprises, but is not limited to cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of cyclic aliphatic group further comprises, but is never limited to cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-thiazolinyl, 1-cyclopentyl-2-thiazolinyl, 1-cyclopentyl-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, etc.And described " cycloalkyl " refers to monovalence or multivalence, saturated, containing the monocycle of 3-12 carbon atom.Unless otherwise detailed instructions, cycloalkyl contains 3-12 carbon atom, and other embodiment is, cycloalkyl contains 3-8 carbon atom, and other embodiment is that cycloalkyl contains 3-6 carbon atom.Cycloalkyl can be further substituted, and this substituting group is selected from, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl group, alkylamino etc.
Term " cycloalkyl alkylidene group " represents that alkyl group can be replaced by one or more group of naphthene base, and wherein alkyl and group of naphthene base have implication as described in the present invention.Some of them embodiment is, cycloalkyl alkylidene group refers to " more rudimentary cycloalkyl alkylidene group " group, and group of naphthene base is connected to C 1-6alkyl group on.Other embodiment is that group of naphthene base is connected to C 1-4alkyl group on.Other embodiment is that group of naphthene base is connected to C 1-3alkyl group on.Such example comprises, but is not limited to cyclopropyl ethyl, cyclopentyl-methyl, cyclohexyl methyl etc.Cycloalkyl alkylidene group can be further substituted, and this substituting group can be, but is not limited to, deuterium, and fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl group, alkylamino, etc.
Term " heterocycle ", " heterocyclic radical " or " heterocycle " commutative use herein, all refer to monocycle or bicyclic system, wherein the upper one or more atoms of ring are independent is optionally replaced by heteroatoms, ring can be completely saturated or comprise one or more degrees of unsaturation, but be never the fragrant same clan, only have a tie point to be connected to other molecules and get on.One or more ring hydrogen atoms are independent optionally to be replaced by one or more substituting groups described in the invention.Some of them embodiment is, " heterocycle ", " heterocyclic radical " or " heterocycle " group be 3-7 ring monocycle (2-6 carbon atom and be selected from N, O, P, the 1-3 of a S heteroatoms, is optionally replaced and obtains looking like SO, SO by one or more Sauerstoffatom at this S or P 2, PO, PO 2group, when described ring is triatomic ring, wherein only have a heteroatoms), or the dicyclo of 7-10 unit (4-9 carbon atom and be selected from N, O, P, the 1-3 of a S heteroatoms, is optionally replaced and obtains looking like SO, SO by one or more Sauerstoffatom at this S or P 2, PO, PO 2group).
Heterocyclic radical can be carbon back or heteroatoms base.The example of heterocycle comprises, but be not limited to, pyrrolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, thioxane base, piperazinyl, homopiperazine base, azelidinyl, oxa-cyclobutyl, thia cyclobutyl, homopiperidinyl, epoxypropyl, nitrogen heterocyclic heptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulphur azatropylidene base, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxy amyl group, pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidyl imidazolinyl, imidazolidyl, 1, 2, 3, 4-tetrahydro isoquinolyl, 5-methyl isophthalic acid, 3-Dioxol-4-yl, 1, 3-dioxole-2-ketone-4-base.The example of heterocyclic group also comprises, encircles pyrimidine dione base and 1,1-dioxy thio-morpholinyl that two carbon atoms are replaced by oxygen (=O).And described heterocyclic radical is independent optionally to be replaced by the one or more substituting groups in the present invention, and wherein substituting group can be, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl group, alkylamino, etc.
Term " heterocyclic radical alkylidene group " represents that alkyl group can be replaced by one or more heterocyclic radical groups, and wherein alkyl and heterocyclic radical group have implication as described in the present invention.Some of them embodiment is, heterocyclic radical alkylidene group refers to " more rudimentary heterocyclic radical alkylidene group " group, and heterocyclic radical group is connected to C 1-6alkyl group on.Other embodiment is that heterocyclic radical group is connected to C 1-4alkyl group on.Such example comprises, but is not limited to (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl, (piperidin-4-yl) methyl etc.Heterocyclic radical alkylidene group can be further substituted, and this substituting group may be, but not limited to,, deuterium, and fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl group, alkylamino, etc.
Term " heteroatoms " represents one or more O, S, and N, P and Si, comprise N, the form of S and any oxidation state of P; The form of primary, secondary, tertiary amine and quaternary ammonium salt; Or the substituted form of the hydrogen in heterocycle on nitrogen-atoms, for example, N(is as the N in 3,4-dihydro-2 h-pyrrole base), NH(is as the NH in pyrrolidyl) or the pyrrolidyl that replaces as N-of NR(in NR).
Term " halogen " refers to F, Cl, Br or I.
Term " H " represents single hydrogen atom.Such atomic group can be connected with other groups, is for example connected with Sauerstoffatom, forms oh group.
Term " D " represents single D atom.Such atomic group is connected with a methyl, forms list-deuterated methyl (CDH 2), two D atoms are connected with a methyl, form two-deuterated methyl (CD 2h), and three D atoms are connected with a methyl, form three-deuterated methyl (CD 3).
Term " aryl " can be used separately or as most of " aralkyl ", " aralkoxy " or " aryloxy alkyl ", represent to contain altogether the monocycle of 6-14 ring, dicyclo, carbocyclic ring system with three rings, wherein, at least one member ring systems is aromatic, and wherein each member ring systems comprises 3-7 ring, and only has an attachment point to be connected with the rest part of molecule.Term " aryl " can and term " aromatic nucleus " exchange use, aromatic nucleus can comprise phenyl, naphthyl and anthracene.And described aryl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl group, alkylamino etc.
Term " aryl alkylene " represents that alkyl group can be replaced by one or more aromatic yl group, wherein alkyl and aromatic yl group have implication as described in the present invention, some of them embodiment is, aryl alkylene group refers to " more rudimentary aryl alkylene " group, and aromatic yl group is connected to C 1-6alkyl group on.Other embodiment is that aryl alkylene group refers to containing C 1-4" the benzene alkylene " of alkyl.Other embodiment is that aryl alkylene group refers to containing C 1-2" the benzene alkylene " of alkyl.Wherein specific examples comprises benzyl, diphenyl methyl, styroyl etc.Aryl alkylene can be further substituted, and this substituting group can be, but is not limited to, deuterium, and fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl group, alkylamino, etc.
Term " heteroaryl " can be used separately or as most of " heteroaralkyl ", represent the monocycle containing 5-14 annular atoms, dicyclo, and three-ring system, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more heteroatomss, wherein each member ring systems comprises 5-7 ring, and only has an attachment point to be connected with molecule rest part.Term " heteroaryl " can be used with term " fragrant heterocycle " or " heteroaromatics " exchange.And described heteroaryl can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl group, alkylamino etc.
Other embodiment is, virtue heterocycle comprises following monocycle, but be not limited to these monocycles: 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, pyrazinyl, 1, 3, 5-triazinyl, also comprise following dicyclo, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl (as 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl).
Term " heteroaryl alkylidene group " represents that alkyl group can be replaced by one or more heteroaryl groups, wherein alkyl and heteroaryl groups have implication as described in the present invention, some of them embodiment is, heteroaryl alkylidene group refers to " more rudimentary heteroaryl alkylidene group " group, and heteroaryl groups is connected to C 1-6alkyl group on.Other embodiment is that heteroaryl groups is connected to C 1-4alkyl group on.Wherein specific examples comprises 2-picolyl, 3-furans ethyl etc.Heteroaryl alkylidene group can be further substituted, and this substituting group may be, but not limited to,, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl group, alkylamino etc.
No matter term " carboxyl " is to use separately or be used in conjunction with other terms, as " carboxyalkyl ", expression-CO 2h; No matter term " carbonyl ", be to use separately or be used in conjunction with other terms,, as " aminocarboxyl " or " acyloxy ", represent-(C=O)-; Term " acyl group " represents-(C=O) R, and wherein, R is alkyl, described " alkyl " has implication of the present invention.
The term using in the present invention " alkoxyl group ", relates to alkyl, defined as the present invention, by Sauerstoffatom (" alkoxyl group "), is connected in main carbochain, such example comprises, but is not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, etc.
Term " alkylamino " or " alkylamino " comprise " N-alkylamino " and " N, N-dialkyl amido ", and wherein amino group is replaced by one or two alkyl group respectively independently.Some of them embodiment is that alkylamino is one or two C 1-6alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.Other embodiment is that alkylamino is C 1-3more rudimentary alkylamino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to N-methylamino-, N-ethylamino, N, N-dimethylamino, N, N-diethylin etc.
The term that used in the present invention " undersaturated " represents that part contains one or more degrees of unsaturation.
Term " comprises " for open language, comprises the content that the present invention is specified, but does not get rid of otherwise content.
Picture is described in the invention, and key of substituting group picture is connected to the member ring systems (as shown below) forming on the ring at center and represents that substituting group can replace any commutable position on ring.For example, formula a represents the substituted position of any possibility on B ring, shown in b.
Unless other aspects show, structural formula described in the invention comprises that all isomeric forms are (as enantiomerism, diastereo-isomerism, and rotamerism (or conformational isomerism)): the R, the S configuration that for example contain asymmetric center, (Z) of two keys, (E) isomer, and (Z), the conformer of (E).Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.
Term used in the present invention " tautomer " or " tautomeric form " expression have the structure isomeride of different-energy can cross low energy barrier, thereby transforms mutually.For example, proton tautomerism body (being prototropy) comprises by proton shifting and carries out change, as the change of keto-enol formula and imines-enamine isomerization.Valence tautomers comprises by some bonding electronss recombinates and carries out change.
Unless other aspects show, within all tautomeric forms of compound of the present invention are included in scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atoms.
Term used in the present invention " prodrug ", represents that a compound is converted into the compound shown in formula (I) in vivo.Such conversion is hydrolyzed by prodrug or the impact that is precursor structure through enzymatic conversion in blood or tissue in blood.Prodrug compounds of the present invention can be ester, and what in existing invention, ester can be used as prodrug has phenyl ester class, an aliphatics (C 1-24) ester class, acyloxy methyl ester class, carbonic ether, amino formate and amino acid esters.For example a compound in the present invention comprises OH group, its acidylate can be obtained to the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that hydroxyl phosphorylation on parent obtains.Can be with reference to Publication about Document about the complete discussion of prodrug: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol.14, A.C.S.Symposium Series; Roche et al., ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs:Design and Clinical Applications, Nature Reviews Drug Discovery, 2008,7,255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J.Med.Chem., 2008,51,2328-2345, every piece of document is contained in this by reference.
" meta-bolites " refers to that concrete compound or its salt is in vivo by the resulting product of metabolism.The meta-bolites of a compound can identify by the known technology in affiliated field, and its activity can be by adopting the method for test to characterize as described in the invention.Such product can be by the oxidation of drug compound process, reduces, and hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise compound of the present invention is fully contacted to the meta-bolites that for some time produces with Mammals.
The definition of neutral body chemistry of the present invention and the use of convention are conventionally with reference to Publication about Document: Parker et al., ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York and Eliel et al., " Stereochemistry of Organic Compounds ", John Wiley & Sons, Inc., New York, 1994. compounds of the present invention can comprise asymmetric center or chiral centre, therefore have different steric isomers.The stereoisomeric forms in any ratio that compound of the present invention is all, include, but not limited to, diastereomer, and enantiomer, atropisomer, and their mixture, as racemic mixture, formed a part of the present invention.A lot of organic compound all exist with optical activity form, i.e. the plane of their capable Plane of rotation polarized light.When describing optically active compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for naming the symbol of compound plane polarized light rotation, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical structure of these steric isomers is identical, but their three-dimensional arrangement is different.Specific steric isomer can be enantiomorph, and the mixture of isomer is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause in chemical reaction process, there is no stereoselectivity or stereospecificity.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt is for we are known in affiliated field, as document: Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmacol Sci, 1977,66,1-19, records.The salt that pharmaceutically acceptable nontoxic acid forms comprises, but is not limited to, and the inorganic acid salt that react formation with amino group has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by the additive method recorded on books document as ion exchange method.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtaining by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N +(C 1-4alkyl) 4salt.The present invention also intends having conceived the formed quaternary ammonium salt of compound of the group of any comprised N.Water-soluble or oil soluble or disperse product to obtain by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, and potassium, calcium, magnesium, etc.Pharmacy acceptable salt further comprises suitable, nontoxic ammonium, the amine positively charged ion that quaternary ammonium salt and gegenions form, and as halogenide, oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to one or more solvent molecules and the formed associated complex of compound of the present invention.The solvent that forms solvate comprises, but is not limited to water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, monoethanolamine.Term " hydrate " refers to that solvent molecule is the formed associated complex of water.
When term " blocking group " or " PG " refer to a substituting group and other reacted with functional groups, be commonly used to blocking-up or protect special functional.For example; " amino blocking group " refers to that a substituting group is connected to block or protect in compound amino functional with amino group; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC), the sub-methoxycarbonyl (Fmoc) of carbobenzoxy-(Cbz) (CBZ) and 9-fluorenes.Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refer to the substituting group of carboxyl be used for blocking-up or protection carboxyl functional, comprise-CH of general carboxyl-protecting group 2cH 2sO 2ph, cyano ethyl, 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl, 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl; 2-(diphenylphosphino) ethyl, nitro-ethyl, etc.Can reference for the general description of blocking group: Greene et al.; Protective Groups in Organic Synthesis; John Wiley & Sons; New York; 1991and Kocienski et al., Protecting Groups, Thieme; Stuttgart, 2005.
compound
The present invention relates to Wei Luofeini (vemurafenib) prodrug, its pharmacy acceptable salt, and pharmaceutical preparation, to protein kinase, the disease that especially B-Raf kinases regulates or the treatment of illness have potential purposes.Particularly, the present invention relates to a kind of compound as shown in the formula (I):
Figure BDA0000372253260000201
Or its raceme, steric isomer, geometrical isomer, tautomer, solvate, oxynitride, meta-bolites or pharmacy acceptable salt, shown in wherein X and Y are defined as follows.
Each X and Y are H independently ,-C (=O) R 3,-C (=O) OR 4,-C (R 1r 2) OC (=O) R 3,-C (R 1r 2) OC (=O) OR 4or-C (R 1r 2) OP (=O) (OR 4) (OR 4a) and when Y is H, X can not be H or ethanoyl.
In some embodiments, each X and Y be independently H or-C (R 1r 2) OP (=O) (OH) 2, and X and Y can not be H simultaneously.
And in other embodiments, each X and Y are H independently ,-C (=O) R 3,-C (=O) OR 4,-C (R 1r 2) OC (=O) R 3,-C (R 1r 2) OC (=O) OR 4, and when Y is H, X can not be H or ethanoyl.
In some embodiments, acyl group fragment (C (=O) R 3) be the group that a-amino acid or its optical isomer form.
In some embodiments, a-amino acid is Isoleucine, leucine, Methionin, methionine(Met), phenylalanine, Threonine, tryptophane, α-amino-isovaleric acid, L-Ala, asparagine, aspartic acid, L-glutamic acid, glutamine, proline(Pro), Serine, p-tyrosine, arginine, Histidine, halfcystine, glycine, sarkosine, N, N-N-methylsarcosine, homoserine, norvaline, nor-leucine, ornithine, homocysteine, hyperphenylalaninemia, phenylglycocoll, o-tyrosine, m-tyrosine or oxyproline, when a-amino acid is aspartic acid or L-glutamic acid, can be that any one carbonyl in its structure is connected with molecule rest part.
In other embodiment, described a-amino acid is Isoleucine, leucine, Methionin, methionine(Met), phenylalanine, Threonine, tryptophane, α-amino-isovaleric acid, L-Ala, asparagine, aspartic acid, L-glutamic acid, glutamine, proline(Pro), Serine, tyrosine, arginine or Histidine, wherein said each amino acid whose alpha-position is all S configuration.
In each structure of above-mentioned X, Y, each R 1and R 2be H independently, D, C 1-6alkyl, C 1-6haloalkyl, C 3-6cycloalkyl ,-(C 1-4alkylidene group)-(C 3-6cycloalkyl), C 3-6heterocyclic radical or-(C 1-4alkylidene group)-(C 3-6heterocyclic radical), wherein, described each R 1and R 2be connected with carbon atom respectively, or R 1and R 2after being connected, be connected with carbon atom, or R 1, R 2and together with the carbon atom connected with them, form and replace or the individual former molecular carbocyclic ring of unsubstituted 3-8 or heterocycle;
Be R 1, R 2together with the carbon atom being connected with them, can form 3-8 former molecular carbocyclic ring or heterocycle, also can not form carbocyclic ring or heterocycle, for other structures well known to those skilled in the art, as C-R 1-R 2, C-R 2-R 1or R 1-C-R 2deng.
And in some embodiments, described each R 1and R 2be H, D or C independently 1-3alkyl.
In each structure of above-mentioned X, Y, each R 3be H independently, D, C 1-10alkyl, C 1-10haloalkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl or-(C 1-6alkylidene group)-(5-10 former molecular heteroaryl), wherein, described each C 1-10alkyl, C 1-10haloalkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl and-(C 1-6alkylidene group)-(5-10 former molecular heteroaryl) is not substituted or optionally by 1,2,3 or 4 are independently selected from D, F, Cl, Br, I ,-OH ,-NH 2, C 1-6alkyl, C 1-6haloalkyl, C 1-6alkoxyl group and C 1-6the substituting group of alkylamino replaces;
In other embodiment, each R 3be C independently 1-10alkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl or-(C 1-6alkylidene group)-(5-10 former molecular heteroaryl), wherein, described each C 1-10alkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl and-(C 1-6alkylidene group)-(5-10 former molecular heteroaryl) is not substituted or optionally by 1,2,3 or 4 are independently selected from D, F, OH ,-OMe ,-NH 2,-NHMe ,-NMe 2and C 1-3the substituting group of alkyl replaces.
In each structure of above-mentioned X, Y, each R 4and R 4abe H independently, C 1-10alkyl, C 1-10haloalkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl or-(C 1-6alkylidene group)-(5-10 former molecular heteroaryl), wherein, described each C 1-10alkyl, C 1-10haloalkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl and-(C 1-6alkylidene group)-(5-10 former molecular heteroaryl) is not substituted or optionally by 1,2,3 or 4 are independently selected from D, F, Cl ,-OH ,-NH 2, oxo (=O), C 1-6alkyl, C 1-6haloalkyl, C 1-6alkoxyl group and C 1-6the substituting group of alkylamino replaces.
In some embodiments, each R 4and R 4abe H independently, C 1-10alkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical) or C 6-10aryl, wherein, described each C 1-10alkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical) and C 6-10aryl is not substituted or optionally by 1,2,3 or 4 are independently selected from D, F, OH ,-OMe ,-NH 2,-NHMe ,-NMe 2, oxo (=O) and C 1-3the substituting group of alkyl replaces.
In some embodiments, described formula (I) compound pharmacy acceptable salt is its an alkali metal salt, alkaline earth salt, ammonium salt or N +(C 1-4alkyl) 4salt.
In other embodiment, described formula (I) compound pharmacy acceptable salt is its sodium salt, lithium salts, sylvite, calcium salt, magnesium salts, ammonium salt, quaternary ammonium salt, or their combination.
In some embodiments, described formula (I) compound pharmacy acceptable salt can be inorganic salt, organic salt or their combination, wherein, described inorganic salt are hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt or their combination, described organic salt is acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, pyruvate salt, oxalate, glycollate, salicylate, glucuronate, galacturonic hydrochlorate, Citrate trianion, tartrate, aspartate, glutaminate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate or their combination.
The compound of formula of the present invention (I) structure includes but not limited to following particular compound or its raceme, steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or its prodrug:
Figure BDA0000372253260000241
Figure BDA0000372253260000261
Unless other aspects show, all raceme, steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and the pharmaceutically acceptable prodrugs of compound of the present invention all belong to scope of the present invention.
Specifically, salt is pharmacy acceptable salt.Term " pharmaceutically acceptable " comprises that material or composition must be to be applicable to chemistry or toxicologically, relevant with the Mammals that forms other components of preparation and be used for the treatment of.
The salt of compound of the present invention also comprise for the preparation of or purifying formula (I) shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula (I), but pharmacy acceptable salt not necessarily.
If compound of the present invention is alkaline, conceivable salt can prepare by any suitable method providing on document, for example, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, ethyl sulfonic acid, etc.
If compound of the present invention is acid, conceivable salt can prepare by suitable method, as, use mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, the organic salt obtaining from amino acid, and as glycine and arginine, ammonia, as uncle's ammonia, parahelium and tertiary ammonia, and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.
The present invention also comprises the application of compound of the present invention and pharmacy acceptable salt thereof, and the disease of mediation occurs for the production of pharmaceutical prod treatment acute and chronic blood vessel, comprises that those are described in the invention.The application of compound of the present invention in producing cancer therapy drug.Compound of the present invention alleviates for the production of a kind of medical supplies equally, stops, and controls or treat the disease being mediated by B-Raf.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises compound and at least one pharmaceutically acceptable carrier of formula (I) representative, the required effective treatment consumption of combination of assistant agent or thinner.
The present invention comprises the disease that mediation occurs treatment patient vessel equally, or the method to this illness sensitivity, and the treatment significant quantity that the method comprises use formula (I) representative compound is treated patient.
composition, preparation and administration
According on the other hand, the feature of pharmaceutical composition of the present invention comprises the compound of formula (I), the compound that the present invention is listed, or the compound in embodiment, and pharmaceutically acceptable carrier, assistant agent, or vehicle.In composition of the present invention, the amount of compound can suppress the protein kinase in biological sample or patient body effectively detectablely.
There is free form in compound of the present invention, or suitable, as pharmaceutically acceptable derivates.According to the present invention, pharmaceutically acceptable derivates comprises, but be not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of ester class, or can be directly or indirectly according to other any adducts or derivatives of needing administration of patient, the described compound in other aspects of the present invention, its meta-bolites or his residue.
Picture is described in the invention, and the pharmaceutically acceptable composition of the present invention further comprises pharmaceutically acceptable carrier, assistant agent, or vehicle, these are applied as the present invention, comprise any solvent, thinner, or other liquid excipients, dispersion agent or suspension agent, tensio-active agent, isotonic agent, thickening material, emulsifying agent, sanitas, solid binder or lubricant, etc., be suitable for distinctive target formulation.As described with Publication about Document: Troy et al., Remington:The Science and Practice of Pharmacy, 21st ed., 2005, Lippincott Williams & Wilkins, Philadelphia and Swarbrick et al., Encyclopedia of Pharmaceutical Technology, eds.1988-1999, Marcel Dekker, New York.The comprehensive content of document herein, shows that different carriers can be applicable to preparation and their known preparation methods of pharmaceutically acceptable composition.Carrier medium and the inconsistent scope of compound of the present invention except any routine, the any bad biological effect that for example produced or the interaction producing in the mode being harmful to any other component of pharmaceutically acceptable composition, their purposes is also the scope that the present invention considers.
The material that can be used as pharmaceutically acceptable carrier comprises, but be not limited to, ion-exchanger, aluminium, aluminum stearate, Yelkin TTS, serum protein, as human serum protein, buffer substance is as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloid silicon, Magnesium Trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanolin, sugar, as lactose, dextrose plus saccharose, starch is as W-Gum and potato starch, the derivative of Mierocrystalline cellulose and it is as Xylo-Mucine, ethyl cellulose and rhodia, natural gum powder, Fructus Hordei Germinatus, gelatin, talcum powder, auxiliary material is as cocoa butter and suppository wax, oily as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil, glycols compound, as propylene glycol and polyoxyethylene glycol, ester class is as ethyl oleic acid ester and ethyl laurate, agar, buffer reagent is as magnesium hydroxide and aluminium hydroxide, Lalgine, pyrogen-free water, Deng oozing salt, Lin Ge (family name) solution, ethanol, phosphate buffer solution, and other nontoxic proper lubrication agent are as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, tinting material, releasing agent, dressing dress material, sweeting agent, seasonings and spices, sanitas and antioxidant.
Composition of the present invention can be oral administration, drug administration by injection, and spraying inhalation, topical, per rectum administration, nose administration, containing taking administration, vagina administration or by the administration of the property implanted medicine box.Term as used herein " through what inject " comprises subcutaneous, vein, intramuscular, IA, in synovial membrane (chamber), intrasternal, in film, intraocular, in liver, intralesional, and the injection of encephalic or infusion techniques.Preferred composition is oral administration, to intraperitoneal administration or intravenous injection.The injection system of composition sterile of the present invention can be suspension water or oleaginous.These suspension can adopt suitable dispersion agent, wetting agent and suspension agent to manufacture by formula according to known technology.Aseptic injection can be aseptic parenteral solution or suspension, is nontoxic acceptable thinner or solvent of injection, as 1,3 butylene glycol solution.These acceptable vehicle and solvent can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, aseptic nonvolatile oil can be used as solvent or suspension medium by convention.
With this end in view, the nonvolatile oil of any gentleness can be list or the DG synthesizing.Lipid acid, as the glyceride derivative of oleic acid and it can be used for the preparation of injectable, as natural pharmaceutically acceptable grease, as sweet oil or Viscotrol C, their polyoxyethylene deriv particularly.These oil solutions or suspension can comprise long-chain alcohol thinner or dispersion agent, and as carboxymethyl cellulose or similar dispersion agent, the pharmaceutical preparation that is generally used for pharmaceutically acceptable formulation comprises emulsion and suspension.The tensio-active agent that other are conventional, as Tweens, the reinforcer of spans and other emulsifying agents or bioavailability, is generally used for pharmaceutically acceptable solid, liquid, or other formulations, and can be applied to the preparation of drug target preparation.
The pharmaceutically acceptable composition of the present invention can be to carry out oral administration with any acceptable oral dosage form, comprising, but be not limited to capsule, tablet, water suspension processed or solution.About tablet, orally use, carrier generally comprises lactose and W-Gum.Lubricant, as Magnesium Stearate, is all typically added.For capsule oral administration, suitable thinner comprises lactose and dry W-Gum.When oral administration is water suspension processed, its effective constituent is comprised of emulsifying agent and suspension agent.If expect these formulations, some sweeting agent, seasonings or tinting material also can be added.
In addition, the pharmaceutically acceptable composition of the present invention can be with the form rectal administration of suppository.These can be by reagent and suitable non-perfusion adjuvant are mixed with and are formed, this adjuvant be at room temperature solid but next in the temperature of rectum be liquid, thereby in rectum, melt and discharge medicine.Such material comprises cocoa butter, beeswax, and polyethylene glycols.The pharmaceutically acceptable composition of the present invention can be topical, and particularly during local application, the therapeutic goal that relates to region or organ easily reaches, as the disease of eye, skin or lower intestinal tract.Suitable local application's preparation can prepare and be applied to these fields or organ.
Above-mentioned rectal suppository or suitable enema can be applied to the local application of lower intestine.Local skin spot is medication so also.For local application, pharmaceutically acceptable composition can be prepared into suitable ointment by formulation method, and this ointment packets is suspended in or is dissolved in one or more carriers containing activeconstituents.The carrier compound of topical of the present invention comprises, but is not limited to mineral oil, whiteruss, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.In addition, pharmaceutically acceptable composition can be prepared into suitable lotion or emulsion, and this lotion or emulsion comprise activeconstituents and is suspended in or is dissolved in one or more pharmaceutically acceptable carriers.Suitable carrier comprises, but is not limited to mineral oil, Arlacel-60 (Arlacel-60), polysorbate60 (Polysorbate 60), cetyl esters wax, palmityl alcohol, 2-Standamul G, phenylcarbinol and water.
For composition eye use, pharmaceutically acceptable, can be prepared into preparation; as waited micronize suspension oozing, the Sterile Saline of pH regulator or other aqueous solution, preferably; the Sterile Saline of isotonic solution and pH regulator or other aqueous solution, can add disinfection preservative as benzalkonium chloride.In addition, for eye use, pharmaceutically acceptable composition can be prepared into ointment as vaseline oil by pharmaceutical formulation.The pharmaceutically acceptable composition of the present invention can carry out administration by gaseous solvents or the inhalation of nose.Such composition can prepare according to the known technology of pharmaceutical formulation, maybe can be prepared into salts solution, with phenylcarbinol or other suitable sanitass, absorption enhancer, fluorocarbon or other conventional solubilizing agent or dispersion agent, improve bioavailability.
The liquid dosage form of oral administration comprises, but is not limited to pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.Except active ingredient beyond the region of objective existence, liquid dosage form can comprise known general inert diluent, for example, and water or other solvents, solubilizing agent and emulsifying agent, as ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, grease (cottonseed particularly, Semen arachidis hypogaeae, corn, microorganism, olive, castor-oil plant and sesame oil), glycerine, Tetrahydrofurfuryl Alcohol, polyoxyethylene glycol, sorbitan alcohol fatty acid ester, and their mixture.Except the thinner of inertia, oral compositions also can comprise assistant agent as wetting agent, emulsifying agent or suspension agent, sweeting agent, seasonings and perfume compound.
Injection, as aseptic parenteral solution or oleaginous suspension can adopt suitable dispersion agent, wetting agent and suspension agent to prepare by pharmaceutical formulation according to known technology.Aseptic injection can be nontoxic through acceptable thinner or solvent are made parenterally aseptic parenteral solution, suspension or emulsion, for example, and 1,3 butylene glycol solution.Acceptable vehicle and solvent can be water, Lin Ge (family name) solution, U.S.P. and isotonic sodium chlorrde solution.In addition, aseptic nonvolatile oil is by convention as solvent or suspension medium.With this end in view the nonvolatile oil of any gentleness can comprise synthetic list or DG.In addition, lipid acid can be applied to injection as oleic acid.
Injection can be aseptic, filters, or mix disinfectant with the form of aseptic solid composite as defended strainer by bacterium, and disinfectant can be dissolved in or be scattered in sterilized water or other aseptic injection media before use.In order to extend the effect of compound of the present invention, conventionally need to slow down by subcutaneous injection or intramuscularly the absorption of compound.Can realize like this problem of utilizing liquid suspension to solve crystal or amorphous material poorly water-soluble.The specific absorption of compound depends on its dissolution rate, depends on successively grain size and crystal shape.In addition, can by compound, in oils vehicle, dissolve or disperse the delay of compound injection administration to absorb.
Injection storage form is by biodegradable polymkeric substance, and as many lactic acid-polyglycolide forms, the microcapsule matrix of compound completes.The controlled release ratio of compound depends on the ratio of compound formation polymkeric substance and the character of particular polymer.Other biodegradable polymers comprise poly-(positive ester class) and gather (acid anhydrides).Injection storage form also can embed liposome or the microemulsion compatible with bodily tissue by compound and prepare.
Some of them embodiment is, the composition of rectum or vagina administration is suppository, suppository can be by mixing compound of the present invention to prepare with auxiliary material or the carrier of suitable non-perfusion, as cocoa butter, polyoxyethylene glycol, or suppository wax, they are solid but next for liquid at body temperature in room temperature, therefore in vagina or cavity of tunica vaginalis, just melt release of active compounds.
The solid dosage of oral administration comprises capsule, tablet, pill, pulvis and granula.In these formulations, active compound mixes with at least one pharmaceutically acceptable inert excipient or carrier, as Trisodium Citrate or calcium phosphate or filling agent or a) weighting agent as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid, b) tackiness agent is as carboxymethyl cellulose, alginate, gelatin, Povidone, sucrose and gum arabic, c) wetting Agent for Printing Inks is as glycerine, d) disintegrating agent is as agar, calcium carbonate, potato starch or tapioca (flour), Lalgine, some silicate and sodium carbonate, e) retarding agent solution is as paraffin, f) absorption enhancer is as quaternary ammonium compounds, g) wetting agent is as hexadecanol and glyceryl monostearate, h) absorption agent is as white bole and bentonite, i) lubricant is as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sulfuric acid,monododecyl ester, sodium salt, and their mixture.As for capsule, tablet and pill, these formulations can comprise buffer reagent.
The solids composition of similar type can be that weighting agent riddles soft or hard capsule, and the auxiliary material using has lactose and high molecular polyoxyethylene glycol etc.The agent of solid dosage photo, lozenge, capsule, pill and granula can be by dressings, add shell prepares as known coating method on enteric coating and other drug preparation.They can optionally comprise opalizer, or preferably, in certain part of enteron aisle, at random, with the unique activeconstituents in the method release composition postponing.As implant compositions can comprise polymer material and wax.
Active compound can form microcapsule formulations with together with one or more vehicle described in the invention.The agent of solid dosage photo, lozenge, capsule, pill and granula can or add shell by dressing, as enteric coating, controlled release coat and other known drug formulation process.In these solid dosages, active compound can mix with at least one inert diluent, as sucrose, and lactose or starch.Such formulation also can comprise the substance except inert diluent as general application, if compressing tablet lubricant and other compression aids are as Magnesium Stearate and Microcrystalline Cellulose.As for capsule, tablet and pill, these formulations can comprise buffer reagent.They can optionally comprise tranquilizer, or preferably, in certain part of enteron aisle, with the unique activeconstituents in the method release composition postponing arbitrarily.Applicable implant compositions can comprise, but be not limited to polymer and wax.
Compound of the present invention by part or through the formulation of percutaneous drug delivery, comprise ointment, paste, emulsion, lotion, gelifying agent, pulvis, solution, sprays, inhalation, paster.Activeconstituents mixes mutually with pharmaceutically acceptable carrier and any essential sanitas or essential buffer reagent under aseptic condition.The pharmaceutical preparation of ophthalmology, ear drop and eye drops are all the scopes that the present invention considers.In addition, the present invention also considers the application of transdermal patch, and it has more advantage aspect control compound is delivered in body, and such formulation can prepare by dissolving or decentralized compound in suitable medium.Absorption enhancer can increase compound through the flow of skin, and through-rate is controlled film or compound is scattered in to polymer matrix or gelatin is controlled its speed.
Compound of the present invention is preferably prepared into dose unit type to alleviate the homogeneity of dosage and dosage by pharmaceutical formulation.Term " dosage " unit's type " refer to that herein patient obtains suitably treating the physical dispersion unit of required medicine.Yet, should be appreciated that compound of the present invention or composition total usage every day will be judged and determine according to reliable medical science scope by doctor in charge.Concrete effective dose level will depend on that many factors comprise the illness that is treated and the seriousness of illness for any one special patient or organism, the activity of particular compound, concrete composition used, patient's age, body weight, healthy state, sex and food habits, administration time, the discharge rate of route of administration and particular compound used, the time length for the treatment of, medicinal application in drug combination or with specific compound coupling, and the known factor of some other pharmaceutical field.
The change of consumption that can produce the compound of the present invention of single dosage form composition in conjunction with carrier substance is depended on and is cured mainly and special mode of administration.Some of them embodiment is that composition can be prepared into dosage at the inhibitor of 0.01-200mg/kg body weight/day by formulation method, accepts the amount of composition carry out administration by patient.
Compound of the present invention can carry out administration with only pharmaceutical agents or in conjunction with one or more other additional treatment (pharmacy) agent, wherein drug combination causes acceptable untoward reaction, and this has special meaning for high proliferative disease as the treatment of cancer.In this case, compound of the present invention can be in conjunction with known cytotoxic agent, single transduction inhibitor or other antitumor and anticancer agents, and their mixture and combination.Picture is used in the present invention, the disease that the normal drug treatment of additional treatment agent is special, known exactly " treating suitably disease "." additional treatment agent " used in the present invention comprises that chemotherapeutic agent or other antiproliferative medicines can be in conjunction with compounds for treating proliferative disease of the present invention or cancers.
Chemotherapeutic agent or other anti-proliferative drugs comprise histon deacetylase (HDAC) (HDAC) inhibitor, include, but are not limited to, SAHA, MS-275, MGO103, and the described compound of those following patents: WO2006/010264, WO03/024448, WO2004/069823, US2006/0058298, US2005/0288282, WO00/71703, WO01/38322, WO01/70675, WO03/006652, WO2004/035525, WO2005/030705, WO2005/092899, comprise with demethylation reagent, but be not limited to, 5-nitrogen-2 '-the Deoxyribose cytidine (5-aza-dC) of mixing, azacitidine (Vidaza), Decitabine (Decitabine) and with the described compound of Publication about Document: US6, 268137, US5, 578, 716, US5, 919, 772, US6, 054, 439, US6, 184, 211, US6, 020, 318, US6, 066, 625, US6, 506, 735, US6, 221, 849, US6, 953, 783, US11/393, 380.
Other embodiment is that chemotherapeutics or other anti-proliferative drugs can be in conjunction with compounds for treating proliferative disease of the present invention and cancers.Known chemotherapeutics comprises, but be not limited to, can combine with cancer therapy drug of the present invention other therapies or the cancer therapy drug of use, operation, (a little example is as gamma-radiation for radiotherapy, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy and system isotope therapy), endocrinotherapy, taxanes (taxol (taxol), Docetaxel (taxotere) etc.), platinum derivatives (cis-platinum (cisplatin), carboplatin (carboplatin)), biological response modifier (Interferon, rabbit, interleukin), tumour necrosis factor (TNF, TRAIL receptor target thing), overheated and psychrotherapy, alleviate the reagent (as antiemetic) of any untoward reaction, with other approved chemotherapeutics, include, but are not limited to, alkanisation medicine (mustargen (mechlorethamine), Chlorambucil (chlorambucil), endoxan (cyclophosphamide), melphalan (melphalan), ifosfamide (ifosfamide)), metabolic antagonist (methotrexate (methotrexate), pemetrexed (pemetrexed) etc.), purine antagonist and pyrimidine antagonist (6-MP (6-mercaptopurine), 5 FU 5 fluorouracil (5-fluorouracil), cytosine arabinoside (cytarabile), gemcitabine (gemcitabine)), spindle poison (vinealeucoblastine(VLB) (vinblastine), vincristine(VCR) (vincristine), vinorelbine (vinorelbine)), podophyllotoxin (Etoposide (etoposide), irinotecan (irinotecan), Hycamtin (topotecan)), microbiotic (Dx (doxorubicin), bleomycin (bleomycin), mitomycin (mitomycin)), nitrosourea (carmustine (carmustine), lomustine (lomustine)), (KSP passes through mitotic kinesin inhibitors to cell division cycle inhibitor, CENP-E and CDK inhibitor), enzyme (asparaginase (asparaginase)), hormone (tamoxifen (tamoxifen), Leuprolide (leuprolide), flutamide (flutamide), megestrol (megestrol), dexamethasone (dexamethasone) etc.).Angiogenesis inhibitor reagent (Avastin (avastin) etc.).Monoclonal antibody (Baily monoclonal antibody (belimumab), brentuximab, Cetuximab (cetuximab), WAY-CMA 676 (gemtuzumab), her monoclonal antibody (ipilimumab), ofatumumab, Victibix (panitumumab), Lucentis (ranibizumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab)).Kinase inhibitor (imatinib (imatinib), Sutent (sunitinib), Xarelto (sorafenib), Tarceva (erlotinib), Gefitinib (gefitinib), Dasatinib (dasatinib), AMN107 (nilotinib), lapatinibditosylate (lapatinib), gram Zhuo is for Buddhist nun (crizotinib), ruxolitinib, vemurafenib, vandetanib, pazopanib, etc.).Medicine suppress or the approach that activates cancer as mTOR, HIF (hypoxia inducible factor) approach and other.Cancer therapy more widely forum is shown in http:// www.nci.nih.gov/, the oncology list of medications of FAD approval is shown in http:// www.fda.gov/cder/cancer/druglist-rame.htm, and Merck handbook, the 18 edition .2006, all contents are all to combine reference.
Other embodiment is that compound of the present invention can be in conjunction with cytotoxin carcinostatic agent.Such carcinostatic agent can be inner the finding of the 13 edition the Merck index (2001).These carcinostatic agents comprise, but be never limited to, asparaginase, bleomycin, carboplatin, carmustine, Chlorambucil, cis-platinum, L-ASP, endoxan, cytosine arabinoside, Dacarbazine, dactinomycin, daunorubicin, Zorubicin (Dx), epirubicin, Etoposide, 5-fluor-uracil, hexamethyl trimeric cyanamide, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, mustargen, Ismipur, mesna, methotrexate, ametycin, mitoxantrone, prednisolone, prednisone, Procarbazine, raloxifene, streptozocin, tamoxifen, Tioguanine, Hycamtin, vinealeucoblastine(VLB), vincristine(VCR), and vindesine.
Comprise with other suitable cytotoxic drugs of compound drug combination of the present invention, but be not limited to, these are applied to the compound of neoplastic disease treatment admittedly, as with described in Publication about Document: Goodman and Gilman ' s The Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill.), these carcinostatic agents comprise, but be never limited to, aminoglutethimide (aminoglutethimide), l-Asparaginase, azathioprine, 5-azacytidine, CldAdo (cladribine), busulfan (busulfan), stilboestrol, 2 ', 2 '-difluoro dCDP choline, Docetaxel, red hydroxyl nonyl VITAMIN B4 (erythrohydroxynonyladenine), Ethinylestradiol, 5 FU 5 fluorouracil deoxynucleoside, floxuridine monophosphate, fludarabine phosphate (fludarabine phosphate), Fluoxymesterone (fluoxymesterone), flutamide (flutamide), Hydroxyprogesterone caproate bp 98, idarubicin (idarubicin), Interferon, rabbit, medroxyprogesterone acetate, Magace, melphalan (melphalan), mitotane (mitotane), taxol, pentostatin (pentostatin), N-phosphoric acid ethanoyl-L-Aspartic acid (PALA), Plicamycin (plicamycin), Me-CCNU (semustine), teniposide (teniposide), Uniteston, phosphinothioylidynetrisaziridine (thiotepa), trimethylammonium trimeric cyanamide, urine nucleosides and vinorelbine.
Other cytotoxin class carcinostatic agents suitable and compound combined utilization of the present invention comprise newfound cytotoxic substance, comprising, but be not limited to, oxaliplatin (oxaliplatin), gemcitabine (gemcitabine), capecitabine (capecitabine), Macrolide antitumour drug and natural or synthetic derivative thereof, Temozolomide (temozolomide) (Quinn et al., J.Clin.Oncology, 2003, 21 (4), 646-651), tositumomab (bexxar), trabedectin (Vidal et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract3181), with kinesin spindle body protein inhibitor Eg5 (Wood et al., Curr.Opin.Pharmacol.2001, 1, 370-377).
Other embodiment is that compound of the present invention can be in conjunction with other signal transduction inhibitors.What is interesting is that signal transduction inhibitor is using EGFR family as target, as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000,60 (Suppl.l), 15-23; Harari et al., Oncogene, 2000,19 (53), 6102-6114) with their parts separately.Such reagent comprises, but is never limited to, and antibody therapy is as Herceptin (trastuzumab), Cetuximab (cetuximab), her monoclonal antibody (ipilimumab) and handkerchief trastuzumab (pertuzumab).Such therapy also comprises, but be never limited to, small molecules kinase inhibitor is as imatinib (imatinib), Sutent (sunitinib), Xarelto (sorafenib), Tarceva (erlotinib), Gefitinib (gefitinib), Dasatinib (dasatinib), AMN107 (nilotinib), lapatinibditosylate (lapatinib), Ke Zhuo is for Buddhist nun (crizotinib), ruxolitinib, vemurafenib, vandetanib, pazopanib, Ah method is for Buddhist nun (afatinib), amuvatinib, Axitinib (axitinib), SKI-606 (bosutinib), brivanib, canertinib, cabozantinib, AZD2171 (cediranib), dabrafenib, dacomitinib, , danusertib, dovitinib, foretinib, ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), niraparib, oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, fork clip is for Buddhist nun (saracatinib), saridegib, tandutinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib, volasertib, BMS-540215, BMS777607, JNJ38877605, TKI258, GDC-0941 (Folkes, et al., J.Med.Chem.2008, 51, 5522), BZE235, etc..
Other embodiment is that compound of the present invention can bonding histone deacetylase inhibitors.Such reagent comprises, but be never limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract3024), LBH-589 (Beck et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract3025), MS-275 (Ryan et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract2452), FR-901228 (Piekarz et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract3028) and MGCDOI03 (US6, 897, 220).
Other embodiment is that compound of the present invention can be in conjunction with other carcinostatic agents as proteasome inhibitor and m-TOR inhibitor.These comprise, but be never limited to Velcade (Bortezomib) (Mackay et al., Proceedings of the American Society for Clinical Oncology, 2004,23, Abstract3109), and CCI-779 (Wu et al., Proceedings of the American Association of Cancer Research, 2004,45, abstract3849).Compound of the present invention can also, in conjunction with other carcinostatic agents as topoisomerase enzyme inhibitor, include, but not limited to camptothecine.
Those additional treatment agent can separate administration with the composition that comprises compound of the present invention, as a part for many dosage regimens.Or those therapeutical agents can be parts for one-pack type, form single composition together with compound of the present invention.If administration is as a part for many dosage regimens, two promoting agents can transmit mutually simultaneously continuously or within for some time, thereby obtain destination agent activity.
The change that can produce the compound of one-pack type and the consumption of additional treatment agent (those compositions that comprise an additional treatment agent are as described in the invention) in conjunction with carrier substance is depended on and is cured mainly and special mode of administration.Normally, the amount of composition additional treatment of the present invention agent comprises therapeutical agent as the amount of the normal administration of unique promoting agent using being no more than composition.On the other hand, the scope of the amount of existing disclosed composition additional treatment agent is approximately the 50%-100% of existing composition normal amount, and the reagent comprising is as unique active therapeutic agent.In the composition that comprises additional treatment agent at those, additional treatment agent will play synergy with compound of the present invention.
the application of compound and composition
Above-claimed cpd provided by the invention and pharmaceutical composition can be used for for the preparation of the medicine that protects, processes, treats or alleviate proliferative disease, also can be for the preparation of for suppressing or regulate the medicine of protein kinase activity.
Particularly, in composition of the present invention the amount of compound effectively detectablely arrestin kinases as the activity of B-Raf.The compounds of this invention will treat or reduce the deleterious effect of B-Raf signal response to patient as antitumor drug.
Compound of the present invention can be applied to, but is never limited to, and by the significant quantity of compound of the present invention or composition, patient's administration is prevented or treated patient's proliferative disease.Such disease comprises cancer, especially metastatic carcinoma, atherosclerosis and pulmonary fibrosis.
The treatment that compound of the present invention can be applied to knurl comprises cancer and metastatic carcinoma, further includes, but are not limited to, and cancer is as bladder cancer, mammary cancer, colorectal carcinoma, kidney, liver cancer, lung cancer (comprising small cell lung cancer), esophagus cancer, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer, and skin carcinoma (comprising squamous cell carcinoma); Lymphsystem hematopoiesis tumour (comprises leukemia, acute lymphoblastic tumour leukemia, acute lymphoblastic leukemia, B cell lymphoma, t cell lymphoma, He Jiejin (family name) lymphoma, non-hodgkin's (family name) lymphoma, hairy cell leukemia and Burkitt lymphoma); Marrow system hematopoiesis tumour (comprising acute and chronic myelocytic leukemia, myelodysplastic syndrome, and promyelocyte leukemia); The tumour of mesenchymal cell origin (comprise fibrosarcoma and rhabdosarcoma, and other sarcomas, as soft tissue and cartilage); Maincenter peripheral nervous system knurl (comprising astrocytoma, neuroblastoma, neurospongioma, and schwannoma); With other tumours (comprising melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicle knurl and Ka Bo Ji (family name) sarcoma).
Compound of the present invention and pharmaceutical composition also can be used for treating for example corneal graft rejection of eye disease, and the new vessel of eye forms, and retinal neovascularization forms and comprises that damage or metainfective new vessel form; Diabetic retinopathy; Terry's sign disease, and neovascular glaucoma; Retinal ischemia; Vitreous hemorrhage; Ulcer disease is as stomach ulcer; Pathological but non-malignant situation, as vascular tumor, comprises baby's hemangioendothelioma, the hemangiofibroma of nasopharynx and ANB; Female repro ductive system is disorderly as endometriosis.These compounds and pharmaceutical composition are equally also used for the treatment of oedema and the too high situation of vascular permeability.
Compound of the present invention and pharmaceutical composition can also be for the treatment of the situation relevant to diabetes as diabetic retinopathy and microangiopathies.The situation that compound of the present invention and pharmaceutical composition reduce for cancer patients's volume of blood flow equally.Compound of the present invention and pharmaceutical composition shift to reduce to patient tumors also beneficial effect.
Compound of the present invention and pharmaceutical composition, except useful to human treatment, also can be applicable to the animal of veterinary treatment pet, introduced variety and the animal on farm, comprise Mammals, rodent etc.The example of other animal comprises horse, dog and cat.At this, compound of the present invention comprises its pharmaceutically acceptable derivates.
Plural form is being applied to compound, and in the situation of salt etc., it also means single compound, salt etc.
The methods for the treatment of that comprises compound of the present invention or composition administration, further comprise the administration to patient's additional treatment agent (combination therapy), wherein additional treatment agent is selected from: chemotherapy, antiproliferative or anti-inflammatory agent, wherein additional treatment agent is applicable to treated disease, and additional treatment agent can with compound of the present invention or composition Combined Preparation, compound of the present invention or composition be as single formulation, or the compound separating or composition are as a part for multi-form.Additional treatment agent can from compound of the present invention administration simultaneously or administration when different.The latter's situation, administration can be staggered and be carried out as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, within 1 month or 2 months, carries out.
The present invention comprises equally to expressing the cytostatic method of B-Raf, and this method comprises compound of the present invention or composition and cells contacting, thus cell growth inhibiting.The cell of the suppressed growth of energy comprises: breast cancer cell, colorectal cancer cell, lung carcinoma cell, papillary carcinoma cell, prostate cancer cell, lymphoma cell, colon cancer cell, pancreatic cancer cell, ovarian cancer cell, cervical cancer cell, central nervous system cancer cells, human osteosarcoma cell, kidney cancer cell, hepatocellular carcinoma cells, transitional cell bladder carcinoma cell line, stomach cancer cell, head or carcinoma of neck cell, melanoma cell and leukemia cell.
The invention provides the method that suppresses B-Raf kinase activity in biological sample, this method comprises compound of the present invention or composition is contacted with biological sample.Term used in the present invention " biological sample " refers to the sample of live body outside, include, but not limited to cell cultures or cell extraction; The examination of living tissue material obtaining from Mammals or its extract; Blood, saliva, urine, ight soil, seminal fluid, tears, or other living tissue liquid substance and extracts thereof.Suppress kinase activity, particularly B-Raf kinase activity in biological sample, can be used for the known multiple use of one of ordinary skill in the art.Such purposes comprises, but is never limited to hematometachysis, organ transplantation, biological sample storage and biological assay.
" significant quantity " of compound of the present invention or pharmaceutically acceptable composition or " effective dose " refer to the significant quantity of processing or alleviating the severity of illness that one or more the present invention mentions.The method according to this invention, compound and composition can be the severity that any dosage and any route of administration are come effectively for the treatment of or palliated a disease.Essential measuring accurately changes the situation according to patient, and this depends on race, the age, and patient's general condition, the severity of infection, special factor, administering mode, etc.Compound or composition can with one or more other treatment agent Combined Preparation, as discussed in the present invention.
Compound of the present invention or its pharmaceutical composition can be applied to the dressing of implantable medical device, as prosthese, and artificial valve, artificial blood vessel, stem and catheter.For example, vascular stem, has been used to overcome restenosis (after damage, vessel wall shrinks again).Yet patient uses stem or other implantable devices, and by having, clot forms or the risk of platelet activation.The pharmaceutically acceptable composition precoating device that these disadvantageous effects can comprise compound of the present invention by use stops or alleviates.
The general preparation method of suitable dressing and the dressing of implantable device is in document US6,099,562; US5,886,026; And US5, describe to some extent in 304,121, dressing be typically biocompatible polymer material as hydrogel polymer, poly-methyl two silicon ethers, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), ethane-acetic acid ethyenyl ester, and composition thereof.Dressing can optionally further be covered by suitable dressing, as fluoro Simethicone, and polysaccharidase, polyoxyethylene glycol, phospholipid, or their combination, come performance group compound to control the feature discharging.Another aspect of the present invention comprises the implantable device that uses compound coating of the present invention.Compound of the present invention also can be coated on the medical instruments in implantable, as pearl, or " medicine storage institute " is provided with polymkeric substance or other molecular mixing, therefore with the comparison of pharmaceutical aqueous solution administering mode, allow drug release to have longer time limit.
the synthetic method of compound
For describing the present invention, below listed embodiment.But need be appreciated that and the invention is not restricted to these embodiment, only be to provide the method for the present invention of putting into practice.
Usually, compound of the present invention can prepare by method described in the invention, unless there is further instruction, wherein substituent definition is suc as formula shown in (I).Reaction scheme below and embodiment are for further illustrating content of the present invention.
The professional in affiliated field will recognize: chemical reaction described in the invention can be used for preparing suitably many other compounds of the present invention, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.For example; according to the present invention, the synthetic of the compound of those non-illustrations can successfully be completed by modifying method by those skilled in the art; as suitable protection, disturb group, by utilizing other known reagent except described in the invention, or reaction conditions is made to the modification of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, are decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as Aldrich Chemical Company, and Arco Chemical Company and Alfa Chemical Company does not have during use through being further purified, unless other aspects show.General reagent is from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu chemical company limited, Tianjin good fortune chemical reagent factory in morning, Wuhan Xin Huayuan development in science and technology company limited, Qingdao ，He Haiyang Chemical Plant, Qingdao of Teng Long chemical reagent company limited buys and obtains.
Anhydrous tetrahydro furan, dioxane, toluene, ether is through sodium Metal 99.5, to reflux to be dried to obtain.Anhydrous methylene chloride and chloroform are through hydrolith, to reflux to be dried to obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reaction is generally at nitrogen or argon gas direct draught or on anhydrous solvent, overlaps a drying tube (unless showing aspect other), and reaction flask is suitable soft rubber ball beyond the Great Wall all, and substrate is squeezed into by syringe.Glassware was all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDCl 3, d 6-DMSO, CD 3oD or d 6-acetone is solvent (report YippmWei unit), uses TMS (0ppm) or chloroform (7.25ppm) as reference standard.When there is multiplet, by the abbreviation of using below: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, two triplets).Coupling constant, represents with hertz (Hz).
The condition of Algorithm (MS) data is: and Agilent1200 or Agilent6120Series LCMS (pillar model: Zorbax SB-C18,2.1 * 30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Moving phase: 5-95%(is containing the CH of 0.1% formic acid 3cN) at (H that contains 0.1% formic acid 2o) ratio in, detects with UV at 210/254nm, by low-response EFI pattern (ESI).
The characteristic manner of pure compound is: Agilent1100Series high speed liquid chromatography (HPLC), detects with UV at 210nm and 254nm.Pillar operation at 40 ℃ conventionally.
The use of brief word below runs through the present invention:
BOC, Boc tert-butoxycarbonyl
BSA bovine serum albumin
BF 3.Et 2o boron trifluoride ether solution
CDCl 3deuterochloroform
CHCl 3chloroform
CH 2cl 2, DCM methylene dichloride
CH 3sO 2cl, MsCl Tosyl chloride
Cs 2cO 3cesium carbonate
CuI cuprous iodide
DAST diethylaminosulfur trifluoride
DBU 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene
DCE 1,2-ethylene dichloride
DEAD diethyl azodiformate
DEAD diethyl azodiformate
DIAD diisopropyl azodiformate
DIBAL diisobutyl aluminium hydride
DIEA, DIPEA diisopropyl ethyl amine
DMAP DMAP
DMF DMF
DME 1,2-glycol dimethyl ether
DMSO dimethyl sulfoxide (DMSO)
DPPA diphenyl phosphate azide
EDCI 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
EtOAc, EA ethyl acetate
Et 2o ether
Et 3n, TEA triethylamine
EtOCOCl Vinyl chloroformate
FBS foetal calf serum
G gram
H hour
HATU O-(7-nitrogen benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester
HBr Hydrogen bromide
HBTU O-benzotriazole-N, N, N ', N '-tetramethyl-urea hexafluorophosphate
HCl hydrochloric acid
H 2hydrogen
H 2o water
H 2o 2hydrogen peroxide
HOAc, AcOH acetic acid
HOBt I-hydroxybenzotriazole
K 2cO 3salt of wormwood
KOH potassium hydroxide
KH potassium hydride KH
LiHMDS LHMDS
NaHMDS sodium hexamethyldisilazide
LDA lithium diisopropyl amido
MCPBA metachloroperbenzoic acid
MeCN, CH 3cN acetonitrile
MeI methyl iodide
MeOH, CH 3oH methyl alcohol
MgSO 4magnesium sulfate
ML, ml milliliter
Min minute
N 2nitrogen
NaBH 4sodium borohydride
NaBH 3cN sodium cyanoborohydride
NaCl sodium-chlor
NaH sodium hydride
NaHCO 3sodium bicarbonate
NaH 2pO 4sODIUM PHOSPHATE, MONOBASIC
NaI sodium iodide
NaO (t-Bu) sodium tert-butoxide
NaOH sodium hydroxide
Na 2sO 4sodium sulfate
NH 3ammonia
NH 4cl ammonia chloride
NMP N-Methyl pyrrolidone
PBS phosphate buffered saline (PBS)
P (t-Bu) 3three (tertiary butyl) phosphine
Pd/C palladium/carbon
Pd 2(dba) 3two (dibenzyl subunit acetone) palladium
Pd (dppf) Cl 2two (diphenylphosphino) ferrocene palladium chlorides of 1,1-
Pd (OAc) 2palladium
Pd (PPh 3) 4tetrakis triphenylphosphine palladium
PE sherwood oil (60-90 ℃)
POCl 3phosphorus oxychloride
PyBop 1H-benzotriazole-1-base oxygen tripyrrole alkyl hexafluorophosphate
RT, rt, r.t. room temperature
Rt retention time
SnCl 4tin chloride
TBAB Tetrabutyl amonium bromide
TBAHSO 44-butyl ammonium hydrogen sulfate
TBTU O-(1H-benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester
TFA trifluoroacetic acid
TEAC bis-(tetraethyl ammonium) carbonate
THF tetrahydrofuran (THF)
μ L microlitre
ZnCl 2protochloride zinc
Following synthetic schemes has been described the come into the open step of compound of preparation the present invention.Wherein, each R 1be H or alkyl independently, each R 2be H, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl independently, M is basic metal or alkaline-earth metal, can be specifically Na, Li, K, Ca, Mg, etc., n is 0,1 or 2.
Synthetic schemes 1
Figure BDA0000372253260000451
As formula ( 4a) and ( 4b) shown in ester derivative can prepare by synthetic schemes 1:
Acyl chlorides ( 1) and aldehyde ( 2) suitable Lewis acid as: under zinc chloride, tin chloride, Eorontrifluoride etherate solution effects, generate chlorine alkyl ester ( 3).Reaction is under condition of no solvent or at methylene dichloride, and chloroform, carries out in the inert solvents such as 1,2-ethylene dichloride, and the applicable reaction times is 0.5～24 hour, and temperature range is between-40 ℃ to 40 ℃.Then, under alkaline condition, chloro alkyl ester ( 3) react with Wei Luofeini (vemurafenib), the azaindole compound that obtains replacing ( 4a), ( 4b) or ( 4a) and ( 4b), i.e. the compound of formula (I) definition.Applicable alkali comprises triethylamine, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride KH, two (trimethyl silicon based) sodium amide, two (trimethyl silicon based) potassium amide, lithium diisopropylamine (LDA), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene etc.Reaction is at DMF, methyl-sulphoxide, and tetrahydrofuran (THF), dioxane, carries out in the inert solvents such as 1,2-glycol dimethyl ether, and the applicable reaction times is 0.5～24 hour, and temperature range is between-20 ℃ to 60 ℃.
Synthetic schemes 2
Figure BDA0000372253260000461
As formula ( 8) shown in carbonates derivative can prepare by synthetic schemes 2:
The chloro-formic ester that chlorine alkyl replaces ( 5) and alcohol ( 6) at suitable alkali as pyridine, triethylamine, diisopropyl ethyl amine, under the effect of 2,6-lutidine, generate chlorine alkyl carbonate ( 7).Reaction is at methylene dichloride, and chloroform, carries out in the inert solvents such as 1,2-ethylene dichloride, and temperature range is between-15 ℃ to 40 ℃.Then, at applicable alkali as triethylamine, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride KH, two (trimethyl silicon based) sodium amide, two (trimethyl silicon based) potassium amide, lithium diisopropylamine (LDA), under the assistance of 1,8-diazabicyclo [5.4.0], 11 carbon-7-alkene (DBU), carbonic ether ( 7) react with Wei Luofeini (vemurafenib), obtain target compound ( 8), i.e. the compound of formula (I) definition.Reaction is at DMF, methyl-sulphoxide, and tetrahydrofuran (THF), carries out in the inert solvents such as dioxane or 1,2-glycol dimethyl ether (DME), and the applicable reaction times is 0.5～24 hour, and temperature range is between-20 ℃ to 40 ℃.
Synthetic schemes 3
Figure BDA0000372253260000471
As formula ( 12) shown in derivative of amino ester can prepare by synthetic schemes 3:
Chlorine alkyl chloride sulphonate ( 13) with the amino acid of amido protecting ( 9) at suitable alkali as sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, cesium carbonate, triethylamine, diisopropyl ethyl amine, 2,6-lutidine and catalyzer, as TBAHSO 4effect under, generate chlorine alkyl ester ( 10).Reaction is at methylene dichloride, chloroform, and water, carries out in 1,2-ethylene dichloride equal solvent, and temperature range is between-20 ℃ to 40 ℃.Then, under alkaline condition, by chlorine alkyl ester ( 10) to be added to Wei Luofeini (vemurafenib) upper, obtain compound ( 11).React applicable alkali and comprise potassium hydroxide, sodium hydroxide, sodium hydride or 1,8-diazabicyclo [5.4.0], 11 carbon-7-alkene (DBU) etc.Reaction is at DMF, methylene dichloride, and methyl-sulphoxide, tetrahydrofuran (THF), carries out in the inert solvents such as dioxane or 1,2-glycol dimethyl ether, and the applicable reaction times is 0.5～24 hour, and temperature range is between-10 ℃ to 40 ℃.Amino protecting group includes, but not limited to tertbutyloxycarbonyl (Boc), under acidic conditions, can remove compound ( 11) in Boc protection, for example, with the dichloromethane solution of trifluoroacetic acid (TFA) or the ethyl acetate solution of hydrogenchloride, process, obtain compound ( 12), i.e. the compound of formula (I) definition.
Synthetic schemes 4
Figure BDA0000372253260000481
As formula ( 18) shown in phosphoric acid and phosphoric acid salt derivative can prepare by synthetic schemes 4:
Chlorine alkyl chloride sulphonate ( 13) with the suitable salt of the phosphodiester of protection, as di(2-ethylhexyl)phosphate tert-butyl ester sylvite ( 14), at alkali and catalyzer, as TBAHSO 4effect under, generate chlorine alkylphosphonic acid carboxylic acid di tert butyl carbonate ( 15).Suitable alkali comprises sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, cesium carbonate, triethylamine, diisopropyl ethyl amine, 2,6-lutidine etc.Reaction is at methylene dichloride, and water, carries out in trichloromethane or 1,2-ethylene dichloride equal solvent, and temperature range is between-20 ℃ to 40 ℃.Then, under alkaline condition, by chlorine alkylphosphonic acid carboxylic acid di tert butyl carbonate ( 15) to be added to Wei Luofeini (vemurafenib) upper, obtain di(2-ethylhexyl)phosphate tert-butyl ester derivative ( 16).Applicable alkali comprises potassium hydroxide, sodium hydroxide, sodium hydride or 1,8-diazabicyclo [5.4.0], 11 carbon-7-alkene (DBU) etc.Reaction is at DMF, methyl-sulphoxide, and tetrahydrofuran (THF), carries out in the inert solvents such as dioxane or 1,2-glycol dimethyl ether, and the applicable reaction times is 0.5～24 hour, and temperature range is between-10 ℃ to 40 ℃.Compound ( 16) in the tertiary butyl (protecting group), can under acidic conditions, remove, for example, use the dichloromethane solution of trifluoroacetic acid or the ethyl acetate solution of hydrogenchloride to process, obtain phosphate cpd ( 17).Gained compound ( 17) with suitable alkali, as the aqueous solution of sodium hydroxide or potassium hydroxide, processing can obtain phosphoric acid salt ( 18), compound ( 17) and compound ( 18) be the compound of formula (I) definition.
Synthetic schemes 5
As formula ( 19) shown in acyl Ammonia derivative can prepare by synthetic schemes 5:
Under alkaline condition, acyl chlorides ( 1) react with Wei Luofeini (vemurafenib), obtain target compound ( 19), i.e. the compound of formula (I) definition.Applicable alkali comprises potassium hydroxide, sodium hydroxide, and triethylamine, etc.Reaction is at DMF, chloroform, and methylene dichloride, carries out in the inert solvents such as Isosorbide-5-Nitrae-dioxane, and the applicable reaction times is 0.5～24 hour, and temperature range is between-20 ℃ to 40 ℃.
Synthetic schemes 6
As formula ( 21) shown in acyl ammonia ester derivative can prepare by synthetic schemes 6:
Under alkaline condition, chloro-formic ester ( 20) react with Wei Luofeini (vemurafenib), obtain target compound ( 21), i.e. the compound of formula (I) definition.Applicable alkali comprises potassium hydroxide, sodium hydroxide, and triethylamine, etc.Reaction is at DMF, chloroform, and methylene dichloride, carries out in the inert solvents such as Isosorbide-5-Nitrae-dioxane, and the applicable reaction times is 0.5～24 hour, and temperature range is between-20 ℃ to 40 ℃.
Synthetic schemes 7
Figure BDA0000372253260000501
As formula ( 24) shown in aminoacyl Ammonia derivative can prepare by synthetic schemes 7:
Suitable alkali and catalyzer as the effect of EDCI under, the amino acid of amido protecting ( 22) react with Wei Luofeini (vemurafenib), obtain Boc protection azaindole compound ( 23).Applicable alkali comprises triethylamine, 4-phenyl pyrimidine etc.Reaction is at DMF, and methylene dichloride, carries out in the inert solvents such as dioxane or 1,2-glycol dimethyl ether, and the applicable reaction times is 0.5～24 hour, and temperature range is between-10 ℃ to 40 ℃.Amino protecting group includes, but not limited to tertbutyloxycarbonyl (Boc), and reaction is carried out in the inert solvents such as DMF.Compound ( 23) in protecting group (Boc), can under acidic conditions, remove, for example, use the dichloromethane solution of trifluoroacetic acid or the ethyl acetate solution of hydrogenchloride, obtain target compound ( 24), i.e. the compound of formula (I) definition.
Synthetic schemes 8
Figure BDA0000372253260000502
As formula ( 28) shown in ring derivative of amino ester can prepare by synthetic schemes 8:
Chlorine alkyl chloride sulphonate ( 13) with the acid of amido protecting ( 25) at alkali as sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, cesium carbonate, triethylamine, diisopropyl ethyl amine, 2,6-lutidine and catalyzer, as TBAHSO 4effect under, generate chlorine alkyl ester ( 26).Reaction is at methylene dichloride, and chloroform, carries out in the inert solvents such as 1,2-ethylene dichloride, and temperature range is between-20 ℃ to 40 ℃.Then, under alkaline condition, by chlorine alkyl ester ( 26) to be added to Wei Luofeini (vemurafenib) upper, the azaindole compound that obtains replacing ( 27), i.e. the compound of formula (I) definition.React applicable alkali and comprise potassium hydroxide, sodium hydroxide, sodium hydride or 1,8-diazabicyclo [5.4.0], 11 carbon-7-alkene (DBU) etc.Reaction is at DMF, methyl-sulphoxide, and tetrahydrofuran (THF), carries out in the inert solvents such as dioxane or 1,2-glycol dimethyl ether, and the applicable reaction times is 0.5～24 hour, and temperature range is between-10 ℃ to 40 ℃.Amino protecting group includes, but not limited to tertbutyloxycarbonyl (Boc), under acidic conditions, can remove replacement azaindole compound ( 27) in Boc protection, for example, with the dichloromethane solution of trifluoroacetic acid (TFA) or the ethyl acetate solution of hydrogenchloride, process, obtain target compound ( 28), i.e. the compound of formula (I) definition.
The present invention adopts following methods to carry out biological test to the compound shown in formula (I):
1, bioanalytical method
Adopt LC/MS/MS system to analyze, comprise Agilent1200 series vacuum degassing furnace, binary syringe pump, orifice plate automatic sampler, post thermostat container, tri-grades of level Four bar mass spectrographs of Agilent G6430 in charged spray ionization (ESI) source.Quantitative analysis is carried out under MRM pattern, and the parameter of MRM conversion is as shown in Table A:
The parameter of Table A MRM conversion
Many reaction detection scanning 490.2→383.1
Cracked voltage 230V
Capillary voltage 55V
Dryer temperature 350℃
Spraying gun 40psi
Moisture eliminator flow velocity 10L/min
Analyze and use Agilent XDB-C18,2.1x30mm, 3.5 μ M posts, inject 5 μ L samples.Analysis condition: the aqueous formic acid that moving phase is 0.1% (A) and 0.1% formic acid methanol solution (B).Flow velocity is 0.4mL/min.Eluent gradient is as shown in table B:
Table B eluent gradient
Time The gradient of Mobile phase B
0.5min 5%
1.0min 95%
2.2min 95%
2.3min 5%
5.0min Stop
In addition, the series of the Agilent6330 in addition LC/MS/MS spectrograph for analyzing, is equipped with G1312A binary syringe pump, G1367A automatic sampler and G1314C UV detector; LC/MS/MS spectrograph adopts ESI radioactive source.Each analyte is carried out to suitable positively charged ion models treated to use reference liquid and best analysis is carried out in MRM conversion.During analyzing, use Capcell MP-C18 post, specification is: 100x4.6mm I.D., 5 μ M (Phenomenex, Torrance, California, USA).Moving phase is 5mM ammonium acetate, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70:30, v/v); Flow velocity is 0.6mL/min; Column temperature remains on room temperature; Inject 20 μ L samples.
2, the stability analysis of compound in people and rats'liver particulate
(1) people or rat liver microsomes are placed in to polypropylene test tube and hatch, and guide it to copy.Typically hatch mixed solution and comprise people or rat liver microsomes (0.5mg protein/mL), compound to be analyzed (5 μ M) and cumulative volume are NADPH (1.0mM) potassium phosphate buffer (PBS of 200 μ L, 100mM, pH value is 7.4), by compound dissolution to be analyzed in DMSO, and use PBS to be diluted, the concentration that makes its final DMSO solution is 0.05%.And hatch in the water-bath communicating with air at 37 ℃, preincubate adds albumen in backward mixed solution in 3 minutes and starts reaction.In different time points (0,5,10,15,30 and 60min), add the ice-cold acetonitrile termination reaction of same volume.Sample is preserved until carry out LC/MS/MS analysis at-80 ℃.
The concentration of compound in people or rat liver microsomes mixtures incubated is to measure by the method for LC/MS/MS.The linearity range of concentration range is determined by each test-compound.
Parallel microsome of hatching test use sex change is as negative control, and hatching at 37 ℃, reacts and stop at different time point (0,15 and 60 minute).
Dextromethorphane Hbr (70 μ Μ) is as positive control, and hatching at 37 ℃, reacts and stop at different time point (0,5,10,15,30 and 60 minutes).In each measuring method, all comprise positive and negative control sample, to guarantee the integrity of microsome hatching system.
(2) stability data of compound of the present invention in people or rat liver microsomes also can be obtained by following test: people or rat liver microsomes are placed in to polypropylene test tube and hatch, and guide it to copy.Typical mixtures incubated comprises people or rat liver microsomes (ultimate density: 0.5mg albumen/mL), compound to be analyzed (ultimate density: 1.5 μ M) and cumulative volume be that the K-buffered soln of 30 μ L is (containing 1.0mM EDTA, 100mM, pH7.4).By compound dissolution to be analyzed, in DMSO, and with K-buffered soln dilution, the ultimate density that makes DMSO is 0.2%.After preincubate 10 minutes, add 15 μ L NADPH (ultimate density: 2mM) carry out enzymatic reaction, whole test is carried out in the incubation tube of 37 ℃.In different time points (0,15,30 and 60 minutes), add 135 μ L acetonitriles (containing IS) termination reaction.With 4000rpm centrifugal 10 minutes, except Deproteinization, collect supernatant liquid, with LC-MS/MS, analyze.
In above-mentioned test, ketanserin (1 μ M) is selected as positive control, hatching at 37 ℃, and reaction stops at different time point (0,15,30 and 60 minutes).In each measuring method, all comprise positive control sample, to guarantee the integrity of microsome hatching system.
The present invention adopts following methods to carry out data analysis, to obtain stability analysis result:
For each reaction, the concentration (representing with per-cent) by compound in people or rat liver microsomes are hatched is mapped by the per-cent of Relative Zero time point, with this, infers CLint CL in body int(ref.:Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y.Prediction of human hepatic clearance from vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition2001,29:1316-1324.)
3, the compounds of this invention Pharmacokinetic Evaluation in animal body
The present invention adopt following methods to the compounds of this invention the pharmacokinetic in mouse, rat, dog or monkey body assess:
The compounds of this invention is with the aqueous solution of the aqueous solution or 2%HPMC+1% twen-80, the salt brine solution of 5%DMSO+5%, and 4%MC or capsule form are carried out administration.For intravenous administration, animal gives 1 or the dosage of 2mg/kg.For oral dosage (p.o.), rat and mouse are 5 or 10mg/kg, and dog and monkey are 7-100mg/kg.At time point, be 0.25,0.5,1.0,2.0,3.0,4.0,6.0,8.0, within 12 and 24 hours, get blood (0.3mL), and 3,000 or 4,000rpm under centrifugal 10 minutes.Collect plasma solutions, and at-20 ℃ or-70 ℃, preserve until carry out above-mentioned LC/MS/MS analysis.
4, xenotransplantation tumor model
The drug effect of the compounds of this invention is to evaluate by the standard muroid model of transplantation tumor, and method is as follows:
Human tumor cells (for example, the strain of Colo-205 human colon cancer cell) after cultivating, collecting, (BALB/cA nu/nu, Shanghai SLAC Animal Lab.) (for group of solvents n=10, for each dosage group n=8) in the female nude mouse body in age in week in rear veutro subcutaneous vaccination in 6-7.When gross tumor volume reaches 100-250mm 3time, animal is divided into solvent control group (aqueous solution of 2%HPMC+1% twen-80) and compound group randomly.Following adopted compound carries out gastric infusion (3-50mpk/dose is dissolved in the aqueous solution of 2%HPMC+1% twen-80) to animal, starting Anywhere in 0 to 15 day from tumor cell inoculation, and conventionally carry out once every day in test.
4.1 tumor growths suppress (TGI) and analyze
The crystallization growth of tumour is to evaluate by the relation of gross tumor volume and time.The major axis of Subcutaneous tumor (L) and minor axis (W) measure weekly twice by calipers, and the volume of tumour (TV) is by formula (L * W 2)/2) calculate.TGI is calculated by the intermediate value of group of solvents mouse tumor volume and the difference of medicine group mouse tumor volume intermediate value, with the percentage of solvent control group gross tumor volume intermediate value, recently represents, by following formula, calculates:
Figure BDA0000372253260000541
Primary statistics is analyzed by repeating variance determination and analysis (RMANOVA) and is completed.Next by Scheffe psot hoc test method, carry out multiple comparisons.Separate solvent (2%HPMC+1% twen-80, etc.) negative contrast.
Result shows, compound provided by the invention shows good transformation period, clearance rate and good pharmacokinetic property, and the growth of tumour is also had to good restraining effect.
Below in conjunction with embodiment, compound provided by the invention, pharmaceutical composition and application thereof are further described.
embodiment 1:3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluoro phenyl (the third alkylsulfonyl) urethanum
Figure BDA0000372253260000551
By N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.2g, 0.41mmol) be suspended in 1, in 4-dioxane (15mL), and add successively wherein Vinyl chloroformate (EtOCOCl, 44mg, 0.41mmol) and triethylamine (0.14g, 1.38mmol).Reaction solution at room temperature stirred after 1.5 hours, concentrating under reduced pressure, and residue is through silica gel column chromatography (n-hexane/ethyl acetate (v/v)=4/1) purifying, and obtaining title compound is white solid (0.12g, 50%).
LC-MS(ESI,pos.ion)m/z562.1[M+H] +；
1H?NMR(400MHz,CDCl 3)δ1.08(t,J=7.2Hz,3H),1.29(t,J=7.2Hz,3H),1.92-2.05(m,2H),3.61(br,1H),3.70(br,1H),4.27-4.32(q,J=7.2Hz,2H),7.08-7.13(m,1H),7.45-7.51(m,3H),7.78(d,J=8.4Hz,2H),7.98(d,J=2.0Hz,1H),8.65(d,J=1.9Hz,1H),8.89(d,J=2.0Hz,1H),10.81(s,1H)。
(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-bis-for embodiment 2:N- fluorophenyl)-N-(the third alkylsulfonyl) benzamide
Figure BDA0000372253260000552
By N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.2g, 0.41mmol) be suspended in dioxane (15mL), and add wherein Benzoyl chloride (57mg, 0.41mmol) and triethylamine (0.14g, 1.38mmol).Reaction solution is in stirring at room after 1 hour, concentrating under reduced pressure.Residue is through silica gel column chromatography (n-hexane/ethyl acetate (v/v)=4/1) purifying, and obtaining title compound is white solid (0.14g, 55%).
LC-MS(ESI,pos.ion)m/z594.1[M+H] +；
1H?NMR(400MHz,CDCl 3)δ1.10(t,J=7.4Hz,3H),1.92-2.05(m,2H),3.74(t,J=7.6Hz,2H),6.27-6.32(q,J=7.2Hz,2H),7.06-7.10(m,1H),7.39(t,J=7.6Hz,2H),7.46-7.63(m,6H),8.16(d,J=7.0Hz,1H),8.65(d,J=2.1Hz,1H),8.84(d,J=2.0Hz,1H),10.08(s,1H)。
(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-bis-for embodiment 3:N- fluorophenyl)-N-(the third alkylsulfonyl) isobutyramide
Figure BDA0000372253260000561
Under room temperature, by N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.2g, 0.41mmol) and triethylamine (2mL) be suspended in (10mL) in chloroform, and add wherein isobutyryl chloride (173 μ L, 1.64mmol).Reaction solution is in stirring at room after 16 hours, concentrating under reduced pressure, and residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/1 is to 1/2) purifying, and obtaining title compound is white solid (2mg, 0.8%).
LC-MS(ESI,pos.ion)m/z560.1[M+H] +；
1H?NMR(400MHz,CDCl 3)δ1.04-1.15(t,J=7.4Hz,3H),1.12(s,3H),1.13(s,3H),1.88-1.99(m,2H),2.46-2.54(m,1H),3.55-3.80(m,2H),7.14-7.20(m,1H),7.46-7.55(m,3H),7.60-7.45(d,J=8.4Hz,2H),7.77(s,1H),8.64-8.68(d,J=2.0Hz,1H),8.86-8.90(m,1H),10.20(s,1H)。
embodiment 4:N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4- difluorophenyl)-N-(the third alkylsulfonyl) amine acetate
Figure BDA0000372253260000571
This step title compound prepares with reference to the described method of embodiment 3, use N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.2g, 0.41mmol), triethylamine (1mL) and Acetyl Chloride 98Min. (116 μ L, 1.64mmol) 1,4-dioxane (10mL) solution, preparing title compound is white solid (69mg, 31.8%).
LC-MS(ESI,pos.ion)m/z532.1[M+H] +；
1H?NMR(400MHz,CDCl 3)δ1.04-1.11(t,J=7.4Hz,3H),1.89-2.00(m,2H),2.12(s,3H),3.50-3.75(m,2H),7.15-7.21(m,1H),7.47-7.51(m,2H),7.50-7.55(m,1H),7.61-7.65(m,2H),7.79(s,1H),8.65-8.80(d,J=2.1Hz,1H),8.85-8.92(m,1H),10.93(s,1H)。
(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-bis-for embodiment 5:N- fluorophenyl)-N-(the third alkylsulfonyl) niacinamide
Figure BDA0000372253260000572
This step title compound prepares with reference to the described method of embodiment 3, use N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.1g, 0.2mmol), triethylamine (228 μ L, 1.6mmol) with nicotine acyl chloride hydrochloride (146mg, the preparation of chloroform 0.2mmol) (10mL) solution, thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, obtaining title compound is white solid (35mg, 28.9%).
LC-MS(ESI,pos.ion)m/z595.1[M+H] +；
1H?NMR(400MHz,d 6-DMSO)δ1.02-1.08(t,J=7.4Hz,3H),1.83-1.93(m,2H),3.86-3.93(m,2H),7.37-7.44(m,1H),7.44-7.50(m,1H),7.55-7.60(m,2H),7.74-7.82(m,2H),7.96-8.04(m,1H),8.25-8.29(m,1H),8.59(s,1H),8.64-8.67(m,1H),8.72-8.75(m,1H),8.77-8.80(m,1H),9.06-9.09(m,1H),13.11(s,1H)。
embodiment 6:(S)-2-amino-N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3- carbonyl)-2,4 difluorobenzene base)-3-methyl-N-(the third alkylsulfonyl) butanamide hydrochloride
Figure BDA0000372253260000581
step 1) (S)-1-(N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4- difluorophenyl) the third sulfoamido)-3-methyl isophthalic acid-oxo-butanes-2-yl) t-butyl carbamate
By N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2; 3-b] pyridine-3-carbonyl)-2; 4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.3g; 0.61mmol), Valine (0.28g, 1.29mmol) and the 4-phenyl pyrimidine (9mg of Boc protection; 0.06mmol) be dissolved in N; in dinethylformamide (2mL), and add wherein EDCI (234mg, 1.23mmol).Reaction solution after 16 hours, adds ethyl acetate (30mL) dilution in stirring at room, and gained mixture water (30mLx3) is washed.Organic phase Na 2sO 4dry, and concentrating under reduced pressure.Residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1 is to 2/1) purifying, and obtaining title compound is white solid (41mg, 29.1%).
LC-MS(ESI,neg.ion)m/z686.6[M-H] -；
step 2) (S)-2-amino-N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl base)-2,4 difluorobenzene base)-3-methyl-N-(the third alkylsulfonyl) butanamide hydrochloride
By (S)-1-(N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl) the third sulfoamido)-3-methyl isophthalic acid-oxo-butanes-2-base-t-butyl carbamate (50mg, 0.07mmol) be suspended in saturated HCl ethyl acetate solution (2mL), reaction solution is in stirring at room after 2 hours, concentrating under reduced pressure, obtaining title compound is white solid (49mg, 99%).
LC-MS(ESI,pos.ion)m/z589.2[M+H] +。
embodiment 7:7a (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl) methyl pivalate
7b (N-(3-(5-(4-chloro-phenyl-)-1-((pivaloyl oxygen) methyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl base)-2,4 dichloro benzene base) the third sulfoamido) methyl pivalate
Figure BDA0000372253260000591
Under room temperature, by N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (SN) (0.1g, 0.20mmol) and Et 3n (57 μ L, 0.41mmol) is dissolved in DMF (1mL), and adds wherein chloromethyl pivalate (35 μ L, 0.25mmol).Reaction is in stirring at room after 24 hours, concentrating under reduced pressure.Residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1 is to 1/1) purifying; obtain (5-(4 chloro-phenyl-)-3-(2; the fluoro-3-of 6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2; 3-b] pyridine-1-yl) methyl pivalate (30mg; 23%) and (N-(3-(5-(4-chloro-phenyl-)-1-((pivaloyl oxygen) methyl)-1H-pyrrolo-[2; 3-b] pyridine-3-carbonyl)-2; 4-dichlorophenyl) the third sulfoamido) methyl pivalate (20mg; 13.3%), be white solid.
7a (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,3-b] pyridine-1-yl) methyl pivalate
LC-MS(ESI,pos.ion)m/z604.1[M+H] +；
1H?NMR(400MHz,CDCl 3)δ1.04-1.10(t,J=7.4Hz,3H),1.16(s,9H),1.86-1.96(m,2H),3.10-3.16(m,2H),6.27(s,2H),6.58-6.65(br,1H),7.04-7.10(m,1H),7.46-7.51(m,2H),7.59-7.63(m,2H),7.69-7.77(m,1H),7.84(s,1H),8.67-8.70(d,J=2.2Hz,1H),8.84-8.87(d,J=2.2Hz,1H)。
7b (N-(3-(5-(4-chloro-phenyl-)-1-((pivaloyl oxygen) methyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl base)-2,4 dichloro benzene base) the third sulfoamido) methyl pivalate
LC-MS(ESI,pos.ion)m/z718.2[M+H] +;
1H?NMR(400MHz,CDCl 3)δ1.02-1.08(t,J=7.4Hz,3H),1.15(s,9H),1.18(s,9H),1.87-1.97(m,2H),3.13-3.19(m,2H),5.65(s,2H),6.28(s,2H),7.06-7.12(m,1H),7.45-7.50(m,2H),7.54-7.60(m,1H),7.59-7.64(m,2H),7.92(s,1H),8.66-8.69(d,J=2.2Hz,1H),8.84-8.87(d,J=2.1Hz,1H)。
embodiment 8:(N-(3-(1-(acetyl-o-methyl)-5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyrrole pyridine-3-carbonyl)-2,4 difluorobenzene base) the third sulfoamido) methyl acetic acid ester
step 1) chloromethyl acetate
In the mixture of Acetyl Chloride 98Min. (10mL, 94.6mmol) and zinc chloride (25mg, 186mmol), add paraformaldehyde (2.84g, 94.6mmol).Reaction solution after 40 minutes, rises to 60 ℃ in stirring at room, continues to stir 16 hours.Reaction is finished, and is cooled to room temperature, and mixture is filtered to (100%PE) with short silicagel column.Filtrate is at 30 ℃ of concentrating under reduced pressure, and gained raffinate is in 60 ℃ of underpressure distillation, and obtaining title compound is colorless oil (2.34g, 15.3%).
1H?NMR(400MHz,CDCl 3)δ1.18-1.23(d,J=7.0Hz,6H),2.56-2.68(m,1H),5.72(s,2H)。
step 2) (N-(3-(1-(acetyl-o-methyl)-5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine -3-carbonyl)-2,4 difluorobenzene base) the third sulfoamido) methyl acetic acid ester
Under room temperature, by N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.1g, 0.2mmol) and triethylamine (57 μ L, 0.4mmol) be dissolved in DMF (1mL), and add wherein chloromethyl acetate (23 μ L, 0.3mmol).Reaction solution stirring at room 16 as a child after, concentrating under reduced pressure, residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1 is to 1/1) purifying, obtaining title compound is white solid (52mg, 40.3%).
LC-MS(ESI,pos.ion)m/z634.1[M+H] +；
1H?NMR(400MHz,CDCl 3)δ1.03-1.09(t,J=7.4Hz,3H),2.07-2.12(d,J=4.9Hz,2H),3.13-3.17(m,2H),5.64(s,2H),6.28(s,2H),7.07-7.13(m,1H),7.46-7.51(m,2H),7.56-7.64(m,3H),7.93(s,1H),8.67-8.70(d,J=2.2Hz,1H),8.85-8.88(d,J=2.2Hz,1H)。
embodiment 9:(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) methyl isobutyrate
Figure BDA0000372253260000611
step 1) isopropylformic acid chloromethyl ester
This step title compound prepares with reference to the method for embodiment 8 steps 1, use isobutyryl chloride (10mL, 94.6mmol), zinc chloride (25mg, 186mmol) and paraformaldehyde (2.84g, 94.6mmol) preparation, obtaining title compound is colorless oil (5.52g, 42.9%).
1H?NMR(400MHz,CDCl 3)δ1.18-1.23(d,J=7.0Hz,6H),2.56-2.68(m,1H),5.72(s,2H)。
step 2) (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) methyl isobutyrate
Under room temperature, by N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.1g, 0.2mmol) and triethylamine (57 μ L, 0.40mmol) be dissolved in DMF (1mL), and add wherein isopropylformic acid chloromethyl ester (34mg, 0.25mmol).Reaction solution is in stirring at room after 16 hours, concentrating under reduced pressure.Residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1 is to 3/1) purifying, and obtaining title compound is white solid (45mg, 37.5%).
LC-MS(ESI,pos.ion)m/z590.1[M+H] +；
1H?NMR(400MHz,CDCl 3)δ1.04-1.10(t,J=7.4Hz,3H),1.85-1.96(m,2H),2.54-2.62(m,1H),3.09-3.15(m,2H),6.27(s,2H),6.51(s,1H),7.04-7.10(m,1H),7.46-7.51(m,2H),7.58-7.63(m,2H),7.70-7.77(m,1H),7.84(s,1H),8.67-8.70(d,J=2.2Hz,1H),8.85-8.88(d,J=2.2Hz,1H)。
embodiment 10:1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl) propionic acid ethyl ester
Figure BDA0000372253260000621
step 1) 1-chloroethyl propionic ester
At 0 ℃, in the mixture of propionyl chloride (10mL, 114.56mmol) and zinc chloride (25mg, 186mmol), add paraformaldehyde (7.76mL, 137.48mmol).Reaction solution, filters with short silicagel column (100% sherwood oil) after 16 hours in stirring at room.Filtrate is at 20 ℃ of concentrating under reduced pressure, and gained raffinate is in 25～27 ℃ of underpressure distillation, and obtaining title compound is colorless oil (4.7g, 30%).
1H?NMR(400MHz,CDCl 3)δ1.14-1.20(t,J=7.6Hz,3H),1.77-1.80(d,J=5.8Hz,3H),2.41(q,J=7.6Hz,2H),6.51-6.60(q,J=5.8Hz,1H)。
step 2) 1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) propionic acid ethyl ester
By N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.2g, 0.41mmol) be dissolved in N, in dinethylformamide (1mL), and wherein add triethylamine (165mg, 1.64mmol), mixture stirs after 10 minutes at 10 ℃, in 30 minutes, drips Tetrabutyl amonium bromide (264mg successively in system, N 1.64mmol), DMF (0.5mL) solution of dinethylformamide (0.5mL) solution and 1-chloroethyl propionic ester (67mg, 0.41mmol).Reaction solution stirs after 3 hours at 10 ℃, with ethyl acetate (40mL) dilution, and filters.Filtrate decompression is concentrated, and residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, and obtaining title compound is white solid (141mg, 58%).
LC-MS(ESI,neg.ion)m/z588.3[M-H] -；
1H?NMR(400MHz,CDCl 3)δ1.00-1.17(m,6H),1.85-2.00(m,5H)，2.26-2.41(m,2H),3.08-3.17(m,2H),6.50-6.80(br,1H),7.03-7.12(m,1H),7.35-7.42(m,1H),7.42-7.51(d,J=8.2Hz,2H),7.56-7.64(d,J=8.4Hz,2H),7.65-7.76(m,1H),7.77(s,1H),8.63-8.70(m,1H),8.77-8.83(m,1H)。
embodiment 11:1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl)-2-methyl-propyl propionic ester
Figure BDA0000372253260000631
step 1) 1-chloro-2-methyl propyl group propionic ester
-20 ℃, in the mixture of propionyl chloride (10mL, 115mmol) and zinc chloride (25mg, 186mmol), add isobutyric aldehyde (12.5mL, 138mmol).Reaction solution stirs after 2 hours at 0 ℃, returns to room temperature, continues to stir 16 hours.Reaction is finished, and short silicagel column for mixture (100% sherwood oil) filters.Filtrate is at 40 ℃ of concentrating under reduced pressure, and gained raffinate is in 90 ℃ of underpressure distillation, and obtaining title compound is colorless oil (0.52g, 2.7%).
1H?NMR(400MHz,CDCl 3)δ1.03-1.08(m,6H),1.15-1.20(t,J=7.5Hz,3H),2.10-2.20(m,1H),2.35-2.45(q,J=7.6Hz,1H),6.30-6.32(d,J=4.7Hz,1H)。
step 2) 1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl)-2-methyl-propyl propionic ester
This step title compound prepares with reference to the described method of embodiment 10 step 2, be about to N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2, 3-b] pyridine-3-carbonyl)-2, 4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.2g, 0.4mmol) be dissolved in N, in dinethylformamide (1mL), and add successively wherein potassium hydroxide (46mg, 0.8mmol), Tetrabutyl amonium bromide (264mg, N 0.81mmol), dinethylformamide (0.5mL) solution, and 1-chloro-2-methyl propyl group propionic ester (81mg, N 0.49mmol), dinethylformamide (0.5mL) solution, it is white solid (114mg that reaction makes title compound, 45.0%).
LC-MS(ESI,neg.ion)m/z616.3[M-H] -;
1H?NMR(400MHz,CDCl 3)δ0.77-0.85(d,J=6.8Hz,3H),1.03-1.20(m,9H),2.30-2.48(m,2H),2.68-2.80(m,1H),3.09-3.17(m,2H),4.12-4.27(m,2H),6.66(br,1H),6.87-6.83(d,J=9.2Hz,1H),7.03-7.10(m,1H),7.44-7.50(d,J=8.4Hz,2H),7.57-7.63(d,J=8.4Hz,2H),7.68-7.77(m,2H),8.65-8.70(d,J=2.0Hz,1H),8.78-8.83(m,1H)。
embodiment 12:1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl) ethyl valerate
Figure BDA0000372253260000641
step 1) 1-chloroethyl valerate
At-20 ℃, in the mixture of valeryl chloride (5mL, 41.5mmol) and zinc chloride (25mg, 186mmol), add acetaldehyde (2mL, 49.5mmol), reaction solution stirs after 1 hour at 0 ℃, returns to room temperature, continues to stir 2 hours.Reaction is finished, and short silicagel column for mixture (100%PE) filters, and filtrate is at 40 ℃ of concentrating under reduced pressure, and gained raffinate is in 60 ℃ of underpressure distillation, and obtaining title compound is colorless oil (5.5g, 81%).
1H?NMR(400MHz,CDCl 3)δ0.90-0.94(t,J=7.3Hz,3H),1.32-1.40(m,2H),1.58-1.65(m,2H),1.77-1.79(d,J=5.8Hz,3H),2.33-2.37(t,J=7.5Hz,2H),6.52-6.57(q,J=5.8Hz,1H)；
13C?NMR(400MHz,CDCl 3)δ13.7,22.2,25.2,26.7,33.980.6,171.5。
step 2) 1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) ethyl valerate
By N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.3g, 0.61mmol) be dissolved in dry N, in dinethylformamide (2.5mL), and add wherein potassium hydroxide (69mg, 1.23mmol), mixture stirs after 0.5 hour at 10 ℃, in 30 minutes, to DMF (0.5mL) solution that drips 1-chloroethyl valerate (0.1g, 0.61mmol) in system.Reaction solution stirs after 16 hours at 10 ℃, with ethyl acetate dilution, and filters.Filtrate decompression is concentrated, and residue obtains thick product through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=7/1) purifying.Thick product recrystallization in petrol ether/ethyl acetate (10/1), obtaining title compound is white solid (0.14g, 37.8%).
LC-MS(ESI,neg.ion)m/z615.5[M-H] -；
1H?NMR(400MHz,CDCl 3)δ0.83-0.87(t,J=7.3Hz,3H),1.04-1.08(t,J=7.4Hz,3H),1.24-1.30(m,2H),1.53-1.59(m,2H),1.86-1.92(m,2H),1.92-1.94(d,J=6.3Hz,3H),2.29-2.34(m,2H),3.10-3.14(m,2H),6.53(br,1H),7.05-7.10(m,1H),7.35-7.40(q,J=6.3Hz,1H),7.46-7.48(d,J=8.5Hz,2H),7.58-7.60(d,J=8.5Hz,2H),7.68-7.74(td,J=8.9,5.5Hz,1H),7.76(s,1H),8.66-8.67(d,J=2.1Hz,1H),8.80-8.81(d,J=2.0Hz,1H)。
embodiment 13:1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl) ethyl cyclopentane carboxylicesters
Figure BDA0000372253260000651
step 1) 1-chloroethyl cyclopentane-carboxylic acid ester
The mixture of pentamethylene formyl chloride (5g, 37.7mmol) and zinc chloride (25mg, 186mmol) is cooled to-20 ℃, and adds wherein acetaldehyde (1.83g, 41.5mmol).Reaction solution stirs after 1 hour at 0 ℃, returns to room temperature, continues to stir 2 hours.Reaction is finished, and short silicagel column for mixture (100%DCM) filters.Filtrate concentrates at 40 ℃, and gained raffinate is in 55 ℃ of underpressure distillation, and obtaining title compound is colorless oil (5.6g, 85%).
1H?NMR(400MHz,CDCl 3)δ1.57-1.62(m,2H),1.68-1.72(m,2H),1.78-1.79(d,J=5.8Hz,3H),1.80-1.93(m,4H),2.69-2.80(m,1H),6.52-6.57(q,J=5.8Hz,1H)；
13C?NMR(400MHz,CDCl 3)δ25.2,25.9,25.9,29.9,30.0,43.8,80.8,183.5。
step 2) 1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) ethyl cyclopentane carboxylicesters
This step title compound prepares with reference to the described method of embodiment 12 step 2, be about to N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2, 3-b] pyridine-3-carbonyl)-2, 4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.3g, 0.61mmol) be dissolved in anhydrous N, in dinethylformamide (2.5mL) solution, and add wherein potassium hydroxide (69mg, 1.23mmol) with 1-chloroethyl cyclopentane-carboxylic acid ester (108mg, N 0.61mmol), dinethylformamide (0.5mL) solution, the thick product of reaction gained is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1) purifying, and use sherwood oil recrystallization, obtaining title compound is white solid (147mg, 38%).
LC-MS(ESI,neg.ion)m/z627.5[M-H] -；
1H?NMR(400MHz,CDCl 3)δ1.04-1.08(t,J=7.4Hz,3H),1.23-1.29(m,2H),1.29-1.33(m,2H),1.61-1.66(m,2H),1.77-1.81(m,2H),1.86-1.89(m,2H),1.90-1.92(d,J=6.2Hz,3H),2.71-2.75(m,1H),3.10-3.14(m,2H),6.47(br,1H),7.05-7.10(m,1H),7.35-7.40(q,J=6.3Hz,1H),7.46-7.48(d,J=8.5Hz,2H),7.58-7.60(d,J=8.4Hz,2H),7.70-7.74(td,J=9.0Hz,5.5Hz,1H),7.75(s,1H),8.66-8.67(d,J=2.1Hz,1H),8.80-8.81(d,J=2.1Hz,1H)。
embodiment 14:1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl) ethyl isobutyrate
step 1) 1-isopropylformic acid chloromethyl ester
At-20 ℃, in the mixture of isobutyryl chloride (10mL, 94.7mmol) and zinc chloride (25mg, 186mmol), add acetaldehyde (5g, 113.6mmol).Reaction solution stirs after 16 hours at 0 ℃, returns to room temperature, continues to stir 2 hours.Short silicagel column for mixture (100%PE) filters, and filtrate concentrates at 30 ℃, and gained raffinate is in 65 ℃ of underpressure distillation, and obtaining title compound is colorless oil (2.64g, 18.5%).
1H?NMR(400MHz,CDCl 3)δ1.15-1.25(m,6H),1.77-1.82(d,J=5.8Hz,3H),2.50-2.63(m,1H),6.50-6.60(q,J=5.8Hz,1H)。
step 2) 1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) ethyl isobutyrate
By N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.5g, 1.02mmol) and potassium hydroxide (115mg, 2.04mmol) are suspended in dry N, in dinethylformamide (4mL), be cooled to 10 ℃, and in 0.5 hour, drip wherein 1-isopropylformic acid chloromethyl ester (37mg, DMF 0.25mmol) (1mL) solution.Reaction solution stirs after 3 hours at 10 ℃, adds ethyl acetate (40mL) dilution, and filters.Filtrate decompression is concentrated, and residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1 is to 4/1) purifying, and obtaining title compound is white solid (0.39g, 63.3%).
LC-MS(ESI,pos.ion)m/z626.0[M+Na] +；
1H?NMR(400MHz,CDCl 3)δ1.03-1.12(m,6H),1.13-1.20(d,J=7.0Hz,3H),1.85-1.97(m,5H),2.50-2.60(m,1H),3.09-3.17(m,2H),6.55(s,1H),7.04-7.10(m,1H),7.35-7.42(m,1H),7.46-7.51(d,J=8.4Hz,2H),7.57-7.63(d,J=8.4Hz,2H),7.68-7.75(m,1H),7.76(s,1H),8.67-8.70(d,J=2.1Hz,1H),8.78-8.84(d,J=1.8Hz,1H)。
embodiment 15:(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b]-1-yl) methylpropionate
step 1) chloromethyl propionic ester
In the mixture of paraformaldehyde (3.37g, 112.3mmol) and zinc chloride (25mg, 186mmol), add propionyl chloride (10mL, 112.3mmol).Reaction solution after 40 minutes, is heated to 60 ℃ in stirring at room, continues to stir 16 hours.Reaction is finished, and is cooled to room temperature, and mixture filters (100% sherwood oil) with short silicagel column.Filtrate is at 20 ℃ of concentrating under reduced pressure, and raffinate is in 40 ℃ of underpressure distillation, and obtaining title compound is colorless oil (9.8g, 70%).
1H?NMR(400MHz,CDCl 3)δ1.16-1.19(d,J=7.56Hz,3H),2.39-2.45(dd,J=7.56Hz,2H),5.71(s,2H)。
step 2) (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b]-1-yl) methylpropionate
The method that this step title compound is described with reference to embodiment 14 steps 2 prepares, be about to N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2, 3-b] pyridine-3-carbonyl)-2, 4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.3g, 0.61mmol) be dissolved in anhydrous N, in dinethylformamide (2.5mL) solution, and add wherein potassium hydroxide (69mg, 1.23mmol) with chloromethyl propionic ester (75mg, N 0.61mmol), dinethylformamide (0.5mL) solution, thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, and by recrystallizing methanol, obtaining title compound is white solid (145mg, 41.4%).
LC-MS(ESI,neg.ion)m/z574.1[M-H] -；
1H?NMR(400MHz,CDCl 3)δ1.04-1.08(t,J=7.4Hz,3H),1.09-1.13(t,J=7.5Hz,3H),1.87-1.93(m,2H),2.34-2.40(d,J=7.5Hz,2H),3.09-3.13(m,2H),6.27(s,2H),6.63(br,1H),7.04-7.09(m,1H),7.45-7.49(m,2H),7.58-7.61(m,2H),7.70-7.75(td,J=5.5Hz,9.0Hz,1H),7.85(s,1H),8.67-8.68(d,J=2.2Hz,1H),8.84-8.85(d,J=2.1Hz,1H)。
embodiment 16:1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl)-2-methyl-propyl isobutyrate
Figure BDA0000372253260000681
step 1) 1-chloro-2-methyl propyl group isobutyrate
At-20 ℃, in the mixture of isobutyryl chloride (10mL, 94.7mmol) and zinc chloride (25mg, 186mmol), add isobutyric aldehyde (10.4mL, 113.6mmol).Reaction solution stirs after 1 hour at 0 ℃, returns to room temperature, continues to stir 2 hours.Reaction is finished, and short silicagel column for mixture (100% sherwood oil) filters.Filtrate is at 40 ℃ of concentrating under reduced pressure, and gained raffinate is in 75 ℃ of underpressure distillation, and obtaining title compound is colorless oil (13.48g, 79.3%).
1H?NMR(400MHz,CDCl 3)δ1.04-1.08(dd,J=3.68,3.08Hz,6H),1.19-1.22(d,J=7.04Hz,6H),2.12-2.21(m,1H),2.57-2.65(m,J=7.04Hz,1H),6.29-6.31(d,J=4.72Hz,1H)。
step 2) 1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl)-2-methyl-propyl isobutyrate
The method that this step title compound is described with reference to embodiment 14 steps 2 prepares, be about to N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.3g, 0.61mmol) be dissolved in dry N, in dinethylformamide (2.5mL), add successively wherein KOH (69mg, 1.23mmol), 1-chloro-2-methyl propyl group isobutyrate (108mg, DMF 0.61mmol) (0.5mL) solution.Thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, and in methyl alcohol recrystallization, obtaining title compound is white solid (47mg, 13.4%).
LC-MS(ESI,neg.ion)m/z629.5[M-H] -；
1H?NMR(400MHz,CDCl 3)δ1.04-1.08(t,J=7.4Hz,3H),1.08-1.12(m,6H),1.86-1.95(m,2H)，2.54-2.61(m,1H),3.09-3.14(m,2H),6.27(s,2H),6.67(br,1H),7.04-7.09(m,1H),7.46-7.49(m,2H),7.59-7.61(m,2H),7.70-7.75(td,J=5.5,9.0Hz,1H),7.85(s,1H),8.67-8.68(d,J=2.1Hz,1H),8.84-8.85(d,J=2.1Hz,1H)。
embodiment 17:(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) methyl 2-(piperidin-4-yl) acetic ester hydrochloride
Figure BDA0000372253260000691
step 1) 4-(2-(chloromethyl)-2-oxoethyl) piperidines-1-carboxylic acid tert-butyl ester
2-(1-(tertbutyloxycarbonyl) piperidin-4-yl) acetic acid (1g, 4.1mmol) is dissolved in to DCM (25mL) and H 2in O (25mL), and add wherein sodium bicarbonate (1.38g, 16.4mmol) and 4-butyl ammonium hydrogen sulfate (0.14g, 0.41mmol).Mixture stirs after 10 minutes at 0 ℃, to methylene dichloride (5mL) solution that adds chloromethyl chlorsulfonic acid ester (499 μ L, 5.5mmol) in system.Reaction solution stirring at room 20 hours, reaction is finished, and salt solution for mixture (25mL) is washed, anhydrous Na 2sO 4dry, and concentrating under reduced pressure.Residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purifying, and obtaining title compound is colorless oil (826mg, 69.1%).
1H?NMR(400MHz,CDCl 3)δ1.11-1.24(m,2H),1.65-1.74(m,2H),1.90-2.03(m,1H),2.30-2.35(d,J=7.1Hz,2H),2.66-2.70(m,2H),4.00-4.16(m,2H),5.71(s,2H)。
step 2) 4-(2-((5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl) methoxyl group)-2-oxoethyl) piperidines-1-carboxylic acid tert-butyl ester
This step title compound prepares with reference to the described method of embodiment 14 step 2, be about to N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2, 3-b] pyridine-3-carbonyl)-2, 4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.1g, 0.2mmol) be dissolved in N, in dinethylformamide (0.9mL), and add wherein potassium hydroxide (23mg, 0.4mmol), and 4-(2-(chloromethyl)-2-oxoethyl) piperidines-1-carboxylic acid tert-butyl ester (60mg, N 0.2mmol), dinethylformamide (0.1mL) solution, the thick product of reaction gained is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1 is to 2/1) purifying, obtaining title compound is white solid (86mg, 56.6%).
LC-MS(ESI,neg.ion)m/z742.4[M-H] -；
1H?NMR(400MHz,CDCl 3)δ1.02-1.15(m,5H),1.43(s,9H),1.52-1.60(m,2H),1.70-1.87(m,3H),2.26-2.30(d,J=7.0Hz,2H),2.58-2.70(m,2H),3.10-3.15(m,2H),3.96-4.06(m,2H),6.28(s,2H),7.03-7.10(m,1H),7.46-7.50(m,2H),7.58-7.64(m,2H),7.69-7.77(m,1H),7.83(s,1H),8.66-8.70(d,J=2.2Hz,1H),8.84-8.87(d,J=2.2Hz,1H)。
step 3) (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) methyl 2-(piperidin-4-yl) acetic ester hydrochloride
By 4-(2-((5-(4-chloro-phenyl-)-3-(2; the fluoro-3-of 6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2; 3-b] pyridine-1-yl) methoxyl group)-2-oxoethyl) piperidines-1-carboxylic acid tert-butyl ester (78mg; 0.1mmol) be suspended in saturated HCl ethyl acetate solution (2mL); reaction solution at room temperature stirred after 2 hours; concentrating under reduced pressure, obtaining title compound is white solid (75mg, 100%).
LC-MS(ESI,pos.ion)m/z645.2[M+H] +；
1H?NMR(400MHz,d 6-DMSO)δ0.96-1.00(t,J=7.4Hz,3H),1.30-1.40(m,2H)，1.71-1.80(m,4H),1.87-1.97(m,1H),2.30-2.35(d,J=7.0Hz,2H),2.75-2.87(m,2H),3.13-3.22(m,4H),6.31(s,2H),7.31-7.38(m,1H),7.58-7.70(m,3H),7.79-7.85(m,2H),8.48(s,1H),8.67-8.70(m,2H),8.80-8.82(d,J=2.2Hz,1H),9.84(s,1H)。
embodiment 18:(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) methyl 2-amino-3 Methylbutanoic acid ester hydrochloride
Figure BDA0000372253260000711
step 1) chloromethyl 2-((tertbutyloxycarbonyl) amino)-3 Methylbutanoic acid ester
This step title compound prepares with reference to the described method of embodiment 17 step 1, is about to 2-((tertbutyloxycarbonyl) amino)-3 Methylbutanoic acid (1g, 4.6mmol) and is dissolved in DCM (25mL) and H 2o (25.ML) in, and add successively wherein sodium bicarbonate (1.55g, 18.4mmol), 4-butyl ammonium hydrogen sulfate (156mg, 0.46mmol), and methylene dichloride (5mL) solution of chloromethyl chlorsulfonic acid ester (559 μ L, 5.5mmol), it is colorless oil (877mg, 71.8%) that reaction makes title compound.
1H?NMR(400MHz,CDCl 3)δ0.92-0.94(d,J=6.9Hz,3H),0.99-1.01(d,J=6.9Hz,3H),1.45(s,9H),2.17-2.23(m,1H),4.25-4.29(m,1H),5.02-5.04(d,J=8.3Hz,1H),5.62-5.64(d,J=6.0,2H),5.87-5.89(d,J=6.0Hz,1H)。
step 2) (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) methyl 2-((tertbutyloxycarbonyl) amino)-3 Methylbutanoic acid ester
This step title compound prepares with reference to the described method of embodiment 14 step 2, be about to N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2, 3-b] pyridine-3-carbonyl)-2, 4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.1g, 0.2mmol) be dissolved in N, in dinethylformamide (0.9mL), and add wherein potassium hydroxide (23mg, 0.4mmol) with chloromethyl 2-((tertbutyloxycarbonyl) amino)-3 Methylbutanoic acid ester (54mg, N 0.2mmol), dinethylformamide (0.1mL) solution, the thick product of reaction gained is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1 is to 3/1) purifying, obtaining title compound is white solid (82mg, 55.8%).
LC-MS(ESI,neg.ion)m/z716.5[M-H] -；
1H?NMR(400MHz,CDCl 3)δ0.70-0.77(d,J=6.7Hz,3H),0.81-0.85(d,J=6.5Hz,3H),1.03-1.10(t,J=7.4Hz,3H),1.39(s,9H),1.85-1.96(m,2H)，1.98-2.10(m,1H),3.09-3.15(m,2H),4.17-4.23(m,1H),4.89-4.95(m,1H),6.26-6.40(dd,J=10.6,35.8Hz,2H),6.75(br,1H),7.03-7.10(m,1H),7.46-7.51(m,2H),7.58-7.64(m,2H),7.70-7.77(m,1H),7.83(s,1H),8.66-8.70(d,J=2.2Hz,1H),8.84-8.87(d,J=2.1Hz,1H)。
step 3) (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) methyl 2-amino-3 Methylbutanoic acid ester hydrochloride
This step title compound prepares with reference to the described method of embodiment 17 step 3; use (5-(4-chloro-phenyl-)-3-(2; the fluoro-3-of 6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2; 3-b] pyridine-1-yl) methyl 2-((tertbutyloxycarbonyl) amino)-3 Methylbutanoic acid ester (78mg; 0.11mmol) with saturated HCl ethyl acetate solution (2mL); it is white solid (40mg, 54%) that reaction makes title compound.
LC-MS(ESI,pos.ion)m/z619.2[M+H] +；
1H?NMR(400MHz,d 6-DMSO)δ0.80-0.90(t,J=6.9Hz,6H),0.95-1.01(d,J=7.4Hz,3H),1.71-1.82(m,2H),2.05-2.15(m,1H),3.12-3.20(m,2H),3.94-3.98(d,J=4.5Hz,1H),6.40-6.57(dd,J=10.6,35.4Hz,2H),7.30-7.39(m,1H),7.58-7.70(m,3H),7.78-7.87(d,J=8.5Hz,2H),8.53(s,2H),8.68(s,1H),8.79-8.85(d,J=2.1Hz,1H)。
embodiment 19:(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) methyl 2-Padil ester hydrochloride
step 1) chloromethyl 2-((tertbutyloxycarbonyl) amino) acetic ester
This step title compound prepares with reference to the described method of embodiment 17 step 1, be about to 2-((tertbutyloxycarbonyl) amino) acetic acid (1g, 5.7mmol) be dissolved in methylene dichloride (25mL) and water (25mL), and add successively wherein sodium bicarbonate (1.92g, 22.8mmol), 4-butyl ammonium hydrogen sulfate (194mg, 0.57mmol) with chloromethyl chlorsulfonic acid ester (693 μ L, methylene dichloride 6.8mmol) (5mL) solution, it is colorless oil (911mg, 71.3%) that reaction makes title compound.
step 2) (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) methyl 2-((tertbutyloxycarbonyl) amino) acetic ester
This step title compound prepares with reference to the described method of embodiment 14 step 2, be about to N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2, 3-b] pyridine-3-carbonyl)-2, 4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.1g, 0.2mmol) be dissolved in N, in dinethylformamide (0.9mL), and add wherein potassium hydroxide (23mg, 0.4mmol) with chloromethyl 2-((tertbutyloxycarbonyl) amino) acetic ester (46mg, DMF 0.2mmol) (0.1mL) solution, the thick product of reaction gained is through silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=4/1 is to 3/1) purifying, obtaining title compound is white solid (46mg, 33.3%).
LC-MS(ESI,pos.ion)m/z:677.1[M+H] +;
1H?NMR(400MHz,d 6-DMSO)δ1.00-1.06(t,J=7.4Hz,3H),1.34(s,9H),1.77-1.87(m,2H),3.17-3.24(m,2H),3.72-3.77(d,J=6.1Hz,2H),6.38(s,2H),7.26-7.32(t,J=6.1Hz,1H),7.35-7.42(m,1H),7.63-7.73(m,3H),7.85-7.90(d,J=8.6Hz,2H),8.55(s,1H),8.73(s,1H),8.85-8.88(d,J=2.2Hz,1H),9.85-9.90(br,1H)。
step 3) (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) methyl 2-Padil ester hydrochloride
This step title compound prepares with reference to the described method of embodiment 17 step 3; use (5-(4-chloro-phenyl-)-3-(2; the fluoro-3-of 6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2; 3-b] pyridine-1-yl) methyl 2-((tertbutyloxycarbonyl) amino) acetic ester (46mg; 0.07mmol) with saturated HCl ethyl acetate solution (2mL); it is white solid (36mg, 83.7%) that reaction makes title compound.
LC-MS(ESI,pos.ion)m/z577.1[M+H] +；
1H?NMR(400MHz,d 6-DMSO)δ0.95-1.00(d,J=7.4Hz,3H),1.70-1.80(m,2H),3.12-3.18(m,2H),3.85(s,1H),6.44(s,2H),7.30-7.37(m,1H),7.58-7.72(m,3H),7.79-7.84(m,2H),8.50-8.82(m,2H),8.51(s,1H),8.66(s,1H),8.80-8.82(d,J=2.2Hz,1H),9.84(s,1H)。
embodiment 20:(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) methyl 2-(methylamino) ethyl acetate hydrochloride
Figure BDA0000372253260000741
step 1) chloromethyl 2-((tertbutyloxycarbonyl) (methyl) amino) acetic ester
This step title compound prepares with reference to the described method of embodiment 17 step 1, be about to 2-((tertbutyloxycarbonyl) (methyl) amino) acetic acid (1g, 5.29mmol) be dissolved in methylene dichloride (25mL) and water (25mL), and add successively wherein sodium bicarbonate (1.78g, 21.2mmol), 4-butyl ammonium hydrogen sulfate (0.18g, 0.53mmol), and chloromethyl chlorsulfonic acid ester (638 μ L, DCM 6.35mmol) (5mL) solution, preparing title compound is colorless oil (0.87g, 69.4%).
1H?NMR(400MHz,CDCl 3)δ1.43(s,9H),2.94-2.96(d,J=5.0Hz,1H),3.97-4.05(d,J=33.9Hz,2H),5.74-5.75(d,J=4.0Hz,1H)。
step 2) (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) methyl 2-((tertbutyloxycarbonyl) (methyl) amino) acetic ester
This step title compound prepares with reference to the described method of embodiment 14 step 2, be about to N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2, 3-b] pyridine-3-carbonyl)-2, 4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.3g, 0.61mmol) be dissolved in DMF (2.5mL), and add wherein potassium hydroxide (69mg, 1.23mmol), with chloromethyl 2-((tertbutyloxycarbonyl) (methyl) amino) acetic ester (145mg, N 0.61mmol), dinethylformamide (0.5mL) solution, the thick product of reaction gained is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, obtaining title compound is colorless oil (0.33g, 77.9%).
LC-MS(ESI,neg.ion)m/z689.4[M-H] -；
1H?NMR(400MHz,CDCl 3)δ0.88-0.94(t,J=7.1Hz,3H),1.43(s,9H),1.89-1.91(m,2H),2.89(s,3H),3.08-3.13(m,2H),3.91-4.00(d,J=32.7Hz,2H),6.33(s,2H),6.78(br,1H),7.03-7.10(m,1H),7.47-7.50(m,2H),7.59-7.62(m,2H),7.70-7.75(m,1H),7.82-7.86(m,1H),8.66-8.68(d,J=1.6Hz,1H),8.85-8.87(d,J=1.6Hz,1H)。
step 3) (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) methyl 2-(methylamino) ethyl acetate hydrochloride
By (5-(4-chloro-phenyl-)-3-(2; the fluoro-3-of 6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2; 3-b] pyridine-1-yl) methyl 2-((tertbutyloxycarbonyl) (methyl) amino) acetic ester (0.33g; 0.48mmol) be suspended in saturated HCl ethyl acetate solution (3mL); reaction solution is in stirring at room after 3 hours; filter, obtaining title compound is white solid (168mg, 56%).
LC-MS(ESI,pos.ion)m/z591.1[M+H] +；
LC-MS(ESI,neg.ion)m/z588.5[M-H] -；
1H?NMR(400MHz,d 6-DMSO)δ0.96-1.00(t,J=7.4Hz,3H),1.73-1.79(m,2H),2.49-2.51(m,3H),3.13-3.17(m,2H),4.02(s,2H),6.45(s,2H),7.32-7.36(m,1H),7.59-7.62(dd,J=2.0,6.6Hz,2H),7.62-7.67(m,1H),7.80-7.83(dd,J=2.0,6.6Hz,2H),8.51(s,1H),8.67(br,1H),8.80-8.81(d,J=2.2Hz,1H),8.99(br,1H)。
embodiment 21:(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) methyl 2-amino-2-methyl propionate salts hydrochlorate
Figure BDA0000372253260000751
step 1) chloromethyl 2-((tertbutyloxycarbonyl) amino)-2 Methylpropionic acid ester
This step title compound prepares with reference to the described method of embodiment 17 step 1, be about to 2-((tertbutyloxycarbonyl) amino)-2 Methylpropionic acid (1.07g, 5.29mmol) be dissolved in methylene dichloride (25mL) and water (25mL), and add successively wherein sodium bicarbonate (1.78g, 21.2mmol), 4-butyl ammonium hydrogen sulfate (0.18g, 0.53mmol), with chloromethyl chlorsulfonic acid ester (638 μ L, DCM 6.35mmol) (5mL) solution, it is white solid (1.16g, 87.7%) that reaction makes title compound.
1H?NMR(400MHz,CDCl 3)δ1.43(s,9H),1.51(s,6H),4.90(m,1H),5.74-5.75(d,J=4.0Hz,1H)。
step 2) (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) methyl 2-((tertbutyloxycarbonyl) amino)-2 Methylpropionic acid ester
This step title compound prepares with reference to the described method of embodiment 14 step 2, be about to N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2, 3-b] pyridine-3-carbonyl)-2, 4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.3g, 0.61mmol) be dissolved in methylene dichloride (2.5mL), and add wherein potassium hydroxide (69mg, 0.4mmol), with chloromethyl 2-((tertbutyloxycarbonyl) amino)-2 Methylpropionic acid ester (158mg, N 0.61mmol), dinethylformamide (0.5mL) solution, the thick product of reaction gained is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1 is to 3/1) purifying, obtaining title compound is white solid (339mg, 78.7%).
LC-MS(ESI,pos.ion)m/z705.2[M+H] +；
1H?NMR(400MHz,CDCl 3)δ1.02-1.06(t,J=7.4Hz,3H),1.21(s,9H),1.41(s,6H),1.85-1.92(m,2H),2.89(s,3H),3.07-3.12(m,2H),4.93(br,1H),6.31(s,2H),7.01-7.05(m,1H),7.45-7.49(m,2H),7.57-7.61(m,2H),7.67-7.73(m,1H),7.87(s,1H),8.64-8.65(d,J=2.2Hz,1H),8.83-8.84(d,J=2.2Hz,1H)。
step 3) (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) methyl 2-amino-2-methyl propionate salts hydrochlorate
By (5-(4-chloro-phenyl-)-3-(2; the fluoro-3-of 6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2; 3-b] pyridine-1-yl) methyl 2-((tertbutyloxycarbonyl) amino)-2 Methylpropionic acid ester (339mg; 0.48mmol) be suspended in saturated HCl ethyl acetate solution (3mL); reaction solution is in stirring at room after 5 hours; filter, obtaining title compound is white solid (224mg, 72.6%).
LC-MS(ESI,pos.ion)m/z605.2[M+H] +；
LC-MS(ESI,neg.ion)m/z603.3[M-H] -；
1H?NMR(400MHz,d 6-DMSO)δ0.95-0.99(t,J=7.4Hz,3H),1.40(s,6H),1.73-1.79(m,2H),3.12-3.16(m,2H),6.44(s,2H),7.32-7.36(m,1H),7.59-7.61(dd,J=2.0,6.6Hz,2H),7.62-7.67(m,1H),7.80-7.83(dd,J=2.0,6.6Hz,2H),8.48(br,2H),8.52(s,1H),8.67(br,1H),8.79-8.80(d,J=2.2Hz,1H)。
embodiment 22:(2S)-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl) methyl 2-amino-3 methylvaleric acid ester hydrochloride
Figure BDA0000372253260000771
step 1) (2S)-chloromethyl 2-((tertbutyloxycarbonyl) amino)-3 methylvaleric acid ester
This step title compound prepares with reference to the described method of embodiment 17 step 1, be about to L-2-((tertbutyloxycarbonyl) amino)-3 methylvaleric acid (1g, 4.31mmol) be dissolved in methylene dichloride (25mL) and water (25mL), and add wherein sodium bicarbonate (1.55g, 18.4mmol), 4-butyl ammonium hydrogen sulfate (156mg, 0.46mmol), with chloromethyl chlorsulfonic acid ester (559 μ L, methylene dichloride 5.5mmol) (5mL) solution, it is colorless oil (0.91g, 76.1%) that reaction makes title compound.
1H?NMR(400MHz,CDCl 3)δ0.91-0.95(t,J=7.4Hz,3H),0.96-0.98(d,J=6.9Hz,3H),1.24-1.29(m,2H),1.44(s,9H),1.87-1.93(m,1H),4.29-4.33(m,1H),4.97-5.00(m,1H),5.61-5.63(d,J=6.0Hz,1H),5.87-5.89(d,J=6.0Hz,1H)。
step 2) (2S)-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl) methyl 2-((tertbutyloxycarbonyl) amino)-3 methylvaleric acid ester
This step title compound prepares with reference to the described method of embodiment 14 step 2, be about to N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2, 3-b] pyridine-3-carbonyl)-2, 4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.3g, 0.61mmol) be dissolved in N, in dinethylformamide (2.5mL), and add successively wherein potassium hydroxide (69mg, 1.22mmol), (2S)-chloromethyl 2-((tertbutyloxycarbonyl) amino)-3 methylvaleric acid ester (171mg, N 0.61mmol), dinethylformamide (0.5mL) solution, the thick product of reaction gained is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1 is to 3/1) purifying, obtaining title compound is white solid (288mg, 64%).
LC-MS(ESI,pos.ion)m/z733.1[M+H] +；
1H?NMR(400MHz,CDCl 3)δ0.69-0.72(t,J=7.3Hz,3H),0.77-0.79(d,J=7.3Hz,3H),0.84-0.91(m,2H),1.04-1.09(t,J=7.4Hz,3H),1.39(s,9H),1.72-1.79(m,1H),1.87-1.94(m,2H),3.09-3.14(m,2H),4.25-4.27(m,1H),4.89(br,1H),6.26-6.29(d,J=10.6Hz,1H),6.36-6.40(d,J=10.6Hz,1H),6.63(br,1H),7.04-7.09(m,1H),7.47-7.50(dd,J=2.0,6.6Hz,2H),7.59-7.62(dd,J=2.0,6.6Hz,2H),7.71-7.79(td,J=5.5,9.0Hz,1H),7.83(s,1H),8.67-8.68(d,J=2.1Hz,1H),8.85-8.86(d,J=2.1Hz,1H)。
step 3) (2S)-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl) methyl 2-amino-3 methylvaleric acid ester hydrochloride
By (2S)-(5-(4-chloro-phenyl-)-3-(2; the fluoro-3-of 6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2; 3-b] pyridine-1-yl) methyl 2-((tertbutyloxycarbonyl) amino)-3 methylvaleric acid ester (285mg; 0.45mmol) be suspended in saturated HCl ethyl acetate solution (3mL); reaction solution stirs after 10 hours at 0 ℃; filter, obtaining title compound is white solid (0.21g, 80.8%).
LC-MS(ESI,pos.ion)m/z633.1[M+H] +；
1H?NMR(400MHz,d 6-DMSO)δ0.69-0.72(t,J=7.0Hz,3H),0.75-0.78(d,J=6.1Hz,3H),0.95-1.00(t,J=7.4Hz,3H),1.03-1.07(m,2H),1.72-1.79(m,2H),1.79-1.84(m,1H),3.12-3.16(m,2H),3.95-3.97(m,1H),6.37-6.41(d,J=10.6Hz,1H),6.51-6.55(d,J=10.6Hz,1H),7.31-7.36(m,1H),7.58-7.61(d,J=8.2Hz,2H),7.62-7.67(m,1H),7.80-7.83(d,J=8.4Hz,2H),8.52(s,1H),8.55-8.63(m,2H),8.67(s,1H),8.80-8.82(d,J=2.2Hz,1H),9.88(br,1H)。
embodiment 23:(S)-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl) methyl 2-amino-4-methylvaleric acid ester hydrochloride
Figure BDA0000372253260000791
step 1) (S)-chloromethyl 2-((tertbutyloxycarbonyl) amino)-4-methylpent acid esters
This step title compound prepares with reference to the described method of embodiment 17 step 1, be about to L-2-((tertbutyloxycarbonyl) amino)-4-methylvaleric acid (1g, 4.31mmol) be dissolved in methylene dichloride (25mL) and water (25mL), add wherein sodium bicarbonate (1.55g, 18.4mmol), 4-butyl ammonium hydrogen sulfate (156mg, 0.46mmol), and chloromethyl chlorsulfonic acid ester (559 μ L, methylene dichloride 5.5mmol) (5mL) solution, it is colorless oil (0.98g, 81.1%) that reaction makes title compound.
1H?NMR(400MHz,CDCl 3)δ0.94-0.97(dd,J=1.2,6.5Hz,6H),1.44(s,9H),1.50-1.54(m,1H),1.70-1.76(m,1H),4.33-4.35(m,1H),4.83-4.86(m,1H),5.61-5.63(d,J=6.0Hz,1H),5.85-5.87(d,J=6.0Hz,1H)。
step 2) (S)-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) methyl 2-((tertbutyloxycarbonyl) amino)-4-methylpropionate
This step title compound prepares with reference to the described method of embodiment 14 step 2, be about to N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2, 3-b] pyridine-3-carbonyl)-2, 4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.3g, 0.61mmol) be dissolved in N, in dinethylformamide (2.5mL), and add wherein potassium hydroxide (69mg, 1.22mmol), (S)-chloromethyl 2-((tertbutyloxycarbonyl) amino)-4-methylpent acid esters (179mg, N 0.61mmol), dinethylformamide (0.5mL) solution, the thick product of reaction gained is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1 is to 3/1) purifying, obtaining title compound is white solid (287mg, 62.8%).
LC-MS(ESI,pos.ion)m/z:733.1[M+H] +；
1H?NMR(400MHz,CDCl 3)δ0.82-0.85(d,J=6.2Hz,6H),0.89-0.93(m,1H),1.04-1.09(t,J=7.4Hz,3H),1.24-1.27(m,2H),1.36(s,9H),1.87-1.94(m,2H),3.09-3.14(m,2H),4.25-4.27(m,1H),4.79(br,1H),6.26-6.29(d,J=10.6Hz,2H),6.35-6.38(d,J=10.6Hz,2H),6.68(br,1H),7.04-7.09(m,1H),7.47-7.50(dd,J=2.0,6.6Hz,2H),7.59-7.62(dd,J=2.0,6.6Hz,2H),7.70-7.77(td,J=5.5,9.0Hz,1H),7.83(s,1H),8.67-8.68(d,J=2.1Hz,1H),8.85-8.86(d,J=2.1Hz,1H)。
step 3) (S)-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) methyl 2-amino-4-methylvaleric acid ester hydrochloride
By (S)-(5-(4-chloro-phenyl-)-3-(2; the fluoro-3-of 6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2; 3-b] pyridine-1-yl) methyl 2-((tertbutyloxycarbonyl) amino)-4-methylpropionate (284mg; 0.39mmol) be suspended in saturated HCl ethyl acetate solution (3mL); reaction solution stirs after 10 hours at 0 ℃; concentrating under reduced pressure; petrol ether/ethyl acetate for residue (1/1) mixed solution is washed; obtaining title compound is white solid (204mg, 78.7%).
LC-MS(ESI,pos.ion)m/z633.1[M+H] +；
1H?NMR(400MHz,d 6-DMSO)δ0.73-0.76(t,J=5.4Hz,6H),0.84-0.85(m,1H),0.95-1.00(t,J=7.4Hz,3H),1.16-1.18(m,2H),1.72-1.79(m,2H),3.12-3.17(m,2H),3.99-4.03(m,1H),6.41-6.49(dd,J=10.5,19.5Hz,2H),7.31-7.35(m,1H),7.58-7.61(dd,J=2.0,6.6Hz,2H),7.61-7.66(m,1H),7.80-7.83(dd,J=2.0,6.6Hz,2H),8.47(br,2H),8.51(s,1H),8.67(br,1H),8.80-8.81(d,J=2.2Hz,1H),9.84(s,1H)。
embodiment 24:1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl) ethyl 2-amino-3-methyl butyl ester hydrochloride
Figure BDA0000372253260000801
step 1) 1-chloromethyl SULPHURYL CHLORIDE
1-chloroethyl chloro-formic ester (10g, 69.94mmol) is cooled to 0 ℃, and drips wherein chlorsulfonic acid (8.96g, 76.94mmol).Reaction solution stirs after 16 hours at 0 ℃, with methylene dichloride (15mL) and water (15mL) cancellation.Organic phase is used Na successively 2cO 3the aqueous solution (20mL) and salt solution (20mL) are washed, anhydrous Na 2sO 4dry, and concentrating under reduced pressure.Raffinate is in 54 ℃ of underpressure distillation, and obtaining title compound is colorless oil (4.5g, 36%).
1H?NMR(400MHz,CDCl 3)δ1.98-1.99(d,J=5.8Hz,3H),6.46-6.50(q,J=5.8Hz,1H)；
13C?NMR(100MHz,CDCl 3)δ26.3,91.1。
step 2) 2-((tertbutyloxycarbonyl) amino)-3 Methylbutanoic acid 1-chloroethene ester
This step title compound is with reference to synthetic the obtaining of method of embodiment 17 steps 1, be about to 2-((tertbutyloxycarbonyl) amino)-3 Methylbutanoic acid (3g, 13.81mmol) be dissolved in methylene dichloride (75mL) and water (75mL), and add wherein sodium bicarbonate (4.64g, 55.23mmol), 4-butyl ammonium hydrogen sulfate (469mg, 1.38mmol), with 1-chloroethyl chlorsulfonic acid ester (2.97g, methylene dichloride 16.57mmol) (15mL) solution, the thick product of reaction gained is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=100/1 is to 50/1) purifying, obtaining title compound is white solid (3g, 78%).
1H?NMR(400MHz,CDCl 3)δ0.90-0.92(m,3H),0.97-0.99(m,3H),1.45(s,9H),1.79-1.81(m,3H),2.14-2.19(m,1H),4.22-4.25(m,1H),4.99-5.01(m,1H),6.53-6.57(dd,J=5.7,11Hz,1H)。
step 3) 1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) ethyl 2-((tertbutyloxycarbonyl) amino)-3-methyl butyl ester
This step title compound obtains with reference to the described method of embodiment 14 step 2 is synthetic.Be about to N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2, 3-b] pyridine-3-carbonyl)-2, 4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.3g, 0.61mmol) be dissolved in anhydrous N, in dinethylformamide (2.5mL), and add successively wherein potassium hydroxide (69mg, 1.22mmol), with 1-chloroethyl 2-((tertbutyloxycarbonyl) amino)-3 Methylbutanoic acid ester (172mg, N 0.61mmol), dinethylformamide (0.5mL) solution, the thick product of reaction gained is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1 is to 3/1) purifying, obtaining title compound is orange (0.29g, 65%).
1H?NMR(400MHz,CDCl 3)δ0.82-0.92(m,6H),0.92-0.94(t,J=7.4Hz,3H),1.25(s,9H),1.89-1.96(m,5H),2.10-2.13(m,1H),3.11-3.12(m,2H),4.17-4.21(m,1H),6.95-7.13(m,2H),7.40-7.47(m,2H),7.58-7.60(m,2H),7.80-7.82(m,1H),8.01(s,1H),8.63-8.65(m,1H),8.80-8.83(m,1H)。
step 4) 1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) ethyl 2-amino-3-methyl butyl ester hydrochloride
By 1-(5-(4-chloro-phenyl-)-3-(2; the fluoro-3-of 6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2; 3-b] pyridine-1-yl) ethyl 2-((tertbutyloxycarbonyl) amino)-3 Methylbutanoic acid ester (0.29g; 0.39mmol) be suspended in saturated HCl ethyl acetate solution (4mL); reaction solution is in stirring at room after 2 hours; filter, obtaining title compound is white solid (0.15g, 57%).
LC-MS(ESI,pos.ion)m/z634.1[(M+H) +-HCl]；
1H?NMR(400MHz,CDCl 3)δ0.85-0.89(m,6H),0.98-0.99(t,J=7.4Hz,3H),1.76-1.89(m,3H),1.92-2.03(m,3H),3.00-3.13(m,2H),4.00-4.05(m,1H),6.95-7.13(m,2H),7.40-7.47(m,2H),7.58-7.60(m,2H),7.80-7.82(m,1H),8.01(s,1H),8.63-8.65(m,1H),8.80-8.83(m,1H)。
embodiment 25 (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) methyl acid phosphate sodium
Figure BDA0000372253260000821
step 1) di(2-ethylhexyl)phosphate tertiary butyl chloride methyl ester
This step title compound prepares with reference to the method for embodiment 17 steps 1, be about to di(2-ethylhexyl)phosphate tert-butyl ester sylvite (1g, 4.03mmol) be dissolved in methylene dichloride (20mL) and water (20mL), and add wherein sodium bicarbonate (1.34g, 16.1mmol), 4-butyl ammonium hydrogen sulfate (136mg, 0.40mmol), with chloromethyl SULPHURYL CHLORIDE (452 μ l, methylene dichloride 4.41mmol) (5mL) solution, it is colorless oil (1.02g, 95.3%) that reaction makes title compound.
1H?NMR(400MHz,CDCl 3)δ1.51(s,18H),5.62-5.66(d,J=14.9Hz,2H)；
13C?NMR(100MHz,CDCl 3)δ29.9,73.3,84.1。
step 2) ((5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) methyl) di(2-ethylhexyl)phosphate tertiary butyl ester
By N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.4g, 0.82mmol) be dissolved in N, in dinethylformamide (3.5mL), and add wherein KOH (91mg, 1.63mmol), mixture stirs after 20 minutes at 10 ℃, in 30 minutes, to the DMF solution (1mL) that drips di(2-ethylhexyl)phosphate tertiary butyl chloride methyl ester (0.21g, 0.82mmol) in system.Reaction solution stirs after 16 hours at 10 ℃, with ethyl acetate (100mL) dilution.Mixture H 2o (100mL) washes, and extracts with methylene dichloride (100mLx2).By the organic phase concentrating under reduced pressure merging, gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1) purifying, and obtaining title compound is colorless oil (0.28g, 47.2%).
LC-MS(ESI,pos.ion)m/z712.2[M+H] +；
1H?NMR(400MHz,CDCl 3)δ1.03-1.07(t,J=7.4Hz,3H),1.35(s,18H),1.84-1.94(m,2H),3.07-3.11(m,2H),6.13-6.17(d,J=13.0Hz,2H),7.01-7.06(m,1H),7.46-7.49(d,J=8.4Hz,2H),7.58-7.60(d,J=8.4Hz,2H),7.67-7.74(td,J=8.9Hz,5.6Hz,1H),7.96(s,1H),8.67-8.68(d,J=2.1Hz,1H),8.87-8.88(d,J=2.0Hz,1H)。
step 3) (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) methyl dihydrogen phosphate ester
By ((5-(4-chloro-phenyl-)-3-(2; the fluoro-3-of 6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2; 3-b] pyridine-1-yl) methyl) di(2-ethylhexyl)phosphate tertiary butyl ester (1g; 1.4mmol) be dissolved in methylene dichloride (25mL); and add wherein trifluoroacetic acid (1.6mL; 2.4g, 21mmol).Reaction solution is in stirring at room after 2 hours, concentrating under reduced pressure.Gained residue is washed through ethyl acetate (20mL), and obtaining title compound is white solid (0.56g, 66.5%).
LC-MS(ESI,pos.ion)m/z600.0[M+H] +；
1H?NMR(400MHz,d 6-DMSO)δ0.94-0.98(t,J=7.4Hz,3H),1.70-1.77(m,2H),3.10-3.14(m,2H),6.03-6.06(d,J=9.6Hz,2H),7.29-7.33(m,1H),7.57-7.60(d,J=8.5Hz,2H),7.60-7.65(m,1H),7.80-7.82(d,J=8.5Hz,2H),8.42-8.43(m,1H),8.65(s,1H),8.79-8.80(d,J=2.1Hz,1H),9.82(br,1H)。
step 4) (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) methyl acid phosphate sodium
Under room temperature; by (5-(4-chloro-phenyl-)-3-(2; the fluoro-3-of 6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2; 3-b] pyridine-1-yl) methyl dihydrogen phosphate ester (396mg; 0.66mmol) be dissolved in tetrahydrofuran (THF) (20mL); and drip wherein water (0.3mL) and tetrahydrofuran (THF) (4mL) solution of NaOH (58mg, 1.45mmol).Reaction solution, filters after 4 hours in stirring at room, and obtaining title compound is white solid (401mg, 94.4%).
LC-MS(ESI,pos.ion)m/z600.0[M+H] +；
1H?NMR(400MHz,D 2O)δ0.82-0.86(t,J=7.4Hz,3H),1.62-1.68(m,2H),2.88-2.92(m,2H),5.79-5.82(d,J=9.6Hz,2H),6.96-7.01(m,1H),7.27-7.30(d,J=8.5Hz,2H),7.31-7.37(td,J=9.3Hz,6.0Hz,1H),7.41-7.43(d,J=8.5Hz,2H),8.34-8.35(m,2H),8.46-8.47(d,J=2.0Hz,1H)。
embodiment 26:(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) methylethyl carbonic ether
Figure BDA0000372253260000841
step 1) carbonic acid ethyl chloromethyl ester
By chloromethylchloroformate (10g, 78.2mmol) be dissolved in methylene dichloride (200mL), be cooled to-20 ℃, and add wherein ethanol (5mL, 85.9mmol) and the methylene dichloride of pyridine (7.5mL, 93.2mmol) (50mL) solution.Reaction solution stirs after 1 hour at 0 ℃, returns to room temperature, continues to stir 2 hours.Mixture uses the 1N HCl aqueous solution (300mL) and salt solution (200mL) to wash successively, anhydrous Na 2sO 4dry, and concentrating under reduced pressure, obtaining title compound is colorless oil (8.75g, 81.1%).Compound is not purified, is directly used in next step reaction.
1H?NMR(400MHz,CDCl 3)δ1.32-1.36(t,J=7.2Hz,3H),4.26-4.31(m,J=7.2Hz,2H),5.72(s,2H)。
step 2) (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) methylethyl carbonic ether
By N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.1g, 0.2mmol) and triethylamine (114 μ L, 0.8mmol) be dissolved in N, in dinethylformamide (0.6mL), and add wherein Tetrabutyl amonium bromide (132mg, N 0.4mmol), dinethylformamide (0.2mL) solution, mixed solution stirs after 0.5 hour at 10 ℃, in system, drips chloromethyl ethyl carbonate ester (34mg, DMF 0.25mmol) (0.2mL) solution.Reaction solution stirs 3 hours at 10 ℃.Reaction is finished, ethyl acetate for mixture (40mL) dilution, and filter.Filtrate decompression is concentrated, and residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, and obtaining title compound is white solid (85mg, 73%).
LC-MS(ESI,pos.ion)m/z592.0[M+H] +；
1H?NMR(400MHz,CDCl 3)δ1.05-1.10(t,J=7.4Hz,3H),1.25-1.32(t,J=7.2Hz,3H),1.85-1.97(m,2H),3.09-3.16(m,2H),4.18-4.25(q,J=7.1Hz,2H),6.29(s,2H),6.51(s,1H),7.04-7.10(m,1H),7.46-7.51(d,J=8.5Hz,2H),7.57-7.63(d,J=8.5Hz,2H),7.70-7.77(m,1H),7.86(s,1H),8.67-8.70(d,J=2.1Hz,1H),8.83-8.85(d,J=2.1Hz,1H)。
embodiment 27:(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) isopropyl methyl carbonic ether
step 1) chloromethyl sec.-propyl carbonic ether
This step title compound prepares with reference to the described method of embodiment 26 step 1, be about to chloromethyl chlorsulfonic acid ester (10g, 78.2mmol) be dissolved in methylene dichloride (200mL), and add wherein Virahol (6.6mL, 86.2mmol) and pyridine (7.5mL, methylene dichloride 93.2mmol) (50mL) mixed solution, it is colorless oil (9.63g, 81%) that reaction makes title compound.Compound, without purification, is directly used in next step.
1H?NMR(400MHz,CDCl 3)δ1.33(s,3H),1.34(s,3H),4.92-4.99(m,J=6.3Hz,1H),5.72(s,3H)。
step 2) (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) isopropyl methyl carbonic acid
By N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.2g, 0.41mmol) and potassium hydroxide (46mg, 0.82mmol) be dissolved in DMF (1.5mL), and in 30 minutes, to DMF (0.5mL) solution that adds chloromethyl sec.-propyl carbonic ether (62mg, 0.41mmol) in system.Reaction solution, dilutes by ethyl acetate (40mL) after 3 hours 10 ℃ of reactions.Mixture is filtered, and filtrate decompression is concentrated, and gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purifying, and obtaining title compound is white solid (105mg, 43%).
LC-MS(ESI,pos.ion)m/z606.0[M+H] +；
1H?NMR(400MHz,CDCl 3)δ1.04-1.10(t,J=7.4Hz,3H),1.20-1.35(m,6H),1.85-1.95(m,2H),3.09-3.15(m,2H),4.84-4.92(m,1H),6.28(s,2H),6.56(s,1H),7.03-7.10(m,1H),7.46-7.51(d,J=8.5Hz,2H),7.57-7.63(d,J=8.5Hz,2H),7.69-7.77(m,1H),7.87(s,1H),8.66-8.70(d,J=2.1Hz,1H),8.83-8.87(d,J=2.1Hz,1H)。
embodiment 28:1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl) ethyl diethyldithiocarbamate carbonic ether
Figure BDA0000372253260000861
step 1) 1-chloroethyl ethyl carbonate ester
This step title compound prepares with reference to the described method of embodiment 26 step 1, be about to 1-chloroethyl chloro-formic ester (10g, 69.9mmol) be dissolved in methylene dichloride (200mL), and add wherein ethanol (4.5mL, 77.2mmol) and pyridine (6.8mL, methylene dichloride 84.5mmol) (50mL) mixed solution, it is colorless oil (9.32g, 87.7%) that reaction makes title compound.Product is not purified, is directly used in next step reaction.
1H?NMR(400MHz,CDCl 3)δ1.32-1.36(t,J=7.1Hz,3H),1.82-1.84(d,J=5.8Hz,3H),4.24-4.30(q,J=7.1Hz,2H),6.41-6.46(q,J=5.8Hz,1H)。
step 2) 1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) ethyl diethyldithiocarbamate carbonic ether
By N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.1g, 0.2mmol) be dissolved in N, in dinethylformamide (1mL), and add wherein salt of wormwood (85mg, 0.6mmol), mixture is in stirring at room after 10 minutes, add successively Tetrabutyl amonium bromide (132mg, 0.4mmol), and 1-chloroethyl ethyl carbonate ester (35mg, DMF 0.25mmol) (0.1mL) solution.Reaction solution was stirring at room 16 hours, and reaction is finished, by ethyl acetate mixture for (40mL) dilution, and filtration.Filtrate decompression is concentrated, and gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, and obtaining title compound is white solid (61mg, 50%).
LC-MS(ESI,neg.ion)m/z603.5[M-H] -;
1H?NMR(400MHz,CDCl 3)δ1.04-1.10(t,J=7.4Hz,3H),1.25-1.33(t,J=7.1Hz,3H)，1.85-1.93(m,2H),1.93-2.00(d,J=6.3Hz,3H),3.09-3.17(m,2H),4.12-4.27(m,2H),6.55(br,1H),7.04-7.10(m,1H),7.29-7.36(q,J=6.3Hz,1H),7.45-7.50(m,2H),7.57-7.63(m,2H),7.68-7.77(m,1H),7.79(s,1H),8.67-8.70(d,J=2.2Hz,1H),8.80-8.84(d,J=2.1Hz,1H)。
embodiment 29:1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl) ethyl cyclohexyl carbonic ether
Figure BDA0000372253260000871
step 1) 1-chloromethyl cyclohexyl carbonic ether
This step title compound prepares with reference to the method described in embodiment 26 steps 1, be about to 1-chloroethyl carbonate chloride (5g, 35mmol) be dissolved in methylene dichloride (100mL), and add wherein hexalin (3.9g, 38.5mmol) and pyridine (3.3g, mixture 42mmol), it is colourless liquid (7g, 96.9%) that reaction makes title compound.Products therefrom is not purified, is directly used in next step reaction.
1H?NMR(400MHz,CDCl 3)δ1.28-1.25(m,1H)，1.30-1.42(m,2H),1.48-1.58(m,3H),1.74-1.78(m,2H)1.82-1.83(d,J=5.8Hz,3H)，1.91-1.96(m,2H),4.66-4.72(m,1H),6.41-6.45(m,1H)。
step 2) 1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) ethyl cyclohexyl carbonic ether
By N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (SN) (5g, 10.2mmol) is dissolved in tetrahydrofuran (THF) (36mL), and add wherein potassium hydroxide (1.1g, 20.4mmol).Reaction solution is in stirring at room after 0.5 hour, to tetrahydrofuran (THF) (9mL) solution that adds 1-chloromethyl cyclohexyl carbonic ether (2.3g, 11.2mmol) in system.Reaction solution refluxes 16 hours, and reaction is finished, and mixture is cooled to room temperature, and dilutes with tetrahydrofuran (THF) (50mL).Filter, filtrate decompression is concentrated, and gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=8/1) purifying, and obtaining title compound is white solid (3.49g, 51.9%).
LC-MS(ESI,neg.ion)m/z657.5[M-H] -；
1H?NMR(400MHz,CDCl 3)δ1.05-1.08(t,J=7.4Hz,3H)，1.20-1.58(m,8H),1.72(m,2H),1.89-1.94(m,5H),3.10-3.14(m,2H),4.59(m,1H),6.40-6.50(d,J=1.7Hz,1H),7.04-7.09(m,1H),7.30-7.33(m,1H),7.46-7.48(m,1H),7.58-7.60(m,1H),7.71-7.74(m,1H),7.79(s,1H),8.67(d,J=2.2Hz,1H),8.81-8.82(d,J=2.0Hz,1H)。
embodiment 30:1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl) ethyl sec.-propyl carbonic ether
step 1) 1-chloroethyl sec.-propyl carbonic ether
By 1-chloroethyl carbonate chloride (10g, 69.9mmol) be dissolved in methylene dichloride (200mL), be cooled to-20 ℃, add wherein Virahol (5.9mL, 76.9mmol) and the DCM of pyridine (6.75mL, 83.9mmol) (50mL) solution.Reaction solution after 2 hours, returns to room temperature 0 ℃ of reaction, continues to stir 2 hours.Reaction is finished, and mixture uses the 1N HCl aqueous solution (250mLx2) and salt solution (250mL) to wash successively, anhydrous Na 2sO 4dry, and concentrating under reduced pressure, obtaining title compound is colorless oil (9.6g, 82.4%).Compound is not purified, is directly used in next step reaction.
1H?NMR(400MHz,CDCl 3)δ1.31-1.34(m,6H),1.81-1.82(d,J=5.84Hz,3H),4.88-4.98(m,1H),6.41-6.45(dd,J=5.84Hz,1H)。
step 2) 1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo- [2,3-b] pyridine-1-yl) ethyl sec.-propyl carbonic ether
The method that this step title compound is described with reference to embodiment 26 steps 2 prepares.Be about to N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2, 3-b] pyridine-3-carbonyl)-2, 4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.3g, 0.61mmol), potassium hydroxide (69mg, 1.23mmol) be dissolved in dry N, in dinethylformamide (2mL), and add wherein Tetrabutyl amonium bromide (396mg, N 1.23mmol), dinethylformamide (0.5mL) solution, with 1-chloromethyl sec.-propyl carbonic ether (102mg, N 0.61mmol), dinethylformamide (0.5mL) solution, thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/5) purifying, and in methyl alcohol recrystallization, obtaining title compound is white solid (42mg, 11.1%).
LC-MS(ESI,neg.ion)m/z:617.4[M-H] -；
1H?NMR(400MHz,CDCl 3)δ1.04-1.08(t,J=7.4Hz,3H),1.22-1.29(m,6H),1.87-1.94(m,5H),3.10-3.14(m,2H),4.84-4.87(m,1H),6.59(br,1H),7.04-7.09(m,1H),7.30-7.34(dd,J=6.2Hz,1H),7.46-7.48(d,J=8.5Hz,2H),7.58-7.60(d,J=8.5Hz,2H),7.69-7.75(td,J=5.5,9.0Hz,1H),7.79(s,1H),8.67-8.68(d,J=2.2Hz,1H),8.81-8.82(d,J=2.0Hz,1H)。
embodiment 31 (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) methyl benzol carbonate
Figure BDA0000372253260000901
step 1) chloromethyl phenyl carbonic ether
Chloromethyl chloro-formic ester (1g, 7.8mmol) is dissolved in methylene dichloride (40mL), is cooled to-20 ℃, in 20 minutes, methylene dichloride (10mL) solution that adds wherein phenol (730mg, 7.8mmol) and pyridine (750 μ L, 9.3mmol).Reaction solution stirs after 4 hours at 0 ℃, returns to room temperature, continues to stir 1 hour.Reaction is finished, and mixture uses the 1N HCl aqueous solution (50mL) and salt solution (50mL) to wash successively, anhydrous Na 2sO 4dry, and concentrating under reduced pressure.Gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=100/1) purifying, and obtaining title compound is colorless oil (847mg, 58.2%).
1H?NMR(400MHz,CDCl 3)δ5.84(s,2H),7.22-7.27(d,J=8.2Hz,2H),7.28-7.34(t,J=7.4Hz,1H),7.40-7.49(t,J=7.8Hz,2H)。
step 2) (5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole cough up also [2,3-b] pyridine-1-yl) methyl benzol carbonate
By N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfanilamide (SN) (0.1g, 0.2mmol), Tetrabutyl amonium bromide (132mg, 0.4mmol) and triethylamine (114 μ L, 0.80mmol) be dissolved in N, in dinethylformamide (1mL), and add wherein chloromethyl phenyl carbonic ether (46mg, 0.25mmol).Reaction solution, with ethyl acetate (40mL) dilution, and filters after 12 hours in stirring at room.Filtrate decompression is concentrated, and gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, and obtaining title compound is white solid (10mg, 7.7%).
LC-MS(ESI,pos.ion)m/z640.0[M+H] +；
1H?NMR(400MHz,CDCl 3)δ0.98-1.12(t,J=7.4Hz,3H),1.80-1.90(m,2H),3.02-3.09(m,2H),6.40(s,2H),6.51(s,1H),7.02-7.08(m,1H),7.11-7.16(d,J=7.6Hz,2H),7.25-7.30(m,1H),7.37-7.42(m,2H),7.46-7.52(d,J=8.4Hz,2H),7.57-7.64(d,J=8.4Hz,2H),7.67-7.75(m,1H),7.88(s,1H),8.70-8.73(d,J=2.1Hz,1H),8.87-8.90(d,J=2.1Hz,1H)。
embodiment 32:1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl base)-1H-pyrrolo-[2,3-b] pyridine-1-yl) ethyl phosphonic acid sodium
Figure BDA0000372253260000911
step 1) 1-chloroethyl SULPHURYL CHLORIDE
At 0 ℃, in 40 minutes, in 1-chloroethyl chloro-formic ester (54.4mL, 504mmol), add chlorsulfonic acid (49.0mL, 729mmol), add rear system and stir 2 hours at 0 ℃.Reaction solution is warming up to 5 ℃ to be stirred after 10 minutes, slowly add wherein DCM (500mL) and trash ice (20g), cancellation reaction, then use successively saturated sodium bicarbonate aqueous solution (400mL) and saturated common salt water washing (400mL), merge organic phase, after anhydrous sodium sulfate drying, it is faint yellow solid (54.2g, 60%) that concentrating under reduced pressure obtains title compound.
1H?NMR(400MHz,CDCl 3):δ1.98-2.00(d,J=5.8Hz,3H),6.46-6.51(q,J=5.8Hz,1H)。
step 2) the di(2-ethylhexyl)phosphate tertiary butyl-1-chloro-ethyl ester
This step title compound prepares with reference to the method for embodiment 17 steps 1, be about to di(2-ethylhexyl)phosphate tert-butyl ester sylvite (33g, 133mmol) be dissolved in methylene dichloride (600mL) and water (600mL), and add wherein sodium bicarbonate (44.6g, 531mmol), 4-butyl ammonium hydrogen sulfate (4.52g, 13.3mmol), with 1-chloroethyl SULPHURYL CHLORIDE (26g, methylene dichloride 146mmol) (100mL) solution, it is colorless oil (14.3g, 40%) that reaction makes title compound.
1H?NMR(400MHz,CDCl 3):δ1.52(s,18H),1.81(d,J=5.6Hz,3H),6.17-6.24(m,1H)。
step 3) 1-((5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) ethyl) di(2-ethylhexyl)phosphate tertiary butyl ester
By N-(3-(5-(4-chloro-phenyl-)-1H-pyrrolo-[2; 3-b] pyridine-3-carbonyl)-2; 4-difluorophenyl)-propane-1-sulfanilamide (SN) (9.8g; 20mmol) be dissolved in N; in dinethylformamide (120mL); and add wherein KOH (4.48g; 80mmol); potassiumiodide (0.33g; 2mmol), under normal temperature, in nitrogen protection, in 5 minutes, in system, drip the chloro-ethyl ester (10.9g of the di(2-ethylhexyl)phosphate tertiary butyl-1-; DMF solution (20mL) 40mmol).Reaction solution stirs after 6 hours at 50 ℃, with ethyl acetate (700mL) dilution.Mixture is used H successively 2o (400mLx3) and saturated aqueous common salt (400mL) are washed, and add methylene dichloride (20mL) after organic phase concentrating under reduced pressure, have solid to occur, filtration under diminished pressure, and after filtrate is concentrated, obtaining title compound crude product is brown solid (31g, 106%).
LC-MS(ESI,pos.ion)m/z:724.2[M-1]。
step 4) 1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) ethyl phosphonic acid two hydrogen esters
By 1-((5-(4-chloro-phenyl-)-3-(2; the fluoro-3-of 6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2; 3-b] pyridine-1-yl) ethyl) di(2-ethylhexyl)phosphate tertiary butyl ester (20g; crude product) be dissolved in ethyl acetate (30mL); and add wherein phosphoric acid (85%, 90mL).Reaction solution after 2 minutes, adds water (200mL) cancellation reaction in stirring at room.Gained mixture extracts through ethyl acetate (300mLx3), merges organic phase, and dry rear pressurization concentrates and obtains title compound is brown solid (19.5g, 74%).
LC-MS(ESI,pos.ion)m/z:612.1[M-1];
1H?NMR(400MHz,DMSO-d 6):δ0.95(t,J=7.4Hz,3H),1.65-1.81(m,5H),3.11(t,J=7.4Hz,2H),6.75-6.87(m,1H),7.28(t,J=8.8Hz,1H),7.57(d,J=8.3Hz,2H),7.51-7.72(m,1H),7.77(d,J=8.3Hz,2H),8.31-8.35(m,1H),8.57-8.61(m,1H),8.69-8.74(m,1H),9.85(br,1H)。
step 5) 1-(5-(4-chloro-phenyl-)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H- pyrrolo-[2,3-b] pyridine-1-yl) ethyl phosphonic acid sodium
Under room temperature; by 1-(5-(4-chloro-phenyl-)-3-(2; the fluoro-3-of 6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2; 3-b] pyridine-1-yl) ethyl phosphonic acid two hydrogen ester (4g; 6.5mmol) be dissolved in the mixing solutions of ethyl acetate (20mL) and tetrahydrofuran (THF) (10mL); and drip wherein at normal temperatures water (1mL) solution of NaOH (0.57g, 14.3mmol).Reaction solution, after stirred overnight at room temperature, filters, and at 45 ℃ of gained solids, drying under reduced pressure is after 10 hours, and obtaining title compound is white solid (4.0g, 93%).
LC-MS(ESI,pos.ion)m/z:612.1[M-1];
1H?NMR(400MHz,D 2O):δ0.88(t,J=7.4Hz,3H),1.65-1.75(m,2H),1.74(d,J=5.9Hz,3H),2.93(t,J=7.5Hz,2H),6.55-6.62(m,1H),7.04(t,J=8.8Hz,1H),7.40(d,J=8.4Hz,2H),7.37-7.44(m,1H),7.55(d,J=8.2Hz,2H),8.32(br,1H),8.41-8.47(m,1H),8.55(d,J=1.8Hz,1H)。
Biological test
The compound that adopts method and apparatus mentioned above to prepare the embodiment of the present invention carries out bioanalysis.
The stability of embodiment A in people and rat liver microsomes
People or rat liver microsomes are placed in to polypropylene test tube and hatch, and guide it to copy.Typically hatch mixed solution and comprise people or rat liver microsomes (0.5mg protein/mL), target compound (5 μ M) and cumulative volume are NADPH (1.0mM) potassium phosphate buffer (PBS of 200 μ L, 100mM, pH value is 7.4), by compound dissolution in DMSO, and use PBS to be diluted, the concentration that makes its final DMSO solution is 0.05%.And hatch in the water-bath communicating with air at 37 ℃, preincubate adds albumen in backward mixed solution in 3 minutes and starts reaction.In different time points (0,5,10,15,30 and 60min), add the ice-cold acetonitrile termination reaction of same volume.Sample is preserved until carry out LC/MS/MS analysis at-80 ℃.
The concentration of compound in people or rat liver microsomes mixtures incubated is to measure by the method for LC/MS/MS.The linearity range of concentration range is determined by each test-compound.
Parallel microsome of hatching test use sex change is as negative control, and hatching at 37 ℃, reacts and stop at different time point (0,15 and 60 minute).
Dextromethorphane Hbr (70 μ Μ) is as positive control, and hatching at 37 ℃, reacts and stop at different time point (0,5,10,15,30 and 60 minutes).In each measuring method, all comprise positive and negative control sample, to guarantee the integrity of microsome hatching system.
For each reaction, the concentration (representing with per-cent) by compound in people or rat liver microsomes are hatched is mapped by the per-cent of Relative Zero time point, with this, infers CLint CL in body int(ref.:Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y.Prediction of human hepatic clearance from vivo animalexperiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition2001,29:1316-1324.).Result is referring to table 1, the experimental result of compound stability in people and rat liver microsomes that table 1 provides for part embodiment of the present invention.
The experimental result of compound stability in people and rat liver microsomes that table 1 part embodiment of the present invention provides (1 μ M)
Figure BDA0000372253260000941
FTV: be converted into rapidly Vemurafenib; NT: test; ND: do not detect
As shown in Table 1, when the compounds of this invention is incubated in people and rat liver microsomes, compound of the present invention shows good transformation period (T 1/2) and clearance rate (CL int).
Same, the stability of the compound that part embodiment of the present invention provides in people and rat plasma is also evaluated.Experimental result is referring to table 2, the experimental result of compound stability in people and rat plasma that table 2 provides for part embodiment of the present invention.
The experimental result of compound stability in people and rat plasma that table 2 part embodiment of the present invention provides (2 μ M)
Figure BDA0000372253260000951
NT: test
As shown in Table 2, compound of the present invention shows good transformation period (T in people and rat plasma 1/2).
Embodiment B the compounds of this invention Pharmacokinetic Evaluation in animal body
The present invention to the compounds of this invention the pharmacokinetic in mouse, rat, dog or monkey body assess.
Vemurafenib and the compounds of this invention are carried out to administration with solution form.At time point, be 0.25,0.5,1.0,2.0,3.0,4.0,6.0,8.0, within 12 and 24 hours, get blood (0.3mL), and 3,000 or 4,000rpm under centrifugal 10 minutes.Collect plasma solutions, and at-20 ℃ or-70 ℃, preserve until carry out above-mentioned LC/MS/MS analysis.Result arrives table 7 referring to table 3.
The medicine of table 3Vemurafenib in SD rat body is for the experimental result of feature
Figure BDA0000372253260000961
NT: test
Table 4 part embodiment of the present invention provides the experimental result (PO, 10mg/kg) of the medicine of compound in SD rat body for feature
Figure BDA0000372253260000962
Figure BDA0000372253260000971
The medicine of table 5Vemurafenib in beagle dog body is for the experimental result of feature
Figure BDA0000372253260000972
NT: test
Table 6 part embodiment of the present invention provides the experimental result of the medicine of compound in beagle dog body for feature
Figure BDA0000372253260000973
Table 7 embodiment of the present invention 25 provides the experimental result of the medicine of compound in monkey body for feature
Figure BDA0000372253260000974
Result shows, during by compound oral administration provided by the invention, compound of the present invention shows good pharmacokinetic property, comprises desirable transformation period (T 1/2) bioavailability of becoming reconciled.
Embodiment C xenotransplantation tumor model
Adopt method mentioned above to set up Colo-205 transplanted tumor model, and adopt method mentioned above to analyze.In Colo-205 transplanted tumor model, by embodiment compound (qd) or twice (bid) oral administration every day (p.o.) once a day, and continue 15 days, result is referring to table 8, the transplanted tumor result of study of the compound that table 8 provides for the embodiment of the present invention.
The transplanted tumor result of study of the compound that table 8 part embodiment of the present invention provides
Figure BDA0000372253260000981
As shown in Table 8, under 20mg/kg dosage, the compounds of this invention has meaning statistically, can suppress the growth of nude mice by subcutaneous tumour.
Finally, it should be noted that other modes are used for implementing the present invention in addition.Correspondingly, embodiments of the invention are to describe as illustration, but are not limited to content described in the invention, may be also the modification done within the scope of the present invention or the equivalents added in the claims.All publications that the present invention quotes or patent all will be as reference of the present invention.

Claims (20)

1. a compound as shown in the formula (I):
Figure FDA0000372253250000011
Or its raceme, steric isomer, geometrical isomer, tautomer, solvate, oxynitride, meta-bolites or pharmacy acceptable salt, wherein:
Each X and Y are H independently ,-C (=O) R 3,-C (=O) OR 4,-C (R 1r 2) OC (=O) R 3,-C (R 1r 2) OC (=O) OR 4or-C (R 1r 2) OP (=O) (OR 4) (OR 4a), and when Y is H, X can not be H or ethanoyl;
Each R 1and R 2be H independently, D, C 1-6alkyl, C 1-6haloalkyl, C 3-6cycloalkyl ,-(C 1-4alkylidene group)-(C 3-6cycloalkyl), C 3-6heterocyclic radical or-(C 1-4alkylidene group)-(C 3-6heterocyclic radical), wherein, described each R 1and R 2be connected with carbon atom respectively, or R 1and R 2after being connected, be connected with carbon atom, or R 1, R 2and together with the carbon atom connected with them, form and replace or the individual former molecular carbocyclic ring of unsubstituted 3-8 or heterocycle;
Each R 3be H independently, D, C 1-10alkyl, C 1-10haloalkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl or-(C 1-6alkylidene group)-(5-10 former molecular heteroaryl), wherein, described each C 1-10alkyl, C 1-10haloalkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl and-(C 1-6alkylidene group)-(5-10 former molecular heteroaryl) is not substituted or optionally by 1,2,3 or 4 are independently selected from D, F, Cl, Br, I ,-OH ,-NH 2, C 1-6alkyl, C 1-6haloalkyl, C 1-6alkoxyl group and C 1-6the substituting group of alkylamino replaces;
Each R 4and R 4abe H independently, C 1-10alkyl, C 1-10haloalkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl or-(C 1-6alkylidene group)-(5-10 former molecular heteroaryl), wherein, described each C 1-10alkyl, C 1-10haloalkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl and-(C 1-6alkylidene group)-(5-10 former molecular heteroaryl) is not substituted or optionally by 1,2,3 or 4 are independently selected from D, F, Cl ,-OH ,-NH 2, oxo (=O), C 1-6alkyl, C 1-6haloalkyl, C 1-6alkoxyl group and C 1-6the substituting group of alkylamino replaces.
2. compound according to claim 1, wherein, each R 1and R 2be H, D or C independently 1-3alkyl.
3. compound according to claim 1, wherein, each R 3be C independently 1-10alkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl or-(C 1-6alkylidene group)-(5-10 former molecular heteroaryl), wherein, described each C 1-10alkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical), C 6-10aryl ,-(C 1-6alkylidene group)-(C 6-10aryl), 5-10 former molecular heteroaryl and-(C 1-6alkylidene group)-(5-10 former molecular heteroaryl) is not substituted or optionally by 1,2,3 or 4 are independently selected from D, F, OH ,-OMe ,-NH 2,-NHMe ,-NMe 2and C 1-3the substituting group of alkyl replaces.
4. compound according to claim 1, wherein, each R 4and R 4abe H independently, C 1-10alkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical) or C 6-10aryl, wherein, described each C 1-10alkyl, C 3-8cycloalkyl ,-(C 1-6alkylidene group)-(C 3-8cycloalkyl), C 3-8heterocyclic radical ,-(C 1-6alkylidene group)-(C 3-8heterocyclic radical) and C 6-10aryl is not substituted or optionally by 1,2,3 or 4 are independently selected from D, F, OH ,-OMe ,-NH 2,-NHMe ,-NMe 2, oxo (=O) and C 1-3the substituting group of alkyl replaces.
5. compound according to claim 1, wherein, each X and Y be independently H or-C (R 1r 2) OP (=O) (OH) 2, and X and Y can not be H simultaneously.
6. compound according to claim 1, wherein, each X and Y are H independently ,-C (=O) R 3,-C (=O) OR 4,-C (R 1r 2) OC (=O) R 3,-C (R 1r 2) OC (=O) OR 4, and when Y is H, X can not be H or ethanoyl.
7. compound according to claim 6, wherein, acyl group fragment (C (=O) R 3) be the group that a-amino acid or its optical isomer form.
8. compound according to claim 7, wherein, a-amino acid is Isoleucine, leucine, Methionin, methionine(Met), phenylalanine, Threonine, tryptophane, α-amino-isovaleric acid, L-Ala, asparagine, aspartic acid, L-glutamic acid, glutamine, proline(Pro), Serine, p-tyrosine, arginine, Histidine, halfcystine, glycine, sarkosine, N, N-N-methylsarcosine, homoserine, norvaline, nor-leucine, ornithine, homocysteine, hyperphenylalaninemia, phenylglycocoll, o-tyrosine, m-tyrosine or oxyproline.
9. compound according to claim 8, wherein, a-amino acid is Isoleucine, leucine, Methionin, methionine(Met), phenylalanine, Threonine, tryptophane, α-amino-isovaleric acid, L-Ala, asparagine, aspartic acid, L-glutamic acid, glutamine, proline(Pro), Serine, tyrosine, arginine or Histidine, wherein, described each amino acid whose alpha-position is all S configuration.
10. compound according to claim 1, wherein, described pharmacy acceptable salt is an alkali metal salt, alkaline earth salt, ammonium salt or N +(C 1-4alkyl) 4salt.
11. compounds according to claim 10, wherein, described pharmacy acceptable salt is sodium salt, lithium salts, sylvite, calcium salt, magnesium salts, ammonium salt, quaternary ammonium salt, or their combination.
12. compounds according to claim 1, wherein, described pharmacy acceptable salt is inorganic salt, organic salt or their combination, wherein, described inorganic salt are hydrochlorides, hydrobromate, vitriol, nitrate, phosphoric acid salt or their combination, described organic salt is acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, pyruvate salt, oxalate, glycollate, salicylate, glucuronate, galacturonic hydrochlorate, Citrate trianion, tartrate, aspartate, glutaminate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate or their combination.
13. compounds according to claim 1, have following one of them structure:
Figure FDA0000372253250000041
Figure FDA0000372253250000051
Figure FDA0000372253250000061
14. 1 kinds of pharmaceutical compositions comprise compound and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination described in claim 1-13 any one.
15. pharmaceutical compositions according to claim 14, wherein further also comprise additional treatment agent, described additional treatment agent is selected from chemotherapeutic agent, antiproliferative, be used for the treatment of atherosclerotic medicine, be used for the treatment of the medicine of pulmonary fibrosis or their combination.
16. pharmaceutical compositions according to claim 15, wherein said additional treatment agent is Chlorambucil (chlorambucil), melphalan (melphalan), endoxan (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busulfan), carmustine (carmustine), lomustine (lomustine), streptozotocin (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), Dacarbazine (dacarbazine), Temozolomide (temozolomide), Procarbazine (procarbazine), methotrexate (methotrexate), Fluracil (fluorouracil), cytosine arabinoside (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vinealeucoblastine(VLB) (vinblastine), vincristine(VCR) (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), Etoposide (etoposide), ET-743 (trabectedin), gengshengmeisu (dactinomycin), Dx (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), ametycin (mitomycin), ipsapirone (ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analogue (gonadorelin analogues), megestrol (megestrol), prednisone (prednisone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon alpha (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Ah method is for Buddhist nun (afatinib), alisertib, amuvatinib, A Pa is for Buddhist nun (apatinib), Axitinib (axitinib), Velcade (bortezomib), SKI-606 (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, Ke Zhuo is for Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), imatinib (imatinib), iniparib, lapatinibditosylate (lapatinib), lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, fork clip is for Buddhist nun (saracatinib), saridegib, Xarelto (sorafenib), Sutent (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, volasertib, alemtuzumab (alemtuzumab), rhuMAb-VEGF (bevacizumab), brentuximab vedotin, block appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), method wood monoclonal antibody (ofatumumab) difficult to understand, Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab), or their combination.
Pharmaceutical composition described in 17. 1 kinds of rights to use requirement 1-13 any one described in compound or claim 14-16 any one is for the preparation of the purposes of protecting, process, treat or alleviate the medicine of patient's proliferative disease.
18. according to the purposes of compound described in claim 17 or pharmaceutical composition, and wherein said proliferative disease is metastatic carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, mammary cancer, kidney, liver cancer, lung cancer, skin carcinoma, thyroid carcinoma, brain tumor, neck cancer, prostate cancer, carcinoma of the pancreas, the cancer of central nervous system, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
19. 1 kinds of rights to use require compound described in 1-13 any one or the pharmaceutical composition described in claim 14-16 any one to come to require compound described in 1-13 any one or right to use to require the pharmaceutical composition described in 14-16 any one to contact with described biological sample for the preparation of suppressing or regulate the purposes of protein kinase activity, described purposes to comprise right to use in biological sample.
20. purposes according to claim 19, wherein said protein kinase is B-Raf.
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CN112888698A (en) * 2018-09-25 2021-06-01 美国政府(由卫生和人类服务部的部长所代表) 2 ' -halo-4 ' -thio-2 ' -deoxy-5-azacytidine analogs and methods of use thereof

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WO2011063159A1 (en) * 2009-11-18 2011-05-26 Plexxikon, Inc. Compounds and methods for kinase modulation, and indications therefor
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CN102574799A (en) * 2009-08-03 2012-07-11 霍夫曼-拉罗奇有限公司 Process for the manufacture of pharmaceutically active compounds
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CN104496822A (en) * 2014-12-15 2015-04-08 扬州三友合成化工有限公司 Preparation method of 1-chloroethyl cyclohexyl propyl carbonate
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