Pyridazin-3-carboxamide compound as TYK2 inhibitor

Abstract

The present invention provides a pyridazin-3-carboxamide compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, raceme, solvate, hydrate, polymorphic form, prodrug, or isotopic variant thereof. The present invention further provides a pharmaceutical composition comprising the compound, a preparation method for the pharmaceutical composition, and a use of the pharmaceutical composition in treatment or prevention of TYK2 kinase-mediated diseases.

Description

It can be seen from the experimental data that the compound of the present invention had a good binding effect on TYK2 JH2 pseudokinase. Test Example B: Determination of the effects of the compound of the present invention on IL-2-induced STAT5 phosphorylation (JAK1 / 3) in CD3+ cell subpopulations in human PBMC Purpose: The purpose of this test example was to test the inhibitory effect of the compound on IL-2-induced STAT5 phosphorylation using protein phosphorylation flow cytometric analysis technology. Experimental method: Human PBMC cells were pre-incubated with the compounds, STAT5 was induced to phosphorylate under appropriate stimulation conditions, and corresponding cell subpopulations and targets were stained. Flow cytometry was used to read cell data and analyze the strength of phosphorylated antibody signals under different compound concentrations. PBMCs were resuspended and dispensed into a 96-well plate, 62.5 uL well. 3.5 uL of 20X compound working solutions were added and incubated at 37°C for 30 minutes. 5 uL of PE Mouse Anti-Human CD3 (BD) was added and incubated at 37°C in the dark for 30 minutes. 4 uL of 20X IL-2 (R&D) was added to each well and incubated at 37°C in the dark for 20 minutes. All cells in the 96-well plate were transferred to a deep-well plate, 400 uL of a fixation working solution (Biolegend) was added to each well, and incubated at room temperature in the dark for 20 minutes. The cells were washed twice with PBS, and 400 uL of Perm Buffer III (BD) was added and incubated at 4°C in the dark for 40 minutes. The cells were washed twice with PBS, and 100 uL of a STAT5 pY694 antibody working solution (BD) was added and incubated at room temperature for 40 minutes. After washing once with PBS, the cells were resuspended in 200 uL of a staining buffer and transferred to a sample plate. The antibody fluorescence intensity was analyzed using FlowJo software, and the IC50 of the compound was calculated using XL-Fit software. 2023283530   06 Oct 2026 Experimental results: Compound number IL-2-induced CD3+ pSTAT5 (JAK1 / 3) in hPBMC (IC50, gM) Compound 7 >30 Compound 9 >30 Compound 17 >30 BMS-986165 0.409 It can be seen from the experimental data results that the compound of the present invention had lower inhibitory activity on the JAK1 / 3 signaling pathway and had better selectivity. Test Example C: Pharmacokinetic evaluation of the compound of the present invention by intravenous injection or oral gavage in mice Purpose: The purpose of this test example was to evaluate the pharmacokinetic properties of the compound of the present invention. The inventors evaluated the pharmacokinetic properties of the compound of the present invention in mice. Animal information is shown in Table 1. Table 1: Information table of the test animals of the present invention Germline Grade Sex Weight Age Source ICR mice SPF Male 26-32 g 6-8 weeks Shanghai Xipuer-Bikai Experimental Animal Co., Ltd. Experimental method: The compound of the present invention was administered to the test animals in the form of 5% DMA + 5% Solutol + 90% saline or 5% ethanol + 5% TPGS + 90% PEG300 solvent. The animals were fasted for 12 hours before administration and had free access to water. For the intravenous administration group, the dose was 1 mg / kg. The drug was administered by intragastric administration at a dose of 10 mg / kg. After the drug administration, blood was intravenously drawn from the animals at the following time points (blood volume was approximately 0.3 mL): 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 and 24 h. EDTA-K2 was pre-added to blood collection tubes as 2023283530   06 Oct 2026 an anticoagulant, and the blood samples were centrifuged at 6800 g for 6 min to collect plasma, which was then stored at -80°C. Sample preparation for LC-MS / MS assay: 15 uL of plasma samples was used for protein precipitation with 300 uL of methanol containing 100 ng / mL IS (IS was tolbutamide). The mixture was vortexed for 1 min and then centrifuged at 18000 g for 10 min. 300 uL of the supernatant was transferred to a 96-well plate. 2 uL of the supernatant was subjected to LC-MS / MS analysis. The analysis results showed that the compound of the present invention had good pharmacokinetic properties in mice. Group Intravenous administration group Intragastric administration group Tested substance Dose (mg / kg) Tmax (h) Cmax (ng / mL) AUClast (h * ng / mL) T1 / 2 (h) Cl (mL / min / kg) Vz (L / kg) F (%) Compound 7 1 0.08 3622 2700 1.51 6.13 0.81 \ Compound 9 1 0.08 3731 2778 4.30 6.09 1.80 \ Compound 17 1 0.08 3398 1855 3.61 9.13 2.77 \ Compound 7 10 0.83 3460 7854 3.75 \ \ 29.09 Compound 9 10 0.67 9217 20135 4.64 \ \ 72.48 Compound 17 10 0.67 5636 17469 5.03 \ \ 94.13

Claims

1. A compound represented by general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof:whereinX is CR’ or N;Y is CR’;R1 is selected from the group consisting of a C1-6 alkyl, a C2-6 alkenyl, a C2-6 alkynyl, a C3-7 cycloalkyl, a 3- to 7-membered heterocyclyl, a C6-10 aryl and a 5- to 10-membered heteroaryl, and the group is optionally substituted with one or more deuteriums until fully deuterated;R2 is selected from the group consisting of a C1-6 alkyl, a C1-6 haloalkyl, a C2-6 alkenyl, a C2-6 alkynyl, a C3-7 cycloalkyl, a 3- to 7-membered heterocyclyl, a C6-10 aryl and a 5- to 10-membered heteroaryl, and the group is optionally substituted with one or more deuteriums until fully deuterated;R3 is selected from the group consisting of an -L-C1-6 alkyl, an -L-C1-6 haloalkyl, an -L-C3-7 cycloalkyl, an -L-3- to 7-membered heterocyclyl, an -L-C6-10 aryl and an -L-5- to 10-membered heteroaryl, and the group is optionally substituted with one or more deuteriums until fully deuterated;R4 is selected from the group consisting of H, a C1-6 alkyl and a C1-6 haloalkyl, and the group is optionally substituted with one or more deuteriums until fully deuterated;each group of R1, R2, R3 and R4 is optionally substituted with 1, 2, 3 or 4 R;2023283530   06 Oct 2026wherein L is selected from the group consisting of a bond, -C(O)- and -C(S)-;R is selected from the group consisting of D, a halogen, CN, a C1-6 alkyl and a C1-6 haloalkyl; andR’ is selected from the group consisting of H, D, a halogen and CN,provided that the compound is not                 H v .

2. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof according to claim 1, whereinX is CR’ or N;Y is CR’;R1 is selected from the group consisting of a C1-6 alkyl, a C3-7 cycloalkyl and a 3- to 7-membered heterocyclyl, and the group is optionally substituted with one or more deuteriums until fully deuterated;R2 is selected from the group consisting of a C1-6 alkyl, a C1-6 haloalkyl, a C3-7 cycloalkyl and a 3- to 7-membered heterocyclyl, and the group is optionally substituted with one or more deuteriums until fully deuterated;R3 is selected from the group consisting of an -L-C3-7 cycloalkyl, an -L-3- to 7-membered heterocyclyl, a C6-10 aryl and a 5- to 6-membered heteroaryl, and the group is optionally substituted with one or more deuteriums until fully deuterated;R4 is selected from the group consisting of H, a C1-6 alkyl and a C1-6 haloalkyl, and the group is optionally substituted with one or more deuteriums until fully deuterated;each group of R1, R2, R3 and R4 is optionally substituted with 1, 2, 3 or 4 R;wherein L is selected from the group consisting of -C(O)- and -C(S)-;2023283530   06 Oct 2026R is selected from the group consisting of D, a halogen and CN; andR’ is selected from the group consisting of H, D, a halogen and CN.

3. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof according to claim 1 or 2, wherein X is CR’, preferably CH.

4. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof according to any one of claims 1 to 3, wherein Y is CH or CF.

5. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof according to any one of claims 1 to 4, wherein R1 is selected from the group consisting of a C1-6 alkyl, a C2-6 alkenyl, a C2-6 alkynyl, a C3-7 cycloalkyl and a 3- to 7-membered heterocyclyl, and the group is optionally substituted with one or more deuteriums until fully deuterated; preferably, R1 is selected from the group consisting of a C1-6 alkyl and a C3-7 cycloalkyl, and the group is optionally substituted by one or more deuteriums until fully deuterated; preferably, R1 is a C1-6 alkyl, which is optionally substituted by one or more deuteriums until fully deuterated; and preferably, R1 is a C3-7 cycloalkyl.

6. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof according to any one of claims 1 to 5, wherein R2 is selected from the group consisting of a C1-6 alkyl, a C1-6 haloalkyl, a C2-6 alkenyl, a C2-6 alkynyl, a C3-7 cycloalkyl and a 3- to 7-membered heterocyclyl, and the group is optionally substituted with one or more deuteriums until fully deuterated; preferably, R2 is selected from the group consisting of a C1-6 alkyl, a C1-6 haloalkyl and a C3-7 cycloalkyl, and the group is optionally substituted with one or more deuteriums until fully deuterated; and preferably, R2 is a C1-6 alkyl, which is optionally substituted by one or more deuteriums until fully deuterated.

7. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof according to any one of claims 1 to 6, wherein R3 is selected from the group consisting of a -C(O)-C3-7 cycloalkyl and a 5- to 6-2023283530   06 Oct 2026membered heteroaryl, and the group is optionally substituted with one or more deuteriums until fully deuterated; and preferably, R3 is a -C(O)-C3-7 cycloalkyl.

8. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof according to any one of claims 1 to 7, wherein R4 is selected from the group consisting of a C1-6 alkyl and a C1-6 haloalkyl, and the group is optionally substituted with one or more deuteriums until fully deuterated; and preferably, R4 is a C1-6 alkyl, which is optionally substituted by one or more deuteriums until fully deuterated.

9. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate,solvate, hydrate, polymorph, prodrug or isotopic variant thereof according to any one of claims 1to 8, which has the following general formula:(II),(III), or(IV),wherein each group is as defined in any one of claims 1 to 8.

10. The compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof according to claim 1, wherein the compound is selected from the group consisting of:2023283530   06 Oct 20262023283530   06 Oct 2026and11. A pharmaceutical composition comprising the compound, or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof according to any one of claims 1 to 10, and a mixture thereof, and apharmaceutically acceptable excipient.

12. A pharmaceutical composition as claimed in claim 11, wherein the pharmaceutical composition further comprises other therapeutic agents.

13. A use of the compound or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof according to any one of claims 1 to 10, and a mixture thereof in the preparation of a medicament for treating and / or2023283530   06 Oct 2026preventing a TYK2 kinase-mediated disease.

14. A use of the compound or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof according to any one of claims 1 to 10, and a mixture thereof, or the pharmaceutical composition according to claim 11 or 12 in the treatment and / or prevention of a TYK2 kinase-mediated disease.

15. A method for treating and / or preventing a TYK2 kinase-mediated disease in a subject, comprising administering to the subject the compound or the pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof according to any one of claims 1 to 10, and a mixture thereof, or the pharmaceutical composition according to claim 11 or 12.

16. The use according to claim 13 or the use of the compound or pharmaceutical composition according to claim 14 or the method according to claim 15, wherein the TYK2 kinase-mediated disease is selected from the group consisting of an autoimmune disease, a skin disease, an allergic disease, organ rejection, cancer, dry eye disease, myelofibrosis and polycythemia vera.

17. The use or method of claim 16, wherein the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease or autoimmune thyroid disease; the skin disease is psoriasis, a rash or atopic dermatitis; the allergic disease is asthma or rhinitis; the organ transplant rejection is allograft rejection or graft-versus-host disease; and the cancer is renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, prostate cancer, head and neck cancer, thyroid cancer, lung cancer, glioblastoma, melanoma, lymphoma or leukemia.

18. The use according to claim 13 or the use of the compound or pharmaceutical composition according to claim 14 or the method according to claim 15, wherein the TYK2 kinase-mediated disease is selected from rheumatoid arthritis, psoriasis, ulcerative colitis and Crohn's disease.