Aminopyrimidine derivative, and pharmaceutical composition thereof and use thereof

Abstract

The present disclosure provides a compound represented by formula I, or a racemate, stereoisomer, tautomer, isotopically labeled compound, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug thereof. The compound of the present disclosure has excellent PDE4B inhibitory activity, particularly selective PDE4B inhibitory activity, and especially selective PDE4B / 4D inhibitory activity, and can be used for the treatment of inflammatory respiratory diseases, inflammatory bowel diseases, arthritic diseases, inflammatory skin diseases, inflammatory eye diseases and diseases of the peripheral or central nervous system, or cancers. In addition, the compound of the present disclosure also has specific tissue distribution and / or low hERG inhibition, and thus has promising prospects for tissue-targeted drug application and reduced tissue toxicity.

Description

Aminopyrimidine 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 28, 2025 with the China National Intellectual Property Administration, application number 202510384819.0, entitled "Aminopyrimidine 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 PDE4B inhibitors, pharmaceutical compositions thereof, and uses, and belongs to the field of chemical pharmaceuticals. Background Technology

[0003] Fibrosis is a general term for a large group of diseases that can occur in almost all human tissues. Fibrotic tissues and organs gradually lose their normal function, severely impacting patients' quality of life and even endangering their lives. Taking pulmonary fibrosis as an example, fibrotic tissue loses its original elasticity, making it increasingly difficult for the lungs to expand and contract during breathing, thus reducing lung capacity and severely weakening the patient's mobility.

[0004] Idiopathic pulmonary fibrosis (IPF) is a progressive pulmonary fibrosis disease. This type of pulmonary fibrosis progresses rapidly and can lead to death within a few years, even shorter than the survival time of many cancer patients. Due to the gradual worsening of pulmonary fibrosis and the unpredictable nature of disease progression, IPF patients suffer unimaginable "dysphagia" and may die from respiratory failure and / or heart failure at any time. Furthermore, because the vast majority of IPF patients present with atypical clinical manifestations, it is easily missed and often misdiagnosed as chronic obstructive pulmonary disease, bronchial asthma, or other lung diseases. The median survival time after a diagnosis of IPF is only 2.5 to 5 years.

[0005] In China, the European Union, the United States, and Japan, IPF is defined as a rare disease, with approximately 3 million people worldwide affected. The disease primarily affects individuals over 50 years of age, and is more prevalent in men than women. Large-scale epidemiological studies on the incidence of IPF in China are not yet publicly available. Given China's large population, the disease burden of IPF on individuals, families, society, and public health resources remains significant.

[0006] 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.

[0007] Although preclinical evidence suggests that PDE4 inhibitors are associated with anti-inflammatory and anti-fibrotic effects, potentially reducing inflammation and fibrotic remodeling in lung disease, many PDE4 inhibitors have caused gastrointestinal side effects due to their selectivity differences, leading to the termination of clinical trials. Therefore, there is a need to develop PDE4B inhibitors that exhibit better selectivity and / or lower gastrointestinal side effects.

[0008] Invention Overview

[0009] To address the aforementioned technical problems, this disclosure provides compounds of Formula I, their racemates, stereoisomers, tautomers, isotope labels, solvates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs:

[0010] R f R g R h R i They are either hydrogen or deuterium, each independently.

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

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

[0013] Ring A is -C 3-20 cycloalkyl-, -C 3-20 Cycloalkenyl-, -3-20 heterocyclic alkyl-, -5-20 heterocyclic alkenyl-, -C 6-20 Aryl-, -5-20 heteroaryl-, -C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20Cycloalkyl-5-20 heteroaryl-,-3-20 heterocycloalkyl-C 6-20 aryl-,-3-20 heterocyclic alkyl-, 5-20 heteroaryl-,-5-20 heterocyclic alkenyl-, C 6-20 aryl-,-5-20 heterocyclic alkenyl 5-20 heteroaryl-,-C 5-20 cycloalkenyl-C 6-20 Aryl-, -C 5-20 Cycloalkenyl 5-20 heteroaryl-, -3-20 heterocycloalkyl 5-20 heteroaryl-C 3-20 cycloalkyl-;

[0014] Ring B is 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;

[0015] R a Represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-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-,-OR1.1 -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 and NR 1.2 R 1.3 ;

[0016] R b Represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-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-,-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 1-10Alkyl-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 and NR 1.2 R 1.3 ;

[0017] R c -YZ;

[0018] Y represents chemical bond, -O-, -S-, -NR q -, -S(=O)-, -S(=O)2-, -C(=O-), and the following groups without substitution or with optional substitution: -C 1-6 Alkylene -C(=O)-NH-, -C(=O)-NH-C 1-6 Alkylene-, -C(=O)-NH-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene-O-, C 2-6 imidene group, C 2-6 Ethyne group, C 1-6 Alkyloxy; 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;

[0019] Each Z is the same or different, and independently represents hydrogen, deuterium, and C. 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, -3-20-membered heterocycloalkyl-C 6-20 Aryl, 3-20 membered heterocyclic alkyl-C 6-20 aryl-, 3-20-membered heterocyclic alkyl-5-20-membered heteroaryl, 3-20-membered heterocyclic alkyl-5-20-membered heteroaryl-, -5-20-membered heterocyclic alkenyl-C 6-20 Aryl, 5-20 membered heterocyclic alkenyl-C 6-20 aryl-, -5-20-membered heterocyclic alkenyl-5-20-membered heteroaryl, 5-20-membered heterocyclic alkenyl-5-20-membered heteroaryl-, -C 5-20 Cycloalkenyl-C 6-20 Aryl, C 5-20 Cycloalkenyl-C 6-20 Aryl-, -C 5-20 Cycloalkenyl-5-20 heteroaryl, C 5-20 cycloalkenyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 cycloalkyl 5-20-membered heteroaryl, C 3-20 Cycloalkyl 5-20-membered heteroaryl-, -3-20-membered heterocycloalkyl 5-20-membered heteroaryl-, -3-20-membered heterocycloalkyl- 6-20 Aryl, 3-20 membered heterocyclic alkyl benzo[C] 6-20 aryl-, -3-20-membered heterocyclic alkyl 5-20-membered heteroaryl, 3-20-membered heterocyclic alkyl 5-20-membered heteroaryl-, -5-20-membered heterocyclic alkenyl decyl 6-20 Aryl, 5-20 membered heterocyclic alkenyl benzo[C] 6-20 aryl-, -5-20 quinone heterocyclic alkenyl 5-20 quinone heteroaryl, 5-20 quinone heterocyclic alkenyl 5-20 quinone heteroaryl-, -C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 cycloalkenyl-C 6-20 Aryl-, -C 5-20 Cycloalkenyl 5-20 quinone heteroaryl, C 5-20 cycloalkenyl 5-20-membered heteroaryl-, wherein each C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20The aryl and 5-20 membered heteroaryl groups can be independently monocyclic or polycyclic; the above groups can be unsubstituted or arbitrarily substituted at the ortho, para, meta, or N, O, and S atoms, each optionally substituted by one, two, or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 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-membered heteroaryl, C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 Cycloalkyl-5-20-membered 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 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 1-10Alkyl-SO2R 1.1 or SO2-NR 1.2 R 1.3 And each of the substituents may be unsubstituted or optionally further substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, OH, OR 1.1 Halogenated, oxo-substituted, thio-substituted, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- Aryl and NR 1.2 R 1.3 ;

[0020] T stands for C, chemical bond, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, or 5-20 membered heterocyclic alkenyl;

[0021] R1 indicates absence, hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-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-,-OR 1.1 -COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1-10 Alkyl-COR 1.1 -COONR1.1 -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 and NR 1.2 R 1.3 ;

[0022] R1 ’ Indicates non-existence, hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C6-20 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-,-OR 1.1 -COOR 1.1 -C 1-10 Alkyl-COOR 1.1 -COR 1.1 -C 1-10 Alkyl-COR 1.1 -COONR 1.1 -C 1-10 Alkyl-COONR 1.1 -CONOH, -C 1-10 Alkyl-CONOH, -CO-NR 1.1 -C 1-10 Alkyl-CO-NR 1.1 -CH=CHCOOR 1.1 -CO-NR 1.1 -CH2CO-NR 1.1 -CH=CHCO-NR 1.1 -NR 1.2 R 1.3 -C 1-10 Alkyl-NR 1.2 R 1.3 -SR 1.1 -C 1-10 Alkyl-SR 1.1 -SOR 1.1 -C 1-10 Alkyl-SOR 1.1 -SO2-R 1.1 -C 1-10 Alkyl-SO2R 1.1 -SO2-NR 1.2 R 1.3 or -C 1-10 Alkyl-SO2-NR 1.2 R 1.3Each of the stated groups may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 6-20- aryl, OR 1.1 and NR 1.2 R 1.3 ;

[0023] The condition is that when T is a chemical bond, R1 and R1 ’ It does not exist;

[0024] Or, R1 and R1 ’ Together they represent oxygenation and carbon. 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 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 1.1CH = CHCOOR 1.1 CO-NR 1.1 CH2CO-NR 1.1 CH=CHCO-NR 1.1 NR 1.2 R 1.3 C 1-10 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 ;

[0025] 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;

[0026] R1.2 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: OH, deuterium, halogen, C 1-6 Alkyl, C 6-20- Aryl and COOR 1.1 ;

[0027] Or, R 1.2 and R 1.3 Together with the atoms attached thereto, a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or bridged heterocycle is formed, comprising 1, 2, 3 or 4 independent heteroatoms selected from N, S or O. The heterocycle may be unsubstituted or optionally substituted at the ortho, para, or meta positions 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-NR1.1 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 .

[0028] 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;

[0029] 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;

[0030] According to embodiments of the present invention, "single ring or multiple rings" means single ring, two rings (or "double rings", such as fused rings, spiral rings, bridge rings), three rings or more rings.

[0031] 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.

[0032] According to an embodiment of the present invention, T represents C or a chemical bond.

[0033] According to embodiments of the present invention, examples of ring A may be selected from the following groups:

[0034] In this context, "--" represents a chemical bond.

[0035] According to embodiments of the present invention, examples of ring B may be selected from the following groups:

[0036] In this context, "--" represents a chemical bond.

[0037] According to embodiments of this disclosure, the compound of formula I may be selected from the following compounds:

[0038] 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:

[0039] And optionally, the compound of formula I may be derived into its stereoisomers, tautomers, isotopic labels, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs;

[0040] Wherein, LG is a leaving group, such as Cl, Br or I;

[0041] R1, R1', R a R b R c R f R g R h R i A, B, and T each have the definitions described above independently.

[0042] According to embodiments of this disclosure, the reaction can be carried out with protecting groups affixed to compounds of formula S1 and S2, if desired. For example, the protecting group can be selected from amino protecting groups, hydroxyl protecting groups, etc. Suitable protecting groups can be selected from C...1-40 Alkyl, C 6-20 Aryl C 1-40 Alkyl groups, such as tert-butyl, isopropyl, benzyl, tert-butoxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenemethoxycarbonyl (Fmoc), and trifluoroacetyl.

[0043] 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.

[0044] This disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the following: a compound of Formula I, a racemic mixture, a stereoisomer, a tautomer, an isotope label, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof.

[0045] According to embodiments of this disclosure, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.

[0046] According to embodiments of this disclosure, the pharmaceutical composition may further contain one or more additional therapeutic agents. These additional therapeutic agents may be selected from therapeutic agents having the same or different targets as the compounds of this disclosure, such as cancer therapeutic agents.

[0047] This disclosure also provides the use of at least one of the compounds of Formula I, their racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds in the preparation of pharmaceuticals.

[0048] The drug can be used to prevent or treat diseases.

[0049] The present invention also provides a method for preventing or treating a disease, comprising administering to a patient in need at least one of a compound of Formula I, a racemic mixture, a stereoisomer, a tautomer, an isotope label, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof.

[0050] According to an embodiment of the present invention, the disease may be a PDE4-mediated disease, particularly a PDE4B-mediated disease.

[0051] For example, the drug can be used to prevent or treat diseases mediated by PDE4 (such as PDE4B).

[0052] According to embodiments of the present invention, the diseases include, but are not limited to, inflammatory diseases of the respiratory tract, inflammatory bowel disease, arthritic diseases, inflammatory diseases of the skin, inflammatory diseases of the eyes, diseases of the peripheral or central nervous system, degenerative diseases of the central nervous system, Alzheimer's disease (AD), non-alcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF) or related pulmonary hypertension, chronic obstructive pulmonary disease (COPD) or related pulmonary hypertension, hepatic fibrosis (HF), renal fibrosis, benign prostatic hyperplasia (BPH), gastroesophageal reflux disease, obstructive sleep apnea, and coronary artery disease or cancer.

[0053] According to embodiments of the present invention, the cancer includes, but is not limited to, one of the following: stomach cancer, bladder cancer, leukemia, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, external genital cancer, urogenital tract cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosa cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, testicular cancer, and / or thyroid cancer.

[0054] According to embodiments of the present invention, since the compounds of this disclosure have specific tissue distribution and / or low hERG inhibitory effects, the diseases are preferably selected from those diseases that are particularly advantageous for prevention or treatment with compounds having specific tissue distribution and / or low hERG inhibitory effects.

[0055] For example, the lesions (i.e., the parts where the disease occurs) of the disease include the respiratory, digestive, excretory, and / or reproductive systems, such as the liver, kidneys, and / or prostate. For this purpose, the drug can be a targeted drug for the respiratory, digestive, excretory, and / or reproductive systems, such as a liver-targeting drug, a kidney-targeting drug, and / or a prostate-targeting drug.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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

[0068] The disclosed compounds exhibit excellent PDE4B inhibitory activity, especially selective PDE4B inhibitory activity, particularly selective PDE4B / 4D inhibitory activity.

[0069] The disclosed compounds can be used to treat inflammatory diseases of the respiratory tract, inflammatory bowel disease, arthritic diseases, inflammatory skin diseases, inflammatory eye diseases, and diseases or cancers of the peripheral or central nervous system. Furthermore, the disclosed compounds exhibit specific tissue distribution and / or low hERG inhibition, thus showing promising potential for tissue-targeted drug applications and improved tissue toxicity.

[0070] Terminology Definitions and Explanations

[0071] 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.

[0072] 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.

[0073] 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.

[0074] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0075] 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.

[0076] 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 ... 2-3Alkenyl). 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.

[0077] Term "C" 2-20 "Alkyne group" should be understood as representing a straight-chain or branched monovalent hydrocarbon group containing one, two, or more triple bonds and having 2 to 20 carbon atoms, preferably "C". 2-10 "Alkyne group". The term "C" 2-10 "Alkyne" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one, two or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., "C"). 2-6 The alkynyl group ("C") has 2 or 3 carbon atoms ("C") 2-3The alkynyl group is, for example, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynyl, 1-methylprop-2-alkynyl, 2-methylbut-3-alkynyl, 1-methylbut-3-alkynyl, 1-methylbut-2-alkynyl, 3-methylbut-1-alkynyl, 1-ethylprop-2-alkynyl, 3-methylpent-4-alkynyl, 2-methylpent-4-alkynyl, 1-methylpent-4-alkynyl -Alynyl, 2-methylpentan-3-ynyl, 1-methylpentan-3-ynyl, 4-methylpentan-2-ynyl, 1-methylpentan-2-ynyl, 4-methylpentan-1-ynyl, 3-methylpentan-1-ynyl, 2-ethylbutan-3-ynyl, 1-ethylbutan-3-ynyl, 1-ethylbutan-2-ynyl, 1-propylpropan-2-ynyl, 1-isopropylpropan-2-ynyl, 2,2-dimethylbutan-3-ynyl, 1,1-dimethylbutan-3-ynyl, 1,1-dimethylbutan-2-ynyl, or 3,3-dimethylbutan-1-ynyl. In particular, the ynyl group is ethynyl, propan-1-ynyl, or propan-2-ynyl.

[0078] 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.

[0079] 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.

[0080] 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;

[0081] 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.

[0082] 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.

[0083] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0084] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0085] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms.

[0086] 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.

[0087] 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

[0088] 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.

[0089] 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;

[0090] Those skilled in the art will understand that the compounds shown in Formula I can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] "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 36C1. 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.

[0097] 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.

[0098] 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.

[0099] 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).

[0100] Unless otherwise defined, in the compounds of Formula I within the context of this disclosure, when some substituents are defined as two or more connected groups (e.g., "group 1-group 2", "group 1-group 2-group 3", "group 1 with group 2", "group 1 with group 2 with group 3", where group 1, group 2, and group 3 are the same as or different from each other), the position where the substituents form bonds in the compounds of Formula I is not particularly limited. For example, group 1, group 2, or group 3 (if present) may each be bonded to a connecting position in the compounds of Formula I, as long as the bonding conforms to valence bond theory. Furthermore, the connection position between the two connected groups (e.g., group 1 and group 2, group 2 and group 3) is not particularly limited, as long as the connection conforms to valence bond theory.

[0101] It should be understood that for the above forms “group 1-group 2”, “group 1-group 2-group 3”, “group 1-group 2”, “group 1-group 2-group 3”, if a chemical bond “-” is added only to the left or right of a group, it means that its connection position in the compound of formula I has been determined as the group at the added “-” position.

[0102] For example, for -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-C 6-20 Aryl-, -C 1-6 Alkylene -C(=O)-NH-, -C(=O)-NH-C 1-6 Alkylene groups, etc., indicate the position of the group containing the "-" in the structure of compound I. For 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 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20 heteroaryl-,-3-20 heterocycloalkyl-C 6- 20 aryl-,-3-20 heterocyclic alkyl-, 5-20 heteroaryl-,-5-20 heterocyclic alkenyl-, C 6-20 aryl-,-5-20 heterocyclic alkenyl 5-20 heteroaryl-,-C 5-20 cycloalkenyl-C 6-20 Aryl-, -C 5-20 Cycloalkenyl 5-20 heteroaryl-, -3-20 heterocycloalkyl 5-20 heteroaryl-C 3-20 cycloalkyl-, C3-20 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-membered heteroaryl groups, with groups on either side capable of bonding to the linking positions in the compound.

[0103] For example, when both sides of a group in the context of this application are drawn with "--" representing chemical bonds, it means that either side can combine with other groups in the structure of Formula I. For example, each structure in the group specifically exemplified by group A (including but not limited to) (etc.), either side of which can be -NH- from compound I or with R1 and R 1’ The carbon atoms that are linked together are bonded; or, each structure in the group of a specific example of group B (including but not limited to) (etc.), either side of which can be R in compound I. c Or it may be combined with a pyrimidine group. Detailed Implementation

[0104] 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.

[0105] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0106] Abbreviations: DMF: N,N-dimethylformamide; DCM: dichloromethane; DIEA: N,N-diisopropylethylamine; TEA: triethylamine; PE: petroleum ether; EA: ethyl acetate; MeCN: acetonitrile; Et2O: diethyl ether; DMSO: dimethyl sulfoxide; EtOAc: ethyl acetate; THF: tetrahydrofuran; TFA: trifluoroacetic acid; MeOH: methanol; EtOH: ethanol; NaH: sodium hydride; MeI: iodomethane; EtI: ethane iodide; HFP: 1,1,1,3,3,3-hexafluoro-2-propanol; DHP: 3,4-dihydro-2H-pyran; PPTS: pyridine 4-methylbenzenesulfonate; PPh3: triphenylphosphine; DEAD: diethyl azodicarbonate; MsCl: methanesulfonyl chloride; TMSOTf: trimethylsilyl trifluoromethanesulfonate; m-CPBA: m-chloroperoxybenzoic acid

[0107] Analytical methods

[0108] 1. Nuclear magnetic resonance (NMR) spectra were recorded using a 400 MHz British Brär AVANCE III 500 instrument. Chemical shifts were reported in ppm using the tritium-substituted residual solvent as an internal standard. Peak magnifications are expressed as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; dt, triplet of doublet; q, tetrodot; m, multiplet; br s, broad singlet.

[0109] 2. The purity analysis of the samples was performed on a Waters HPLC / Waters MS system.

[0110] Chromatographic conditions 1:

[0111] Chromatographic column: Waters X-Bridge-C18 50mm*4.6mm*3.5μm

[0112] The column temperature was 40℃.

[0113] Sample temperature: room temperature

[0114] Detection of UV 214 nm and UV 254 nm

[0115] Flow rate: 2 mL / min.

[0116] Mobile phase A: Water (0.05% TFA)

[0117] Mobile phase B: MeCN (0.05% TFA)

[0118] Gradient program: B from 5% to 100% takes 1.6 minutes, and 100% is held for 1.4 minutes.

[0119] Chromatographic conditions 2:

[0120] Chromatographic column: Waters X Brdige C18 (4.6mm x 50mm x 3.5μm)

[0121] The column temperature was 40℃.

[0122] Sample temperature: room temperature

[0123] Detection of UV 214 nm and UV 254 nm

[0124] Flow rate: 2 mL / min.

[0125] Mobile phase A: Water (0.01 mol / L NH4HCO3) B: MeCN

[0126] Mobile phase B: MeCN

[0127] Gradient program: B from 5% to 100%, for 1.6 minutes, then hold at 100% for 1.4 minutes.

[0128] 3. Preparative HPLC was performed on a Gilson 281.

[0129] Flow rate: 20 mL / min.

[0130] Chromatographic column: X-Select 10μm 19*250mm column

[0131] Wavelength: 254 nm or 214 nm

[0132] Solvent A: Water (10 mM NH4HCO3) and Solvent B: MeCN.

[0133] Example 1: Synthesis Example

[0134] 1. Synthesis scheme:

[0135] 2. Experimental Section:

[0136] 2.1

[0137] (R)-2-(4-((2-(5-chlorothiophen-2-yl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)methyl acetate (02159-1)

[0138] Methyl (R)-2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (70 mg, 0.19 mmol), (5-chlorothieno-2-yl)boronic acid (30.59 mg, 0.19 mmol), RuPhosPdG2 (13.88 mg, 0.02 mmol), K3PO4 (120 mg, 0.57 mmol), and water (0.5 mL) in 1,4-dioxane (4 mL) were stirred at 85 °C under argon protection for 4 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent, and the crude product was purified by column chromatography (DCM / MeOH = 0–1 / 10, silica gel-CS12 g, 20 mL / min, silica gel, UV 254) to give a yellow solid product (45 mg, yield 52.9%).

[0139] ESI-MS m / z calcd for [C 19 H 15 ClFN3O3S2][M+H] + 452.0; found: 452.2

[0140] 2.2

[0141] (R)-2-(4-((2-(5-chlorothiophen-2-yl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX02159)

[0142] Methyl (R)-2-(4-((2-(5-chlorothiophene-2-yl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (40 mg, 0.09 mmol) was added to a MeOH / THF solution (3 mL, v / v = 1 / 1) to adjust the pH of the reaction mixture to 12. The mixture was stirred at room temperature for 3 hours under nitrogen protection. After the starting material was consumed, the pH of the mixture was adjusted to 6 with a 1N HCl aqueous solution. The mixture was then concentrated, and the crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give a white solid product (17.06 mg, yield 44.0%).

[0143] ESI-MS m / z calcd for [C 18 H 13 ClFN3O3S2][M+H] +438.0; found: 437.7

[0144] 1 H NMR (400MHz, DMSO-d6) δ10.02(br,1H),7.75(d,J=4.0Hz,1H),7.67(dd,J=12.4,2.0Hz,1H),7.53(dd,J=8.4,2.0Hz,1H),7.34( t,J=8.8Hz,1H),7.27(d,J=4.0Hz,1H),3.77–3.68(m,1H),3.57(s,2H),3.47–3.40(m,1H),3.34–3.28(m,1H),3.16–3.11(m,1H)

[0145] Example 2: Synthesis Example

[0146] 1. Synthesis scheme:

[0147] 2. Experimental Section:

[0148] 2.1

[0149] 2-(2-fluoro-4-nitrophenyl)tert-butyl acetate (021120-1)

[0150] At 0 °C, tert-butanol (185.93 g, 2.51 mol), pyridine (100.50 g, 1.25 mol), and phosphorus oxychloride (50.63 g, 326.62 mmol) were added to a solution of 2-(2-fluoro-4-nitrophenyl)acetic acid (50 g, 251.25 mmol) in chloroform (500 mL). The mixture was then stirred overnight at room temperature until the starting material was consumed. The reaction solution was concentrated, and the crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 1, silica gel-CS120 g, 80 mL / min, silica gel, UV 254) to give a yellow solid product (60.0 g, yield 93.6%).

[0151] ESI-MS m / z calcd for [C 12 H 14 FNO3][MH] + :254.1; found:254.2

[0152] 2.2

[0153] 2-(4-amino-2-fluorophenyl)tert-butyl acetate (021120-2)

[0154] Pd / C (15 g) was added to a solution of tert-butyl 2-(2-fluoro-4-nitrophenyl)acetate (60.0 g, 235.3 mmol) in EA (500 mL). The mixture was stirred overnight at room temperature under hydrogen protection. After the starting material was consumed, the mixture was filtered and concentrated to give a yellow oily product (52.5 g, 99.1% yield).

[0155] ESI-MS m / z calcd for [C 12 H 16 FNO2][M-56+H] + :170.1; found:170.3

[0156] 2.3

[0157] 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)tert-butyl acetate (021120-3)

[0158] TEA (47.13 g, 466.6 mmol) and 2,4-dichloro-6,7-dihydrothiophene[3,2-d]pyrimidine (48.06 g, 233.3 mmol) were added to a solution of tert-butyl 2-(4-amino-2-fluorophenyl)acetate (52.5 g, 233.3 mmol) in ethanol (500 mL). The mixture was then stirred at 95 °C for 3 days, the solvent was removed by vacuum distillation, ice water (300 mL) was added, and the mixture was extracted three times with EA (300 mL). The combined organic layers were washed with saturated brine (300 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-CS120 g, 80 mL / min, silica gel, UV 254) to give a yellow solid product (52.0 g, yield 56.3%).

[0159] ESI-MS m / z calcd for [C 18 H 19 ClFN3O2S][M+H] + 396.1; found: 396.3

[0160] 2.4

[0161] (R)-2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)tert-butyl acetate (021120-4)

[0162] To a solution of 2-(4-((2-chloro-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)tert-butyl acetate (40.0 g, 101.26 mmol) and S-1,1'-bi-2-naphthol (2.89 g, 10.13 mmol) in DCM (300 mL), add tetraisopropoxide titanium (2.88 g, 10.13 mmol) and water (1.82 g, 101.26 mmol). After stirring the mixture overnight at room temperature, 70% tert-butyl hydrogen peroxide aqueous solution (13.67 g, 106.32 mmol) was added in one go. The mixture was then stirred at room temperature for 2 hours until the reaction was complete. The reaction solution was directly wet-loaded and purified by column chromatography (DCM / MeOH = 1 / 0 to 10 / 1, silica gel-CS120 g, 80 mL / min, silica gel, UV 254). The resulting orange-yellow crude solid was recrystallized from DCM / MTBE (v / v = 1 / 3) to give a yellow solid compound (34.5 g, yield 82.7%, ee = 100%).

[0163] ESI-MS m / z calcd for [C 18 H 19 ClFN3O3S][M+H] + 412.1; found: 412.0

[0164] 2.5

[0165] (R)-2-(4-((2-(5-chlorothiophen-2-yl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)tert-butyl acetate (021120-5)

[0166] To a solution of (R)-2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)tert-butyl acetate (16.0 g, 38.93 mmol) in 1,4-dioxane / water (v / v = 20 / 1, 10.5 mL), 2-(5-chlorothieno-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (9.97 g, 40.87 mmol), RuPhosPdG2 (2.99 g, 3.89 mmol) and K3PO4 (20.61 g, 97.33 mmol) were added, and the mixture was stirred overnight at 85 °C under argon protection. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography (DCM / MeOH = 0-1 / 10, silica gel-CS120g, 80mL / min, silica gel, UV 254) to obtain a yellowish-brown solid crude product. It was recrystallized twice with EA to obtain a yellow solid product (11.0g, yield 57.3%, purity 86.65%).

[0167] ESI-MS m / z calcd for [C 22 H 21 ClFN3O3S2][M+H] + 494.1; found: 493.9

[0168] 2.6

[0169] (R)-2-(4-((2-(5-chlorothiophene-2-yl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl-6,6-d2)amino)-2-fluorophenyl)tert-butyl acetate-d2(021120-6)

[0170] To a solution of (R)-2-(4-((2-(5-chlorothiophene-2-yl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)tert-butyl acetate (11.0 mg, 22.31 mmol), the pH of the mixture was adjusted to 12 by adding 40% NaOD in D2O solution to a MeOD (50 mL) solution. The mixture was stirred for 4 hours at room temperature under argon protection. After the starting materials were consumed, the pH of the reaction solution was adjusted to 6-7 with deuterated hydrochloric acid solution under ice bath conditions. Water (100 mL) was added, and the mixture was extracted four times with EA (100 mL). The combined organic layers were washed with saturated brine (100 mL), dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by reversed-phase column chromatography [MeCN / H2O, X-Select 10 μm 19*250 mm, 80 mL / min, UV 254] to obtain a white solid product (3.41 g, yield 30.7%, ee = 100%).

[0171] ESI-MS m / z calcd for [C 22 H 17 D4ClFN3O3S2][M+H] + 498.1; found: 498.0

[0172] 2.7

[0173] (R)-2-(4-((2-(5-chlorothiophene-2-yl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl-6,6-d2)amino)-2-fluorophenyl)-2,2-d2 acid (MX021120)

[0174] TFA (15 mL) was added to a solution of (R)-2-(4-((2-(5-chlorothiophene-2-yl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl-6,6-d2)amino)-2-fluorophenyl)tert-butyl acetate-d2 (3.41 g, 6.86 mmol) in DCM (40 mL), and the mixture was stirred at room temperature for 2 hours. After the starting material was consumed, the solvent was removed under reduced pressure, and the crude product was recrystallized from methanol to give a pale yellow solid product (1.70 g, ee = 100%, yield 56.2%).

[0175] ESI-MS m / z calcd for [C 18 H9D4ClFN3O3S2][M+H] + :442.0; found:442.0

[0176] 1 H NMR (400MHz, DMSO-d6) δ12.48(s,1H),10.26(s,1H),7.74(d,J=4.0Hz,1H),7.69(dd,J=12.4,2.0Hz ,1H),7.55(dd,J=8.4,2.0Hz,1H),7.36(t,J=8.4Hz,1H),7.27(d,J=4.0Hz,1H),3.45–3.11(m,2H).

[0177] 1. Synthesis scheme:

[0178] 2. Experimental Section:

[0179] 2.1

[0180] (R)-2-(2-fluoro-4-((2-(4-morpholinophenyl-D4)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)tert-butyl acetate (021191-1)

[0181] To a solution of (R)-2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)tert-butyl acetate (140 mg, 0.34 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl-D4)morpholine (199 mg, 0.68 mol), K2CO3 (141 g, 1.02 mmol), and Pd(PPh3)2Cl2 (24 mg, 0.03 mmol) were added. The mixture was reacted at 80 °C under nitrogen protection for 4 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography (MeOH / DCM = 0–5%, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to obtain a brown solid crude product. The crude product was washed twice with methanol to obtain a brown solid product (104 mg, yield 56.38%).

[0182] ESI-MS m / z calcd for [C 28 H 27 D4FN4O4S][M+H] + :543.2; found:543.0

[0183] 2.2

[0184] (R)-2-(2-fluoro-4-((2-(4-morpholinophenyl-D4)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid(MX021191)

[0185] TFA (1 mL) was added to a solution of (R)-2-(2-fluoro-4-((2-(4-morpholinophenyl-D4)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid tert-butyl ester (95 mg, 0.18 mmol) in DCM (3 mL). The mixture was stirred at room temperature for 16 hours. After the starting material was consumed, the solvent was removed under reduced pressure, and the crude product was washed with methanol to give a grayish-white solid product (77.17 mg, yield 90.60%).

[0186] ESI-MS m / z calcd for [C 24 H 19D4FN4O4S][M+H] + 487.2; found: 487.0

[0187] 1 H NMR (400MHz, DMSO-d6) δ12.47(s,1H),10.05(s,1H),7.76(dd,J=12.4,2.0Hz,1H),7.58(dd,J=8.4,2.0Hz,1H), 7.35(t,J=8.4Hz,1H),3.76–3.68(m,5H),3.63(s,2H),3.44–3.39(m,1H),3.29–3.26(m,5H),3.14–3.09(m,1H).

[0188] 1. Synthesis scheme:

[0189] 2. Experimental Section:

[0190] 2.1

[0191] 2-Bromo-5-chloro-3,4-Dideuteratedthiophene (021196-1)

[0192] To a solution of 2-bromo-5-chlorothiophene (400 mg, 2.03 mmol) in toluene (10 mL), D₂O (1.62 g, 81.22 mmol), Ag₂CO₃ (280 mg, 1.02 mmol), and 2-dicyclohexylphospho-2'-methylbiphenyl (372 mg, 1.02 mmol) were added sequentially. The mixture was stirred overnight in air at 100 °C. After the reaction was complete, a saturated aqueous solution of ammonium chloride (20 mL) was added to the mixture, and the mixture was extracted twice with DCM (20 mL). The organic layers were combined, washed with brine (20 mL), filtered, dried, and concentrated. The crude product was purified by column chromatography (EA / PE = 1 / 20, Silica-CS 20 g, 30 mL / min, silica gel, UV 254) to give a colorless oily product (300 mg, yield 74%).

[0193] ESI-MS m / z calcd for[C4D2BrClS][M]:198; found:198

[0194] 2.2

[0195] 2-(5-chloro-3,4-dideuteratedthiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (021196-2)

[0196] To a THF solution of 2-bromo-5-chloro-3,4-dideuterated thiophene (160 mg, 0.802 mmol) in 5 mL, a 2.5 M nBuLi THF solution (0.48 mL, 1.2 mmol) was slowly added dropwise at -78 °C. The mixture was stirred for 1 hour at -78 °C under nitrogen atmosphere. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxoborane (240 mg, 1.283 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, 20 mL of saturated NH4Cl aqueous solution was added, and the mixture was extracted twice with DCM (20 mL). The organic layers were combined, washed with brine (20 mL), filtered, dried, and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 1–1 / 10, Silica-CS 20 g, 30 mL / min, silica gel, UV 254) to give a colorless oily product (140 mg, yield 71%).

[0197] ESI-MS m / z calcd for [C 10 H 12 D2BClO2S][M]:246;found:246

[0198] 2.3

[0199] (R)-tert-butyl-2-(4-((2-(5-chloro-3,4-dideuteratedthiophene-2-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (021196-3)

[0200] 2-(5-chloro-3,4-dideuteratedthiophene-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (140 mg, 0.569 mmol) and (R)-tert-butyl-2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (234 mg, 0.569 mmol) were dissolved in a mixture of 1,4-dioxane and water (v / v 3:1, 5 mL), and PdCl2(dppf)·2DCM (46 mg, 0.0569 mmol) and K2CO3 (236 mg, 0.569 mmol) were added. The mixture was stirred at 100 °C for 2 hours under nitrogen atmosphere. After the reaction was complete, the solvent was removed, and the crude product was purified by silica gel column chromatography (MeOH / DCM = 0 / 1 to 1 / 20, silica gel-CS 20g, 20mL / min, silica gel, UV 254) to obtain a brown solid product (202mg, yield 72%).

[0201] ESI-MS m / z calcd for [C 22 H19 D2ClFN3O3S2][M+H] + 496.1; found: 495.9

[0202] 2.4

[0203] (R)-2-(4-((2-(5-chloro-3,4-dideuteratedthiophene-2-yl)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX021196)

[0204] (R)-tert-butyl-2-(4-((2-(5-chloro-3,4-dideuteratedthiophen-2-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (180 mg, 0.363 mmol) was dissolved in a TFA / DCM mixture (v / v 1:5, 5 mL), and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the crude product was subjected to preparative HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give a grayish-white solid product (57.18 mg, yield 36%).

[0205] 1 H NMR (400MHz, DMSO-d6) δ12.43(br,1H),10.24(s,1H),7.75(s,0.03H),7.69(dd,J=12.4,1.6Hz,1H),7.55(dd,J=8.4,1.6Hz,1H) ,7.36(t,J=8.4Hz,1H),7.27(s,0.03H),3.77–3.69(m,1H),3.63(s,2H),3.48–3.40(m,1H),3.34–3.28(m,1H),3.16–3.11(m,1H)

[0206] 1. Synthesis scheme:

[0207] 2. Experimental Section:

[0208] 2.1

[0209] tert-Butyl 2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (021206-1)

[0210] 2 g (5.0 mmol) of tert-butyl 2-(4-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate was dissolved in acetic acid (26 mL), and hydrogen peroxide (1.8 mL) was added. The mixture was stirred at room temperature for 2 hours. After the starting material was consumed, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic layers were combined, 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 / 0, silica gel-CS 12 g, 30 mL / min, UV 254) to give a white solid product (1.7 g, yield 81.7%).

[0211] ESI-MS m / z calcd for [C 18 H 19 ClFN3O3S][M+H] + 412.1; found: 412.2

[0212] 2.2

[0213] tert-butyl 2-(4-((2-(5-chlorothiophene-2-yl-3,4-dihydroxy-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate (021206-2)

[0214] 400 mg (1.62 mmol) of tert-butyl 2-(4-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate was dissolved in a mixed solvent of 1,4-dioxane / water (2 mL, v / v = 4:1). R-1 (657 mg, 1.62 mmol), RuPhos (75 mg, 0.162 mmol), Pd(Ph3P)2Cl2 (113 mg, 0.162 mmol), and K3PO4 (849 mg, 4 mmol) were added. The mixture was stirred overnight at 100 °C under nitrogen protection. After the starting material was consumed, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 0, silica gel-CS 12 g, 30 mL / min, UV 254) to give a white solid product (253 mg, yield 52%).

[0215] ESI-MS m / z calcd for [C 22 H 19 D2ClFN3O3S2][M+H] +496.1; found: 496.2

[0216] 2.3

[0217] 2-(4-((2-(5-chlorothiophene-2-yl-3,4-dihydroxy)-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX021206)

[0218] (S)-2-(4-((2-(5-chlorothiophene-2-yl-3,4-dihydroxy-5-oxo-6,7-dihydrothiopheno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid (MX021207)

[0219] 358 mg (0.72 mmol) of tert-butyl 2-(4-((2-(5-chlorothiophene-2-yl-3,4-dihydroxy-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-fluorophenyl)acetate was dissolved in a TFA / DCM mixture (v / v 1:5, 5 mL), and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure, and the crude product was subjected to preparative HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give a white solid product MX021206 (32 mg, yield 10%). 20 mg of this product was resolved by SFC to give a white solid product MX021207 (8 mg).

[0220] MX021206

[0221] 1 H NMR (400MHz, DMSO-d6) δ7.72(s,0.05H),7.63(dd,J=12.4,2.0Hz,1H),7.50(dd,J=8.4,1.6Hz,1H),7.31(t,J=8.8Hz,1H),7. 24(s,0.05H),3.77–3.68(m,1H),3.59(s,2H),3.47–3.40(m,1H),3.30(dd,J=17.6,8.4Hz,1H),3.13(dd,J=13.6,6.4Hz,1H)

[0222] MX021207

[0223] 1H NMR (400MHz, DMSO-d6) δ7.72(s,0.05H),7.63(dd,J=12.4,2.0Hz,1H),7.50(dd,J=8.4,1.6Hz,1H),7.32(t,J=8.8Hz,1H),7. 24(s,0.05H),3.77–3.68(m,1H),3.59(s,2H),3.47–3.40(m,1H),3.30(dd,J=17.6,8.4Hz,1H),3.13(dd,J=13.6,6.4Hz,1H)

[0224] The compounds prepared according to the above method or with reference to the above method and their mass spectrometry data are summarized in Table 1 below:

[0225] Table 1: Compounds from Examples

[0226] Example 2: PDE4B2 / PDE4D2 enzyme activity inhibition experiment

[0227] The inhibitory activity of compounds on PDE4B2 / 4D2 enzymes was tested using the FP method. Solutions of PDE4B2 / PDE4D2 (BPS, Cat:60042 / 60040) enzyme and substrate (FAM-cyclic adenosine monophosphate) (BPS, Cat:60200) were prepared in reaction buffer (1×IMAP reaction buffer containing 1 mM DTT and 0.1% BSA). The final working concentrations of PDE4B2, PDE4D2, and FAM-cyclic adenosine monophosphate were 0.0075 nM, 0.1 nM, and 100 nM, respectively. The positive control MX02018 (BI1015550) was used in PDE4B2 / PDE4D2 at an initial concentration of 3 μM, diluted 3-fold, and applied to 10 concentration doses. The test compounds were also used in PDE4B2 / PDE4D2 at an initial concentration of 3 μM, diluted 3-fold, and applied to 10 concentration doses.

[0228] The stock solution of the test compound was heated and vortexed to mix thoroughly, and a 300 μM starting concentration working solution was prepared. Then, it was serially diluted 3 times to obtain 10 different final concentration working solutions. This part of the reaction was carried out in dilution source plates. 0.05 μL of the compound diluted in 100% DMSO from the Source plate was transferred to a 384-well plate (Corning 4514) using acoustic liquid delivery technology (Echo 655). The plate was centrifuged at 1000 rpm for 1 minute to achieve a final DMSO concentration of 1%. 2.5 μL of PDE4B2 / PDE4D2 enzyme solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, then incubated at 25°C for 10 min. 2.5 μL of substrate (FAM-cyclic adenosine monophosphate) solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, then incubated at 25°C for 60 min. 15 μL of the binding agent mixture was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, then incubated at 25°C for 60 min. The FP signal was read using BMG (PHERAstar FSX), and the IC was obtained using GraphPad Prism software. 50 Fitting values ​​and nonlinear regression curves.

[0229] The activity test results of some of the compounds in the examples are summarized in Table 2 below:

[0230] Table 2: Activity test results of compounds from some examples

[0231] Note: A represents IC 50 <1nM; B represents 1nM≤IC 50 <20nM; C represents 20nM≤IC 50 <100nM; D represents ≥100nM.

[0232] The above experimental results demonstrate that the compound disclosed herein possesses excellent selective inhibitory activity against PDE4B.

[0233] 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

1. Compounds of Formula I, their racemates, stereoisomers, tautomers, isotope-labeled compounds, solvates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs: R f R g R h R i Each can be independently hydrogen or deuterium; m represents 0, 1, 2, 3, 4 or 5; n represents 0, 1, 2, 3, 4, or 5; Ring A is -C 3-20 cycloalkyl-, -C 3-20 Cycloalkenyl-, -3-20 heterocyclic alkyl-, -5-20 heterocyclic alkenyl-, -C 6-20 Aryl-, -5-20 heteroaryl-, -C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20 heteroaryl-,-3-20 heterocycloalkyl-C 6-20 aryl-,-3-20 heterocyclic alkyl-, 5-20 heteroaryl-,-5-20 heterocyclic alkenyl-, C 6-20 aryl-,-5-20 heterocyclic alkenyl 5-20 heteroaryl-,-C 5-20 cycloalkenyl-C 6-20 Aryl-, -C 5-20 Cycloalkenyl 5-20 heteroaryl-, -3-20 heterocycloalkyl 5-20 heteroaryl-C 3-20 cycloalkyl-; Ring B is 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; R a Represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-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-,-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 ;in, 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 and NR 1.2 R 1.3 ; R b Represents hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-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-,-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 and NR 1.2 R 1.3 ; R c is -Y-Z; Y represents chemical bond, -O-, -S-, -NR q -, -S(=O)-, -S(=O)2-, -C(=O-), and the following groups without substitution or with optional substitution: -C 1-6 Alkylene -C(=O)-NH-, -C(=O)-NH-C 1-6 Alkylene-, -C(=O)-NH-, -C 1-6 alkylene-, -C 1-6 Alkylene -NH-, -C 1-6 Alkylene-O-, C 2-6 imidene group, C 2-6 Ethyne group, C 1-6 Alkyloxy group; wherein, "optional substitution" means that the group is substituted by one, two or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 2-10 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl; Each Z is the same or different, and independently represents hydrogen, deuterium, and C. 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl-, -3-20-membered heterocycloalkyl-C 6-20 Aryl, 3-20 membered heterocyclic alkyl-C 6-20 aryl-, 3-20-membered heterocyclic alkyl-5-20-membered heteroaryl, 3-20-membered heterocyclic alkyl-5-20-membered heteroaryl-, -5-20-membered heterocyclic alkenyl-C 6-20 Aryl, 5-20 membered heterocyclic alkenyl-C 6-20 aryl-, -5-20-membered heterocyclic alkenyl-5-20-membered heteroaryl, 5-20-membered heterocyclic alkenyl-5-20-membered heteroaryl-, -C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 cycloalkenyl-C 6-20 Aryl-, -C 5-20 Cycloalkenyl-5-20 heteroaryl, C 5-20 cycloalkenyl-5-20-membered heteroaryl-,-C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, -C 3-20 Cycloalkyl 5-20-membered heteroaryl, C 3-20 Cycloalkyl 5-20-membered heteroaryl-, -3-20-membered heterocycloalkyl 5-20-membered heteroaryl-, -3-20-membered heterocycloalkyl- 6-20 Aryl, 3-20 membered heterocyclic alkyl benzo[C] 6-20 aryl-, -3-20-membered heterocyclic alkyl 5-20-membered heteroaryl, 3-20-membered heterocyclic alkyl 5-20-membered heteroaryl-, -5-20-membered heterocyclic alkenyl decyl 6-20 Aryl, 5-20 membered heterocyclic alkenyl benzo[C] 6-20 aryl-, -5-20 quinone heterocyclic alkenyl 5-20 quinone heteroaryl, 5-20 quinone heterocyclic alkenyl 5-20 quinone heteroaryl-, -C 5-20 cycloalkenyl-C 6-20 Aryl, C 5-20 cycloalkenyl-C 6-20 Aryl-, -C 5-20 Cycloalkenyl 5-20 quinone heteroaryl, C 5-20 cycloalkenyl 5-20-membered heteroaryl-, wherein each C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 The aryl group and the 5-20 membered heteroaryl group can be independently monocyclic or polycyclic; the above groups can be unsubstituted or arbitrarily substituted at the ortho, para, meta, or N, O, and S atoms, each of which may be independently and optionally substituted by one, two, or more substituents selected from the following: deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 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-membered heteroaryl, C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 Cycloalkyl-5-20-membered 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 CONOH, C 1-10 Alkyl-CONOH, CO-NR 1.1 C 1- 10 Alkyl-CO-NR 1.1 CH = CHCOOR 1.1 CO-NR 1.1 CH2CO-NR 1.1 CH=CHCO-NR 1.1 NR 1.2 R 1.3 C 1-10 Alkyl-NR 1.2 R 1.3 SR 1.1 C 1-10 Alkyl-SR 1.1 SOR 1.1 C 1-10 Alkyl-SOR 1.1 SO2-R 1.1 C 1-10 Alkyl-SO2R 1.1 or SO2-NR 1.2 R 1.3 And each of the substituents may be unsubstituted or optionally further substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, OH, OR 1.1 Halogenated, oxo-substituted, thio-substituted, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- Aryl and NR 1.2 R 1.3 ; T stands for C, chemical bond, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, or 5-20 membered heterocyclic alkenyl; R1 indicates absence, hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-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-,-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 and NR 1.2 R 1.3 ; R1' indicates absence, hydrogen, deuterium, halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-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-,-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 and NR 1.2 R 1.3 ; The condition is that when T is a chemical bond, R1 and R1 ’ It does not exist; Or, R1 and R1 ’ Together they represent oxygenation and carbon. 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 Alkyl-COOR 1.1 COR 1.1 C 1-10 Alkyl-COR 1.1 COONR 1.1 C 1-10 Alkyl-COONR 1.1 CONOH, C 1-10 Alkyl-CONOH, CO-NR 1.1 C 1-10 Alkyl-CO-NR 1.1 CH = CHCOOR 1.1 CO-NR 1.1 CH2CO-NR 1.1 CH=CHCO-NR 1.1 NR 1.2 R 1.3 C 1-10 Alkyl-NR 1.2 R 1.3 SR 1.1 C 1-10 Alkyl-SR 1.1 SOR 1.1 C 1-10 Alkyl-SOR 1.1 SO2-R 1.1 C 1-10 Alkyl-SO2R 1.1 or SO2-NR 1.2 R 1.3 Each substituent may be unsubstituted or optionally substituted sequentially by one, two or more substituents selected from the following: hydrogen, deuterium, OH, OR. 1.1 Halogen, oxo, thio, -CN, -OH, -SH, -NH2, -NO2, monohalogenated or polyhalogenated C 1-6 Alkyl groups (such as -CF3, -CHF2, -CH2F), C 1- 6-alkyl, C 6-20- Aryl and NR 1.2 R 1.3 ; R 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; 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: OH, deuterium, 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 bridged heterocycle containing 1, 2, 3 or 4 independent heteroatoms selected from N, S or O. The heterocycle may be unsubstituted or optionally substituted at the ortho, para, or meta positions by one, two or more substituents selected from: deuterium, halogen, OH, oxo, thio, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as CF3, CHF2, CH2F), OR 1.1 C 1-3 -alkyl-OR 1.1 SR 1.1 C 1-3 -alkyl-SR 1.1 SO-R 1.1 C 1-3 -alkyl-SOR 1.1 SO2-R 1.1 C 1-3 -alkyl-SO2R 1.1 COOR 1.1 CH2COOR 1.1 CH2CH2COOR 1.1 CH = CHCOOR 1.1 CO-NR 1.1 CH2CO-NR 1.1 ,CH2CH2CO-NR 1.1 ,CH=CHCO-NR 1.1 ,COR 1.1 CH2COR 1.1 C 1-6 Alkyl alcohols, monocyclic or bicyclic C 3-10 cycloalkyl, C 6-20- Aryl, C 1-6 Alkyl, C 6-20- Aryl-C 1-6 Alkyl, 5-20 membered heteroaryl-C 1-6 Alkyl, C 1- 3-alkyl-(monocyclic or polycyclic-C) 6-20- Aryl), 3-20 membered heterocyclic group -C 6-20- Aryl, 3-20 membered heterocyclic, 5-20 membered heteroaryl C 1- 3-alkyl-OR 1.1 NR 1.2 R 1.3 C 6-20- Aryl and NR 1.2 R 1.3 .

2. The compound of Formula I according to claim 1, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug, wherein: Heterocyclic groups represent 3-11 member saturated or partially saturated monocyclic or bicyclic rings 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 have aromaticity. The heteroaryl group preferably represents a 5- to 10-membered 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. Preferably, the halogen-substituted alkyl group is a monohalogenated, dihalogenated, trihalogenated, or more halogenated C. 1-6 Alkyl groups, such as -CF3, -CHF2, -CH2F.

3. The compound of Formula I according to claim 1 or 2, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein ring A is selected from the following groups: in, "--" represents a chemical bond.

4. The compound of Formula I according to any one of claims 1-3, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein ring B is selected from the following groups: in, "--" represents a chemical bond.

5. The compound of Formula I according to any one of claims 1-4, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein the compound of Formula I is selected from the following compounds:

6. A method for preparing the compound of Formula I according to any one of claims 1-5, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein the method comprises reacting the compound of Formula S1 with the compound of Formula S2 to obtain the compound of Formula I: And optionally, the compound of formula I may be derived into its stereoisomers, tautomers, isotopic labels, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs; in, LG is a leaving group, such as Cl, Br or I; R1, R1', R a R b R c R f R g R h R i A, B, and T each have the definition as described in any one of claims 1-5 independently.

7. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the following: a compound of Formula I as claimed in any one of claims 1-5, a racemic mixture, a stereoisomer, a tautomer, an isotope label, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof; Preferably, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.

8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition may further contain one or more additional therapeutic agents; Preferably, the additional therapeutic agent is selected from cancer therapeutic agents.

9. A method for preventing or treating a disease, comprising administering to a patient in need at least one of the compounds of Formula I as described in any one of claims 1-5, their racemic mixtures, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds thereof.

10. The method of claim 9, wherein the disease is a PDE4-mediated disease, particularly a PDE4B-mediated disease; For example, the disease is selected from inflammatory diseases of the respiratory tract, inflammatory bowel disease, arthritis, inflammatory skin diseases, inflammatory eye diseases, diseases of the peripheral or central nervous system, degenerative diseases of the central nervous system, Alzheimer's disease (AD), non-alcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF) or pulmonary hypertension associated with it, chronic obstructive pulmonary disease (COPD) or pulmonary hypertension associated with it, hepatic fibrosis (HF), renal fibrosis, benign prostatic hyperplasia (BPH), gastroesophageal reflux disease, obstructive sleep apnea, and coronary artery disease or cancer; Preferably, the cancer is selected from one of the following: stomach cancer, bladder cancer, leukemia, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, external genital cancer, urogenital tract cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosa cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, testicular cancer, and / or thyroid cancer.

Images