Pyridine or pyridazine derivative, and pharmaceutical composition and use thereof

Abstract

The present disclosure provides a compound represented by the following formula H, and a racemate, stereoisomer, tautomer, isotopically labeled compound, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug thereof. The compound of the present disclosure has excellent dual-target inhibitory activity against PDE4 and TYK2, which will facilitate the development of multispecific targeted drugs for different patient populations, which will be particularly advantageous for improving therapeutic efficacy and / or reducing side effects, and enhancing patient compliance and quality of life.

Description

Pyridine or pyridazine derivatives and their pharmaceutical compositions and uses

[0001] This application claims priority to the prior art of the applicant's earlier patent application filed on April 15, 2025 with the China National Intellectual Property Administration, application number 202510471118.0, entitled "Pyridine or pyridazine derivatives and pharmaceutical compositions thereof and uses thereof". The entire contents of the aforementioned earlier application are incorporated herein by reference. Technical Field

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

[0003] Phosphodiesterases (PDEs) hydrolyze intracellular second messengers (cAMP, cyclic adenosine monophosphate or cGMP, cyclic guanosine monophosphate), degrading intracellular cAMP or cGMP and thus terminating the biochemical processes mediated by these second messengers. cAMP and cGMP play crucial regulatory roles in cellular activity, and their concentrations are primarily determined by the balance between the synthesis of adenylate cyclases and the hydrolytic activity of phosphodiesterases (PDEs). PDEs are widely distributed in the human body, and their physiological effects are involved in multiple research areas. In recent years, PDEs have attracted widespread attention as novel therapeutic targets, becoming a new research hotspot, with clinical studies of PDE4 inhibitors and their multi-target inhibitors receiving particular emphasis.

[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 PDE4 and TYK2. Summary of the Invention

[0006] To address the aforementioned technical problems, this disclosure provides compounds represented by formula H, their racemic mixtures, 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-, -C 1-6 Alkylene -C(=O)-, -C(=O)-C 1-6 Alkylene-, -C(=O)-C(=O)-, -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-, -OC 1-6 Alkylene-, -OC 1-6 Alkylene -NH-, -OC 1-6 Alkylene -C(=O)-NH-, -OC 1-6 Alkylene-C(=O)-NR 1.1 -、-C 2-6 imidene-, -C 2-6 -, -C ethynyl 1-6alkeneoxy-; 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-acetylinyl, 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 1-6 Alkylene -C(=O)-, -C(=O)-C 1-6 Alkylene-, -C(=O)-C(=O)-, -C(=O)-NH-C 1-6 alkylene-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene-O-, -OC 1-6 Alkylene-, -OC 1-6 Alkylene -NH-, -OC 1-6 Alkylene -C(=O)-NH-, -OC 1-6 Alkylene-C(=O)-NR 1.1 -、-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 1-6Alkyl-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-, -C 1-6 Alkylene -C(=O)-, -C(=O)-C 1-6 Alkylene-, -C(=O)-C(=O)-, -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-, -OC 1-6 Alkylene-, -OC 1-6 Alkylene -NH-, -OC 1-6 Alkylene -C(=O)-NH-, -OC 1-6 Alkylene-C(=O)-NR 1.1 -、-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 1-6 Alkylene -C(=O)-, -C(=O)-C 1-6 Alkylene-, -C(=O)-C(=O)-, -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-, -OC 1-6 Alkylene-, -OC 1-6 Alkylene -NH-, -OC 1-6 Alkylene -C(=O)-NH-, -OC 1-6 Alkylene-C(=O)-NR 1.1 -、-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 1-6 Alkylene -C(=O)-, -C(=O)-C 1-6 Alkylene-, -C(=O)-C(=O)-, -C(=O)-NH-C 1-6Alkylene-, -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-, -OC 1-6 Alkylene-, -OC 1-6 Alkylene -NH-, -OC 1-6 Alkylene -C(=O)-NH-, -OC 1-6 Alkylene-C(=O)-NR 1.1 -、-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] X6 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-, -OC 1-6 Alkylene-, -OC 1-6 Alkylene -NH-, -OC 1-6 Alkylene -C(=O)-NH-, -OC 1-6 Alkylene-C(=O)-NR 1.1 -、-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;

[0019] 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 ;

[0020] 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;

[0021] 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;

[0022] 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;

[0023] 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 5-20cycloalkenyl 5-20 quinone heteroaryl groups;

[0024] 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 -SOR1.1 -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] 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-NR1.1 -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;

[0026] 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-C6-20 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 -NR q SO2-R 1.1 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. 1-6Alkyl 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;

[0027] Or, R2 and 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 1.1CONOH, 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 ;

[0028] 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 3-20cycloalkyl-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 -NR q SO2-R 1.1 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;

[0029] Or, R a With R b Together with the atoms it is attached to, it forms the following groups that are fused with ring A or ring B: 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 ;

[0030] 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 6-20Aryl-, -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 -NR q SO2-R 1.1 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;

[0031] Or, R2 and 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 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 ;

[0032] 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 3-20Cycloalkyl-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 -NR q SO2-R 1.1 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 R1.3 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;

[0033] 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-NR1.1 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 ;

[0034] R f Represents X7-R3;

[0035] X7 represents a chemical bond or -CH2-, -O-, -S-, -NH-, -S(O)-, -S(O)2- or -C(O)-;

[0036] R3 represents H (such as hydrogen or deuterium), halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F, -CH2CF3), -NR 1.2 R 1.3 No substitution or optional use by 1, 2 or more R d1 The following groups are substituted: C 5-20 Cycloalkenyl, 3-20 membered heterocyclic, 5-20 membered heteroaryl, 6-20 membered aryl;

[0037] R g Represents -X8-R4;

[0038] X8 represents a chemical bond or -CH2-, -O-, -S-, -NH-, -S(O)-, -S(O)2- or -C(O-);

[0039] R4 represents H (such as hydrogen, deuterium), halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F, -CH2CF3), -NR 1.2 R 1.3 No substitution or optional use by 1, 2 or more R d2 The following groups are substituted: C 5-20 Cycloalkenyl, 3-20 membered heterocyclic, 5-20 membered heteroaryl, 6-20 membered aryl;

[0040] The condition is R f R g Not both H;

[0041] Or, R f R g Together with the atoms they are attached to, they form unsubstituted or optionally substituted with one, two or more R atoms. d3 The following groups are substituted: C 5-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 3-20 membered heterocyclic alkenyl, 5-20 membered heteroaryl, 6-20 membered aryl;

[0042] Each R d1 R d2 R d3 They may be the same or different, and are independently selected from H, deuterium, halogen, OH, CN, NO2, oxo (=O), thio (=S), SO, SO2, unsubstituted, or optionally substituted by one, two, or more Rs. e The following groups are substituted: C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 1-20 Alkyloxy, C 2-20 alkenyloxy group, C 2-20 alkynyloxy group, C 3-20 Cycloalkyloxy, C 3-20 Cycloalkenyloxy, C 3-20 Cycloalkynyloxy group, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, C 1-20 Alkyl thio, C 2-20alkenyl thio, C 2-20 alkynyl thioyl, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 Cycloalkynylthio, C 6-20 Arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclic thio, NH2, -C(O)R 31 -CH2-C(O)R 31 -C(O)OR 32 -CH2C(O)OR 32 -C(O)NHR 32 -CH2C(O)NHR 32 -OC(O)R 33 -S(O)2R 34 -S(O)2OR 35 -OS(O)2R 36 -P(O)(OR) 37 (OR) 38 );

[0043] Alternatively, when two or more R-selected groups are present on the same group. d1 R d2 R d3 When substituents are present, the two substituents can form an unsubstituted or optionally substituted group with one, two or more R atoms together with the atoms they are attached to. e The following groups are substituted: C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic;

[0044] Each R d21 They may be the same or different, and are independently selected from chemical bonds, H, deuterium, halogen, OH, CN, NO2, oxo (=O), thio (=S), SO, SO2, unsubstituted, or optionally substituted by one, two, or more Rs. a The following groups are substituted: C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 1-20 Alkyloxy, C 2-20 alkenyloxy group, C 2-20 alkynyloxy group, C 3-20 Cycloalkyloxy, C 3-20Cycloalkenyloxy, C 3-20 Cycloalkynyloxy group, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, C 1-20 Alkyl thio, C 2-20 alkenyl thio, C 2-20 alkynyl thioyl, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 Cycloalkynylthio, C 6-20 Arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclic thio, NH2, -C(O)R 11 -CH2-C(O)R 11 -C(O)OR 12 -CH2C(O)OR 12 -C(O)NHR 12 -CH2C(O)NHR 12 -OC(O)R 13 -S(O)2R 14 -S(O)2OR 15 -OS(O)2R 16 -P(O)(OR) 17 (OR) 18 );

[0045] Alternatively, when two or more R-selected groups are present on the same group. d21 When substituents are present, the two substituents can form an unsubstituted or optionally substituted group with one, two or more R atoms together with the atoms they are attached to. e The following groups are substituted: C 3-20 cycloalkyl, C 3- 20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic;

[0046] Each R e Whether identical or different, they are independently selected from hydrogen, deuterium, halogen, OH, CN, NO2, NH2, SH, oxo (=O), thio (=S), methanesulfonyl, ethanesulfonyl, methanesulfonamide, ethanesulfonamide, carboxylic acid, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as CF3, CHF2, CH2F), OC(O)NH2, OC(O)NR 1.2 R 1.3 NR q -CONR 1.2 R 1.3 NR q -C(O)R 1.1NR 1.2 R 1.3 OR 1.1 C 1-6 -alkyl-OR 1.1 C 1-6 -alkyl-OC 1-6 -alkyl-COOR 1.1 C 1-6 -alkyl-OC 1-6 -Alkenyl-COOR 1.1 C 1-6 -alkyl-OC 1-6 -alkyl-CONR 1.2 R 1.3 -OC 1-6 -alkyl-CONR 1.2 R 1.3 -OC 1-6 -alkyl-COOR 1.1 -OC 1-6 -alkyl-O-CO-C 1-6 -alkyl-NR 1.2 R 1.3 -OC 1-6 -alkyl-OC 1-6 -alkyl-COOR 1.1 C 1-6 -alkyl-O-PO(ONa)2, C 1-6 -alkyl-O-PO(OH)2, C 1-6 -alkyl-O-PO(OR) 1.1 2. C 1-6 -alkyl-OC(O)-OR 1.1 C 1-6 -alkyl-OC(O)-NR 1.2 R 1.3 C 1-6 -alkyl-OC(=O)-C 1-6 -alkyl-(OC) 1-6 -alkyl) n C 1-6 -alkyl-OC(=O)-C 1-6 -alkyl-COOR 1.1 C 1-6 -alkyl-OC(=O)-C 1-6 -alkyl, C 1-6 -alkyl-OC(=O)-C 3-10 -cycloalkyl, C 1-6 -alkyl-OC(=O)-3-10 membered heterocyclic alkyl, C 1-6 -alkyl-OC(=O)-C 6-20 Aryl, C1-6 -alkyl-OC(=O)-5-20-membered heteroaryl, C 1-6 -alkyl-OC(=O)-C 1-6 -Alkenyl-COOR 1.1 C 1-6 -alkyl-NC(=O)-C 1-6 -alkyl-COOR 1.1 C 1-6 -alkyl-NC(=O)-OC 1-6 -alkyl-COOR 1.1 C 1-6 -alkyl-NC(=O)-NC 1-6 -alkyl-COOR 1.1 SR 1.1 C 1-6 -alkyl-SR 1.1 SO-R 1.1 C 1-6 -Alkyl-SOR 1.1 SO2-R 1.1 C 1-6 -alkyl-SO2R 1.1 COOR 1.1 C 1-6 -alkyl-COOR 1.1 CH = CHCOOR 1.1 CO-NR 1.2 R 1.3 C 1-6 -alkyl-CO-NR 1.2 R 1.3 CH=CHCO-NR 1.2 R 1.3 COR 1.1 C 1-6 -alkyl-COR 1.1 Single-ring or double-ring 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-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 Or C 6-20-Aryl; each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: deuterium, OH, CN, C 1-6 -alkyl-CN, C 1-6 -alkyl-NH2, -SH, -NH2, -NHOH, -C 1- 6- Alkyl-NHOH, -C 1-6- Alkyl-CO - NHOH, -CO-NHOH, -C 1-6- Alkyl-NH-CO-N R 1.2 R 1.3 -NR 1.1 CN, -CHO, guanidino, quaternary ammonium salt, C 2-6 -Alkenyl, -OC 3-8 -cycloalkyl, COOR 1.1 C 1-6 -alkyl-COOR 1.1 CONHR 1.1 C 1-6 -alkyl-CONHR 1.1 -OR 1.1 Oxygenated, halogenated, 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 ;

[0047] R5 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-, C2-6 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 -C(O)NOH, -C 1-10 Alkyl-C(O)NOH, -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 3-20Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 2-10 alkenyl and C 2-10 alkynyl group;

[0048] R6 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 -C(O)NOH, -C 1-10 Alkyl-C(O)NOH, -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 -C1-10 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;

[0049] Alternatively, R5 and R6 together with the atoms they are attached to 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, wherein each of the above groups may be unsubstituted or optionally substituted by 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-5-20 heteroaryl, C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 Cycloalkyl-5-20 heteroaryl, C 2-10 alkenyl, C 2-6alkynyl group, 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 C(O)NOH, C 1-10 Alkyl-C(O)NOH, 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 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 ;

[0050] Alternatively, when R5 or R6 has two or more substituents, the two substituents can form an unsubstituted or optionally substituted atom with one, two or more R atoms. e The following groups are substituted: C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic;

[0051] Each R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 They are selected independently from H, halogens, OH, CN, NO2, oxo (=O), thio (=S), and C, whether they are the same or different. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, NH2;

[0052] 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), C1-10- Alkyl, C 3-20 cycloalkyl and C 6-20- Aryl;

[0053] 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 ;

[0054] 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-SO2R1.1 ,-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 .

[0055] According to an embodiment of the present invention, in the compound represented by formula H, X1, X2, X3, X4, X5 and X6 are not simultaneously chemical bonds.

[0056] According to an embodiment of the present invention, in the compound represented by formula H, A, B, C and D are not simultaneously chemical bonds.

[0057] According to embodiments of the present invention, the heterocyclic group preferably comprises a 3-11 member saturated or partially saturated monocyclic or bicyclic ring containing 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 containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O. The ring can be any fused ring or bridged ring; heterocyclic alkenyl groups represent 3-11-membered monocyclic or bicyclic rings 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; heterocyclic alkynyl groups represent 3-11-membered monocyclic or bicyclic rings containing 1, 2, 3, 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;

[0058] According to embodiments of the present invention, the heteroaryl group preferably comprises 1, 2, 3 or 4 aromatic groups of 5-10 members, which are independently selected from N, S or O heteroatoms, and the bicyclic group can be any fused ring;

[0059] 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.

[0060] According to an embodiment of the present invention, R f R g It forms together with the atoms it is connected to. like

[0061] According to an embodiment of the present invention, the compound represented by formula H has the structure shown in formula I:

[0062] Wherein, the groups in Formula I, such as W, m, n, p, q, X1, X2, X3, X4, X5, X6, A, B, C, D, R1, R2, R... a R b R c R d R e R f R g R d21 It has the definition described above;

[0063] U represents -(CH2) t -、O、S、NR q S(=O), S(=O)2 or C(=O), where t represents 0, 1, 2 or 3;

[0064] v represents 0, 1, 2, 3, 4 or 5;

[0065] Each R d22 They may be the same or different, and are independently selected from chemical bonds, H, deuterium, halogen, OH, CN, NO2, oxo (=O), thio (=S), SO, SO2, unsubstituted, or optionally substituted by one, two, or more Rs. a The following groups are substituted: C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 1-20 Alkyloxy, C 2-20 alkenyloxy group, C 2-20 alkynyloxy group, C 3-20 Cycloalkyloxy, C 3-20 Cycloalkenyloxy, C 3-20 Cycloalkynyloxy group, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, C 1-20 Alkyl thio, C 2-20 alkenyl thio, C 2-20 alkynyl thioyl, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 Cycloalkynylthio, C 6-20 Arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclic thio, NH2, -C(O)R 11 -CH2-C(O)R 11 -C(O)OR 12 -CH2C(O)OR 12 -C(O)NHR 12 -CH2C(O)NHR 12 -OC(O)R 13 -S(O)2R 14 -S(O)2OR 15 -OS(O)2R 16 -P(O)(OR) 17 (OR) 18 );

[0066] Alternatively, when two or more R-selected groups are present on the same group. d21 R d22 When substituents are present, the two substituents can form an unsubstituted or optionally substituted group with one, two or more R atoms together with the atoms they are attached to.e The following groups are substituted: C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 heteroaryl, 3-20 heterocyclic.

[0067] According to an embodiment of the present invention, R a With 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 1.1CH = 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 ;

[0068] According to embodiments of the present invention, A may preferably be selected from the following groups, wherein each group is independently surrounded by 0, 1, 2 or 3 R groups. a Group substitution:

[0069] Among them, R a As defined above, "--" represents a chemical bond.

[0070] According to embodiments of the present invention, B may preferably be selected from the following groups, wherein each group is independently surrounded by 0, 1, 2 or 3 R groups. b Group substitution:

[0071] Among them, R b As defined above, "--" represents a chemical bond.

[0072] According to embodiments of the present invention, C may preferably be selected from the following groups, wherein each group is independently surrounded by 0, 1, 2 or 3 R groups. c Group substitution:

[0073] Among them, R c As defined above, "--" represents a chemical bond.

[0074] According to embodiments of the present invention, D may preferably be selected from the following groups, wherein each group is independently surrounded by 0, 1, 2 or 3 R groups. d Group substitution:

[0075] Among them, R d As defined above, "--" represents a chemical bond.

[0076] According to embodiments of this disclosure, the compound of formula H may be selected from the following compounds:

[0077] According to embodiments of this disclosure, the compound represented by formula H, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug exhibits excellent inhibitory activity against at least PDE4 and TYK2.

[0078] According to embodiments of this disclosure, the compound represented by formula H, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug may have inhibitory activity against PDE4 and TYK2.

[0079] This disclosure also provides a method for preparing compounds of formula H, their racemates, stereoisomers, tautomers, isotope labels, solvates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs, wherein the method comprises reacting a compound of formula H1 with a compound of formula H2 to obtain a compound of formula H:

[0080] And optionally, the compound of formula H may be derived into its stereoisomers, tautomers, isotopic labels, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs;

[0081] Each LG is an independent leaving group, such as Cl, Br or I;

[0082] Other groups such as A, B, C, D, X1, X2, X3, X4, X5, X6, R1, R2, R5, R6, R a R b R c R d R e R f R g 、Rd 21 m, n, p, and q each have the definitions described above independently.

[0083] 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:

[0084] And optionally, the compound of formula I may be derived into its stereoisomers, tautomers, isotopic labels, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs;

[0085] Each LG is an independent leaving group, such as Cl, Br or I;

[0086] Other groups such as A, B, C, D, X1, X2, X3, X4, X5, X6, R1, R2, R a R b R c R d R e R f R g 、Rd 21 、Rd 22 U, m, n, p, q, and v each have the definitions described above independently.

[0087] According to embodiments of this disclosure, the reaction can be carried out with a protecting group affixed to the compound shown in Formula S1 or 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.

[0088] 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.

[0089] This disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the following: a compound represented by formula H, a racemic mixture, a stereoisomer, a tautomer, an isotope label, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof.

[0090] According to embodiments of this disclosure, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0091] According to embodiments of this disclosure, the pharmaceutical composition may further comprise one or more additional therapeutic agents.

[0092] This disclosure also provides the use of at least one of the compounds of formula H, their racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds in the preparation of pharmaceuticals.

[0093] The drug can be used to prevent or treat diseases or conditions mediated by at least PDE4 and TYK2.

[0094] For example, the drug can be used to prevent or treat diseases or conditions mediated by PDE4 and TYK2.

[0095] According to an embodiment of this disclosure, the PDE4 is selected from one, two or more of PDE4A, PDE4B, PDE4C and PDE4D.

[0096] The present invention also provides a method for preventing or treating diseases or conditions mediated by at least PDE4 and TYK2, comprising administering to a patient in need at least one of a compound of formula H, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

[0097] According to embodiments of this disclosure, the disease is selected from diseases or conditions mediated by PDE4 and TYK2.

[0098] According to embodiments of the present invention, the disease or condition includes, but is not limited to, at least one selected from the following: autoimmune and / or inflammatory diseases selected from psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis; atopic dermatitis; lung diseases selected from idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD); asthma; sarcoidosis; graft-versus-host disease (GVHD); chronic inflammation selected from ankylosing spondylitis and uveitis; giant cell arteritis (GCA); tumors, such as solid tumors, such as lung cancer, colorectal cancer, melanoma, glioblastoma, and brain tumors; cardiovascular diseases and / or metabolic disorders, such as atherosclerosis and diabetic nephropathy; neurological diseases, such as multiple sclerosis (MS) and Alzheimer's disease (AD); and fibrotic diseases, such as fibrosis or sclerosis of the kidneys, liver, or skin.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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

[0111] Not wanting to be confined to existing theories, the inventors discovered that the disclosed compound, due to its excellent dual-target inhibitory activity against PDE4 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.

[0112] Terminology Definitions and Explanations

[0113] 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.

[0114] 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.

[0115] 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.

[0116] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0117] 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.

[0118] 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.

[0119] Term "C" 2-20 "Alkyne group" should be understood as representing a straight-chain 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") 2-3The 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.

[0120] 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.

[0121] 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.

[0122] 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;

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] For example, when both sides of a group in the context of this application are drawn with "--" representing chemical bonds, it indicates that either side can be combined with other groups in the structure of Formula H or Formula I. For instance, in the compound of Formula H or Formula I, each structure of the group specifically exemplified by group A can be combined with the X1 or X5 group in the compound of Formula H or Formula I on either side; or, each structure of the group specifically exemplified by group B can be combined with the X5 or X6 group in the compound of Formula H or Formula I on either side; or, each structure of the group specifically exemplified by group C can be combined with the X3 or X4 group in the compound of Formula H or Formula I on either side; or, each structure of the group specifically exemplified by group D can be combined with the X4 group in the compound of Formula H or Formula I on either side.

[0128] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0129] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0130] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms.

[0131] 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.

[0132] 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

[0133] 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.

[0134] 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;

[0135] Those skilled in the art will understand that the compounds represented by Formula H or 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; and 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] "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.

[0142] 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.

[0143] 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.

[0144] 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

[0145] 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.

[0146] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0147] 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; Boc: tert-butoxycarbonyl.

[0148] Analysis method:

[0149] 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.

[0150] 2. The purity analysis of the samples was performed on a Waters HPLC / Waters MS system.

[0151] Chromatographic conditions 1:

[0152] Chromatographic column: Waters X-Bridge-C18 50mm*4.6mm*3.5μm

[0153] The column temperature was 40℃.

[0154] Sample temperature: room temperature

[0155] Detection of UV 214 nm and UV 254 nm

[0156] Flow rate: 2 mL / min.

[0157] Mobile phase A: Water (0.05% TFA)

[0158] Mobile phase B: MeCN (0.05% TFA)

[0159] Gradient program: B from 5% to 100% takes 1.6 minutes, and 100% is held for 1.4 minutes.

[0160] Chromatographic conditions 2:

[0161] Chromatographic column: Waters X Brdige C18 (4.6mm x 50mm x 3.5μm)

[0162] The column temperature was 40℃.

[0163] Sample temperature: room temperature

[0164] Detection of UV 214 nm and UV 254 nm

[0165] Flow rate: 2 mL / min.

[0166] Mobile phase A: Water (0.01 mol / L NH4HCO3) B: MeCN

[0167] Mobile phase B: MeCN

[0168] Gradient program: B from 5% to 100%, for 1.6 minutes, then hold at 100% for 1.4 minutes.

[0169] 3. Preparative HPLC was performed on a Gilson 281.

[0170] Flow rate: 20 mL / min.

[0171] Column: X-Select 10μm 19*250mm column

[0172] Wavelength: 254 nm or 214 nm

[0173] Solvent A: Water (10 mM NH4HCO3) and Solvent B: MeCN.

[0174] Example 1: Synthesis Example

[0175] 1. Synthesis scheme:

[0176] 2. Experimental Section:

[0177] 2.1

[0178] 6-Amino-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-D3-pyridazine-3-carboxamide (07001-1)

[0179] Pd₂(dba)₃ (243 mg, 0.27 mmol), xantphos (154 mg, 0.27 mmol), and Cs₂CO₃ (2.59 g, 7.96 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 (1.0 g, 2.65 mmol) and tert-butyl carbamate (1.55 g, 13.27 mmol) in 1,4-dioxane (25 mL). The mixture was reacted at 120 °C under nitrogen protection for 16 h. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography (MeOH / DCM = 0–10%, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to obtain the crude product. The crude product was purified by reverse-phase column chromatography (MeCN / H2O = 0–30%, C-18CS 40 g, 50 mL / min, C-18, UV 254) to give a yellow solid product (0.3 g, yield 31.63%).

[0180] ESI-MS m / z calcd for [C 16 H 15 D3N8O2][M+H] + :358.2; found:358.2

[0181] 2.2

[0182] 6-(4-bromobenzamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-D3-pyridazine-3-carboxamide (07001-2)

[0183] 6-amino-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-D3-pyridazine-3-carboxamide (80 mg, 0.22 mmol) and 4-bromobenzoyl chloride (98 mg, 0.44 mmol) were reacted in acetone (3 mL) with TEA (44 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness, dissolved in methanol, and K2CO3 (121 mg, 0.88 mmol) was added. The mixture was stirred at room temperature for 4 hours. After the starting materials were consumed, water (10 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 over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 10, silica gel-CS 40 g, 40 mL / min, silica gel, UV). 254), yielding a colorless oily product (120 mg, yield 99.9%).

[0184] ESI-MS m / z calcd for [C 23 H 18 D3BrN8O3][M+H] + :540.2; found:540.3

[0185] 2.3

[0186] 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzamido)-N-methyl-D3-pyridazine-3-carboxamide (07001-3)

[0187] 6-(4-bromobenzamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-D3-pyridazin-3-carboxamide (120 mg, 0.22 mmol) was added to a solution of 1,4-dioxane (6.0 mL) with B2Pin2 (113 mg, 0.44 mmol), AcOK (43 mg, 0.44 mmol), and Pd(dppf)Cl2 (9 mg, 0.01 mmol). The mixture was stirred at 100 °C under nitrogen protection for 8 hours. After the starting material was consumed, the mixture was cooled, filtered, concentrated under reduced pressure, and the crude product was used directly in the next reaction.

[0188] ESI-MS m / z calcd for [C 29 H 30 D3BN8O5][M+H]+ :588.3; found:588.4

[0189] 2.4

[0190] (R)-6-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-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 (MX07001)

[0191] To a solution of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzamido)-N-methyl-D3-pyridazine-3-carboxamide (123 mg, 0.21 mmol) in 1,4-dioxane / water (6.0 mL, v / v = 5 / 1), (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (60 mg, 0.21 mmol), K2CO3 (58 mg, 0.42 mmol), and Pd(dppf)Cl2 (8 mg, 0.01 mmol) were added. The mixture was heated to 80 °C and stirred for 8 hours under nitrogen protection. After cooling, the product was added to water (10 mL) and extracted three times with DCM (10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, 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 give a white solid product (28.03 mg, yield 18.75%).

[0192] ESI-MS m / z calcd for [C 34 H 32 D3N 11 O5S][M+H] + 713.3; found: 713.2

[0193] 1H NMR(400MHz,DMSO-d6)δ11.44(br,1H),11.04(s,1H),9.19(s,1H),8.58(s,1H),8.40(d,J=8.4Hz,2H), 8.29(s,1H),8.18(s,1H),8.11(d,J=8.4Hz,2H),7.69(dd,J=8.0,1.6Hz,1H),7.62(dd,J=8.0,1.6Hz,1H ),7.32(t,J=8.0Hz,1H),4.95(t,J=5.6Hz,1H),3.96(s,3H),3.88–3.80(m,2H),3.76(s,3H),3.71–3.63 (m,1H),3.42–3.37(m,1H),3.28–3.32(m,1H),3.08–3.03(m,1H),2.44–2.33(m,4H),1.89–1.83(m,2H).

[0194] 1. Synthesis scheme:

[0195] 2. Experimental Section:

[0196] 2.1

[0197] ((5-bromopyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (07006-1)

[0198] 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (400 mg, 1.06 mmol) and 5-bromo-2-aminopyridine (220 mg, 1.28 mmol) were added to a solution of 1,4-dioxane (8 mL) with Pd2(dba)3 (48 mg, 0.05 mmol), DPPF (59 mg, 0.11 mmol) and Cs2CO3 (691 mg, 2.12 mmol). The mixture was stirred overnight under nitrogen protection at 100°C. 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 column chromatography (MeOH / DCM = 0 / 1 to 1 / 10, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give a yellow solid product (101 mg, yield 18.6%).

[0199] ESI-MS m / z calcd for [C 21 H 17 D3BrN9O2][M+H] + :513.1; found:515.0

[0200] 2.2

[0201] 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)amino)pyridazine-3-carboxamide (07006-2)

[0202] To a solution of 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (100 mg, 0.20 mmol) in 1,4-dioxane (mL), B2Pin2 (200 mg, 0.40 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol), and AcOK (39 mg, 0.40 mmol) were added. The mixture was stirred at 100 °C under nitrogen protection for 8 hours. After the starting material was consumed, the mixture was cooled, filtered, concentrated under reduced pressure, and the crude product was used directly in the next reaction step.

[0203] ESI-MS m / z calcd for [C 27 H 29 D3BN9O4][M+H + :561.3; found:479.4

[0204] 2.3

[0205] (R)-6-((5-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (MX07006)

[0206] Add (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (56 mg, 0.18 mmol), Pd(dppf)Cl2 (8 mg, 0.009 mmol), and K2CO3 (54 mg, 0.36 mmol) to a solution of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (100 mg, 0.18 mmol) in 1,4-dioxane / water (6.0 mL, v / v = 5 / 1). The mixture was stirred at 80°C under nitrogen protection for 8 hours. After the starting material was consumed, it was cooled and added to water (10 mL), and extracted three times with EA (10 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 give a white solid product (2.41 mg, yield 1.98%).

[0207] ESI-MS m / z calcd for [C 32 H 31 D3N 12 O4S][M+H] + :686.3; found:686.2

[0208] 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),10.57(s,1H),9.12(s,1H),9.09(d,J=2.0Hz,1H),8.57(s,1H ),8.49(dd,J=8.8,2.0Hz,1H),8.40(s,1H),8.06(s,1H),7.72–7.62(m,3H),7.32(t,J=8.0Hz,1H),4 .60(t,J=5.6Hz,1H),3.96(s,3H),3.83–3.82(m,2H),3.76(s,3H),3.65–3.39(m,1H),3.39–3.37(m, 1H),3.26–3.17(m,1H),3.05–3.00(m,1H),2.45–2.32(m,2H),2.03–1.96(m,2H),1.91–1.85(m,2H).

[0209] 1. Synthesis scheme:

[0210] 2. Experimental Section:

[0211] 2.1

[0212] 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridazine-3-carboxamide (07007-1)

[0213] Palladium on carbon (20 mg) was added to a solution of tert-butyl-6-((5-(((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)amino)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid ester (50 mg, 0.08 mmol) in methanol (4.0 mL). The reaction mixture was stirred at room temperature for 3 hours under hydrogen protection. Then, HCl / MeOH (3.0 mL) solution was added. The reaction mixture was stirred at room temperature for 2 hours under hydrogen protection. After the starting material was consumed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product which was directly used in the next reaction step.

[0214] ESI-MS m / z calcd for [C 26 H 27 D3N 10 O2][M+H] + :518.3; found:518.3

[0215] 2.2

[0216] (R)-6-((5-(1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (MX07007)

[0217] DIEA (74 mg, 0.58 mmol) was added to a solution of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridazin-3-carboxamide (50 mg, 0.096 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (28 mg, 0.096 mmol) in DMF (2 mL). The mixture was stirred at 90 °C for 2 hours, cooled to room temperature, 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 (22.48 mg, yield 30.5%).

[0218] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.09(s,1H),9.09(s,1H),8.56(s,1H),8.19(s,1H),8. 09(d,J=1.6Hz,1H),7.66–7.61(m,3H),7.53(d,J=8.4Hz,1H),7.35–7.31(m,2H),4.86–4.81(m ,3H),3.95(s,3H),3.75(s,3H),3.72(d,J=4.8Hz,2H),3.46–3.37(m,1H),3.25–3.17(m,1H),2 .97–2.79(m,5H),2.40–2.27(m,2H),2.18–2.14(m,2H),1.80–1.71(m,4H),1.56–1.47(m,2H).

[0219] 1. Synthesis scheme:

[0220] 2. Experimental Section:

[0221] 2.1 4,6-Dichloro-N-(methyl-d3)nicotinamide (07008-1)

[0222] Under ice bath conditions, (COCl)₂ (0.8 mL, 10.4 mmol) was added to a solution of 4,6-dichloronicotinic acid (1 g, 5.2 mmol) in DCM (8 mL). The mixture was stirred at room temperature for 2 hours under nitrogen protection. The solvent was removed by vacuum distillation, and the crude product was added to DCM (8 mL), CD₃NH₂·HCl (728 mg, 10.4 mmol), and TEA (525 mg, 10.4 mmol). The mixture was then stirred at room temperature for 2 hours. After the reaction was complete, 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 (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid product (798 mg, yield 74.2%).

[0223] ESI-MS m / z calcd for[C7H3D3Cl2N2O][M+H] + :208.0; found:208.0

[0224] 2.2

[0225] 6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide (07008-2)

[0226] 1 M LiHMDS (5 mL) was added to a solution of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (500 mg, 2.4 mmol) in THF (10 mL), and the mixture was stirred for 10 min. Then, a mixture of 4,6-dichloro-N-(methyl-d3)nicotinamide (300 mg, 2.4 mmol) was added, and the mixture was stirred at room temperature for 3 h. After the starting material was consumed, the pH of the reaction mixture was adjusted to 6 with 1 N HCl aqueous solution. The mixture was extracted twice with EA (30 mL), and the combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1–1 / 10, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give a yellow solid product (778 mg, yield 86.4%).

[0227] ESI-MS m / z calcd for [C 17 H 14 D3ClN6O2][M+H] + :376.2; found:376.2

[0228] 2.3

[0229] (R)-6-((5-(4-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide(07008-3)

[0230] Add 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide (48 mg, 0.11 mmol) and (R)-2-(6-aminopyridin-3-yl)-4-((1-(((tert-butyldimethylsiloxy)methyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (40 mg, 0.11 mmol) to a solution of 1,4-dioxane (6 mL) to Brettp hosPd-G3 (20 mg, 0.02 mmol) and Cs2CO3 (65 mg, 0.2 mmol). The mixture was stirred overnight at 100 °C under nitrogen protection. After the starting material was consumed, water (30 mL) was added to the mixture, and it was extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried with anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 1, silica gel-CS12 g, 40 mL / min, silica gel, UV 254) to give a yellow solid product (32 mg, yield 37.6%).

[0231] ESI-MS m / z calcd for [C 39 H 46 D3N 11 O4SSi][M+H] + 799.4; found: 799.2

[0232] 2.4

[0233] (R)-6-((5-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide (MX07008)

[0234] Add 1 mL of trifluoroacetic acid to a solution of (R)-6-((5-(4-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide (32 mg, 0.04 mmol) in DCM (2 mL) (100 mg, 0.27 mmol). Stir the mixture at room temperature for 2 hours. Concentrate the mixture, and after the starting material has been consumed, cool it and add it to water (10 mL), and extract three times with EA (10 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 white solid product (8.34 mg, yield 30.48%).

[0235] 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),10.15(s,1H),9.08(d,J=2.0Hz,1H),8.56(s,1H),8.53–8.52(m,2H),8. 44(dd,J=8.8,2.0Hz,1H),8.15(s,1H),8.04(s,1H),7.71(d,J=8.8Hz,1H),7.61(d,J=8.8Hz,1H),7.57(dd,J=7 .6,1.2Hz,1H),7.28(t,J=8.0Hz,1H),4.96(t,J=5.6Hz,1H),3.95(s,3H),3.84–3.80(m,2H),3.76(s,3H),3.6 7–3.59(m,1H),3.38–3.36(m,1H),3.23–3.17(m,1H),3.04–2.99(m,1H),2.45–2.33(m,4H),1.91–1.85(m,2H).

[0236] 1. Synthesis scheme:

[0237] 2. Experimental Section:

[0238] 2.1

[0239] 4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (07103-1)

[0240] Lithium chloride (62 mg, 1.48 mmol) and triethylamine (224 mg, 2.22 mmol) were added to a solution of 5-bromo-2-nitropyridine (300 mg, 1.48 mmol) and piperazine-1-carboxylic acid tert-butyl ester (412 mg, 2.22 mmol) in dimethyl sulfoxide (8 mL). The mixture was stirred overnight at 65 °C under nitrogen protection. After the starting material was consumed, water (10 mL) was added to the mixture, and a yellow solid precipitated. The solid was filtered, washed with water, and dried to give a yellow solid product (402 mg, yield 88.4%).

[0241] ESI-MS m / z calcd for [C 14 H 20 N4O4][M+H] + :309.2; found:309.2

[0242] 2.2

[0243] 4-(6-aminopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (07103-2)

[0244] Palladium on carbon (100 mg) was added to a solution of 4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (400 mg, 1.30 mmol) in ethanol (10 mL). The mixture was stirred at room temperature under hydrogen protection for 3 hours. After the starting material was consumed, the reaction solution was filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 10, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give a purple solid product (278 mg, yield 76.9%).

[0245] ESI-MS m / z calcd for [C 14 H 22 N4O2][M+H] + :279.2; found:279.1

[0246] 2.3

[0247] 4-(6-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)amino)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (07103-3)

[0248] To a solution of 4-(6-aminopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.54 mmol) in 1,4-dioxane (5 mL), 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (203 mg, 0.54 mmol), Pd2(dba)3 (49 mg, 0.05 mmol), xantphos (31 mg, 0.05 mmol), and cesium carbonate (352 mg, 1.08 mmol) were added. The mixture was stirred at 110°C under nitrogen protection for 24 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 column chromatography (MeOH / DCM = 0 / 1 to 1 / 10, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give a light yellow solid product (301 mg, yield 90.2%).

[0249] ESI-MS m / z calcd for [C 30 H 34 D3N 11 O4][M+H] + :619.3; found:619.2

[0250] 2.4

[0251] 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(((5-(piperazin-1-yl)pyridin-2-yl)amino)pyridazin-3-carboxamide(07103-4)

[0252] TFA (0.8 mL) was added to a solution of 120 mg (0.19 mmol) of tert-butyl piperazine-1-carboxylate (DCM) in 4.0 mL of DCM. The reaction mixture was stirred at room temperature for 1 hour under nitrogen protection. After the starting material was consumed, the mixture was concentrated by vacuum distillation to obtain a crude product which was directly used in the next reaction step.

[0253] ESI-MS m / z calcd for [C 25 H 26 D3N 11 O2][M+H]+ :519.3; found:519.2

[0254] 2.5

[0255] (R)-6-((5-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (MX07103)

[0256] DIEA (147 mg, 1.14 mmol) was added to a solution of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(((5-(piperazin-1-yl)pyridin-2-yl)amino)pyridazin-3-carboxamide (100 mg, 0.19 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothiopheno[3,2-d]pyrimidine 5-oxide (55 mg, 0.19 mmol) in DMF (2 mL). The mixture was stirred at 90 °C for 3 hours, cooled to room temperature, and concentrated. The crude product was analyzed by preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV). 254) Purification yielded a white solid compound (57.28 mg, yield 39.2%).

[0257] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.93(s,1H),9.06(s,1H),8.57(s,1H),8.06(s,1H),7.93(d,J=2. 4Hz,1H),7.62(t,J=8.4Hz,2H),7.55(d,J=8.8Hz,1H),7.48(dd,J=8.8,2.8Hz,1H),7.44(s,1H),7.34(t, J=8.0Hz,1H),4.85(t,J=5.6Hz,1H),3.95(s,3H),3.89(s,4H),3.76–3.73(m,5H),3.47–3.39(m,1H),3.2 6–3.18(m,1H),3.12(s,4H),2.98–2.85(m,2H),2.40–2.27(m,2H),2.21–2.16(m,2H),1.82–1.72(m,2H).

[0258] 1. Synthesis scheme:

[0259] 2. Experimental Section:

[0260] 2.1

[0261] 6-Amino-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-tert-butyl carboxylate (07104-1)

[0262] To a mixture of 800 mg (4.62 mmol) of 5-bromo-2-aminopyridine in 10 mL (v / v = 4 / 1) of 1,4-dioxane and water, 1.43 g (4.62 mmol) of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.43 g (4.62 mmol), potassium carbonate (1.91 g (13.86 mmol), and Pd(dppf)Cl2·DCM (375 mg (0.46 mmol)) were added. The mixture was stirred at 100 °C under nitrogen protection for 3 hours. After the starting material was consumed, water (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 (50 mL), dried with anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 9, silica gel-CS 40 g, 30 mL / min, silica gel, UV 254) to give a white solid product (1.2 g, yield 94.5%).

[0263] ESI-MS m / z calcd for [C 15 H 21 [N3O2][M+H] + :276.2; found:276.2

[0264] 2.2

[0265] tert-Butyl 6-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)amino)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid ester (07104-2)

[0266] To a solution of 6-amino-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (300 mg, 1.09 mmol) in 1,4-dioxane (5 mL), 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (410 mg, 1.09 mmol), Pd2(dba)3 (100 mg, 0.11 mmol), xantphos (64 mg, 0.11 mmol), and cesium carbonate (711 mg, 2.18 mmol) were added. 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 column chromatography (MeOH / DCM = 0 / 1 to 1 / 10, silica gel-CS 20 g, 40 mL / min, silica gel, UV 254) to give a light yellow solid product (433 mg, yield 64.6%).

[0267] ESI-MS m / z calcd for [C 31 H 33 D3N 10 O4][M+H] + :616.3; found:616.2

[0268] 2.3

[0269] 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-yl)amino)pyridazine-3-carboxamide (07104-3)

[0270] 0.8 mL of TFA was added to a solution of tert-butyl-6-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)amino)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid ester (100 mg, 0.16 mmol) in DCM (4.0 mL). The reaction mixture was stirred at room temperature for 2 hours under nitrogen protection. After the starting material was consumed, the mixture was concentrated by vacuum distillation to obtain a crude product which was directly used in the next reaction step.

[0271] ESI-MS m / z calcd for [C 26 H25 D3N 10 O2][M+H] + :516.3; found:516.2

[0272] 2.4

[0273] (R)-6-((1'-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (MX07104)

[0274] DIEA (120 mg, 0.93 mmol) was added to a solution of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1',2',3',6'-tetrahydro-[3,4'-bipyridin]-6-yl)amino)pyridazine-3-carboxamide (80 mg, 0.16 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (45 mg, 0.16 mmol) in DMF (2 mL). The mixture was stirred at 90 °C for 2 hours, cooled to room temperature, 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 (31.01 mg, yield 25.3%).

[0275] 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),10.23(s,1H),9.10(s,1H),8.57(s,1H),8.29(d,J=1.6Hz,1H) ,8.18(s,1H),7.84(dd,J=8.4,1.6Hz,1H),7.66–7.60(m,3H),7.40–7.33(m,2H),6.27(s,1H),4.86( t,J=5.6Hz,1H),4.36(s,2H),3.99–3.95(m,5H),3.78–3.72(m,5H),3.48–3.39(m,1H),3.26–3.18(m ,1H),2.98–2.84(m,2H),2.51–2.49(m,2H),2.42–2.29(m,2H),2.23–2.18(m,2H),1.83–1.73(m,2H).

[0276] 1. Synthesis scheme:

[0277] 2. Experimental Section:

[0278] 2.1

[0279] (R)-2-(4-aminophenyl)-4-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (07145-1)

[0280] To a solution of (R)-4-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (100 mg, 0.25 mmol) in 1,4-dioxane (3 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)aniline (110 mg, 0.50 mmol), potassium carbonate (104 mg, 0.75 mmol), and Pd(PPh3)4 (29 mg, 0.025 mmol) were added. The mixture was stirred overnight at 100 °C under nitrogen protection. After the starting material was consumed, water (20 mL) was added, and the mixture was extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 5, silica gel-CS20g, 30mL / min, silica gel, UV 254) to give a yellow oily product (88mg, yield 76.9%).

[0281] ESI-MS m / z calcd for [C 23 H 34 N4O2SSi][M+H] + :459.2; found:459.2

[0282] 2.6

[0283] (R)-6-((4-(4-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide(07145-2)

[0284] Pd2(dba)3 (21 mg, 0.02 mmol), xantphos (26 mg, 0.045 mmol), and cesium carbonate (98 mg, 0.3 mmol) were added to a solution of (R)-2-(4-aminophenyl)-4-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (70 mg, 0.15 mmol) and 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide (86 mg, 0.23 mmol) in 1,4-dioxane (4 mL). The mixture was microwaved at 130℃ under nitrogen protection for 1 hour. 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 column chromatography (MeOH / DCM = 0 / 1 to 1 / 9, silica gel-CS 20 g, 40 mL / min, silica gel, UV 254) to give a light yellow solid product (25 mg, yield 20.9%).

[0285] ESI-MS m / z calcd for [C 40 H 47 D3N 10 O4SSi][M+H] + :798.4; found:798.3

[0286] 2.7

[0287] (R)-6-((4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide (MX07145)

[0288] Add TFA (0.4 mL) to a solution of (R)-6-((4-(4-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide (21 mg, 0.026 mmol) in DCM (2 mL). The mixture was stirred for 2 hours under nitrogen protection at room temperature. After the starting material was consumed, water (10 mL) was added to the mixture, and it was extracted twice with EA (20 mL). The combined organic layers were washed with saturated sodium bicarbonate (20 mL x 2) and 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 (10.2 mg, yield 57.4%).

[0289] 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),9.41(s,1H),8.55(s,1H),8.48(d,J=2.4Hz,2H),8.22(d,J=8 .8Hz,2H),7.86(s,1H),7.76(d,J=8.8Hz,2H),7.57(dd,J=9.6,7.6Hz,2H),7.27(t,J=8.0Hz,1H),6 .65(s,1H),4.92(t,J=5.6Hz,1H),3.95(s,3H),3.83(d,J=6.0Hz,2H),3.74(s,3H),3.65–3.57(m,1 H),3.39–3.35(m,1H),3.20–3.14(m,1H),3.03–2.98(m,1H),2.43–2.32(m,4H),1.86–1.82(m,2H).

[0290] 1. Synthesis scheme:

[0291] 2. Experimental Section:

[0292] 2.1

[0293] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)-3,3,3-trideuteron-1-one (A-1)

[0294] 2-Methoxy-3-(1-methyl-1H-1,2,4-trideuterated propane-1-one) (300 mg, 1.45 mmol) and concentrated hydrochloric acid (0.3 mL) were added to a solution of 1-(4,6-dichloropyridin-3-yl)-3,3,3-trideuterated propane-1-one (6 mL) in ethanol (6 mL). The reaction mixture was stirred overnight at 80 °C. 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 40 g, 40 mL / min, silica gel, UV 254) to give a colorless oily product (246 mg, yield 45%).

[0295] ESI-MS m / z calcd for [C 18 H 15 D3ClN5O2][M+H] + 375.1; found: 375.0

[0296] 2.2

[0297] (R)-2-(6-aminopyridin-3-yl)-4-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (07146-1)

[0298] Add 5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridin-2-amine (132 mg, 0.60 mmol), potassium carbonate (164 mg, 1.20 mmol), and Pd(PPh3)4 (56 mg, 0.05 mmol) to a solution of (R)-4-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-2-chloro-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (200 mg, 0.48 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1). The mixture was stirred overnight at 100°C under nitrogen protection. After the starting material was consumed, the reaction solution was concentrated under reduced pressure after cooling. The crude product was purified by column chromatography (EA / PE = 0-100%, silica gel-CS 12g, 20mL / min, silica gel, UV 254) to obtain a yellow solid product (203mg, yield 88%).

[0299] ESI-MS m / z calcd for [C 22 H 33 N5O2SSi][M+H] + :460.2; found:460.2

[0300] 2.3

[0301] (R)-1-(6-((5-(4-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)-3,3,3-trideuteratedpropane-1-one (07146-2)

[0302] Add 1-(6-chloro-4-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (80 mg, 0.16 mmol) to a solution of (R)-2-(6-aminopyridin-3-yl)-4-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)pyridin-3-yl)-3,3,3-trideuterated propane-1-one (60 mg, 0.16 mmol), Cs2CO3 (108 mg, 0.32 mmol), and Breetphos Pd-G3 (16 mg, 0.016 mmol) to a solution of (R)-2-(6-aminopyridin-3-yl)-4-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)pyridin-3-yl)-3,3,3-trideuterated propane-1-one (60 mg, 0.16 mmol), Cs2CO3 (108 mg, 0.32 mmol), and Breetphos Pd-G3 (16 mg, 0.016 mmol) to a solution of 1,4-dioxane (5 mL). The mixture was stirred overnight at 100°C under nitrogen protection. After the starting material was consumed, the reaction solution was concentrated under reduced pressure after cooling. The crude product was purified by column chromatography (MeOH / DCM = 0-10%, silica gel-CS 12g, 20mL / min, silica gel, UV 254) to obtain a yellow solid product (42mg, yield 30%).

[0303] ESI-MS m / z calcd for [C 40 H 47 D3N 10 O4SSi][M+H] + :798.4; found:798.3

[0304] 2.4

[0305] (R)-3,3,3-trideuterated-1-(6-((5-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propane-1-one (MX07146)

[0306] Add 0.5 mL of TFA to a solution of (R)-1-(6-((5-(4-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)-3,3,3-trideuterated propane-1-one (42 mg, 0.05 mmol) in DCM (2.0 mL). The mixture was stirred at room temperature for 2 hours. After the starting material was consumed, the reaction solution was 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 white solid product (4.69 mg, yield 13%).

[0307] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.33(s,1H),9.08(d,J=2.0Hz,1H),8.88(s,1H),8.57(s,1H),8. 45(dd,J=8.8,2.0Hz,1H),8.18(s,1H),8.04(s,1H),7.74(d,J=8.0Hz,1H),7.67–7.62(m,2H),7.31(t,J =8.0Hz,1H),4.95(t,J=5.6Hz,1H),3.96(s,3H),3.84–3.79(m,2H),3.76(s,3H),3.67–3.59(m,1H),3.3 9–3.37(m,1H),3.23–3.17(m,1H),3.09(s,2H),3.05–2.99(m,1H),2.45–2.33(m,4H),1.91–1.86(m,2H).

[0308] 1. Synthesis scheme:

[0309] 2. Experimental Section:

[0310] 2.1

[0311] 3-(2-Methoxy-3-nitrophenyl)-1-methyl-1H-pyrazole (07147-1)

[0312] To a solution of 1-bromo-2-methoxy-3-nitrobenzene (2.0 g, 8.60 mmol) in 1,4-dioxane / water (25 mL, v / v = 4 / 1), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrazole (1.78 g, 8.60 mmol), potassium phosphate (4.58 g, 21.6 mmol), and Pd(dppf)Cl2 (604 mg, 0.86 mmol) were added. The mixture was stirred overnight at 120 °C under nitrogen protection. After the starting material was consumed, the reaction solution was cooled and concentrated under reduced pressure. The crude product was purified by column chromatography (EA / PE = 0–100%, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give a yellow solid product (2.01 g, yield 99%).

[0313] ESI-MS m / z calcd for [C 11 H 11 N3O3][M+H + :234.1; found:234.2

[0314] 2.2

[0315] 2-Methoxy-3-(1-Methyl-1H-pyrazol-3-yl)aniline (07147-2)

[0316] Pd / C (400 mg) was added to a solution of 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-pyrazole (2.0 g, 8.58 mmol) in MeOH (30 mL). The mixture was stirred overnight at room temperature under hydrogen protection. After the starting material was consumed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to give a yellow solid product (1.71 g, 98% yield).

[0317] ESI-MS m / z calcd for [C 11 H 13 N3O][M+H] + :204.1; found:204.3

[0318] 2.3

[0319] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)pyridin-3-yl)-3,3,3-trideuterated propane-1-one (07147-3)

[0320] 2-Methoxy-3-(1-methyl-1H-pyrazole-3-yl)aniline (400 mg, 2.00 mmol) and concentrated hydrochloric acid (0.4 mL) were added to a solution of 1-(4,6-dichloropyridin-3-yl)-3,3,3-trideuterated propane-1-one (400 mg, 2.00 mmol) in ethanol (8 mL). The reaction mixture was stirred overnight at 80 °C. 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 40 g, 40 mL / min, silica gel, UV 254) to give a colorless oily product (397 mg, yield 54%).

[0321] ESI-MS m / z calcd for [C 19 H 16 D3ClN4O2][M+H] + :374.1; found:374.3

[0322] 2.4

[0323] (6-((4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-5-(3,3,3-trideuteronyl)pyridin-2-yl)amino)pyridin-3-yl)boronic acid (07147-4)

[0324] To a solution of 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)pyridin-3-yl)-3,3,3-trideuteron-1-one (80 mg, 0.21 mmol) in 1,4-dioxane (4 mL), 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)pyridin-2-amine (46 mg, 0.21 mmol), Cs₂CO₃ (137 mg, 0.42 mmol), dppf (11 mg, 0.02 mmol), and Pd₂(dba)₃ (23 mg, 0.02 mmol) were added. The mixture was stirred in a microwave at 100 °C under nitrogen protection for 1.5 hours. After the starting materials were consumed, the reaction solution was used directly for the next step.

[0325] ESI-MS m / z calcd for [C 24 H 22 D3BN6O4][M+H] + 476.2; found: 476.3

[0326] 2.5

[0327] (R)-3,3,3-trideuterated-1-(6-((5-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)pyridin-3-yl)propane-1-one (MX07147)

[0328] To the reaction solution used in the previous step to synthesize (6-((4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-5-(3,3,3-trideuteronyl)pyridin-2-yl)amino)pyridin-3-yl)boronic acid, (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (60 mg, 0.21 mmol), potassium carbonate (58 mg, 0.42 mmol), water (1 mL), and Pd(dppf)Cl2 (14 mg, 0.02 mmol) were added. The mixture was stirred at 80 °C under nitrogen protection for 4 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 preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to obtain a white solid product (9.10 mg, yield 6%).

[0329] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.32(s,1H),9.08(d,J=2.0Hz,1H),8.88(s,1H),8.45(dd,J=8.4,2.0 Hz,1H),8.17(s,1H),8.03(s,1H),7.78(d,J=2.0Hz,1H),7.69(d,J=7.6Hz,1H),7.63–7.60(m,2H),7.26(t,J =8.0Hz,1H),6.75(d,J=2.0Hz,1H),4.94(t,J=5.6Hz,1H),3.92(s,3H),3.84–3.83(m,2H),3.67–3.59(m,4H) ,3.39–3.37(m,1H),3.23–3.17(m,1H),3.09(s,2H),3.04–2.99(m,1H),2.45–2.33(m,4H),1.92–1.87(m,2H).

[0330] 1. Synthesis scheme:

[0331] 2. Experimental Section:

[0332] 2.1

[0333] 4,6-Dichloro-N-(methyl-d3)nicotinamide (A-1)

[0334] At 0°C, 1 drop of DMF and 1.78 mL of oxaloyl chloride (20.32 mmol) were added to a solution of 4,6-dichloronicotinic acid (3.0 g, 15.63 mmol) in 30 mL of DCM. The mixture was stirred for 0.5 hours under nitrogen protection at room temperature. After the starting material was consumed, the reaction solution was concentrated under reduced pressure. The crude product was dissolved in 30 mL of DCM and cooled to 0°C. A solution of deuterated methylamine hydrochloride (1.43 g, 20.32 mmol) dissolved in 2 mL of DCM and DIEA (8.19 mL, 46.9 mmol) were added dropwise to the reaction solution. The mixture was stirred for 2 hours under nitrogen protection at room temperature. After the starting material was consumed, the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography (PE / EA = 1 / 0 to 1 / 1, silica gel-CS 80 g, 40 mL / min, silica gel, UV 254) to give a white solid product (2.57 g, yield 79.4%).

[0335] ESI-MS m / z calcd for[C7H3D3Cl2N2O][M+H] + :208.0; found:208.2

[0336] 2.2

[0337] 6-Chloro-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide (A-2)

[0338] At 0 °C, 2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)aniline (307 mg, 1.52 mmol) and LiHMDS (5.07 mL, 1.0 M in THF) were added to a solution of 4,6-dichloro-N-(methyl-d3)nicotinamide (300 mg, 1.45 mmol) in tetrahydrofuran (5 mL). The mixture was stirred at room temperature for 3 hours. After the starting material was consumed, water (10 mL) was added to dilute the mixture, and the pH was adjusted to 9 with 1 N HCl. The solid precipitated, filtered, and the filter cake was concentrated and dried under reduced pressure to obtain a white solid product (363 mg, yield 67%).

[0339] ESI-MS m / z calcd for [C 18 H 15 D3ClN5O2][M+H] + 375.1; found: 375.3

[0340] 2.3

[0341] tert-Butyl-6-amino-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid ester (07153-1)

[0342] Pd(dppf)Cl2 (249 mg, 0.34 mmol) and potassium carbonate (1.42 g, 10.29 mmol) were added to a solution of 5-bromopyridin-2-amine (600 mg, 3.43 mmol) and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-5,6-dihydropyridin-1(2H)-carboxylic acid ester (1.17 g, 3.77 mmol) in 1,4-dioxane and water (9 mL, v / v = 5 / 1). The mixture was stirred at 100°C under nitrogen protection for 5 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 column chromatography (PE / EA = 1 / 0~0 / 1 silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to obtain a light yellow solid product (513 mg, yield 54.4%).

[0343] ESI-MS m / z calcd for [C 15 H 21 [N3O2][M+H] + :276.2; found:276.2

[0344] 2.4

[0345] tert-Butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylic acid ester (07153-2)

[0346] Palladium on carbon (200 mg) was added to a solution of tert-butyl-6-amino-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid ester (500 mg, 1.82 mmol) in methanol (10 mL). The mixture was stirred at room temperature under hydrogen protection for 2 hours. After the starting material was consumed, the reaction solution was filtered, concentrated under reduced pressure, and the crude product was subjected to column chromatography (PE / EA = 1 / 0 to 0 / 1, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give a purple solid product (415 mg, yield 82.3%).

[0347] ESI-MS m / z calcd for [C 15 H 23 [N3O2][M+H] + :278.2; found:278.2

[0348] 2.5

[0349] tert-Butyl 4-(6-((4-((2-methoxy-3-(1-methyl-1H-pyrazole-3-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-2-yl)amino)pyridin-3-yl)piperidine-1-carboxylic acid ester (07153-3)

[0350] To a solution of tert-butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylic acid ester (120 mg, 0.43 mmol) in 1,4-dioxane (5 mL), 6-chloro-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide (162 mg, 0.43 mmol), Pd2(dba)3 (39 mg, 0.043 mmol), xantphos (25 mg, 0.043 mmol), and cesium carbonate (280 mg, 0.86 mmol) were added. The mixture was sealed and stirred overnight under nitrogen protection at 110°C. 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 column chromatography (MeOH / DCM = 0 / 1 to 1 / 9, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give a light yellow solid product (113 mg, yield 42.8%).

[0351] ESI-MS m / z calcd for [C 33 H 37 D3N8O4][M+H] + :616.3; found:616.5

[0352] 2.6

[0353] 4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((5-(piperidin-4-yl)pyridin-2-yl)amino)nicotinamide(07103-4)

[0354] TFA (0.4 mL) was added to a solution of tert-butyl 4-(6-((4-(((2-methoxy-3-(1-methyl-1H-pyrazole-3-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-2-yl)amino)pyridin-3-yl)piperidine-1-carboxylic acid ester (40 mg, 0.065 mmol) in DCM (2.0 mL). The reaction mixture was stirred at room temperature for 2 hours under nitrogen protection. After the starting material was consumed, the mixture was concentrated by vacuum distillation to obtain a crude product which was directly used in the next reaction step.

[0355] ESI-MS m / z calcd for [C 28 H 29 D3N8O2][M+H] + :516.3; found:516.3

[0356] 2.5

[0357] (R)-6-((5-(1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide (MX07153)

[0358] DIEA (45 mg, 0.35 mmol) was added to a solution of 4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((5-(piperidin-4-yl)pyridin-2-yl)amino)nicotinamide (30 mg, 0.058 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (17 mg, 0.058 mmol) in DMF (2 mL). The mixture was stirred at 90 °C for 2 hours, cooled to room temperature, 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 (15.68 mg, yield 35.3%).

[0359] 1 H NMR (400MHz, DMSO-d6) δ10.71(s,1H),9.63(s,1H),8.45(d,J=7.6Hz,2H),8.06(s,1H),7.92(s,1H),7 .77(d,J=2.0Hz,1H),7.58–7.47(m,4H),7.31(s,1H),7.23(t,J=8.0Hz,1H),6.73(d,J=2.0Hz,1H),4. 83(t,J=5.2Hz,3H),3.91(s,3H),3.72(d,J=5.2Hz,2H),3.61(s,3H),3.46–3.37(m,1H),3.25–3.20(m ,1H),2.97–2.80(m,5H),2.39–2.31(m,2H),2.19–2.14(m,2H),1.80–1.71(m,4H),1.55–1.46(m,2H).

[0360] 1. Synthesis scheme:

[0361] 2. Experimental Section:

[0362] 2.1

[0363] (R)-4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((5-(1-(5-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)pyridin-2-yl)amino)nicotinamide (MX07155)

[0364] DIEA (45 mg, 0.35 mmol) was added to a solution of 4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((5-(piperidin-4-yl)pyridin-2-yl)amino)nicotinamide (30 mg, 0.058 mmol) and (R)-2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (17 mg, 0.058 mmol) in DMF (2 mL). The mixture was stirred at 90 °C for 2 hours, cooled to room temperature, 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 (20.93 mg, yield 47.1%).

[0365] 1 H NMR (400MHz, DMSO-d6) δ10.71(s,1H),9.63(s,1H),8.45(d,J=8.0Hz,2H),8.06(d,J=2.0Hz,1 H),7.93(s,1H),7.77(d,J=2.0Hz,1H),7.58–7.47(m,5H),7.23(t,J=8.0Hz,1H),6.73(d,J=2 .4Hz,1H),4.87(d,J=12.0Hz,2H),4.20–4.15(m,1H),3.91–3.87(m,5H),3.61(s,3H),3.47–3 .35(m,3H),3.25–3.18(m,1H),2.98–2.76(m,5H),1.80(d,J=12.4Hz,4H),1.68–1.49(m,4H).

[0366] 1. Synthesis scheme:

[0367] 2. Experimental Section:

[0368] 2.1

[0369] N-(2-methoxy-4-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)phenyl)-2-((trideuterated methyl)amino)acetamide (07160-1)

[0370] 2-((trideuterated methyl)amino)-N-(2-methoxy-4-(4-chloropyrimidin-2-ylamino)phenyl)acetamide (100 mg, 0.217 mmol) was added to a solution of 1,4-dioxane (2.0 mL) with 4-(N-Boc-piperazin-1-yl)benzonitrile (60 mg, 0.217 mmol), Pd2(dba)3 (20 mg, 0.0021 mmol), Xantphos (12.5 mg, 0.0021 mmol), and Cs2CO3 (176 mg, 0.54 mmol). 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 (10 mL), and extracted three times with EA (10 mL). The combined organic layers were washed with saturated brine (10 mL), dried with anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (DCM / MeOH = 1 / 0 to 1 / 1, silica gel-CS 10 g, 16 mL / min, silica gel, UV 254) to give a white solid product (60 mg, yield 40.2%).

[0371] ESI-MS m / z calcd for [C 32 H 36 D3N9O4][M+H + :617.3; found:617.3

[0372] 2.2

[0373] N-[4-({4-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}amino)pyridin-2-yl]-2-(trideuterated methyl)-1H-benzo[d]imidazol-5-carboxamide (07160-2)

[0374] N-(2-methoxy-4-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)phenyl)-2-((trideuterated methyl)amino)acetamide (107 mg, 0.17 mmol) was stirred at room temperature for 1 hour in a TFA / DCM solution (3 mL, v / v = 5 / 1). After the starting material was consumed, the mixture was distilled off the solvent under reduced pressure, cooled, and added to water (10 mL). The pH was adjusted with sodium bicarbonate, and the mixture was extracted three times with EA (10 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 = 1 / 0 to 1 / 1, silica gel-CS 10 g, 16 mL / min, silica gel, UV 254) to give a white solid product (72 mg, yield 80.3%).

[0375] ESI-MS m / z calcd for [C 27H 28 D3N9O2][M+H] + :517.2; found:517.3

[0376] 2.3

[0377] (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((2-(1-methyl-1H-indazol-5-yl)pyrimidin-4-yl)amino)phenyl)-4-(4-methylpiperazin-1-yl)furano[3,4-c]pyridine-1-carboxamide (MX07160)

[0378] N-[4-({4-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}amino)pyridin-2-yl]-2-(trideuteratedmethyl)-1H-benzo[d]imidazolium-5-carboxamide (72 mg, 0.14 mmol), (S)-7-chloro-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-amine-3-oxide (40.1 mg, 0.14 mmol) was added to a solution of N-[4-(4-(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}amino)pyridin-2-yl]-2-(trideuteratedmethyl)-1H-benzo[d]imidazolium-3-amine-3-oxide (40.1 mg, 0.14 mmol) in DMF (2.0 mL). DIEA (43 mg, 0.33 mmol) was added to the solution. The mixture was reacted at 85 °C under nitrogen protection for 2 hours. After the starting material was consumed, the crude product was subjected to preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV). 254) Purification yielded a white solid compound (12.4 mg, yield 13.1%).

[0379] 1 H NMR (400MHz, DMSO-d6) δ10.71(s,1H),9.61(s,1H),9.66(s,1H),8.55(s,1H),8.45(d,J=4.4Hz,2H),8.06(d, J=2Hz,1H),7.94(s,1H),7.65(dd,J=1.2,8.0Hz,1H),7.58–7.47(m,3H),7.34(s,1H),7.29(t,J=8.0Hz,1H),4 .86–4.80(m,3H),3.95(s,3H),3.74(s,3H),3.72(d,J=5.6Hz,2H,3.43–3.37(m,1H),3.24–3.19(m,1H),2.96 –2.85(m,2H),2.85–2.79(m,2H),2.38–2.29(m,2H),2.18–2.14(m,2H),1.80–1.73(m,4H),1.53–1.49(m,2H).

[0380] 1. Synthesis scheme:

[0381] 2. Experimental Section:

[0382] 2.1

[0383] tert-butyl-4-(6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d) 3 Pyridin-2-yl)amino)pyridin-3-yl)piperidine-1-carboxylic acid ester (07161-1)

[0384] 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propane-3,3,3-d 3 A mixture of 1,4-dioxane (5 mL) containing tert-butyl-4-(6-aminopyridin-3-yl)piperidine-1-carboxylic acid ester (30 mg, 0.11 mmol), cesium carbonate (108 mg, 0.33 mmol), Brettphos (12 mg, 0.022 mmol), Brettphos Pd G3 (10 mg, 0.011 mmol), and Pd2(dba)3 (18 mg, 0.02 mmol) was placed in a sealed tube. The tube was then purged with argon to remove air. The tube was then sealed and stirred overnight at 110 °C. After the starting material was consumed, the mixture was concentrated, and the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 10, silica gel-CS 12 g, 30 mL / min, silica gel, UV 254) to give a yellow oily product (41 mg, yield 62%).

[0385] ESI-MS m / z calcd for [C 33 H 37 D3N8O4][M+H] + :616.3; found:616.4

[0386] 2.2

[0387] 1-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridin-3-yl)propane-3,3,3-d 3 -1-keto(07161-2)

[0388] tert-butyl-4-(6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d) 3 Pyridin-2-yl)amino)pyridin-3-yl)piperidin-1-carboxylic acid ester (40 mg, 0.07 mmol) was added to a solution of DCM (1.5 mL) with TFA (0.5 mL). The reaction mixture was stirred at room temperature for 1 hour under nitrogen protection. After the starting material was consumed, the mixture was concentrated by vacuum distillation, and the TFA was removed by azeotropic distillation with DCM (5 mL × 3) to give a yellow oily product (35 mg, 100% yield).

[0389] ESI-MS m / z calcd for [C 28 H 29 D3N8O2][M+H] + :516.3; found:516.3

[0390] 2.3

[0391] (R)-1-(6-((5-(1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)propane-3,3,3-d 3 -1-keto (MX07161)

[0392] To 1-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridin-3-yl)propane-3,3,3-d 3 1-one (35 mg, 0.068 mmol) was added to a solution of DMF (2 mL) and DIEA (44 mg, 0.34 mmol) with (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (20 mg, 0.068 mmol). The mixture was stirred at 85 °C for 2 hours. After the starting material was consumed, the mixture was concentrated by vacuum distillation. 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 product (13.31 mg, yield 26%).

[0393] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),9.88(s,1H),8.83(s,1H),8.56(s,1H),8.08(d,J=1.6Hz,1H ),7.96(s,1H),7.69(d,J=7.6Hz,1H),7.62–7.58(m,2H),7.50(d,J=8.8Hz,1H),7.35–7.31(m,2H), 4.85–4.82(m,3H),3.95(s,3H),3.74–3.72(m,5H),3.46–3.36(m,1H),3.25–3.17(m,1H),3.05(s,2 H),2.97–2.77(m,5H),2.39–2.29(m,2H),2.19–2.14(m,2H),1.80–1.73(m,4H),1.56–1.46(m,2H).

[0394] 1. Synthesis scheme:

[0395] 2. Experimental Section:

[0396] 2.1

[0397] (R)-2-(6-aminopyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (07166-1)

[0398] (R)-2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (500 mg, 1.737 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridin-2-amine (382 mg, 1.737 mmol) were dissolved in 1,4-dioxane / water solution (15 mL, v / v 5:1), and Pd(PPh3)4 (401 mg, 0.347 mmol) and K2CO3 (719 mg, 5.0 mmol) were added. The mixture was stirred overnight at 100 °C under nitrogen atmosphere. After the reaction was completed, the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (MeOH / DCM = 0 / 1 to 1 / 10, silica gel-CS 20g, 40mL / min, silica gel, UV 254) to obtain a brown solid product (264mg, yield 44%).

[0399] ESI-MS m / z calcd for [C16 H 19 [N5O2S][M+H] + 346.1; found: 345.9

[0400] 2.2

[0401] (R)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((5-(5-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)amino)-N-(trideuterated methyl)nicotinamide (MX07166)

[0402] (R)-2-(6-aminopyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (100 mg, 0.29 mmol) and 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(trideuterated methyl)nicotinamide (109 mg, 0.29 mmol) were dissolved in 1,4-dioxane (5 mL), and Brettphos Pd-G3 (53 mg, 0.058 mmol) and Cs₂CO₃ (284 mg, 0.87 mmol) were added. The mixture was stirred overnight at 100 °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 / 5, silica gel-CS 12g, 20mL / min, silica gel, UV 254), and then purified by preparative HPLC [MeCN / H2O, X-Select 10μm 19×250mm, 20mL / min, UV 254] to obtain a white solid product (52.84mg, yield 26.7%).

[0403] 1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),10.16(s,1H),9.12(s,1H),8.56–8.49(m,4H),8. 16–8.09(m,2H),7.71–7.65(m,2H),7.57(d,J=7.6Hz,1H),7.30(t,J=7.6Hz,1H),4.47(b r,1H),3.98–3.95(m,5H),3.77(s,3H),3.69–3.61(m,1H),3.53–3.48(m,2H),3.40–3.3 6(m,1H),3.22(dd,J=16.8,8.4Hz,1H),3.04(dd,J=13.2,7.2Hz,1H),1.88–1.66(m,4H).

[0404] 1. Synthesis scheme:

[0405] 2. Experimental Section:

[0406] 2.1

[0407] 1-(2-Methoxy-3-nitrophenyl)acetone (R-1a)

[0408] 1-(2-hydroxy-3-nitrophenyl)ethyl ketone (4.0 g, 22.08 mmol) and potassium carbonate (12.2 g, 88.32 mmol) in a reaction mixture of 1-(2-hydroxy-3-nitrophenyl) ethyl ketone (4.0 g, 22.08 mmol) and potassium carbonate (12.2 g, 88.32 mmol) in DMF (80 mL) were stirred for 20 min at 20 °C under argon protection. Iodimethane (9.4 g, 66.24 mmol) was added to the solution. The mixture was then stirred at room temperature under argon protection for 16 h. The reaction was quenched with water (60 mL) and extracted three times with EA (150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 100–15 / 85, silica gel-CS 80 g, 45 mL / min, silica gel, UV 254) to give a yellow oily product (4.2 g, 97% yield).

[0409] ESI-MS m / z calcd for[C9H9NO4][M+H] + :196.1; found:196.4

[0410] 2.2

[0411] 2-Bromo-1-(2-methoxy-3-nitrophenyl)ethyl ketone (R-1b)

[0412] Copper bromide (4.8 g, 21.54 mmol) was stirred in a reaction mixture of CHCl3 (30 mL) and EA (30 mL) at 90 °C under argon protection for 15 min. A chloroform (15 mL) solution of 1-(2-methoxy-3-nitrophenyl)ethyl ketone (2.1 g, 10.77 mmol) was slowly added dropwise to the solution. The mixture was then stirred at 80 °C for 3 h under argon protection. The reaction mixture was filtered and concentrated, the reaction was quenched with water (60 mL), and extracted three times with EA (150 mL). The combined organic layers were extracted with a saturated aqueous sodium bicarbonate solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 100–15 / 85, silica gel-CS 40 g, 45 mL / min, silica gel, UV 254) to give a yellow solid product (2.2 g, 75% yield).

[0413] ESI-MS m / z calcd for[C9H8BrNO4][M+H] + :274.0; found:274.1

[0414] 2.3

[0415] 2-(2-Methoxy-3-nitrophenyl)-4-methylmorpholin-2-ol (R-1c)

[0416] 2-(methylamino)ethanol (1.1 g, 14.65 mmol) was added to a reaction mixture of 2-bromo-1-(2-methoxy-3-nitrophenyl)ethyl ketone (2.0 g, 7.33 mmol) and toluene (30 mL) under argon protection at 20 °C. The mixture was then stirred at room temperature for 24 h under argon protection. The reaction was quenched with water (20 mL) and 1 M dilute hydrochloric acid solution (10 mL), and extracted with EA (40 mL). The combined aqueous phases were cooled with ice, adjusted to alkalinity with ammonia, and extracted three times with EA (40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 100–100 / 0, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to give a yellow solid product (760 mg, yield 39%).

[0417] ESI-MS m / z calcd for [C 12 H 16 [N2O5][M+H] + :269.1; found:269.0

[0418] 2.4

[0419] 2-(2-Methoxy-3-nitrophenyl)-4-methylmorpholine (R-1d)

[0420] TES (2.08 g, 17.89 mmol) was added to a solution of 2-(2-methoxy-3-nitrophenyl)-4-methylmorpholin-2-ol (4.0 g, 22.08 mmol) in DCE (10 mL) under argon protection at 0 °C. The mixture was stirred for 10 min. TFA (2.5 mL) was slowly added to the solution. The mixture was then stirred at 80 °C for 12 h under argon protection. The reaction was quenched with saturated sodium bicarbonate aqueous solution (25 mL), and the mixture was extracted three times with DCM (90 mL). The combined organic layers were extracted with saturated saline aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 100–100 / 0, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to give a yellow solid product (760 mg, yield 39%).

[0421] ESI-MS m / z calcd for [C 12 H 16 N₂O₄][M+H] + :253.1; found:253.4

[0422] 2.5

[0423] 2-Methoxy-3-(4-methylmorpholin-2-yl)aniline (07178-R-1)

[0424] Pd / C (200 mg) and NH4COOH (1.4 g) were added to a solution of 2-(2-methoxy-3-nitrophenyl)-4-methylmorpholine (480 mg, 1.9 mmol) in MeOH (20 mL). The mixture was then stirred at room temperature for 12 hours under argon protection. The reaction solution was filtered and concentrated, and extracted three times with water (10 mL) and saturated sodium bicarbonate aqueous solution (20 mL) and EA (90 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oily product (450 mg, crude product).

[0425] ESI-MS m / z calcd for [C 12 H 18 N₂O₂][M+H] + :223.1; found:223.4

[0426] 2.6

[0427] 6-Chloro-4-((2-methoxy-3-(4-methylmorpholin-2-yl)phenyl)amino)-N-methyl-d3-nicotinamide (07178-1)

[0428] Under argon protection at 0°C, 10.4 mL of LiHMDS (10.4 mmol) was added to a solution of 4,6-dichloro-N-(methyl-d3)nicotinamide (618 mg, 2.97 mmol) and 2-methoxy-3-(4-methylmorpholino-2-yl)aniline (660 mg, 2.97 mmol) in 25 mL of THF. The reaction was stirred for 40 min. The reaction was quenched with an aqueous solution (20 mL), and the mixture was extracted three times with EA (60 mL). The combined organic layers were extracted with a saturated saline solution (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (DCM / MeOH = 10 / 0 to 1 / 10, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give a yellow oily product (964 mg, yield 82%).

[0429] ESI-MS m / z calcd for [C 19 H 20 D3ClN4O3][M+H] + :394.2; found:394.3

[0430] 2.7

[0431] 4-((2-methoxy-3-(4-methylmorpholin-2-yl)phenyl)amino)-N-methyld3-6-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)phenyl)amino)nicotinamide(07178-2)

[0432] A mixture of 6-chloro-4-((2-methoxy-3-(4-methylmorpholin-2-yl)phenyl)amino)-N-methyl-d3-nicotinamide (125 mg, 0.32 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)aniline (70 mg, 0.32 mmol), cesium carbonate (209 mg, 0.64 mmol), Xantphos (17 mg, 0.03 mmol), and Pd2(dba)3 (14 mg, 0.015 mmol) in 1,4-dioxane (8 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 100 °C. After the starting materials were consumed, the crude product was concentrated and purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 10, silica gel-CS20g, 30mL / min, silica gel, UV 254) to obtain a yellow solid product (70mg, yield 38%).

[0433] ESI-MS m / z calcd for [C 31 H 37 D3BN5O5][M+H] + :577.3; found:577.0

[0434] 2.8

[0435] 6-((4-(hydroxymethyl)cyclobutyl)amino)-5-(R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)amino)-4-((2-methoxy-3-(4-methylmorpholin-2-yl)phenyl)amino)-N-methyl-d3-nicotinamide (MX07178)

[0436] To a solution of 4-((2-methoxy-3-(4-methylmorpholin-2-yl)phenyl)amino)-N-methyld3-6-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)amino)nicotinamide (60 mg, 0.1 mmol) in 1,4-dioxane / water (6 mL, v / v = 5 / 1), (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (36 mg, 0.125 mmol), K₂CO₃ (41 mg, 0.3 mmol), and Pd(dppf)Cl₂·DCM (8 mg, 0.01 mmol) were added. The mixture was heated to 100 °C and stirred overnight under nitrogen protection. After cooling and concentration, the crude product was purified by column chromatography (MeOH / DCM = 0 / 10–1.5 / 8.5, 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 give a white solid product (23.97mg, yield 29%).

[0437] 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),9.41(s,1H),8.48(d,J=3.6Hz,2H),8.22(d,J=8.8Hz,2H),7.88(s,1H),7.74(d,J=8.8Hz,2 H),7.42–7.40(m,1H),7.22–7.17(m,2H),6.57(s,1H),4.93(t,J=6.0Hz,1H),4.76(dd,J=9.6,2.0Hz,1H),3.94(dd,J=10.8,2.0H z,1H),3.83(d,J=5.6Hz,2H),3.74–3.69(m,4H),3.63–3.57(m,1H),3.38–3.36(m,1H),3.20–3.14(m,1H),3.03–2.98(m,1H),2.8 3(d,J=11.2Hz,1H),2.72–2.69(m,5H),2.40–2.37(m,1H),2.34–2.30(m,3H),2.20(s,3H),2.12–2.05(m,1H),1.88–1.80(m,3H).

[0438] 1. Synthesis scheme:

[0439] 2. Experimental Section:

[0440] 2.1

[0441] (S)-N-(4-(4-cyclopropyl-3-(2,2,2-trideuterylpropionyl)phenyl)-6-methoxyquinazoline-7-yl)-4-(2-methyl-1,3-dioxolane-2-yl)benzamide (07179-1)

[0442] 2-Methoxy-4-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)-N-(2,2,2-trideuteronyl)aniline (100 mg, 0.266 mmol) was added to a solution of 1,4-dioxane (2.0 mL) with 4-(5,5-dimethyl-1,3,2-dioxaborhexane-2-yl)aniline (70 mg, 0.32 mmol), Pd2(dba)3 (24 mg, 0.026 mmol), DPPF (14.7 mg, 0.026 mmol), and Cs2CO3 (216 mg, 0.665 mmol). The mixture was microwave-treated at 110 °C for 1.5 h. After the starting material was consumed, the mixture was cooled and added to water (30 mL), and extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried with anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (DCM / MeOH = 1 / 0 to 1 / 1, silica gel-CS 10 g, 16 mL / min, silica gel, UV 254) to give a white solid product (60 mg, yield 40.2%).

[0443] ESI-MS m / z calcd for [C 30 H 32 D3BN6O4][M+H] + :558.2; found:558.2

[0444] 2.2

[0445] (S)-N-(4-(4-cyclopropyl-3-(2,2,2-trideuteropropionyl)phenyl)-7-methoxyquinazoline-6-yl)-4-(2-((S)-4-(methanesulfonyl)piperazin-1-yl)pyrimidin-5-yl)benzamide (MX07179)

[0446] (S)-N-(4-(4-cyclopropyl-3-(2,2,2-trideuteronyl)phenyl)-6-methoxyquinazoline-7-yl)-4-(2-methyl-1,3-dioxolane-2-yl)benzamide (50 mg, 0.09 mmol) was added to a solution of 1,4-dioxane / water (3 mL, v / v = 5 / 1) with (S)-7-chloro-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-amine-3-oxide (31 mg, 0.10 mmol), Pd(dppf)Cl2.DCM (7.5 mg, 0.009 mmol) and K2CO3 (30 mg, 0.225 mmol). The mixture was stirred at 100°C under nitrogen protection for 3 hours. After the initial raw materials were consumed, the crude product obtained by evaporating the solvent 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 (4.6mg, yield 7.5%).

[0447] 1 H NMR(400MHz,DMSO-d6)δ10.86(s,1H),9.61(s,1H),8.88(s,1H),8.56(s,1H),8.23(d,J=8.8Hz,2H),7 .89(s,1H),7.78(d,J=8.8Hz,2H),7.76(dd,J=1.2,7.6Hz,1H),7.58(dd,J=1.2,7.6Hz,1H),7.29(t,J= 7.6Hz,1H),6.57(s,1H),4.92(t,J=5.6Hz,1H),3.95(s,3H),3.82(d,J=6.0Hz,2H),3.72(s,3H),3.38– 3.33(m,1H),3.21–3.16(m,1H),3.06(s,2H),3.02–2.98(m,1H),2.43–2.30(m,4H),1.86–1.82(m,2H).

[0448] 1. Synthesis scheme:

[0449] 2. Experimental Section:

[0450] 2.1

[0451] tert-Butyl 4-(4-aminophenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid ester (07180-R-1a)

[0452] To a solution of 4-bromoaniline (1 g, 5.8 mmol) in 1,4-dioxane / water (12 mL, v / v = 5 / 1), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid ester (2.33 g, 7.5 mmol), K3PO4 (2 g, 9.3 mmol), and Pd(dppf)Cl2·DCM (250 mg, 0.3 mmol) were added. The mixture was heated to 100 °C and stirred overnight under nitrogen protection. After cooling and concentration, the crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 1, silica gel-CS 40 g, 30 mL / min, silica gel, UV 254) to give a yellow solid product (1.3 g, yield 82%).

[0453] ESI-MS m / z calcd for [C 16 H 22 N₂O₂][M+H] + :275.2; found:275.0

[0454] 2.2

[0455] tert-Butyl 4-(4-aminophenyl)piperidine-1-carboxylic acid ester (07180-R-1)

[0456] Pd / C (400 mg) was added to a solution of tert-butyl-4-(4-aminophenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid ester (1.3 g, 4.74 mmol) in methanol (20 mL). The mixture was stirred at room temperature under hydrogen protection for 2 hours. After the starting material was consumed, the mixture was filtered and concentrated to give a yellow solid product (1.4 g, 100% yield).

[0457] ESI-MS m / z calcd for [C 10 H 12 D3N3O4][M+H] + :245.1; found:245.4

[0458] 2.3

[0459] tert-Butyl 4-(4-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(methyl-d3-carbamoyl)pyridin-2-yl)amino)phenyl)piperidine-1-carboxylic acid ester (07180-1)

[0460] A mixture of 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-d3-nicotinamide (120 mg, 0.32 mmol), tert-butyl-4-(4-aminophenyl)piperidine-1-carboxylic acid ester (120 mg, 0.43 mmol), cesium carbonate (300 mg, 0.92 mmol), Xantphos (30 mg, 0.052 mmol), and Pd2(dba)3 (30 mg, 0.033 mmol) in 1,4-dioxane (10 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 material was consumed, the crude product was concentrated and purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 10, silica gel-CS20g, 26mL / min, silica gel, UV 254) to obtain a yellow solid product (53mg, yield 27%).

[0461] ESI-MS m / z calcd for [C 33 H 37 D3N8O4][M+H] + :616.3; found:615.9

[0462] 2.4

[0463] 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyld3-6-((4-(piperidin-4-yl)phenyl)amino)nicotinamide(07161-2)

[0464] TFA (0.5 mL) was added to a solution of tert-butyl-4-(4-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(methyl-d3-carbamoyl)pyridin-2-yl)amino)phenyl)piperidin-1-carboxylic acid ester (53 mg, 0.086 mmol) in DCM (2.0 mL). The reaction mixture was stirred at room temperature for 1 hour under nitrogen protection. After the starting material was consumed, the mixture was concentrated by vacuum distillation, and the TFA was removed by azeotropic distillation with DCM (5 mL × 3) to give a yellow oily product (44 mg, yield: crude product).

[0465] ESI-MS m / z calcd for [C 28 H 29 D3N8O2][M+H] + :516.3; found:516.3

[0466] 2.5

[0467] (R)-6-((4-(1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)phenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-d3-nicotinamide (MX07180)

[0468] Add (R)-2-chloro-4-((1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyld3-6-((4-(piperidin-4-yl)phenyl)amino)nicotinamide (44 mg, 0.085 mmol) to a solution of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (25 mg, 0.085 mmol) to a solution of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (1.5 mL, DIEA) and ... to a solution of DIEA and (1.5 mL, DIEA) to a solution of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyld3-6-((4-(piperidin-4-yl)phenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (1.5 mL, DIEA) to a solution of DIEA and (1.5 mL, DIEA) to a solution of 4-((2-meth The mixture was stirred at 85°C for 2 hours. After the starting material was consumed, the mixture was concentrated by vacuum distillation. 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 (23.34mg, yield 36%).

[0469] 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),8.98(s,1H),8.54((s,1H),8.39(d,J=10.8Hz,2H),7.55– 7.48(m,4H),7.30(s,1H),7.24(t,J=8.0Hz,1H),7.11(d,J=8.4Hz,2H),6.54(s,1H),4.85–4.78( m,3H),3.94(s,3H),3.75–3.70(m,5H),3.43–3.37(m,1H),3.25–3.18(m,1H),2.96–2.83(m,1H) ,2.78–2.67(m,1H),2.39–2.30(m,2H),2.18–2.14(m,2H),1.80–1.73(m,4H),1.52–1.47(m,2H).

[0470] 1. Synthesis scheme:

[0471] 2. Experimental Section:

[0472] 2.1

[0473] 4-(1-Methyl-1H-pyrazol-4-yl)-2-[4-(tert-butyloxycarbonyl)piperazin-1-yl]amino-6-[3-(trideuteromethyl)propamido]pyrimidin-5-yloxybenzene (07183-1)

[0474] 5-(1-methyl-1H-pyrazol-4-yl)-2-[(2-chloro-6-[3-(trideuteromethyl)propamido]pyrimidin-4-yl)amino]anisole (184 mg, 0.49 mmol) was added to a solution of 1,4-dioxane (2.0 mL) with N-Boc-piperazine (117 mg, 0.59 mmol), Pd2(dba)3 (44 mg, 0.049 mmol), BINAP (30.5 mg, 0.049 mmol), and Cs2CO3 (400 mg, 1.22 mmol). The mixture was stirred overnight at 100 °C under nitrogen protection. After the starting material was consumed, the mixture was cooled and added to water (30 mL), and extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried with anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (DCM / MeOH = 1 / 0 to 1 / 1, silica gel-CS 10 g, 16 mL / min, silica gel, UV 254) to give a white solid product (130 mg, yield 46.5%).

[0475] ESI-MS m / z calcd for [C 28 H 34 D3N7O4][M+H + :539.3; found:539.4

[0476] 2.2

[0477] 5-(1-Methyl-1H-pyrazol-4-yl)-2-[(4-piperazin-1-yl)amino]-6-[3-(trideuteromethyl)propamido]pyrimidin-5-yloxyanisole (07183-2)

[0478] The mixture was stirred at room temperature for 2 hours in a solution of 4-(1-methyl-1H-pyrazol-4-yl)-2-[[4-(tert-butyloxycarbonyl)piperazin-1-yl]amino]-6-[[3-(trideuteratedmethyl)propionyl]amino]pyrimidin-5-yloxybenzene (65 mg, 0.12 mmol) in trifluoroacetic acid / dichloromethane (3 mL, v / v = 5 / 1). After the starting material was consumed, the solvent was removed by vacuum distillation. After cooling, the mixture was added to water (10 mL), the pH was adjusted with sodium bicarbonate, and the mixture was extracted three times with EA (10 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 = 1 / 0 to 1 / 1, silica gel-CS 10 g, 16 mL / min, silica gel, UV 254) to give a white solid product (50 mg, yield 94.4%).

[0479] ESI-MS m / z calcd for [C 23 H 26 D3N7O2][M+H] + 439.3; found: 439.2

[0480] 2.3

[0481] (S)-N-(1-Cyano-2-((5-Cyano-4-(4-(cyclopropylcarbamoyl)phenyl)pyrimidin-2-yl)amino)ethyl)-4-(2H-1,2,3-triazol-2-ylmethyl)benzamide (MX07183)

[0482] 5-(1-methyl-1H-pyrazol-4-yl)-2-[(4-piperazin-1-yl)amino]-6-[3-(trideuterated methyl)propamido]pyrimidin-5-yloxyanisole (53 mg, 0.11 mmol), (S)-7-chloro-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-amine-3-oxide (32 mg, 0.11 mmol) was reacted with DIPEA (43 mg, 0.33 mmol) in a solution of N,N-dimethylformamide (2.0 mL). The mixture was reacted at 90 °C under nitrogen protection for 3 hours. After the starting material was consumed, the crude product was subjected to preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV). 254) Purification yielded a white solid product (10 mg, yield 12.0%).

[0483] 1H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.70(s,1H),8.54(s,1H),7.57(dd,J=1.2,7.6Hz,1H),7.50(d,J=8.0Hz,1H),7.3 2(s,1H),7.22(t,J=8.0Hz,1H),7.09(d,J=7.6Hz,1H),6.15(s,1H),4.82(t,J=5.6Hz,1H),4.49(d,J=12.0Hz,2H),4.13( t,J=3.2Hz,1H),3.42(s,3H),3.74–3.66(m,5H),3.44–3.35(m,1H),3.24–3.13(m,1H),3.07(d,J=8.0Hz,2H),2.92(s,2 H),2.90–2.82(m,2H),2.38–2.25(m,2H),2.17–2.12(m,2H),1.90(d,J=12Hz,2H),1.82–1.70(m,2H),1.34–1.28(m,2H).

[0484] 1. Synthesis scheme:

[0485] 2. Experimental Section:

[0486] 2.1

[0487] 3-(4-Nitrophenoxy)azacyclobutane-1-carboxylic acid tert-butyl ester (07186-1)

[0488] 4-Nitrophenol (150 mg, 1.08 mmol) was added to a DMF (5 mL) solution along with tert-butyl 3-(p-toluenesulfonyloxy)azacyclobutane-1-carboxylate (353 mg, 1.08 mmol) and Cs₂CO₃ (704 mg, 2.16 mmol). The mixture was stirred overnight at 80 °C under nitrogen protection. After the starting material was consumed, the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 0, silica gel-CS 20 g, 30 mL / min, silica gel-CS, UV 254) to give a white solid product (271 mg, yield 85%).

[0489] ESI-MS m / z calcd for [C 14 H 18 [N₂O₅][M+Na] + :317.1; found:317.2

[0490] 2.2

[0491] 3-(4-aminophenoxy)azacyclobutane-1-carboxylic acid tert-butyl ester (07186-2)

[0492] Pd / C (85 mg, 0.08 mmol) was added to a methanol (5 mL) solution of tert-butyl 3-(4-nitrophenoxy)azacyclobutane-1-carboxylate (241 mg, 0.82 mmol). The mixture was stirred overnight at room temperature under hydrogen protection. After the starting material was consumed, the reaction solution was filtered, concentrated under reduced pressure, and the crude product was used directly in the next reaction step.

[0493] ESI-MS m / z calcd for [C 14 H 20 [N2O3][M-55] + :209.1; found:209.2

[0494] 2.3

[0495] 3-(4-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(3,3,3-trideuteronyl)pyridin-2-yl)amino)phenoxy)azacyclobutane-1-carboxylic acid tert-butyl ester (07186-3)

[0496] To a solution of tert-butyl 3-(4-aminophenoxy)azacyclobutane-1-carboxylate (101 mg, 0.24 mmol) in 1,4-dioxane (4 mL), 1-(6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)-3,3,3-trideuterium-1-one (90 mg, 0.24 mmol), Pd2(dba)3 (18 mg, 0.024 mmol), Cs2CO3 (156 mg, 0.48 mmol), and xantphos (12 mg, 0.024 mmol) were added. The mixture was stirred overnight at 110 °C. After the starting material was consumed, the mixture was cooled and added to water (10 mL), and extracted three times with EA (10 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 column chromatography (MeOH / DCM = 0 / 1 to 1 / 0, silica gel-CS 12 g, 20 mL / min, silica gel-CS, UV 254) to give a white solid product (64 mg, yield 44%).

[0497] ESI-MS m / z calcd for [C 32 H 34D3N7O5][M+H] + :603.3; found:603.3

[0498] 2.4

[0499] 1-(6-((4-(azacyclobutane-3-yloxy)phenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)-3,3,3-trideuterated-1-one (07186-4)

[0500] 64 mg (0.11 mmol) of tert-butyl 3-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(3,3,3-trideuteronyl)pyridin-2-yl)amino)phenoxy)azacyclobutane-1-carboxylic acid tert-butyl ester was added to a solution of dichloromethane (2 mL). The mixture was stirred at room temperature for 1 hour. After the starting material was consumed, the reaction solution was filtered and concentrated under reduced pressure to give a white solid product (52 mg, 95% yield), which was used directly in the next step of the reaction.

[0501] ESI-MS m / z calcd for [C 27 H 26 D3N7O3][M+H] + :503.2; found:502.9

[0502] 2.5

[0503] (R)-1-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((4-((1-(5-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)azacyclobutane-3-yl)oxo)phenyl)amino)pyridin-3-yl)-3,3,3-trideuterated-1-one (MX07186)

[0504] To a solution of 1-(6-((4-(azacyclobutane-3-yloxy)phenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridin-3-yl)-3,3,3-trideuterated-1-one (52 mg, 0.10 mmol) in DMF (2.0 mL), (R)-2-chloro-4-((tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (29 mg, 0.10 mmol) and DIEA (26 mg, 0.20 mmol) were added. The mixture was stirred at 85 °C for 2 hours. After the starting material was consumed, the mixture was cooled and added to water (10 mL), and extracted three times with EA (10 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 give a white solid product (7 mg, yield 10%).

[0505] 1 H NMR (400MHz, DMSO-d6) δ10.85(s,1H),9.17(s,1H),8.78(s,1H),8.56(s,1H),7.61(d,J=8Hz ,2H),7.56–7.49(m,3H),7.27(t,J=8Hz,1H),6.82(d,J=9.2Hz,2H),6.41(s,1H),5.06–5.04( m,1H),4.49–4.45(m,2H),4.21–4.16(m,1H),3.95(s,5H),3.89–3.85(m,2H),3.72(s,3H),3. 46–3.35(m,3H),3.26–3.18(m,1H),3.01–2.86(m,4H),1.78–1.75(m,2H),1.67–1.58(m,2H).

[0506] 1. Synthesis scheme:

[0507] 2. Experimental Section:

[0508] 2.1

[0509] (R)-(1-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl isobutyrate (A-1)

[0510] To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (350 mg, 1.22 mmol), DMAP (224 mg, 1.83 mmol) and isobutyric anhydride (210 mg, 1.34 mmol) were added to NMP (5 mL). The reaction mixture was stirred at 40 °C for 2 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, 20 mL / min, silica gel, UV 254) to give a colorless oily product (202 mg, yield 46%).

[0511] ESI-MS m / z calcd for [C 15 H 20 ClN3O3S][M+H] + :358.1; found:358.1

[0512] 2.2

[0513] 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridin-2-yl)amino)-N-(trideuterated methyl)nicotinamide (07222-1)

[0514] Add 5-(4,4,5,5-tetramethyl-1,3,2-dioxolane-3-yl)phenyl)amino)-N-(trideuterated methyl)nicotinamide (400 mg, 1.07 mmol) to a solution of 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(trideuterated methyl)nicotinamide (235 mg, 1.07 mmol), cesium carbonate (696 mg, 2.14 mmol), Xantphos (64 mg, 0.11 mmol), BINAP (68 mg, 0.11 mmol) and Pd2(dba)3 (99 mg, 0.11 mmol) to a solution of 1,4-dioxane (10 mL). The mixture was stirred for 1.5 hours under nitrogen protection at 100°C in a microwave oven. After the starting material was consumed, the reaction solution was cooled and concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH / DCM = 0-10%, silica gel-CS 20g, 20mL / min, silica gel, UV 254) to obtain a brown oily product (301mg, yield 50%).

[0515] ESI-MS m / z calcd for [C 28 H 30 D3BN8O4][M+H] + :560.3; found:560.4

[0516] 2.3

[0517] (R)-(1-((2-(6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(trideuteratedmethyl)carbamoyl)pyridin-2-yl)amino)pyridin-3-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl isobutyrate (MX07222)

[0518] Add (R)-( ... The mixture was stirred at 100°C under nitrogen protection for 3 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 preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to obtain a white solid product (20.04 mg, yield 15%).

[0519] 1H NMR (400MHz, DMSO-d6) δ10.71(s,1H),10.15(s,1H),9.07(d,J=2.0Hz,1H),8.56–8.52(m,3H),8.44(dd,J= 8.8,2.0Hz,1H),8.34(s,1H),8.13(s,1H),7.69(d,J=7.6Hz,1H),7.63(d,J=8.8Hz,1H),7.58(d,J=7.6Hz,1 H),7.27(t,J=8.0Hz,1H),4.56–4.53(m,2H),3.95(s,3H),3.76(s,3H),3.68–3.60(m,1H),3.39–3.36(m,1H ),3.25–3.18(m,2H),3.04–2.99(m,1H),2.42–2.33(m,4H),1.97–1.88(m,2H),1.06(dd,J=6.8,2.8Hz,6H).

[0520] 1. Synthesis scheme:

[0521] 2. Experimental Section:

[0522] 2.1

[0523] tert-Butyl 4-(5-aminopyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid ester (07228-1)

[0524] To a solution of 2-amino-5-bromopyrazine (500 mg, 1.91 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.11 g, 3.62 mmol), and K₂CO₃ (500 mg, 3.62 mmol) in 1,4-dioxane (5 mL) and H₂O (0.5 mL), Pd(dppf)Cl₂ (260 mg, 0.362 mmol) was added at 25 °C. The resulting reaction mixture was stirred at 100 °C for 3 hours. After the starting material was completely consumed, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (DCM / MeOH = 1 / 0 to 1 / 5, silica gel-CS 4 g, 30 mL / min, silica gel, UV 254) to give a white solid (821 mg, yield 86.16%).

[0525] ESI-MS m / z calcd for [C 14 H₂ON₄O₂][M+H] +:277.1; found:277.0

[0526] 2.2

[0527] 4-(5-aminopyrazin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (07228-2)

[0528] Pd / C (200 mg) was added to a 20 mL solution of tert-butyl-4-(5-aminopyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid ester (721 mg, 2.61 mmol) in MeOH under nitrogen protection. The reaction mixture was purged with hydrogen three times. The mixture was stirred overnight at room temperature under 1 atm hydrogen pressure. The reaction mixture was concentrated to give the crude product (427 mg, yield 58.79%).

[0529] ESI-MS m / z calcd for [C 14 H 22 N4O2][M+H]+:279.1; found:223.1[M-56]

[0530] 2.3

[0531] tert-Butyl 4-(5-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-2-yl)amino)pyrazin-2-yl)piperidine-1-carboxylic acid ester (07228-3)

[0532] Pd₂(dba)₃ (128 mg, 0.14 mmol) was 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)nicotinamide (323 mg, 0.86 mmol), Xantphos (81 mg, 0.14 mmol), and Cs₂CO₃ (465 mg, 1.43 mmol) in 1,4-dioxane (4 mL) at 25 °C. The reaction was stirred overnight at 100 °C. LC-MS showed that the reactants were completely consumed. The reaction solution was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (PE / EA = 1 / 0 to 1 / 0, silica gel-CS 4 g, 30 mL / min, silica gel, UV 254) to give a brown solid (262 mg, yield 59.03%).

[0533] ESI-MS m / z calcd for [C 22 H 27 N5O2][M+H]+:618.33; found:618.0

[0534] 2.4

[0535] 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((5-(piperidin-4-yl)pyrazin-2-yl)amino)nicotinamide(07228-4)

[0536] TFA (0.5 mL) was added dropwise to a 2.5 mL solution of tert-butyl 4-(5-((4-(((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-2-yl)amino)pyrazin-2-yl)piperidine-1-carboxylic acid ester (130 mg, 0.210 mmol) in DCM at 25 °C. The resulting reaction mixture was stirred at 25 °C for 3 hours. After the starting material was completely consumed, the reaction mixture was concentrated under reduced pressure to give a residue (112 mg, crude product).

[0537] ESI-MS m / z calcd for [C 26 H 27 D3N 10 O2][M+H]+:518.2;found:518.0

[0538] 2.5

[0539] (R)-6-((5-(1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)pyrazin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide (MX07228)

[0540] To a solution of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((5-(piperidin-4-yl)pyrazin-2-yl)amino)nicotinamide (108 mg, 0.210 mmol) and DIEA (81.4 mg, 0.63 mmol) in DMF (2.5 mL), R)-2-chloro-4-[(1-hydroxymethylcyclobutyl)amino]-6,7-dihydrothieno[3,2-d]pyridine-5-oxide (90.4 mg, 0.315 mmol) was added at 25 °C. The resulting reaction mixture was stirred at 25 °C for 2 hours. After the starting materials were completely consumed, the reaction mixture was concentrated under reduced pressure. 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 white solid product (40.98 mg, yield 25.54%).

[0541] 1 H NMR(400MHz,DMSO-d6)δ10.72(s,1H),9.95(s,1H),8.90(s,1H),8.55–8.50(m,3H),8. 13(s,1H),7.72(s,1H),7.62–7.54(m,2H),7.33–7.27(m,2H),4.85–4.77(m,3H),3.94( s,3H),3.74(s,5H),3.46–3.38(m,1H),3.26–3.18(m,1H),3.02–2.96(m,4H),2.92–2. 83(m,1H),2.43–2.27(m,2H),2.16–2.14(m,2H),1.86–1.73(m,4H),1.63–1.57(m,2H).

[0542] 1. Synthesis scheme:

[0543] 2. Experimental Section:

[0544] 2.1

[0545] 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (07236-1)

[0546] Lithium chloride (126 mg, 2.96 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (469 mg, 2.36 mmol) and triethylamine (299 mg, 2.96 mmol) were added to a solution of 5-bromo-2-nitropyridine (400 mg, 1.97 mmol) in dimethyl sulfoxide (10 mL), and the mixture was stirred overnight at 65 °C. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification was performed by silica gel column chromatography (THF / PE = 7:13, silica gel-CS 20 g, 40 mL / min, silica gel, UV 214) to give a yellow solid (376 mg, yield 59.6%).

[0547] ESI-MS m / z calcd for [C 15 H 20 N4O4][M+H] + :321.34; found:321.0

[0548] 2.2

[0549] 6-(6-aminopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (07236-2)

[0550] Palladium on carbon (50 mg, 10% wt) was added to an ethanolic solution (10 mL) of 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (376 mg, 1.17 mmol) under a hydrogen atmosphere at room temperature, and the reaction mixture was stirred overnight at room temperature. The mixture was filtered, and the filtrate was evaporated to dryness under vacuum to give a brown solid product (189 mg, yield 68.2%).

[0551] ESI-MS m / z calcd for [C 15 H 22 N4O2][M+H] + :291.17; found:291.1

[0552] 2.3

[0553] 6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(3-deuterated methylcarbamoyl)pyridin-2-yl)amino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (03371-3)

[0554] To a solution of tert-butyl 6-(6-aminopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (140 mg, 0.48 mmol) and 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-3-deuterated methylnicotinamide (216 mg, 0.58 mmol) in 1,4-dioxane (2.5 mL), cesium carbonate (469 mg, 1.44 mmol), tris(dibenzylene-BASEacetone)palladium (44 mg, 0.048 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (28 mg, 0.048 mmol) were added, and the reaction mixture was then stirred in a microwave at 110 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1, silica gel 12g, 40mL / min, silica gel, UV 214) to obtain a green solid product (86mg, yield 28.6%).

[0555] ESI-MS m / z calcd for [C 32 H 35 D3N 10 O4][M+H] + :630.33; found:630.0

[0556] 2.4

[0557] 6-((5-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-3-deuterated methylnicotinamide (07236-4)

[0558] TFA (0.5 mL) was added to a DCM (5 mL) solution of 6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(3-deuterated methylcarbamoyl)pyridin-2-yl)amino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (86 mg, 0.14 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated to obtain a crude yellow oil (56 mg), which was then used directly for the next reaction.

[0559] ESI-MS m / z calcd for [C 27 H 27 D3N 10 O2][M+H] + :530.27; found:530.3

[0560] 2.5

[0561] (R)-6-((5-(6-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-2,6-diazaspiro[3.3]heptane-2-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-3-deuterated methylnicotinamide (MX07236)

[0562] At room temperature, DIEA (43 mg, 0.33 mmol) was added to a DMF (3 mL) solution of 6-((5-(2,6-diazaspiro[3.3]heptane-2-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-3-deuterated nicotinamide (56 mg, 0.11 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (32 mg, 0.11 mmol). The reaction mixture was then stirred at 9 °C for 3 hours. After the reaction was completed, the reaction solution was purified by preparative HPLC [MeCN / H2O (0.5% HCOOH), X-Select 10μm 19*250mm, 20mL / min, UV 254] to obtain a yellow solid product (24.01mg, yield 28%).

[0563] 1 H NMR (400MHz, DMSO-d6) δ10.70(s,1H),9.40(s,1H),8.56(s,1H),8.42(d,J=9.6Hz,2H),7.70(s,1H),7. 62(dd,J=8.0,1.2Hz,1H),7.53–7.45(m,3H),7.38(s,1H),7.25(t,J=8.0Hz,1H),6.91(dd,J=8.8,3.2Hz ,1H),4.87(t,J=5.6Hz,1H),4.18(s,3H),3.97–3.93(m,7H),3.75(s,3H),3.73–3.67(m,2H),3.44–3.36 (m,1H),3.27–3.17(m,2H),2.96–2.83(m,2H),2.45–2.29(m,2H),2.15–2.10(m,2H),1.82–1.69(m,2H).

[0564] 1. Synthesis scheme:

[0565] 2. Experimental Section:

[0566] 2.1

[0567] (R)-(1-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl 2,2-dimethylbutyrate (A-1)

[0568] Under nitrogen protection at 0 °C, DIEA (201 mg, 1.56 mmol) was added to a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (150 mg, 0.52 mmol) and DMAP (19 mg, 0.16 mmol) in DCM (6.5 mL). The mixture was stirred at 0 °C for 0.2 h, followed by dropwise addition of a solution of 2,2-dimethylbutyryl chloride (140 mg, 1.05 mmol) in DCM (1.5 mL). The mixture was stirred at room temperature for 2 h, and after the starting materials were consumed, the reaction was quenched with saturated sodium bicarbonate (10 mL), and the mixture was extracted three times with DCM (30 mL). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The crude product was purified by column chromatography (PE / EA = 10 / 0 to 2 / 8, silica gel-CS12 g, 30 mL / min, silica gel, UV 254) to give a yellow solid product (156 mg, yield 77.9%).

[0569] ESI-MS m / z calcd for [C 17 H 24 ClN3O3S][M+H] + 386.1; found: 386.2

[0570] 2.2

[0571] 6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(methyl-d3-carbamoyl)pyridin-2-yl)amino)pyridin-3-yl)boronic acid (07224-1)

[0572] A mixture of 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-d3-nicotinamide (120 mg, 0.32 mmol), 2-aminopyridine-5-boronic acid, pinacol ester (70 mg, 0.32 mmol), cesium carbonate (261 mg, 0.80 mmol), Xantphos (29 mg, 0.05 mmol), BINAP (31 mg, 0.05 mmol), and Pd2(dba)3 (29 mg, 0.032 mmol) in 1,4-dioxane (5 mL) was placed into a sealed tube. The tube was then purged with argon to remove air. The tube was then sealed with a pressure cap and stirred overnight at 110 °C. After the starting materials were consumed, the crude product was concentrated and purified by high-pressure HPLC (MeCN / H2O (10 mmol / L NH4HCO3), C18, 25 mL / min, UV 254) to obtain a yellow solid product (83 mg, yield 54.3%).

[0573] ESI-MS m / z calcd for [C 22 H 20 D3BN8O4][M+H] + :478.2; found:478.2

[0574] 2.3

[0575] (R)-(1-((2-(6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(methyl-d3-carbamoyl)pyridin-2-yl)amino)pyridin-3-yl)-5-oxo-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)cyclobutane-2-yl)amino)pyridin-3-yl)-5-oxo-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl 2,2-dimethylbutyrate (MX07244)

[0576] The reaction mixture of 6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(methyl-d3-carbamoyl)pyridin-2-yl)amino)pyridin-3-yl)boronic acid (30 mg, 0.063 mmol), (R)-(1-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl 2,2-dimethylbutyrate (12 mg, 0.063 mmol), Pd(dppf)Cl2.DCM (5 mg, 0.0063 mmol), K2CO3 (26 mg, 0.19 mmol) and water (0.5 mL) in 1,4-dioxane (2.5 mL) was stirred for 3 hours at 110 °C under argon protection. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography (DCM / MeOH = 0–100%, silica gel-CS 20g, 25mL / min, silica gel, UV 254). The product was then purified by preparative HPLC [MeCN / H2O (10mmol / L NH4HCO3), X-Select 10μm 19*250mm, 20mL / min, UV 254] to give a white solid product (11.01mg, yield 22.3%).

[0577] 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),10.16(s,1H),9.07(d,J=2.0Hz,1H),8.56–8.52(m,3H),8.44(dd,J= 8.8,2.0Hz,1H),8.31(s,1H),8.12(s,1H),7.70–7.57(m,3H),7.26(t,J=8.0Hz,1H),4.55–4.46(m,2H),3. 95(s,3H),3.76(s,3H),3.68–3.60(m,1H),3.38–3.33(m,1H),3.28–3.18(m,1H),3.05–3.00(m,1H),2.45– 2.33(m,2H),2.01–1.90(m,2H),1.47(dd,J=14.8,7.6Hz,2H),1.06(d,J=3.2Hz,6H),0.68(t,J=7.6Hz,3H).

[0578] 1. Synthesis scheme:

[0579] 2. Experimental Section:

[0580] 2.1

[0581] tert-Butyl 5-(6-nitropyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid ester (07245-1)

[0582] To a solution of 5-bromo-2-nitropyridine (500 mg, 2.50 mmol) in 1,4-dioxane (10 mL), tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid ester (530 mg, 2.50 mmol), cesium carbonate (2.01 g, 6.25 mmol), Xantphos (140 mg, 0.25 mmol), and Pd2(dba)3 (230 mg, 0.25 mmol) were added. The mixture was stirred overnight at 100 °C under nitrogen protection. After the starting material was consumed, the reaction solution was concentrated under reduced pressure after cooling. The crude product was purified by column chromatography (EA / PE = 0–100%, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give a yellow solid product (422 mg, yield 51.4%).

[0583] ESI-MS m / z calcd for [C 16 H 22 [N4O4][M-56+H] + :279.2; found:279.2

[0584] 2.2

[0585] tert-Butyl 5-(6-aminopyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylic acid ester (07245-2)

[0586] Pd / C (100 mg) was added to a solution of tert-butyl-5-(6-nitropyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid ester (400 mg, 1.20 mmol) in MeOH (5 mL). The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After the starting material was consumed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to give a yellow solid product (255 mg, yield 70.1%).

[0587] ESI-MS m / z calcd for [C 16 H 24 N4O2][M+H] + :305.2; found:305.4

[0588] 2.3

[0589] tert-Butyl 5-(6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-2-yl)amino)pyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylic acid ester (07245-3)

[0590] To a solution of tert-butyl 5-(6-aminopyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid ester (100 mg, 0.33 mmol) in 1,4-dioxane (5 mL), 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide (70 mg, 0.33 mmol), cesium carbonate (266 mg, 0.82 mmol), Xantphos (19 mg, 0.033 mmol) and Pd2(dba)3 (30 mg, 0.033 mmol) were added. The mixture was stirred overnight at 110°C under nitrogen protection. After the starting material was consumed, the reaction solution was concentrated under reduced pressure after cooling. The crude product was purified by column chromatography (EA / PE = 0-100%, silica gel-CS 40g, 40mL / min, silica gel, UV 254) to obtain a yellow solid product (58mg, yield 27.9%).

[0591] ESI-MS m / z calcd for [C 33 H 37 D3N 10 O4][M+H] + :644.3; found:644.6

[0592] 2.4

[0593] 6-((5-(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide(07245-4)

[0594] 50 mg (0.08 mmol) of tert-butyl 5-(6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-2-yl)amino)pyridin-3-yl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylic acid ester (TFA) (1 mL) was added to a solution of DCM (2 mL). The mixture was stirred at room temperature for 2 hours. After the starting material was consumed, the reaction solution was concentrated under reduced pressure to give a yellow oily product (48 mg, yield 98.5%).

[0595] ESI-MS m / z calcd for [C 28 H 29 D3N 10 O2][M+H] + :544.3; found:544.0

[0596] 2.5

[0597] 6-((5-(5-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrolo-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)(1H)-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide (MX07245)

[0598] Add (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,4-c]pyrrolo-2(1H)-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide (48 mg, 0.09 mmol) to a DMF (2 mL) solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (25 mg, 0.09 mmol) and DIEA (46 mg, 0.36 mmol). The mixture was stirred at 90℃ under nitrogen protection for 3 hours. After the starting material was consumed, the reaction solution 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 (15.12mg, yield 21.2%).

[0599] 1 H NMR(400MHz,DMSO-d6)δ10.70(s,1H),9.33(s,1H),8.55(s,1H),8.42(s,1H),8.39(s,1H),7.72(s,1 H),7.62(d,J=8.0Hz,1H),7.58(d,J=2.8Hz,1H),7.51–7.45(m,2H),7.29–7.24(m,2H),7.03(dd,J=9. 2,2.8Hz,1H),4.85(t,J=5.6Hz,1H),3.95(s,3H),3.80–3.72(m,7H),3.50–3.38(m,5H),3.21–3.20(m ,3H),3.12–3.05(m,2H),2.95–2.82(m,2H),2.42–2.28(m,2H),2.17–2.13(m,2H),1.80–1.69(m,2H).

[0600] 1. Synthesis scheme:

[0601] 2. Experimental Section:

[0602] 2.1

[0603] 2-Chloro-4-(2-methylpyrrolidone-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (07249-1)

[0604] 2,4-Dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (2.0 g, 9.71 mmol) was added to a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine in DMF (15 mL) along with 2-methylpyrrolidine (825 mg, 9.71 mmol) and DIEA (2.50 g, 19.42 mmol). The mixture was stirred overnight at room temperature. After the starting material was consumed, water (50 mL) was added, and the mixture was extracted three times with DCM (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 / 1 to 1 / 1, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give a yellow oily product (2.10 g, yield 85.4%).

[0605] ESI-MS m / z calcd for [C 11 H 14 ClN3S][M+H]+:256.1; found:256.2

[0606] 2.2

[0607] (5R)-2-chloro-4-(2-methylpyrrolidone-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (07249-2)

[0608] To a solution of 2-chloro-4-(2-methylpyrrolidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (2.10 g, 8.24 mmol) and S-1,1'-bi-2-naphthol (202 mg, 0.83 mmol) in DCM (40 mL), tetraisopropoxide titanium (204 mg, 0.83 mmol) and water (297 mg, 16.48 mmol) were added. The mixture was stirred overnight at room temperature, and a single addition of 70% tert-butyl hydroperoxide aqueous solution (1.59 g, 12.36 mmol) was added. The mixture was then stirred at room temperature for 1 hour. The reaction solution was purified by column chromatography (DCM / MeOH = 1 / 0–10 / 1, Silica-CS 40 g, 40 mL / min, silica gel, UV 254) to give a yellow solid product (824 mg, yield 37.0%).

[0609] ESI-MS m / z calcd for [C 11 H 14 ClN3OS][M+H]+:272.1; found:272.2

[0610] 2.3

[0611] 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((5-((5R)-4-(2-methylpyrrolidone-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)amino)nicotinamide (MX07249)

[0612] To a solution of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((5-(4,4,5,5-tetramethyl-1,3,2-dioxoron-2-yl)pyridin-2-yl)amino)nicotinamide (400 mg, 0.715 mmol), 5R)-2-chloro-4-(2-methylpyrrolidone-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (96.9 mg, 0.357 mmol) and K2CO3 (197.6 mg, 1.43 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL), Pd(dppf)Cl2 (104 mg, 0.143 mmol) was added at 25 °C. The resulting reaction mixture was stirred at 90°C for 3 hours. After the starting material was completely consumed, the reaction mixture was concentrated under reduced pressure, and 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 product (34.43 mg, yield 7.2%).

[0613] 1 H NMR(400MHz,DMSO-d6)δ10.73(s,1H),10.14(s,1H),9.11(s,1H),8.57–8.48(m ,4H),8.17(s,1H),8.00(s,1H),7.91–7.90(m,2H),7.59–7.57(m,1H),7.27(t, J=8Hz,1H),4.68–4.67(m,1H),4.00–3.96(m,4H),3.72–3.63(m,6H),3.31–3.2 6(m,1H),3.14–3.10(m,1H),2.33–2.08(m,3H),1.77(s,1H),1.32–1.23(m,3H).

[0614] 1. Synthesis scheme:

[0615] 2. Experimental Section:

[0616] 2.1

[0617] (R)-6-((1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (MX07251)

[0618] To a DMF (3 mL) solution of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(piperidin-4-ylamino)pyridazine-3-carboxamide (65 mg, 0.147 mmol), (R)-2-chloro-4-[(1-hydroxymethylcyclobutyl)amino]-5-oxo-6,7-dihydrothieno[3,2-d]pyridine (63.5 mg, 0.221 mmol) and DIEA (75.9 mg, 0.588 mmol) were added. The mixture was stirred at 90 °C for 2 hours. After the starting materials were completely consumed, the reaction solution was concentrated under reduced pressure. 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 white solid product (25.24 mg, yield 24.6%).

[0619] 1 H NMR (400MHz, DMSO-d6) δ10.68(s,1H),8.94(s,1H),8.55(s,1H),7.59(d,J=7.6Hz,1H),7.49(d,J=7.2Hz, 1H),7.37(s,1H),7.24(t,J=8Hz,1H),6.96–6.92(m,1H),6.39(s,1H),4.85(t,J=5.6Hz,1H),4.50–4.43( m,2H),4.17–4.16(m,1H),3.94(s,3H),3.76–3.70(m,5H),3.44–3.36(m,1H),3.28–3.08(m,3H),2.95–2. 83(m,2H),2.39–2.25(m,2H),2.18–2.10(m,2H),2.00–1.93(m,2H),1.83–1.70(m,2H),1.35–1.22(m,2H).

[0620] 1. Synthesis scheme:

[0621] 2. Experimental Section:

[0622] 2.1

[0623] (R)-6-((5-(4-((1-(hydroxymethyl)cyclopentyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-d3-nicotinamide (MX07252)

[0624] (R)-2-chloro-4-((1-(hydroxymethyl)cyclopentyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (30 mg, 0.10 mmol), 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-d3-6-((5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridin-2-yl)amino)nicotinamide (80 mg, 0.12 mmol), Pd(dppf)Cl2.DCM (8 mg, 0.01 mmol), K2CO3 (41 mg, 0.30 mmol) and water (0.5 mL) were reacted in a 1,4-dioxane (2.5 mL) mixture and stirred for 3 hours at 110 °C under argon protection. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography (DCM / MeOH = 0–100%, silica gel-CS 20g, 25mL / min, silica gel, UV 254). The product was then purified by preparative HPLC [MeCN / H2O (10mmol / L NH4HCO3), X-Select 10μm 19*250mm, 20mL / min, UV 254]. Chiral column separation yielded a white solid product (16.19mg, yield 23.2%).

[0625] 1H NMR (400MHz, DMSO-d6) δ10.74(s,1H),10.17(s,1H),9.10(d,J=2.0Hz,1H),8.56(s,1H),8.54–8.53(m,2H),8.45( dd,J=8.8,2.4Hz,1H),8.16(s,1H),7.71(dd,J=8.0,1.2Hz,1H),7.62(d,J=8.8Hz,1H),7.57(dd,J=7.6,1.2Hz,1H ),7.28(t,J=8.0Hz,1H),7.23(s,1H),4.97(t,J=5.8Hz,1H),3.95(s,3H),3.79–3.74(m,5H),3.66–3.58(m,1H),3 .44–3.37(m,1H),3.23–3.17(m,1H),3.05–3.00(m,1H),2.21–2.13(m,2H),1.99–1.93(m,2H),1.74–1.63(m,4H).

[0626] 1. Synthesis scheme:

[0627] 2. Experimental Section:

[0628] 2.1

[0629] trans-2-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclopentanol (07254-1)

[0630] Trans-2-aminocyclopentanol (0.22 g, 2.17 mmol) was added to a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (0.45 g, 2.17 mmol) in DMF (8 mL) and DIEA (1.40 g, 10.87 mmol). The mixture was stirred overnight at 90 °C. After the starting material was consumed, the reaction was quenched with water (15 mL) and extracted three times with EA (30 mL). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum distillation. The crude product was purified by column chromatography (DCM / MeOH = 100 / 0–95 / 5, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give a yellow oily product (510 mg, yield 86.6%).

[0631] ESI-MS m / z calcd for [C 11 H 14 ClN3OS][M+H]+ :272.1; found:272.3

[0632] 2.2

[0633] (R)-2-chloro-4-((trans-2-hydroxycyclopentyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (A-1)

[0634] Under nitrogen protection at room temperature, Ti(i-PrO)₄ (51 mg, 0.18 mmol) and H₂O (66 mg, 3.68 mmol) were added to a solution of trans-2-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclopentanol (500 mg, 1.84 mmol) and S(-)-Binol (51 mg, 0.18 mmol) in DCM (10 mL). The mixture was stirred overnight at room temperature, followed by the dropwise addition of t-BuOOH (207 mg, 2.30 mmol) solution. The mixture was stirred at room temperature for 2 hours, and the crude product obtained after consuming the starting material was purified by column chromatography (DCM / MeOH = 10 / 0 to 90 / 10, silica gel-CS 40 g, 30 mL / min, silica gel, UV 254) to give a yellow solid product (376 mg, yield 71.2%).

[0635] ESI-MS m / z calcd for [C 11 H 14 ClN3O2S][M+H] + :288.1; found:288.1

[0636] 2.3

[0637] 6-((5-((R)-4-((trans-2-hydroxycyclopentyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide (MX07254)

[0638] (R)-2-chloro-4-((trans-2-hydroxycyclopentyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (55 mg, 0.19 mmol), 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-d3-6-((5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridin-2-yl)amino)nicotinamide (129 mg, 0.23 mmol), Pd(dppf)Cl2.DCM (16 mg, 0.02 mmol), K2CO3 (79 mg, 0.57 mmol) and water (0.6 mL) were reacted in a 1,4-dioxane (3.0 mL) mixture and stirred for 3 hours at 110 °C under argon protection. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography (DCM / MeOH = 0–100%, silica gel-CS 20g, 25mL / min, silica gel, UV 254). The product was purified by preparative HPLC [MeCN / H2O (10mmol / L NH4HCO3), X-Select 10μm 19*250mm, 20mL / min, UV 254] to obtain white solid products MX07254-P1 (7.45mg, yield 5.7%) and MX07254-P2 (21.73mg, yield 16.7%).

[0639] MX07254-P1 1 H NMR (400MHz, DMSO-d6) δ10.74 (s, 1H), 10.15 (s, 1H), 9.16 (d, J = 2.0

[0640] Hz,1H),8.56–8.51(m,4H),8.09–8.05(m,2H),7.70(d,J=8.0Hz,2H),7.56(dd,J=8.0,1.6 Hz,1H),7.30(t,J=8.0Hz,1H),4.80(d,J=4.4Hz,1H),4.44–4.40(m,1H),4.17–4.12(m,1H) ,3.95(s,3H),3.76(s,3H),3.68–3.60(m,1H),3.40–3.37(m,1H),3.26–3.19(m,1H),3.06 –3.01(m,1H),2.22–2.13(m,1H),1.95–1.87(m,1H),1.80–1.67(m,2H),1.62–1.51(m,2H).

[0641] MX07254-P2 1H NMR (400MHz, DMSO-d6) δ10.74 (s, 1H), 10.15 (s, 1H), 9.16 (d, J = 2.0

[0642] Hz,1H),8.56–8.51(m,4H),8.13(d,J=6.8Hz,1H),8.06(s,1H),7.70(d,J=8.0Hz,2H),7.56(dd ,J=8.0,1.6Hz,1H),7.30(t,J=8.0Hz,1H),4.85(d,J=4.8Hz,1H),4.43–4.40(m,1H),4.17–4.1 3(m,1H),3.96(s,3H),3.76(s,3H),3.69–3.61(m,1H),3.40–3.35(m,1H),3.25–3.19(m,1H),3 .06–3.01(m,1H),2.19–2.15(m,1H),1.94–1.87(m,1H),1.78–1.68(m,2H),1.60–1.52(m,2H).

[0643] 1. Synthesis scheme:

[0644] 2. Experimental Section:

[0645] 2.1

[0646] 4-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)morpholine (07255-1)

[0647] Morpholine (841 mg, 9.66 mmol) and DIEA (2.5 g, 19.32 mmol) were added to a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (2 g, 9.66 mmol) in DMF (20 mL). The mixture was stirred overnight at 100 °C under nitrogen protection. After the starting material was consumed, the mixture was cooled and added to water (200 mL), and extracted three times with EA (50 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 column chromatography (MeOH / DCM = 0 / 1 to 1 / 10, silica gel-CS 80 g, 30 mL / min, silica gel-CS, UV 254) to give a yellow solid product (2.2 g, yield 88.6%).

[0648] ESI-MS m / z calcd for [C 10 H 12 ClN3OS][M+H] +:258.0; found:258.1

[0649] 2.2

[0650] 2-Chloro-4-morpholino-6,7-dihydrothiopheno[3,2-d]pyrimidine-5-oxide (07255-2)

[0651] To a solution of 4-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)morpholine (1.1 g, 4.26 mmol) in DCM (15 mL), tetraisopropoxytitanium (121 mg, 0.43 mmol), S-1,1'-bi-2-naphthol (122 mg, 0.43 mmol), and H₂O (154 mg, 8.52 mmol) were added. The mixture was stirred overnight at room temperature under nitrogen protection. Subsequently, tert-butyl hydroperoxide (70%) (1.09 g, 8.52 mmol) was added dropwise at 0 °C, and the reaction was continued at room temperature for 2 hours. After the starting materials were consumed, the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 10, silica gel-CS 80g, 30mL / min, silica gel-CS, UV 254) to obtain a yellow solid product (723mg, yield 62.2%).

[0652] ESI-MS m / z calcd for [C 10 H 12 ClN3O2S][M+H] + :274.0; found:274.1

[0653] 2.3

[0654] N-Trideuterylmethyl-4-[(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino]-6-[(5-(4-morpholinyl-5-oxide-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)amino]nicotinamide (MX07255)

[0655] To a solution of 2-chloro-4-morpholino-6,7-dihydrothiopheno[3,2-d]pyrimidine-5-oxide (39 mg, 0.13 mmol) in 1,4-dioxane / water (3 mL, v / v = 5 / 1), N-trideuterylmethyl-4-[(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino]-6-[(5-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclo-2-yl)pyridin-2-yl)amino]nicotinamide (75 mg, 0.13 mmol), Pd(dppf)Cl2.DCM (9.5 mg, 0.013 mmol) and K2CO3 (45 mg, 0.33 mmol) were added. The mixture was stirred at 100°C under nitrogen protection for 3 hours. After the starting material was consumed, it 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 give a white solid product (21.6 mg, yield 24.8%).

[0656] 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),10.15(s,1H),9.12(d,J=2.4Hz,1H),8.57(s,1H) ,8.54–8.51(m,3H),7.87(s,1H),7.82(d,J=9.2Hz,1H),7.65(d,J=8Hz,1H),7.57(d,J= 8Hz,1H),7.28(t,J=8Hz,1H),4.07–4.06(m,4H),3.95(s,3H),3.78(t,J=4.4Hz,4H),3. 76(s,3H),3.71–3.67(m,1H),3.41–3.37(m,1H),3.31–3.29(m,1H),3.18–3.13(m,1H).

[0657] 1. Synthesis scheme:

[0658] 2. Experimental Section:

[0659] 2.1

[0660] 2-Chloro-N-cyclohexyl-6,7-dihydrothieno[3,2-d]pyrimidine-4-amino(07256-1)

[0661] Cyclohexylamine (247 mg, 2.90 mmol) and DIPEA (934 mg, 7.23 mmol) were added to a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (500 mg, 2.41 mmol) in DMF (15 mL). The mixture was stirred at 90 °C for 24 hours under nitrogen protection. The reaction solution was quenched with water (100 mL) and extracted with EA (100 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 1, silica gel-CS20 g, 25 mL / min, silica gel, UV 254) to give a yellow oily product (625 mg, yield 96.5%).

[0662] ESI-MS m / z calcd for [C 12 H 16 ClN3S][M+H] + :270.1; found:270.1.

[0663] 2.2

[0664] (R)-2-chloro-4-(cyclohexylamino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (07256-2)

[0665] S-1,1'-bi-2-naphthol (66 mg, 0.23 mmol), tetraisopropyl titanate (65 mg, 0.23 mmol), and water (84 mg, 4.64 mmol) were added to a solution of 2-chloro-N-cyclohexyl-6,7-dihydrothieno[3,2-d]pyrimidine-4-amino (625 mg, 2.32 mmol) in DCM (20 mL). The mixture was stirred at room temperature in an open container for 24 hours, and then tert-butyl hydroperoxide (358 mg, 2.78 mmol) was added, followed by stirring at room temperature for another 2 hours. The reaction mixture was purified by column chromatography (MeOH / DCM = 0 / 1–2 / 3, silica gel-CS20 g, 25 mL / min, silica gel, UV 254) to give a yellow oily product (633 mg, 95.8% yield).

[0666] ESI-MS m / z calcd for [C 12 H 16 ClN3OS][M+H] + :286.1; found:286.1.

[0667] 2.3

[0668] 4-[(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino]-N-trideuteratedmethyl-6-[(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)amino]nicotinamide (07256-4)

[0669] To a solution of 6-chloro-4-[(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino]-N-trideuterium nicotinamide (60 mg, 0.16 mmol) in 1,4-dioxane (10 mL), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-amine (42 mg, 0.19 mmol), Pd2(dba)3 (29 mg, 0.03 mmol), XantPhos (34 mg, 0.06 mmol), BINAP (37 mg, 0.06 mmol), and cesium carbonate (156 mg, 0.48 mmol) were added. The reaction mixture was stirred at 120 °C for 24 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was used directly for the next reaction.

[0670] ESI-MS m / z calcd for [C 28 H 30 D3BN8O4][M+H] + :560.3; found:560.2.

[0671] 2.4

[0672] (R)-6-[(5-(4-(cyclohexylamino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-ylamino]-4-

[0673] [(2-Methoxy-3-(1-Methyl-1H-1,2,4-triazol-3-yl)phenyl)amino]-N-trideuterated methylnicotinamide (MX07256)

[0674] (R)-2-chloro-4-(cyclohexylamino)-6,7-dihydrothiopheno[3,2-d]pyrimidine-5-oxide (46 mg, 0.16 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), potassium carbonate (66 mg, 0.48 mmol), and water (2.5 mL) were added to the reaction solution from the previous step. The reaction solution was stirred at 100 °C for 3 hours. After cooling to room temperature, water (30 mL) was added and the mixture was extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over 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 product (12.68 mg, yield 11.6%).

[0675] 1 H NMR (400MHz, DMSO-d6) δ10.74(s,1H),10.16(s,1H),9.11(d,J=2.0Hz,1H),8.56–8.46(m,4H),8.15(br ,1H),8.05(d,J=7.6Hz,1H),7.71(d,J=8.0Hz,1H),7.63–7.55(m,2H),7.29(t,J=7.6Hz,1H),4.24–4.20 (m,1H),3.95(s,3H),3.76(s,3H),3.67–3.59(m,1H),3.39–3.36(m,1H),3.24–3.18(m,1H),3.05–3.00 (m,1H),1.95–1.93(m,2H),1.81–1.80(m,2H),1.71–1.68(m,1H),1.46–1.39(m,4H),1.23–1.16(m,1H).

[0676] 1. Synthesis scheme:

[0677] 2. Experimental Section:

[0678] 2.1

[0679] 2-Chloro-4-(piperidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (07257-1)

[0680] To a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (500 mg, 2.41 mmol) in DMF (15 mL), piperidine (247 mg, 2.90 mmol) and DIPEA (934 mg, 7.23 mmol) were added. The mixture was stirred at 90 °C for 24 hours under nitrogen protection. The reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 1, silica gel-CS20 g, 25 mL / min, silica gel, UV 254) to give a colorless oily product (601 mg, yield 97.6%).

[0681] ESI-MS m / z calcd for [C 11 H 14 ClN3S][M+H] + :256.1; found:256.1.

[0682] 2.2

[0683] 2-Chloro-4-(piperidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (07257-2)

[0684] S-1,1'-bi-2-naphthol (66 mg, 0.23 mmol), tetraisopropyl titanate (65 mg, 0.23 mmol), and water (85 mg, 4.70 mmol) were added to a solution of 2-chloro-4-(piperidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (601 mg, 2.35 mmol) in DCM (20 mL). The mixture was stirred at room temperature in an open container for 24 hours, and then tert-butyl hydroperoxide (363 mg, 2.82 mmol) was added, followed by stirring at room temperature for another 2 hours. The reaction mixture was purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 1, silica gel-CS20 g, 25 mL / min, silica gel, UV 254) to give a yellow oily product (260 mg, yield 40.7%).

[0685] ESI-MS m / z calcd for [C 11 H 14 ClN3OS][M+H] + :272.1; found:272.1.

[0686] 2.3

[0687] 4-[(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino]-N-trideuteratedmethyl-6-[(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)amino]nicotinamide (07257-4)

[0688] To a solution of 6-chloro-4-[(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino]-N-trideuterium nicotinamide (60 mg, 0.16 mmol) in 1,4-dioxane (10 mL), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-amine (42 mg, 0.19 mmol), Pd2(dba)3 (29 mg, 0.03 mmol), XantPhos (34 mg, 0.06 mmol), BINAP (37 mg, 0.06 mmol), and cesium carbonate (156 mg, 0.48 mmol) were added. The reaction mixture was stirred at 120 °C for 24 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was used directly for the next reaction.

[0689] ESI-MS m / z calcd for [C 28 H 30 D3BN8O4][M+H] + :560.3; found:560.2.

[0690] 2.4 4-[(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino]-N-trideuteratedmethyl-6-[(5-(5-oxo-4-(piperidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)amino]nicotinamide (MX07257)

[0691] 2-Chloro-4-(piperidin-1-yl)-6,7-dihydrothiopheno[3,2-d]pyrimidine-5-oxide (43 mg, 0.16 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), potassium carbonate (66 mg, 0.48 mmol), and water (2.5 mL) were added to the reaction solution from the previous step. The reaction solution was stirred at 100 °C for 3 hours. After cooling to room temperature, water (30 mL) was added and the mixture was extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over 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 product (19.62 mg, yield 18.3%).

[0692] 1 H NMR(400MHz,DMSO-d6)δ10.72(s,1H),10.14(s,1H),9.11(d,J=2.0Hz,1H),8.56–8 .46(m,4H),7.92(s,1H),7.79(d,J=8.8Hz,1H),7.68–7.66(m,1H),7.58–7.56(m,1H ),7.27(t,J=7.6Hz,1H),4.10–3.99(m,4H),3.95(s,3H),3.76(s,3H),3.71–3.63( m,1H),3.41–3.35(m,1H),3.30–3.24(m,1H),3.14–3.09(m,1H),1.75–1.62(m,6H).

[0693] 1. Synthesis scheme:

[0694] 2. Experimental Section:

[0695] 2.1

[0696] (R)-(1-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl isobutyl carbonate (07259-1)

[0697] To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (200 mg, 0.69 mmol), DMAP (170 mg, 1.39 mmol), pyridine (275 mg, 3.48 mmol), and isobutyl carbonate (284 mg, 2.09 mmol) were added to DMF (5 mL). The reaction mixture was stirred at room temperature for 3 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, 20 mL / min, silica gel, UV 254) to give a colorless oily product (260 mg, yield 96.3%).

[0698] ESI-MS m / z calcd for [C 16 H 22 ClN3O4S][M+H] + 388.1; found: 388.8

[0699] 2.2

[0700] (R)-Isobutyl((1-((2-(6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-((methyl-d3)carbamoyl)pyridin-2-yl)amino)pyridin-3-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl)carbonate(MX07259)

[0701] Add (R)-( ... The mixture was stirred at 100°C under nitrogen protection for 3 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 preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to obtain a white solid product (16.30 mg, yield 17.5%).

[0702] 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),10.16(s,1H),9.07(d,J=2.0Hz,1H),8.56(s,1H),8.54–8.52(m,2H),8.48( s,1H),8.44(dd,J=8.8,2.0Hz,1H),8.15(s,1H),7.70(d,J=7.2Hz,1H),7.63–7.58(m,2H),7.29(t,J=8.0Hz,1H),4 .66(q,J=10.8Hz,2H),3.95(s,3H),3.81(d,J=6.4Hz,2H),3.76(s,3H),3.69–3.60(m,1H),3.33–3.29(m,1H),3.2 5–3.19(m,1H),3.05–3.00(m,1H),2.46–2.33(m,4H),2.00–1.91(m,2H),1.88–1.78(m,1H),0.82(d,J=6.8Hz,6H).

[0703] 1. Synthesis scheme:

[0704] 2. Experimental Section:

[0705] 2.1

[0706] 4-[(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (07260-1)

[0707] 2,4-Dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (2 g, 9.66 mmol) was added to a DMF (20 mL) solution along with DIEA (3.73 g, 28.9 mmol) and 4-aminopiperidine-1-carboxylic acid tert-butyl ester (1.93 g, 9.66 mmol). The mixture was stirred overnight at 90 °C under nitrogen protection. After the starting material was consumed, the reaction solution was filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 0, silica gel-CS 20 g, 30 mL / min, silica gel-CS, UV 254) to give a white solid product (1.8 g, yield 50%).

[0708] ESI-MS m / z calcd for [C 16 H 23 ClN4O2S][M+H] + :371.2; found:371.2

[0709] 2.2

[0710] 3-(4-aminophenoxy)azacyclobutane-1-carboxylic acid tert-butyl ester (07260-2)

[0711] 4-[(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (1.8 g, 4.85 mmol) was added to a solution of DCM (50 mL) with S(-)-Binol (138 mg, 0.48 mmol), Ti(i-PrO)4 (137 mg, 0.48 mmol), and H2O (174 mg, 9.7 mmol). The mixture was stirred overnight at room temperature, and then t-BuOOH (1.34 g, 5.82 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the starting material was consumed, the reaction solution was purified by column chromatography (DCM / MeOH = 0 / 1 to 2 / 1, silica gel-CS 20 g, 30 mL / min, silica gel-CS, UV 254) to give a yellow solid product (1.2 g, yield 63.9%).

[0712] ESI-MS m / z calcd for [C 16 H 23 ClN4O3S][M+H] +:387.3; found:387.3

[0713] 2.3

[0714] (R)-tert-butyl-4-[(2-[(6-[(4-[(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino]-5-((trideuteratedmethyl)formyl)pyridin-2-yl)amino]pyridin-3-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (07260-4)

[0715] Add (R)-tert-butyl4-[(2-[(6-[(4-[(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino]-5-(trideuterated methylformyl)pyridin-2-yl]amino)pyridin-3-yl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino]piperidin-1-carboxylate (100 mg, 0.17 mmol) to a solution of (R)-tert-butyl4-[(2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino]piperidin-1-carboxylate (2 mL, 1,4-dioxane and 0.2 mL, 100 mg, 0.17 mmol) to water. [3] Piperidine-1-carboxylic acid ester (69.1 mg, 0.17 mmol), Pd(dppf)Cl2 (13 mg, 0.017 mmol), K2CO3 (49.4 mg, 0.35 mmol). The mixture was stirred at 100 °C for 3 hours. After the starting material was consumed, it was cooled and added to water (10 mL), and extracted three times with EA (10 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 (MeOH / DCM = 0 / 1 to 1 / 3, silica gel-CS 20 g, 30 mL / min, silica gel-CS, UV 254) to give a yellow solid product (100 mg, yield 71%).

[0716] ESI-MS m / z calcd for [C 38 H 41 D3N 12 O5S][M+H] + :784.3; found:784.3

[0717] 2.4

[0718] (R)-4-[(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino]-6-[(5-(5-oxo-4-(piperidin-4-ylamino)-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)amino]-N-(trideuterated methyl)nicotinamide (MX07260)

[0719] Add TFA (1 mL) to a solution of (R)-tert-butyl-4-[(2-[(6-[(4-[(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino]-5-((trideuteratedmethyl)formyl)pyridin-2-yl)amino]pyridin-3-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino]piperidine-1-carboxylic acid ester (90 mg, 0.11 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 1 hour. After the starting materials were consumed, the reaction solution was concentrated under reduced pressure and 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 white solid product (13.4 mg, yield 17.0%).

[0720] 1 H NMR(400MHz,DMSO-d6)δ10.74(s,1H),10.16(s,1H),9.11(s,1H),8.56-8.46(m,4 H),8.12–8.10(m,2H),7.71–7.56(m,3H),7.31-7.27(t,J=16.0Hz,1H),4.28-4.2 5(m,1H),3.95(s,3H),3.75(s,3H),3.67–3.59(m,1H),3.38(m,2H),3.24–3.18(m ,1H),3.04–3.01(m,3H),2.67–2.63(m,2H),1.85–1.83(m,2H),1.55–1.47(m,2H).

[0721] 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):

[0722] Example 2: Enzyme activity inhibition experiment of the disclosed compound

[0723] 2.1 TYK2 enzyme activity inhibition experiment

[0724] 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.

[0725] 2.2 PDE4B2 / PDE4D2 enzyme activity inhibition experiment

[0726] The inhibitory activity of compounds on PDE4B2 / 4D2 enzymes was tested using the FP method. Solutions of PDE4B2 / PDE4D2 (BPS, Cat:60042 / 60040) enzyme and substrate (FAM-cyclic adenosine monophosphate) (BPS, Cat:60200) were prepared in reaction buffer (1×IMAP reaction buffer containing 1 mM DTT and 0.1% BSA). The final working concentrations of PDE4B2, PDE4D2, and FAM-cyclic adenosine monophosphate were 0.0075 nM, 0.1 nM, and 100 nM, respectively. The positive control MX02018 (BI1015550) was used in PDE4B2 / PDE4D2 at an initial concentration of 3 μM, diluted 3-fold, and applied to 10 concentration doses. The test compounds were also used in PDE4B2 / PDE4D2 at an initial concentration of 3 μM, diluted 3-fold, and applied to 10 concentration doses.

[0727] The stock solution of the test compound was heated and vortexed to mix thoroughly, and a 300 μM starting concentration working solution was prepared. Then, it was serially diluted 3 times to obtain 10 different final concentration working solutions. This part of the reaction was 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 PDE4B2 / PDE4D2 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 substrate (FAM-cyclic adenosine 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. The FP signal was read using BMG (PHERAstar FSX), and the IC was obtained using GraphPad Prism software. 50 Fitting values ​​and nonlinear regression curves.

[0728] 2.3 Test Results

[0729] The test results for the exemplary compounds disclosed herein are summarized in the table below:

[0730] Note: A+ represents IC 50 ≤1nM; A represents 1nM <IC 50 ≤10nM; B represents 10nM <IC 50 ≤100nM; C represents 100nM <IC 50 ≤3μM; D represents 3μM <IC50 ≤30μM.

[0731] The above experimental results demonstrate that the disclosed compounds possess excellent dual-target (TYK2 and PDE4) 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 represented by formula H, 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-, -C 1-6 Alkylene -C(=O)-, -C(=O)-C 1-6 Alkylene-, -C(=O)-C(=O)-, -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-, -OC 1-6 Alkylene-, -OC 1-6 Alkylene -NH-, -OC 1-6 Alkylene -C(=O)-NH-, -OC 1-6 Alkylene-C(=O)-NR 1.1 -、-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-acetylinyl, 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 1-6 Alkylene -C(=O)-, -C(=O)-C 1-6 Alkylene-, -C(=O)-C(=O)-, -C(=O)-NH-C 1-6 alkylene-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene-O-, -OC 1-6 Alkylene-, -OC 1-6 Alkylene -NH-, -OC 1-6 Alkylene -C(=O)-NH-, -OC 1-6 Alkylene-C(=O)-NR 1.1 -、-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-, -C 1-6 Alkylene -C(=O)-, -C(=O)-C 1-6 Alkylene-, -C(=O)-C(=O)-, -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-, -OC 1-6 Alkylene-, -OC 1-6 Alkylene -NH-, -OC 1-6 Alkylene -C(=O)-NH-, -OC 1-6 Alkylene-C(=O)-NR 1.1 -、-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 1-6 Alkylene -C(=O)-, -C(=O)-C 1-6 Alkylene-, -C(=O)-C(=O)-, -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-, -OC 1-6 Alkylene-, -OC 1-6 Alkylene -NH-, -OC 1-6 Alkylene -C(=O)-NH-, -OC 1-6 Alkylene-C(=O)-NR 1.1 -、-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 1-6 Alkylene -C(=O)-, -C(=O)-C 1-6 Alkylene-, -C(=O)-C(=O)-, -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-, -OC 1-6 Alkylene-, -OC 1-6 Alkylene -NH-, -OC 1-6 Alkylene -C(=O)-NH-, -OC 1-6 Alkylene-C(=O)-NR 1.1 -、-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; X6 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-, -OC 1-6 Alkylene-, -OC 1-6 Alkylene -NH-, -OC 1-6 Alkylene -C(=O)-NH-, -OC 1-6 Alkylene-C(=O)-NR 1.1 -、-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 -NR q SO2-R 1.1 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 and 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 -NR q SO2-R 1.1 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 With R b Together with the atoms it is attached to, it forms the following groups that are fused with ring A or ring B: 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 -NR q SO2-R 1.1 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 and 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 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 -NR q SO2-R 1.1 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 f Represents X7-R3; X7 represents a chemical bond or -CH2-, -O-, -S-, -NH-, -S(O)-, -S(O)2- or -C(O)-; R3 represents H (such as hydrogen or deuterium), halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F, -CH2CF3), -NR 1.2 R 1.3 No substitution or optional use by 1, 2 or more R d1 The following groups are substituted: C 5-20 Cycloalkenyl, 3-20 membered heterocyclic, 5-20 membered heteroaryl, 6-20 membered aryl; R g Represents -X8-R4; X8 represents a chemical bond or -CH2-, -O-, -S-, -NH-, -S(O)-, -S(O)2- or -C(O-); R4 represents H (such as hydrogen, deuterium), halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F, -CH2CF3), -NR 1.2 R 1.3 No substitution or optional use by 1, 2 or more R d2 The following groups are substituted: C 5-20 Cycloalkenyl, 3-20 membered heterocyclic, 5-20 membered heteroaryl, 6-20 membered aryl; The condition is R f R g Not both H; Or, R f R g Together with the atoms they are attached to, they form unsubstituted or optionally substituted with one, two or more R atoms. d3 The following groups are substituted: C 5-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 3-20 membered heterocyclic alkenyl, 5-20 membered heteroaryl, 6-20 membered aryl; Each R d1 R d2 R d3 They may be the same or different, and are independently selected from H, deuterium, halogen, OH, CN, NO2, oxo (=O), thio (=S), SO, SO2, unsubstituted, or optionally substituted by one, two, or more Rs. e The following groups are substituted: C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 1-20 Alkyloxy, C 2-20 alkenyloxy group, C 2-20 alkynyloxy group, C 3-20 Cycloalkyloxy, C 3-20 Cycloalkenyloxy, C 3-20 Cycloalkynyloxy group, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, C 1-20 Alkyl thio, C 2-20 alkenyl thio, C 2-20 alkynyl thioyl, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 Cycloalkynylthio, C 6-20 Arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclic thio, NH2, -C(O)R 31 -CH2-C(O)R 31 -C(O)OR 32 -CH2C(O)OR 32 -C(O)NHR 32 -CH2C(O)NHR 32 -OC(O)R 33 -S(O)2R 34 -S(O)2OR 35 -OS(O)2R 36 -P(O)(OR) 37 (OR) 38 ); Alternatively, when two or more R-selected groups are present on the same group. d1 R d2 R d3 When substituents are present, the two substituents can form an unsubstituted or optionally substituted group with one, two or more R atoms together with the atoms they are attached to. e The following groups are substituted: C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic; Each R d21 They may be the same or different, and are independently selected from chemical bonds, H, deuterium, halogen, OH, CN, NO2, oxo (=O), thio (=S), SO, SO2, unsubstituted, or optionally substituted by one, two, or more Rs. a The following groups are substituted: C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 1-20 Alkyloxy, C 2-20 alkenyloxy group, C 2-20 alkynyloxy group, C 3-20 Cycloalkyloxy, C 3-20 Cycloalkenyloxy, C 3-20 Cycloalkynyloxy group, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, C 1-20 Alkyl thio, C 2-20 alkenyl thio, C 2-20 alkynyl thioyl, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 Cycloalkynylthio, C 6-20 Arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclic thio, NH2, -C(O)R 11 -CH2-C(O)R 11 -C(O)OR 12 -CH2C(O)OR 12 -C(O)NHR 12 -CH2C(O)NHR 12 -OC(O)R 13 -S(O)2R 14 -S(O)2OR 15 -OS(O)2R 16 -P(O)(OR) 17 (OR) 18 ); Alternatively, when two or more R-selected groups are present on the same group. d21 When substituents are present, the two substituents can form an unsubstituted or optionally substituted group with one, two or more R atoms together with the atoms they are attached to. e The following groups are substituted: C 3-20 cycloalkyl, C 3- 20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic; Each R e Whether identical or different, they are independently selected from hydrogen, deuterium, halogen, OH, CN, NO2, NH2, SH, oxo (=O), thio (=S), methanesulfonyl, ethanesulfonyl, methanesulfonamide, ethanesulfonamide, carboxylic acid, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as CF3, CHF2, CH2F), OC(O)NH2, OC(O)NR 1.2 R 1.3 NR q -CONR 1.2 R 1.3 NR q -C(O)R 1.1 NR 1.2 R 1.3 OR 1.1 C 1-6 -alkyl-OR 1.1 C 1-6 -alkyl-OC 1-6 -alkyl-COOR 1.1 C 1-6 -alkyl-OC 1-6 -Alkenyl-COOR 1.1 C 1-6 -alkyl-OC 1-6 -alkyl-CONR 1.2 R 1.3 -OC 1-6 -alkyl-CONR 1.2 R 1.3 -OC 1-6 -alkyl-COOR 1.1 -OC 1-6 -alkyl-O-CO-C 1-6 -alkyl-NR 1.2 R 1.3 -OC 1-6 -alkyl-OC 1-6 -alkyl-COOR 1.1 C 1-6 -alkyl-O-PO(ONa)2, C 1-6 -alkyl-O-PO(OH)2, C 1-6 -alkyl-O-PO(OR) 1.1 2. C 1-6 -alkyl-OC(O)-OR 1.1 C 1-6 -alkyl-OC(O)-NR 1.2 R 1.3 C 1-6 -alkyl-OC(=O)-C 1-6 -alkyl-(OC) 1-6 -alkyl) n C 1-6 -alkyl-OC(=O)-C 1-6 -alkyl-COOR 1.1 C 1-6 -alkyl-OC(=O)-C 1-6 -alkyl, C 1-6 -alkyl-OC(=O)-C 3-10 -cycloalkyl, C 1-6 -alkyl-OC(=O)-3-10 membered heterocyclic alkyl, C 1-6 -alkyl-OC(=O)-C 6-20 Aryl, C 1-6 -alkyl-OC(=O)-5-20-membered heteroaryl, C 1-6 -alkyl-OC(=O)-C 1-6 -Alkenyl-COOR 1.1 C 1-6 -alkyl-NC(=O)-C 1-6 -alkyl-COOR 1.1 C 1-6 -alkyl-NC(=O)-OC 1-6 -alkyl-COOR 1.1 C 1-6 -alkyl-NC(=O)-NC 1-6 -alkyl-COOR 1.1 SR 1.1 C 1-6 -alkyl-SR 1.1 SO-R 1.1 C 1-6 -Alkyl-SOR 1.1 SO2-R 1.1 C 1-6 -alkyl-SO2R 1.1 COOR 1.1 C 1-6 -alkyl-COOR 1.1 CH = CHCOOR 1.1 CO-NR 1.2 R 1.3 C 1-6 -alkyl-CO-NR 1.2 R 1.3 CH=CHCO-NR 1.2 R 1.3 COR 1.1 C 1-6 -alkyl-COR 1.1 Single-ring or double-ring 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-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 Or C 6-20- Aryl; each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: deuterium, OH, CN, C 1-6 -alkyl-CN, C 1-6 -alkyl-NH2, -SH, -NH2, -NHOH, -C 1- 6- Alkyl-NHOH, -C 1-6- Alkyl-CO - NHOH, -CO-NHOH, -C 1-6- Alkyl-NH-CO-N R 1.2 R 1.3 -NR 1.1 CN, -CHO, guanidino, quaternary ammonium salt, C 2-6 -Alkenyl, -OC 3-8 -cycloalkyl, COOR 1.1 C 1-6 -alkyl-COOR 1.1 CONHR 1.1 C 1-6 -alkyl-CONHR 1.1 -OR 1.1 Oxygenated, halogenated, 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 ; R5 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 -C(O)NOH, -C 1-10 Alkyl-C(O)NOH, -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; R6 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 -C(O)NOH, -C 1-10 Alkyl-C(O)NOH, -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; Alternatively, R5 and R6 together with the atoms they are attached to 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, wherein each of the above groups may be unsubstituted or optionally substituted by 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-5-20 heteroaryl, C 3-20 cycloalkyl-C 6-20 Aryl, 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 Alkyl-COOR 1.1 COR 1.1 C 1-10 Alkyl-COR 1.1 COONR 1.1 C 1-10 Alkyl-COONR 1.1 C(O)NOH, C 1-10 Alkyl-C(O)NOH, 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 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 ; Alternatively, when R5 or R6 has two or more substituents, the two substituents can form an unsubstituted or optionally substituted atom with one, two or more R atoms. e The following groups are substituted: C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic; Each R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 They are selected independently from H, halogens, OH, CN, NO2, oxo (=O), thio (=S), and C, whether they are the same or different. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, NH2; 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, C 3-20 cycloalkyl 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 ; For example, the compound represented by formula H has the structure shown in formula I: Wherein, the groups in Formula I, such as W, m, n, p, q, X1, X2, X3, X4, X5, X6, A, B, C, D, R1, R2, R... a R b R c R d R e R f R g R d21 It has the definition described above; U represents -(CH2) t -、O、S、NR q S(=O), S(=O)2 or C(=O), where t represents 0, 1, 2 or 3; v represents 0, 1, 2, 3, 4 or 5; Each R d22 They may be the same or different, and are independently selected from chemical bonds, H, deuterium, halogen, OH, CN, NO2, oxo (=O), thio (=S), SO, SO2, unsubstituted, or optionally substituted by one, two, or more Rs. a The following groups are substituted: C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 1-20 Alkyloxy, C 2-20 alkenyloxy group, C 2-20 alkynyloxy group, C 3-20 Cycloalkyloxy, C 3-20 Cycloalkenyloxy, C 3-20 Cycloalkynyloxy group, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, C 1-20 Alkyl thio, C 2-20 alkenyl thio, C 2-20 alkynyl thioyl, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 Cycloalkynylthio, C 6-20 Arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclic thio, NH2, -C(O)R 11 -CH2-C(O)R 11 -C(O)OR 12 -CH2C(O)OR 12 -C(O)NHR 12 -CH2C(O)NHR 12 -OC(O)R 13 -S(O)2R 14 -S(O)2OR 15 -OS(O)2R 16 -P(O)(OR) 17 (OR) 18 ); Alternatively, when two or more R-selected groups are present on the same group. d21 R d22 When substituents are present, the two substituents can form an unsubstituted or optionally substituted group with one, two or more R atoms together with the atoms they are attached to. e The following groups are substituted: C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 heteroaryl, 3-20 heterocyclic.

2. The compound of claim 1, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein: In the compounds represented by formula H or formula I, X1, X2, X3, X4, X5, and X6 are not simultaneously chemical bonds, and A, B, C, and D are not simultaneously chemical bonds.

3. The compound of claim 1 or 2, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein: R f R g It forms together with the atoms it is connected to. like 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: A is selected from the following groups, each of which is independently bounded by 0, 1, 2 or 3 R groups. a Group substitution: Among them, R a As defined in any one of claims 1-3, "--" represents a chemical bond; And / or, B is selected from the following groups, each of which is independently bounded by 0, 1, 2 or 3 R groups. b Group substitution: Among them, R b As defined in any one of claims 1-3, "--" 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, each of which is independently bounded by 0, 1, 2 or 3 R groups. c Group substitution: Among them, R c As defined in any one of claims 1-4, "--" represents a chemical bond; And / or, D is selected from the following groups, each of which is independently bounded by 0, 1, 2 or 3 R groups. d Group substitution: Among them, R d As defined in any one of claims 1-4, "--" represents a chemical bond.

6. The compound of claim 1, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein the compound may be selected from the following compounds:

7. A method for preparing the compound, racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug as described in any one of claims 1-6, wherein the preparation method comprises reacting a compound of formula H1 with a compound of formula H2 to obtain a compound of formula H: And optionally, the compound of formula H may be derived into its stereoisomers, tautomers, isotopic labels, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs; in, Each LG is independently a leaving group, such as Cl, Br, or I; Other groups such as A, B, C, D, X1, X2, X3, X4, X5, X6, R1, R2, R5, R6, R a R b R c R d R e R f R g 、Rd 21 m, n, p, and q each have the definition as described in any one of claims 1-6; For example, the preparation method includes reacting a compound of formula S1 with a compound of formula S2 to obtain a 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; Each LG is an independent leaving group, such as Cl, Br or I; Other groups such as A, B, C, D, X1, X2, X3, X4, X5, X6, R1, R2, R a R b R c R d R e R f R g 、Rd 21 、Rd 22 U, m, n, p, q, v each have the definition as described in any one of claims 1-6.

8. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of any one of claims 1-6, a racemic mixture, a stereoisomer, a tautomer, an isotope label, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof; Optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients; Optionally, the pharmaceutical composition may further comprise one or more additional therapeutic agents.

9. A method for preventing or treating a disease or condition mediated by at least PDE4 and TYK2, comprising administering to a patient in need at least one of the compounds of any one of claims 1-6, their racemic mixtures, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds thereof. For example, the disease or condition mentioned is selected from those mediated by PDE4 and TYK2.

10. The method of claim 8 or 9, wherein the disease or condition includes, but is not limited to, at least one selected from: autoimmune and / or inflammatory diseases selected from psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis; atopic dermatitis; lung diseases selected from idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD); asthma; sarcoidosis; graft-versus-host disease (GVHD); chronic inflammation selected from ankylosing spondylitis and uveitis; giant cell arteritis (GCA); tumors, such as solid tumors, such as lung cancer, colorectal cancer, melanoma, glioblastoma, and brain tumors; cardiovascular diseases and / or metabolic disorders, such as atherosclerosis and diabetic nephropathy; neurological diseases, such as multiple sclerosis (MS) and Alzheimer's disease (AD); and fibrotic diseases, such as fibrosis or sclerosis of the kidneys, liver, or skin.

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