CN110204537A - A kind of 1,2,5- oxadiazole derivatives of the inhibitor as indoleamine 2,3-dioxygenase - Google Patents

Abstract

The invention belongs to 1,2,5- oxadiazole derivatives technical fields, and in particular to a kind of 1,2, the 5- oxadiazole derivatives or its pharmaceutically acceptable salt of the inhibitor as indoleamine 2,3-dioxygenase.1 as IDO inhibitor, 2,5- oxadiazole derivatives or its pharmaceutically acceptable salt, structure is as shown in following formula I:

Description

A kind of 1,2,5- oxadiazoles of the inhibitor as indoleamine 2,3-dioxygenase spread out Biology

Technical field

The invention belongs to 1,2,5- oxadiazole derivatives technical fields, and in particular to one kind is used as indoleamine 2, and 3- is bis- to be added The 1 of the inhibitor of oxygenase, 2,5- oxadiazole derivatives.

Background technique

Tryptophan (Trp) is one kind required for biosynthesis albumen, niacin and neurotransmitter serotonin (thrombocytin) Essential amino acid.L- tryptophan degradation is N- formyl by enzyme indoleamine 2,3-dioxygenase (also known as INDO or IDO) catalysis Base-kynurenin first and rate-limiting step.In people's cell, Trp exhaustion is caused to be famous interferon by IDO activity (IFN-γ)-induction type antimicrobial effect mechanism.The activation of IFN-γ Induced by Stimulation IDO, causes Trp to exhaust, thus presses down System relies on intracellular pathogen such as mouse toxoplasma (Toxoplasma gondii) and the chlamydia trachomatis (Chlamydia of Trp Trachomatis growth).

Studies have shown that IDO also works during many, as it 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)；Immunosupress (Logan et al., 2002, Immunology, 105:478-87).Several evidences are also shown that IDO exists It is risen during mammal pregnancy, drug resistance of tumor (tumor resistance), chronic infection and autoimmune disease etc. Effect.

So effectively inhibiting IDO that can increase the level of the virus specific t cell in mouse HIV model, while reducing infection The number (Portula et al., 2005, Blood, 106:2382-90) of the macrophage of virus.

Currently, having small point that more exploitation treats or prevents the IDO of IDO related disease (such as those described above disease) Sub- inhibitor.For example, reporting oxadiazoles and other heterocycle IDO suppression in US 2006/0258719 and US 2007/0185165 Preparation.The compound with indoles amine -2,3- dioxygenase (IDO) inhibitory activity is reported in WO 2004/094409；And beauty State's patent application publication number 2004/0234623 is related to by the way that the inhibitor of indoles amine -2,3- dioxygenase and other is administered in combination The method that form of therapy comes treating cancer or infected patient.

For another example Incyte company crosses high flux screening and obtains a series of N- hydroxyamidines analog derivatives, and is laid out in China Corresponding patent application CN200980134351.9, which disclose the indoleamine 2,3-dioxygenase that is used as of structure shown in formula I The 1 of inhibitor, 2,5- dioxazoles.

But currently, the research and development of indoles amine -2,3- dioxygenase inhibitor be in early stage, it has been disclosed that IDO inhibit Agent cannot be considered in terms of various performances such as inhibitory activity, pharmacokinetics and safety also to meet the needs of clinical production.

Therefore, there is an urgent need to develop the IDO activity inhibitors of new construction out in the market.

Summary of the invention

Goal of the invention of the invention is to provide a kind of while having excellent IDO inhibitory activity and infiltrative as indoles Amine 2, the 1 of the inhibitor of 3- dioxygenase, 2,5- oxadiazole derivatives.

In order to achieve the above-mentioned object of the invention, one of technical solution of the invention provides the IDO that is used as of following formula I such as and presses down The 1 of preparation, 2,5- oxadiazole derivatives or its pharmaceutically acceptable salt,

Wherein, R1 and R2 does not take independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C10 alkyl, substitution or The C3-C10 naphthenic base in generation, substituted or unsubstituted C1-C10 halogenated alkyl, substituted or unsubstituted C1-C10 hydroxyalkyl take Generation or unsubstituted C1-C10 alkoxy；

R is-X-Z-A, and the X is selected from oxygen atom or methylene；

Z is selected from covalent bond or following bivalent group: substituted or unsubstituted C1-C4 alkylidene, imide, substitution or not Substituted C1-C4 alkylene oxide group or substituted or unsubstituted C1-C4 alkylene amino；

A is selected from the heteroaryl or Q- of the Heterocyclylalkyl of substituted or unsubstituted C3-C14, substituted or unsubstituted C3-C14 NH(SO₂)NH₂, wherein Q is selected from C2-C6 alkylidene；

And when Z is methylene, A is selected from Heterocyclylalkyl, the substituted or unsubstituted C3- of substituted or unsubstituted C3-C14 The heteroaryl of C14.

Preferably, R1 and R2 is independently selected from halogen, cyano, unsubstituted C5-7 naphthenic base or unsubstituted C1-4 alcoxyl Base；

X is methylene,

Z is selected from methylene, imide, methylene oxygroup or methylene amino；

A be selected from substituted or unsubstituted imidazole radicals, substituted or unsubstituted thienyl, substituted or unsubstituted pyrazolyl, Substituted or unsubstituted pyrazoles -4- base, substituted or unsubstituted pyridyl group, takes substituted or unsubstituted 1- methyl-pyrazol-4-yl Generation or unsubstituted pyriconyl or substituted or unsubstituted ring butyl- 3- alkene -1,2- diketo.

Preferably, described " substitution ", which refers to, has one or more substituent groups selected from the group below:

Halogen, hydroxyl, cyano, amido, C1-C4 alkyl ,-(SO₂)NH₂、-(SO₂)CH₃, C1-C4 alkylamino radical, phenyl, ammonia Oximido, five to hexa-member heterocycle, wherein hetero atom can be nitrogen, oxygen, sulphur.

It is further preferred that R1 is bromine, R2 is fluorine.

Preferably, 1 as IDO inhibitor provided by the invention, 2,5- oxadiazole derivatives or its is pharmaceutically acceptable Salt, the compound selected from such as flowering structure:

Preferably, 1 as IDO inhibitor of offer of the invention such as following formula Ⅹ, 2,5- oxadiazole derivatives or its medicine Acceptable salt on,

R1 and R2 is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 naphthenic base, substituted or unsubstituted C1-C10 halogenated alkyl, substituted or unsubstituted C1-C10 hydroxyalkyl replace Or unsubstituted C1-C10 alkoxy；

A is selected from the Heterocyclylalkyl of substituted or unsubstituted C5-C7, and wherein substituent group is-(SO₂)NH₂Or-(SO₂)CH₃。

It is further preferred that 1 as IDO inhibitor of the formula Ⅹ, 2,5- oxadiazole derivatives or its pharmaceutically may be used The salt of receiving, the compound selected from such as flowering structure:.

Preferably, 1 as IDO inhibitor of offer of the invention such as following formula Ⅺ, 2,5- oxadiazole derivatives or its medicine Acceptable salt on,

Ⅺ(CGT-9018)。

The compound of the present invention is intended to include all possible geometric isomer.Describe the cis- of the compounds of this invention and Trans- geometric isomer, they are separated into the mixture or individual isomeric forms of isomers.The knot indicated with wave Key in composition is intended to mean that, the cis and trans isomer of the representation cis or trans isomers or arbitrary proportion Mixture.

The compound of the present invention also includes tautomeric form.Tautomeric form is originated from pair of singly-bound and neighbouring double bond It changes, and associated proton migrates.

The compound of the present invention may also include all isotopes for appearing in the atom in intermediate or final compound.Together Position element includes having those of same atoms number but different quality number atom.For example, the isotope of hydrogen includes tritium and deuterium.

The invention also includes the salt of compound described herein." salt " used herein refers to the derivative of disclosed compound Object, wherein the acid or alkali by will be present are partially converted into its salt form to modify parent compound.The example of salt includes but not It is limited to: inorganic acid (such as HCl, HBr, H2SO4) or organic acid (such as acetic acid, benzoic acid, the trifluoro second of the bases such as amine Acid) salt；The alkali (Li, Na, K, Mg, Ca) of the acidic groups such as carboxylic acid or organic (trialkyl ammonium) salt etc..Pass through routine Chemical method can synthesize salt of the invention from the parent compound containing alkalinity or acidic moiety.In general, in water or organic In solvent or in two kinds of mixture, by make these compounds free acid or alkali form and stoichiometry it is appropriate Alkali or acid reaction, can prepare such salt；Generally, it is preferred to non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile (ACN)。

" pharmaceutically acceptable salt " of the invention includes the subset of above-mentioned " salt ", they be from for example nontoxic inorganic or The conventional non-toxic salts for the parent compound that organic acid is formed.The list of suitable salt is referring to Remington ' s Pharmaceutical Sciences, the 17th edition, Mack Publishing Company, Easton, Pa., 1985, the Page 1418 and Journal of Pharmaceutical Science, 66,2 (1977), each are whole simultaneously by reference Enter herein.Phrase " pharmaceutically acceptable " is used herein to mean that such compound, substance, composition and/or dosage form, It is contacted suitable for the tissue with humans and animals within a reasonable range of medical judgment, without excessive toxicity, stimulation, mistake Quick reaction or other problems or complication, match with reasonable interests/Hazard ratio.

Composition

Another technical solution of the invention provides a kind of pharmaceutical composition, contains one or more use as described above Make the 1 of IDO inhibitor, 2,5- oxadiazole derivatives or its pharmaceutically acceptable salt as active constituent, and at least one medicine Acceptable carrier combination on.

When preparing composition of the invention, usually active constituent is mixed with excipient, with figuration dilution agent, or loading Such as capsule, sachet, paper or other vessel forms carrier in.When excipient is used as diluent, it can be solid, half Solid or liquid substance, solvent, carrier or medium as active constituent.Therefore, composition can be following form: tablet, Pill, powder agent, pastille, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (solid or In liquid medium), containing being for example up to the ointment of 10% (calculating by weight) reactive compound, soft hard-gelatin capsules, bolt Agent, Sterile injectable solution and aseptic packaging powder agent.

When preparing preparation, reactive compound can be crushed to obtain appropriate particle size, then with other at subassembly.If Reactive compound is essentially insoluble, can be ground into the granularity less than 200 mesh.If reactive compound is substantially soluble in water, It can be by crushing adjustment granularity to obtain substantially uniform distribution in the formulation, for example, about 40 mesh.

Certain examples of suitable excipient include lactose, dextrose, sucrose, sorbierite, mannitol, starch, Arab Glue, calcium phosphate, alginates, bassora gum, gelatin, calcium silicates, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup And methylcellulose.Preparation may also include that lubricant, such as talcum powder, magnesium stearate and mineral oil；Wetting agent；Emulsifier and Suspending agent；Preservative, such as methyl benzoate and benzoic acid hydroxy propyl ester；Sweetener and corrigent.Using known in the art Method can prepare the present composition, release to provide the quick-release, sustained release or delay of active constituent after being administered to patient It puts.

About 5 to about 100mg, more typically from about 10 can be contained by unit dosage forms compositions formulated, every dose to about 30mg's Active constituent.Term " unit dosage forms " refers to physically separated unit, is suitable for as people experimenter and other lactations The unit dose of animal, each unit contain the predetermined amount for being computed the required curative effect of generation mixed with the drug excipient for being suitable for Active material.

The range of the effective dose of reactive compound can be very big, is usually administered by pharmacy effective dose.However, it will be understood that The amount for the compound actually applied usually determines by doctor according to correlation circumstance, and the situation includes illness to be treated, selection Administration route, the practical compound of application, the age of individual patients, weight and reaction, the severity of patient symptom etc..

For preparing solid composite such as tablet, main active is mixed with drug excipient, it is pre- to form solid Preparation compositions, the homogeneous mixture containing the compounds of this invention.When these pre-preparation compositions are referred to as uniform, activity at Divide and be generally evenly distributed in composition, causes the composition that can easily be further divided into equally effective unit dosage forms, such as Tablet, pill and capsule.Then the solid pre-formulation is further divided into the unit dosage forms of the above-mentioned type, contain such as 0.1 to About 500mg inventive compound.

It can be by tablet or coating of pill of the invention or compound in other ways, to be provided the agent of long-acting advantage Type.For example, tablet or pill may include interior dosage and external dose component, the latter is the former housing form.Two kinds of components can It is separated by enteric layer, the enteric layer is disintegrated under one's belt for preventing, so that interior component is completely passed through duodenum or delay is released It puts.Many kinds of substance can be used for such enteric layer or coating, and substance of this kind includes a variety of polymer acids and polymer acid and such as worm The mixture of the substances such as glue, cetanol and cellulose acetate.

The liquid form that can wherein mix the compounds of this invention and composition for oral or injection administration includes: water-soluble Liquid, the syrup of appropriate flavoring, aqueous or oil-based suspension and with edible oil (such as cottonseed oil, sesame oil, coconut oil or peanut Oil) flavoring emulsion and elixir and similar pharmaceutical media.

Composition for sucking or being blown into includes: pharmaceutically in or mixtures thereof acceptable aqueous or organic solvent Solution and suspension and powder agent.Liquid or solid composition pharmaceutically can may be used containing be suitable for as described above The excipient of receiving.In certain embodiments, the composition realizes part or complete by the administration of oral or nasal respiratory route Body effect.Composition can be made to be atomized using inert gas.Atomized soln directly can be sucked by atomising device or atomising device can It is connect with mask curtain or intermittent positive pressure breathing machine.From the device for delivering preparation in a suitable manner, ground or nasal administration can be taken orally Solution, suspension or powder composition.

The amount for being administered to the compound or composition of patient is different with following factors: the drug of application, administration purpose (example Such as prevent or treat), the state of patient, administration mode.It, can be to be enough to cure or at least partly inhibit in treatment use Composition is administered to the patient suffered from the disease by the amount of disease and its complication symptom.Effective dose depends on treated disease The judgement of diseased state and attending clinician, the judgement depend on such as age of the severity of disease, patient, weight and one As the factors such as situation.

The composition applied to patient can be aforementioned pharmaceutical compositions form.It can be by these by conventional sterilization techniques Composition sterilizing, or can be with filtration sterilization.Aqueous solution can be packed, for using as former state, or freeze-drying, it before administration will freeze-drying system Product are combined with sterile aqueous carrier.The pH of compound preparations is usually 3-11, more preferable 5-9, most preferably 7-8.It is appreciated that making It will lead to the formation of drug salts with certain aforementioned excipients, carrier or stabilizer.

The therapeutic dose of the compounds of this invention can be different with following factors: for example, the particular use for the treatment of, application chemical combination The judgement of the mode of object, the health of patient and state and the doctor that prescribes.Ratio of the compounds of this invention in pharmaceutical composition Example or concentration can be different with many factors: including dosage, chemical characteristic (such as hydrophobicity) and administration route.For example, for Parenteral administration can provide the compounds of this invention water-soluble in the physiological buffer containing the about 0.1- about 10%w/v compound In liquid.Certain exemplary dosage ranges are about 1 μ g/kg- about 1g/kg body weight/day.In certain embodiments, dosage range is about 0.01mg/kg- about 100mg/kg body weight/day.Dosage will likely depend on this class variable, the type of such as disease or illness and Development degree, the general health status of specific patient, the relative biological effectiveness of selected compound, excipient preparation and its Administration route.Dose-response curve can be with extrapolated effective dose derived from by external or animal model test system.

The compounds of this invention can also be prepared with one or more additional active ingredient combinations, and the active constituent can wrap Include any drug, such as antivirotic, vaccine, antibody, immunopotentiating agent, immunosuppressor, anti-inflammatory agent etc..

Purposes

Another technical solution of the invention provides a kind of 1,2,5- oxadiazoles for being used as IDO inhibitor as described above Derivative or its pharmaceutically acceptable salt or containing their purposes of any pharmaceutical composition in medicine preparation, it is described Drug is used to inhibit the immunosupress of patient.

It, can be effective invention additionally provides by giving patient to apply a effective amount of compound or composition as described herein Ground inhibits the immunosupress (such as immunosupress of IDO- mediation) of patient.It is known that the immunosupress that IDO- is mediated is under It is associated to state content: for example, cancer, tumour growth, transfer, virus infection, virus replication etc..

Invention additionally provides by the individual present invention for applying therapeutically effective amount or dosage for needing this treatment Compound or its pharmaceutical composition, treatment and IDO activity in individual (such as patient) or expression (including abnormal activity and/or mistake Expression) related disease method.Exemplary diseases may include directly or indirectly with IDO expression of enzymes or activity (such as be overexpressed or Abnormal activity) related any disease, obstruction and illness.The relevant disease of IDO- also include can by adjust enzymatic activity give it is pre- Any disease, obstruction and illness anti-, alleviate or cure.The example of the relevant disease of IDO- includes: cancer；Virus infection, example Such as HIV infection, HCV infection；Depression；Neurodegenerative disorders, such as Alzheimer's disease and Huntington disease；Wound；Age Relevant cataract；Organ transplant (such as organ-graft refection) and autoimmune disease, including asthma, rheumatoid joint Inflammation, multiple sclerosis, allergia inflammation, inflammatory bowel disease, psoriasis and systemic loupus erythematosus.It can be treated by context of methods Examples of cancer includes the cancer of colon, pancreas, mammary gland, prostate, lung, brain, ovary, uterine neck, testis, kidney, head and neck；Lymph cancer； Leukaemia；Melanoma etc..

Preferably, the drug is for cancer, virus infection, depression, neurodegenerative disorders, the wound for treating patient Wound, age-dependent cataract, organ-graft refection or autoimmune disease.

Preferably, the cancer is selected from colon cancer, cancer of pancreas, breast cancer, prostate cancer, lung cancer, the cancer of the brain, oophoroma, palace Neck cancer, carcinoma of testis, kidney, head and neck cancer, lymph cancer and leukaemia.

Preferably, the drug is used to treat the melanoma of patient.

Another technical solution of the invention provides a kind of 1,2,5- oxadiazoles for being used as IDO inhibitor as described above Derivative or its pharmaceutically acceptable salt in preparation treatment obesity and/or are lacked containing their any pharmaceutical compositions Purposes in mass formed by blood stasis drug.

Term " cell " used herein is intended to mean that external, in vitro or intracorporal cell.In certain embodiments, Isolated cells can be a part of the tissue sample cut off from organism (such as mammal).In certain embodiments, Cell in vitro can be the cell in cell culture.In certain embodiments, internal cell be live in organism (such as Mammal) in cell.

Term " contact " used herein, which refers to, to be put together in specified portions in vitro system or vivo system.Example Such as, making IDO enzyme includes that the compounds of this invention is administered to individual or patient's (example with IDO with the compounds of this invention " contact " Such as people), and, for example, the compounds of this invention is introduced into the sample of the cell or Purified preparations containing the enzyme containing IDO.

The term " individual " being used interchangeably herein or " patient " refer to any animal including mammal, It is preferred that mouse, rat, other rodents, rabbit, dog, cat, pig, ox, sheep, horse or primate, optimal to choose.

Phrase " therapeutically effective amount " used herein, which refers to, to cause to study people in tissue, system, animal, individual or people Member, animal doctor, doctor or other clinicians biology being look for or medical response reactive compound or drug amount.

Terms used herein " treatment " indicate: 1) preventing disease；For example, in easy infection disease, illness or obstacle but still It does not undergo or occurs to prevent disease, illness or obstacle in disease pathology or the individual of symptom；2) inhibit disease；For example, decent Go through or occur to inhibit in the pathology of disease, illness or obstacle or the individual of symptom disease, illness or obstacle (that is, prevent pathology and/ Or the further development of symptom)；Or 3) alleviate disease；For example, in pathology or the disease of just undergoing or occur disease, illness or obstacle Alleviate disease, illness or obstacle (i.e. reverse pathology and/or symptom) in the individual of shape.

It preferably, further include antivirotic, chemotherapeutics or other anticancer agents, immunopotentiating agent, immune suppression in the drug Preparation, radiation, antitumor and antiviral vaccine, cytokine therapy (such as IL2, GM-CSF etc.) and/or tyrosine kinase suppression Preparation.The medicament can be used to treat the relevant diseases of IDO-, obstruction and illness.These medicaments can be combined with the compounds of this invention In single dosage form or these medicaments can be used as separated dosage form and apply simultaneously or successively.

It is expected that with the compounds of this invention associated be suitable for antivirotic may include that nucleosides and nucleotide reverse transcriptase press down Preparation (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTD, protease inhibitors and other antiviral agents.

Suitable NRTI example includes: Zidovudine (AZT)；Didanosine (ddl)；Zalcitabine (ddC)；Stavudine (d4T)；Lamivudine (3TC)；Abacavir (1592U89)；Adefovir dipivoxil [two (POM)-PMEA]；Luo Buka Wei (BMS-180194)；BCH-10652；Emtricitabine [(-)-FTC]；(also known as β-L-D4C is named as β-L- to β-L-FD4 The fluoro- cytidene of 2 ', 3 '-dicleoxy-5-)；DAPD, ((-)-β-D-2,6 ,-diamino-purine dioxolane)；With Lip river moral Adenosine (FddA).Typically suitable NNRTI includes nevirapine (BI-RG-587)；Delavirdine (BHAP, U-90152)； Efavirenz (DMP-266)； PNU-142721；AG-1549；MKC-442 (1- (ethoxy-methyl) -5- (1- Methylethyl) - 6- (phenyl methyl)-(2,4 (1H, 3H)-hybar X)；(+)-calanolide A (calanolide A) (NSC-675451) and B.Typically suitable protease inhibitors includes inverase (Ro 31-8959)；Ritonavir (ABT-538)；Indinavir (MK-639)；Nai Feinawei (AG-1343)；Amprenavir (141W94)；Lasinavir (BMS- 234475)；DMP-450；BMS-2322623；ABT-378；With AG-1 549.Other antivirotics include hydroxycarbamide, Li Bawei Woods, IL-2, IL-12, pentafuside and Yissum item number 11607.

Suitable chemotherapeutics or other anticancer agents include, for example, alkylating agent (including but not limited to mustargen, aziridine spread out Biology, alkyl sulfonate esters, nitroso ureas and triazenes), such as uracil mustard, mustargen (chlormethine), cyclophosphamide (CytoxanTM), ifosfamide, melphalan, Chlorambucil, pipobroman, triethylene-melamine, phosphinothioylidynetrisaziridine, white disappear Peace, Carmustine, lomustine, streptozotocin, Dacarbazine and Temozolomide.

In the treatment of melanoma, being suitble to the medicament being applied in combination with the compounds of this invention includes: Dacarbazine (DTIC), optionally and other chemotherapeutics such as Carmustine (BCNU) and cis-platinum；By DTIC, BCNU, cis-platinum and tamoxifen " the Dartmouth scheme " of sweet smell composition；The combination of cis-platinum, vincaleukoblastinum and DTIC；Or Temozolomide.In the treatment of melanoma, Compound according to the present invention can also be combined with immunotherapy medicaments, the immunotherapy medicaments include cell factor such as Interferon-' alpha ', interleukin-22 and tumor necrosis factor (TNF).

In the treatment of melanoma, the compounds of this invention can also be applied in combination with vaccine therapy.Vaccines against melanoma exists Some aspects are similar to the antiviral epidemic disease for preventing the disease as caused by virus (such as polio, morbilli and parotitis) Seedling.The part (referred to as antigen) of the melanoma cells of decrease or melanoma cells can be injected into patient, to stimulate body Immune system, to destroy melanoma cells.

Use superthermal isolation limb perfusion technology (hyperthermic isolated limb perfusion Technique), the pharmaceutical agent combinations including one or more the compounds of this invention can also be used, treatment is limited on arm or leg Melanoma.Circulation in relation to limbs is temporarily isolating by the treatment method with body other parts, and the chemotherapeutics of high dose is infused In the artery for injecting supply limbs, so that high dose is supplied to tumor region, without internal is exposed to these dosage, Otherwise it may cause serious side effect.In general, fluid is warmed to 102 ° to 104 ℉.Melphalan is in chemotherapy operation Most common drug.It can be applied together with another medicament of referred to as tumor necrosis factor (TNF) (referring to about cell The part of the factor).

Suitable chemotherapeutics or other anticancer agents include, for example: antimetabolite (including but not limited to antifol, phonetic Pyridine analog, purine analogue and adenosine deaminase inhibitors), such as methotrexate (MTX), 5 FU 5 fluorouracil, floxuridine, arabinose born of the same parents Glycosides, Ismipur, 6- thioguanine, fludarabine phosphate, Pentostatin and gemcitabine.

Suitable chemotherapeutics or other anticancer agents further include, such as: certain natural products and its derivative (such as catharanthus roseus Alkaloid, antitumor antibiotics, enzyme, lymphokine and epipodophyllotoxin), for example, it is vincaleukoblastinum, vincristine, eldisine, rich Bleomycin, actinomycin D, daunorubicin, Doxorubicin, epirubicin, idarubicin, cytarabine, taxol (TAXOLTM), plicamycin, deoxycoformycin, Mitomycin-C, L-ASP, interferon (especially IFN-a), according to Support pool glycosides and Teniposide.

Other cytotoxic agents include Noviburn (navelbene), CPT-11, Anastrozole, Letrozole, capecitabine, Reloxafine, cyclophosphamide, ifosfamide and Droloxifene.

What is be also suitable is cytotoxic agent, such as: epipodophyllotoxin；Antitumor enzyme；Topoisomerase enzyme inhibitor；Third kappa Hydrazine；Mitoxantrone；Platinum coordination complex, such as cis-platinum and carboplatin；Biological respinse modifier；Growth inhibitor；Anti-hormonal therapy Agent；Folinic acid；Tegafur；And hemopoieticgrowth factor.

Other anticancer agents include Antybody therapy agent, for example, trastuzumab (Herceptin), costimulatory molecules (such as CTLA-4,4-1BB and PD-1) antibody or cell factor (IL-10, TGF-β etc.) antibody.

Other anticancer agents further include retardance those of immune cell migration, for example, chemokine receptors (including CCR2 and CCR4 antagonist).

Other anticancer agents further include those of enhancing immune system, such as adjuvant or the transfer of adoptive T cell.

Anti-cancer vaccine includes dendritic cells, synthetic peptide, DNA vaccination and recombinant virus.

The method for safely and effectively applying most of such chemotherapeutics, is known to the skilled in the art.In addition, Their application describes in normative document.For example, " Physicians ' Desk Reference " (PDR, for example, 1996edition, Medical Economics Company, Montvale, NJ) in, the application of a variety of chemotherapeutics is described, Disclosure of which is incorporated herein by reference, as completely illustrated it.

Term is explained

Unless stated to the contrary, otherwise following that there are following meanings with term in the specification and in the claims.

Term " alkyl " refers to the aliphatic hydrocarbon groups of saturation, straight chain and branched group including 1 to 20 carbon atom.It is preferred that Alkyl containing 1 to 10 carbon atom, the alkyl of further preferably 1 to 6 carbon atom, most preferably 1 to 4 carbon atom Alkyl, most preferably methyl.Non-limiting embodiment includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary fourth Base, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- first Base butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methylpent Base, 4- methyl amyl, 2,3- dimethylbutyl, n-heptyl, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methyl oneself Base, 2,3- dimethyl amyl group, 2,4- dimethyl amyl group, 2,2- dimethyl amyl group, 3,3- dimethyl amyl group, 2- ethylpentyl, 3- Ethylpentyl, n-octyl, 2,3- dimethylhexanyl, 2,4- dimethylhexanyl, 2,5- dimethylhexanyl, 2,2- dimethylhexanyl, 3,3- dimethylhexanyls, 4,4- dimethylhexanyl, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- methyl -2- ethyl Amyl, 2- methyl -3- ethylpentyl, n-nonyl, 2- methyl -2- ethylhexyl, 2- methyl -3- ethylhexyl, 2,2- diethyl Amyl, positive decyl, 3,3- diethylhexyl, 2,2- diethylhexyl and its various branched isomers etc..More preferably contain The low alkyl group of 1 to 6 carbon atom, non-limiting example include methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, Tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- dimethyl butyrate Base, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl Amyl, 4- methyl amyl, 2,3- dimethylbutyl etc..Alkyl can be substituted or unsubstituted, when substituted, substituent group It can be substituted on any workable tie point, the substituent group is preferably one or more following groups, is independently selected From alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, heterocycle Alkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, amino, alkyl halide Base, hydroxyalkyl, carboxyl or carboxylate.

Term " naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon Atom preferably includes 3 to 12 carbon atoms, and more preferable cycloalkyl ring includes 3 to 10 carbon atoms, and most preferably cycloalkyl ring includes 3 to 6 carbon atoms, most preferably cyclopropyl or cyclopenta.The non-limiting example of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, Cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc., preferably ring Propyl, cyclopenta.Polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring.Naphthenic base can be optionally replacing or not Replace, when substituted, substituent group is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkane Oxygroup, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, ring Alkoxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, amino, halogenated alkyl, hydroxyalkyl, carboxyl or carboxylic acid Ester group.

Term " Heterocyclylalkyl " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 Annular atom, wherein one or more annular atoms be selected from nitrogen, oxygen or S (O) m (wherein m be 0 to 2 integer) hetero atom, but not Loop section including-O-O- ,-O-S- or-S-S-, remaining annular atom are carbon.3 to 12 annular atoms are preferably included, wherein 1~4 A is hetero atom, and more preferable heterocycloalkyl ring includes 3 to 10 annular atoms, and more preferable heterocycloalkyl ring includes 5 to 6 ring originals Son.The non-limiting example of monocyclic heterocycloalkyl includes pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, height Piperazinyl, pyranose, tetrahydrofuran base etc..Polycyclic Heterocyclylalkyl includes the Heterocyclylalkyl of loop coil, condensed ring and bridged ring.Heterocyclylalkyl It can be optionally substituted or unsubstituted, when substituted, substituent group is preferably one or more following groups, is independently selected From alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, naphthenic base, heterocycle Alkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, amino, alkyl halide Base, hydroxyalkyl, carboxyl or carboxylate.

Term " aryl " refers to that 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle are (namely shared The ring of adjacent carbon atoms pair) group, preferably 6 to 10 yuan, more preferable phenyl and naphthalene, most preferably phenyl.The aryl rings can To condense on heteroaryl, Heterocyclylalkyl or cycloalkyl ring, wherein being aryl rings with the ring that precursor structure links together

Heteroaryl can be it is optionally substituted or unsubstituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyanogen Base, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, amino, Halogenated alkyl, hydroxyalkyl, carboxyl or carboxylate.

Term " alkoxy " refers to-O- (alkyl) and-O- (unsubstituted naphthenic base), wherein alkyl, naphthenic base definition such as It is upper described.Non-limiting example includes methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, penta oxygen of ring Base, cyclohexyloxy etc..Alkoxy can be optionally it is substituted or unsubstituted, when substituted, substituent group be preferably one or Multiple following groups, independently selected from for alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl Base, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkane Sulfenyl, amino, halogenated alkyl, hydroxyalkyl, carboxyl or carboxylate.

" halogenated alkyl " refers to that alkyl is replaced by one or more halogens, and wherein alkyl is as defined above." hydroxyl " refer to- OH group." hydroxyalkyl " refers to the alkyl being optionally substituted by a hydroxyl group, and wherein alkyl is as defined above." halogen " refer to fluorine, chlorine, bromine or Iodine, preferably fluorine or iodine.

" amino " refers to-NH2." cyano " refers to-CN." nitro " refers to-NO2." oxo base " refers to=O." carboxyl " refers to-C (O) OH. " carboxylate " refers to-C (O) O (alkyl) or (naphthenic base), and wherein alkyl, naphthenic base are as defined above.

" optional " or " optionally " mean ground described later event or environment can with but need not occur, which includes The occasion that the event or environment occur or do not occur.For example, meaning that alkyl can " optionally by alkyl-substituted Heterocyclylalkyl group " With but necessarily exist, the explanation include Heterocyclylalkyl group by alkyl-substituted situation and Heterocyclylalkyl group it is not alkyl-substituted Situation.

" substituted " refers to one or more hydrogen atoms in group, preferably at most 5, more preferably 1-3 hydrogen atom Replaced independently of one another by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, this Field technical staff, which can determine in the case where not paying excessive make great efforts and (pass through experiment or theoretical), may or impossible take Generation.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key Fixed.

Synthetic method

The compounds of this invention can be prepared by a variety of methods known to organic synthesis field technical staff.Use hereinafter institute In the method stated and synthetic organic chemistry field known synthetic method or those skilled in the art will appreciate related change Method can synthesize the compound of the present invention.

Using following universal method and regulation, the compounds of this invention can be prepared by facile raw material calmly.It should be appreciated that When providing typical or preferred process conditions (i.e. reaction temperature, time, the molar ratio of reactant, solvent, pressure etc.)；It removes It is non-to be otherwise noted, it is possible to use other process conditions.Optimum reaction condition can be different with specific reactant used or solvent, But those skilled in the art can determine such condition by classical algorithm.

Processes described herein can be monitored according to any suitable method known in the art.For example, passing through spectrophotometric Method such as NMR spectrum (such as 1H or 13C), infrared spectroscopy, spectrophotometry (such as UV-visible light) or Mass spectrography, or by chromatography such as high performance liquid chromatography (HPLC) or thin-layered chromatography, product can be monitored and formed.Pass through Any appropriate method known in the art can be purified by the compound that reaction obtains.For example, in suitable adsorbent Chromatography (middle pressure), HPLC or preparative thin layer chromatography, distillation, distillation, grinding on (for example, silica gel, aluminium oxide etc.) or again Crystallization.

The preparation of compound may include the protection and deprotection of different chemical groups.Those skilled in the art can be easily It determines to protection and de-protected needs, and the selection to suitable protecting group.Protecting group chemistry can be found in, for example, Wuts and Greene, Greene ' s Protective Groups in Organic Synthesis, the 4th edition, John Wiley& Sons:New York, 2006, it is incorporated herein by reference in their entirety.

The reaction of methods described herein can be carried out in a suitable solvent, and the technical staff of organic synthesis field can be easily Select the suitable solvent.In the temperature reacted, i.e., in the boiling point temperature range of the setting temperature from solvent to solvent Temperature, suitable solvent do not react substantially with raw material (reactant), intermediate or product.Can a kind of solvent or it is a kind of with It is specifically reacted in the mixture of upper solvent.According to reaction step, the solvent suitable for specific reaction step can choose. Suitable solvent includes water, alkane (or mixtures thereof pentane class, hexane class, heptane class, hexamethylene etc.), arsol (benzene,toluene,xylene etc.), alcohols (methanol, ethyl alcohol, isopropanol etc.), ethers (such as dialkyl ether, methyl- tert Butyl ether (MTBE), tetrahydrofuran (THF), esters (ethyl acetate, butyl acetate etc.), halogenation solvent (such as dichloro Methane (DCM), chloroform, dichloroethanes, tetrachloroethanes), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, second Nitrile (ACN), hexamethyl phosphoramide (HMPA) and N-Methyl pyrrolidone (NMP).Such solvent can with the aqueous of them or Anhydrous form uses.

By any one of a variety of methods known in the art, the racemic mixture of compound can be split.One Instance method includes fractional recrystallization, wherein using " chiral resolution acid ", which is the organic acid of the forming salt of optically-active.It is suitable for The resolving agent of fractional recrystallization method is, such as: optically-active acid, such as D and L-type tartaric acid, diacetyl tartaric acid, dibenzoyl wine Stone acid, mandelic acid, malic acid, lactic acid or the camphorsulfonic acid of different optically-actives.By in the resolving agent (such as two for being filled with optically-active Nitro benzoyl phenylglycine) column on elute, also removable racemic mixture.Those skilled in the art can determine suitable Suitable eluting solvent composition.

For example, preparing the following institute of general synthetic route of the compound of the present invention Formulas I using following reaction paths and technology Show:

Wherein, compound I-A is a kind of known structure, its synthesis reported in the literature (WO2014066834, CN106565696).I-A and I-B reaction generates I-C, generates corresponding amidoxime compound I-D under alkaline condition；Compound I-B Sometimes there is blocking group, in this case, finally need to slough protecting group and generate I-D.

Amino protecting group carries out desired turn often in organic synthesis for preventing undesirable amino reaction Change.Amino protecting group allows easily to be covalently attached on nitrogen-atoms, and selectively cracks from nitrogen-atoms.Art technology Different amino protecting group known to personnel is broadly classified as alkoxy carbonyl (such as ethoxy carbonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9- fluorenylmethoxycarbonyl groups (Fmoc) etc.), acyl group (such as acetyl group (Ac), benzoyl (Bz)), the sulfonyl (mesyl, trifyl etc.), aralkyl (such as benzyl, diphenyl methyl, triphen such as Ylmethyl (trityl) etc.), alkenyl alkyl (allyl, prenyl etc.), Diarylmethylidene (diarylmethyleneyl) ((C6H5) 2C=N etc.) and silicyl (such as t-butyldimethylsilyl, three Isopropyl silyl etc.).The chemistry of amino protecting group may refer to: Wuts and Greene, Greene ' s Protective Groups in Organic Synthesis, the 4th edition, the 696-926 pages, John Wiley&Sons:New York, 2006.

Compared with prior art, the beneficial effects of the present invention are:

A kind of general formula compound I of structure novel is provided；

The experimental results showed that in embodiment provided by the invention part of compounds simultaneously have excellent IDO inhibitory activity and Permeance property.Embodiment compound provided by the invention is expected to be used for the treatment of cancer as tumor cells immunotherapy medicaments.

Specific embodiment

The present invention is done below by specific embodiment and is further described in more detail.It provides for the purpose of illustration following real Example is applied, they should not in any way limit the present invention.Skilled in the art will readily recognize that can be changed or modify a variety of Nonessential parameter is to obtain substantially the same result.According to one or more measurements provided herein, embodiment is found Closing object is IDO inhibitor.

Embodiment 1 synthesizes CGT-9009

Step 1 synthesizes MC-105-2

At room temperature by LiAlH₄Compound MC-105-1 is added portionwise in (1.2g, 31.6mmol, 1.58eq) In THF (20mL) solution of (2.84g, 20mmol, 1.0eq).Reaction is stirred at room temperature 20 minutes.With the ammonium chloride of saturation (2mL) solution quenching reaction simultaneously stirs 10 minutes.Obtained mixture filtering, filtrate are concentrated to get brown oil crude product chemical combination Object MC-105-2 (2.5g, 97%yield).

Step 2 synthesizes MC-105-3

MsCl (2mL) is slowly added drop-wise to compound MC-105-2 (2.5g, 19.5mmol, 1.0 eq) and three at room temperature In methylene chloride (25mL) solution of ethamine (2.5mL).Reaction uses the bicarbonate being saturated after reacting half an hour at room temperature Sodium (30mL) solution is quenched.The reaction being quenched is washed after being stirred at room temperature 1 hour with saturated sodium-chloride (50mL X 2).It is organic Mutually it is dry be concentrated to the thick intermediate of thick brown oil intermediate (3.5g, 87%yield) (1.04g, 5.0mmol, It 1.0eq) is directly dissolved with DMSO (10mL), sodium azide (1g) then is added.Reaction mixture stirs anti-under the conditions of 80 degree It answers 1 hour.Then reaction solution is cooled to room temperature and ethyl acetate (50mL) is used to dilute.The saturation chlorination of obtained white mixture Sodium solution (50 mL X 3) washing.The dry concentration of organic phase.Residue is pure by chromatographed on silica gel (EtOAc/PE=1/20) Change obtains brown oil compound MC-105-3 (320mg, 42%yield).

Step 3 synthesizes MC-105-4

Compound MC-105-3 (320mg, 2.0mmol) and Pd/C (50mL) are mixed into MeOH (10mL) at room temperature.So Reaction solution reacts 16 hours under the conditions of atmosphere of hydrogen afterwards.Reaction solution filters after reaction, and filtrate is concentrated to get brown oil Compound MC-105-4 (260mg, 100%yield).

Step 4 synthesizes MC-105-5

Compound MC-105-4 (254mg, 2.0mmol, 1.86eq) and compound MC-101-007 (400mg, 1.07mmol, 1.0eq) THF (5mL) solution react fully reacting after ten minutes under the conditions of 35 degree.Reaction solution is directly concentrated. Residue by chromatographed on silica gel (EtOAc/PE=1/3) purifying obtain brown oil compound MC-105-5 (450mg, 93%yield).

Step 5 synthesizes CGT-9009

At room temperature by sodium hydroxide (56mg, 1.44mmol, 8.0eq) be added to compound MC-105-5 (80mg, 0.18mmol, 1.0eq) tetrahydrofuran (3mL) and water (1mL) solution in.Reaction is reacted 1 hour at room temperature.Reaction terminates Reaction solution is diluted with 25mL water afterwards, and obtained mixture is extracted with ethyl acetate (25mL X 3).It is residual after the dry concentration of organic phase Object is stayed to obtain compound as white solid CGT-9009 (20mg, 27%yield) by efficiently preparing chromatographic separation and purification

¹H NMR (400MHz, DMSO-d6) δ 11.45 (s, 1H), 8.89 (s, 1H), 7.36-7.34 (d, J=4.8Hz, 1H), 7.19 (t, J=8.8Hz, 1H), 7.10 (d, J=6.4Hz, 1H), 6.98-6.96 (m, 1H), 6.91 (s, 1H), 6.76 (t, J=4.4Hz, 1H), 6.34-6.31 (m, 1H), 3.50-3.45 (m, 2H), 3.10 (d, J=6.8 Hz, 2H)

¹⁹F NMR(376.5MHz,DMSO-d6)δ-117.798

HPLC:@254nm:99.61% ,@214nm:99.76%.

LCMS:M+1=428.0

Embodiment 2: synthesis CGT-9016

Step 1 synthesizes MC-113-1

Under the conditions of 0 degree by the tert-butyl alcohol (451mg, 6.09mmol, 10.50eq) be added to chlorosulfonic acid isocyanate (818mg, 5.8mmol, 10.0eq) methylene chloride (5mL) solution in and with this condition react 1 hour.Then this solution is added to It is cooled to 0 degree of compound MC-149-3 (250mg, 0.58mmol, 1.0eq) and the methylene chloride of triethylamine (2mL) in advance In (10mL) solution.Saturated sodium bicarbonate (20mL) quenching reaction after reaction mixture reacts 2 hours under the conditions of 0 degree.It obtains Mixture with methylene chloride (20mL) extract.Organic phase is dry be concentrated to get yellow solid compound MC-113-1 (500mg, It is overweight).

Step 2 synthesizes CGT-9016

The TFA (2mL) and methylene chloride (5mL) solution of compound MC-113-1 (500mg, 0.58mmol, 1.0eq) exists Intermediate is concentrated to get after reacting 1 hour under the conditions of 25 degree.The hydrogen-oxygen of 2N is added in the intermediate after being dissolved with tetrahydrofuran (5mL) Change sodium solution (2mL).Reaction mixture reacts 1 hour at room temperature.It is diluted with water to reaction mixture after reaction. Obtained mixture is extracted with ethyl acetate (20 mLX2).The dry concentration of organic phase.Residue is by efficiently preparing chromatographic isolation Purifying obtains compound as white solid CGT-9016 (8mg, 2%).

LCMS:M+1=484.0

¹H NMR(400MHz,DMSO-d6)δ8.48(s,0.45H),7.13-7.11(m,1H),7.06-7.02 (m, 1H),6.86-6.82(m,1H),3.71-3.62(m,6H),3.48-3.46(m,2H),3.28-3.19(m,2H).

¹⁹F NMR(376.5MHz,DMSO-d6)δ-117.84.

Embodiment 3 synthesizes CGT-9019

Step 1 synthesizes MC-154-3

Compound MC-154-1 (372mg, 1mmol, 1.0eq) is dissolved in THF (4mL) at room temperature.Then add in the solution Enter cesium carbonate (656mg, 2mmol, 2.0eq), MC-154-2 (217mg, 1mmol, 1.0 eq) and water (2mL).Reaction mixture It is reacted 0.5 hour under the conditions of 20 degree.Then reaction solution is diluted with water (10mL).Obtained mixture ethyl acetate (20mL X 2) extraction.The dry concentration of organic phase.Residue is purified by chromatographed on silica gel (ethyl acetate/petroleum ether=1/5~1/3) Obtain light tan solid compound MC-154-3 (300mg, 55%).

Step 2 synthesizes MC-154-4

Methylene chloride (5mL) solution of compound MC-154-3 (300mg, 0.55mmol, 1.0eq) and TFA (2mL) exists It is reacted 1 hour under the conditions of 30 degree.Then reaction solution is concentrated to get light brown oily compound MC-154-4 (310mg).

Step 3 synthesizes MC-154-5

Under the conditions of 0 degree by the tert-butyl alcohol (428mg, 5.78mmol, 10.50eq) be added to chlorosulfonic acid isocyanate (776mg, 5.5mmol, 10.0eq) methylene chloride (5mL) solution in and with this condition react 1 hour.Then this solution is added to It is cooled to 0 degree of compound MC-154-4 (310mg, 0.55mmol, 1.0eq) and the methylene chloride of triethylamine (1mL) in advance In (5mL) solution.Saturated sodium bicarbonate (20mL) quenching reaction after reaction mixture reacts 2 hours under the conditions of 0 degree.It obtains Mixture is extracted with methylene chloride (20 mL).Organic phase is dry be concentrated to get yellow solid compound MC-154-5 (350mg, 79%).

Step 4 synthesizes CGT-9019

The TFA (2mL) and methylene chloride (5mL) solution of compound MC-154-5 (250mg, 0.48mmol, 1.0eq) exists Intermediate is concentrated to get after reacting 1 hour under the conditions of 25 degree.The hydrogen-oxygen of 2N is added in the intermediate after being dissolved with tetrahydrofuran (5mL) Change sodium solution (2mL).Reaction mixture reacts 1 hour at room temperature.It is diluted with water to reaction mixture after reaction. Obtained mixture is extracted with ethyl acetate (20 mLX2).The dry concentration of organic phase.Residue is by efficiently preparing chromatographic isolation Purifying obtains compound as white solid CGT-9019 (2.9mg, 2%).

LCMS:M+1=497.0

¹H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.86(s,1H),8.17-8.14(m,1H), 7.20- 7.11(m,2H),6.83-6.81(m,1H),6.58-6.46(m,4H),3.88-3.86(m,2H),3.27-3.22 (m,2H), 2.97-2.93(m,2H).

¹⁹F NMR(376.5MHz,DMSO-d6)δ-118.03.

Embodiment 4 synthesizes CGT-9020

Step 1 synthesizes MC-159-3

0 DEG C by sodium hydrogen (123mg, 3.08mmol, 1.05eq) be added to compound MC-159-1 (210mg, 3.08mmol, In tetrahydrofuran (3mL) solution 1.05eq).Chemical combination is added at 0 DEG C after reaction being stirred at room temperature 0.5 hour in the mixture Tetrahydrofuran (1mL) solution of object MC-159-2 (702mg, 2.94mmol, 1.0eq).Rear reaction solution is added to be stirred at room temperature Then water (20mL) quenching reaction is used in reaction 16 hours.Compound is extracted with ethyl acetate (20mL X 3), organic phase water The washing of (20mL X 2) and saturated sodium-chloride water solution (20 mL), then dry filter, filtrate decompression concentration obtain brown oil Shape target product MC-159-3 (550 mg).

Step 2 synthesizes MC-159-4

Trifluoroacetic acid (6mL) is added to the 1,2- dichloroethanes (20mL) of compound MC-159-3 (550mg) at room temperature In solution, reaction 2 hours is stirred at room temperature in reaction solution, is then concentrated under reduced pressure, is obtained brown oil target product MC-159-4 (720mg)。

Step 3 synthesizes MC-159-5

At room temperature by cesium carbonate (3.0g, 9.21mmol, 6.5eq) be added to compound MC-159-4 (720mg, 3.08mmol, 2.2eq) and compound MC-101-007 (530mg, 1.42mmol, 1.0eq) water (2mL) and tetrahydrofuran In the mixed solution of (20mL), reaction 16 hours is stirred at room temperature in reaction.Water (30mL) quenching reaction is used after fully reacting, Compound is extracted with ethyl acetate (30mL X 2), and organic phase is washed with water (20mL) and saturated sodium-chloride water solution (20mL), Then dry filter, filtrate decompression concentration.Residue is pure with silica gel column chromatography method (eluent gradient: EA/PE=1/2) Change, obtains yellow solid target compound MC-159-005 (230mg, 37%yield).

Step 4 synthesizes CGT-9020

Potassium carbonate (218mg) is added to the first of compound MC-159-5 (230mg, 0.526mmol, 1.0eq) at room temperature In alcohol (2.5mL) solution, reaction solution is heated to 40 DEG C and reacts 2 hours.Reaction solution is concentrated under reduced pressure after fully reacting, then uses second Acetoacetic ester (10mL) dilutes agitation and filtration, filtrate decompression concentration.Residue with silica gel column chromatography method (eluent gradient: MeOH/DCM=1/100 it) purifies, obtains yellow solid target compound CGT-9020 (150mg, 70%yield).

LCMS:M+1=412.0

1H NMR (400MHz, CDCl3) δ 10.45 (br, 1H), 7.51 (br, 1H), 7.36 (d, J=2.0Hz, 1H), 7.19 (dd, J=5.6Hz, 2.4Hz, 1H), 7.03 (t, J=8.4Hz, 1H), 6.93-6.89 (m, 2H), 6.30 (s, 1H), 5.96 (t, J=6.0Hz, 1H), 4.41 (t, J=5.6Hz, 2H), 3.78 (dd, J=11.2Hz, 6.0Hz, 2H)

Embodiment 5 synthesizes CGT-9021

Step 1 synthesizes MC-164A-1

Compound SM1 (1.0g, 10.52mmol, 1.0eq.) is dissolved in DMF (50mL), it is small to be cooled to 0 degree of reaction half When, DMF (10mL) solution of 0 degree of dropwise addition SM2 (2.8g, 11.5mmol, 1.1eq.).Reaction 16 hours is stirred at room temperature in mixture. LCMS detection reaction, after reaction, reaction solution is diluted with water, and is extracted with ethyl acetate, and is obtained after the dry concentration of organic phase Residue obtains compound as white solid by chromatographed on silica gel (ethyl acetate/petroleum ether=1/4- pure ethyl acetate) purifying MC-164A-1 (1.4g, 55%) and compound MC164B-1 (400mg, 15%).

Step 2 synthesizes MC-164A-2

At room temperature, in the methylene chloride (5mL) of compound MC-164A-2 (500mg, 2.10mmol, 1.0eq.) 2mL trifluoroacetic acid is added in solution.Reaction solution reacts 2 hours at room temperature.Reaction solution is directly concentrated to get shallowly after reaction Yellow oily crude product compound MC-164A-2 (260mg, trifluoroacetate).

Step 3 synthesizes MC-164A-3

By compound MC-101-007 (260mg, 0.70mmol, 1.0eq.), MC-164A-2 (260mg, 1.88 mmol, 2.7eq.) it is dissolved in tetrahydrofuran (20mL) with triethylamine (425mg, 4.20,6.0eq.).After 40 degree are reacted 4 hours, LCMS detection reaction, after having reacted, the residue that reaction solution is concentrated to get passes through chromatographed on silica gel (ethyl acetate/petroleum ether =1/1) purifying obtains faint yellow solid compound MC-164A-3 (200mg, 61%).

Step 4 synthesizes CGT-9021

Compound MC-164A-3 (200mg, 0.43mmol, 1.0eq) is dissolved in tetrahydrofuran at room temperature 5mL sodium hydroxide (1N) solution is added in (10mL).Room temperature reaction 1 hour.It is diluted with water, obtains to reaction solution after reaction Mixture be extracted with ethyl acetate.Organic phase is dry to be concentrated to get pale yellowish oil, and residue is by efficiently preparing chromatography point Light yellow solid Compound CGT-9021 (72 mg, 38% yield) is obtained from purifying.

¹H NMR (400MHz, DMSO-d6): δ 11.41 (s, 1H), 8.87 (s, 1H), 7.51-7.49 (dd, J= 1.6Hz, 1H), 7.41-7.37 (m, 1H), 7.20-7.16 (t, J=8.8Hz, 1H), 7.11-7.10 (dd, J=2.8 Hz, 1H),6.76-6.67(m,1H),6.39-6.35(m,2H),6.18-6.15(m,1H),4.11-4.08(m,2H), 3.55- 3.52(m,2H).

¹⁹F NMR(376.5MHz,DMSO-d6)δ-117.82,-118.39

HPLC:@254nm:99.89% ,@214nm:99.75%.

LCMS:M+1=439.2

Embodiment 6 synthesizes CGT-9022

Step 1 synthesizes MC-164B-2

At room temperature, in the methylene chloride (5mL) of compound MC-164B-1 (400mg, 1.68mmol, 1.0eq.) 2mL trifluoroacetic acid is added in solution.Reaction solution reacts 2 hours at room temperature.Reaction solution is directly concentrated to get shallowly after reaction Yellow oily crude product compound MC-164B-2 (200mg, trifluoroacetate).

Step 2 synthesizes MC-164B-3

By compound MC-101-007 (200mg, 0.54mmol, 1.0eq.), MC-164A-2 (200mg, 1.45 mmol, 2.7eq.) it is dissolved in tetrahydrofuran (20mL) with triethylamine (328mg, 3.24,6.0eq.).After 40 degree are reacted 4 hours, LCMS detection reaction, after having reacted, the residue that reaction solution is concentrated to get passes through chromatographed on silica gel (ethyl acetate/petroleum ether =1/5) purifying obtains faint yellow solid compound MC-164B-3 (200mg, 80%).

Step 3 synthesizes CGT-9022

Compound MC-164B-3 (200mg, 0.43mmol, 1.0eq) is dissolved in tetrahydrofuran at room temperature 5mL sodium hydroxide (1N) solution is added in (10mL).Room temperature reaction 1 hour.It is diluted with water, obtains to reaction solution after reaction Mixture be extracted with ethyl acetate.Organic phase is dry to be concentrated to get pale yellowish oil, and residue is by efficiently preparing chromatography point Light yellow solid Compound CGT-9022 (35 mg, 18% yield) is obtained from purifying.

¹H NMR (400MHz, DMSO-d6): δ 11.48 (s, 1H), 8.87 (s, 1H), 8.17-8.16 (d, J=3.2Hz, 1H), 7.77-7.70 (m, 1H), 7.18-7.09 (m, 2H), 7.00-6.97 (t, J=6Hz, 1H), 6.84-6.75 (m, 2H), 6.40-6.37 (t, t=6Hz, 2H), 4.46-4.43 (m, 2H), 3.63-3.59 (m, 2H)

¹⁹F NMR(376.5MHz,DMSO-d6)δ-117.80,-118.35

HPLC:@254nm:99.60% ,@214nm:99.86%.

LCMS:M+1=437.1

Embodiment 7 synthesizes CGT-9023

Step 1 synthesizes MC-160-3

Compound MC-160-2 (2.6g, 14.98mmol, 1.0eq) is dissolved in N,N-dimethylformamide at room temperature In (20mL) and diisopropyl ethyl amine (5.8g, 44.91mmol, 3.0eq) mixture is added it is stirred to react 3 minutes backward systems Middle addition HATU (6.8g, 17.96mmol, 1.2eq) and compound MC-160-1 (2.0g, 14.96mmol, 1.0eq).Reaction Liquid is diluted after reacting at room temperature 2 hours with ethyl acetate (200mL), then uses saturated sodium-chloride water solution (200mL X 6) Washing, dry concentration, residue are purified with silica gel column chromatography method (eluent gradient: MeOH/DCM=1/100), obtain purple Color solid target compound MC-160-3 (1.3g, 34% yield)

Step 2 synthesizes MC-160-4

Trifluoroacetic acid (2.5mL) is added to the methylene chloride (2.5 mL) of compound MC-160-3 (250mg) at room temperature It is stirred 2 hours in solution.Reaction solution is concentrated under reduced pressure after fully reacting, obtains brown oil target compound MC-160-4 (280mg)。

Step 3 synthesizes MC-160-5

At room temperature through cesium carbonate (962mg, 2.952mmol, 3.0eq) be added to compound MC-160-4 (280mg, 0.984mmol, 1.0eq) and compound MC-101-007 (366mg, 0.984mmol, 1.0eq) water (1mL) and tetrahydrofuran In the mixed solution of (3mL) and it is stirred to react 16 hours.Reaction is quenched with water (15mL) and is extracted with ethyl acetate (15mL X 2) It takes, organic phase is washed with water (15mL) and saturated sodium-chloride water solution (15mL), then dry filter, filtrate decompression concentration., residual Excess is purified with silica gel column chromatography method (eluent gradient: EA/PE=1/2), obtains yellow solid target compound MC- 160-005 (145mg, 31%yield).

Step 4 synthesizes CGT-9023

Potassium carbonate (150mg) is added to the methanol of compound MC-160-5 (145mg, 0.30mmol, 1.0eq) at room temperature In (2mL) solution, it is then heated to 40 DEG C and reacts 2 hours.Reaction solution is concentrated under reduced pressure after fully reacting, residue acetic acid second Ester EA (10mL) washing.Filtrate decompression concentration, residue silica gel column chromatography method (eluent gradient: MeOH/DCM=1/ 100) it purifies, obtains yellow solid target compound CGT-9023 (25mg, 18%yield).

LCMS:M-1=453.1

1H NMR(400MHz,CDCl3)δ11.64(s,1H),10.20(brs,1H),8.90(s,1H),7.86 (s, 1H), 7.46 (s, 1H), 7.20 (t, J=8.8Hz, 1H), 7.14 (dd, J=6.0Hz, 2.8Hz, 1H), 6.85-6.81 (m, 1H), 6.55 (t, J=5.6Hz, 1H), 4.04 (d, J=5.2Hz, 2H), 3.79 (s, 3H)

Embodiment 8 synthesizes CGT-9024

Step 1 synthesizes MC-160-6

At room temperature by borine-tetrahydrofuran (1N, 2.5mL) solution be added to compound MC-160-3 (250mg, 0.984mmol, 1.0eq) tetrahydrofuran (5mL) solution in stir 3 hours.Add at 0 DEG C into reaction solution after fully reacting Enter concentrated hydrochloric acid (36%, 5mL) and is stirred to react 1 hour.Reaction solution is concentrated under reduced pressure after fully reacting, obtains brown solid target Compound MC-160-6 (250mg).

Step 2 synthesizes MC-160-7

At room temperature by cesium carbonate (960mg, 2.952mmol, 3.0eq) be added to compound MC-160-6 (250 mg, 0.984mmol, 1.0eq) and compound MC-101-007 (366mg, 0.984mmol, 1.0eq) water (1 mL) and tetrahydrofuran In the mixed solution of (5mL), reaction 16 hours is stirred at room temperature in reaction.Water (15mL) quenching reaction is used after fully reacting, is changed It closes object to be extracted with ethyl acetate (15mL X 2), organic phase is washed with water (10mL) and saturated sodium-chloride water solution (10mL), so Dry filter afterwards, filtrate decompression concentration.Residue is purified with silica gel column chromatography method (eluent gradient: EA/PE=1/2), Obtain yellow solid target compound MC-160-7 (120mg, 26%yield).

Step 3 synthesizes CGT-9024

Potassium carbonate (120mg) is added to the first of compound MC-160-7 (120mg, 0.258mmol, 1.0eq) at room temperature In alcohol (2mL) solution, reaction solution is heated to 40 DEG C and reacts 2 hours.Reaction solution is concentrated under reduced pressure after fully reacting, then uses acetic acid Ethyl ester (10mL) dilutes agitation and filtration, filtrate decompression concentration.Residue silica gel column chromatography method (eluent gradient: MeOH/ DCM=1/100 it) purifies, obtains yellow solid target compound CGT-9024 (25mg, 22%yield).

LCMS:M+1=441.2

¹H NMR(400MHz,CDCl3)δ11.52(s,1H),8.91(s,1H),7.59(br,1H),7.33(br, 1H), 7.11 (dd, J=6.0Hz, 2.4Hz, 1H), 6.80-6.75 (m, 1H), 6.33 (t, J=5.6Hz, 1H), 3.78 (s, 3H), 3.49-3.44(m,2H),3.26(br,2H).

Embodiment 9 synthesizes CGT-9026

Step 1 synthesizes MC-157-2

SM (0.9g, 8.03mmol, 1.0eq) is added in SOCl2 (3.82g, 32.11mmol), stirs 30 at 70 DEG C Minute reaction solution concentration is spin-dried for obtaining MC18-157-2 (1.0g, yield95%).

Step 2 synthesizes MC-157-4

By MC-157-2 (1.0g, 7.66mmol, 1.0eq), MC-157-3 (1.56g, 8.42mmol, 1.1eq) and carbonic acid Hydrogen sodium (1.4g, 16.67mmol) is added in DMF (30mL), is stirred overnight under 100 degrees Celsius.Reaction solution 300mL acetic acid second Ester dilution, 100mL saturated common salt water washing, anhydrous sodium sulfate are dried to obtain solid, and solid passes through column purification (petroleum ether: acetic acid Ethyl ester=1:0 to 10:1) obtain yellow solid MC-157-4 (1.1g, 4.56mmol, yield 59%).

Step 3 synthesizes MC-157-5

MC-157-4 (300mg, 1.24mmol, 1.0eq) is added in HCl (6N, 30mL), is stirred overnight at 110 DEG C. Reaction solution is spin-dried for obtaining white solid MC-157-5 (300mg, crude product, 11.24mmol).

Step 4 synthesizes MC-157-7

By MC-157-5 (300mg, 1.24mmol, crude product), MC-157-6 (200mg, 0.54mmol) and Cs2CO3 (703mg, 2.15mmol), which is added in THF (30mL) under room temperature, is stirred overnight the filtering of reaction solution, and filtrate crosses column (petroleum after being spin-dried for Ether: ethyl acetate=20:1 to 1:1) purifying obtain white solid MC-157-7 (100 mg, 0.229mmol, yield42%).

Step 5 synthesizes CGT-9026

MC-157-7 (100mg, 0.229mmol, 1.0eq) is added in NaOH (1N1mL) stirring at normal temperature one hour.Reaction Liquid is extracted with ethyl acetate (20mL*2), and organic phase drying is prepared plate purifying (EA) after being spin-dried for and obtains white solid CGT- 9026 (77.6mg, 0.189mmol, yield82%).

LCMS:M+1=412.1

¹H NMR(400MHz,DMSO-d6)δ11.47(s,1H),8.88(s,1H),7.47(s,2H), 7.20-7.16 (m, 1H), 7.12-7.10 (m, 1H), 6.77-6.73 (m, 1H), 6.23-6.20 (t, J=12HZ, 1H), 3.21-3.20 (m, 2H), 2.75-2.71 (t, J=16HZ, 2H).

Embodiment 10 synthesizes CGT-9027

Step 1 synthesizes MC-158-1

MC-157-4 (200mg, 0.83mmol, 1.0eq) is dissolved into 10mL tetrahydrofuran, sodium hydrogen is added at 0 DEG C (20mg) reaction is stirred 15 minutes at 0 DEG C.Then iodomethane (59mg, 1.66 mmol, 2.0eq) are added, normal-temperature reaction one Hour.25mL water is added in reaction solution, three times with ethyl acetate 35mL extraction.Organic phase saturated common salt water washing, anhydrous slufuric acid It is spin-dried for obtaining yellow solid MC-158-1 (150mg, 49%) after sodium is dry.

Step 2 synthesizes MC-158-2

MC-158-1 (150mg, 0.59mmol, 1.0eq) is added to 25mL hydrochloric acid (6M), and to be stirred to react 16 at 110 DEG C small When.Reaction solution is directly spin-dried for obtaining yellow solid MC-158-2 (150mg, crude).

Step 3 synthesizes MC-158-3

By SM1 (200mg, 0.53mmol, 1.0eq), MC-158-2 (150mg, crude), cesium carbonate (1.0 g, 3.07mmol, 6.0eq) it is dissolved into the in the mixed solvent of 15mL tetrahydrofuran and water ratio 5:1, it is stirred to react 30 points at normal temperature Clock.Water 50mL is added, three times with ethyl acetate 25mL extraction.Organic phase saturated common salt water washing, anhydrous sodium sulfate are dry To crude product, crude product obtains yellow solid MC-158-3 (110mg, 46%) with plate (petroleum ether: ethyl acetate 1:1) purifying is prepared.

Step 4 synthesizes CGT-9027

MC-158-3 (110mg, 0.24mmol, 1.0eq) is dissolved into the mixing of 6mL tetrahydrofuran and water mixing ratio 5:1 In solvent, sodium hydroxide (30mg, 0.73mmol) reaction solution is added and is reacted 30 minutes in stirring at normal temperature.Reaction plus water 20mL, Three times with ethyl acetate 25mL extraction, organic phase saturated common salt water washing, the dry vacuum of anhydrous sodium sulfate are spin-dried for obtaining crude product, White solid CGT-9027 is prepared through hplc (mobile phase 0.1%FA/CH3CN/H2O) separation in crude product (55.3mg, 53%).

LCMS:M+1=426.1

¹H NMR(400MHz,DMSO-d6)δ11.47(s,1H),8.88(s,1H),7.51(s,1H),7.28 (s,1H), 7.20-7.16 (t, J=16Hz, 1H), 7.12-7.10 (m, 1H), 6.78-6.70 (m, 1H), 6.21 (m, 1H), 3.76 (s, 3H),2.71-2.67(m,2H),1.23(s,2H)。

Embodiment 11 synthesizes CGT-9028

Step 1 synthesizes MC-163-2

By MC-163-1 (2g, 17.68mmol, 1.0eq), p-methyl benzenesulfonic acid (336mg, 1.768mmol, 0.1eq) dissolution In 40mL tetrahydrofuran, DHP (1.6g, 19.448mmol, 1.1eq) is then added at normal-temperature reaction 16 hours.Reaction solution Water 25mL is added, ethyl acetate 35mL is extracted three times, and organic phase saturated common salt water washing, anhydrous sodium sulfate drying obtains after being spin-dried for To crude product, grease MC-158-1 (3.5g, 99%) is obtained by column purification (petroleum ether: ethyl acetate 20:1 to 5:1)

Step 2 synthesizes MC-163-3

MC-163-3 (450mg, 2.28mmol, 1.0eq) is dissolved in MeOH (5mL), Pd/C (100mg) is added and exists The filtering of stirring at normal temperature 16hrs. reaction solution is spin-dried for obtaining yellow solid MC-163-3 (400 mg, crude product) under H2.

Step 3 synthesizes MC-163-4

By MC-163-3 (400mg, 2.4mmol, 1.0eq), SM (420mg, 2.4mmol) is dissolved in DMF (20mL), Then HATU (1.82g, 4.8mmol) is added, DIEA (1.1g, 7.2mmol) was at normal-temperature reaction 16 hours.Water is added in reaction solution 25mL, ethyl acetate 25mL are extracted three times, organic phase saturated common salt water washing, and anhydrous sodium sulfate drying obtains thick after being spin-dried for Product obtain yellow solid MC-163-4 (870mg, 95%) by column purification (petroleum ether: ethyl acetate 2:1).

Step 4 synthesizes MC-163-5

MC-163-4 (870mg, 2.7mmol, 1.0eq) is dissolved in DCM (15mL), addition TFA (2.5 g, 0.73mmol) reaction is stirred 16 hours under 40 degrees Celsius.Reaction solution vacuum is spin-dried for obtaining crude product MC-163-5 (2g).

Step 5 synthesizes MC-163-6

MC-163-5 (2g, crude) is dissolved in tetrahydrofuran (50mL), cesium carbonate (10g, 18.8 mmol) are added and adjust Then SM1 (700mg, 1.88mmol) is added in pH > 7, react stirring at normal temperature half an hour.Water 50mL, ethyl acetate is added in reaction solution 25mL is extracted three times, and organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, crude product is obtained after being spin-dried for, by hplc system It is standby to obtain yellow solid MC-163-6 (30mg).

Step 6 synthesizes CGT-9028

MC-163-6 (30mg, 0.06mmol) is dissolved in THF/H2O 5:1 (6mL), sodium hydroxide is then added (13mg, 0.3mmol) reacts stirring at normal temperature half an hour.Reaction solution filtering obtains white solid CGT- through hplc preparation purifying 9028 (2.3mg, 8%yield)

LCMS:M+1=441.1

¹H NMR(400MHz,DMSO-d6)δ8.48(s,2H),8.19(s,1H),7.85-7.83(m,1H), 7.50- 7.46 (m, 1H), 7.18-7.14 (t, J=16Hz, 1H), 6.91 (s, 1H), 3.71 (s, 2H).

Embodiment 12 synthesizes CGT-9029

Step 1 synthesizes MC-165-2

By MC-165-1 (2.64g, 10mmol, 1.0eq), SM1 (1.75g, 10mmol, 1.0eq) is dissolved in DMF In (30mL), HATU (5.7g, 15mmol, 1.5eq) reaction is then added at stirring at normal temperature 16 hours.Reaction plus water 50mL are used Ethyl acetate (50mL*3) extracts organic phase saturated common salt water washing, and anhydrous sodium sulfate is dry, and vacuum is spin-dried for obtaining yellow solid Body MC-158-1 (600mg, 26%).

Step 2 synthesizes MC-165-3

MC-165-2 (600mg, 2.5mmol, 1.0eq) is added in 4M hydrochloric acid dioxane, stirring at normal temperature 16 hours. Reaction solution vacuum is spin-dried for, and obtains white solid MC-165-3 (400 mg, crude) three times with 50 ml methanol bands.

Step 3 synthesizes MC-165-4

By MC-165-3 (100mg, 0.56mmol, 1.0eq), SM2 (229mg, 0.62mmol, 1.1eq) is dissolved in DMF 0 DEG C of addition Et3N (170mg, 1.68mmol) in (20mL), reaction are stirred 1 hour at 0 DEG C.30 milliliters of water are added in reaction solution, use Ethyl acetate 50mL is extracted three times.Organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, and vacuum is spin-dried for obtaining red solid Body MC-165-4 (150mg, 50%).

Step 4 synthesizes CGT-9029

MC-165-4 (150mg, 0.32mmol, 1.0eq) is dissolved in DMF (5mL), 10% potassium hydroxide aqueous solution is added Five milliliters.Reaction is stirred 2 hours at 50 c.Reaction solution filter liquor send HPLC (mobile phase 0.1%FA/ CH3CN/H2O) preparative separation purifies to obtain white solid CGT-9029 (22.6mg, 15%).

LCMS:M+1=439.2

¹H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.89(s,1H),8.31(s,2H), 7.22-7.17 (t, J=20HZ, 1H), 7.15-7.13 (m, 1H), 6.82-6.80 (m, 1H), 6.74 (s, 2H), 6.57 (s, 1H), 4.11- 4.09 (d, J=12HZ, 2H)

Embodiment 13 synthesizes CGT-9003

Compound MC-001-3 (200mg, 0.52mmol, 1.0eq) is dissolved in THF (5mL) at room temperature.Then in the solution It is added cesium carbonate aqueous solution (2N, 5mL), SM1 (290mg, 0.78mmol, 1.5eq).Reaction mixture reacts under the conditions of 25 degree 1 hour.Then sodium hydrate aqueous solution (2N, 2mL) is added, reaction is reacted 1 hour at room temperature, and reaction solution is dilute with water (20mL) The mixture obtained after releasing is extracted with ethyl acetate (20mL X 2).The dry concentration of organic phase.Residue is by efficiently preparing color Spectrum isolates and purifies to obtain compound as white solid CGT-9003 (120mg, 35%).

¹H NMR(400MHz,DMSO-d6):δ11.49(br,2H),8.91(s,2H),7.19-7.10(m, 4H), 6.76-6.72(m,2H),6.36-6.32(m,2H),3.47-3.44(m,4H).

¹⁹F NMR(376.5MHz,DMSO-d6):δ-117.83,-118.37.

HPLC:@254nm:99.33% ,@214nm:99.67%.

LCMS:M+1=659.0

Embodiment 14 synthesizes CGT-9010

Step 1 synthesizes MC-149-2

Compound MC-149-1 (632mg, 1.7mmol, 1.0eq) is dissolved in THF (5mL) at room temperature.Then in the solution It is added cesium carbonate (1.7g, 5.1mmol, 3.0eq), SM1 (408mg, 2.0mmol, 1.2 eq) and water (5mL).Reaction mixture It is reacted 0.5 hour under the conditions of 25 degree.Then reaction solution is diluted with water (30mL).Obtained mixture ethyl acetate (30mL X 2) extraction.The dry concentration of organic phase.Residue is purified by chromatographed on silica gel (ethyl acetate/petroleum ether=1/5~1/3) Obtain light tan solid compound MC-001-2 (750mg, 83%).

Step 2 synthesizes MC-149-3

Methylene chloride (5 mL) solution of compound MC-149-2 (750mg, 1.4mmol, 1.0eq) and TFA (2mL) is 25 It is reacted 2 hours under the conditions of degree.Then reaction solution is concentrated to get light brown oily compound.Oily intermediate methylene chloride Potassium carbonate (2g) is added in the solution after (10mL) dissolution.Reaction mixture filters after being stirred at room temperature 30 minutes, filtrate concentration Obtain crude product yellow solid compound MC-149-3 (600mg, 99%).

Step 3 synthesizes CGT-9010

Compound MC-149-3 (150mg, 0.35mmol, 1.0eq) is dissolved in THF (4mL) at room temperature.Then in the solution Cesium carbonate aqueous solution (2N, 4mL) and SM2 (143mg, 0.39mmol, 1.1eq) is added.Reaction mixture is anti-under the conditions of 25 degree It answers 1 hour.Then sodium hydrate aqueous solution (2N, 2mL) is added in reaction solution.Reaction is after the reaction was continued at room temperature 1 hour It is diluted with water (20mL).Obtained mixture is extracted with ethyl acetate (20mL X 2).The dry concentration of organic phase.Residue passes through Efficiently preparing chromatographic separation and purification obtains compound as white solid CGT-9010 (7mg, 2%).

¹H NMR(400MHz,DMSO-d6):δ11.50(s,2H),8.88(s,2H),7.21-7.11(m, 4H),6.81- 6.76(m,2H),6.24-6.20(m,2H),3.65-3.61(m,4H),3.44-3.38(m,4H).

19F NMR(376.5MHz,DMSO-d6):δ-117.82.

HPLC:@254nm:89.80% ,@214nm:94.31%.

LCMS:M+1=702.9

Embodiment 15 synthesizes CGT-9012

Step 1 synthesizes MC-117-3

Compound MC-117-1 (500mg, 1.34mmol, 1.0eq) is dissolved in THF (5mL) at room temperature.Then in the solution It is added cesium carbonate (657mg, 2.02mmol, 1.5eq), MC-117-2 (404mg, 2.02mmol, 1.5eq) and water (2mL).Instead Mixture is answered to react at room temperature 2 hours.Then reaction solution is diluted with water (20mL).Obtained mixture ethyl acetate (20mL X 3) extraction.The dry concentration of organic phase.Residue is pure by chromatographed on silica gel (ethyl acetate/petroleum ether=1/10) Change obtains light tan solid compound MC-117-3 (630mg, 89%)

Step 2 synthesizes MC-117-4

TFA (10mL) solution of compound MC-117-3 (630mg, 1.20mol, 1.0eq) reacts 3 under the conditions of room temperature Hour.Then reaction solution is concentrated to get light brown oily compound MC-117-4 (870mg, overweight).

Step 3 synthesizes MC-117-5

Under the conditions of 0 degree by the tert-butyl alcohol (787mg, 10.62mol, 10.5eq) be added to chlorosulfonic acid isocyanate (1.43 g, 10.11mmol, 10.0eq) methylene chloride (10mL) solution in and with this condition react 1 hour.Then this solution is added To be cooled to 0 degree in advance compound MC-117-4 (430mg, 1.01mmol, 1.0 eq) and triethylamine (614mg, 6.07mmol, 6.0eq) methylene chloride (15mL) solution in.Reaction mixture uses water after reacting 2 hours under the conditions of 0 degree (30mL) quenching reaction.Obtained mixture is extracted three times with methylene chloride (30mL), and organic phase is with saturated salt solution (20mL) It washes twice.Organic phase drying is concentrated to get yellow solid compound MC-117-5 (400mg, 65%).

Step 4 synthesizes MC-117-6

TFA (10mL) solution of compound MC-117-5 (400mg, 0.662mol, 1.0eq) reacts 3 at room temperature Hour.Then reaction solution is concentrated to get light brown oily compound MC-117-6 (320mg, 96%).

Step 5 synthesizes CGT-9012

Potassium carbonate is added after being dissolved with methanol (5mL) in compound MC-117-6 (320mg, 0.635mmol, 1.0eq) (263mg,1.904mmol,3.0eq).Reaction mixture reacts 3 hours under the conditions of 40 degree.To react mixing after reaction Object is diluted with water (20mL).Obtained mixture is extracted with ethyl acetate (20mLX3).The dry concentration of organic phase.Residue is logical It crosses and efficiently prepares chromatographic separation and purification and obtain compound as white solid CGT-9012 (92mg, 30%)

¹H NMR (400MHz, DMSO-d6): δ 11.5 (br, 1H), 8.90 (br, 1H), 7.17 (t, J=8.8 Hz, 1H), 7.13 (dd, J=6.0Hz, 2.4Hz, 1H), 6.80-6.76 (m, 2H), 6.20 (t, J=6.0Hz, 1H), 3.86-3.83 (m, 1H),3.38-3.20(m,4H),1.87-1.79(m,3H),1.70-1.68(m,1H).

HPLC:@254nm:98.04% ,@214nm:98.03%.

LCMS:M+1=478.0

Embodiment 16 synthesizes CGT-9013

Step 1 synthesizes MC-118-1

Under the conditions of 20 degree, compound MC-101-007 (500mg, 1.34mol, 1.0eq), (S) -1-N- tertiary butyloxycarbonyl Base -2- (amino-ethyl) pyrrolidines (500mg, 2.50mmol, 1.8eq), cesium carbonate (873mg, 2.68mmol, 2.0eq) and four Hydrogen furans/water (10/10mL) mixture is stirred to react 3 hours.Reaction solution is extracted with ethyl acetate (50mLX2) after reaction It takes.The residue obtained after the dry concentration of organic phase is used to be purified by chromatographed on silica gel (ethyl acetate/petroleum ether=1/10) Obtain compound as white solid MC-118-1 (660mg, 93%).

Step 2 synthesizes MC-118-2

5mL trifluoroacetic acid is added to compound MC-118-1 (660mg, 1.26mol, 1.0 eq) two at room temperature In chloromethanes (10mL) solution.Then reaction at room temperature is reacted overnight.Reaction has terminated reaction solution and has been concentrated to get thick production Product light yellow solid Compound MC-118-2 (800mg, trifluoroacetate).

Step 3 synthesizes MC-118-3

The tert-butyl alcohol (549mg, 7.41mmol, 10.5eq) is added drop-wise to compound chlorosulphonyl isocyanate under condition of ice bath In (998mg, 7.06mmol, 10.0eq) methylene chloride (10mL) solution.After being carried out 1 hour under reaction solution condition of ice bath, by this Reaction solution be added drop-wise to ice bath protection compound MC-118-2 (300mg, 0.706mmol, 1.0eq) and triethylamine (714mg, 7.06mmol, 10.0eq) methylene chloride (10mL) solution in.The protection of reaction solution ice bath lower reaction 2 hours.To the end of reacting Reaction solution cold water (50mL) quenched dilution afterwards.Then mixture is extracted with methylene chloride (50mLX2).The dry concentration of organic phase Obtain light yellow solid crude product compound MC-118-3 (500mg, crude product).

Step 4 synthesizes MC-118-4

5mL is added in methylene chloride (10mL) solution of compound MC-118-3 (500mg, crude product) at room temperature Trifluoroacetic acid.Reaction solution reacts overnight at room temperature.Reaction solution is directly concentrated to get pale yellowish oil crude product after reaction Compound MC-118-4 (400mg, trifluoroacetate).

Step 5 synthesizes CGT-9013

5mL sodium hydroxide is added in compound MC-118-4 (400mg, trifluoroacetate) methanol (10mL) solution (1N) solution.Reaction carries out 1 hour under 25 degree of parts.It is diluted to reaction solution after reaction with water (50mL), obtained mixing Object is extracted with ethyl acetate (50mL X 3).Organic phase is dry to be concentrated to get pale yellowish oil, and residue is by efficiently preparing color Spectrum isolates and purifies to obtain compound as white solid CGT-9013 (32mg, 8% yield).

¹H NMR(400MHz,DMSO-d6):δ11.49(s,1H),8.86(s,1H),7.20-7.11(m,2H), 6.80- 6.76 (m, 3H), 6.19 (t, J=6.0Hz, 1H), 3.85-3.83 (m, 1H), 3.38-3.19 (m, 4H), 1.86-1.78 (m, 3H),1.71-1.68(m,1H).

19F NMR(376.5MHz,DMSO-d6)δ-117.89,-118.40

HPLC:@254nm:99.48% ,@214nm:99.14%.

LCMS:M-1=478.0

Embodiment 17 synthesizes CGT-9014

Step 1 synthesizes MC-123-2

Under the conditions of zero degree by MsCl (139mg, 1.21mmol, 1.2eq) be added drop-wise to compound MC-123-1 (430mg, 1.01mmol, 1.0eq) and methylene chloride (20mL) solution of triethylamine (614mg, 6.07mmol, 6.0eq) in.Reaction mixing Object reacts 2 hours under condition of ice bath.Then reaction solution is diluted with cold water (30mL).Obtained mixture methylene chloride (30mL) is extracted three times.Organic phase, which is washed to dry afterwards twice with saturated salt solution (30mL), is concentrated to get light yellow solid Compound MC-123-2 (400 mg, 78%).

Step 2 synthesizes CGT-9014

By potassium carbonate (329mg, 2.38mmol, 3.0eq) be added to compound MC-123-1 (400mg, 0.79mmol, In methanol (5mL) solution 1.0eq).Reaction mixture reacts 3 hours under the conditions of 40 degree.To react mixing after reaction Object is diluted with water (20mL).Obtained mixture is extracted with ethyl acetate (20 mLX3).The dry concentration of organic phase.Residue is logical It crosses and efficiently prepares chromatographic separation and purification and obtain compound as white solid CGT-9014 (101.4mg, 26%)

¹H NMR (400MHz, DMSO-d6): δ 11.53 (br, 1H), 8.89 (br, 1H), 7.18 (t, J=8.8Hz, 1H), 7.11 (dd, J=6.0Hz, 2.4Hz, 1H), 6.80-6.76 (m, 1H), 6.27 (t, J=6.0Hz, 1H), 3.90-3.87 (m,1H),3.40-3.22(m,4H),2.91(s,3H),1.97-1.70(m,4H).

¹⁹F NMR(376.5MHz,DMSO-d6):δ-117.94,-118.38.

HPLC:@254nm:99.57% ,@214nm:99.58%.

LCMS:M+1=479.0

Embodiment 18 synthesizes CGT-9015

Step 1 synthesizes MC-124-1

Under the conditions of 0 degree by MsCl (0.11mL, 1.41mmol, 1.5eq) be added drop-wise to compound MC-118-2 (400mg, 0.94mmol, 1.0eq) and methylene chloride (5mL) solution of triethylamine (0.65mL, 4.70mmol, 5.0eq) in.Reaction mixing Object reacts 2 hours under condition of ice bath.Then reaction solution is diluted with cold water (50mL).Obtained mixture methylene chloride (50mLX2) extraction, organic phase drying are concentrated to get light yellow solid crude product compound MC-124-1 (350mg, crude product).

Step 2 synthesizes CGT-9015

5mL1N hydroxide is added in methanol (10mL) solution of compound MC-124-1 (350mg, crude product) at room temperature Sodium solution, reaction solution react 2 hours under 25 degree of parts.Reaction solution is diluted with water (30mL) after reaction, obtained mixture (50mL X 3) is extracted with ethyl acetate.Then organic phase convection drying is concentrated.Obtained residue is by efficiently preparing chromatography It isolates and purifies to obtain compound as white solid CGT-9015 (82mg, 24% yield).

¹H NMR(400MHz,DMSO-d6)δ11.50(brs,1H),8.87(brs,1H),7.20-7.12(m, 2H), 6.79 (dd, J=7.2Hz, 3.2Hz, 1H), 6.28-6.25 (t, J=6.0Hz, 1H), 3.91-3.89 (m, 1.0H), 3.40- 3.18(m,4H),2.91(s,3H),1.95-1.81(m,3H),1.74-1.69(m,1H).

¹⁹F NMR(376.5MHz,DMSO-d6)δ-117.85,-118.39

HPLC:@254nm:99.38% ,@214nm:99.49%.

LCMS:M+1=479.1

Embodiment 19 synthesizes CGT-9017

TFA (2mL) and methylene chloride (5 mL) solution of compound MC-153-1 (200mg, 0.33mmol, 1.0eq) exists Intermediate is concentrated to get after reacting 1 hour under the conditions of 25 degree.The hydrogen of 2N is added in the intermediate after being dissolved with tetrahydrofuran (5 mL) Sodium hydroxide solution (2mL).Reaction mixture reacts 1 hour at room temperature.It is dilute to reaction mixture water after reaction It releases.Obtained mixture is extracted with ethyl acetate (20mLX2).The dry concentration of organic phase.Residue is by efficiently preparing chromatography It isolates and purifies to obtain compound as white solid CGT-9017 (23mg, 7%).

LCMS:M+1=478.1

¹H NMR(400MHz,DMSO-d6)δ11.52(s,1H),8.90(s,1H),7.20-7.10(m, 2H),6.78- 6.73(m,3H),6.40-6.37(m,1H),3.32-3.09(m,5H),2.90-2.86(m,1H), 2.55-2.53(m,1H), 1.94-1.90(m,1H),1.59-1.54(m,1H).

¹⁹F NMR(376.5MHz,DMSO-d6)δ-117.72,-118.40.

Embodiment 20 synthesizes CGT-9018

Step 1 synthesizes MC-116-1

By compound SM1 (1.61g, 10.0mmol, 1.0eq), triphenylphosphine (2.75g, 10.5,1.05eq) and SM2 (1.71g, 1.71mmol, 1.05eq.) is dissolved in dry tetrahydrofuran (50mL), be cooled to 0 degree of dropwise addition DEAD (1.82g, 10.5mmol,1.05eq.).Reaction 16 hours is stirred at room temperature in mixture.Contact plate detection reaction, after reaction, reaction solution concentration The residue obtained afterwards obtains compound as white solid MC- by chromatographed on silica gel (ethyl acetate/petroleum ether=1/2) purifying 116-1 (2.83g, 92%).

Step 2 synthesizes MC-116-2

A hydrazine hydrate (0.146mL, 4.71mmol, 1.03eq.) is added to compound MC-116-1 at room temperature In (1.4g, 4.57mol, 1.0eq.) ethyl alcohol (10mL) solution.Then reaction at room temperature is reacted overnight.Contact plate detection is anti- It answers, after reaction, reaction solution filtering, the residue that filtrate is concentrated to get passes through chromatographed on silica gel (ethyl acetate/petroleum ether =1/2) purifying obtains colorless oil compound MC-116-2 (448mg, 55%).

Step 3 synthesizes MC-116-3

By compound MC-101-007 (200mg, 0.54mmol, 1.0eq.) and MC-116-2 (200mg, 1.13 mmol, It 2.1eq.) is dissolved in tetrahydrofuran (10mL).After 40 degree are reacted 4 hours, LCMS detection reaction, after having reacted, reaction solution is dense The obtained residue that contracts obtains compound as white solid MC- by chromatographed on silica gel (ethyl acetate/petroleum ether=1/5) purifying 116-3 (280mg, 83%).

Step 4 synthesizes MC-116-4

It is molten in the methylene chloride of compound MC-116-3 (50mg, 0.10mmol, 1.0eq.) (5 mL) at room temperature 1mL trifluoroacetic acid is added in liquid.Reaction solution reacts overnight at room temperature.Reaction solution is directly concentrated to get light yellow after reaction Oily crude product compound MC-116-4 (200mg, trifluoroacetate).

Step 5 synthesizes MC-116-5

The tert-butyl alcohol (389mg, 5.25mmol, 10.5eq.) is added drop-wise to compound chlorine sulphonyl isocyanic acid under condition of ice bath In ester (708mg, 5.0mmol, 10.0eq.) methylene chloride (5mL) solution.After being carried out 1 hour under reaction solution condition of ice bath, by this Reaction solution be added drop-wise to ice bath protection compound MC-116-4 (200mg, 0.50mmol, 1.0eq) and triethylamine (531mg, 5.25mmol, 10.5eq) methylene chloride (5mL) solution in.The protection of reaction solution ice bath lower reaction 2 hours.To after reaction Reaction solution cold water (50mL) quenched dilution.Then mixture is extracted with methylene chloride (50mL X 2).The dry concentration of organic phase Obtain light yellow solid crude product compound MC-116-5 (500mg, crude product).

Step 6 synthesizes CGT-9018

2mL is added in methylene chloride (10mL) solution of compound MC-116-5 (500mg, crude product) at room temperature Trifluoroacetic acid.Reaction solution reacts 2 hours at room temperature.Reaction solution is directly concentrated after reaction, obtains pale yellowish oil and slightly produces Product compound, which is dissolved in tetrahydrofuran (10mL), is added 5mL sodium hydroxide (1N) solution.It is small that reaction carries out 1 under 25 degree of parts When.It is diluted to reaction solution after reaction with water (50 mL), obtained mixture is extracted with ethyl acetate (50mL X 3).Have Machine is mutually dry to be concentrated to get pale yellowish oil, and residue obtains compound as white solid by efficiently preparing chromatographic separation and purification CGT-9018 (21 mg, 5% yield).

¹H NMR(400MHz,DMSO-d6):δ11.49(s,1H),9.78(s,1H),8.95(s,1H), 7.22-7.17 (t, J=8.8Hz, 1H), 7.12-7.10 (m, 1H), 6.79-6.75 (m, 1H), 6.10-6.54 (m, 3H), 3.96-3.91 (t, J=6.0Hz, 2H), 3.16-3.12 (m, 2H)

¹⁹F NMR(376.5MHz,DMSO-d6)δ-117.22,-118.20

HPLC:@254nm:98.59% ,@214nm:98.59%.

LCMS:M+1=454.1.

Embodiment 21 synthesizes CGT-9201

Step 1 synthesizes CGT-9201-1

At room temperature by cesium carbonate (880.4mg, 2.68mmol, 2.0eq) be added to compound MC-101-007 (500mg, 1.34mmol, 1.0eq), tetrahydrofuran/water of N- tertbutyloxycarbonyl -1,2- ethylenediamine (428.8mg, 2.0mmol, 2.0eq) In the solution of (5/1mL).Reaction is stirred 0.5 hour at 20 °C.Water (10mL) is added in reaction solution, obtained mixing Object is extracted with ethyl acetate (25mL*3).Organic phase is washed with saturated salt solution (20mL*2), dry filter concentration.What is obtained is residual Excess purifies to obtain yellow solid compound CGT-9201- with the method for chromatographed on silica gel (ethyl acetate/petroleum ether=1/3) 1 (517mg, yield 79.3%).

Step 2 synthesizes CGT-9201-2

The compound CGT-9201-1's (570mg, 1.17mmol, 1.0 eq) that 3mL trifluoroacetic acid is added at room temperature In methylene chloride (20mL) solution.Reaction room temperature carry out 1 hour, reaction solution with sodium bicarbonate aqueous solution adjust PH to 9 then Crude product light yellow solid Compound CGT-9201-2 (325mg, yield are directly concentrated to get with methylene chloride (30*2) extraction 71.9%).

Step 3 synthesizes CGT-9201-3

CGT-9201-2 (200mg, 0.52mmol) and triethylamine (263mg, 2.6mmol) are dissolved in ethyl alcohol (10ml), stirred It mixes 5 minutes and then chemical combination object space diethyl phthalate (105.5mg, 0.62mmol) is dissolved in ethyl alcohol (5ml) and be added drop-wise in mixture Continue stirring 3 hours and finally continues compound methylamine hydrochloride (49.5mg, 0.78 mmol) addition reaction to stir 15 hours Drying is concentrated to get crude product pale yellowish oil compound (230mg).

Step 4 synthesizes CGT-9201

At room temperature by potassium carbonate (82.8mmol, 0.6mmol) be added to compound CGT-9201-3 (200mg, In methanol (5mL) solution 0.40mmol)).Reaction carries out 3 hours at room temperature.It is concentrated to solvent after reaction.Residual Object obtains compound as white solid CGT-9201 (20mg, 11%) by efficiently preparing chromatographic separation and purification

LCMS:M+1=468.1,470.1 (LCMS:MC18-71-008-1)

1H NMR (400MHz, DMSO-d6) δ 11.47 (s, 1H), 8.88 (s, 1H), 7.19 (t, J=4.4 Hz, 1H), 7.12 (m, 1H), 6.76 (m, 1H), 6.31 (t, J=2.2Hz, 1H), 3.69 (m, 2H), 3.42 (m, 2H), 3.14 (s, 3H) (HNMR:MC18-71-008-1)。

Embodiment 22 synthesizes CGT-9030

Step 1 synthesizes MC-105-10

Compound MC-105-4 (254mg, 2.0mmol, 1.58eq) and compound MC-101-009 (400mg, 1.26 Mmol, 1.0eq) THF (5mL) solution react fully reacting after ten minutes under the conditions of 35 degree.Reaction solution is directly concentrated.It is remaining Object by chromatographed on silica gel (EtOAc/PE=1/3) purifying obtain brown oil compound MC-105-10 (420mg, 83% yield)。

Step 2 synthesizes CGT-9030

At room temperature by sodium hydroxide (56mg, 1.44mmol, 8.0eq) be added to compound MC-105-10 (71.7 mg, 0.18mmol, 1.0eq) tetrahydrofuran (3mL) and water (1mL) solution in.Reaction is reacted 1 hour at room temperature.Reaction terminates Reaction solution is diluted with 25mL water afterwards, and obtained mixture is extracted with ethyl acetate (25 mL × 3).It is residual after the dry concentration of organic phase Object is stayed to obtain compound as white solid CGT-9030 (21mg, 27%yield) by efficiently preparing chromatographic separation and purification.

LCMS:M+1=373.1.

Embodiment 23 synthesizes CGT-9031

Step 1 synthesizes MC-164A-7

By compound MC-101-018 (227mg, 0.70mmol, 1.0eq.), MC-164A-2 (260mg, 1.88 mmol, 2.7eq.) it is dissolved in tetrahydrofuran (20mL) with triethylamine (425mg, 4.20,6.0eq.).After 40 degree are reacted 4 hours, LCMS detection reaction, after having reacted, the residue that reaction solution is concentrated to get passes through chromatographed on silica gel (ethyl acetate/petroleum ether =1/1) purifying obtains faint yellow solid compound MC-164A-7 (170mg, 58%).

Step 2 synthesizes CGT-9031

Compound MC-164A-7 (170mg, 0.41mmol, 1.0eq) is dissolved in tetrahydrofuran at room temperature 5mL sodium hydroxide (1N) solution is added in (10mL).Room temperature reaction 1 hour.It is diluted with water, obtains to reaction solution after reaction Mixture be extracted with ethyl acetate.Organic phase is dry to be concentrated to get pale yellowish oil, and residue is by efficiently preparing chromatography point Light yellow solid Compound CGT-9031 (69 mg, 43% yield) is obtained from purifying.

LC-MS:M+1=389.1.

Embodiment 24 synthesizes CGT-9032

Step 1 synthesizes MC-164B-15

By compound MC-101-013 (195mg, 0.54mmol, 1.0eq.), MC-164B-2 (200mg, 1.45 mmol, 2.7eq.) it is dissolved in tetrahydrofuran (20mL) with triethylamine (328mg, 3.24,6.0eq.).After 40 degree are reacted 5 hours, LCMS Detection reaction, after having reacted, the residue that reaction solution is concentrated to get passes through chromatographed on silica gel (ethyl acetate/petroleum ether=1/ 5) purifying obtains faint yellow solid compound MC-164B-15 (195mg, 80%).

Step 2 synthesizes CGT-9032

Compound MC-164B-15 (195mg, 0.43mmol, 1.0eq) is dissolved in tetrahydrofuran at room temperature 5mL sodium hydroxide (1N) solution is added in (10mL).Room temperature reaction 1 hour.It is diluted with water, obtains to reaction solution after reaction Mixture be extracted with ethyl acetate.Organic phase is dry to be concentrated to get pale yellowish oil, and residue is by efficiently preparing chromatography point Light yellow solid Compound CGT-9032 (38mg, 21% yield) is obtained from purifying.

LCMS:M+1=427.1.

25 indoleamine 2,3-dioxygenase of embodiment (IDO) enzyme assay

It prepares IDO1 test buffer: containing 400 μM of L-Trps (Cat#T8941-25G, Sigma), 20 mM Vitamin Cs Sour (Cat#A4034-100G, Sigma), 20 μM of methylenum careuleum (Cat#M9140-25G, Sigma) and 1000U/ml catalase It is dissolved in 100mM PBS buffer solution, buffer solution ph=6.5

The untested compound (100X) and 1 μ L for measuring concentration are added needed for 1 μ L in the IDO1 test buffer of 98 μ L 100ng/ μ L IDO1 enzyme (Mei Dixi self-control).IDO1 and test buffer need to be preheating to 37 DEG C.It is anti-in 37 DEG C of thermostatic water baths Answer 30min.50 μ L, 30% trichloroacetic acid (Cat#T0699-100ML, Sigma) is added.It is reacted in 52 DEG C of thermostatic water baths 30min.12000g is centrifuged 10min at room temperature.Take 100 μ L supernatants into 96 hole detection plates and 100 μ L Ehrlich ' s Reagent (4- dimethylaminobenzaldehyde (Cat# 156477-25g, Sigma)) mixing.It is measured and is inhaled in 480nm with M5 microplate reader Light value.

Data analysis

Inhibiting rate %=(OD_positive―OD_sample)/(OD_positive―OD_negative) * 100%

With software Graphpad Prism 6 and use calculation formula log (inhibitor) vs.normalized Response carries out IC50 curve matching and calculates IC50 value, calculated result such as the following table 1.

Embodiment 26IDO inhibitor tests the IDO1 enzymatic activity that Hela cell induces

It collects logarithmic growth phase Hela human cervical carcinoma cell (Cat#CCL-2, ATCC), counts, adjustment cell concentration is extremely 5000 every holes, by cell inoculation in 96 well culture plates, every hole adds 100 μ L cell suspensions.For cell at 37 DEG C, 100% is opposite Humidity is incubated for 24 hours in 5%CO2 incubator.It will be candidate with culture medium DMEM culture medium (Cat#11995-040, GIBCO) Compound and reference material are diluted to set effect final concentration, and IFN-gamma concentration 50ng/mL, liquid is changed in 200 holes μ L/ altogether It is added to Hela cell, multiple holes test.Cell is placed in 37 DEG C, 100% relative humidity, is incubated for 48 hours in 5%CO2 incubator. 140 hole μ L/ cells and supernatants are taken, detection IDO1 cellular level inhibits efficiency.15 hole μ L/ trichloroacetic acids are added.52 DEG C of perseverances It is reacted 30 minutes in warm water tank.12000g is centrifuged 10 minutes at room temperature.Take 100 μ L/ hole supernatants into 96 hole detection plates and 100 μ M5 is used in the hole L/ Euclidean liquid (Ehrlich ' s Reagent, 4- dimethylaminobenzaldehyde (Cat#156477-25g, Sigma)) mixing Microplate reader measures light absorption value in 480nm.

Data analysis

Inhibiting rate=(OD_positive―OD_sample)/(OD_positive―OD_negative) * 100%

With software Graphpad Prism 6 and use calculation formula log (inhibitor) vs. normalized Response-variable slope carries out IC50 curve matching and calculates IC50 value.

In following table 1, IDO the and Hela cell IC50 data of the compound of embodiment 1-24 offer, meter are provided Calculate result such as the following table 1.

The enzyme inhibition activity data and Hela cell inhibitory activity data of each compound of table 1

Compound provided by the invention all has excellent zymetology and cytology IDO it can be seen from the data of table 1 as above Inhibitory activity.

The detection of 26 Medicated Permeation performance of embodiment

The present invention is using MDCKII-hMDR1 cell monolayer model to the embodiment 1-24 compound provided and controlization The two-way transmembrane transport and outlet characteristic for closing object CGT-9002 are assessed.Wherein the corresponding structural formula of CGT-9002 is such as following formula A compound, wherein R1 is NH2, R2 Br, R3 F.

Cell culture: by MDCKII-hMDR1 cell culture in DMEM in high glucose culture solution (Hyclone) during test In, 10% fetal calf serum (GIBCO) and mycillin (each 100 units/mL) are contained in culture solution, cell contains 5% at 37 DEG C CO₂Incubator in cultivated.

Before transport experiment starts, first with HBSS buffer (137mM NaCl, the 4.17mM NaHCO of preheating₃, 0.34mM Na₂HPO₄, 5.37mM KCl, 0.44mM KH₂PO₄, 1.26mM CaCl₂, 0.49mM MgCl₂, 0.41mM MgSO₄, 5.55mM D-Glucose, 10mM HEPES, pH 7.4) MDCKII-hMDR1 cell monolayer is washed 3 times, it is placed in It is incubated under the conditions of 37 DEG C 30 minutes, then measures TEER value with cell resistance instrument (Millicell-ERS2) to confirm cell list The integrality and tight type of layer.

In transport experiment, by MDCKII-hMDR1 cell with 1x 10⁵The density in a/hole is inoculated in 12 hole Transwell Culture plate (Corning Costar, article No. #3401,1.12cm², 0.4 μm of aperture) filter membrane on, the MDCKII- after inoculation HMDR1 cell will form complete cell monolayer, including the expression of P-gp outlet transporter and transepithelial cell resistance after 5 days (TEER) it is formed.Period every other day replaces a culture solution, the top side (Apical Side, A) of Transwell filter membrane and base The culture solution capacity of bottom side (Basolateral Side, B) is respectively 0.5mL and 1.5mL.When by the side filter membrane A Transwell or After the HBSS buffer of the side person B replaces with test compound, transport experiment has started, finally small by being incubated for 2 at 37 DEG C When, transport experiment terminates.

50 μ L sample solution addition, 100 μ L, which are respectively taken out, in the two sides of Transwell filter membrane contains internal standard chemical combination (tolbutamide) acetonitrile and mixing, for needing diluted sample (such as 10 times dilutions), take the dilution of 5 μ L sample solutions with In 45 μ L HBSS buffers, acetonitrile and mixing that 100 μ L contain internal standard compound is added, then with 13000rpm, 4 DEG C of centrifugations 10min finally draws 10 μ L supernatants for LC-MS/MS sample analysis.For each compound, A → B and the direction B → A Transport experiment be three multiple pipes, i.e. n=3.

LC-MS/MS sample analysis

Sample analysis passes through series connection and the triple level Four matter of API4000 by high performance liquid chromatography, highly effective liquid phase chromatographic system Spectrum (Applied Biosystems) is connected, and wherein the triple level Four mass spectrums of API4000 are equipped with an electro-spray ionization (ESI) source.Superpurity nitrogen is used as gas curtain gas, GAS1, auxiliary gas (GAS2) and collision gas.Data are soft by Analyst 1.5 Part is acquired.

Data analysis:

Apparent permeability coefficients (Papp) are calculated by compound through the speed of MDCKII-hMDR1 cell monolayer, are counted Value size is related to the absorption of the compound in vivo, after the compound concentration that the side A and the side B are measured by LC-MS/MS method, The Papp value in A → B or the direction B → A: P is calculated according to the following formula_app(A→B)or P_app(B→A)=(dQ/dt)/(A*C₀)= (C_2h*V)/(t*A*C₀)

In above-mentioned formula, dQ/dt is infiltration rate, i.e., the chemical combination object amount penetrated within the dt time, C₀For the medicine that side is administered Object initial concentration, A are surface area, that is, membrane area of cell monolayer.

The judgment criteria of the penetrating speed of transmembrane transport is as follows:

Low pass is saturating: P_app(A→B)<1x 10^-6cm/s

In it is penetrating: P_app(A→B)1-10x 10^-6cm/s

High penetration: P_app(A→B)>10x 10^-6cm/s

In the P for obtaining compound_app(A→B)And P_app(B→A)After value, the outer parallelism (Efflux Ratio, ER) of compound is i.e. It can be calculated by following equation:

Efflux Ratio (ER)=P_app(B→A)/P_app(A→B)

When outer parallelism >=2, it is believed that the compound is the substrate of outlet transporter.

Experimental result

Test statistics result such as the following table 2.

The cell traffic test result statistical conditions for the compound that 2 1-24 of the embodiment of the present invention of table is provided

It can be seen that section Example compound of the present invention according to the data that table 2 as above provides to be substantially better than referring to chemical combination Object (CGT-9002) has good permeability, is not only able to satisfy the requirement of drug absorption, but also can be sent to enough drugs To target organ, other than the simple passive diffusion for passing through lipid layer, P- glycoprotein by the accumulation of drug selectivity and is being distributed in It played an important role in terms of target organ.

The foregoing describe basic principle of the invention and specific embodiments, but the present invention is not by the limit of above-described embodiment System, without departing from the purpose of the present invention, industry technical staff can carry out various changes and modifications to it, these changes Change and improvement is each fallen in scope of protection of the present invention.

Claims (10)

1. a kind of 1 as IDO inhibitor, 2,5- oxadiazole derivatives or its pharmaceutically acceptable salt, structure such as following formula I It is shown:

Wherein, R1 and R2 is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 naphthenic base, substituted or unsubstituted C1-C10 halogenated alkyl, substituted or unsubstituted C1-C10 hydroxyalkyl or replace or Unsubstituted C1-C10 alkoxy；

R is-X-Z-A, and the X is selected from oxygen atom or methylene；

Z is selected from covalent bond or following bivalent group: substituted or unsubstituted C1-C4 alkylidene, imide, substituted or unsubstituted C1-C4 alkylene oxide group or substituted or unsubstituted C1-C4 alkylene amino；

A is selected from the heteroaryl or Q-NH of the Heterocyclylalkyl of substituted or unsubstituted C3-C14, substituted or unsubstituted C3-C14 (SO₂)NH₂, wherein Q is selected from C2-C6 alkylidene；

And when Z is methylene, A is selected from Heterocyclylalkyl, the substituted or unsubstituted C3-C14 of substituted or unsubstituted C3-C14 Heteroaryl.

2. it is used as 1,2, the 5- oxadiazole derivatives or its pharmaceutically acceptable salt of IDO inhibitor as described in claim 1,

The R1 and R2 is independently selected from halogen, cyano, C5-C7 naphthenic base or C1-C4 alkoxy；

X is methylene,

Z is selected from methylene, imide, methylene oxygroup or methylene amino；

A is selected from substituted or unsubstituted imidazole radicals, substituted or unsubstituted thienyl, substituted or unsubstituted pyrazolyl, substitution Or unsubstituted pyrazoles -4- base, substituted or unsubstituted 1- methyl-pyrazol-4-yl, substituted or unsubstituted pyridyl group, substitution or Unsubstituted pyriconyl or substituted or unsubstituted ring butyl- 3- alkene -1,2- diketo.

3. it is used as 1,2, the 5- oxadiazole derivatives or its pharmaceutically acceptable salt of IDO inhibitor as described in claim 1, Compound selected from such as flowering structure:

。

4. it is used as 1,2, the 5- oxadiazole derivatives or its pharmaceutically acceptable salt of IDO inhibitor as described in claim 1, Its structure is as shown in following formula Ⅹ:

R1 and R2 is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3- C10 naphthenic base, substituted or unsubstituted C1-C10 halogenated alkyl, substituted or unsubstituted C1-C10 hydroxyalkyl or replace or not Substituted C1-C10 alkoxy；

A is selected from the Heterocyclylalkyl of substituted or unsubstituted C5-C7, and wherein substituent group is-(SO₂)NH₂Or-(SO₂)CH₃。

5. it is used as 1,2, the 5- oxadiazole derivatives or its pharmaceutically acceptable salt of IDO inhibitor as claimed in claim 4, Compound selected from such as flowering structure:

6. it is used as 1,2, the 5- oxadiazole derivatives or its pharmaceutically acceptable salt of IDO inhibitor as described in claim 1, Its structure is as shown in following formula Ⅺ:

7. a kind of method of compound shown in preparation formula I comprising following steps:

(a) I-A and I-B are in Cs₂CO₃Reaction generates compound I-C under catalytic action；

(b) compound I-C is deprotected under alkaline condition generates corresponding amidoxime compound I-D.

8. a kind of pharmaceutical composition is used as IDO inhibition containing one or more as above of any of claims 1-6 The 1 of agent, 2,5- oxadiazole derivatives or its pharmaceutically acceptable salt are pharmaceutically acceptable as active constituent and at least one Carrier combination.

9. a kind of 1,2,5- oxadiazole derivatives or its pharmacy for being used as IDO inhibitor as described in any one of claim 1-6 It goes up acceptable salt or containing their purposes of any pharmaceutical composition in medicine preparation, the drug is suffered from for inhibiting The immunosupress of person.

10. purposes as claimed in claim 8, the drug is used for treating cancer, virus infection, depression, neurodegenerative disease Disease, wound, age-dependent cataract, organ-graft refection, autoimmune disease, melanoma, obesity or ischemic disease；

Preferably, further include in the drug antivirotic, chemotherapeutics or other anticancer agents, immunopotentiating agent, immunosuppressor, Radiation, antitumor and antiviral vaccine, cytokine therapy and/or tyrosine kinase inhibitor.