CN108727453A - Novel PD-1 inhibitor and its application - Google Patents

Novel PD-1 inhibitor and its application Download PDF

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Publication number
CN108727453A
CN108727453A CN201710261800.2A CN201710261800A CN108727453A CN 108727453 A CN108727453 A CN 108727453A CN 201710261800 A CN201710261800 A CN 201710261800A CN 108727453 A CN108727453 A CN 108727453A
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alkyl
carcinoma
hydrogen
cancer
compound
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李洪林
朱丽丽
王霞
全丽娜
刁妍妍
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East China University of Science and Technology
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East China University of Science and Technology
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    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
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    • C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
    • C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
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    • C07J1/0003—Androstane derivatives
    • C07J1/0033—Androstane derivatives substituted in position 17 alfa and 17 beta
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    • C07J1/0033—Androstane derivatives substituted in position 17 alfa and 17 beta
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    • C07J5/0007—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa
    • C07J5/0023—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa substituted in position 16
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    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
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    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
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    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
    • C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
    • C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
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    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
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    • C07J53/002—Carbocyclic rings fused
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    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
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    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
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    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
    • C07J7/0045—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16
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    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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Abstract

The present invention relates to as PD-1 blocking agents steroid derivatives and its application.Specifically, relevant disease and preparation that the present invention relates to compound shown in following formula I, the pharmaceutical composition containing compounds of Formula I and the compounds to mediate in treatment PD-1 treat the purposes during PD-1 mediates the drug of relevant disease：

Description

Novel PD-1 inhibitor and its application
Technical field
The present invention relates to medicinal chemistry arts；In particular it relates to target the steroid derivatives of hPD-1 albumen And its application.
Background technology
It is generally known that there is a powerful and complicated immune system in human body, it can externally resist bacterium and the disease of invasion Poison can internally remove the cell of damage and aging, or even can also monitor the cell of mutation.Immune system is broadly divided into antigen Presenting cells (APC) and T cell.APC can process and offer antigen, and T cell receives the specific antigen letter that APC offers Number, then under the action of the costimulatory molecules on the surfaces APC, it is continuous Proliferative Activated.The activation of T cell not only needs APC to provide The first signal stimulation, and need costimulatory molecules provide second signal stimulation.These costimulatory molecules not only carry For enhancing immune costimulatory signal, but also the coinhibitory signals for inhibiting immune are provided, its two collective effect is to reach item The immune effect of part.These coinhibitory signals are referred to as immunologic test point.There is a series of inhibitive abilities of immunity on T cell surface Molecule, such as PD-1, CTLA-4, Tim-3, SLAM, these inhibitive ability of immunity molecules can with its corresponding ligand binding to It activates immunosupress to adjust access, leads to the failure of T cell function.Wherein, PD-1/PD-L1 accesses are a current research Hot spot.
PD-1 is the important immunosupress receptor in one, T cell surface, and the immunoglobulin being made of 288 amino acid surpasses Family I type transmembrane glycoproteins, be initially by Subtractive Hybridization Technique from mouse be in apoptotic state hybridoma and hematopoiesis ancestral it is thin Born of the same parents be clone obtain, be considered related to Apoptosis and be named as programmed death molecule -1 (programmed death-1, PD-1).PD-1 albumen is in mainly inductivity up-regulated expression in T cell, B cell, NK cells.PD-L1 and PD-L2 is the two of PD-1 A endogenic ligand, PD-L1 have expression in the T cell of activation, B cell, monocyte and a plurality of types of tumour cells, And PD-L2 is mainly expressed on macrophage, dendritic cells, the stroma cell of derived from bone marrow and the individual tumor cell of activation. Therefore, PD-L1 ratios PD-L2 is more commonly.Numerous studies show that the PD-1 in the T cell of activation can be notable with the interaction of its ligand The biological function of depression effect T cell, consequently, it is possible to cause the immunologic escape of some tumours, autoimmune disease, The generation of disease of viral infection etc..Block the interaction of PD-1 and PD-L1/PD-L2 that there is good application prospect.
The antibody for being directed to PD-1 and PD-L1 accesses at present is broadly divided into two kinds：1, in conjunction with PD-1, to block PD-1 with The interaction of PD-L1；2, in conjunction with PD-L1, to block the interaction of PD-1 and PD-L1.Antibody in conjunction with PD-1 is main Using Nivolumab and Pembrolizumab as representative；Antibody in conjunction with PD-L1 is mainly with BMS-936559 and MPDL3280A It represents.But the antibody drug of these macromoleculars has the shortcomings that production cost is high, is also easy to produce immunogenicity.Therefore it researchs and produces It is at low cost, be not likely to produce immunogenicity, easily penetrate tissue, the small-molecule drug with better stability is with good application Foreground.It combines it is reported that the compound BMS-8, BMS-202 and PD-L1 of the research of Shi Guibao companies have, is set for us well Meter blocks the small-molecule drug of the interaction of PD-1/PD-L1 to provide reference.
In conclusion research and development micromolecular inhibitor has as the drug candidate for blocking PD-1/PD-L1 to interact Important clinical meaning and application prospect.
Invention content
It is this small the purpose of the present invention is to provide the small-molecule drug that can be used as blocking PD-1/PD-L1 interactions Molecular drug should have that production cost is low, be not likely to produce immunogenicity, easily penetrates tissue, have many advantages, such as better stability.
In a first aspect, the present invention provides compound or its pharmaceutically acceptable salt, prodrug, solvate shown in Formulas I Purposes in preparing PD-1 inhibitor：
In formula,
A, B, C, D are each independently selected from saturated or unsaturated 5-6 members carbocyclic ring or heterocycle；
R1It is selected from：Hydrogen, carbonyl, hydroxyl, C1-C6 alkoxies, C1-C6 alkyl, carboxyl, sulfonate group, cyano, N, N- dioxanes Base, C1-C6 alkyl carbonyloxies, C1-C6 alkyl carbonyloxies methyl, oximino；
M is 0-6, preferably any integer of 1-4；
R2It is selected from：Hydrogen, C1-C6 alkyl；
R3It is selected from：Hydrogen, halogen；
R4It is selected from：Hydrogen, carbonyl, hydroxyl, the substituted-phenyl (benzene preferably replaced by the substituted or unsubstituted amino of C1-6 alkyl Base), 5 yuan or 6 circle heterocyclic rings substitution formyloxy；Or R3And R4The composition that can link together contains heteroatomic 3-5 members Ring preferably comprises 3 membered rings of oxygen；
R5It is selected from：Hydrogen, hydroxyl, C1-C6 alkyl；
R6It is independently selected from：Hydrogen, hydroxyl, substituted or unsubstituted C1-C10 linear or branched alkyl groups, carbonyl, acetenyl, C1- C10 alkyl formyl radicals, C1-C10 halogenated alkyls formoxyl, methylol formoxyl, acetoxyl group C1-6 acyl groups, C1-C6 alkyl ammonia It is base formoxyl, the C1-C6 alkyl of carboxyl substitution, C1-C10 alkyl carbonyloxies, substituted or unsubstituted C2-C10 alkenyls, halogenated The formyloxy that C1-C3 alkylthio groups formoxyl, 4- (2- sulfonic groups ethylamino-) -2- butyl, 5 yuan or 6 circle heterocyclic rings replace；
N is 1 or 2；Alternatively, two R6Can linking together, it is substituted or unsubstituted containing heteroatomic 3-6 members to constitute Ring preferably comprises 5 membered rings of oxygen；
R7It is selected from：Hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 carbalkoxies, 13,16- naphthenic base, 16,17- epoxy groups, 15,16- Naphthenic base；Alternatively, R6And R7Can linking together, it is substituted or unsubstituted containing 1-3 heteroatomic 3-6 membered rings to constitute, excellent Select 5 membered rings containing 2 oxygen；
R13For hydrogen；
Alternatively, R7And R13It can link together and constitute substituted or unsubstituted 3-5 members carbocyclic ring, preferably 3 yuan of carbocyclic rings；
R8It is selected from：Hydrogen, halogen, hydroxyl, C1-C6 alkyl；
R9It is selected from：Hydrogen, hydroxyl, C1-C6 alkane thioester substrate, C1-C10 alkyl halides sulfinyl, C1-C6 alkoxy formoxyls；
R10It is selected from：Hydrogen, halogen, carbonyl, C1-C6 alkyl；Alternatively, R9And R10The composition that can link together substitution does not take The 3-5 member carbocyclic rings in generation, preferably 3 yuan of carbocyclic rings；
R11It is selected from：Hydrogen, C1-C6 alkyl；
R12It is selected from：Hydrogen, hydroxyl, C1-C6 alkyl；O is 1 or 2；Alternatively, R11And R12Composition can be linked together containing miscellaneous The 3-5 membered rings of atom preferably comprise 3 membered rings of oxygen.
In a particular embodiment, A is phenyl ring, hexamethylene, cyclohexene or cyclohexadiene；B rings are hexamethylene or hexamethylene Alkene；C rings are thiacyclohexane or cyclohexene；D rings are pentamethylene or cyclopentene.
In a particular embodiment, the compound such as general formula II, III, IV, V, VI, VII, VIII, IX, X, XI, Shown in XII：
R1It is selected from：
R2It is selected from：
R3It is selected from：
R4It is selected from： R5It is selected from：
R6It is selected from：
R7It is selected from：
R8It is selected from：
R9It is selected from：
R10It is selected from：
M is 0-4, preferably any integer of 1-4.
In a particular embodiment,
R1It is selected from：
R2It is selected from：
R3It is selected from：
R4It is selected from：
R5It is selected from：
R6It is selected from：
R7It is selected from：
R8It is selected from：
R9It is selected from：
R10It is selected from：
M is 0-4, preferably any integer of 1-4；
R11And R13Respectively hydrogen；
R12It is selected from：Hydrogen, methyl.
In a particular embodiment,
R1It is selected from：
R2It is selected from：
R3It is selected from：
R4It is selected from：
R5It is selected from：
R6It is selected from：
R7It is selected from：
R8It is selected from：
R9It is selected from：
R10It is selected from：
M is 0-4, preferably any integer of 1-4；
R11、R12And R13Respectively hydrogen.
In second aspect, the present invention provides following compound or its pharmaceutically acceptable salt, prodrug, solvate are being made Purposes in standby PD-1 inhibitor：
In a particular embodiment, the compound of the present invention is following compound：
Preferably, the compound is following compound：
In a particular embodiment, the purposes be used to prepare inhibit PD-1 combined or inhibited with PD-L1 tumour or Treat bacterium, virus or the drug of fungus-caused infection or treatment inflammatory disease.
In a particular embodiment, the tumour includes but not limited to：Melanoma, lung cancer (preferably non-small cell lung Cancer), kidney, oophoroma, prostate cancer, breast cancer, colon cancer, osteocarcinoma, cancer of pancreas, cutaneum carcinoma, head and neck cancer, uterine cancer, rectum Cancer, cancer of anus, gastric cancer, carcinoma of testis, carcinoma of fallopian tube, carcinoma of endometrium, cervix cancer, carcinoma of vagina, carcinoma of vulva, Hodgkin's disease, Non-Hodgkin's lymphoma, cancer of the esophagus, carcinoma of small intestine, internal system cancer, thyroid cancer, parathyroid carcinoma, adrenal, soft tissue Sarcoma, carcinoma of urethra, carcinoma of penis, acute myeloid leukaemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphatic Chronic myeloid leukemia, children solid tumor, lymphocytic lymphoma, carcinoma of urinary bladder, kidney or carcinoma of ureter, carcinoma of renal pelvis, central nervous system System (CNS) tumour, primary CNS lymphoma, Tumor Angiongesis, ridge axis tumor, brain stem glioma, pituitary adenoma, card wave Western sarcoma, epidermoid carcinoma, squamous cell carcinoma, t cell lymphoma；
The virus includes but not limited to：Hepatitis virus (A type, B-mode and the third type), spore exanthema virus, influenza virus, adenopathy Poison, coronavirus, measles virus, dengue fever virus, poliovirus, hydrophobin；
The bacterium includes but not limited to：Chlamydia, rickettsia, mycobacteria, staphylococcus, pneumococcus, suddenly Disorderly, lockjaw；
The fungi includes but not limited to：Candida, aspergillus, Blastomyces dermatitidis；
The inflammatory disease includes but not limited to：Ankylosing spondylitis, autoimmune hemolytic anemia, arthritis, again Disease myasthenia, systemic loupus erythematosus, rheumatoid arthritis, pernicious anaemia, polymyositis.
In the third aspect, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition contains first aspect present invention The compound or its pharmaceutically acceptable salt, prodrug, solvate and pharmaceutically acceptable carrier or figuration Agent.
In a particular embodiment, described pharmaceutical composition also includes the drug that other inhibition PD-1 are combined with PD-L1.
In a particular embodiment, the drug that other inhibition PD-1 are combined with PD-L1 is staurosporine.
In a preferred embodiment, the present invention provides a kind of method that inhibition PD-1 is combined with PD-L1, including step： PD-1 is inhibited to be combined with PD-L1 using the compound of the present invention or pharmaceutical composition.
In a preferred embodiment, the method that the inhibition PD-1 is combined with PD-L1 is the non-treatment carried out in vitro Method.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.
Description of the drawings
Fig. 1 shows the people PD-1 albumen after purification of embodiment 2 through 14%SDS-PAGE Gel electrophoresis results.The purpose item Band position size is about 13kDa, is consistent with theoretical size.
Fig. 2 shows that embodiment 3 purifies the Western blot qualification figures of descendant PD-1.
Fig. 3 shows that micromolecular compound 2 is schemed with the SPR of human PD-L 1 protein competition combination people's PD-1 albumen, shows that this is small Molecular compound can block the combination of people PD-1 and human PD-L 1.
Fig. 4 a show MTT experiment of the micromolecular compound 2 in tumour cell and T cell co-culture system, show that this is small Molecular compound 443 can be by blocking people PD-1 albumen and human PD-L 1 albumen, to make T cell generate one to tumour cell Fixed lethal effect.
Fig. 4 b show micromolecular compound 2 tumour cell with combine positive drug staurosporine in T cell co-culture system (STS) MTT experiment being administered, show the micromolecular compound 443 and positive drug staurosporine (STS) administering drug combinations compare individually to The effect of medicine is more preferable.
Specific implementation mode
After extensive and in-depth study, it was unexpectedly found that a series of steroid derivatives, these derive inventor Object can competitively with people's PD-1 protein bindings, to order the small molecule of blocking agent as research PD-1/PD-L1 immunologic tests Lead drug, and then provide material base for the exploitation of antitumor drug.The present invention is completed on this basis.
Unless otherwise defined, all technical and scientific terms used herein have and disclosed invention fields Technical staff be commonly understood by identical meaning.It is of the invention for ease of understanding, relational language of the present invention is made as follows Definition, but the scope of the present invention is not limited to these specific definition.
Group definition
Herein, " PD-1 albumen " refers to an important Inhibitory receptor on T cell surface in human body.There are two it Ligand, respectively PD-L1 and PD-L2.After PD-L1 is combined with the PD-1 in the T cell of activation, plays and inhibit the anti-swollen of T cell Tumor acts on.Therefore, PD-1/PD-L1 accesses are blocked to have positive effect for inhibition or killing tumor cell.
Herein, " alkyl " refers to the branched-chain or straight-chain alkyl for the saturation that carbon chain lengths are 1-10 carbon atom, preferably Alkyl includes the alkyl or cycloalkyl of long 2-8 carbon atom, 1-6,1-4 carbon atom, 1-3 carbon atom not etc..Alkyl Example includes but not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, heptyl, ring methane etc..Alkyl can be with Replaced by one or more substituent groups, such as is replaced by halogen or halogenated alkyl.For example, alkyl can be taken by 1-4 fluorine atom The alkyl or alkyl in generation can be the alkyl replaced by fluoro-alkyl.
Herein, " alkoxy " refers to alkyl-substituted oxygroup.Preferred alkoxy is the alcoxyl of long 1-6 carbon atom Base, the alkoxy of more preferably long 1-4 carbon atom.The example of alkoxy includes but not limited to methoxyl group, ethyoxyl, propoxyl group Deng.
Herein, " halogen " refers to fluorine, chlorine, bromine and iodine.In a preferred embodiment, halogen is chlorine or fluorine.
The compound of the present invention
Inventors have surprisingly discovered that a series of steroid derivatives, these compounds are horizontal in molecule and animal Display can be in conjunction with PD-1 in test, and blocks the interaction of PD-1 and PD-L1, while toxicity is relatively low, safety is preferable, With good patent medicine foreground.
In a particular embodiment, the compound of the present invention is compound shown in following formula I or its is pharmaceutically acceptable Salt, prodrug or solvate：
In formula,
A, B, C, D are each independently selected from saturated or unsaturated 5-6 members carbocyclic ring or heterocycle；
R1It is selected from the group：Hydrogen, carbonyl, hydroxyl, C1-C6 alkoxies, C1-C6 alkyl, carboxyl, sulfonate group, cyano, N, N- Dialkyl group, C1-C6 alkyl carbonyloxies, C1-C6 alkyl carbonyloxies methyl, oximino；M is 0-6, preferably any of 1-4 Integer；
R2It is selected from：Hydrogen, C1-C6 alkyl；
R3It is selected from：Hydrogen, halogen；
R4It is selected from：Hydrogen, carbonyl, hydroxyl, the substituted-phenyl (benzene preferably replaced by the substituted or unsubstituted amino of C1-6 alkyl Base), 5 yuan or 6 circle heterocyclic rings substitution formyloxy；Or R3And R4The composition that can link together contains heteroatomic 3-5 members Ring preferably comprises 3 membered rings of oxygen；
R5It is selected from：Hydrogen, hydroxyl, C1-C6 alkyl；
R6It is independently selected from：Hydrogen, hydroxyl, substituted or unsubstituted C1-C10 linear or branched alkyl groups, carbonyl, acetenyl, C1- C10 alkyl formyl radicals, C1-C10 halogenated alkyls formoxyl, methylol formoxyl, acetoxyl group C1-6 acyl groups, C1-C6 alkyl ammonia It is base formoxyl, the C1-C6 alkyl of carboxyl substitution, C1-C10 alkyl carbonyloxies, substituted or unsubstituted C2-C10 alkenyls, halogenated The formyloxy that C1-C3 alkylthio groups formoxyl, 4- (2- sulfonic groups ethylamino-) -2- butyl, 5 yuan or 6 circle heterocyclic rings replace；
N is 1 or 2；Alternatively, two R6Can linking together, it is substituted or unsubstituted containing heteroatomic 3-6 members to constitute Ring preferably comprises 5 membered rings of oxygen；
R7It is selected from：Hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 carbalkoxies, 13,16- naphthenic base, 16,17- epoxy groups, 15,16- Naphthenic base；Alternatively, R6And R7Can linking together, it is substituted or unsubstituted containing 1-3 heteroatomic 3-6 membered rings to constitute, excellent Select 5 membered rings containing 2 oxygen；
R13For hydrogen；
Alternatively, R7And R13It can link together and constitute substituted or unsubstituted 3-5 members carbocyclic ring, preferably 3 yuan of carbocyclic rings；
R8It is selected from：Hydrogen, halogen, hydroxyl, C1-C6 alkyl；
R9It is selected from：Hydrogen, hydroxyl, C1-C6 alkane thioester substrate, C1-C10 alkyl halides sulfinyl, C1-C6 alkoxy formoxyls；
R10It is selected from：Hydrogen, halogen, carbonyl, C1-C6 alkyl；Alternatively, R9And R10The composition that can link together substitution does not take The 3-5 member carbocyclic rings in generation, preferably 3 yuan of carbocyclic rings；
R11It is selected from the group：Hydrogen, C1-C6 alkyl；
R12It is selected from the group：Hydrogen, hydroxyl, C1-C6 alkyl；O is 1 or 2；Alternatively, R11And R12The composition that can link together contains There are heteroatomic 3-5 membered rings, preferably comprises 3 membered rings of oxygen.
In a preferred embodiment, A can be phenyl ring, hexamethylene, cyclohexene or cyclohexadiene；B rings be hexamethylene or Cyclohexene；C rings are thiacyclohexane or cyclohexene；D rings are pentamethylene or cyclopentene.For example, compound shown in Formulas I can be such as general formula Shown in II, III, IV, V, VI, VII, VIII, IX, X, XI, XII：
In formula, R1It is selected from：
R2It is selected from：
R3It is selected from：
R4It is selected from： R5It is selected from：
R6It is selected from：
R7It is selected from：
R8It is selected from：
R9It is selected from：
R10It is selected from：
M is 0-4, preferably any integer of 1-4.
In a particular embodiment, all substituent groups in general formula of the invention can be of the invention specific open respectively Any compound in corresponding group.
Specifically, the compound of the present invention includes but not limited to：The compound that number is 1-65.
Since the compound of the present invention and people's PD-1 albumen have good binding affinity, these compound energy conducts The conditioning agent of blocking agent or conciliation PD-1/PD-L1 combination degrees that PD-1/PD-L1 is combined.Therefore, the compounds of this invention can It is used to prepare and PD-1 is inhibited to be combined or inhibited tumour or treatment bacterium, virus or fungus-caused infection or treatment scorching with PD-L1 The drug of property disease；For example, a kind of pharmaceutical composition, the composition contains the compounds of this invention or its pharmacy of therapeutically effective amount Upper acceptable salt, prodrug or solvate and pharmaceutically acceptable carrier or excipient.
The compound of the present invention obviously can also with other mechanism blocking PD-1/PD-L1 accesses drug and other Antitumor drug is combined to enhance mutual effect.Therefore, may also include in aforementioned pharmaceutical compositions it is pharmaceutically acceptable its He blocks the drug of PD-1/PD-L1 accesses.For example, the drug of other blocking PD-1/PD-L1 accesses includes but not limited to： Target PD-1 albumen nivolumab, pembrolizumab, pidilizumab and target PD-L1 MPDL3280A, MDX1105, MEDI4736 etc..In a preferred embodiment, the pharmaceutical composition may also include other antitumor drugs, The antitumor drug includes but not limited to：Ipilimumab,ramucirumab,trametinib,ceritini, Dabrafenib etc..
The compounds of this invention can be applied as a pharmaceutically acceptable salt, the example of the pharmaceutically acceptable salt Son includes but not limited to：Inorganic and acylate, such as hydrochloride, hydrobromate, sulfate, citrate, lactate, winestone Hydrochlorate, maleate, fumarate, mandelate and oxalates；And with alkali such as sodium hydroxyl, three (hydroxymethyl) amino first The inorganic and organic alkali salt that alkane (TRIS, amine butantriol) and N-METHYL-ALPHA-L-GLUCOSAMINE are formed.
Those skilled in the art are known, and the specific dosage form of pharmaceutical composition of the invention is depending on to be used to prescription Formula.For example, the adoptable administering mode of pharmaceutical composition of the present invention includes but not limited to：It is parenteral, subcutaneously, vein, muscle, abdomen Intracavitary, transdermal, oral cavity, encephalic, nasal cavity or topical route form of medication, for treating tumour or other diseases.And pharmaceutical composition In object the content of active constituent can by medical domain technical staff according to, such as patient gender, the age, general health Etc. actual conditions independently determine.
Activity based on the compound of the present invention, those skilled in the art it is contemplated that can be prepared into inhibit PD-1 with The drug or inhibit tumour or treat bacterium, virus or the medicine of fungus-caused infection or treatment inflammatory disease that PD-L1 is combined Object.
In a specific embodiment, the tumour includes but not limited to：Melanoma, lung cancer (preferably non-small cell lung Cancer), kidney, oophoroma, prostate cancer, breast cancer, colon cancer, osteocarcinoma, cancer of pancreas, cutaneum carcinoma, head and neck cancer, uterine cancer, rectum Cancer, cancer of anus, gastric cancer, carcinoma of testis, carcinoma of fallopian tube, carcinoma of endometrium, cervix cancer, carcinoma of vagina, carcinoma of vulva, Hodgkin's disease, Non-Hodgkin's lymphoma, cancer of the esophagus, carcinoma of small intestine, internal system cancer, thyroid cancer, parathyroid carcinoma, adrenal, soft tissue Sarcoma, carcinoma of urethra, carcinoma of penis, acute myeloid leukaemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphatic Chronic myeloid leukemia, children solid tumor, lymphocytic lymphoma, carcinoma of urinary bladder, kidney or carcinoma of ureter, carcinoma of renal pelvis, central nervous system System (CNS) tumour, primary CNS lymphoma, Tumor Angiongesis, ridge axis tumor, brain stem glioma, pituitary adenoma, card wave Western sarcoma, epidermoid carcinoma, squamous cell carcinoma, t cell lymphoma.
In other embodiments, the drug that the inhibition PD-1 is combined with PD-L1 can be additionally used in treat bacterium, virus or Fungal infection.For example, infection caused by following virus：Hepatitis virus (A type, B-mode and the third type), spore exanthema virus, influenza virus, Adenovirus, coronavirus, measles virus, dengue fever virus, poliovirus, hydrophobin etc.；Following bacterium causes Infection：Chlamydia, rickettsia, mycobacteria, staphylococcus, pneumococcus, cholera, lockjaw etc.；Or following fungi Caused pathogenic infection：Candida, aspergillus, Blastomyces dermatitidis etc..
In other embodiments, the drug that the inhibition PD-1 is combined with PD-L1 can be also used for treatment inflammatory disease, Including but not limited to：Ankylosing spondylitis, autoimmune hemolytic anemia, arthritis, myasthenia gravis, systemic red yabbi Sore, rheumatoid arthritis, pernicious anaemia, polymyositis etc..
On the basis of the compound of the present invention or pharmaceutical composition, tied the present invention also provides PD-1 and PD-L1 is blocked The method of conjunction, the step of combination with PD-L1 including the use of the compound of the present invention or pharmaceutical composition blocking PD-1.Specific In embodiment, the method that the blocking PD-1 is combined with PD-L1 is external non-therapeutic.
Advantages of the present invention：
1. a series of present invention firstly discovers that steroid derivatives；
2. the compound of the present invention can have good combination with people's PD-1 albumen, wherein binding affinity highestization The combination situation of conjunction object and people's PD-1 albumen is better than the combination situation of natural PD-L1 albumen and people's PD-1 albumen；
3. there is the compound of the present invention higher specificity, tissue affinity to be not likely to produce immunogenicity and have Preferable tissue permeability；
4. the production cost of the compound of the present invention is relatively low.
Technical scheme of the present invention is further described below in conjunction with specific implementation case, but following case study on implementation is not constituted Limitation of the present invention, the various method of administration that all principles and technological means according to the present invention use, belongs to the present invention Range.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal condition, or is built according to manufacturer The condition of view.Unless otherwise stated, otherwise percentage and number are calculated by weight.
1. people's PD-1 expression vector establishments of embodiment
The 34-150 amino acids of target gene behaviour PD-1 are chosen according to pertinent literature.Utilize two enzymes of NCoI and NdeI Target gene is cloned on pET-28a carriers by enzyme site.First according to two restriction enzyme site design specificity of NCoI and NdeI People's PD-1 genes are carried out PCR amplification by primer.Vector plasmid and PCR product are utilized respectively using the method for tradition clone later Two restriction enzymes of NCoI and NdeI carry out double digestion, then are attached to form recombination matter under the action of T4 ligases Grain, finally will be in recombinant plasmid transformed to bacillus coli DH 5 alpha competent cell.Rear picking monoclonal is incubated overnight to be identified.
The expression and purification of 2. people's PD-1 albumen of embodiment
Overnight, then plasmid is transformed into expression by upgrading grain for the small training of bacterium solution that sequence exactly matches after the sequencing of selection company In host E.coli BL21 (DE3), expressed.Picking is transformed into the monoclonal of E.coli BL21 (DE3), is placed in containing card In 20mL 2 × YT culture mediums of that mycin in 37 DEG C of shaking table overnight incubation.Next day by small training product be transferred to containing card that In the TB culture mediums of mycin, culture is 0.6-0.8 to OD600 at 37 DEG C, and 0.5mM IPTG are added and induce 5-7h at 37 DEG C.? Under 4000rpm centrifugation receive bacterium, with lysis buffer (50mM Tris-HCl, pH 8.0,50mM NaCl, 1mM DTT, 0.5mM EDTA, 5% glycerine) cracking Escherichia coli, then high pressure is broken again, centrifuges 60min at 12000rpm, takes precipitation.It is miscellaneous with washing Buffer solution (20mM Tris-HCl, pH 8.0,2M urea, 2.5%Triton X-100) wash it is miscellaneous three times, take precipitation.Then it uses again Dissolve buffer solution (20mM Tris-HCl, pH 8.0,8M urea) soluble protein, centrifuging and taking supernatant.Take the ultrafiltration concentration pipe of 3kDa Protein concentrate is added to renaturation buffer (50mM Tris-HCl, pH 8.0, the 50mM L-Arg, 24mM of 1L to 5mL or so NaCl, 1mM KCl, 1mM EDTA) in, with dilution method, renaturation is for 24 hours at 4 DEG C.The concentration tube protein concentrate of 3kDa is then used, until Albumen is fitted into bag filter by 20mL or so, in elution buffer (50mM Tris-HCl, pH 8.0,150mM NaCl, 1mM DTT dialysed overnight in), in order to displace the L-Arg in renaturation buffer.Cation exchange column and molecule are crossed in concentration Sieve is purified.Albumen after excessively complete molecular sieve is subjected to 14%SDS-PAGE gel electrophoresises, the purity of protein after purification Identification. The results are shown in Figure 1, purified obtained molecular weight of albumen in 13kDa or so, people's PD-1 albumen for being obtained with theoretical calculation Molecular weight is consistent, and purity of protein is higher.
The identification of 3. people's PD-1 albumen of embodiment
People's PD-1 albumen after purification is subjected to 14%SDS-PAGE gel electrophoresises, then carries out transferring film, setting transferring film electricity Stream is 300mA, and the transferring film time is 45min.Then film is closed into 2h at room temperature with 5% skimmed milk power.It is anti-with mouse after taking-up People PD-1 monoclonal antibodies are incubated overnight at 4 DEG C, are rinsed in 1 × TBST solution three times, with the anti-mouse monoclonal antibody of goat It is incubated at room temperature 2h, is rinsed three times in 1 × TBST solution.After developer solution is added, in Full-automatic chemiluminescence image analysis Develop under system.As a result as indicated with 2, there is protein band between 10-15kDa, and can develop under PD-1 antibody, therefore say The bright obtained albumen that purifies is strictly people's PD-1 albumen.
Embodiment 4.SPR carries out the screening of micromolecular compound and combines the measurement in Changshu
Compound 1-42 purchases used in example are in Adamas, TCI, Sigma, J&K company, compound 43-53 purchases In specs companies, compound 54-65 is given by The 2nd Army Medical College Zhang Weidong professor.
Micromolecular compound is carried out surface plasma body resonant vibration (SPR) by Biacore T200 to carry out and people's PD-1 eggs The screening of combination situation between white, the measurement of progress binding constant after the relatively high compound of the value that meets with a response.Specific experiment Steps are as follows：Albumen after purification is changed into liquid to 50mM Hepes, pH 8.0,250mM NaCl, 1mM DTT buffer solutions first In, albumen is diluted to 50 μ g/ml with the sodium acetate of pH4.5, using amino coupled kit by albumen coupling in CM7 chips On, with the flow velocity combination 600s of 10 μ l/min, last coupling amount is about 15000RU.After coupling.CM7 chips are used slow Fliud flushing (1.05 × PBS, 0.05%P20) is balanced to stable state.Then use running buffer (1.05 × PBS, 0.05%P20, 1%DMSO) by a series of diluted chemical compound to various concentrations, chip surface, 30 μ L/min of flow velocity, knot are flowed through with running buffer Close time 90s, Dissociation time 120s.Final data is analyzed with BIAevaluation2.0 softwares, is fitted to obtain KD using stable state Value.The KD values of surveyed compound are listed in the following table 1.
The binding affinity of the micromolecular compound and recombined human PD-1 albumen of 1. present invention of table
Embodiment 5. carries out the combination of identifier PD-1 and micromolecular compound with thermophoresis
By purified people PD-1 albumen with assay buffer (50mM Hepes, pH8.0,250mM NaCl, 1mM DTT) Be diluted to 0.5mg/ml, add thermophoresis dyestuff to final concentration of 3 ×, compound is added to 400 μM of final concentration, finally takes 20 μ L are added in 96 orifice plates, are incubated 10min on ice.Fluorescent value variation is detected with Quantstudio flex 6RT-PCR, if Constant temperature degree is slowly ramped to 95 DEG C from 25 DEG C, detects the power of fluorescent value in real time in temperature-rise period.With Protein Thermal △ Tm values are calculated in Shift Software v1.0.Parallel three groups are tested every time.The results are shown in Table 2, compound in table 2 Tm values be more than 1.5 DEG C, it is believed that have combination between albumen, and the conformation between people PD-1 can be stablized.
Δ Tm value of 2. compound effects of table before and after PD-1
Id △Tm(℃)
1 1.64
2 1.68
13 2.09
21 3.18
25 3.45
30 21.47
42 18.03
6. human PD-L 1 albumen of embodiment and the SPR of 2 competitive binding PD-1 of micromolecular compound are tested
According to the result in examples detailed above as a result, the present inventor chooses the compound 2 and emulative combination PD- of human PD-L 1 1, probe into whether micromolecular compound 2 can block the combination of PD-1 and PD-L1.The purchase of human PD-L 1 albumen sticks up god in Beijing justice State Bioisystech Co., Ltd.Steps are as follows for specific experiment, by the method for amino coupled that 50 μ g/ml human PD-L 1s albumen are even It is linked on CM5 chips.Coupling amount is about 3780RU.The compound 2 of various concentration and 3 μM of people PD-1 albumen are incubated on ice 30min.Chip surface is flowed through with running buffer (1.05 × PBS, 0.05%P20,1%DMSO), 30 μ L/min of flow velocity, in conjunction with Time 90s, Dissociation time 120s.Final data is analyzed with BIAevaluation2.0 softwares, and the results are shown in Figure 3.With small 2 concentration of molecular compound increases, and makes the people's PD-1 albumen being incorporated on human PD-L 1 albumen reduction, therefore response reduces.The reality It tests result and may indicate that micromolecular compound 2 can block the combination of people PD-1 and human PD-L 1.
The MTT cell experiments of 7. micromolecular compound of embodiment, 2 administering drug combinations
Utilize the expression quantity of human PD-L 1 albumen in Western blot experiment detection BxPC-3 cells.As a result BxPC- is shown Human PD-L 1 can be inherently expressed in 3, after the stimulation of 500U/ml IFN-γ is added, the expression quantity of PD-L1 increased.
MTT cell experiments are as follows, carry out plating cells first, and IFN-γ (500U/ is used in advance for 5000 per hole Ml the tumour cell BxPC-3) stimulated.It adds later and uses PHA in advance, 10000 T cell Jurkat that PMA was activated are total It cultivates or is not added with Jurkat to compare, while the micromolecular compound 2 of various concentration is added, cultivate 72h.As a result such as Fig. 4 institutes Show.
Steps are as follows for the MTT experiment of administering drug combinations, carries out plating cells first, and IFN-γ is used in advance per 5000, hole The tumour cell BxPC-3 that (500U/ml) was stimulated.It adds later and uses PHA, 10000 T cells that PMA was activated in advance Jurkat is co-cultured, while 12.5 μM of compounds 2 are added, and the positive drug staurosporine that next day is added 0.5 μM carries out administering drug combinations. Continue to cultivate 48h.It is eventually adding MTT, after being incubated 4h, siphons away culture medium, MTT is dissolved with 100 μ l DMSO, it is surveyed at 490nm Light absorption value.The results are shown in Figure 4.
It discusses：The steroid micromolecular compound 2 of the present invention has with people's PD-1 albumen to be combined well, and can be certain The conformation for stablizing people's PD-1 albumen in degree, using SPR measurings, its KD value between people's PD-1 albumen is 0.93 μM.And And found by the experiment of micromolecular compound 2 and the emulative combination people PD-1 of human PD-L 1, which is combining people PD-1 While can block the combination of people PD-1 and human PD-L 1.Our small molecule is learnt finally by the MTT experiment of administering drug combinations Compound 2 can be by blocking the combination of people PD-1 and human PD-L 1 that Jurkat cell is made to have certain killing to tumour cell Effect, and it is better with staurosporine administering drug combinations.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To be made various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (12)

1. the use of compound shown in Formulas I or its pharmaceutically acceptable salt, prodrug, solvate in preparing PD-1 inhibitor On the way：
In formula,
A, B, C, D are each independently selected from saturated or unsaturated 5-6 members carbocyclic ring or heterocycle；
R1It is selected from：Hydrogen, carbonyl, hydroxyl, C1-C6 alkoxies, C1-C6 alkyl, carboxyl, sulfonate group, cyano, N, N- dialkyl group, C1-C6 alkyl carbonyloxies, C1-C6 alkyl carbonyloxies methyl, oximino；
M is 0-6, preferably any integer of 1-4；
R2It is selected from：Hydrogen, C1-C6 alkyl；
R3It is selected from：Hydrogen, halogen；
R4It is selected from：Hydrogen, carbonyl, hydroxyl, substituted-phenyl (phenyl preferably replaced by the substituted or unsubstituted amino of C1-6 alkyl), 5 Member or the formyloxy of 6 circle heterocyclic rings substitution；Or R3And R4The composition that can link together contains heteroatomic 3-5 membered rings, preferably Containing 3 aerobic membered rings；
R5It is selected from：Hydrogen, hydroxyl, C1-C6 alkyl；
R6It is independently selected from：Hydrogen, hydroxyl, substituted or unsubstituted C1-C10 linear or branched alkyl groups, carbonyl, acetenyl, C1-C10 alkane Base formoxyl, C1-C10 halogenated alkyls formoxyl, methylol formoxyl, acetoxyl group C1-6 acyl groups, C1-C6 alkyl carbamoyls C1-C6 alkyl, C1-C10 alkyl carbonyloxies, substituted or unsubstituted C2-C10 alkenyls, the halogenated C1-C3 that base, carboxyl replace The formyloxy that alkylthio group formoxyl, 4- (2- sulfonic groups ethylamino-) -2- butyl, 5 yuan or 6 circle heterocyclic rings replace；
N is 1 or 2；Alternatively, two R6Can linking together, it is substituted or unsubstituted containing heteroatomic 3-6 membered rings to constitute, excellent Choosing is containing 5 aerobic membered rings；
R7It is selected from：Hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 carbalkoxies, 13,16- naphthenic base, 16,17- epoxy groups, 15,16- cycloalkanes Base；Alternatively, R6And R7Can linking together, it is substituted or unsubstituted containing 1-3 heteroatomic 3-6 membered rings to constitute, and preferably contains There are 5 membered rings of 2 oxygen；
R13For hydrogen；
Alternatively, R7And R13It can link together and constitute substituted or unsubstituted 3-5 members carbocyclic ring, preferably 3 yuan of carbocyclic rings；
R8It is selected from：Hydrogen, halogen, hydroxyl, C1-C6 alkyl；
R9It is selected from：Hydrogen, hydroxyl, C1-C6 alkane thioester substrate, C1-C10 alkyl halides sulfinyl, C1-C6 alkoxy formoxyls；
R10It is selected from：Hydrogen, halogen, carbonyl, C1-C6 alkyl；Alternatively, R9And R10Can linking together, it is substituted or unsubstituted to constitute 3-5 member carbocyclic rings, preferably 3 yuan of carbocyclic rings；
R11It is selected from：Hydrogen, C1-C6 alkyl；
R12It is selected from：Hydrogen, hydroxyl, C1-C6 alkyl；O is 1 or 2；Alternatively, R11And R12The composition that can link together contains hetero atom 3-5 membered rings, preferably comprise 3 membered rings of oxygen.
2. purposes as described in claim 1, which is characterized in that A is phenyl ring, hexamethylene, cyclohexene or cyclohexadiene；B rings are Hexamethylene or cyclohexene；C rings are thiacyclohexane or cyclohexene；D rings are pentamethylene or cyclopentene.
3. purposes as claimed in claim 1 or 2, which is characterized in that the compound such as general formula II, III, IV, V, VI, VII, Shown in VIII, IX, X, XI, XII：
R1It is selected from：
R2It is selected from：
R3It is selected from：
R4It is selected from：
R5It is selected from：
R6It is selected from：
R7It is selected from：
R8It is selected from：
R9It is selected from：
R10It is selected from：
M is 0-4, preferably any integer of 1-4.
4. purposes as claimed in claim 1 or 2, which is characterized in that
R1It is selected from：
R2It is selected from：
R3It is selected from：
R4It is selected from：
R5It is selected from：
R6It is selected from：
R7It is selected from：
R8It is selected from：
R9It is selected from：
R10It is selected from：
M is 0-4, preferably any integer of 1-4；
R11And R13Respectively hydrogen；
R12It is selected from：Hydrogen, methyl.
5. purposes as claimed in claim 4, which is characterized in that
R1It is selected from：
R2It is selected from：
R3It is selected from：
R4It is selected from：
R5It is selected from：
R6It is selected from：
R7It is selected from：
R8It is selected from：
R9It is selected from：
R10It is selected from：
M is 0-4, preferably any integer of 1-4；
R11、R12And R13Respectively hydrogen.
The purposes of compound below 6. or its pharmaceutically acceptable salt, prodrug, solvate in preparing PD-1 inhibitor：
7. purposes as claimed in claim 6, which is characterized in that the compound is following compound：
Preferably, the compound is following compound：
8. purposes as described in claim 1, which is characterized in that the purposes is to be used to prepare that PD-1 is inhibited to be combined with PD-L1 Or inhibits tumour or treat bacterium, virus or the drug of fungus-caused infection or treatment inflammatory disease.
9. purposes as claimed in claim 8, which is characterized in that the tumour includes but not limited to：Melanoma, lung cancer are (excellent Select non-small cell lung cancer), kidney, oophoroma, prostate cancer, breast cancer, colon cancer, osteocarcinoma, cancer of pancreas, cutaneum carcinoma, head and neck cancer, Uterine cancer, the carcinoma of the rectum, cancer of anus, gastric cancer, carcinoma of testis, carcinoma of fallopian tube, carcinoma of endometrium, cervix cancer, carcinoma of vagina, carcinoma of vulva, Hodgkin's disease, non-Hodgkin's lymphoma, cancer of the esophagus, carcinoma of small intestine, internal system cancer, thyroid cancer, parathyroid carcinoma, on kidney Gland cancer, soft tissue sarcoma, carcinoma of urethra, carcinoma of penis, acute myeloid leukaemia, chronic myelogenous leukemia, the white blood of acute lymphoblastic Disease, chronic lymphocytic leukemia, children solid tumor, lymphocytic lymphoma, carcinoma of urinary bladder, kidney or carcinoma of ureter, carcinoma of renal pelvis, Central nervous system (CNS) tumour, primary CNS lymphoma, Tumor Angiongesis, ridge axis tumor, brain stem glioma, hypophysis Adenoma, Kaposi sarcoma, epidermoid carcinoma, squamous cell carcinoma, t cell lymphoma；
The virus includes but not limited to：Hepatitis virus (A type, B-mode and the third type), spore exanthema virus, influenza virus, adenovirus, Coronavirus, measles virus, dengue fever virus, poliovirus, hydrophobin；
The bacterium includes but not limited to：Chlamydia, mycobacteria, staphylococcus, pneumococcus, cholera, is broken rickettsia Cold；
The fungi includes but not limited to：Candida, aspergillus, Blastomyces dermatitidis；
The inflammatory disease includes but not limited to：Ankylosing spondylitis, autoimmune hemolytic anemia, arthritis, severe flesh Inability, systemic loupus erythematosus, rheumatoid arthritis, pernicious anaemia, polymyositis.
10. a kind of pharmaceutical composition, described pharmaceutical composition contains compound or its medicine described in any one of claim 1-8 Acceptable salt, prodrug, solvate and pharmaceutically acceptable carrier or excipient on.
11. pharmaceutical composition as claimed in claim 10, which is characterized in that described pharmaceutical composition also includes other inhibition The drug that PD-1 is combined with PD-L1.
12. pharmaceutical composition as claimed in claim 11, which is characterized in that other inhibition PD-1 were combined with PD-L1 Drug is staurosporine.
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