CN117285533A - CD47/SIRP alpha small molecule inhibitor, application thereof and anti-tumor pharmaceutical composition - Google Patents

CD47/SIRP alpha small molecule inhibitor, application thereof and anti-tumor pharmaceutical composition Download PDF

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CN117285533A
CN117285533A CN202311581982.3A CN202311581982A CN117285533A CN 117285533 A CN117285533 A CN 117285533A CN 202311581982 A CN202311581982 A CN 202311581982A CN 117285533 A CN117285533 A CN 117285533A
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CN117285533B (en
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杨杰
童荣生
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Sichuan Peoples Hospital of Sichuan Academy of Medical Sciences
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Abstract

The invention relates to a CD47/SIRP alpha small molecule inhibitor, application thereof and an anti-tumor pharmaceutical composition, belonging to the technical field of anti-tumor drugs. The invention solves the technical problem of providing a novel CD47/SIRP alpha small molecule inhibitor. The structural formula of the CD 47/SIRPalpha small molecule inhibitor is shown as a formula I. The invention develops a novel small molecular compound of CD47, can be used as a CD47/SIRP alpha small molecular inhibitor, targets a CD47-SIRP alpha channel, blocks the combination of CD47/SIRP alpha, greatly activates the immunity of the organism, enhances the immune therapeutic effect of tumor, and is used for developing novel tumor immunityThe therapeutic drugs provide ideas.

Description

CD47/SIRP alpha small molecule inhibitor, application thereof and anti-tumor pharmaceutical composition
Technical Field
The invention relates to a CD47/SIRP alpha small molecule inhibitor, application thereof and an anti-tumor pharmaceutical composition, belonging to the technical field of anti-tumor drugs.
Background
Malignant tumors have seriously threatened the health of human beings, and the death number of the malignant tumors reaches 960 ten thousand according to the WHO statistics in 2018, so that the new occurrence rate of the malignant tumors is expected to be increased by about 60% in 2040, and the cancer has become the biggest public health problem worldwide. In recent years, emerging tumor immunotherapy, such as immune checkpoint inhibitor therapy, is one of the most clinically successful tumor immunotherapy. The immune checkpoint inhibitor has low antibody response rate (15-30%) in clinical treatment, needs to monitor biomarkers (such as PD-L1 positive detection) at the same time, has obvious immune side effects (30-50% of patients show side effects and even possibly have fatal risks), and has the problems of drug resistance and the like. To date, no prospective study has clearly standardized strategies for dealing with specific immune-related adverse events and drug resistance, and existing therapeutic approaches are clinically very limited. Thus, there is a great clinical need to find an immune checkpoint treatment regimen for a novel target.
Macrophages in the innate immune system have important bridge functions through phagocytosis, antigen presentation and activation of T cell adaptive immune responses, and are the first line of defense against cell damage and malignant transformation, and phagocytosis is mainly regulated by the CD 47-sirpa complex. Inhibiting formation of CD47-SIRP alpha complex, activating phagocytic function of tumor-associated macrophages (TAMs), activating immune system via Antigen Presenting Cells (APCs), etc., and inhibiting immune escape, thereby preventing tumor occurrence and development. Thus, the development of novel immune checkpoint anti-tumor drugs targeting the CD 47-sirpa pathway is one of the very potential targets.
The research and development of drugs targeting the CD47-SIRP alpha pathway are mainly divided into drugs such as antibodies, small molecule inhibitors and the like. At present, monoclonal antibodies such as CD47 monoclonal antibody Hu5F9-G4, SIRP alpha-Fc fusion protein ALX148 and the like have large molecular weight, long half life and large potential side effects. Compared with antibody drugs, the small molecular drugs have small molecular weight, short metabolic half-life, easy monitoring of blood concentration and controllable side effects. CD 47-sirpa small molecule inhibitors have been reported to fall into three main categories: 1) Inhibiting CD47/SIRP alpha binding, such as NCG-3, pep-20, etc.; 2) Inhibition of CD47/SIRP alpha expression by transcription, translation, such as RRx-001; 3) By post-translational modification of CD 47/SIRPalpha, such as the glutamine cyclase isozyme (QPCTL) inhibitor SEN177. However, the existing small molecular medicines have certain off-target property and potential blood toxicity, and most of the small molecular medicines are still in an early research and development stage. Therefore, development of a novel small molecule drug targeting the CD47/SIRP alpha signal pathway is needed in the future.
Disclosure of Invention
Aiming at the defects, the invention solves the technical problem of providing a novel CD47/SIRP alpha small molecule inhibitor.
The structural formula of the CD 47/SIRPalpha small molecule inhibitor is shown as a formula I:
wherein X is 1 Selected from H or N; x is X 2 Selected from CH 2 Or C 2 H 4 ；
R 1 Selected from-H, -CH 3 、-C 2 H 5 、
；
R 2 Selected from-OH,
。
In some embodiments of the invention, R 1 Selected from-CH 3 、
Or (b)；R 2 Selected from->
Or (b)
。
The invention also provides an isomer, pharmaceutically acceptable salt or hydrate of the CD 47/SIRPalpha small molecule inhibitor.
Pharmaceutically acceptable salts include, but are not limited to, salts of the compounds of formula I with inorganic acids such as trifluoroacetate, hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, hydrobromic acid and nitric acid, and salts with various organic acids such as malic acid, maleic acid, citric acid, fumaric acid, tartaric acid, succinic acid, acetic acid, lactic acid, p-toluenesulfonic acid, methanesulfonic acid, palmitic acid and the like.
The invention also provides application of the CD47/SIRP alpha small molecule inhibitor, isomer, pharmaceutically acceptable salt or hydrate in preparing antitumor drugs.
The CD 47/SIRPalpha small molecule inhibitor can block the combination of CD 47/SIRPalpha, can greatly activate the immunity in vivo, strengthen the tumor immunotherapy effect, and can be applied to the preparation of antitumor drugs.
In some embodiments of the invention, the anti-tumor agent is an agent that targets the CD 47-sirpa pathway.
The invention also provides an anti-tumor pharmaceutical composition.
The anti-tumor pharmaceutical composition contains an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises the CD47/SIRP alpha small molecule inhibitor or an isomer, pharmaceutically acceptable salt or hydrate thereof.
In some embodiments, the pharmaceutically acceptable salt is trifluoroacetate, sulfate, hydrochloride, acetate or nitrate.
In one embodiment of the invention, the active ingredient of the antitumor pharmaceutical composition further comprises PD-1 mab or PD-L1 mab.
In some embodiments, the PD-1 mab is a nano Wu Liyou mab, a palbociclib mab, a cimiput Li Shan mab, a terlipressin Li Shan mab, a singeing Li Shan mab, or a carrilizumab; PD-L1 monoclonal antibody is Abilib, ab-Lu-Bill antibody, du-Va-Lu antibody, en Wo Lishan antibody or Shu Geli monoclonal antibody.
Compared with the prior art, the invention has the following beneficial effects:
the invention develops a novel small molecular compound of CD47, can be used as a small molecular inhibitor of CD47/SIRP alpha, targets a CD47-SIRP alpha channel, blocks the combination of CD47/SIRP alpha, greatly activates the immunity of the organism, enhances the immune therapeutic effect of tumors, and provides a thinking for developing novel drugs for immune therapy of tumors.
Drawings
FIG. 1 is a schematic diagram of the binding capacity test of different compounds of example 2 to CD 47/SIRPalpha.
FIG. 2 is a schematic representation of the docking simulation of compound R-21 with CD 47/SIRPa in example 2. Wherein, A is the graph of the action mode of the CD47 protein and the compound R-21, B is the graph of the pocket mode of the compound R-21 molecule in the CD47 protein, C is the schematic diagram of the compound R-21 in the CD47 protein position, and D is the graph of the key amino acid action mode of the compound R-21 and the CD47 protein.
FIG. 3 is a graph showing the inhibitory activity of the compounds R-21 and NCG-3 of example 3 against various tumor cells and normal hepatocytes.
FIG. 4 is a fluorescent marker graph of the inhibition of CD 47/SIRPalpha by compound R-21 of example 3 in Hela cells. Wherein, panel a is a labeled CD47 protein; panel B is a graph of binding to SIRPalpha protein added.
FIG. 5 is a graph showing the results of flow assays of bone marrow derived macrophage BMDM (labeled with anti-F4/80 staining) derived from NOD mice and carboxyfluorescein diacetate succinimidyl ester (CFSE) labeled HeLa cells of example 4 after 6h incubation in different dosing groups.
FIG. 6 is a graph showing the anti-tumor effect of compound R-21 of example 5 in HeLa tumor model NOD/SCID mice.
Detailed Description
The structural formula of the CD 47/SIRPalpha small molecule inhibitor is shown as a formula I:
wherein X is 1 Selected from H or N; x is X 2 Selected from CH 2 Or C 2 H 4 ；
R 1 Selected from-H, -CH 3 、-C 2 H 5 、
；
R 2 Selected from-OH,
Or (b)
。
In some embodiments of the invention, R 1 Selected from-CH 3 、
Or (b)；R 2 Selected from->
Or (b)。
In some embodiments, the CD 47/sirpa small molecule inhibitor has the structural formula:
。
the invention also provides an isomer, pharmaceutically acceptable salt or hydrate of the CD 47/SIRPalpha small molecule inhibitor.
Pharmaceutically acceptable salts include, but are not limited to, salts of the compounds of formula I with inorganic acids such as trifluoroacetate, hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, hydrobromic acid and nitric acid, and salts with various organic acids such as malic acid, maleic acid, citric acid, fumaric acid, tartaric acid, succinic acid, acetic acid, lactic acid, p-toluenesulfonic acid, methanesulfonic acid, palmitic acid and the like.
The invention also provides application of the CD47/SIRP alpha small molecule inhibitor, isomer, pharmaceutically acceptable salt or hydrate in preparing antitumor drugs.
The CD 47/SIRPalpha small molecule inhibitor can block the combination of CD 47/SIRPalpha, can greatly activate the immunity in vivo, strengthen the tumor immunotherapy effect, and can be applied to the preparation of antitumor drugs.
In some embodiments of the invention, the anti-tumor agent is an agent that targets the CD 47-sirpa pathway.
The invention also provides an anti-tumor pharmaceutical composition.
The anti-tumor pharmaceutical composition contains an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises the CD47/SIRP alpha small molecule inhibitor or an isomer, pharmaceutically acceptable salt or hydrate thereof.
The CD 47/sirpa small molecule inhibitor or an isomer, a pharmaceutically acceptable salt or hydrate thereof of the present invention may be used alone or in combination with pharmaceutically acceptable excipients in the form of a pharmaceutical composition, and when used in the form of a pharmaceutical composition, a therapeutically effective amount of the CD 47/sirpa small molecule inhibitor or an isomer, a pharmaceutically acceptable salt or hydrate thereof of the present invention is usually combined with one or more pharmaceutically acceptable carriers or diluents to prepare a suitable administration form or dosage form. Accordingly, the present invention also provides an anti-neoplastic pharmaceutical composition comprising a therapeutically effective amount of a CD 47/sirpa small molecule inhibitor of the present invention or an isomer, pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable carrier.
The antitumor drug composition of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal, nasal, vaginal, topical, parenteral, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or by means of an explanted reservoir, with oral, intramuscular, intraperitoneal or intravenous modes of administration being preferred.
In some embodiments, the pharmaceutically acceptable salt is trifluoroacetate, sulfate, hydrochloride, acetate or nitrate.
In one embodiment of the invention, the active ingredient of the antitumor pharmaceutical composition further comprises PD-1 mab or PD-L1 mab.
In some specific embodiments, the PD-1 mab is sodium Wu Liyou mab (Nivolumab), pamglizumab (Pembrolizumab), cimapril Li Shan antibody (Cemiplimab), terlipressiab Li Shan antibody (Toripalimab), singedi Li Shan antibody (Cindilimab), or carlizumab (Camrelizumab); the PD-L1 monoclonal antibody is Abelizumab (Atezolizumab), avistuzumab (Avelumab), cerstuzumab (Durvalumab), en Wo Lishan antibody (Envolizumab) or Shu Geli monoclonal antibody (Shuglizumab).
The following describes the invention in more detail with reference to examples, which are not intended to limit the invention thereto.
Example 1 Synthesis of Compounds
The compounds listed in table 1 were synthesized.
1. Preparation of Compound R-21
Dissolving the compound 1 and the compound 2 in ethanol, adding a proper amount of dehydrating agent for reaction to obtain a compound 3, reacting the compound 3 with a compound 4 in an aqueous solution of NaOH and methanol to obtain a compound 5, carrying out reflux reaction on the compound 5 by thionyl chloride to obtain an acyl chloride intermediate, and condensing the acyl chloride intermediate with the compound 6 to obtain the target compound R-21. The specific synthesis method is as follows:
compound 3 [2- ((3, 5-dimethyl-1H-pyrazol-4-yl) methyl) pyrido [3,4-e][1,2,4]Triazolo [1,5-c ]]Pyrimidine-5-thiols]Is prepared from the following steps: 2- (3, 5-dimethyl-1H-pyrazol-4-yl) acetyl hydrazide (5 g,29.73 mmol), 4-thionitrosyl nitrile (5.36 g, 35.67 mmol), tiCl 4 (11.28 g, 59.45 mmol) was added to 50 mL ethanol and the reaction was refluxed with stirring under argon atmosphere 12 h. The reaction was monitored by TLC, after completion of the reaction mixture was concentrated in vacuo, 500mL of water was added, extracted twice with ethyl acetate (2 x 400 mL), the organic phases were combined, washed with brine and dried over anhydrous MgSO 4. The organic layer was concentrated in vacuo and purified by silica gel chromatography to give 7.87g of a pale yellow solid. The yield was 84.99%. 1 H NMR (400 MHz, DMSO- d6) δ 9.53-9.50 (m,1H), 8.48 – 8.35 (m, 1H), 7.45 (d, J = 14.9 Hz, 1H), 4.02 (s, 2H), 1.96 (s, 6H). ESI-MS: mass calcd for [M + H] + (C 14 H 13 N 7 S) 312.10; found m/z, 312.09.
Compound 5 [2- ((2- ((3, 5-dimethyl-1H-pyrazol-4-yl) methyl) pyrido [3, 4-e)][1,2,4]Triazolo [1,5-c ]]Pyrimidin-5-yl) thio) -3- (1, 2, 4-oxadiazol-5-yl) propionic acid]Is prepared from the following steps: compound 3 (2.00 g, 6.42 mmol), compound 2-bromo-3- (1, 2, 4-oxadiazol-5-yl) propionic acid (2.13 g, 9.63 mmol) was dissolved in NaOH (2N) methanol in water (methanol: water=2:1), after argon substitution, was reacted for 1h with microwaves at 120 ℃ and tlc monitored the reaction. After the reaction was completed, the reaction mixture was concentrated in vacuo, 200mL of water was added, extracted twice with ethyl acetate (2X 200 mL), the organic phases were combined, washed with brine, and dried over anhydrous MgSO 4 And (5) drying. The organic layers were combined, concentrated in vacuo and purified by silica gel chromatography to give 1.5. 1.5 g as an off-white solid. The yield was 51.72%. 1 H NMR (400 MHz, DMSO- d6) δ 9.52-9.50 (m, 1H), 8.51– 8.38 (m, 1H), 7.45 (d, J = 15.2 Hz, 1H), 6.92 (s, 1H), 4.48(t, J = 15.6 Hz, 1H),4.03 (s, 2H), 3.68 (dd, J = 24.8, 15.5 Hz, 1H), 3.05 (dd, J = 24.8, 15.7 Hz, 1H), 1.95 (s, 6H). ESI-MS: mass calcd for [M + H] + (C 19 H 17 N 9 O 3 S) 451.12; found m/z, 451.11.
The compound R-21 [6- (3- (2- (((3, 5-dimethyl-1H-pyrazol-4-yl) methyl) pyrido [3, 4-e)][1,2,4]Triazolo [1,5-c ]]Pyrimidin-5-yl) thio) -3- (1, 2, 4-oxadiazol-5-yl) propionyl) ureido) nicotinic acid]Is prepared from the following steps: compound 5 (300 mg, 0.66 mmol), SOCl 2 (158.1 mg, 1.33 mmol) was dissolved in anhydrous DCM, the temperature was raised to reflux for 3-4 h, after the completion of TLC monitoring the reaction, 6-ureido nicotinic acid (180.56 mg, 0.996 mmol), triethylamine (80.69 mg, 0.80 mmol) was distilled off under vacuum under reduced pressure under inert gas atmosphere, and 6h was reacted at room temperature in 5 mL DMSO to complete the reaction by TLC monitoring. The reaction liquid was added to 100mL of water, extracted twice with ethyl acetate (2×100 mL), and the organic phases were combined, washed with brine and dried over anhydrous MgSO 4. The organic layer was concentrated in vacuo and purified by silica gel chromatography to afford 12290mg of off-white solid was obtained in 30.3% yield. 1 H NMR (400 MHz, DMSO- d6) δ 9.51– 9.43 (m, 2H), 8.23 (d, J = 3.2Hz, 1H), 7.97 (dd, J =14.9, 2.9 Hz, 1H), 7.62 (d, J = 15.0 Hz, 1H), 7.49 (d, J = 14.9 Hz, 1H), 7.26 (s, 1H), 4.52 (t, J = 14.4 Hz, 1H), 4.19 (dd, J = 24.8, 14.4 Hz, 1H), 4.03 (s,2H), 3.11dd, J = 24.8, 14.4 Hz, 1H), 1.92 (s, 6H). 13 C NMR (100 MHz, DMSO- d6) δ 176.82 (s), 171.25 (s), 165.51 (s),162.06 (s), 159.02 (s), 156.68 (s), 152.98 (s), 151.99 (s), 150.82 (s), 150.31 (s), 149.36 (s), 147.78 (s), 146.95 (s), 145.51 (s), 137.90 (s), 137.03 (s),121.31 (s), 112.51 (s), 111.99 (s), 104.52 (s), 103.91 (s), 43.92 (s), 31.48 (s), 26.52(s), 13.41 (s), 10.31 (s). ESI-MS: mass calcd for [M + H] + (C 26 H 22 N 12 O 5 S) 615.16; found m/z, 615.16.
2. Preparation of the Compound R-6 [2- ((2- ((3, 5-dimethyl-1H-pyrazol-4-yl) methyl) - [1,2,4] triazolo [1,5-c ] quinazolin-5-yl) thio) -N- ((5-fluoropyridin-2-yl) carbamoyl) butyramide ]
Preparation method As for Compound R-21, starting material 2- ((2- ((3, 5-dimethyl-1H-pyrazol-4-yl) methyl) - [1,2, 4)]Triazolo [1,5-c ]]Quinazolin-5-yl) thio) butanoic acid (200 mg, 0.504 mmol) with starting SOCl 2 After the reaction to give an intermediate, the intermediate was reacted with 5-fluoropyridin-2-amine (84.07 mg, 0.757 mmol) and purified by silica gel chromatography to give 99.86 mg as an off-white solid in 37.1% yield. 1 H NMR (400 MHz, DMSO ) δ 9.53 (br, 1H),8.13-8.06 (m, 2H), 7.87 (dd, J = 16.0, 2.8 Hz, 1H), 7.79 (m, 1H), 7.60 – 7.39 (m, 3H), 4.14 – 3.81 (m, 3H), 1.97– 1.83 (m, 8H), 0.97 (t, J = 13.4 Hz,3H). ESI-MS: mass calcd for [M + H] + (C 25 H 24 FN 9 O 2 S) 534.17; found m/z, 534.18.
3. Preparation of the Compound R-8 [6- (3- (2- (((3, 5-dimethyl-1H-pyrazol-4-yl) methyl) - [1,2,4] triazolo [1,5-c ] quinazolin-5-yl) thio) butanoyl) ureido) nicotinic acid ]
Preparation method and compound R-21, willStarting material 2- ((2- ((3, 5-dimethyl-1H-pyrazol-4-yl) methyl) - [1,2, 4)]Triazolo [1,5-c ]]Quinazolin-5-yl) thio) butanoic acid (200 mg, 0.504 mmol) with starting SOCl 2 After the reaction to afford intermediate, the reaction was taken with 6-aminonicotinic acid (104.52 mg, 0.757 mmol) and purified by silica gel chromatography to afford 79.3. 79.3 mg as an off-white solid in 28.1% yield. 1 H NMR (400 MHz, DMSO ) δ 9.51 (s, 1H),8.27 (d, J = 3.1 Hz, 1H), 8.16-8.02 (m, 2H), 7.94 (dd, J = 15.0, 3.0 Hz, 1H), 7.75 (td, J = 14.9, 3.1 Hz, 1H), 7.63-7.42 (m, 2H), 4.13 – 3.81 (m, 3H), 2.15 – 1.72(m, 8H), 0.99 (t, J = 13.4 Hz, 3H).ESI-MS: mass calcd for [M + H] + (C 26 H 25 N 9 O 4 S) 560.17; found m/z, 560.18.
4. Preparation of the Compound R-13 [2- ((2- (2- (3, 5-dimethyl-1H-pyrazol-4-yl) ethyl) pyrido [3,4-e ] [1,2,4] triazolo [1,5-c ] pyrimidin-5-yl) thio) -N- ((5-fluoropyridin-2-yl) carbamoyl) -3- (4H-imidazol-5-yl) propanamide ]
Preparation method the same as for Compound R-21, starting material 2- ((2- (2- (3, 5-dimethyl-1H-pyrazol-4-yl) ethyl) pyrido [3, 4-e)][1,2,4]Triazolo [1,5-c ]]Pyrimidin-5-yl) thio) -3- (4H-imidazol-5-yl) propionic acid (200 mg, 0.504 mmol) with starting SOCl 2 After the reaction afforded intermediate, 5-fluoropyridin-2-amine (72.56 mg, 0.757 mmol) was reacted and purified by silica gel chromatography to give 90.45 mg as a pale brown solid in 34.9% yield. 1 H NMR (400 MHz, DMSO ) δ 9.59 – 9.47 (m, 2H), 8.46 – 8.37(m, 1H), 7.97 (dd, J = 16.0, 2.8 Hz, 1H), 7.73 (s, 1H), 7.52 – 7.28 (m, 3H), 4.21 (s, 2H), 3.82(t, J = 13.8 Hz, 1H), 3.63– 3.38 (m, 3H), 3.20 (dd, J = 24.8, 13.9Hz, 1H), 2.89-2.80 (m, 2H), 1.91 (s, 6H).ESI-MS: mass calcd for [M + H] + (C 27 H 25 FN 12 O 2 S) 601.19; found m/z, 600.19.
5. Preparation of the Compound R-15 [2- ((2- ((3, 5-dimethyl-1H-pyrazol-4-yl) methyl) pyrido [3,4-e ] [1,2,4] triazolo [1,5-c ] pyrimidin-5-yl) thio) -N- ((5-fluoropyridin-2-yl) carbamoyl) -3- (1, 2, 4-oxadiazol-5-yl) propanamide ]
Preparation method As for Compound R-21, starting material 2- ((2- ((3, 5-dimethyl-1H-pyrazol-4-yl) methyl) pyrido [3, 4-e)][1,2,4]Triazolo [1,5-c ]]Pyrimidin-5-yl) thio) -3- (1, 2, 4-oxadiazol-5-yl) propionic acid (200 mg, 0.443 mmol) with starting SOCl 2 After the reaction to afford intermediate, 5-fluoropyridin-2-amine (74.5 mg, 0.664 mmol) was reacted and purified by silica gel chromatography to afford 100.38 mg as a white brown solid in 38.5% yield. 1 H NMR (400 MHz, DMSO ) δ 9.51-9.47 (m,2H), 8.48 – 8.36 (m, 1H), 7.98 – 7.85 (m, 1H), 7.51 – 7.38 (m, 3H), 6.84 (s, 1H), 4.65 (t, J = 13.8 Hz, 1H), 4.01 – 3.80 (m, 3H), 3.52 (dd, J = 24.8, 13.8 Hz, 1H), 1.90 (s,6H).ESI-MS: mass calcd for [M + H] + (C 25 H 21 FN 12 O 3 S) 589.15; found m/z, 589.16.
6. Preparation of Compound R-28 [ (2- ((2- (3, 5-dimethyl-1H-pyrazol-4-yl) methyl) pyrido [3,4-e ] [1,2,4] triazolo [1,5-c ] pyrimidin-5-yl) thio) -3- (1, 2, 4-oxadiazol-5-yl) propionyl) carbamoyl) glycine ]
Preparation method As for Compound R-21, starting material 2- ((2- ((3, 5-dimethyl-1H-pyrazol-4-yl) methyl) pyrido [3, 4-e)][1,2,4]Triazolo [1,5-c ]]Pyrimidin-5-yl) thio) -3- (1, 2, 4-oxadiazol-5-yl) propionic acid (200 mg, 0.443 mmol) with starting SOCl 2 After the reaction to afford intermediate, it was reacted with glycine (49.88 mg, 0.664 mmol) and purified by silica gel chromatography to afford 71.1 mg as an off-white solid in 29.1% yield. 1 H NMR (400 MHz, DMSO ) δ 9.52 (br, 1H),8.53 – 8.38 (m, 1H), 7.81 (s, 1H), 7.45 (d, J = 14.9 Hz, 1H), 6.85 (s, 1H), 4.76 (t, J = 14.4 Hz, 1H), 4.01 (d, J = 16.1 Hz,4H), 3.93-3.69 (m, 1H), 3.22-3.09 (m, 1H), 1.92 (s, 6H). ESI-MS: mass calcd for [M + H] + (C 22 H 21 N 11 O 5 S) 552.14; found m/z, 552.15.
7. Preparation of the compound R-30 [6- (3- (2- (((3, 5-dimethyl-1H-pyrazol-4-yl) methyl) pyrido [3,4-e ] [1,2,4] triazolo [1,5-c ] pyrimidin-5-yl) thio) -3-phenylpropionyl) ureido) nicotinic acid ].
Preparation method As for Compound R-21, starting material 2- ((2- ((3, 5-dimethyl-1H-pyrazol-4-yl) methyl) pyrido [3, 4-e)][1,2,4]Triazolo [1,5-c ]]Pyrimidin-5-yl) thio) -3-phenylpropionic acid (200 mg, 0.653 mmol) with starting SOCl 2 After reaction to afford intermediate, the reaction was taken with 6-aminonicotinic acid (90.17 mg, 0.664 mmol) and purified by silica gel chromatography to afford 95.1 mg as an off-white solid in 35.1% yield. 1 H NMR (400 MHz, DMSO ) δ 9.56 – 9.48 (m, 2H), 8.50 – 8.36(m, 1H), 8.26 (d, J = 3.0 Hz, 1H), 7.93 (dd, J = 14.9, 2.9 Hz, 1H), 7.62 (d, J = 14.9 Hz, 1H), 7.45 (d, J = 14.9 Hz, 1H), 7.32 – 7.08(m, 5H), 5.26 - 5.17 (m, 1H), 4.02 (s, 2H), 3.48 - 3.25 (m, 1H), 3.20 – 3.28 (m, 1H), 1.91 (s, 6H).ESI-MS: mass calcd for [M + H] + (C 30 H 26 N 10 O 4 S) 623.18; found m/z, 623.19.
8. Preparation of the Compound R-32 [6- (3- (2- (((3, 5-dimethyl-1H-pyrazol-4-yl) methyl) pyrido [3,4-e ] [1,2,4] triazolo [1,5-c ] pyrimidin-5-yl) thio) -3- (pyridin-4-yl) propionyl) ureido) nicotinic acid ]
Preparation method As for Compound R-21, starting material 2- ((2- ((3, 5-dimethyl-1H-pyrazol-4-yl) methyl) pyrido [3, 4-e)][1,2,4]Triazolo [1,5-c ]]Pyrimidin-5-yl) thio) -3- (pyridin-4-yl) propionic acid (200 mg, 0.433 mmol) with starting SOCl 2 After reaction to afford intermediate, the reaction was taken with 6-aminonicotinic acid (90.0 mg, 0.652 mmol) and purified by silica gel chromatography to afford 95.7. 95.7 mg as an off-white solid in 35.3% yield. 1 H NMR (400 MHz, DMSO ) δ 9.61 – 9.48 (m, 2H), 8.57 (d, J = 14.9 Hz, 2H), 8.45 – 8.36 (m, 1H), 8.23 (d, J = 3.1 Hz, 1H), 7.92 (dd, J =14.9, 2.9 Hz, 1H), 7.61 (d, J = 15.0 Hz, 1H), 7.42 (d, J = 14.9 Hz, 1H), 7.15 (d, J = 15.1 Hz, 2H), 5.03 – 4.05 (m, 1H),4.28 – 3.98 (m, 3H), 3.73 – 3.60 (m, 1H), 1.93 (s, 6H).ESI-MS: mass calcd for [M + H] + (C 30 H 26 N 10 O 4 S) 624.18; found m/z, 624.18.
Example 2 fluorescence resonance energy transfer assessment of the ability of molecules of interest to inhibit binding of CD47/SIPR alpha
The synthesized target small molecules are respectively dissolved in DMSO and prepared into a solution with the concentration of 20 mM, the solution is tested by using a CD 47/SIRPalpha analysis kit, then the compounds are respectively further diluted by using a Detection buffer solution, 2 mu L/hole with a certain concentration gradient (0.5-20 mu M) is added into a 500-micropore test plate, the positive control group is NCG-3, and the blank group is DMSO. Then 4. Mu.L of Tag1-CD47 and Tag 2-SIRPalpha are added to each well, after incubation at room temperature of 0.5. 0.5 h, 5. Mu.L of the corresponding antibody is added to each well, and incubation is carried out at room temperature of 1.5-2. 2 h. The fluorescence absorbance was measured at 665 nm using a VICTOR Nivo multifunctional enzyme-labeled instrument (PerkinElmer, inc., USA) and the corresponding IC was calculated by GraphPad Prism5 software 50 Values, the results of which are shown in Table 2 and FIG. 1.
Wherein the IC 50 Mean ± standard deviation of three measurements; NCG-3 is a positive drug NCGC00138783.
FIG. 1 is a schematic diagram of a small molecule binding capacity test to CD 47/SIRPa obtained from the data of Table 2, wherein P<0.05 vs DMSO；**P<0.01 vs DMSO；***P<0.001 vs DMSO. As can be seen from the in vitro activity test results, when the compound is substituted with R 1 Is substituted by oxadiazole groups, R 2 Can obviously promote the activity of compound molecules when being substituted by allophanate, wherein the optimal molecular compound R-21 is IC in an in vitro activity test 50 Reaches 21.8 mu M, has about 3 times of positive molecule NCG-3 (IC) on the inhibition activity of CD47/SIRP alpha 50 =63.6 μm), compound R-21 was found to CD47 protein by further molecular docking (Discovery Studio 3.5, usa) simulation (PDB code:2 JJS) as shown in fig. 2.
FIG. 2 is a schematic diagram of the butt joint simulation of a compound R-21 and a CD 47/SIRPalpha, wherein, A is a diagram of the action mode of the CD47 protein and the compound R-21, B is a diagram of the pocket mode of the compound R-21 molecule on the CD47 protein, C is a schematic diagram of the compound R-21 on the CD47 protein position, and D is a diagram of the key amino acid action mode of the compound R-21 and the CD47 protein. It can be seen that compound R-21 can bind tightly to CD47 protein, the carbonyl group of compound R-21, which is linked to 6- [ (aminocarbonyl) amino ] pyridine-3-carboxylic acid, can form a key hydrogen bond with Asn-93 by the author, the carboxyl terminus can form a hydrogen bond with Ser-77 and Arg-59, the N atom in the three-membered ring formed by triazolo [1,5-c ] quinazoline can form a pi-key hydrogen bond with Phe-55, the dimethylpyrazole ring can form a pi-pi interaction with Lys-6 and Cys-8, and the N atom in the oxadiazole group can form a key hydrogen bond with Thr-62. Compared with the positive molecule NCG-3, the combination mode of the compound R-21 and the CD47 protein is more stable, and the in vitro HTRF experimental test result is also demonstrated. The compound R-21 and the CD47 protein have stable effects according to in vitro biological activity tests and docking results.
EXAMPLE 3 testing of Compound R-21 for cell proliferation
The tumor cell lines used in this experiment were NCI-H1395, H3122, HT29, hela, jurkat, and human normal hepatocytes LO2, which were purchased from ATCC, USA, or from the cell bank of the national academy of sciences. Cell culture conditions were in accordance with ATCC culture rules, and the medium was RPMI 1640, L-15, DMEM supplied by Gibco corporation; 37 o C，5%CO 2 1% penicillin/streptomycin (V/V), 10% Gibco fetal bovine serum. MTT method was used to test its inhibitory activity against growth of different cell lines. The method comprises collecting tumor cells in logarithmic growth phase at 1.5-3.5X10 3 Is inoculated in 96-well plates, 5% CO 2 Incubation was carried out at 37℃for 24h, target molecules were added at the indicated concentrations, the positive control group was NCG-3, and the blank group was DMSO. After 72h MTT was added and incubated at 37℃for a further 2-4 h. Absorbance values (OD) of the 96-well plates were measured at 570 nm using a Spectra MAX M5 microplate spectrophotometer (molecular Devices, USA) and the corresponding IC50 values were calculated by GraphPad Prism5 software, the results of which are shown in table 3 and fig. 3.
Wherein, IC50 is the average value of three measurements.+ -. Standard deviation; NCG-3 is a positive drug NCGC00138783.
MTT results show that the compound R-21 has limited inhibition activity on tumor cell proliferation in vitro, which indicates that the target compound R-21 molecule has weak direct inhibition capability on tumor cells in vitro, and the compound R-21 molecule can play an anti-tumor role by blocking the binding function of CD47/SIRP alpha, and has no direct anti-tumor activity in vitro. The action mechanism of the compound R-21 on the CD47/SIRP alpha protein is further verified through a fluorescence labeling experiment, and the detail is shown in figure 4. In the figure, panel a is a labeled CD47 protein; panel B is a graph of binding to SIRPalpha protein added.
Evaluation of Compound R-21 effect on phagocytic Capacity by performing flow cytometry in column 4
Bone marrow-derived macrophages of NOD mice of 7-10 weeks of age were isolated at 1.0-1.5X10 per well 3 Inoculating into 96-well plate, adding serum-free culture medium, and adding 5% CO 2 Overnight at 37 ℃. At 3X 10 per well 3 Adding HeLa cell strain marked by carboxyl fluorescein diacetate succinimidyl ester (CFSE) at density, adding CFSE cell proliferation tracking reagent, adding specified concentration of compound R-21 molecule, NCG-3 as positive control group, DMSO as blank control group, incubating at 37deg.C for 6h, collecting cells, marking initial macrophage with anti-F4/80, and analyzing and processing experiment result by flow cytometry, shown in figure 5. As can be seen from FIG. 5, compound R-21 at the same concentration as the positive drug is capable of significantly inducing macrophage production and increasing phagocytosis, thereby activating cellular immune activity.
Example 5 anti-tumor experiment of Compound R-21 in mice
HeLa cells in log phase (6X 10) 6 ) Subcutaneously injected into 6-7 week old female NOD/SCID mice. Once the average tumor volume increases to about 100-120 mm 3 Each mouse cell model group was randomly divided into 7 groups (n=8 per group). Respectively blank groups (5% DMSO,20% PEG,2% Tween-80, physiological saline), molecular administration group PD-L1 monoclonal antibody (Atezolizumab, 5 mg/kg), and chemical groupCompound R-21 (50 mg/kg) +PD-L1 mab (5 mg/kg), compound R-21 (100 mg/kg) +PD-L1 mab (5 mg/kg), wherein PD-L1 mab (Atezolizumab) is administered by intravenous injection after being dissolved in physiological saline, and small molecules are administered by gastric lavage after being dissolved in formulation (5% DMSO,20% PEG,2% Tween-80, physiological saline). Tumor size and body weight were measured every two days with an experimental period of 21 days. Tumor volume was measured with vernier calipers and calculated as [0.5 x shortest diameter 2 x longest diameter]. The inhibition of tumor growth was calculated using the following formula: 100× {1- [ final tumor volume of treatment group-tumor volume initial]Final tumor volume of vehicle treated group-tumor volume initial]]}. The results are shown in FIG. 6.
In the HeLa xenograft model of NOD/SCID mice, the combination of compound R-21 with PD-L1 mab 5mg/kg (Atezolizumab) greatly enhanced the anti-tumor effect in vivo, and the Tumor Growth Inhibition (TGI) was observed to be 75.29%,90.57% and the tumor growth inhibition rate of the PD-L1 mab Atezolizumab group was only 54.6% when the compound R-21 was used at 50mg/kg, 100mg/kg, respectively. In vivo anti-tumor experiments prove that the compound R-21 can greatly enhance the effect of tumor immunotherapy.

Claims (10)

  1. A small molecule inhibitor of cd 47/sirpa, characterized by a structural formula represented by formula i:
    wherein X is 1 Selected from H or N; x is X 2 Selected from CH 2 Or C 2 H 4 ；
    R 1 Selected from-H, -CH 3 、-C 2 H 5 、
    ；
    R 2 Selected from-OH,
    Or->。
  2. 2. The CD 47/sirpa small molecule inhibitor of claim 1, wherein: r is R 1 Selected from-CH 3 、
    R 2 Selected from->
    。
  3. 3. The CD 47/sirpa small molecule inhibitor of claim 1, wherein: the structural formula is at least one of the following structural formulas:
    。
  4. 4. an isomer, pharmaceutically acceptable salt or hydrate of the CD 47/sirpa small molecule inhibitor of any one of claims 1-3.
  5. 5. Use of a CD 47/sirpa small molecule inhibitor or an isomer, a pharmaceutically acceptable salt or a hydrate thereof according to any one of claims 1 to 3 in the preparation of an antitumor drug.
  6. 6. The use according to claim 5, characterized in that: the antitumor drug is a drug targeting the CD47-SIRP alpha pathway.
  7. 7. An antitumor pharmaceutical composition, characterized in that: comprises an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises the CD47/SIRP alpha small molecule inhibitor or an isomer, pharmaceutically acceptable salt or hydrate thereof as claimed in any one of claims 1 to 3.
  8. 8. The antitumor pharmaceutical composition according to claim 7, characterized in that: the pharmaceutically acceptable salt is trifluoroacetate, sulfate, hydrochloride, acetate or nitrate.
  9. 9. The antitumor pharmaceutical composition according to claim 7, characterized in that: the active ingredient also comprises PD-1 monoclonal antibody or PD-L1 monoclonal antibody.
  10. 10. The antitumor pharmaceutical composition according to claim 9, characterized in that: PD-1 monoclonal antibody is nano Wu Liyou monoclonal antibody, palbociclib monoclonal antibody, cimiput Li Shan antibody, terlipressin Li Shan antibody, xindi Li Shan antibody or Carrilizumab; PD-L1 monoclonal antibody is Abilib, ab-Lu-Bill antibody, du-Va-Lu antibody, en Wo Lishan antibody or Shu Geli monoclonal antibody.
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