Amide-disubstituted pyridine or pyridazine derivative, and pharmaceutical composition and use thereof

Abstract

Provided in the present disclosure is a compound represented by formula I, or a racemate, stereoisomer, tautomer, isotopically labeled compound, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug thereof. The compound of the present disclosure exhibits excellent dual-target inhibitory activity against PDE5 and TYK2, which facilitates the development of multispecific targeted drugs for different patient populations, and thus is particularly beneficial for improving the therapeutic effect and / or reducing side effects, and enhancing patient compliance and quality of life.

Description

Amide disubstituted pyridine or pyridazine derivatives, their pharmaceutical compositions and uses

[0001] This application claims priority to the prior art of the applicant's earlier patent application filed on March 26, 2025 with the China National Intellectual Property Administration, application number 202510367778.4, entitled "Amide Disubstituted Pyridine or Pyridazine Derivatives and Pharmaceutical Compositions and Uses Thereof Thereof", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure relates to amide-disubstituted pyridine or pyridazine derivatives, pharmaceutical compositions thereof, and uses, and belongs to the field of chemical pharmaceuticals. Background Technology

[0003] The development of PDE5 (phosphodiesterase 5) inhibitors began in the 1980s, initially with the goal of treating cardiovascular diseases, particularly angina. PDE5 inhibitors work by inhibiting the PDE5 enzyme, preventing the breakdown of cGMP, thereby enhancing the NO-cGMP signaling pathway. Although PDE5 inhibitors have achieved significant success in treating erectile dysfunction (ED) and pulmonary hypertension (PAH), some limitations and side effects remain. These include the need for improved activity, ineffectiveness in some patients, and side effects such as headache, indigestion, nasal congestion, and visual disturbances.

[0004] Tyrosine kinase 2 (TYK2) is an intracellular kinase belonging to the JAK kinase family. It regulates immune responses by inhibiting the TYK2 enzyme, blocking the JAK-STAT signaling pathway. The development of TYK2 inhibitors began with in-depth research into the role of the JAK-STAT pathway in immune regulation. The world's first TYK2 inhibitor was Deucravacitinib (trade name: Sotyktu) from BMS, which was approved by the US FDA in September 2022 for the treatment of moderate to severe plaque psoriasis in adults and was approved for marketing in China in November 2023. Currently, TYK2 inhibitors have shown significant efficacy in treating psoriasis, and there are reports indicating potential efficacy in Crohn's disease and ulcerative colitis, as well as potential in the treatment of systemic lupus erythematosus. Common side effects of TYK2 inhibitors include upper respiratory tract infections, headache, diarrhea, and nausea.

[0005] There are currently no reports of research and development on dual-target inhibitors of PDE5 and TYK2. Summary of the Invention

[0006] To address the aforementioned technical problems, this disclosure provides compounds of Formula I, their racemates, stereoisomers, tautomers, isotope labels, solvates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0007] in:

[0008] W represents N or CH;

[0009] m represents 0, 1, 2, 3, 4 or 5;

[0010] n represents 0, 1, 2, 3, 4, or 5;

[0011] p represents 0, 1, 2, 3, 4 or 5;

[0012] q represents 0, 1, 2, 3, 4, or 5;

[0013] X1 represents chemical bonds, -NH-C(=O)-, -C(=O)-NH-, -NH-C(=O)-NH-, -NH-C(=O)-O-, -O-, -S-, -NR q -, -S(=O)-, -S(=O)2-, -C(=O-), and the following groups without substitution or with optional substitution: -C 1-6 Alkylene -C(=O)-NH-, -NH-C(=O)-C 1-6 Alkylene-, -NH-C(=O)-C 3-20 Cycloalkyl-,-C(=O)-NH-C 1-6 Alkylene-, -NH-C 1- 6-alkylene-C(=O)-, -C 1-6 alkylene-, -C 1-6 Alkyl-NH-, -NH-C 1-6 alkylene-, -C 1-6 Alkylene -O-, -C 2- 6-Ideenyl-, -C 2-6 -, -C ethynyl 1-6 alkeneoxy-; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 1-6 Alkyl-SO2-C 1-6 Alkyl, C 1-6 Alkyl-SO-C 1-6 Alkyl, C 2-10 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl;

[0014] X2 represents chemical bonds, -C(=O)-, -NH-C(=O)-, -C(=O)-NH-, -NH-C(=O)-NH-, -NH-C(=O)-O-, -O-, -S-, -NR q -、-S(=O)-、-S(=O)2- The following groups are unsubstituted or optionally substituted: -C 1-6 Alkylene -C(=O)-NH-, -C(=O)-NH-C 1-6 alkylene-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene -O-, -C 2-6 imidene-, -C 2-6 -, -C ethynyl 1-6 alkeneoxy-; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 1-6 Alkyl-SO2-C 1-6 Alkyl, C 1-6 Alkyl-SO-C 1-6 Alkyl, C 2-10 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl;

[0015] X3 represents chemical bonds, -O-, -S-, and -NR. q -, -S(=O)-, -S(=O)2-, -C(=O-), and the following groups without substitution or with optional substitution: -C 1-6 Alkylene -C(=O)-NH-, -C(=O)-NH-C 1-6 Alkylene-, -NH-C(=O)-, -NH-C(=O)-NH-, -NH-C(=O)-O-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene -O-, -C 2-6 imidene-, -C 2-6 -, -C ethynyl 1-6 alkeneoxy-; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C.1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 1-6 Alkyl-SO2-C 1-6 Alkyl, C 1-6 Alkyl-SO-C 1-6 Alkyl, C 2- 10 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl;

[0016] X4 represents chemical bonds, -O-, -S-, and -NR. q -, -S(=O)-, -S(=O)2-, -C(=O-), and the following groups without substitution or with optional substitution: -C 1-6 Alkylene -C(=O)-NH-, -C(=O)-NH-C 1-6 Alkylene-, -NH-C(=O)-, -NH-C(=O)-NH-, -NH-C(=O)-O-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene -O-, -C 2-6 imidene-, -C 2-6 -, -C ethynyl 1-6 alkeneoxy-; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 1-6 Alkyl-SO2-C 1-6 Alkyl, C 1-6 Alkyl-SO-C 1-6 Alkyl, C 2- 10 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl;

[0017] X5 represents chemical bonds, -O-, -S-, and -NR. q -, -S(=O)-, -S(=O)2-, -C(=O-), and the following groups without substitution or with optional substitution: -C 1-6 Alkylene -C(=O)-NH-, -C(=O)-NH-C1-6 Alkylene-, -NH-C(=O)-, -NH-C(=O)-NH-, -NH-C(=O)-O-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene -O-, -C 2-6 imidene-, -C 2-6 -, -C ethynyl 1-6 alkeneoxy-; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 1-6 Alkyl-SO2-C 1-6 Alkyl, C 1-6 Alkyl-SO-C 1-6 Alkyl, C 2- 10 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl;

[0018] R q Selected from H, C 1-20 Alkyl, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 aryl, 5-20 heteroaryl, wherein each group may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 and NR 1.2 R 1.3 ;

[0019] A represents a chemical bond, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 Cycloalkyl 5-20-membered heteroaryl, 3-20-membered heterocycloalkyl 3-C 6-20 aryl, 3-20 membered heterocyclic alkyl and 5-20 membered heteroaryl, 5-20 membered heterocyclic alkenyl and C 6-20 Aryl, 5-20 membered heterocyclic alkenyl and 5-20 membered heteroaryl, C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 cycloalkenyl 5-20 quinone heteroaryl groups;

[0020] B is a chemical bond, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 Cycloalkyl 5-20-membered heteroaryl, 3-20-membered heterocycloalkyl 3-C 6- 20 aryl, 3-20 membered heterocyclic alkyl and 5-20 membered heteroaryl, 5-20 membered heterocyclic alkenyl and C 6-20 Aryl, 5-20 membered heterocyclic alkenyl and 5-20 membered heteroaryl, C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 cycloalkenyl 5-20 quinone heteroaryl groups;

[0021] C is a chemical bond, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 Cycloalkyl 5-20-membered heteroaryl, 3-20-membered heterocycloalkyl 3-C 6- 20 aryl, 3-20 membered heterocyclic alkyl and 5-20 membered heteroaryl, 5-20 membered heterocyclic alkenyl and C 6-20 Aryl, 5-20 membered heterocyclic alkenyl and 5-20 membered heteroaryl, C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 cycloalkenyl 5-20 quinone heteroaryl groups;

[0022] D represents a chemical bond, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20Cycloalkyl 5-20-membered heteroaryl, 3-20-membered heterocycloalkyl 3-C 6- 20 aryl, 3-20 membered heterocyclic alkyl and 5-20 membered heteroaryl, 5-20 membered heterocyclic alkenyl and C 6-20 Aryl, 5-20 membered heterocyclic alkenyl and 5-20 membered heteroaryl, C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 cycloalkenyl 5-20 quinone heteroaryl groups;

[0023] R1 represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, and C. 1-6 Alkyl, C 2-10 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20-membered heteroaryl, C 1-6 Alkyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -OR 1.1 -COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1-10 Alkyl-COR 1.1 -COONR 1.1 -C 1-10 Alkyl-COONR 1.1 -CONOH, -C 1-10 Alkyl-CONOH, -CO-NR 1.1 -C 1-10 Alkyl-CO-NR 1.1 -CH=CHCOOR 1.1 -CO-NR 1.1 -CH2CO-NR 1.1-CH=CHCO-NR 1.1 -NR 1.2 R 1.3 -C 1-10 Alkyl-NR 1.2 R 1.3 -SR 1.1 -C 1-10 Alkyl-SR 1.1 -SOR 1.1 -C 1- 10 Alkyl-SOR 1.1 -SO2-R 1.1 -C 1-10 Alkyl-SO2R 1.1 -SO2-NR 1.2 R 1.3 or -C 1-10 Alkyl-SO2-NR 1.2 R 1.3 Each of the stated groups may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 NR 1.2 R 1.3 C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 2-10 alkenyl and C 2-10 alkynyl group;

[0024] R2 represents hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -NO2, and C. 1-6 Alkyl, C 2-10 alkenyl, C 3-20 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -OR 1.1 -COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1- 10 Alkyl-COR 1.1 -COONR 1.1 -C 1-10Alkyl-COONR 1.1 -CONOH, -C 1-10 Alkyl-CONOH, -CO-NR 1.1 -C 1-10 Alkyl-CO-NR 1.1 -CH=CHCOOR 1.1 -CO-NR 1.1 -CH2CO-NR 1.1 -CH=CHCO-NR 1.1 -NR 1.2 R 1.3 -C 1-10 Alkyl-NR 1.2 R 1.3 -SR 1.1 -C 1-10 Alkyl-SR 1.1 -SOR 1.1 -C 1-10 Alkyl-SOR 1.1 -SO2-R 1.1 -C 1-10 Alkyl-SO2R 1.1 -SO2-NR 1.2 R 1.3 or -C 1-10 Alkyl-SO2-NR 1.2 R 1.3 Each of the stated groups may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 NR 1.2 R 1.3 C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 2-10 alkenyl and C 2-10 alkynyl group;

[0025] R a Represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-10 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20-membered heteroaryl, C 1-6 Alkyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -OR 1.1 -COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1-10 Alkyl-COR 1.1 -COONR 1.1 -C 1-10 Alkyl-COONR 1.1 -CONOH, -C 1-10 Alkyl-CONOH, -CO-NR 1.1 -C 1-10 Alkyl-CO-NR 1.1 -CH=CHCOOR 1.1 -CO-NR 1.1 -CH2CO-NR 1.1 -CH=CHCO-NR 1.1 -NR 1.2 R 1.3 -C 1-10 Alkyl-NR 1.2 R 1.3 -SR 1.1 -C 1-10 Alkyl-SR 1.1 -SOR 1.1 -C 1- 10 Alkyl-SOR 1.1 -SO2-R 1.1 -C 1-10 Alkyl-SO2R 1.1 -SO2-NR 1.2 R 1.3 or -C 1-10 Alkyl-SO2-NR 1.2R 1.3 Each of the stated groups may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 NR 1.2 R 1.3 C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 2-10 alkenyl and C 2-10 alkynyl group;

[0026] Or, R2, R a Together with the atoms attached to it, it forms the following groups fused with ring A: C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 membered heteroaryl, which may be unsubstituted or optionally substituted with one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 2-10 alkenyl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20 heteroaryl, C 1-6 Alkyl-5-20 heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3- 20 Cycloalkyl-5-20 heteroaryl, C 3-20 Cycloalkyl-5-20 heteroaryl-, C 2-10 alkenyl, C 2-6 alkynyl group, OR 1.1 COOR 1.1 C 1-10 -COOR 1.1COR 1.1 C 1-10 -COR 1.1 COONR 1.1 C 1-10 -COONR 1.1 CONOH, C 1-10 -CONOH, CO-NR 1.1 C 1-10 -CO-NR 1.1 CH = CHCOOR 1.1 CO-NR 1.1 CH2CO-NR 1.1 CH=CHCO-NR 1.1 NR 1.2 R 1.3 C 1-10 -NR 1.2 R 1.3 SR 1.1 C 1-10 -SR 1.1 SOR 1.1 C 1-10 -SOR 1.1 SO2-R 1.1 C 1-10 -SO2R 1.1 or SO2-NR 1.2 R 1.3 Each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, OH, OR. 1.1 Halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- Aryl and NR 1.2 R 1.3 ;

[0027] R b Represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-10 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C1-6 Alkyl-5-20-membered heteroaryl, C 1-6 Alkyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -OR 1.1 -COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1-10 Alkyl-COR 1.1 -COONR 1.1 -C 1-10 Alkyl-COONR 1.1 -CONOH, -C 1-10 Alkyl-CONOH, -CO-NR 1.1 -C 1-10 Alkyl-CO-NR 1.1 -CH=CHCOOR 1.1 -CO-NR 1.1 -CH2CO-NR 1.1 -CH=CHCO-NR 1.1 -NR 1.2 R 1.3 -C 1-10 Alkyl-NR 1.2 R 1.3 -SR 1.1 -C 1-10 Alkyl-SR 1.1 -SOR 1.1 -C 1- 10 Alkyl-SOR 1.1 -SO2-R 1.1 -C 1-10 Alkyl-SO2R 1.1 -SO2-NR 1.2 R 1.3 or -C 1-10 Alkyl-SO2-NR 1.2 R 1.3Each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1- 6-alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 NR 1.2 R 1.3 C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 2-10 alkenyl and C 2-10 alkynyl group;

[0028] Or, R a R b Together with the atoms it is attached to, they form C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 membered heteroaryl, which may be unsubstituted or optionally substituted with one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1- 6-alkyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 2-10 alkenyl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20 heteroaryl, C 1-6 Alkyl-5-20 heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20 heteroaryl, C 3-20 Cycloalkyl-5-20 heteroaryl-, C 2-10 alkenyl, C 2-6 alkynyl group, OR 1.1 COOR 1.1 C 1-10 -COOR 1.1 COR 1.1 C1-10 -COR 1.1 COONR 1.1 C 1-10 -COONR 1.1 CONOH, C 1-10 -CONOH, CO-NR 1.1 C 1-10 -CO-NR 1.1 CH = CHCOOR 1.1 CO-NR 1.1 CH2CO-NR 1.1 CH=CHCO-NR 1.1 NR 1.2 R 1.3 C 1-10 -NR 1.2 R 1.3 SR 1.1 C 1-10 -SR 1.1 SOR 1.1 C 1-10 -SOR 1.1 SO2-R 1.1 C 1-10 -SO2R 1.1 or SO2-NR 1.2 R 1.3 Each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, OH, OR. 1.1 Halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- Aryl and NR 1.2 R 1.3 ;

[0029] R c Represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-10 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6Alkyl-5-20-membered heteroaryl, C 1-6 Alkyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -OR 1.1 -COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1-10 Alkyl-COR 1.1 -COONR 1.1 -C 1-10 Alkyl-COONR 1.1 -CONOH, -C 1-10 Alkyl-CONOH, -CO-NR 1.1 -C 1-10 Alkyl-CO-NR 1.1 -CH=CHCOOR 1.1 -CO-NR 1.1 -CH2CO-NR 1.1 -CH=CHCO-NR 1.1 -NR 1.2 R 1.3 -C 1-10 Alkyl-NR 1.2 R 1.3 -SR 1.1 -C 1-10 Alkyl-SR 1.1 -SOR 1.1 -C 1- 10 Alkyl-SOR 1.1 -SO2-R 1.1 -C 1-10 Alkyl-SO2R 1.1 -SO2-NR 1.2 R 1.3 or -C 1-10 Alkyl-SO2-NR 1.2 R 1.3Each of the stated groups may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 NR 1.2 R 1.3 C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 2-10 alkenyl and C 2-10 alkynyl group;

[0030] Or, R2, R c Together with the atoms attached to it, it forms the following groups fused with the ring C: C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 membered heteroaryl, which may be unsubstituted or optionally substituted with one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 2-10 alkenyl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20 heteroaryl, C 1-6 Alkyl-5-20 heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3- 20 Cycloalkyl-5-20 heteroaryl, C 3-20 Cycloalkyl-5-20 heteroaryl-, C 2-10 alkenyl, C 2-6 alkynyl group, OR 1.1 COOR 1.1 C 1-10 -COOR 1.1 COR1.1 C 1-10 -COR 1.1 COONR 1.1 C 1-10 -COONR 1.1 CONOH, C 1-10 -CONOH, CO-NR 1.1 C 1-10 -CO-NR 1.1 CH = CHCOOR 1.1 CO-NR 1.1 CH2CO-NR 1.1 CH=CHCO-NR 1.1 NR 1.2 R 1.3 C 1-10 -NR 1.2 R 1.3 SR 1.1 C 1-10 -SR 1.1 SOR 1.1 C 1-10 -SOR 1.1 SO2-R 1.1 C 1-10 -SO2R 1.1 or SO2-NR 1.2 R 1.3 Each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, OH, OR. 1.1 Halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- Aryl and NR 1.2 R 1.3 ;

[0031] R d Represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-10 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C1-6 Alkyl-5-20-membered heteroaryl, C 1-6 Alkyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -OR 1.1 -COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1-10 Alkyl-COR 1.1 -COONR 1.1 -C 1-10 Alkyl-COONR 1.1 -CONOH, -C 1-10 Alkyl-CONOH, -CO-NR 1.1 -C 1-10 Alkyl-CO-NR 1.1 -CH=CHCOOR 1.1 -CO-NR 1.1 -CH2CO-NR 1.1 -CH=CHCO-NR 1.1 -NR 1.2 R 1.3 -C 1-10 Alkyl-NR 1.2 R 1.3 -SR 1.1 -C 1-10 Alkyl-SR 1.1 -SOR 1.1 -C 1- 10 Alkyl-SOR 1.1 -SO2-R 1.1 -C 1-10 Alkyl-SO2R 1.1 -SO2-NR 1.2 R 1.3 or -C 1-10 Alkyl-SO2-NR 1.2 R 1.3Each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1- 6-alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 NR 1.2 R 1.3 C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 2-10 alkenyl and C 2-10 alkynyl group;

[0032] Or, R c With R d Together with the atoms it is attached to, they form C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 membered heteroaryl, which may be unsubstituted or optionally substituted with one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1- 6-alkyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 2-10 alkenyl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20 heteroaryl, C 1-6 Alkyl-5-20 heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20 heteroaryl, C 3-20 Cycloalkyl-5-20 heteroaryl-, C 2-10 alkenyl, C 2-6 alkynyl group, OR 1.1 COOR 1.1 C 1-10 -COOR 1.1 COR 1.1 C1-10 -COR 1.1 COONR 1.1 C 1-10 -COONR 1.1 CONOH, C 1-10 -CONOH, CO-NR 1.1 C 1-10 -CO-NR 1.1 CH = CHCOOR 1.1 CO-NR 1.1 CH2CO-NR 1.1 CH=CHCO-NR 1.1 NR 1.2 R 1.3 C 1-10 -NR 1.2 R 1.3 SR 1.1 C 1-10 -SR 1.1 SOR 1.1 C 1-10 -SOR 1.1 SO2-R 1.1 C 1-10 -SO2R 1.1 or SO2-NR 1.2 R 1.3 Each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, OH, OR. 1.1 Halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- Aryl and NR 1.2 R 1.3 ;

[0033] R e -YZ;

[0034] Y represents chemical bond, -O-, -S-, -NR q -, -S(=O)-, -S(=O)2-, -C(=O-), and the following groups without substitution or with optional substitution: -C 1-6 Alkylene -C(=O)-NH-, -C(=O)-NH-C 1-6 Alkylene-, -C(=O)-NH-, -C 1-6 alkylene-, -C 1- 6-alkylene-NH-,-C 1-6 Alkylene-O-, C2-6 imidene group, C 2-6 Ethyne group, C 1-6 Alkyloxy; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl;

[0035] Each Z is the same or different, and independently represents hydrogen, deuterium, and C. 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6- 20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, -3-20-membered heterocycloalkyl-C 6-20 Aryl, 3-20 membered heterocyclic alkyl-C 6-20 aryl-, -3-20-membered heterocyclic alkyl-5-20-membered heteroaryl, 3-20-membered heterocyclic alkyl-5-20-membered heteroaryl-, -5-20-membered heterocyclic alkenyl-C 6-20 Aryl, 5-20 membered heterocyclic alkenyl-C 6-20 aryl-, -5-20-membered heterocyclic alkenyl-C 5-20 heteroaryl, C 5-20 Heterocyclic alkenyl-C 5-20 heteroaryl-, -C 5-20 Cycloalkenyl-C 6-20 Aryl, C 5-20 Cycloalkenyl-C 6-20 Aryl-, -C 5-20 Cycloalkenyl-5-20 heteroaryl, C 5-20 cycloalkenyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 cycloalkyl 5-20-membered heteroaryl, C 3-20Cycloalkyl 5-20-membered heteroaryl-, -3-20-membered heterocycloalkyl 5-20-membered heteroaryl-, -3-20-membered heterocycloalkyl- 6- 20 Aryl, 3-20 membered heterocyclic alkyl benzo[C] 6-20 aryl-,-3-20-membered heterocyclic alkyl benzo-C 5-20 Heteroaryl, 3-20 membered heterocyclic alkyl phenocrysts 5- 20 Heteroaryl-, -5-20-membered heterocyclic alkenyl benzo[C] 6-20 aryl-, 5-20 membered heterocyclic alkenyl benzo[C] 6-20 aryl-, -5-20 quinone heterocyclic alkenyl 5-20 quinone heteroaryl, 5-20 quinone heterocyclic alkenyl 5-20 quinone heteroaryl-, -C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 cycloalkenyl-C 6-20 Aryl-, -C 5-20 Cycloalkenyl 5-20 quinone heteroaryl, C 5-20 cycloalkenyl 5-20-membered heteroaryl-, wherein each C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 The aryl group and the 5-20 membered heteroaryl group can be independently monocyclic or polycyclic; the above groups can be unsubstituted or arbitrarily substituted at the ortho, para, meta, or N, O, and S atoms, each of which may be independently and optionally substituted by one, two, or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-5-20-membered heteroaryl, C 3-20 cycloalkyl-C 6-20 Aryl, C 3- 20 cycloalkyl-5-20-membered heteroaryl, OR 1.1 COOR 1.1 C 1-10 Alkyl-COOR 1.1 COR 1.1 C 1-10 Alkyl-COR 1.1COONR 1.1 C 1-10 Alkyl-COONR 1.1 CONOH, C 1-10 Alkyl-CONOH, CO-NR 1.1 C 1-10 Alkyl-CO-NR 1.1 CH = CHCOOR 1.1 CO-NR 1.1 CH2CO-NR 1.1 CH=CHCO-NR 1.1 NR 1.2 R 1.3 C 1-10 Alkyl-NR 1.2 R 1.3 SR 1.1 C 1-10 Alkyl-SR 1.1 SOR 1.1 C 1-10 Alkyl-SOR 1.1 SO2-R 1.1 C 1-10 Alkyl-SO2R 1.1 or SO2-NR 1.2 R 1.3 And each of the substituents may be unsubstituted or optionally further substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, OH, OR 1.1 Halogenated, oxo-substituted, thio-substituted, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- Aryl and NR 1.2 R 1.3 ;

[0036] Each R 1.1 Is it H or selected from C? 1-6- Alkyl, C 3-20 -cycloalkyl, C 5-20 -cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, -C 6-20- Aryl-C 1-6 -alkyl, -C 1-6 -alkyl-C 6-20- Aryl, -5-20 heteroaryl-C 1-6 -alkyl, 5-20-membered heteroaryl-C 1-6 -alkyl-, -3-20 membered heterocyclic-C 1-6 -alkyl, 3-20 membered heterocyclic -C 1-6-alkyl-, -C 3-10 -cycloalkyl-C 1-6 -alkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl-, monocyclic or bicyclic C 6-20 -aryl, 5-20 membered heteroaryl and 5-20 membered heterocyclic groups, and each group may be unsubstituted or optionally substituted with substituents selected from the following: halogen, deuterium, OH, CN, NO2, NH2, oxo (=O), thio (=S), CF3, CHF2, CH2F, O-(C 1-3 -alkyl), C 1-10- Alkyl and C 6-20- Aryl;

[0037] Each R 1.2 and R 1.3 Same or different, representing H or selected from C independently. 1-6- Alkyl, monocyclic or bicyclic C 3-10- Cycloalkyl, monocyclic or bicyclic C 6-20- Aryl-C 1-6 -alkyl, monocyclic or bicyclic 5-20 membered heteroaryl-C 1-6- Alkyl, monocyclic or bicyclic C 6-20- Aryl, monocyclic or bicyclic 3-20 membered heterocyclic rings, monocyclic or bicyclic 5-20 membered heteroaromatic rings, -CO-NH2, -CO-NH-CH3, -CO-N(CH3)2, -SO2-(C 1-6 -alkyl), -SO2-(C 3-10 -cycloalkyl), -SO2-(3-10 membered heterocycloalkyl), -SO2-(C 5-10 -cycloalkenyl), -SO2-(5-20 membered heterocyclic alkenyl), -CO-R 1.1 and -COOR 1.1 The group, and each group may be unsubstituted or optionally substituted with one, two or more substituents selected from the following: deuterium, OH, halogen, C 1-6 -alkyl, C 6-20- Aryl and COOR 1.1 ;

[0038] Or, R 1.2 and R 1.3 Together with the atoms attached thereto, it forms a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged heterocycle containing 1, 2, 3 or 4 independent heteroatoms selected from N, S or O, wherein the heterocycle is unsubstituted or optionally substituted at the ortho, para or meta position by one, two or more substituents selected from: deuterium, halogen, OH, oxo, thio, monohalogenated or polyhalogenated C 1-6Alkyl groups (such as CF3, CHF2, CH2F), OR 1.1 -C 1- 3-alkyl-OR 1.1 SR 1.1 -C 1-3 -alkyl-SR 1.1 ,-SO-R 1.1 ,-C 1-3 -alkyl-SOR 1.1 ,-SO2-R 1.1 ,-C 1-3 -alkyl-SO2R 1.1 ,-COOR 1.1 ,-CH2COOR 1.1 ,-CH2CH2COOR 1.1 ,-CH=CHCOOR 1.1 ,-CO-NR 1.1,- CH2CO-NR 1.1 ,-CH2CH2CO-NR 1.1 ,-CH=CHCO-NR 1.1 ,-COR 1.1 ,-CH2COR 1.1 ,-C 1-6 -alkyl alcohols, monocyclic or bicyclic C 3-10 -cycloalkyl, C 6-20- Aryl, C 1-6 -alkyl, C 6-20- Aryl-C 1-6 -alkyl, 5-20-membered heteroaryl-C 1-6 Alkyl, C 1-3 -alkyl-(monocyclic or polycyclic-C) 6-20- Aryl), 3-20 membered heterocyclic group -C 6-20- Aryl, 3-20 membered heterocyclic, 5-20 membered heteroaryl C 1-3 -alkyl-OR 1.1 NR 1.2 R 1.3 C 6-20- Aryl and NR 1.2 R 1.3 .

[0039] According to embodiments of the present invention, the heterocyclic group is a 3-11 member saturated or partially saturated monocyclic or bicyclic ring comprising 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O. The bicyclic ring can be any fused ring or bridged ring, but it does not possess aromaticity. The heterocyclic group can be a heterocyclic alkyl, heterocyclic alkenyl, or heterocyclic alkynyl group. For example, a heterocyclic alkyl group represents a 3-11 member saturated monocyclic or bicyclic ring comprising 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O. The bicyclic ring can be any fused ring or bridged ring; the heterocyclic alkenyl group represents a 3-11 member monocyclic or bicyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, and containing 1, 2 or more double bonds, wherein the bicyclic ring can be any fused ring or bridged ring; the heterocyclic alkynyl group represents a 3-11 member monocyclic or bicyclic ring containing 1, 2 or 4 heteroatoms independently selected from N, S or O, and containing 1, 2 or more triple bonds, wherein the bicyclic ring can be any optional fused ring or optional bridged ring;

[0040] According to an embodiment of the present invention, the heteroaryl group is a 5-10 member monocyclic or bicyclic aromatic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, and the bicyclic group can be any fused ring;

[0041] According to embodiments of the present invention, "single ring or multiple rings" means single ring, two rings (such as fused rings, spiral rings, bridged rings), three rings or more rings.

[0042] According to embodiments of the present invention, the halogen-substituted alkyl group can be a monohalogenated, dihalogenated, trihalogenated, or more halogenated C14 group. 1-6 Alkyl groups, such as -CF3, -CHF2, -CH2F.

[0043] According to an embodiment of the present invention, A can be selected from the following groups, wherein each of the following groups can be 0, 1, 2 or 3 R groups. a Group substitution:

[0044] Among them, R a As defined above, "--" represents a chemical bond.

[0045] According to an embodiment of the present invention, B may be selected from the following groups, wherein each of the following groups may be replaced by 0, 1, 2 or 3 Rb groups:

[0046] Among them, R b As defined above, "--" represents a chemical bond.

[0047] According to an embodiment of the present invention, C can be selected from the following groups, wherein each of the following groups can be 0, 1, 2 or 3 R groups. c Group substitution:

[0048] Among them, R c As defined above, "--" represents a chemical bond.

[0049] According to an embodiment of the present invention, D can be selected from the following groups, wherein each of the following groups can be 0, 1, 2 or 3 R groups. d Group substitution:

[0050] Among them, R d As defined above, "--" represents a chemical bond.

[0051] According to embodiments of this disclosure, the compound of formula I may be selected from the following compounds:

[0052] According to embodiments of this disclosure, the compound represented by Formula I, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug exhibits excellent inhibitory activity against at least PDE5 and TYK2.

[0053] According to embodiments of this disclosure, the compound represented by Formula I, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug may have inhibitory activity against PDE5 and TYK2.

[0054] This disclosure also provides a method for preparing compounds of Formula I, their racemates, stereoisomers, tautomers, isotope labels, solvates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs, wherein the method comprises reacting a compound of Formula S1 with a compound of Formula S2 to obtain a compound of Formula I:

[0055] And optionally, the compound of formula I may be derived into its stereoisomers, tautomers, isotopic labels, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs;

[0056] Wherein, LG is a leaving group, such as Cl, Br or I;

[0057] Other groups such as A, B, C, D, W, X1, X2, X3, X4, X5, R1, R2, Ra R b R c R d R e m, n, p, and q each have the definitions described above independently.

[0058] According to embodiments of this disclosure, the reaction can be carried out with protecting groups provided on compounds of formula S1 and S2, if desired. For example, the protecting group can be selected from amino protecting groups, hydroxyl protecting groups, etc. Suitable protecting groups can be selected from C... 1-40 Alkyl, C 6-20 Aryl C 1-40 Alkyl groups, such as tert-butyl, isopropyl, benzyl, tert-butoxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenemethoxycarbonyl (Fmoc), and trifluoroacetyl.

[0059] According to embodiments of this disclosure, the preparation method can be carried out in the presence of a solvent such as an organic solvent. For example, the organic solvent can be selected from at least one of the following: alcohols, such as methanol, ethanol, isopropanol, n-butanol; ethers, such as ethyl propyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexylmethyl ether, dimethyl ether, diethyl ether, dimethyl ethylene glycol, biphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, dichlorodiethyl ether, and others. Polyethers of ethylene oxide and / or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, and those that may be substituted with fluorine and chlorine atoms, such as methylene chloride, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, chlorobenzene, bromobenzene, xylene; esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate and dimethyl carbonate, dibutyl carbonate or ethylene carbonate.

[0060] This disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the following: a compound of Formula I, a racemic mixture, a stereoisomer, a tautomer, an isotope label, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof.

[0061] According to embodiments of this disclosure, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.

[0062] According to embodiments of this disclosure, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0063] This disclosure also provides the use of at least one of the compounds of Formula I, their racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds in the preparation of pharmaceuticals.

[0064] The drug can be used to prevent or treat diseases mediated by at least PDE5 and TYK2.

[0065] For example, the drug can be used to prevent or treat diseases mediated by PDE5 and TYK2.

[0066] According to an embodiment of this disclosure, the PDE5 is selected from PDE5A.

[0067] The present invention also provides a method for preventing or treating diseases mediated by at least PDE5 and TYK2, comprising administering to a patient in need at least one of a compound of formula I, its racemic, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

[0068] According to embodiments of this disclosure, the diseases are selected from those mediated by PDE5 and TYK2.

[0069] According to embodiments of the present invention, the diseases include, but are not limited to, at least one selected from the following: autoimmune and / or inflammatory diseases, selected from psoriasis, rheumatoid arthritis, inflammatory bowel disease (IBD); lung diseases, selected from pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF); tumors, such as solid tumors, such as lung cancer, colorectal cancer, melanoma, glioblastoma, brain tumors; cardiovascular diseases and / or metabolic disorders, such as atherosclerosis, diabetic nephropathy; nervous system diseases, such as multiple sclerosis, Alzheimer's disease (AD); fibrotic diseases, such as fibrosis or sclerosis of the kidneys, liver, or skin.

[0070] When administered as a medicine, the compounds disclosed herein may be given in the form of pharmaceutical compositions. These compositions may be prepared in a manner well known in the pharmaceutical art and may be administered via a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration may be local (e.g., transdermal, skin, eye, and mucous membrane delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal, intranasal), oral, or parenteral. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single large dose or via, for example, a continuous infusion pump. Topically administered pharmaceutical compositions and formulations may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional drug carriers, water, powder or oily bases, thickeners, etc., may be necessary or required.

[0071] In preparing the compositions of this disclosure, the active ingredient is typically mixed with an excipient, diluted by the excipient, or contained in a carrier such as a capsule, pouch, paper, or other container. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid substance, serving as a solvent, carrier, or medium for the active ingredient. Therefore, the compositions can be in the following forms: tablets, pills, powders, lozenges, pouches, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or soluble in a liquid solvent); ointments containing, for example, up to 10% by weight of the active compound; soft and hard gelatin capsules; suppositories; sterile injectable solutions; and sterile packaged powders.

[0072] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. Formulations may also contain: lubricants such as talc, magnesium stearate, and mineral oil; humectants; emulsifiers and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners and flavoring agents. The compositions disclosed herein can be formulated using methods known in the art to provide immediate, sustained, or delayed release of the active ingredient upon administration to a patient.

[0073] Compositions can be formulated in unit dosage forms, each containing approximately 5 to 1000 mg, more typically approximately 100 to 500 mg of active ingredient. The term "unit dosage form" refers to a physically isolated single-dose unit suitable for use in human patients and other mammals, each unit containing a predetermined amount of active substance, calculated to produce the desired therapeutic effect, when mixed with suitable pharmaceutical excipients.

[0074] The effective dose range of an active compound can be quite wide, and it is usually administered at the pharmaceutically effective dose. However, it is understood that the actual amount of compound administered is usually determined by the physician based on relevant circumstances, including the condition being treated, the route of administration chosen, the actual compound administered, the patient's age, weight, and response, and the severity of the patient's symptoms.

[0075] For the preparation of solid compositions, such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preform composition containing a homogeneous mixture of the compounds disclosed herein. When these preform compositions are referred to as homogeneous, it means that the active ingredient is generally uniformly distributed throughout the composition, such that the composition can be readily divided into equivalent dosage forms, such as tablets, pills, and capsules. The solid preform is then divided into dosage forms of the aforementioned type containing, for example, about 0.1 to 1000 mg of the active ingredient disclosed herein.

[0076] The tablets or pills disclosed herein can be coated or combined to obtain dosage forms that provide the advantage of prolonged action. For example, the tablets or pills contain an internal dose and an external dose component, the latter being a coated form of the former. The two components can be separated by an enteric coating layer, which serves to prevent disintegration in the stomach, allowing the internal component to pass through the duodenum intact or to delay release. A variety of substances can be used for such enteric coatings or coatings, including a variety of high molecular weight acids and mixtures of high molecular weight acids with such substances such as shellac, cetyl alcohol, and cellulose acetate.

[0077] The compounds and compositions disclosed herein may be incorporated into liquid forms for oral or injectable administration, including aqueous solutions, suitably flavored syrups, water or oil suspensions; and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil; as well as elixirs and similar pharmaceutical solvents.

[0078] Compositions for inhalation or inhalation include solutions and suspensions, and powders, dissolved in pharmaceutically acceptable water or organic solvents or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered orally or via nasal inhalation to achieve local or systemic effects. The composition can be nebulized using an inert gas. The nebulized solution can be inhaled directly from a nebulizer, or the nebulizer can be connected to a face mask or intermittent positive pressure ventilation machine. Solutions, suspensions, or powder compositions can be administered orally or nasally by a device that delivers the formulation in a suitable manner.

[0079] The amount of compound or composition given to a patient is not fixed and depends on the drug being administered, the purpose of administration (e.g., prevention or treatment), the patient's condition, the method of administration, etc. In therapeutic applications, a sufficient amount of the composition may be given to a patient with an existing disease to cure or at least partially suppress the symptoms of the disease and its complications. The effective dose should depend on the disease state being treated and the judgment of the attending clinician, which depends on factors such as the severity of the disease, the patient's age, weight, and general condition.

[0080] The compositions administered to patients may be in the form of the pharmaceutical compositions described above. These compositions may be sterilized using conventional sterilization techniques or filterable sterilization. The aqueous solutions may be used as is, or lyophilized; prior to administration, the lyophilized formulation may be mixed with a sterile aqueous carrier. The pH of the compound formulation is typically 3–11, more preferably 5–9, and most preferably 7–8. It is understood that the use of certain of the aforementioned excipients, carriers, or stabilizers may result in the formation of drug salts.

[0081] The therapeutic dose of the disclosed compound may be determined based on factors such as the specific therapeutic use, the method of administration, the patient's health and condition, and the prescribing physician's judgment. The proportion or concentration of the disclosed compound in the pharmaceutical composition may not be fixed and may depend on various factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the disclosed compound may be provided, for example, by means of a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg body weight / day. In some embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage is likely to depend on variables such as the type and severity of the disease or condition, the general health status of the specific patient, the relative biological potency of the selected compound, the excipient formulation, and the route of administration. The effective dose can be obtained by extrapolation from dose-response curves derived from in vitro or animal model testing systems. Beneficial effects

[0082] Not wanting to be confined to existing theories, the inventors discovered that the disclosed compound, due to its excellent dual-target inhibitory activity against PDE5 and TYK2, will help in the development of multispecific targeted drugs for different patient populations. This will be particularly beneficial for improving treatment efficacy and / or reducing side effects, as well as improving patient compliance and quality of life.

[0083] Terminology Definitions and Explanations

[0084] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0085] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-20" is equivalent to describing each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each integer value in the numerical range "11-40", namely 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. Furthermore, when certain numerical ranges are described as "numbers", it should be understood that they describe the two endpoints of the range, each integer within the range, and each decimal within the range. For example, "numbers from 0 to 10" should be understood to describe not only each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each of these integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9.

[0086] It should be understood that in the description of 1, 2 or more, "more" should refer to an integer greater than 2, such as an integer greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0087] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0088] Term "C" 1-20 "Alkyl" should be understood as referring to a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 20 carbon atoms. For example, "C 1-10 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 1-6 "Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0089] Term "C" 2-20 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one, two or more double bonds and having 2 to 20 carbon atoms, preferably "C". 2-10 "Alkenyl". "C" 2-10 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one, two or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., C...). 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C24, C34, C4 ... 2-3 Alkenyl). It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pentyl-1-enyl, (Z)-pentyl-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl 2-Methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0090] Term "C" 2-20 "Alkyne group" should be understood as representing a straight or branched monovalent hydrocarbon group containing one, two or more triple bonds and having 2 to 20 carbon atoms, preferably "C". 2-10 "Alkyne group". The term "C" 2-10"Alkyne" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one, two or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., "C"). 2-6 The alkynyl group ("C") has 2 or 3 carbon atoms ("C") 2-3 The alkynyl group is, for example, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynyl, 1-methylprop-2-alkynyl, 2-methylbut-3-alkynyl, 1-methylbut-3-alkynyl, 1-methylbut-2-alkynyl, 3-methylbut-1-alkynyl, 1-ethylprop-2-alkynyl, 3-methylpent-4-alkynyl, 2-methylpent-4-alkynyl, 1-methylpent-4-alkynyl -Alynyl, 2-methylpentan-3-ynyl, 1-methylpentan-3-ynyl, 4-methylpentan-2-ynyl, 1-methylpentan-2-ynyl, 4-methylpentan-1-ynyl, 3-methylpentan-1-ynyl, 2-ethylbutan-3-ynyl, 1-ethylbutan-3-ynyl, 1-ethylbutan-2-ynyl, 1-propylpropan-2-ynyl, 1-isopropylpropan-2-ynyl, 2,2-dimethylbutan-3-ynyl, 1,1-dimethylbutan-3-ynyl, 1,1-dimethylbutan-2-ynyl, or 3,3-dimethylbutan-1-ynyl. In particular, the ynyl group is ethynyl, propan-1-ynyl, or propan-2-ynyl.

[0091] Term "C" 3-20 "Cycloalkyl" should be understood to refer to monovalent monocyclic, bicyclic (e.g., fused, bridged, spirocyclic), or tricyclic alkanes that are saturated or unsaturated (e.g., partially unsaturated), having 3 to 20 carbon atoms, preferably "C". 3-10 cycloalkyl. The term "C" 3- 10 "Cycloalkyl" should be understood to refer to a saturated monovalent monocyclic, bicyclic (e.g., bridged, spirocyclic) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The C... 3-10 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; or bicyclic hydrocarbon groups, such as borneolyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl; or tricyclic hydrocarbon groups, such as adamantyl.

[0092] Those skilled in the art should understand that the term "C" 3-20 "Cycloalkyl" does not possess aromaticity. Furthermore, when the above "C" 3-20 When the cycloalkyl group is unsaturated, it can have more than one carbon-carbon double bond and / or more than one carbon-carbon triple bond. Specifically, when the "C" is unsaturated... 3-20 When a cycloalkyl group has a carbon-carbon double bond, it can also be called a "C60" cycloalkyl group. 3-20 "Cycloalkenyl"; when "C 3-20 When a cycloalkyl group has a carbon-carbon triple bond, it can also be called a "C60" cycloalkyl group. 3-20 Cycloynyl group.

[0093] Unless otherwise defined, the term "3-20 membered heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6-, or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring (such as a fused ring, bridged ring, or spirocyclic ring), or a 10-, 11-, 12-, 13-, 14-, or 15-membered tricyclic ring system, and contains at least one, for example, 1, 2, 3, 4, 5, or more heteroatoms selected from O, S, and N, wherein N and S may optionally be oxidized to various oxidation states to form nitrides, -S(O)-, or -S(O)2- states. Preferably, the heterocyclic group may be selected from "3-10 membered heterocyclic groups". The term "3-10 membered heterocyclic group" means a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S, and N. The heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. Specifically, the heterocyclic group can include, but is not limited to: 4-membered rings, such as azirrobutyl or oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolealkyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazineyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group can be benzofused. The heterocyclic group can be bicyclic, such as, but not limited to, a 5,5-membered ring, like a hexahydrocyclopentano[c]pyrrolo-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazinolo-2(1H)-yl ring. The heterocyclic group can be partially unsaturated, meaning it can contain one, two, or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrroloyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. When the 3-20-membered heterocyclic group is linked to other groups to form the compounds of this disclosure, the carbon atom on the 3-20-membered heterocyclic group can be linked to other groups, or the heterocyclic atom on the 3-20-membered heterocyclic group ring can be linked to other groups. For example, when the 3-20 membered heterocyclic group is selected from piperazine, the nitrogen atom on the piperazine group can be attached to other groups. Or when the 3-20 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom at its para position can be attached to other groups. For example, the substituted 4-10 membered heterocyclic group can be selected from: 1-methylpyrrolyl, 1-ethylpyrrolyl, 1-cyclopropylpyrrolyl, 1-cyclopropylmethylpyrrolyl, 5-methyl-4,5-dihydropyridazine-3(2H)-keto, 1-methylazine-butyl, 1-methylpiperidinyl;

[0094] Term "C"6-20 "Aryl" should preferably be understood to represent a monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring), or tricyclic hydrocarbon ring having 6 to 20 carbon atoms and possessing monovalent aromaticity or partial aromaticity. It can be a monoaromatic ring or a polyaromatic ring fused together, preferably "C". 6-14 "Aromatic". The term "C" 6-14 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14 Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. When the C 6-20 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0095] The term "5-20-membered heteroaryl" should be understood to include monocyclic, bicyclic (e.g., fused, bridged, spirocyclic), or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, for example, "5-14-membered heteroaryl". The term "5-14-membered heteroaryl" should also be understood to include monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, and in each case, may be benzo[a]fused. "Hyperaryl" also refers to a group in which the heteroaryl ring is fused with one, two, or more aryl, alicyclic, or heterocyclic rings, wherein the root or point of the connection is on the heteroaryl ring. Non-limiting examples of the term heteroaryl include, for example, pyridyl, pyrazinyl, furanyl, thiopheneyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazonyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, 1,2,4-Thiadiazolyl, pyridazinyl; and 1-, 2-, 3-, 5-, 6-, 7- or 8-indazinyl, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8-purinel, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinazinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6- Naphthidyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-pyrolinyl, 2-, 4-, 6- or 7-pteridyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH carbazole, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazole carbazole, 1 -, 3-, 4-, 5-, 6-, 7-, 8- or 9-carboline, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-pyridyl, 2-, 3-, 4-, 5- 6, 8, 9, or 10-phenanthroline, 1, 2, 3, 4, 6, 7, 8, or 9-phenazinyl, 1, 2, 3, 4, 6, 7, 8, 9, or 10-phenthiazinyl, 1, 2, 3, 4, 6, 7, 8, 9, or 10-phenazinyl, 2, 3, 4, 5, 6, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolinyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino[2,3-c]carbazoleyl, 2-, 3-, 5-, 6- or 7-2H-furano[3 ,2-b]-pyranyl, 2-,3-,4-,5-,7- or 8-5H-pyrido[2,3-d]-o-azinyl, 1-,3- or 5-1H-pyrazolo[4,3-d]-thiazolyl, 2-,4- or 5-1H-imidazo[4,5-d]thiazolyl, 3-,5- or 8-pyrazolo[2,3-d]pyridazinyl, 2-,3- 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furanzo[3,4-c]cenolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10- or 11-4H-pyrido[2,3-c]carbazolel, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2,4] Triazine, 7-benzo[b]thiophene, 2-, 4-, 5-, 6- or 7-benzozozolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6- or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7- or 8-benzoazine, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-1H-pyrrolo[1,2-b][2]benzozapinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thiophene, 2-, 4-, 5-, 6-, or 7-benzozozolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-20-membered heteroaryl group is linked to other groups to form the compounds disclosed herein, the carbon atom on the 5-20-membered heteroaryl ring may be linked to other groups, or the heteroatom on the 5-20-membered heteroaryl ring may be linked to other groups. When the 5-20-membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution sites; for example, hydrogen atoms bonded to carbon atoms on the heteroaryl ring can be substituted, or hydrogen atoms bonded to heteroatoms on the heteroaryl ring can be substituted.

[0096] Unless otherwise defined, in the compounds described in this disclosure, when both sides of a substituent can bond to a linking position in the compound, the specific location of the substituent bonding in the compound is not particularly limited. For example, either end of the substituent can bond to a linking position in the compound, as long as the bonding conforms to valence bond theory. Alternatively, when a substituent is defined as two connected groups (e.g., in the form of "group 1-group 2" or "group 1 with group 2," where group 1 and group 2 may be the same or different), the specific location of the substituent bonding in the compound is not particularly limited. For example, group 1 can bond to a linking position in the compound, or group 2 can bond to a linking position in the compound, as long as the bonding conforms to valence bond theory. Furthermore, the connection position between the two connected groups (e.g., group 1 and group 2, group 1 with group 2) is not particularly limited, as long as the connection conforms to valence bond theory.

[0097] For example, for C, including but not limited to C 1-6 Alkyl-C 6-20 Aryl, C 1-6Alkyl-5-20-membered heteroaryl, C 3-20 cycloalkyl-C 6- 20 Aryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 Cycloalkyl 5-20-membered heteroaryl, 3-20-membered heterocycloalkyl 3-C 6-20 aryl, 3-20 membered heterocyclic alkyl and 5-20 membered heteroaryl, 5-20 membered heterocyclic alkenyl and C 6-20 Aryl, 5-20 membered heterocyclic alkenyl and 5-20 membered heteroaryl, C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 Substituents of cycloalkenyl 5-20 heteroaryl groups, wherein the group on either side of each substituent can be bonded to a linking position in the compound.

[0098] For example, when both sides of a group in the context of this application are drawn with "--" representing chemical bonds, it means that either side can combine with other groups in the structure of Formula I. For example, each structure in the group specifically exemplified by group A (including but not limited to) Either side of the compound can be bonded to either the X1 or X5 group in Formula I; or, each structure of the group specifically exemplified by group C (including but not limited to) ), and either side of it can be bonded to the X3 or X4 group in the compound of formula I.

[0099] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0100] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0101] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms.

[0102] Unless otherwise stated, heterocyclic, 5-20 membered heteroaryl, or heteroarylene includes all possible isomers, such as their positional isomers. Thus, for some illustrative, non-limiting examples, it may include forms in which one, two, or more of the following positions (if present) are substituted or bonded to other groups, including pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thiophene or thiophene includes thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0103] The term "oxo" refers to the substitution of a non-oxygen atom with a hydrogen atom or a lone pair of electrons by an oxygen atom, for example, After being oxidized, it becomes After being oxidized, it becomes

[0104] Unless otherwise stated, the definitions of terms in this document also apply to groups containing the term, such as C. 1-6 The definition of alkyl also applies to C 1-6 Alkyloxy, C 3-8 cycloalkyl-C 1-6 Alkyl groups, etc.

[0105] In the context of this disclosure, the "-", "--", "---" or "---" on the substituent base are used interchangeably. All are intended to label the substituents for use in connecting chemical bonds;

[0106] Those skilled in the art will understand that the compounds shown in Formula I can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.

[0107] The compounds disclosed herein may exist as solvates (such as hydrates), wherein the compounds of this disclosure contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0108] As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., that the substance can be administered to an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0109] Those skilled in the art will understand that the compounds of this disclosure can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form inner salts.

[0110] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds disclosed herein can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form, and attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant; while in phenols, the enol form is dominant. This disclosure encompasses all tautomeric forms of the compounds.

[0111] Based on their molecular structure, the compounds disclosed herein can be chiral, and therefore may exist in various enantiomeric forms. Thus, these compounds can exist in racemic or optically active forms. The compounds disclosed herein cover isomers of each chiral carbon in the R or S configuration, or mixtures thereof, or racemates. The compounds or intermediates of this disclosure can be isolated as enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in both R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomer separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate, or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile. The corresponding stable isomers can be separated according to known methods, such as extraction, filtration, or column chromatography.

[0112] "Isotope" refers to all isotopes of atoms appearing in the compounds of this invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for inclusion in the compounds of this invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, respectively, for example, but not limited to, [examples of isotopes]. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 31 P, 32 P, 35 S, 18 F and 36 C1. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples, using suitable isotope-labeled reagents instead of non-isotope-labeled preparations. Such compounds have a variety of potential uses, for example, as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological, or pharmacokinetic properties.

[0113] The term "prodrug" refers to a compound of this disclosure that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of this disclosure are prepared by modifying a functional group in the compound; this modification can be performed conventionally or removed in vivo to yield the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group in the compound of this disclosure. When a prodrug of this disclosure is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group.

[0114] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0115] The term “therapeutic effective amount” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). Detailed Implementation

[0116] The technical solutions of this disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of this disclosure and should not be construed as limiting the scope of protection of this disclosure. All technologies implemented based on the above content of this disclosure are covered within the scope of protection intended by this disclosure.

[0117] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0118] Abbreviations: DMF: N,N-dimethylformamide; DCM: dichloromethane; DIEA: N,N-diisopropylethylamine; TEA: triethylamine; PE: petroleum ether; EA: ethyl acetate; MeCN: acetonitrile; Et2O: diethyl ether; DMSO: dimethyl sulfoxide; EtOAc: ethyl acetate; THF: tetrahydrofuran; TFA: trifluoroacetic acid; AcOH: acetic acid; MeOH: methanol; EtOH: ethanol; NaH: sodium hydride; MeI: iodomethane; EtI: ethane iodide; HFP: 1,1,1,3,3,3-hexafluoro-2-propanol; DHP: 3,4-dihydro-2H-pyran; PPTS: pyridine 4-methylbenzenesulfonate; PPh3: triphenylphosphine; DEAD: diethyl azodicarbonate; MsCl: methanesulfonyl chloride; TMSOTf: trimethylsilyl trifluoromethanesulfonate; m-CPBA: m-chloroperoxybenzoic acid; Boc: tert-butoxycarbonyl.

[0119] Analysis method:

[0120] 1. Nuclear magnetic resonance (NMR) spectra were recorded using a 400 MHz Bruker AVANCE III 500 instrument. Chemical shifts were reported in ppm using the tritium-substituted residual solvent as an internal standard. Peak magnifications were expressed as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; dt, triplet of doublet; q, quartet; m, multiplet; br s, broad singlet.

[0121] 2. The purity analysis of the samples was performed on a Waters HPLC / Waters MS system.

[0122] Chromatographic conditions 1:

[0123] Chromatographic column: Waters X-Bridge-C18 50mm*4.6mm*3.5μm

[0124] The column temperature was 40℃.

[0125] Sample temperature: room temperature

[0126] Detection of UV 214 nm and UV 254 nm

[0127] Flow rate: 2 mL / min.

[0128] Mobile phase A: Water (0.05% TFA)

[0129] Mobile phase B: MeCN (0.05% TFA)

[0130] Gradient program: B from 5% to 100% takes 1.6 minutes, and 100% is held for 1.4 minutes.

[0131] Chromatographic conditions 2:

[0132] Chromatographic column: Waters X Brdige C18 (4.6mm x 50mm x 3.5μm)

[0133] The column temperature was 40℃.

[0134] Sample temperature: room temperature

[0135] Detection of UV 214 nm and UV 254 nm

[0136] Flow rate: 2 mL / min.

[0137] Mobile phase A: Water (0.01 mol / L NH4HCO3) B: MeCN

[0138] Mobile phase B: MeCN

[0139] Gradient program: B from 5% to 100%, for 1.6 minutes, then hold at 100% for 1.4 minutes.

[0140] 3. Preparative HPLC was performed on a Gilson 281.

[0141] Flow rate: 20 mL / min.

[0142] Chromatographic column: X-Select 10μm 19*250mm column

[0143] Wavelength: 254 nm or 214 nm

[0144] Solvent A: Water (10 mM NH4HCO3) and Solvent B: MeCN.

[0145] Example 1: Synthesis Example

[0146] 1. Synthesis scheme:

[0147] 2. Experimental Section:

[0148] 2.1

[0149] 6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylic acid ethyl ester (A-1)

[0150] To a solution of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (612 mg, 3.0 mmol) in acetonitrile (20 mL), ethyl 4,6-dichloropyridazine-3-carboxylate (663 mg, 3.0 mmol) and DIPEA (1.16 g, 9.0 mmol) were added. The mixture was stirred at 130 °C for 24 hours in a sealed tube. After cooling to room temperature, the mixture was concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 0–100%, Silica-CS 20 g, 25 mL / min, silica gel, UV 254) to give a yellow solid (588 mg, yield 50.51%).

[0151] ESI-MS m / z calcd for [C 17 H 17 ClN6O3][M+H] + 389.1; found: 389.3

[0152] 2.2

[0153] 6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-D3-pyridazine-3-carboxamide (A-2)

[0154] Ethyl 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate (290 mg, 0.75 mmol) was added to a solution of 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate (10 mL) with methyl-D3-amine hydrochloride (158 mg, 2.24 mmol) and TEA (755 mg, 7.46 mmol). The mixture was stirred at 25 °C under nitrogen protection for 16 hours. The mixture was concentrated. The crude product was purified by silica gel column chromatography (MeOH / DCM = 0–5%, Silica-CS 20 g, 25 mL / min, silica gel, UV 254) to give a yellow solid product (216 mg, yield 76.85%).

[0155] ESI-MS m / z calcd for [C 16 H 13 D3ClN7O2][M+H] +:377.1; found:377.4

[0156] 2.3

[0157] 3-(4,5-Diethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxybenzonitrile (05001-1)

[0158] To a solution of 2-(5-bromo-2-propoxyphenyl)-5,6-diethylpyrimidin-4(3H)-one (365 mg, 1.00 mmol) in DMF (3 mL), cuprous cyanide (448 mg, 5.00 mmol) and pyridine (0.5 mL) were added. The mixture was stirred at 140 °C for 24 hours. After cooling to room temperature, the mixture was concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 0–50%, Silica-CS 20 g, 25 mL / min, silica gel, UV 254) to give a yellow solid product (122 mg, yield 39.18%).

[0159] ESI-MS m / z calcd for [C 18 H 21 [N3O2][M+H] + :312.2; found:312.4

[0160] 2.4

[0161] 3-(4,5-Diethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxybenzamide (05001-2)

[0162] To a solution of 3-(4,5-diethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxybenzonitrile (90 mg, 0.29 mmol), NaOH (46 mg, 1.16 mmol) and hydrogen peroxide (33% aqueous solution, 0.2 mL) were added. The mixture was stirred at 30 °C for 1 hour. After cooling to room temperature, the reaction solution was adjusted to neutral by adding acetic acid. The reaction solution was purified by reverse-phase column chromatography (MeCN / H₂O = 0–60%, C-18CS 40 g, 50 mL / min, C-18, UV 254) to give a white solid product (45 mg, yield 47.27%).

[0163] ESI-MS m / z calcd for [C 18 H 23 N3O3][M+H + :330.2; found:330.2

[0164] 2.5

[0165] 6-(3-(4,5-diethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxybenzamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-D3-pyridazine-3-carboxamide (MX05001)

[0166] To a solution of 3-(4,5-diethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxybenzamide (35 mg, 0.11 mmol) and 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-D3-pyridazine-3-carboxamide (44 mg, 0.12 mmol) in 1,4-dioxane (5 mL), Pd2(dba)3 (10 mg, 0.01 mmol), xantphos (6 mg, 0.01 mmol), and Cs2CO3 (104 mg, 0.32 mmol) were added. The mixture was stirred at 110 °C under nitrogen protection for 16 hours. The reaction mixture was concentrated, and the crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L HCOOH), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give a yellow solid product (9.86 mg, yield 13.86%).

[0167] ESI-MS m / z calcd for [C 34 H 35 D3N 10 O5][M+H] + :670.3; found:670.4

[0168] 1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),11.32(s,1H),11.02(s,1H),9.16(s,1H),8.57(s,1H),8.3 2(d,J=2.4Hz,1H),8.26(s,1H),8.20–8.17(m,1H),7.69–7.67(m,1H),7.62–7.60(m,1H),7.32(t ,J=8.0Hz,1H),7.27(d,J=9.2Hz,1H),4.11(t,J=6.4Hz,2H),3.95(s,3H),3.75(s,3H),2.59–2.5 1(m,4H),1.79–1.73(m,2H),1.19(t,J=7.2Hz,3H),1.05(t,J=7.2Hz,3H),0.98(t,J=7.2Hz,3H).

[0169] 1. Synthesis scheme:

[0170] 2. Experimental Section:

[0171] 2.1

[0172] 2-(5-bromo-2-(cyclopropylmethoxy)phenyl)-6,7-dihydro-3H-cyclopentano[d]pyrimidin-4(5H)-one (05006-1)

[0173] To a solution of 5-bromo-2-(cyclopropylmethoxy)benzimidazole amide (300 mg, 1.12 mmol) in methanol (5 mL), ethyl 2-oxocyclopentanecarboxylate (175 mg, 1.12 mmol) and sodium methoxide (60 mg, 1.12 mmol) were added. The reaction mixture was stirred at 70 °C for 4 hours. After the reactants were consumed, water (50 mL) was added, and the mixture was extracted three times with EA (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE = 0–100%, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give a yellow solid product (328 mg, yield 81%).

[0174] ESI-MS m / z calcd for [C 17 H 17 BrN2O2][M+H] + :361.1; found:361.1

[0175] 2.2

[0176] 4-(cyclopropylmethoxy)-3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)benzonitrile (05006-2)

[0177] To a solution of 2-(5-bromo-2-(cyclopropylmethoxy)phenyl)-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one (300 mg, 0.78 mmol), dppf (411 mg, 0.39 mmol), Zn(CN)₂ (910 mg, 7.80 mmol), zinc powder (52 mg, 0.78 mmol), and Pd₂(dba)₃ (71 mg, 0.08 mmol) were added to 8 mL of DMF. The mixture was stirred at 105 °C under nitrogen protection for 2 hours. After the starting material was consumed, water (50 mL) was added, and the mixture was extracted three times with EA (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE = 0–100%, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give a yellow solid product (185 mg, yield 72%).

[0178] ESI-MS m / z calcd for [C 18 H 17 [N3O2][M+H] + :308.1; found:308.3

[0179] 2.3

[0180] 4-(cyclopropylmethoxy)-3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopentano[d]pyrimidin-2-yl)benzamide (05006-3)

[0181] 185 mg, 0.53 mmol of 4-(cyclopropylmethoxy)-3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopentano[d]pyrimidin-2-yl)benzonitrile (2 mL) was added to a methanol (2 mL) solution with 2 M sodium hydroxide aqueous solution (2 mL) and H₂O₂ (0.2 mL). The mixture was stirred at 30 °C under nitrogen protection for 2 hours. After the starting material was consumed, water (20 mL) was added, and the mixture was extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE = 0–100%, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give a white solid product (122 mg, yield 72%).

[0182] ESI-MS m / z calcd for [C 18 H 19 N3O3][M+H + :326.1; found:326.0

[0183] 2.4

[0184] 6-(4-(cyclopropylmethoxy)-3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopentano[d]pyrimidin-2-yl)benzamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(trideuteratedmethyl)pyridazine-3-carboxamide (MX05006)

[0185] Add 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(trideuterated methyl)pyridazine-3-carboxamide (50 mg, 0.15 mmol), Xantphos (10 mg, 0.015 mmol), cesium carbonate (98 mg, 0.30 mmol), and Pd2(dba)3 (15 mg, 0.015 mmol) to a solution of 4-(cyclopropylmethoxy)-3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)benzamide (50 mg, 0.15 mmol), Xantphos (10 mg, 0.015 mmol), cesium carbonate (98 mg, 0.30 mmol), and Pd2(dba)3 (15 mg, 0.015 mmol) to a solution of 1,4-dioxane (4.0 mL). The mixture was stirred overnight at 110°C under nitrogen protection. After the starting material was consumed, the reaction solution was concentrated. The crude product was purified by preparative HPLC (MeCN / H2O (10mmol / L NH4HCO3), X-Select 10μm 19*250mm, 20mL / min, UV 254) to obtain a white solid product (21.16mg, yield 21%).

[0186] 1H NMR (400MHz, DMSO-d6) δ12.04(s,1H),11.37(s,1H),11.02(s,1H),9.16(s,1H),8.58(s,1H),8.39(d,J=2.4 Hz,1H),8.27(s,1H),8.19(dd,J=8.8,2.4Hz,1H),7.68(dd,J=8.0,1.6Hz,1H),7.61(dd,J=8.0,1.2Hz,1H), 7.32(t,J=7.6Hz,1H),7.25(d,J=8.8Hz,1H),4.05(d,J=7.2Hz,2H),3.95(s,3H),3.75(s,3H),2.85(t,J=7. 6Hz,2H),2.70(t,J=7.2Hz,2H),2.06–1.98(m,2H),1.29–1.23(m,1H),0.59–0.54(m,2H),0.42–0.38(m,2H).

[0187] 1. Synthesis scheme:

[0188] 2. Experimental Section:

[0189] 2.1

[0190] 5-Bromo-2-cyclopropoxybenzonitrile (05007-1)

[0191] At room temperature, cyclopropanol (914 mg, 15.75 mmol) and cesium carbonate (5.13 g, 15.75 mmol) were added to a solution of 5-bromo-2-fluorobenzonitrile (2.1 g, 10.5 mmol) in DMF (30 mL). The mixture was stirred overnight at 70 °C under nitrogen protection. After the starting material was consumed, water (90 mL) was added to the mixture, and the mixture was extracted three times with EA (100 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 1 to 1 / 3, silica gel-CS 80 g, 40 mL / min, silica gel, UV 254) to give a white solid product (2.3 g, yield 92.4%).

[0192] ESI-MS m / z calcd for [C 10 H8BrNO][M+H] + :238.0; found:238.1

[0193] 2.2

[0194] (E)-5-bromo-2-cyclopropoxy-N'-hydroxybenzimidazole amide (05007-2)

[0195] At room temperature, hydroxylamine hydrochloride (1.85 g, 26.58 mmol) and sodium bicarbonate (2.23 g, 26.58 mmol) were added to a methanol (30 mL) solution of 2.1 g bromo-2-cyclopropoxybenzonitrile (8.86 mmol) at room temperature. The reaction mixture was stirred for 16 hours under nitrogen protection at 80 °C. After the starting material was consumed, the mixture was concentrated by vacuum distillation. Water (50 mL) was added to the mixture, and it was extracted three times with EA (50 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 1 to 1 / 3, silica gel-CS 80 g, 40 mL / min, silica gel, UV 254) to give a white solid product (2.1 g, yield 87.9%).

[0196] ESI-MS m / z calcd for [C 10 H 11 BrN2O2][M+H] + :271.0; found:271.0

[0197] 2.3

[0198] 5-Bromo-2-cyclopropoxybenzimidazole amide (05007-3)

[0199] (E)-5-bromo-2-cyclopropoxy-N'-hydroxybenzimidazole amide (2.1 g, 7.78 mmol) was added to a solution of acetic acid (70 mL) with Raney nickel (500 mg) and ammonium formate (4.9 g, 77.8 mmol). The reaction mixture was stirred at 100 °C under argon for 2 hours. After the starting material was consumed, the mixture was filtered, and water (100 mL) was added to the filtrate. The mixture was then extracted three times with EA (100 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid product (1.7 g, yield 86.0%).

[0200] ESI-MS m / z calcd for [C 10 H 11 BrN2O][M+H] + :255.0; found:255.0

[0201] 2.4

[0202] 2-(5-bromo-2-cyclopropoxyphenyl)-6,7-dihydro-3H-cyclopentano[d]pyrimidin-4(5H)-one (05007-4)

[0203] At room temperature, methyl 2-oxocyclopentanecarboxylate (442 mg, 2.83 mmol) and potassium carbonate (651 mg, 4.72 mmol) were added to a solution of 5-bromo-2-cyclopropoxybenzimidazole amide (600 mg, 2.36 mmol) in DMF (10 mL). The mixture was stirred at 100 °C under nitrogen protection for 4 hours. After the starting material was consumed, water (50 mL) was added to the mixture, and the mixture was extracted twice with EA (50 mL). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 1 to 1 / 1, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give a yellow oily product (427 mg, yield 52.3%).

[0204] ESI-MS m / z calcd for [C 16 H 15 BrN2O2][M+H] + :347.0; found:347.0

[0205] 2.5

[0206] 4-Cyclopropoxy-3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopentano[d]pyrimidin-2-yl)benzonitrile (05007-5)

[0207] At room temperature, zinc cyanide (379 mg, 3.24 mmol), zinc powder (527 mg, 8.1 mmol), DPPF (44 mg, 0.08 mmol), and Pd2(dba)3 (73 mg, 0.08 mmol) were added to a solution of 2-(5-bromo-2-cyclopropoxyphenyl)-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one (280 mg, 0.81 mmol) in DMF (8 mL). The mixture was stirred at 105 °C under nitrogen protection for 2 hours. After the starting material was consumed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (EA / PA = 0 / 1 to 1 / 0, silica gel-CS 20 g, 40 mL / min, silica gel, UV 254) to give a pale yellow solid product (222 mg, yield 93.6%).

[0208] ESI-MS m / z calcd for [C 17 H 15 [N3O2][M+H]+ :294.1; found:294.2

[0209] 2.6

[0210] 4-Cyclopropoxy-3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopentano[d]pyrimidin-2-yl)benzamide (05007-6)

[0211] At room temperature, sodium hydroxide (27.3 mg, 0.68 mmol) and hydrogen peroxide (1 d) were added to a solution of 4-cyclopropoxy-3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)benzonitrile (100 mg, 0.34 mmol) in H₂O / MeOH (4 mL, 1 / 1). The mixture was stirred at 30°C for 2 hours under nitrogen protection. The solvent was removed by concentration under reduced pressure, and the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 9, silica gel-CS 12 g, 30 mL / min, silica gel, UV 254) to give a yellow oily product (66 mg, yield 62.3%).

[0212] ESI-MS m / z calcd for [C 17 H 17 N3O3][M+H + :312.1; found:312.1

[0213] 2.7

[0214] 6-(4-Cyclopropoxy-3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopentano[d]pyrimidin-2-yl)benzamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (MX05007)

[0215] Add 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (80 mg, 0.21 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), xantphos (12 mg, 0.02 mmol), and cesium carbonate (137 mg, 0.42 mmol) to a solution of 4-cyclopropoxy-3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)benzamide (66 mg, 0.21 mmol) in 1,4-dioxane (5 mL). The mixture was stirred at 110°C under nitrogen protection for 16 hours. After the starting material was consumed, water (20 mL) was added to the mixture, and it was extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to give a white solid compound (37 mg, yield 26.8%).

[0216] 1 H NMR (400MHz, DMSO-d6) δ11.70(br,2H),11.01(s,1H),9.16(s,1H),8.57(s,1H),8.29(d,J=2. 4Hz, 1H), 8.27 (s, 1H), 8.22 (dd, J = 8.8, 2.4Hz, 1H), 7.69 (dd, J = 7.6, 1.2Hz, 1H), 7.61 (dd, J = 8. 0, 1.2Hz, 1H), 7.55 (d, J = 8.8Hz, 1H), 7.32 (t, J = 8.0Hz, 1H), 4.03–4.00 (m, 1H), 3.96 (s, 3H), 3. 75(s,3H),2.83(t,J=7.2Hz,2H),2.69(t,J=7.2Hz,2H),2.05–1.97(m,2H),0.87–0.80(m,4H).

[0217] 1. Synthesis scheme:

[0218] 2. Experimental Section:

[0219] 2.1

[0220] 5-Bromo-2-(2,2,2-trifluoroethoxy)benzonitrile (05008-1)

[0221] Cesium carbonate (3.29 g, 10.1 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (1.4 g, 6.06 mmol) were added to a solution of 5-bromo-2-hydroxybenzonitrile (1.0 g, 5.05 mmol) in acetonitrile (30 mL). The mixture was stirred at 50 °C under nitrogen protection for 2 hours. After cooling to room temperature, the mixture was concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0–30%, Silica-CS 40 g, 50 mL / min, silica gel, UV 254) to give a white solid product (1.2 g, yield 84.85%).

[0222] 2.2

[0223] (Z)-5-Bromo-N'-hydroxy-2-(2,2,2-trifluoroethoxy)benzamide (05008-2)

[0224] Hydroxylamine hydrochloride (0.89 g, 12.86 mmol) and potassium carbonate (1.78 g, 12.86 mmol) were added to a solution of 5-bromo-2-(2,2,2-trifluoroethoxy)benzonitrile (1.2 g, 4.29 mmol) in methanol (20 mL). The mixture was stirred at 90 °C under nitrogen protection for 16 hours. The methanol was removed from the mixture by concentration. The mixture was filtered and dried under vacuum to give a white solid product (0.9 g, yield 67.09%).

[0225] ESI-MS m / z calcd for[C9H8BrF3N2O2][M+H] + :313.0; found:313.0

[0226] 2.3

[0227] 5-Bromo-2-(2,2,2-trifluoroethoxy)benzimidamine (05008-3)

[0228] To a solution of (Z)-5-bromo-N'-hydroxy-2-(2,2,2-trifluoroethoxy)benzimidamine (0.9 g, 2.87 mmol) in acetic acid (20 mL), Raney-Ni (200 mg) and ammonium formate (0.9 g, 14.37 mmol) were added. The mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the mixture was filtered and concentrated. The crude product was dissolved in water (100 mL), and the solution was washed with ethyl acetate (30 mL). The pH of the aqueous phase was then adjusted to 8 with potassium carbonate. The mixture was extracted twice with ethyl acetate (100 mL), the organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid product (0.6 g, yield 70.26%).

[0229] ESI-MS m / z calcd for[C9H8BrF3N2O][M+H] + :297.0; found:297.1

[0230] 2.4

[0231] 2-(5-bromo-2-(2,2,2-trifluoroethoxy)phenyl)-6,7-dihydro-3H-cyclopentano[d]pyrimidin-4(5H)-one (05008-4)

[0232] Sodium methoxide (218 mg, 4.04 mmol) was added to a solution of 5-bromo-2-(2,2,2-trifluoroethoxy)benzimidamine (300 mg, 1.01 mmol) and methyl 2-ethyl-3-oxovalerate (315 mg, 2.02 mmol) in methanol (10 mL). The mixture was stirred at 70 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0–60%, Silica-CS 20 g, 25 mL / min, silica gel, UV 254) to give a yellow solid product (290 mg, yield 73.79%).

[0233] ESI-MS m / z calcd for [C 15 H 12 BrF3N2O2][M+H] + :389.0; found:389.0

[0234] 2.5

[0235] 3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)-4-(2,2,2-trifluoroethoxy)benzonitrile (05008-5)

[0236] To a solution of 2-(5-bromo-2-(2,2,2-trifluoroethoxy)phenyl)-6,7-dihydro-3H-cyclopentano[d]pyrimidin-4(5H)-one (270 mg, 0.69 mmol) in DMF (6 mL), zinc cyanide (244 mg, 2.08 mmol), zinc powder (454 mg, 6.94 mmol), Pd2(dba)3 (64 mg, 0.07 mmol), and DPPF (39 mg, 0.07 mmol) were added. The mixture was stirred at 105 °C under nitrogen protection for 2 hours. The reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (MeOH / DCM = 0–5%, Silica-CS 25 g, 25 mL / min, silica gel, UV 254) to give a yellow solid product (195 mg, yield 83.83%).

[0237] ESI-MS m / z calcd for [C 16 H 12 F3N3O2][M+H] + :336.1; found:336.0

[0238] 2.6

[0239] 3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)-4-(2,2,2-trifluoroethoxy)benzamide (05008-6)

[0240] Sodium hydroxide (66 mg, 1.66 mmol) and hydrogen peroxide (33% aqueous solution, 0.2 mL) were added to a methanol / water solution (6 mL, v / v = 2:1). The mixture was stirred at 30 °C under nitrogen protection for 1 hour. The reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (MeOH / DCM = 0–10%, Silica-CS 25 g, 25 mL / min, silica gel, UV 254) to give a white solid product (95 mg, yield 48.73%).

[0241] ESI-MS m / z calcd for [C 16 H 14 F3N3O3][M+H] + :354.1; found:354.0

[0242] 2.5

[0243] 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-D3-6-(3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopentano[d]pyrimidin-2-yl)-4-(2,2,2-trifluoroethoxy)benzamido)pyridazine-3-carboxamide (MX05008)

[0244] Pd2(dba)3 (15 mg, 0.02 mmol), xantphos (10 mg, 0.02 mmol), and cesium carbonate (161 mg, 0.49 mmol) were added to a solution of 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-D3-pyridazine-3-carboxamide (68 mg, 0.18 mmol) and 3-(4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)-4-(2,2,2-trifluoroethoxy)benzamide (58 mg, 0.16 mmol) in 1,4-dioxane (6 mL). The mixture was stirred at 110 °C under nitrogen protection for 16 hours. The reaction mixture was concentrated, and the crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L HCOOH), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give a yellow solid product (16.11 mg, yield 14.15%).

[0245] 1 H NMR(400MHz,DMSO-d6)δ12.25(s,1H),11.40(s,1H),11.02(s,1H),9.17(s,1 H),8.57(s,1H),8.29–8.22(m,3H),7.68(d,J=8.0Hz,1H),7.61(d,J=7.2Hz,1 H),7.40(dJ=8.4Hz,1H),7.31(t,J=8.0Hz,1H),4.96–4.89(m,2H),3.95(s,3 H),3.75(s,3H),2.84(t,J=7.6Hz,2H),2.71–2.68(m,2H),2.06–2.00(m,2H).

[0246] 1. Synthesis scheme:

[0247] 2. Experimental Section:

[0248] 2.1

[0249] 4-Ethoxy-3-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzonitrile (05009-1)

[0250] 5-(5-bromo-2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (120 mg, 0.31 mmol) was added to a DMF (5 mL) solution along with Zn(CN)2 (145 mg, 1.21 mmol), DPPF (17 mg, 0.03 mmol) and Pd2(dba)3 (28 mg, 0.03 mmol). The reaction mixture was stirred at 105 °C for 2 hours in an oil bath. After the starting material was consumed, water (30 mL) was added to the mixture, and the mixture was extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 10, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to obtain a yellow solid product (95 mg, yield 91.3%).

[0251] ESI-MS m / z calcd for [C 18 H 19 [N5O2][M+H] + :338.1; found:338.4

[0252] 2.2

[0253] 4-Ethoxy-3-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzamide (05009-2)

[0254] At room temperature, 0.1 mL of H₂O₂ was added to a solution of 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzonitrile (85 mg, 0.25 mmol) in MeOH / 2N NaOH (1 mL, v / v = 1 / 1). The mixture was then stirred at 30 °C for 1 hour, followed by the addition of water (10 mL) and extraction twice with EA (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give a yellow solid product (88 mg, yield 99.2%).

[0255] ESI-MS m / z calcd for [C 18 H 21 [N5O3][M+H] + :356.1; found:356.4

[0256] 2.3 6-(4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzamide)-4-((2-methoxy-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (MX05009)

[0257] Pd2(dba)3 (9 mg, 0.01 mmol), xantphos (12 mg, 0.02 mmol), and Cs2CO3 (130 mg, 0.40 mmol) were added to a solution of 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (56 mg, 0.20 mmol) and 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzamide (70 mg, 0.20 mmol) in 1,4-dioxane (8 mL). The mixture was stirred overnight at 100°C under nitrogen protection. After the starting material was consumed, water (20 mL) was added to the mixture, and it was extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L HCOOH), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to obtain a white solid product (40.23 mg, yield 28.94%).

[0258] 1H NMR (400MHz, DMSO-d6) δ12.18(s,1H),11.32(s,1H),11.02(s,1H),9.16(s,1H),8.57( s,1H),8.27–8.26(m,2H),8.20(dd,J=4.0,2.4Hz,1H),7.68(dd,J=9.2,1.6Hz,1H),7.6 1(dd,J=7.6,1.2Hz,1H),7.33–7.25(m,2H),4.22–4.17(m,5H),3.95(s,3H),3.75(s,3 H),2.80–2.76(m,2H),1.77–1.71(m,2H),1.34(t,J=7.2Hz,3H),0.93(t,J=7.2Hz,3H).

[0259] 1. Synthesis scheme:

[0260] 2. Experimental Section:

[0261] 2.1

[0262] 2-(5-bromo-2-propoxyphenyl)-5-cyclopropyl-6-methylpyrimidin-4(3H)-one (05060-2)

[0263] Ethyl 2-cyclopropyl-3-oxobutyrate (1.0 g, 5.88 mmol) and 5-bromo-2-propoxybenzimidazolamide hydrochloride (800 mg, 2.72 mmol) were dissolved in methanol (25 mL), and sodium methoxide (720 mg, 13.33 mmol) was added. The mixture was stirred overnight at 70 °C under nitrogen atmosphere. After the reaction was complete, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (EA / DCM = 0 / 1 to 1 / 1, Silica-CS 20 g, 20 mL / min, silica gel, UV 254) to give a white solid product (980 mg, 99% yield).

[0264] ESI-MS m / z calcd for [C 17 H 19 BrN2O2][M+H] + :363.1; found:363.0

[0265] 2.2

[0266] 3-(5-Cyclopropyl-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxybenzonitrile (05060-3)

[0267] To a DMF (5 mL) solution of 2-(5-bromo-2-propoxyphenyl)-5-cyclopropyl-6-methylpyrimidin-4(3H)-one (300 mg, 0.83 mmol), Zn (539 mg, 8.3 mmol), Zn(CN)₂ (387 mg, 3.31 mmol), 1,1'-bis(diphenylphosphine)ferrocene (45 mg, 0.083 mmol), and Pd₂(dba)₃ (75 mg, 0.083 mmol) were added. The reaction mixture was stirred at 105 °C under nitrogen for 2 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (EA / DCM = 0 / 1 to 1 / 1, Silica-CS 12 g, 20 mL / min, silica gel, UV 254) to give a white solid product (202 mg, yield 79%).

[0268] ESI-MS m / z calcd for [C 18 H 19 [N3O2][M+H] + :310.1; found:310.2

[0269] 2.3

[0270] 3-(5-Cyclopropyl-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxybenzamide (05060-4)

[0271] 3-(5-cyclopropyl-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxybenzonitrile (202 mg, 0.654 mmol) was dissolved in methanol (6 mL), and 2N NaOH (6 mL) was added, followed by 2 drops of 30% hydrogen peroxide solution. The mixture was stirred at 30 °C for 2 hours under nitrogen atmosphere. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0 / 1 to 1 / 5, silica gel-CS12 g, 30 mL / min, silica gel, UV 254) to give a white solid product (158 mg, yield 76%).

[0272] ESI-MS m / z calcd for [C 18 H 21 N3O3][M+H + :328.2; found:328.2

[0273] 2.4

[0274] 6-(3-(5-cyclopropyl-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxybenzamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(trideuteratedmethyl)pyridazine-3-carboxamide (MX05060)

[0275] 50 mg (0.153 mmol) of 3-(5-cyclopropyl-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxybenzamide and 57 mg (0.153 mmol) of 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(trideuterated methyl)pyridazine-3-carboxamide were dissolved in a solution of 1,4-dioxane (5 mL). Pd₂(dba)₃ (14 mg, 0.0153 mmol), XantPhos (18 mg, 0.0306 mmol), BINAP (19 mg, 0.0306 mmol), and Cs₂CO₃ (150 mg, 0.459 mmol) were added. The mixture was stirred overnight at 110 °C under nitrogen atmosphere. After the reaction was completed, the solvent was removed under reduced pressure. The crude product was subjected to silica gel column chromatography (MeOH / DCM = 0 / 1 to 1 / 20, silica gel-CS12g, 20mL / min, silica gel, UV 254) and preparative HPLC [MeCN / H2O (10mmol / L NH4HCO3), X-Select 10μm 19×250mm, 20mL / min, UV 254] to give a white solid product (13.25mg, yield 13%).

[0276] 1 H NMR(400MHz,DMSO-d6)δ11.92(br,1H),11.31(br,1H),11.02(s,1H),9.15(s,1H),8.57(s,1H),8.33(d,J =2.4Hz,1H),8.26(s,1H),8.19(dd,J=8.8,2.4Hz,1H),7.68(dd,J=7.6,1.2Hz,1H),7.61(dd,J=8.0,1.2Hz ,1H),7.32(t,J=8.0Hz,1H),7.26(d,J=9.2Hz,1H),4.11(t,J=6.4Hz,2H),3.95(s,3H),3.75(s,3H),2.39( s,3H),1.78–1.73(m,2H),1.59–1.55(m,1H),0.98(t,J=7.2Hz,3H),0.95–0.91(m,2H),0.85–0.79(m,2H).

[0277] 1. Synthesis scheme:

[0278] 2. Experimental Section:

[0279] 2.1

[0280] 6-Chloro-4-((2-methoxyethyl)amino)pyridazine-3-carboxylic acid ethyl ester (05064-1)

[0281] At room temperature, HTMP (380 mg, 2.70 mmol) was added to a solution of 4,6-dichloropyridazine-3-carboxylic acid ethyl ester (400 mg, 1.80 mmol) and 2-methoxyethylamine (162 mg, 2.16 mmol) in DMF (3 mL). The mixture was then stirred at 110 °C for 16 hours, followed by the addition of water (20 mL) and extraction twice with EA (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give a white solid product (208 mg, yield 44.6%).

[0282] ESI-MS m / z calcd for [C 10 H 14 ClN3O3][M+H] + :260.0; found:260.1

[0283] 2.2

[0284] 6-Chloro-4-((2-methoxyethyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (05064-2)

[0285] At room temperature, ethyl 6-chloro-4-((2-methoxyethyl)amino)pyridazine-3-carboxylate (200 mg, 0.77 mmol) and CD3NH2.HCl (215 mg, 3.08 mmol) in EtOH (5 mL) were mixed with TEA (155 mg, 1.54 mmol). The mixture was then stirred overnight at 70 °C, followed by the addition of water (20 mL) and extraction twice with EA (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give a yellow solid product (108 mg, yield 56.8%).

[0286] ESI-MS m / z calcd for [C9H] 10 D3ClN4O2][M+H] + :248.1; found:248.2

[0287] 2.3

[0288] 6-(4-(4-ethyl-1,6-dihydropyrimidin-2-yl)-3-propoxybenzamido)-4-((2-methoxyethyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (MX05064)

[0289] 6-chloro-4-((2-methoxyethyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (126 mg, 0.40 mmol) and 3-(4,5-diethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxybenzamide (100 mg, 0.40 mmol) were added to a solution of 1,4-dioxane / DMF (4 mL, v / v = 1 / 1) along with Pd2(dba)3 (18 mg, 0.02 mmol), xantphos (23 mg, 0.04 mmol), BINAP (23 mg, 0.04 mmol), Cs2CO3 (260 mg, 0.80 mmol), and t-BuONa (78 mg, 0.80 mmol). The mixture was stirred under nitrogen protection at 100°C in a microwave oven for 8 hours. After the starting material was consumed, water (20 mL) was added to the mixture, and it was extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L HCOOH), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to obtain a white solid product (10.03 mg, yield 4.64%).

[0290] 1 H NMR (400MHz, DMSO-d6) δ12.18(br,1H),11.12(br,1H),8.94(t,J=5.2Hz,1H),8.89(s,1H),8.36( d,J=2.4Hz,1H),8.21(dd,J=8.4,2.4Hz,1H),7.73(s,1H),7.28(d,J=9.2Hz,1H),4.12(t,J=6.4H z,2H),3.59(t,J=5.2Hz,2H),3.38–3.37(m,2H),3.32–3.31(m,4H),2.62–2.56(m,2H),2.47–2.4 5(m,1H),1.81–1.73(m,2H),1.21(t,J=7.6Hz,3H),1.06(t,J=7.6Hz,3H),0.98(t,J=7.2Hz,3H).

[0291] 1. Synthesis scheme:

[0292] 2. Experimental Section:

[0293] 2.1

[0294] 2-Chloro-5-(cyclopropylmethoxy)isoniacaldehyde (05066-2)

[0295] At -78°C, LDA (8.17 mL, 16.3 mmol) was added dropwise to a THF (50 mL) solution of 2-chloro-5-(cyclopropylmethoxy)pyridine (2.0 g, 10.9 mmol). The mixture was stirred at -78°C for 0.5 h. Then DMF (1.59 g, 21.8 mmol) was added dropwise. The reaction was stirred at -78°C for 1 h under nitrogen protection. After the starting material was consumed, the reaction was quenched with saturated NH4Cl solution, extracted with EA (50 mL * 3), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography. Silicon-CS 80 g, 80 mL / min, silica gel, UV 254) yielded a yellow oily product (1.54 g, yield 67.0%).

[0296] ESI-MS m / z calcd for [C 10 H 10 ClNO2],[M+H + :212.0; found:212.2

[0297] 2.2

[0298] 2-(2-chloro-5-(cyclopropylmethoxy)pyridin-4-yl)quinazolin-4(3H)-one (05066-3)

[0299] A solution of 2-chloro-5-(cyclopropylmethoxy)isoniazol (1.54 g, 7.30 mmol) and 2-aminobenzamide (993 mg, 7.30 mmol) in DMSO (10 mL) was stirred overnight at 100 °C with an open container. After the starting material was consumed, it was poured into H2O (100 mL), and the resulting solid was purified by column chromatography (PE / THF = 1%–50%, silica gel-CS 40 g, 60 mL / min, silica gel, UV 254) to obtain a white solid (1.0 g, yield 41.9%).

[0300] ESI-MS m / z calcd for [C 17 H 14 [ClN3O2],[M+H] + :328.1; found:328.1

[0301] 2.3

[0302] tert-butyl (5-(cyclopropylmethoxy)-4-(4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)carbamate (05066-4)

[0303] Compound 2-(2-chloro-5-(cyclopropylmethoxy)pyridin-4-yl)quinazolin-4(3H)-one (50 mg, 0.153 mmol) was dissolved in 1,4-dioxane (5 mL), and Boc-amino (NH2Boc, 21.4 mg, 0.183 mmol), Pd2(dba)3 (14.0 mg, 0.0153 mmol), X-Phos (10.9 mg, 0.0229 mmol), and Cs2CO3 (124 mg, 0.381 mmol) were added sequentially. The mixture was stirred at 100 °C for 16 hours under nitrogen protection. After the starting material was consumed, the reaction solution was concentrated, and the crude product was purified by column chromatography (PE / THF = 1%–20%, silica gel-CS 20 g, 50 mL / min, UV 254) to give a yellow oily product (87 mg, 100% yield).

[0304] ESI-MS m / z calcd for [C 22 H 24 [N4O4], [M+H] + 409.2; found: 409.3

[0305] 2.4

[0306] 2-Amino-5-(cyclopropylmethoxy)polyglycoside-4-acyl)quinazolin-4(3H)-one (05066-5)

[0307] The compound tert-butyl (5-(cyclopropylmethoxy)-4-(4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)carbamate (87 mg, 0.213 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added at room temperature. The mixture was stirred at room temperature for 2 hours. After the starting material was consumed, the mixture was washed successively with saturated sodium bicarbonate aqueous solution (5 mL × 2), and then extracted with dichloromethane (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (PE / THF = 1%–50%; silica gel-CS 20 g, 30 mL / min, UV 254) to give a yellow oily product (50 mg, yield 76%).

[0308] ESI-MS m / z calcd for [C 17 H 16[N4O2], [M+H] + :309.1; found:309.3

[0309] 2.5

[0310] 6-((5-(cyclopropylmethoxy)-4-(4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl(amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyrazin-3-carboxamide (MX05066)

[0311] The compound 2-amino-5-(cyclopropylmethoxy)polyglycoside-4-acyl)quinazolin-4(3H)-one (50 mg, 0.153 mmol) was dissolved in 1,4-dioxane (5 mL), and R-1 (21.4 mg, 0.183 mmol), Pd2(dba)3 (14.0 mg, 0.0153 mmol), X-Phos (10.9 mg, 0.0229 mmol), and Cs2CO3 (124 mg, 0.381 mmol) were added sequentially. The mixture was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed (monitored by LCMS), the reaction solution was concentrated and purified sequentially by column chromatography (PE / THF = 1%–100%; column: Silica-CS12g; flow rate: 50 mL / min; detection wavelength: UV 254) and preparative HPLC (MeCN / H2O (10 mmol / L formic acid), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to obtain a yellow solid compound (2.07 mg, yield 5.2%).

[0312] 1 H NMR(400MHz,DMSO-d6)δ12.28(brs,1H),10.99(s,1H),10.14(s,1H),9.11(s,1 H),8.57(s,1H),8.21–8.17(m,3H),7.89–7.87(m,1H),7.82(s,1H),7.77-7.75 (m,1H),7.64-7.60(m,1H),7.34(t,J=8.0Hz,1H),4.01(d,J=6.8Hz,2H),3.96( s,3H),3.76(s,3H),1.23-1.187(m,1H),0.51–0.49(m,2H),0.33-0.32(m,2H).

[0313] 1. Synthesis scheme:

[0314] 2. Experimental Section:

[0315] 2.1

[0316] 2-Chloro-5-propoxypyridine (05067-1)

[0317] At 0°C, sodium hydride (1.4 g, 34.9 mmol) was added to a solution of 6-chloropyridin-3-ol (3 g, 23.3 mmol) in DMF (40 mL). The mixture was stirred at 0°C for half an hour, and then 1-bromopropane (4.3 g, 34.9 mmol) was added. The mixture was stirred at room temperature under nitrogen protection for 3 hours. After the starting material was consumed, the reaction was quenched with ice water (50 mL) and extracted three times with EA (60 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 1 to 1 / 5, silica gel-CS 120 g, 45 mL / min, silica gel, UV 254) to give a yellow oily product (3.52 g, yield 88.4%).

[0318] ESI-MS m / z calcd for [C8H] 10 ClNO][M+H + :172.1; found:172.2

[0319] 2.2

[0320] 2-Chloro-5-propoxyisocyanuric acid (05067-2)

[0321] At -78°C, LDA (6.58 mL, 2.0 M in THF) was added to a solution of 2-chloro-5-propoxypyridine (1.5 g, 8.77 mmol) in tetrahydrofuran (20 mL). The mixture was stirred under nitrogen protection at -78°C for half an hour, and DMF (1.28 g, 17.54 mmol) was added dropwise. The mixture was stirred under nitrogen protection at -78°C for another 2 hours. After the starting material was consumed, a saturated ammonium chloride solution (30 mL) was added to the mixture, and the mixture was extracted three times with EA (50 mL). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 1 to 1 / 6, silica gel-CS 80 g, 40 mL / min, silica gel, UV 254) to give a white solid product (1.0 g, yield 57.3%).

[0322] ESI-MS m / z calcd for [C9H] 10ClNO2][M+H] + :200.0; found:200.2

[0323] 2.3

[0324] 2-Chloro-5-propoxyisocyanuric acid nitrile (05067-3)

[0325] At room temperature, hydroxylamine hydrochloride (2.37 g, 34.16 mmol) was added to a solution of 2-chloro-5-propoxyisononial (1.7 g, 8.54 mmol) in ethanol (25 mL). The reaction mixture was stirred at 75 °C under nitrogen protection for half an hour. After the starting material was consumed, the mixture was concentrated by vacuum distillation. The mixture was dissolved in ethyl acetate (30 mL) and washed with saturated sodium bicarbonate solution (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Pyridine (12.14 g, 153.7 mmol) and MsCl (1.47 g, 12.8 mmol) were added to the mixture, and the reaction mixture was stirred at 75 °C under nitrogen protection for 2 hours. Water (30 mL) was added to the mixture, and the mixture was extracted twice with dichloromethane (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 1 to 1 / 3, silica gel-CS 40 g, 35 mL / min, silica gel, UV 254) to give a yellow solid product (1.4 g, yield 83.8%).

[0326] ESI-MS m / z calcd for[C9H9ClN2O][M+H] + :197.0; found:197.1

[0327] 2.4

[0328] (Z)-2-chloro-N'-hydroxy-5-propoxyisonicotinamide (05067-4)

[0329] At room temperature, hydroxylamine hydrochloride (993 mg, 14.29 mmol) and sodium bicarbonate (2.1 g, 25.00 mmol) were added to a methanol (25 mL) solution of 1.4 g (7.14 mmol) of 2-chloro-5-propoxyisonicotinamide (2.1 g, 25.00 mmol). The reaction mixture was stirred for 16 hours under nitrogen protection at 90 °C. After the starting material was consumed, the mixture was concentrated by vacuum distillation. Water (50 mL) was added to the mixture, and it was extracted three times with EA (70 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 1–1 / 3, silica gel-CS 80 g, 40 mL / min, silica gel, UV 254) to give a white solid product (1.35 g, yield 82.6%).

[0330] ESI-MS m / z calcd for [C9H] 12 ClN3O2][M+H] + :230.1; found:230.0

[0331] 2.5

[0332] 2-Chloro-5-propoxyisocyanimide (05067-5)

[0333] At room temperature, (Z)-2-chloro-N'-hydroxy-5-propoxyisonicotinamide (1.3 g, 5.68 mmol) was added to a solution of acetic acid (20 mL) with Raney nickel (500 mg) and ammonium formate (3.58 g, 56.8 mmol). The reaction mixture was stirred at 100 °C under argon for 2 hours. After the starting material was consumed, the mixture was filtered, and water (50 mL) was added to the filtrate. The mixture was then extracted three times with EA (50 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid product (1.1 g, 91.0% yield).

[0334] ESI-MS m / z calcd for [C9H] 12 ClN3O][M+H] + :214.1; found:214.0

[0335] 2.6

[0336] 2-(2-Chloro-5-propoxypyridin-4-yl)-5-cyclopentyl-6-methylpyrimidin-4(3H)-one (05067-6)

[0337] At room temperature, methyl 2-cyclopentyl-3-oxobutyrate (311 mg, 1.69 mmol) and sodium methoxide (305 mg, 5.64 mmol) were added to a methanol (5 mL) solution of 300 mg, 1.41 mmol, 2-chloro-5-propoxyisonicotinamide. The mixture was stirred overnight under nitrogen protection at 75 °C. After the starting material was consumed, water (30 mL) was added to the mixture, and the mixture was extracted twice with EA (50 mL). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 1 to 1 / 1, silica gel-CS 40 g, 35 mL / min, silica gel, UV 254) to give a yellow oily product (73 mg, yield 14.9%).

[0338] ESI-MS m / z calcd for [C 18 H 22 ClN3O2][M+H] + :348.1; found:348.0

[0339] 2.7

[0340] 6-((4-(5-cyclopentyl-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-5-propoxypyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (MX05067)

[0341] At room temperature, 6-amino-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (50 mg, 0.14 mmol), sodium tert-butoxide (27 mg, 0.28 mmol), Xantphos (8.1 mg, 0.014 mmol), and Pd2(dba)3 (12.8 mg, 0.014 mmol) were added to a solution of 2-(2-chloro-5-propoxypyridin-4-yl)-5-cyclopentyl-6-methylpyrimidin-4(3H)-one (50 mg, 0.14 mmol), tert-butoxide (2 mL), Xantphos (8.1 mg, 0.014 mmol), and Pd2(dba)3 (12.8 mg, 0.014 mmol) in a sealed tube under nitrogen protection at 120 °C for 16 hours. After the starting material was consumed, water (20 mL) was added to the mixture, and the mixture was extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated. The mixture was purified by silica gel column chromatography (MeOH / DCM = 0 / 1–1 / 10, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to obtain the crude product. The crude product was purified by preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to give a white solid compound (29.03 mg, yield 31.0%).

[0342] 1 H NMR(400MHz,DMSO-d6)δ12.12(s,1H),10.98(s,1H),10.11(s,1H),9.10(s,1H),8.57(s,1 H),8.14(s,1H),8.01(s,1H),7.84(s,1H),7.63(d,J=8.0Hz,2H),7.33(t,J=8.0Hz,1H),4. 07(t,J=6.4Hz,2H),3.96(s,3H),3.75(s,3H),3.10(t,J=8.8Hz,1H),2.33(s,3H),1.99–1. 92(m,2H),1.82–1.78(m,2H),1.74–1.67(m,4H),1.64–1.59(m,2H),0.95(t,J=7.2Hz,3H).

[0343] 1. Synthesis scheme:

[0344] 2. Experimental Section:

[0345] 2.1

[0346] 2-(5-bromo-2-propoxyphenyl)-5-(2,5-dihydrofuran-3-yl)-6-methylpyrimidin-4(3H)-one (05073-1)

[0347] Add 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane ((588.0 mg, 3.0 mmol), K3PO4 (637.0 mg, 3.0 mmol) and 1,4-dioxane / water (11.0 mL, v / v) to a mixed solvent of 2-(5-bromo-2-propoxyphenyl)-5-iodo-6-methylpyrimidin-4(3H)-one (450.0 mg, 1.0 mmol) and 1,4-dioxane / water (11.0 mL, v / v) to a mixed solvent of 1,4-dioxane / water (10:1). Pd(Ph3P)4 (116.0 mg, 0.1 mmol). The mixture was stirred at 90 °C under nitrogen protection. After the starting material was completely consumed, water (25 mL) was added, followed by extraction three times with dichloromethane (30 mL each time). The organic layers were combined, washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by column chromatography (methanol / dichloromethane = 0 / 1 to 1 / 10, silica gel-CS20 g, 40 mL / min, UV 254) to give a yellow oily product (440.0 mg, purity 75%, yield 84.4%).

[0348] ESI-MS m / z calcd for [C 18 H 19 BrN2O3][M+1] + :391.1; found:391.2.

[0349] 2.2

[0350] 3-(5-(2,5-dihydrofuran-3-yl)-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxybenzonitrile (05073-2)

[0351] Zn (552.0 mg, 8.44 mmol), DPPF (47 mg, 0.0844 mmol), and Pd2(dba)3 (77.3 mg, 0.0844 mmol) were added to a solution of 2-(5-bromo-2-propoxyphenyl)-5-(2,5-dihydrofuran-3-yl)-6-methylpyrimidin-4(3H)-one (440.0 mg, 75% purity, 0.844 mmol) in DMSO (15 mL). The mixture was stirred overnight at 130 °C. After the starting material was consumed, water (50 mL) was added, followed by extraction with dichloromethane (30 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (methanol / dichloromethane = 0 / 1 to 1 / 20, silica gel-CS20 g, 40 mL / min, silica gel, UV). 254) Purification yielded a yellow solid product (550 mg, purity 42.0%, yield 80.97%).

[0352] ESI-MS m / z calcd for [C 19 H 19 [N3O3][M+1] + :338.1; found:338.3.

[0353] 2.3

[0354] 3-(5-(2,5-dihydrofuran-3-yl)-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxybenzamide (05073-3)

[0355] Sodium hydroxide (274.0 mg, 6.85 mmol) was added to a mixed solution of 3-(5-(2,5-dihydrofuran-3-yl)-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxybenzonitrile (550.0 mg, 42% purity, 0.685 mmol) in methanol (15.0 mL) and hydrogen peroxide (0.5 mL). The mixture was stirred at 30 °C for 6 hours under nitrogen protection. After the starting material was consumed, water (50 mL) was added, and the mixture was extracted three times with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried with anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (methanol / dichloromethane = 0 / 1 to 1 / 10, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give a yellow solid product (150 mg, purity 80.0%, yield 33.76%).

[0356] ESI-MS m / z calcd for [C 19 H 21[N3O4][M+1] + :356.2; found:356.4.

[0357] 2.4

[0358] 3-(4-Methyl-6-oxo-5-(tetrahydrofuran-3-yl)-1,6-dihydropyrimidin-2-yl)-4-propoxybenzamide (05073-4)

[0359] Rh(PPh3)3Cl (62.4 mg) was added to a methanol (15.0 mL) solution of 3-(5-(2,5-dihydrofuran-3-yl)-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxybenzamide (150 mg, 80% purity, 0.338 mmol). The mixture was stirred overnight at 50 °C under hydrogen (1 MPa) in an autoclave. After the starting material was consumed, the mixture was filtered and concentrated. The crude product was purified by column chromatography (methanol / dichloromethane = 0 / 1 to 1 / 10, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give a yellow solid product (110 mg, 90.0% purity, 82.04% yield).

[0360] ESI-MS m / z calcd for [C 19 H 23 [N3O4][M+1] + :358.2; found:358.4.

[0361] 2.5

[0362] 4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-N-(trideuteratedmethyl)-6-(3-(4-methyl-6-oxo-5-(tetrahydrofuran-3-yl)-1,6-dihydropyrimidin-2-yl)-4-propoxybenzamide)nicotinamide (MX05073)

[0363] A mixture of 3-(4-methyl-6-oxo-5-(tetrahydrofuran-3-yl)-1,6-dihydropyrimidin-2-yl)-4-propoxybenzamide (71.5 mg, 0.2 mmol), 1,4-dioxane (3 mL), and DMF (3 mL) was placed in a microwave-safe reaction tube. Pd2(dba)3 (18.5 mg, 0.02 mmol), xantphos (23.0 mg, 0.04 mmol), BINAP (25.0 mg, 0.04 mmol), NaOMe (22.0 mg, 0.4 mmol), and t-BuOK (45.0 mg, 0.4 mmol) were added sequentially. After degassing with argon gas through a syringe for 1 minute, the mixture was stirred at 130 °C under microwave conditions for 3 hours. After the starting materials were consumed, water (20 mL) was added, and the mixture was extracted three times with dichloromethane (20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC [methylcyano / water, X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give the title product (32.0 mg, yield 23.0%) as a white solid.

[0364] 1 H NMR (400MHz, DMSO-d6) δ12.04(s,1H),10.72(d,J=8.4Hz,2H),8.64(s,1H),8.59(s,1H),8.31(d,J=2.4Hz,1H),8.22( s,1H),8.16(dd,J=8.8,2.4Hz,1H),7.78(d,J=2.0Hz,1H),7.63(dd,J=7.6,0.8Hz,1H),7.46(d,J=7.6Hz,1H),7.25–7 .20(m,2H),6.74(d,J=2.4Hz,1H),4.11(t,J=6.4Hz,2H),3.98–3.94(m,1H),3.92(s,3H),3.86–3.77(m,3H),3.62(s, 3H),3.53–3.44(m,1H),2.38(s,3H),2.35–2.26(m,1H),2.02–1.93(m,1H),1.80–1.72(m,2H),0.98(t,J=7.6Hz,3H).

[0365] 1. Synthesis scheme:

[0366] 2. Experimental Section:

[0367] 2.1

[0368] 6-((3-(5-cyclopentyl-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxyphenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-d3-nicotinamide (MX05078)

[0369] A mixture of 2-(5-amino-2-propoxyphenyl)-5-cyclopentyl-6-methylpyrimidin-4(3H)-one (36 mg, 0.11 mmol), 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-d3-nicotinamide (48 mg, 0.13 mmol), cesium carbonate (106 mg, 0.33 mmol), Brettphos (10 mg, 0.02 mmol), and Brettphos Pd G3 (12 mg, 0.01 mmol) in 1,4-dioxane (3.5 mL) was placed into a sealed tube. The tube was then purged with argon to remove air. The tube was then capped and stirred overnight at 110 °C. After the starting materials were consumed, the product was concentrated and purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 10, silica gel-CS12g, 30mL / min, silica gel, UV 254). The crude product was then purified by preparative HPLC (MeCN / H2O (10mmol / L NH4HCO3), X-Select 10μm 19*250mm, 20mL / min, UV 254) to obtain a white solid product (27.54mg, yield 28%).

[0370] 1 H NMR (400MHz, DMSO-d6) δ11.68(s,1H),10.52(s,1H),9.10(s,1H),8.55(s,1H),8.40(d,J=6.8 Hz,2H),8.00(d,J=2.8Hz,1H),7.78(dd,J=8.8,2.4Hz,1H),7.52(dd,J=7.6,3.2Hz,2H),7.18– 7.10(m,2H),6.56(s,1H),4.03(t,J=6.4Hz,2H),3.95(s,3H),3.73(s,3H),3.12–3.07(m,1H) ,2.32(s,3H),1.99–1.93(m,2H),1.83–1.68(m,6H),1.66–1.58(m,2H),1.00(t,J=7.6Hz,3H).

[0371] 1. Synthesis scheme:

[0372] 2. Experimental Section:

[0373] 2.1

[0374] 5-Bromo-2-propoxybenzonitrile (05079-1)

[0375] At 25°C, bromopropane (4.23 g, 30.46 mmol) was added to a DMF (30 mL) solution of 5-bromo-2-hydroxybenzonitrile (3 g, 15.23 mmol) and potassium carbonate (4.2 g, 18.27 mmol). The mixture was stirred overnight at 80°C. After the starting material was completely consumed, 25 mL of water was added to quench the reaction, and the mixture was extracted twice with ethyl acetate (EA) (100 mL each time). The organic layers were combined, washed with 100 mL of brine, dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 1, silica gel-CS 20 g, 60 mL / min, silica gel, UV 254) to obtain the target product, which was a colorless oil (2.3 g, yield 63.2%).

[0376] ESI-MS m / z calcd for [C 10 H 10 BrNO][M+H] + 239.99; found: 242.1

[0377] 2.2

[0378] 5-Bromo-N-hydroxy-2-propoxybenzimidazole carboxamide (05079-2)

[0379] Hydroxylamine hydrochloride (1.74 g, 25.08 mmol) was added to a solution of 5-bromo-2-propoxybenzonitrile (2 g, 8.36 mmol), potassium carbonate (3.46 g, 25.08 mmol) in EtOH (20 mL) and water (4 mL). The mixture was then stirred overnight at 80 °C. After the starting material was consumed, the reaction solution was concentrated to obtain the crude product (2.23 g).

[0380] ESI-MS m / z calcd for [C 10 H 13 BrN2O2][M+H] + :273.0; found:273.0

[0381] 2.3

[0382] 5-Bromo-2-propoxybenzimidazole carboxamide (05079-3)

[0383] At room temperature, Raney-Ni (200 mg) and ammonium formate (2.8 g, 44.7 mmol) were added to a 20 mL acetic acid solution of 5-bromo-N-hydroxy-2-propoxybenzimidazole carboxamide (2.03 g, 7.46 mmol). The mixture was then stirred at 100 °C for 2 h. After the starting material was consumed, the reaction mixture was filtered and concentrated under reduced pressure. The crude product was dissolved in 200 mL of water, and the pH was adjusted to 10 with potassium carbonate (K₂CO₃). The mixture was extracted twice with 200 mL of dichloromethane (DCM). The organic phase was washed with 100 mL of brine, dried over anhydrous sodium sulfate (Na₂SO₄), filtered, concentrated under reduced pressure, and dissolved in 50 mL of ethyl acetate (EA). The product precipitated and was filtered to give the target product (1.3 g, 68% yield).

[0384] ESI-MS m / z calcd for [C 10 H 13 BrN2O][M+H] + ::257.02; found:257.2

[0385] 2.4

[0386] 2-(5-bromo-2-propoxyphenyl)-5,6-diethylpyrimidin-4(3H)-one (05079-4)

[0387] At room temperature, ethyl 2-ethyl-3-oxovalerate (1.16 mg, 5.85 mmol) and sodium methoxide (315 mg, 5.85 mmol) were added to a methanol (50 mL) solution of 5-bromo-2-propoxybenzimidazole carboxamide (500 mg, 1.95 mmol). The mixture was then stirred overnight at 80 °C. After the starting material was consumed, the reaction solution was concentrated to obtain the crude product. The crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 0, silica gel-CS12 g, 40 mL / min, silica gel, UV 254) to give a brown oily product (158 mg, yield 22.2%).

[0388] ESI-MS m / z calcd for [C 17 H 21 BrN2O2][M+H] + 365.0; found: 367.2

[0389] 2.5

[0390] 6-[(3-(4,5-diethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxyphenyl)amino]-4-[(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino]-N-(trideuterated methyl)nicotinamide (MX05079)

[0391] At room temperature, Pd2(dba)3 (29.3 mg, 0.032 mmol) was added to a solution of 2-(5-bromo-2-propoxyphenyl)-5,6-diethylpyrimidin-4(3H)-one (60 mg, 0.164 mmol), 6-amino-4-[(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino]-N-(trifluoromethyl)nicotinamide (87.7 mg, 0.246 mmol), Cs2CO3 (106.8 mg, 0.328 mmol), xantphos (18.5 mg, 0.032 mmol) in 1,4-dioxane (3 mL). The reaction was heated at 130 °C for 1 hour under microwave. After the starting materials were consumed, the reaction solution was concentrated, and the crude product was analyzed by preparative HPLC [MeCN / H2O (10 mmol / L)]. Purification was performed using X-Select (10 μm 19*250 mm, 20 mL / min, UV 254) to obtain a white solid product (3.18 mg, yield 3.02%).

[0392] 1 H NMR(400MHz,DMSO-d6)δ11.77(s,1H),10.51(s,1H),9.10(s,1H),8.55(s,1H),8.40(s,2H),7 .97(d,J=2.4Hz,1H),7.80(dd,J=8.8,2.4Hz,1H),7.51(t,J=7.2Hz,2H),7.18–7.10(m,2H),6 .55(s,1H),4.02(t,J=6.4Hz,2H),3.95(s,3H),3.73(s,3H),2.60–2.54(m,3H),2.46–2.44(m ,1H),1.78–1.73(m,2H),1.20(t,J=7.6Hz,3H),1.05(t,J=7.6Hz,3H),0.982(t,J=7.6Hz,3H).

[0393] 1. Synthesis scheme:

[0394] 2. Experimental Section:

[0395] 2.1

[0396] 3-((2-chloro-5-(trideuterylmethylcarbamoyl)pyridin-4-yl)amino)-2-methoxybenzoic acid (05080-1)

[0397] To a solution of 4,6-dichloro-N-trideuterium nicotinamide (50 mg, 0.24 mmol) in tetrahydrofuran (3 mL), 3-amino-2-methoxybenzoic acid (40 mg, 0.24 mmol) and LiHMDS (1 M in THF) (1.68 mL, 1.68 mmol) were added at 0 °C. The mixture was stirred at room temperature for 2 hours under nitrogen protection. After the starting material was consumed, 1 M HCl was added to adjust the pH of the reaction mixture to 7, and the mixture was extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 0, silica gel-CS 12 g, 30 mL / min, silica gel, UV 254) to give a white solid product (40 mg, yield 49%).

[0398] ESI-MS m / z calcd for [C 15 H 11 D3ClN3O4][M+H] + :339.1; found:339.0

[0399] 2.2

[0400] 6-Chloro-4-(2-methoxy-3-((2-morpholinoethyl)carbamoyl)phenyl)amino-N-trideuterated methylnicotinamide (05080-2)

[0401] To a solution of 3-((2-chloro-5-(trideuterylmethylcarbamoyl)pyridin-4-yl)amino)-2-methoxybenzoic acid (40 mg, 0.12 mmol), DIEA (31 mg, 0.24 mmol), HATU (90 mg, 0.24 mmol), and 2-morpholinoethylamine (15 mg, 0.12 mmol) were added. The mixture was stirred overnight at room temperature under nitrogen protection. After the starting material was consumed, the mixture was cooled and added to water (20 mL), and extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM / MeOH = 0 / 1 to 1 / 0, silica gel-CS 12 g, 30 mL / min, silica gel-CS, UV 254) to give a white solid product (46 mg, yield 85%).

[0402] ESI-MS m / z calcd for [C 21 H 23 D3ClN5O4][M+H] + :451.2; found:451.0

[0403] 2.3

[0404] 6-[(3-(5-cyclopentyl-4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxyphenyl)amino]-4-[(2-methoxy-3-[(2-morpholinylethyl)carbamoyl]phenyl)amino]-N-trideuterated methylnicotinamide (MX05080)

[0405] 6-Chloro-4-(2-methoxy-3-((2-morpholinoethyl)carbamoyl)phenyl)amino-N-trideuterated methylnicotinamide (55 mg, 0.12 mmol) was mixed with 5-amino-2-propoxy-2-(5-cyclopentyl-6-methylpyrimidin-4(3H)-one)benzene (40 mg, 0.12 mmol), Brettphos Pd-G3 (11 mg, 0.012 mmol), Brettphos (6.5 mg, 0.012 mmol), and Cs₂CO₃ (80 mg, 0.24 mmol) in a solution of 1,4-dioxane (2 mL). The mixture was stirred overnight at 110 °C under nitrogen protection. After the starting material was consumed, the mixture was cooled and added to water (20 mL), and extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried with anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to obtain a yellow solid product (5.45 mg, yield 6%).

[0406] 1H NMR (400MHz, DMSO-d6) δ10.54(s,1H),9.11(s,1H),8.41(s,2H),8.32(t,J=5.2Hz,1H),7.99(d,J=2.8Hz ,1H),7.78(d,J=8.8Hz,1H),7.56(d,J=8Hz,1H),7.34(d,J=7.6Hz,1H),7.12–7.10(m,2H),6.51(s,1H), 4.03(t,J=6.4Hz,2H),3.75(s,3H),3.58(t,J=4.4Hz,4H),3.43–3.39(m,2H),3.11–3.07(m,1H),2.47–2 .42(m,4H),2.32(s,3H),1.99–1.95(m,2H),1.83–1.73(m,4H),1.70–1.58(m,4H),0.99(t,J=7.2Hz,3H).

[0407] The compounds prepared by the above method or obtained by referring to the above method are summarized in the table below (where the prefix MX is omitted):

[0408] Example 2: Enzyme activity inhibition experiment of the disclosed compound

[0409] 2.1 TYK2 enzyme activity inhibition experiment

[0410] The inhibition of TYK2 enzyme activity by compounds was tested using the FP method. TYK2 (Sino, Cat: MF14Ju3009) enzyme solution and JH2 probe1 (BPS, Cat: 78103) substrate solution were prepared in reaction buffer (50 mM HEPES (pH 7.5) (Solarbio, Cat: H1095)). The final working concentrations of TYK2 and JH2 probe1 were 100 nM and 1 nM, respectively. The positive control BMS-986165 was initially prepared at a concentration of 1 μM on TYK2, diluted 4-fold, 10 doses. The initial concentrations of the test compounds on TYK2 were all 10 μM, diluted 3-fold, 10 doses. The stock solutions of the test compounds were vortexed thoroughly to prepare working solutions with a concentration of 2 μM, and then serially diluted 3-fold to obtain 10 different concentrations of working solutions. This part of the reaction was performed in dilution source plates. 0.05 μL of the compound diluted in 100% DMSO from the Source plate was transferred to a 384-well plate (Corming 4514) using acoustic liquid delivery technology (Echo 655). The plate was centrifuged at 1000 rpm for 1 minute to achieve a final DMSO concentration of 0.5%. 5 μL of TYK2 enzyme solution was then transferred to the 384-well plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. 5 μL of Substrate (JH2 probe 1) solution was then transferred to the 384-well plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 60 minutes. Finally, the FP signal was read using BMG (PHERAstar FSX). The IC was obtained using GraphPad Prism software. 50 Fitting values ​​and nonlinear regression curves.

[0411] 2.2 PDE5A1 enzyme activity inhibition experiment

[0412] The inhibitory effect of compounds on PDE5A1 enzyme activity was tested using the FP method. PDE5A1 (BPS, Cat: 60050) enzyme and substrate (FAM-cyclic guanosine monophosphate) (BPS, Cat: 60201) solutions were prepared in reaction buffer (1×IMAP Reaction Buffer containing 0.1% BSA with 1 mM DTT). The final concentrations of PDE5A1 and FAM-cyclic guanosine monophosphate were 1 nM and 100 nM, respectively. The positive control, Sildenafil citrate, was initially diluted 3-fold to 10 doses on PDE5A1. The test compounds were initially diluted 3-fold to 10 doses on PDE5A1. The stock solution of the test compound was heated and vortexed to mix thoroughly. 6 μL of the compound was added to 54 μL of DMSO and mixed evenly to prepare a 1 mM starting working solution. The solution was then serially diluted 3 times to obtain 10 different final working solutions. All of these reactions were carried out in dilution source plates. 0.05 μL of the compound diluted in 100% DMSO from the Source plate was transferred to a 384-well plate (Corning 4514) using acoustic liquid delivery technology (Echo 655). The plate was centrifuged at 1000 rpm for 1 minute to achieve a final DMSO concentration of 1%. 2.5 μL of PDE5A1 enzyme solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, then incubated at 25°C for 10 min. 2.5 μL of Sub (FAM-cyclic guanosine monophosphate) solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, then incubated at 25°C for 60 min. 15 μL of the binding agent mixture was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, then incubated at 25°C for 60 min. Finally, the FP signal was read using BMG (PHERAstar FSX). IC50 was obtained using GraphPad Prism software. 50 Fitting values ​​and nonlinear regression curves.

[0413] 2.3 Test Results

[0414] The test results for the exemplary compounds disclosed herein are summarized in the table below:

[0415] Note: A represents IC 50 ≤10nM; B represents 10nM <IC 50 ≤100nM; C represents 100nM <IC 50 ≤3μM; D represents 3μM <IC 50 ≤30μM.

[0416] The above experimental results demonstrate that the disclosed compounds possess excellent dual-target (TYK2 and PDE5) inhibitory activity. These compounds facilitate the development of multispecific targeted therapies for different patient populations, which will be particularly beneficial for improving treatment efficacy and / or reducing side effects, thereby enhancing patient compliance and quality of life.

Claims

1. Compounds of Formula I, their racemates, stereoisomers, tautomers, isotope-labeled compounds, solvates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs: in: W represents N or CH; m represents 0, 1, 2, 3, 4 or 5; n represents 0, 1, 2, 3, 4, or 5; p represents 0, 1, 2, 3, 4 or 5; q represents 0, 1, 2, 3, 4, or 5; X1 represents chemical bonds, -NH-C(=O)-, -C(=O)-NH-, -NH-C(=O)-NH-, -NH-C(=O)-O-, -O-, -S-, -NR q -, -S(=O)-, -S(=O)2-, -C(=O-), and the following groups without substitution or with optional substitution: -C 1-6 Alkylene -C(=O)-NH-, -NH-C(=O)-C 1-6 Alkylene-, -NH-C(=O)-C 3-20 Cycloalkyl-,-C(=O)-NH-C 1-6 Alkylene-, -NH-C 1- 6-alkylene-C(=O)-, -C 1-6 alkylene-, -C 1-6 Alkyl-NH-, -NH-C 1-6 alkylene-, -C 1-6 Alkylene -O-, -C 2- 6-Ideenyl-, -C 2-6 -, -C ethynyl 1-6 alkeneoxy-; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 1-6 Alkyl-SO2-C 1-6 Alkyl, C 1-6 Alkyl-SO-C 1-6 Alkyl, C 2-10 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl; X2 represents chemical bonds, -C(=O)-, -NH-C(=O)-, -C(=O)-NH-, -NH-C(=O)-NH-, -NH-C(=O)-O-, -O-, -S-, -NR q -、-S(=O)-、-S(=O)2- The following groups are unsubstituted or optionally substituted: -C 1-6 Alkylene -C(=O)-NH-, -C(=O)-NH-C 1-6 alkylene-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene -O-, -C 2-6 imidene-, -C 2-6 -, -C ethynyl 1-6 alkeneoxy-; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 1-6 Alkyl-SO2-C 1-6 Alkyl, C 1-6 Alkyl-SO-C 1-6 Alkyl, C 2-10 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl; X3 represents chemical bonds, -O-, -S-, and -NR. q -, -S(=O)-, -S(=O)2-, -C(=O-), and the following groups without substitution or with optional substitution: -C 1-6 Alkylene -C(=O)-NH-, -C(=O)-NH-C 1-6 Alkylene-, -NH-C(=O)-, -NH-C(=O)-NH-, -NH-C(=O)-O-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene -O-, -C 2-6 imidene-, -C 2-6 -, -C ethynyl 1-6 alkeneoxy-; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 1-6 Alkyl-SO2-C 1-6 Alkyl, C 1-6 Alkyl-SO-C 1-6 Alkyl, C 2- 10 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl; X4 represents chemical bonds, -O-, -S-, and -NR. q -, -S(=O)-, -S(=O)2-, -C(=O-), and the following groups without substitution or with optional substitution: -C 1-6 Alkylene -C(=O)-NH-, -C(=O)-NH-C 1-6 Alkylene-, -NH-C(=O)-, -NH-C(=O)-NH-, -NH-C(=O)-O-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene -O-, -C 2-6 imidene-, -C 2-6 -, -C ethynyl 1-6 alkeneoxy-; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 1-6 Alkyl-SO2-C 1-6 Alkyl, C 1-6 Alkyl-SO-C 1-6 Alkyl, C 2- 10 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl; X5 represents chemical bonds, -O-, -S-, and -NR. q -, -S(=O)-, -S(=O)2-, -C(=O-), and the following groups without substitution or with optional substitution: -C 1-6 Alkylene -C(=O)-NH-, -C(=O)-NH-C 1-6 Alkylene-, -NH-C(=O)-, -NH-C(=O)-NH-, -NH-C(=O)-O-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene -O-, -C 2-6 imidene-, -C 2-6 -, -C ethynyl 1-6 alkeneoxy-; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 1-6 Alkyl-SO2-C 1-6 Alkyl, C 1-6 Alkyl-SO-C 1-6 Alkyl, C 2- 10 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl; R q Selected from H, C 1-20 Alkyl, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-20 aryl, 5-20 heteroaryl, wherein each group may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 and NR 1.2 R 1.3 ; A represents a chemical bond, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 Cycloalkyl 5-20-membered heteroaryl, 3-20-membered heterocycloalkyl 3-C 6- 20 aryl, 3-20 membered heterocyclic alkyl and 5-20 membered heteroaryl, 5-20 membered heterocyclic alkenyl and C 6-20 Aryl, 5-20 membered heterocyclic alkenyl and 5-20 membered heteroaryl, C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 Cycloalkenyl 5-20 quinone heteroaryl groups; B is a chemical bond, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 Cycloalkyl 5-20-membered heteroaryl, 3-20-membered heterocycloalkyl 3-C 6- 20 aryl, 3-20 membered heterocyclic alkyl and 5-20 membered heteroaryl, 5-20 membered heterocyclic alkenyl and C 6-20 Aryl, 5-20 membered heterocyclic alkenyl and 5-20 membered heteroaryl, C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 Cycloalkenyl 5-20 quinone heteroaryl groups; C is a chemical bond, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 Cycloalkyl 5-20-membered heteroaryl, 3-20-membered heterocycloalkyl 3-C 6- 20 aryl, 3-20 membered heterocyclic alkyl and 5-20 membered heteroaryl, 5-20 membered heterocyclic alkenyl and C 6-20 Aryl, 5-20 membered heterocyclic alkenyl and 5-20 membered heteroaryl, C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 Cycloalkenyl 5-20 quinone heteroaryl groups; D represents a chemical bond, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 Cycloalkyl 5-20-membered heteroaryl, 3-20-membered heterocycloalkyl 3-C 6- 20 aryl, 3-20 membered heterocyclic alkyl and 5-20 membered heteroaryl, 5-20 membered heterocyclic alkenyl and C 6-20 Aryl, 5-20 membered heterocyclic alkenyl and 5-20 membered heteroaryl, C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 Cycloalkenyl 5-20 quinone heteroaryl groups; R1 represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, and C. 1-6 Alkyl, C 2-10 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20-membered heteroaryl, C 1-6 Alkyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -OR 1.1 -COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1-10 Alkyl-COR 1.1 -COONR 1.1 -C 1-10 Alkyl-COONR 1.1 -CONOH, -C 1-10 Alkyl-CONOH, -CO-NR 1.1 -C 1-10 Alkyl-CO-NR 1.1 -CH=CHCOOR 1.1 -CO-NR 1.1 -CH2CO-NR 1.1 -CH=CHCO-NR 1.1 -NR 1.2 R 1.3 -C 1-10 Alkyl-NR 1.2 R 1.3 -SR 1.1 -C 1-10 Alkyl-SR 1.1 -SOR 1.1 -C 1- 10 Alkyl-SOR 1.1 -SO2-R 1.1 -C 1-10 Alkyl-SO2R 1.1 -SO2-NR 1.2 R 1.3 or -C 1-10 Alkyl-SO2-NR 1.2 R 1.3 Each of the stated groups may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 NR 1.2 R 1.3 C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 2-10 alkenyl and C 2-10 alkynyl group; R2 represents hydrogen, deuterium, halogen, -CN, -OH, -SH, -NH2, -NO2, and C. 1-6 Alkyl, C 2-10 alkenyl, C 3-20 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -OR 1.1 -COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1- 10 Alkyl-COR 1.1 -COONR 1.1 -C 1-10 Alkyl-COONR 1.1 -CONOH, -C 1-10 Alkyl-CONOH, -CO-NR 1.1 -C 1-10 Alkyl-CO-NR 1.1 -CH=CHCOOR 1.1 -CO-NR 1.1 -CH2CO-NR 1.1 -CH=CHCO-NR 1.1 -NR 1.2 R 1.3 -C 1-10 Alkyl-NR 1.2 R 1.3 -SR 1.1 -C 1-10 Alkyl-SR 1.1 -SOR 1.1 -C 1-10 Alkyl-SOR 1.1 -SO2-R 1.1 -C 1-10 Alkyl-SO2R 1.1 -SO2-NR 1.2 R 1.3 or -C 1-10 Alkyl-SO2-NR 1.2 R 1.3 Each of the stated groups may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 NR 1.2 R 1.3 C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 2-10 alkenyl and C 2-10 alkynyl group; R a Represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-10 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20-membered heteroaryl, C 1-6 Alkyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -OR 1.1 -COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1-10 Alkyl-COR 1.1 -COONR 1.1 -C 1-10 Alkyl-COONR 1.1 -CONOH, -C 1-10 Alkyl-CONOH, -CO-NR 1.1 -C 1-10 Alkyl-CO-NR 1.1 -CH=CHCOOR 1.1 -CO-NR 1.1 -CH2CO-NR 1.1 -CH=CHCO-NR 1.1 -NR 1.2 R 1.3 -C 1-10 Alkyl-NR 1.2 R 1.3 -SR 1.1 -C 1-10 Alkyl-SR 1.1 -SOR 1.1 -C 1- 10 Alkyl-SOR 1.1 -SO2-R 1.1 -C 1-10 Alkyl-SO2R 1.1 -SO2-NR 1.2 R 1.3 or -C 1-10 Alkyl-SO2-NR 1.2 R 1.3 Each of the stated groups may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 NR 1.2 R 1.3 C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 2-10 alkenyl and C 2-10 alkynyl group; Or, R2, R a Together with the atoms attached to it, it forms the following groups fused with ring A: C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 membered heteroaryl, which may be unsubstituted or optionally substituted with one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 2-10 alkenyl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20 heteroaryl, C 1-6 Alkyl-5-20 heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3- 20 Cycloalkyl-5-20 heteroaryl, C 3-20 Cycloalkyl-5-20 heteroaryl-, C 2-10 alkenyl, C 2-6 alkynyl group, OR 1.1 COOR 1.1 C 1-10 -COOR 1.1 COR 1.1 C 1-10 -COR 1.1 COONR 1.1 C 1-10 -COONR 1.1 CONOH, C 1-10 -CONOH, CO-NR 1.1 C 1-10 -CO-NR 1.1 CH = CHCOOR 1.1 CO-NR 1.1 CH2CO-NR 1.1 CH=CHCO-NR 1.1 NR 1.2 R 1.3 C 1-10 -NR 1.2 R 1.3 SR 1.1 C 1-10 -SR 1.1 SOR 1.1 C 1-10 -SOR 1.1 SO2-R 1.1 C 1-10 -SO2R 1.1 or SO2-NR 1.2 R 1.3 Each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, OH, OR. 1.1 Halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- Aryl and NR 1.2 R 1.3 ; R b Represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-10 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20-membered heteroaryl, C 1-6 Alkyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -OR 1.1 -COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1-10 Alkyl-COR 1.1 -COONR 1.1 -C 1-10 Alkyl-COONR 1.1 -CONOH, -C 1-10 Alkyl-CONOH, -CO-NR 1.1 -C 1-10 Alkyl-CO-NR 1.1 -CH=CHCOOR 1.1 -CO-NR 1.1 -CH2CO-NR 1.1 -CH=CHCO-NR 1.1 -NR 1.2 R 1.3 -C 1-10 Alkyl-NR 1.2 R 1.3 -SR 1.1 -C 1-10 Alkyl-SR 1.1 -SOR 1.1 -C 1- 10 Alkyl-SOR 1.1 -SO2-R 1.1 -C 1-10 Alkyl-SO2R 1.1 -SO2-NR 1.2 R 1.3 or -C 1-10 Alkyl-SO2-NR 1.2 R 1.3 Each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1- 6-alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 NR 1.2 R 1.3 C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 2-10 alkenyl and C 2-10 alkynyl group; Or, R a R b Together with the atoms it is attached to, they form C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 membered heteroaryl, which may be unsubstituted or optionally substituted with one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1- 6-alkyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 2-10 alkenyl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20 heteroaryl, C 1-6 Alkyl-5-20 heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20 heteroaryl, C 3-20 Cycloalkyl-5-20 heteroaryl-, C 2-10 alkenyl, C 2-6 alkynyl group, OR 1.1 COOR 1.1 C 1-10 -COOR 1.1 COR 1.1 C 1-10 -COR 1.1 COONR 1.1 C 1-10 -COONR 1.1 CONOH, C 1-10 -CONOH, CO-NR 1.1 C 1-10 -CO-NR 1.1 CH = CHCOOR 1.1 CO-NR 1.1 CH2CO-NR 1.1 CH=CHCO-NR 1.1 NR 1.2 R 1.3 C 1-10 -NR 1.2 R 1.3 SR 1.1 C 1-10 -SR 1.1 SOR 1.1 C 1-10 -SOR 1.1 SO2-R 1.1 C 1-10 -SO2R 1.1 or SO2-NR 1.2 R 1.3 Each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, OH, OR. 1.1 Halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- Aryl and NR 1.2 R 1.3 ; R c Represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-10 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20-membered heteroaryl, C 1-6 Alkyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -OR 1.1 -COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1-10 Alkyl-COR 1.1 -COONR 1.1 -C 1-10 Alkyl-COONR 1.1 -CONOH, -C 1-10 Alkyl-CONOH, -CO-NR 1.1 -C 1-10 Alkyl-CO-NR 1.1 -CH=CHCOOR 1.1 -CO-NR 1.1 -CH2CO-NR 1.1 -CH=CHCO-NR 1.1 -NR 1.2 R 1.3 -C 1-10 Alkyl-NR 1.2 R 1.3 -SR 1.1 -C 1-10 Alkyl-SR 1.1 -SOR 1.1 -C 1- 10 Alkyl-SOR 1.1 -SO2-R 1.1 -C 1-10 Alkyl-SO2R 1.1 -SO2-NR 1.2 R 1.3 or -C 1-10 Alkyl-SO2-NR 1.2 R 1.3 Each of the stated groups may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 NR 1.2 R 1.3 C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 2-10 alkenyl and C 2-10 alkynyl group; Or, R2, R c Together with the atoms it is attached to, it forms a C that is fused with the ring C. 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 membered heteroaryl, which may be unsubstituted or optionally substituted with one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 2-10 alkenyl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20 heteroaryl, C 1-6 Alkyl-5-20 heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20 heteroaryl, C 3-20 Cycloalkyl-5-20 heteroaryl-, C 2-10 alkenyl, C 2-6 alkynyl group, OR 1.1 COOR 1.1 C 1-10 -COOR 1.1 COR 1.1 C 1-10 -COR 1.1 COONR 1.1 C 1-10 -COONR 1.1 CONOH, C 1-10 -CONOH, CO-NR 1.1 C 1-10 -CO-NR 1.1 CH = CHCOOR 1.1 CO-NR 1.1 CH2CO-NR 1.1 CH=CHCO-NR 1.1 NR 1.2 R 1.3 C 1-10 -NR 1.2 R 1.3 SR 1.1 C 1-10 -SR 1.1 SOR 1.1 C 1-10 -SOR 1.1 SO2-R 1.1 C 1-10 -SO2R 1.1 or SO2-NR 1.2 R 1.3 Each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, OH, OR. 1.1 Halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- Aryl and NR 1.2 R 1.3 ; R d Represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-10 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20-membered heteroaryl, C 1-6 Alkyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -OR 1.1 -COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1-10 Alkyl-COR 1.1 -COONR 1.1 -C 1-10 Alkyl-COONR 1.1 -CONOH, -C 1-10 Alkyl-CONOH, -CO-NR 1.1 -C 1-10 Alkyl-CO-NR 1.1 -CH=CHCOOR 1.1 -CO-NR 1.1 -CH2CO-NR 1.1 -CH=CHCO-NR 1.1 -NR 1.2 R 1.3 -C 1-10 Alkyl-NR 1.2 R 1.3 -SR 1.1 -C 1-10 Alkyl-SR 1.1 -SOR 1.1 -C 1- 10 Alkyl-SOR 1.1 -SO2-R 1.1 -C 1-10 Alkyl-SO2R 1.1 -SO2-NR 1.2 R 1.3 or -C 1-10 Alkyl-SO2-NR 1.2 R 1.3 Each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1- 6-alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 NR 1.2 R 1.3 C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 2-10 alkenyl and C 2-10 alkynyl group; Or, R c With R d Together with the atoms it is attached to, they form C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 membered heteroaryl, which may be unsubstituted or optionally substituted with one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1- 6-alkyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 2-10 alkenyl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20 heteroaryl, C 1-6 Alkyl-5-20 heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20 heteroaryl, C 3-20 Cycloalkyl-5-20 heteroaryl-, C 2-10 alkenyl, C 2-6 alkynyl group, OR 1.1 COOR 1.1 C 1-10 -COOR 1.1 COR 1.1 C 1-10 -COR 1.1 COONR 1.1 C 1-10 -COONR 1.1 CONOH, C 1-10 -CONOH, CO-NR 1.1 C 1-10 -CO-NR 1.1 CH = CHCOOR 1.1 CO-NR 1.1 CH2CO-NR 1.1 CH=CHCO-NR 1.1 NR 1.2 R 1.3 C 1-10 -NR 1.2 R 1.3 SR 1.1 C 1-10 -SR 1.1 SOR 1.1 C 1-10 -SOR 1.1 SO2-R 1.1 C 1-10 -SO2R 1.1 or SO2-NR 1.2 R 1.3 Each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, OH, OR. 1.1 Halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- Aryl and NR 1.2 R 1.3 ; R e is -Y-Z; Y represents chemical bond, -O-, -S-, -NR q -, -S(=O)-, -S(=O)2-, -C(=O-), and the following groups without substitution or with optional substitution: -C 1-6 Alkylene -C(=O)-NH-, -C(=O)-NH-C 1-6 Alkylene-, -C(=O)-NH-, -C 1-6 alkylene-, -C 1- 6-alkylene-NH-,-C 1-6 Alkylene-O-, C 2-6 imidene group, C 2-6 Ethyne group, C 1-6 Alkyloxy group; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl; Each Z is the same or different, and independently represents hydrogen, deuterium, and C. 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6- 20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, -3-20-membered heterocycloalkyl-C 6-20 Aryl, 3-20 membered heterocyclic alkyl-C 6-20 aryl-, -3-20-membered heterocyclic alkyl-5-20-membered heteroaryl, 3-20-membered heterocyclic alkyl-5-20-membered heteroaryl-, -5-20-membered heterocyclic alkenyl-C 6-20 Aryl, 5-20 membered heterocyclic alkenyl-C 6-20 aryl-, -5-20-membered heterocyclic alkenyl-C 5-20 heteroaryl, C 5-20 Heterocyclic alkenyl-C 5-20 heteroaryl-, -C 5-20 Cycloalkenyl-C 6-20 Aryl, C 5-20 Cycloalkenyl-C 6-20 Aryl-, -C 5-20 Cycloalkenyl-5-20 heteroaryl, C 5-20 cycloalkenyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 cycloalkyl 5-20-membered heteroaryl, C 3-20 Cycloalkyl 5-20-membered heteroaryl-, -3-20-membered heterocycloalkyl 5-20-membered heteroaryl-, -3-20-membered heterocycloalkyl- 6- 20 Aryl, 3-20 membered heterocyclic alkyl benzo[C] 6-20 aryl-,-3-20-membered heterocyclic alkyl benzo-C 5-20 Heteroaryl, 3-20 membered heterocyclic alkyl phenocrysts 5- 20 Heteroaryl-, -5-20-membered heterocyclic alkenyl benzo[C] 6-20 aryl-, 5-20 membered heterocyclic alkenyl benzo[C] 6-20 aryl-, -5-20 quinone heterocyclic alkenyl 5-20 quinone heteroaryl, 5-20 quinone heterocyclic alkenyl 5-20 quinone heteroaryl-, -C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 cycloalkenyl-C 6-20 Aryl-, -C 5-20 Cycloalkenyl 5-20 quinone heteroaryl, C 5-20 cycloalkenyl 5-20-membered heteroaryl-, wherein each C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 The aryl group and the 5-20 membered heteroaryl group can be independently monocyclic or polycyclic; the above groups can be unsubstituted or arbitrarily substituted at the ortho, para, meta, or N, O, and S atoms, each of which may be independently and optionally substituted by one, two, or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-5-20-membered heteroaryl, C 3-20 cycloalkyl-C 6-20 Aryl, C 3- 20 cycloalkyl-5-20-membered heteroaryl, OR 1.1 COOR 1.1 C 1-10 Alkyl-COOR 1.1 COR 1.1 C 1-10 Alkyl-COR 1.1 COONR 1.1 C 1-10 Alkyl-COONR 1.1 CONOH, C 1-10 Alkyl-CONOH, CO-NR 1.1 C 1-10 Alkyl-CO-NR 1.1 CH = CHCOOR 1.1 CO-NR 1.1 CH2CO-NR 1.1 CH=CHCO-NR 1.1 NR 1.2 R 1.3 C 1-10 Alkyl-NR 1.2 R 1.3 SR 1.1 C 1-10 Alkyl-SR 1.1 SOR 1.1 C 1-10 Alkyl-SOR 1.1 SO2-R 1.1 C 1-10 Alkyl-SO2R 1.1 or SO2-NR 1.2 R 1.3 And each of the substituents may be unsubstituted or optionally further substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, OH, OR 1.1 Halogenated, oxo-substituted, thio-substituted, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- Aryl and NR 1.2 R 1.3 ; Each R 1.1 Is it H or selected from C? 1-6- Alkyl, C 3-20 -cycloalkyl, C 5-20 -cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, -C 6-20- Aryl-C 1-6 -alkyl, -C 1-6 -alkyl-C 6-20- Aryl, -5-20 heteroaryl-C 1-6 -alkyl, 5-20-membered heteroaryl-C 1-6 -alkyl-, -3-20 membered heterocyclic-C 1-6 -alkyl, 3-20 membered heterocyclic -C 1-6 -alkyl-, -C 3-10 -cycloalkyl-C 1-6 -alkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl-, monocyclic or bicyclic C 6-20 -aryl, 5-20 membered heteroaryl and 5-20 membered heterocyclic groups, and each group may be unsubstituted or optionally substituted with substituents selected from the following: halogen, deuterium, OH, CN, NO2, NH2, oxo (=O), thio (=S), CF3, CHF2, CH2F, O-(C 1-3 -alkyl), C 1-10- Alkyl and C 6-20- Aryl; Each R 1.2 and R 1.3 Same or different, representing H or selected from C independently of each other. 1-6- Alkyl, monocyclic or bicyclic C 3-10- Cycloalkyl, monocyclic or bicyclic C 6-20- Aryl-C 1-6 -alkyl, monocyclic or bicyclic 5-20 membered heteroaryl-C 1-6- Alkyl, monocyclic or bicyclic C 6-20- Aryl, monocyclic or bicyclic 3-20 membered heterocyclic rings, monocyclic or bicyclic 5-20 membered heteroaromatic rings, -CO-NH2, -CO-NH-CH3, -CO-N(CH3)2, -SO2-(C 1-6 -alkyl), -SO2-(C 3-10 -cycloalkyl), -SO2-(3-10 membered heterocycloalkyl), -SO2-(C 5-10 -cycloalkenyl), -SO2-(5-20 membered heterocyclic alkenyl), -CO-R 1.1 and -COOR 1.1 The group, and each group may be unsubstituted or optionally substituted with one, two or more substituents selected from the following: deuterium, OH, halogen, C 1-6 -alkyl, C 6-20- Aryl and COOR 1.1 ; Or, R 1.2 and R 1.3 Together with the atoms attached thereto, it forms a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged heterocycle containing 1, 2, 3 or 4 independent heteroatoms selected from N, S or O, wherein the heterocycle is unsubstituted or optionally substituted at the ortho, para or meta position by one, two or more substituents selected from: deuterium, halogen, OH, oxo, thio, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as CF3, CHF2, CH2F), OR 1.1 -C 1-3 -alkyl-OR 1.1 SR 1.1 -C 1-3 -alkyl-SR 1.1 ,-SO-R 1.1 ,-C 1-3 -alkyl-SOR 1.1 ,-SO2-R 1.1 ,-C 1-3 -alkyl-SO2R 1.1 ,-COOR 1.1 ,-CH2COOR 1.1 ,-CH2CH2COOR 1.1 ,-CH=CHCOOR 1.1 ,-CO-NR 1.1,- CH2CO-NR 1.1 ,-CH2CH2CO-NR 1.1 ,-CH=CHCO-NR 1.1 ,-COR 1.1 ,-CH2COR 1.1 ,-C 1-6 -alkyl alcohols, monocyclic or bicyclic C 3-10 -cycloalkyl, C 6-20- Aryl, C 1-6 -alkyl, C 6-20- Aryl-C 1-6 -alkyl, 5-20-membered heteroaryl-C 1-6 Alkyl, C 1- 3-alkyl-(monocyclic or polycyclic-C) 6-20- Aryl), 3-20 membered heterocyclic group -C 6-20- Aryl, 3-20 membered heterocyclic, 5-20 membered heteroaryl C 1- 3-alkyl-OR 1.1 NR 1.2 R 1.3 C 6-20- Aryl and NR 1.2 R 1.3 .

2. The compound of claim 1, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein: The heterocyclic group is a 3-11 member saturated or partially saturated monocyclic or bicyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O. Preferably, the halogen-substituted alkyl group is selected from monohalogenated, dihalogenated, trihalogenated, or more halogenated C4 groups. 1-6 Alkyl groups, such as -CF3, -CHF2, -CH2F.

3. The compound of claim 1 or 2, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein: A is selected from the following groups, where each of the following groups is marked with 0, 1, 2 or 3 R groups. a Group substitution: Among them, R a As defined in claim 1 or 2, "--" represents a chemical bond.

4. The compound according to any one of claims 1-3, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein B may be selected from the following groups, wherein each of the following groups is substituted by 0, 1, 2, or 3 Rb groups: in, R b As defined above, "--" represents a chemical bond.

5. The compound according to any one of claims 1-4, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein C is selected from the following groups, wherein each of the following groups is marked with 0, 1, 2, or 3 R... c Group substitution: in, R c As defined in any one of claims 1-4, "--" represents a chemical bond.

6. The compound of any one of claims 1-5, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein D is selected from the following groups, each of which is marked with 0, 1, 2, or 3 R's. d Group substitution: in, R d As defined in any one of claims 1-5, "--" represents a chemical bond.

7. The compound according to any one of claims 1-6, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein the compound of formula I is selected from the following compounds:

8. A method for preparing the compound of any one of claims 1-7, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein the preparation method comprises reacting the compound of formula S1 with the compound of formula S2 to obtain the compound of formula I: And optionally, the compound of formula I may be derived into its stereoisomers, tautomers, isotopic labels, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs; in, LG is a leaving group, such as Cl, Br or I; A, B, C, D, W, X1, X2, X3, X4, X5, R1, R2, R a R b R c R d R e m, n, p, and q each have the definition as described in any one of claims 1-7 independently.

9. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of any one of claims 1-7, a racemic mixture, a stereoisomer, a tautomer, an isotope label, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof.

10. A method for preventing or treating a disease mediated by at least PDE5 and TYK2, comprising administering to a patient in need at least one of the compounds of any one of claims 1-7, their racemic mixtures, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds thereof. Preferably, the disease is selected from at least one of the following: autoimmune and / or inflammatory diseases, selected from psoriasis, rheumatoid arthritis, inflammatory bowel disease (IBD); lung diseases, selected from pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF); tumors, such as solid tumors, such as lung cancer, colorectal cancer, melanoma, glioblastoma, brain tumors; cardiovascular diseases and / or metabolic disorders, such as atherosclerosis, diabetic nephropathy; nervous system diseases, such as multiple sclerosis, Alzheimer's disease (AD); fibrotic diseases, such as fibrosis or sclerosis of the kidneys, liver, or skin.

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