CN109824621A - Oxadiazoles and thiadiazoles compounds and preparation method and use thereof - Google Patents
Oxadiazoles and thiadiazoles compounds and preparation method and use thereof Download PDFInfo
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- CN109824621A CN109824621A CN201910248020.3A CN201910248020A CN109824621A CN 109824621 A CN109824621 A CN 109824621A CN 201910248020 A CN201910248020 A CN 201910248020A CN 109824621 A CN109824621 A CN 109824621A
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- alkyl
- thiadiazole compound
- compound
- pharmaceutically acceptable
- added
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- RDWZQVGVBTYCBD-QRPNPIFTSA-N tert-butyl (2s)-2-amino-3-[(2-methylpropan-2-yl)oxy]propanoate;hydrochloride Chemical compound Cl.CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C RDWZQVGVBTYCBD-QRPNPIFTSA-N 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
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Abstract
本发明公开了一种噁二唑类和噻二唑类化合物及其制备方法和用途，该类化合物如下式Ⅰ或式Ⅱ所示，本发明的噁二唑类或噻二唑类化合物或其药学上可接受的盐、消旋体、旋光异构体或溶剂化合物可以调控PD‑1/PD‑L1及VISTA信号通路，作为能够阻断PD‑1/PD‑L1及VISTA信号通路的双靶点免疫检查点抑制剂，可以应用在制备抗肿瘤药物中。 The invention discloses an oxadiazole and thiadiazole compound and a preparation method and application thereof. The compound is shown in the following formula I or II. The oxadiazole or thiadiazole compound of the present invention or its Pharmaceutically acceptable salts, racemates, optical isomers or solvent compounds can modulate PD-1/PD-L1 and VISTA signaling pathways, as dual targets that can block PD-1/PD-L1 and VISTA signaling pathways The point immune checkpoint inhibitor can be used in the preparation of antitumor drugs.
Description
Technical field
The invention belongs to biomedicine fields, and in particular to can block the double of PD-1/PD-L1 and VISTA signal path
Furodiazole and thiadiazole compound of target spot immunologic test point inhibitor and preparation method thereof and as in tumour immunity
The purposes of immunologic test point inhibitor.
Background technique
Malignant tumour is a kind of disease for seriously threatening human health and life.For at present, the mode packet of oncotherapy
Include operation, radiotherapy, chemotherapy and targeted therapy etc..Immunotherapy of tumors refers to anti-to improve by stimulation body immune system
Tumour immunity effect, to inhibit a kind for the treatment of method with killing tumor cell.The research of immunization therapy has last 100 years and goes through
History, with oncology, the comprehensive development of immunology and molecular biology and Cross slot interference, immunization therapy achieves various
Achievement brings new hope for oncotherapy.
Immunologic test point inhibitor is immunotherapy medicaments burning hoter at present.Tumour cell passes through up-regulation immunologic test
The expression of point receptor inhibits immunocyte T cell activity, completes the immunologic escape of tumour cell.Immunologic test point inhibitor is then
It is to release the inhibition of immunocyte T cell, activation body kills the immune of tumour cell by inhibiting immunologic test point access
Wound, realizes the effect of oncotherapy.At present, it has been found that immunologic test point have CTLA-4 (cytotoxic T lymphocyte-
Associated antigen-4), PD-1 (Programmed cell death 1) and TIM3 (T cell membrane 3)
Deng (see Drew M.Pardoll, Nature Review Cancer, 2012,12,252).
Programmed death receptor 1 (PD-1) is an immunoglobulin like protein, belongs to CD28 superfamily.PD-1 is by 288 amino
Acid composition, possesses immune globulin variable region domain and cytosolic domain.Unlike CTLA-4 and other family proteins,
PD-1 is single molecule structure, and the PD-1 albumen of people and mouse has about 60% same amino acid sequence, and CTLA-4 is only
16%.PD-1 is as a kind of immunologic test point inhibitor, in T cell, the B cell, nature that thymocyte has expression, and activates
Killing cell and dendritic cells can raise the expression of PD-1.It is shown in the multinomial research about PD-1 deficient mice, these
PD-1 deficient mice is susceptible to suffer from autoimmune disease.PD-1 has two class native ligands, PD-L1 and PD-L2.When in the T cell of activation
When adjusting the expression of PD-1, body can inhibit T cell active by generating the ligand of PD-1 in conjunction with PD-1.However tumour
Cell also can by expressing PD-L1, thus inhibit body antineoplastic immune activity (see Yasumasa Ishida,
Yasutoshi Agata,et al.The EMBO Journal,1992,11, 3887).Therefore, inhibit PD-1/PD-L1 signal
Access can repair antitumor immunity of organism activity, also become one by the research of the inhibitor of target spot of PD-1/PD-L1 signal path
Item research hotspot.
2014, Bristol Myers Squibb and Mo Shadong had listed the monoclonal antibody for targeting PD-1/PD-L1 respectively
Nivolumab and pembrolizumab is used for the treatment of melanoma.Subsequent Roche and AstraZeneca also list respective anti-
The monoclonal antibody drug atezolizumab and durvalumab of PD-1/PD-L1.The auspicious Dan Ke with Paekche Divine Land of domestic perseverance
Grand drug also enters three phases clinic, it is contemplated that lists within the year.The PD-1/PD-L1 signal pathway inhibitor listed at present
It is monoclonal antibody drug, however monoclonal antibody drug oral administration biaavailability is poor, and produces costly difficult.Face
Bed research is also shown, and monoclonal antibody drug results in a variety of machines due to itself longer half-life period and immune response difficult to control
The immune-related adverse reaction of body.
The area V Ig repressor (VISTA) is a kind of transmembrane protein, belongs to immunoglobulin class, extracellular domain and PD-
L1 is homologous, also known as PD-1 homologous protein (PD-1H), similar with PD-1/PD-L1, and VISTA is also that a kind of immunologic test point inhibits
Access has inhibiting effect 7 for the response of T cell.Because the similitude of VISTA and PD-1, researcher are probing into always VISTA
A possibility that with PD-1 synergistic treatment.Pass through the research of the immune response for VISTA and PD-1 gene knockout mouse, it was demonstrated that
VISTA is to be different from PD-1/PD-L1 access for the inhibition function of t cell activation, logical for design VISTA and PD-1/PD-L1
The Immunotherapy regimens of road collaboration provide theoretical basis (see Liu J, Yuan Y, et al.Proceedings of the
National Academy of Sciences,2015,112, 6682-6687.)。
So far, in the market still without the small of the PD-1/PD-L1 signal path of non-antibody class and VISTA signal path
Molecule inhibitor.Therefore, developing, there is the novel PD-1/PD-L1 and VISTA signal path small molecule of good anti-tumor activity to press down
Preparation is of great significance, and provides help to make up the blank of this kind of medical clinical application.
Summary of the invention
Goal of the invention: for existing PD-1/PD-L1 monoclonal antibody medicine production valuableness, drug administration by injection and range of tumor treatment are needed
The defects of limited, it to be a kind of PD-1/PD-L1 and VISTA that the present invention provides a kind of furodiazole and thiadiazole compounds
Double target spot molecule inhibitor compounds；A series of bis- target spot small molecule immune inspections of PD-1/PD-L1 of the invention and VISTA
Point inhibitor can treat a variety of related neoplasms by regulating and controlling PD-1/PD-L1 and VISTA signal path with tumour immunotherapy
Disease.
The present invention also provides the preparation method of the furodiazole and thiadiazole compound, pharmaceutical composition and its medicine
Purposes, the compound can be used for tumour immunotherapy, the treatment and prevention for tumour.
Technical solution: to achieve the goals above, one kind furodiazole as shown in following formula I or formula II as described herein
Or thiadiazole compound:
Wherein, X is O or S；
R1, R2 are amino acid side chain or C1-6Alkyl；The C1-6Alkyl can optionally be taken by following one or more
Replace for base: carboxyl, amino, hydroxyl, naphthenic base, aryl, heterocycle, alkenyl, alkynyl；Optionally C1-6In alkyl two to
Three carbon atoms can become a part of 3 to 7 yuan of carbocyclic rings or heterocycle；Wherein the carbocyclic ring, heterocycle are optionally selected from alkyl, alkane
Oxygroup, carboxyl, hydroxyl, 1 to 6 in halogen identical or different group replace；
R3 is hydrogen or C1-6Alkyl；Wherein C1-6Alkyl can optionally be replaced by following one or more substituent groups: carboxylic
Base, amino, hydroxyl, naphthenic base, aryl, heterocycle, alkenyl, alkynyl；Optionally C1-6Two to three carbon atoms in alkyl can
A part as 3 to 7 yuan of carbocyclic rings or heterocycle；Wherein the carbocyclic ring, heterocycle are optionally selected from alkyl, alkoxy, carboxyl, hydroxyl
1 to 6 identical or different group in base, halogen replaces；
R4 is hydrogen, dimethyl, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.
Preferably, the compound includes its pharmaceutically acceptable salt, raceme, optical isomer or solvent chemical combination
Object.
Further, the compound includes any of the following structure:
The preparation method of furodiazole or thiadiazole compound of the present invention, includes the following steps:
Furodiazole or thiadiazole compound of the present invention, including its pharmaceutically acceptable salt, raceme, rotation
Photoisomer or solvated compounds are being prepared as the application in immunologic test point inhibitor.
Furodiazole or thiadiazole compound of the present invention, including its pharmaceutically acceptable salt, raceme, rotation
Photoisomer or solvated compounds have the inhibition of double target spot inhibitory activity of PD-1/PD-L1 and VISTA signal path in preparation
Application in agent.
Furodiazole or thiadiazole compound of the present invention, including its pharmaceutically acceptable salt, raceme, rotation
Photoisomer or solvated compounds application in preparation of anti-tumor drugs.
A kind of pharmaceutical composition, wherein containing furodiazole of the present invention or thiadiazole compound or its pharmaceutically
Acceptable salt, raceme, optical isomer or solvated compounds are as active constituent and pharmaceutically acceptable carrier.
Described pharmaceutical composition is capsule, powder, tablet, granule, pill, injection, syrup, oral solution, suction
Enter agent, ointment, suppository or patch.
The utility model has the advantages that compared with prior art, the present invention has the advantage that
Double target spots that novel furodiazole of the invention or thiadiazole compound are one kind PD-1/PD-L1 and VISTA press down
Preparation plays synergistic effect by the inhibition to two immunologic test point accesses, preferably plays the immunization therapy to tumour and makees
With.
Furodiazole or thiadiazole compound provided by the invention are as a kind of immunologic test point micromolecular inhibitor, knot
Structure is novel, and Orally-administrable solves the treatment and drug resistant defect of monoclonal antibody para-immunity checkpoint inhibitor, and as small molecule
Inhibitor preparation is simple, facilitates industrial production.
Specific embodiment
The invention will be further described with reference to embodiments.
Embodiment 1
a)
N-Fmoc-O- tert-butyl-Serine (2.6g, 10mmol) is dissolved in the anhydrous THF of 30mL, under the conditions of -5 DEG C
Triethylamine (1.54mL, 11mmol) and isobutyl chlorocarbonate (1.5g, 11mmol) are added according to this.Temperature is kept to stir half an hour
Afterwards, 7mol/L methanolic ammonia solution (7mL, 50mmol) is added.After charging, room temperature reaction half an hour, TLC detection reaction are moved to
Raw material disappears, and filters out solid.Gained filtrate is concentrated, petroleum ether: ethyl acetate=4:1 column chromatography obtains white solid 2.56g
(yield: 99%).1H NMR(300MHz,CDCl3) δ 6.65 (s, 1H), 6.12 (s, 1H), 5.50 (d, J=5.3Hz, 1H),
4.19 (s, 1H), 3.79 (dd, J=8.5,3.6Hz, 1H), 3.40 (t, J=8.0Hz, 1H), 1.46 (s, 9H), 1.20 (s,
9H).
b)
By product (2.56g, 9.85mmol) 30mL pyridinium dissolution a), trifluoromethanesulfanhydride anhydride is added dropwise under the conditions of 0 DEG C
(2.6mL,14.8mmol).After charging, room temperature reaction 2 hours is moved to, TLC detects reaction raw materials and disappears.It is pumped with oil pump
200mL methylene chloride is added in pyridine, and three times, saturated common salt washing is primary for washing, and organic phase is concentrated, petroleum ether in each 30mL:
Ethyl acetate=12:1 column chromatography, obtains white solid 2.12g (yield: 89%).1H NMR (300MHz,CDCl3)δ5.24(s,
1H), 4.66 (s, 1H), 3.63 (dd, J=9.2,3.3Hz, 1H), 3.53 (dd, J=9.3,4.1Hz, 1H), 1.46 (s, 9H),
1.22(s,9H).
c)
By b) product (2.12g, 8.62mmol) and hydroxylamine hydrochloride (9g, 12.9mmol) with 30mL ethyl alcohol dissolve, stirring
In the case where be added dropwise triethylamine (1.8mL, 12.9mmol).Reaction is moved into 90 DEG C of condition heating stirring reactions overnight.TLC inspection
Survey reaction raw materials to disappear, concentration, petroleum ether: ethyl acetate=2:1 column chromatography obtains white solid 2.28g (yield: 96%).1H
NMR(300MHz,CDCl3)δ5.39(s,1H),5.01(s,2H),4.24(s,1H),3.70–3.49 (m,2H),1.44(s,
9H),1.19(s,9H).
d)
N- methylmorpholine (3.3mL, 29.8mmol) is instilled to the chloro- 4,6- dimethoxy -1,3,5- triazine of 2- of 20mL
It in the Isosorbide-5-Nitrae-dioxane solution of (CDMT, 1.74g, 9.9mmol), is stirred at room temperature after ten minutes, then instills the Fmoc- of 15mL
It is small to be stirred to react 1 under the conditions of 40 DEG C for N- trityl-altheine (5.9g, 9.9mmol) Isosorbide-5-Nitrae-dioxane solution
When, then instill the c of 10mL) Isosorbide-5-Nitrae-dioxane solution of product (2.28g, 8.27mmol).2 are stirred to react under the conditions of 100 DEG C
Hour, TLC detects reaction raw materials and disappears.200mL methylene chloride is added in concentration, and twice, saturated common salt washing is primary, often for washing
Organic phase is concentrated, petroleum ether in secondary 30mL: ethyl acetate=6:1 column chromatography obtains faint yellow solid 4.45g (yield: 65%).1H
NMR(300MHz,CDCl3) δ 7.78 (d, J=5.8Hz, 2H), 7.61 (d, J=6.4Hz, 2H), 7.41 (d, J=6.8Hz,
2H), 7.34-7.13 (m, 18H), 5.37 (s, 1H), 5.03 (s, 1H), 4.44 (d, J=7.9Hz, 1H), 4.33 (d, J=
9.6Hz, 1H), 4.25 (d, J=7.1Hz, 1H), 4.15 (d, J=7.4Hz, 2H), 3.71 (d, J=16.6Hz, 2H), 1.49
(s,9H),1.10(s,9H).
e)
The 25mL dichloromethane solution of product (4.45g, 5.38mmol) d) is dissolved, the diethylamine of 5mL, room temperature is added dropwise
It is stirred to react 5 hours, TLC detects raw material and disappears.Concentration, oil pump pump diethylamine.It is beaten with petroleum ether: ethyl acetate=15:1
Slurry, filters to obtain white solid 3.9g (yield: 87%).1H NMR(300MHz,CDCl3)δ8.00(s, 1H),7.26(m,15H),
5.40 (s, 1H), 4.99 (s, 1H), 4.58 (d, J=9.4Hz, 1H), 4.14 (d, J=7.8Hz, 1H), 3.72 (d, J=
17.9Hz,2H),2.94–2.71(m,2H),1.48(s,9H),1.11(s,9H).HRMS(ESI): 636.3159[M+Na]+.
f)
Monoethyl malonate (660mg, 5mmol) 10mL methylene chloride dissolves, and is added HOBT (1.01g, 7.5mmol)
With EDCI (1.43g, 7.5mmol), stirring after ten minutes, is added ethyl benzyl amine (743mg, 5.5mmol).It is stirred at room temperature 1 hour
Afterwards, TLC detects raw material and disappears.Concentration is added 100mL methylene chloride, is washed once with 10% dilute hydrochloric acid, and washing is primary, saturation food
Salt washing is primary, and organic phase is concentrated, petroleum ether in each 15mL: ethyl acetate=8:1 column chromatography obtains colourless liquid 933mg and (receives
Rate: 75%).1H NMR(300MHz,CDCl3) δ 7.35 (m, 5H), 4.91 (s, 2H), 4.01 (q, J=6.8Hz, 2H), 3.51
(s, 2H), 3.27 (q, J=4.7Hz, 2H), 1.31 (t, J=5.5Hz, 3H), 1.12 (t, J=4.9Hz, 3H)
g)
The 15mL methanol of product (933mg, 3.75mmol) f) is dissolved, the hydrogen-oxygen of the 1M of 4mL is added dropwise under stirring state
Change sodium solution, react at room temperature 2 hours, TLC detects raw material and disappears.With 10% dilute hydrochloric acid solution tune PH to 1.Concentration is added
10mL water is extracted with dichloromethane twice, each 50mL, merges organic phase, saturated common salt washing is primary, and anhydrous sodium sulfate is dry
It is dry.It is concentrated to give colourless liquid 680mg (yield: 82%).1H NMR(300MHz,CDCl3) δ8.89(s,1H),7.55–7.31
(m, 5H), 4.96 (s, 2H), 3.61 (s, 2H), 3.17 (q, J=4.9Hz, 2H), 1.14 (t, J=4.5Hz, 3H)
h)
By product (53mg, 0.24mmol) g) with 5mL methylene chloride dissolve, be added HOBT (41mg, 0.3mmol) and
After ten minutes, product (123mg, 0.2mmol) d) is added in EDCI (58mg, 0.3mmol), stirring.Room temperature reaction 2 hours, TLC
Raw material is detected to disappear.Concentration is added 30mL methylene chloride, is washed once with 10% dilute hydrochloric acid, and washing is primary, saturated common salt washing one
Secondary, organic phase is concentrated, methylene chloride in each 10mL: methanol=80:1 column chromatography obtains white solid 129mg (yield: 80%).1H NMR(300MHz,CDCl3) δ 8.12 (s, 1H), 7.66 (s, 1H), 7.46-7.30 (m, 5H), 5.33 (t, J=2.1Hz,
1H), 5.28 (t, J=3.1Hz, 1H), 4.88 (s, 2H), 3.89 (d, J=2.5Hz, 2H), 3.41 (q, J=4.3Hz 2H),
3.15 (s, 2H), 2.91 (d, J=1.2Hz 2H), 1.46 (s, 9H), 1.18 (t, J=2.1Hz 3H), 1.10 (s, 9H)
i)
The 5mL methylene chloride of product (129mg, 0.16mmol) h) is dissolved, under stirring state, instills 0.5mL trifluoro
Acetic acid and 0.1mL tri isopropyl silane.After room temperature reaction 2 hours, TLC detects raw material and disappears.Concentration, by obtained solid HPLC
It isolates and purifies to obtain compound 1.1H NMR(300MHz,CDCl3) δ 7.58-7.38 (m, 5H), 5.52 (t, J=3.3Hz, 3H),
4.65 (s, 2H), 4.23-3.97 (m, 3H), 3.61-3.36 (m, 2H), 3.33 (s, 2H), 3.10 (t, J=2.1Hz, 2H),
1.16 (t, J=2.6Hz 3H) .LCMS:419.5 [M+H]+.
Embodiment 2
a)
2,2- dimethyl malonic esters (940mg, 5mmol) 15mL ethyl alcohol dissolves, and hydrogen-oxygen is added under stirring state
Change potassium (280mg, 5mmol).After room temperature reaction 4 hours, TLC detects raw material and disappears.Methylene chloride 100mL is added in concentration, uses
10% dilute hydrochloric acid solution tune PH to 1 is washed 1 time, and saturated common salt is washed 1 time, and anhydrous sodium sulfate is dry.It is concentrated to give colourless liquid
680mg (yield: 85%).1H NMR(300MHz,CDCl3) δ 6.7 (s, 1H), 4.32 (q, J=3.5Hz, 2H), 1.43 (s,
6H), 1.22 (t, J=2.4Hz, 3H)
b)
The 10mL methylene chloride of product (680mg, 4.25mmol) a) is dissolved, addition HOBT (859mg,
6.38mmol) after ten minutes, it is added ethyl benzyl amine (632mg, 4.68mmol) with EDCI (1.22g, 6.38mmol), stirring.Room
After temperature stirring 2 hours, TLC detects raw material and disappears.Concentration is added 100mL methylene chloride, is washed once with 10% dilute hydrochloric acid, washes
Once, saturated common salt washing is primary, and organic phase is concentrated, petroleum ether in each 15mL: ethyl acetate=8:1 column chromatography obtains colourless liquid
Body 919mg (yield: 78%).1H NMR(300MHz,CDCl3) δ 7.79-7.58 (m, 5H), 4.85 (s, 2H), 4.02 (q, J=
5.6Hz, 2H), 3.78 (q, J=4.5Hz, 2H), 1.52 (s, 6H), 1.24 (t, J=2.3Hz, 3H), 1.11 (t, J=
2.9Hz,3H).
c)
The 15mL methanol of product (919mg, 3.32mmol) b) is dissolved, the hydrogen-oxygen of the 1M of 4mL is added dropwise under stirring state
Change sodium solution, react at room temperature 2 hours, TLC detects raw material and disappears.With 10% dilute hydrochloric acid solution tune PH to 1.Concentration is added
10mL water is extracted with dichloromethane twice, each 50mL, merges organic phase, saturated common salt washing is primary, and anhydrous sodium sulfate is dry
It is dry.It is concentrated to give colourless liquid 727mg (yield: 88%).1H NMR(300MHz,CDCl3) δ7.80–7.61(m,5H),6.89
(s, 1H), 4.91 (s, 2H), 3.78 (q, J=4.1Hz, 2H), 1.46 (s, 6H), 1.16 (t, J=2.2Hz, 3H)
d)
By product (60mg, 0.24mmol) c) with 5mL methylene chloride dissolve, be added HOBT (41mg, 0.3mmol) and
After ten minutes, product (123mg, 0.2mmol) e) in embodiment 1 is added in EDCI (58mg, 0.3mmol), stirring.Room temperature reaction
2 hours, TLC detected raw material and disappears.Concentration is added 30mL methylene chloride, is washed once with 10% dilute hydrochloric acid, and washing is primary, saturation
Salt washing is primary, and organic phase is concentrated, methylene chloride in each 10mL: methanol=80:1 column chromatography obtains white solid 100mg
(yield: 59%).1H NMR(300MHz,CDCl3)δ8.16(s,1H),7.53 (s,1H),7.49–7.21(m,15H),5.25
(t, J=2.2Hz, 1H), 5.18 (t, J=1.8Hz, 1H), 3.72 (d, J=4.2Hz, 2H), 3.33 (q, J=3.1Hz, 2H),
3.10 (s, 2H), 2.87 (d, J=2.1Hz, 2H), 1.46 (s, 9H), 1.37 (s, 6H), 1.18 (t, J=4.1Hz, 3H),
1.10(s,9H).
e)
The 5mL methylene chloride of product (100mg, 0.118mmol) d) is dissolved, under stirring state, instills 0.5mL tri-
Fluoroacetic acid and 0.1mL tri isopropyl silane.After room temperature reaction 2 hours, TLC detects raw material and disappears.Concentration, obtained solid is used
HPLC isolates and purifies to obtain compound 2.1H NMR (300MHz, MeOD) δ 5.24 (t, J=2.4Hz, 1H), 5.01 (t, J=
1.7Hz, 1H), 3.65 (d, J=4.1Hz, 2H), 3.14 (q, J=4.1Hz, 2H), 3.01 (s, 2H), 2.71 (d, J=
2.1Hz, 2H), 1.37 (s, 6H), 1.14 (t, J=2.9Hz, 3H) .LCMS 447.3 [M+H]+.
Embodiment 3-48
Embodiment 49
a)
N-Boc-O- tert-butyl-L-threonine (2.75g, 10mmol) and potassium carbonate (2.07g, 15mmol) are used
30mLDMF dissolution.Under stirring state, 0.75mL iodomethane is added dropwise.Half an hour is reacted at room temperature, TLC detects raw material and disappears.Oil pump is taken out
DMF is removed, 200mL ethyl acetate is added, twice, saturated common salt washing is primary, each 30mL for washing, and anhydrous sodium sulfate is dry.It is dense
Contracting, obtains white solid 2.77g (yield: 96%).1H NMR(300MHz,CDCl3) δ 5.8 (s, 1H), 4.75 (d, J=6.9Hz,
2H), 4.41 (t, J=6.1Hz, 1H), 3.31 (s, 3H), 1.41 (s, 9H), 1.24 (t, J=4.5Hz, 3H), 1.12 (s,
9H).
b)
Product (2.77g, 9.6mmol) a) is dissolved with 30mL, under stirring state, one hydrazine hydrate of dropwise addition (3.9mL,
76.8mmol).It is stirred overnight under the conditions of 90 DEG C, TLC detects raw material and disappears.200mL ethyl acetate is added in concentration, washes twice,
Saturated common salt washing is primary, and anhydrous sodium sulfate is dry.Organic phase is concentrated, obtains white solid 2.55g (yield: 92%).1H NMR
(300MHz,CDCl3) δ 7.95 (s, 1H), 5.59 (s, 1H), 4.13 (d, J=5.2Hz, 2H), 3.90 (s, 2H), 1.46 (s,
9H), 1.25 (s, 9H), 1.07 (d, J=6.2Hz, 3H)
c)
Fmoc-N- trityl-L-Glutamine (6.472g, 10.6mmol) methylene chloride of 50mL is dissolved, 0 DEG C
Under the conditions of HOBT (2.15g, 15.9mmol) and EDCI (3.04g, 15.9mmol) is added.After ten minutes, production b) is added in stirring
Object (2.55g, 8.8mmol).Room temperature reaction 1 hour, TLC detect raw material and disappear.200mL methylene chloride is added in concentration, uses
10% dilute hydrochloric acid is washed once, and washing is primary, and saturated common salt washing is primary.Organic phase, methylene chloride: methanol=80:1 column layer is concentrated
Analysis, obtains white solid 6.13g (yield: 79%).1H NMR (300MHz, CDCl3) δ 8.85 (d, J=13.5Hz, 2H), 7.78
(d, J=7.4Hz, 2H), 7.60 (d, J=7.4Hz, 2H), 7.42 (t, J=7.4 Hz, 2H), 7.34-7.24 (m, 17H),
7.17 (s, 1H), 5.80 (d, J=5.9Hz, 1H), 5.53 (d, J=5.1Hz, 1H), 4.39 (d, J=7.3Hz, 2H), 4.11
(d, J=4.9Hz, 1H), 2.84 (s, 1H), 2.62 (s, 1H), 2.14 (d, J=28.9 Hz, 2H), 1.48 (s, 9H), 1.29
(s, 9H), 1.16 (t, J=7.8Hz, 3H)
d)
Product (6.13g, 6.95mmol) c) is dissolved with tetrahydrofuran (40mL) and DMF (8mL), is stirred under the conditions of 0 DEG C
It mixes, triphenylphosphine (3.65g, 13.9mmol) and elemental iodine (3.53g, 13.9mmol) is added according to this, is stirred to react after twenty minutes,
It is added dropwise triethylamine (1.4mL, 10.4mmol).Room temperature reaction 2 hours is moved to, TLC detects raw material and disappears.200mL second is added in concentration
Acetoacetic ester, twice, saturated common salt washing is primary, each 30mL for washing.Organic phase, petroleum ether: ethyl acetate=2:1 column layer is concentrated
Analysis, obtains white solid 4.68g (yield: 78%).1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.79 (d, J=
7.2Hz, 2H), 7.62 (d, J=7.5Hz, 2H), 7.39 (d, J=7.3Hz, 2H), 7.38-7.22 (m, 17H), 6.85 (s,
1H), 5.81 (d, J=5.7Hz, 1H), 5.54 (d, J=5.0Hz, 1H), 4.43 (d, J=7.0Hz, 2H), 4.20 (d, J=
4.3Hz, 1H), 2.45 (s, 1H), 2.22 (d, J=19.9Hz, 2H), 1.51 (s, 9H), 1.31 (s, 9H), 1.23 (t, J=
7.8Hz,3H).
e)
The 25mL methylene chloride of product (4.68g, 5.42mmol) d) is dissolved, 5mL diethylamine is added dropwise under stirring state.
Room temperature reaction 4 hours, TLC detect raw material and disappear.Concentration, oil pump pump diethylamine, petroleum ether: ethyl acetate=15:1 mashing,
Filter to obtain white solid 2.5g (yield: 72%).1H NMR(300MHz,CDCl3)δ8.18(s, 1H),7.41–7.23(m,
15H), 6.82 (s, 1H), 5.72 (d, J=5.7Hz, 1H), 5.69 (d, J=5.0Hz, 1H), 4.42 (d, J=7.0Hz, 2H),
4.18 (d, J=4.3Hz, 1H), 2.41 (s, 1H), 2.28 (d, J=19.9Hz, 2H), 1.55 (s, 9H), 1.33 (s, 9H),
1.21 (t, J=7.8Hz, 3H)
f)
Monoethyl malonate (660mg, 5mmol) 10mL methylene chloride dissolves, and is added HOBT (1.01g, 7.5mmol)
With EDCI (1.43g, 7.5mmol), stir after ten minutes, addition O- tert-butyl-L-serine tert-butyl ester hydrochloride (1.4g,
5.5mmol) and triethylamine (0.8mL, 5.5mmol).After being stirred at room temperature 1 hour, TLC detects raw material and disappears.Concentration is added
100mL methylene chloride is washed once with 10% dilute hydrochloric acid, and washing is primary, and saturated common salt washing is primary, and each 15mL is concentrated organic
Phase, petroleum ether: ethyl acetate=8:1 column chromatography obtains white solid 1.44g (yield: 87%).1H NMR (300MHz,CDCl3)
δ 5.61 (s, 1H), 4.52 (q, J=4.2Hz, 2H), 4.32 (d, J=8.1Hz, 1H), 4.15 (d, J=6.3Hz, 1H), 3.98
(d, J=6.1Hz, 1H), 3.33 (s, 2H), 1.45 (s, 9H), 1.21 (t, 4.1Hz, 3H), 1.15 (s, 9H)
g)
The 15mL methanol of product (1.44g, 4.35mmol) f) is dissolved, the hydrogen of the 1M of 4.5mL is added dropwise under stirring state
Sodium hydroxide solution reacts at room temperature 2 hours, and TLC detects raw material and disappears.With 10% dilute hydrochloric acid solution tune PH to 1.Concentration is added
10mL water is extracted with dichloromethane twice, each 50mL, merges organic phase, saturated common salt washing is primary, and anhydrous sodium sulfate is dry
It is dry.It is concentrated to give white solid 1.03g (yield: 78%)1H NMR(300MHz,CDCl3) δ7.01(s,1H),5.55(s,1H),
4.41 (d, J=8.1Hz, 1H), 4.21 (d, J=6.3Hz, 1H), 3.99 (d, J=6.1 Hz, 1H), 3.29 (s, 2H), 1.44
(s,9H),1.12(s,9H).
h)
By product (73mg, 0.24mmol) g) with 5mL methylene chloride dissolve, be added HOBT (41mg, 0.3mmol) and
After ten minutes, product (128mg, 0.2mmol) e) is added in EDCI (58mg, 0.3mmol), stirring.Room temperature reaction 2 hours, TLC
Raw material is detected to disappear.Concentration is added 30mL methylene chloride, is washed once with 10% dilute hydrochloric acid, and washing is primary, saturated common salt washing one
Secondary, organic phase is concentrated, methylene chloride in each 10mL: methanol=80:1 column chromatography obtains white solid 112mg (yield: 61%).1H NMR(300MHz,CDCl3)δ8.11(s,1H),7.31– 7.20(m,15H),7.00(s,1H),6.84(s,1H),5.92
(s, 1H), 5.79 (d, J=5.1Hz, 1H), 5.51 (d, J=5.2Hz, 1H), 4.53 (d, J=7.4Hz, 2H), 4.37 (d, J
=8.0Hz, 1H), 4.21 (d, J=4.4Hz, 1H), 4.17 (d, J=6.2Hz, 1H), 3.39 (d, J=6.4Hz, 1H), 3.24
(s, 2H), 2.51 (s, 1H), 2.24 (d, J=18.7Hz, 2H), 1.52 (s, 9H), 1.38 (s, 18H), 1.21 (t, J=
7.7Hz,3H),1.14(s,9H).
i)
The 5mL methylene chloride of product (112mg, 0.12mmol) h) is dissolved, under stirring state, instills 0.5mL trifluoro
Acetic acid and 0.1mL tri isopropyl silane.After room temperature reaction 2 hours, TLC detects raw material and disappears.Concentration, by obtained solid HPLC
It isolates and purifies to obtain compound 49.1H NMR (300MHz, MeOD) δ 5.80 (d, J=5.4Hz, 1H), 5.52 (d, J=
4.9Hz, 1H), 4.58 (d, J=6.8Hz, 2H), 4.39 (d, J=7.9Hz, 1H), 4.24 (d, J=4.88Hz, 1H), 4.19
(d, J=6.7Hz, 1H), 3.45 (d, J=6.7Hz, 1H), 3.27 (s, 2H), 2.49 (s, 1H), 2.34 (d, J=18.9Hz,
2H), 1.20 (t, J=8.1Hz, 3H) .LCMS 403.1 [M+H]+.
Embodiment 50
a)
Product (680mg, 4.25mmol) in embodiment 2 a) 10mL methylene chloride is dissolved, HOBT is added
After ten minutes, O- tert-butyl-L- serine uncle is added in (859mg, 6.38mmol) and EDCI (1.22g, 6.38mmol), stirring
Butyl ester hydrochloric acid (1.19g, 4.68mmol).After being stirred at room temperature 2 hours, TLC detects raw material and disappears.100mL dichloromethane is added in concentration
Alkane is washed once with 10% dilute hydrochloric acid, and washing is primary, and saturated common salt washing is primary, and organic phase, petroleum ether: second is concentrated in each 15mL
Acetoacetic ester=8:1 column chromatography, obtains white solid 1.05g (yield: 69%).1H NMR (300MHz,CDCl3)δ6.15(s,1H),
4.54 (q, J=4.7Hz, 2H), 4.30 (d, J=8.3Hz, 1H), 4.11 (d, J=6.5Hz, 1H), 3.94 (d, J=5.5Hz,
1H),3.41(s,2H),1.55(s,3H),1.43(s,15H),1.20(t,4.1 Hz,3H),1.14(s,9H).
b)
The 15mL methanol of product (1.05g, 2.93mmol) a) is dissolved, the hydrogen-oxygen of the 1M of 4mL is added dropwise under stirring state
Change sodium solution, react at room temperature 2 hours, TLC detects raw material and disappears.With 10% dilute hydrochloric acid solution tune PH to 1.Concentration is added
10mL water is extracted with dichloromethane twice, each 50mL, merges organic phase, saturated common salt washing is primary, and anhydrous sodium sulfate is dry
It is dry.It is concentrated to give white solid 708mg (yield: 73%).1H NMR(300MHz,CDCl3) δ 7.03 (d, J=7.0Hz, 1H),
4.57 (dt, J=7.9,2.8Hz, 1H), 3.83 (dd, J=8.9,2.7Hz, 1H), 3.59 (dd, J=8.9,3.0Hz, 1H),
1.55(s,12H),1.17(s,9H).
c)
By product (79mg, 0.24mmol) b) with 5mL methylene chloride dissolve, be added HOBT (41mg, 0.3mmol) and
After ten minutes, product (128mg, 0.2mmol) e) in embodiment 49 is added in EDCI (58mg, 0.3mmol), stirring.Room temperature is anti-
It answers 2 hours, TLC detects raw material and disappears.Concentration is added 30mL methylene chloride, is washed once with 10% dilute hydrochloric acid, and washing is primary, satisfies
Primary with salt washing, organic phase is concentrated, methylene chloride in each 10mL: methanol=80:1 column chromatography obtains white solid 126mg
(yield: 66%).1H NMR(300MHz,CDCl3)δ8.20(s,1H),7.33 –7.21(m,15H),7.04(s,1H),6.79
(s, 1H), 5.90 (s, 1H), 5.78 (d, J=5.0Hz, 1H), 5.49 (d, J=5.4Hz, 1H), 4.52 (d, J=7.7Hz,
2H), 4.40 (d, J=7.8Hz, 1H), 4.19 (d, J=4.1Hz, 1H), 4.15 (d, J=5.8Hz, 1H), 3.42 (d, J=
6.7Hz, 1H), 3.21 (s, 2H), 2.53 (s, 1H), 2.21 (d, J=19.4Hz, 2H), 1.59 (s, 3H), 1.51 (s, 12H),
1.34 (s, 18H), 1.19 (t, J=7.4Hz, 3H), 1.12 (s, 9H)
d)
The 5mL methylene chloride of product (126mg, 0.13mmol) c) is dissolved, under stirring state, instills 0.5mL trifluoro
Acetic acid and 0.1mL tri isopropyl silane.After room temperature reaction 2 hours, TLC detects raw material and disappears.Concentration, by obtained solid HPLC
Isolate and purify compound 50.1H NMR (300MHz, MeOD) δ 5.78 (d, J=5.4Hz, 1H), 5.51 (d, J=4.9Hz,
1H), 4.53 (d, J=6.8Hz, 2H), 4.34 (d, J=7.9Hz, 1H), 4.23 (d, J=4.88Hz, 1H), 4.16 (d, J=
6.7Hz, 1H), 3.47 (d, J=6.7Hz, 1H), 3.23 (s, 2H), 2.47 (s, 1H), 2.36 (d, J=18.9Hz, 2H),
1.59 (s, 3H), 1.50 (s, 3H), 1.19 (t, J=8.1Hz, 3H) .LCMS 431.3 [M+H]+.
Embodiment 51-60
Embodiment 61
a)
N-Boc-O- tert-butyl-l-tyrosine (3.37g, 10mmol) and potassium carbonate (2.07g, 15mmol) are used
30mLDMF dissolution.Under stirring state, 0.75mL iodomethane is added dropwise.Half an hour is reacted at room temperature, TLC detects raw material and disappears.Oil pump is taken out
DMF is removed, 200mL ethyl acetate is added, twice, saturated common salt washing is primary, each 30mL for washing, and anhydrous sodium sulfate is dry.It is dense
Contracting, obtains white solid 3.41g (yield: 97%).1H NMR(300MHz,CDCl3) δ 7.31 (d, J=6.2Hz, 2H), 6.92
(d, J=6.1Hz, 2H), 6.34 (s, 1H), 4.54 (t, J=7.1Hz, 1H), 4.21 (s, 3H), 4.01 (d, J=5.6Hz,
2H),1.40(s,9H),1.32(s,9H).
b)
Product (3.41g, 9.7mmol) a) is dissolved with 30mL, under stirring state, one hydrazine hydrate of dropwise addition (3.94mL,
77.6mmol).It is stirred overnight under the conditions of 90 DEG C, TLC detects raw material and disappears.200mL ethyl acetate is added in concentration, washes twice,
Saturated common salt washing is primary, and anhydrous sodium sulfate is dry.Organic phase is concentrated, obtains white solid 3.1g (yield: 91%).1H NMR
(300MHz,CDCl3) δ 8.01 (s, 1H), 7.33 (d, J=6.0Hz, 2H), 6.98 (d, J=6.4 Hz, 2H), 6.21 (s,
1H), 5.59 (t, J=7.1Hz, 1H), 4.01 (s, 3H), 3.67 (d, J=5.6Hz, 1H), 3.49 (d, J=5.5Hz, 1H),
1.40(s,9H),1.32(s,9H).
c)
Fmoc-N- trityl-altheine (6.32g, 10.6mmol) methylene chloride of 50mL is dissolved, 0 DEG C
Under the conditions of HOBT (2.15g, 15.9mmol) and EDCI (3.04g, 15.9mmol) is added.After ten minutes, production b) is added in stirring
Object (3.1g, 8.8mmol).Room temperature reaction 1 hour, TLC detect raw material and disappear.200mL methylene chloride is added, with 10% in concentration
Dilute hydrochloric acid is washed once, and washing is primary, and saturated common salt washing is primary.Organic phase is concentrated, methylene chloride: methanol=80:1 column chromatography,
Obtain white solid 5.81g (yield: 71%).1H NMR(300MHz,CDCl3) δ 8.41 (d, J=15.1Hz, 2H), 7.97 (d, J
=7.1Hz, 2H), 7.62 (d, J=7.3Hz, 2H), 7.40 (t, J=7.1 Hz, 2H), 7.34-7.19 (m, 19H), 7.17 (s,
1H), 7.01 (s, 2H), 5.89 (d, J=6.1Hz, 1H), 5.57 (d, J=5.8Hz, 1H), 4.48 (d, J=7.9Hz, 2H),
4.16 (d, J=5.4Hz, 1H), 2.91 (s, 1H), 2.57 (s, 1H), 2.22 (d, J=19.8Hz, 2H), 1.49 (s, 18H),
1.21(s,9H).
d)
Product (5.81g, 6.25mmol) c) is dissolved with tetrahydrofuran (40mL), addition lawesson reagent (3.79g,
9.38mmol), under the conditions of 75 DEG C after heating stirring four hours, TLC detects raw material and disappears.Methylene chloride 200mL is added in concentration,
Twice, saturated common salt washing is primary, each 30mL for washing.Organic phase is concentrated, petroleum ether: ethyl acetate=2:1 column chromatography obtains white
Color solid 4.12g (yield: 71%).1H NMR(300MHz,CDCl3) δ 7.81 (d, J=7.2Hz, 2H), 7.54 (d, J=
7.1Hz, 2H), 7.37 (d, J=6.8Hz, 2H), 7.31-7.15 (m, 19H), 7.09 (s, 1H), 6.91 (d, J=6.8Hz,
2H), 5.75 (d, J=5.8Hz, 1H), 5.49 (d, J=6.1Hz, 1H), 4.38 (d, J=6.9Hz, 2H), 4.13 (d, J=
5.7Hz, 1H), 2.87 (s, 1H), 2.55 (s, 1H), 2.23 (d, J=20.1Hz, 2H), 1.45 (s, 18H), 1.18 (s, 9H)
e)
The 25mL methylene chloride of product (4.12g, 4.44mmol) d) is dissolved, 5mL diethylamine is added dropwise under stirring state.
Room temperature reaction 4 hours, TLC detect raw material and disappear.Concentration, oil pump pump diethylamine, petroleum ether: ethyl acetate=15:1 mashing,
Filter to obtain white solid 2.6g (yield: 83%).1H NMR(300MHz,CDCl3)δ7.34–7.19 (m,17H),7.12(s,
1H), 6.91 (d, J=6.4Hz 2H), 5.82 (d, J=6.1Hz, 1H), 5.42 (d, J=6.3Hz, 1H), 4.31 (d, J=
7.1Hz, 2H), 4.16 (d, J=5.9Hz, 1H), 2.91 (s, 1H), 2.61 (s, 1H), 2.29 (d, J=22.3Hz, 2H),
1.41(s,18H),1.15(s,9H).
f)
The product (73mg, 0.24mmol) of embodiment 49g) 5mL methylene chloride is dissolved, addition HOBT (41mg,
0.3mmol) and after ten minutes, product (141mg, 0.2mmol) e) is added in EDCI (58mg, 0.3mmol), stirring.Room temperature is anti-
It answers 2 hours, TLC detects raw material and disappears.Concentration is added 30mL methylene chloride, is washed once with 10% dilute hydrochloric acid, and washing is primary, satisfies
Primary with salt washing, organic phase is concentrated, methylene chloride in each 10mL: methanol=80:1 column chromatography obtains white solid 152mg
(yield: 79%).1H NMR(300MHz,CDCl3)δ8.11(s,1H),7.31 –7.20(m,17H),7.00(s,1H),6.84
(d, J=6.5Hz, 1H), 5.92 (s, 1H), 5.79 (d, J=5.1Hz, 1H), 5.51 (d, J=5.2Hz, 1H), 4.53 (d, J
=7.1Hz, 2H), 4.41 (d, J=7.5Hz, 1H), 4.24 (d, J=4.7Hz, 1H), 4.11 (d, J=6.4Hz, 1H), 3.31
(d, J=6.1Hz, 1H), 3.22 (s, 2H), 2.51 (s, 1H), 2.21 (d, J=20.6Hz, 2H), 1.52 (s, 9H), 1.38
(s,18H),1.14(s,9H).
g)
The 5mL methylene chloride of product (152mg, 0.16mmol) f) is dissolved, under stirring state, instills 0.5mL trifluoro
Acetic acid and 0.1mL tri isopropyl silane.After room temperature reaction 2 hours, TLC detects raw material and disappears.Concentration, by obtained solid HPLC
It isolates and purifies to obtain compound 61.1H NMR (300MHz, MeOD) δ 6.84 (d, J=6.8Hz, 2H), 5.92 (s, 2H), 5.79
(d, J=5.1Hz, 1H), 5.51 (d, J=5.2Hz, 1H), 4.53 (d, J=7.1Hz, 2H), 4.41 (d, J=7.5Hz, 1H),
4.24 (d, J=4.7Hz, 1H), 4.11 (d, J=6.4Hz, 1H), 3.31 (d, J=6.1Hz, 1H), 3.22 (s, 2H), 2.51
(s, 1H), 2.21 (d, J=20.6Hz, 2H) .LCMS 481.2 [M+H]+.
Embodiment 62
a)
The product (79mg, 0.24mmol) of embodiment 50b) 5mL methylene chloride is dissolved, addition HOBT (41mg,
0.3mmol) and EDCI (58mg, 0.3mmol), after ten minutes, embodiment 61e is added in stirring) product (141mg,
0.2mmol).Room temperature reaction 2 hours, TLC detect raw material and disappear.Concentration is added 30mL methylene chloride, washes one with 10% dilute hydrochloric acid
Secondary, washing is primary, and saturated common salt washing is primary, and organic phase is concentrated, methylene chloride in each 10mL: methanol=80:1 column chromatography obtains
White solid 131mg (yield: 63%).1H NMR(300MHz,CDCl3)δ8.20 (s,1H),7.38–7.24(m,17H),
7.05 (s, 1H), 6.87 (d, J=6.7Hz, 1H), 5.95 (s, 1H), 5.83 (d, J=5.5Hz, 1H), 5.60 (d, J=
5.7Hz, 1H), 4.59 (d, J=7.0Hz, 2H), 4.51 (d, J=7.1Hz, 1H), 4.33 (d, J=4.3Hz, 1H), 4.15
(d, J=6.1Hz, 1H), 3.37 (d, J=6.1Hz, 1H), 3.24 (s, 2H), 2.59 (s, 1H), 2.31 (d, J=22.1Hz,
2H),1.62(s,3H),1.51(s,12H),1.35(s,18H),1.16(s,9H).
b)
The 5mL methylene chloride of product (131mg, 0.13mmol) a) is dissolved, under stirring state, instills 0.5mL trifluoro
Acetic acid and 0.1mL tri isopropyl silane.After room temperature reaction 2 hours, TLC detects raw material and disappears.Concentration, by obtained solid HPLC
It isolates and purifies to obtain compound 62.1H NMR (300MHz, MeOD) δ 6.81 (d, J=6.4Hz, 2H), 5.87 (s, 2H), 5.74
(d, J=5.6Hz, 1H), 5.57 (d, J=5.4Hz, 1H), 4.49 (d, J=7.7Hz, 2H), 4.34 (d, J=7.1Hz, 1H),
4.20 (d, J=4.9Hz, 1H), 4.04 (d, J=6.1Hz, 1H), 3.24 (d, J=6.7Hz, 1H), 3.14 (s, 2H), 2.54
(s, 1H), 2.25 (d, J=17.8Hz, 2H), 1.58 (s, 3H), 1.49 (s, 3H) .LCMS 509.1 [M+H]+.
Embodiment 63-66
Embodiment 67
Tablet
By compound 1 (50g) obtained in embodiment 1, hypromellose E (150g), starch (200g), povidone
K30 is appropriate and magnesium stearate (1g) mixes, granulation, tabletting.
Furthermore, it is possible to compound made from embodiment 1-66 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..
Test example 1
Pharmacological testing proves, what the furodiazole or thiadiazole compound of invention can be used as or prepared
The bis- target spot micromolecular inhibitors of PD-1/PD-L1 and VISTA have PD-1/PD-L1 and VISTA dual restraining activities, can be used for making
Standby anti-tumor drug.Here is the pharmacological results of the compounds of this invention:
The measurement of pharmacological evaluation A:PD-1/PD-L1 inhibitory activity:
(1) experimental facilities and reagent
1, HTRF kit is purchased from Cisbio company (CAT#63ADK000CPAPEG), including following reagent: Anti-
Tag1-Cyptate；Anti-Tag2-XL665/d2；Tag1-PD-L1；Tag2-PD-1；Dilution Buffer；
Detection Buffer
2, SpectraMax i3X multi-function microplate reader (Molecular Device)
3,384 shallow bore hole plate (Nunc, CAT#264706)
(2) experimental method:
1, experimental procedure:
1.1PD-1 recombinant protein and PD-L1 recombinant protein are diluted to 500nM and 50nM with Dilution Buffer respectively.
1.2 small molecule compounds 20 dissolved with Dilution Buffer dilution 200uM DMSO are again to 10uM.
The PD-1 and 4ul that 1.3 untested compound, the 4ul that successively addition 2ul has diluted into 384 holes have diluted dilute
PDL-1.It mixes well, is placed at room temperature for 15min.
1.4 dilute anti-Tag1-Eu with Detection buffer3+(1:25) and anti-Tag2-XL665 (1:100).
Then 10 μ l antibody mixed liquors are added in the good detection reagent of isometric mixed diluting, every reacting hole.Sealer is incubated at room temperature 2h.
1.5 detect fluorescence signal (320nm stimulation, 665nm, 615nm hair with SpectraMax i3X multi-function microplate reader
It penetrates).
2, experiment flow
HTRF PD-1/PD-L1binding assay kit experiment flow is as follows:
3, data are analyzed
Emission Ratio (ER)=665nm Emission signal/615nm Emission signal
Compound PD-/PD-L1 inhibiting rate=(ERpositive―ER sample)/(ERpositive―ERnegative) * 100%.
The measurement of pharmacological evaluation B:VISTA inhibitory activity:
(1) experimental facilities and reagent
1, ELISA kit is purchased from R&D Systems (CAT#DY-285) detection IFN-γ burst size, and anti-human source CD3 is anti-
Body, recombination human source VISTA albumen (R&D Systems, CAT#7126-B7)
2, SpectraMax i3X multi-function microplate reader (Molecular Device)
3,384 shallow bore hole plate (Nunc, CAT#264706)
(2) experimental method
1. experimental procedure:
1.1 add to the source of people VISTA (2.5 μ g/ml) of recombination and anti-human source CD3 antibody (2.5 μ g/ml) on 96 orifice plates, 4
DEG C overnight save.
The addition of anti-human source VISTA antibody is incubated for 30min by 1.2 next day altogether.Later, it is washed with 1*PBS, and test is added
Compound is incubated for 30min altogether.Isolated PBMC (0.1*106cell/well) and anti-human source CD28 antibody (1 μ g/ml) adds
Enter instrument connection.At 37 DEG C, 5%CO2Under conditions of, continue to be incubated for 72h.
1.3, through 4 DEG C, after the pelleted by centrifugation separation of 200g*5min, collect supernatant.Then by using ELISA's
IFN-γ detection method determines the release conditions of IFN-γ.
1.4 compound VISTA inhibiting rates are human body PBMC cell IFN-γ release redemption rate.
Following table is that the compounds of this invention PD-1/PD-L1 and VISTA access inhibiting rate is horizontal:
Above-mentioned pharmacological evaluation proves that the compounds of this invention has PD-1/PD-L1 and VISTA dual restraining activities, can adjust
Control PD-1/PD-L1 and VISTA signal path, as can block PD-1/PD-L1 and VISTA signal path double target spots be immunized
Checkpoint inhibitor, using in the preparation of antitumor drugs.
Claims (9)
1. a kind of furodiazole or thiadiazole compound as shown in following formula I or formula II:
Wherein, X is O or S；
R1, R2 are amino acid side chain or C1-6Alkyl；The C1-6Alkyl optionally can be by following one or more substituent groups
Replace: carboxyl, amino, hydroxyl, naphthenic base, aryl, heterocycle, alkenyl, alkynyl；Optionally C1-6Two to three in alkyl
Carbon atom can become a part of 3 to 7 yuan of carbocyclic rings or heterocycle；Wherein the carbocyclic ring, heterocycle are optionally selected from alkyl, alcoxyl
Base, carboxyl, hydroxyl, 1 to 6 in halogen identical or different group replace；
R3 is hydrogen or C1-6Alkyl；Wherein C1-6Alkyl can optionally be replaced by following one or more substituent groups: carboxyl, ammonia
Base, hydroxyl, naphthenic base, aryl, heterocycle, alkenyl, alkynyl；Optionally C1-6Two to three carbon atoms in alkyl can become 3
To a part of 7 yuan of carbocyclic rings or heterocycle；Wherein the carbocyclic ring, heterocycle are optionally selected from alkyl, alkoxy, carboxyl, hydroxyl, halogen
1 to 6 identical or different group in base replaces；
R4 is hydrogen, dimethyl, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.
2. furodiazole according to claim 1 or thiadiazole compound, which is characterized in that the compound includes it
Pharmaceutically acceptable salt, raceme, optical isomer or solvated compounds.
3. furodiazole according to claim 1 or thiadiazole compound, which is characterized in that the compound include with
Any one lower structure:
4. the preparation method of a kind of claim 1-3 any furodiazole or thiadiazole compound, which is characterized in that
Include the following steps:
5. a kind of described in any item furodiazoles of claims 1 to 3 or thiadiazole compound, including its is pharmaceutically acceptable
Salt, raceme, optical isomer or solvated compounds preparation as the application in immunologic test point inhibitor.
6. a kind of described in any item furodiazoles of claims 1 to 3 or thiadiazole compound, including its is pharmaceutically acceptable
Salt, raceme, optical isomer or solvated compounds preparation have PD-1/PD-L1 and VISTA signal path double target spots
Application in the inhibitor of inhibitory activity.
7. a kind of described in any item furodiazoles of claims 1 to 3 or thiadiazole compound, including its is pharmaceutically acceptable
Salt, raceme, optical isomer or solvated compounds application in preparation of anti-tumor drugs.
8. a kind of pharmaceutical composition, wherein containing the described in any item furodiazoles of claims 1 to 3 or thiadiazole compound
Or its pharmaceutically acceptable salt, raceme, optical isomer or solvated compounds are as active constituent and pharmaceutically acceptable
Carrier.
9. pharmaceutical composition according to claim 8, which is characterized in that described pharmaceutical composition is capsule, powder, piece
Agent, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository or patch.
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| CN111718310B (en) * | 2019-08-19 | 2021-06-11 | 中国药科大学 | Phenyl-substituted five-membered heterocyclic compound, and preparation method, application and pharmaceutical composition thereof |
| CN115057831A (en) * | 2022-05-13 | 2022-09-16 | 中国医科大学附属盛京医院 | Thiadiazoles and their application in the preparation of KKLC1 protein inhibitors |
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