Pyrimidine-hydroxypurine derivatives and pharmaceutical compositions and uses thereof

Abstract

The present disclosure provides a compound represented by formula H below, or a racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug thereof; the compounds of the present disclosure, by virtue of their excellent multi-target inhibitory activity against PDE1, PDE2 and PDE4, 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

Pyrimidine-hydroxypurine derivatives, their pharmaceutical compositions and uses

[0001] This application claims priority to the prior art of the applicant's earlier patent application filed on March 26, 2025 with the China National Intellectual Property Administration, application number 202510367782.0, entitled "Pyrimidine-hydroxypurine 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 pyrimidine-hydroxypurine derivatives, pharmaceutical compositions thereof, and uses, and belongs to the field of chemical pharmaceuticals. Background Technology

[0003] Phosphodiesterases (PDEs) are a crucial therapeutic target for many diseases, and their inhibitors can be used to treat a wide range of conditions. PDEs are the only family of enzymes in the body that hydrolyze the important intracellular second messengers cAMP and cGMP, and consist of 11 subfamilies (PDE1-11). Drugs with inhibitory activity against PDEs can treat a variety of diseases.

[0004] For example:

[0005] Three subtypes of PDE1 are known: PDE1A, PDE1B, and PDE1C. PDE1A and PDE1B exhibit strong hydrolytic activity towards cGMP, while PDE1C shows no significant difference in its hydrolytic activity towards cAMP and cGMP. PDE1A is mainly distributed in vascular smooth muscle cells and regulates smooth muscle tone. PDE1B is mainly distributed in the nervous system and participates in physiological activities such as learning, memory, and immune regulation. PDE1C is mainly distributed in the brain and smooth muscle cells and may be involved in the proliferation of vascular smooth muscle cells and signal transmission in the central nervous system.

[0006] There is one subtype of PDE2, PDE2A. PDE2 is expressed in many tissues and cells, such as the central nervous system, platelets, cardiomyocytes, and endothelial cells. PDE2 plays an important role in regulating myocardial contraction, improving cognitive function, and long-term memory.

[0007] The PDE4 subfamily comprises four subtypes (PDE4A, PDE4B, PDE4C, and PDE4D), each exhibiting different tissue distributions: PDE4A is ubiquitous, with relatively high expression in adipose tissue, brain, heart, and testes; PDE4B is also widely distributed, particularly showing high expression in the lungs, immune cells, brain, heart, and skeletal muscle; PDE4C is mainly expressed in the testes and other tissues, with low expression in the lungs and no expression in blood and immune cells; PDE4D is mainly expressed in the brain, immune cells, and skeletal muscle cells. Therefore, the PDE4B subtype shows higher expression in the lungs compared to the other subtypes. In vitro studies targeting PDE4B in pulmonary fibrosis have demonstrated the important role of PDE4B inhibition in anti-inflammatory and anti-fibrotic processes. Inhibition of PDE4B leads to increased intracellular cAMP levels, which in turn activates protein kinase A (PKA) and cAMP directly activates exchanger protein (EPAC), reducing the synthesis and release of pro-inflammatory cytokines and increasing the synthesis of anti-inflammatory cytokines.

[0008] Although there is preclinical evidence that PDE4 inhibitors are associated with anti-inflammatory and anti-fibrotic effects and have the potential to reduce inflammation and fibrotic remodeling in lung diseases, many PDE4 inhibitors have caused gastrointestinal side effects due to their selectivity differences, leading to the termination of clinical trials.

[0009] Targeted drugs are a class of drugs designed to specifically inhibit pathogenic factors (such as protein molecules or gene fragments). The unique mechanisms of action and therapeutic advantages of targeted drugs are of great significance for disease treatment, reducing side effects, and improving patients' quality of life. While targeted drugs offer unique therapeutic advantages and bring significant clinical benefits, they also have limitations such as high cost, narrow applicability, susceptibility to drug resistance, and certain toxic side effects. These limitations necessitate the development of novel targeted drugs or technologies. Among these, the development of dual-target or multi-target drugs, especially those with synergistic effects, will offer remarkable advantages in improving efficacy and reducing drug resistance. Summary of the Invention

[0010] 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:

[0011] in:

[0012] X1 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 1-6Alkylene -C(=O)-NH-, -C(=O)-NH-C 1-6 Alkylene-, -C(=O)-NH-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene -O-, -C 2-6 imidene-, -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 (=O), thio (=S), -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl;

[0013] X2 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(=O)-NH-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene -O-, -C 2-6 imidene-, -C 2-6 -, -C ethynyl 1-6 alkeneoxy-; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 2-10 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl;

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

[0015] R f Represents -X4-R3;

[0016] X4 represents a chemical bond or -CH2-, -O-, -S-, -NH-, -S(O)-, -S(O)2- or -C(O)-;

[0017] 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), C 1-6 Alkyl, -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;

[0018] R g Represents -X5-R4;

[0019] X5 represents a chemical bond or -CH2-, -O-, -S-, -NH-, -S(O)-, -S(O)2- or -C(O)-;

[0020] 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), C 1-6 Alkyl, -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;

[0021] The condition is R f R g Not both H;

[0022] Or, R f R g Together with the atoms it is attached to, it forms an unsubstituted or optionally substituted group with one, two or more R atoms. d3 The following groups are substituted: C 5-20 Cycloalkenyl, C 5-20 Cycloalkyl, 3-20 membered heterocycloalkyl, 3-20 membered heterocycloalkenyl, 5-20 membered heteroaryl, 6-20 membered aryl;

[0023] 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 with 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 6-20aryloxy 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 aryl thio, 5-20 membered heteroaryl thio, 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 );

[0024] 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;

[0025] 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-,-C3-20 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), C1-6 -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] 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;

[0027] 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, C1-6 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 ;

[0028] 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;

[0029] 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;

[0030] 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;

[0031] Ring C is C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 membered heteroaryl, wherein C 3-20 Among cycloalkenyl and 5-20 membered heterocyclic alkenyl groups, except for those with... In addition to double bonds, the fused sites may optionally contain or not contain additional unsaturated bonds (such as double or triple bonds);

[0032] 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 -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;

[0033] R b Represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-10 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20-membered heteroaryl, C 1-6 Alkyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -OR 1.1-COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1-10 Alkyl-COR 1.1 -COONR 1.1 -C 1-10 Alkyl-COONR 1.1 -CONOH, -C 1-10 Alkyl-CONOH, -CO-NR 1.1 -C 1-10 Alkyl-CO-NR 1.1 -CH=CHCOOR 1.1 -CO-NR 1.1 -CH2CO-NR 1.1 -CH=CHCO-NR 1.1 -NR 1.2 R 1.3 -C 1-10 Alkyl-NR 1.2 R 1.3 -SR 1.1 -C 1-10 Alkyl-SR 1.1 -SOR 1.1 -C 1-10 Alkyl-SOR 1.1 -SO2-R 1.1 -C 1-10 Alkyl-SO2R 1.1 -SO2-NR 1.2 R 1.3 or -C 1-10 Alkyl-SO2-NR 1.2 R 1.3 Each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 NR 1.2 R 1.3 C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 2-10 alkenyl and C 2-10 alkynyl group;

[0034] Or, Ra 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-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 -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 ;

[0035] R1 represents hydrogen, deuterium, and carbon. 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=CHCOOR1.1 -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, 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, C 2-10 alkynyl group;

[0036] R2 represents hydrogen, deuterium, 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, C3-20 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, 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;

[0037] 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, 5-20-membered heteroaryl-C 1-6 -alkyl, 3-20 membered heterocyclic -C 1-6 -alkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl, monocyclic or bicyclic C 6-20 -aryl, 5-20 membered heteroaryl and heterocyclic, which may be unsubstituted or optionally substituted with substituents selected from the following: halogen, deuterium, OH, CN, NO2, NH2, oxo (=O), thio (=S), CF3, CHF2, CH2F, O-(C 1-3 -alkyl), C 1-10- Alkyl and C 6-20- Aryl;

[0038] 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 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 ;

[0039] Or, R 1.2 and R 1.3Together 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 ;

[0040] R d21Selected from chemical bonds, H, deuterium, halogens, OH, CN, NO2, oxo (=O), thio (=S), SO, SO2, unsubstituted or optionally with 1, 2 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 aryl thio, 5-20 membered heteroaryl thio, 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 );

[0041] Each R e They may be the same or different, and are independently selected from hydrogen, deuterium, halogen, OH, CN, NO2, NH2, SH, oxo (=O), thio (=S), methanesulfonyl, ethanesulfonyl, methanesulfonamide, ethanesulfonamide, carboxylic acid, C 1-6 Alkyl, O-CONH2, O-CONR 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) r 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 NR1.2 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 - NR 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 ;

[0042] Each R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 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;

[0043] t represents 0, 1, 2, or 3;

[0044] m represents 0, 1, 2, 3, 4 or 5;

[0045] n represents 0, 1, 2, 3, 4, or 5;

[0046] r represents 0, 1, 2, 3, 4, or 5.

[0047] According to an embodiment of the present invention, the compound represented by formula H has the structure represented by formula I:

[0048] Wherein, the groups in Formula I, such as A, B, C, X1, X2, X3, R, etc. a R b R e R f R g R1, R2, R d21 R d22 v, m, n have the definitions described above;

[0049] U represents -(CH2) t -、O、S、NR q S(=O), S(=O)2 or C(=O)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 ;

[0050] Each R d21 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, C6-20 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 aryl thio, 5-20 membered heteroaryl thio, 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 );

[0051] 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 membered heteroaryl, 3-20 membered heterocyclic;

[0052] v represents 0, 1, 2, 3, 4, or 5.

[0053] According to embodiments of the present invention, the heterocyclic group preferably represents a 3-11 member saturated or partially saturated monocyclic or bicyclic ring comprising 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O, wherein the bicyclic ring can be any fused ring or bridged ring, but it does not possess aromaticity; wherein the heterocyclic group can be a heterocyclic alkyl, heterocyclic alkenyl, or heterocyclic alkynyl; for example, a heterocyclic alkyl group represents a 3-11 member saturated monocyclic or bicyclic ring comprising 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O, wherein... The bicyclic ring can be any fused ring or bridged ring; the heterocyclic alkenyl group represents a 3-11 member monocyclic or bicyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, and containing 1, 2 or more double bonds, wherein the bicyclic ring can be any fused ring or bridged ring; the heterocyclic alkynyl group represents a 3-11 member monocyclic or bicyclic ring containing 1, 2 or 4 heteroatoms independently selected from N, S or O, and containing 1, 2 or more triple bonds, wherein the bicyclic ring can be any optional fused ring or optional bridged ring;

[0054] According to embodiments of the present invention, the heteroaryl group preferably represents a 5-10 member monocyclic or bicyclic aromatic group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, wherein the bicyclic group may be any fused ring;

[0055] 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.

[0056] According to an embodiment of the present invention, R f R g Together with the pyrimidine group attached thereto, it forms like

[0057] According to embodiments of the present invention, the halogen-substituted alkyl group can be a monohalogenated, dihalogenated, trihalogenated, or more halogenated C14 group. 1-6 Alkyl groups, such as -CF3, -CHF2, -CH2F.

[0058] According to an embodiment of the present invention, A may preferably be selected from the following groups:

[0059] In this context, "--" represents a chemical bond.

[0060] According to an embodiment of the present invention, B may preferably be selected from the following groups:

[0061] In this context, "--" represents a chemical bond.

[0062] According to an embodiment of the present invention, the structural unit Preferred selections are from the following groups:

[0063] In this context, "--" represents a chemical bond.

[0064] According to an embodiment of the present invention, the structural unit Preferred selections are from the following groups:

[0065] In this context, "--" represents a chemical bond.

[0066] According to embodiments of this disclosure, the compound of formula H may be selected from the following compounds:

[0067] 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 two or three of PDE1, PDE2, and PDE4.

[0068] 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 two or three of PDE1, PDE2, and PDE4.

[0069] 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:

[0070] Wherein, LG is a leaving group, such as Cl, Br or I;

[0071] Other groups such as A, B, C, X1, X2, X3, R a R b R e R f R g R1, R2, R5, R6, R d21 m and n independently possess the definitions described above;

[0072] Optionally, the preparation method further includes the step of forming the compound of formula H into its racemic, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug by known methods.

[0073] 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:

[0074] Wherein, LG is a leaving group, such as Cl, Br or I;

[0075] Other groups such as A, B, C, X1, X2, X3, U, R a R b R e R f R g R1, R2, R d21 R d22 v, m, and n each have the definitions described above independently;

[0076] Optionally, the preparation method further includes the step of forming the compound of Formula I into its racemic, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug by known methods.

[0077] According to embodiments of this disclosure, the reaction can be carried out with a protecting group affixed to the compound of formula H1, formula H2, formula S1, or formula 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.

[0078] 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.

[0079] 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.

[0080] According to embodiments of this disclosure, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0081] According to embodiments of this disclosure, the pharmaceutical composition may further comprise one or more additional therapeutic agents.

[0082] 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.

[0083] The drug can be used to prevent or treat diseases mediated by at least two or three of PDE1, PDE2, and PDE4.

[0084] For example, the drug can be used to prevent or treat diseases mediated by two or three of PDE1, PDE2, and PDE4.

[0085] According to the embodiments of this disclosure, the PDE1 is selected from one, two, or three of PDE1A, PDE1B, and PDE1C.

[0086] According to an embodiment of this disclosure, the PDE2 is selected from PDE2A.

[0087] According to the embodiments of this disclosure, the PDE4 is selected from one, two, three or more of PDE4A, PDE4B (such as PDE4B2), PDE4C and PDE4D (such as PDE4D2).

[0088] According to an embodiment of this disclosure, the PDE5 is selected from PDE5A.

[0089] The present invention also provides a method for preventing or treating diseases mediated by at least two or three of PDE1, PDE2 and PDE4, comprising administering to a patient in need at least one of a compound of formula H, its racemic, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

[0090] According to embodiments of this disclosure, the disease is selected from two or three of PDE1, PDE2 and PDE4 mediated diseases.

[0091] According to embodiments of the present invention, the diseases include, but are not limited to, at least one selected from the following: inflammatory respiratory diseases, inflammatory bowel disease (Crohn's disease, ulcerative colitis), arthritic diseases, inflammatory dermatitis, psoriasis, atopic dermatitis and other inflammatory skin diseases, rheumatoid arthritis (RA), inflammatory eye diseases, diseases of the peripheral or central nervous system, degenerative diseases of the central nervous system, Alzheimer's disease (AD), Parkinson's disease, schizophrenia, depression (such as major depressive disorder (MDD)), bipolar disorder, non-alcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), hepatic fibrosis (HF), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), renal fibrosis, and benign prostatic hyperplasia. Hyperplasia (BPH), gastroesophageal reflux disease, obstructive sleep apnea, coronary artery disease, heart failure (HF), hypertension, ischemic heart disease, atherosclerosis, liver fibrosis, cirrhosis, systemic sclerosis (scleroderma), diabetic nephropathy, cancer-related solid tumors (such as lung cancer, colorectal cancer, pancreatic cancer), glioblastoma, brain tumors, leukemia and lymphoma, and obesity associated with metabolic disorders.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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

[0104] The compounds disclosed herein possess excellent multi-target inhibitory activity against PDE1, PDE2, and PDE4, which will facilitate 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 enhancing patient compliance and quality of life.

[0105] Terminology Definitions and Explanations

[0106] 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.

[0107] 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.

[0108] 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.

[0109] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0110] 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.

[0111] 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.

[0112] 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") 2-3 The alkynyl group is, for example, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynyl, 1-methylprop-2-alkynyl, 2-methylbut-3-alkynyl, 1-methylbut-3-alkynyl, 1-methylbut-2-alkynyl, 3-methylbut-1-alkynyl, 1-ethylprop-2-alkynyl, 3-methylpent-4-alkynyl, 2-methylpent-4-alkynyl, 1-methylpent-4-alkynyl -Alynyl, 2-methylpentan-3-ynyl, 1-methylpentan-3-ynyl, 4-methylpentan-2-ynyl, 1-methylpentan-2-ynyl, 4-methylpentan-1-ynyl, 3-methylpentan-1-ynyl, 2-ethylbutan-3-ynyl, 1-ethylbutan-3-ynyl, 1-ethylbutan-2-ynyl, 1-propylpropan-2-ynyl, 1-isopropylpropan-2-ynyl, 2,2-dimethylbutan-3-ynyl, 1,1-dimethylbutan-3-ynyl, 1,1-dimethylbutan-2-ynyl, or 3,3-dimethylbutan-1-ynyl. In particular, the ynyl group is ethynyl, propan-1-ynyl, or propan-2-ynyl.

[0113] 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.

[0114] 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.

[0115] 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;

[0116] 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 Aryl. 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.

[0117] 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.

[0118] Unless otherwise defined, in the compounds described in this disclosure, when a substituent is defined as a subunit or a group whose structure can be bonded to a linking position in the compound from both sides, the specific position of the substituent in the compound is not particularly limited. For example, it can be either end of the subunit or a group whose structure can be bonded to a linking position in the compound from both sides, as long as the bonding conforms to valence bond theory. Alternatively, when a substituent is defined as two connected groups (such as in the form of "group 1-group 2" or "group 1 plus group 2", where group 1 and group 2 are the same or different), the specific position of the substituent in the compound is not particularly limited. For example, group 1 can be bonded to a linking position in the compound, or group 2 can be bonded 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 (such as group 1 and group 2) is not particularly limited, as long as the connection conforms to valence bond theory.

[0119] For example, for -C 1-6Alkylene -C(=O)-NH-, -C(=O)-NH-C 1-6 Alkylene-, -C(=O)-NH-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene-O-, C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 5-20 heteroaryl, C 3-20 Heterocyclic alkyl and C 6-20 Aryl, C 3-20 Heterocyclic alkyl and C 5-20 heteroaryl, C 5-20 Heterocyclic alkenyl C 6-20 Aryl, C 5-20 Heterocyclic alkenyl C 5-20 heteroaryl, C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 cycloalkenyl-C 5-20 heteroaryl, -C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Heterocyclic alkyl-C 6-20 Aryl, C 3-20 Heterocyclic alkyl-C 5-20 heteroaryl, C 5-20 Heterocyclic alkenyl-C 6-20 Aryl, C 5-20 Heterocyclic alkenyl-C 5-20 heteroaryl, C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 cycloalkenyl-C 5-20 heteroaryl, C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 5-20 heteroaryl, C 3-20 Heterocyclic alkyl and C 6-20 Aryl, C 3-20 Heterocyclic alkyl and C 5-20 heteroaryl, C 5-20 Heterocyclic alkenyl C 6-20 Aryl, C 5-20 Heterocyclic alkenyl C 5-20 heteroaryl, C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 cycloalkenyl-C 5-20A heteroaryl group can be bonded to a linking position in the compound by either side of the group.

[0120] For example, when both sides of a group in the context of this application are drawn with "--" representing chemical bonds, it means that either side can combine with other groups in the structure of formula H. For example, each structure in the group specifically exemplified by group A (including but not limited to) ), either side of which can be bonded to the X1 or X2 group in compound H; or, each structure in the group of specific examples of group B (including but not limited to) ), and either side of it can be bonded to the X2 or X3 group in the compound of formula H.

[0121] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0122] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0123] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms.

[0124] 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.

[0125] 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

[0126] 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.

[0127] 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;

[0128] Those skilled in the art will understand that the compounds represented by Formula H can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] "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.

[0135] 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.

[0136] 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.

[0137] 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

[0138] 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.

[0139] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0140] Glossary of Terms

[0141] DMF: N,N-dimethylformamide

[0142] DCM: Dichloromethane

[0143] DIEA: N,N-Diisopropylethylamine

[0144] TEA: Triethylamine

[0145] PE: Petroleum ether

[0146] EA: Ethyl acetate

[0147] MeCN: Acetonitrile

[0148] Et2O: Diethyl ether

[0149] DMSO: Dimethyl sulfoxide

[0150] EtOAc: Ethyl acetate

[0151] THF: Tetrahydrofuran

[0152] TFA: Trifluoroacetic acid

[0153] AcOH: Acetic acid

[0154] MeOH: Methanol

[0155] EtOH: Ethanol

[0156] NaH: Sodium hydride

[0157] MeI: Methyl iodoform

[0158] EtI: Ethyl iodide

[0159] HFP: 1,1,1,3,3,3-Hexafluoro-2-propanol

[0160] DHP:3,4-Dihydro-2H-pyran

[0161] PPTS: Pyridine 4-methylbenzenesulfonic acid

[0162] PPh3: Triphenylphosphine

[0163] DEAD: Diethyl azodicarbonate

[0164] MsCl: Methylsulfonyl chloride

[0165] TMSOTf: Trimethylsilyl trifluoromethanesulfonate

[0166] m-CPBA: m-chloroperoxybenzoic acid

[0167] Boc: tert-butoxycarbonyl

[0168] Analytical methods

[0169] 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.

[0170] 2. The purity analysis of the samples was performed on a Waters HPLC / Waters MS system.

[0171] Chromatographic conditions 1:

[0172] Chromatographic column: Waters X-Bridge-C18 50mm*4.6mm*3.5μm

[0173] The column temperature was 40℃.

[0174] Sample temperature: room temperature

[0175] Detection of UV 214 nm and UV 254 nm

[0176] Flow rate: 2 mL / min.

[0177] Mobile phase A: Water (0.05% TFA)

[0178] Mobile phase B: MeCN (0.05% TFA)

[0179] Gradient program: B from 5% to 100% takes 1.6 minutes, and 100% is held for 1.4 minutes.

[0180] Chromatographic conditions 2:

[0181] Chromatographic column: Waters X Brdige C18 (4.6mm x 50mm x 3.5μm)

[0182] The column temperature was 40℃.

[0183] Sample temperature: room temperature

[0184] Detection of UV 214 nm and UV 254 nm

[0185] Flow rate: 2 mL / min.

[0186] Mobile phase A: Water (0.01 mol / L NH4HCO3) B: MeCN

[0187] Mobile phase B: MeCN

[0188] Gradient program: B from 5% to 100%, for 1.6 minutes, then hold at 100% for 1.4 minutes.

[0189] 3. Preparative HPLC was performed on a Gilson 281.

[0190] Flow rate: 20 mL / min.

[0191] Column: X-Select 10μm 19*250mm column

[0192] Wavelength: 254 nm or 214 nm

[0193] Solvent A: Water (10 mM NH4HCO3) and Solvent B: MeCN.

[0194] Example 1: Synthesis Example

[0195] 1. Synthesis scheme:

[0196] 2. Experimental Section:

[0197] 2.1

[0198] 4-((7-(cyclopropylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (06001-1)

[0199] At room temperature, tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (300 mg, 1.1 mmol) and Cs₂CO₃ (585 mg, 1.82 mmol), TBAI (30 mg, 0.09 mmol) were added to a solution of 7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (200 mg, 0.91 mmol) in DMF (5.0 mL). The mixture was then stirred at 50 °C for 2 h. After the starting material was consumed, water (10 mL) was added, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 4, silica gel-CS 12 g, 30 mL / min, silica gel, UV 254) to give a colorless oily product (198 mg, yield 52.9%).

[0200] ESI-MS m / z calcd for [C 21 H 31 N5O4][M+H + 362.2; found: 361.8

[0201] 2.2

[0202] 7-(cyclopropylmethyl)-3-methyl-1-(piperidin-4-ylmethyl)-1H-purine-2,6(3H,7H)-dione (06001-2)

[0203] TFA (1 mL) was added to a solution of tert-butyl piperidine-1-carboxylate (198 mg, 0.47 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the crude product was used directly for the next reaction.

[0204] ESI-MS m / z calcd for [C 17 H 24 N4O2][M+H] + 317.2; found: 317.8

[0205] 2.3

[0206] (R)-7-(cyclopropylmethyl)-1-((1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)methyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (MX06001)

[0207] To a solution of 7-(cyclopropylmethyl)-3-methyl-1-(piperidin-4-ylmethyl)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.32 mmol) in DMF (3 mL), (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (60 mg, 0.21 mmol) and DIEA (135 mg, 1.05 mmol) were added. The mixture was stirred at 80 °C under nitrogen protection 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 obtain a white solid product (13.30 mg, yield 11.2%).

[0208] ESI-MS m / z calcd for [C 27 H 36 [N8O4S][M+H] + :569.2; found:569.3

[0209] 1H NMR (400MHz, DMSO-d6) δ8.13(s,1H),7.28(s,1H),4.83(t,J=5.6Hz,1H),4.61–4.58(m,2H),4.11(d ,J=7.2Hz,2H),3.79(d,J=6.8Hz,1H),3.73–3.66(m,2H),3.43(s,3H),3.42–3.35(m,2H),3.24–3.18 (m,1H),2.93–2.79(m,4H),2.39–2.25(m,2H),2.17–2.10(m,2H),2.07–2.01(m,1H),1.80–1.69(m, 2H),1.61–1.58(m,2H),1.34–1.28(m,1H),1.16–1.07(m,2H),0.52–0.46(m,2H),0.44–0.39(m,2H).

[0210] 1. Synthesis scheme:

[0211] 2. Experimental Section:

[0212] 2.1

[0213] 7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (06002-1)

[0214] Under ice bath conditions, NaH (396 mg, 9.9 mmol) and (bromomethyl)cyclopropane (1.58 g, 11.75 mmol) were added to a solution of 1.5 g of 3-methylxanthine (9.04 mmol) in 15 mL of DMSO. The mixture was then brought to room temperature and stirred overnight. After the starting material was consumed, the mixture was allowed to stand to precipitate a solid. The solid was filtered, and the filter cake was washed three times with water and three times with methanol to obtain a yellow solid product (1.1 g, yield 55.3%).

[0215] ESI-MS m / z calcd for [C 10 H 12 N4O2][M+H] + :221.1; found:221.2

[0216] 2.2

[0217] 1-(4-Bromobenzyl)-7-(Cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (06002-2)

[0218] At room temperature, 1-bromo-4-(bromomethyl)benzene (271 mg, 1.09 mmol) and Cs₂CO₃ (593 mg, 1.82 mmol), and TBAI (33 mg, 0.09 mmol) were added to a DMF (5 mL) solution of 7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (200 mg, 0.91 mmol). The mixture was then stirred at 50 °C for 2 h. After the starting material was consumed, water (10 mL) was added, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 4, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give a yellow oily product (322 mg, yield 91.2%).

[0219] ESI-MS m / z calcd for [C 17 H 17 BrN4O2][M+H] + 389.0; found: 388.7

[0220] 2.3

[0221] 7-(cyclopropylmethyl)-3-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzyl)-1H-purine-2,6(3H,7H)-dione (06002-3)

[0222] To a solution of 1-(4-bromobenzyl)-7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (200 mg, 0.68 mmol) in 1,4-dioxane (2 mL), B2Pin2 (353 mg, 1.39 mmol), KOAc (200 mg, 2.04 mmol), and Pd(dppf)Cl2 (55 mg, 0.07 mmol) were added. The mixture was stirred overnight at 80 °C under nitrogen protection. After the starting material was consumed, the reaction solution was cooled, filtered, and concentrated under reduced pressure. The crude product was used directly in the next reaction step.

[0223] ESI-MS m / z calcd for [C 23 H 29 BN4O4][M+H] + 437.2; found: 436.8

[0224] 2.4

[0225] (R)-7-(cyclopropylmethyl)-1-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)benzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (MX06002)

[0226] To a solution of 7-(cyclopropylmethyl)-3-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)benzyl)-1H-purine-2,6(3H,7H)-dione (14 mg, 0.05 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1), (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (20 mg, 0.05 mmol), K₂CO₃ (14 mg, 0.10 mmol), and Pd(dppf)Cl₂ (4 mg, 0.005 mmol) were added. The mixture was heated to 80 °C and stirred for 8 hours under nitrogen protection. After cooling, it 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 (5.22 mg, yield 18.6%).

[0227] ESI-MS m / z calcd for [C 28 H 31 N7O4S][M+H]+:562.2; found:562.4

[0228] 1 H NMR (400MHz, DMSO-d6) δ8.24(d,J=8.4Hz,2H),8.17(s,1H),8.03(s,1H),7.40(d,J=8 .4Hz,2H),5.13(s,2H),4.92(t,J=5.6Hz,1H),4.12(d,J=7.2Hz,2H),3.82–3.78(m,2 H),3.65–3.59(m,1H),3.45(s,3H),3.23–3.17(m,1H),3.04–3.00(m,1H),2.40–2.30 (m,5H),1.85–1.78(m,2H),1.36–1.32(m,1H),0.53–0.48(m,2H),0.42–0.40(m,2H).

[0229] 1. Synthesis scheme:

[0230] 2. Experimental Section:

[0231] 2.1

[0232] 1-(4-Bromobenzyl)-3,7-Dimethyl-1H-purine-2,6(3H,7H)-dione (06003-1)

[0233] At room temperature, 1-bromo-4-(bromomethyl)benzene (750 mg, 3.0 mmol) and Cs₂CO₃ (1.96 g, 6.0 mmol) were added to a solution of 3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (540 mg, 3.0 mmol) in MeCN (10 mL). The mixture was stirred overnight at room temperature, then water (30 mL) was added, and the mixture was stirred for 5 minutes. The mixture was then extracted twice with EA (30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE = 0–100%, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give a colorless oily product (680 mg, yield 64.95%).

[0234] ESI-MS m / z calcd for [C 14 H 13 BrN4O2][M+H] + :349.0; found:349.0

[0235] 2.2

[0236] 3,7-Dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzyl)-1H-purine-2,6(3H,7H)-dione (06003-2)

[0237] To a solution of 1-(4-bromobenzyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (35 mg, 1.0 mmol) in 1,4-dioxane (20 mL), B2Pin2 (2.54 g, 10 mmol), KOAc (980 mg, 10 mmol), and Pd(dppf)Cl2 (72.0 mg, 0.1 mmol) were added. The mixture was stirred overnight at 100 °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 / 1 to 1 / 3, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give a brown solid product (200 mg, yield 50.5%).

[0238] ESI-MS m / z calcd for [C 20 H 25 BN4O4][M+H] + :397.2; found:397.4

[0239] 2.3

[0240] (R)-1-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)benzyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (MX06003)

[0241] To a solution of (3,7-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzyl)-1H-purine-2,6(3H,7H)-dione (80 mg, 0.2 mmol) in 1,4-dioxane / water (10 mL, v / v = 4:1), (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (57.6 mg, 0.2 mmol), K₂CO₃ (55.2 mg, 0.4 mmol), and Pd(dppf)Cl₂ (15 mg, 0.02 mmol) were added. The mixture was stirred at 80 °C under nitrogen protection for 8 hours. After the reaction was complete, the solvent was removed by vacuum distillation. The crude product was analyzed by preparative HPLC [MeCN / H₂O (10 mmol / L)]. Purification was performed using NH4HCO3, X-Select (10 μm, 19*250 mm, 20 mL / min, UV 254) to obtain a light yellow solid product (42 mg, 40.26%).

[0242] ESI-MS m / z calcd for [C25 H 27 [N7O4S][M+H] + :522.2; found:522.2

[0243] 1 H NMR (400MHz, DMSO-d6) δ8.24(d,J=8.4Hz,2H),8.06(s,1H),8.01(s,1H),7.40(d,J=8.4Hz,2H),5.12(s,2H),4.90(t,J=5.6 1H), 3.90(s,3H),3.83–3.76(m,2H),3.67–3.59(m,1H),3.44(s,3H),3.39–3.33(m ,1H),3.24–3.17(m,1H),3.04–2.99(m,1H),2.43–2.28(m,4H),1.86–1.76(m,2H).

[0244] 1. Synthesis scheme:

[0245] 2. Experimental Section:

[0246] 2.1

[0247] 1-(4-Bromo-2-fluorobenzyl)-7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (06004-1)

[0248] At room temperature, 4-bromo-1-(bromomethyl)-2-fluorobenzene (439 mg, 1.64 mmol) and Cs₂CO₃ (887 mg, 2.72 mmol), TBAI (51 mg, 0.14 mmol) were added to a DMF (5.0 mL) solution of 7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (300 mg, 1.36 mmol). The mixture was then stirred at 50 °C for 2 h. After the starting material was consumed, water (10 mL) was added, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 4, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give a yellow oily product (531 mg, yield 96.2%).

[0249] ESI-MS m / z calcd for [C 17 H 16 BrFN4O2][M+H]+ :407.0; found:409.2

[0250] 2.2

[0251] 7-(cyclopropylmethyl)-1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (06004-2)

[0252] To a solution of 1-(4-bromo-2-fluorobenzyl)-7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (100 mg, 0.25 mmol) in 1,4-dioxane (2 mL), B2Pin2 (125 mg, 0.50 mmol), KOAc (73 mg, 0.75 mmol), and Pd(dppf)Cl2 (20 mg, 0.03 mmol) were added. The mixture was stirred overnight at 80 °C under nitrogen protection. After the starting material was consumed, the reaction solution was cooled, filtered, and concentrated under reduced pressure. The crude product was used directly in the next reaction step.

[0253] ESI-MS m / z calcd for [C 23 H 28 BFN4O4][M+H] + :455.2; found:455.2

[0254] 2.3

[0255] (R)-7-(cyclopropylmethyl)-1-(2-fluoro-4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)benzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (MX06004)

[0256] To a solution of 7-(cyclopropylmethyl)-1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (77 mg, 0.17 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1), (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg, 0.17 mmol), K₂CO₃ (47 mg, 0.34 mmol), and Pd(dppf)Cl₂ (7 mg, 0.008 mmol) were added. The mixture was heated to 80 °C and stirred for 8 hours under nitrogen protection. After cooling, it 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 (4.99 mg, yield 5.07%).

[0257] ESI-MS m / z calcd for [C 28 H 30 FN7O4S][M+H]+:580.2; found:580.3

[0258] 1 H NMR (400MHz, DMSO-d6) δ8.18(s,1H),8.10(s,1H),8.04(d,J=8.8Hz,1H),7.98(d,J=12.0Hz ,1H),7.26(t,J=8.0Hz,1H),5.16(s,2H),4.92(t,J=5.6Hz,1H),4.12(d,J=7.2Hz,2H),3.7 9–3.78(m,2H),3.68–3.59(m,1H),3.46(s,3H),3.24–3.10(m,1H),3.05–3.00(m,1H),2.43 –2.29(m,5H),1.85–1.92(m,2H),1.36–1.24(m,1H),0.53–0.48(m,2H),0.43–0.40(m,2H).

[0259] 1. Synthesis scheme:

[0260] 2. Experimental Section:

[0261] 2.1

[0262] 1-Bromo-4-(1-Bromoethyl)benzene (06005-1)

[0263] 1-(4-bromophenyl)ethanol (2.0 g, 10.0 mmol) was added to a solution of DCM (20 mL) with PBr3 (1.5 g, 7.50 mmol), and the reaction mixture was stirred at room temperature for 4 hours. After the starting material was consumed, water (30 mL) was added to the mixture, and the mixture was extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (30 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 solid product (2.18 g, yield 83%).

[0264] ESI-MS m / z calcd for[C8H8Br2][M+H] + :262.9; found:263.1

[0265] 2.2

[0266] 1-(1-(4-bromophenyl)ethyl)-7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (06005-2)

[0267] At room temperature, Cs₂CO₃ (652 mg, 2.00 mmol) and TBAI (369 mg, 1.00 mmol) were added to a solution of 1-bromo-4-(1-bromoethyl)benzene (250 mg, 1.00 mmol) and 7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (220 mg, 1.00 mmol) in DMF (5 mL). The mixture was then stirred at 50 °C for 2 hours, followed by the addition of water (20 mL) and extraction twice with EA (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give a yellow solid product (370 mg, 97% yield).

[0268] ESI-MS m / z calcd for [C 18 H 19 BrN4O2][M+H] + 403.1; found: 403.2

[0269] 2.3

[0270] 7-(cyclopropylmethyl)-3-methyl-1-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)ethyl)-1H-purine-2,6(3H,7H)-dione (06005-3)

[0271] To a solution of 1-(1-(4-bromophenyl)ethyl)-7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (200 mg, 0.50 mmol) in 1,4-dioxane (5 mL), B2Pin2 (254 mg, 1.00 mmol), KOAc (147 mg, 1.50 mmol), and Pd(dppf)Cl2 (35 mg, 0.05 mmol) were added. The mixture was stirred overnight at 100 °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 (MeOH / DCM = 0 / 1 to 1 / 1, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give a brown solid product (89 mg, yield 40%).

[0272] ESI-MS m / z calcd for [C 24 H 31 BN4O4][M+H] + 451.2; found: 451.3

[0273] 2.4

[0274] 7-(cyclopropylmethyl)-1-(1-(4-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (MX06005)

[0275] To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (32 mg, 0.11 mmol), 7-(cyclopropylmethyl)-3-methyl-1-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)ethyl)-1H-purine-2,6(3H,7H)-dione (50 mg, 0.11 mmol), K₂CO₃ (32 mg, 0.33 mmol), and Pd(dppf)Cl₂ (8 mg, 0.011 mmol) were added. The mixture was stirred at 90 °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 (13.67 mg, yield 19%).

[0276] ESI-MS m / z calcd for [C 29 H 33 [N7O4S][M+H] + :576.2; found:576.3

[0277] 1 H NMR (400MHz, DMSO-d6) δ8.24(d,J=8.4Hz,2H),8.14(s,1H),7.98(s,1H),7.40(d,J =8.0Hz,2H),6.28–6.23(m,1H),4.90(t,J=5.6Hz,1H),4.10(d,J=6.4Hz,2H),3.84– 3.79(m,2H),3.76–3.58(m,1H),3.40–3.34(m,4H),3.23–3.17(m,1H),3.04–2.99( m,1H),2.45–2.28(m,4H),1.84–1.76(m,5H),1.18–1.12(m,1H),0.51–0.40(m,4H).

[0278] 1. Synthesis scheme:

[0279] 2. Experimental Section:

[0280] 2.1

[0281] 1-((5-chloropyridin-2-yl)methyl)-7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (06006-1)

[0282] At room temperature, 5-chloro-2-(chloromethyl)pyridine (147 mg, 0.91 mmol) and Cs₂CO₃ (590 mg, 1.82 mmol), TBAI (30 mg, 0.09 mmol) were added to a DMF (5.0 mL) solution of 7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (200 mg, 0.91 mmol). The mixture was then stirred at 50 °C for 2 h. After the starting material was consumed, water (10 mL) was added, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 4, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give a yellow oily product (289 mg, yield 92.3%).

[0283] ESI-MS m / z calcd for [C 16 H 16 ClN5O2][M+H] + :346.1; found:346.1

[0284] 2.2

[0285] 7-(cyclopropylmethyl)-3-methyl-1-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridin-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione(06006-2)

[0286] To a solution of 1-((5-chloropyridin-2-yl)methyl)-7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (120 mg, 0.35 mmol) in 1,4-dioxane (2 mL), B2Pin2 (177 mg, 0.69 mmol), KOAc (68 mg, 0.70 mmol), X-phos (15 mg, 0.03 mmol), and Pd(dppf)Cl2 (14 mg, 0.02 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, filtered, concentrated under reduced pressure, and the crude product was used directly in the next reaction step.

[0287] ESI-MS m / z calcd for [C 22 H 28 BN5O4][M+H + 438.2; found: 438.3

[0288] 2.3

[0289] (R)-7-(cyclopropylmethyl)-1-((5-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)methyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (MX06006)

[0290] To a solution of 7-(cyclopropylmethyl)-3-methyl-1-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione (45 mg, 0.10 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1), (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (30 mg, 0.10 mmol), K₂CO₃ (34 mg, 0.25 mmol), and Pd(dppf)Cl₂ (4 mg, 0.005 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 (7.57 mg, yield 13.47%).

[0291] ESI-MS m / z calcd for [C 27 H 30 N8O4S][M+H]+:563.2; found:563.2

[0292] 1H NMR (400MHz, DMSO-d6) δ9.27(d,J=8.8Hz,1H),8.51(dd,J=8.2,2.2Hz,1H),7.95(d,J=13.2Hz,2 H),7.40(d,J=8.0Hz,1H),5.25(s,2H),4.92(t,J=5.6Hz,1H),4.11(d,J=7.2Hz,2H),3.80–3.76( m,2H),3.68–3.60(m,1H),3.46(s,3H),3.40–3.34(m,1H),3.25–3.19(m,1H),3.05–3.00(m,1H) ,2.39–2.29(m,4H),1.82–1.78(m,2H),1.35–1.31(m,1H),0.53–0.48(m,2H),0.43–0.49(m,2H).

[0293] 1. Synthesis scheme:

[0294] 2. Experimental Section:

[0295] 2.1

[0296] 4-(4-((7-(cyclopropylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (06007-1)

[0297] To a solution of 1-(4-bromobenzyl)-7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (350 mg, 0.90 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (558 mg, 1.80 mmol), K₂CO₃ (248 mg, 1.80 mmol), and Pd(dppf)Cl₂ (37 mg, 0.05 mmol) were added to 1,4-dioxane / water (8 mL, v / v = 4 / 1). The mixture was stirred at 80 °C under nitrogen protection for 8 h. After the starting material was consumed, water (10 mL) was added, and the mixture was extracted twice with DCM (10 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 (EA / PE = 0 / 1 to 1 / 4, silica gel-CS20 g, 30 mL / min, silica gel, UV 254) to give a yellow oily product (365 mg, yield 82.8%).

[0298] ESI-MS m / z calcd for [C 27 H 33 [N5O4][M-56+H] + :492.3; found:436.4

[0299] 2.2

[0300] 7-(cyclopropylmethyl)-3-methyl-1-(4-(1,2,3,6-tetrahydropyridin-4-yl)benzyl)-1H-purine-2,6(3H,7H)-dione (06007-2)

[0301] TFA (0.2 mL) was added to a solution of tert-butyl 4-(4-((7-(cyclopropylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.20 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the crude product was used directly for the next reaction.

[0302] ESI-MS m / z calcd for [C 22 H 25 [N5O2][M+H] + :392.2; found:392.3

[0303] 2.3

[0304] (R)-7-(cyclopropylmethyl)-1-(4-(1-(4-((1-hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)benzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (MX06007)

[0305] To a solution of 7-(cyclopropylmethyl)-3-methyl-1-(4-(1,2,3,6-tetrahydropyridin-4-yl)benzyl)-1H-purine-2,6(3H,7H)-dione (94 mg, 0.21 mmol), (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (60 mg, 0.21 mmol) and DIEA (135 mg, 1.05 mmol) were added to DMF (3 mL). The mixture was stirred at 80 °C under nitrogen protection 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 obtain a white solid product (11.43 mg, yield 8.48%).

[0306] ESI-MS m / z calcd for [C 33 H 38 N8O4S][M+H]+:643.3; found:643.3

[0307] 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),7.38(d,J=7.6Hz,3H),6.28(d,J=8.0Hz,2H),6.21(s,1H ),5.05–5.04(m,2H),4.84(t,J=5.6Hz,1H),4.33–4.31(m,2H),4.11(d,J=7.2Hz,2H),3.96(t ,J=5.6Hz,2H),3.75–3.73(m,2H),3.46–3.38(m,5H),3.26–3.17(m,1H),2.97–2.83(m,2H),2 .41–2.17(m,5H),1.82–1.72(m,2H),1.35–1.29(m,1H),0.52–0.46(m,2H),0.43–0.39(m,2H).

[0308] 1. Synthesis scheme:

[0309] 2. Experimental Section:

[0310] 2.1

[0311] 1-(1-(4-bromophenyl)ethyl)-7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (06008-1)

[0312] At room temperature, 1-bromo-4-(1-bromoethyl)benzene (240 mg, 0.91 mmol) and Cs₂CO₃ (595 mg, 1.82 mmol), TBAI (33 mg, 0.09 mmol) were added to a DMF (5.0 mL) solution of 7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (200 mg, 0.91 mmol). The mixture was then stirred at 50 °C for 2 h. After the starting material was consumed, water (10 mL) was added, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 4, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give a yellow oily product (362 mg, yield 98.7%).

[0313] ESI-MS m / z calcd for [C 18 H 19 BrN4O2][M+H] + :403.0; found:405.3

[0314] 2.2

[0315] 4-(4-(1-(7-(cyclopropylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (06008-2)

[0316] To a solution of 1-(1-(4-bromophenyl)ethyl)-7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (300 mg, 0.75 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (461 mg, 1.49 mmol), K₂CO₃ (205 mg, 1.49 mmol), and Pd(dppf)Cl₂ (30 mg, 0.04 mmol) were added to 1,4-dioxane / water (10 mL, v / v = 4 / 1). The mixture was stirred at 80 °C under nitrogen protection for 8 h. After the starting material was consumed, water (10 mL) was added, and the mixture was extracted twice with DCM (10 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 (EA / PE = 0 / 1 to 1 / 4, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give a yellow oily product (372 mg, yield 98.2%).

[0317] ESI-MS m / z calcd for [C 28 H 35 [N5O4][M-56+H] + :506.2; found:449.8

[0318] 2.3

[0319] 7-(cyclopropylmethyl)-3-methyl-1-(1-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)-1H-purine-2,6(3H,7H)-dione (06008-3)

[0320] TFA (0.3 mL) was added to a solution of tert-butyl 4-(4-(1-(7-(cyclopropylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.25 mmol) in DCM (3 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the crude product was used directly for the next reaction.

[0321] ESI-MS m / z calcd for [C 23 H 27 [N5O2][M+H] + :406.2; found:406.2

[0322] 2.4

[0323] 7-(cyclopropylmethyl)-1-(1-(4-(1-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (MX06008)

[0324] To a solution of 7-(cyclopropylmethyl)-3-methyl-1-(1-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)-1H-purine-2,6(3H,7H)-dione (85 mg, 0.21 mmol) in DMF (3 mL), (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (60 mg, 0.21 mmol) and DIEA (135 mg, 1.05 mmol) were added. The mixture was stirred at 80 °C under nitrogen protection 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 (15.86 mg, yield 11.52%).

[0325] ESI-MS m / z calcd for [C 34 H 40 N8O4S][M+H]+:657.3; found:656.7

[0326] 1H NMR (400MHz, DMSO-d6) δ8.13(s,1H),7.59(br,1H),7.38(d,J=8.4Hz,2H),7.25(d,J=8.4Hz, 2H),6.22–6.20(m,2H),4.34–4.31(m,2H),4.09(d,J=7.2Hz,2H),3.96(t,J=5.6Hz,2H),3.80 –3.65(m,4H),3.54–3.38(m,5H),3.27–3.20(m,1H),3.03–2.96(m,1H),2.92–2.87(m,1H),2. 38–2.18(m,4H),1.82–1.75(m,5H),1.31–1.29(m,1H),0.51–0.49(m,2H),0.41–0.40(m,2H).

[0327] 1. Synthesis scheme:

[0328] 2. Experimental Section:

[0329] 2.1

[0330] tert-Butyl 4-(4-((7-(cyclopropylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)phenyl)piperidine-1-carboxylic acid ester (06018-1)

[0331] Pd / C (20 mg) was added to a methanol (5 mL) solution of tert-butyl 4-(4-((7-(cyclopropylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid ester (100 mg, 0.20 mmol). The mixture was stirred for 48 hours under a hydrogen atmosphere. After filtration, the reaction solution was concentrated to give a yellow solid product, which was used directly in the next reaction step.

[0332] ESI-MS m / z calcd for [C 27 H 35 [N5O4][M-55] + 438.3; found: 438.2

[0333] 2.2

[0334] 7-(cyclopropylmethyl)-3-methyl-1-(4-(piperidin-4-yl)benzyl)-1H-purine-2,6(3H,7H)-dione (06018-2)

[0335] Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl 4-(4-((7-(cyclopropylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)phenyl)piperidin-1-carboxylic acid ester (100 mg, 0.20 mmol) in dichloromethane (5 mL). The mixture was stirred at room temperature for 4 hours under nitrogen protection. The mixture was then concentrated and used directly in the next reaction step.

[0336] ESI-MS m / z calcd for [C 22 H 27 [N5O2][M+H] + :394.2; found:394.2

[0337] 2.3

[0338] (R)-7-(cyclopropylmethyl)-1-(4-(1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)benzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (MX06018)

[0339] DIEA (90 mg, 0.69 mmol) was added to a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (50 mg, 0.17 mmol) and 7-(cyclopropylmethyl)-3-methyl-1-(4-(piperidin-4-yl)benzyl)-1H-purine-2,6(3H,7H)-dione (78 mg, 0.20 mmol) in DMF (3 mL). The mixture was stirred at 80 °C under nitrogen protection for 2 hours. The reaction mixture was concentrated, and the crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L HCOOH), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give a white solid product (13.16 mg, yield 11.75%).

[0340] 1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.36(s,1H),7.23–7.21(m,2H),7.18–7.16(m,2H),5.0 2(s,2H),4.85–4.78(m,3H),4.11(d,J=7.2Hz,2H),3.71(d,J=5.2Hz,2H),3.43(s,3H),3.40– 3.36(m,1H),3.23–3.16(m,1H),2.95–2.76(m,5H),2.42–2.25(m,2H),2.17–2.13(m,2H),1. 77–1.72(m,4H),1.52–1.43(m,2H),1.34–1.30(m,1H),0.52–0.48(m,2H),0.43–0.39(m,2H).

[0341] 1. Synthesis scheme:

[0342] 2. Experimental Section:

[0343] 2.1

[0344] tert-Butyl 4-(4-(methoxycarbonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid ester (06047-1)

[0345] Pd(dppf)Cl2 (469 mg, 0.64 mmol) and Cs2CO3 (6.96 g, 21.37 mmol) were added to a solution of methyl 4-iodobenzoate (2.8 g, 10.69 mmol) and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid ester (3.47 g, 11.22 mmol) in 1,4-dioxane / water (50 mL, v / v = 4:1). The mixture was stirred at 80 °C for 16 h under nitrogen protection. After cooling to room temperature, the mixture was concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 0–35%, Silica-CS 40 g, 50 mL / min, silica gel, UV 254) to give a white solid product (2.65 g, yield 78.14%).

[0346] ESI-MS m / z calcd for [C 18 H 23 NO4][M-55 + :262.2; found:262.2

[0347] 2.2

[0348] tert-Butyl 4-(4-(dideuterated hydroxymethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid ester (06047-2)

[0349] At 0 °C, LiAlD4 (317 mg, 7.56 mmol) was slowly added to a solution of tert-butyl-4-(4-(methoxycarbonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid ester (1.2 g, 3.78 mmol) in tetrahydrofuran (20 mL). The mixture was stirred for 1 hour under nitrogen protection at room temperature, and the reaction was terminated by adding sodium sulfate decahydrate (0.5 g). The mixture was concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0–50%, Silica-CS 20 g, 25 mL / min, silica gel, UV 254) to give a white solid product (688 mg, yield 62.45%).

[0350] ESI-MS m / z calcd for [C 17 H 21 [D2NO3][M-55] + :236.2; found:236.2

[0351] 2.3

[0352] tert-Butyl 4-(4-(dideuterated bromomethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid ester (06047-3)

[0353] 400 mg (1.37 mmol) of tert-butyl-4-(4-(dideuterated hydroxymethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid ester (10 mL) was added to a solution of dichloromethane with carbon tetrabromide (1.78 mmol) and triphenylphosphine (1.78 mmol). The mixture was stirred for 1 hour at room temperature under nitrogen protection, and the stirring was stopped. The reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (EA / PE = 0–50%, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to give a white solid product (244 mg, yield 50.19%).

[0354] ESI-MS m / z calcd for [C 17 H 20 D2BrNO2][M-55] + :298.1; found:298.1

[0355] 2.4

[0356] tert-Butyl 4-(4-((7-(cyclopropylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)dideuter-methyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid ester (06047-4)

[0357] Cs₂CO₃ (412 mg, 1.26 mmol) and TBAI (70 mg, 0.19 mmol) were added to a DMF (6 mL) solution of tert-butyl-4-(4-(dideuterated bromomethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid ester (224 mg, 0.63 mmol) and 7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (209 mg, 0.95 mmol). The mixture was stirred at 50 °C for 2 hours under nitrogen protection. After cooling to room temperature, the mixture was concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 0–50%, Silica-CS 20 g, 25 mL / min, silica gel, UV 254) to give a yellow solid product (113 mg, yield 36.21%).

[0358] ESI-MS m / z calcd for [C 27 H 31 D2N4O5][M-55] + 438.3; found: 438.2

[0359] 2.5

[0360] 7-(cyclopropylmethyl)-1-(dideuterium(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)methyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (06047-5)

[0361] Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl 4-(4-((7-(cyclopropylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)dideuter-methyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid ester (100 mg, 0.20 mmol) in dichloromethane (3 mL). The mixture was stirred at room temperature for 2 hours under nitrogen protection. The mixture was then concentrated and used directly for the next reaction step.

[0362] ESI-MS m / z calcd for [C 22 H 23 D2N5O2][M+H] + :394.2; found:394.2

[0363] 2.6

[0364] (R)-7-(cyclopropylmethyl)-1-(bisdeuterium(4-(1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)methyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (MX06047)

[0365] DIEA (156 mg, 1.21 mmol) was added to a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (58 mg, 0.20 mmol) and 7-(cyclopropylmethyl)-1-(dideuterium(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)methyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (79 mg, 0.20 mmol) in DMF (3 mL). The mixture was stirred at 80 °C under nitrogen protection for 2 hours. The reaction mixture was concentrated, and the crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L HCOOH), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give a white solid product (17.08 mg, yield 13.14%).

[0366] 1 H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.41–7.37(m,3H),7.29–7.27(m,2H),6.21(s,1H),4.87–4 .85(m,1H),4.33–4.30(m,2H), 4.11(d,J=7.2Hz,2H),3.96(t,J=5.2Hz,2H),3.75–3.73(m,2H), 3.46–3.38(m,5H),3.34–3.32(m,1H),3.24–3.16(m,1H),2.97–2.84(m,2H),2.38–2.29(m,2H), 2.21–2.16(m,2H),1.81–1.75(m,2H),1.34–1.30(m,1H),0.52–0.48(m,2H),0.43–0.39(m,2H).

[0367] 1. Synthesis scheme:

[0368] 2. Experimental Section:

[0369] 2.1

[0370] 1-((5-bromopyridin-2-yl)methyl)-7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (06052-1)

[0371] 7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (300 mg, 1.36 mmol) and 5-bromo-2-(chloromethyl)pyridine (337 mg, 1.64 mmol) were added to a DMF (5 mL) solution along with Cs₂CO₃ (889 mg, 2.72 mmol) and TBAI (50 mg, 0.14 mmol). The reaction mixture was stirred at 50 °C for 2 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 (PE / EA = 0%–95%, silica gel-CS 20 g, 27 mL / min, silica gel, UV 254) to give a colorless oily product (499 mg, yield 94.2%).

[0372] ESI-MS m / z calcd for [C 16 H 16 BrN5O2][M+H] + :391.2; found:391.2

[0373] 2.2

[0374] 6-((7-(cyclopropylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-tert-butyl carboxylate (06052-2)

[0375] To a solution of 1-((5-bromopyridin-2-yl)methyl)-7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (300 mg, 0.75 mmol) in 1,4-dioxane / water (6.0 mL, v / v = 5 / 1), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridin-1(2H)-carboxylic acid tert-butyl ester (257 mg, 0.83 mmol), Pd(dppf)Cl2 (28 mg, 0.03 mmol) and K2CO3 (191 mg, 1.38 mmol) were added. The mixture was stirred at 80°C under nitrogen protection for 8 hours. After the starting material was consumed, water (10 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; 1:10] = 23%, silica gel-CS 20 g, 27 mL / min, silica gel, UV 254) to obtain a colorless oily product (212 mg, yield 63.0%).

[0376] ESI-MS m / z calcd for [C 26 H 32 N6O4][M+H] + 493.3; found: 493.3

[0377] 2.3

[0378] 7-(cyclopropylmethyl)-3-methyl-1-((1',2',3',6'-tetrahydro-[3,4'-bipyridin]-6-yl)methyl)-1H-purine-2,6(3H,7H)-dione (06052-3)

[0379] Trifluoroacetic acid (0.3 mL) was added dropwise to a solution of tert-butyl 6-((7-(cyclopropylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid (140 mg, 0.29 mmol) in 3.0 mL of 1,4-dioxane under ice bath conditions. The mixture was then stirred at room temperature for 2 hours. After the starting material was consumed, the reaction solution was concentrated under reduced pressure, and the crude product was used directly in the next reaction step.

[0380] ESI-MS m / z calcd for [C 21 H 24 N6O2][M+H] + :393.4; found:393.4

[0381] 2.4

[0382] (R)-7-(cyclopropylmethyl)-1-((1'-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1',2',3',6'-tetrahydro-[3,4'-bipyridin]-6-yl)methyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (MX06052)

[0383] DIEA (0.5 mL) was added to a solution of 7-(cyclopropylmethyl)-3-methyl-1-((1',2',3',6'-tetrahydro-[3,4'-bipyridin]-6-yl)methyl)-1H-purine-2,6(3H,7H)-dione (114 mg, 0.29 mmol) in DMF (5.0 mL). After the mixture became alkaline, (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (83 mg, 0.29 mmol) was added, followed by stirring at 100 °C for 2 hours. After the starting material was consumed, water (20 mL) was added, and the mixture was extracted three times with EA (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 10, silica gel-CS 20 g, 27 mL / min, silica gel, UV 254) to give a white oily product (126.20 mg, yield 67.66%).

[0384] 1 H NMR (400MHz, DMSO-d6) δ8.54(s,1H),8.18(s,1H),7.79(d,J=8.4Hz,1H),7.42(s,1H),7.24(d,J=8 .0Hz,2H),6.32(s,1H),5.17(s,2H),4.86(t,J=5.6Hz,1H),4.35–4.34(m,2H),4.10(d,J=7.2Hz,1H ),3.97(s,2H),3.74(d,J=4.8Hz,2H),3.51–3.40(m,4H),3.24–3.17(m,1H),2.97–2.63(m,4H),2.3 8–2.30(m,2H),2.19(s,2H),1.81–1.77(m,2H),1.31(s,1H),0.50–0.49(m,2H),0.41–0.40(m,2H).

[0385] 1. Synthesis scheme:

[0386] 2. Experimental Section: Using compounds 06103-0 and R-1 as raw materials, and following the procedure in Example MX06052, compound MX06103 was obtained. The product was a white solid (72.6 mg, yield 56.1%).

[0387] 1 H NMR (400MHz, DMSO-d6) δ8.17(s,1H),7.41(s,1H),7.27(dd,J=12.0,1.2Hz,1H),7.19(dd,J=9.2,1.2Hz,1H), 7.09(t,J=8.0Hz,1H),6.31(br,1H),5.10(s,2H),4.85(t,J=5.6Hz,1H),4.34(br,2H),4.11(d,J=6.8Hz,2H) ,3.95(t,J=5.2Hz,2H),3.74(d,J=5.6Hz,2H),3.46–3.38(m,4H),3.24–3.17(m,1H),2.97–2.84(m,2H),2.51 –2.49(m,2H),2.41–2.27(m,2H),2.21–2.16(m,2H),1.81–1.72(m,2H),1.36–1.28(m,1H),0.52–0.39(m,4H).

[0388] 1. Synthesis scheme:

[0389] 2. Experimental Section: Using compounds 06107-0 and R-1 as raw materials, and following the procedure in Example MX06052, compound MX06107 was obtained. The product was a white solid (61.14 mg, yield 50%).

[0390] 1H NMR(400MHz,DMSO-d6)δ8.82(s,2H),8.19(s,1H),7.43(s,1H),6.45(s,1H),5.26(s,2H),4.85(t,J =5.4Hz,1H),4.37(brs,2H),4.10(d,J=7.2Hz,2H),3.97(t,J=5.2Hz,2H),3.74(d,J=5.2Hz,2H),3.4 5(s,3H),3.42–3.38(m,1H),3.24–3.17(m,1H),2.97–2.84(m,2H),2.54–2.51(m,2H),2.38–2.27(m, 2H),2.21–2.14(m,2H),1.81–1.75(m,2H),1.35–1.26(m,2H),0.52–0.46(m,2H),0.42–0.38(m,2H).

[0391] 2. Synthesis scheme:

[0392] 2. Experimental Section:

[0393] 2.1

[0394] 4-(4-(1-(7-(cyclopropylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (06109-1)

[0395] Pd / C (38 mg) was added to a solution of tert-butyl 4-(4-(1-(7-(cyclopropylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (358 mg, 0.71 mmol) in MeOH (10 mL). The mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure. The crude product was purified by column chromatography (EA / PE = 0–70%, silica gel-CS 40 g, 50 mL / min, silica gel, UV 254) to give a colorless oily product (359 mg, yield 99.9%).

[0396] ESI-MS m / z calcd for [C 28 H 37 [N5O4][M-56+H] + :508.2; found:452.0

[0397] 2.2

[0398] 7-(cyclopropylmethyl)-3-methyl-1-(1-(4-(piperidin-4-yl)phenyl)ethyl)-1H-purine-2,6(3H,7H)-dione (06109-2)

[0399] Under ice bath conditions, trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 4-(4-(1-(7-(cyclopropylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)phenyl)piperidin-1-carboxylate (359 mg, 0.71 mmol) in DCM (5 mL) at 0 °C. The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated, and the crude product was used directly in the next reaction step.

[0400] ESI-MS m / z calcd for [C 23 H 29 [N5O2][M+H] + 408.2; found: 408.3

[0401] 2.3

[0402] 7-(cyclopropylmethyl)-1-(1-(4-(1-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)phenyl)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (MX06109)

[0403] To a solution of 7-(cyclopropylmethyl)-3-methyl-1-(1-(4-(piperidin-4-yl)phenyl)ethyl)-1H-purine-2,6(3H,7H)-dione (284 mg, 0.70 mmol) in DMF (4 mL), (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (200 mg, 0.70 mmol) and DIEA (451 mg, 3.50 mmol) were added. The mixture was stirred at 80 °C under nitrogen protection 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 obtain a white solid product (168.82 mg, yield 36.65%).

[0404] 1 H NMR(400MHz, DMSO-d6)δ8.13(s,1H),7.35(s,1H),7.19(q,J=8.4Hz,4H),6.19–6.17( m,1H),4.85–4.79(m,3H),4.10–4.09(m,2H),3.72–3.71(m,2H),3.44–3.33(m,4H),3 .24–3.16(m,1H),2.96–2.76(m,5H),2.39–2.26(m,2H),2.17–2.13(m,2H),1.78–1.7 0(m,7H),1.53–1.44(m,2H),1.31–1.30(m,1H),0.51–0.46(m,2H),0.41–0.40(m,2H).

[0405] 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):

[0406] Example 2: PDE enzyme activity inhibition experiment of the disclosed compound

[0407] 2.1PDE4B2

[0408] The inhibitory activity of compounds on PDE4B2 enzyme was tested using the FP method. Solutions of PDE4B2 (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 and FAM-cyclic adenosine monophosphate were 0.0075 nM, 0.1 nM, and 100 nM, respectively. The positive control MX02018 (BI1015550) was used at an initial concentration of 3 μM on PDE4B2, diluted 3-fold, and applied to 10 concentration doses. The test compounds were also tested at an initial concentration of 3 μM on PDE4B2, diluted 3-fold, and applied to 10 concentration doses.

[0409] 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 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.

[0410] 2.2 PDE1A / 2A enzyme activity inhibition experiment

[0411] The inhibitory effects of the compounds on PDE1A / 2A enzyme activity were tested using the FP method. PDE1A (BPS, Cat: 60010), PDE2A (BPS, Cat: 60020) enzymes, and substrate (FAM-cyclic adenosine monophosphate) (BPS, Cat: 60201) solutions were prepared in reaction buffer (1mM DTT-contained 1×IMAP Reaction Buffer containing 0.1% BSA). The final concentrations of PDE1A, PDE2A, and FAM-cyclic guanosine monophosphate were 2 nM, 0.5 nM, and 100 nM, respectively. Positive controls Bay 60-7550 were used at an initial concentration of 100 μM for PDE1A, diluted 3-fold, and 10 doses. Positive controls Bay 60-7550 were used at an initial concentration of 100 nM for PDE2A, diluted 3-fold, and 10 doses. The initial concentration of the test compounds on PDE1A / 2A was 30 μM, diluted 3-fold, and 10 dose. The stock solution of the test compound was heated and vortexed to mix thoroughly. 6 μL of the compound was added to 54 μL of DMSO and mixed thoroughly to prepare a 1 mM starting concentration working solution. This was then serially diluted 3-fold to obtain 10 different final concentration working solutions. All reactions were carried out on 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 PDE1A / 2A enzyme solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, then incubated at 25°C for 10 min. 2.5 μL of Sub (FAM-cyclic 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. Finally, the FP signal was read using BMG (PHERAstar FSX). IC50 was obtained using GraphPad Prism software. 50 Fitting values ​​and nonlinear regression curves.

[0412] 2.3 Test Results

[0413] The test results for the exemplary compounds disclosed herein are summarized in the table below:

[0414] Note: A represents IC 50 <1nM; B represents 1nM≤IC 50 <50nM; C represents 50nM≤IC 50 <5uM

[0415] The above experimental results demonstrate that the disclosed compound possesses excellent multi-target inhibitory activity against PDE1, PDE2, and PDE4, which will contribute to the development of multi-specific targeted drugs for different patient populations. This will be particularly beneficial for improving treatment efficacy and / or reducing side effects, as well as enhancing patient compliance and quality of life.

[0416] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the protection scope of the present invention is not limited to the above exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the protection scope of the claims of this application.

Claims

Compounds represented by formula H, their racemates, stereoisomers, tautomers, isotope-labeled compounds, solvates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs: in: X1 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(=O)-NH-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene -O-, -C 2-6 imidene-, -C 2-6 -, -C ethynyl 1-6 alkeneoxy-; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo (=O), thio (=S), -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl; X2 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(=O)-NH-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene -O-, -C 2-6 imidene-, -C 2-6 -, -C ethynyl 1-6 alkeneoxy-; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 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(=O)-NH-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene -O-, -C 2-6 imidene-, -C 2-6 -, -C ethynyl 1-6 alkeneoxy-; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 1-6 Alkyl-SO2-C 1-6 Alkyl, C 1-6 Alkyl-SO-C 1-6 Alkyl, C 2-10 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl; R f Represents -X4-R3; X4 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), C 1-6 Alkyl, -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 -X5-R4; X5 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), C 1-6 Alkyl, -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 it is attached to, it forms an unsubstituted or optionally substituted group with one, two or more R atoms. d3 The following groups are substituted: C 5-20 Cycloalkenyl, C 5-20 Cycloalkyl, 3-20 membered heterocycloalkyl, 3-20 membered heterocycloalkenyl, 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 with 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 aryl thio, 5-20 membered heteroaryl thio, 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; 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; 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; Ring C is C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 membered heteroaryl, wherein C 3-20 Among cycloalkenyl and 5-20 membered heterocyclic alkenyl groups, except for those with... In addition to double bonds, the fused sites may optionally contain or not contain additional unsaturated bonds (such as double or triple bonds); R a Represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-10 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20-membered heteroaryl, C 1-6 Alkyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -OR 1.1 -COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1-10 Alkyl-COR 1.1 -COONR 1.1 -C 1-10 Alkyl-COONR 1.1 -CONOH, -C 1-10 Alkyl-CONOH, -CO-NR 1.1 -C 1-10 Alkyl-CO-NR 1.1 -CH=CHCOOR 1.1 -CO-NR 1.1 -CH2CO-NR 1.1 -CH=CHCO-NR 1.1 -NR 1.2 R 1.3 -C 1-10 Alkyl-NR 1.2 R 1.3 -SR 1.1 -C 1-10 Alkyl-SR 1.1 -SOR 1.1 -C 1-10 Alkyl-SOR 1.1 -SO2-R 1.1 -C 1-10 Alkyl-SO2R 1.1 -SO2-NR 1.2 R 1.3 or -C 1-10 Alkyl-SO2-NR 1.2 R 1.3 Each of the stated groups may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 NR 1.2 R 1.3 C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 2-10 alkenyl and C 2-10 alkynyl group; R b Represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-10 alkenyl, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkyl-5-20-membered heteroaryl, C 1-6 Alkyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -OR 1.1 -COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1-10 Alkyl-COR 1.1 -COONR 1.1 -C 1-10 Alkyl-COONR 1.1 -CONOH, -C 1-10 Alkyl-CONOH, -CO-NR 1.1 -C 1-10 Alkyl-CO-NR 1.1 -CH=CHCOOR 1.1 -CO-NR 1.1 -CH2CO-NR 1.1 -CH=CHCO-NR 1.1 -NR 1.2 R 1.3 -C 1-10 Alkyl-NR 1.2 R 1.3 -SR 1.1 -C 1-10 Alkyl-SR 1.1 -SOR 1.1 -C 1-10 Alkyl-SOR 1.1 -SO2-R 1.1 -C 1-10 Alkyl-SO2R 1.1 -SO2-NR 1.2 R 1.3 or -C 1-10 Alkyl-SO2-NR 1.2 R 1.3 Each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 NR 1.2 R 1.3 C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 Cycloalkenyl, 5-20 membered heterocyclic alkenyl, C 2-10 alkenyl and C 2-10 alkynyl group; Or, R a 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-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 -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 ; R1 represents hydrogen, deuterium, 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, 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, C 2-10 alkynyl group; R2 represents hydrogen, deuterium, 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, 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; 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, 5-20-membered heteroaryl-C 1-6 -alkyl, 3-20 membered heterocyclic -C 1-6 -alkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl, monocyclic or bicyclic C 6-20 -aryl, 5-20 membered heteroaryl and heterocyclic, which may be unsubstituted or optionally substituted with substituents selected from the following: halogen, deuterium, OH, CN, NO2, NH2, oxo (=O), thio (=S), CF3, CHF2, CH2F, O-(C 1-3 -alkyl), C 1-10- Alkyl and C 6-20- Aryl; Each R 1.2 and R 1.3 Same or different, representing H or selected from C independently. 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 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 ; R d21 Selected from chemical bonds, H, deuterium, halogens, OH, CN, NO2, oxo (=O), thio (=S), SO, SO2, unsubstituted or optionally with 1, 2 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 aryl thio, 5-20 membered heteroaryl thio, 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 ); Each R e They may be the same or different, and are independently selected from hydrogen, deuterium, halogen, OH, CN, NO2, NH2, SH, oxo (=O), thio (=S), methanesulfonyl, ethanesulfonyl, methanesulfonamide, ethanesulfonamide, carboxylic acid, C 1-6 Alkyl, O-CONH2, O-CONR 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) r 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 - NR 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 ; Each R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 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; t represents 0, 1, 2, or 3; m represents 0, 1, 2, 3, 4 or 5; n represents 0, 1, 2, 3, 4, or 5; r represents 0, 1, 2, 3, 4, or 5; For example, the compound represented by formula H has the structure shown in formula I: Wherein, the groups in Formula I, such as A, B, C, X1, X2, X3, R, etc. a R b R e R f R g R1, R2, R d21 R d22 v, m, n have the definitions described above; U represents -(CH2) t -、O、S、NR q S(=O), S(=O)2 or C(=O)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 ; Each R d21 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 aryl thio, 5-20 membered heteroaryl thio, 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 membered heteroaryl, 3-20 membered heterocyclic; v represents 0, 1, 2, 3, 4, or 5. The compound of claim 1, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug, wherein: Preferably, the heterocyclic group represents 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 bicyclic ring can be... It is any fused ring or bridged ring; heterocyclic alkenyl represents a 3-11 member monocyclic or bicyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, containing 1, 2 or more double bonds, wherein the bicyclic ring can be any fused ring or bridged ring; heterocyclic alkynyl represents a 3-11 member monocyclic or bicyclic ring containing 1, 2 or 4 heteroatoms independently selected from N, S or O, containing 1, 2 or more triple bonds, wherein the bicyclic ring can be any optional fused ring or optional bridged ring; Preferably, the heteroaryl group represents a 5-10 member monocyclic or bicyclic aromatic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, wherein the bicyclic group can be any fused ring; "Single ring or multiple rings" means single ring, two rings (such as fused ring, spiral ring, bridged ring), three rings or more rings; Preferably, R f R g Together with the pyrimidine group attached thereto, it forms like Preferably, the halogen-substituted alkyl group is selected from monohalogenated, dihalogenated, trihalogenated, or more halogenated C4 groups. 1-6 Alkyl groups, such as -CF3, -CHF2, -CH2F. The compound of claim 1 or 2, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein A is selected from the following groups: in, "--" represents a chemical bond. The compound, racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug as described in any one of claims 1-3, wherein B is selected from the following groups: in, "--" represents a chemical bond. The compound, racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug as described in any one of claims 1-4, wherein Selected from the following groups: in, "--" represents a chemical bond; Preferably, Selected from the following groups: The compound of claim 1, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug, wherein the compound of formula H is selected from the following compounds: A method for preparing the compound of any one of claims 1-6, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein the method comprises reacting a compound of formula H1 with a compound of formula H2 to obtain a compound of formula H: in, LG is a leaving group, such as Cl, Br or I; Other groups such as A, B, C, X1, X2, X3, R a R b R e R f R g R1, R2, R5, R6, R d21 m and n independently have the definitions described in any one of claims 1-6; Optionally, the preparation method further includes the step of forming the compound represented by formula H into its racemic, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug by a known method. 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: Wherein, LG is a leaving group, such as Cl, Br or I; A, B, C, X1, X2, X3, U, R a R b R e R f R g R1, R2, R d21 R d22 v, m, and n each have the definition as described in any one of claims 1-6; Optionally, the preparation method further includes the step of forming the compound of Formula I into its racemic, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug by known methods. A pharmaceutical composition comprising 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. Optionally, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients. A method for preventing or treating a disease mediated by at least two or three of PDE1, PDE2, and PDE4, 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. The method of claim 9, wherein the disease includes, but is not limited to, at least one selected from the following: inflammatory respiratory diseases, inflammatory bowel disease (Crohn's disease, ulcerative colitis), arthritic diseases, inflammatory dermatitis, psoriasis, atopic dermatitis and other inflammatory skin diseases, rheumatoid arthritis (RA), inflammatory eye diseases, diseases of the peripheral or central nervous system, degenerative diseases of the central nervous system, Alzheimer's disease (AD), Parkinson's disease, schizophrenia, depression (such as major depressive disorder (MDD)), bipolar disorder, non-alcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), hepatic fibrosis (HF), idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), renal fibrosis, and benign prostatic hyperplasia. Hyperplasia (BPH), gastroesophageal reflux disease, obstructive sleep apnea, coronary artery disease, heart failure (HF), hypertension, ischemic heart disease, atherosclerosis, liver fibrosis, cirrhosis, systemic sclerosis (scleroderma), diabetic nephropathy, cancer-related solid tumors (such as lung cancer, colorectal cancer, pancreatic cancer), glioblastoma, brain tumors, leukemia and lymphoma, and obesity associated with metabolic disorders.

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