CN103626765B - Substituted azaindole compounds and salt, compositions and purposes - Google Patents
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- 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
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- 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 the substituted nitrogen heterocyclic Benzazole compounds with formula (I) structure, its pharmaceutically acceptable salt, and pharmaceutical preparation, for regulating the activity of protein kinase, and regulate iuntercellular or the response of intracellular signal.The present invention also relates to comprise the pharmaceutical composition of the compounds of this invention, and uses this medicine composite for curing mammal, the particularly method of mankind's hyperproliferative disease.
Description
This application claims and submitted Patent Office of the People's Republic of China, Application No. 201210307104.8, invention on 08 27th, 2012 to
The Chinese patent application of entitled " substituted azaindole compounds and salt thereof and using method " and on 04 03rd, 2013
Submit to Patent Office of the People's Republic of China, Application No. 201310116870.0, invention entitled " substituted azaindole compounds and salt thereof and
Using method " the priority of Chinese patent application, entire contents is hereby incorporated by the application.
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to a kind of substituted azaindole compounds and salt, compositions
And purposes.
Background technology
Kinases, as the extended familys in albumen, has become as the class major target class in drug research.Human gene checks order
Confirming, having more than 500 protein kinases and be present in human gene, they are referred to as human kinase group.These protein kinases, base
In structure, being divided into 7 families, wherein, 388 serine/threonine kinases are divided into 5 families, including AGC, CAMK, CMGC,
CK1 and STE；90 tyrosine kinase are then divided into 2 families, i.e. TK (tyrosine kinase) family (58) and TKL (tyrosine-kinase
Enzyme sample) family (32)；It addition, the atypia kinases that also 40 architectural differences are bigger.Many effective drug targets all come
Come from TK family, such as EGF-R ELISA (EGFR), vascular endothelial growth factor receptor (VEGFR), platelet-derived
Growth factor receptors (PDGFR).Recent clinical data shows, uses B-Raf inhibitor can treat because of B-RafV600ESudden change
The melanoma caused, thus ratify Wei Luofeini (vemurafenib) treatment and shift melanoma late period.
Kinases can be by separate signal path and two kinds of approach regulation and control growth of cancer cells of synergistic signal transduction, such as,
Ras/Raf/MEK/ERK mitogen activated protein kinase (MAPK) path, the cell that can mediate various growth signals is corresponding,
In cancerous cell, this path is usually lacked of proper care.Raf family is made up of serine/threonine kinases A-Raf, B-Raf and C-Raf (Raf-1),
They can phosphorylation and activation MEK, but only B-Raf produces sudden change in various cancers；And modal B-Raf sudden change
Occur at 600 (BRAF of codonV600EOn), glutamic acid is replaced by valine.After B-Raf gene mutation, pass through constitutive character
Activate and MAPK path is amplified, even if there is no any growth signals, it is possible to cause the growth of malignant tumor.
2002, an important research showed, in all of melanoma patient, there is BRAF gene more than 50%
Activating mutations.Except melanoma, the BRAF sudden change of activation is also present in colorectal cancer (40% mis-match repair deficient occurs), the first of 50%
Shape papillocarcinoma of breast and 30% rudimentary serous ovarian cancer in.Although other Raf substructure, such as A-Raf and C-Raf, also
Some signal path can be activated, but only B-Raf can activate MAPK path.
Melanoma is transformed by a kind of special pigment cell's melanocyte.Melanoma can occur at skin (table
Skin), eyes (tunica uvea), or mucosal tissue (mucosa).Although in European descent crowd, melanoma comes the of skin cancer
Three (after squamous cell carcinoma and basal cell carcinoma), but the skin carcinoma patient of death is nearly all melanoma patient.One
Denier is diffused into organ, and melanoma becomes as the clinical disease the most thorny, M & M is the highest.Instantly, clinical
The melanoma patient of IV phase, the average survival time rate is 6-10 month, and this situation, in Past 30 Years, does not all have the biggest change.
Wei Luofeini (vemurafenib) (trade nameOnce code name PLX4032 was used) it is a kind of little molecule B-
Raf kinase, the cancer drawn by the BRAF sudden change activated for treatment.The first of Wei Luofeini (vemurafenib) is fitted
Answer disease be melanoma (> 50% exist activate BRAF sudden change), the application on other solid tumor the most under study for action, such as Colon and rectum
There is the BRAF sudden change activated in cancer (> 10%).The kinase assay purified proves Wei Luofeini (vemurafenib) and the like
Can efficiently suppress B-Raf activity, the selectivity of V600E sudden change is higher than wild type 3 times.
In preclinical internal and external model are tested, Wei Luofeini (vemurafenib) and homologue thereof can
Suppression B-RafV600EThe growth of positive melanoma cells strain.Clinical I is interim, and Advanced Colon Cancer patient uses oral capsule twice daily
Capsule, dosage progressively increases to 600mg from 200mg.Owing to the releasing effect of crystal formation preparation is general, therefore, Wei Luofeini
(vemurafenib) microdeposit powder in bulk (MBP) dosage form it has been made into, in order to improve the bioavailability of medicine.
Wei Luofeini (vemurafenib) poorly water-soluble, water solubility rate is low, and bioavailability is the highest, be especially administered orally to
During medicine.Poor bioavailability makes patient that medicine not reach intended absorption, thus the intended dosage of impact or treatment are imitated
Really.Additionally, for the low medicine of bioavailability, food can affect it and absorb, and need to adjust dosage at any time, it is seen then that this medicine absorbs
Instability, needs a safe-dosaging limits the widest.Due to this medicine must at high doses, can be only achieved efficient system or
Targeting 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 homologue of crude drug, after administration, becomes activated medicine shape through biological conversion in the body or metabolism
Formula.Usually, prodrug, by improving the pharmacokinetics character of former medicine at one or more aspects, improves therapeutic effect, and it is permissible
Overcoming the former medicine multiple difficulty in terms of dosage form and metabolism, such as, water solublity is low, poor stability, and oral administration biaavailability is inadequate,
First pass effect is substantially and toxicity.
The defect of Wei Luofeini (vemurafenib) is that bioavailability is low, big (the approval agent of MBP dosage form of oral dose
Amount is every day 2 times, each 960mg), but it is to melanomatous significant curative effect so that it is become the drug substrate received much concern, grind
The person of studying carefully is expected that by synthesizing Wei Luofeini (vemurafenib) analog, improves oral administration biaavailability.Therefore, for improving
Bioavailability, the prodrug synthesizing it is necessary, especially enters the NH on azaindole and/or aromatic amide base
Row is modified, and gastrointestinal can be conducive to absorb.The analog that so obtains easy (reduce dosage and use frequency), efficiently,
Side effect is little, additionally, may also be fabricated which intravenous dosage form or slow release formulation.
Summary of the invention
In view of this, the invention provides a kind of new substituted azaindole compounds and raceme, stereoisomerism
Body, geometric isomer, tautomer, solvate, nitrogen oxides, metabolite or pharmaceutically acceptable salt, described
Each compound is Wei Luofeini (vemurafenib) prodrug, inhibited to protein kinase, may be used for preparation prevention and
The medicine of the treatment such proliferative disease of cancer.
Compound for protein cheese kinase activity involved in the present invention has inhibitory action, particularly to B-Raf protein kinase
Inhibitory action.
Particularly, present invention also offers the pharmaceutically acceptable compositions of involved compound, involved combination
Thing 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):
Or its raceme, stereoisomer, geometric isomer, tautomer, solvate, nitrogen oxides, metabolism is produced
Thing or pharmaceutically acceptable salt, wherein:
Each X and Y independently be H ,-C (=O) R3,-C (=O) OR4,-C (R1R2)OC(=O)R3,-C (R1R2)OC(=O)OR4Or-
C(R1R2)OP(=O)(OR4)(OR4a), and when Y is H, X can not be H or acetyl group；
Each R1And R2Independently be H, D, C1-6Alkyl, C1-6Haloalkyl, C3-6Cycloalkyl ,-(C1-4Alkylidene)-(C3-6Ring
Alkyl), C3-6Heterocyclic radical or-(C1-4Alkylidene)-(C3-6Heterocyclic radical), described each R1And R2It is connected with carbon atom respectively, or R1With
R2It is connected with carbon atom after Xiang Lianing, or R1, R2And together with the carbon atom being connected with them, formed and replace or unsubstituted 3-8
Individual former molecular carbocyclic ring or heterocycle；
Each R3Independently be H, D, C1-10Alkyl, C1-10Haloalkyl, C3-8Cycloalkyl ,-(C1-6Alkylidene)-(C3-8Cycloalkanes
Base), C3-8Heterocyclic radical ,-(C1-6Alkylidene)-(C3-8Heterocyclic radical), C6-10Aryl ,-(C1-6Alkylidene)-(C6-10Aryl), 5-10
Former molecular heteroaryl or-(C1-6Alkylidene)-(5-10 former molecular heteroaryl), and wherein, described each C1-10Alkyl,
C1-10Haloalkyl, C3-8Cycloalkyl ,-(C1-6Alkylidene)-(C3-8Cycloalkyl), C3-8Heterocyclic radical ,-(C1-6Alkylidene)-(C3-8Miscellaneous
Ring group), C6-10Aryl ,-(C1-6Alkylidene)-(C6-10Aryl), 5-10 former molecular heteroaryl and-(C1-6Alkylidene)-
(5-10 former molecular heteroaryl) is unsubstituted or is optionally independently selected from D, F, Cl, Br, I ,-OH by 1,2,3 or 4 ,-
NH2, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl and C1-6The substituent group of alkylamino is replaced；
Each R4And R4aIndependently be H, C1-10Alkyl, C1-10Haloalkyl, C3-8Cycloalkyl ,-(C1-6Alkylidene)-(C3-8Ring
Alkyl), C3-8Heterocyclic radical ,-(C1-6Alkylidene)-(C3-8Heterocyclic radical), C6-10Aryl ,-(C1-6Alkylidene)-(C6-10Aryl), 5-10
Individual former molecular heteroaryl or-(C1-6Alkylidene)-(5-10 former molecular heteroaryl), and wherein, described each C1-10Alkane
Base, C1-10Haloalkyl, C3-8Cycloalkyl ,-(C1-6Alkylidene)-(C3-8Cycloalkyl), C3-8Heterocyclic radical ,-(C1-6Alkylidene)-
(C3-8Heterocyclic radical), C6-10Aryl ,-(C1-6Alkylidene)-(C6-10Aryl), 5-10 former molecular heteroaryl and-(C1-6Alkylene
Base)-(5-10 former molecular heteroaryl) is unsubstituted or is optionally independently selected from D, F, Cl ,-OH by 1,2,3 or 4 ,-
NH2, oxo (=O), C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl and C1-6The substituent group of alkylamino is replaced.
In some embodiments, each R1And R2Independently be H, D or C1-3Alkyl.
In other embodiments, each R3Independently be C1-10Alkyl, C3-8Cycloalkyl ,-(C1-6Alkylidene)-(C3-8
Cycloalkyl), C3-8Heterocyclic radical ,-(C1-6Alkylidene)-(C3-8Heterocyclic radical), C6-10Aryl ,-(C1-6Alkylidene)-(C6-10Aryl), 5-
10 former molecular heteroaryls or-(C1-6Alkylidene)-(C6-10Aryl), wherein, described each C1-10Alkyl, C3-8Cycloalkyl ,-
(C1-6Alkylidene)-(C3-8Cycloalkyl), C3-8Heterocyclic radical ,-(C1-6Alkylidene)-(C3-8Heterocyclic radical), C6-10Aryl ,-(C1-6Alkylene
Base)-(C6-10Aryl), 5-10 former molecular heteroaryl and-(C1-6Alkylidene)-(C6-10Aryl) unsubstituted or optionally
It is independently selected from D, F, OH ,-OMe ,-NH by 1,2,3 or 42,-NHMe ,-NMe2And C1-3The substituent group of alkyl is replaced.
In some embodiments, each R4And R4aIndependently be H, C1-10Alkyl, C3-8Cycloalkyl ,-(C1-6Alkylidene)-
(C3-8Cycloalkyl), C3-8Heterocyclic radical ,-(C1-6Alkylidene)-(C3-8Heterocyclic radical) or C6-10Aryl, wherein, described each C1-10Alkyl,
C3-8Cycloalkyl ,-(C1-6Alkylidene)-(C3-8Cycloalkyl), C3-8Heterocyclic radical ,-(C1-6Alkylidene)-(C3-8Heterocyclic radical) and C6-10Virtue
Base is unsubstituted or is optionally independently selected from D, F, OH ,-OMe ,-NH by 1,2,3 or 42,-NHMe ,-NMe2, oxo (=O) and
C1-3The substituent group of alkyl is replaced.
In other embodiments, each X and Y independently be H or-C (R1R2)OP(=O)(OH)2, and X and Y can not be same
Time be H.
In some embodiments, each X and Y independently be H ,-C (=O) R3,-C (=O) OR4,-C (R1R2)OC(=O)R3,-C
(R1R2)OC(=O)OR4, and when Y is H, X can not be H or acetyl group.
In other embodiments, acyl moieties (-C (=O) R3) it is a-amino acid or the formation of its optical isomer
Group.
In some embodiments, a-amino acid is isoleucine, leucine, lysine, methionine, phenylalanine, Soviet Union
Propylhomoserin, tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, glutamine, proline, silk ammonia
Acid, p-tyrosine, arginine, histidine, cysteine, glycine, sarcosine, DMG, homoserine,
Norvaline, nor-leucine, ornithine, homocysteine, homophenylalanin, phenylglycine, o-tyrosine, m-tyrosine
Or hydroxyproline.
In other embodiments, described a-amino acid is isoleucine, leucine, lysine, methionine, phenylpropyl alcohol
Propylhomoserin, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, glutamine, proline,
Serine, tyrosine, arginine or histidine, wherein, each amino acid whose alpha-position described is all S configuration.
In some embodiments, described formula (I) compound pharmaceutically acceptable salt is its alkali metal salt, alkaline-earth metal
Salt, ammonium salt or N+(C1-4Alkyl)4Salt.
In other embodiments, described formula (I) compound pharmaceutically acceptable salt is its sodium salt, lithium salts, potassium
Salt, calcium salt, magnesium salt, ammonium salt, quaternary ammonium salt, or combinations thereof.
In some embodiments, described formula (I) compound pharmaceutically acceptable salt can be its inorganic salt, organic salt
Or combinations thereof, wherein, described inorganic salt is hydrochlorate, hydrobromate, sulfate, nitrate, phosphate or they
Combination, described organic salt is acetate, maleate, succinate, mandelate, fumarate, malonate, malic acid
Salt, 2 hydroxy propanoic acid salt, pyruvate, oxalates, glycollate, salicylate, glucuronate salt, galacturonic acid hydrochlorate,
Citrate, tartrate, aspartate, glutamate, Glu, benzoate, cinnamate, tosilate, benzenesulfonic acid
Salt, mesylate, esilate, fluoroform sulphonate, or combinations thereof.
On the other hand, present invention also offers a kind of pharmaceutical composition, comprise the compounds of this invention and pharmaceutically acceptable
Carrier, excipient, diluent, adjuvant, vehicle, or combinations thereof.
In some embodiments, pharmaceutical composition of the present invention, also comprise additional treatment agent, described additional treatment
Agent is selected from chemotherapeutic agent, antiproliferative, is used for treating atherosclerotic medicine, for treating the medicine of pulmonary fibrosis
Thing, or combinations thereof.
In some embodiments, described additional treatment agent is chlorambucil (chlorambucil), melphalan
(melphalan), cyclophosphamide (cyclophosphamide), ifosfamide (ifosfamide), busulfan
(busulfan), carmustine (carmustine), lomustine (lomustine), streptozotocin (streptozocin),
Cisplatin (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), dacarbazine
(dacarbazine), temozolomide (temozolomide), procarbazine (procarbazine), methotrexate
(methotrexate), fluorouracil (fluorouracil), cytosine arabinoside (cytarabine), gemcitabine
(gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vinblastine
(vinblastine), vincristine (vincristine), vinorelbine (vinorelbine), paclitaxel (paclitaxel),
Docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), etoposide
(etoposide), ET-743 (trabectedin), dactinomycin (dactinomycin), doxorubicin
(doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone
(mitoxantrone), bleomycin (bleomycin), ametycin (mitomycin), ipsapirone
(ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analog
(gonadorelin analogues), megestrol (megestrol), prednisone (prednisone), dexamethasone
(dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon-ALPHA
(interferon alfa), calcium folinate (leucovorin), sirolimus (sirolimus), temsirolimus
(temsirolimus), everolimus (everolimus), Afatinib (afatinib), alisertib, amuvatinib,
A Pa replaces Buddhist nun (apatinib), Axitinib (axitinib), bortezomib (bortezomib), SKI-606
(bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, gram Zhuo are for Buddhist nun
(crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib,
Erlotinib (erlotinib), foretinib, ganetespib, gefitinib (gefitinib), ibrutinib, angstrom gram replace
Buddhist nun (icotinib), imatinib (imatinib), iniparib, Lapatinib (lapatinib), lenvatinib,
Linifanib, linsitinib, Masitinib (masitinib), momelotinib, for husky Buddhist nun (motesanib), come that
For Buddhist nun (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib
(pazopanib)、pictilisib、ponatinib、quizartinib、regorafenib、rigosertib、
Rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Sorafenib (sorafenib), relax
Buddhist nun for Buddhist nun (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib,
Trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib,
Volasertib, alemtuzumab (alemtuzumab), bevacizumab (bevacizumab), brentuximab vedotin, card
Appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), promise monoclonal antibody (denosumab), lucky trastuzumab
(gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), method wood monoclonal antibody difficult to understand
(ofatumumab), Victibix (panitumumab), Rituximab (rituximab), tositumomab
(tositumomab), Herceptin (trastuzumab) or combinations thereof.
On the other hand, present invention also offers use compound of the present invention or described pharmaceutical composition prepare for
Protect, process, treat or alleviate the purposes of the medicine of patient's proliferative disease.
In some embodiments, proliferative disease of the present invention be metastatic carcinoma, colon cancer, adenocarcinoma of stomach, bladder cancer,
Breast carcinoma, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, skin carcinoma, thyroid carcinoma, the brain cancer, neck cancer, carcinoma of prostate, cancer of pancreas, central nervous system
(CNS) cancer, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
On the other hand, present invention also offers use compound of the present invention or pharmaceutical composition is prepared for giving birth to
Suppression or the purposes of regulation protein kinase activity in thing specimen, described purposes comprises use the compounds of this invention or pharmaceutical composition
Contact with described biological sample.
Some embodiments wherein, protein kinase of the present invention is B-Raf.
On the other hand, the present invention provides some pharmaceutical compositions, and it comprises the present invention change as kinases inhibitor
Compound, or its stereoisomer, geometric isomer, tautomer, solvate, metabolite, or it is pharmaceutically acceptable
Salt, pharmaceutically acceptable carrier, diluent, adjuvant, vehicle, or combinations thereof.
In some embodiments, pharmaceutical composition provided by the present invention comprises and can press down as the response of B-Raf kinase signal
The compound of preparation, or its stereoisomer, geometric isomer, tautomer, solvate, metabolite, or its pharmacy
Upper acceptable salt, or pharmaceutically acceptable carrier, diluent, adjuvant, vehicle, or combinations thereof.
In other embodiments, compound of the present invention is Wei Luofeini (vemurafenib) prodrug.Separately
In outer embodiments, pharmaceutical composition of the present invention the most also comprises additional treatment agent.
On the other hand, the present invention relates to suppress protein kinase activity method, the method comprise the compounds of this invention or its
Pharmaceutical composition contacts with described kinases.In some embodiments, the method that the present invention relates to suppress the response of B-Raf signal,
The method comprises the compounds of this invention or its pharmaceutical composition contacts with described receptor.Other embodiment is, at cell
Or multicellular organisms suppresses protein kinase receptor activity, the particularly activity of suppression B-Raf signal response.According to the present invention
Described method, the method comprise use the compounds of this invention or its pharmaceutical composition described multicellular organisms is carried out to
Medicine.In some embodiments, described multicellular organisms refers to mammal.In other embodiment, described how thin
Born of the same parents' organism refers to the mankind.In some embodiments, the method for the invention further comprises additional treatment agent with described
Kinases contacts.
On the other hand, the present invention relates to a kind of method suppressing cell-proliferation activity, described method comprises the use present invention
Compound or effective therapeutic dose of its pharmaceutical composition energy Inhibit proliferaton and cells contacting.In some embodiments, institute of the present invention
Method of stating further comprises additional treatment agent and cells contacting.
On the other hand, the present invention relates to a kind of method treating Patient cells's proliferative disease, described method comprises use
Patient is administered by effective therapeutic dose of the compounds of this invention or its pharmaceutical composition.In some embodiments, institute of the present invention
Method of stating further comprises the administration of additional treatment agent.
On the other hand, the present invention relates to a kind of method suppressing patient tumors to grow, described method comprises the use present invention
Patient is administered by effective therapeutic dose of compound or its pharmaceutical composition.In some embodiments, the method for the invention
Further comprise the administration of additional treatment agent.
On the other hand, the method that the present invention relates to the preparation of compound, separation and purification that formula (I) is comprised.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspects and
The content of his aspect will make more specific complete description below.
Detailed description of the invention
Definition and general terms
The present invention will list the document corresponding to the content of the materialization determined in detail, and embodiment is all attended by structure
Formula and the diagram of chemical formula.The present invention has and expectedly contains all of choice, variant and coordinate, and these may be as right
Existing invention field it is included in like that defined in requirement.Those skilled in the art will identify many similar or equivalent to
This described method and material, these can apply in the practice of the present invention.The present invention is limited to absolutely not method and material
Description.Have a lot of document and similar material distinguish with the present patent application or conflict, including but be not limited to term
Definition, the usage of term, the technology of description, or the scope controlled as the present patent application.
Unless other aspects show, the present invention will apply defined below.
According to the purpose of the present invention, chemical element according to the periodic table of elements, CAS version and chemical drugs handbook, 75,thEd,
1994 define." Organic Chemistry, " the Thomas Sorrell it addition, organic chemistry General Principle is shown in,
University Science Books,Sausalito:1999,and "March′s Advanced Organic
Chemistry, " by Michael B.Smith and Jerry March, John Wiley&Sons, New York:2007,
The most all of content has all merged list of references.
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, as
General formula compound above, or as example special inside embodiment, subclass, and the compounds that the present invention is comprised.
Should be appreciated that " optionally substituted " this term and " substituted " this term can exchange use.It is said that in general, term " replaces
" or " replacement ", represent that the one or more hydrogen atoms in given structure are replaced by concrete substituent group.Unless other aspect tables
Bright, an optional substituted radical can have a substituent group to replace in each commutable position of group.When given
Structural formula in more than one position can be selected from one or more substituent groups of concrete group and replaced, then substituent group is permissible
Replace in each position identical or differently.Wherein said substituent group it may be that but be not limited to, deuterium, fluorine, chlorine, bromine, iodine,
Oxo, alkyl, haloalkyl, hydroxyl, amino, alkoxyl, alkylamino, ester group, carboxyl, etc..
Terminology used in the present invention " alkyl " or " alkyl group ", represent the saturated straight chain containing 1-20 carbon atom or side chain
Monovalence Hydrocarbon atomic group.Wherein said alkyl group can be replaced by one or more substituent groups individually optionally.
Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom, and 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, alkyl base
Group is containing 1-4 carbon atom, and other embodiment is, alkyl group contains 1-3 carbon atom, and other embodiment is, alkane
Base group contains 1-2 carbon atom.
The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-pro-pyl (n-
Pr ,-CH2CH2CH3), isopropyl (i-Pr, i-propyl ,-CH (CH3)2), normal-butyl (n-Bu, n-butyl ,-
CH2CH2CH2CH3), isobutyl group (i-Bu, i-butyl ,-CH2CH(CH3)2), sec-butyl (s-Bu, s-butyl ,-CH (CH3)
CH2CH3), the tert-butyl group (t-Bu, t-butyl ,-C (CH3)3), n-pentyl (n-pentyl ,-CH2CH2CH2CH2CH3), 2-amyl group (-
CH(CH3)CH2CH2CH3), 3-amyl group (-CH (CH2CH3)2), 2-methyl-2-butyl (-C (CH3)2CH2CH3), 3-methyl-2-fourth
Base (-CH (CH3)CH(CH3)2), 3-methyl isophthalic acid-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butene base (-CH2CH(CH3)
CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH3)CH2CH2CH2CH3), 3-hexyl (-CH
(CH2CH3)(CH2CH2CH3)), 2-methyl-2-amyl group (-C (CH3)2CH2CH2CH3), 3-methyl-2-amyl group (-CH (CH3)CH
(CH3)CH2CH3), 4-methyl-2-amyl group (-CH (CH3)CH2CH(CH3)2), 3-methyl-3-amyl group (-C (CH3)(CH2CH3)2),
2-methyl-3-amyl group (-CH (CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C (CH3)2CH(CH3)2), 3,3-diformazans
Base-2-butyl (-CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..And alkyl can be substituted or non-substituted, its
Middle substituent group it may be that but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl,
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.
Terminology used in the present invention " alkylidene ", represents and eliminates two hydrogen atoms from straight or branched saturated hydrocarbon
The saturated bivalent hydrocarbon radical obtained.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom, some of them embodiment
Being that alkylidene group contains 1-6 carbon atom, other embodiment is, alkylidene group contains 1-4 carbon atom, additionally
Some embodiments are, alkylidene group contains 1-3 carbon atom, and other embodiment is, alkylidene group contains 1-2 carbon
Atom.The example of alkylidene group includes, but is not limited to, methylene (-CH2-), ethylidene (-CH2CH2-), ethylidine (-CH
(CH3)-), secondary isopropyl (-CH (CH3)CH2-) etc..Alkylidene can be further substituted, and this substituent group is selected from, but does not limit
In, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl, alkylamino, cycloalkyl, heterocyclic radical, virtue
Base, heteroaryl etc..
Term " thiazolinyl " represents the monovalent hydrocarbon of straight or branched, and at least one of which position is undersaturated condition, i.e. one
Individual C-C is sp2Double bond.Unless otherwise detailed instructions, thiazolinyl contains 2-12 carbon atom, and some of them embodiment is that thiazolinyl contains
There is 2-8 carbon atom；Other embodiment is, thiazolinyl contains 2-6 carbon atom；Other embodiment is that thiazolinyl contains
2-4 carbon atom.The concrete example of thiazolinyl includes, but is not limited to, vinyl (-CH=CH2), pi-allyl (-CH2CH=CH2) etc.
Deng.The group of its alkenyl groups can be replaced by one or more substituent groups described in the invention individually optionally, including
Group has negation, " just ", " E " or the location of " Z ".
Term " alkynyl " represents the monovalent hydrocarbon of straight or branched, and at least one of which position is undersaturated condition, i.e. one
Individual C-C is sp tri-key.Unless otherwise detailed instructions, alkynyl contains 2-12 carbon atom；In certain embodiments, alkynyl contains 2-
8 carbon atoms；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, acetenyl (-C ≡ CH), propargyl (-CH2C ≡ CH) etc.
Deng.Wherein hydrocarbyl group can be replaced by one or more substituent groups described in the invention individually optionally.
Term " haloalkyl ", " halogenated alkenyl " or " halogenated alkoxy " represents alkyl, alkenyl or alkoxy base
Being replaced by one or more halogen atoms, its alkenyl groups and alkoxyl have implication of the present invention, such example
Comprise, but be not limited to, trifluoromethyl, trifluoromethoxy etc..Haloalkyl can be further substituted, and this substituent group is selected from, but
It is not limited to, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl, alkylamino etc..
Term " carbocyclic ring " or " carbocylic radical " refer to monovalence or multivalence, non-aromatic, and saturated or part unsaturation, containing 3-12
The monocycle of 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.Suitably cyclic aliphatic group includes, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.Ring-type fat
The example of fat race group farther includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, 1-cyclopenta-1-thiazolinyl, 1-ring
Amyl group-2-thiazolinyl, 1-cyclopenta-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 3-12 carbon atom
Monocycle.Unless otherwise detailed instructions, cycloalkyl contains 3-12 carbon atom, and other embodiment is, cycloalkyl contains 3-8
Carbon atom, other embodiment is, cycloalkyl contains 3-6 carbon atom.Cycloalkyl can be further substituted, and this substituent group is selected
From, but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl, alkylamino etc..
Term " cycloalkyl alkylidene " represents that alkyl group can be replaced by one or more groups of naphthene base, wherein alkane
Base and group of naphthene base have implication as described in the present invention.Some of them embodiment is, cycloalkyl alkylidene group refers to " relatively
Rudimentary cycloalkyl alkylidene " group, i.e. group of naphthene base be connected to C1-6Alkyl group on.Other embodiment is, ring
Alkyl group is connected to C1-4Alkyl group on.Other embodiment is that group of naphthene base is connected to C1-3Alkyl group
On.Such example includes, but is not limited to, cyclopropylethyl, cyclopentyl-methyl, cyclohexyl methyl etc..Cycloalkyl alkylene
Base can be further substituted, and this substituent group is it may be that but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkane
Base, haloalkyl, alkoxyl, alkylamino, etc..
Term " heterocycle ", " heterocyclic radical " or " heterocycle " is used interchangeably herein, all referring to monocycle or bicyclic system, its
On medium ring, one or more atoms are replaced by hetero atom individually optionally, and ring can be fully saturated or comprise one or many
Individual degree of unsaturation, but it is definitely not the fragrance same clan, only one of which junction point is connected to other molecules up.On one or more rings
Hydrogen atom is replaced by one or more substituent groups described in the invention individually optionally.Some of them embodiment is, " miscellaneous
Ring ", " heterocyclic radical " or " heterocycle " group is monocycle (2-6 the carbon atom and miscellaneous former selected from N, the 1-3 of O, P, S of 3-7 ring
Son, is optionally replaced by one or more oxygen atoms at this S or P and obtains as SO, SO2, PO, PO2Group, when described ring
During for three-membered ring, only one of which hetero atom), or dicyclo (4-9 the carbon atom and individual selected from N, the 1-3 of O, P, S of 7-10 unit
Hetero atom, is optionally replaced by one or more oxygen atoms at this S or P and obtains as SO, SO2, PO, PO2Group).
Heterocyclic radical can be carbon back or hetero atom base.The example of heterocycle includes, but is not limited to, pyrrolidinyl, tetrahydrochysene furan
Mutter base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, sulfur
For morpholinyl, thiophene alkyl, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl,
Glycidyl, azacycloheptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulfur azatropylidene base, 2-
Pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranose, 4H-pyranose, dioxacyclohexyl, 1,3-dioxy amyl group,
Pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetra-
Hydrogen isoquinoline base, 5-methyl isophthalic acid, 3-Dioxol-4-yl, 1,3-dioxole-2-ketone-4-base.Heterocyclic group
Example also includes, on ring, two carbon atoms are by oxygen (=O) substituted hybar X base and 1,1-dioxidothiomorpholinyl.And institute
Stating heterocyclic radical to be replaced by the one or more substituent groups in the present invention, wherein substituent group is not it may be that but limit individually optionally
In, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl, alkylamino, etc..
Term " heterocycloalkylene " represents that alkyl group can be replaced by one or more heterocyclyl groups, wherein alkane
Base and heterocyclyl groups have implication as described in the present invention.Some of them embodiment is, heterocycloalkylene group refers to " relatively
Rudimentary heterocycloalkylene " group, i.e. heterocyclyl groups be connected to C1-6Alkyl group on.Other embodiment is, miscellaneous
Cyclic groups is connected to C1-4Alkyl group on.Such example includes, but is not limited to, (5-methyl-2-oxo-1,3-bis-
Oxole-4-base) methyl, (piperidin-4-yl) methyl etc..Heterocycloalkylene can be further substituted, this substituent group
May be, but not limited to, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl, alkylamino, etc.
Deng.
Term " hetero atom " represents one or more O, S, N, P and Si, including the form of any oxidation state of N, S and P；The primary,
Secondary, tertiary amine and the form of quaternary ammonium salt；Or the form that in heterocycle, the hydrogen on nitrogen-atoms is replaced, such as, N(as 3,4-dihydro-
N in 2H-pyrrole radicals), NH(is as the NH in pyrrolidinyl) or NR(as the NR in the substituted pyrrolidinyl of N-).
Term " halogen " refers to F, Cl, Br or I.
Term " H " represents single hydrogen atom.Such atomic group can be connected with other groups, such as with oxygen atom phase
Even, oh group is formed.
Term " D " represents single D-atom.One such atomic group and a methyl are connected, and form list-deuterated methyl
(-CDH2), two D-atoms and a methyl are connected, and form double-deuterated methyl (-CD2And three D-atoms and a first H),
Base is connected, and forms three-deuterated methyl (-CD3).
Term " aryl " can be used alone or as the big portion of " aralkyl ", " aralkoxy " or " aryloxy alkyl "
Point, representing the monocycle containing 6-14 ring altogether, dicyclo, and the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic series
, each of which member ring systems comprises 3-7 ring, and only one of which attachment point is connected with the remainder of molecule.Term " virtue
Base " can use with term " aromatic rings " exchange, aromatic rings can include phenyl, naphthyl and anthracene.And described aryl can be
Substituted or non-substituted, wherein substituent group is it may be that but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkane
Base, haloalkyl, alkoxyl, alkylamino etc..
Term " aryl alkylene " represent alkyl group can be replaced by one or more aromatic yl groups, wherein alkyl and
Aromatic yl group has implication as described in the present invention, and some of them embodiment is, arylalkylene groups refers to the " virtue of lower level
Base alkylidene " group, i.e. aromatic yl group be connected to C1-6Alkyl group on.Other embodiment is, arylalkylene groups
Refer to containing C1-4" the benzene alkylene " of alkyl.Other embodiment is that arylalkylene groups refers to containing C1-2" the benzene of alkyl
Alkylene ".Wherein instantiation includes benzyl, diphenyl methyl, phenethyl etc..Aryl alkylene can be further substituted, should
Substituent group is it may be that but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl, haloalkyl, alkoxyl, alkane
Amino, etc..
Term " heteroaryl " can be used alone or as most of " heteroarylalkyl ", represents containing 5-14 annular atoms
Monocycle, dicyclo, and three-ring system, at least one of which member ring systems is aromatic, and at least one member ring systems comprises one
Or multiple hetero atom, each of which member ring systems comprises 5-7 ring, and only one of which attachment point is connected with molecule remainder.
Term " heteroaryl " can exchange with term " heteroaromatic " or " heteroaromatics " and use.And described heteroaryl can be to take
Generation or non-substituted, wherein substituent group it may be that but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxo, alkyl,
Haloalkyl, alkoxyl, alkylamino etc..
Other embodiment is, heteroaromatic includes following monocycle, but is not limited to these monocycles: 2-furyl, 3-
Furyl, TMSIM N imidazole base, 2-imidazole radicals, 4-imidazole radicals, 5-imidazole radicals, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,
2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrole radicals, 2-pyrrole radicals, 3-pyrrole radicals, 2-pyridine radicals, 3-pyridine radicals, 4-pyrrole
Piperidinyl, 2-pyrimidine radicals, 4-pyrimidine radicals, 5-pyrimidine radicals, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazole
Base, tetrazole radical (such as 5-tetrazole radical), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl
(such as 2-pyrazolyl), isothiazolyl, 1,2,3-di azoly, 1,2,5-di azoly, 1,2,4-di azoly, 1,2,3-triazoles
Base, 1,2,3-thio biphosphole base, 1,3,4-thio biphosphole base, 1,2,5-thio biphosphole base, pyrazinyl, 1,3,5-triazines base；Also
Including following dicyclo, but it is not limited to these dicyclos: benzimidazolyl, benzofuranyl, benzothienyl, indyl (as
2-indyl), purine radicals, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl is (such as 1-isoquinolin
Base, 3-isoquinolyl or 4-isoquinolyl).
Term " heteroarylalkylenyl " represents that alkyl group can be replaced by one or more heteroaryl groups, wherein alkane
Base and heteroaryl groups have implication as described in the present invention, and some of them embodiment is, heteroarylalkylenyl group refers to " relatively
Rudimentary heteroarylalkylenyl " group, i.e. heteroaryl groups be connected to C1-6Alkyl group on.Other embodiment is, miscellaneous
Aromatic yl group is connected to C1-4Alkyl group on.Wherein instantiation includes 2-picolyl, 3-furylethyl etc..Heteroaryl
Base alkylidene can be replaced further, and this substituent group may be, but not limited to, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, oxygen
Generation, alkyl, haloalkyl, alkoxyl, alkylamino etc..
Term " carboxyl ", is either used alone and is still used in conjunction, such as " carboxyalkyl ", expression-CO with other terms2H；Term
" carbonyl ", is either used alone and is still used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", represent-(C=O)-；Art
Language " acyl group " expression-(C=O) R, wherein, R is alkyl, and described " alkyl " has implication of the present invention.
Term " alkoxyl " used in the present invention, relates to alkyl, as defined in the present invention, passes through oxygen atom
(" alkoxyl ") is connected in main carbochain, and such example includes, but is not limited to methoxyl group, ethyoxyl, propoxyl group, fourth
Epoxide, etc..
Term " alkylamino " or " alkyl amino " include " N-alkyl amino " and " N, N-dialkyl amido ", wherein amino base
Group is separately replaced by one or two alkyl group.Some of them embodiment is, alkyl amino is one or two
C1-6The alkylamino group of the lower level that alkyl is connected on nitrogen-atoms.Other embodiment is, alkyl amino is C1-3's
The alkylamino group of lower level.Suitably alkylamino group can be alkyl monosubstituted amino or dialkyl amido, such reality
Example includes, but is not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-lignocaine etc..
The term " undersaturated " used in the present invention represents that part is containing one or more degrees of unsaturation.
It is open language that term " comprises ", i.e. includes the content specified by the present invention, but is not precluded from otherwise
Content.
As described in the invention, substituent group draws member ring systems (the below figure institute formed on a ring being bonded the center of receiving
Show) represent substituent group any commutable position on ring and can replace.Such as, formula a represents and any on B ring may be replaced
Position, as shown in formula b.
Unless other aspects show, structural formula described in the invention includes that all of isomeric forms is (as mapping is different
Structure, diastereo-isomerism, and geometrical isomerism (or conformational isomerism)): such as contain R, S configuration of asymmetric center, (Z) of double bond,
(E) isomer, and (Z), the conformer of (E).Therefore, the single three-dimensional chemical isomer of the compound of the present invention or it is right
Reflect isomer, diastereomer, or the mixture of geometric isomer (or conformer) and broadly fall into the scope of the present invention.
Term used in the present invention " tautomer " or " tautomeric form " represent the structure with different-energy
Isomers can cross low energy barrier, thus inversion of phases mutually.Such as, proton tautomer (i.e. prototropic change) includes passing through
Proton migrates and carries out change, such as keto-enol formula change and imine-enamine isomerization.Valence tautomers bag
Include and recombinated by some bonding electronss and carry out change.
Unless other aspects show, all tautomeric forms of the compound of the present invention are included in the scope of the present invention
Within.It addition, unless other aspects show, the structural formula of compound described in the invention includes one or more different former
The enriched isotope of son.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.
Such conversion is hydrolyzed in blood by prodrug or is that precursor structure is affected through enzymatic conversion in blood or tissue.This
Bright prodrug compounds can be ester, and in existing invention, ester can have phenyl ester class, aliphatic as prodrug
(C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention one
Compound comprises OH group, i.e. can be acylated the compound obtaining prodrug form.Other prodrug form bag
Include phosphate ester, if these phosphate compounds are that the di on parent obtains.Complete about prodrug
Discussion is referred to documents below: 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 document is incorporated herein by this.
" metabolite " refers to that concrete compound or its salt is in vivo by the product obtained by metabolism.One change
The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention
Adopt as stating and experimentally characterize.Such product can be by passing through oxidation, reduction, water to drug compound
Solving, amidated, desamido-effect, esterification, degreasing, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes compound
Metabolite, be fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.
The definition of neutral body of the present invention chemistry and the use of convention are typically referenced to documents below: 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, the compound of 1994. present invention can comprise asymmetric center or chiral centre, therefore exist not
Same stereoisomer.The all of stereoisomeric forms in any ratio of compound of the present invention, include, but not limited to, diastereomer, mapping
Isomer, atropisomer, and their mixture, such as racemic mixture, constitute the part of the present invention.The most organic
Compound all exists with optical active forms, and i.e. they are had the ability the plane of Plane of rotation polarized light.Optical activity is being described
During compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) be used for name
The symbol that compound linearly polarized light rotates, (-) or l refer to that compound is left-handed, prefix (+) or d refer to that compound is dextrorotation
's.The chemical constitution of these stereoisomers is identical, but their stereochemical structure is different.Specific stereoisomer
Can be enantiomer, the mixture of isomer be commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is referred to as
Racemic mixture or racemic modification, this may cause not having in chemical reaction process stereo selectivity or stereoselectivity.Art
Language " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.
" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention.Medicine
On, acceptable salt is known to us at art, such as document: Berge et al., describe
Pharmaceutically acceptable salts in detail in J.Pharmacol Sci, 1977,66,1-19,
Described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, and reacts, with amino group, the nothing formed
Machine hydrochlorate has hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetate, oxalates, Malaysia
Hydrochlorate, tartrate, citrate, succinate, malonate, or by additive method described on books document as from
Sub-exchange process obtains these salt.Other pharmaceutically acceptable salts include adipate, alginate, Ascorbate, Radix Asparagi
Propylhomoserin salt, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, camsilate, cyclopenta third
Hydrochlorate, digluconate, lauryl sulfate, esilate, formates, fumarate, gluceptate, glycerol
Phosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate,
Lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalene sulfonate, nicotinate, nitre
Hydrochlorate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionic acid salt, picrate, pivalate,
Propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Obtained by suitable alkali
Salt includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate the group of any comprised N
The quaternary ammonium salt that compound is formed.Water solublity or oil-soluble or dispersion product can be obtained by quaternization.Alkali metal or
Alkali salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt farther includes suitable, nontoxic ammonium,
The amine cation that quaternary ammonium salt and gegenions are formed, such as halogenide, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound,
Nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecule and the present invention is formed
Thing.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second
Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
The when that term " blocking group " or " PG " referring to a substituent group and other reacted with functional groups, it is commonly used to resistance
Disconnected or protect special functional.Such as, " blocking group of amino " refers to that a substituent group is connected with amino group and blocks
Or amino functional in protection compound, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl
(BOC), benzyloxycarbonyl group (CBZ) and 9-fluorenes Asia methoxycarbonyl group (Fmoc).Similarly, " hydroxy-protective group " refers to the replacement of hydroxyl
Base is used for blocking or protect the functional of hydroxyl, suitable blocking group to include acetyl group and silicyl." carboxyl-protecting group
Group " refer to the substituent group of carboxyl for blocking or protect the functional of carboxyl, general carboxyl-protecting group includes-
CH2CH2SO2Ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxyl methyl, 2-is (to toluene
Sulfonyl) ethyl, 2-(p-nitrophenyl sulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro-ethyl, etc..For protection
The description that group is general refers to document: 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 pharmaceutically acceptable salt, and pharmaceutical preparation,
Protein kinase, the disease of especially B-Raf kinases regulation or the treatment of disease there is potential purposes.Particularly, the present invention relates to
And a kind of compound as shown in the formula (I):
Or its raceme, stereoisomer, geometric isomer, tautomer, solvate, nitrogen oxides, metabolism is produced
Thing or pharmaceutically acceptable salt, wherein X and Y is defined as follows shown.
Each X and Y independently be H ,-C (=O) R3,-C (=O) OR4,-C (R1R2)OC(=O)R3,-C (R1R2)OC(=O)OR4Or-
C(R1R2)OP(=O)(OR4)(OR4a) and when Y is H, X can not be H or acetyl group.
In some embodiments, each X and Y independently be H or-C (R1R2)OP(=O)(OH)2, and X and Y can not be simultaneously
H。
And in other embodiments, each X and Y independently be H ,-C (=O) R3,-C (=O) OR4,-C (R1R2)OC(=O)
R3,-C (R1R2)OC(=O)OR4, and when Y is H, X can not be H or acetyl group.
In some embodiments, acyl moieties (-C (=O) R3) it is a-amino acid or the base of its optical isomer formation
Group.
In some embodiments, a-amino acid is isoleucine, leucine, lysine, methionine, phenylalanine, Soviet Union
Propylhomoserin, tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, glutamine, proline, silk ammonia
Acid, p-tyrosine, arginine, histidine, cysteine, glycine, sarcosine, DMG, homoserine,
Norvaline, nor-leucine, ornithine, homocysteine, homophenylalanin, phenylglycine, o-tyrosine, m-tyrosine
Or hydroxyproline, when a-amino acid is aspartic acid or glutamic acid, can be any one carbonyl in its structure with point
Sub-remainder is connected.
In other embodiments, described a-amino acid is isoleucine, leucine, lysine, methionine, phenylpropyl alcohol
Propylhomoserin, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, glutamic acid, glutamine, proline,
Serine, tyrosine, arginine or histidine, each amino acid whose alpha-position wherein said is all S configuration.
In each structure of above-mentioned X, Y, each R1And R2Independently be H, D, C1-6Alkyl, C1-6Haloalkyl, C3-6Cycloalkyl ,-
(C1-4Alkylidene)-(C3-6Cycloalkyl), C3-6Heterocyclic radical or-(C1-4Alkylidene)-(C3-6Heterocyclic radical), wherein, described each R1And R2
It is connected with carbon atom respectively, or R1And R2It is connected with carbon atom after Xiang Lianing, or R1, R2And together with the carbon atom being connected with them,
Form replacement or unsubstituted 3-8 former molecular carbocyclic ring or heterocycle；
I.e. R1, R2And together with the carbon atom being connected with them, 3-8 former molecular carbocyclic ring or heterocycle can be formed, also
Can be formed without carbocyclic ring or heterocycle, other structures being well known to those skilled in the art, such as C-R1-R2、C-R2-R1Or R1-C-R2
Deng.
And in some embodiments, described each R1And R2Independently be H, D or C1-3Alkyl.
In each structure of above-mentioned X, Y, each R3Independently be H, D, C1-10Alkyl, C1-10Haloalkyl, C3-8Cycloalkyl ,-
(C1-6Alkylidene)-(C3-8Cycloalkyl), C3-8Heterocyclic radical ,-(C1-6Alkylidene)-(C3-8Heterocyclic radical), C6-10Aryl ,-(C1-6Alkylene
Base)-(C6-10Aryl), 5-10 former molecular heteroaryl or-(C1-6Alkylidene)-(5-10 former molecular heteroaryl),
Wherein, described each C1-10Alkyl, C1-10Haloalkyl, C3-8Cycloalkyl ,-(C1-6Alkylidene)-(C3-8Cycloalkyl), C3-8Heterocycle
Base ,-(C1-6Alkylidene)-(C3-8Heterocyclic radical), C6-10Aryl ,-(C1-6Alkylidene)-(C6-10Aryl), 5-10 is former molecular
Heteroaryl and-(C1-6Alkylidene)-(5-10 former molecular heteroaryl) unsubstituted or optionally by 1,2,3 or 4 independence
Selected from D, F, Cl, Br, I ,-OH ,-NH2, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl and C1-6The substituent group of alkylamino is taken
Generation；
In other embodiments, each R3Independently be C1-10Alkyl, C3-8Cycloalkyl ,-(C1-6Alkylidene)-(C3-8
Cycloalkyl), C3-8Heterocyclic radical ,-(C1-6Alkylidene)-(C3-8Heterocyclic radical), C6-10Aryl ,-(C1-6Alkylidene)-(C6-10Aryl), 5-
10 former molecular heteroaryls or-(C1-6Alkylidene)-(5-10 former molecular heteroaryl), and wherein, described each C1-10Alkane
Base, C3-8Cycloalkyl ,-(C1-6Alkylidene)-(C3-8Cycloalkyl), C3-8Heterocyclic radical ,-(C1-6Alkylidene)-(C3-8Heterocyclic radical), C6-10
Aryl ,-(C1-6Alkylidene)-(C6-10Aryl), 5-10 former molecular heteroaryl and-(C1-6Alkylidene)-(5-10 atom
The heteroaryl of composition) unsubstituted or be optionally independently selected from D, F, OH ,-OMe ,-NH by 1,2,3 or 42,-NHMe ,-NMe2
And C1-3The substituent group of alkyl is replaced.
In each structure of above-mentioned X, Y, each R4And R4aIndependently be H, C1-10Alkyl, C1-10Haloalkyl, C3-8Cycloalkyl ,-
(C1-6Alkylidene)-(C3-8Cycloalkyl), C3-8Heterocyclic radical ,-(C1-6Alkylidene)-(C3-8Heterocyclic radical), C6-10Aryl ,-(C1-6Alkylene
Base)-(C6-10Aryl), 5-10 former molecular heteroaryl or-(C1-6Alkylidene)-(5-10 former molecular heteroaryl),
Wherein, described each C1-10Alkyl, C1-10Haloalkyl, C3-8Cycloalkyl ,-(C1-6Alkylidene)-(C3-8Cycloalkyl), C3-8Heterocycle
Base ,-(C1-6Alkylidene)-(C3-8Heterocyclic radical), C6-10Aryl ,-(C1-6Alkylidene)-(C6-10Aryl), 5-10 is former molecular
Heteroaryl and-(C1-6Alkylidene)-(5-10 former molecular heteroaryl) unsubstituted or optionally by 1,2,3 or 4 independence
Selected from D, F, Cl ,-OH ,-NH2, oxo (=O), C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl and C1-6The substituent group of alkylamino
Replaced.
In some embodiments, each R4And R4aIndependently be H, C1-10Alkyl, C3-8Cycloalkyl ,-(C1-6Alkylidene)-
(C3-8Cycloalkyl), C3-8Heterocyclic radical ,-(C1-6Alkylidene)-(C3-8Heterocyclic radical) or C6-10Aryl, wherein, described each C1-10Alkyl,
C3-8Cycloalkyl ,-(C1-6Alkylidene)-(C3-8Cycloalkyl), C3-8Heterocyclic radical ,-(C1-6Alkylidene)-(C3-8Heterocyclic radical) and C6-10Virtue
Base is unsubstituted or is optionally independently selected from D, F, OH ,-OMe ,-NH by 1,2,3 or 42,-NHMe ,-NMe2, oxo (=O) and
C1-3The substituent group of alkyl is replaced.
In some embodiments, described formula (I) compound pharmaceutically acceptable salt is its alkali metal salt, alkaline-earth metal
Salt, ammonium salt or N+(C1-4Alkyl)4Salt.
In other embodiments, described formula (I) compound pharmaceutically acceptable salt is its sodium salt, lithium salts, potassium
Salt, calcium salt, magnesium salt, ammonium salt, quaternary ammonium salt, or combinations thereof.
In some embodiments, described formula (I) compound pharmaceutically acceptable salt can be inorganic salt, organic salt or
Combinations thereof, wherein, described inorganic salt is hydrochlorate, hydrobromate, sulfate, nitrate, phosphate or combinations thereof,
Described organic salt is acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-
Hydracrylate, pyruvate, oxalates, glycollate, salicylate, glucuronate salt, galacturonic acid hydrochlorate, citric acid
Salt, tartrate, aspartate, glutamate, Glu, benzoate, cinnamate, tosilate, benzene sulfonate, first sulphur
Hydrochlorate, esilate, fluoroform sulphonate or combinations thereof.
The compound of formula (I) structure of the present invention includes but not limited to compound or its raceme, vertical in detail below
Body isomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable
Salt or its prodrug:
Unless other aspects show, all of raceme of compound of the present invention, stereoisomer, geometric isomer, mutually
Tautomeric, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug broadly fall into the present invention
Scope.
Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " includes that material or compositions must
Must be suitable for chemistry or toxicologically, with composition preparation other components and for treatment mammal relevant.
The salt of the compound of the present invention also includes the intermediate for compound shown in preparation or purification formula (I) or formula (I)
The salt of the enantiomer that shown compound separates, but it is not necessarily pharmaceutically acceptable salt.
If the compound of the present invention is alkaline, the most conceivable salt can by provide on document any suitably
Method prepares, and such as, uses mineral acid, example hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid etc..Or use organic
Acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, acetone acid, oxalic acid, glycolic and salicylic acid；Pyrans
Saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and tartaric acid；Aminoacid, such as aspartic acid and paddy
Propylhomoserin；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, ethyl sulfonic acid, etc..
If the compound of the present invention is acid, the most conceivable salt can be prepared by suitable method, e.g.,
Use inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxide, etc.
Deng.Suitably salt includes, but is not limited to, the organic salt obtained from aminoacid, and such as glycine and arginine, ammonia, such as primaquine, secondary
Ammonia and tertiary ammonia, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtain from sodium, calcium, potassium, magnesium, manganese, ferrum, copper, zinc, aluminum and lithium
Inorganic salt.
The present invention also comprises the application of compound of the present invention and pharmaceutically acceptable salt thereof, is i.e. used for producing doctor
There is the disease of mediation in medicine product treatment acute and chronic blood vessel, described in the invention including those.The compound of the present invention is being given birth to
Produce the application in cancer therapy drug.The compound of the present invention is equally used for producing a kind of medical supplies and alleviates, and stops, controls or control
Treat the disease mediated by B-Raf.The present invention comprises pharmaceutical composition, and this pharmaceutical composition includes the chemical combination representated by formula (I)
Thing and at least one pharmaceutically acceptable carrier, effectively treat consumption needed for the combination of adjuvant or diluent.
The present invention comprises treatment patient vessel equally and the disease of mediation, or the method sensitive to this disease, the method occurs
Comprise the therapeutically effective amount of compound representated by use formula (I) patient is treated.
Compositions, preparation and administration
According on the other hand, the feature of the pharmaceutical composition of the present invention includes the compound of formula (I), listed by the present invention
Compound in compound, or embodiment, and pharmaceutically acceptable carrier, adjuvant, or excipient.In the compositions of the present invention
The amount of compound can the most detectably suppress biological sample or protein kinase in the patient.
There is free form in the compound of the present invention, or suitably, as pharmaceutically acceptable derivates.According to this
Bright, pharmaceutically acceptable derivates includes, but is not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of esters, or energy
Directly or indirectly according to other any adduct or derivants of needing to be administered of patient, described by other aspects of the present invention
Compound, its metabolite or his residue.
As described in the invention, the pharmaceutically acceptable compositions of the present invention comprises pharmaceutically acceptable load further
Body, adjuvant, or excipient, these are applied as the present invention, including any solvent, diluent, or other liquid excipients, point
Powder or suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, preservative, solid binder or lubricant, etc.,
It is suitable for distinctive target formulation.As described by documents below: 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 content of comprehensive document herein, shows that different carriers can be applicable to pharmaceutically acceptable
The preparation of compositions and preparation method known to them.Compound not phase except carrier medium and the present invention of any routine
The scope held, such as produced any bad biological effect or any other component with pharmaceutically acceptable compositions
The interaction produced in harmful manner, their purposes is also the scope that the present invention is considered.
Can include, but is not limited to as the material of pharmaceutically acceptable carrier, ion-exchanger, aluminum, aluminium stearate, ovum
Phospholipid, serum albumin, such as human albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, saturated vegetable butter
The partial glyceride mixtures of fat acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorination
Sodium, zinc salt, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymerization
Body, lanoline, sugar, such as lactose, dextrose plus saccharose；Starch such as corn starch and potato starch；Cellulose and its derivant
Such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate；Natural gum powder；Fructus Hordei Germinatus；Gelatin；Pulvis Talci；Adjuvant such as cacao bean
Fat and suppository wax；Oil is such as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum Sesami, olive oil, Semen Maydis oil and Oleum Glycines；Glycols chemical combination
Thing, such as propylene glycol and Polyethylene Glycol；Esters such as ethyl oleate and Ethyl Lauroyl acid esters；Agar；Buffer agent such as magnesium hydroxide and
Aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge (family name) solution；Ethanol, phosphate buffer solution, and other are nontoxic
Proper lubrication agent such as sodium laurylsulfate and magnesium stearate, coloring agent, releasing agent, coating agents, sweeting agent, flavoring agent and perfume (or spice)
Material, preservative and antioxidant.
The compositions of the present invention can be oral administration, drug administration by injection, Aerosol inhalation, topical, and per rectum is administered,
Nose administration, buccal administration, vagina administration or be administered by implantable medicine box.Term used herein " through injection " includes
Subcutaneous, vein, intramuscular, IA, in synovial membrane (chamber), intrasternal, in film, ophthalmic, in liver, focus
In, and the injection of intracranial or infusion techniques.Preferably compositions is oral administration, to Intraperitoneal medication or intravenous injection.This
The injection system of the composition sterile of invention can be water or oleaginous suspension.These suspensions can be according to known skill
Art uses suitable dispersant, wetting agent and suspending agent to press formula manufacture.Aseptic injection can be aseptic parenteral solution or suspension
Liquid, is to inject nontoxic acceptable diluent or solvent, such as 1,3 butylene glycol solution.These acceptable excipient and solvents
Can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, aseptic nonvolatile oil can be made by convention
For solvent or suspension media.
With this end in view, the nonvolatile oil of any gentleness can be list or the DG of synthesis.Fat
Acid, as oleic acid and its glyceride ester derivatives can be used for the preparation of injectable, as natural pharmaceutically acceptable oil
Fat, such as olive oil or Oleum Ricini, particularly their polyoxyethylene deriv.These oil solutions or suspension can comprise long-chain
Alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents, be generally used for the medicine system of pharmaceutically acceptable dosage form
Agent includes emulsion and suspension.Other conventional surfactants, such as Tweens, spans and other emulsifying agents or biological medicament
The hardening agent of efficiency, is generally used for pharmaceutically acceptable solid, liquid, or other dosage forms, it is possible to be applied to drug target
The preparation of preparation.
The pharmaceutically acceptable compositions of the present invention can be to carry out oral administration with any acceptable peroral dosage form, its
In include, but is not limited to, capsule, tablet, water suspension or solution.Orally using about tablet, carrier generally comprises breast
Sugar and corn starch.Lubricant, such as magnesium stearate, is the most typically added.Capsule oral is administered, suitable diluent bag
Include lactose and dry corn starch.When oral administration is water suspension, its effective ingredient is made up of emulsifying agent and suspending agent.
If it is desired to obtain these dosage forms, some sweeting agent, flavoring agent or coloring agent can also be added.
It addition, the pharmaceutically acceptable compositions of the present invention can be with the form rectally of suppository.These can pass through
Reagent is mixed with suitable non-perfusing accessory drugs and forms, this accessory drugs be at room temperature solid but at a temperature of rectum then
For liquid, thus melt in the rectum and discharge medicine.Such material includes cocoa butter, Cera Flava, and polyethylene glycols.This
Inventing pharmaceutically acceptable compositions can be topical, particularly during local application, relates to controlling of region or organ
Treat target easily to reach, such as the disease of eye, skin or lower intestinal tract.Suitably topical preparations can prepare and be applied to
These fields or organ.
Above-mentioned rectal suppository or suitably enema can apply to the local application of lower intestine.Local skin speckle also may be used
With such medication.For local application, pharmaceutically acceptable compositions can be prepared as suitable ointment by formulation method, should
Ointment packets is suspended or dissolved in one or more carrier containing active component.The carrier compound of topical of the present invention includes,
But it is not limited to mineral oil, liquid paraffin, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifing wax and water.
It addition, pharmaceutically acceptable compositions can be prepared as suitable lotion or Emulsion, this lotion or Emulsion comprise active component
It is suspended in or is dissolved in one or more pharmaceutically acceptable carrier.Suitably carrier includes, but is not limited to, mineral oil, department
Dish-60(Arlacel-60), polysorbate60 (polysorbate 60), cetyl esters wax, palmityl alcohol, 2-octyl group 12
Alkanol, benzyl alcohol and water.
Preparation be can be prepared as, such as isotonic micronized suspension, pH for ophthalmically acceptable, pharmaceutically acceptable compositions
The Sterile Saline of regulation or other aqueous solutions, it is preferable that isosmotic solution and the Sterile Saline of pH regulator or other aqueous solutions, permissible
Add disinfection preservative such as benzalkonium chloride.It addition, for ophthalmically acceptable, pharmaceutically acceptable compositions can be by pharmaceutical formulation system
Standby one-tenth ointment such as vaseline oil.The pharmaceutically acceptable compositions of the present invention can by the gaseous solvents of nose or inhalant carry out to
Medicine.Such compositions can prepare according to the known technology of pharmaceutical formulation, or can be prepared as saline solution, uses benzene first
Alcohol or other suitable preservative, absorption enhancer, fluorocarbon or other conventional solubilizing agents or dispersant improve biology
Availability.
The liquid dosage form of oral administration includes, but is not limited to, pharmaceutically acceptable Emulsion, microemulsion, solution, suspends
Liquid, syrup and elixir.In addition to the active compound, liquid dosage form can comprise known general inert diluent, such as, water
Or other solvents, solubilizing agent and emulsifying agent, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
Propylene glycol, 1,3 butylene glycol, dimethylformamide, oils and fats (particularly Semen Gossypii, Semen arachidis hypogaeae, Semen Maydis, microorganism, Fructus Canarii albi, Semen Ricini and
Oleum Sesami), glycerol, Tetrahydrofurfuryl Alcohol, Polyethylene Glycol, sorbitan alcohol fatty acid ester, and their mixture.Except lazy
Outside the diluent of property, Orally administered composition can also comprise adjuvant such as wetting agent, emulsifying agent or suspending agent, sweeting agent, flavoring agent
And aromatic.
Injection, as aseptic parenteral solution or oleaginous suspension can according to known technology use suitable dispersant,
Wetting agent and suspending agent are prepared by pharmaceutical formulation.Aseptic injection can be nontoxic through the most acceptable diluent
Or aseptic parenteral solution, suspension or the emulsion that solvent is made, such as, 1,3 butylene glycol solution.Acceptable excipient and solvent
Can be water, Lin Ge (family name) solution, U.S.P. and isotonic sodium chlorrde solution.It addition, aseptic nonvolatile oil is by convention
As solvent or suspension media.The nonvolatile oil of the most any gentleness can include that the list of synthesis or two glycosyl are sweet
Oil diester.It addition, fatty acid such as oleic acid can apply to injection.
Injection can be aseptic, as filtered by antibacterial defence filter, or the form with aseptic solid composite
Mix biocide, during biocide can be dissolved in or be scattered in disinfectant or other sterile injectable medium before use.In order to prolong
The effect of the compound of the long present invention, it usually needs slowed down the absorption of compound by subcutaneous injection or intramuscular injection.So
Can realize utilizing liquid suspension to solve crystal or the problem of amorphous material poorly water-soluble.The absorbance of compound depends on
Its dissolution, depends on grain size and crystal shape successively.Furthermore it is possible to dissolved in oil vehicles by compound
Or the delay having disperseed compound injection to be administered absorbs.
Injection storage form is to form chemical combination by biodegradable polymer, such as many lactic acid-polyglycolide
The microcapsule matrix of thing completes.The controlled release ratio of compound depends on that compound forms ratio and the particular polymer of polymer
Character.Other biodegradable polymers include poly-(positive esters) and poly-(anhydride).Injection storage form can also be passed through
Compound embeds the liposome compatible with bodily tissue or microemulsion prepares.
Some of them embodiment is, the compositions of rectum or vagina administration is suppository, and suppository can be by by the present invention's
The adjuvant of compound and suitable non-perfusing or carrier mix and prepare, as wax-like in cocoa butter, Polyethylene Glycol, or suppository
Thing, they are solid in room temperature but are the most then liquid, therefore just melt release of active in vagina or cavity of tunica vaginalis and close
Thing.
The solid dosage forms of oral administration includes capsule, tablet, pill, powder and granule.In these dosage forms, active ingredient
Thing mixes with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or calcium phosphate or filler or a)
Filler such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binding agent such as carboxymethyl cellulose, alginate, bright
Glue, polyvidon, sucrose and arabic gum, c) wetting agent such as glycerol, d) disintegrating agent such as agar, calcium carbonate, potato starch
Or tapioca, alginic acid, some silicate and sodium carbonate, e) blocker solution such as paraffin, f) absorption enhancer such as quaternary ammonium
Compound, g) wetting agent such as hexadecanol and glyceryl monostearate, h) absorbent such as kaolin and Bentonite, i) lubricant such as Talcum
Powder, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium laurylsulfate, and their mixture.As for capsule, tablet and ball
Agent, these dosage forms can comprise buffer agent.
The solid composite of similar type can be that filler riddles soft or hard capsule, and the adjuvant used has breast
Sugared and high molecular Polyethylene Glycol etc..Solid dosage forms photo agent, lozenge, capsule, pill and granule can pass through coating, shell adding
Coating method as known on enteric coating and other drug preparation prepares.They can optionally comprise opacifier, or
Preferably, in certain part of intestinal, at random, with the sole active agent in the method release composition of delay.As implanted
Compositions can comprise multimeric species and wax.
Reactive compound can form microcapsule formulations together with one or more excipient described in the invention.Solid
Dosage form photo agent, lozenge, capsule, pill and granule can pass through coating or shell adding, such as enteric coating, controlled release coat and other public affairs
The drug formulation process known.In these solid dosage formss, reactive compound can mix with at least one inert diluent, such as sugarcane
Sugar, lactose or starch.Such dosage form can also comprise substance besides inert diluents as general application, as
Tableting lubricant and other compression aids such as magnesium stearate and microcrystalline Cellulose.As for capsule, tablet and pill, these dosage forms can
To comprise buffer agent.They can optionally comprise tranquilizer, or preferably, in certain part of intestinal, with arbitrarily postpone
Sole active agent in method release composition.Applicable implant compositions can include, but is not limited to, polymer and
Wax.
The compound of the present invention by local or include ointment through the dosage form of percutaneous drug delivery, paste, Emulsion, lotion, solidifying
Colloid, powder, solution, spray, inhalant, paster.Active component under sterile conditions with pharmaceutically acceptable carrier
Mix mutually with any required preservative or required buffer agent.The pharmaceutical preparation of ophthalmology, ear drop and eye drop are all these
The scope of bright consideration.It addition, present invention further contemplates that the application of transdermal patch, it is delivered to internal aspect at control compound has
More advantage, such dosage form can be prepared in suitable medium by dissolving or decentralized compound.Absorb and promote
Enter agent and can increase compound through the flow of skin, through-rate control thin film or compound is scattered in polymer matrix or
Gelatin controls its speed.
The compound of the present invention is preferably prepared as dosage unit form to alleviate the equal of dosage and dosage by pharmaceutical formulation
Even property.Term " dosage " unit type " the physical dispersion unit of required medicine is suitably treated referred to herein as patient.But, should
Understand the compound of the present invention or total usage compositions every day will judge to come according to reliable medical science scope by the doctor in charge
Determine.For any one special patient or organism, concrete effective dose level will depend upon which that many factors include being controlled
The disease treated and the seriousness of disease, the activity of particular compound, concrete compositions used, the age of patient, body weight, health
Situation, sex and dietary habit, administration time, route of administration and the discharge rate of particular compound used, during treatment lasting
Between, medicinal application is combined in drug combination or with specific compound, and factor known to some other pharmaceutical field.
The change of the consumption that can produce the compound of the present invention of single dosage form composition in conjunction with carrier mass is depended on
Cure mainly and special mode of administration.Some of them embodiment is, compositions can be prepared as dosage at 0.01-by formulation method
The inhibitor of 200mg/kg body weight/day, the amount being accepted compositions by patient is administered.
The compound of the present invention can be with only pharmaceutical agents or combine other additional treatment (pharmacy one or more
) agent is administered, wherein drug combination causes acceptable untoward reaction, and this has for the treatment of high proliferative disease such as cancer
There is special meaning.In this case, the compound of the present invention can be in conjunction with known cytotoxic agent, and single transduction suppresses
Agent or other antitumor and anticancer agents, and their mixture and combination.As used in the present invention, additional treatment agent is normally administered and controls
Treat special disease, it is simply that known " treating disease suitably "." additional treatment agent " used in the present invention includes Chemo-Therapy
Treat medicine or other antiproliferative medicines can be in conjunction with the compounds for treating proliferative disease of the present invention or cancer.
Chemotherapeutic agent or other anti-proliferative drugs include histon deacetylase (HDAC) (HDAC) inhibitor, including but also
It is not limited to, SAHA, MS-275, MGO103, and those compounds described by following patent: WO2006/010264, WO03/
024448,WO2004/069823,US2006/0058298,US2005/0288282,WO00/71703,WO01/38322,
WO01/70675, WO03/006652, WO2004/035525, WO2005/030705, WO2005/092899, and demethylation examination
Agent includes, but is not limited to, the miscellaneous nitrogen of 5--2 '-deoxycytidine (5-aza-dC), azacitidine (Vidaza), decitabine
(Decitabine) compound and described by documents below: 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, chemotherapeutics or other anti-proliferative drugs can increase in conjunction with the compounds for treating of the present invention
Growing property disease and cancer.Known chemotherapeutics includes, but is not limited to, can use with anti-cancer agent in combination of the present invention other
Therapy or cancer therapy drug, operation, X-ray therapy (a little example such as gamma-radiation, neutron beam X-ray therapy, electron beam evaporation therapy,
Proton therapy, brachytherapy and system isotope therapy), incretotherapy, taxanes (paclitaxel
(taxol), Docetaxel (taxotere) etc.), platinum derivatives (cisplatin (cisplatin), carboplatin (carboplatin)),
Biological response modifier (interferon, interleukin), tumor necrosis factor (TNF, TRAIL receptor target thing), cross hot and cold
Freeze therapy, alleviate the reagent (such as Bendectin) of any untoward reaction, and other approved chemotherapeutics, including but do not limit
In, alkylating drug (chlormethine (mechlorethamine), chlorambucil (chlorambucil), cyclophosphamide
(cyclophosphamide), L-Sarcolysinum (melphalan), ifosfamide (ifosfamide)), antimetabolite (first ammonia butterfly
Purine (methotrexate), pemetrexed (pemetrexed) etc.), purine antagonist and Pyrimidine antagonists (6-MP (6-
Mercaptopurine), 5-fluorouracil (5-fluorouracil), cytosine arabinoside (cytarabile), gemcitabine
(gemcitabine)), (vinblastine (vinblastine), vincristine (vincristine), Changchun is auspicious for spindle poison
Shore (vinorelbine)), podophyllotoxin (etoposide (etoposide), irinotecan (irinotecan), hycamtin
(topotecan)), antibiotic (doxorubicin (doxorubicin), bleomycin (bleomycin), mitomycin
(mitomycin)), nitroso ureas (carmustine (carmustine), lomustine (lomustine)), cell division cycle
Inhibitor (KSP passes through mitotic kinesin inhibitors, CENP-E and CDK inhibitor), enzyme (asparaginase
(asparaginase)), hormone (tamoxifen (tamoxifen), leuprorelin (leuprolide), flutamide
(flutamide), megestrol (megestrol), dexamethasone (dexamethasone) etc.).Angiogenesis inhibitor reagent
(Avastin (avastin) etc.).Monoclonal antibody (Baily monoclonal antibody (belimumab), brentuximab, Cetuximab
(cetuximab), gemtuzumab Ozogamicin Mylotarg CDP 771 (gemtuzumab), her monoclonal antibody (ipilimumab), ofatumumab, Victibix
(panitumumab), Lucentis (ranibizumab), Rituximab (rituximab), tositumomab
(tositumomab), Herceptin (trastuzumab)).Inhibitors of kinases (imatinib (imatinib), Sutent
(sunitinib), Sorafenib (sorafenib), Erlotinib (erlotinib), gefitinib (gefitinib), reach sand
For Buddhist nun (dasatinib), AMN107 (nilotinib), Lapatinib (lapatinib), gram Zhuo replaces Buddhist nun (crizotinib),
Ruxolitinib, vemurafenib, vandetanib, pazopanib, etc.).The approach of Drug inhibition or activation cancer is such as
MTOR, HIF (hypoxia inducible factor) approach and other.The wide forum for the treatment of of cancer seeshttp:// www.nci.nih.gov/, the oncologic inventory of FAD accreditation is shown inhttp://www.fda.gov/cder/cancer/ druglist-rame.htm, and Merck Manual, the 18th edition .2006, all of content is all combined with list of references.
Other embodiment is, the compound of the present invention can be in conjunction with cytotoxic anticancer agent.Such anticarcinogen can
To find the 13rd edition Merck index (2001) is inner.These anticarcinogen include, but are not limited to, asparaginase, rich next
Mycin, carboplatin, carmustine, chlorambucil, cisplatin, L-ASP, cyclophosphamide, cytosine arabinoside, dacarbazine, put
Line rhzomorph D, daunorubicin, amycin (doxorubicin), epirubicin, etoposide, 5-fluorouracil, hexamethyl melamine
Amine, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, chlormethine, Ismipur, mesna, first ammonia butterfly
Purine, ametycin, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, sulfur
Guanine, hycamtin, vinblastine, vincristine, and vindesine.
Include, but is not limited to other suitable cytotoxic drugs of the compound drug combination of the present invention, these
It is applied to the compound of neoplastic disease treatment admittedly, as described in documents below: Goodman and Gilman ' s
The Pharmacological Basis of Therapeutics(Ninth Edition,1996,McGraw-Hill.)；This
A little anticarcinogen include, but are not limited to, aminoglutethimide (aminoglutethimide), l-asparaginase, azathioprine, 5-
Azacytidine, cladribine (cladribine), busulfan (busulfan), diethylstilbestrol, 2 ', 2 '-difluoro dCDP
Choline, Docetaxel, red hydroxyl nonyl adenine (erythrohydroxynonyladenine), ethinylestradiol, 5-
Fluorodeoxyuridine, floxuridine monophosphate, fludarabine phosphate (fludarabine phosphate), fluorine first
Testosterone (fluoxymesterone), flutamide (flutamide), hydroxyprogesterone caproate, idarubicin (idarubicin), interference
Element, medroxyprogesterone acetate, megestrol acetate, melphalan (melphalan), mitotane (mitotane), paclitaxel, spray department he
Fourth (pentostatin), N-phosphate base-L-Aspartic acid (PALA), plicamycin (plicamycin), methyl cyclohexane is sub-
Nitre urea (semustine), teniposide (teniposide), testosterone propionate, phosphinothioylidynetrisaziridine (thiotepa), trimethyl melamine
Amine, urine nucleoside and vinorelbine.
Other are suitably and the cytotoxin class anticarcinogen of compound use in conjunction of the present invention includes newfound cell
Toxic substance, including, but be not limited to, oxaliplatin (oxaliplatin), gemcitabine (gemcitabine), card training
His shore (capecitabine), Macrolide antineoplastic agent and naturally occurring or synthetic derivant, 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), and kinesin spindle protein inhibitor Eg5 (Wood et
al.,Curr.Opin.Pharmacol.2001,1,370-377)。
Other embodiment is, the compound of the present invention can be in conjunction with other signal transduction inhibitors.What is interesting is letter
Number transduction inhibitor 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) and the joining of each of which
Body.Such reagent includes, but is not limited to, antibody therapy such as Herceptin (trastuzumab), Cetuximab
(cetuximab), her monoclonal antibody (ipilimumab) and handkerchief trastuzumab (pertuzumab).Such therapy also includes, but
It is not limited to, small molecule kinase inhibitors such as imatinib (imatinib), Sutent (sunitinib), Sorafenib
(sorafenib), Erlotinib (erlotinib), gefitinib (gefitinib), Dasatinib (dasatinib), Ni Luo
For Buddhist nun (nilotinib), Lapatinib (lapatinib), gram Zhuo replaces Buddhist nun (crizotinib), ruxolitinib,
Vemurafenib, vandetanib, pazopanib, Afatinib (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, saracatinib (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, the compound of the present invention can be with bonding histone deacetylase inhibitors.Such
Reagent includes, but is not 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, the compound of the present invention can be in conjunction with other anticarcinogen such as proteasome inhibitor and m-
TOR inhibitor.These include, but are not limited to, bortezomib (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).The compound of the present invention can be combined with other anticarcinogen such as topoisomerase enzyme inhibitor, including but
It is not limited to camptothecine.
Those additional treatment agent can separate administration with the compositions of the compound comprising the present invention, as many dosage regimens
A part.Or, those therapeutic agents can be a part for one-pack type, mixes formation list with the compound of the present invention
Individual compositions.If being administered as the parts of many dosage regimens, two activating agents can be simultaneously continuously or in a period of time
Interior transmission mutually, thus obtain destination agent activity.
(those comprise one and add can to produce the consumption of the compound of one-pack type and additional treatment agent in conjunction with carrier mass
The compositions of therapeutic agent is as described in the invention) change depend on curing mainly and special mode of administration.Normally, the present invention
The amount of compositions additional treatment agent will comprise the therapeutic agent normal amount being administered as unique activating agent less than compositions.Separately
On the one hand, the scope of the amount of existing disclosed compositions additional treatment agent is about the 50%-100% of existing compositions normal amount, bag
The reagent contained is as sole active therapeutic agent.In those comprise the compositions of additional treatment agent, additional treatment agent will be with this
Bright compound plays synergism.
Compound and the application of compositions
Above-claimed cpd and pharmaceutical composition that the present invention provides can be used for preparation for protecting, process, treat or alleviating
The medicine of proliferative disease, it is also possible to for preparation for suppressing or regulate the medicine of protein kinase activity.
Specifically, in the compositions of the present invention, the amount of compound can the most detectably suppress protein kinase such as B-
The activity of Raf.The compounds of this invention is harmful to treating patient or reduce B-Raf signal response as antitumor drug
Effect.
The compound of the present invention can apply to, but is not limited to, and uses the compound of the present invention or the effective of compositions
Patient is administered by amount prevents or treats patient's proliferative disease.Such disease includes cancer, especially metastatic carcinoma, tremulous pulse medicated porridge
Sample hardening and pulmonary fibrosis.
The compound of the present invention can apply to the treatment of tumor and includes cancer and metastatic carcinoma, farther includes but does not limit
In, cancer such as bladder cancer, breast carcinoma, colon cancer, renal carcinoma, hepatocarcinoma, pulmonary carcinoma (includes small cell lung cancer), esophageal carcinoma, carcinoma of gallbladder, ovum
Nest cancer, cancer of pancreas, gastric cancer, cervical cancer, thyroid carcinoma, carcinoma of prostate, and skin carcinoma (including squamous cell carcinoma)；Lymphsystem is made
(including leukemia, the Cystic leukemia of acute lymphoblastic, acute lymphoblastic leukemia, B cell lymphoma, T is thin for hematoma tumor
Born of the same parents' lymphoma, He Jiejin (family name) lymphoma, non-hodgkin's (family name) lymphoma, hairy cell leukemia and Burkitt lymphoma)；Bone
Medullary system hematopoetic tumor (includes that acute and chronic myelocytic leukemia, myelodysplastic syndrome, and promyelocyte are white
Disorders of blood)；The tumor of mesenchymal cell origin (includes fibrosarcoma and rhabdomyosarcoma, and other sarcomas, such as soft tissue and soft
Bone)；Maincenter peripheral nervous system tumor (includes astrocytoma, neuroblastoma, glioma, and schwannoma)；With
Other tumors (include melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum,
Keratoacanthoma, thyroid follicle tumor and Ka Bo Ji (family name) sarcoma).
The compound of the present invention and pharmaceutical composition can be additionally used in treatment eye disease such as corneal graft rejection, eye new
Angiogenic is formed, and retinal neovascularazation includes that damage or metainfective new vessels are formed；Diabetic retinopathy；
Retrolental fibroplasia, and neovascular glaucoma；Retinal ischemia；Vitreous hemorrhage；Ulcer disease is such as
Gastric ulcer；Pathological but non-malignant situation such as hemangioma is bad including baby's hemangioendothelioma, nasopharynx and avascular bone
Dead fibrohemangioma；Female repro ductive system is disorderly such as endometriosis.These compounds and pharmaceutical composition are the most also used
In the situation that treatment edema and vascular permeability are too high.
The compound of the present invention and pharmaceutical composition can be also used for processing the situation such as diabetic relevant to diabetes
Retinopathy and microangiopathy.The compound of the present invention and pharmaceutical composition are equally used for the feelings that cancer patient's blood flow reduces
Condition.Patient tumors transfer is reduced by the compound of the present invention and pharmaceutical composition also beneficial effect.
The compound of the present invention and pharmaceutical composition, in addition to useful to human treatment, apply also for veterinary treatment and dote on
Thing, the animal of introduced variety and the animal on farm, including mammal, rodent etc..The example of other animal
Including horse, Canis familiaris L. and cat.Here, the compound of the present invention includes its pharmaceutically acceptable derivates.
Plural form is being applied to compound, and in the case of salt etc., it also means single compound, salt etc..
The Therapeutic Method that the compound comprising the present invention or compositions are administered, farther includes patient's additional treatment agent
The administration of (therapeutic alliance), wherein additional treatment agent is selected from: chemotherapy, antiproliferative or antiinflammatory, wherein additional treatment agent
Be applicable to treated disease, and additional treatment agent can with the compound of the present invention or compositions administering drug combinations, the present invention's
Compound or compositions are as single dosage form, or separate compound or compositions are as a part for multi-pharmaceutics.Additional treatment
Agent can be administered simultaneously with the compound of the present invention or not be administered simultaneously.The situation of the latter, administration can be staggered and be carried out as 6 is little
Time, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, within 1 month or 2 months, carry out.
The present invention comprises equally to the cytostatic method expressing B-Raf, and the method includes the chemical combination of the present invention
Thing or compositions and cells contacting, thus cell growth inhibiting.The cell that can be suppressed growth includes: breast cancer cell, colon
Rectum cancer cell, lung carcinoma cell, papillary carcinoma cell, prostate gland cancer cell, lymphoma cell, colon cancer cell, cancer of pancreas is thin
Born of the same parents, ovarian cancer cell, cervical cancer cell, central nervous system's cancerous cell, human osteosarcoma cell, kidney cancer cell, hepatocarcinoma
Cell, transitional cell bladder carcinoma cell line, stomach cancer cell, head or carcinoma of neck cell, melanoma cell and leukaemia.
The invention provides the method suppressing B-Raf kinase activity in biological sample, the method includes the present invention's
Compound or compositions contact with biological sample.Term used in the present invention " biological sample " refers to the specimen of vitro,
Include, but not limited to, cell is cultivated or cell extraction；The biopsy material obtained from mammal or its extract；Blood
Liquid, saliva, urine, feces, seminal fluid, tear, or other living tissue liquid substance and extracts thereof.Kinases in suppression biological sample
Activity, particularly B-Raf kinase activity, can be used for multiple use known to one of ordinary skill in the art.Such purposes includes,
But it is not limited to, hematometachysis, organ transplantation, biological sample storage and bioassay.
The compound of the present invention or " effective dose " of pharmaceutically acceptable compositions or " effective dose " refer to process or
Alleviate the effective dose that one or more present invention is previously mentioned the severity of disease.The method according to the invention, compound and combination
Thing can be any dosage and any route of administration is efficiently used for the order of severity that processes or palliate a disease.Required standard
Situation according to patient is changed by true amount, and this depends on race, the age, the generic condition of patient, the order of severity of infection,
Special factor, administering mode, etc..Compound or compositions can with one or more other therapeutic agents administering drug combinations, as
The present invention is discussed.
The compound of the present invention or its pharmaceutical composition can apply to the coating of implantable medical device, such as prosthese,
Artificial valve, artificial blood vessel, stem and catheter.Such as, vascular stem, have been used for overcoming restenosis (vessel wall after injury
Shrink again).But, patient uses stem or other implantable devices to be formed having clot or the risk of platelet activation.These
Disadvantageous effect can be hindered by the pharmaceutically acceptable compositions precoating device of the compound that use comprises the present invention
Stop or alleviate.
Suitably the method that is typically prepared of the coating of coating and implantable device is at document US6,099,562;US5,886,
026;And US5, it being described in 304,121, coating is the most biocompatible polymeric material such as hydrogel polymeric
Body, poly-methyl two silicon ether, polycaprolactone, Polyethylene Glycol, polylactic acid, ethane-acetic acid ethyenyl ester, and mixture.Coating can
Optionally further to be covered by suitable coating, such as fluoro simethicone, polyase, Polyethylene Glycol, phospholipid, or
Combinations thereof, carrys out performing combination thing and controls the feature of release.Another aspect of the present invention includes the compound using the present invention
The implantable device of coating.The compound of the present invention can also be coated on the medical instruments in implantable, such as pearl, or
There is provided " medicine storage institute " with polymer or other molecular mixing, therefore compare with pharmaceutical aqueous solution administering mode, it is allowed to medicine
Thing release has longer time limit.
The synthetic method of compound
For describing the present invention, it is listed below embodiment.But it is to be understood that the invention is not restricted to these embodiments, simply
The method putting into practice the present invention is provided.
Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further
Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment are used for being further illustrated by this
The content of invention.
The professional of art is it will be appreciated that chemical reaction described in the invention can be used to prepare perhaps suitably
Other compounds of many present invention, and it is considered as the model in the present invention for other method of the compound of preparing the present invention
Within enclosing.Such as, the synthesis according to the compound of those non-illustrations of the present invention can be successfully by those skilled in the art
Completed by method of modifying, as group is disturbed in suitable protection, by utilizing reagent known to other except described in the invention
, or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged
Ground is applicable to the preparation of other compounds of the present invention.
The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business
Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical
Company, the most not through being further purified, unless other aspects show during use.General reagent is western Gansu Province chemical industry from Shantou
Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Tianjin good fortune chemistry in morning
Chemical reagent work, Wuhan Xin Huayuan development in science and technology company limited, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao purchase
Can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride
It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, normal hexane, N,N-dimethylacetamide and N, N-
Dimethylformamide is to be dried in advance through anhydrous sodium sulfate to use.
Hereinafter reaction is usually and overlaps a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects
Show), reaction bulb the most suitable rubber closure, substrate is squeezed into by syringe.Glass drying oven is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum with
CDCl3、d6-DMSO、CD3OD or d6-acetone is solvent (report is in units of ppm), with TMS (0ppm) or chloroform (7.25ppm)
As reference standard.When multiplet occurs when, the abbreviation by following for use: s (singlet, unimodal), d (doublet, double
Peak), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of
Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant, represents with hertz (Hz).
The condition of Algorithm (MS) data is: Agilent1200 or Agilent6120Series LCMS (pillar
Model: Zorbax SB-C18,2.1 × 30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Flowing phase: 5-95%(is containing 0.1%
The CH of formic acid3CN) at (H containing 0.1% formic acid2O) ratio in, detects at 210/254nm UV, by low-response EFI pattern
(ESI)。
The characteristic manner of pure compound is: Agilent1100Series high speed liquid chromatography (HPLC), at 210nm
Detect with 254nm UV.Pillar generally operates at 40 DEG C.
The use of brief word below runs through the present invention:
BOC, Boc tert-butoxycarbonyl
BSA bovine serum albumin
BF3.Et2O boron trifluoride ether solution
CDCl3Deuterochloroform
CHCl3Chloroform
CH2Cl2, DCM dichloromethane
CH3SO2Cl, MsCl paratoluensulfonyl chloride
Cs2CO3Cesium carbonate
CuI Hydro-Giene (Water Science).
DAST diethylaminosulfur trifluoride
DBU 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene
DCE 1,2-dichloroethanes
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-dimethoxy-ethane
DMSO dimethyl sulfoxide
DPPA diphenyl phosphate azide
EDCI 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
EtOAc, EA ethyl acetate
Et2O ether
Et3N, TEA triethylamine
EtOCOCl ethyl chloroformate
FBS hyclone
G gram
H hour
HATU O-(7-nitrogen BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester
HBr hydrobromic acid
HBTU O-BTA-N, N, N ', N '-tetramethylurea hexafluorophosphate
HCl hydrochloric acid
H2Hydrogen
H2O water
H2O2Hydrogen peroxide
HOAc, AcOH acetic acid
HOBt I-hydroxybenzotriazole
K2CO3Potassium carbonate
KOH potassium hydroxide
KH hydrofining
LiHMDS LHMDS
NaHMDS sodium hexamethyldisilazide
LDA lithium diisopropyl amido
MCPBA metachloroperbenzoic acid
MeCN, CH3CN acetonitrile
MeI iodomethane
MeOH, CH3OH methanol
MgSO4Magnesium sulfate
ML, ml milliliter
Min minute
N2Nitrogen
NaBH4Sodium borohydride
NaBH3CN sodium cyanoborohydride
NaCl sodium chloride
NaH sodium hydride
NaHCO3Sodium bicarbonate
NaH2PO4Sodium dihydrogen phosphate
NaI sodium iodide
NaO (t-Bu) sodium tert-butoxide
NaOH sodium hydroxide
Na2SO4Sodium sulfate
NH3Ammonia
NH4Cl ammonia chloride
NMP N-Methyl pyrrolidone
PBS phosphate buffered saline (PBS)
P(t-Bu)3Three (tert-butyl group) phosphine
Pd/C palladium/carbon
Pd2(dba)3Double (dibenzyl subunit acetone) palladium
Pd(dppf)Cl2Double (diphenylphosphino) the ferrocene palladium chloride of 1,1-
Pd(OAc)2Palladium
Pd(PPh3)4Tetrakis triphenylphosphine palladium
PE petroleum ether (60-90 DEG C)
POCl3Phosphorus oxychloride
PyBop 1H-benzotriazole-1-base oxygen tripyrrole alkyl hexafluorophosphate
RT, rt, r.t. room temperature
Rt retention time
SnCl4Stannic chloride
TBAB tetrabutyl ammonium bromide
TBAHSO44-butyl ammonium hydrogen sulfate
TBTU O-(1H-benzotriazole-1-base)-N, N, N ', N '-tetramethylurea Tetrafluoroboric acid ester
TFA trifluoroacetic acid
TEAC bis-(tetraethyl ammonium) carbonate
THF oxolane
μ L microlitre
ZnCl2Protochloride zinc
Following synthetic schemes describes the preparation present invention and comes into the open the step of compound.Wherein, each R1Independently be H or alkane
Base, each R2Independently be H, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, M is alkali metal or alkaline-earth metal, the most permissible
It is Na, Li, K, Ca, Mg, etc., n is 0,1 or 2.
Synthetic schemes 1
As formula (4a) and (4bEsters derivative shown in) can be prepared by synthetic schemes 1:
Acyl chlorides (1) and aldehyde (2) at suitable lewis acid such as: zinc chloride, stannic chloride, Eorontrifluoride etherate solution effects
Under, generation chlorine Arrcostab (3).Reaction is under condition of no solvent or at atent solvents such as dichloromethane, chloroform, 1,2-dichloroethanes
In carry out, be suitable for response time be 0.5～24 hour, temperature range is between-40 DEG C to 40 DEG C.Then, in alkalescence condition
Under, chloro Arrcostab (3) react with Wei Luofeini (vemurafenib), obtain substituted azaindole compounds (4a), (4b)
Or (4a) and (4b), the compound that i.e. formula (I) defines.Be suitable for alkali include triethylamine, potassium hydroxide, sodium hydroxide, sodium hydride,
Hydrofining, double (trimethyl is silica-based) Sodamide., double (trimethyl is silica-based) potassamide, lithium diisopropylamine (LDA), 1,8-phenodiazine
Miscellaneous dicyclo [5.4.0] 11 carbon-7-alkene etc..Reaction is at DMF, dimethyl sulfoxide, oxolane, dioxy six
Ring, is carried out in the atent solvent such as 1,2-dimethoxy-ethane, and the response time being suitable for is 0.5～24 hour, and temperature range is-20
DEG C between 60 DEG C.
Synthetic schemes 2
As formula (8Carbonates derivant shown in) can be prepared by synthetic schemes 2:
The substituted chloro-formate of chlorine alkyl (5) and alcohol (6) at suitable alkali such as: pyridine, triethylamine, diisopropyl ethyl
Amine, under the effect of 2,6-lutidines, generation chlorine alkyl carbonate (7).Reaction is at dichloromethane, chloroform, 1,2-bis-chloroethene
Carrying out in the atent solvents such as alkane, temperature range is between-15 DEG C to 40 DEG C.Then, at applicable alkali such as: triethylamine, hydroxide
Potassium, sodium hydroxide, sodium hydride, hydrofining, double (trimethyl is silica-based) Sodamide., double (trimethyl is silica-based) potassamide, diisopropyl
Lithamide. (LDA), under the assistance of 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU), carbonic ester (7) and Wei Luofeini
(vemurafenib) reaction, obtain target compound (8), the compound that i.e. formula (I) defines.Reaction is at N, N-dimethyl formyl
Amine, dimethyl sulfoxide, oxolane, dioxane or 1, the atent solvent such as 2-dimethoxy-ethane (DME) is carried out, be suitable for is anti-
Being 0.5～24 hour between Ying Shi, temperature range is between-20 DEG C to 40 DEG C.
Synthetic schemes 3
As formula (12Derivative of amino ester shown in) can be prepared by synthetic schemes 3:
Chlorine alkyl chloride sulphonic acid ester (13) with the aminoacid of amido protecting (9) at suitable alkali such as: sodium bicarbonate, bicarbonate
Potassium, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropyl ethyl amine, 2,6-lutidines and catalyst, as
TBAHSO4Effect under, generate chlorine Arrcostab (10).Reaction is at dichloromethane, chloroform, and water, in 1,2-dichloroethanes equal solvent
Carrying out, temperature range is between-20 DEG C to 40 DEG C.Then, in the basic conditions, by chlorine Arrcostab (10) it is added to Wei Luofeini
(vemurafenib) on, obtain compound (11).The alkali that reaction is suitable for includes potassium hydroxide, sodium hydroxide, sodium hydride or 1,8-
Diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU) etc..Reacting at DMF, dichloromethane, diformazan is sub-
Sulfone, oxolane, dioxane or 1, the atent solvent such as 2-dimethoxy-ethane is carried out, the response time being suitable for be 0.5～
24 hours, temperature range was between-10 DEG C to 40 DEG C.Amino protecting group includes, but not limited to tertbutyloxycarbonyl (Boc), acid
Under the conditions of, removable compound (11Boc protection in), such as, with dichloromethane solution or the hydrogen chloride of trifluoroacetic acid (TFA)
Ethyl acetate solution process, obtain compound (12), the compound that i.e. formula (I) defines.
Synthetic schemes 4
As formula (18Phosphoric acid shown in) and phosphoric acid salt derivant can be prepared by synthetic schemes 4:
Chlorine alkyl chloride sulphonic acid ester (13) with the salt of the suitably di-phosphate ester of protection, as di(2-ethylhexyl)phosphate tert-butyl ester potassium salt (14),
Alkali and catalyst, such as TBAHSO4Effect under, generate chlorine alkyl phosphoric acid di tert butyl carbonate (15).Suitably alkali includes sodium bicarbonate,
Potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropyl ethyl amine, 2,6-lutidines etc..React
Dichloromethane, water, chloroform or 1,2-dichloroethanes equal solvent is carried out, temperature range is between-20 DEG C to 40 DEG C.Connect
, in the basic conditions, by chlorine alkyl phosphoric acid di tert butyl carbonate (15) be added on Wei Luofeini (vemurafenib), obtain phosphoric acid
Di tert butyl carbonate derivant (16).The alkali being suitable for includes potassium hydroxide, sodium hydroxide, sodium hydride or 1,8-diazabicyclo
[5.4.0] 11 carbon-7-alkene (DBU) etc..Reaction is at DMF, dimethyl sulfoxide, oxolane, dioxane
Or 1, the atent solvent such as 2-dimethoxy-ethane is carried out, the response time being suitable for is 0.5～24 hour, and temperature range is-10
DEG C between 40 DEG C.Compound (16The tert-butyl group (protection group) in), can remove in acid condition, such as, uses trifluoro
The ethyl acetate solution of the dichloromethane solution of acetic acid or hydrogen chloride processes, obtain phosphate cpd (17).Gained compound
(17) with suitable alkali, such as sodium hydroxide or the aqueous solution of potassium hydroxide, process i.e. can get phosphate (18), compound (17)
With compound (18) it is the compound that formula (I) defines.
Synthetic schemes 5
As formula (19Acyl amide derivatives shown in) can be prepared by synthetic schemes 5:
In the basic conditions, acyl chlorides (1) react with Wei Luofeini (vemurafenib), obtain target compound (19), i.e.
The compound that formula (I) defines.The alkali being suitable for includes potassium hydroxide, sodium hydroxide, triethylamine, etc..Reaction is at N, N-dimethyl
Methanamide, chloroform, dichloromethane, the atent solvent such as Isosorbide-5-Nitrae-dioxane is carried out, the response time being suitable for is 0.5～24 little
Time, temperature range is between-20 DEG C to 40 DEG C.
Synthetic schemes 6
As formula (21Acyl urethane analog derivative shown in) can be prepared by synthetic schemes 6:
In the basic conditions, chloro-formate (20) react with Wei Luofeini (vemurafenib), obtain target compound
(21), the compound that i.e. formula (I) defines.The alkali being suitable for includes potassium hydroxide, sodium hydroxide, triethylamine, etc..Reaction is at N, N-
Dimethylformamide, chloroform, dichloromethane, the atent solvent such as Isosorbide-5-Nitrae-dioxane is carried out, the response time being suitable for be 0.5～
24 hours, temperature range was between-20 DEG C to 40 DEG C.
Synthetic schemes 7
As formula (24Aminoacyl amide derivatives shown in) can be prepared by synthetic schemes 7:
Under the effect of suitable alkali and catalyst such as EDCI, the aminoacid of amido protecting (22) and Wei Luofeini
(vemurafenib) reaction, obtain Boc protection azaindole compounds (23).The alkali being suitable for includes triethylamine, and 4-phenyl is phonetic
Pyridine etc..React at DMF, dichloromethane, dioxane or 1, the atent solvent such as 2-dimethoxy-ethane enters
OK, the response time being suitable for is 0.5～24 hour, and temperature range is between-10 DEG C to 40 DEG C.The protection group of amino includes, but
Being not limited to, tertbutyloxycarbonyl (Boc), reaction is carried out in the atent solvents such as DMF.Compound (23In)
Protection group (Boc), can remove in acid condition, such as, uses dichloromethane solution or the second of hydrogen chloride of trifluoroacetic acid
Acetate solution, obtain target compound (24), the compound that i.e. formula (I) defines.
Synthetic schemes 8
As formula (28Ring derivative of amino ester shown in) can be prepared by synthetic schemes 8:
Chlorine alkyl chloride sulphonic acid ester (13) with the acid of amido protecting (25) at alkali such as: sodium bicarbonate, potassium bicarbonate, sodium carbonate,
Potassium carbonate, cesium carbonate, triethylamine, diisopropyl ethyl amine, 2,6-lutidines and catalyst, such as TBAHSO4Effect
Under, generation chlorine Arrcostab (26).React at dichloromethane, chloroform, the atent solvent such as 1,2-dichloroethanes is carried out, temperature range
Between-20 DEG C to 40 DEG C.Then, in the basic conditions, by chlorine Arrcostab (26) it is added to Wei Luofeini (vemurafenib)
On, obtain substituted azaindole compounds (27), the compound that i.e. formula (I) defines.The alkali that reaction is suitable for includes potassium hydroxide,
Sodium hydroxide, sodium hydride or 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU) etc..Reaction is at N, N-dimethyl methyl
Amide, dimethyl sulfoxide, oxolane, dioxane or 1, the atent solvent such as 2-dimethoxy-ethane is carried out, the reaction being suitable for
Time is 0.5～24 hour, and temperature range is between-10 DEG C to 40 DEG C.Amino protecting group includes, but not limited to tertiary butyloxycarbonyl
Base (Boc), under acid condition, removable substituted azaindole compounds (27Boc protection in), such as, uses trifluoroacetic acid
(TFA) ethyl acetate solution of dichloromethane solution or hydrogen chloride processes, obtain target compound (28), i.e. formula (I) definition
Compound.
The present invention uses following methods that the compound shown in formula (I) carries out biologic test:
1, bioanalytical method
LC/MS/MS system is used to be analyzed, including Agilent1200 series vacuum degassing furnace, binary syringe pump, hole
Plate automatic sampler, post calorstat, tri-grades of level Four bar mass spectrographs of Agilent G6430 in charged spray ionization (ESI) source.Quantitatively
Analyze carry out under MRM pattern, MRM conversion parameter as in Table A:
The parameter of Table A MRM conversion
| Many reaction detection scan | 490.2→383.1 |
| Fragmentation voltage | 230V |
| Capillary voltage | 55V |
| Dryer temperature | 350℃ |
| Nebulizer | 40psi |
| Exsiccator flow velocity | 10L/min |
Analyze and use Agilent XDB-C18,2.1x30mm, 3.5 μM post, inject 5 μ L sample.Analysis condition: flowing phase
It is aqueous formic acid (A) and the formic acid methanol solution (B) of 0.1% of 0.1%.Flow velocity is 0.4mL/min.Eluent gradient such as table B
Shown in:
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 |
Additionally, also have Agilent6330 series LC/MS/MS spectrogrph for analyze, inject equipped with G1312A binary
Pump, G1367A automatic sampler and G1314C UV detector；LC/MS/MS spectrogrph uses ESI radioactive source.Use titer pair
Each analyte carries out suitable cation models treated and MRM conversion carries out optimal analysis.Use during analyzing
Capcell MP-C18 post, specification is: 100x4.6mm I.D., 5 μMs (Phenomenex, Torrance, California,
USA).Flowing is 5mM ammonium acetate mutually, 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 is maintained at room temperature；Inject 20 μ L sample.
2, compound stability analysis in people and rat liver microsomes
(1) people or rat liver microsomes are placed in polypropylen tubes hatch, and guide it to replicate.Typically hatch mixing
Liquid includes people or rat liver microsomes (0.5mg protein/mL), and compound to be analyzed (5 μMs) and cumulative volume are 200 μ L
NADPH (1.0mM) kaliumphosphate buffer (PBS, 100mM, pH value is 7.4), is analysed to compound dissolution in DMSO, and makes
Diluted with PBS so that it is the concentration of final DMSO solution is 0.05%.And the water-bath communicated with air at 37 DEG C is entered
Row is hatched, and adds albumen and start reaction in 3 minutes backward mixed liquors of preincubate.At different time points (0,5,10,15,30
And 60min), add same volume ice-cold acetonitrile and terminate reaction.Sample preserves until carrying out LC/MS/MS analysis at-80 DEG C.
Compound concentration in people or rat liver microsomes mixtures incubated is that the method by LC/MS/MS measures
's.The range of linearity of concentration range is determined by each test-compound.
Parallel hatch test and use the microsome of degeneration as negative control, hatch at 37 DEG C, react when different
Between point (0,15 and 60 minute) terminate.
Dextromethorphan (70 μ Μ), as positive control, is hatched at 37 DEG C, react different time point (0,5,10,
15,30 and 60 minutes) terminate.Each assay method all includes the positive and negative control sample, to ensure that microsome is hatched
The integrity of system.
(2) compound of the present invention stability data in people or rat liver microsomes also can be obtained by tests below
To: people or rat liver microsomes are placed in polypropylen tubes and hatch, and guide it to replicate.Typical mixtures incubated includes people
Or rat liver microsomes (ultimate density: 0.5mg albumen/mL), compound to be analyzed (ultimate density: 1.5 μMs) and cumulative volume are
The K-buffer solution (containing 1.0mM EDTA, 100mM, pH7.4) of 30 μ L.It is analysed to compound dissolution in DMSO, and uses K-
Buffer solution dilutes, and the ultimate density making DMSO is 0.2%.After preincubate 10 minutes, add 15 μ L NADPH (ultimate density:
2mM) carrying out enzymatic reaction, whole test is carried out in the incubation tube of 37 DEG C.At different time points (0,15,30 and 60 point
Clock), add 135 μ L acetonitrile (containing IS) and terminate reaction.It is centrifuged 10 minutes with 4000rpm, removes albumen, collect the supernatant, use
LC-MS/MS analyzes.
In above-mentioned test, ketanserin (1 μM) is selected as positive control, hatches at 37 DEG C, and reaction is in the different time
Point (0,15,30 and 60 minute) terminates.Each assay method all includes positive control sample, to ensure that microsome hatches body
The integrity of system.
The present invention uses following methods to carry out data analysis, to obtain stability analysis result:
Each is reacted, compound concentration (as a percentage) in people or rat liver microsomes are hatched is pressed
The plotted as percentage of Relative Zero time point, infers internal CLint CL with thisint(ref.:Naritomi Y,
Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of human
hepatic clearance from in 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 uses following methods to the compounds of this invention pharmacokinetics in mice, rat, dog or monkey body
Research is estimated:
The compounds of this invention with aqueous solution or the aqueous solution of 2%HPMC+1% twen-80, the saline solution of 5%DMSO+5%, 4%
MC or capsule form are administered.For intravenous administration, animal gives the dosage of 1 or 2mg/kg.For oral dose
(p.o.), rat and mice are 5 or 10mg/kg, and dog and monkey are 7-100mg/kg.It is 0.25 at time point, 0.5,1.0,
Within 2.0,3.0,4.0,6.0,8.0,12 and 24 hours, take blood (0.3mL), and 3,000 or 4, be centrifuged 10 minutes under 000rpm.Receive
Collection plasma solutions, and preserve at-20 DEG C or-70 DEG C until carrying out above-mentioned LC/MS/MS and analyzing.
4, Xenograft Tumor Models
The drug effect of the compounds of this invention is that the standard Murine models by transplantation tumor is evaluated, and method is as follows:
Human tumor cells (such as, Colo-205 human colon cancer cell strain) cultivates, collect after, in rear veutro subcutaneous vaccination in
(BALB/cA nu/nu, Shanghai SLAC Animal Lab.) in the female nude mice body of 6-7 week old (for group of solvents n=10, for
Each dosage group n=8).When gross tumor volume reaches 100-250mm3Time, animal is divided into solvent control group (2%HPMC+ randomly
The aqueous solution of 1% twen-80) and compound group.Follow-up employing compound on animals carry out gastric infusion (3-50mpk/dose, molten
Solution is in the aqueous solution of 2%HPMC+1% twen-80), from 0 to 15 days after tumor cell inoculation Anywhere from the beginning of, and
And generally carry out once every day in test.
4.1 Tumor growth inhibition (TGI) are analyzed
The crystallization growth of tumor is to be evaluated by the relation of gross tumor volume Yu time.The major axis of Subcutaneous tumor
(L) being measured weekly twice by caliper with short axle (W), the volume (TV) of tumor passes through formula (L × W2)/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-median, with solvent
The percentage ratio of matched group gross tumor volume intermediate value represents, is calculated by following formula:
Primary statistics analysis completes by repeating variance mensuration analysis (RMANOVA).Followed by Scheffe
Psot hoc test method carries out multiple comparisons.Separate solvent (2%HPMC+1% twen-80, etc.) it is negative control.
Result shows, the compound that the present invention provides shows good half-life, clearance rate and good medicine for power
Learning character, the growth to tumor also has good inhibitory action.
The compound, pharmaceutical composition and the application thereof that there is provided the present invention below in conjunction with embodiment are further described.
Embodiment 1:3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base (third
Sulfonyl) urethanes
By N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-
1-sulfanilamide (0.2g, 0.41mmol) is suspended in Isosorbide-5-Nitrae-dioxane (15mL), and is sequentially added into ethyl chloroformate wherein
(EtOCOCl, 44mg, 0.41mmol) and triethylamine (0.14g, 1.38mmol).After reactant liquor is stirred at room temperature 1.5 hours,
Concentrating under reduced pressure, residue is through silica gel column chromatography (n-hexane/ethyl acetate (v/v)=4/1) purification, and it is white for obtaining title compound
Color solid (0.12g, 50%).
LC-MS(ESI,pos.ion)m/z562.1[M+H]+；
1H NMR(400MHz,CDCl3)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)。
Embodiment 2:N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene
Base)-N-(the third sulfonyl) Benzoylamide
By N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-
1-sulfanilamide (0.2g, 0.41mmol) is suspended in dioxane (15mL), and be added thereto to Benzenecarbonyl chloride. (57mg,
0.41mmol) with triethylamine (0.14g, 1.38mmol).After reactant liquor is stirred at room temperature 1 hour, concentrating under reduced pressure.Residue is through silicon
Plastic column chromatography (n-hexane/ethyl acetate (v/v)=4/1) purification, obtaining title compound is white solid (0.14g, 55%).
LC-MS(ESI,pos.ion)m/z594.1[M+H]+；
1H NMR(400MHz,CDCl3)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)。
Embodiment 3:N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene
Base)-N-(the third sulfonyl) isobutyramide
Under room temperature, by N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene
Base)-propane-1-sulfanilamide (0.2g, 0.41mmol) and triethylamine (2mL) be suspended in chloroform (10mL), and be added thereto to different
Butyl chloride (173 μ L, 1.64mmol).After reactant liquor is stirred at room temperature 16 hours, concentrating under reduced pressure, residue is through silica gel column chromatography
(petrol ether/ethyl acetate (v/v)=1/1 to 1/2) purification, obtaining title compound is white solid (2mg, 0.8%).
LC-MS(ESI,pos.ion)m/z560.1[M+H]+；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene
Base)-N-(the third sulfonyl) ammonium acetate
This step title compound prepares with reference to the method described by embodiment 3, i.e. uses N-(3-(5-(4-chlorobenzene
Base)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (0.2g, 0.41mmol), three
Ethamine (1mL) and Isosorbide-5-Nitrae-dioxane (10mL) solution of chloroacetic chloride (116 μ L, 1.64mmol), prepare title compound
For white solid (69mg, 31.8%).
LC-MS(ESI,pos.ion)m/z532.1[M+H]+；
1H NMR(400MHz,CDCl3)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)。
Embodiment 5:N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene
Base)-N-(the third sulfonyl) nicotiamide
This step title compound prepares with reference to the method described by embodiment 3, i.e. uses N-(3-(5-(4-chlorobenzene
Base)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (0.1g, 0.2mmol), three second
Prepared by chloroform (10mL) solution of amine (228 μ L, 1.6mmol) and nicotine acyl chloride hydrochloride (146mg, 0.2mmol), thick product warp
Silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, obtain title compound be white solid (35mg,
28.9%)。
LC-MS(ESI,pos.ion)m/z595.1[M+H]+；
1H NMR(400MHz,d6-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-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,
4-difluorophenyl)-3-methyl-N-(the third sulfonyl) butanamide hydrochloride
Step 1) (S)-1-(N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-difluoro
Phenyl) the third sulfoamido)-3-methyl isophthalic acid-oxo-butanes-2-base) t-butyl carbamate
By N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-
1-sulfanilamide (0.3g, 0.61mmol), Boc protection Valine (0.28g, 1.29mmol) and 4-phenyl pyrimidine (9mg,
0.06mmol) it is dissolved in DMF (2mL), and is added thereto to EDCI (234mg, 1.23mmol).Reaction
After liquid is stirred at room temperature 16 hours, adding ethyl acetate (30mL) dilution, gained mixture water (30mLx3) is washed.Organic facies is used
Na2SO4It is dried, and concentrating under reduced pressure.Residue, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1 to 2/1) purification, obtains
It is white solid (41mg, 29.1%) to title compound.
LC-MS(ESI,neg.ion)m/z686.6[M-H]-；
Step 2) (S)-2-amino-N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4-
Difluorophenyl)-3-methyl-N-(the third sulfonyl) butanamide hydrochloride
By (S)-1-(N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene
Base) the third sulfoamido)-3-methyl isophthalic acid-oxo-butanes-2-base-t-butyl carbamate (50mg, 0.07mmol) is suspended in saturated
HCl ethyl acetate solution (2mL) in, after reactant liquor is stirred at room temperature 2 hours, concentrating under reduced pressure, it is white for obtaining title compound
Color solid (49mg, 99%).
LC-MS(ESI,pos.ion)m/z589.2[M+H]+。
Embodiment 7:7a (5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) methyl pivalate
7b (N-(3-(5-(4-chlorphenyl)-1-((pivaloyl oxygen) methyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl
Base)-2,4 dichloro benzene base) the third sulfoamido) methyl pivalate
Under room temperature, by N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene
Base)-propane-1-sulfanilamide (0.1g, 0.20mmol) and Et3N (57 μ L, 0.41mmol) is dissolved in DMF (1mL), and wherein
Add chloromethyl pivalate (35 μ L, 0.25mmol).After reaction is stirred at room temperature 24 hours, concentrating under reduced pressure.Residue is through silicon
Plastic column chromatography (petrol ether/ethyl acetate (v/v)=4/1 to 1/1) purification, obtains (5-(4 chlorphenyl)-3-(2,6-bis-fluoro-3-
(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,3-b] pyridine-1-base) methyl pivalate (30mg, 23%) and (N-
(3-(5-(4-chlorphenyl)-1-((pivaloyl oxygen) methyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 dichloro benzene
Base) the third sulfoamido) methyl pivalate (20mg, 13.3%), it is white solid.
7a (5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,3-b]
Pyridine-1-base) methyl pivalate
LC-MS(ESI,pos.ion)m/z604.1[M+H]+；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-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,CDCl3)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-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl
Base)-2,4 difluorobenzene base) the third sulfoamido) methyl acetic acid ester
Step 1) chloromethyl acetate
Paraformaldehyde is added in the mixture of chloroacetic chloride (10mL, 94.6mmol) and zinc chloride (25mg, 186mmol)
(2.84g,94.6mmol).After reactant liquor is stirred at room temperature 40 minutes, rise to 60 DEG C, continue stirring 16 hours.Reaction is finished, cooling
To room temperature, mixture is filtered (100%PE) with short silicagel column.Filtrate is steamed in 60 DEG C of decompressions at 30 DEG C of concentrating under reduced pressure, gained residual liquid
Evaporating, obtaining title compound is colorless oil (2.34g, 15.3%).
1H NMR(400MHz,CDCl3)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-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl
Base)-2,4 difluorobenzene base) the third sulfoamido) methyl acetic acid ester
Under room temperature, by N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene
Base)-propane-1-sulfanilamide (0.1g, 0.2mmol) and triethylamine (57 μ L, 0.4mmol) be dissolved in N,N-dimethylformamide
(1mL) in, and it is added thereto to chloromethyl acetate (23 μ L, 0.3mmol).Reactant liquor be stirred at room temperature 16 as a child after, decompression
Concentrating, residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1 to 1/1) purification, and it is white for obtaining title compound
Color solid (52mg, 40.3%).
LC-MS(ESI,pos.ion)m/z634.1[M+H]+；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) methyl isobutyrate
Step 1) isopropylformic acid. chloromethyl ester
This step title compound prepares with reference to the method for embodiment 8 step 1, i.e. use isobutyryl chloride (10mL,
94.6mmol), prepared by zinc chloride (25mg, 186mmol) and paraformaldehyde (2.84g, 94.6mmol), obtains title compound and is
Colorless oil (5.52g, 42.9%).
1H NMR(400MHz,CDCl3)δ1.18-1.23(d,J=7.0Hz,6H),2.56-2.68(m,1H),5.72(s,
2H)。
Step 2) (5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl isobutyrate
Under room temperature, by N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene
Base)-propane-1-sulfanilamide (0.1g, 0.2mmol) and triethylamine (57 μ L, 0.40mmol) be dissolved in DMF (1mL), and wherein
Add isopropylformic acid. chloromethyl ester (34mg, 0.25mmol).After reactant liquor is stirred at room temperature 16 hours, concentrating under reduced pressure.Residue is through silicon
Plastic column chromatography (petrol ether/ethyl acetate (v/v)=4/1 to 3/1) purification, obtain title compound be white solid (45mg,
37.5%)。
LC-MS(ESI,pos.ion)m/z590.1[M+H]+；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrroles
And [2,3-b] pyridine-1-base) propionic acid ethyl ester
Step 1) 1-chloroethyl propionic ester
At 0 DEG C, in the mixture of propionyl chloride (10mL, 114.56mmol) and zinc chloride (25mg, 186mmol), add
Paraformaldehyde (7.76mL, 137.48mmol).After reactant liquor is stirred at room temperature 16 hours, by short silicagel column (100% petroleum ether) mistake
Filter.Filtrate is at 20 DEG C of concentrating under reduced pressure, and gained residual liquid is in 25～27 DEG C of decompression distillations, and obtaining title compound is colorless oil
(4.7g,30%)。
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) propionic acid ethyl ester
By N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-
1-sulfanilamide (0.2g, 0.41mmol) is dissolved in DMF (1mL), and wherein add triethylamine (165mg,
1.64mmol), mixture is after 10 DEG C of stirrings 10 minutes, in 30 minutes, drips tetrabutyl ammonium bromide successively in system
N,N-dimethylformamide (0.5mL) solution of (264mg, 1.64mmol) and 1-chloroethyl propionic ester (67mg, 0.41mmol)
N,N-dimethylformamide (0.5mL) solution.Reactant liquor, after 10 DEG C of stirrings 3 hours, dilutes by ethyl acetate (40mL), and
Filter.Filtrate reduced in volume, residue, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification, obtains titled
Compound is white solid (141mg, 58%).
LC-MS(ESI,neg.ion)m/z588.3[M-H]-；
1H NMR(400MHz,CDCl3) δ 1.00-1.17 (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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrroles
And [2,3-b] pyridine-1-base)-2-methyl-propyl propionic ester
Step 1) 1-chloro-2-methyl propyl group propionic ester
-20 DEG C, in the mixture of propionyl chloride (10mL, 115mmol) and zinc chloride (25mg, 186mmol), add isobutyl
Aldehyde (12.5mL, 138mmol).Reactant liquor, after 0 DEG C of stirring 2 hours, recovers to room temperature, continues stirring 16 hours.Reaction is finished, mixed
Compound short silicagel column (100% petroleum ether) filters.Filtrate, obtains in 90 DEG C of decompression distillations at 40 DEG C of concentrating under reduced pressure, gained residual liquid
Title compound is colorless oil (0.52g, 2.7%).
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base)-2-methyl-propyl propionic ester
This step title compound prepares with reference to the method described by embodiment 10 step 2, will N-(3-(5-(4-
Chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (0.2g, 0.4mmol)
It is dissolved in DMF (1mL), and is sequentially added into potassium hydroxide (46mg, 0.8mmol), tetrabutyl bromine wherein
Change DMF (0.5mL) solution of ammonium (264mg, 0.81mmol), and 1-chloro-2-methyl propyl group propionic ester
DMF (0.5mL) solution of (81mg, 0.49mmol), it is white solid that reaction prepares title compound
(114mg,45.0%)。
LC-MS(ESI,neg.ion)m/z616.3[M-H]-;
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrroles
And [2,3-b] pyridine-1-base) ethylpentanoic ester
Step 1) 1-chloroethyl valerate
At-20 DEG C, in the mixture of valeric chloride (5mL, 41.5mmol) and zinc chloride (25mg, 186mmol), add second
Aldehyde (2mL, 49.5mmol), reactant liquor, after 0 DEG C of stirring 1 hour, recovers to room temperature, continues stirring 2 hours.Reaction is finished, mixing
Thing short silicagel column (100%PE) filters, and filtrate in 60 DEG C of decompression distillations, obtains titled at 40 DEG C of concentrating under reduced pressure, gained residual liquid
Compound is colorless oil (5.5g, 81%).
1H NMR(400MHz,CDCl3)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,CDCl3)δ13.7,22.2,25.2,26.7,33.980.6,171.5。
Step 2) 1-(5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) ethylpentanoic ester
By N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-
1-sulfanilamide (0.3g, 0.61mmol) is dissolved in dry DMF (2.5mL), and is added thereto to hydroxide
Potassium (69mg, 1.23mmol), mixture is after 10 DEG C of stirrings 0.5 hour, in 30 minutes, drips 1-chloroethyl penta in system
N,N-dimethylformamide (0.5mL) solution of acid esters (0.1g, 0.61mmol).Reactant liquor, after 10 DEG C of stirrings 16 hours, is used
Diluted ethyl acetate, and filter.By filtrate reduced in volume, residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=7/
1) purification obtains thick product.Thick product recrystallization in petrol ether/ethyl acetate (10/1), obtains title compound solid for white
Body (0.14g, 37.8%).
LC-MS(ESI,neg.ion)m/z615.5[M-H]-；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrroles
And [2,3-b] pyridine-1-base) ethyl cyclopentane carboxylate
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 DEG C,
And it is added thereto to acetaldehyde (1.83g, 41.5mmol).Reactant liquor, after 0 DEG C of stirring 1 hour, recovers to room temperature, continues stirring 2
Hour.Reaction is finished, and mixture short silicagel column (100%DCM) filters.Filtrate is steamed in 55 DEG C of decompressions at 40 DEG C of concentrations, gained residual liquid
Evaporating, obtaining title compound is colorless oil (5.6g, 85%).
1H NMR(400MHz,CDCl3)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,CDCl3)δ25.2,25.9,25.9,29.9,30.0,43.8,80.8,183.5。
Step 2) 1-(5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) ethyl cyclopentane carboxylate
This step title compound prepares with reference to the method described by embodiment 12 step 2, will N-(3-(5-(4-
Chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (0.3g, 0.61mmol)
Be dissolved in anhydrous DMF (2.5mL) solution, and be added thereto to potassium hydroxide (69mg, 1.23mmol) and
DMF (0.5mL) solution of 1-chloroethyl cyclopentane-carboxylic acid ester (108mg, 0.61mmol), reaction gained is thick
Product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1) purification, and uses petroleum ether recrystallization, obtains title compound
Thing is white solid (147mg, 38%).
LC-MS(ESI,neg.ion)m/z627.5[M-H]-；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrroles
And [2,3-b] pyridine-1-base) ethyl isobutyrate
Step 1) 1-isopropylformic acid. chloromethyl ester
At-20 DEG C, add in the mixture of isobutyryl chloride (10mL, 94.7mmol) and zinc chloride (25mg, 186mmol)
Acetaldehyde (5g, 113.6mmol).Reactant liquor, after 0 DEG C of stirring 16 hours, recovers to room temperature, continues stirring 2 hours.Mixture is used
Short silicagel column (100%PE) filters, and filtrate is 30 DEG C of concentrations, and gained residual liquid is in 65 DEG C of decompression distillations, and obtaining title compound is nothing
Color grease (2.64g, 18.5%).
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) ethyl isobutyrate
By N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-
1-sulfanilamide (0.5g, 1.02mmol) and potassium hydroxide (115mg, 2.04mmol) are suspended in dry N,N-dimethylformamide
(4mL), in, it is cooled to 10 DEG C, and in 0.5 hour, the N of dropping 1-isopropylformic acid. chloromethyl ester (37mg, 0.25mmol) wherein,
Dinethylformamide (1mL) solution.Reactant liquor, after 10 DEG C of stirrings 3 hours, adds ethyl acetate (40mL) dilution, and mistake
Filter.Filtrate reduced in volume, residue, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1 to 4/1) purification, is marked
Topic compound is white solid (0.39g, 63.3%).
LC-MS(ESI,pos.ion)m/z626.0[M+Na]+；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b]-1-base) methylpropionate
Step 1) chloromethyl propionic ester
In the mixture of paraformaldehyde (3.37g, 112.3mmol) and zinc chloride (25mg, 186mmol), add propionyl
Chlorine (10mL, 112.3mmol).After reactant liquor is stirred at room temperature 40 minutes, it is heated to 60 DEG C, continues stirring 16 hours.Reaction is finished,
Being cooled to room temperature, mixture filters (100% petroleum ether) with short silicagel column.Filtrate is at 20 DEG C of concentrating under reduced pressure, and residual liquid is in 40 DEG C of decompressions
Distillation, obtaining title compound is colorless oil (9.8g, 70%).
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b]-1-base) methylpropionate
The method that this step title compound describes with reference to embodiment 14 step 2 prepares, will N-(3-(5-(4-chlorine
Phenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (0.3g, 0.61mmol) is molten
Solution is in anhydrous DMF (2.5mL) solution, and is added thereto to potassium hydroxide (69mg, 1.23mmol) and chlorine
DMF (0.5mL) solution of methylpropionate (75mg, 0.61mmol), thick product is through silica gel column chromatography (stone
Oil ether/ethyl acetate (v/v)=4/1) purification, and by recrystallizing methanol, obtain title compound be white solid (145mg,
41.4%)。
LC-MS(ESI,neg.ion)m/z574.1[M-H]-；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrroles
And [2,3-b] pyridine-1-base)-2-methyl-propyl isobutyrate
Step 1) 1-chloro-2-methyl propyl group isobutyrate
At-20 DEG C, in the mixture of isobutyryl chloride (10mL, 94.7mmol) and zinc chloride (25mg, 186mmol), add
Enter isobutylaldehyde (10.4mL, 113.6mmol).Reactant liquor, after 0 DEG C of stirring 1 hour, recovers to room temperature, continues stirring 2 hours.Instead
Should finish, mixture short silicagel column (100% petroleum ether) filters.Filtrate is steamed in 75 DEG C of decompressions at 40 DEG C of concentrating under reduced pressure, gained residual liquid
Evaporating, obtaining title compound is colorless oil (13.48g, 79.3%).
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base)-2-methyl-propyl isobutyrate
The method that this step title compound describes with reference to embodiment 14 step 2 prepares, will N-(3-(5-(4-chlorine
Phenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (0.3g, 0.61mmol) is molten
Solution, in dry DMF (2.5mL), is sequentially added into KOH (69mg, 1.23mmol), the chloro-2-of 1-wherein
N,N-dimethylformamide (0.5mL) solution of methyl-propyl isobutyrate (108mg, 0.61mmol).Thick product is through silicagel column
Chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification, and recrystallization in methanol, obtaining title compound is white solid
(47mg,13.4%)。
LC-MS(ESI,neg.ion)m/z629.5[M-H]-；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) methyl 2-(piperidin-4-yl) acetic ester hydrochloride
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 DCM (25mL) and H2O
(25mL) in, and be added thereto to sodium bicarbonate (1.38g, 16.4mmol) and 4-butyl ammonium hydrogen sulfate (0.14g,
0.41mmol).Mixture, after 0 DEG C of stirring 10 minutes, adds chloromethyl chlorosulfonic acid ester (499 μ L, 5.5mmol) in system
Dichloromethane (5mL) solution.Reactant liquor is stirred at room temperature 20 hours, and reaction is finished, and mixture saline (25mL) is washed, anhydrous Na2SO4
It is dried, and concentrating under reduced pressure.Residue, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1) purification, obtains titled
Compound is colorless oil (826mg, 69.1%).
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrroles
And [2,3-b] pyridine-1-base) methoxyl group)-2-oxoethyl) piperidines-1-carboxylic acid tert-butyl ester
This step title compound prepares with reference to the method described by embodiment 14 step 2, will N-(3-(5-(4-
Chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (0.1g, 0.2mmol)
It is dissolved in DMF (0.9mL), and is added thereto to potassium hydroxide (23mg, 0.4mmol), and 4-(2-(chlorine
Methyl)-2-oxoethyl) N,N-dimethylformamide (0.1mL) of piperidines-1-carboxylic acid tert-butyl ester (60mg, 0.2mmol) is molten
Liquid, the reaction thick product of gained, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1 to 2/1) purification, obtains title compound
Thing is white solid (86mg, 56.6%).
LC-MS(ESI,neg.ion)m/z742.4[M-H]-；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl 2-(piperidin-4-yl) acetic ester hydrochloride
By 4-(2-((5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) methoxyl group)-2-oxoethyl) piperidines-1-carboxylic acid tert-butyl ester (78mg, 0.1mmol) is suspended in saturated
HCl ethyl acetate solution (2mL) in, after reactant liquor is stirred at room temperature 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,d6-DMSO) δ 0.96-1.00 (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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) methyl 2-amino-3 Methylbutanoic acid ester hydrochloride
Step 1) chloromethyl 2-((tertbutyloxycarbonyl) amino)-3 Methylbutanoic acid ester
This step title compound prepares with reference to the method described by embodiment 17 step 1, will 2-((tertiary fourth oxygen
Carbonyl) amino)-3 Methylbutanoic acid (1g, 4.6mmol) is dissolved in DCM (25mL) and H2O(25.ML) in, and add the most successively
Enter sodium bicarbonate (1.55g, 18.4mmol), 4-butyl ammonium hydrogen sulfate (156mg, 0.46mmol), and chloromethyl chlorosulfonic acid ester
Dichloromethane (5mL) solution of (559 μ L, 5.5mmol), reaction prepare title compound be colorless oil (877mg,
71.8%)。
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl 2-((tertbutyloxycarbonyl) amino)-3 Methylbutanoic acid ester
This step title compound prepares with reference to the method described by embodiment 14 step 2, will N-(3-(5-(4-
Chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (0.1g, 0.2mmol)
It is dissolved in DMF (0.9mL), and is added thereto to potassium hydroxide (23mg, 0.4mmol) and chloromethyl 2-
DMF (0.1mL) solution of ((tertbutyloxycarbonyl) amino)-3 Methylbutanoic acid ester (54mg, 0.2mmol), instead
Answering the thick product of gained through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1 to 3/1) purification, obtaining title compound is
White solid (82mg, 55.8%).
LC-MS(ESI,neg.ion)m/z716.5[M-H]-；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl 2-amino-3 Methylbutanoic acid ester hydrochloride
This step title compound prepares with reference to the method described by embodiment 17 step 3, i.e. uses (5-(4-chlorine
Phenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,3-b] pyridine-1-base) methyl 2-
((tertbutyloxycarbonyl) amino)-3 Methylbutanoic acid ester (78mg, 0.11mmol) and saturated HCl ethyl acetate solution (2mL), instead
Should prepare title compound is white solid (40mg, 54%).
LC-MS(ESI,pos.ion)m/z619.2[M+H]+；
1H NMR(400MHz,d6-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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) methyl 2-glycine ester hydrochloride
Step 1) chloromethyl 2-((tertbutyloxycarbonyl) amino) acetas
This step title compound prepares with reference to the method described by embodiment 17 step 1, will 2-((tertiary fourth oxygen
Carbonyl) amino) acetic acid (1g, 5.7mmol) is dissolved in dichloromethane (25mL) and water (25mL), and is sequentially added into carbon wherein
Acid hydrogen sodium (1.92g, 22.8mmol), 4-butyl ammonium hydrogen sulfate (194mg, 0.57mmol) and chloromethyl chlorosulfonic acid ester (693 μ L,
Dichloromethane (5mL) solution 6.8mmol), it is colorless oil (911mg, 71.3%) that reaction prepares title compound.
Step 2) (5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl 2-((tertbutyloxycarbonyl) amino) acetas
This step title compound prepares with reference to the method described by embodiment 14 step 2, will N-(3-(5-(4-
Chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (0.1g, 0.2mmol)
It is dissolved in DMF (0.9mL), and is added thereto to potassium hydroxide (23mg, 0.4mmol) and chloromethyl 2-
DMF (0.1mL) solution of ((tertbutyloxycarbonyl) amino) acetas (46mg, 0.2mmol), the reaction thick product of gained is through silicagel column
Chromatography (ethyl acetate/petroleum ether (v/v)=4/1 to 3/1) purification, obtaining title compound is white solid (46mg, 33.3%).
LC-MS(ESI,pos.ion)m/z:677.1[M+H]+;
1H NMR(400MHz,d6-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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl 2-glycine ester hydrochloride
This step title compound prepares with reference to the method described by embodiment 17 step 3, i.e. uses (5-(4-chlorine
Phenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,3-b] pyridine-1-base) methyl 2-
((tertbutyloxycarbonyl) amino) acetas (46mg, 0.07mmol) and saturated HCl ethyl acetate solution (2mL), reaction prepares
Title compound is white solid (36mg, 83.7%).
LC-MS(ESI,pos.ion)m/z577.1[M+H]+；
1H NMR(400MHz,d6-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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) methyl 2-(methylamino) ethyl acetate hydrochloride
Step 1) chloromethyl 2-((tertbutyloxycarbonyl) (methyl) amino) acetas
This step title compound prepares with reference to the method described by embodiment 17 step 1, will 2-((tertiary fourth oxygen
Carbonyl) (methyl) amino) acetic acid (1g, 5.29mmol) is dissolved in dichloromethane (25mL) and water (25mL), and depends on wherein
Secondary addition sodium bicarbonate (1.78g, 21.2mmol), 4-butyl ammonium hydrogen sulfate (0.18g, 0.53mmol), and chloromethyl chlorine sulphur
DCM (5mL) solution of acid esters (638 μ L, 6.35mmol), prepare title compound be colorless oil (0.87g,
69.4%)。
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl 2-((tertbutyloxycarbonyl) (methyl) amino) acetas
This step title compound prepares with reference to the method described by embodiment 14 step 2, will N-(3-(5-(4-
Chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (0.3g, 0.61mmol)
It is dissolved in DMF (2.5mL), and is added thereto to potassium hydroxide (69mg, 1.23mmol), and chloromethyl 2-((tertiary butyloxycarbonyl
Base) (methyl) amino) DMF (0.5mL) solution of acetas (145mg, 0.61mmol), reaction gained is thick
Product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, and obtaining title compound is colorless oil
(0.33g,77.9%)。
LC-MS(ESI,neg.ion)m/z689.4[M-H]-；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl 2-(methylamino) ethyl acetate hydrochloride
By (5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,3-b]
Pyridine-1-base) methyl 2-((tertbutyloxycarbonyl) (methyl) amino) acetas (0.33g, 0.48mmol) is suspended in saturated HCl
In ethyl acetate solution (3mL), after reactant liquor is stirred at room temperature 3 hours, filtering, 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,d6-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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) methyl 2-amino-2-methyl propionate hydrochloride
Step 1) chloromethyl 2-((tertbutyloxycarbonyl) amino)-2 Methylpropionic acid ester
This step title compound prepares with reference to the method described by embodiment 17 step 1, will 2-((tertiary fourth oxygen
Carbonyl) amino)-2 Methylpropionic acid (1.07g, 5.29mmol) is dissolved in dichloromethane (25mL) and water (25mL), and to it
In be sequentially added into sodium bicarbonate (1.78g, 21.2mmol), 4-butyl ammonium hydrogen sulfate (0.18g, 0.53mmol), and chloromethyl chlorine
DCM (5mL) solution of sulphonic acid ester (638 μ L, 6.35mmol), reaction prepare title compound be white solid (1.16g,
87.7%)。
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl 2-((tertbutyloxycarbonyl) amino)-2 Methylpropionic acid ester
This step title compound prepares with reference to the method described by embodiment 14 step 2, will N-(3-(5-(4-
Chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (0.3g, 0.61mmol)
It is dissolved in dichloromethane (2.5mL), and is added thereto to potassium hydroxide (69mg, 0.4mmol), and chloromethyl 2-((tertiary fourth oxygen
Carbonyl) amino) DMF (0.5mL) solution of-2 Methylpropionic acid ester (158mg, 0.61mmol), reacts gained
Thick product, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1 to 3/1) purification, obtains title compound solid for white
Body (339mg, 78.7%).
LC-MS(ESI,pos.ion)m/z705.2[M+H]+；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl 2-amino-2-methyl propionate hydrochloride
By (5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,3-b]
Pyridine-1-base) methyl 2-((tertbutyloxycarbonyl) amino)-2 Methylpropionic acid ester (339mg, 0.48mmol) is suspended in saturated
In HCl ethyl acetate solution (3mL), after reactant liquor is stirred at room temperature 5 hours, filtering, 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,d6-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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole
Cough up also [2,3-b] pyridine-1-base) methyl 2-amino-3 methylvaleric acid ester hydrochloride
Step 1) (2S)-chloromethyl 2-((tertbutyloxycarbonyl) amino)-3 methylvaleric acid ester
This step title compound prepares with reference to the method described by embodiment 17 step 1, will L-2-((tertiary fourth
Oxygen carbonyl) amino)-3 methylvaleric acid (1g, 4.31mmol) is dissolved in dichloromethane (25mL) and water (25mL), and wherein
Add sodium bicarbonate (1.55g, 18.4mmol), 4-butyl ammonium hydrogen sulfate (156mg, 0.46mmol), and chloromethyl chlorosulfonic acid ester
Dichloromethane (5mL) solution of (559 μ L, 5.5mmol), reaction prepare title compound be colorless oil (0.91g,
76.1%)。
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrroles
And [2,3-b] pyridine-1-base) methyl 2-((tertbutyloxycarbonyl) amino)-3 methylvaleric acid ester
This step title compound prepares with reference to the method described by embodiment 14 step 2, will N-(3-(5-(4-
Chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (0.3g, 0.61mmol)
It is dissolved in DMF (2.5mL), and is sequentially added into potassium hydroxide (69mg, 1.22mmol) wherein, and
(2S) N, the N-dimethyl formyl of-chloromethyl 2-((tertbutyloxycarbonyl) amino)-3 methylvaleric acid ester (171mg, 0.61mmol)
Amine (0.5mL) solution, reaction the thick product of gained through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1 to 3/1) purification,
Obtaining title compound is white solid (288mg, 64%).
LC-MS(ESI,pos.ion)m/z733.1[M+H]+；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrroles
And [2,3-b] pyridine-1-base) methyl 2-amino-3 methylvaleric acid ester hydrochloride
By (2S)-(5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl 2-((tertbutyloxycarbonyl) amino)-3 methylvaleric acid ester (285mg, 0.45mmol) is suspended in saturated
HCl ethyl acetate solution (3mL) in, reactant liquor, after 0 DEG C of stirring 10 hours, filters, and obtains title compound solid for white
Body (0.21g, 80.8%).
LC-MS(ESI,pos.ion)m/z633.1[M+H]+；
1H NMR(400MHz,d6-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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrole
Cough up also [2,3-b] pyridine-1-base) methyl 2-amino-4-methylvaleric acid ester hydrochloride
Step 1) (S)-chloromethyl 2-((tertbutyloxycarbonyl) amino)-4-methylpent acid esters
This step title compound prepares with reference to the method described by embodiment 17 step 1, will L-2-((tertiary fourth
Oxygen carbonyl) amino)-4-methylvaleric acid (1g, 4.31mmol) is dissolved in dichloromethane (25mL) and water (25mL), adds wherein
Enter sodium bicarbonate (1.55g, 18.4mmol), 4-butyl ammonium hydrogen sulfate (156mg, 0.46mmol), and chloromethyl chlorosulfonic acid ester
Dichloromethane (5mL) solution of (559 μ L, 5.5mmol), reaction prepare title compound be colorless oil (0.98g,
81.1%)。
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) methyl 2-((tertbutyloxycarbonyl) amino)-4-methylpropionate
This step title compound prepares with reference to the method described by embodiment 14 step 2, will N-(3-(5-(4-
Chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (0.3g, 0.61mmol)
It is dissolved in DMF (2.5mL), and is added thereto to potassium hydroxide (69mg, 1.22mmol), and (S)-chlorine
The N,N-dimethylformamide of methyl 2-((tertbutyloxycarbonyl) amino)-4-methylpent acid esters (179mg, 0.61mmol)
(0.5mL) solution, the reaction thick product of gained, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1 to 3/1) purification, obtains
It is white solid (287mg, 62.8%) to title compound.
LC-MS(ESI,pos.ion)m/z:733.1[M+H]+；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) methyl 2-amino-4-methylvaleric acid ester hydrochloride
By (S)-(5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl 2-((tertbutyloxycarbonyl) amino)-4-methylpropionate (284mg, 0.39mmol) is suspended in saturated
HCl ethyl acetate solution (3mL) in, reactant liquor 0 DEG C stirring 10 hours after, concentrating under reduced pressure, residue petroleum ether/acetic acid
Ethyl ester (1/1) mixed liquor is washed, and obtaining title compound is white solid (204mg, 78.7%).
LC-MS(ESI,pos.ion)m/z633.1[M+H]+；
1H NMR(400MHz,d6-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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrroles
And [2,3-b] pyridine-1-base) ethyl 2-amino-3-methylbutyl butenoate hydrochlorate
Step 1) 1-chloromethyl sulfonic acid chloride
1-chloroethylchloroformate ester (10g, 69.94mmol) is cooled to 0 DEG C, and drip wherein chlorosulfonic acid (8.96g,
76.94mmol).Reactant liquor is after 0 DEG C of stirring 16 hours, with dichloromethane (15mL) and water (15mL) cancellation.Organic facies is successively
Use Na2CO3Aqueous solution (20mL) and saline solution (20mL) are washed, anhydrous Na2SO4It is dried, and concentrating under reduced pressure.Residual liquid is in 54 DEG C of decompressions
Distillation, obtaining title compound is colorless oil (4.5g, 36%).
1H NMR(400MHz,CDCl3)δ1.98-1.99(d,J=5.8Hz,3H),6.46-6.50(q,J=5.8Hz,1H)；
13C NMR(100MHz,CDCl3)δ26.3,91.1。
Step 2) 2-((tertbutyloxycarbonyl) amino)-3 Methylbutanoic acid 1-chloroethene ester
This step title compound obtains with reference to the method synthesis of embodiment 17 step 1, will 2-((tertbutyloxycarbonyl) ammonia
Base)-3 Methylbutanoic acid (3g, 13.81mmol) is dissolved in dichloromethane (75mL) and water (75mL), and is added thereto to carbonic acid
Hydrogen sodium (4.64g, 55.23mmol), 4-butyl ammonium hydrogen sulfate (469mg, 1.38mmol), and 1-chloroethyl chlorosulfonic acid ester
Dichloromethane (15mL) solution of (2.97g, 16.57mmol), the reaction thick product of gained is through silica gel column chromatography (petroleum ether/acetic acid
Ethyl ester (v/v)=100/1 to 50/1) purification, obtaining title compound is white solid (3g, 78%).
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) ethyl 2-((tertbutyloxycarbonyl) amino)-3-methylbutyl butenoate
This step title compound obtains with reference to the method synthesis described by embodiment 14 step 2.Will N-(3-(5-(4-
Chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (0.3g, 0.61mmol)
It is dissolved in anhydrous DMF (2.5mL), and is sequentially added into potassium hydroxide (69mg, 1.22mmol) wherein,
N,N-dimethylformamide with 1-chloroethyl 2-((tertbutyloxycarbonyl) amino)-3 Methylbutanoic acid ester (172mg, 0.61mmol)
(0.5mL) solution, the reaction thick product of gained, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1 to 3/1) purification, obtains
It is orange (0.29g, 65%) to title compound.
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) ethyl 2-amino-3-methylbutyl butenoate hydrochlorate
By 1-(5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,3-
B] pyridine-1-base) ethyl 2-((tertbutyloxycarbonyl) amino)-3 Methylbutanoic acid ester (0.29g, 0.39mmol) is suspended in saturated
In HCl ethyl acetate solution (4mL), after reactant liquor is stirred at room temperature 2 hours, filtering, obtaining title compound is white solid
(0.15g,57%)。
LC-MS(ESI,pos.ion)m/z634.1[(M+H)+-HCl]；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) methyl acid phosphate sodium
Step 1) di(2-ethylhexyl)phosphate tertiary butyl chloride methyl ester
This step title compound prepares with reference to the method for embodiment 17 step 1, will di(2-ethylhexyl)phosphate tert-butyl ester potassium salt
(1g, 4.03mmol) is dissolved in dichloromethane (20mL) and water (20mL), and be added thereto to sodium bicarbonate (1.34g,
16.1mmol), 4-butyl ammonium hydrogen sulfate (136mg, 0.40mmol), and the dichloro of chloromethyl sulfonic acid chloride (452 μ l, 4.41mmol)
Methane (5mL) solution, it is colorless oil (1.02g, 95.3%) that reaction prepares title compound.
1H NMR(400MHz,CDCl3)δ1.51(s,18H),5.62-5.66(d,J=14.9Hz,2H)；
13C NMR(100MHz,CDCl3)δ29.9,73.3,84.1。
Step 2) ((5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl) di(2-ethylhexyl)phosphate tertiary butyl ester
By N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-
1-sulfanilamide (0.4g, 0.82mmol) is dissolved in DMF (3.5mL), and be added thereto to KOH (91mg,
1.63mmol), mixture is after 10 DEG C of stirrings 20 minutes, in 30 minutes, drips di(2-ethylhexyl)phosphate tertiary butyl chloride methyl in system
The N,N-dimethylformamide solution (1mL) of ester (0.21g, 0.82mmol).Reactant liquor, after 10 DEG C of stirrings 16 hours, uses acetic acid
Ethyl ester (100mL) dilutes.Mixture H2O (100mL) washes, and extracts with dichloromethane (100mLx2).The organic facies that will merge
Concentrating under reduced pressure, gained residue, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1) purification, obtains title compound
For colorless oil (0.28g, 47.2%).
LC-MS(ESI,pos.ion)m/z712.2[M+H]+；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl dihydrogen phosphate ester
By ((5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,3-b]
Pyridine-1-base) methyl) di(2-ethylhexyl)phosphate tertiary butyl ester (1g, 1.4mmol) is dissolved in dichloromethane (25mL), and is added thereto to
Trifluoroacetic acid (1.6mL, 2.4g, 21mmol).After reactant liquor is stirred at room temperature 2 hours, concentrating under reduced pressure.Gained residue is through acetic acid
Ethyl ester (20mL) is washed, and obtaining title compound is white solid (0.56g, 66.5%).
LC-MS(ESI,pos.ion)m/z600.0[M+H]+；
1H NMR(400MHz,d6-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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl acid phosphate sodium
Under room temperature, by (5-(4-chlorphenyl)-3-(2,6-bis-fluoro-3-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) methyl dihydrogen phosphate ester (396mg, 0.66mmol) is dissolved in oxolane (20mL), and to it
The water (0.3mL) of middle dropping NaOH (58mg, 1.45mmol) and oxolane (4mL) solution.Reactant liquor is stirred at room temperature 4 hours
After, filter, obtaining title compound is white solid (401mg, 94.4%).
LC-MS(ESI,pos.ion)m/z600.0[M+H]+；
1H NMR(400MHz,D2O)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) methyl ethyl carbonate
Step 1) carbonic acid ethyl chloromethyl ester
Chloro-methyl-chloroformate (10g, 78.2mmol) is dissolved in dichloromethane (200mL), is cooled to-20 DEG C, and to
Wherein add dichloromethane (50mL) solution of ethanol (5mL, 85.9mmol) and pyridine (7.5mL, 93.2mmol).Reactant liquor exists
After 0 DEG C is stirred 1 hour, recover to room temperature, continue stirring 2 hours.Mixture is successively with 1N HCl/water solution (300mL) and Sal
Water (200mL) is washed, anhydrous Na2SO4It is dried, and concentrating under reduced pressure, obtaining title compound is colorless oil (8.75g, 81.1%).
Compound is the most purified, is directly used in next step reaction.
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl ethyl carbonate
By N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-
1-sulfanilamide (0.1g, 0.2mmol) and triethylamine (114 μ L, 0.8mmol) are dissolved in DMF (0.6mL), and
Being added thereto to DMF (0.2mL) solution of tetrabutyl ammonium bromide (132mg, 0.4mmol), mixed liquor is 10
DEG C stirring 0.5 hour after, in system drip chloromethyl ethyl carbonate ester (34mg, 0.25mmol) DMF
(0.2mL) solution.Reactant liquor stirs 3 hours at 10 DEG C.Reaction is finished, and mixture ethyl acetate (40mL) dilutes, and filters.Filter
Liquid concentrating under reduced pressure, residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, and obtaining title compound is
White solid (85mg, 73%).
LC-MS(ESI,pos.ion)m/z592.0[M+H]+；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) isopropyl methyl carbonic ester
Step 1) chloromethyl butylperoxyisopropyl carbonate
This step title compound prepares with reference to the method described by embodiment 26 step 1, will chloromethyl chlorine sulphur
Acid esters (10g, 78.2mmol) is dissolved in dichloromethane (200mL), and is added thereto to isopropanol (6.6mL, 86.2mmol)
With dichloromethane (50mL) mixed liquor of pyridine (7.5mL, 93.2mmol), it is colorless oil that reaction prepares title compound
(9.63g,81%).Compound is the most purified, is directly used in next step.
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) isopropyl methyl carbonic acid
By N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-
1-sulfanilamide (0.2g, 0.41mmol) and potassium hydroxide (46mg, 0.82mmol) are dissolved in N,N-dimethylformamide (1.5mL)
In, and in 30 minutes, in system, add N, the N-dimethyl formyl of chloromethyl butylperoxyisopropyl carbonate (62mg, 0.41mmol)
Amine (0.5mL) solution.Reactant liquor, after 10 DEG C of reactions 3 hours, dilutes by ethyl acetate (40mL).Mixture is filtered, filtrate
Concentrating under reduced pressure, gained residue, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, obtains title compound
For white solid (105mg, 43%).
LC-MS(ESI,pos.ion)m/z606.0[M+H]+；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrroles
And [2,3-b] pyridine-1-base) ethyl diethyldithiocarbamate carbonic ester
Step 1) 1-chloroethylethyl carbonic ester
This step title compound prepares with reference to the method described by embodiment 26 step 1, will 1-chloroethyl chlorine
Formic acid esters (10g, 69.9mmol) is dissolved in dichloromethane (200mL), and is added thereto to ethanol (4.5mL, 77.2mmol)
With dichloromethane (50mL) mixed liquor of pyridine (6.8mL, 84.5mmol), it is colorless oil that reaction prepares title compound
(9.32g,87.7%).Product is the most purified, is directly used in next step reaction.
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) ethyl diethyldithiocarbamate carbonic ester
By N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-
1-sulfanilamide (0.1g, 0.2mmol) is dissolved in DMF (1mL), and be added thereto to potassium carbonate (85mg,
0.6mmol), after mixture is stirred at room temperature 10 minutes, it is sequentially added into tetrabutyl ammonium bromide (132mg, 0.4mmol), and 1-chlorine
N,N-dimethylformamide (0.1mL) solution of ethyl diethyldithiocarbamate carbonic ester (35mg, 0.25mmol).Reactant liquor is stirred at room temperature 16
Hour, reaction is finished, and mixture ethyl acetate (40mL) is diluted, and filters.Filtrate reduced in volume, gained residue is through silica gel
Column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification, obtaining title compound is white solid (61mg, 50%).
LC-MS(ESI,neg.ion)m/z603.5[M-H]-;
1H NMR(400MHz,CDCl3) δ 1.04-1.10 (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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrroles
And [2,3-b] pyridine-1-base) cyclohexyl carbonate
Step 1) 1-chloromethylcyclohexyl carbonic ester
This step title compound prepares with reference to the method described in embodiment 26 step 1, will 1-chloroethyl carbonic acid
Acyl chlorides (5g, 35mmol) is dissolved in dichloromethane (100mL), and is added thereto to Hexalin (3.9g, 38.5mmol) and pyrrole
The mixture of pyridine (3.3g, 42mmol), it is colourless liquid (7g, 96.9%) that reaction prepares title compound.Products therefrom is without pure
Change, be directly used in next step reaction.
1H NMR(400MHz,CDCl3) δ 1.28-1.25 (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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) cyclohexyl carbonate
By N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-
1-sulfanilamide (5g, 10.2mmol) is dissolved in oxolane (36mL), and be added thereto to potassium hydroxide (1.1g,
20.4mmol).After reactant liquor is stirred at room temperature 0.5 hour, in system add 1-chloromethylcyclohexyl carbonic ester (2.3g,
Oxolane (9mL) solution 11.2mmol).Reactant liquor refluxes 16 hours, and reaction is finished, and mixture is cooled to room temperature, and uses
Oxolane (50mL) dilutes.Filtering, filtrate reduced in volume, gained residue is through silica gel column chromatography (petrol ether/ethyl acetate
(v/v)=8/1) purification, obtaining title compound is white solid (3.49g, 51.9%).
LC-MS(ESI,neg.ion)m/z657.5[M-H]-；
1H NMR(400MHz,CDCl3) δ 1.05-1.08 (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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrroles
And [2,3-b] pyridine-1-base) ethylisopropyl base carbonic ester
Step 1) 1-chloroethyl butylperoxyisopropyl carbonate
1-chloroethyl carbonate chloride (10g, 69.9mmol) is dissolved in dichloromethane (200mL), is cooled to-20 DEG C,
It is added thereto to DCM (50mL) solution of isopropanol (5.9mL, 76.9mmol) and pyridine (6.75mL, 83.9mmol).Reactant liquor
After 0 DEG C of reaction 2 hours, recover to room temperature, continue stirring 2 hours.Reaction is finished, and mixture is successively with 1N HCl/water solution
(250mLx2) wash with saline solution (250mL), anhydrous Na2SO4It is dried, and concentrating under reduced pressure, obtaining title compound is colorless oil
Thing (9.6g, 82.4%).Compound is the most purified, is directly used in next step reaction.
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) ethylisopropyl base carbonic ester
The method that this step title compound describes with reference to embodiment 26 step 2 prepares.Will N-(3-(5-(4-chlorine
Phenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-1-sulfanilamide (0.3g, 0.61mmol),
Potassium hydroxide (69mg, 1.23mmol) is dissolved in dry DMF (2mL), and is added thereto to the tetrabutyl
DMF (0.5mL) solution of ammonium bromide (396mg, 1.23mmol), and 1-chloromethyl butylperoxyisopropyl carbonate
DMF (0.5mL) solution of (102mg, 0.61mmol), thick product is through silica gel column chromatography (petroleum ether/acetic acid
Ethyl ester (v/v)=1/5) purification, and recrystallization in methanol, obtaining title compound is white solid (42mg, 11.1%).
LC-MS(ESI,neg.ion)m/z:617.4[M-H]-；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) methyl benzol carbonate
Step 1) chloromethyl phenyl carbonic ester
Chloromethyl chloro-formate (1g, 7.8mmol) is dissolved in dichloromethane (40mL), is cooled to-20 DEG C, in 20 points
In clock, it is added thereto to phenol (730mg, 7.8mmol) and dichloromethane (10mL) solution of pyridine (750 μ L, 9.3mmol).
Reactant liquor, after 0 DEG C of stirring 4 hours, recovers to room temperature, continues stirring 1 hour.Reaction is finished, and mixture is molten with 1N HCl/water successively
Liquid (50mL) and saline solution (50mL) are washed, anhydrous Na2SO4It is dried, and concentrating under reduced pressure.Gained residue is through silica gel column chromatography (oil
Ether/ethyl acetate (v/v)=100/1) purification, obtaining title compound is colorless oil (847mg, 58.2%).
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,
3-b] pyridine-1-base) methyl benzol carbonate
By N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-
1-sulfanilamide (0.1g, 0.2mmol), tetrabutyl ammonium bromide (132mg, 0.4mmol) and triethylamine (114 μ L, 0.80mmol) dissolve
In DMF (1mL), and it is added thereto to chloromethyl phenyl carbonic ester (46mg, 0.25mmol).Reactant liquor
After being stirred at room temperature 12 hours, dilute by ethyl acetate (40mL), and filter.Filtrate reduced in volume, gained residue is through silica gel
Column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification, obtaining title compound is white solid (10mg, 7.7%).
LC-MS(ESI,pos.ion)m/z640.0[M+H]+；
1H NMR(400MHz,CDCl3)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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrroles
And [2,3-b] pyridine-1-base) ethyl phosphonic acid sodium
Step 1) 1-chloroethyl sulfonic acid chloride
At 0 DEG C, in 40 minutes, in 1-chloroethylchloroformate ester (54.4mL, 504mmol), add chlorosulfonic acid
(49.0mL, 729mmol), adds rear system and stirs 2 hours at 0 DEG C.After reactant liquor being warming up to 5 DEG C of stirrings 10 minutes, slowly
Being added thereto to DCM (500mL) and trash ice (20g), cancellation is reacted, the most successively with saturated sodium bicarbonate aqueous solution (400mL)
Washing (400mL) with saturated aqueous common salt, merge organic facies, anhydrous sodium sulfate is dried, and being concentrated under reduced pressure to give title compound is
Faint yellow solid (54.2g, 60%).
1H NMR(400MHz,CDCl3):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 tert-butyl group-1-chloro-ethyl ester
This step title compound prepares with reference to the method for embodiment 17 step 1, will di(2-ethylhexyl)phosphate tert-butyl ester potassium salt
(33g, 133mmol) is dissolved in dichloromethane (600mL) and water (600mL), and be added thereto to sodium bicarbonate (44.6g,
531mmol), 4-butyl ammonium hydrogen sulfate (4.52g, 13.3mmol), and the dichloromethane of 1-chloroethyl sulfonic acid chloride (26g, 146mmol)
Alkane (100mL) solution, it is colorless oil (14.3g, 40%) that reaction prepares title compound.
1H NMR(400MHz,CDCl3):δ1.52(s,18H),1.81(d,J=5.6Hz,3H),6.17-6.24(m,1H)。
Step 3) 1-((5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) ethyl) di(2-ethylhexyl)phosphate tertiary butyl ester
By N-(3-(5-(4-chlorphenyl)-1H-pyrrolo-[2,3-b] pyridine-3-carbonyl)-2,4 difluorobenzene base)-propane-
1-sulfanilamide (9.8g, 20mmol) is dissolved in DMF (120mL), and be added thereto to KOH (4.48g,
80mmol), potassium iodide (0.33g, 2mmol), under room temperature in nitrogen protection, in 5 minutes, in system, drip the tertiary fourth of di(2-ethylhexyl)phosphate
The N,N-dimethylformamide solution (20mL) of the chloro-ethyl ester of base-1-(10.9g, 40mmol).Reactant liquor is little 50 DEG C of stirrings 6
Shi Hou, dilutes by ethyl acetate (700mL).Mixture uses H successively2O (400mLx3) and saturated aqueous common salt (400mL) are washed, organic
Adding dichloromethane (20mL) after phase concentrating under reduced pressure, have solid to occur, filtration under diminished pressure, it is thick that filtrate obtains title compound after concentrating
Product are brown solid (31g, 106%).
LC-MS(ESI,pos.ion)m/z:724.2[M-1]。
Step 4) 1-(5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) ethyl phosphonic acid two hydrogen ester
By 1-((5-(4-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-[2,3-
B] pyridine-1-base) ethyl) di(2-ethylhexyl)phosphate tertiary butyl ester (20g, crude product) is dissolved in ethyl acetate (30mL), and is added thereto to
Phosphoric acid (85%, 90mL).After reactant liquor is stirred at room temperature 2 minutes, (200mL) cancellation that adds water is reacted.Gained mixture is through acetic acid second
Ester (300mLx3) extracts, and merges organic facies, and it is brown solid (19.5g, 74%) that dried pressurization is concentrated to give title compound.
LC-MS(ESI,pos.ion)m/z:612.1[M-1];
1H NMR(400MHz,DMSO-d6):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-chlorphenyl)-3-(the fluoro-3-of 2,6-bis-(the third sulfoamido) benzoyl)-1H-pyrrolo-
[2,3-b] pyridine-1-base) ethyl phosphonic acid sodium
Under room temperature, by 1-(5-(4-chlorphenyl)-3-(2,6-bis-fluoro-3-(the third sulfoamido) benzoyl)-1H-pyrroles
And [2,3-b] pyridine-1-base) ethyl phosphonic acid two hydrogen ester (4g, 6.5mmol) is dissolved in ethyl acetate (20mL) and oxolane
(10mL) in mixed solution, and water (1mL) solution of NaOH (0.57g, 14.3mmol) is dripped the most wherein.Reaction
After liquid is stirred at room temperature overnight, filtering, at gained solid 45 DEG C, drying under reduced pressure is after 10 hours, obtains title compound solid for white
Body (4.0g, 93%).
LC-MS(ESI,pos.ion)m/z:612.1[M-1];
1H NMR(400MHz,D2O):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)。
Biologic test
The compound using method as discussed above and equipment to prepare the embodiment of the present invention carries out bioanalysis.
Embodiment A stability in people and rat liver microsomes
People or rat liver microsomes are placed in polypropylen tubes and hatch, and guide it to replicate.Typically hatch mixed liquor
Including people or rat liver microsomes (0.5mg protein/mL), target compound (5 μMs) and the NADPH that cumulative volume is 200 μ L
(1.0mM) kaliumphosphate buffer (PBS, 100mM, pH value is 7.4), by compound dissolution in DMSO, and uses PBS that it is dilute
Release so that it is the concentration of final DMSO solution is 0.05%.And the water-bath communicated with air at 37 DEG C is hatched, incubate in advance
Educate and 3 minutes backward mixed liquors add albumen and starts reaction.At different time points (0,5,10,15,30 and 60min), add
Enter same volume ice-cold acetonitrile and terminate reaction.Sample preserves until carrying out LC/MS/MS analysis at-80 DEG C.
Compound concentration in people or rat liver microsomes mixtures incubated is that the method by LC/MS/MS measures
's.The range of linearity of concentration range is determined by each test-compound.
Parallel hatch test and use the microsome of degeneration as negative control, hatch at 37 DEG C, react when different
Between point (0,15 and 60 minute) terminate.
Dextromethorphan (70 μ Μ), as positive control, is hatched at 37 DEG C, react different time point (0,5,10,
15,30 and 60 minutes) terminate.Each assay method all includes the positive and negative control sample, to ensure that microsome is hatched
The integrity of system.
Each is reacted, compound concentration (as a percentage) in people or rat liver microsomes are hatched is pressed
The plotted as percentage of Relative Zero time point, infers internal CLint CL with thisint(ref.:Naritomi Y,
Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of human
hepatic clearance from in vivo animalexperiments and in vitro metabolic
studies with liver microsomes from animals and humans.Drug Metabolism and
Disposition2001,29:1316-1324.).Result sees table 1, the compound that table 1 provides for section Example of the present invention
The experimental result of stability in people and rat liver microsomes.
The experimental result (1 of compound stability in people and rat liver microsomes that table 1 section Example of the present invention provides
μM)
FTV: be quickly converted to Vemurafenib；NT: test；ND: be not detected by
As shown in Table 1, when the compounds of this invention being incubated in people and rat liver microsomes, compound table of the present invention
Reveal good half-life (T1/2) and clearance rate (CLint)。
Same, compound that section Example of the present invention the is provided stability in people and rat plasma is also commented
Estimate.Experimental result sees table 2, compound stability in people and rat plasma that table 2 provides for section Example of the present invention
Experimental result.
The experimental result (2 μMs) of compound stability in people and rat plasma that table 2 section Example of the present invention provides
NT: test
As shown in Table 2, compound of the present invention shows good half-life (T in people and rat plasma1/2)。
Embodiment B the compounds of this invention Pharmacokinetic Evaluation in animal body
The compounds of this invention pharmacokinetic in mice, rat, dog or monkey body is commented by the present invention
Estimate.
Vemurafenib and the compounds of this invention are administered in the form of a solution.It is 0.25 at time point, 0.5,1.0,
Within 2.0,3.0,4.0,6.0,8.0,12 and 24 hours, take blood (0.3mL), and 3,000 or 4, be centrifuged 10 minutes under 000rpm.Receive
Collection plasma solutions, and preserve at-20 DEG C or-70 DEG C until carrying out above-mentioned LC/MS/MS and analyzing.Result sees table 3 to table 7.
Table 3Vemurafenib medicine in SD rat body is for the experimental result of feature
NT: test
Table 4 section Example of the present invention provide compound medicine in SD rat body for feature experimental result (PO,
10mg/kg)
Table 5Vemurafenib medicine in beagle dog body is for the experimental result of feature
NT: test
Table 6 section Example of the present invention provides compound medicine in beagle dog body for the experimental result of feature
Table 7 embodiment of the present invention 25 provides compound medicine in monkey body for the experimental result of feature
Result shows, during the compound oral administration present invention provided, compound of the present invention shows good
Pharmacokinetic property, including preferable half-life (T1/2) bioavailability become reconciled.
Embodiment C Xenograft Tumor Models
Use method as discussed above to set up Colo-205 Transplanted tumor model, and use method as discussed above to carry out point
Analysis.In Colo-205 Transplanted tumor model, by embodiment compound (qd) once a day or (bid) oral administration twice daily
(p.o.), and continuing 15 days, result sees 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 section Example of the present invention provides
As shown in Table 8, under 20mg/kg dosage, the compounds of this invention has meaning statistically, can suppress nude mice skin
The growth of lower tumor.
Finally it should be noted that also have other modes to be used for implementing the present invention.Correspondingly, embodiments of the invention are
To illustratively illustrate, but be not limited to content described in the invention, it is also possible to be made within the scope of the present invention
Amendment or the equivalents added in the claims.All publications or patent cited in the present invention all will be as these
Bright list of references.
Claims (14)
1. the compound as shown in formula (I):
Or its raceme, stereoisomer, geometric isomer, tautomer, nitrogen oxides or pharmaceutically acceptable salt, its
In:
Each X and Y independently be H ,-C (R1R2) OC (=O) R3,-C (R1R2) OC (=O) OR4Or-C (R1R2) OP (=O) (OR4)
(OR4a), and when Y is H, X can not be H；
Each R1And R2Independently be H, D, C1-6Alkyl or C1-6Haloalkyl；
Each R3Independently be H, D, C1-10Alkyl or C1-10Haloalkyl, wherein, described each C1-10Alkyl and C1-10Haloalkyl is not
It is replaced or is optionally independently selected from D ,-OH ,-NH by 1,2,3 or 42, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl and
C1-6The substituent group of alkylamino is replaced；
Each R4And R4aIndependently be H, C1-10Alkyl or C1-10Haloalkyl, wherein, described each C1-10Alkyl and C1-10Haloalkyl
Unsubstituted or be optionally independently selected from D, F, Cl ,-OH ,-NH by 1,2,3 or 42, oxo (=O), C1-6Alkyl, C1-6Halo
Alkyl, C1-6Alkoxyl and C1-6The substituent group of alkylamino is replaced.
Compound the most according to claim 1, wherein, each R1And R2Independently be H, D or C1-3Alkyl.
Compound the most according to claim 1, wherein, each X and Y independently be H or-C (R1R2) OP (=O) (OH)2, and X
Can not be H with Y simultaneously.
Compound the most according to claim 1, wherein, described pharmaceutically acceptable salt is alkali metal salt, alkaline-earth metal
Salt, ammonium salt or N+(C1-4Alkyl)4Salt.
Compound the most according to claim 4, wherein, described pharmaceutically acceptable salt is sodium salt, lithium salts, potassium salt, calcium
Salt, magnesium salt, ammonium salt, quaternary ammonium salt, or combinations thereof.
Compound the most according to claim 1, wherein, described pharmaceutically acceptable salt is inorganic salt, organic salt or it
Combination, wherein, described inorganic salt is hydrochlorate, hydrobromate, sulfate, nitrate, phosphate or combinations thereof,
Described organic salt is acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-
Hydracrylate, pyruvate, oxalates, glycollate, salicylate, glucuronate salt, galacturonic acid hydrochlorate, citric acid
Salt, tartrate, aspartate, glutamate, Glu, benzoate, cinnamate, tosilate, benzene sulfonate, first sulphur
Hydrochlorate, esilate, fluoroform sulphonate or combinations thereof.
Compound the most according to claim 1, has a structure of one of:
8. a pharmaceutical composition, comprises the compound described in claim 1-7 any one and pharmaceutically acceptable carrier,
Excipient, diluent, adjuvant, vehicle or combinations thereof.
Pharmaceutical composition the most according to claim 8, the most also comprises additional treatment agent, and described adding is controlled
Treat agent and be selected from chemotherapeutic agent, antiproliferative, be used for treating atherosclerotic medicine, for treating the medicine of pulmonary fibrosis
Thing or combinations thereof.
Pharmaceutical composition the most according to claim 9, wherein said additional treatment agent is chlorambucil
(chlorambucil), melphalan (melphalan), cyclophosphamide (cyclophosphamide), ifosfamide
(ifosfamide), busulfan (busulfan), carmustine (carmustine), lomustine (lomustine), chain urea is helped
Rhzomorph (streptozocin), cisplatin (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), reach
Carbazine (dacarbazine), temozolomide (temozolomide), procarbazine (procarbazine), methotrexate
(methotrexate), fluorouracil (fluorouracil), cytosine arabinoside (cytarabine), gemcitabine
(gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vinblastine
(vinblastine), vincristine (vincristine), vinorelbine (vinorelbine), paclitaxel (paclitaxel),
Docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), etoposide
(etoposide), ET-743 (trabectedin), dactinomycin (dactinomycin), doxorubicin
(doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone
(mitoxantrone), bleomycin (bleomycin), ametycin (mitomycin), ipsapirone
(ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analog
(gonadorelin analogues), megestrol (megestrol), prednisone (prednisone), dexamethasone
(dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon-ALPHA
(interferon alfa), calcium folinate (leucovorin), sirolimus (sirolimus), temsirolimus
(temsirolimus), everolimus (everolimus), Afatinib (afatinib), alisertib, amuvatinib,
A Pa replaces Buddhist nun (apatinib), Axitinib (axitinib), bortezomib (bortezomib), SKI-606
(bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, gram Zhuo replaces Buddhist nun
(crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib,
Erlotinib (erlotinib), foretinib, ganetespib, gefitinib (gefitinib), ibrutinib, angstrom gram replaces
Buddhist nun (icotinib), imatinib (imatinib), iniparib, Lapatinib (lapatinib), lenvatinib,
Linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), comes that
For Buddhist nun (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib
(pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib,
Rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Sorafenib (sorafenib), relaxes
Buddhist nun replace Buddhist nun (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib,
Trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib,
Volasertib, alemtuzumab (alemtuzumab), bevacizumab (bevacizumab), brentuximab vedotin, card
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 difficult to understand
(ofatumumab), Victibix (panitumumab), Rituximab (rituximab), tositumomab
(tositumomab), Herceptin (trastuzumab), or combinations thereof.
11. 1 kinds use compound described in claim 1-7 any one or the medicine described in claim 8-10 any one
Compositions prepares the purposes of the medicine for protecting, process, treat or alleviate patient's proliferative disease.
12. according to compound described in claim 11 or the purposes of pharmaceutical composition, and wherein said proliferative disease is transfer
Cancer, colon cancer, adenocarcinoma of stomach, bladder cancer, breast carcinoma, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, skin carcinoma, thyroid carcinoma, cerebroma, neck cancer, prostatitis
Adenocarcinoma, cancer of pancreas, the cancer of central nervous system, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
Medicine described in 13. 1 kinds of compounds used described in claim 1-7 any one or claim 8-10 any one
Compositions prepares the purposes of medicine for suppressing or regulate protein kinase activity in biological sample, and described purposes comprises
Use compound described in claim 1-7 any one or use pharmaceutical composition described in claim 8-10 any one with
Described biological sample contact.
14. purposes according to claim 13, wherein said protein kinase is B-Raf.
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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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