Novel deuterated JAK2 inhibitor as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to a novel deuterated JAK2 inhibitor or pharmaceutically acceptable salt thereof. Compared with the prior art, the compound or the pharmaceutically acceptable salt thereof provided by the invention has better JAK2 inhibition activity, and the JAK2 inhibition target selectivity of the compound or the pharmaceutically acceptable salt thereof is obviously superior to that of the existing compound, so that the compound or the pharmaceutically acceptable salt thereof has better druggability.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to a novel deuterated JAK2 inhibitor and a pharmaceutically acceptable salt thereof. Background Art

[0002] The protein kinase family has emerged as a major pathogenic factor in numerous diseases. Among them, the JAK family of cellular protein tyrosine kinases (JAK1, Jak2, Jak3, and Tyk2) plays a key role in cytokine signaling. Gain-of-function or mutational analyses suggest that JAK1 and JAK3 are more closely associated with immune regulation, while JAK2 is directly involved in erythrocyte and platelet production. Loss-of-function analyses suggest that JAK1 and JAK2 loss-of-function can cause embryonic lethality in mice. However, no diseases associated with JAK1 or JAK2 loss-of-function have been identified in humans, perhaps indirectly highlighting the importance of JAK1 / 2 physiological functions. Loss-of-function JAK3 can cause severe combined immunodeficiency, providing the basis for targeting JAK3 to modulate autoimmune diseases, as discussed later. The function of TYK2 is less well-studied, but there are reports that it can cause defects related to intrinsic immunity. JAK kinases sense extracellular signals, such as interferons, interleukins, and growth factors, by binding to receptors and transmitting this information to STATs. Cytokines activate JAKs upon binding to their receptors, which then phosphorylate the cytokine receptors and activate the signal transducer and activator of transcription (STAT) family. In recent years, the therapeutic potential of JAK inhibitors has focused on diseases affecting various immune system pathologies. These include atopy, cell-mediated hypersensitivity reactions (allergic contact dermatitis, hypersensitivity pneumonitis), systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriasis, and transplantation (graft rejection, graft-versus-host disease). JAK kinase inhibitors such as ruxolitinib and tofacitinib are already marketed for the treatment of diseases such as myelofibrosis and rheumatoid arthritis.

[0003] Although a series of JAK inhibitors have been disclosed, there is still a need to develop new JAK inhibitor compounds with better efficacy and lower side effects, especially JAK2 selective inhibitors. Summary of the Invention

[0004] In order to overcome the problems existing in the prior art, the purpose of the present invention is to provide a novel deuterated JAK2 inhibitor.

[0005] In order to achieve the above-mentioned and other related purposes, the present invention adopts the following technical solutions: A compound as shown in formula I, or a pharmaceutically acceptable salt thereof: Wherein: R1 is deuterated methyl or hydrogen; R2 is hydrogen, methyl or deuterated methyl; when R1 is hydrogen, R2 cannot be hydrogen.

[0006] Typical compounds of the present invention include the following compounds: The second object of the present invention is to provide a method for synthesizing the above-mentioned compound: (1) Intermediate 1 and intermediate 2 undergo condensation reaction to obtain intermediate 3; (2) Intermediate 3 is oxidized to obtain intermediate 4; (3) Intermediate 4 is reduced to obtain intermediate 5; (4) The hydroxyl group of intermediate 5 is activated and undergoes a cyclization reaction to prepare universal intermediate 6; (5) Intermediate 6 and intermediate 7 undergo condensation reaction to obtain final product I; The definitions of the groups in the above steps are as described above.

[0007] The third object of the present invention is to provide a compound for use as a novel deuterated JAK inhibitor in the preparation of a medicament for preventing or treating JAK-related diseases, specifically mainly for preventing or treating the following diseases: autoimmune system diseases, inflammatory diseases, pain diseases, respiratory diseases, airway diseases, lung diseases, lung inflammation and injury, pulmonary hypertension, gastrointestinal diseases, allergic diseases, infectious diseases, trauma and tissue damage diseases, fibrotic diseases, eye diseases, joint diseases, muscle diseases, bone diseases, skin diseases, kidney diseases, hematopoietic system diseases, liver diseases, oral diseases, metabolic diseases, heart diseases, vascular diseases, neuroinflammatory diseases, neurodegenerative diseases, sepsis, genetic diseases or cancer.

[0008] The inflammatory and autoimmune diseases include systemic lupus erythematosus, lupus nephritis, arthritis, psoriasis, Crohn's disease, rheumatoid arthritis, ulcerative colitis, atopic dermatitis, gout, alopecia areata, vitiligo, hidradenitis suppurativa, type I diabetes, chronic kidney disease, acute kidney injury, chronic obstructive pulmonary disease, asthma, bronchitis or graft-versus-host disease.

[0009] The cancers include breast cancer, lung cancer, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, vaginal cancer, leukemia, myelofibrosis, multiple myeloma or lymphoma.

[0010] The compounds of the present invention can be used in the form of compositions for the treatment of related cancers and other diseases via oral administration, injection, or other methods. For oral administration, they can be prepared into conventional solid preparations such as tablets, powders, or capsules; for injection, they can be prepared into injection solutions or lyophilized powder injections.

[0011] The fourth object of the present invention is to provide a stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt thereof of the compound as described in the first aspect.

[0012] The fifth object of the present invention is to provide a composition comprising a therapeutically effective amount of the above-mentioned compound, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

[0013] Pharmaceutically acceptable salts include, for example, salts formed with inorganic acids, salts formed with organic acids, and the like. Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, and the like. Non-limiting examples of salts formed with organic acids include, but are not limited to, salts formed with formic acid, acetic acid, trifluoroacetic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and the like.

[0014] The carrier mentioned refers to a conventional carrier in the pharmaceutical field, such as: diluents, excipients such as water, etc.; binders such as cellulose derivatives, gelatin, polyvinyl pyrrolidone, etc.; fillers such as starch, etc.; disintegrants such as calcium carbonate, sodium bicarbonate; in addition, other auxiliary agents such as flavoring agents and sweeteners can also be added to the composition.

[0015] Various dosage forms of the composition of the present invention can be prepared by conventional methods in the medical field, wherein the content of the active ingredient is 0.1% to 99.5% (by weight).

[0016] The dosage of the present invention can vary according to the route of administration, the patient's age, weight, the type and severity of the disease being treated, etc., and the daily dose is 0.001-30 mg / kg body weight (oral) or 0.005-30 mg / kg body weight (injection).

[0017] Compared with the prior art, the compounds provided by the present invention, their stereoisomers and pharmaceutically acceptable salts thereof have better Janus kinase inhibitory activity, and their selectivity for JAK2 inhibition targets is significantly better than that of existing compounds. They have the potential to be developed into more selective JAK2 inhibitors and have broad application prospects. DETAILED DESCRIPTION

[0018] The technical solution of the present application is further described below by specific embodiments. Those skilled in the art should understand that the embodiments are merely to help understand the present application and should not be regarded as specific limitations of the present application. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work are within the scope of protection of the present invention.

[0019] Example 1: Synthesis of Intermediate 6 Operation steps: Step 1, synthesis of intermediate 3.

[0020] Intermediate 1 (10 g, 43.8 mmol) and Intermediate 2 (10.8 g, 43.8 mmol) were added to DMSO (100 mL) and microwave-treated at 150°C for 2 h. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain solid Intermediate 3 (12.9 g, 67% yield). MS (ESI): m / s [M+H] + =439.5.

[0021] Step 2, synthesis of intermediate 4.

[0022] Potassium peroxygen sulfate (14 g, 45.6 mmol) was added to a solution of intermediate 3 (10 g, 22.8 mmol) in DMF (200 mL). The reaction mixture was stirred at room temperature overnight and monitored for completion by HPLC. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain solid intermediate 4 (7.1 g, 66% yield). MS (ESI): m / s [M+H] + =471.5.

[0023] Step 3, synthesis of intermediate 5.

[0024] Sodium borohydride (1.6 g, 42.4 mmol) was added to a solution of intermediate 4 (10 g, 21.2 mmol) in THF (100 mL). The reaction mixture was stirred at room temperature overnight and monitored for completion by TLC. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain intermediate 5 (7.1 g, 78% yield) as a white solid. MS (ESI): m / s [M+H] + =429.5.

[0025] Step 4, synthesis of intermediate 6.

[0026] To a solution of compound 5 (10 g, 23.3 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (5.3 g, 46.6 mmol) and triethylamine (7.0 g, 69.9 mmol). The reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored for completion by TLC. The reaction mixture was concentrated to dryness under reduced pressure, and DBU (3.54 g, 23.3 mmol) was added to a DMF (100 mL) solution. The reaction mixture was stirred at 80°C for 1 hour, and the reaction was monitored for completion by HPLC. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified on a silica gel column to obtain intermediate 6 (5.3 g, 55% yield). MS (ESI): m / s [M+H] + =411.5.

[0027] Example 2: Synthesis of Compound 1 Synthesis route: Steps: Intermediate 6 (10 g, 24.3 mmol) and intermediate 7-1 (12.6 g, 60.75 mmol) were added to trifluoroacetic acid (50 mL) and the system was heated to an internal temperature of 100°C for 12 h. The reaction was monitored for completion by HPLC. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was separated on a silica gel column to obtain compound 1 (9.18 g, 72% yield). MS (ESI): m / s [M+H] + =525.7.

[0028] Example 3: Synthesis of Compound 2 Synthesis route: Steps: The operation steps and purification method are as in Example 2, with a yield of 73%. MS (ESI): m / s [M+H] + =539.7.

[0029] Example 4: Synthesis of Compound 3 Synthesis route: Steps: The operation steps and purification method are as in Example 2, with a yield of 71%. MS (ESI): m / s [M+H] + =539.7.

[0030] Example 5: Synthesis of Compound 4 Synthesis route: Steps: The operation steps and purification method are as in Example 2, with a yield of 78%. MS (ESI): m / s [M+H] + =528.7.

[0031] Example 6: Synthesis of Compound 5 Synthesis route: Steps: The operation steps and purification method are as in Example 2, with a yield of 74%. MS (ESI): m / s [M+H] + =528.7.

[0032] Example 7: Synthesis of Compound 6 Synthesis route: Steps: The operation steps and purification method are as in Example 2, with a yield of 70%. MS (ESI): m / s [M+H] + =511.6.

[0033] Example 8: Synthesis of Compound 7 Synthesis route: Steps: The operation steps and purification method are as in Example 2, with a yield of 71%. MS (ESI): m / s [M+H] + =511.6.

[0034] Biological testing Test Example 1: JAK1, JAK2, and JAK3 activity test Compound preparation: The compounds were dissolved in 100% DMSO to prepare 10 mM stock solutions and stored at -20°C.

[0035] Kinase reaction process: (1) Prepare 1× Kinase buffer.

[0036] (2) Preparation of compound concentration gradient: The starting concentration of the test compound was 500 nM. The compound was diluted to a 100-fold final concentration in 100% DMSO in the 384 source plate. The compound was diluted 3-fold using a Precision RT-PCR agarose gel for 12 concentrations. 250 nL of the compound at 100-fold final concentration was transferred to the destination plate, OptiPlate-384F, using an Echo 550 dispenser.

[0037] (3) Prepare a kinase solution with a final concentration of 2.5 times using 1× Kinase buffer.

[0038] (4) Add 10 μL of kinase solution at 2.5 times the final concentration to the compound wells and positive control wells respectively; add 10 μL of 1× Kinase buffer to the negative control wells.

[0039] (5) Centrifuge at 1000 rpm for 30 seconds, shake the reaction plate to mix, and incubate at room temperature for 10 minutes.

[0040] (6) Use 1× Kinase buffer to prepare a mixed solution of ATP and Kinase substrate at 5 / 3 times the final concentration.

[0041] (7) Add 15 μL of a mixed solution of ATP and substrate at 5 / 3 times the final concentration to start the reaction.

[0042] (8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake to mix, and incubate at room temperature for the corresponding time.

[0043] (9) Add 30 μL of stop detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and shake to mix.

[0044] (10) Read the conversion rate using Caliper EZ Reader.

[0045] Data Analysis: The calculation formula is as follows: Where: Conversion%_sample is the conversion rate reading of the sample; Conversion%_min is the mean of the negative control wells, representing the conversion rate reading of the wells without enzyme activity; Conversion%_max is the mean of the positive control well ratio, representing the conversion rate reading of the wells without compound inhibition.

[0046] Fitting the dose-effect curve: The logarithmic concentration value was used as the X-axis and the percentage inhibition rate was used as the Y-axis. The log (inhibitor) vs. response-Variable slope analysis software GraphPad Prism 5 was used to fit the dose-effect curve to obtain the IC50 value of each compound on the enzyme activity. The calculation formula is: Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)) The above experimental results are shown in Table 1.

[0047] Table 1 Compound enzyme test results Compound <![CDATA[JAK1( nM )]]> <![CDATA[JAK2( nM )]]> <![CDATA[JAK3( nM )]]> JAK1 / JAK2 JAK3 / JAK2 Felotinib 75 5 344 15 69 Control compound 1 215 3 1322 72 441 Control compound 2 210 2.2 1500 95 682 Control compound 3 80 1.1 619 73 563 Compound 1 120 0.4 1430 300 3575 Compound 2 184 0.5 1521 368 3042 Compound 3 190 0.8 1399 237.5 1748.7 Compound 4 221 0.6 1533 368.3 2555 Compound 5 209 0.6 1490 348.3 2483.3 Compound 6 178 0.7 1437 254.2 2052.8 Compound 7 199 0.7 1522 284.3 2174.3 Note: The above reference compounds and compounds of the present invention are all measured under the same experimental conditions.

[0048] Conclusion: The compounds of the present invention have better selectivity for JAK2 target than the positive control filzotinib, control compound 1, control compound 2 and control compound 3.

[0049] Test Example 2: Cell Proliferation Experiment HEL92.1.7 cell proliferation assay Experimental steps: (1)Packing a. Digest and resuspend the cells and count them using an automated cell counter; b. Dilute the cell suspension to the desired density; c. Plate 100 μl of cells in each well and culture at 37°C overnight; (2) Compound preparation a. Prepare a dilution solution of the compound to a final concentration of 200 times; b. Dilute the compound in culture medium to a final concentration 3 times that of the compound. Add 50 μl of compound to each well, using wells containing the same volume of DMSO as controls. Incubate at 37°C, 5% CO2 for 72 hours. (3) Detection a. Equilibrate the cell plate to room temperature; b. Add 40 μL Cell reagent to each well, shake for 2 minutes, and let it stand for 10 minutes; c. Detect using EnVision.

[0050] Data Analysis: (1) IC50 was calculated using GraphPad Prism 5.

[0051] (2)%Inh=(Max signal-Compound signal) / (Max signal-Min signal)×100%.

[0052] (3) Max signal is the positive control well, which contains only DMSO with the same volume as the compound.

[0053] (4) Min signal is the negative control well, containing only culture medium.

[0054] TF-1 cell proliferation assay (1) Cell plating a. Prepare complete culture medium.

[0055] b. Resuscitate cells and culture cells.

[0056] c. Centrifuge the cells, resuspend, count, plate, and place the culture plate in a CO2 incubator overnight.

[0057] (2) Preparation and addition of compounds a. Prepare the compound into a 10 mM stock solution using DMSO, dilute 10 mM to a working concentration, and then gradually dilute the solution to obtain multiple concentration gradients of the compound.

[0058] b. Pipette 0.5ul from the corresponding compound plate and add it to the cell culture plate incubated overnight.

[0059] c. Incubate in a 37°C incubator for 72 hours.

[0060] (3) Detection and analysis a. Prepare the CellTiter Glo assay reagent.

[0061] b. Add the detection reagent to the culture plate, mix well, let it stand, and read the plate.

[0062] The inhibition rate formula is (1-(the value of the corresponding well-the average value of BLANK) / (the average value of the DMSO control-the average value of BLANK))*100%) The curve fitting tool (XL fit) formula is Data Analysis: (XLfit software: Fit model: Dose response one site / f(x)205[fit=(A+((BA) / (1+((C / x)^D))))]) The above experimental results are shown in Table 2.

[0063] Table 2. Cell proliferation test results Note: The above reference compounds and compounds of the present invention are all measured under the same experimental conditions.

[0064] Conclusion: The compounds of the present invention have significant proliferation inhibitory activity against HEL92.1.7 and TF-1, and the inhibitory activity is superior to that of the positive control filzotinib, control compound 1, control compound 2 and control compound 3.

[0065] Test Example 3: Pharmacokinetics of the Compounds of the Invention Forty-four male Sprague-Dawley rats, weighing 200-250 g, were administered with the compound of the present invention and a control compound, each rat receiving a 30 mg / kg dose (at a concentration of 3 mg / ml) via oral gavage. The rats were divided into 11 groups, each consisting of four rats. The rats were fasted for 12 hours prior to the experiment and had free access to water. 0.1 mL of blood was collected from the retroorbital venous plexus.

[0066] SD rats source: Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. Dosage: Single oral administration Sampling points: 5min, 15min, 30min, 1h, 2h, 4h, 8h, 24h Preparation of standard curve and quality control samples: Take an appropriate amount of stock solution and dilute it with 50% acetonitrile water to make standard working solutions of 0.04, 0.10, 0.20, 0.40, 1.00, 2.00, and 4.00 μg / mL, and quality control working solutions of 0.10, 1.00, and 3.00 μg / mL. 47.5 μL of blank rat plasma was added with 2.50 μL of standard curve working solution and quality control working solution to prepare standard curves containing analyte concentrations of 2.00, 5.00, 10.00, 20.00, 50.00, 100.00, and 200.00 ng / mL and quality control samples at concentrations of 5.00, 50.00, and 150.00 ng / mL. 200 μL of acetonitrile (containing the internal standard loratadine, 5 ng / mL) was added to each sample. After vortexing for 3 minutes, the mixture was centrifuged at 15,000 rpm and 4°C for 15 minutes. 100 μL of the supernatant was collected for LC-MS / MS analysis. Results were calculated using WinNonlin 8.0.

[0067] The pharmacokinetic parameters are shown in Table 3.

[0068] Table 3: Pharmacokinetic parameters of preferred compounds Conclusion: The compounds of the present invention exhibit good pharmacokinetic properties and have obvious pharmacokinetic advantages compared with the positive control filzotinib, control compound 1, control compound 2 and control compound 3.

[0069] Test Example 4: Acute toxicity test of the compound of the present invention The compounds of the present invention and positive control drugs were subjected to acute toxicity experiments.

[0070] (1) Experimental plan ①. Observe the toxicity symptoms and death of ICR mice after oral administration of the positive control drug and the compound of the present invention, and compare their acute toxicity.

[0071] ②. Solvent preparation: Weigh an appropriate amount of Tween-80 and dilute it with deionized water to a concentration of 5% (g / v) Tween-80.

[0072] ③. Dosage preparation: Weigh the required test sample separately and prepare suspensions with 5% Tween 80 solution at concentrations of 25.00, 50.00, 75.00, 100.00, 125.00 and 150.00 mg / mL (equivalent to 500, 1000, 1500, 2000, 2500 and 3000 mg / kg, respectively).

[0073] ④. Administration route: The test sample and the vehicle control group (0.5% Tween-80) were both administered orally.

[0074] ⑤. Dosage frequency: Single dose, fast overnight before administration.

[0075] ⑥. Dosage volume: 20mL / kg.

[0076] Observation of general symptoms: On the day of administration, observe once approximately 0.5, 1, 2, 4, and 6 hours after the first dose; on the 2nd to 6th day of the observation period, observe twice a day, once in the morning and once in the afternoon.

[0077] Observations include but are not limited to: general condition, behavioral activities, gait posture, eyes, mouth, nose, gastrointestinal tract, skin and hair, and urogenital tract.

[0078] (2) Statistical analysis Body weight data were expressed as mean ± standard deviation, and the groups were compared using Levene's test and one-way analysis of variance, and if differences were shown, Dunnett-t test was used.

[0079] (3) Experimental results The compounds of the present invention and the positive control drug were subjected to acute toxicity experiments as described above. The experimental results are shown in Table 4.

[0080] In the MTD test, the tolerance of animals to drugs is examined. When the dose reaches the point where the animal is on the verge of death, it is the maximum tolerated dose.

[0081] Table 4: Results of acute toxicity test of the compounds of the present invention and the positive control drug after single oral administration Compound MTD (mg / kg) Compound MTD (mg / kg) Felotinib 250 Control compound 1 2500 Control compound 2 2500 Control compound 3 1500 Compound 1 >3000 Compound 2 >3000 Compound 3 >3000 Compound 4 >3000 Compound 5 >3000 Compound 6 >3000 Compound 7 >3000 -- -- Note: MTD: Maximum tolerated dose.

[0082] The results showed that the MTD (maximum tolerated dose) of the compounds of the present invention among the above-mentioned test substances were all greater than 3000 mg / kg, and the acute toxicity was lower than that of the positive control drug.

[0083] Although we have described several embodiments of the present invention, it is apparent that our basic examples can be modified to provide other embodiments utilizing the compounds and methods of the present invention. It should be understood, therefore, that the scope of the invention is to be defined by the appended claims rather than by the specific embodiments presented by way of example.

Claims

1. A novel deuterated JAK2 inhibitor as shown in Formula I or a pharmaceutically acceptable salt thereof, in: R1 is deuterated methyl or hydrogen; R2 is hydrogen, methyl or deuterated methyl; when R1 is hydrogen, R2 cannot be hydrogen.

2. The novel deuterated JAK2 inhibitor or a pharmaceutically acceptable salt thereof according to claim 1, wherein: Selected from the following compounds:

3. A method for preparing the novel deuterated JAK2 inhibitor or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, characterized in that The steps include: (1) Intermediate 1 and intermediate 2 undergo condensation reaction to obtain intermediate 3; (2) Intermediate 3 is oxidized to obtain intermediate 4; (3) Intermediate 4 is reduced to obtain intermediate 5; (4) The hydroxyl group of intermediate 5 is activated and undergoes a cyclization reaction to prepare universal intermediate 6; (5) Intermediate 6 and intermediate 7 undergo condensation reaction to obtain final product I; The definitions of the groups in the above steps are as described above.

4. The novel deuterated JAK2 inhibitor or a pharmaceutically acceptable salt thereof according to claim 1, wherein: Selected from salts formed with inorganic acids, inorganic acids include hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid or phosphoric acid.

5. The novel deuterated JAK2 inhibitor or a pharmaceutically acceptable salt thereof according to claim 1, wherein: Selected from salts formed with organic acids, inorganic acids include formic acid, acetic acid, trifluoroacetic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, maleic acid, tartaric acid, citric acid or succinic acid. 6 . Use of the novel deuterated JAK2 inhibitor or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of a medicament for preventing or treating JAK-related diseases.

7. The use according to claim 6, characterized in that The JAK-related diseases include autoimmune system diseases, inflammatory diseases, pain diseases, respiratory diseases, airway diseases, lung diseases, lung inflammation and injury, pulmonary hypertension, gastrointestinal diseases, allergic diseases, infectious diseases, trauma and tissue damage diseases, fibrotic diseases, eye diseases, joint diseases, muscle diseases, bone diseases, skin diseases, kidney diseases, hematopoietic system diseases, liver diseases, oral diseases, metabolic diseases, heart diseases, vascular diseases, neuroinflammatory diseases, neurodegenerative diseases, sepsis, genetic diseases or cancer.

8. A composition comprising a therapeutically effective amount of the novel deuterated JAK2 inhibitor according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

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