CN110407765A - 1,2,5- furodiazole derivative, preparation method and its application in medicine - Google Patents

1,2,5- furodiazole derivative, preparation method and its application in medicine Download PDF

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CN110407765A
CN110407765A CN201910350384.2A CN201910350384A CN110407765A CN 110407765 A CN110407765 A CN 110407765A CN 201910350384 A CN201910350384 A CN 201910350384A CN 110407765 A CN110407765 A CN 110407765A
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alkyl
pharmaceutically acceptable
stereoisomer
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CN110407765B (en
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陈焕明
梁波
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Shanghai Zhi Meng Medical Science & Technology Co Ltd
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to a kind of 1,2,5- furodiazole derivative, preparation method and its applications in medicine.Specifically, the invention discloses general formula A compound represented or its stereoisomers or optical isomer or its pharmaceutically acceptable salt.Purposes the invention also discloses the preparation method of above compound and its in terms of as IDO inhibitor.

Description

1,2,5- furodiazole derivative, preparation method and its application in medicine
Technical field
The invention belongs to biomedicine fields, in particular to a kind of 1,2,5- furodiazole derivatives, its preparation side Method and its application in medicine.
Background technique
Tryptophan (Trp) is one kind required for biosynthesis albumen, niacin and neurotransmitter serotonin (thrombocytin) Essential amino acid.L-Trp is degraded to N- formoxyl-by enzyme indoleamine 2,3-dioxygenase (also known as INDO or IDO) catalysis First and rate-limiting step of kynurenin.In people's cell, Trp exhaustion is caused to be famous interferon (IFN- by IDO activity γ)-induction type antimicrobial effect mechanism.The activation of IFN-γ Induced by Stimulation IDO, causes Trp to exhaust, thus inhibits to rely on The intracellular pathogen of Trp such as mouse toxoplasma (Toxoplasma gondii) and chlamydia trachomatis (Chlamydia Trachomatis growth).
IDO activity also has antiproliferative effect to kinds of tumor cells, and can be in body during allogene tumor rejection Inside observe IDO induce, show the enzyme may work during tumor rejection (Daubener et al., 1999, Adv.Exp.Med.Biol., 467:517-24；Taylor et al., 1991, FASEB J., 5:2516-22).
It has been observed that the HeLa cell co-cultured with peripheral blood lymphocytes (PBL) is obtained by the active up-regulation of IDO Immunosupress phenotype.It has also been proposed that the IDO activity in tumour cell can be used for weakening antitumor response (Logan et al., 2002, Immunology, 105:478-87).Recently, the immunoregulation effect, IDO of Trp exhaustion fetus in preventing uterus are arranged It works in the Immunosuppression of reprimand and is much paid close attention to.
In view of instruction IDO is in immunosupress, drug resistance of tumor and/or repulsion, chronic infection, HIV infection, AIDS (packet Include its form of expression, such as cachexia, dementia and diarrhea), autoimmune disease or illness (such as rheumatoid arthritis) With the experimental data of the effect in immunological tolerance and prevention uterus fetus repulsion, need for by inhibiting IDO activity Inhibit the therapeutic agent of tryptophan degradation.When T cell is by HIV suppressions such as pregnancy, malignant tumour and HIV, can be pressed down with IDO Preparation activates T cell, to enhance t cell activation.IDO is inhibited to can also be neurology or neuropsychiatric disease or illness The critical treatment strategy of (such as depression) patient.
As it can be seen that IDO inhibitor is still the research emphasis and hot spot of this field.
Summary of the invention
The object of the present invention is to provide a kind of novel 1,2,5- oxadiazole derivatives that can be used as IDO inhibitor.
The object of the present invention is to provide the preparation methods of above compound.
It is also an object of this invention to provide above compounds as indoleamine 2,3-dioxygenase (dioxygenase) Application in inhibitor is used for treating cancer and other illnesss.
First aspect present invention provides compound shown in formula A or its stereoisomer or optical isomer or its medicine Acceptable salt on:
Wherein: W is CH2, NH, O, S, SO or SO2；
M is 1,2,3 or 4；
R1 is selected from the group: halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1- C6 alkoxy；T is 1,2,3 or 4；
M is SO2, S (=O) (=NH), PO2, P (=O) (=NH), C=O, S=O or P=O when, Y be NH or CH2；n It is 1,2,3,4 or 5；R2 is the substituent group on ring；
Or
M is SO2When, Y is nothing；N is 0；R2 is connect with the sulphur atom in M；With
R2 is hydrogen, halogen, C1-C6 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl； Wherein, the C1-C6 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl are optionally by one Or replaced multiple substituent groups selected from halogen, nitro, cyano, amido or hydroxyl.
In another preferred example, W is CH2, NH, O, S, SO or SO2；
M is 1,2,3 or 4；
R1 is selected from the group: halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1- C6 alkoxy；T is 1,2,3 or 4；
M is SO2, S (=O) (=NH), PO2, P (=O) (=NH), C=O, S=O or P=O when, Y be NH or CH2；n It is 1,2,3,4 or 5；R2 is the substituent group on ring；
Or
M is SO2When, Y is nothing；N is 0；R2 is connect with the sulphur atom in M；With
R2 is hydrogen, C1-C6 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl；Wherein, The C1-C6 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl are optionally by one or more Replaced a substituent group selected from halogen, nitro, cyano, amido or hydroxyl.
In another preferred example, the compound is as shown in formula B:
Each group definition is the same.
In another preferred example, the compound is shown in formula I:
Wherein:
W is CH2, NH, O, S, SO or SO2；
M is 1,2,3 or 4；
When X is O or NH；When Z is S P；Y is NH or CH2；N is 1,2,3,4 or 5；R2 is the substitution on ring Base；
Or
When X is O；When Z is S；Y is nothing；N is 0；R2 is connect with Z；
R2 is hydrogen, halogen, C1-C6 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl； Wherein, the C1-C6 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl are optionally by one Or replaced multiple substituent groups selected from halogen, nitro, cyano, amido or hydroxyl.
In another preferred example, the compound is shown in formula I:
Wherein:
W is CH2, NH, O, S, SO or SO2；
M is 1,2,3 or 4；
When X is O or NH；When Z is S P；Y is NH or CH2；N is 1,2,3,4 or 5；R2 is the substitution on ring Base；
Or
When X is O；When Z is S；Y is nothing；N is 0；R2 is connect with Z；
R2 is hydrogen, C1-C6 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl；Wherein, The C1-C6 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl are optionally by one or more Replaced a substituent group selected from halogen, nitro, cyano, amido or hydroxyl.
In another preferred example, the compound is shown in formula I:
Wherein:
W is NH or O；
M is 1 or 2；
When X is O；When Z is S；Y is NH；N is 2 or 3；R2 is the substituent group on ring；
Or
When X is O；When Z is S；Y is nothing；N is 0；R2 is connect with Z；
R2 is hydrogen, halogen or C1-C6 alkyl.
In another preferred example, the compound is as shown in Formula II:
Wherein:
W is CH2, NH, O, S, SO or SO2；
M is 1,2,3 or 4；
A is C, S or P；
Y is NH or CH2；
N is 1,2,3,4 or 5；
R2 is the substituent group on ring；R2 is hydrogen, C1-C6 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkenyl, C2-C6 alkenyl Or C2-C6 alkynyl；Wherein the C1-C6 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl Optionally replaced one or more substituent groups selected from halogen, nitro, cyano, amido or hydroxyl.
In another preferred example, the compound is selected from the group:
In another preferred example, the compound is selected from the group:
Second aspect of the present invention provides a kind of pharmaceutical composition, comprising compound described in first aspect present invention or its Stereoisomer or optical isomer or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier.
Third aspect present invention provides compound or its stereoisomer or light described in a kind of first aspect present invention The purposes for learning pharmaceutical composition described in isomers or its pharmaceutically acceptable salt or second aspect of the present invention, is used to prepare IDO inhibitor；And/or it is used to prepare the drug for preventing or treating IDO related disease.
In another preferred example, the disease is selected from the group: cancer, Alzheimer disease, virus infection, neurodegeneration Illness, wound, organ-graft refection, autoimmune disease, depression, anxiety disorder, cataract, mental handicape and AIDS.
In another preferred example, the disease is the disease for the tryptophan metabolic pathway pathological characteristics that IDO is mediated.
Fourth aspect present invention provides compound described in first aspect present invention or its stereoisomer or optics is different The preparation method of structure body or its pharmaceutically acceptable salt, the method includes the steps: in atent solvent, by compound A1 It is reacted with compound A2, to form compound A；
Wherein, n, m, M, Y, R1, R2 and t are as defined above；
W ' is NH2When, G is CHO or NO2；Or W ' be OH or SH when, G NO2；Or W ' be CHO when, G NH2；
W is NH, O or S.
In another preferred example, when Y is NH, the method includes the steps:
(a) in atent solvent, compound A1 ' and compound A2 are reacted, to form compound A-13；
(b) in atent solvent, compound A-13 is subjected to deprotection reaction, to form compound A；
Wherein, Y ' is N- amino protecting group, and the amino protecting group is selected from the group: p-methoxyphenyl, benzyl, tertiary fourth oxygen Carbonyl, acetyl group, benzyloxycarbonyl group, tablet held before the breast by officials methoxycarbonyl group (Fmoc)；Other each group definitions are the same.
In another preferred example, the method includes the steps: in atent solvent, by compound A1 and compound A2 ' into Row reaction, to form compound B；
In the above formulas, each group definition is the same.
The present invention also provides a kind of prevention or the methods for the treatment of IDO related disease, and the method includes to pair needed As application the compounds of this invention or pharmaceutical composition.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, In This no longer tires out one by one states.
Specific embodiment
The present inventor is surprised to find that the 1 of a kind of structure novel, 2,5- oxadiazoles by extensive and in-depth research for the first time Derivative has excellent IDO inhibitory activity, can be used for the diseases such as treating cancer.The present invention is completed on this basis.
Term
Except illustrate place, "or" referred to herein have meaning identical with "and/or" (refer to "or" and "and").
In place of illustrating, among all compounds of the invention, each asymmetric carbon atom (chiral centre) can be optional Ground is the mixture of R configuration or S configuration or R configuration and S configuration.
As used herein, when individually or as other substituent group a part, term " alkyl " refers to containing only the straight of carbon atom Chain (that is, unbranched) or the group of branched saturated hydrocarbon group or straight chain and branch combination.Before alkyl there is carbon atom number to limit When (such as C1-C6 alkyl), refer to that the alkyl contains 1-6 carbon atom.Including methyl, ethyl, propyl, isopropyl, butyl, different Butyl, sec-butyl, tert-butyl or similar group.
As used herein, term " C1-C6 alkoxy " refers to C1-C6 alkyl-oxygen-, including methoxyl group, ethyoxyl, propoxyl group, Isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or similar group.
As used herein, when individually or as other substituent group a part, term " C3-C6 naphthenic base " refers to 3-6 The cyclic saturated hydrocarbon base of a carbon atom, for example including cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl or similar group.
As used herein, when individually or as other substituent group a part, term " C3-C6 cycloalkenyl " refers to 3-6 The annulus unsaturated alkyl of a carbon atom, for example including cyclopropanyl, cyclobutane base, cyclopentenyl, cyclohexenyl group or class Like group.
As used herein, when individually or as other substituent group a part, term " C2-C6 alkenyl " refers to 2-6 The branch of a carbon atom or the unsaturated alkyl containing alkenyl of straight chain, for example including vinyl, acrylic, cyclobutenyl, amylene Base, hexenyl or similar group.
As used herein, when individually or as other substituent group a part, term " C2-C6 alkynyl " refers to 2-6 The branch of carbon atom or the unsaturated alkyl containing alkynyl of straight chain, for example including acetenyl, propinyl, butynyl, pentynyl, Hexin base or similar group.
" halogen " is fluorine, chlorine, bromine or iodine." halogenated " refers to fluoro, chloro, bromo or iodo.
As used herein, symbolIndicate singly-bound.
Active constituent
The compounds of this invention refers to general formula A compound represented or its stereoisomer or optical isomer or its pharmacy Upper acceptable salt.
" pharmaceutically acceptable salt " refers to the compounds of this invention and pharmaceutically acceptable inorganic acid and organic acid It is formed by salt, wherein preferred inorganic acid includes (but being not limited to): hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid；It is preferred that Organic acid include (but being not limited to): formic acid, acetic acid, propionic acid, succinic acid, naphthalenedisulfonic acid (1,5), asiatic acid, oxalic acid, wine Stone acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, horse Come sour, malic acid, sulfamic acid, benzenpropanoic acid, gluconic acid, ascorbic acid, niacin, isonicotinic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, lemon Lemon acid and amino acid.
" stereoisomer " or " optical isomer " refers to that asymmetric carbon atom involved by the compounds of this invention can be R Configuration, or S configuration, or combinations thereof.
Preparation method
The compound of the present invention can be prepared by method commonly used in the art, can also be according to method documented by the application Preparation.Reaction can be under conditions of familiar to those skilled in the art involved in preparation method of the present invention
Pharmaceutical composition and method of administration
Since the compounds of this invention with the excellent inhibitory activity to IDO, the compounds of this invention and contains this Invention compound be main active pharmaceutical composition can be used for treating, prevent and alleviates by with IDO activity or express Measure relevant disease.According to the prior art, the compounds of this invention can be used for treating following disease (but being not limited to): various cancers Disease, such as lung cancer, bladder cancer, breast cancer, gastric cancer, liver cancer, saliva adenosarcoma, oophoroma, prostate cancer, cervical carcinoma, epithelium are thin Born of the same parents' cancer, Huppert's disease, cancer of pancreas, lymthoma, chronic myelogenous leukemia, lymphocytic leukemia, cutaneous T-cell lymph Tumor etc.；Alzheimer disease, virus infection, neurodegenerative disorders, wound, organ-graft refection, autoimmune disease, depression Disease, anxiety disorder, cataract, mental handicape and AIDS.
Pharmaceutical composition of the invention is comprising the compounds of this invention within the scope of safe and effective amount and can pharmacologically receive Excipient or carrier.
" safe and effective amount " refers to: the amount of compound is enough to be obviously improved the state of an illness, and is unlikely to generate serious Side effect.In general, pharmaceutical composition contains 1-2000mg the compounds of this invention/agent, more preferably, contain the 5-200mg present invention Compound/agent.Preferably, described is " one " for a capsule or tablet.
" the pharmaceutically acceptable carrier " refers to: one or more biocompatible solids or liquid filler are solidifying Glue substance, they are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as In composition each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the medicine of compound Effect.Pharmaceutically acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose Sodium, cellulose ethanoate etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as beans Oil, sesame oil, peanut oil, olive oil etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite), emulsifier (such as), wetting agent (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, apyrogeneity Water etc..
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representative method of application includes (but being not limited to): in oral, tumor, rectum, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations In type, reactive compound is mixed at least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with Following compositions mixing: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) it bonds Agent, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, example Such as, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates, And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti Pure and mild glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, talcum, calcium stearate, tristearin Or mixtures thereof sour magnesium, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form also may include Buffer.
Coating and shell material preparation can be used in solid dosage forms such as tablet, sugar-pill, capsule, pill and granule, such as casing and Other materials well known in the art.They may include opacifying agent, also, reactive compound or compound in this composition Release can discharge in certain a part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material And wax material.When necessary, reactive compound can also be with one of above-mentioned excipient or a variety of formation microencapsulation forms.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture. In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl formyl The mixture of amine and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste Agent, corrigent and fragrance.
In addition to active compounds, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene Sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.For local administration The dosage form of the compounds of this invention includes ointment, powder, patch, stock solution and inhalant.Active constituent aseptically with Physiologically acceptable carrier and any preservative, buffer, or the propellant that may be needed when necessary are mixed together.
The compounds of this invention can be administered alone, or be administered in combination with other pharmaceutically acceptable compounds.
It is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment when using pharmaceutical composition (such as people), wherein dosage is the effective dosage pharmaceutically thought when application, for the people of 60kg weight, day is to medicament Amount is usually 1~2000mg, preferably 5~500mg.Certainly, specific dosage be also contemplated that administration route, patient health situation etc. because Element, within the scope of these are all skilled practitioners technical ability.
Main advantages of the present invention are:
The present invention provides the compounds that can be used for IDO inhibitor of a kind of structure novel.
IDO inhibitor of the invention has excellent activity.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are weight percent and weight Number.
Experimental material used in following embodiment and reagent can obtain unless otherwise instructed from commercially available channel.
The preparation of 1 compound 201 of embodiment
Step 1: 2-N- (4- anisyl) sulphonyl ammonia) acetic acid methyl ester (compound 2)
4- aminoanisole (1.8g, 14.6mmol) and pyridine (1.4g, 17.4mmol) are dissolved in acetonitrile (35mL), it will Solution cools down under ice bath and 2- (chlorosulfonyl) methyl acetate (compound 1,2.5g, 14.5mmol) is slowly added dropwise.Reaction solution It is stirred at room temperature overnight.Reaction mixture removes solvent in rotary vacuum evaporator, and residue is molten with methylene chloride (100mL) Solution, is washed with 1N hydrochloric acid (40mL) and saturated salt solution (40mL), anhydrous sodium sulfate dries, filters, and filtrate is concentrated to get respectively Purple oily compound 2 crude product (3.46g, yield: 92%).
1H NMR(400MHz,CDCl3):δ7.30-7.28(m,2H),6.97(brs,1H),6.90-6.88(m,2H), 3.92(s,2H),3.83(s,3H),3.80(s,3H).MS(ESI):Calcd.for C10H13NO5S 259；Found 282[M+ Na]+.
Step 2: 2- (4- anisyl) -1,1- dioxidoisothiazolidin -5- methyl formate (3)
At room temperature, to the N of compound 2 (3.2g, 14.5mmol) and potassium carbonate (5.1g, 36.9mmol), N- dimethyl Glycol dibromide (4.2g, 22.3mmol) is added in the mixture of formamide (40mL).Reaction mixture is heated to 70 DEG C simultaneously It is stirred overnight.Reaction solution is cooled to room temperature, and water (150mL) dilution is added and is extracted with ethyl acetate (100mL x 3).Acetic acid second Ester is mutually washed with saturated salt solution (200mL), and anhydrous sodium sulfate dries, filters, and filtrate is obtained shallowly after being spin-dried for silica gel column purification Yellow solid compound 3 (1.8g, yield: 50%).
1H NMR(400MHz,CDCl3): δ 7.28-7.25 (m, 2H), 6.92-6.89 (m, 2H), 4.27-4.23 (dd, J= 6.8Hz,2.0Hz,1H),3.89(s,3H),3.85-3.79(m,4H),3.72-3.65(m,1H),2.91-2.81(m,1H), 2.67-2.57(m,1H).MS(ESI):Calcd.for C12H15NO5S 285；Found 286[M+H]+,308[M+Na]+.
Step 3: 5- methylol -2- (4- anisyl) -1,1- dioxidoisothiazolidin (4)
Compound 3 (1.7g, 6.0mmol) is dissolved in methanol (60mL), sodium borohydride is added portionwise under ice bath (0.5g,12mmol).Reaction mixture is stirred at room temperature overnight.The reaction of 1N hydrochloric acid is slowly added into reaction mixture, Temperature control is at 20 DEG C hereinafter, pH is transferred to 7 or so end.Obtained mixture vacuum concentration uses ethyl acetate after removing methanol (100mL x 3) extraction.Ethyl acetate phase is washed with saturated salt solution (100mL), and anhydrous sodium sulfate is dried, filtered and concentrated. Mixture obtains pale yellowish oil compound 4 (1.3g, yield: 80%) with silica gel column separating purification.
1H NMR(400MHz,CDCl3):δ7.30-7.20(m,2H),6.95-6.86(m,2H),4.16-4.09(m,1H), 4.04-3.97(m,1H),3.82(s,3H),3.72-3.60(m,2H),3.60-3.50(m,1H),2.74(brs,1H),2.58- 2.48(m,1H),2.42-2.30(m,1H).MS(ESI):Calcd.for C11H15NO4S 257；Found 258[M+H]+,280 [M+Na]+.
Step 4: 2- (4- anisyl) -1,1- dioxidoisothiazolidin -5- formaldehyde (5)
Compound 4 (0.7g, 2.7mmo) is dissolved in methylene chloride (10mL), is added under ice bath to the solution by portions Dess-Martin oxidant (1.2g, 2.8mmol).Reaction mixture is stirred at room temperature overnight.Reaction solution is evaporated in rotatory vacuum Solvent is removed in instrument, residue obtains yellow oil 5 (0.4g, yield: 58%) with silica gel column purification.
MS(ESI):Calcd.for C11H13NO4S 255；Found 256[M+H]+.
Step 5: 4- (the bromo- 4- fluorophenyl of 3-) -3- (4- (((2- (4- anisyl) -1,1- dihydroxy isothiazolidine -5- Base) methyl) amino) -1,2,5- oxadiazoles -3- base) -1,2,4- oxadiazoles -5 (4H) -one (7)
At room temperature, to compound 6 (0.36g, 1.05mmol), triethylsilane (0.5g, 4.3mmol) and methane sulfonic acid Compound 5 (0.4g, 1.56mmol) is added in methylene chloride (10mL) solution of (0.41g, 4.26mmol).Reaction mixture exists 30 DEG C are stirred overnight.Reaction solution adds water (25mL) to dilute, methylene chloride (40mL x 3) extraction, and organic phase is dry with anhydrous sodium sulfate Dry, filtering obtains compound as white solid 7 (290mg, yield: 47%) with silica gel column purification after filtrate concentration.
MS(ESI):Calcd.for C21H18BrFN6O6S 580；Found 581[M+H]+.
Step 6: 4- (the bromo- 4- fluorophenyl of 3-) -3- (4- (((1,1- dihydroxy isothiazolidine -5- base) methyl) amino) - 1,2,5- oxadiazoles -3- base) -1,2,4- oxadiazoles -5 (4H) -one (8)
Compound 7 (290mg, 0.5mmol) is dissolved in acetonitrile (5mL), ammonium ceric nitrate is added dropwise under ice bath in solution Water (5mL) solution of (820mg, 1.5mmol).Reaction mixture continues stirring 1 hour under ice bath.Reaction solution adds water (20mL) It dilutes and ethyl acetate (20mL x 4) is used to extract.Ethyl acetate phase is dried, filtered with anhydrous sodium sulfate, filter vacuum concentration. Obtained mixture purifies to obtain compound as white solid 8 (140mg, yield: 58%) with preparation TLC plate.
MS(ESI):Calcd.for C14H12BrFN6O5S 474；Found 475[M+H]+.
Step 7: (Z)-N- (the bromo- 4- fluorophenyl of 3-) -4- (((1,1- dihydroxy isothiazolidine -5- base) methyl) amino) - The miscellaneous oxa- amidine (201) of N'- hydroxyl -1,2,5- oxadiazoles -3- carbon
At room temperature, sodium hydrate aqueous solution is added into methanol (2mL) solution of compound 8 (140mg, 0.29mmol) (2N,0.5mL).Reaction mixture continues stirring 2 hours in room temperature.Reaction solution adds water (20mL) to dilute, ethyl acetate (25mL x 3) it extracts.Ethyl acetate phase is dried, filtered with anhydrous sodium sulfate, filter vacuum concentration.Crude product preparative high-performance liquid chromatographic is pure Change obtains colorless oil target compound 201 (10mg, yield: 7.7%).
1H NMR(300MHz,DMSO-d6):δ8.86(s,1H),7.17-7.06(m,2H),6.93(s,1H),6.78- 6.71(m,1H),6.54-6.47(m,1H),3.65-3.53(m,1H),3.54-3.38(m,1H),3.20-3.02(m,3H), 2.84-2.74(m,1H),2.45-2.30(m,1H),2.08-1.90(m,1H).MS(ESI):Calcd.for C13H14BrFN6O4S 448；Found 449[M+H]+.HPLC purity:98.8% (214nm)/99.6% (254nm)
Embodiment 2 prepare compound 201-P1 and compound 201-P2
Compound 201-P1 and compound 201-P2 enantiomter each other, can by with chiral HPLC to compound 201 carry out chiral resolution acquisition.Chiral resolution condition is as follows: chromatographic column OJ-H；Column size is 5 μm,Mobile phase is CO2/ IPA (0.2%DEA)=70/30；Flow velocity=40g/min；Temperature 37.8 ℃；Pressure 150-160bar.The retention time of compound 201-P1 is 5.9min, and the retention time of compound 201-P2 is 5.34min。
Compound 201-P11H NMR(300MHz,DMSO-d6):δ8.86(s,1H),7.17-7.06(m,2H),6.93 (s,1H),6.78-6.71(m,1H),6.54-6.47(m,1H),3.65-3.53(m,1H),3.54-3.38(m,1H),3.20- 3.02(m,3H),2.84-2.74(m,1H),2.45-2.30(m,1H),2.08-1.90(m,1H).MS(ESI):Calcd.for C13H14BrFN6O4S 448；Found 449[M+H]+.
Compound 201-P21H NMR(300MHz,DMSO-d6):δ8.86(s,1H),7.17-7.06(m,2H),6.93 (s,1H),6.78-6.71(m,1H),6.54-6.47(m,1H),3.65-3.53(m,1H),3.54-3.38(m,1H),3.20- 3.02(m,3H),2.84-2.74(m,1H),2.45-2.30(m,1H),2.08-1.90(m,1H).MS(ESI):Calcd.for C13H14BrFN6O4S 448；Found 449[M+H]+.
3 prepare compound 202 of embodiment
Step 1: 2-N- (4- anisyl) sulphonyl ammonia) acetic acid methyl ester (compound 2)
Under ice cooling, 4, toward the acetonitrile of 4- aminoanisole (9.0g, 72.4mmol) and pyridine (7.0g, 88.6mmol) (160mL)) 2- (chlorosulfonyl) methyl acetate (compound 1,12.5g, 72.4mmol) is slowly added dropwise in solution.Reaction is in room temperature Lower stirring 3 hours.Reaction mixture steams in rotary vacuum evaporator walks solvent, and residue is dissolved with methylene chloride (300mL), 1N hydrochloric acid (100mL x 2) is used respectively, saturated salt solution (100mL) washing, anhydrous sodium sulfate is dry, is concentrated to get purple later Oily compound 2 (15.5g, yield: 82.5%).
HNMR (400MHz, CDCl3): δ 7.29 (d, J=8.8Hz, 2H), 6.97 (s, 1H), 6.89 (d, 2H, J= 8.8Hz),3.92(s,2H),3.83(s,3H),3.80(s,3H).MS(ESI):Calcd.for C10H13NO5S 259； Found 260[M+H]+,282[M+Na]+.
Step 2: the own ring -6- carboxylate methyl ester -1,1- dioxide (compound 3) of 2- (4- anisyl) -1,2- thiophene a word used for translation
At room temperature, toward the N of compound 2 (1.4g, 5.4mmol) and potassium carbonate (2.2g, 16.2mmol), N- dimethyl methyl 1,3- dibromopropane (1.53g, 7.56mmol) is added in amide (30mL) mixture.Reaction is heated to 70 DEG C and is stirred overnight.Instead It answers liquid to be cooled to room temperature, water (200mL) dilution is added, mixed liquor is extracted with ethyl acetate (100mL x 3), combined organic phase It is dried, filtered and concentrated with anhydrous sodium sulfate.Residue with silica gel column purification obtain yellow oily compound 3 (1.2g, yield: 69%).
HNMR (400MHz, CDCl3): δ 7.24 (d, J=8.8Hz, 2H), 6.87 (d, J=8.8Hz, 2H), 3.95-3.86 (m,1H),3.82(s,3H),3.80(s,3H),3.67-3.60(m,1H),2.64-2.45(m,2H),2.14-2.06(m,1H), 1.97-1.87(m,1H),1.65-1.55(m,1H).MS(ESI):Calcd.for C13H17NO5S 299；Found 300[M+ H]+,322[M+Na]+.
Step 3: the own ring -6- methylol -1,1- dioxide (compound 4) of 2- (4- methoxyphenyl) -1,2- thiophene a word used for translation
Under ice cooling, 4, hydroboration is added portionwise in methanol (20mL) solution of past compound 3 (1.1g, 3.7mmol) Sodium (0.4g, 10.5mmol).Reaction is stirred at room temperature overnight.At 20 DEG C hereinafter, being reacted with 1N hydrochloric acid, pH is transferred to 7 left sides It is right.Reaction mixture steams in rotary vacuum evaporator walks methanol, residue methylene chloride (30mL) and water (20mL) dilution, Water phase is extracted with methylene chloride (30mL), and combined organic phase is dried, filtered and concentrated with anhydrous sodium sulfate.Residue silica gel Column purification obtains yellow oily compound 4 (1.0g, yield: 99%).
HNMR (400MHz, CDCl3): δ 7.26 (d, J=8.8Hz, 2H), 6.99 (d, J=8.8Hz, 2H), 4.19-4.12 (m,1H),4.03-3.95(m,1H),3.80(s,3H),3.60-3.52(m,1H),3.37-3.29(m,1H),2.52-2.35 (m,1H),2.32-2.22(m,2H),2.00-1.87(m,2H),1.65-1.50(m,1H).MS(ESI):Calcd.for C12H17NO4S 271；Found 272[M+H]+,294[M+Na]+.
Step 4: the own ring -6- formaldehyde -1,1- dioxide (compound 5) of 2- (4- methoxyphenyl) -1,2- thiophene a word used for translation
Under ice cooling, 4, it is added portionwise in methylene chloride (15mL) solution of past compound 4 (0.9g, 3.3mmol) Dess-Martin reagent (2.1g, 4.95mmol).Reaction is stirred at room temperature 3 hours.Reaction solution sodium thiosulfate solution (50mL x 2) is quenched, methylene chloride (30mL x 3) extraction.Combined organic phase is dried, filtered and is spin-dried for anhydrous sodium sulfate It obtains yellow oily crude Compound 5 (0.9g), compound 5, which is not further purified, to be directly used in next step.
Step 5: 4- (the bromo- 4- fluorophenyl of 3-) -3- (4 (- (2 (4- methoxyphenyl) -1,1- dihydroxy -1,2- thiophene a word used for translations oneself Ring -6- base) methyl) amino -1,2,5- oxadiazoles -3- base) -1,2,4- oxadiazoles -5 (4H) -one (compound 7)
At room temperature, toward compound 6 (0.78g, 2.3mmol), triethylsilane (2.1g, 18.0mmol) and methane sulfonic acid The methylene chloride (20mL) of (1.6g, 16.6mmol)) crude Compound 5 (0.9g, 3.3mmol) is added in solution.Reaction heating It is stirred overnight to 30 DEG C.Reaction solution is directly concentrated, and residue obtains compound as white solid 7 (450mg, receipts with silica gel column purification Rate: 33%).
HNMR(400MHz,CDCl3):δ8.10-7.97(m,1H),7.67-7.61(m,1H),7.38-7.31(m,1H), 7.30-7.22(m,2H),6.94-6.85(m,2H),5.98-5.95(m,1H),4.05-3.93(m,2H),3.82(s,3H), 3.86-3.74(m,1H),3.65-3.48(m,2H),2.36-2.26(m,1H),2.24-2.12(m,1H),2.00-1.90(m, 2H).MS(ESI):Calcd.for C22H20BrFN6O6S 594；Found 595[M+H]+.
Step 6: 4- (the bromo- 4- fluorophenyl of 3-) -3- (4- (((the own ring -6- base of 1,1- dihydroxy -1,2- thiophene a word used for translation) methyl) ammonia Base -1,2,5- oxadiazoles -3- base) -1,2,4- oxadiazoles -5 (4H) -one (compound 8)
Under ice cooling, 4, cerous ammonium nitrate is added dropwise in acetonitrile (5mL) solution of past compound 7 (450mg, 0.76mmol) Water (5mL) solution of (1.25g, 2.28mmol).Reaction continues stirring 1 hour under ice bath.Water (40mL) is added in mixture Quenching reaction, is extracted with ethyl acetate (25mL x 3), and combined organic phase is dried, filtered and concentrated with anhydrous sodium sulfate.It is residual Excess purifies to obtain yellow solid compound 8 (300mg, yield: 81%) with preparation TLC plate.
HNMR(400MHz,d6-DMSO):δ8.12-8.07(m,1H),7.76-7.68(m,1H),7.65-7.57(m, 1H),7.02-6.95(m,1H),6.83-6.76(m,1H),3.78-3.69(m,1H),3.52-3.40(m,2H),3.20-3.05 (m,2H),2.09-2.01(m,1H),1.80-1.55(m,2H),1.51-1.38(m,1H).MS(ESI):Calcd.for C15H14BrFN6O5S 488；Found 489[M+H]+.
Step 7: N- (the bromo- 4- fluorophenyl of 3-) -4- (((the own ring -6- base of 1,1- dihydroxy -1,2- thiophene a word used for translation) methyl) ammonia Base) the miscellaneous oxa- amidine (compound 202) of-N '-hydroxyl -1,2,5- oxadiazoles -3- carbon
At room temperature, sodium hydroxide water is slowly added dropwise in methanol (6mL) solution of past compound 8 (300mg, 0.61mmol) Solution (2N, 2mL).Reaction is stirred at room temperature 2 hours.Water (25mL) dilute reaction solution is added and with ethyl acetate (30mL x 3) Extraction.Combined organic phase is dried, filtered and concentrated with anhydrous sodium sulfate.Residue purifies to obtain white admittedly with preparation TLC plate Body compound 202 (150mg, yield: 53%).
HNMR(400MHz,d6-DMSO):δ11.48(s,1H),8.93(s,1H),7.21-7.16(m,1H),7.14- 7.09(m,1H),7.00-6.93(m,1H),6.80-6.72(m,1H),6.52-6.46(m,1H),3.72-3.63(m,1H), 3.45-3.35 (m, 1H), 3.29-3.20 (m, 1H), 3.17-3.03 (m, 2H), 1.98-1.86 (m, 1H), 1.71-1.54 (m, 2H),1.50-1.35(m,1H).MS(ESI):Calcd.for C14H16BrFN6O4S 462；Found 463[M+H]+ .HPLC:95.3% (214nm)/96.5% (254nm)
4 prepare compound 203 of embodiment
Step 1: 4- (the bromo- 4- fluorophenyl of 3-) -3- (4- nitroso -1,2,5- oxadiazoles -3- base) -1,2,4- oxadiazoles - 5 (4H) -one (compound 2)
Under water-bath, trifluoroacetic acid (6mL) and dichloroethanes (10mL) mixing toward compound 1 (1.0g, 2.9mmol) are molten Urea peroxide (urea.H is added in liquid2O2)(2.2g,23.4mmol).Reaction is stirred at room temperature overnight.Monitoring discovery is about Urea peroxide (2.2g, 23.4mmol) is added again in 50% starting material left, and reaction continues to be stirred overnight at room temperature.Reaction solution ice Water quenching is gone out, and water phase is extracted with methylene chloride (50mL x 3), and combined organic phase is dried, filtered and concentrated with anhydrous sodium sulfate. Residue obtains compound as white solid 4 (0.8g, yield: 74%) with silica gel column purification.
HNMR(400MHz,CDCl3):δ7.64-7.60(m,2H),7.28-7.26(m,1H).
Step 2: 4- (the bromo- 4- fluorophenyl of 3-) -3- (4- ((2- (4- anisyl) -1,1- dihydroxy isothiazolidine -5- Base) methoxyl group) -1,2,5- oxadiazoles -3- base) -1,2,4- oxadiazoles -5 (4H) -one (compound 4)
At room temperature, 1mol/ is added dropwise in anhydrous tetrahydro furan (10mL) solution of past compound 3 (200mg, 0.78mmol) The potassium tert-butoxide tetrahydrofuran solution (0.66mL, 0.66mmol) of L, after being stirred at room temperature 2 minutes be added compound 2 (227mg, 0.61mmol), reaction continues to be stirred at room temperature 30 minutes.Reaction solution is directly spin-dried for, and obtaining 4 crude product of compound, (0.4g, content is about 20%), it is yellow oil, does not purify and be directly used in next step.
MS(ESI):Calcd.for C21H17BrFN5O7S 581；Found 582[M+H]+.
Step 3: 4- (the bromo- 4- fluorophenyl of 3-) -3- (4- ((1,1- dihydroxy isothiazolidine -5- base) methoxyl group) -1,2, 5- oxadiazoles -3- base) -1,2,4- oxadiazoles -5 (4H) -one (compound 5)
Under ice cooling, 4, cerous nitrate is added dropwise in acetonitrile (15mL) solution of past 4 crude product of compound (400mg, 0.6mmol) Water (6mL) solution of amine (1.64g, 3mmol).Reaction continues stirring 1 hour under ice bath.It is dilute that water (30mL) is added in reaction solution It releases, ethyl acetate (25mL x 3) extraction is added, organic phase is dried, filtered and concentrated with anhydrous sodium sulfate.Residue preparation TLC plate purifies to obtain yellow oily compound 5 crude product (60mg, yield: 20%).
MS(ESI):Calcd.for C14H12BrFN5O6S 475；Found 476[M+H]+.
Step 4: N- (the bromo- 4- fluorophenyl of 3-) -4- ((1,1- dihydroxy isothiazolidine -5- base) methoxyl group)-N '-hydroxyl - The miscellaneous oxa- amidine (compound 203) of 1,2,5- oxadiazoles -3- carbon
At room temperature, sodium hydrate aqueous solution is added in methanol (5mL) solution of past compound 5 (60mg, 0.126mmol) (2N, 2mL, 4mmol).Reaction is stirred at room temperature 2 hours.Reaction solution concentration removes methanol, water (20mL) is added and with 1N hydrochloric acid It adjusts between pH to 7-8, is extracted with ethyl acetate (25mL x 3), combined organic phase is dried, filtered simultaneously with anhydrous sodium sulfate Concentration.Residue purifies to obtain clear oil compound 203 (10mg, yield: 53%) with preparation TLC plate.
HNMR (400MHz, CD3OD): δ 7.98-7.94 (m, 1H), 7.64-7.58 (m, 1H), 7.21-7.14 (t, J= 8.8Hz,1H),4.58-4.47(m,2H),3.64-3.56(m,1H),2.65-2.54(m,1H),2.23-2.10(m,2H), 1.65-1.55(m,1H).MS(ESI):Calcd.for C13H14BrFN5O5S 449；Found 450[M+H]+.HPLC: 87.6% (214nm)/96.7% (254nm)
5 prepare compound 204 of embodiment
Step 1: 4- amino-N '-hydroxyl -1,2,5- oxadiazoles -3- carbonamidine (compound 4)
Under ice cooling, 4, sodium nitrite is added portionwise in water (2.2L) solution of past malononitrile (115g, 17.7mol) (244g, 35.4mol) and acetic acid (200mL).It is 2 small that reaction is slowly warmed to room temperature that the reaction was continued after stirring 30 minutes under ice bath When.Obtained mixed solution is cooled to 0-10 DEG C, then be slowly added dropwise hydroxylamine hydrochloride (368g, 53.1mol) water (350mL) it is molten Liquid, reaction continue to stir 1 hour at such a temperature.Obtained mixed solution slowly adjusts pH with sodium hydroxide to 10 or so.Instead It should be heated to 100 DEG C and be stirred overnight.Under ice bath, with the salt acid for adjusting pH of 6N to neutrality, and continue stirring until solid is analysed Out, it filters, washs filter cake with water (400mL x 2), obtain compound as white solid 4 (170g, yield: 68.2%) after dry.
MS(ESI):Calcd.for C3H5N5O2 143；Found 144[M+H]+.
Step 2: 4- Amino-N-hydroxy -1,2,5- oxadiazoles -3- carbonamidine chlorine (compound 5)
At 45 DEG C or so, compound 4 (143g, 1.0mol) is dissolved completely in acetic acid (1L), 6N hydrochloric acid (500mL) and water In the mixed solution of (2L).Sodium chloride (175.5g, 3mol) is added into clear mixed solution, system is cooled with an ice bath, 1 Water (200mL) solution of sodium nitrite (67.6g, 980mmol) is slowly added dropwise in hour.Reaction continues stirring 1.5 under ice bath Hour.Solid is precipitated, and is filtered with suction funnel, washs filter cake with water (300mL x 2), is dried in vacuo, obtains white solid Close object 5 (78.5g, yield: 48.4%).
MS(ESI):Calcd.for C3H3ClN4O2 162；Found 163[M+H]+.
Step 3: 4- amino-N '-hydroxy-n-(2- (methyl sulphonyl) ethyl) -1,2,5- oxadiazoles -3- carbonamidine (chemical combination Object 7)
Under ice cooling, 4, toward compound 5 (1g, 6.15mmol) and 2- (methylsulfonyl) ethylamine hydrochloride (6,0.98g, Triethylamine (1.56g, 15.37mmol) is added in ethyl acetate (20mL) solution 6.15mmol).It is small that reaction is stirred at room temperature 3 When.Reaction mixture is diluted with water (25mL), and ethyl acetate (40mL x 3) extraction, combined organic phase is with 1N hydrochloric acid (50mL) It respectively washed once with saturated salt solution (25mL), anhydrous sodium sulfate is dried, filtered and concentrated to obtain the crude product chemical combination of yellow oily Object 7 (1.2g) is not further purified to be directly used in and react in next step
MS(ESI):Calcd.for C6H11N5O4S 249；Found 250[M+H]+.
Step 4: N '-hydroxyl -4- ((2- (mesyl) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine (compound 8)
At room temperature, potassium hydroxide is added portionwise in water (20mL) solution of past compound 7 (1.2g, 4.8mmol) (0.84g, 15mmol).Reaction is heated to 100 DEG C and is stirred overnight.Reaction solution adds water (40mL) to dilute, with ethyl acetate (50mL X 4) it extracts, combined organic phase is dried, filtered and concentrated to obtain yellow oily crude Compound 8 with anhydrous sodium sulfate (0.4g) is not further purified to be directly used in and react in next step.
MS(ESI):Calcd.for C6H11N5O4S 249；Found 250[M+H]+.
Step 5: N- hydroxyl -4- ((2- (mesyl) ethyl) amino) -1,2,5- oxadiazoles -3- carbonamidine chlorine (compound 9)
Under ice cooling, 4, toward the acetic acid of compound 8 (0.5g, 2.0mmol) and sodium chloride (0.35g, 6.0mmol) Water (5mL) solution of sodium nitrite (140mg, 2.0mmol) is slowly added dropwise in the mixed solution of (8mL) and 6N hydrochloric acid (10mL). Reaction continues to stir 1 hour under ice bath.Water (40mL) dilution is added in reaction solution, and ethyl acetate (50mL x 4) extraction is organic It is mutually dry with anhydrous sodium sulfate, yellow oily crude Compound 9 (250mg) is obtained after concentration, and direct use is not further purified It is reacted in next step.
MS(ESI):Calcd.for C6H9ClN4O4S 268；Found 269[M+H]+.
Step 6: N- (the bromo- 4- fluorophenyl of 3-)-N '-hydroxyl -4- ((2- (mesyl) ethyl) amino) -1,2,5- is disliked Diazole -3- carbonamidine (compound 204)
Toward compound 9 (0.25g, 0.93mmol) water (10mL) solution in be added the bromo- 4- fluoroaniline of 3- (10,0.16g, 0.84mmol) and sodium bicarbonate (117mg, 1.40mmol).Mixed liquor is heated to 60 DEG C and stirs 1 hour.It is added in mixture 0.5N hydrochloric acid (20mL) quenching reaction is extracted with ethyl acetate (50mL x 4).Organic phase is dried, filtered simultaneously with anhydrous sodium sulfate Concentration.Residue purifies to obtain Red oil compound 204 (80mg, yield: 22.6%) with preparation TLC plate.
HNMR (400MHz, d6-DMSO): δ 11.50 (s, 1H), 8.91 (s, 1H), 7.22-7.15 (t, J=8.8Hz, 1H), 7.13-7.09 (dd, J=6.0Hz, J=2.8Hz, 1H), 6.80-6.73 (m, 1H), 6.53-6.46 (t, J=6.0Hz, 1H), 3.72-3.64 (q, J=2.4Hz, 2H), 3.48-3.43 (t, J=2.4Hz, 2H), 3.05 (s, 3H) .MS (ESI): Calcd.for C12H13BrFN5O4S 421；Found 422/424 [M+H]+.HPLC:98.1% (214nm)/98.1% (254nm).
Experimental example 1 indole amine 2,3-dioxygenase 1 (IDO-1) micromolecular inhibitor screening test
Compound gradient dilution
Step 1: untested compound is diluted to 1mM with 100% DMSO from storage concentration.
Step 2: being diluted to the 8th point again with 100%DMSO 3 using the compound of 1mM as first point.Then turn 1 In the compound that μ L has diluted to 96 orifice plates, the final concentration of DMSO is 1%, the ultimate density of compound be 10000nM, 3333.33nM、1111.1nM、370.4nM、123.5nM、41.2nM、13.7nM、4.6nM。
Laboratory operating procedures
1, configure the MES solution of 50mM pH6.5；
2, with the IDO enzyme solutions of the MES solution of 50mM pH6.5 configuration 6mL 16.84ng/ul, (final enzyme concentration is 8.42ng/ul), then 50ul enzyme solutions are added in 96 orifice plates for having turned to have compound, 1000rpm is centrifuged 1 minute, 25 DEG C incubator is incubated for 30 minutes；
3,2X substrate solution is configured, containing 40mM ascorbic acid, 300 μM of L-Trps, 4500
Units/mL catalase and 20 μM of methylene blues；
4,50ul 2X substrate solution is added to added with (final substrate in the reaction plate of 1ul untested compound and 50ul enzyme The concentration of each ingredient in solution are as follows: 20mM ascorbic acid, 150 μM of L-Trps, 2250units/mL catalase and 10 μM Methylene blue), 2000rpm is centrifuged 1 minute, is incubated for 40 minutes in 25 DEG C of incubators；
5, the configuration of reaction terminating liquid: weighing 1.8g trichloroacetic acid, with 6ml ddH2O melt into quality volume fraction is 30% Solution of trichloroacetic acid；
6, the solution of trichloroacetic acid of 50ul 30% is added to molten added with 1ul untested compound, 50ul enzyme and 50ul substrate In the reaction plate of liquid, it is incubated for 30 minutes in 60 DEG C of incubators, then 2000rpm is centrifuged 5 minutes；
7, from absorption 30ul supernatant in reaction plate into a 96 new hole flat undersides；
8, the configuration of 2% ehrlich reagent: it is molten to weigh 0.12g paradime thylaminobenzaldehyde, with 6ml glacial acetic acid melt into volume The ehrlich reagent that mass fraction is 2%；
9, the ehrlich reagent of 30ul 2% is added into 96 orifice plates of existing 30ul supernatant, 1000rpm is centrifuged 1 minute, It is placed at room temperature for after ten minutes with Spark 10M reading (492nm).
Experimental result
The test result of the IDO enzyme inhibition activity of each compound is as shown in table 1:
Compound number IC50(nM)
NLG919 (positive control) 83.77
Compound 201 43.2
Compound 201-P1 45.0
Compound 201-P2 37.4
Compound 202 50.3
NLG919 structure is as follows:
The pharmacokinetic of 2 compound 201 of experimental example
Compound configuration: compound 201 is configured to concentration with 0.5% methylated cellulose aqueous solution as the mixed of 0.5mg/mL Suspension carries out gastric infusion, is configured to concentration with 400/60% water of 10%DMSO/30%PEG and carries out for the solution of 0.5mg/mL Intravenously administrable.
Experimental design: healthy SD rat 6, male carries out jugular vein intubation, 200~250 grams of weight when experiment.Vein The free diet drinking-water of administration group；Fasting 12 hours before gastric infusion group is administered, free water, unified feed in 4 hours after administration.Tool Body arrangement see the table below:
Sample acquisition: each time point 3 big at the time point set above through jugular vein blood collection after the administration of SD rat Mouse, every animal collect about 0.25mL whole blood, and EDTA-K2 is anticoagulant, and 8000rpm is centrifuged 6min, separated plasma, in -80 DEG C of refrigerators Middle freezing.Using the concentration of compound in liquid chromatography tandem mass spectrometry measurement blood plasma.
Experimental result: according to gained plasma drug concentration data, using Phoenix1.3 software (Pharsight company, the U.S.) Non- compartment model calculates the pharmacokinetic parameter after administration.
Pharmacokinetic parameter after SD rat intravenous injection 1mg/kg and stomach-filling 5mg/kg compound 201:
Experiment conclusion: compound 201 has good pharmacokinetic property.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (10)

1. compound shown in formula A or its stereoisomer or optical isomer or its pharmaceutically acceptable salt:
Wherein:
W is CH2, NH, O, S, SO or SO2；
M is 1,2,3 or 4；
R1 is selected from the group: halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkane Oxygroup；T is 1,2,3 or 4；
M is SO2, S (=O) (=NH), PO2, P (=O) (=NH), C=O, S=O or P=O when, Y be NH or CH2；N be 1, 2,3,4 or 5；R2 is the substituent group on ring；
Or
M is SO2When, Y is nothing；N is 0；R2 is connect with the sulphur atom in M；With
R2 is hydrogen, halogen, C1-C6 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl；Its In, the C1-C6 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl optionally by one or Replaced multiple substituent groups selected from halogen, nitro, cyano, amido or hydroxyl.
2. compound as described in claim 1 or its stereoisomer or optical isomer or its pharmaceutically acceptable salt, It is characterized in that,
W is CH2, NH, O, S, SO or SO2；
M is 1,2,3 or 4；
R1 is selected from the group: halogen, cyano, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkane Oxygroup；T is 1,2,3 or 4；
M is SO2, S (=O) (=NH), PO2, P (=O) (=NH), C=O, S=O or P=O when, Y be NH or CH2；N be 1, 2,3,4 or 5；R2 is the substituent group on ring；
Or
M is SO2When, Y is nothing；N is 0；R2 is connect with the sulphur atom in M；With
R2 is hydrogen, C1-C6 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl；Wherein, described C1-C6 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl are optionally selected by one or more Replaced substituent group from halogen, nitro, cyano, amido or hydroxyl.
3. compound as claimed in claim 1 or 2 or its stereoisomer or optical isomer or its is pharmaceutically acceptable Salt, which is characterized in that the compound is as shown in formula B:
Each group definition is the same.
4. compound as claimed in claim 1 or 2 or its stereoisomer or optical isomer or its is pharmaceutically acceptable Salt, which is characterized in that the compound is shown in formula I:
Wherein:
W is NH or O；
M is 1 or 2；
When X is O；When Z is S；Y is NH；N is 2 or 3；R2 is the substituent group on ring；
Or
When X is O；When Z is S；Y is nothing；N is 0；R2 is connect with Z；
R2 is hydrogen, halogen or C1-C6 alkyl.
5. compound as claimed in claim 1 or 2 or its stereoisomer or optical isomer or its is pharmaceutically acceptable Salt, which is characterized in that the compound is selected from the group:
6. a kind of pharmaceutical composition, which is characterized in that include compound as described in claim 1 or its stereoisomer or light Learn isomers or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier.
7. compound as described in claim 1 or its stereoisomer or optical isomer or its pharmaceutically acceptable salt Or the purposes of pharmaceutical composition as claimed in claim 6, which is characterized in that
It is used to prepare IDO inhibitor；And/or
It is used to prepare the drug for preventing or treating IDO related disease.
8. purposes as claimed in claim 7, which is characterized in that the disease is selected from the group: cancer, Alzheimer disease, Virus infection, neurodegenerative disorders, wound, organ-graft refection, autoimmune disease, depression, anxiety disorder, cataract, Mental handicape and AIDS.
9. compound as described in claim 1 or its stereoisomer or optical isomer or its pharmaceutically acceptable salt Preparation method, which is characterized in that comprising steps of compound A1 and compound A2 are reacted in atent solvent, thus Form compound A；
Wherein, n, m, M, Y, R1, R2 and t are as defined above；
W ' is NH2When, G is CHO or NO2；Or W ' be OH or SH when, G NO2；Or W ' be CHO when, G NH2；
W is NH, O or S.
10. preparation method as claimed in claim 9, which is characterized in that when Y is NH, the method includes the steps:
(a) in atent solvent, compound A1 ' and compound A2 are reacted, to form compound A-13；
(b) in atent solvent, compound A-13 is subjected to deprotection reaction, to form compound A；
Wherein, Y ' is N- amino protecting group, and the amino protecting group is selected from the group: p-methoxyphenyl, benzyl, tertiary butyloxycarbonyl Base, acetyl group, benzyloxycarbonyl group, tablet held before the breast by officials methoxycarbonyl group (Fmoc)；Other each group definitions are the same.
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