CN116496280B - Deuterated acrylamide JAK3 inhibitor medicine and application thereof - Google Patents

Deuterated acrylamide JAK3 inhibitor medicine and application thereof Download PDF

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CN116496280B
CN116496280B CN202310745179.2A CN202310745179A CN116496280B CN 116496280 B CN116496280 B CN 116496280B CN 202310745179 A CN202310745179 A CN 202310745179A CN 116496280 B CN116496280 B CN 116496280B
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deuterated
pharmaceutically acceptable
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CN116496280A (en
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刘春河
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Henan Yaokang Zhongtuo Pharmaceutical Technology Co ltd
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Beijing Kexiang Zhongsheng Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The application provides deuterated compounds of deuterated acrylamide JAK3 inhibitor and pharmaceutically acceptable salts thereof, which remarkably improve the inhibiting activity on JAK3 enzyme, further improve the pharmacokinetic property of the JAK3 inhibitor and reduce the dosage and possible toxic and side effects. The deuterated acrylamide compound of the JAK3 inhibitor shown in the following formula I has the following structure:

Description

Deuterated acrylamide JAK3 inhibitor medicine and application thereof
Technical Field
The application belongs to the field of biological medicine, and in particular relates to a deuterated acrylamide JAK3 inhibitor medicine and application thereof.
Background
AK/STAT (Janus protein tyrosine kinase/signal transducer and activator of transcription, janus protein tyrosine kinase/signal transducer and transcriptional activator) signaling pathway is an important cytokine signaling pathway discovered during the study of interferons by people in the 90 s of the 20 th century, and can accomplish signal transduction from cytoplasm into nucleus. The mammalian JAK family has four members, JAK1, JAK2, JAK3 and TYK2, respectively. The signaling pathway is associated with immunity, inflammation, cell proliferation, differentiation, survival, apoptosis, and the like. Autoimmune diseases are a large class of diseases caused by tissue injury due to immune response of an organism to autoantigens, and include Rheumatoid Arthritis (RA), psoriasis, alopecia areata and other diseases, and are characterized by unclear pathogenesis, fewer targets and lack of effective therapeutic drugs. JAK is a new target for treating autoimmune diseases, and 7 JAK small molecule inhibitors are currently marketed for treating different autoimmune diseases. However, with clinical application of JAK inhibitors, side effects such as opportunistic infections and anemia are gradually revealed. The reason for this is mainly the non-selective inhibition of different subtypes of JAK kinase. JAK kinase comprises four subtypes of JAK1, JAK2, JAK3 and Tyk2, and JAK-STAT signal pathway formed by the JAK-STAT signal pathway and downstream effector molecule STAT (signal transducers and activators of transcription) regulates inflammation and immune signals of more than 50 cytokines in vivo, so that the non-selective inhibition of JAK tends to influence physiological effects of the cytokines, thereby causing corresponding side effects. Therefore, the development of highly selective JAK inhibitors is currently a trend and direction of the development of such drugs. ritlecitinib is a novel oral targeted JAK3 inhibitor developed by pyroxene. Studies have shown that ritlecithinib blocks the activity of signaling molecules and immune cells, which are thought to be responsible for alopecia areata. Ritlecitinib is more advantageous in terms of reduced toxicity compared to the first generation of ubijak inhibitors.
The deuterated medicine not only replaces one or more carbon-hydrogen bonds of the medicine molecules with carbon-deuterium bonds, but also overcomes the defects of easy metabolism, large side effect and the like of the original medicine by improving the pharmacokinetics property of the original medicine.
The application is a deuterated acrylamide JAK3 inhibitor drug, which can further improve the pharmacokinetics property of the current JAK3 inhibitor drug ritlecitinib and reduce the administration dosage and possible toxic and side effects.
Disclosure of Invention
The application provides deuterated compounds of a deuterated acrylamide JAK3 inhibitor, namely ritlecitinib and pharmaceutically acceptable salts thereof, which can further improve the pharmacokinetic properties of the deuterated acrylamide compounds of the JAK3 inhibitor, namely ritlecitinib and pharmaceutically acceptable salts thereof, and reduce the administration dosage and possible toxic and side effects.
In order to achieve the above object, the present application provides a deuterated acrylamide compound of JAK3 inhibitor represented by the following formula i:
wherein R is 1 , R 2 , R 3 Independently selected from H or deuterium, and R 1 , R 2 , R 3 Not all hydrogen;
R 4 , R 5 , R 6 independently selected from H or deuterium, and R 4 , R 5 , R 6 Not all hydrogen;
R 7 deuterium, n=0, 1,2 or 3.
The deuterated acrylamide compound of the JAK3 inhibitor has the structure as follows:
deuterated acrylamide compounds of the JAK3 inhibitor and pharmaceutically acceptable salts thereof are selected from methanesulfonate, maleate, hydrochloride or phosphate.
The deuterated acrylamide compound and pharmaceutically acceptable salt thereof disclosed by the application comprise application of the deuterated acrylamide compound in preparation of antitumor drugs.
The deuterated acrylamide compound and the pharmaceutically acceptable salt thereof comprise the deuterated acrylamide compound and the pharmaceutically acceptable salt thereof as active ingredients and pharmaceutically acceptable carriers.
The deuterated acrylamide compound and the pharmaceutical composition of the pharmaceutically acceptable salt thereof are selected from capsules, powder, tablets, granules, pills, injection, syrup, oral liquid, inhalant, ointment, suppository or patch.
The beneficial effects are that: compared with the prior art, the application has the following advantages:
the application provides deuterated acrylamide JAK3 inhibitor medicaments, which remarkably improve the inhibiting activity on JAK3 enzyme, further improve the pharmacokinetic property of the JAK3 inhibitor and reduce the administration dosage and possible toxic and side effects.
Detailed Description
The following description of the technical solutions in the embodiments of the present application will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
Example 1: preparation of Compound 1
Synthesis method
Intermediate 1 (3 mmol) was dissolved in DMF (3 mL), sodium hydrogen (6 mmol) was added at 0deg.C and the reaction was continued for half an hour with stirring, SEM chloride (6 mmol) was added dropwise to the reaction solution and the reaction was continued overnight at room temperature. TLC detection was complete, water was added, extraction was performed with ethyl acetate, and the organic phase was collected and concentrated to afford intermediate 2.
Intermediate 2 (3 mmol) was dissolved in t-butanol (3 mmol), intermediate 3 (3 mmol) and DIPEA (8 mmol) were added, and the mixture was stirred at 80 ℃ for 16 hours. After concentration, intermediate 4 is obtained by column chromatography.
To a solution of intermediate 4 (0.5 mmol) in N, N-dimethylformamide (10 mL) was added potassium hydroxide (2 mmol,4 eq) and elemental iodine (1 mmol,2 eq), reacted for 3 hours at room temperature, monitored by TLC for completion of the reaction, quenched by addition of saturated sodium sulfite solution, extracted with ethyl acetate (10 ml x 2) in the aqueous phase, washed with water (20 ml x 2), dried over anhydrous sodium sulfate in saturated brine (20 mL) and concentrated column chromatography to afford intermediate 5.
Sodium acetate (1 mmol,2 eq) was added to deuterated acetic acid solution (8 mL) of intermediate 5 (0.5 mmol), the reaction was completed for 2 hours, the reaction was completed by TLC at room temperature for 24 hours, and the reaction was concentrated under reduced pressure to obtain intermediate 6 by column chromatography.
Intermediate 6 (1 mmol) was dissolved in 2mL of trifluoroacetic acid, stirred at room temperature for 4 hours, the organic phase was concentrated, 2mL of methanol was added, 1mL of ethylenediamine was further added, and the mixture was left to stir at room temperature overnight, after which the solvent was concentrated, column chromatography was performed to give intermediate 8.
Intermediate 8 (0.1 mmol) was dissolved in THF (1 mL), nitrogen blanketed, 0.1mL of triethylamine was added, deuterated acryloyl chloride (0.05 mmol) was slowly added at 0deg.C and the reaction stirred for 20min. The solvent was concentrated and column chromatographed to give example 1. 1 H NMR (500 MHz, Chloroform-d) δ 8.28 (s, 1H), 6.47 (s, 1H), 3.98 – 3.75 (m, 1H), 3.54 (dd, J = 10.8, 3.5 Hz, 1H), 3.36 – 3.24 (m, 1H), 3.20 (ddd, J = 11.8, 6.7, 5.0 Hz, 1H), 1.92 (dddd, J = 13.0, 6.6, 5.4, 4.0 Hz, 1H), 1.85 – 1.64 (m, 3H), 1.24 (d, J = 6.0 Hz, 3H).
Example 2: preparation of Compound 2
Synthetic route
Intermediate 4 (3 mmol) in example 1 was dissolved in dichloromethane (100 mL), sodium carbonate (11 mmol) and iodine chloride (6 mmol) were added and the reaction was stirred at room temperature for 20 hours. Adding saturated sodium thiosulfate solution for quenching, washing twice with saturated sodium bicarbonate, spin-drying the solvent, and performing column chromatography to obtain an intermediate 9.
Sodium acetate (1 mmol,2 eq) was added to deuterated acetic acid solution (8 mL) of intermediate 9 (0.5 mmol), and the reaction was completed for 2 hours, room temperature for 24 hours, TLC detection reaction was complete, and concentrated under reduced pressure, followed by column chromatography to obtain intermediate 10.
Example 2 can be prepared by substituting intermediate 6 for intermediate 10 by the synthetic method of example 1. 1 H NMR (500 MHz, Chloroform-d) δ 8.29 (s, 1H), 7.68 (d, J = 10.1 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 4.03 – 3.86 (m, 1H), 3.78 (dd, J = 10.8, 3.5 Hz, 1H), 3.70 (qdd, J = 7.4, 6.3, 4.1 Hz, 1H), 3.51 (dd, J = 10.9, 5.8 Hz, 1H), 2.01 – 1.84 (m, 1H), 1.84 – 1.69 (m, 2H), 1.69 – 1.50 (m, 1H), 1.15 (d, J = 7.3 Hz, 3H).
Example 3: preparation of Compound 3
Referring to the synthesis of intermediate 2, intermediate 1 can be replaced with intermediate 11.
Referring to the synthetic method of example 1, example 3 can be prepared by substituting intermediate 6 for intermediate 12. 1 H NMR (500 MHz, Chloroform-d) δ 8.91 (t, J = 2.1 Hz, 1H), 7.56 (d, J = 10.1 Hz, 1H), 7.19 (qd, J = 4.5, 2.2 Hz, 2H), 4.01 – 3.83 (m, 1H), 3.80 – 3.63 (m, 2H), 3.51 (dd, J = 10.9, 5.8 Hz, 1H), 1.98 – 1.84 (m, 1H), 1.84 – 1.67 (m, 2H), 1.67 – 1.46 (m, 1H), 1.15 (d, J = 7.3 Hz, 3H).
Example 4: preparation of Compound 4
Synthetic route
Intermediate 4 (3 mmol) was dissolved in dichloromethane (100 mL), sodium carbonate (11 mmol) and iodine chloride (6 mmol) were added and the reaction stirred at 40℃for 24 hours. Adding saturated sodium thiosulfate solution for quenching, washing twice with saturated sodium bicarbonate, spin-drying the solvent, and performing column chromatography to obtain an intermediate 13.
Sodium acetate (1 mmol,2 eq) was added to deuterated acetic acid solution (8 mL) of intermediate 13 (0.5 mmol), the reaction was completed for 2 hours, the reaction was completed by TLC at room temperature for 24 hours, and the reaction was concentrated under reduced pressure and subjected to column chromatography to obtain intermediate 10.
Example 4 can be prepared by substituting intermediate 6 for intermediate 14 by the synthetic method of example 1. 1 H NMR (500 MHz, Chloroform-d) δ 9.07 (s, 1H), 8.36 (s, 1H), 8.08 (d, J = 10.1 Hz, 1H), 4.00 – 3.87 (m, 1H), 3.78 (dd, J = 10.8, 3.5 Hz, 1H), 3.70 (qdd, J = 7.4, 6.3, 4.1 Hz, 1H), 3.51 (dd, J = 10.9, 5.8 Hz, 1H), 1.98 – 1.87 (m, 1H), 1.84 – 1.70 (m, 2H), 1.65 – 1.52 (m, 1H), 1.15 (d, J = 7.3 Hz, 3H).
Example 5: preparation of Compound 5
Synthetic route
Sodium acetate (1 mmol,2 eq) was added to deuterated acetic acid solution (8 mL) of intermediate 15 (0.5 mmol), the reaction was completed for 2 hours, the reaction was completed by TLC at room temperature for 24 hours, and the reaction was concentrated under reduced pressure to obtain intermediate 16 by column chromatography.
Example 5 can be prepared by substituting intermediate 6 for intermediate 14 by the synthetic method of example 1. 1 H NMR (500 MHz, Chloroform-d) δ 8.87 (s, 1H), 7.61 (d, J = 10.2 Hz, 1H), 4.05 – 3.87 (m, 1H), 3.78 (dd, J = 11.0, 3.5 Hz, 1H), 3.70 (qdd, J = 7.4, 6.3, 4.1 Hz, 1H), 3.51 (dd, J = 10.9, 5.8 Hz, 1H), 1.97 – 1.85 (m, 1H), 1.82 – 1.69 (m, 2H), 1.66 – 1.52 (m, 1H), 1.15 (d, J = 7.3 Hz, 3H).
Example 6: preparation of Compound 6
Intermediate 20 can be obtained by referring to the synthetic route of the 001-4 compound in WO2022002210 using intermediate 17 as a starting material.
Referring to the synthetic procedure of example 1, example 6 can be prepared by substituting intermediate 3 for intermediate 20. 1 H NMR (500 MHz, Chloroform-d) δ 8.31 – 8.12 (m, 2H), 7.92 (s, 1H), 7.36 (s, 1H), 4.01 – 3.83 (m, 1H), 3.72 – 3.58 (m, 2H), 3.52 (dd, J = 10.9, 5.8 Hz, 1H), 2.05 – 1.90 (m, 1H), 1.90 – 1.82 (m, 1H), 1.82 – 1.67 (m, 2H).
Example 7: preparation of Compound 7
Referring to the synthetic procedure of example 4, example 7 can be prepared by substituting intermediate 3 for intermediate 20. 1 H NMR (500 MHz, Chloroform-d) δ 9.07 (s, 1H), 8.31 (s, 1H), 8.08 (d, J = 10.1 Hz, 1H), 4.03 – 3.83 (m, 1H), 3.73 – 3.56 (m, 2H), 3.52 (dd, J = 10.9, 5.8 Hz, 1H), 2.02 – 1.92 (m, 1H), 1.92 – 1.85 (m, 1H), 1.84 – 1.73 (m, 2H).
Example 8: preparation of Compound 8
Referring to the synthetic procedure of example 5, example 8 can be prepared by substituting intermediate 3 for intermediate 20. 1 H NMR (500 MHz, Chloroform-d) δ 8.88 (s, 1H), 7.59 (d, J = 10.3 Hz, 1H), 4.06 – 3.81 (m, 1H), 3.69 – 3.56 (m, 2H), 3.52 (dd, J = 10.9, 5.8 Hz, 1H), 2.02 – 1.93 (m, 1H), 1.92 – 1.83 (m, 1H), 1.83 – 1.73 (m, 2H).
Example 9: preparation of Compound 9
Referring to the synthetic procedure of example 3, example 9 can be prepared by substituting intermediate 3 for intermediate 20. 1 H NMR (500 MHz, Chloroform-d) δ 8.91 (t, J = 2.2 Hz, 1H), 7.56 (d, J = 10.0 Hz, 1H), 7.38 (dd, J = 4.4, 2.2 Hz, 1H), 7.19 (dd, J = 4.5, 2.1 Hz, 1H), 4.06 – 3.88 (m, 1H), 3.72 – 3.59 (m, 2H), 3.52 (dd, J = 10.9, 5.8 Hz, 1H), 1.96 (dddd, J = 12.1, 8.3, 6.1, 3.7 Hz, 1H), 1.88 (dddd, J = 13.7, 8.0, 6.1, 4.1 Hz, 1H), 1.84 – 1.71 (m, 2H).
Example 10: preparation of Compound 10
Referring to the synthetic procedure of example 2, example 10 can be prepared by substituting intermediate 3 for intermediate 20. 1 H NMR (500 MHz, Chloroform-d) δ 8.25 (s, 1H), 7.68 (d, J = 10.1 Hz, 1H), 7.28 (d, J = 2.5 Hz, 1H), 4.06 – 3.84 (m, 1H), 3.70 – 3.56 (m, 2H), 3.52 (dd, J = 10.9, 5.8 Hz, 1H), 1.96 (dddd, J = 12.1, 8.3, 6.1, 3.7 Hz, 1H), 1.92 – 1.83 (m, 1H), 1.83 – 1.71 (m, 2H).
Test example 1: JAK3 enzyme Activity assay
The compounds tested included: inventive compounds of examples 1-10, comparative example 1: compounds of patent WO2022/002210A1Compound of comparative example 2: the compounds of comparative example 1 and comparative example 2 were both self-made by ritlecitinib (Li Texi tinib).
The test article was dissolved in Dimethylsulfoxide (DMSO) to a stock concentration of 30 mM. The test compound plates at a maximum concentration of 600 μm also contained positive control wells containing known inhibitors to define 100% inhibition and DMSO to define negative control wells without inhibition, giving 11-point semi-logarithmic serial dilutions in DMSO. Compound plate was subjected to 1: the 60 dilutions were such that the highest concentration of the final assay compound was 10 μm and the DMSO concentration was 2%. The test article and assay control are added to 384 well plates. The reaction mixture contained 20mM HEPES (pH=7.4), 10mM magnesium chloride, 0.01% Bovine Serum Albumin (BSA), 0.0005% Tween 20, 4. Mu.M or 1mM ATP.
JAK3 assay containing l μm JAKtide the assay was started by adding 1nm JAK3 enzyme and incubating for 75 minutes at room temperature for JAK3. The enzyme concentration and incubation time of each new enzyme preparation were optimized and slightly modified over time to ensure 20% -30% phosphorylation, with final concentrations of 10mM edta,0.1% coating agent and 100mM HEPES (ph=7.4) to stop the assay. Assay plates were placed on a Caliper Life Science Lab Chip 3000 (LC 3000) instrument and wells were sampled using appropriate separation conditions to measure non-phosphorylated and phosphorylated peptides.
IC 50 Analysis: inhibition ratio=1- (experimental well read-negative control well read)/(positive control well read-negative control well read), and the corresponding IC can be calculated by inputting the drug concentration and the corresponding inhibition ratio into GraphPad Prism 5 treatment 50 . Table 1 represents the inhibitory activity of the compounds of the present application against JAK3 kinaseData.
Table 1: enzymatic data for JAK3 inhibition by the inventive example compounds
Numbering of compounds IC 50 (nM)
Example 1 0.2
Example 2 0.7
Example 3 0.9
Example 4 0.8
Example 5 0.3
Example 6 0.5
Example 7 0.2
Example 8 0.5
Example 9 0.7
Example 10 0.3
Compound of comparative example 1 (WO 2022/002210A 1) 1.3
Compound of comparative example 2 (ritlecitinib) 1.5
The above results indicate that the compounds of the present application have excellent inhibitory effects on JAK3 and are better than the compounds of comparative example 1 and comparative example 2.
Test example 2: pharmacokinetic experiments of Compounds
Experimental apparatus and materials
The high-speed refrigerated centrifuge, vortex shaker (Vortex Genius 3), high-speed centrifuge (Eppendorf 5415D), disposable syringe, pipette (Eppendorf), SD male rats used in the experiments were all purchased from university of dulcimer, EDTA-K2 vacuum blood collection tube, physiological saline. All oral rats were fasted for 12 hours prior to dosing, were free to drink water, and were fed freely during dosing.
(II) Experimental procedure
The compound of example 1, the compound of comparative example 1 (WO 2022/002210A 1) and the compound of comparative example 2 (ritlecitinib) were dissolved using DMSO/solutol/water (10/10/80) to give clear solutions, the dose of the compound administered intranasally was 25 mg/kg and the dose of the compound administered to the tail vein was 5 mg/kg. Blood was continuously drawn from the fundus venous plexus 0.5 mL into heparin tubes 2 min, 10 min, 30 min, 1 h, 2h, 3 h, 5 h, 8 h, 12h, 16 h, 24 h, 5 min, 15 min, 30 min, 1 h, 2h, 3 h, 5 h, 8 h, 12h, 16 h, 24 h after intranasal administration, and 0.5 mL heparin tubes from the fundus venous plexus. After centrifugation of the sample at 8000 r for 10 min at 4℃the upper plasma layer was taken and stored at-20℃for 0.15. 0.15 mL, after which LC-MS/MS analysis was performed. The data were analyzed by the WinNolin non-compartmental model to obtain key pharmacokinetic parameters.
(III) results of experiments
TABLE 2 pharmacokinetic parameters
The data in Table 2 shows that the increased half-life and peak concentration of the compound of example 1 of the present application administered orally, relative to the compound of ritlecithinib and comparative example 1 (WO 2022/002210A 1), is significantly effective in improving the dosage administered, thereby reducing the toxic side effects of high dosage administration.
It will be apparent to those skilled in the art that the present disclosure is not limited to the foregoing illustrative embodiments, but may be embodied in other specific forms without departing from the essential attributes thereof. It is therefore intended that all aspects be regarded as illustrative rather than restrictive, reference being made to the appended claims rather than to the foregoing embodiments, the references cited are intended to be embraced therein by the appended claims rather than the foregoing examples, and that all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
All patents, patent applications, and literature references cited in this specification are hereby incorporated by reference in their entirety. In the event of inconsistencies, the present disclosure, including the definitions, will be convincing.

Claims (5)

1. A deuterated acrylamide compound and pharmaceutically acceptable salts thereof, wherein the compound is represented by any one of the following structural formulas:
。
2. deuterated acrylamide compound according to claim 1 and pharmaceutically acceptable salts thereof, characterized in that the pharmaceutically acceptable salts are selected from methanesulfonate, maleate, hydrochloride or phosphate.
3. Use of deuterated acrylamides and pharmaceutically acceptable salts thereof according to claim 1 in the preparation of antitumor drugs.
4. The pharmaceutical composition of deuterated acrylamide compounds and pharmaceutically acceptable salts thereof according to claim 1, wherein the pharmaceutical composition consists of the deuterated acrylamide compounds and pharmaceutically acceptable salts thereof as an active ingredient and a pharmaceutically acceptable carrier.
5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is selected from the group consisting of capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories, and patches.
CN202310745179.2A 2023-06-25 2023-06-25 Deuterated acrylamide JAK3 inhibitor medicine and application thereof Active CN116496280B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106061973A (en) * 2013-12-05 2016-10-26 辉瑞公司 Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides
WO2022002210A1 (en) * 2020-07-02 2022-01-06 南京明德新药研发有限公司 Pyrimidopyrrolyl deuterated compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106061973A (en) * 2013-12-05 2016-10-26 辉瑞公司 Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides
WO2022002210A1 (en) * 2020-07-02 2022-01-06 南京明德新药研发有限公司 Pyrimidopyrrolyl deuterated compounds

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氘代作用在药物研究中的应用;江文峰等;《齐鲁药事》;第29卷(第11期);第682页右栏第5-12行 *

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