CN109776445A - Benzoxadiazole class compound and preparation method thereof and medical usage - Google Patents

Benzoxadiazole class compound and preparation method thereof and medical usage Download PDF

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CN109776445A
CN109776445A CN201910247771.3A CN201910247771A CN109776445A CN 109776445 A CN109776445 A CN 109776445A CN 201910247771 A CN201910247771 A CN 201910247771A CN 109776445 A CN109776445 A CN 109776445A
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CN109776445B (en
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孙宏斌
刘鎏
姚智颖
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

The invention discloses a kind of benzoxadiazole class compound and preparation method thereof and medical usages, shown in the benzoxadiazole class compound structure such as formula (I), such compound or its pharmaceutically acceptable salt, tautomer, mesomer, racemic modification, stereoisomer, metabolite, metabolic precursor thereof, prodrug or solvate significantly inhibit PD-1/PD-L1 protein-protein interaction, it thus can be applied to the inhibitor that preparation has PD-1/PD-L1 inhibitory activity, and be applied to the immunization therapy of tumour as immunologic test point inhibitor；

Description

Benzoxadiazole class compound and preparation method thereof and medical usage
Technical field
The invention belongs to biomedicine fields, and in particular to a kind of benzoxadiazole with PD-1/PD-L1 inhibitory activity Class compound, the invention further relates to the preparation method of such compound and its as PD-1/PD-L1 inhibitor medical usage and Pharmaceutical composition for immunotherapy of tumors.
Background technique
Programmed death receptor 1 (PD-1) is mainly expressed in T cell surface, is important in the access of immunity of organism checkpoint The factor.And the ligand of tumor cell surface height expression PD-1, i.e. programmed death ligand 1 (PD-L1), when itself and T cell surface PD-1 combine after, the ITIM (Tyr223) and ITSM (Tyr248) tyrosine motif of PD-1 is phosphorylated respectively, then recruitment Protein tyrosine phosphatase SHP 2 and SHP-1, by dephosphorylation signal transduction intermediate (such as CD3 ζ and PLC γ 1 etc.), The downward for leading to T cell receptor (TCR) signal makes the immunosurveillance (Immunity 2016,44 of neoplastic cells escape body (5):955-972).PD-1 in conjunction with PD-L1 after can also be by reducing relevant with effector cell function cell factor (such as IFN-γ, IL-2 and TNF α) and the expression of transcription factor (such as GATA-3, T-bet and Eomes) inhibit the immune function of T cell Energy (Science Signaling 2012,5 (230): ra46).Studies have shown that the immunologic test for inhibiting PD-1/PD-L1 to mediate Point access, can block tumour to the immunosuppressive action of T cell, to activate T cell to the lethal effect of tumour.
Compared with traditional antitumor therapy, one of maximum advantage of immunotherapy is exactly that curative effect has persistence.Than Such as, in melanoma, the patients with terminal of America and Europe 20% or so is able to achieve clinical cure.Relative to targeted therapies, immunotherapy With broader spectrum of anticancer effect, and relative to chemotherapy, its whole side effect is much smaller.The PD-1/PD-L1 listed at present Inhibitor is all monoclonal antibodies inhibitor, there is pembrolizumab, the sieve of Nivolumab, Merck company of BMS company The Atezolizumab of the family name and Durvaluman of AstraZeneca.It and is even more up to several in the PD-1/PD-L1 antibody inhibition ground Ten kinds.PD-1/PD-L1 micromolecular inhibitor is also in development phase early period at present.Curis and Aurigene company develops jointly CA-170 the clinical research of I phase (WO2016142833) is completed at present.BMS company discloses small point of a kind of benzyl phenyl ethers Sub- PD1/PD-L1 inhibitor (WO2015160641；WO2015034820).Micromolecular inhibitor has relative to large biological molecule Apparent advantage, since its molecular weight is smaller, permeable membrane is strong, can generate better curative effect to some solid tumors.And small point Sub- drug often has better bioavilability and compliance, has better pharmacokinetic parameter, is suitble to oral administration, And cost is relatively low.
In conclusion clinically needing to develop active novel PD-1/PD-L1 micromolecular inhibitor high, toxic side effect is small.
Summary of the invention
Goal of the invention: in view of the problems of the existing technology, the present invention provides a kind of novel benzoxadiazole class compound, Benzoxadiazole class compound of the invention significantly inhibits PD-1/PD-L1 protein-protein interaction, because And it can be applicable to the inhibitor that preparation has PD-1/PD-L1 inhibitory activity, and be applied to tumour as immunologic test point inhibitor Immunization therapy.
The present invention also provides the preparation method of the benzoxadiazole class compound and its intermediate, pharmaceutical composition and its Medical usage.
Technical solution: to achieve the goals above, the present invention provides a kind of benzoxadiazole class as shown in following formula (I) Close object:
R1It is selected from: H, C1-C4The C that alkyl, X replace1-C4Alkyl, Heterocyclylalkyl or-(CH2)nAr；The X be selected from F, Cl, Br、I、OH、C(O)OH、C(O)NH2、NH2, morpholinyl, piperidyl, piperazinyl, nafoxidine base or N, N- dimethylamino；Institute Stating n is 1,2,3 or 4；Ar is substituted or non-substituted aryl or heteroaryl；
R2It is selected from :-(CH2)mCHO、-(CH2)mOH or-(CH2)mNR8R9；
M is 0,1,2,3 or 4；
R8It is selected from: H, C1-C4Alkyl or benzyl；
R9Selected from it is following any one:
P is 0,1,2,3 or 4；
R10It is selected from: H, benzyl or methyl；
R11It is selected from: H or C1-C3Alkyl；
R12It is selected from: H, C1-C3Alkyl or benzyl；
R13It is selected from: H, C1-C3Alkyl or benzyl；
R14It is selected from: H, C1-C6Alkyl or C1-C6Alkoxy carbonyl group；
R15It is selected from: H or C1-C4Alkyl；
Alternatively, R8And R9N atom connected to them is formed together a ring, selected from it is following any one:
S is 0,1 or 2；
T is 1,2 or 3；
Q is selected from: S, O, NH, NCH3、N(CH2)2OH or CHR17a；R17aIt is selected from: the C that H, OH, hydroxyl replace1-C3Alkyl or C (O)OH；
R16It is selected from: the C that H, C (O) OH, hydroxyl replace1-C4Alkyl or C (O) NHSO2R19；
R17It is selected from: the C that H, C (O) OH, hydroxyl replace1-C4Alkyl, OH, C (O) or C (O) NHSO2R19；
R18It is selected from: C1-C4Alkoxy carbonyl group, C1-C6The C that alkyl, C (O) OH, F, Cl, Br, I, OH, hydroxyl replace1-C4Alkyl, NRaRbOr phenyloxycarbonyl；Wherein, the phenyl of phenyloxycarbonyl is optionally by F, Cl, Br, I, OH, CN, NO2、NH2、CF3、 CF2CF3、OCF3、OCF2CF3、SO2NH2、C(O)OH、C(O)NH2Or NHC (O) NH2Replace；RaAnd RbIndependently selected from: H, C1-C4 Alkoxy carbonyl group or C1-C4Alkyl-carbonyl；
R19It is selected from: CF3, cyclopropyl, C1-C4Alkyl, dimethylamino or methyl substituted imidazole radicals；
R3、R4、R5、R6And R7It is each independently selected from: H, Rc、ORc、SRc、S(O)Rc、S(O)2Rc、C(O)Rc、C(O)OH、C (O)ORc、OC(O)Rc、NHRc、N(Rc)2、C(O)NH2、C(O)NHRc、C(O)N(Rc)2、NH(CO)Rc、NRc(CO)Rc、NH(CO) ORc、NRc(CO)ORc、NH(CO)NH2、NH(CO)NHRc、NH(CO)N(Rc)2、NRc(CO)NHRc、NRc(CO)N(Rc)2、SO2NH2、 SO2NHRc、SO2N(Rc)2、NHSO2Rc、NRcSO2Rc、NHSO2NHRc、NHSO2N(Rc)2、NRcSO2NHRc、NRcSO2N(Rc)2、C (O)NHNOH、C(O)NHNORc、C(O)NHSO2Rc、C(NH)NH2、C(NH)NHRc、C(NH)N(Rc)2、F、Cl、Br、I、CN、NO2、 NH2、OH、CF3、CF2CF3、OCF3Or OCF2CF3；
RcIt is selected from: phenyl, heteroaryl, naphthenic base, cycloalkenyl, Heterocyclylalkyl, heterocycloalkenyl, substituted or non-substituted C1-C4 Alkyl, alkenyl or alkynyl；
Alternatively, R4、R5、R6And R7Among every two and their atoms for being connected to be formed together it is substituted or non-substituted Phenyl ring, substituted or non-substituted hetero-aromatic ring, substituted or non-substituted cycloalkanes hydrocarbon ring, substituted or non-substituted heterocycloalkane ring or Substituted or non-substituted heterocyclic alkene ring；
W is selected from: H, F, Cl, Br, I, CN, NO2、NH2、OH、CF3、CF2CF3、OCF3、OCF2CF3、C1-C4Alkyl, alkenyl, Alkynyl, alkoxy, alkylthio group, naphthenic base, halogenated alkyl, halogenated alkoxy, halogenated alkylthio, halogenated cycloalkyl or heterocycle alkane Base.
In certain embodiments, the benzoxadiazole class compound includes its pharmaceutically acceptable salt, mutually variation Structure body, mesomer, racemic modification, stereoisomer, metabolite, metabolic precursor thereof, prodrug or solvate.
In certain preferred aspects, the R in the benzoxadiazole class compound1For-(CH2)nAr；Wherein, n It is 1；Ar is substituted or non-substituted aryl or heteroaryl；
R2For-(CH2)mNR8R9；Wherein, m is 1；
R8It is selected from: H or C1-C4Alkyl；
R9Selected from it is following any one:
P is 1 or 2；
R10It is H；
R11It is selected from: H or C1-C3Alkyl；
R12It is selected from: H or C1-C3Alkyl；
R13It is selected from: H or C1-C3Alkyl；
R14It is selected from: H, C1-C6Alkyl or C1-C6Alkoxy carbonyl group；
R15It is selected from: H or C1-C4Alkyl；
Alternatively, R8And R9N atom connected to them is formed together a ring, selected from it is following any one:
S is 0 or 1；
T is 2 or 3；
Q is selected from: S, O, NH, NCH3、N(CH2)2OH or CHR17a；R17aIt is selected from: the C that H, OH, hydroxyl replace1-C3Alkyl or C (O)OH；
R16It is selected from: the C that H, C (O) OH, hydroxyl replace1-C4Alkyl or C (O) NHSO2R19；
R17It is selected from: the C that H, C (O) OH, hydroxyl replace1-C4Alkyl, OH, C (O) or C (O) NHSO2R19；
R18It is selected from: C1-C4Alkoxy carbonyl group, C1-C6The C that alkyl, C (O) OH, F, Cl, Br, I, OH, hydroxyl replace1-C4Alkane Base ,-NRaRbOr phenyloxycarbonyl；The phenyl of phenyloxycarbonyl is optionally by F, Cl, Br, I, OH, CN, NO2、NH2、CF3、CF2CF3、 OCF3、OCF2CF3、SO2NH2、C(O)OH、C(O)NH2Or NHC (O) NH2Replace；RaAnd RbIt is each independently selected from: H, C1-C4Alkane Oxygen carbonyl or C1-C4Alkyl-carbonyl；
R19It is selected from: CF3, cyclopropyl, C1-C4Alkyl, dimethylamino or methyl substituted imidazole radicals；
R3、R4、R5、R6And R7It is each independently selected from: H, Rc、ORc、SRc、S(O)Rc、S(O)2Rc、C(O)Rc、C(O)OH、C (O)ORc、OC(O)Rc、NHRc、N(Rc)2、C(O)NH2、C(O)NHRc、C(O)N(Rc)2、NH(CO)Rc、NRc(CO)Rc、NH(CO) ORc、NRc(CO)ORc、NH(CO)NH2、NH(CO)NHRc、NH(CO)N(Rc)2、NRc(CO)NHRc、NRc(CO)N(Rc)2、SO2NH2、 SO2NHRc、SO2N(Rc)2、NHSO2Rc、NRcSO2Rc、NHSO2NHRc、NHSO2N(Rc)2、NRcSO2NHRc、NRcSO2N(Rc)2、C (O)NHNOH、C(O)NHNORc、C(O)NHSO2Rc、C(NH)NH2、C(NH)NHRc、C(NH)N(Rc)2、F、Cl、Br、I、CN、NO2、 NH2、OH、CF3、CF2CF3、OCF3Or OCF2CF3；
RcIt is selected from: phenyl, heteroaryl, naphthenic base, cycloalkenyl, Heterocyclylalkyl, heterocycloalkenyl, substituted or non-substituted C1-C4 Alkyl, alkenyl or alkynyl；
Alternatively, R4、R5、R6And R7Among every two and their atoms for being connected to be formed together it is substituted or non-substituted Phenyl ring, substituted or non-substituted hetero-aromatic ring, substituted or non-substituted cycloalkanes hydrocarbon ring, substituted or non-substituted heterocycloalkane ring or Substituted or non-substituted heterocyclic alkene ring；
W is selected from: H, F, Cl, Br, I, CN, NO2、NH2、OH、CF3、CF2CF3、OCF3、OCF2CF3、C1-C4Alkyl, alkenyl, Alkynyl, alkoxy, alkylthio group, naphthenic base, halogenated alkyl, halogenated alkoxy, halogenated alkylthio, halogenated cycloalkyl or heterocycle alkane Base.
Further, the Ar in the benzoxadiazole class compound is substituted or non-substituted aryl or heteroaryl, It is selected from: phenyl, pyridyl group, pyrimidine radicals, quinolyl, isoquinolyl, indazolyl, isoxazolyl, oxadiazoles base, naphthalene, thiazolyl Or imidazole radicals；The substituted or non-substituted aryl or heteroaryl are unsubstituted or are independently selected by one or two or three Replaced following substituent group: C1-C4Alkyl, C1-C4Alkoxy, C1-C4Alkoxy carbonyl group, C1-C4Alkyl sulphonyl, hydroxyl take The C in generation1-C4Alkyl, F, Cl, Br, I, CN, NO2、NH2、OH、CF3、CF2CF3、OCF3、OCF2CF3、C(O)OH、C(O)NH2, morpholine Base, piperidyl, nafoxidine base, piperazinyl, N, N- dimethylamino, THP trtrahydropyranyl, unsubstituted or substituted phenyl.
Further, the R in the benzoxadiazole class compoundcBe selected from: phenyl, heteroaryl, naphthenic base, cycloalkenyl, Heterocyclylalkyl, heterocycloalkenyl, substituted or non-substituted C1-C4Alkyl, alkenyl or alkynyl；The substituted or non-substituted C1-C4Alkane Base is unsubstituted or each independently is selected from replaced following substituent group by one or two or three: Rg、OH、(O)、C (O)OH、CN、NH2、F、Cl、Br、I、CF3、CF2CF3、NC(Rh)(Ri)、Rj、ORj、SRj、S(O)Rj、S(O)2Rj、NHRj、N (Rj)2、C(O)Rj、C(O)NH2、C(O)NHRj、C(O)N(Rj)2、NHC(O)Rj、NRjC(O)Rj、NHSO2Rj、NHC(O)ORj、 SO2NHRj、SO2N(Rj)2、NHC(O)NH2、NHC(O)NHRj, pyrrolidin-1-yl, piperidin-1-yl, piperazine -1- base, 4- methyl - Piperazine -1- base, morpholine -4- base, thiomorpholine -1,1- dioxo -4- base, NHC (O) CH (CH3)NHC(O)CH(CH3) NH or NHC (O)CH(CH3)NHC(O)-CH(CH3)NHRj；
RgSpirane base selected from 2~5 carbon, each of which is unsubstituted or by OH, (O), CN, NH2、F、Cl、Br、I、 CF3、CF2CF3、NH(CH3) or N (CH3)2Replace；
RhAnd RiAlkyl selected from independent choice, or be aziridine -1- base, azacyclo- together with the N that they are connected to Butane -1- base, pyrrolidin-1-yl or piperidin-1-yl, it is each have one it is not substituted or by O, C (O), CNOH, CNOCH3、S、S(O)、S(O)2Or the CH of NH substitution2Part；
RjIt is selected from: phenyl, heteroaryl, naphthenic base, cycloalkenyl, Heterocyclylalkyl, heterocycloalkenyl, C1-C4Alkyl, alkenyl or alkynes Base.
Embodiment more preferably, benzoxadiazole class compound of the present invention or its is pharmaceutically acceptable Salt, tautomer, mesomer, racemic modification, stereoisomer, metabolite, metabolic precursor thereof, prodrug or solvate are Compound as shown in table 1 below:
The structure and name of 1 compound of table
Benzoxadiazole class compound of the invention can be used as pharmaceutical salts use.The salt can be at least one of following acid Hydrochlorate: galactosaccharic acid, D- glucuronic acid, phosphoglycerol, hippuric acid, isethionic acid, lactobionic acid, maleic acid, 1,5- naphthalene two Sulfonic acid, naphthalene-2-sulfonic acid, neopentanoic acid, terephthalic acid (TPA), thiocyanic acid, cholic acid, dodecyl sulfuric acid, benzene sulfonic acid, citric acid, D- Glucose, glycolic, lactic acid, malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, first Acid, hydroiodic acid, hydrobromic acid, Loprazolam, niacin, nitric acid, orotic acid, oxalic acid, picric acid, L-Glutimic acid, saccharinic acid, bigcatkin willow Acid, gentianic acid, p-methyl benzenesulfonic acid, valeric acid, palmitinic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid, 4- benzene sulphur Acid, ethane disulfonic acid, ethylsuccinic acid, fumaric acid, 3- hydroxyl naphthalene -2- formic acid, 1- hydroxyl naphthalene -2- formic acid, oleic acid, endecatylene Acid, ascorbic acid, camphoric acid, camphorsulfonic acid, dichloroacetic acid, ethane sulfonic acid.On the other hand, which is also possible to change of the invention Close object and metal (including sodium, potassium, calcium etc.) ion or pharmaceutically acceptable amine (including ethylenediamine, tromethamine etc.) or ammonium from The salt that son is formed.
The present invention also provides the benzoxadiazole class compound or its pharmaceutically acceptable salt, tautomer, Mesomer, racemic modification, stereoisomer, metabolite, metabolic precursor thereof, prodrug or solvate have PD-1/ in preparation Application in the inhibitor of PD-L1 inhibitory activity.
The inventors discovered that benzoxadiazole class compound shown in formula (I) is the suppression of immunologic test point PD-1/PD-L1 Preparation.The results of study such as homogeneous phase time discrimination fluorescence experiment show that formula (I) compound has the interaction of PD-1 and PD-L1 There is good inhibiting effect, and the proliferative capacity of T cell can be increased significantly, promotes the generation of immune factor, and activate T cell Antineoplastic immune activity, thus can be used for the immunization therapy of tumour.Therefore, benzoxadiazole class compound of the invention, packet Before including its pharmaceutically acceptable salt, tautomer, mesomer, racemic modification, stereoisomer, metabolite, metabolism Body, prodrug or solvate can be used for preparing immunotherapy of tumors drug as immunologic test point inhibitor.
Benzoxadiazole class compound of the invention can be used for the immunization therapy of tumour.The tumour includes but is not limited to: Osteocarcinoma, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic system leukaemia, chronic lymphocytic system are white Blood disease, myeloproliferative disease, Huppert's disease, myelodysplastic syndrome, hodgkin's lymphomas, non-Hodgkins Lymthoma, hemangioma, granulation tumor, vitiligoidea, meningosarcoma, glioma, astrocytoma, medulloblastoma, room pipe Film tumor, gonioma (pinealoma), glioblastoma multiforme, Oligodendroglioma, neurinoma, at view Retinulae tumor, fibroneuroma, sarcoma, cancer of the esophagus, gastric cancer, cancer of pancreas, colorectal cancer, colon and rectum carcinoma, kidney, forefront Gland cancer, lymph cancer, carcinoma of testis, interstitial cell cancer, lung cancer, liver cancer, cutaneum carcinoma, chromoma and basal-cell carcinoma etc..
In certain embodiments, formula of the invention (I) compound can be used alone.And in certain embodiments, this Formula (I) compound of invention can be used in combination with other one or more anti-tumor drugs.It may be selected to dislike with benzo of the invention The anti-tumor drug that diazoles compound is used in combination includes but is not limited to: chemotherapeutics, as docetaxel, taxol, Abraxane, Doxorubicin, oxaliplatin, carboplatin, cis-platinum, Irinotecan, gemcitabine and cyclophosphamide etc.；Immunologic test point Inhibitor, (such as such as CTLA-4 inhibitor (such as Yervoy), PD-1 inhibitor (such as Keytruda and Opdivo), PD-L1 inhibitor Tecentriq), LAG-3 inhibitor (such as BMS986016, REGN3767 and LAG525), TIM-3 inhibitor (such as TSR-022 and MBG-453), TIGIT inhibitor (such as MTIG7192A), B7H4 inhibitor and VISTA inhibitor (such as JNJ-61610588)； Antibody drug conjugate (ADC), such as Kadcyla；Kinase inhibitor, (such as such as SHP-2 inhibitor, B-RAF inhibitor Vemurafenib), mek inhibitor (such as Cobimetinib) and Btk inhibitor (such as Ibrutinib)；IDO inhibitor is (such as Epacadostat) etc..
The present invention also provides a kind of pharmaceutical compositions for immunotherapy of tumors, wherein containing as described in the present invention Benzoxadiazole class compound or its pharmaceutically acceptable salt, tautomer, meso shown in the formula (I) of therapeutically effective amount Body, racemic modification, stereoisomer, metabolite, metabolic precursor thereof, prodrug or solvate are as active constituent and pharmaceutically may be used The carrier of receiving.The carrier that can arbitrarily mix can change according to dosage form, form of medication etc..The example of carrier include excipient, Adhesive, disintegrating agent, lubricant, corrigent, flavouring agent, colorant and sweetener etc..Described pharmaceutical composition can be capsule The preparations such as agent, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository and patch Conventional dosage form on.
Further, described pharmaceutical composition be capsule, powder, tablet, granule, pill, injection, syrup, Oral solution, inhalant, ointment, suppository or patch.
In order to shape the pharmaceutical composition of tablet form, it can be used this field any known and widely used figuration Agent.For example, carrier, such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, avicel cellulose and silicon Acid etc.；Adhesive, such as water, ethyl alcohol, propyl alcohol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose Element, lac, methylcellulose and potassium phosphate, polyvinylpyrrolidone etc.；Disintegrating agent, such as dried starch, mosanom, agar powder and sea Band powder, sodium bicarbonate, calcium carbonate, the aliphatic ester of polyethylene sorbitan, lauryl sodium sulfate, glycerol monostearate Ester, starch and lactose etc.；Disintegration inhibitor, such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil and fat；Adsorption enhancer, such as Quaternary amine alkali and lauryl sodium sulfate etc.；Wetting agent, such as glycerol, starch；Adsorbent, such as starch, lactose, kaolin, swelling Soil and colloid silicic acid etc.；And lubricant, such as pure talcum, stearate, boric acid powder and polyethylene glycol etc..It can also basis It needs to select common coated material that sugar coated tablet is made, applies gelatin film tablet, enteric coated tablets, film coated tablets, duplicature tablet And multilayer tablet.
In order to shape the pharmaceutical composition of pill, it can be used this field any of and widely used figuration Agent, for example, carrier, such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talcum powder etc.；Adhesive, such as Arabic tree Rubber powder, tragacanth gum powder, gelatin and ethyl alcohol etc.；Disintegrating agent, such as agar and Kelp Powder.
In order to shape the pharmaceutical composition of suppository form, it can be used this field any known and widely used inborn nature Agent, for example, polyethylene glycol, coconut oil, higher alcohol, the ester of higher alcohol, gelatin and semi-synthetic glyceride etc..
In order to prepare the pharmaceutical composition of injection form, can be made after solution or suspension liquid disinfectant and blood isoosmotic pressure Injection.When preparing injection, it is possible to use any commonly employed carrier in the art.For example, water, ethyl alcohol, propylene glycol, ethyoxyl The isooctadecanol of change, isooctadecanol and the aliphatic ester of polyethylene sorbitan of polyoxy etc..In addition, can also be added logical Normal lytic agent, buffer and analgesic etc..
In described pharmaceutical composition, the diluent can be diluent conventional in the art.
The pharmaceutical composition can be oral form, be also possible to sterile injectable aqueous form, can be according to this Any known method preparation for preparing Pharmaceutical composition in field is taken orally or injectable composition.
The preparation of benzoxadiazole class compound of the invention can refer to the progress of the method in embodiment, particularly, work as institute State the R in formula (I) compound2For-(CH2)mNR8R9, and when m is 1, the preparation of benzoxadiazole class compound of the invention can be joined It is carried out according to following synthetic route or improved method.
In said synthesis route, Y is bromine, chlorine, iodine, p-methyl benzenesulfonic acid ester, methanesulfonates or triflate；R1、 R3、R4、R5、R6、R7、R8、R9It is consistent with the definition in the formula (I) compound with the definition of W.The synthesis of the compound is specific The following steps are included:
(1) it is reacted to obtain compound M-3 in the presence of alkali with compound M-2 by compound M-1: used solvent packet It includes but is not limited to: benzene, toluene, chloroform, n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, methyl tertiary butyl ether(MTBE), acetic acid Ethyl ester, propyl acetate, butyl acetate, methanol, ethyl alcohol, acetone, tetrahydrofuran, ether, acetonitrile, N,N-dimethylformamide, two First sulfoxide or the mixed solvent optionally formed with these solvents, preferably acetone, n,N-Dimethylformamide, tetrahydrofuran, second Nitrile or methylene chloride；Used alkali includes but is not limited to: triethylamine, diisopropylethylamine, 1,8- diazacyclo [5,4,0] ten One alkene -7, potassium carbonate, sodium carbonate, saleratus or sodium bicarbonate；Reaction temperature be 0 DEG C to 150 DEG C, preferable temperature be 50 DEG C extremely 100℃；
(2) reacted to obtain compound M-4 with azide by compound M-3: used solvent includes but is not limited to: Benzene, toluene, chloroform, n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, methyl tertiary butyl ether(MTBE), ethyl acetate, acetic acid third Ester, butyl acetate, methanol, ethyl alcohol, acetone, tetrahydrofuran, ether, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or use The mixed solvent that these solvents optionally form, preferably acetone, n,N-Dimethylformamide, tetrahydrofuran or acetonitrile；It is used Azide includes but is not limited to: sodium azide or potassium azide；Reaction temperature be 0 DEG C to 150 DEG C, preferable temperature be 50 DEG C extremely 100℃；
(3) obtain compound M-5 through cyclization reaction by compound M-4: used solvent includes but is not limited to: benzene, first Benzene, chloroform, n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, methyl tertiary butyl ether(MTBE), ethyl acetate, propyl acetate, second Acid butyl ester, methanol, ethyl alcohol, acetone, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide are appointed with these solvents Select the mixed solvent of composition, preferably acetone, n,N-Dimethylformamide, tetrahydrofuran, toluene or acetonitrile；Reaction temperature is room temperature To 200 DEG C, preferable temperature is 50 DEG C to 150 DEG C；
(4) by compound M-5 and R1OH reacts in the presence of alkali obtains compound M-6: used solvent include but It is not limited to: benzene, toluene, chloroform, n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, methyl tertiary butyl ether(MTBE), acetic acid second Ester, propyl acetate, butyl acetate, acetone, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or molten with these The mixed solvent that agent optionally forms, preferably acetone, n,N-Dimethylformamide, tetrahydrofuran or acetonitrile；Used alkali includes But it is not limited to: triethylamine, diisopropylethylamine, 1,8- diazacyclo [5,4,0] hendecene -7, potassium carbonate, sodium carbonate, bicarbonate Potassium or sodium bicarbonate；Reaction temperature is -20 DEG C to 100 DEG C, and preferable temperature is room temperature to 50 DEG C；
(5) reacted under the action of deoxidier by compound M-6 and obtain compound M-7: used solvent includes but not Be limited to: benzene, toluene, chloroform, n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, methyl tertiary butyl ether(MTBE), ethyl acetate, Propyl acetate, butyl acetate, acetone, methanol, ethyl alcohol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or The mixed solvent optionally formed with these solvents, preferably n,N-Dimethylformamide, tetrahydrofuran or acetonitrile；Used deoxidation Agent includes but is not limited to: triphenylphosphine, triethyl phosphine, tributylphosphine or tricyclohexyl phosphine；Reaction temperature is 0 DEG C to 150 DEG C, excellent Selecting temperature is 50 DEG C to 120 DEG C；
(6) by compound M-7 and NHR8R9Carry out reductive amination process to obtain compound (Ia): used solvent includes But be not limited to: acetic acid, benzene, toluene, chloroform, n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, methyl tertiary butyl ether(MTBE), Ethyl acetate, propyl acetate, butyl acetate, methanol, ethyl alcohol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide Or the mixed solvent optionally formed with these solvents；Used reducing agent includes but is not limited to: sodium borohydride, triacetyl oxygen Base sodium borohydride or sodium cyanoborohydride；Reaction temperature is -20 DEG C to 80 DEG C, and preferable temperature is 0 DEG C to 50 DEG C；
(7) alternatively, obtaining compound M-8 through reduction reaction by compound M-7, used reducing agent includes but unlimited In: sodium borohydride or potassium borohydride；M-8 is esterified to obtain compound M-9 through halogenation or sulfonic acid again, used halogenating agent include but It is not limited to: PPh3/CBr4、PBr3、POBr3、HBr、PCl3、POCl3, HCl or HI, used sulfonic acid esterifying reagent is (in alkali Under effect) include but is not limited to: paratoluensulfonyl chloride, mesyl chloride, methanesulfonic acid acid anhydride, trifluoromethanesulfchloride chloride or trifluoromethanesulfonic acid Acid anhydride；M-9 in the presence of alkali with NHR8R9It is alkylated reaction and obtains compound (Ia), used alkali includes but is not limited to: Triethylamine, diisopropylethylamine, 1,8- diazacyclo [5,4,0] hendecene -7, potassium carbonate, sodium carbonate, saleratus or carbonic acid Hydrogen sodium.
Formula (I) compound of the invention or its pharmaceutically acceptable salt, tautomer, mesomer, racemic modification, Stereoisomer, metabolite, metabolic precursor thereof, the dosage of prodrug or solvate according to patient age, weight, symptom and can give Medicine approach etc. and suitably change.For adult, in oral administration, the lower limit of single administration amount is 0.1mg (preferably 1mg), The upper limit is 1000mg (preferably 500mg)；In intravenously administrable, the lower limit of single administration amount is 0.01mg (preferably 0.1mg), the upper limit It is 500mg (preferably 250mg).This dosage range can also be deviateed according to the difference of disease degree and the difference of dosage form.
The utility model has the advantages that compared with prior art, the present invention has the advantage that
(1) novel benzoxadiazole class compound of the invention can significantly inhibit the interaction of PD-1/PD-L1, and Activity is significantly better than known PD-1/PD-L1 inhibitor BMS-1016.It is of particular importance that benzoxadiazole class of the invention Compound can block significantly PD-L1 to the inhibiting effect of T cell, and inhibiting tumour cells T cell can be blocked to be proliferated and divide The effect of IFN-γ is secreted, thus has effects that enhance T cell antineoplastic immune.Therefore, the compound of the present invention is as immune Checkpoint PD-1/PD-L1 inhibitor can be used for preparing the drug of immunotherapy of tumors.
(2) synthetic route of benzoxadiazole class compound of the invention is ingenious in design, simple and easy to do, and raw material is cheaply easy , synthesis technology is safe and environment-friendly, is easy to large-scale production.
(3) benzoxadiazole class compound of the invention is as novel PD-1/PD-L1 micromolecular inhibitor, than existing PD-1/PD-L1 monoclonal antibody class drug has many advantages, such as low in cost, easily prepared and potential immune response Small side effects, i.e., It can be used alone, can also be expected to become novel tumor immunization therapy medicine with chemotherapeutic or other immunotherapy of tumors drug combinations Object.
Detailed description of the invention
Fig. 1 is that benzoxadiazole class compounds block PD-L1 inhibits human peripheral blood single nucleus cell (PBMC) to secrete IFN- The effect figure of γ: blank control group, activation group, the compound group of inhibition group and various concentration human PBMC after 48 hrs The secretion situation (p < 0.001 n=3, * p < 0.05, * * p < 0.01, * * *) of IFN-γ；
Fig. 2 is the effect figure of benzoxadiazole class compounds block inhibiting tumour cells human T-cell proliferation: blank control Group, activation group, the proliferative conditions of the T cell of the compound group of inhibition group and various concentration after 48 hrs；
Fig. 3 is the effect figure of benzoxadiazole class compounds block inhibiting tumour cells human T-cell's secretion of gamma-IFN: blank Secretion situation (the n of control group, activation group, the T cell of the compound group of inhibition group and various concentration IFN-γ after 48 hrs P < 0.001=3, * p < 0.05, * * p < 0.01, * * *).
Specific embodiment
The contents of the present invention are illustrated below by embodiment.In the present invention, embodiments discussed below be in order to It preferably illustrates the present invention, is not for limiting the scope of the invention.In the premise without departing substantially from the spirit and scope of the present invention Under, various change and modification can be carried out to the present invention.
Embodiment 1
N- ((5- ((3- cyanobenzyls) oxygroup) -7- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) benzo [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 1)
Synthetic route:
The synthesis of compound I-2
It takes compound M-2 (1.8g) to be dissolved in anhydrous propanone (30mL), anhydrous sodium bicarbonate (1.3g) and the tetrabutyl is added Iodate amine (TBAI, 300mg), and it is slowly added to I-1 (2g), argon gas protection, 70 DEG C of oil bath heatings.Reaction stops after about 6 hours Heating, evaporating solvent under reduced pressure are added ethyl acetate (25mL) dilution, are washed with water (10mL x3) and saturated salt solution (10mL x2) It washs, anhydrous sodium sulfate is dry.Evaporating solvent under reduced pressure, residue are pure through column chromatography (eluant, eluent: petrol ether/ethyl acetate=3:1) Change, obtains faint yellow solid compound I-2 (2.14g).
The synthesis of compound I-3
It takes compound I-2 (2.33g) to be dissolved in acetonitrile (50mL), is slowly added in batches sodium azide (493mg), 75 DEG C of oil Bath heating.Stop heating after reaction about 5 hours, evaporating solvent under reduced pressure obtains the crude product (2.78g) of yellow solid compound I-3.
The synthesis of compound I-4
It takes the crude product (2.78g) of compound I-3 to be dissolved in toluene (30mL), is placed in 110 DEG C of oil bath heatings.Reaction about 5 hours Stop heating afterwards, stand 2 hours, there is solid precipitation, filters, obtain yellow solid compound I-4 (1.2g).
The synthesis of compound I-5
It takes compound I-4 (500mg) to be added in acetonitrile (15mL), Anhydrous potassium carbonate (364mg) and 3- methylol benzene is added Formonitrile HCN (176mg), reaction solution stop reaction after normal-temperature reaction 12 hours, and evaporating solvent under reduced pressure is added ethyl acetate (25mL) Dilution, is washed with water (10mL x3) and saturated salt solution (10mL x2), and anhydrous sodium sulfate is dry.Evaporating solvent under reduced pressure, it is remaining Object obtains yellow solid compound I-5 (449mg) through column chromatography (eluant, eluent: petrol ether/ethyl acetate=1:1) purifying.
The synthesis of compound I-6
It takes compound I-5 (449mg) to be dissolved in n,N-Dimethylformamide (5mL), is added triphenylphosphine (240mg), 90 DEG C Oil bath heating.Stop heating after reaction about 6 hours, be added water (10mL), is extracted with ethyl acetate (10mL x3), anhydrous slufuric acid Sodium is dry.Evaporating solvent under reduced pressure, residue are purified through column chromatography (eluant, eluent: petrol ether/ethyl acetate=2:1), and it is solid to obtain yellow Body compound I-6 (159mg).
The synthesis of compound I-7
It takes D-Ser carbethoxy hydrochloride (214mg) to be dissolved in the mixed solvent (3:1,4mL) of methylene chloride and methanol, is added N,N-diisopropylethylamine (163mg) is stirred at room temperature 20 minutes, and compound I-6 (150mg) and triacetoxy boron hydride is added Sodium (STAB, 267mg) stops reaction after room temperature reaction 12 hours.Evaporating solvent under reduced pressure, residue chromatograph (eluant, eluent: stone through column Oily ether/ethyl acetate=1:1) purifying, obtain yellow oily compound I-7 (135mg).
The synthesis of compound 1
It takes compound I-7 (135mg) to be dissolved in the mixed solvent (2:1,3mL) of methanol and tetrahydrofuran, a hydronium(ion) is added Lithia (24mg), after room temperature reaction 5 hours, evaporating solvent under reduced pressure, residue chromatographs (eluant, eluent: methanol/water=1:1) through column Purifying, obtains faint yellow solid compound 1 (46mg):1H NMR (300MHz, DMSO) δ 8.04 (s, 1H), 7.95 (d, J= 7.9Hz, 1H), 7.84 (d, J=7.7Hz, 1H), 7.64 (t, J=7.8Hz, 1H), 7.54 (d, J=7.4Hz, 1H), 7.51- 7.42 (m, 2H), 7.39 (d, J=6.8Hz, 1H), 7.37-7.29 (m, 3H), 7.29-7.17 (m, 2H), 5.46 (s, 2H), 5.44 (s, 2H), 3.89 (s, 2H), 3.79 (s, 1H), 3.45 (dd, J=9.6,5.4Hz, 1H), 3.19 (t, J=9.5Hz, 1H), 2.60 (dd, J=9.2,5.3Hz, 1H), 2.24 (s, 3H) .ESI-MS:m/z 587.18957 [M+Na]+。
Embodiment 2
N- (2- (((5- ((3- cyanobenzyls) oxygroup) -7- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) benzo [c] [1,2,5] oxadiazoles -4- base) methyl) amino) ethyl) acetamide (compound 2)
Referring to the method for embodiment 1, the D-Ser carbethoxy hydrochloride in embodiment 1 is substituted for N- acetyl group second two Compound 2 is made in amine:1H NMR(300MHz,CDCl3) δ 7.73 (s, 1H), 7.71-7.60 (m, 2H), 7.54 (t, J= 7.7Hz, 1H), 7.40 (m, J=13.3,6.7Hz, 4H), 7.29 (m, 4H), 6.58 (s, 1H), 6.28 (s, 1H), 5.38 (s, 2H), 5.21 (s, 2H), 4.09 (s, 2H), 3.34 (dd, J=10.8,5.3Hz, 2H), 2.74 (t, J=5.6Hz, 2H), 2.28 (s,3H),1.95(s,3H).HRMS(ESI):m/z 562.24496[M+H]+。
Embodiment 3
N- ((5- ((3- cyanobenzyls) oxygroup) -7- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) benzo [c] [1,2,5] oxadiazoles -4- base) methyl) glycine (compound 3)
Referring to the method for embodiment 1, the D-Ser carbethoxy hydrochloride in embodiment 1 is substituted for glycine methyl ester hydrochloric acid Compound 3 is made in salt:1H NMR(300MHz,CD3OD)δ7.95–7.83(m,2H),7.75–7.54(m,3H),7.50–7.21 (m,7H),6.96(s,1H),5.44(s,2H),5.40(s,2H),4.05(s,2H),3.18(s,2H),2.27(s,3H).MS (ESI):m/z 533.3[M-H]+。
Embodiment 4
N- ((5- ((4- cyanobenzyls) oxygroup) -7- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) benzo [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 4)
Referring to the method for embodiment 1, the 3- methylol benzonitrile in embodiment 1 is substituted for 4- methylol benzonitrile, is made Obtain compound 4:1H NMR(500MHz,CD3OD) δ 7.77 (d, J=7.8Hz, 2H), 7.71 (d, J=7.8Hz, 2H), 7.51- 7.43 (m, 3H), 7.39 (t, J=7.1Hz, 1H), 7.33 (d, J=7.4Hz, 2H), 7.31-7.27 (m, 2H), 7.00 (s, 1H),5.49(s,2H),5.47(s,2H),4.35–4.19(m,2H),3.86–3.74(m,2H),3.28(t,1H).HRMS (ESI):m/z 587.18979[M+H]+。
Embodiment 5
N- ((5- (pyridin-3-yl methoxyl group) -7- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) benzo [c] [1, 2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 5)
Referring to the method for embodiment 1, the 3- methylol benzonitrile in embodiment 1 is substituted for 3- pyridinemethanol, obtainedization Close object 5:1H NMR(500MHz,CD3OD) δ 8.75 (s, 1H), 8.56 (s, 1H), 8.07 (d, J=6.6Hz, 1H), 7.52 (d, J =6.1Hz, 2H), 7.46 (t, J=7.2Hz, 2H), 7.39 (t, J=7.1Hz, 1H), 7.33-7.27 (m, 4H), 7.07 (s, 1H),5.50(s,2H),5.45(s,2H),4.20(s,2H),3.79(s,2H),3.27–3.19(m,1H).HRMS(ESI):m/z 563.18947[M+Na]+。
Embodiment 6
N- ((5- (3- luorobenzyl) oxygroup) -7- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) benzo [c] [1,2, 5] oxadiazoles -4- base) methyl)-D-Ser (compound 6)
Referring to the method for embodiment 1, the 3- methylol benzonitrile in embodiment 1 is substituted for 3- fluoro benzyl alcohol, chemical combination is made Object 6:1H NMR (300MHz, DMSO) δ 7.67-6.96 (m, 13H), 5.44 (s, 2H), 5.39 (s, 2H), 3.99 (d, J= 16.8Hz, 1H), 3.92 (d, J=12.5Hz, 1H), 3.48 (s, 1H), 2.79 (s, 1H), 2.22 (s, 3H), 1.99 (s, 1H) .HRMS(ESI):m/z 580.18710[M+Na]+。
Embodiment 7
N- ((5- ((3- chlorobenzyl) oxygroup) -7- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) benzo [c] [1, 2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 7)
Referring to the method for embodiment 1, the 3- methylol benzonitrile in embodiment 1 is substituted for 3- chlorobenzyl alcohol, chemical combination is made Object 7:1H NMR(300MHz,CD3OD)δ7.70–7.57(m,2H),7.57–7.53(m,1H),7.48–7.34(m,6H),7.34– 7.22 (m, 4H), 6.93 (s, 1H), 5.40 (s, 2H), 5.34 (s, 2H), 4.13 (d, J=13.5Hz, 1H), 4.07 (d, J= 13.4Hz, 1H), 3.73 (dd, J=10.7,5.6Hz, 1H), 3.66 (dd, J=10.6,6.0Hz, 1H), 3.16 (t, J= 5.8Hz,1H),2.26(s,3H).MS(ESI):m/z 596.3[M+Na]+。
Embodiment 8
N- ((5- ((5- cyanopyridine -3- base) methoxyl group) -7- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) benzene And [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 8)
Referring to the method for embodiment 1, the 3- methylol benzonitrile in embodiment 1 is substituted for 5- (methylol) nicotinic acid nitrile, is made Obtain compound 8:1H NMR(300MHz,DMSO)δ9.08(s,1H),9.01(s,1H),8.48(s,1H),7.64–7.19(m, 9H),5.54(s,2H),5.49(s,2H),4.13–3.96(m,2H),3.53–3.46(m,2H),3.05(t,1H),2.25(s, 3H).MS(ESI):m/z 588.3[M+Na]+。
Embodiment 9
N- ((5- ((2- cyanopyridine -4- base) methoxyl group) -7- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) benzene And [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 9)
Referring to the method for embodiment 1, the 3- methylol benzonitrile in embodiment 1 is substituted for 2- cyano -4- methylol pyrrole Compound 9 is made in pyridine:1H NMR (300MHz, MeOD) δ 8.72 (d, J=4.9Hz, 1H), 8.27 (s, 1H), 7.91-7.80 (m, 1H), 7.48-7.38 (m, 3H), 7.35 (t, J=7.2Hz, 1H), 7.31-7.25 (m, 2H), 7.25-7.18 (m, 2H), 6.98(s,1H),5.60(s,2H),5.47(s,2H),4.60(s,1H),4.54(s,1H),4.02(s,1H),3.86(s,1H), 3.61 (s, 1H), 2.26 (d, J=8.2Hz, 3H) .HRMS (ESI): m/z 566.18910 [M+H]+。
Embodiment 10
N- ((5- ((3- cyanobenzyls) oxygroup) -7- ((3- (2,3- dihydrobenzo [b] [1,4] dioxine -6- Base) -2- methylbenzyl) oxygroup) benzo [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 10)
Synthetic route:
The synthesis of compound A-2
It takes compound A-1 (5g) to be dissolved in methanol (60mL), is slowly added dropwise at room temperature the concentrated sulfuric acid (10mL), about 15 minutes It finishes, 85 DEG C of oil bath heatings.Stop heating after reaction about 10 hours, evaporating solvent under reduced pressure is extracted with ethyl acetate (50mL x3) It takes, saturated sodium carbonate (30mL x3) and saturated salt solution (25mL x2) washing, anhydrous sodium sulfate are dry.Evaporating solvent under reduced pressure, Residue obtains faint yellow oily compound A-2 (5.1g) through column chromatography (eluant, eluent: petrol ether/ethyl acetate=50:1) purifying.
The synthesis of compound A-3
It takes compound A-2 (3g), benzodioxane -4- borate (3.8g), [1,1 '-bis- (diphenylphosphine) ferrocene] Palladium chloride dichloromethane complex (530mg), Anhydrous potassium carbonate (3.5g), 18- crown- 6- ether (345mg) are added to 100mL In three-necked bottle, argon gas protection, ventilation is three times.Toluene (21mL) is added at room temperature, dehydrated alcohol (7mL), water (3.5mL).90℃ Oil bath heating stops heating after reaction about 5 hours, evaporating solvent under reduced pressure is diluted, suction filtered through kieselguhr with ethyl acetate 25mL, female Liquid is extracted with ethyl acetate (45mL x3), saturated salt solution (30mL x2) washing, and anhydrous sodium sulfate is dry.It removes under reduced pressure molten Agent, residue are purified through column chromatography (eluant, eluent: petrol ether/ethyl acetate=8:1), obtain faint yellow oily compound A-3 (3.96g)。
The synthesis of compound A-4
Compound A-3 (3.96g) is taken to be dissolved in the in the mixed solvent of methanol (15mL) and tetrahydrofuran (15mL), under ice bath It is slowly added to a hydronium(ion) lithia (1.5g), stops reaction, evaporating solvent under reduced pressure after reacting at room temperature about 6 hours.1N hydrochloric acid PH=2~3 are adjusted in acidification, are precipitated compound as white solid A-4 (3.3g).
The synthesis of compound A-5
Compound A-4 (3.96g) is taken, is dissolved in anhydrous tetrahydro furan (45mL), borine tetrahydro is slowly added dropwise under ice salt bath Furans compound (29mL) reacts the reaction of stopping in about 5 hours at room temperature, adds water quenching reaction under ice bath.With ethyl acetate (50mL X3) extraction and saturated salt solution (25mL x2) washing, anhydrous sodium sulfate are dry.Evaporating solvent under reduced pressure obtains white solid chemical combination Object A-5 (3.0g).
The synthesis of compound A-6
It takes compound A-5 (3.0g), triphenylphosphine (6.2g) is dissolved in anhydrous tetrahydro furan (30mL), is delayed under ice bath It is slow that carbon tetrabromide (7.8g) is added, stop reaction after reacting at room temperature about 4 hours.Evaporating solvent under reduced pressure uses methylene chloride Suction filtered through kieselguhr after (30mL) dilution, mother liquor are purified through column chromatography (eluant, eluent: petrol ether/ethyl acetate=5:1), are obtained faint yellow Oily compound A-6 (3.6g).
The synthesis of compound II-1
It takes compound M-2 (521mg) to be dissolved in anhydrous propanone (10mL), anhydrous sodium bicarbonate (635mg) He Siding is added Base iodate amine (TBAI, 100mg), and it is slowly added to A-6 (640mg), argon gas protection, 70 DEG C of oil bath heatings.After reaction about 6 hours Stop heating, ethyl acetate (10mL) dilution is added, with water (10mL x3) and saturated salt solution (10mL in evaporating solvent under reduced pressure X2 it) washs, anhydrous sodium sulfate is dry.Evaporating solvent under reduced pressure, residue through column chromatograph (eluant, eluent: petrol ether/ethyl acetate=3: 1) it purifies, obtains faint yellow solid compound II-1 (854mg).
The synthesis of compound 10
Referring to the method for embodiment 1, the compound I-2 in embodiment 1 is substituted for compound II-1, compound is made 10:1H NMR(300MHz,CD3OD) δ 7.91 (d, J=1.5Hz, 2H), 7.77-7.52 (m, 4H), 7.44 (dd, J=6.7, 1.9Hz, 1H), 7.27-7.19 (m, 2H), 6.95 (s, 1H), 6.89 (d, J=7.9Hz, 1H), 6.78-6.71 (m, 2H), 5.43 (s, 2H), 5.40 (s, 2H), 4.29 (s, 5H), 4.15 (d, J=13.5Hz, 1H), 4.09 (d, J=13.5Hz, 1H), 3.74 (dd, J=10.7,5.6Hz, 1H), 3.65 (dd, J=10.7,6.2Hz, 1H), 3.36 (d, J=4.9Hz, 1H), 3.17 (t, J =5.9Hz, 1H) .HRMS (ESI): m/z623.21392 [M+H]+。
Embodiment 11
N- ((5- ((2- cyanopyridine -4- base) methoxyl group) -7- ((3- (2,3- dihydrobenzo [b] [1,4] dioxa hexamethylene Alkene -6- base) -2- methylbenzyl) oxygroup) benzo [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 11)
Referring to the method for embodiment 10, the 3- methylol benzonitrile in embodiment 10 is substituted for 2- cyano -4- methylol Compound 11 is made in pyridine:1H NMR(300MHz,CD3OD) δ 8.69 (d, J=5.0Hz, 1H), 8.02 (s, 1H), 7.72 (d, J =4.3Hz, 1H), 7.38 (dd, J=5.8,3.2Hz, 1H), 7.20 (dd, J=8.2,5.5Hz, 2H), 6.94-6.83 (m, 2H), 6.79-6.68 (m, 2H), 5.46 (s, 2H), 5.40 (s, 2H), 4.28 (s, 4H), 4.21 (d, J=13.5Hz, 1H), 4.14 (d, J=13.5Hz, 1H), 3.75 (dd, J=10.7,5.5Hz, 1H), 3.66 (dd, J=10.7,6.1Hz, 1H), 3.19 (t, J=5.8Hz, 1H), 2.25 (s, 3H) .MS (ESI): m/z 624.2 [M+Na]+。
Embodiment 12
N- ((5- (pyridin-3-yl methoxyl group) -7- ((bromo- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) benzo [c] [1,2, 5] oxadiazoles -4- base) methyl)-Serine (compound 12)
Synthetic route:
The synthesis of compound B-2
It takes compound B-1 (4.2g, 2.8mL) to be dissolved in water (10mL), is slowly added under ice salt bath hydrochloric acid (6mL), stirring 5 Minute, the aqueous solution of sodium nitrite (1.88g) is slowly added dropwise, finishes within 20 minutes, after being stirred 30 minutes under ice salt bath, to reaction solution In the aqueous solution of potassium iodide (7.5g) is slowly added dropwise, stop reaction after reacting 8 hours at room temperature.The saturation of sodium thiosulfate is added Aqueous solution (35mL) is extracted with ethyl acetate (50mL x3), saturated salt solution (25mL x3) washing, and anhydrous sodium sulfate is dry. Evaporating solvent under reduced pressure, residue are purified through column chromatography (eluant, eluent: petroleum ether), obtain faint yellow oily compound B-2 (5.2g)
The synthesis of compound B-3
It taking phenyl boric acid (1.08g), tetrakis triphenylphosphine palladium (465mg), natrium carbonicum calcinatum (1.28g) is placed in three-necked bottle, Argon gas protection.Compound B-2 (2.39g) is dissolved in toluene (8mL), reaction flask is added, is added toluene (22mL), water (3mL), 80 DEG C of oil bath heatings.Stop heating after reaction about 4 hours, evaporating solvent under reduced pressure is diluted with ethyl acetate (15mL), and diatomite is taken out Filter, mother liquor are purified through column chromatography (eluant, eluent: petroleum ether), obtain faint yellow oily compound B-3 (1.78g).
The synthesis of compound B-4
Compound B-3 (1.6g) is taken, is dissolved in carbon tetrachloride (50mL), is added N- bromo-succinimide (1.21g), point It criticizes and benzoyl peroxide (10mg) is added, 90 DEG C of oil bath heatings.Stop heating after reaction about 6 hours, evaporating solvent under reduced pressure is remaining Object obtains colorless oil compound B-4 (1.43g) through column chromatography (eluant, eluent: petroleum ether) purifying.
The synthesis of compound III-1
It takes compound M-2 (638mg) to be dissolved in anhydrous propanone (10mL), anhydrous sodium bicarbonate (405mg) He Siding is added Base iodate amine (TBAI, 200mg), and it is slowly added to B-4 (800mg), argon gas protection, 70 DEG C of oil bath heatings.After reaction about 6 hours Stop heating, ethyl acetate (15mL) dilution is added, with water (10mL x3) and saturated salt solution (10mL in evaporating solvent under reduced pressure X2 it) washs, anhydrous sodium sulfate is dry.Evaporating solvent under reduced pressure, residue through column chromatograph (eluant, eluent: petrol ether/ethyl acetate=5: 1) it purifies, obtains faint yellow solid compound III-1 (726mg).
The synthesis of compound 12
Referring to the method for embodiment 1, the I-2 in embodiment 1 is substituted for III-1,3- methylol benzonitrile is substituted for 3- pyridinemethanol, and D-Ser carbethoxy hydrochloride is substituted for Serine carbethoxy hydrochloride, compound 12 is made:1H NMR (300MHz,CD3OD) δ 8.69 (s, 1H), 8.53 (d, J=4.0Hz, 1H), 8.12 (d, J=7.9Hz, 1H), 7.66 (d, J= 6.4Hz, 1H), 7.57-7.32 (m, 8H), 6.97 (s, 1H), 5.54 (s, 2H), 5.42 (s, 2H), 4.14 (d, J=13.5Hz, 1H), 4.08 (d, J=13.5Hz, 1H), 3.74 (dd, J=10.7,5.6Hz, 1H), 3.65 (dd, J=10.6,6.3Hz, 1H), 3.16 (t, J=5.9Hz, 1H) .HRMS (ESI): m/z 627.08574 [M+Na]+。
Embodiment 13
N- ((5- (pyridin-3-yl methoxyl group) -7- ((bromo- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) benzo [c] [1,2, 5] oxadiazoles -4- base) methyl)-D-Ser (compound 13)
Referring to the method for embodiment 12, the Serine carbethoxy hydrochloride in embodiment 12 is substituted for D-Ser ethyl ester Compound 13 is made in hydrochloride:1H NMR(300MHz,CD3OD) δ 8.67 (d, J=1.5Hz, 1H), 8.51 (dd, J=4.9, 1.5Hz, 1H), 8.10 (d, J=7.6Hz, 1H), 7.65 (dd, J=7.6,1.6Hz, 1H), 7.54-7.33 (m, 7H), 6.96 (s, 1H), 5.53 (s, 2H), 5.40 (s, 2H), 4.13 (d, J=13.4Hz, 1H), 4.06 (d, J=13.6Hz, 1H), 3.72 (dd, J=10.7,5.6Hz, 1H), 3.63 (dd, J=10.7,6.2Hz, 1H), 3.15 (t, J=5.9Hz, 1H) .HRMS (ESI):m/z 629.08200[M+Na]+。
Embodiment 14
N- ((5- ((2- cyanopyridine -4- base) methoxyl group) -7- ((chloro- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) benzo [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 14)
Synthetic route:
The synthesis of compound C-2
It takes compound C-1 (6.15g) to be dissolved in anhydrous tetrahydro furan (50mL), borine tetrahydro furan is slowly added dropwise under ice salt bath Mutter compound (60mL), reacts the reaction of stopping in about 5 hours at room temperature, adds water quenching reaction under ice bath.With ethyl acetate (50mL X4) extraction and saturated salt solution (30mL x2) washing, anhydrous sodium sulfate are dry.Evaporating solvent under reduced pressure obtains white solid chemical combination Object C-2 (5.18g).
The synthesis of compound C-3
It takes compound C-2 (2.5g), phenyl boric acid (1.6g), [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloro Methane complex compound (180mg), acetic anhydride potassium (2.1g), 18- crown- 6- ether (581mg) are added in 100mL three-necked bottle, argon gas Protection, ventilation is three times.Toluene (21mL) is added at room temperature, dehydrated alcohol (7mL) and water (3.5mL).90 DEG C of oil bath heatings, reaction Stop heating after about 5 hours, evaporating solvent under reduced pressure is diluted, suction filtered through kieselguhr, mother liquor ethyl acetate with ethyl acetate 25mL (45mL x3) extraction, saturated salt solution (30mL x2) washing, anhydrous sodium sulfate are dry.Evaporating solvent under reduced pressure, residue is through column (eluant, eluent: petrol ether/ethyl acetate=4:1) purifying is chromatographed, colorless oil compound C-3 (2.2g) is obtained.
The synthesis of compound C-4
It takes compound C-3 (2.2g), triphenylphosphine (5.3g) is dissolved in anhydrous tetrahydro furan (30mL), is delayed under ice bath It is slow that carbon tetrabromide (6.6g) is added, stop reaction after reacting at room temperature about 4 hours.Evaporating solvent under reduced pressure uses methylene chloride Suction filtered through kieselguhr after (25mL) dilution, mother liquor are purified through column chromatography (eluant, eluent: petrol ether/ethyl acetate=5:1), obtain colorless oil Shape compound C-4 (2.4g).
The synthesis of compound IV-1
It takes compound IV-1 (1.6g) to be dissolved in anhydrous propanone (25mL), anhydrous sodium bicarbonate (1.3g) and the tetrabutyl is added Iodate amine (TBAI, 500mg), and it is slowly added to C-4 (2.03g), argon gas protection, 70 DEG C of oil bath heatings.Reaction stops after about 6 hours It only heats, evaporating solvent under reduced pressure, ethyl acetate (15mL) dilution is added, with water (10mL x3) and saturated salt solution (10mL x2) Washing, anhydrous sodium sulfate are dry.Evaporating solvent under reduced pressure, residue chromatograph (eluant, eluent: petrol ether/ethyl acetate=5:1) through column Purifying, obtains faint yellow solid compound IV-1 (960mg).
The synthesis of compound 14
Referring to the method for embodiment 1, the I-2 in embodiment 1 is substituted for IV-1,3- methylol benzonitrile is substituted for 2- cyanogen Compound 14 is made in base -4- hydroxymethylpyridine:1H NMR(300MHz,CD3OD) δ 8.67 (d, J=5.0Hz, 1H), 8.01 (s, 1H), 7.71 (dd, J=5.4,1.0Hz, 1H), 7.61 (dd, J=7.1,2.3Hz, 1H), 7.48-7.32 (m, 7H), 6.85 (s, 1H), 5.51 (s, 2H), 5.45 (s, 2H), 4.19 (d, 1H), 4.15 (d, J=13.2Hz, 1H), 3.74 (dd, 1H), 3.66 (dd, J=10.9,6.3Hz, 1H), 3.19 (t, J=5.8Hz, 1H) .MS (ESI): m/z 624.3 [M+K]+。
Embodiment 15
N- ((5- ((3- cyanobenzyls) oxygroup) -7- ((2- cyano-[1,1'- biphenyl] -3- base) methoxyl group)-benzo [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 15)
Synthetic route:
The synthesis of compound D-2
It takes compound D-1 (10g) to be dissolved in methanol (75mL), is slowly added dropwise at room temperature the concentrated sulfuric acid (20mL), about 15 points Clock finishes, 85 DEG C of oil bath heatings.Stop heating after reaction about 15 hours, evaporating solvent under reduced pressure is extracted with ethyl acetate (60mL x4) It takes, saturated sodium carbonate (50mL x3) and saturated salt solution (100mL x4) washing, anhydrous sodium sulfate are dry.Evaporating solvent under reduced pressure, Residue obtains faint yellow oily compound D-2 (9.0g) through column chromatography (eluant, eluent: petrol ether/ethyl acetate=50:1) purifying.
The synthesis of compound D-3
It takes compound D-2 (9.0g) to be dissolved in water (50mL), is slowly added under ice salt bath hydrochloric acid (20mL), stir 10 points The aqueous solution of sodium nitrite (3.2g) is slowly added dropwise in clock, finishes within about 30 minutes, under ice salt bath after stir about 45 minutes, Xiang Fanying The aqueous solution of potassium iodide (8.4g) is slowly added dropwise in liquid, stops reaction after reacting 8 hours at room temperature.With the saturation of sodium thiosulfate Aqueous solution (60mL), ethyl acetate (100mL x3) extraction, saturated salt solution (80mL x3) washing, anhydrous sodium sulfate are dry.Subtract Solvent is evaporated off in pressure, and residue is purified through column chromatography (eluant, eluent: petrol ether/ethyl acetate=50:1), obtains faint yellow oily chemical combination Object D-3 (11g).
The synthesis of compound D-4
It takes compound D-3 (11g), cuprous cyanide (11.5g), tris(dibenzylideneacetone) dipalladium (604mg), double diphenyl Phosphine ferrocene (730mg), acetic anhydride potassium (6.5g), 18- crown- 6- ether (873mg) are added in 100mL three-necked bottle, and argon gas is protected Three times, anhydrous Isosorbide-5-Nitrae-dioxane 40mL, 110 DEG C of oil bath heatings are added in shield, ventilation.Stop heating, decompression after reaction about 5 hours Solvent is evaporated off, is diluted with ethyl acetate (40mL), suction filtered through kieselguhr, mother liquor chromatographs (eluant, eluent: petrol ether/ethyl acetate through column =3:1) purifying, obtain compound as white solid D-4 (3.47g).
The synthesis of compound D-5
It takes compound D-4 (1.5g), phenyl boric acid (914mg), [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloro Methane complex compound (257mg), acetic anhydride potassium (1.2g), 18- crown- 6- ether (330mg) are added in 50mL three-necked bottle, and argon gas is protected Shield, ventilation is three times.Toluene (18mL) is added at room temperature, dehydrated alcohol (6mL), water (3mL).90 DEG C of oil bath heatings.Reaction about 5 is small When after stop heating, evaporating solvent under reduced pressure, with ethyl acetate 25mL dilute, suction filtered through kieselguhr, mother liquor ethyl acetate (40mL X3 it) extracts, saturated salt solution (40mL x3) washing, anhydrous sodium sulfate is dry.Evaporating solvent under reduced pressure, residue (are washed through column chromatography De- agent: petroleum ether/methylene chloride=30:1) purifying, obtain colorless oil compound D-5 (1.4g).
The synthesis of compound D-6
Compound D-5 (1.41g) is taken to be dissolved in the in the mixed solvent of methanol (10mL) and tetrahydrofuran (10mL), under ice bath It is slowly added to a hydronium(ion) lithia (619mg), stops reaction, evaporating solvent under reduced pressure after reacting at room temperature about 6 hours.1N hydrochloric acid PH=2~3 are adjusted in acidification, are precipitated compound as white solid D-6 (1.36g).
The synthesis of compound D-7
Compound D-6 (1.36g) is taken, is dissolved in anhydrous tetrahydro furan (30mL), borine tetrahydro is slowly added dropwise under ice salt bath Furans compound (12mL) reacts the reaction of stopping in about 5 hours at room temperature, adds water quenching reaction under ice bath.With ethyl acetate (30mL X3) extraction and saturated salt solution (25mL x3) washing, anhydrous sodium sulfate are dry.Evaporating solvent under reduced pressure obtains white solid chemical combination Object D-7 (952mg).
The synthesis of compound D-8
It takes compound D-7 (948mg), triphenylphosphine (1.78g) is dissolved in anhydrous tetrahydro furan (30mL), under ice bath It is slowly added to carbon tetrabromide (2.2g), stops reaction after reacting at room temperature about 4 hours.Evaporating solvent under reduced pressure uses methylene chloride (20mL) dilution, suction filtered through kieselguhr, mother liquor are purified through column chromatography (eluant, eluent: petrol ether/ethyl acetate=5:1), obtain yellow oil Shape compound D-8 (1.2g).
The synthesis of compound VI-1
It takes compound M-2 (968mg) to be dissolved in anhydrous propanone (35mL), anhydrous sodium bicarbonate (750mg) He Siding is added Base iodate amine (TBAI, 850mg), and it is slowly added to D-8 (1.18g), argon gas protection, 70 DEG C of oil bath heatings.After reaction about 6 hours Stop heating, ethyl acetate (35mL) dilution is added, with water (20mL x3) and saturated salt solution (15mL in evaporating solvent under reduced pressure X2 it) washs, anhydrous sodium sulfate is dry.Evaporating solvent under reduced pressure, residue through column chromatograph (eluant, eluent: petrol ether/ethyl acetate=3: 1) it purifies, obtains faint yellow solid compound VI-1 (1.38g).
The synthesis of compound 15
Referring to the method for embodiment 1, the I-2 in embodiment 1 is substituted for VI-1,3- methylol benzonitrile is substituted for 2- cyanogen Compound 15 is made in base -4- hydroxymethylpyridine:1H NMR(300MHz,CD3OD) δ 8.69 (d, J=5.1Hz, 1H), 8.02 (s, 1H),7.84–7.70(m,3H),7.65–7.55(m,3H),7.56–7.45(m,3H),6.97(s,1H),5.62(s,2H), 5.48 (s, 2H), 4.21 (d, J=13.5Hz, 1H), 4.14 (d, J=13.4Hz, 1H), 3.75 (dd, J=10.6,5.5Hz, 1H), 3.66 (dd, J=10.7,6.3Hz, 1H), 3.19 (t, J=5.9Hz, 1H) .MS (ESI): m/z 615.4 [M+K]+。
Embodiment 16
N- ((5- ((3- cyanobenzyls) oxygroup) -7- ((2- cyano-[1,1'- biphenyl] -3- base) methoxyl group)-benzo [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 16)
Referring to the method for embodiment 15, the 2- cyano -4- hydroxymethylpyridine in embodiment 15 is substituted for 3- methylol benzene Compound 16 is made in formonitrile HCN:1H NMR(300MHz,CD3OD) δ 7.94-7.85 (m, 2H), 7.79 (d, J=2.8Hz, 1H), 7.78 (s, 1H), 7.69 (d, J=7.7Hz, 1H), 7.65-7.56 (m, 4H), 7.56-7.47 (m, 3H), 7.01 (s, 1H), 5.63 (s, 2H), 5.40 (s, 3H), 4.16 (d, J=13.5Hz, 1H), 4.09 (d, J=13.5Hz, 1H), 3.73 (dd, J= 10.7,5.7Hz, 1H), 3.64 (dd, J=10.6,6.2Hz, 1H), 3.16 (t, J=5.7Hz, 1H) .HRMS (ESI): m/z 598.16974[M+Na]+。
Embodiment 17
N- ((5- ((2- cyanopyridine -4- base) methoxyl group) -7- ([1,1'- biphenyl] -3- ylmethoxy) benzo [c] [1, 2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 17)
Referring to the method for embodiment 1, the I-1 in embodiment 1 is substituted for 3- phenylbenzyl bromine, by 3- methylol benzonitrile It is substituted for 2- cyano -4- hydroxymethylpyridine, compound 17 is made:1H NMR (300MHz, DMSO) δ 8.65 (d, J=5.0Hz, 1H), 7.96 (s, 1H), 7.74 (s, 1H), 7.68-7.56 (m, 4H), 7.49-7.40 (m, 4H), 7.35 (t, J=7.3Hz, 1H), 6.84 (s, 1H), 5.46 (s, 2H), 5.40 (s, 2H), 4.19 (d, J=13.4Hz, 1H), 4.12 (d, J=13.4Hz, 1H), 3.75 (dd, J=10.7,5.5Hz, 1H), 3.66 (dd, J=10.6,6.2Hz, 1H), 3.18 (t, J=5.9Hz, 1H) .MS(ESI):m/z 590.3[M+K]+。
Embodiment 18
2- (((5- (pyridin-3-yl methoxyl group) -7- ((bromo- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) benzo [c] [1, 2,5] oxadiazoles -4- base) methyl) amino) second -1- alcohol (compound 18)
Referring to the method for embodiment 12, the Serine carbethoxy hydrochloride in embodiment 12 is substituted for ethanol amine, is made Compound 18:MS (ESI): m/z 562.3 [M+H]+。
Embodiment 19
(S) -2- (((5- (pyridin-3-yl methoxyl group) -7- ((bromo- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) benzo [c] [1,2,5] oxadiazoles -4- base) methyl) amino) -2- phenylacetic acid (compound 19)
Referring to the method for embodiment 12, the Serine carbethoxy hydrochloride in embodiment 12 is substituted for L- phenylglycine first Compound 19:MS (ESI): m/z 652.3 [M+H] is made in ester hydrochloride+。
Embodiment 20
(R) -2- (((5- (pyridin-3-yl methoxyl group) -7- ((bromo- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) benzo [c] [1,2,5] oxadiazoles -4- base) methyl) amino) -2- phenylacetic acid (compound 20)
Referring to the method for embodiment 12, the Serine carbethoxy hydrochloride in embodiment 12 is substituted for D-PG first Compound 20:MS (ESI): m/z 652.3 [M+H] is made in ester hydrochloride+。
Embodiment 21
(2R, 4R)-N- ((5- (pyridin-3-yl methoxyl group) -7- ((bromo- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) benzo [c] [1,2,5] oxadiazoles -4- base) methyl) -4- hydroxy-proline (compound 21)
Referring to the method for embodiment 12, the Serine carbethoxy hydrochloride in embodiment 12 is substituted for (2R, 4R) -4- hydroxyl Compound 21:MS (ESI): m/z 654.4 [M+Na] is made in base pyrrolidines -2- carboxylate methyl ester hydrochloride+。
Embodiment 22
N- ((5- ((3- cyanobenzyls) oxygroup) -7- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) benzo [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser ethyl ester (compound 22)
Compound 22 (I-7 i.e. in embodiment 1): MS (ESI): m/z 593.3 [M+ is made referring to the method for embodiment 1 H]+。
Embodiment 23
N- ((5- ((3- cyanobenzyls) oxygroup) -7- ((3- (2,3- dihydrobenzo [b] [1,4] dioxine -6- Base) -2- methylbenzyl) oxygroup) benzo [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser ethyl ester (compound 23)
Referring to the method for embodiment 10, can be prepared by compound 23:MS (ESI) without hydrolysis: 651.3 [M+H of m/z ]+。
Embodiment 24
N- ((5- ((2- cyanopyridine -4- base) methoxyl group) -7- ((3- (2,3- dihydrobenzo [b] [1,4] dioxa hexamethylene Alkene -6- base) -2- methylbenzyl) oxygroup) benzo [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser ethyl ester (compound 24)
Referring to the method for embodiment 10, the 3- methylol benzonitrile in embodiment 10 is substituted for 2- cyano -4- methylol Pyridine, and can be prepared by compound 24:MS (ESI): m/z 674.6 [M+Na] without hydrolysis+。
Embodiment 25
N- ((5- (pyridin-3-yl methoxyl group) -7- ((bromo- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) benzo [c] [1,2, 5] oxadiazoles -4- base) methyl)-D-Ser ethyl ester (compound 25)
Referring to the method for embodiment 12, the Serine carbethoxy hydrochloride in embodiment 12 is substituted for D-Ser ethyl ester Hydrochloride, and can be prepared by compound 25:MS (ESI): m/z 634.5 [M+Na] without hydrolysis+。
Embodiment 26
N- ((5- (pyridin-3-yl methoxyl group) -7- ((bromo- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) benzo [c] [1,2, 5] oxadiazoles -4- base) methyl)-D-Ser carbethoxy hydrochloride (compound 26)
Compound 25 obtained in embodiment 25 is added in ethanol solution hydrochloride, is stirred overnight, is filtered, compound is made 26, MS (ESI): m/z 656.5 [M+Na]+。
Embodiment 27
N- ((5- ((2- cyanopyridine -4- base) methoxyl group) -7- ((chloro- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) benzo [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser ethyl ester (compound 27)
Referring to the method for embodiment 14, can be prepared by compound 27:MS (ESI) without hydrolysis: 615.1 [M+H of m/z ]+。
Embodiment 28
N- ((5- ((5- (sulfonyloxy methyl) pyridin-3-yl) methoxyl group) -7- ((chloro- [1,1 '-the biphenyl] -3- base of 2-) methoxy Base) benzo [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 28)
Referring to the method for embodiment 14, the 2- cyano -4- hydroxymethylpyridine in embodiment 14 is substituted for (5- (methyl sulphur Acyl group) pyridin-3-yl) methanol, compound 28:MS (ESI): m/z 640.2 [M+H] is made+。
Embodiment 29
N- ((5- ((5- (sulfonyloxy methyl) pyridin-3-yl) methoxyl group) -7- ((bromo- [1,1 '-the biphenyl] -3- base of 2-) methoxy Base) benzo [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 29)
Referring to the method for embodiment 13, the 3- pyridinemethanol in embodiment 13 is substituted for (5- (methyl sulphonyl) pyridine- 3- yl) methanol, compound 29:MS (ESI): m/z 684.5 [M+H] is made+。
Embodiment 30
N- ((5- ((2- cyanopyridine -4- base) methoxyl group) -7- ((bromo- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) benzo [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 30)
Referring to the method for embodiment 13, the 3- pyridinemethanol in embodiment 13 is substituted for 2- cyano -4- hydroxymethylpyridine, Compound 30 is made:1H NMR(300MHz,Methanol-d4) δ 8.71 (d, J=5.1Hz, 1H), 8.27 (s, 1H), 7.85 (d, J=5.1Hz, 1H), 7.61-7.53 (m, 1H), 7.53-7.27 (m, 7H), 6.94 (s, 1H), 5.61 (s, 2H), 5.54 (s, 2H), 4.67 (d, J=4.9Hz, 2H), 4.03 (dd, J=11.8,3.9Hz, 1H), 3.86 (dd, J=11.8,6.9Hz, 1H), 3.73–3.62(m,1H).MS(ESI):m/z 631.5[M+H]+。
Embodiment 31
N- ((5- ((5- cyanopyridine -3- base) methoxyl group) -7- ((bromo- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) benzo [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 31)
Referring to the method for embodiment 13, the 3- pyridinemethanol in embodiment 13 is substituted for 5- (methylol) nicotinic acid nitrile, is made Compound 31:1H NMR(300MHz,Methanol-d4)δ9.08(s,1H),8.93(s,1H),8.52(s,1H),7.64(d,J =7.7Hz, 1H), 7.51-7.29 (m, 7H), 7.00 (s, 1H), 5.54 (s, 2H), 5.49 (s, 2H), 4.56-4.48 (m, 2H), 4.27–4.20(m,2H),3.81–3.75(m,1H).MS(ESI):m/z631.5[M+H]+。
Embodiment 32
(S)-N- ((5- ((2- cyanopyridine -4- base) methoxyl group) -7- ((bromo- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) Benzo [c] [1,2,5] oxadiazoles -4- base) methyl) piperidines -2- carboxylic acid (compound 32)
Referring to the method for embodiment 30, the D-Ser carbethoxy hydrochloride in embodiment 30 is substituted for (S)-piperidines -2- Compound 32:MS (ESI): m/z 655.5 [M+H] is made in methyl formate hydrochloride+。
Embodiment 33
(S)-N- ((5- (pyridin-3-yl methoxyl group) -7- ((bromo- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) benzo [c] [1,2,5] oxadiazoles -4- base) methyl) piperidines -2- carboxylic acid (compound 33)
Referring to the method for embodiment 12, the Serine carbethoxy hydrochloride in embodiment 12 is substituted for (S)-piperidines -2- Compound 33:MS (ESI): m/z 630.6 [M+H] is made in methyl formate hydrochloride+。
Embodiment 34
(S)-N- ((5- ((5- cyanopyridine -3- base) methoxyl group) -7- ((bromo- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) Benzo [c] [1,2,5] oxadiazoles -4- base) methyl) piperidines -2- carboxylic acid (compound 34)
Synthetic route:
The synthesis of compound E-1
It takes compound III-1 (3.5g) to be dissolved in acetonitrile (50mL), is slowly added in batches sodium azide (740mg), 75 DEG C Oil bath heating.Stop heating after reaction about 5 hours, evaporating solvent under reduced pressure obtains the crude product (3.9g) of yellow solid compound E-1.
The synthesis of compound E-2
It takes the crude product (3.9g) of compound E-1 to be dissolved in toluene (30mL), is placed in 110 DEG C of oil bath heatings.After reaction about 5 hours Stop heating, stand 2 hours, there is solid precipitation, filters, obtain yellow solid compound E-2 (1.7g).
The synthesis of compound E-3
It takes compound E-2 (900mg) to be added in acetonitrile (25mL), Anhydrous potassium carbonate (655mg) and 5- (methylol) is added Nicotinic acid nitrile (320mg), reaction solution stop reaction after normal-temperature reaction 12 hours, and evaporating solvent under reduced pressure is added ethyl acetate (25mL) Dilution, is washed with water (10mL x3) and saturated salt solution (10mL x2), and anhydrous sodium sulfate is dry.Evaporating solvent under reduced pressure, it is remaining Object obtains yellow solid compound E-3 (756mg) through column chromatography (eluant, eluent: petrol ether/ethyl acetate=1:1) purifying.
The synthesis of compound E-4
It takes compound E-3 (756mg) to be dissolved in n,N-Dimethylformamide (5mL), is added triphenylphosphine (365mg), 90 DEG C Oil bath heating.Stop heating after reaction about 6 hours, be added water (10mL), is extracted with ethyl acetate (10mL x3), anhydrous slufuric acid Sodium is dry.Evaporating solvent under reduced pressure, residue are purified through column chromatography (eluant, eluent: petrol ether/ethyl acetate=2:1), and it is solid to obtain yellow Body compound E-4 (460mg).
The synthesis of compound E-5
It takes compound E-4 (460mg) to be dissolved in dehydrated alcohol (10mL), sodium borohydride (28mg) is added under ice bath, reaction Stop reaction after about 3 hours, be added water (10mL), extracted with ethyl acetate (10mL x3), anhydrous sodium sulfate is dry.Decompression is steamed Except solvent, residue is purified through column chromatography (eluant, eluent: petrol ether/ethyl acetate=1:1), obtains yellow solid compound E-5 (420mg)。
The synthesis of compound E-6
It takes compound E-5 (420mg), triphenylphosphine (403mg) is dissolved in anhydrous tetrahydro furan (10mL), under ice bath It is slowly added to carbon tetrabromide (510mg), stops reaction after reacting at room temperature about 4 hours.Evaporating solvent under reduced pressure uses methylene chloride Suction filtered through kieselguhr after (10mL) dilution, mother liquor are purified through column chromatography (eluant, eluent: petrol ether/ethyl acetate=2:1), are obtained faint yellow Solid chemical compound E-6 (233mg).
The synthesis of compound E-7
It takes (S)-piperidines -2- methyl formate hydrochloride (178mg) to be dissolved in n,N-Dimethylformamide (5mL), is added anhydrous Potassium carbonate (91mg) is stirred at room temperature 20 minutes, is added compound E-6 (200mg), 70 DEG C of oil bath heatings.Reaction stops after 12 hours Only react.Evaporating solvent under reduced pressure, residue are purified through column chromatography (eluant, eluent: petrol ether/ethyl acetate=1:1), obtain yellow oil Shape compound E-7 (135mg).
The synthesis of compound 34
It takes compound E-7 (135mg) to be dissolved in the mixed solvent (2:1,3mL) of methanol and tetrahydrofuran, a hydronium(ion) is added Lithia (25mg), after room temperature reaction 5 hours, evaporating solvent under reduced pressure, residue chromatographs (eluant, eluent: methanol/water=1:1) through column Purifying, obtains faint yellow solid compound 34 (70mg): MS (ESI): m/z 655.5 [M+H]+。
Embodiment 35
(S)-N- ((5- ((5- (sulfonyloxy methyl) pyridin-3-yl) methoxyl group) -7- ((bromo- [1,1 '-the biphenyl] -3- base of 2-) Methoxyl group) benzo [c] [1,2,5] oxadiazoles -4- base) methyl) piperidines -2- carboxylic acid (compound 35)
Referring to the method for embodiment 34,5- (methylol) nicotinic acid nitrile in embodiment 34 is substituted for (5- (methyl sulphonyl) Pyridin-3-yl) methanol, compound 35:MS (ESI): m/z 708.6 [M+H] is made+。
Embodiment 36
(S) -2- (((5- ((2- cyanopyridine -4- base) methoxyl group) -7- ((bromo- [1,1'- the biphenyl] -3- base of 2-) methoxy Base) benzo [c] [1,2,5] oxadiazoles -4- base) methyl) amino) -3- hydroxy-2-methyl propionic acid (compound 36)
Referring to the method for embodiment 30, the D-Ser carbethoxy hydrochloride in embodiment 30 is substituted for 2- methyl-L- Compound 36:MS (ESI): m/z 645.5 [M+H] is made in propylhomoserin carbethoxy hydrochloride+。
Embodiment 37
(S) -2- (((5- ((5- cyanopyridine -3- base) methoxyl group) -7- ((bromo- [1,1'- the biphenyl] -3- base of 2-) methoxy Base) benzo [c] [1,2,5] oxadiazoles -4- base) methyl) amino) -3- hydroxy-2-methyl propionic acid (compound 37)
Referring to the method for embodiment 31, the D-Ser carbethoxy hydrochloride in embodiment 31 is substituted for 2- methyl-L- Compound 37:MS (ESI): m/z 645.4 [M+H] is made in propylhomoserin carbethoxy hydrochloride+。
Embodiment 38
(S) -2- (((5- ((5- cyanopyridine -3- base) methoxyl group) -7- ((bromo- [1,1'- the biphenyl] -3- base of 2-) methoxy Base) benzo [c] [1,2,5] oxadiazoles -4- base) methyl) amino) -3- hydroxy-2-methyl propionic acid (compound 38)
Referring to the method for embodiment 12, the Serine carbethoxy hydrochloride in embodiment 12 is substituted for 2- methyl-L- Compound 38:MS (ESI): m/z 620.5 [M+H] is made in propylhomoserin carbethoxy hydrochloride+。
Embodiment 39
(S) -2- (((5- ((2- cyanopyridine -4- base) methoxyl group) -7- ((chloro- [1,1'- the biphenyl] -3- base of 2-) methoxy Base) benzo [c] [1,2,5] oxadiazoles -4- base) methyl) amino) -3- hydroxy-2-methyl propionic acid (compound 39)
Referring to the method for embodiment 27, the D-Ser carbethoxy hydrochloride in embodiment 27 is substituted for 2- methyl-L- Compound 39:MS (ESI): m/z 601.3 [M+H] is made in propylhomoserin carbethoxy hydrochloride+。
Embodiment 40
(S) -2- (((5- ((5- cyanopyridine -3- base) methoxyl group) -7- ((chloro- [1,1'- the biphenyl] -3- base of 2-) methoxy Base) benzo [c] [1,2,5] oxadiazoles -4- base) methyl) amino) -3- hydroxy-2-methyl propionic acid (compound 40)
Referring to the method for embodiment 14, the 2- cyano -4- hydroxymethylpyridine in embodiment 14 is substituted for 3- pyridinemethanol, D-Ser carbethoxy hydrochloride is substituted for 2- methyl-L-serine carbethoxy hydrochloride, and compound 40:MS (ESI): m/z is made 576.0[M+H]+。
Embodiment 41
N- (2- (((5- (pyridin-3-yl methoxyl group) -7- ((chloro- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) benzo [c] [1,2,5] oxadiazoles -4- base) methyl) amino) ethyl) Methanesulfomide (compound 41)
Referring to the method for embodiment 40, the 2- methyl-L-serine carbethoxy hydrochloride in embodiment 40 is substituted for methylsulphur Compound 41:MS (ESI): m/z 595.1 [M+H] is made in acyl group ethamine+。
Embodiment 42
2- (((5- (pyridin-3-yl methoxyl group) -7- ((chloro- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) benzo [c] [1, 2,5] oxadiazoles -4- base) methyl) amino) ethane -1- sulfonic acid (compound 42)
Referring to the method for embodiment 40, the 2- methyl-L-serine carbethoxy hydrochloride in embodiment 40 is substituted for ox sulphur Compound 42:MS (ESI): m/z 582.4 [M+H] is made in acid+。
Embodiment 43
N- (2- (((7- ((chloro- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) -5- ((5- (methyl sulphonyl) pyridine -3- Base) methoxyl group) benzo simultaneously [c] [1,2,5] oxadiazoles -4- base) methyl) amino) ethyl) Methanesulfomide (compound 43)
Referring to the method for embodiment 41, the 3- pyridinemethanol in embodiment 41 is substituted for (5- (methyl sulphonyl) pyridine- 3- yl) methanol, compound 43:MS (ESI): m/z 673.2 [M+H] is made+。
Embodiment 44
N- ((5- (pyridin-3-yl methoxyl group) -7- ((chloro- [1,1'- the biphenyl] -3- base of 2-) methoxyl group) benzo [c] [1,2, 5] oxadiazoles -4- base) methyl)-D-Ser (compound 44)
Referring to the method for embodiment 40, the 2- methyl-L-serine carbethoxy hydrochloride in embodiment 40 is substituted for D- Compound 44:MS (ESI): m/z 562.1 [M+H] is made in propylhomoserin carbethoxy hydrochloride+。
Embodiment 45
N- ((5- ((2- cyanopyridine -4- base) methoxyl group) -7- ((3- (2,3- dihydrobenzo [b] [1,4] dioxa hexamethylene Alkene -6- base) -2- bromobenzyl) oxygroup) benzo [c] [1,2,5] oxadiazoles -4- base) methyl)-D-Ser (compound 45)
Referring to the method for embodiment 30, the phenyl boric acid in embodiment 30 is substituted for benzodioxane -4- borate, is made Obtain compound 45:1H NMR(300MHz,Methanol-d4) δ 8.67 (d, J=5.0Hz, 1H), 8.00 (s, 1H), 7.77-7.51 (m, 4H), 7.42-7.36 (m, 1H), 7.29 (d, J=7.6Hz, 1H), 6.89-6.78 (m, 2H), 5.46 (s, 2H), 5.44 (d, J=7.3Hz, 2H), 4.29 (s, 4H), 4.22-4.05 (m, 2H), 3.79-3.70 (m, 1H), 3.70-3.61 (m, 1H), 3.19 (t, J=5.9Hz, 1H) .MS (ESI): m/z 688.5 [M+H]+。
Embodiment 46
Biological evaluation
1, the compound of the present invention evaluates the inhibitory activity of PD-1/PD-L1 protein-protein interaction
Experiment purpose: using PD-1/PD-L1binding assay kit detection kit (Cisbio company), detects formula (I) compound inhibits the activity of PD-1 and PD-L1 interaction.
Experimental principle: by using anti-Tag1-Europium (HTRF donor) and anti-Tag2-XL665 (HTRF by Body) detection Tag1-PD-L1 and Tag2-PD-1 between interaction.When HTRF donor and HTRF receptor are due to PD-L1 and PD- 1 in conjunction with and close to when, HTRF donor excitation triggering towards HTRF receptor fluorescence resonance energy transfer (FRET), HTRF Receptor emits fluorescence at 665nm again.The signal specific is directly proportional to the degree that PD-1/PD-L1 interacts.Therefore, it blocks The compound or antibody of PD-1/PD-L1 interaction will lead to the reduction of HTRF signal.
Experimental material: 384 porocyte culture plates are purchased from Nunc company；Homogeneous phase time discrimination fluorescence Homogeneous Time-Resolved Fluorescence (HTRF) kit is purchased from Cisbio company；DMSO is purchased from Sigma company.
Laboratory apparatus: Perkin Elmer EnVision multifunctional enzyme mark detector.
Test medicine: formula (I) compound.Sample is configured to mother liquor with DMSO and uses, with diluent buffer when use Dilution uses, and DMSO final concentration is no more than 0.1%.
Experimental program: PD-1/PD-L1 protein-protein interaction inhibits test to use HTRF kit.It is negative right to set up According to group, positive controls and administration group (including positive drug and test-compound), every group of 3 multiple holes.In negative control group, to 2 μ L diluent buffer, 4 μ L are sequentially added in 384 orifice plates through the diluted Tag1-PD-L1 of diluent buffer and 4 μ L Through the diluted Tag2-PD-1 of diluent buffer；In positive controls, 2 μ L diluent are sequentially added into 384 orifice plates Buffer, 4 μ L are through the diluted Tag1-PD-L1 of diluent buffer and 4 μ L diluent buffer；In administration group, to 2 μ L are sequentially added in 384 orifice plates through the diluted test medicine of diluent buffer [positive drug or formula (I) compound], then 4 μ L are added through the diluted Tag1-PD-L1 of diluent buffer and 4 μ L through the diluted Tag2- of diluent buffer in every hole PD-1.After each group adds, after 384 orifice plates are incubated for 15 minutes at 37 DEG C, then to every hole 5 μ L of addition through detection Buffer diluted anti-Tag1-Eu3+ and anti-Tag2-XL665.It is incubated for 1 hour at 37 DEG C to after staying overnight, uses Perkin Elmer Envision multifunctional enzyme mark detector measures the fluorescent value at 665nm and 620nm, HTRF Ratio =(665nm/620nm) * 104.8-10 concentration gradient of each compound test calculates compound using Graphpad software IC50.The compound 1016 (BMS-1016) that this experiment is selected in BMS house journal WO2015160641 is positive drug.Activity is surveyed Test result is shown in Table 2.
Table 2, compound inhibit the protein level activity of PD-1/PD-L1 protein-protein interaction
The experimental results showed that the compound of the present invention has the suppression of significant PD-1/PD-L1 protein-protein interaction System activity.For example, 11 (IC of compound50=2.719nM), 13 (IC of compound50=2.061nM) and 14 (IC of compound50= Activity 1.787nM) etc. is significantly better than positive control BMS-1016 (IC50=32.20nM).Other compounds in the present invention etc. Also all show significant PD-1/PD-L1 inhibitory activity, for example, compound 28,29,30,31,32,33,34,35,37,38, 39,41,43,44 and 45 etc. IC50Value is in 10nM or less.This prompts benzoxadiazole class compound of the invention to can be used as exempting from Epidemic disease checkpoint PD-1/PD-L1 inhibitor.
2, the compound of the present invention blocks hPD-L1 albumen to inhibit human peripheral blood single nucleus cell (PBMC) secretion of gamma-IFN The experiment of effect
The cell factors such as meeting secretion of gamma-IFN, IL-2 and TNF-α after human peripheral blood single nucleus cell (PBMC) activation, and PD-1 protein binding on hPD-L1 (source of people PD-L1) albumen and human PBMC can inhibit the activation of PBMC, reduce cell factor point It secretes.The purpose of this experiment is the ability that detection compound blocks hPD-L1 albumen to inhibit PBMC activation.
Concrete operations are as follows: the human PBMC bought using Sai Ersi Bioisystech Co., Ltd, Australia is inoculated into 96 orifice plates, Every hole is inoculated with 1 X 105A cell.Experiment is divided into five groups, and one group is blank control (PBMC is only added), and one group is activation group (PBMC+anti-CD3/anti-CD28 antibody), one group is inhibition group (PBMC+anti-CD3/anti-CD28 antibody+hPD-L1 Albumen), other two groups are respectively the compound 12 that 1 μM and 10nM is added on the basis of inhibition group.It is used after 48 hours The content of IFN-γ in the IFN-γ ELISA detection kit detection cell supernatant of Biolegend company.Experimental result is aobvious Show, after PBMC is by the effect of anti-CD3/anti-CD28 antibody in activation group, secretion of gamma-IFN is dramatically increased, and illustrates that PBMC is in State of activation；HPD-L1 albumen inhibits PBMC secretion of gamma-IFN in inhibition group, illustrates that the state of activation of PBMC is suppressed；Chemical combination Object 12 has the function of that PD-L1 is significantly blocked to inhibit human PBMC's cell secretion of gamma-IFN (Fig. 1).Other chemical combination in the present invention Object etc. also shows similar effect in this experiment, for example, compound 9,10,11,13,14,15,16,28,29,30,31, 32,33,34,35,37,38,39,41,43,44 and 45 etc. there is significant blocking PD-L1 to inhibit people under 1 μM and 10nM concentration The effect of PBMC cell secretion of gamma-IFN.This shows that the compound of the present invention has and PD-1/PD-L1 is inhibited to interact and then increase The effect of strong T cell immunocompetence.
3, the compound of the present invention blocks the experiment of inhibiting tumour cells human T-cell proliferation function
Human breast cancer cell MDA-MB-231 surface expression has PD-L1 albumen, as the human T-cell and MDA-MB-231 of activation After cell contact, PD-1/PD-L1 access can be activated, and then inhibit the activation of T cell, cause T cell proliferation to slow down, and reduce The release of the cell factors such as IFN-γ, IL-2 and TNF-α.The purpose of this experiment is that detection compound blocks MDA-MB-231 cell Inhibit the ability of human T-cell's proliferation.
Concrete operations are as follows: to be generated to grow to properly by the MDA-MB-231 cell inoculation of logarithmic phase growth into 96 orifice plates Cell density, human T-cell's suspension that sorting is obtained are added in supernatant, activate T cell with anti-CD3/anti-CD28 antibody, Untested compound is added.Pass through the proliferative conditions of flow cytomery T cell after 48 hours.Experiment is divided into six groups, and one group is (T cell is only added) in blank control group, and one group is activation group (T cell+anti-CD3/anti-CD28 antibody), and one group is inhibition Group (T cell+anti-CD3/anti-CD28 antibody and MDA-MB-231), other three groups are respectively to add on the basis of inhibition group Enter the compound 12 of 10 μM, 100nM and 10nM.Experimental result shows that T cell is by anti-CD3/anti-CD28 in activation group After antibody effect, proliferation is dramatically increased, and illustrates T cell in state of activation；Human breast cancer cell MDA-MB-231 and T in inhibition group After cell co-cultures, the decline of T cell proliferative capacity illustrates that the state of activation of T cell is suppressed；Compound 12 has significant Block the ability (Fig. 2) of inhibiting tumour cells human T-cell proliferation.Other compounds in the present invention etc. also show in this experiment Similar effect out, for example, compound 11,13,14,16,28,29,31,34,35,37,43,44 and 45 etc. is in 10 μM, 100nM With the ability under 10nM concentration with significant blocking inhibiting tumour cells human T-cell proliferation.This shows the compound of the present invention The proliferation that can promote T cell, enhances the immune function of T cell, and then the tumour cell that can inhibit PD-1/PD-L1 mediation is immune Escape.
4, the compound of the present invention blocks the experiment of inhibiting tumour cells human T-cell secretion of gamma-IFN effect
As previously mentioned, human breast cancer cell MDA-MB-231 surface expression has PD-L1 albumen, when activation human T-cell with After the contact of MDA-MB-231 cell, PD-1/PD-L1 access can be activated, so reduce the cells such as IFN-γ, IL-2 and TNF-α because The release of son.The purpose of this experiment is the energy that detection compound blocks MDA-MB-231 cell inhibition human T-cell's secretion of gamma-IFN Power.
Concrete operations are as follows: to be generated to grow to properly by the MDA-MB-231 cell inoculation of logarithmic phase growth into 96 orifice plates Cell density, human T-cell's suspension that sorting is obtained are added in supernatant, activate T cell with anti-CD3/anti-CD28 antibody, Untested compound is added.Cell supernatant is detected using the IFN-γ ELISA detection kit of Biolegend company after 48 hours The content of middle IFN-γ.Experiment is divided into six groups, and one group is blank control group (T cell is only added), one group for activation group (T cell+ Anti-CD3/anti-CD28 antibody), one group is inhibition group (T cell+anti-CD3/anti-CD28 antibody+MDA-MB- 231), other three groups are respectively the compound 12 that 10 μM, 100nM and 10nM are added on the basis of inhibition group.Experimental result is aobvious Show, after T cell is by the effect of anti-CD3/anti-CD28 antibody in activation group, secretion of gamma-IFN is dramatically increased, and illustrates T cell In state of activation；After human breast cancer cell MDA-MB-231 and T cell co-culture in inhibition group, the water of T cell secretion of gamma-IFN Flat decline, illustrates that the state of activation of T cell is suppressed；Compound 12 has significant blocking inhibiting tumour cells human T-cell The ability (Fig. 3) of secretion of gamma-IFN.Other compounds in the present invention etc. also show similar effect, example in this experiment Such as, compound 11,13,14,16,28,29,31,34,35,37,43,44 and 45 etc. is under 10 μM, the concentration of 100nM and 10nM With the significant ability for blocking inhibiting tumour cells human T-cell secretion of gamma-IFN effect.This shows that the compound of the present invention can PD-1/PD-L1 is blocked to restore the energy of the cell factors such as the T cell secretion of gamma-IFN of activation to the immunosuppressive action of T cell Power enhances the immunocompetence of T cell, and then enhances the antineoplastic immune activity of T cell.
Embodiment 47
Tablet
By compound 14 (50g) obtained in embodiment 14, hypromellose E (150g), starch (200g), poly- dimension Ketone K30 is appropriate and magnesium stearate (1g) mixes, granulation, tabletting.
Furthermore, it is possible to compound made from Examples 1 to 45 be assigned different according to 2015 editions conventional formulation methods of pharmacopeia Excipient substance be made capsule, powder, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository or Patch etc..

Claims (10)

1. a kind of benzoxadiazole class compound as shown in following formula (I):
R1It is selected from: H, C1-C4The C that alkyl, X replace1-C4Alkyl, Heterocyclylalkyl or-(CH2)nAr；The X be selected from F, Cl, Br, I, OH、C(O)OH、C(O)NH2、NH2, morpholinyl, piperidyl, piperazinyl, nafoxidine base or N, N- dimethylamino；The n is 1,2,3 or 4；Ar is substituted or non-substituted aryl or heteroaryl；
R2It is selected from :-(CH2)mCHO、-(CH2)mOH or-(CH2)mNR8R9；
M is 0,1,2,3 or 4；
R8It is selected from: H, C1-C4Alkyl or benzyl；
R9Selected from it is following any one:
P is 0,1,2,3 or 4；
R10It is selected from: H, benzyl or methyl；
R11It is selected from: H or C1-C3Alkyl；
R12It is selected from: H, C1-C3Alkyl or benzyl；
R13It is selected from: H, C1-C3Alkyl or benzyl；
R14It is selected from: H, C1-C6Alkyl or C1-C6Alkoxy carbonyl group；
R15It is selected from: H or C1-C4Alkyl；
Alternatively, R8And R9N atom connected to them is formed together a ring, selected from it is following any one:
S is 0,1 or 2；
T is 1,2 or 3；
Q is selected from: S, O, NH, NCH3、N(CH2)2OH or CHR17a；R17aIt is selected from: the C that H, OH, hydroxyl replace1-C3Alkyl or C (O) OH；
R16It is selected from: the C that H, C (O) OH, hydroxyl replace1-C4Alkyl or C (O) NHSO2R19；
R17It is selected from: the C that H, C (O) OH, hydroxyl replace1-C4Alkyl, OH, C (O) or C (O) NHSO2R19；
R18It is selected from: C1-C4Alkoxy carbonyl group, C1-C6The C that alkyl, C (O) OH, F, Cl, Br, I, OH, hydroxyl replace1-C4Alkyl, NRaRb Or phenyloxycarbonyl；Wherein, the phenyl of phenyloxycarbonyl is optionally by F, Cl, Br, I, OH, CN, NO2、NH2、CF3、CF2CF3、 OCF3、OCF2CF3、SO2NH2、C(O)OH、C(O)NH2Or NHC (O) NH2Replace；RaAnd RbIt is each independently selected from: H, C1-C4Alkane Oxygen carbonyl or C1-C4Alkyl-carbonyl；
R19It is selected from: CF3, cyclopropyl, C1-C4Alkyl, dimethylamino or methyl substituted imidazole radicals；
R3、R4、R5、R6And R7It is each independently selected from: H, Rc、ORc、SRc、S(O)Rc、S(O)2Rc、C(O)Rc、C(O)OH、C(O) ORc、OC(O)Rc、NHRc、N(Rc)2、C(O)NH2、C(O)NHRc、C(O)N(Rc)2、NH(CO)Rc、NRc(CO)Rc、NH(CO)ORc、 NRc(CO)ORc、NH(CO)NH2、NH(CO)NHRc、NH(CO)N(Rc)2、NRc(CO)NHRc、NRc(CO)N(Rc)2、SO2NH2、 SO2NHRc、SO2N(Rc)2、NHSO2Rc、NRcSO2Rc、NHSO2NHRc、NHSO2N(Rc)2、NRcSO2NHRc、NRcSO2N(Rc)2、C (O)NHNOH、C(O)NHNORc、C(O)NHSO2Rc、C(NH)NH2、C(NH)NHRc、C(NH)N(Rc)2、F、Cl、Br、I、CN、NO2、 NH2、OH、CF3、CF2CF3、OCF3Or OCF2CF3；
RcIt is selected from: phenyl, heteroaryl, naphthenic base, cycloalkenyl, Heterocyclylalkyl, heterocycloalkenyl, substituted or non-substituted C1-C4Alkane Base, alkenyl or alkynyl；
Alternatively, R4、R5、R6And R7Among every two and their atoms for being connected to be formed together substituted or non-substituted phenyl ring, Substituted or non-substituted hetero-aromatic ring, substituted or non-substituted cycloalkanes hydrocarbon ring, substituted or non-substituted heterocycloalkane ring or replace or Non-substituted heterocyclic alkene ring；
W is selected from: H, F, Cl, Br, I, CN, NO2、NH2、OH、CF3、CF2CF3、OCF3、OCF2CF3、C1-C4Alkyl, alkenyl, alkynyl, Alkoxy, alkylthio group, naphthenic base, halogenated alkyl, halogenated alkoxy, halogenated alkylthio, halogenated cycloalkyl or Heterocyclylalkyl.
2. benzoxadiazole class compound according to claim 1, which is characterized in that the compound include its pharmaceutically Acceptable salt, tautomer, mesomer, racemic modification, stereoisomer, metabolite, metabolic precursor thereof, prodrug or molten Agent compound.
3. benzoxadiazole class compound according to claim 1, which is characterized in that the R1For-(CH2)nAr；Wherein, N is 1；Ar is substituted or non-substituted aryl or heteroaryl；
R2For-(CH2)mNR8R9；Wherein, m is 1；
R8It is selected from: H or C1-C4Alkyl；
R9Selected from it is following any one:
P is 1 or 2；
R10It is H；
R11It is selected from: H or C1-C3Alkyl；
R12It is selected from: H or C1-C3Alkyl；
R13It is selected from: H or C1-C3Alkyl；
R14It is selected from: H, C1-C6Alkyl or C1-C6Alkoxy carbonyl group；
R15It is selected from: H or C1-C4Alkyl；
Alternatively, R8And R9N atom connected to them is formed together a ring, selected from it is following any one:
S is 0 or 1；
T is 2 or 3；
Q is selected from: S, O, NH, NCH3、N(CH2)2OH or CHR17a；R17aIt is selected from: the C that H, OH, hydroxyl replace1-C3Alkyl or C (O) OH；
R16It is selected from: the C that H, C (O) OH, hydroxyl replace1-C4Alkyl or C (O) NHSO2R19；
R17It is selected from: the C that H, C (O) OH, hydroxyl replace1-C4Alkyl, OH, C (O) or C (O) NHSO2R19；
R18It is selected from: C1-C4Alkoxy carbonyl group, C1-C6The C that alkyl, C (O) OH, F, Cl, Br, I, OH, hydroxyl replace1-C4Alkyl ,- NRaRbOr phenyloxycarbonyl；The phenyl of phenyloxycarbonyl is optionally by F, Cl, Br, I, OH, CN, NO2、NH2、CF3、CF2CF3、OCF3、 OCF2CF3、SO2NH2、C(O)OH、C(O)NH2Or NHC (O) NH2Replace；RaAnd RbIt is each independently selected from: H, C1-C4Alcoxyl carbonyl Base or C1-C4Alkyl-carbonyl；
R19It is selected from: CF3, cyclopropyl, C1-C4Alkyl, dimethylamino or methyl substituted imidazole radicals；
R3、R4、R5、R6And R7It is each independently selected from: H, Rc、ORc、SRc、S(O)Rc、S(O)2Rc、C(O)Rc、C(O)OH、C(O) ORc、OC(O)Rc、NHRc、N(Rc)2、C(O)NH2、C(O)NHRc、C(O)N(Rc)2、NH(CO)Rc、NRc(CO)Rc、NH(CO)ORc、 NRc(CO)ORc、NH(CO)NH2、NH(CO)NHRc、NH(CO)N(Rc)2、NRc(CO)NHRc、NRc(CO)N(Rc)2、SO2NH2、 SO2NHRc、SO2N(Rc)2、NHSO2Rc、NRcSO2Rc、NHSO2NHRc、NHSO2N(Rc)2、NRcSO2NHRc、NRcSO2N(Rc)2、C (O)NHNOH、C(O)NHNORc、C(O)NHSO2Rc、C(NH)NH2、C(NH)NHRc、C(NH)N(Rc)2、F、Cl、Br、I、CN、NO2、 NH2、OH、CF3、CF2CF3、OCF3Or OCF2CF3；
RcIt is selected from: phenyl, heteroaryl, naphthenic base, cycloalkenyl, Heterocyclylalkyl, heterocycloalkenyl, substituted or non-substituted C1-C4Alkane Base, alkenyl or alkynyl；
Alternatively, R4、R5、R6And R7Among every two and their atoms for being connected to be formed together substituted or non-substituted phenyl ring, Substituted or non-substituted hetero-aromatic ring, substituted or non-substituted cycloalkanes hydrocarbon ring, substituted or non-substituted heterocycloalkane ring or replace or Non-substituted heterocyclic alkene ring；
W is selected from: H, F, Cl, Br, I, CN, NO2、NH2、OH、CF3、CF2CF3、OCF3、OCF2CF3、C1-C4Alkyl, alkenyl, alkynyl, Alkoxy, alkylthio group, naphthenic base, halogenated alkyl, halogenated alkoxy, halogenated alkylthio, halogenated cycloalkyl or Heterocyclylalkyl.
4. any benzoxadiazole class compound according to claim 1~3, which is characterized in that the Ar be replace or Non-substituted aryl or heteroaryl, is selected from: phenyl, pyridyl group, pyrimidine radicals, quinolyl, isoquinolyl, indazolyl, isoxazole Base, oxadiazoles base, naphthalene, thiazolyl or imidazole radicals；The substituted or non-substituted aryl or heteroaryl be it is unsubstituted or by Replaced one or two or three substituent groups independently selected from the following: C1-C4Alkyl, C1-C4Alkoxy, C1-C4Alcoxyl carbonyl Base, C1-C4The C that alkyl sulphonyl, hydroxyl replace1-C4Alkyl, F, Cl, Br, I, CN, NO2、NH2、OH、CF3、CF2CF3、OCF3、 OCF2CF3、C(O)OH、C(O)NH2, morpholinyl, piperidyl, nafoxidine base, piperazinyl, N, N- dimethylamino, oxinane Base, unsubstituted or substituted phenyl.
5. any benzoxadiazole class compound according to claim 1~3, which is characterized in that the RcIt is selected from: phenyl, Heteroaryl, naphthenic base, cycloalkenyl, Heterocyclylalkyl, heterocycloalkenyl, substituted or non-substituted C1-C4Alkyl, alkenyl or alkynyl；It is described Substituted or non-substituted C1-C4Alkyl is unsubstituted or each independently is selected from following substitution by one or two or three Replaced base: Rg、OH、(O)、C(O)OH、CN、NH2、F、Cl、Br、I、CF3、CF2CF3、NC(Rh)(Ri)、Rj、ORj、SRj、S(O) Rj、S(O)2Rj、NHRj、N(Rj)2、C(O)Rj、C(O)NH2、C(O)NHRj、C(O)N(Rj)2、NHC(O)Rj、NRjC(O)Rj、 NHSO2Rj、NHC(O)ORj、SO2NHRj、SO2N(Rj)2、NHC(O)NH2、NHC(O)NHRj, pyrrolidin-1-yl, piperidin-1-yl, Piperazine -1- base, 4- thyl-piperazin -1- base, morpholine -4- base, thiomorpholine -1,1- dioxo -4- base, NHC (O) CH (CH3) NHC(O)CH(CH3) NH or NHC (O) CH (CH3)NHC(O)-CH(CH3)NHRj；
RgSpirane base selected from 2~5 carbon, each of which is unsubstituted or by OH, (O), CN, NH2、F、Cl、Br、I、CF3、 CF2CF3、NH(CH3) or N (CH3)2Replace；
RhAnd RiAlkyl selected from independent choice, or be aziridine -1- base, azetidin together with the N that they are connected to Alkane -1- base, pyrrolidin-1-yl or piperidin-1-yl, it is each have one it is not substituted or by O, C (O), CNOH, CNOCH3、 S、S(O)、S(O)2Or the CH of NH substitution2Part；
RjIt is selected from: phenyl, heteroaryl, naphthenic base, cycloalkenyl, Heterocyclylalkyl, heterocycloalkenyl, C1-C4Alkyl, alkenyl or alkynyl.
6. benzoxadiazole class compound according to claims 1 to 3, which is characterized in that the compound or its pharmacy Upper acceptable salt, tautomer, mesomer, racemic modification, stereoisomer, metabolite, metabolic precursor thereof, prodrug or The compound that solvate is as follows:
7. a kind of preparation method of the described in any item benzoxadiazole class compounds of claim 1~6, which is characterized in that when The R of compound2It is-(CH2)mNR8R9, and when m is 1, the synthetic route of the compound is as follows:
Wherein, Y is bromine, chlorine, iodine, p-methyl benzenesulfonic acid ester, methanesulfonates or triflate；R1、R3、R4、R5、R6、R7、R8、R9 It is consistent with the definition in the formula (I) compound with the definition of W, specifically includes the following steps:
(1) it is reacted to obtain compound M-3 in the presence of alkali with compound M-2 by compound M-1；
(2) it is reacted to obtain compound M-4 with azide by compound M-3；
(3) compound M-5 is obtained through cyclization reaction by compound M-4；
(4) by compound M-5 and R1OH reacts in the presence of alkali obtains compound M-6；
(5) it is reacted under the action of deoxidier by compound M-6 and obtains compound M-7；
(6) by compound M-7 and NHR8R9It carries out reductive amination process and obtains compound (Ia)；
(7) alternatively, obtaining compound M-8 through reduction reaction by compound M-7；M-8 is esterified to obtain chemical combination through halogenation or sulfonic acid again Object M-9；M-9 in the presence of alkali with NHR8R9It is alkylated reaction and obtains compound (Ia).
8. a kind of described in any item benzoxadiazole class compounds of claim 1~6, including its pharmaceutically acceptable salt, Tautomer, mesomer, racemic modification, stereoisomer, metabolite, metabolic precursor thereof, prodrug or solvate are being made Application in the standby inhibitor with PD-1/PD-L1 inhibitory activity.
9. a kind of described in any item benzoxadiazole class compounds of claim 1~6, including its pharmaceutically acceptable salt, Tautomer, mesomer, racemic modification, stereoisomer, metabolite, metabolic precursor thereof, prodrug or solvate conduct Immunologic test point inhibitor is preparing the purposes in immunotherapy of tumors drug.
10. a kind of pharmaceutical composition for immunotherapy of tumors, wherein containing benzene as described in any one of claims 1 to 6 And furodiazole compound or its pharmaceutically acceptable salt, tautomer, mesomer, racemic modification, stereoisomer, Metabolite, metabolic precursor thereof, prodrug or solvate are as active constituent and pharmaceutically acceptable carrier.
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