PDE4b inhibitor, pharmaceutical composition thereof, and use

Abstract

The present application relates to a compound of formula X having PDE4B inhibitory activity, a pharmaceutical composition thereof, and a use. The compound of formula X may be used for PDE4-related diseases and conditions, such as respiratory inflammatory diseases, inflammatory bowel diseases, arthritis, skin inflammatory diseases, eye inflammatory diseases, and peripheral or central nervous system diseases or cancers.

Description

PDE4B inhibitors, pharmaceutical compositions thereof and uses thereof

[0001] This application claims the priority of the following prior applications filed by the applicant with the China National Intellectual Property Office: the invention patent application with the application number 202411248808.1 and the invention title “Pyrimidine Derivatives, Pharmaceutical Compositions Thereof and Uses Thereof” filed on September 6, 2024; and the invention patent application with the application number 202510057036.1 and the invention title “PDE4B Inhibitors, Pharmaceutical Compositions Thereof and Uses Thereof” filed on January 14, 2025. The entire contents of the above-mentioned prior applications are incorporated herein by reference. TECHNICAL FIELD

[0002] The present disclosure relates to PDE4B inhibitors, pharmaceutical compositions thereof and uses thereof, and belongs to the field of chemical drugs. BACKGROUND

[0003] Fibrosis is a general term for a large class of diseases, which can occur in almost all human tissues. The tissues and organs with fibrotic lesions gradually lose normal function, seriously affecting the quality of life of patients, and even endangering life. For example, in the case of pulmonary fibrosis, the fibrotic tissue loses its original elasticity, making it increasingly difficult for the lungs to expand and contract during breathing, and the lung capacity decreases, which seriously weakens the patient's activity.

[0004] Idiopathic pulmonary fibrosis (IPF) is a type of progressive pulmonary fibrosis disease. This type of pulmonary fibrosis progresses rapidly and can lead to patient death within a few years, even shorter than the survival period of many cancer patients. Due to the gradual aggravation of pulmonary fibrosis and the unpredictability of disease progression, IPF patients suffer from the “pain of being unable to breathe” that ordinary people cannot imagine, and may die from respiratory failure and / or heart failure at any time. At the same time, since the clinical manifestations of most IPF patients are atypical, they are more likely to be misdiagnosed as chronic obstructive pulmonary disease, bronchial asthma or other lung diseases. The median survival period of patients after being diagnosed with 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. There are about 3 million IPF patients worldwide. The disease mainly involves patients over 50 years old, with more males than females. There is no large epidemiological study data on the incidence of IPF in China. Due to the large population base in China, the disease burden of IPF on individuals, families, society and public health resources cannot be underestimated.

[0006] The PDE4 subfamily contains four isoforms (PDE4A, PDE4B, PDE4C, and PDE4D), and different isoforms have different tissue distribution: PDE4A is ubiquitous, with relatively high expression in adipose tissue, brain, heart, and testis; PDE4B is also widely distributed, with high levels of expression in lung, immune cells, brain, heart, and skeletal muscle; PDE4C is mainly expressed in testis and other tissues, with low expression in lung and no expression in blood and immune cells; PDE4D is mainly expressed in brain, immune cells, and skeletal muscle cells. Thus, the PDE4B isoform has a higher degree of expression in the lung than other isoforms. In vitro studies targeting PDE4B in pulmonary fibrosis have demonstrated that inhibiting PDE4B plays an important role in anti-inflammation and anti-fibrosis. Inhibiting PDE4B can lead to an increase in intracellular cAMP levels, which in turn activates protein kinase A (PKA) and cAMP direct activation exchange protein (EPAC), reduces the synthesis and release of pro-inflammatory cytokines, and increases the synthesis of anti-inflammatory cytokines.

[0007] Although there is preclinical evidence that PDE4 inhibitors are associated with anti-inflammatory and anti-fibrotic effects, which can reduce inflammation and fibrotic remodeling in lung diseases, many PDE4 inhibitors have gastrointestinal side effects due to their different selectivity, 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] SUMMARY

[0009] To solve the above technical problems, the present disclosure provides a compound represented by the following formula X, a racemate, stereoisomer, tautomer, isotopically labeled, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug thereof:

[0010] wherein:

[0011] X1represents a chemical bond, -O-, -S-, -NR q -, -S(=O)-, -S(=O)2-, -C(=O)-, no substitution or optionally substituted -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 alkylene-, -C 2-6 alkylene-, -C 1-6alkyleneoxy-; wherein "optionally substituted" means that the group is substituted with 1, 2 or more substituents selected from the group consisting of deuterium, halogen, oxo (=0), thioxo (=S), -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalogenated C 1-6 alkyl (e.g. -CF3, -CHF2, -CH2F), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-20 cycloalkyl;

[0012] U represents -(CH2) t -, O, S, -NR q -, -S(=0)-, -S(=0)2- or -C(=0)-, wherein t represents 0, 1, 2 or 3;

[0013] v represents 0, 1, 2, 3, 4 or 5;

[0014] n represents 1 or 2;

[0015] m represents 0, 1, 2, 3, 4 or 5;

[0016] l represents 0, 1, 2, 3, 4 or 5;

[0017] R q is selected from the group consisting of H, C 1-20 alkyl, C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-20 aryl, 5- to 20-membered heteroaryl, each of which can be unsubstituted or in turn optionally substituted with 1, 2 or more substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, thioxo, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalogenated C 1-6 alkyl (e.g. -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 and NR 1.2 R 1.3 ;

[0018] R f , R g , R h , R i are each independently hydrogen or deuterium;

[0019] ring A is a bond, -C 3-20 cycloalkyl-, -C 3-20cycloalkyl-, -3-20 membered heterocycloalkyl-, -5-20 membered heterocycloalkenyl-, -C 6-20 aryl-, -5-20 membered heteroaryl-, -C 3-20 cycloalkyl and C 6-20 aryl-, -C 3-20 cycloalkyl and 5-20 membered heteroaryl-, -3-20 membered heterocycloalkyl and C 6-20 aryl-, -3-20 membered heterocycloalkyl and 5-20 membered heteroaryl-, -5-20 membered heterocycloalkenyl and C 6-20 aryl-, -5-20 membered heterocycloalkenyl and 5-20 membered heteroaryl-, -C 5-20 cycloalkenyl and C 6-20 aryl-, -C 5-20 cycloalkenyl and 5-20 membered heteroaryl-, -3-20 membered heterocycloalkyl and 5-20 membered heteroaryl and C 3-20 cycloalkyl-;

[0020] ring B is a bond, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3-20 membered heterocycloalkyl, 5-20 membered heterocycloalkenyl, C 6-20 aryl, 5-20 membered heteroaryl-, C 3-20 cycloalkyl and C 6-20 aryl, C 3-20 cycloalkyl and 5-20 membered heteroaryl, 3-20 membered heterocycloalkyl and C 6-20 aryl, 3-20 membered heterocycloalkyl and 5-20 membered heteroaryl, 5-20 membered heterocycloalkenyl and C 6-20 aryl, 5-20 membered heterocycloalkenyl and 5-20 membered heteroaryl, C 5-20 cycloalkenyl and C 6-20 aryl, C 5-20 cycloalkenyl and 5-20 membered heteroaryl;

[0021] R a represents hydrogen, deuterium, halogen, oxo, thia, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalogenated C 1-6 alkyl (such as -CF3, -CHF2, -CH2F), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3-20 membered heterocycloalkyl, 5-20 membered heterocycloalkenyl, C 6-20 aryl, 5-20 membered 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, C1-6 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 ; wherein each group can be unsubstituted or in turn optionally substituted with 1, 2, or more substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, thioxo, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhaloC 1-6 alkyl (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C6-20- aryl, OR 1.1 and NR 1.2 R 1.3 ;

[0022] R b represents hydrogen, deuterium, halogen, oxo, thioxo, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalogenated C 1-6 alkyl (such as -CF3, -CHF2, -CH2F), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3- to 20-membered heterocycloalkyl, 5- to 20-membered heterocycloalkenyl, C 6-20 aryl, 5- to 20-membered heteroaryl, -C 1-6 alkyl-C 6-20 aryl, C 1-6 alkyl-C 6-20 aryl-, -C 1-6 alkyl-5- to 20-membered heteroaryl, C 1-6 alkyl-5- to 20-membered heteroaryl-, -C 3-20 cycloalkyl-C 6-20 aryl, C 3-20 cycloalkyl-C 6- 20 aryl-, -C 3-20 cycloalkyl-5- to 20-membered heteroaryl, C 3-20 cycloalkyl-5- to 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-NR1.2 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 ; wherein each of said groups can be unsubstituted or in turn optionally substituted with 1, 2 or more substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, thioxo, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalogenated C 1-6 alkyl (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 and NR 1.2 R 1.3 ;

[0023] or R a and R b together form a C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3- to 20-membered heterocycloalkyl, 5- to 20-membered heterocycloalkenyl, C 6-20 aryl, 5- to 20-membered heteroaryl, and the aforementioned groups can be unsubstituted or in turn optionally substituted with 1, 2 or more substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, thioxo, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalogenated C 1-6 alkyl (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3- to 20-membered heterocycloalkyl, 5- to 20-membered heterocycloalkenyl, C 6-20 aryl, 5- to 20-membered heteroaryl, C 2-10 alkenyl, C 1-6 alkyl-C 6-20 aryl, C 1-6 alkyl-5- to 20-membered heteroaryl, C 3-20 cycloalkyl-C 6-20 aryl, C 3-20cycloalkyl-5-20 heteroaryl, OR 1.1 , COOR 1.1 , C 1-10 alkyl-COOR 1.1 , COR 1.1 , C 1-10 alkyl-COR 1.1 , COONR 1.1 , C 1-10 alkyl-COONR 1.1 , CONOH, C 1-10 alkyl-CONOH, CO-NR 1.1 , C 1-10 alkyl-CO-NR 1.1 , CH=CHCOOR 1.1 , CO-NR 1.1 CH2CO-NR 1.1 , CH=CHCO-NR 1.1 , NR 1.2 R 1.3 , C 1-10 alkyl-NR 1.2 R 1.3 , SR 1.1 , C 1-10 alkyl-SR 1.1 , SOR 1.1 , C 1-10 alkyl-SOR 1.1 , SO2-R 1.1 , C 1-10 alkyl-SO2R 1.1 or SO2-NR 1.2 R 1.3 , wherein each of the substituents can be unsubstituted or in turn optionally substituted by 1, 2 or more substituents selected from the group consisting of hydrogen, deuterium, OH, OR 1.1 , halogen, oxo, thioxo, -CN, -OH, -SH, -NH2, -NO2, -CF3, -CHF2, -CH2F, C 1-6 -alkyl, C 6-20- aryl and NR 1.2 R 1.3 ;

[0024] R c is -Y-Z;

[0025] Y represents a bond, -O-, -S-, -NR q -, -S(=O)-, -S(=O)2-, -C(=O)-, unsubstituted or optionally substituted C 1-6 alkylene-C(=O)-NH-, -C(=O)-NH-C1-6 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 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-20 cycloalkyl;

[0026] Each Z is the same or different, and independently represents hydrogen, deuterium, and C. 3-20 cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocyclic alkyl, 5-20 membered heterocyclic alkenyl, C 6-20 Aryl, 5-20 heteroaryl, -C 3-20 cycloalkyl-C 6-20 Aryl, C 3-20 cycloalkyl-C 6-20 Aryl-, C 3- 20 Cycloalkyl-5-20-membered heteroaryl, C 3-20 Cycloalkyl-5-20-membered heteroaryl, 3-20-membered heterocycloalkyl-C 6-20 Aryl, 3-20 membered heterocyclic alkyl-C 6-20 Aryl, 3-20-membered heterocyclic alkyl-5-20-membered heteroaryl, 3-20-membered heterocyclic alkyl-5-20-membered heteroaryl, 5-20-membered heterocyclic alkenyl-C 6-20 Aryl, 5-20 membered heterocyclic alkenyl-C 6-20 Aryl, 5-20 membered heterocyclic alkenyl-C 5-20 heteroaryl, C 5-20 Heterocyclic alkenyl-C 5-20 heteroaryl, C 5-20 Cycloalkenyl-C 6-20 Aryl, C 5-20 Cycloalkenyl-C 6-20 Aryl, C 5-20 Cycloalkenyl-5-20 heteroaryl, C 5-20 Cycloalkenyl-5-20 heteroaryl, C 3-20 cycloalkyl-C 6-20aryl, C 3-20 cycloalkyl and C 6-20 aryl, C 3-20 cycloalkyl and 5-20 membered heteroaryl, C 3-20 cycloalkyl and 5-20 membered heteroaryl, 3-20 membered heterocycloalkyl and C 6-20 aryl, 3-20 membered heterocycloalkyl and C 6-20 aryl, 3-20 membered heterocycloalkyl and C 5-20 heteroaryl, 3-20 membered heterocycloalkyl and C 5-20 heteroaryl, 5-20 membered heterocycloalkenyl and C 6-20 aryl, 5-20 membered heterocycloalkenyl and C 6-20 aryl, 5-20 membered heterocycloalkenyl and 5-20 membered heteroaryl, 5-20 membered heterocycloalkenyl and 5-20 membered heteroaryl, C 5-20 cycloalkenyl and C 6-20 aryl, C 5-20 cycloalkenyl and C 6-20 aryl, C 5-20 cycloalkenyl and 5-20 membered heteroaryl, C 5-20 cycloalkenyl and 5-20 membered heteroaryl, wherein each C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3-20 membered heterocycloalkyl, 5-20 membered heterocycloalkenyl, C 6-20 aryl, 5-20 membered heteroaryl can independently be monocyclic or polycyclic; the aforementioned groups can be unsubstituted or each independently optionally substituted at an ortho-, para-, meta- or N, O, S atom with 1, 2 or more substituents selected from the group consisting of deuterium, halogen, oxo, thia, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalogenated C 1-6 alkyl (e.g. -CF3, -CHF2, -CH2F), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3-20 membered heterocycloalkyl, 5-20 membered heterocycloalkenyl, C 6-20 aryl, 5-20 membered heteroaryl, C 1-6 alkyl-C 6-20 aryl, C 1-6 alkyl-5-20 membered heteroaryl, C 3-20 cycloalkyl-C 6-20 aryl, C 3-20 cycloalkyl-5-20 membered heteroaryl, OR 1.1 , COOR 1.1 , C 1-10 alkyl-COOR 1.1 , COR 1.1 , C1-10 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 said substituents can be unsubstituted or in turn optionally further substituted by 1, 2 or more substituents selected from the group consisting of hydrogen, deuterium, OH, OR 1.1 , halogen, oxo, thioxo, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalogenated C 1-6 alkyl (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl and NR 1.2 R 1.3 ;

[0027] R 1.1 is H or is selected from the group consisting of C 1-6- alkyl, C 3-20 -cycloalkyl, C 5-20 -cycloalkenyl, 3-20 membered heterocycloalkyl, 5-20 membered heterocycloalkenyl, C 6-20- aryl-C 1-6 -alkyl, 5-20 membered heteroaryl-C 1-6 -alkyl, 3-20 membered heterocyclo-C 1-6 -alkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl, monocyclic or bicyclic C 6-20- aryl, 5-20 membered heteroaryl and heterocycle, which can be unsubstituted or optionally substituted with a substituent selected from the group consisting of halogen, deuterium, OH, CN, NO2, NH2, oxo (=0), thioxo (=S), CF3, CHF2, CH2F, O-(C 1-3 - alkyl), C 1-10- - cycloalkyl, C 6-20- - aryl;

[0028] R 1.2 and R 1.3 , which are identical or different, independently of each other, denote H or a group selected from the group consisting of C 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 heterocycle, monocyclic or bicyclic 5-20 membered heteroaryl ring, 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 heterocycloalkenyl), CO-R 1.1 and COOR 1.1 , which can be unsubstituted or optionally substituted with 1, 2 or more substituents selected from the group consisting of OH, deuterium, halogen, C 1-6 - alkyl, C 6-20- - aryl and COOR 1.1 ;

[0029] Alternatively, R 1.2 and R 1.3 , together with the atom to which they are attached, form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocycle comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, which can be unsubstituted or optionally substituted at the ortho-, para- or meta-position with 1, 2 or more substituents selected from the group consisting of deuterium, halogen, OH, oxo, thioxo, monohalo- or polyhalo-C 1-6 - alkyl (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 , C1-3 -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 alcohol, 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 heterocyclyl-C 6-20- -aryl, 3-20 membered heterocycle, 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 ;

[0030] each R d21 , R d22 is the same or different, independently of one another, selected from a chemical bond, H, deuterium, halogen, OH, CN, NO2, oxo (=0), thioxo (=S), SO, SO2, the following radicals which are unsubstituted or optionally substituted by 1, 2 or more R a C 1-20 -alkyl, C 2-20 -alkenyl, C 2-20 -alkynyl, C 3-20 -cycloalkyl, C 3-20 -cycloalkenyl, C 3-20 -cycloalkynyl, C 6-20 -aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-20 -alkyloxy, C 2-20 -alkenyloxy, C 2-20 -alkynyloxy, C 3-20Cycloalkyloxy, C 3-20 Cycloalkenyloxy, C 3-20 Cycloalkynyloxy group, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, C 1-20 Alkyl thio, C 2-20 alkenyl thio, C 2-20 alkynyl thioyl, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 Cycloalkynylthio, C 6-20 aryl thio, 5-20 membered heteroaryl thio, 3-20 membered heterocyclic thio, NH2, -C(O)R 11 -CH2-C(O)R 11 -C(O)OR 12 -CH2C(O)OR 12 -C(O)NHR 12 -CH2C(O)NHR 12 -OC(O)R 13 -S(O)2R 14 -S(O)2OR 15 -OS(O)2R 16 -P(O)(OR) 17 (OR) 18 );

[0031] Alternatively, when two or more R-selected groups are present on the same group. d21 R d22 When substituents are present, the two substituents can form an unsubstituted or optionally substituted group with one, two or more R atoms together with the atoms they are attached to. e The following groups are substituted: C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic;

[0032] Each R e Whether identical or different, they are independently selected from hydrogen, deuterium, halogen, OH, CN, NO2, NH2, SH, oxo (=O), thio (=S), methanesulfonyl, ethanesulfonyl, methanesulfonamide, ethanesulfonamide, carboxylic acid, monohalogenated or polyhalogenated C. 1-6 Alkyl groups (such as CF3, CHF2, CH2F), O-CONH2, O-CONR 1.2 R 1.3 NR q -CONR 1.2 R 1.3 NR q-C(O)R 1.1 , NR 1.2 R 1.3 , OR 1.1 , C 1-6 -alkyl-OR 1.1 , C 1-6 -alkyl-O-C 1-6 -alkyl-COOR 1.1 , C 1-6 -alkyl-O-C 1-6 -alkenyl-COOR 1.1 , C 1-6 -alkyl-O-C 1-6 -alkyl-CONR 1.2 R 1.3 , -O-C 1-6 -alkyl-CONR 1.2 R 1.3 , -O-C 1-6 -alkyl-COOR 1.1 , -O-C 1-6 -alkyl-O-CO-C 1-6 -alkyl-NR 1.2 R 1.3 , -O-C 1-6 -alkyl-O-C 1-6 -alkyl-COOR 1.1 , C 1-6 -alkyl-O-PO(ONa)2, C 1-6 -alkyl-O-PO(OH)2, C 1-6 -alkyl-O-PO(OR 1.1 )2, C 1-6 -alkyl-O-C(O)-OR 1.1 , C 1-6 -alkyl-O-C(O)-NR 1.2 R 1.3 , C 1-6 -alkyl-O-C(=O)-C 1-6 -alkyl-(O-C 1-6 -alkyl) n , C 1-6 -alkyl-O-C(=O)-C 1-6 -alkyl-COOR 1.1 , C 1-6 -alkyl-O-C(=O)-C 1-6 -alkyl, C 1-6 -alkyl-O-C(=O)-C 3-10 -cycloalkyl, C 1-6 -alkyl-O-C(=O)-3-10 membered heterocycloalkyl, C 1-6 -alkyl-O-C(=O)-C6-20 aryl, C 1-6 -alkyl-O-C(=O)-5-20 membered heteroaryl, C 1-6 -alkyl-O-C(=O)-C 1-6 -alkenyl-COOR 1.1 , C 1-6 -alkyl-N-C(=O)-C 1-6 -alkyl-COOR 1.1 , C 1-6 -alkyl-N-C(=O)-O-C 1-6 -alkyl-COOR 1.1 , C 1-6 -alkyl-N-C(=O)-N-C 1-6 -alkyl-COOR 1.1 , SR 1.1 , C 1-6 -alkyl-SR 1.1 , SO-R 1.1 , C 1-6 -alk-SOR 1.1 , SO2-R 1.1 , C 1-6 -alkyl-SO2R 1.1 , COOR 1.1 , C 1-6 -alkyl-COOR 1.1 , CH=CHCOOR 1.1 , CO-NR 1.2 R 1.3 , C 1-6 -alkyl-CO-NR 1.2 R 1.3 , CH=CHCO-NR 1.2 R 1.3 , COR 1.1 , C 1-6 -alkyl-COR 1.1 , 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 heterocyclyl-C 6-20- -aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C 1-3 -alkyl-OR 1.1 , NR 1.2 R 1.3 or C 6-20-aryl; each of said substituents can in turn be unsubstituted or optionally substituted with 1, 2, or more substituents selected from the group consisting of deuterium, OH, CN, C 1-6 -alkyl-CN, C 1-6 -alkyl-NH2, -SH, -NH2, -NHOH, -C 1-6- alkyl-NHOH, -C 1-6- alkyl-CO-NHOH, -CO-NHOH, -C 1-6- alkyl-NH - CO-NR 1.2 R 1.3 , -NR 1.1 CN, -CHO, guanidino, quaternary ammonium salts, C 2-6 -alkenyl, -O-C 3-8 -cycloalkyl, COOR 1.1 , C 1-6 -alkyl-COOR 1.1 , CONHR 1.1 , C 1-6 -alkyl-CONHR 1.1 , -OR 1.1 , oxo, halogen, mono- or polyhalogenated C 1-6 alkyl (such as CF3, CHF2, CH2F), C 1-6 -alkyl, C 6-20- aryl and NR 1.2 R 1.3 ;

[0033] each R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 41 , R 42 , R 43 , R 44 , R45 R 46 R 47 R 48 R 1-20 R 2-20 R 2-20 R 3-20 R 3-20 R 3-20 R 6-20 R

[0034] Heterocyclyl preferably comprises 1, 2, 3 or 4 heteroatoms independently selected from N, S or O in a 3-11 membered saturated or partially saturated monocyclic or bicyclic ring, which bicyclic ring can be any fused or bridged ring, but which is not aromatic; wherein heterocyclyl can be heterocycloalkyl, heterocycloalkenyl or heterocycloalkynyl; for example, heterocycloalkyl represents a 3-11 membered saturated monocyclic or bicyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, which bicyclic ring can be any fused or bridged ring; heterocycloalkenyl represents a 3-11 membered monocyclic or bicyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, comprising 1, 2 or more double bonds, which bicyclic ring can be any fused or bridged ring; heterocycloalkynyl represents a 3-11 membered monocyclic or bicyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, comprising 1, 2 or more triple bonds, which bicyclic ring can be any optionally fused or optionally bridged ring;

[0035] Heteroaryl preferably comprises 1, 2, 3 or 4 heteroatoms independently selected from N, S or O in a 5-10 membered monocyclic or bicyclic ring and is aromatic, which bicyclic ring can be any fused ring;

[0036] “Monocyclic or polycyclic” means monocyclic, bicyclic (e.g. fused, spiro, bridged), tricyclic or more.

[0037] According to embodiments of the present application, examples of ring A can be selected from the following groups of radicals, leaving out any two H atoms, which can be C atoms or N atoms:

[0038] Preferably, when present, examples of ring A can be selected from the following groups of radicals, leaving out 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 H atoms:

[0039] According to embodiments of the present application, examples of ring A can be selected from the following groups of radicals:

[0040] wherein “—” in the structural formula represents a chemical bond to the group in formula X.

[0041] According to embodiments of the present application, examples of ring B can be selected from the following groups:

[0042] wherein “—” in the structural formula represents a chemical bond to the group in formula X.

[0043] According to embodiments of the present disclosure, the compound of formula X can be selected from the following compounds represented by formula X-1:

[0044] wherein R b , R c , R d21 , R e , R f , R g , R h , R i , and l each independently have the definitions described above.

[0045] According to embodiments of the present disclosure, the compound of formula X can be selected from the following compounds represented by formula IV:

[0046] wherein:

[0047] X1represents a chemical bond, C 1-20 alkylene, O, S, NR q , S(=O), S(=O)2, or C(=O);

[0048] X2represents a chemical bond, C 1-20 alkylene, O, S, NR q , S(=O), S(=O)2, or C(=O);

[0049] U represents -(CH2) t , O, S, NR q , S(=O), S(=O)2, or C(=O), wherein t represents 0, 1, 2, or 3;

[0050] R q is selected from H, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-20 alkyloxy, C 2-20alkenyl, C 2-20 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-20 aryloxy, 5- to 20-membered heteroaryloxy, 3- to 20-membered heterocyclyloxy, C 1-20 alkylthio, C 2-20 alkenylthio, C 2-20 alkynylthio, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 cycloalkynylthio, C 6-20 arythio, 5- to 20-membered heteroarylthio, 3- to 20-membered heterocyclylthio, C 1-8 -heteroalkyl and C 6-20- aryl-, C 1-8 -heteroalkyl-C 6-20- aryl-, NH2, -C(O)R 41 , -C(O)OR 42 , -OC(O)R 43 , -S(O)2R 44 , -S(O)2OR 45 , -OS(O)2R 46 , -P(O)(OR 47 )(OR 48 );

[0051] v represents 0, 1, 2, 3, 4 or 5;

[0052] R c represents hydrogen, a mono- or polycyclic C 6-20 -aryl, a mono- or polycyclic C 6-20 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 6-20 -aryl and a 4- to 12-membered cycloalkenyl, for example C 4-10 cycloalkyl and C 6-20 aryl-, 4- to 10-membered heterocycloalkyl and C 6-20 aryl-, 4- to 10-membered heterocycloalkenyl and C 6-20 aryl-, C 4-10 cycloalkyl-C 6-20 aryl-, 4- to 10-membered heterocycloalkyl-C 6-20 aryl-, 4- to 10-membered heterocycloalkenyl-C 6-20 aryl-, 5- to 20-membered heteroaryl, C 4-10 cycloalkyl and 5- to 20-membered heteroaryl-, 4- to 10-membered heterocycloalkyl and 5- to 20-membered heteroaryl-, 4- to 10-membered heterocycloalkenyl and 5- to 20-membered heteroaryl-, C 4-10cycloalkyl-5-20 membered heteroaryl-, 4-10 membered heterocycloalkyl-5-20 membered heteroaryl-, 4-10 membered heterocycloalkenyl-5-20 membered heteroaryl-, or is selected from 5-20 membered heteroaryl-O-C 6-20 aryl-, 5-20 membered heteroaryl-N-C 6-20 aryl-, 5-20 membered heteroaryl-S-C 6-20 aryl-, 5-20 membered heteroaryl-CH2-C 6-20 aryl-, the aforementioned groups optionally substituted at each occurrence independently at any available aromatic ring carbon by one, two, or more substituents selected from the group consisting of halogen, hydroxyl, CN, NO2, NH2, or by one, two, or more substituents selected from the group consisting of OR 4.1 , COOR 4.1 CH2COOR 4.1 , CH2CH2COOR 4.1 , CH=CHCOOR 4.1 , CO-NR 4.1 CH2CO-NR 4.1 , CH2CH2CO-NR 4.1 , CH=CHCO-NR 4.1 , NR 4.2 R 4.3 , CH2-NR 4.2 R 4.3 , CH2CH2-NR 4.2 R 4.3 , C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 4.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 4.1 , C 3-10 -cycloalkyl, C 1-3 -alkyl-(mono- or polycyclic C 6-20- aryl), 3-10 membered heterocyclyl-C 6-20- aryl, 3-10 membered heterocyclyl, C 1-6 -alkyl, C 1-3 -fluoroalkyl, CF3, CHF2, CH2F, C 6-20- aryl-C 1-6 -alkyl, 3-10 membered heterocyclyl-C 1-6 -alkyl, 5-20 membered heteroaryl-C 1-6- alkyl, C 6-20- aryl, SO2-CH3, SO2-CH2CH3, and SO2-NR 4.2 R 4.3 substituents;

[0053] or R c selected from the group consisting of heterocycle and heteroaryl, which can be optionally substituted at the ortho, para or meta position, each independently optionally with 1, 2 or more groups of halogen, OH, oxo, CF3, CHF2and CH2F, or with 1, 2 or more groups selected from OR 4.1 , C 1-3 -alkyl-OR 4.1 , SR 4.1 , C 1-3 -alkyl-SR 4.1 , SO-R 4.1 , C 1-3 -alkyl-SOR 4.1 , SO2-R 4.1 , C 1-3 -alkyl-SO2R 4.1 , COOR 4.1 , CH2COOR 4.1 , CH2CH2COOR 4.1 , CH=CHCOOR 4.1 , CO-NR 4.1 CH2CO-NR 4.1 , CH2CH2CO-NR 4.1 , CH=CHCO-NR 4.1 , COR 4.1 , CH2COR 4.1 , C 1-6 -alkyl alcohol, mono- 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-(mono- or polycyclic-C 6-20- aryl), 3-10 membered heterocyclyl-C 6-20- aryl, 3-10 membered heterocyclyl, 5-20 membered heteroaryl C 1-3 -alkyl-OR 4.1 and NR 4.2 R 4.3 , which in turn can be independently optionally substituted with 1, 2 or more substituents of OH, OR 4.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- alkyl, C 6-10- aryl and NR 4.2 R 4.3 ;

[0054] Heterocycles represent 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, fused or bridged rings containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O.

[0055] The heteroaryl ring is a 5- to 10-membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; in some embodiments, R4 is selected from 5-membered monocyclic heteroaryl, 5-membered heteroaryl-5-10-membered heteroaryl, 5-membered heteroaryl-4-12-membered cycloalkyl, 5-membered heteroaryl-4-12-membered heterocycloalkyl, 6-membered heteroaryl-phenyl, 6-membered heteroaryl-5-10-membered heteroaryl, 6-membered heteroaryl-6-membered heteroaryl, 6-membered heteroaryl-4-7-membered cycloalkyl, and 6-membered heteroaryl-4-12-membered heterocycloalkyl.

[0056] R 4.1 Is it H or selected from C? 1-6- Alkyl, C 1-6- Alkyl alcohols, C 1-3 - Haloalkyl, mono- or bicyclic, -C 3-10 -cycloalkyl, C 6-20- Aryl-C 1-6 -alkyl, 5-20-membered heteroaryl-C 1-6 -alkyl, 3-10 membered heterocyclic -C 1-6 -alkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl, mono- or bicyclic C 6-20- Aryl, 5-20 membered heteroaryl and heterocyclic compounds, which may optionally be bonded by OH, O-(C 1-3 -alkyl), halogen, C 1-10- Alkyl and C 5-10 The aryl substituents are substituted;

[0057] R 4.2 and R 4.3 H or selected from C can be represented independently of each other. 1-6- Alkyl, mono- or bicyclic C 3-10- cycloalkyl, C 6-20- Aryl-C 1-6 -alkyl, 5-20-membered heteroaryl-C 1-6- Alkyl, mono- or bicyclic C 6-20- Aryl, 3-10 membered heterocyclic group, heteroaryl group, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 4.1 and COOR 4.1 The group, which may optionally be surrounded by one, two or more OH groups, halogens, C groups, 1-6 -alkyl, C 6-20- Aryl and COOR4.1 replace.

[0058] Each R d21 R d22 They may be the same or different, and are independently selected from H, halogen, OH, CN, NO2, oxo (=O), thio (=S), SO, SO2, unsubstituted, or optionally substituted with one, two, or more Rs. e The following groups are substituted: C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 1-20 Alkyloxy, C 2-20 alkenyloxy group, C 2-20 alkynyloxy group, C 3-20 Cycloalkyloxy, C 3-20 Cycloalkenyloxy, C 3-20 Cycloalkynyloxy group, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, C 1-20 Alkyl thio, C 2-20 alkenyl thio, C 2-20 alkynyl thioyl, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 Cycloalkynylthio, C 6-20 aryl thio, 5-20 membered heteroaryl thio, 3-20 membered heterocyclic thio, NH2, -C(O)R 31 -CH2-C(O)R 31 -C(O)OR 32 -CH2C(O)OR 32 -C(O)NHR 32 -CH2C(O)NHR 32 -OC(O)R 33 -S(O)2R 34 -S(O)2OR 35 -OS(O)2R 36 -P(O)(OR) 37 (OR) 38 );

[0059] Alternatively, when two or more R-selected groups are present on the same group. d21 R d22 When substituents are present, the two substituents can form an unsubstituted or optionally substituted group with one, two or more R atoms together with the atoms they are attached to.e substituted lower alkyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-20 aryl, 5- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl;

[0060] each R e are independently of each other, identically or differently, selected from the group consisting of H, halogen, OH, CN, NO2, NH2, oxo (=0), thioxo (=S), O-CONH2, O-CONHR f , NRq-CONHR f , NRq-C(O)R f , NH R f unsubstituted or optionally substituted by 1, 2 or more R f substituted lower alkyl, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, C 3- 20 cycloalkynyl, C 6-20 aryl, 5- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl, C 1-20 alkyloxy, C 2-20 alkenyloxy, C 2-20 alkynyloxy, C 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C 3-20 cycloalkynyloxy, C 6-20 aryloxy, 5- to 20-membered heteroaryloxy, 3- to 20-membered heterocyclyloxy, C 1-20 alkylthio, C 2-20 alkenylthio, C 2-20 alkynylthio, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 cycloalkynylthio, C 6-20 arythio, 5- to 20-membered heteroarylthio, 3- to 20-membered heterocyclylthio, C 1-8 -heteroalkyl and C 6-20- aryl-, C 1-8 -heteroalkyl-C 6-20- aryl-, NH2, -C(O)R 41 , -C(O)OR 42 , -OC(O)R 43 , -S(O)2R 44 , -S(O)2OR 45 , -OS(O)2R 46-P(O)(OR) 47 (OR) 48 );

[0061] Alternatively, when two or more R-selected groups are present on the same group. e When substituents are present, the two substituents can form an unsubstituted or optionally substituted group with one, two or more R atoms together with the atoms they are attached to. f The following groups are substituted: C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic;

[0062] Each R f They may be the same or different, and are independently selected from H, halogen, OH, CN, NO2, oxo (=O), thio (=S), unsubstituted, or optionally substituted by one, two, or more Rs. g The following groups are substituted: C 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 1-20 Alkyloxy, C 2-20 alkenyloxy group, C 2-20 alkynyloxy group, C 3-20 Cycloalkyloxy, C 3-20 Cycloalkenyloxy, C 3-20 Cycloalkynyloxy group, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, C 1-20 Alkyl thio, C 2-20 alkenyl thio, C 2-20 alkynyl thioyl, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 Cycloalkynylthio, C 6-20 aryl thio, 5-20 membered heteroaryl thio, 3-20 membered heterocyclic thio, NH2, -C(O)R 51 -C(O)OR 52 -OC(O)R 53 -S(O)2R 54 -S(O)2OR 55 -OS(O)2R 56 -P(O)(OR) 57 (OR) 58 );

[0063] or, when there are two or more substituents selected from R f on the same group, said two substituents can form, together with the atom(s) to which they are attached, a group selected from the following list: C g cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 3- 20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl; 6-20

[0064] each R g is the same or different, independently of each other, selected from the group consisting of H, halogen, OH, CN, NO2, oxo (=0), thioxo (=S), C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, NH2;

[0065] each R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 are the same or different, independently of each other, selected from the group consisting of H, halogen, OH, CN, NO2, oxo (=0), thioxo (=S), C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-20 ​aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, NH2;

[0066] Rh represents a mono- or polycyclic C 6-20- aryl, a mono- or polycyclic C 6-20 -aryl and a 4-12 membered cycloalkyl or a mono- or polycyclic C 6-20 -aryl and a 4-12 membered cycloalkenyl, which can each independently be optionally substituted at the ortho-, para- or meta-position by 1, 2 or more groups independently selected from F, Cl, Br, OH, CN, NH2, or by 1, 2 or more groups selected from OR 4.1 , COOR 4.1 , CH2COOR 4.1 , CH2CH2COOR 4.1 , CH=CHCOOR 4.1 , CO-NR 4.1 , CH2CO-NR 4.1 , CH2CH2CO-NR 4.1 , CH=CHCO-NR 4.1 , NR 4.2 R 4.3 , CH2-NR 4.2 R 4.3 , CH2CH2-NR 4.2 R 4.3 , C 3-10 -cycloalkyl, C 3-10 -cycloalkenyl, C 1-3 -alkyl-(mono- or polycyclic-C 6-20- aryl), 3-20 membered heterocyclyl-C 6-20- aryl, 3-20 membered heterocyclyl, C 1-6 -alkyl, C 1-3 -fluoroalkyl, C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 4.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 4.1 , CF3, CHF2, CH2F, C 6-20- aryl-C 1-6 -alkyl, 3-10 membered heterocyclyl-C 1-6 -alkyl, 5-20 membered heteroaryl-C 1-6- alkyl, C 6-10 -aryl, SO2-CH3, SO2-CH2CH3and SO2-NR 4.2 R 4.3 independently optionally substituted by 1, 2 or more groups selected from OH, OR4.1 CF3, CHF2, CH2F, oxo, halogen, CF3, CHF2, CH2F, C 1-6 -alkyl, C 6-10- aryl and NR 4.2 R 4.3 substituted by 1, 2 or more substituents selected from the group consisting of halogen, OH, oxo, CF3, CHF2and CH2F, or

[0067] Rhrepresents a group selected from heterocycle or heteroaryl, which is in each case independently at the ortho-, para- or meta-position optionally substituted by 1, 2 or more groups selected from halogen, OH, oxo, CF3, CHF2and CH2F, or 4.1 , C 1- 3-alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 4.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 4.1 , C 1-3 -alkyl-OR 4.1 , SR 4.1 , C 1-3 -alkyl-SR 4.1 , SO-R 4.1 , C 1-3 -alkyl-SOR 4.1 , SO2-R 4.1 , C 1-3 -alkyl-SO2R 4.1 , COOR 4.1 , CH2COOR 4.1 , CH2CH2COOR 4.1 , CH=CHCOOR 4.1 , CO-NR 4.1 CH2CO-NR 4.1 , CH2CH2CO-NR 4.1 , CH=CHCO-NR 4.1 , COR 4.1 , CH2COR 4.1 , mono- or bicyclic C 3-10 -cycloalkyl, mono- or bicyclic C 3-10 -cycloalkenyl, 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-(mono- or polycyclic-C 6-20- aryl), 3-10 membered heterocyclyl-C 6-20-Aryl, 3-10 heterocyclic, 5-20 heteroaryl C 1-3 -alkyl-OR 4.1 and NR 4.2 R 4.3 The substituents are replaced by substituents, which may be independently and optionally selected from OH, OR 4.1 Oxide, halogen, CF3, CHF2, CH2F, C 1-6- Alkyl, C 6-20- Aryl and NR 4.2 R 4.3 One, two or more substituents are substituted;

[0068] Heterocycles represent 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, fused or bridged rings containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O.

[0069] Heteroaryl groups are 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl groups comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

[0070] R 4.1 Is it H or selected from C? 1-6- Alkyl, C 1-6- Alkyl alcohols, C 1-3 - Haloalkyl, C 3-11 - Mono- or diheterocyclic groups, -C 3-10 -cycloalkyl, -C 3-10 -cycloalkenyl, C 6-20- Aryl-C 1-6 -alkyl, 5-20-membered heteroaryl-C 1-6 -alkyl, 3-10 membered heterocyclic -C 1-6 -alkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl, C 3-10 -cycloalkenyl-C 1-6 -alkyl, mono- or bicyclic C 6-20- Aryl, 5-20 membered heteroaryl and heterocyclic compounds, optionally selected from OH, O-(C 1-3 -alkyl), halogen, C 1-10- Alkyl and C 6-20- Aryl group substitution;

[0071] R 4.2 and R 4.3 H or selected from C can be represented independently of each other. 1-6- Alkyl, mono- or bicyclic C 3-10- Cycloalkyl, mono- or bicyclic C 3-10- Cycloalkenyl, C 6-20- Aryl-C 1-6 -alkyl, 5-20-membered heteroaryl-C1-6 alkylene, mono- or bicyclic C 6-20- aryl, 3-10 membered heterocyclyl, heteroarylyl, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 4.1 and COOR 4.1 groups, which can optionally be substituted with 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 4.1 groups.

[0072] The 3-20 membered heterocyclyl represents a saturated or unsaturated non-aromatic ring or ring system, such as a 4-, 5-, 6- or 7-membered monocyclic group, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic (e.g. fused, bridged, spirocyclic) or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and contains at least one, such as 1, 2, 3, 4, 5 or more heteroatoms independently selected from O, S and N, wherein N and S can also optionally be oxidized to various oxidation states to form a nitrogen oxide, -S(O)- or -S(O)2- state;

[0073] The C 6-20 aryl represents a monovalent aromatic or partially aromatic monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, which can be a single aromatic ring or multiple aromatic rings fused together;

[0074] The 5-20 membered heteroaryl represents a monovalent monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic aromatic ring system having 5 to 20 ring atoms and comprising 1, 2, 3, 4, 5 or more heteroatoms independently selected from N, O and S.

[0075] L represents a bond, C 2-20 alkynyl or Cy; wherein L can be attached to X1or R c at any site;

[0076] Cy represents a bond, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, wherein the 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl can optionally be fused to a 4-12 membered cycloalkyl or cycloalkenyl group, with the proviso that when the heterocyclyl group contains a N atom, the heterocyclyl group can be bonded to the carbon atom at the 2-position of the pyrimidine ring in Formula IV via its N atom or C atom;

[0077] L represents alkynyl; a mono- or polycyclic C 6-20-aryl, a mono- or polycyclic C 6-20 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 6-20 -aryl and a 4- to 12-membered cycloalkenyl, each independently optionally substituted at the ortho-, para- or meta-position by 1, 2 or more groups independently selected from F, CI, Br, OH, CN, NH2, or by 1, 2 or more groups selected from OR 4.1 , COOR 4.1 , CH2COOR 4.1 , CH2CH2COOR 4.1 , CH=CHCOOR 4.1 , CO-NR 4.1 , CH2CO-NR 4.1 , CH2CH2CO-NR 4.1 , CH=CHCO-NR 4.1 , NR 4.2 R 4.3 , CH2-NR 4.2 R 4.3 , CH2CH2-NR 4.2 R 4.3 , C 3-10 -cycloalkyl, C 3-10 -cycloalkenyl, C 1-3 -alkyl-(mono- or polycyclic-C 6-20- aryl), 3- to 10-membered heterocyclyl-C 6-20- aryl, 3- to 10-membered heterocyclyl, C 1-6 -alkyl, C 1-3 -fluoroalkyl, C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 4.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 4.1 , CF3, CHF2, CH2F, C 6-20- aryl-C 1-6 -alkyl, 3- to 10-membered heterocyclyl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6- alkyl, C 6-10 -aryl, SO2-CH3, SO2-CH2CH3and SO2-NR 4.2 R 4.3 , each independently optionally substituted by 1, 2 or more groups selected from OH, OR 4.1 , CF3, CHF2, CH2F, oxo, halogen, CF3, CHF2, CH2F, C 1-6 -alkyl, C 6-10-aryl and NR 4.2 R 4.3 substituted by one or more substituents selected from the group consisting of halogen, OH, oxo, CF3, CHF2, CH2F, CN, NH2, NHR

[0078] L represents a group selected from a heterocycle or heteroaryl, each independently optionally substituted at the ortho, para or meta position by one, two or more groups of halogen, OH, oxo, CF3, CHF2and CH2F, or by one, two or more groups selected from OR 4.1 , C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 4.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 4.1 , C 1-3 -alkyl-OR 4.1 , SR 4.1 , C 1-3 -alkyl-SR 4.1 , SO-R 4.1 , C 1-3 -alkyl-SOR 4.1 , SO2-R 4.1 , C 1-3 -alkyl-SO2R 4.1 , COOR 4.1 , CH2COOR 4.1 , CH2CH2COOR 4.1 , CH=CHCOOR 4.1 , CO-NR 4.1 CH2CO-NR 4.1 , CH2CH2CO-NR 4.1 , CH=CHCO-NR 4.1 , COR 4.1 , CH2COR 4.1 , mono- or bicyclic C 3-10 -cycloalkyl, mono- or bicyclic C 3-10 -cycloalkenyl, 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-(mono- or polycyclic-C 6-20- aryl), 3-10 membered heterocyclyl-C 6-20- aryl, 3-10 membered heterocyclyl, 5-20 membered heteroaryl C 1-3 -alkyl-OR 4.1 and NR 4.2 R 4.3The substituents are replaced by substituents, which may be independently and optionally selected from OH, OR 4.1 Oxide, halogen, CF3, CHF2, CH2F, C 1-6- Alkyl, C 6-20- Aryl and NR 4.2 R 4.3 One, two or more substituents are substituted;

[0079] Heterocycles represent 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, fused or bridged rings containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O.

[0080] The heteroaryl group is a 5- to 10-membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; in some embodiments, L is selected from 5-membered monocyclic heteroaryl, 5-membered heteroaryl-5-10-membered heteroaryl, 5-membered heteroaryl-4-12-membered cycloalkyl, 5-membered heteroaryl-4-12-membered cycloalkenyl, 5-membered heteroaryl-4-12-membered heterocycloalkyl, 5-membered heteroaryl-4-12-membered heterocycloalkenyl, 5-membered heteroaryl-4-12-membered heterocycloalkenyl, 6-membered heteroaryl-5-10-membered heteroaryl, 6-membered heteroaryl-6-membered heteroaryl, 6-membered heteroaryl-4-12-membered cycloalkyl, 6-membered heteroaryl-4-12-membered cycloalkenyl, 6-membered heteroaryl-4-12-membered heterocycloalkyl;

[0081] R 4.1 Is it H or selected from C? 1-6- Alkyl, C 1-6- Alkyl alcohols, C 1-3 - Haloalkyl, C 3-11 - Mono- or diheterocyclic groups, -C 3-10 -cycloalkyl, C 6-20- Aryl-C 1-6 -alkyl, 5-20-membered heteroaryl-C 1-6 -alkyl, 3-10 membered heterocyclic -C 1-6 -alkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl, C 3- 10 -cycloalkenyl-C 1-6 -alkyl, mono- or bicyclic C 6-20- Aryl, 5-20 membered heteroaryl and heterocyclic compounds, optionally selected from OH, O-(C 1-3 -alkyl), halogen, C 1-10- Alkyl and C 6-20- Aryl group substitution;

[0082] R 4.2 and R 4.3 H or selected from C can be represented independently of each other. 1-6-alkyl, mono- or bicyclic C 3-10- cycloalkyl, mono- or bicyclic C 3-10- cycloalkenyl, C 6-20- aryl-C 1-6 -alkyl, 5-20 membered heteroaryl-C 1-6 alkylene, mono- or bicyclic C 6-20- aryl, 3-10 membered heterocyclyl, heteroarylyl, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 4.1 and COOR 4.1 groups, which can optionally be substituted with 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 4.1 .

[0083] According to embodiments of the present disclosure, examples of L can be selected from the following groups:

[0084] According to embodiments of the present disclosure, the compound of Formula X can be selected from the following compounds (prefix MX is omitted):

[0085] The present disclosure also provides a method of preparing a compound represented by Formula X, a racemate, stereoisomer, tautomer, isotopically-labeled, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein the method of preparing comprises reacting a compound of Formula A1 with a compound of Formula B1 to obtain a compound represented by Formula X:

[0086] wherein LG is a leaving group, for example, Cl, Br, or I;

[0087] R e , R d21 , R d22, U, R a , R b , R c , R f , R g , R h , R i , A, B, X1independently of one another have the definitions described above;

[0088] and, optionally, derivatizing a compound of Formula X into a stereoisomer, tautomer, isotopically labeled, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug thereof;

[0089] wherein LG is a leaving group, such as Cl, Br, or I;

[0090] Cy, W, R a , R b , R c , R2, R 2’ , R f , R g , R h , R i , m independently of one another have the definitions described above.

[0091] According to embodiments of the present disclosure, the reaction can be performed with protecting groups on the compound of Formula A1and / or B1, if desired. For example, the protecting groups can be selected from amino protecting groups, hydroxyl protecting groups, and the like. Suitable protecting groups can be selected from C 1-40 alkyl, C 6-20 aryl C 1-40 alkyl-, such as tert-butyl, isopropyl, benzyl, tert-butoxycarbonyl (Boc), 2-biphenylyl-2- propyloxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl.

[0092] According to embodiments of the present disclosure, the preparation method can be performed in the presence of a solvent, such as an organic solvent. For example, the organic solvent can be selected from at least one of alcohols, such as methanol, ethanol, isopropanol, n-butanol; ethers, such as ethyl propyl ether, n-butyl ether, anisole, phenetol, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl glycol, diphenyl 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 polyethers of ethylene oxide and / or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, and the like that can 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.

[0093] The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of a compound represented by Formula X (e.g., a compound represented by Formula X-1), a racemate, a stereoisomer, a tautomer, an isotopically-labeled material, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof.

[0094] According to embodiments of the present disclosure, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0095] According to embodiments of the present disclosure, the pharmaceutical composition can further comprise one or more additional therapeutic agents. The additional therapeutic agent can be selected from a therapeutic agent having the same or different target as the compound of the present disclosure, such as a cancer therapeutic agent.

[0096] The present disclosure also provides use of at least one of a compound represented by Formula X (e.g., a compound represented by Formula X-1), a racemate, a stereoisomer, a tautomer, an isotopically-labeled material, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof in the manufacture of a medicament.

[0097] The medicament can be used for preventing or treating a disease.

[0098] The present disclosure also provides a method for preventing or treating a disease, comprising administering to a patient in need thereof at least one of a compound represented by Formula X (e.g., a compound represented by Formula X-1), a racemate, a stereoisomer, a tautomer, an isotopically-labeled material, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof.

[0099] According to embodiments of the present disclosure, the disease can be a PDE4B mediated disease, or at least a PDE4 mediated disease.

[0100] For example, the at least a PDE4 mediated disease is selected from a PDE4 mediated disease, or a disease mediated by at least one (such as 1, 2, 3, or 4) of PDE1, PDE2, PDE3, and PDE5.

[0101] For example, the medicament can be used for preventing or treating a disease mediated by PDE4 and at least one (such as 1, 2, 3, or 4) of PDE1, PDE2, PDE3, and PDE5.

[0102] According to embodiments of the present disclosure, the PDE4 is selected from PDE4A, PDE4B (such as PDE4B2), PDE4C, and PDE4D (such as PDE4D2).

[0103] According to embodiments of the present disclosure, the PDE1 is selected from PDE1A, PDE1B, and PDE1C.

[0104] According to embodiments of the present disclosure, the PDE2 is selected from PDE2A.

[0105] According to embodiments of the present disclosure, the PDE3 is selected from PDE3A and PDE3B.

[0106] According to embodiments of the present disclosure, the PDE5 is selected from PDE5A.

[0107] According to embodiments of the present application, the diseases include, but are not limited to, respiratory tract inflammatory diseases, inflammatory bowel diseases, arthritic diseases, skin inflammatory diseases, psoriasis and other inflammatory skin diseases, rheumatoid arthritis (RA), ocular inflammatory diseases, diseases of the peripheral or central nervous system, degenerative disorders of the central nervous system, Alzheimer's Disease (AD), Non-alcoholic Steatohepatitis (NASH), Idiopathic Pulmonary Fibrosis (IPF) or Pulmonary Hypertension associated therewith, chronic obstructive pulmonary disease (COPD) or Pulmonary Hypertension associated therewith, hepatic fibrosis (HF), Renal fibrosis, benign prostatic hyperplasia (BPH), Gastroesophageal Reflux disease, Obstructive Sleep apnea, Coronary Artery Disease, Heart Failure (HF), Ischemic heart disease, diabetes-related nephropathy, cancer-related solid tumors, leukemia and lymphoma, and obesity associated with metabolic disorders.

[0108] According to embodiments of the present application, the cancers include, but are not limited to, one selected from the group consisting of stomach cancer, bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, cancer of the central nervous system, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gall bladder cancer, gastrointestinal cancer, genital cancer, genitourinary tract cancer, head cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, muscle tissue cancer, neck 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.

[0109] According to embodiments of the present application, the diseases are preferably selected from those diseases for which the use of a compound having a specific tissue distribution and / or low hERG inhibition is particularly advantageous for prevention or treatment.

[0110] For example, the site of the disease (i.e., the portion of the body where the pathology occurs) includes the respiratory system, the digestive system, the excretory system, and / or the reproductive system, such as the liver, the kidneys, and / or the prostate. To this end, the medicament can be a targeted medicament of the respiratory system, the digestive system, the excretory system, and / or the reproductive system, such as a liver-targeted medicament, a kidney-targeted medicament, and / or a prostate-targeted medicament.

[0111] As a medicament, the compounds of the present disclosure can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and they can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. They can be administered topically (e.g., transdermal, transcutaneous, opthalmic, and mucosal including intranasal, vaginal, and rectal delivery), pulmonary (e.g., through the inhalation or insufflation of powders or aerosols, including by nebulizers; intratracheal, intranasal), oral or parenteral. Parenteral administration includes subcutaneous, intravenous, intraarterial, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intracerebroventricular, administration. They can be administered parenterally, in a single dose, or they can be administered by continuous infusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners, and the like can be necessary or desirable.

[0112] In making the compositions of the present disclosure, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, e.g., a capsule, sachet, paper, or other container. When the excipient functions as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, a carrier, or a medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid), ointments containing, e.g., up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0113] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the present disclosure can be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing appropriate

[0114] The compositions can be formulated in unit dosage form for ease of administration and uniformity of dosage. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0115] The effective dosage of active compound will vary widely depending on the particular compound employed, the particular condition being treated, the mode of administration, the age, weight and sex of the patient, the severity of the condition, and other factors. However, the dosage of the active compound is generally in the range of 0.01 to 100 mg / kg, more usually 0.1 to 50 mg / kg, and most usually 0.5 to 10 mg / kg, of body weight per day, administered in one to four doses per day.

[0116] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed essentially evenly throughout the composition so that the composition can be subdivided into equally effective dosage units such as tablets, pills and capsules.

[0117] The tablets or pills of the present disclosure can be coated or otherwise compounded to provide a dosage form affording the release of the active ingredient in a particular fashion. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, with the latter being in turn compressed discrete segments. The inner segment can contain an active ingredient which is intended to be released immediately, while the outer segment(s) contain a compound which acts, for example, as a enteric coating or as an agent which protects the inner segment from the action of enzymes in the gastrointestinal tract. Preferred agents for enteric coatings and agents which act to protect the inner segment from enzymatic action are those which are not hydrosoluble.

[0118] Liquid forms in which the compounds and compositions of the present disclosure can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored suspensions, aqueous or oil suspensions, and flavored, emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0119] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described supra. In certain embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. The compositions can be nebulized by use of inert gases. Nebulized solutions can be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

[0120] 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.

[0121] 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.

[0122] 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

[0123] This disclosure provides novel compounds having a novel pyrimidine fused ring as a novel parent core, novel side chains, novel linkers, and substituents. The compounds of this disclosure exhibit excellent PDE4B inhibitory activity, even at the pmol level. The compounds of this disclosure also exhibit selective PDE4B inhibitory activity, particularly selective inhibitory activity against PDE4D / 4B.

[0124] The compounds of the present disclosure can be used for treating respiratory inflammatory diseases, inflammatory bowel diseases, arthritic diseases, skin inflammatory diseases, eye inflammatory diseases, and diseases of peripheral or central nervous system or cancers. Also, the compounds of the present disclosure have specific tissue distribution and / or low hERG inhibition, thus have promising tissue-targeting drug application prospects and improved tissue toxicity.

[0125] Definitions of terms and explanations

[0126] Unless otherwise indicated, the definitions of groups and terms in the specification and claims hereof, including definitions of examples, illustrative examples, preferred definitions, definitions set forth in tables, definitions of specific compounds in examples, etc., can be combined and / or combined with each other in any manner. The group definitions and compound structures after such combination should be understood to be within the scope of the specification and / or claims.

[0127] Unless otherwise indicated, the numerical ranges recited in the specification and claims hereof, are inclusive of the integers within the recited ranges. For example, a numerical range of "1-20" is inclusive of the integers of 1-10, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and the integers of 11-20, i.e., 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In addition, when certain numerical ranges are described as "numbers", it should be understood that the two endpoints of the range, each integer within the range, and each decimal within the range are recited. For example, "numbers from 0 to 10" should be understood to recite each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, and at least each integer multiplied by 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.

[0128] It should be understood that herein, in describing 1, 2, or more, "more" should mean greater than 2, for example, an integer greater than or equal to 3, for example, 3, 4, 5, 6, 7, 8, 9, or 10.

[0129] The term "halogen" means fluorine, chlorine, bromine, and iodine.

[0130] The term "C 1-20 "alkyl" is understood to mean a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1 to 20 carbon atoms. For example, "C 1-10 "alkyl" means a straight-chain and branched-chain alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, "C 1-6"Alkyl" denotes straight-chained and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl groups are, 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 and the like or isomers thereof.

[0131] The term "C 2-20 "Alkenyl" is to be understood as preferably denoting a straight-chained or branched univalent hydrocarbon group which contains 1, 2 or more double bonds and has 2 to 20 carbon atoms, preferably "C 2-10 "Alkenyl". "C 2-10 "Alkenyl" is to be understood as preferably denoting a straight-chained or branched univalent hydrocarbon group which contains 1, 2 or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, 2, 3, 4, 5 or 6 carbon atoms (i.e. C 2-6 "Alkenyl". "C 2-3Alkynyl). It is to be understood that in case the alkynyl group comprises more than one triple bond, the triple bonds can be separated from each other or conjugated. The alkynyl group is, for example, ethynyl, propynyl, (E)-but-2-ynyl, (Z)-but-2-ynyl, (E)-but-1-ynyl, (Z)-but-1-ynyl, pent-4-ynyl, (E)-pent-3-ynyl, (Z)-pent-3-ynyl, (E)-pent-2-ynyl, (Z)-pent-2-ynyl, (E)-pent-1-ynyl, (Z)-pent-1-ynyl, hex-5-ynyl, (E)-hex-4-ynyl, (Z)-hex-4-ynyl, (E)-hex-3-ynyl, (Z)-hex-3-ynyl, (E)-hex-2-ynyl, (Z)-hex-2-ynyl, (E)-hex-1-ynyl, (Z)-hex-1-ynyl, 1-ethynylpropyl, 1-propynyl, 1-isopropynyl.

[0132] The term "C 2-20 Alkynyl" is to be understood as preferably denoting a straight-chain or branched one- valent hydrocarbon group comprising 1, 2 or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, 2, 3, 4, 5 or 6 carbon atoms (i.e. "C 2-10 Alkynyl"). The term "C 2-10 Alkynyl" is to be understood as preferably denoting a straight-chain or branched one- valent hydrocarbon group comprising 1, 2 or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, 2, 3, 4, 5 or 6 carbon atoms (i.e. "C 2-6 Alkynyl"). The term "C 2-3alkynyl groups). The alkynyl groups are, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0133] The term "C 3-20 Cycloalkyl" is understood to mean a saturated, monovalent, monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic hydrocarbon ring or a tricycloalkane having 3 to 20 carbon atoms, preferably "C 3-10 Cycloalkyl" is understood to mean a saturated, monovalent, monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic hydrocarbon ring or a tricycloalkane having 3 to 20 carbon atoms, preferably "C 3-10 Cycloalkyl" is understood to mean a saturated, monovalent, monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic hydrocarbon ring or a tricycloalkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The C 3-10 Cycloalkyl" is understood to mean a saturated, monovalent, monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic hydrocarbon ring or a tricycloalkane having 3 to 20 carbon atoms, preferably "C

[0134] The term "C 3-20 Cycloalkyl" is understood to mean a saturated, monovalent, monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic hydrocarbon ring or a tricycloalkane having 3 to 20 carbon atoms, preferably "C 3-20 Cycloalkyl" is understood to mean a saturated, monovalent, monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic hydrocarbon ring or a tricycloalkane having 3 to 20 carbon atoms, preferably "C 3-20When 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.

[0135] Unless otherwise defined, the term "3-20 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic (e.g., fused, bridged, spirocyclic) or 10-, 11-, 12-, 13-, 14-, or 15-membered tricyclic ring system, and contains at least one, e.g., 1, 2, 3, 4, 5 or more, heteroatoms selected from O, S, and N, wherein N and S can also be optionally oxidized into various oxidation states to form nitroso, -S(O)-, or -S(O)2- states. Preferably, the heterocyclyl group can be selected from "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S, and N. The heterocyclyl group can be attached to the rest of the molecule by any of the carbon atoms or the nitrogen atom, if present. The heterocyclyl group can include fused or bridged rings as well as spirocyclic rings. In particular, the heterocyclyl group can include, but is not limited to: a 4-membered ring such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl group can be benzo-fused. The heterocyclyl group can be bicyclic, such as, but not limited to, a 5,5 membered ring such as hexahydrocyclopenta[c]pyrrol-2(lH)-yl ring, or a 5,6 membered bicyclic ring such as hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl ring. The heterocyclyl group can be partially unsaturated, i.e., it can contain 1, 2, or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-lH-pyrrolyl, 4H-[l,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[l,4]thiazinyl, or it can be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. The 3-20 membered heterocyclyl group can be attached to other groups through a carbon atom on the 3-20 membered heterocyclyl group or through a heteroatom on the 3-20 membered heterocyclyl ring when the 3-20 membered heterocyclyl group is attached to other groups to form a compound of the disclosure. For example, when the 3-20 membered heterocyclyl group is selected from piperazinyl, the nitrogen atom on the piperazinyl group can be attached to other groups. Or when the 3-20 membered heterocyclyl group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom ortho to the nitrogen atom can be attached to other groups. For example, a substituted 4-10 membered heterocyclyl group can be selected from: 1-methylpyrrolidinyl, 1-ethylpyrrolidinyl, 1-cyclopropylpyrrolidinyl, 1-cyclopropylmethylpyrrolidinyl, 5-methyl-4,5-dihydropyridazin-3(2H)-onyl, 1-methylazetidinyl, 1-methylpiperidinyl;

[0136] The term "C6-20 Aryl" is understood as preferably denoting a monovalent aromatic or partially aromatic, monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, which can be a single aromatic ring or multiple aromatic rings that are fused together, preferably "C 6-14 Aryl". The term "C 6-14 Aryl" is understood as preferably denoting a monovalent aromatic or partially aromatic, monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms ("C 6-14 Aryl"), in particular a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 Aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring having 13 carbon atoms ("C 13 Aryl"), such as fluorenyl; or a ring having 14 carbon atoms ("C 14 Aryl"), such as anthryl. When the C 6-20 Aryl" is substituted, it can be mono- or polysubstituted. Also, there is no restriction on the substitution site, e.g. ortho, para or meta substitution.

[0137] The term "5-20 membered heteroaryl" is to be understood as including a monovalent monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic aromatic ring system having 5 to 20 ring atoms and comprising 1 to 5 heteroatoms independently selected from N, O and S, e.g. "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is to be understood as including a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and comprising 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, additionally in each case, can be benzo-fused. "Heteroaryl" also refers to groups in which the heteroaromatic ring is fused to 1, 2 or more aryl, alicyclic or heterocyclyl rings, with the point of attachment being at the heteroaromatic ring. Non-limiting examples of the term heteroaryl include, for example, pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-oxathiadiazolyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,44-thiazolyl, pyridazinyl; and 1-, 2-, 3-, 5-, 6-, 7- or 8-indolizinyl, 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-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinoxalinyl, 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-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazolylcarbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-oxazinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenoxazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenoxazinyl, 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]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-ortho-oxazinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]-thiazolyl, 2-, 4- or 5-1H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2,4] triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 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-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-1H-pyrrolo[1,2-b][2]benzazapinyl. 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]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-20 membered heteroaryl group is attached to other groups to form a compound of the present disclosure, it can be attached to a carbon atom of the 5-20 membered heteroaryl ring or to a heteroatom of the 5-20 membered heteroaryl ring. When the 5-20 membered heteroaryl group is substituted, it can be mono- or polysubstituted. Also, there is no limitation on the substitution site, for example, a hydrogen attached to a carbon atom of the heteroaryl ring can be substituted, or a hydrogen attached to a heteroatom of the heteroaryl ring can be substituted.

[0138] Unless otherwise defined, in the context of the present disclosure, when a substituent is defined as a group or a structure that can be bonded to a linking position in a compound described herein, there is no particular limitation on the specific position in the compound to which the substituent is bonded, for example, either end of the group or structure that can be bonded to the linking position in the compound can be bonded to the linking position in the compound, as long as the bonding conforms to the valence theory. Alternatively, when a substituent is defined as two groups connected to each other (e.g., in the form of “group 1-group 2” or “group 1 and group 2”, where group 1 and group 2 are the same or different), there is no particular limitation on the specific position in the compound to which the substituent is bonded, for example, either group 1 or group 2 can be bonded to the linking position in the compound, as long as the bonding conforms to the valence theory. Also, there is no particular limitation on the position at which the two groups (e.g., group 1 and group 2) are connected to each other, as long as the connection conforms to the valence theory.

[0139] For example, for -C 3-20 cycloalkyl-, -C 3-20cycloalkenyl-, -3-20 membered heterocycloalkyl-, -5-20 membered heterocycloalkenyl-, -C 6-20 aryl-, -5-20 membered heteroaryl-, -C 3-20 cycloalkyl and C 6-20 aryl-, -C 3-20 cycloalkyl and 5-20 membered heteroaryl-, -3-20 membered heterocycloalkyl and C 6- 20 aryl-, -3-20 membered heterocycloalkyl and 5-20 membered heteroaryl-, -5-20 membered heterocycloalkenyl and C 6-20 aryl-, -5-20 membered heterocycloalkenyl and 5-20 membered heteroaryl-, -C 5-20 cycloalkenyl and C 6-20 aryl-, -C 5-20 cycloalkenyl and 5-20 membered heteroaryl-, -3-20 membered heterocycloalkyl and 5-20 membered heteroaryl and C 3-20 cycloalkyl-, any two groups can be linked to the linking position in the compound.

[0140] It should be understood that when a substituent is defined as three groups connected together (such as in the form of "group 1 - group 2 - group 3" or "group 1 and group 2 and group 3", wherein group 1, group 2 and group 3 are the same or different), there is no particular limitation on the specific position of the linking of the substituent to the compound, for example, according to the connection relationship in the structural formula, any one of group 1, group 2 and group 3 can be connected to other groups in the structural formula, or any two of group 1, group 2 and group 3 can be connected to other groups in the structural formula, as long as the above linking conforms to the valence theory. Also, there is no particular limitation on the connection position between the three groups (such as group 1, group 2 and group 3), as long as the above connection conforms to the valence theory.

[0141] For example, for -3-20 membered heterocycloalkyl and 5-20 membered heteroaryl and C 3-20 cycloalkyl-, which can be 3-20 membered heterocycloalkyl, 5-20 membered heteroaryl, C 3-20 cycloalkyl, any two groups are connected to other groups in the structural formula. Also, 3-20 membered heterocycloalkyl, 5-20 membered heteroaryl, C 3-20 cycloalkyl, there is no particular limitation on the connection position, as long as the above connection conforms to the valence theory.

[0142] It should be understood that when a substituent is described in the form of "group 1 - group 2" in the context of the present disclosure, if a chemical bond "-" is added on the left side of group 1 or on the right side of group 2, it means that the connection position of the compound of formula X has been determined, and the position of the bond in the compound described in formula X is the corresponding group with the added chemical bond.

[0143] The term "spiro" refers to a ring system in which two rings share one ring atom.

[0144] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0145] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0146] Unless otherwise indicated, a heterocyclyl, 5-20 membered heteroaryl or heteroarylenyl group includes all possible isomeric forms thereof, e.g. positional isomers. Thus, for some illustrative, non-limiting examples, forms which can be included are those substituted or bonded at one, two or more positions in its 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) include pyridin-2-yl, pyridin-2-yl ene, pyridin-3-yl, pyridin-3-yl ene, pyridin-4-yl and pyridin-4-yl ene; thienyl or thienylene include thien-2-yl, thien-2-yl ene, thien-3-yl and thien-3-yl ene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

[0147] The term "oxo (=0)" refers to the replacement of a hydrogen or lone pair of electrons on a non-oxygen atom by oxygen, e.g. after being oxo-substituted is after being oxo-substituted is

[0148] Unless otherwise indicated, the definition of a term herein is also applicable to a group containing that term, e.g. C 1-6 The definition of alkyl is also applicable to C 1-6 The definition of alkyl is also applicable to C 3-8 The definition of alkyl is also applicable to C 1-6 The definition of alkyl is also applicable to C

[0149] In the context of the present disclosure, a "—", "—", "—" or "—" in a substituent is intended to mark the chemical bond for which the substituent is used for connection;

[0150] It will be appreciated by those skilled in the art that the compounds of Formula I can exist in various pharmaceutically acceptable salt forms. 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. carboxyl) and a basic center (e.g. amino), they can also form internal salts.

[0151] ​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 compound's crystal lattice. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] Depending on their molecular structure, the compounds of the present disclosure can be chiral and thus various enantiomeric forms can exist. The compounds can thus exist in racemic form or in optically active form. The present disclosure encompasses the isomers in which each chiral carbon is in the R or S configuration or mixtures thereof, racemates. The compounds of the present disclosure, or, alternatively, the intermediates, can be separated into the individual enantiomeric compounds either by classical chemical separation methods or by chiral synthesis using appropriate chiral reagents. In the case of racemic amines, the diastereomeric non- enantiomeric forms are prepared from mixtures thereof by reaction with optically active resolving agents. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, the appropriate N-protected amino acids, e.g. N-benzylphenylalanine or N-benzenesulfonylphenylalanine, or the various optically active camphorsulfonic acids. Chromatographic enantiomeric resolutions can also be advantageously performed with the aid of optically active stationary phases, e.g. dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatizing agents, e.g. isopropylidenal. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, e.g. hexane / isopropanol / acetonitrile. The corresponding stable isomers can be isolated according to known methods, e.g. by extraction, filtration or column chromatography.

[0156] An "isotope" is any atom or molecule that possesses the same atomic number but a different mass number from that characteristic of the element. Examples of isotopes suitable for inclusion in the compounds of the application are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, and include3H,3C,13C,14C,15N,18O,31P,32P,35S,18F and36CI, respectively. Certain isotopically-labelled compounds of the present application, for example those incorporating positron emitting isotopes, are useful in Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) studies for determination of tissue distribution and for imaging brain receptor binding. 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 31 P, 32 P, 35 S, 18 F and 36 C1. Isotopically-labelled compounds of the application can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labelled reagent in place of the non-isotopically labelled reagent otherwise employed. Such compounds, having a stable isotope, are identified by attachment of the designated isotopic atom(s) to the molecule. Such compounds are useful in bioassays for determination of binding affinity and in drug metabolism studies.

[0157] The term "prodrug" means a compound which can be converted under physiological conditions or by solvoiytic cleavage to a biologically active compound of the present disclosure. A prodrug of the present disclosure is prepared by modifying a functional group of the compound in such a way that its effectiveness is retained and its solubility is improved. Prodrugs include compounds wherein a hydroxy or amino group in a compound of the present disclosure is attached to any group which, when the prodrug of the compound of the present disclosure is administered to a mammalian subject, is cleaved to form a free hydroxyl or free amino group, respectively.

[0158] The term "patient" means any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, most preferably humans.

[0159] The term "therapeutically effective amount" means an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease: for example, preventing a disease, disorder, or condition from occurring in an individual that is predisposed or does not yet exhibit symptoms of the disease pathology; (2) inhibiting the disease: for example, arresting the development of a disease, disorder, or condition (i.e., retarding the further development of pathologies and / or symptoms) in an individual that is experiencing or has experienced a pathology or symptoms of the disease; (3) relieving the disease: for example, relieving a disease, disorder, or condition (i.e., reversing the pathology and / or symptoms) in an individual that is experiencing or has experienced a pathology or symptoms of the disease. DETAILED DESCRIPTION

[0160] The technical solutions of the present disclosure will be further described in detail below in conjunction with specific examples. It should be understood that the following examples are only illustratively described and explained for the present disclosure, and should not be interpreted as limiting the scope of protection of the present disclosure. Any technology realized based on the above description of the present disclosure is covered within the scope intended to be protected by the present disclosure.

[0161] Unless otherwise indicated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0162] Table of Abbreviations

[0163] DMF: N,N-dimethylformamide

[0164] DCM: dichloromethane

[0165] DIEA: N,N-diisopropylethylamine

[0166] TEA: triethylamine

[0167] PE: petroleum ether

[0168] EA: ethyl acetate

[0169] MeCN: acetonitrile

[0170] Et2O: diethyl ether

[0171] DMSO: dimethyl sulfoxide

[0172] EtOAc: ethyl acetate

[0173] THF: tetrahydrofuran

[0174] TFA: trifluoroacetic acid

[0175] MeOH: methanol

[0176] EtOH: ethanol

[0177] NaH: sodium hydride

[0178] MeI: methyl iodide

[0179] EtI: ethyl iodide

[0180] HFP: 1,1,1,3,3,3-hexafluoro-2-propanol

[0181] DHP: 3,4-dihydro-2H-pyran

[0182] PPTS: 4-methylphenylsulfonic acid pyridinium

[0183] PPh3: triphenylphosphine

[0184] DEAD: diethyl azodicarboxylate

[0185] MsCl: methylsulfonyl chloride

[0186] TMSOTf: trimethylsilyl triflate

[0187] m-CPBA: meta-chloroperoxybenzoic acid

[0188] Analytical methods

[0189] 1. Nuclear magnetic resonance (NMR) spectra were recorded from a 400 MHz Bruker AVANCE III 500 instrument. Chemical shifts were reported in ppm with a deuterium residual solvent as an internal standard. Peak multiplicities are indicated as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; m, multiplet; br s, broad singlet.

[0190] 2. Purity analysis of samples was performed on a Waters HPLC / Waters MS system.

[0191] Chromatographic conditions 1:

[0192] Column Waters X-Bridge-C18 50 mm*4.6 mm*3.5 μm

[0193] Column temperature 40 °C.

[0194] Sample temperature: room temperature

[0195] Detection UV 214 nm, UV 254 nm

[0196] Flow rate: 2 mL / min: 2 mL / min.

[0197] Mobile phase A: water (0.05% TFA) B: MeCN

[0198] Mobile phase B: MeCN (0.05% TFA)

[0199] Gradient program: B from 5% to 100% for 1.6 min, 100% for 1.4 min.

[0200] Chromatography conditions 2:

[0201] Column: Waters X Brdige C18 Waters X Brdige C18: 4.6 mm*50 mm*3.5 μm

[0202] Column temperature 40 °C.

[0203] Sample temperature: room temperature

[0204] Detection UV 214 nm, UV 254 nm

[0205] Flow rate: 2 mL / min: 2 mL / min.

[0206] Mobile phase A: water (0.01 mol / L NH4HCO3) B: MeCN

[0207] Mobile phase B: MeCN

[0208] Gradient program: B from 5% to 100%, for 1.6 min, 100% for 1.4 min.

[0209] 3. Preparative HPLC was performed on a Gilson 281.

[0210] Flow rate: 20 mL / min: 20 mL / min.

[0211] Column: X-Select 10 μm 19 X-Select 10 μm 19*250 mm column

[0212] Wavelength: 254 nM or 214 nM

[0213] Solvent A water (10 mM NH4HCO3) and solvent B MeCN.

[0214] Example 1 : synthesis

[0215] 1. Synthesis scheme:

[0216] 2. Experimental part:

[0217] 2.1

[0218] 2-Chloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylic acid tert-butyl ester (02454-1)

[0219] To a solution of 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylic acid tert-butyl ester (1 g, 3.46 mmol) and zinc powder (1.12 g, 17.30 mmol) in MeOH (10 mL) was added acetic acid (1.04 g, 17.30 mmol) at room temperature. The mixture was then stirred at 50 °C for 6 hours, concentrated. DCM (30 mL) was added, filtered and concentrated, the crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 4, silica gel-CS 40 g, 30 mL / min, silica gel, UV 254) to give the product as a yellow solid (385 mg, yield 44%).

[0220] ESI-MS m / z calcd for C 11 H 14 ClN3O2][M+H] + : 256.1 ; found: 256.3

[0221] 2.2

[0222] 2-((1-((Benzoyl)oxy)azetidin-3-yl)oxy)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylic acid tert-butyl ester (02454-3)

[0223] To a solution of 3-hydroxyazetidine-1 -carboxylate benzyl ester (246 mg, 1.20 mmol) and potassium carbonate (486 mg, 3.53 mmol) in MeCN (10 mL) was added 2-chloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylic acid tert-butyl ester (300 mg, 1.18 mmol) and DABCO (13.2 mg, 0.12 mmol) at room temperature. The mixture was then stirred at 80 °C under microwave condition for 2 hours, water (30 mL) was added, extracted with EA (40 mL) for three times. The combined organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give the product as yellow solid (309 mg, yield 62%).

[0224] ESI-MS m / z calcd for C 22 H 26 N4O5][M+H] + : 427.2; found: 426.8

[0225] 2.3

[0226] 3-((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)oxy)azetidine-1-carboxylic acid benzyl ester (02454-3)

[0227] To a solution of tert-butyl 2-((1-((benzyloxy)carbonyl)azetidin-3-yl)oxy)-5H- pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (309 mg, 0.73 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 hour under nitrogen protection, after the starting material was consumed, the mixture was concentrated under reduced pressure to give the product as yellow oil (201 mg, yield 85%) which was used directly for the next step.

[0228] ESI-MS m / z calcd for C 17 H 18 N4O3][M+H]+: 327.1; found: 327.0

[0229] 2.4

[0230] 3-((6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)oxy)azetidine-1-carboxylic acid benzyl ester (02454-4)

[0231] To a solution of benzyl 3-((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2- yl)oxy)azetidine-1-carboxylate (201 mg, 0.62 mmol) and paraformaldehyde (92 mg, 3.08 mmol) in DCM (10 mL) was added sodium triacetylboration hydride (394 mg, 1.86 mmol) portionwise at 0 °C. The mixture was stirred at room temperature under nitrogen overnight, after the starting material was consumed, ice water (15 mL) was added to the mixture, the pH was adjusted to 9 with sodium bicarbonate, and extracted with DCM (30 mL) three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, the resulting crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 0, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give the yellow solid product (34 mg, yield 16%).

[0232] ESI-MS m / z calcd for C 18 H 20 N4O3][M+H] + :341.2; found: 341.2

[0233] 2.5

[0234] tert-Butyl 3-((6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2- yl)oxy)azetidine-1-carboxylate (02454-5)

[0235] To a solution of benzyl 3-((6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2- yl)oxy)azetidine-1-carboxylate (34 mg, 0.10 mmol) in MeOH (3 mL) was added Pd / C (10 mg) and di-tert-butyl dicarbonate (44 mg, 0.20 mmol) at room temperature. The mixture was then stirred under hydrogen at room temperature for 2 hours, after the starting material was consumed. It was filtered and concentrated, the crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 0, silica gel-CS 12 g, 30 mL / min, silica gel, UV 254) to give the yellow solid product (18 mg, yield 59%).

[0236] ESI-MS m / z calcd for C 15 H 22 N4O3][M+H] + :307.2; found: 307.0

[0237] 2.6

[0238] 2-(azetidin-3-yloxy)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (02454-6)

[0239] To a solution of tert-butyl 3-((6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2- yl)oxy)azetidine-1-carboxylate (18 mg, 0.059 mmol) in DCM (2 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature under nitrogen for 1 h. After the starting material was consumed, the mixture was concentrated under reduced pressure to give the product as a white solid (10 mg, 83% yield) which was used directly in the next step.

[0240] ESI-MS m / z calcd for C 10 H 14 N4O][M+H] + :207.1; found: 207.3

[0241] 2.7

[0242] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3-((6-methyl-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-2-yl)oxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02454)

[0243] To a solution of 2-(azetidin-3-yloxy)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (10 mg, 0.049 mmol) in DMF (2 mL) was added (R)-2-chloro-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (14 mg, 0.049 mmol) and DIEA (8.9 mg, 0.15 mmol). The mixture was stirred at 100 °C under nitrogen for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure to remove the solvent. The resulting crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (5.68 mg, 26% yield).

[0244] ESI-MS m / z calcd for C 21 H 27 N7O3S][M+H] + :458.2; found: 457.9

[0245] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.45 (s, 1H), 5.43 - 5.37 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.41 (dd, J = 10.4, 6.4 Hz, 2H), 3.95 (d, J = 7.2 Hz, 2H), 3.80 (d, J = 14.4 Hz, 4H), 3.73 - 3.66 (m, 2H), 3.45 - 3.36 (m, 1H), 3.25 - 3.17 (m, 1H), 2.97 - 2.84 (m, 2H), 2.49 (s, 3H), 2.38 - 2.25 (m, 2H), 2.15 - 2.09 (m, 2H), 1.80 - 1.68 (m, 2H).

[0246] 1. Synthesis scheme:

[0247] 2. Experimental section:

[0248] 2.13-Hydroxybicyclo[4.2.0]octa-l,3,5-triene

[0249] 3-Bromobicyclo[4.2.0]octa-l,3,5-triene (20 mg, 0.11 mmol), Pd2(dba)3 (10 mg, 0.01 mmol), tBu-Xphos (5.6 mg, 0.01 mmol), KOH (7.3 mg, 0.1 mmol) and water (0.2 mL) in 1,4-dioxane (2 mL) was stirred at 80 °C under microwave condition for 2 hours, after the starting material was consumed, the reaction was filtered and concentrated under reduced pressure, which was directly used for the next step.

[0250] 2.2

[0251] 3-(Bicyclo[4.2.0]octa-l,3,5-triene-3-yloxy)azetidine-l-carboxylate (02481-2)

[0252] To a solution of 3-hydroxybicyclo[4.2.0]octa-l,3,5-triene (13 mg, 0.11 mmol) and Cs2C03(107 mg, 0.33 mmol) in DMF (3.0 mL) was added tert-butyl 3-(p-tolylsulfonyloxy)azetidine-l-carboxylate (49 mg, 0.13 mmol) at room temperature. The mixture was then stirred at 80 °C overnight, after the starting material was consumed, water (10 mL) was added, extracted with DCM (10 mL) twice. The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 4, silica gel-CS 4 g, 25 mL / min, silica gel, UV 254) to give the product as colorless oil (12 mg, yield 39.7%).

[0253] ESI-MS m / z calcd for C 16 H 21 NO3][M-56+H] + :220.2; found: 220.1

[0254] 2.3

[0255] (R)-2-(3-(bicyclo[4.2.0]octa-l,3,5-trien-3-yloxy)azetidin-l-yl)-4-((l- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02481)

[0256] A solution of tert-butyl 3-(bicyclo[4.2.0]octa-l,3,5-trien-3-yloxy)azetidine-l- carboxylate (12 mg, 0.04 mmol) and (R)-2-chloro-4-((3,3-difluoro-l- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (12 mg, 0.04 mmol) in HFP (2 mL) was stirred at 120 °C under microwave conditions for 2 hours. After the starting material was consumed, water (10 mL) was then added to the mixture, extracted with DCM (10 mL) twice, the combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by preparative HPLC (MeCN / H20 (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254) to give the compound as white solid (1.89 mg, yield 14.8%).

[0257] ESI-MS m / z calcd for C 22 H 26N4O3S][M+H] + 427.2; Found: 426.8

[0258] 1 H NMR (400 MHz, DMSO-d6) δ 7.45 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.69 - 6.65 (m, 2H), 5.05 - 5.04 (m, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.44 - 4.41 (m, 2H), 3.89 - 3.88 (m, 2H), 3.73 - 3.69 (m, 2H), 3.45 - 3.36 (m, 1H), 3.25 - 3.17 (m, 1H), 3.07 - 3.06 (m, 4H), 3.00 - 2.84 (m, 2H), 2.38 - 2.25 (m, 2H), 2.15 - 2.10 (m, 2H), 1.82 - 1.68 (m, 2H).

[0259] 1. Synthesis scheme:

[0260] 2. Experimental part:

[0261] 2.1

[0262] 4-(4-methylpiperazin-1-yl)phenol (02627-1)

[0263] To a solution of 4-(piperazin-1-yl)phenol (150 mg, 0.84 mmol) in MeCN (2 mL) at 0 °C was added acetic acid (0.5 mL), HCHO aqueous solution (37%, 126 mg, 4.21 mmol) and NaBH3CN (106 mg, 1.68 mmol). The mixture was slowly warmed to room temperature and stirred overnight until the starting material was consumed. It was quenched with saturated NH4Cl (20 mL) aqueous solution at 0 °C and extracted with EA (15 mL) three times. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by column chromatography (EA / PE = 0-100%, silica gel-CS 12 g, 15 mL / min, silica gel, UV 254) to give the product as a white solid (103 mg, yield 64%).

[0264] ESI-MS m / z calcd for C 11 H 16 N2O][M+H] + 193.1; Found: 193.0

[0265] 2.2

[0266] 3-(4-(4-methylpiperazin-1-yl)phenoxy)azetidine-1-carboxylic acid tert-butyl ester (02627-2)

[0267] To a solution of 4-(4-methylpiperazin-1-yl)phenol (103 mg, 0.53 mmol) in DMF (3 mL) and Cs2C03(345 mg, 1.06 mmol) was added 3-(p-tolylsulfonyloxy)azetidine-1-carboxylic acid tert-butyl ester (175 mg, 0.53 mmol). The reaction mixture was stirred at 80 °C for 2 hours, then the mixture was distilled under reduced pressure to remove the solvent. Water (50 mL) was added, and extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA / PE = 0-50%, silica gel-CS 12 g, 20 mL / min, silica gel, UV 254) to give the product as a yellow solid (87 mg, yield 47%).

[0268] ESI-MS m / z calcd for C 19 H 29 N3O3][M+H] + :348.2; found: 348.0

[0269] 2.3

[0270] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3-(4-(4-methylpiperazin-1- yl)phenoxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02627)

[0271] A solution of 3-(4-(4-methylpiperazin-1-yl)phenoxy)azetidine-1-carboxylic acid tert-butyl ester (30 mg, 0.08 mmol) and (R)-2-chloro-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (25 mg, 0.08 mmol) in HFP (2 mL) was stirred at 120 °C for 2 hours under microwave conditions. Then water (10 mL) was added to the mixture, extracted twice with DCM (10 mL), the combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by preparative HPLC (MeCN / H20 (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254) to give the compound as a white solid (3.52 mg, yield 8%).

[0272] ESI-MS m / z calcd for C 25 H 34 N6O3S][M+H] + :499.2; found: 499.2

[0273] 1 H NMR (400 MHz, DMSO-d6) δ 7.45 (s, 1H), 6.91 - 6.87 (m, 2H), 6.77 - 6.74 (m, 2H), 5.04 - 5.00 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.41 (dd, J = 9.6, 6.4 Hz, 2H), 3.95 - 3.84 (m, 2H), 3.70 - 3.67 (m, 2H), 3.45 - 3.36 (m, 1H), 3.25 - 3.17 (m, 1H), 3.01 (t, J = 5.2 Hz, 4H), 2.96 - 2.84 (m, 2H), 2.44 (t, J = 4.8 Hz, 4H), 2.38 - 2.25 (m, 2H), 2.21 (s, 3H), 2.14 - 2.10 (m, 2H), 1.79 - 1.68 (m, 2H).

[0274] 1. Synthesis scheme:

[0275] 2. Experimental part:

[0276] 2.1

[0277] 4-(pyrrolidin-1-ylmethyl)phenol (02644-1)

[0278] To a solution of pyrrolidine (200 mg, 2.82 mmol) and p-hydroxybenzaldehyde (312 mg, 2.56 mmol) in DCM (10 mL) was added sodium triacetylboration hydride (814 mg, 3.84 mmol) portionwise at 0 °C. The mixture was stirred at room temperature under nitrogen overnight, after the starting material was consumed, ice water (15 mL) was added to the mixture, the pH was adjusted to 9 with sodium bicarbonate, and extracted with DCM (30 mL) three times. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, the obtained crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 12 g, 30 mL / min, silica gel, UV 254) to give the product as a white solid (336 mg, yield 74%).

[0279] ESI-MS m / z calcd for C 11 H 15 NO][M+H] + :178.1; found: 178.2

[0280] 2.2

[0281] 3-(4-(pyrrolidin-1-ylmethyl)phenoxy)azetidine-1-carboxylic acid tert-butyl ester (02644-2)

[0282] To a solution of 4-(pyrrolidin-1-ylmethyl)phenol (100 mg, 0.56 mmol) and cesium carbonate (548 mg, 1.68 mmol) in DMF (3 mL) was added 3-(p-tolylsulfonyloxy)azetidine-1-carboxylic acid tert-butyl ester (183 mg, 0.56 mmol) at room temperature. Then the mixture was stirred at 80 °C overnight, water (20 mL) was added, extracted with EA (30 mL) for three times. The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 4, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give the product as a yellow solid (132 mg, yield 71%).

[0283] ESI-MS m / z calcd for C 19 H 28 N2O3][M+H] + :333.2; found: 333.2

[0284] 2.3

[0285] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3-(4-(pyrrolidin-1-ylmethyl)phenoxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02644)

[0286] A solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (26 mg, 0.09 mmol) and 3-(4-(pyrrolidin-1-ylmethyl)phenoxy)azetidine-1-carboxylic acid tert-butyl ester (30 mg, 0.09 mmol) in HFP (2 mL) was stirred at 120 °C for 2 hours under microwave condition. After the reaction was completed, the mixture was distilled to remove the solvent under reduced pressure, the crude product was purified by preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254) to give the product as a white solid (10.4 mg, yield 23.9%).

[0287] ESI-MS m / z calcd for C25 H 33 N5O3S][M+H] + :484.2; found: 483.8

[0288] 1 H NMR (400 MHz, DMSO-d6) δ 7.46 (s, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 5.11 - 5.06 (m, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.44 (dd, J = 10.0, 6.4 Hz, 2H), 3.91 (br, 2H), 3.69 (d, J = 7.2 Hz, 2H), 3.49 (s, 2H), 3.43 - 3.37 (m, 1H), 3.25 - 3.17 (m, 1H), 2.97 - 2.84 (m, 2H), 2.39 - 2.25 (m, 6H), 2.15 - 2.09 (m, 2H), 1.79 - 1.65 (m, 6H).

[0289] 1. Synthesis scheme:

[0290] 2. Experimental part: Compound 02645-0 and R1 were used as starting materials to obtain compound MX02645 following the procedure of example MX-02644. White solid product (3.24 mg, yield 3%).

[0291] ESI-MS m / z calcd for C 26 H 36 N6O3S][M+H] + :513.3; found: 513.0

[0292] 1 H NMR (400 MHz, CD3OD) δ 7.27 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 5.11 - 5.08 (m, 1H), 4.53 - 4.49 (m, 2H), 4.05 - 4.03 (m, 2H), 3.95 - 3.86 (m, 2H), 3.59 - 3.53 (m, 1H), 3.48 - 3.47 (m, 2H), 3.41 - 3.33 (m, 1H), 3.13 - 3.05 (m, 2H), 2.60 - 2.22 (m, 15H), 1.92 - 1.84 (m, 2H).

[0293] 1. Synthesis scheme:

[0294] 2. Experimental part:

[0295] 2.1

[0296] (4-Methoxyphenyl)hydrazine hydrochloride (02656-1)

[0297] To a solution of 4-methoxyaniline (4.0 g, 32.52 mmol) in con. HC1 / H20 (30 mL, v / v = 1 / 1)) was added NaNCte (2.24 g, 32.52 mmol) at -10 °C. The mixture was stirred at -10 °C for 45 min, then a solution of SnCl2.2H20 (14.66 g, 65.04 mmol) in water was added slowly dropwise, the mixture was continued to stir at room temperature for 2 h, filtered and the filter cake was washed with diethyl ether, dried in vacuum to give the product as a brown solid (2.67 g, yield 47.1%).

[0298] ESI-MS m / z calcd for [C7H 10 N2O][M+H] + : 139.1; found: 139.3

[0299] 2.2

[0300] 1-(4-Methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (02656-2)

[0301] To a solution of (4-methoxyphenyl)hydrazine hydrochloride (1 g, 5.75 mmol) in EtOH (20 mL) was added R-1(E)-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoic acid ethyl ester (2 g, 8.62 mmol), TEA (1.6 mL, 11.5 mmol), HATU (564 mg, 1.49 mmol). The mixture was stirred at 80 °C for 2 h, after the starting material was consumed, water (20 mL) was added to the mixture, and extracted with EA (30 mL) for three times. The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give the product as a yellow oil (783 mg, yield 43.4%).

[0302] ESI-MS m / z calcd for [C 14 H 13 F3N2O3][M+H] + : 315.1; found: 315.0

[0303] 2.3

[0304] 1-(4-hydroxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (02656-3)

[0305] To a solution of ethyl 1-(4-hydroxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4- carboxylate (400 mg, 1.27 mmol) in DCM (10 mL) was added BBr3(0.1 mL), the reaction mixture was stirred at room temperature for 3 hours under nitrogen protection, after the starting material was consumed, the reaction was quenched with saturated aqueous NaHC03solution (20 mL) and extracted with EA (30 mL) for three times. The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the obtained crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 2, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product as a white solid (304 mg, yield 90.1%).

[0306] ESI-MS m / z calcd for C 11 H7F3N2O3][M+H] + 273.0; found: 273.0

[0307] 2.4

[0308] N-ethyl-1-(4-hydroxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (02656-4)

[0309] To a solution of 1-(4-hydroxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (200 mg, 0.76 mmol) in DMF (6 mL) was added HATU (433 mg, 1.16 mmol), ethylamine (0.4 mL, 0.92 mmol), TEA (0.52 mL, 3.80 mmol). The mixture was stirred at room temperature for 2 hours, after the starting material was consumed, water (20 mL) was added to the mixture and extracted with EA (30 mL) for three times. The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the obtained crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give the product as a white solid (94 mg, yield 41.4%).

[0310] ESI-MS m / z calcd for C 13 H 12 F3N3O2][M+H] +300.1; found: 300.0

[0311] 2.5

[0312] 3-(4-(4-(ethylcarbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)azetidine-1- carboxylic acid tert-butyl ester (02656-5)

[0313] To a solution of N-ethyl-1-(4-hydroxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4- carboxamide (50 mg, 0.17 mmol) in DMF (2 mL) was added 3-(p-tolylsulfonyloxy)azetidine-1- carboxylic acid tert-butyl ester (66 mg, 0.20 mmol), Cs2CO3(111 mg, 0.34 mmol), the mixture was stirred at 80 °C for 2 hours, after the starting material was consumed, water (20 mL) was added to the mixture, and extracted with EA (30 mL) for three times. The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the obtained crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254), to give the product as a white solid (16 mg, yield 20.7%).

[0314] ESI-MS m / z calcd for C 21 H 25 F3N4O4][M-56+H] + 399.1; found: 399.0

[0315] 2.6

[0316] 1-(4-(azetidin-3-yloxy)phenyl)-N-ethyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0317] (02656-6)

[0318] To a solution of 3-(4-(4-(ethylcarbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)azetidine-1- carboxylic acid tert-butyl ester (16 mg, 0.04 mmol) in DCM (2 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, the crude product was used directly for the next reaction.

[0319] ESI-MS m / z calcd for C 16 H 17 F3N4O2][M+H] +: 355.1 ; found: 355.0

[0320] 2.7

[0321] (R)-N-ethyl-1-(4-((1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7- dihydrothieno[3,2-d]pyrimidin-2-yl)azetidin-3-yl)oxy)phenyl)-5- (trifluoromethyl)-1H-pyrazole-4-carboxamide (MX02656)

[0322] To a solution of 1-(4-(azetidin-3-yloxy)phenyl)-N-ethyl-5-(trifluoromethyl)-1H- pyrazole-4-carboxamide (10 mg, 0.03 mmol) in DMF (3 mL) was added (R)-2- chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5- oxide (11 mg, 0.03 mmol) and DIEA (19 mg, 0.15 mmol). The mixture was stirred at 80 °C under nitrogen protection for 2 hours, after the starting material was consumed, cooled and added to water (10 mL) and extracted with EA (10 mL) for three times. The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product which was purified by prep-HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (6.56 mg, yield 36.1%).

[0323] ESI-MS m / z calcd for C 27 H 30 F3N7O4S][M+H] + : 606.2; found: 605.9

[0324] 1H NMR (400 MHz, DMSO-d6) δ 8.51 (t, J = 5.2 Hz, 1H), 8.06 (s, 1H), 7.45 - 7.43 (m, 3H), 7.07 - 7.03 (m, 2H), 5.23 - 5.19 (m, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.52 - 4.48 (m, 2H), 3.98 - 3.96 (m, 2H), 3.74 - 3.69 (m, 2H), 3.46 - 3.44 (m, 1H), 3.28 - 3.14 (m, 3H), 2.98 - 2.84 (m, 2H), 2.39 - 2.56 (m, 2H), 2.16 - 2.11 (m, 2H), 1.83 - 1.64 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H).

[0325] 1. Synthesis scheme:

[0326] 2. Experimental section: Compound 02665-0 was used as starting material and the procedure of Example MX-02481 was followed to obtain compound MX02665. White solid product (10.0 mg, yield 23.0%).

[0327] ESI-MS m / z calcd for C 25 H 32 FN5O3S][M+H] + : 502.2; found: 502.2

[0328] 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.15 (d, J = 10.8 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 5.12 - 5.08 (m, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.46 - 4.40 (m, 2H), 3.95 - 3.91 (m, 2H), 3.80 (d, J = 9.2 Hz, 4H), 3.70 - 3.68 (m, 2H), 3.45 - 3.37 (m, 1H), 3.25 - 3.18 (m, 1H), 2.97 - 2.84 (m, 2H), 2.70 - 2.65 (m, 1H), 2.36 - 2.25 (m, 2H), 2.15 - 2.10 (m, 2H), 1.80 - 1.70 (m, 2H), 1.08 (d, J = 6.0 Hz, 6H).

[0329] 1. Synthesis scheme:

[0330] 2. Experimental Part: Compound MX02666 was obtained following the procedure of example MX02481 using 02666-0 as starting material. White solid product (3.0 mg, yield 12.45%).

[0331] ESI-MS m / z calcd for C 25 H 33 N5O3S][M+H] + :484.2 found: 484.2 [M+H] +

[0332] 1 H NMR (400 MHz, DMSO-d6) δ 7.41 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.68 (dd, J = 8.4, 2.4 Hz, 1H), 5.08 - 5.06 (m, 1H), 4.83 (t, J = 5.6 Hz, 1H), 4.43 (dd, J = 10.4, 6.8 Hz, 2H), 3.90 - 3.87 (m, 2H), 3.80 (d, J = 15.6 Hz, 4H), 3.69 (d, J = 6.0 Hz, 2H), 3.43 - 3.32 (m, 1H), 3.25 - 3.18 (m, 1H), 2.96 - 2.84 (m, 2H), 2.69 - 2.66 (m, 1H), 2.36 - 2.28 (m, 2H), 2.15 - 2.10 (m, 2H), 1.79 - 1.70 (m, 2H), 1.09 (d, J = 6.4 Hz, 6H).

[0333] 1. Synthesis scheme:

[0334] 2. Experimental Part: Compound MX02667 was obtained following the procedure of example MX-02644 using compound 02667-0 and R1 as starting material. White solid product (5.05 mg, yield 7.2%).

[0335] ESI-MS m / z calcd for C 25 H 32 FN5O3S][M+H] + :502.2; found: 502.0

[0336] 1H NMR (400 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.17 (dd, J = 12.0, 1.6 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.93 (t, J = 8.8 Hz, 1H), 5.17 - 5.12 (m, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.45 (dd, J = 9.2, 5.6 Hz, 2H), 3.95 (d, J = 8.0 Hz, 2H), 3.70 (dd, J = 5.6, 1.6 Hz, 2H), 3.50 (s, 2H), 3.45 - 3.37 (m, 1H), 3.26 - 3.18 (m, 1H), 2.97 - 2.85 (m, 2H), 2.42 - 2.40 (m, 4H), 2.35 - 2.25 (m, 2H), 2.16 - 2.10 (m, 2H), 1.80 - 1.68 (m, 6H).

[0337] 1. Synthesis scheme:

[0338] 2. Experimental section: Compound 02668-0 and R1 were used as starting materials, and the operation in Example MX-02644 was referred to, to obtain compound MX02668. White solid compound (3.52 mg, yield 8%).

[0339] ESI-MS m / z calcd for C 26 H 35 FN6O3S][M+H] + : 499.2; found: 499.2

[0340] 1 H NMR (400 MHz, DMSO-d6) δ 7.48 (s, 1H), 7.15 (dd, J = 12.4, 1.6 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.94 (t, J = 8.4 Hz, 1H), 5.17 - 5.12 (m, 1H), 4.85 (t, J = 6.0 Hz, 1H), 4.47 - 4.42 (m, 2H), 3.96 - 3.91 (m, 2H), 3.73 - 3.66 (m, 2H), 3.45 - 3.37 (m, 4H), 3.25 - 3.18 (m, 2H), 2.97 - 2.85 (m, 2H), 2.38 - 2.21 (m, 8H), 2.18 - 2.09 (m, 5H), 1.82 - 1.68 (m, 2H).

[0341] 1. Synthesis scheme:

[0342] 2. Experimental Section: Compound 02671-0 and R1 were used as starting materials to obtain compound MX02671 following the procedure of example MX-02644. White solid compound (1.91 mg, 12.3% yield).

[0343] ESI-MS m / z calcd for C 26 H 34 FN5O3S][M+H] + : 516.2; found: 516.0

[0344] 1 H NMR (400 MHz, DMSO-d6) δ 7.48 (s, 1H), 7.15 (dd, J = 12.4, 1.6 Hz, 1H), 7.04 - 7.02 (m, 1H), 6.93 (t, J = 8.8 Hz, 1H), 5.16 - 5.14 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.47 - 4.43 (m, 2H), 3.96 - 3.94 (m, 2H), 3.70 - 3.67 (m, 2H), 3.45 - 3.39 (m, 1H), 3.37 - 3.35 (m, 2H), 3.25 - 3.17 (m, 1H), 2.97 - 2.85 (m, 2H), 2.38 - 2.25 (m, 6H), 2.15 - 2.11 (m, 2H), 1.79 - 1.71 (m, 2H), 1.51 - 1.46 (m, 4H), 1.39 - 1.37 (m, 2H).

[0345] 1. Synthesis scheme:

[0346] 2. Experimental Section:

[0347] 2. 1 -(4-bromo-3-fluorobenzyl)-4-methylpiperazine (02692-1 )

[0348] To a solution of 1-bromo-4-(bromomethyl)-2-fluorobenzene (300 mg, 1.12 mmol) in MeCN (10 mL) was added 1-methylpiperazine (224 mg, 2.24 mmol) and potassium carbonate (464 mg, 3.36 mmol). The mixture was stirred at 50 °C under nitrogen protection for 2 h. After the starting material was consumed, water (30 mL) was added to the mixture, which was extracted with EA (50 mL) for three times. The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 0, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give the product as a white solid (270 mg, yield 64%).

[0349] ESI-MS m / z calcd for C 12 H 16 BrFN2][M+H] + :287.1; found: 287.1

[0350] 2.24-(2-Fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-5,6-dihydropyridine-1(2H)- carboxylic acid tert-butyl ester (02692-2)

[0351] To a solution of 1-(4-bromo-3-fluorobenzyl)-4-methylpiperazine (150 mg, 0.52 mmol) in a mixture of 1,4-dioxane and water (5 mL, v / v = 4 / 1) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (324 mg, 1.05 mmol), potassium carbonate (215 mg, 1.56 mmol) and Pd(dppf)Cl2(36.6 mg, 0.05 mmol). The mixture was stirred at 100 °C under nitrogen protection overnight. After the starting material was consumed, the reaction mixture was quenched with water and extracted with EA (30 mL) for two times. The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0 ~ 100%, silica gel-CS 12 g, 30 mL / min, silica gel, UV 254) to give the product as a yellow oil (132 mg, yield 65.3%).

[0352] ESI-MS m / z calcd for C 22 H 32 FN3O2][M+H] + :390.3; found: 390.3

[0353] 2.31 -(3-Fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)benzyl)-4-methylpiperazine (02692-3)

[0354] To a solution of tert-butyl 4-(2-fluoro-4-((4-methylpiperazin-1 -yl)methyl)phenyl)- 5,6-dihydropyridine-1 (2H)-carboxylate (60 mg, 0.15 mmol) in DCM (2.5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature under nitrogen for 1 h, after consumption of starting material, the mixture was concentrated under reduced pressure to give the product as a white solid (37 mg, 85% yield) which was used directly in the next step.

[0355] ESI-MS m / z calcd for C 17 H 24 FN3][M+H] + :290.2; found: 290.3

[0356] 2.4 (R)-2-(4-(2-Fluoro-4-((4-methylpiperazin-1 -yl)methyl)phenyl)-5,6- dihydropyridin-1 (2H)-yl)-4-((1 -(hydroxymethyl)cyclobutyl)amino)-6,7- dihydropyrano[3,2-d]pyrimidine 5-oxide (MX02692)

[0357] To a solution of 1 -(3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)benzyl)-4- methylpiperazine (37 mg, 0.13 mmol) and (R)-2-chloro-4-((1 - (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (37 mg, 0.13 mmol) in DMF (2 mL) was added DIEA (0.1 mL). The mixture was stirred at 100 °C for 2 h, cooled to room temperature and concentrated. The crude product was purified by preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254) to give the compound as a white solid (19.39 mg, 27.6% yield).

[0358] ESI-MS m / z calcd for C 28 H 37 FN6O2S][M+H] + :541.3; found: 541.0

[0359] 1H NMR (400 MHz, DMSO-d6) δ 7.42 (s, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.11 - 7.07 (m, 2H), 6.08 (s, 1H), 4.86 (t, J = 5.6 Hz, 1H), 4.34 (br, 2H), 3.96 (t, J = 5.2 Hz, 2H), 3.78 - 3.71 (m, 2H), 3.47 - 3.39 (m, 3H), 3.25 - 3.18 (m, 1H), 2.98 - 2.84 (m, 2H), 2.41 - 2.17 (m, 14H), 2.14 (s, 3H), 1.81 - 1.71 (m, 2H).

[0360] 1. Synthesis scheme:

[0361] 2. Experimental part: Compound MX02693 was obtained following the procedure of example MX02692, starting from 02693-0. White solid product (30.0 mg, yield 54.15%).

[0362] ESI-MS m / z calcd for C 28 H 35 FN6O3S][M+H] + : 555.2 found: 554.8 [M+H] +

[0363] 1 H NMR (400 MHz, DMSO-d6) δ 7.46 - 7.41 (m, 2H), 7.25 - 7.19 (m, 2H), 6.17 (s, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.36 (s, 2H), 3.97 (t, J = 5.2 Hz, 2H), 3.75 - 3.74 (m, 2H), 3.60 - 3.57 (m, 2H), 3.47 - 3.39 (m, 3H), 3.26 - 3.18 (m, 3H), 2.98 - 2.85 (m, 2H), 2.39 - 2.28 (m, 6H), 2.22 - 2.17 (m, 5H), 1.82 - 1.75 (m, 2H).

[0364] 1. Synthesis scheme:

[0365] 2. Experimental part:

[0366] 2.1

[0367] (6-bromopyridin-3-yl)(4-methylpiperazin-1-yl)methanone (02694-1)

[0368] To a solution of 6-bromonicotinic acid (200 mg, 0.99 mmol) in DCM (6 mL) was added 1 -methylpiperazine (119 mg, 1.19 mmol), TEA (0.68 mL, 4.95 mmol), HATU (564 mg, 1.49 mmol). The mixture was stirred at room temperature for 2 hours, after the starting material was consumed, water (20 mL) was added to the mixture, and extracted with EA (30 mL) for three times. The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the obtained crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give the product as a white solid (189 mg, yield 67.5%).

[0369] ESI-MS m / z calcd for C 11 H 14 BrN3O][M+H] + :284.0; found: 284.0

[0370] 2.2

[0371] 5-(4-methylpiperazin-1 -carbonyl)-5',6'-dihydro-[2,4'-bipyridinyl]-1'(2'H)- carboxylic acid tert-butyl ester

[0372] (02694-2)

[0373] To a solution of (6-bromopyridin-3-yl)(4-methylpiperazin-1 -yl)methanone (100 mg, 0.35 mmol) in 1,4-dioxane / water (4 mL, v / v = 4 / 1 ) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylic acid tert-butyl ester (164 mg, 0.53 mmol), K2CO3(145 mg, 1.05 mmol) and Pd(dppf)CI2(14 mg, 0.02 mmol). The mixture was heated to 80 °C and stirred under nitrogen protection for 8 hours. After cooling, water (10 mL) was added, and extracted with DCM (30 mL) for three times. The solvent was removed from the reaction mixture by distillation under reduced pressure, the crude product was purified by column chromatography (EA / PE = 0~1 / 9, silica gel-CS 20 g, 36 mL / min, silica gel, UV 254) to give the product as a colorless oil (52 mg, yield 61.2%).

[0374] ESI-MS m / z calcd for C 21 H 30N4O3][M+H]+:387.2; Found: 387.4

[0375] 2.3

[0376] (4-methylpiperazin-1-yl)(1',2',3',6'-tetrahydro-[2,4'-bipyridinyl]-5-yl)methanone (02694-3)

[0377] To a solution of tert-butyl 5-(4-methylpiperazine-1-carbonyl)-5',6'-dihydro-[2,4'- bipyridinyl]-1'(2'H)-carboxylate (52 mg, 0.13 mmol) in DCM (5 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the crude product was used directly for the next step.

[0378] ESI-MS m / z calcd for C 16 H 22 N4O][M+H] + :287.2; found: 287.2

[0379] 2.4

[0380] (R)-(1'-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-2-yl)-1',2',3',6'-tetrahydro-[2,4'-bipyridinyl]-5-yl)(4-methylpiperazin-1- yl)methanone

[0381] (MX02694)

[0382] To a solution of (4-methylpiperazin-1-yl)(1',2',3',6'-tetrahydro-[2,4'-bipyridinyl]-5- yl)methanone (45 mg, 0.14 mmol) in DMF (3 mL) was added (R)-2-chloro-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (40 mg, 0.14 mmol) and DIEA (36 mg, 0.28 mmol). The mixture was stirred at 80 °C under nitrogen protection for 2 hours. After the starting material was consumed, it was cooled and added to water (10 mL) and extracted with EA (10 mL) for three times. The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product which was purified by prep-HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (6.04 mg, yield 7.5%).

[0383] ESI-MS m / z calcd for C 27 H 35 N7O3S][M+H] + :538.2; found: 538.0

[0384] 1 HNMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 1.6 Hz, 1H), 7.80 (dd, J = 8.0, 2.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H), 6.89 - 6.88 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.42 (s, 2H), 3.98 (t, J = 5.2 Hz, 2H), 3.76 - 3.75 (m, 2H), 3.61 - 3.36 (m, 2H), 3.47 - 3.39 (m, 3H), 3.25 - 3.18 (m, 1H), 2.98 - 2.92 (m, 1H), 2.89 - 2.84 (m, 1H), 2.65 - 2.64 (m, 2H), 2.43 - 2.30 (m, 6H), 2.23 - 2.19 (m, 5H), 1.83 - 1.76 (m, 2H).

[0385] 1. Synthesis scheme:

[0386] 2. Experimental section: Compound MX02695 was obtained starting from compound 02695-0 and R1 following the procedure of example MX-02627. White solid compound (2.28 mg, 5.2% yield).

[0387] ESI-MS m / z calcd for C 26 H 33 FN6O4S][M+H] + :545.2; found: 544.9

[0388] 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.49 (s, 1H), 7.33 (dd, J = 11.6, 2.0 Hz, 1H), 7.20 - 7.18 (m, 1H), 7.05 (t, J = 8.4 Hz, 1H), 5.25 - 5.20 (m, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.50 - 4.46 (m, 2H), 3.99 - 3.97 (m, 2H), 3.70 - 3.40 (m, 2H), 3.45 - 3.37 (m, 3H), 3.25 - 3.18 (m, 2H), 2.97 - 2.85 (m, 2H), 2.38 - 2.28 (m, 6H), 3.45 (s, 3H), 2.16 - 2.11 (m, 2H), 1.80 - 1.71 (m, 2H).

[0389] 1. Synthesis scheme:

[0390] 2. Experimental section:

[0391] 2.1

[0392] 6-chloro-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (A-1)

[0393] To a reaction mixture of 5-bromo-2-chloropyridine (1 g, 5.23 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (2.43 g, 7.85 mmol) and potassium carbonate (2.17 g, 15.69 mmol) in water (2 mL) and 1,4-dioxane (10 mL) was added Pd(dppf)Cl2(381 mg, 0.52 mmol). The reaction mixture was stirred at 100 °C under argon protection for 3 hours. After the starting material was consumed, water (30 mL) was added to the mixture, which was extracted with EA (40 mL) for three times. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by column chromatography (EA / PE = 0~1 / 2, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give the product as a yellow solid (1.26 g, yield 81.9%).

[0394] ESI-MS m / z calcd for C 15 H 19 ClN2O2][M+H] + : 295.1 ; found: 295.2

[0395] 2.2

[0396] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (02698-1)

[0397] To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-1 (2H)-carboxylate (400 mg, 1.29 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature under nitrogen for 1 h, after consumption of starting material, the mixture was concentrated under reduced pressure to give the product as a white solid (256 mg, yield 94.6%) which was used directly in the next step.

[0398] ESI-MS m / z calcd for C 11 H 20 BNO2][M+H] + :210.2; found: 210.4

[0399] 2.3

[0400] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5,6-dihydropyridin-1 (2H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5- oxide (02698-2)

[0401] To a solution of (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6- tetrahydropyridine (100 mg, 0.48 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (137 mg, 0.48 mmol) in DMF (3 mL) was added DIEA (0.3 mL). The mixture was stirred at 100 °C for 2 h, cooled to room temperature and concentrated. The crude product was purified by column chromatography (DCM / MEOH = 0~1 / 9, silica gel-CS 20 g, 35 mL / min, silica gel, UV 254) to give the product as a white solid (105 mg, yield 47.6%).

[0402] ESI-MS m / z calcd for C 22 H 33 BN4O4S][M+H] + :461.2; found: 461.2

[0403] 2.4

[0404] (R)-1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1,2,3,5”,6,6”-hexahydro-[4,2':5',4”-terpyridine]-1””H)-tert-butyl formate (02698-3)

[0405] To a solution of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5,6-dihydropyridin-1(2H)-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (105 mg, 0.23 mmol) and 6-chloro-5',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-carboxylic acid tert-butyl ester (81 mg, 0.27 mmol) in water (1 mL) and 1,4-dioxane (5 mL), potassium carbonate (95 mg, 0.69 mmol) and Pd(dppf)Cl2 (6.8 mg, 0.023 mmol) were added. The reaction mixture was stirred at 85 °C under argon protection for 4 hours. After the starting materials were consumed, water (30 mL) was added to the mixture, and the mixture was extracted three times with EA (40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (DCM / MEOH = 0–1 / 9, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give a yellow solid product (75 mg, yield 58.3%).

[0406] ESI-MS m / z calculated value [C] 31 H 40 N6O4S][M+H] + Measured value: 593.3; Actual value: 593.3

[0407] 2.5

[0408] (R)-2-(1”,2”,3”,5,6,6”-hexahydro-[4,2':5',4”-tripyridine]-1(2H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02698)

[0409] To a solution of (R)-tert-butyl 1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo- 6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1,2,3,5”,6,6”-hexahydro-[4,2’:5’,4”- terpyridin]-1”(2”H)-carboxylate (38 mg, 0.06 mmol) in DCM (2 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 1 h under nitrogen protection, after the starting material was consumed, the reaction was poured into water (15 mL), the pH was adjusted to 9 with saturated sodium bicarbonate solution, extracted with DCM (20 mL) for three times. The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (12.81 mg, yield 43.4%).

[0410] ESI-MS m / z calcd for C 26 H 32 N6O2S][M+H] + :493.2; found: 493.0

[0411] 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.37 (s, 1H), 6.79 (s, 1H), 6.34 (s, 1H), 4.85 (t, J = 5.2 Hz, 1H), 4.41 (br, 2H), 3.97 (t, J = 5.2 Hz, 2H), 3.75 (d, J = 5.2 Hz, 2H), 3.45 - 3.37 (m, 3H), 3.25 - 3.18 (m, 1H), 2.98 - 2.84 (m, 4H), 2.63 (br, 2H), 2.40 - 2.29 (m, 4H), 2.20 (t, J = 8.4 Hz, 2H), 1.83 - 1.74 (m, 2H).

[0412] 1. Synthesis scheme:

[0413] 2. Experimental section:

[0414] 2.1

[0415] N-(4-bromophenyl)-2-chloro-N-methylacetamide (02699-1)

[0416] A solution of 4-bromo-N-methylaniline (3.0 g, 16.21 mmol) in DCM (30 mL) was added 2-chloroacetyl chloride (1.82 g, 16.21 mmol) and K2CO3(2.23 g, 16.21 mmol) at room temperature. After the mixture was stirred at room temperature for 4 h, it was quenched with water (50 mL) and extracted with EA (50 mL) three times. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 0, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give the product as a brown oil (3.79 g, yield 89%).

[0417] ESI-MS m / z calcd for [C9H9BrClNO] [M+H] + : 262.0; found: 262.2

[0418] 2.2

[0419] N-(4-bromophenyl)-N-methyl-2-(4-methylpiperazin-l-yl)acetamide (02699-2)

[0420] To a solution of N-(4-bromophenyl)-2-chloro-N-methylacetamide (1.0 g, 3.80 mmol) in DMF (10 mL) and K2CO3(1.05 g, 7.60 mmol) was added 1-methylpiperazine (380 mg, 3.80 mmol). The reaction mixture was stirred at room temperature overnight, then the mixture was distilled under reduced pressure to remove the solvent. Water (50 mL) was added and extracted with EA (30 mL) twice. The combined organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 1, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give the product as a brown oil (866 mg, yield 70%).

[0421] ESI-MS m / z calcd for [C 14 H 20 BrN3O] [M+H] + : 326.1; found: 326.0

[0422] 2.3

[0423] N-methyl-2-(4-methylpiperazin-l-yl)-N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)acetamide (02699-3)

[0424] To a solution of N-(4-bromophenyl)-N-methyl-2-(4-methylpiperazin-l-yl)acetamide (400 mg, 1.23 mmol) in 1,4-dioxane (10 mL) was added B2Pin2 (625 mg, 2.46 mmol), KOAc (362 mg, 3.69 mmol) and Pd(dppf)Cl2(84 mg, 0.12 mmol). The mixture was stirred at 100 °C under nitrogen overnight. After the starting material was consumed, the reaction was cooled and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 1, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give the product as a brown solid (347 mg, 75% yield).

[0425] ESI-MS m / z calcd for C 20 H 32 BN3O3][M+H] + : 374.3; found: 374.2

[0426] 2.4

[0427] (R)-N-(4-(4-((l-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-2-yl)phenyl)-N-methyl-2-(4-methylpiperazin-l-yl)acetamide (MX02699)

[0428] To a solution of (R)-2-chloro-4-((l-(hydroxymethyl)cyclobutyl)amino)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (46 mg, 0.16 mmol) in 1,4-dioxane / water (2.5 mL, v / v = 4 / 1) was added N-methyl-2-(4-methylpiperazin-l-yl)-N-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetamide (60 mg, 0.16 mmol), K2CO3(47 mg, 0.48 mmol) and Pd(dppf)Cl2(11 mg, 0.016 mmol). The mixture was stirred at 90 °C under nitrogen for 5 h. After the starting material was consumed, water (20 mL) was added and the mixture was extracted with EA (20 mL) three times. The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting 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 the product as a white solid (2.01 mg, 2.5% yield).

[0429] ESI-MS m / z calcd for C 25 H 34 N6O3S][M+H] + :499.2; found: 498.9

[0430] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 8.8 Hz, 2H), 8.10 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 4.94 (t, J = 5.6 Hz, 1H), 3.84 - 3.81 (m, 2H), 3.69 - 3.60 (m, 1H), 3.39 - 3.35 (m, 1H), 3.30 - 3.37 (m, 4H), 3.06 - 2.95 (m, 3H), 2.46 - 2.32 (m, 9H), 2.25 - 2.16 (m, 3H), 2.08 (s, 3H), 1.89 - 1.80 (m, 2H).

[0431] 1. Synthesis scheme:

[0432] 2. Experimental part: Compound 02711-0 and R1 were used as starting materials, and the procedure of Example MX-02699 was followed to obtain compound MX02711. White solid product (9.89 mg, yield 8%).

[0433] ESI-MS m / z calcd for C 27 H 38 N6O3S][M+H] + :527.3; found: 527.4

[0434] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 8.8 Hz, 2H), 8.10 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 4.94 (t, J = 5.6 Hz, 1H), 3.84 - 3.81 (m, 2H), 3.69 - 3.60 (m, 1H), 3.39 - 3.35 (m, 1H), 3.30 - 3.37 (m, 4H), 3.06 - 2.95 (m, 3H), 2.46 - 2.32 (m, 9H), 2.25 - 2.16 (m, 3H), 2.08 (s, 3H), 1.89 - 1.80 (m, 2H).

[0435] 1. Synthesis scheme:

[0436] 2 Experimental part:

[0437] 2.1

[0438] 4-(5-(4-methylpiperazine-l-formyl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester (02720-1)

[0439] A reaction mixture of (6-bromopyridin-3-yl)(4-methylpiperazin-l-yl)methanone, (140 mg, 0.49 mmol), 4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester, (115 mg, 0.54 mmol), Pd2(dba)3(67 mg, 0.07 mmol), Ruphos (46 mg, 0.10 mmol) t-BuONa (70 mg, 0.74 mmol) in 1,4-dioxane (5 mL) was stirred at 100 °C under argon overnight. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent, and the crude product was purified by column chromatography (EA / PE = 0~1 / 9, silica gel-CS 20 g, 36 mL / min, silica gel, UV 254) to give the product as a colorless oil (41 mg, yield 20.2%).

[0440] ESI-MS m / z calcd for C 22 H 33 N5O3][M+H] + : 416.2; found: 416.4

[0441] 2.2

[0442] (6-(4,7-diazaspiro[2.5]octan-4-yl)pyridin-3-yl)(4-methylpiperazin-l-yl)methanone (02720-2)

[0443] To a solution of 4-(5-(4-methylpiperazine-l-formyl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester (41 mg, 0.10 mmol) in DCM (5 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated, and the crude product was used directly for the next reaction.

[0444] ESI-MS m / z calcd for C 17 H 25 N5O][M+H] + : 316.2; found: 316.3

[0445] 2.3

[0446] (R)-(6-(7-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-2-yl)-4,7-diazaspiro[2.5]octan-4-yl)pyridin-3-yl)(4-methylpiperazin-1- yl)methanone

[0447] (MX02720)

[0448] To a solution of (6-(4,7-diazaspiro[2.5]octan-4-yl)pyridin-3-yl)(4- methylpiperazin-1-yl)methanone, (30 mg, 0.09 mmol) in DMF (3 mL) was added (R)-2- chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5- oxide (27 mg, 0.09 mmol) and DIEA (58 mg, 0.45 mmol). The mixture was stirred at 80 °C under nitrogen protection for 2 hours, after the starting material was consumed, cooled and added to water (10 mL) and extracted with EA (10 mL) for three times. The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product which was purified by prep-HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (11.87 mg, yield 23.3%).

[0449] ESI-MS m / z calcd for C 28 H 38 N8O3S][M+H] + :567.3; found: 567.3

[0450] 1 H NMR (400 MHz, DMSO-d6) d 8.24 (d, J = 1.6 Hz, 1H), 8.16 - 8.15 (m, 1H), 7.65 (dd, J = 8.8, 2.4 Hz, 1H), 7.35 - 7.34 (m, 1H), 7.12 (d, J = 8.4 Hz, 1H), 3.84 - 3.67 (m, 9H), 3.51 - 3.50 (m, 5H), 3.24 - 3.17 (m, 2H), 2.93 - 2.83 (m, 2H), 2.32 - 2.20 (m, 6H), 2.14 - 2.13 (m, 5H), 1.78 - 1.73 (m, 2H), 1.01 - 0.90 (m, 4H).

[0451] 1. Synthesis scheme:

[0452] 2. Experimental Part: Compound 02796-0 and R1 were used as starting materials to obtain compound MX02756 following the procedure of example MX-02481. White solid product (11.95 mg, yield 15%).

[0453] ESI-MS m / z calcd for [C 29 H 42 N6O6S2][M+H] + :635.3; found: 635.3

[0454] 1 H NMR (400 MHz, DMSO-d6) δ 7.56 - 7.49 (m, 1H), 7.46 (s, 1H), 7.40 (dd, J = 8.4, 2.0 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 5.14 - 5.09 (m, 1H), 4.85 (s, 1H), 4.48 - 4.44 (m, 2H), 4.13 (q, J = 6.8 Hz, 2H), 3.97 - 3.94 (m, 2H), 3.73 - 3.67 (m, 2H), 3.45 - 3.37 (m, 1H), 3.26 - 3.18 (m, 1H), 2.97 - 2.85 (m, 3H), 2.74 - 2.67 (m, 2H), 2.40 - 2.06 (m, 9H), 1.84 - 1.63 (m, 6H), 1.36 (t, J = 7.2 Hz, 3H), 1.34 - 1.24 (m, 2H).

[0455] 2. Synthesis scheme:

[0456] 2. Experimental Part: Compound 02767-0 and R1 were used as starting materials to obtain compound MX02767 following the procedure of example MX-02711. White solid product (29.91 mg, yield 44.2%).

[0457] ESI-MS m / z calcd for [C 25 H 33 N5O3S][M+H] + :484.2; found: 484.4

[0458] 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 8.4 Hz, 2H), 8.13 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 4.93 (t, J = 5.6 Hz, 1H), 3.86 - 3.79 (m, 2H), 3.69 - 3.61 (m, 3H), 3.41 - 3.36 (m, 4H), 3.25 - 3.19 (m, 1H), 3.07 - 3.01 (m, 1H), 2.72 - 2.65 (m, 1H), 2.51 - 2.32 (m, 6H), 1.88 - 1.82 (m, 2H), 0.97 (d, J = 6.4 Hz, 6H).

[0459] 1. Synthesis scheme:

[0460] 2. Experimental section: Compound MX02804 was obtained by using compound 02804-0 and R-1 as raw materials, following the procedure of example MX02812. White solid compound (2.16 mg, yield 3.6%).

[0461] ESI-MS m / z calcd for C 27 H 39 N7O3S][M+H] + : 542.3; Found: 542.3

[0462] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 2H), 7.36 (s, 1H), 4.85 (t, J = 6.0 Hz, 1H), 4.69 (d, J = 12.0 Hz, 2H), 3.95 (d, J = 6.0 Hz, 2H), 3.76 - 3.71 (m, 2H), 3.45 - 3.38 (m, 1H), 3.29 - 3.13 (m, 1H), 3.12 - 3.01 (m, 3H), 2.95 - 2.83 (m, 2H), 2.78 - 2.68 (m, 2H), 2.39 - 2.25 (m, 2H), 2.18 - 2.14 (m, 5H), 1.94 - 1.57 (m, 11H), 1.32 - 1.23 (m, 2H).

[0463] 1. Synthesis scheme:

[0464] 2. Experimental section: Compound MX02805 was obtained by using compound 02805-0 and R-1 as raw materials, following the procedure of example MX02720. White solid product (30.46 mg, yield 62.8%).

[0465] ESI-MS m / z calcd for [C 27 H 37 N7O3S][M+H] + :540.3;found:540.3

[0466] 1 H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 8.8, 2.4 Hz, 1H), 7.38 - 7.34 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 4.84 (t, J = 5.6 Hz, 1H), 3.92 (br, 2H), 3.70 (d, J = 21.6 Hz, 6H), 3.55 (t, J = 4.4 Hz, 4H), 3.42 - 3.34 (m, 3H), 3.24 - 3.16 (m, 1H), 2.94 - 2.83 (m, 2H), 2.33 - 2.26 (m, 6H), 2.14 (s, 2H), 1.80 - 1.70 (m, 2H), 0.97 (s, 2H), 0.85 (s, 2H).

[0467] 1. Synthesis scheme:

[0468] 2. Experimental part:

[0469] 2.1

[0470] 2-Chloro-5-(2-(pyrrolidin-1-yl)ethoxy)pyrimidine (02812-1)

[0471] To a solution of 2-(pyrrolidin-1-yl)ethanol (500 mg, 4.35 mmol) and 2-chloropyrimidin-5-ol (560 mg, 4.35 mmol) in DOX (10 mL) was added CMBP (2.5 g, 10.70 mmol) at room temperature. Then the mixture was stirred at 100 °C for 6 hours, after which water (20 mL) was added and extracted twice with EA (20 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product as a yellow solid (622 mg, yield 63.0%).

[0472] ESI-MS m / z calcd for [C 10 H 14 ClN3O][M+H] + :228.1;found:228.1

[0473] 2.2

[0474] 4-(5-(2-(pyrrolidin-1-yl)ethoxy)pyrimidin-2-yl)-5,6-dihydropyridine-1(2H)- carboxylic acid tert-butyl ester (02812-2)

[0475] To a solution of 2-chloro-5-(2-(pyrrolidin-1-yl)ethoxy)pyrimidine (300 mg, 1.32 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (612 mg, 1.98 mmol), K2CO3 (364 mg, 2.64 mmol) and Pd(dppf)Cl2 (54 mg, 0.07 mmol). The mixture was heated to 100 °C and stirred under nitrogen protection for 3 hours. After cooling, it was added to water (10 mL) and extracted with EA (20 mL) twice. The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product as a yellow solid (400 mg, yield 81.0%).

[0476] ESI-MS m / z calcd for [C 20 H 30 N4O3][M+H] + : 375.2; found: 375.3

[0477] 2.3

[0478] 4-(5-(2-(pyrrolidin-1-yl)ethoxy)pyrimidin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (02812-3)

[0479] To a solution of 4-(5-(2-(pyrrolidin-1-yl)ethoxy)pyrimidin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (200 mg, 0.53 mmol) in MeOH (10 mL) was added Pd / C (60 mg). The mixture was stirred under hydrogen atmosphere at 50 °C overnight. The reaction solution was filtered with celite and the filtrate was distilled under reduced pressure. The obtained crude product was purified by column chromatography (EA / PE = 0 ~ 70%, silica gel-CS 40 g, 50 mL / min, silica gel, UV 254) to give the product as a colorless oil (181 mg, yield 90.8%).

[0480] ESI-MS m / z calcd for [C 20 H 32 N4O3][M+H] + :377.2; found: 377.4

[0481] 2.4

[0482] 2-(Piperidin-4-yl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyrimidine (02812-4)

[0483] To a solution of tert-butyl 4-(5-(2-(pyrrolidin-1-yl)ethoxy)pyrimidin-2- yl)piperidine-1-carboxylate (180 mg, 0.48 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.3 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the crude product was used directly for the next step.

[0484] ESI-MS m / z calcd for [C 15 H 24 N4O][M+H] + :277.2; found: 277.3

[0485] 2.5

[0486] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(5-(2-(pyrrolidin-1-yl)ethoxy)pyrimidin-2-yl)piperidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02812)

[0487] To a solution of 2-(piperidin-4-yl)-5-(2-(pyrrolidin-1-yl)ethoxy)pyrimidine (45 mg, 0.12 mmol) in DMF (3 mL) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (30 mg, 0.10 mmol) and DIEA (65 mg, 0.50 mmol). The mixture was stirred at 100 °C under nitrogen protection for 2 h. After the starting material was consumed, it was cooled and added to water (10 mL) and extracted with EA (10 mL) for three times. The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product which was purified by prep-HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254] to give the product (16.68 mg, yield 31.65%) as a white solid.

[0488] ESI-MS m / z calcd for [C 26 H 37 N7O3S][M+H] + :528.3;found:528.3

[0489] 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 2H), 7.32 (s, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.70 - 4.67 (m, 2H), 4.19 (t, J = 5.6 Hz, 2H), 3.75 - 3.68 (m, 2H), 3.45 - 3.37 (m, 5H), 3.25 - 3.17 (m, 1H), 3.15 - 3.02 (m, 3H), 2.96 - 2.83 (m, 2H), 2.78 (t, J = 5.6 Hz, 2H), 2.39 - 2.26 (m, 2H), 2.19 - 2.14 (m, 2H), 1.94 - 1.91 (m, 2H), 1.83 - 1.73 (m, 2H), 1.71 - 1.59 (m, 6H).

[0490] 1. Synthesis scheme:

[0491] 2. Experimental section: Compound MX02813 was obtained from compound 02813-0 and R-1 following the procedure of example MX02814. White solid product (6.0 mg, yield 6.7%).

[0492] ESI-MS m / z calcd for [C 24 H 33 N7O3S][M+H] + :500.2; found: 500.3

[0493] 1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 3.2 Hz, 1H), 7.48 (dd, J = 9.2, 3.2 Hz, 1H), 7.42 (s, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.36 - 5.31 (m, 1H), 4.85 (t, J = 5.2 Hz, 1H), 4.39 (dd, J = 9.6, 6.4 Hz, 2H), 3.91 (s, 2H), 3.69 (dd, J = 16.8, 12.0 Hz, 2H), 3.44 - 3.38 (m, 1H), 3.25 - 3.17 (m, 1H), 3.06 (t, J = 4.4 Hz, 4H), 2.96 - 2.84 (m, 2H), 2.44 (t, J = 4.8 Hz, 4H), 2.36 - 2.27 (m, 2H), 2.21 (s, 3H), 2.12 (t, J = 8.8 Hz, 2H), 1.79 - 1.68 (m, 2H).

[0494] 1. Synthesis scheme:

[0495] 2. Experimental section:

[0496] 2.1

[0497] 3-((5-bromopyrimidin-2-yl)oxy)azetidine-1-carboxylic acid tert-butyl ester (02814-1)

[0498] To a solution of 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (500 mg, 2.6 mmol) in THF (3 mL) was added 5-bromo-2-chloropyrimidine (448 mg, 2.6 mmol) and NaH (109 mg, 2.71 mmol) at 0 °C, the mixture was warmed to room temperature and stirred under nitrogen atmosphere for 2 hours. After the starting material was consumed (monitored by LCMS), the reaction mixture was quenched with water (20 mL) and extracted with EA (10 mL) for three times. The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 40 g, 20 mL / min, silica gel, UV 254) to give the product as a yellow solid (501 mg, yield 58.6%).

[0499] ESI-MS m / z calcd for [C 12 H 16 BrN3O3][M-56+H] + : 274.1 ; found: 274.0

[0500] 2.2

[0501] 3-((5-(4-methylpiperazin-1-yl)pyrimidin-2-yl)oxy)azetidine-1-carboxylic acid tert-butyl ester (02814-2)

[0502] To a solution of 4-methylpiperazine (83 mg, 0.84 mmol) in 1,4-dioxane (5 mL), was added 3-((5-bromopyrimidin-2-yl)oxy)azetidine-1-carboxylic acid tert-butyl ester (250 mg, 0.76 mmol), Xantphos (44 mg, 0.07 mmol) and Pd2(dba)3(35 mg, 0.04 mmol), Cs2CO3(371 mg, 1.14 mmol), the reaction was stirred at 100 °C under nitrogen overnight, after the starting material was consumed, water (30 mL) was added to the mixture, extracted with EA (30 mL) twice, the combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 10, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254), to give the product as a yellow oil (66 mg, yield 24.9%).

[0503] ESI-MS m / z calcd for [C 17 H 27 N5O3][M+H] + : 350.2; found: 350.2

[0504] 2.3

[0505] 2-(azetidin-3-yloxy)-5-(4-methylpiperazin-1-yl)pyrimidine (02814-3)

[0506] To a solution of 3-((5-(4-methylpiperazin-1-yl)pyrimidin-2-yl)oxy)azetidine-1-carboxylic acid tert-butyl ester (30 mg, 0.09 mmol) in DCM (2 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the crude product was used directly in the next reaction.

[0507] ESI-MS m / z calcd for [C 12 H 19 N5O][M+H] + : 250.2; found: 250.4

[0508] 2.4

[0509] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3-((5-(4-methylpiperazin-1- yl)pyrimidin-2-yl)oxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02814)

[0510] To a solution of 2-(azetidin-3-yloxy)-5-(4-methylpiperazin-1-yl)pyrimidine (17 mg, 0.07 mmol) in DMF (2 mL) was added (R)-2-chloro-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (20 mg, 0.07 mmol) and DIEA (45 mg, 0.35 mmol). The mixture was stirred at 80 °C under nitrogen protection for 2 hours, after the starting material was consumed, cooled and added to water (10 mL) and extracted with EA (10 mL) for three times. The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product which was purified by prep-HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (17.11 mg, yield 48.89%).

[0511] ESI-MS m / z calcd for [C 23 H 32 N8O3S][M+H] + :501.2; found: 501.3

[0512] 1 HNMR (400 MHz, DMSO-d6) δ 8.35 (s, 2H), 7.45 (s, 1H), 5.35 - 5.30 (m, 1H), 4.86 (t, J = 5.6 Hz, 1H), 4.42 - 4.37 (m, 2H), 3.95 - 3.94 (m, 2H), 3.70 - 3.68 (m, 2H), 3.45 - 3.37 (m, 1H), 3.25 - 3.17 (m, 1H), 3.13 - 3.14 (m, 4H), 2.96 - 2.84 (m, 2H), 2.46 - 2.43 (m, 4H), 2.38 - 2.25 (m, 2H), 2.22 (s, 3H), 2.14 - 2.10 (m, 2H), 1.79 - 1.71 (m, 2H).

[0513] 1. Synthesis scheme:

[0514] 2. Experimental Part: Using compound 02815-0 as the starting material, the procedure in Example MX02812 was referenced to obtain compound MX02815. White solid product (2.59 mg, yield 7.6%).

[0515] ESI-MS m / z calcd for C 27 H 37 N9O3S][M+H] + :568.3; found: 568.3

[0516] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 2H), 7.46 (br, 1H), 5.01 (s, 1H), 4.82 (s, 1H), 4.63 - 4.40 (m, 3H), 4.26 - 4.20 (m, 1H), 3.76 - 3.69 (m, 2H), 3.45 - 3.39 (m, 1H), 3.26 - 3.17 (m, 3H), 3.09 - 3.03 (m, 1H), 2.98 - 2.85 (m, 2H), 2.77 - 2.74 (m, 2H), 2.61 - 2.59 (m, 2H), 2.41 - 2.28 (m, 2H), 2.22 - 2.18 (m, 2H), 2.16 (s, 3H), 2.13 - 2.08 (m, 2H), 1.90 - 1.88 (m, 2H), 1.82 - 1.71 (m, 2H), 1.64 - 1.56 (m, 2H).

[0517] 1. Synthesis scheme:

[0518] 2. Experimental Part: Using compound 02815-0 as the starting material, the procedure in Example MX02812 was referenced to obtain compound MX02815. White solid product (2.59 mg, yield 7.6%).

[0519] ESI-MS m / z calcd for C 26 H 37 N9O3S][M+H] + :568.3; found: 568.3

[0520] 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 2H), 7.36 (s, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.69 (d, J = 12.4 Hz, 2H), 4.53 - 4.47 (m, 1H), 3.72 (dd, J = 17.2, 13.2 Hz, 2H), 3.45 - 3.39 (m, 1H), 3.24 - 3.17 (m, 1H), 3.14 - 3.01 (m, 3H), 2.95 - 2.83 (m, 2H), 2.59 (t, J = 6.0 Hz, 2H), 2.36 - 2.28 (m, 2H), 2.16 - 2.13 (m, 7H), 1.92 (d, J = 12.4 Hz, 4H), 1.80 - 1.73 (m, 2H), 1.67 - 1.58 (m, 4H).

[0521] 1. Synthesis scheme:

[0522] 2. Experimental section: Compound MX02817 was obtained following the procedure of example MX02692, starting from compound 02817-0 and R-1. White solid product (4.97 mg, 2.57% yield).

[0523] ESI-MS m / z calcd for C 25 H 29 N5O2S][M+H] + : 464.2; found: 464.3

[0524] 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.86 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 3.2 Hz, 1H), 7.34 (dd, J = 8.8, 1.6 Hz, 1H), 6.52 (d, J = 2.8 Hz, 1H), 4.94 - 4.91 (m, 1H), 4.33 - 4.30 (m, 2H), 3.76 - 3.75 (m, 2H), 3.60 - 3.53 (m, 1H), 3.18 - 3.14 (m, 1H), 3.04 - 2.99 (m, 1H), 2.68 - 2.65 (m, 2H), 2.35 - 2.24 (m, 11H), 1.84 - 1.77 (m, 2H).

[0525] 1. Synthesis scheme:

[0526] 2. Experimental Part: Compound 02845-0 and R1 were used as starting materials to obtain compound MX02845 following the procedure of example MX-02694. White solid product (14.02 mg, yield 26.45%).

[0527] ESI-MS m / z calcd for [C 28 H 38 N6O3S][M+H] + : 539.3; found: 539.2

[0528] 1 HNMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 8.8 Hz, 1H), 8.23 - 8.21 (m, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 4.80 - 3.71 (m, 2H), 3.72 - 3.71 (m, 2H), 3.46 - 3.36 (m, 1H), 3.35 - 3.30 (m, 1H), 3.23 - 3.20 (m, 1H), 3.18 - 3.09 (m, 1H), 3.04 - 2.84 (m, 5H), 2.81 - 2.78 (m, 2H), 2.37 - 2.29 (m, 2H), 2.19 - 2.14 (m, 5H), 2.08 - 2.02 (m, 2H), 1.89 - 1.86 (m, 2H), 1.80 - 1.73 (m, 4H), 1.70 - 1.55 (m, 4H).

[0529] 1. Synthesis scheme:

[0530] 2. Experimental Part: Compound 02848-0 was used as starting material to obtain compound MX02848-rac following the procedure of example MX02958. White solid product (24.88 mg, yield 26.0%).

[0531] ESI-MS m / z calcd for [C 28 H 34 FN7O2S][M+H] + : 552.3; found: 551.8

[0532] 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 2H), 7.48 - 7.45 (m, 2H), 7.32 (s, 1H), 7.11 (t, J = 8.8 Hz, 2H), 4.83 (t, J = 5.6 Hz, 1H), 4.72 - 4.67 (m, 2H), 3.71 - 3.70 (m, 2H), 3.43 - 3.36 (m, 1H), 3.22 - 3.19 (m, 1H), 3.12 - 3.00 (m, 3H), 2.95 - 2.82 (m, 2H), 2.57 - 2.56 (m, 2H), 2.36 - 2.28 (m, 2H), 2.16 - 2.13 (m, 2H), 1.94 - 1.91 (m, 2H), 1.77 - 1.74 (m, 5H), 1.65 - 1.62 (m, 2H).

[0533] 1. Synthesis scheme:

[0534] 2. Experimental section: Compound 02805-1 and R-1 were used as starting materials, and the operation in Example MX02985 was referred to, to obtain compound MX02888. White solid product (24.01 mg, yield 46.8%).

[0535] ESI-MS m / z calcd for C 26 H 36 N6O3S][M+H] + : 513.3; found: 513.0

[0536] 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 1.6 Hz, 1H), 7.62 (dd, J = 8.0, 2.0 Hz, 1H), 7.33 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.77 (d, J = 12.4 Hz, 2H), 3.72 (dd, J = 16.4, 12.4 Hz, 2H), 3.55 (t, J = 4.4 Hz, 4H), 3.44 (s, 2H), 3.41 - 3.37 (m, 1H), 3.25 - 3.17 (m, 1H), 3.01 - 2.83 (m, 5H), 2.37 - 2.26 (m, 6H), 2.18 - 2.13 (m, 2H), 1.86 - 1.73 (m, 4H), 1.65 - 1.56 (m, 2H).

[0537] 1. Synthesis scheme:

[0538] 2. Experimental Part: Compound 02900-0 and R2 were used as raw materials to obtain compound MX02900 by referring to the operation of Example MX-02814. White solid product (21.62 mg, yield 41.18%).

[0539] ESI-MS m / z calcd for [C 26 H 35 N7O3S][M+H] + :526.2; found: 526.3

[0540] 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 8.8 Hz, 1H), 7.47 (dd, J = 9.2, 3.2 Hz, 1H), 7.42 (s, 1H), 6.78 (d, J = 9.2 Hz, 1H), 5.36 - 5.30 (m, 1H), 4.92 (t, J = 5.6 Hz, 1H), 4.40 - 4.36 (m, 2H), 3.91 - 3.90 (m, 2H), 3.70 - 3.68 (m, 2H), 3.44 - 3.36 (m, 1H), 3.24 - 3.17 (m, 1H), 3.03 - 3.00 (m, 4H), 2.96 - 2.84 (m, 2H), 2.68 - 2.65 (m, 4H), 2.35 - 2.25 (m, 2H), 2.14 - 2.09 (m, 2H), 1.79 - 1.70 (m, 2H), 1.68 - 1.63 (m, 1H), 0.48 - 0.42 (m, 2H), 0.35 - 0.31 (m, 2H).

[0541] 1. Synthesis scheme:

[0542] 2. Experimental Part: Compound 02900-0 and R2 were used as raw materials to obtain compound MX02900 by referring to the operation of Example MX-02814. White solid product (21.62 mg, yield 41.18%).

[0543] ESI-MS m / z calcd for [C 27 H 37 N7O3S][M+H] + :540.3; found: 540.3

[0544] 1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 2.8 Hz, 1H), 7.47 (dd, J = 8.8, 2.8 Hz, 1H), 7.42 (s, 1H), 6.79 (d, J = 9.2 Hz, 1H), 5.36 - 5.31 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.38 (dd, J = 10.0, 6.4 Hz, 2H), 4.00 - 3.82 (m, 2H), 3.73 - 3.65 (m, 2H), 3.44 - 3.36 (m, 1H), 3.25 - 3.17 (m, 1H), 3.08 - 3.06 (m, 4H), 2.96 - 2.82 (m, 2H), 2.58 - 2.56 (m, 4H), 2.38 - 2.25 (m, 2H), 2.22 (d, J = 6.8 Hz, 2H), 2.14 - 2.10 (m, 2H), 1.79 - 1.68 (m, 2H), 0.88 - 0.82 (m, 1H), 0.50 - 0.45 (m, 2H), 0.11 - 0.07 (m, 2H).

[0545] 1. Synthesis scheme:

[0546] 2. Experimental section: Compound 02902-0 was used as starting material and the procedure of Example MX02814 was followed to obtain compound MX02902. White solid product (8.37 mg, 8.0% yield).

[0547] ESI-MS m / z calcd for C 26 H 35 N7O3S][M+H] + : 526.3; Found: 526.3

[0548] 1H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J = 2.8 Hz, 1H), 7.40 - 7.39 (m, 1H), 7.34 (dd, J = 9.2, 2.8 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 5.31 (s, 1H), 4.88 (br, 1H), 4.38 (dd, J = 10.0, 6.4 Hz, 2H), 3.89 (s, 2H), 3.69 (t, J = 11.2 Hz, 2H), 3.44 - 3.36 (m, 1H), 3.28 - 3.17 (m, 5H), 2.96 - 2.83 (m, 2H), 2.77 (d, J = 9.6 Hz, 2H), 2.35 - 2.25 (m, 2H), 2.21 (s, 3H), 2.11 (t, J = 8.4 Hz, 2H), 1.95 - 1.90 (m, 2H), 1.79 - 1.70 (m, 2H), 1.64 (d, J = 7.2 Hz, 2H).

[0549] 1. Synthesis scheme:

[0550] 2. Experimental section: Compound MX02903 was obtained following the procedure of example MX-02814, starting from compound 02903-0 and R1. White solid product (15.21 mg, 29.65% yield).

[0551] ESI-MS m / z calcd for [C 25 H 35 N7O3S][M+H] + : 514.2; found: 514.3

[0552] 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 8.8 Hz, 1H), 7.47 (dd, J = 9.2, 3.2 Hz, 1H), 7.42 (s, 1H), 6.78 (d, J = 9.2 Hz, 1H), 5.36 - 5.30 (m, 1H), 4.86 (t, J = 5.6 Hz, 1H), 4.40 - 4.36 (m, 2H), 3.91 - 3.90 (m, 2H), 3.70 - 3.68 (m, 2H), 3.42 - 3.36 (m, 3H), 3.25 - 3.17 (m, 1H), 2.96 - 2.78 (m, 3H), 2.73 - 2.61 (m, 1H), 2.38 - 2.34 (m, 4H), 2.20 (s, 3H), 2.15 - 2.09 (m, 3H), 1.79 - 1.70 (m, 2H), 1.02 (d, J = 6.4 Hz, 3H).

[0553] 1. Synthesis scheme:

[0554] 2. Experimental section: Compound MX02904 was obtained by following the procedure of Example MX02814, starting from compound 02904-0 and R-1. White solid compound (21.99 mg, 20% yield).

[0555] ESI-MS m / z calcd for C 25 H 35 N7O3S][M+H] + : 514.3; found: 514.4

[0556] 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 2.8 Hz, 1H), 7.47 (dd, J = 8.8, 2.8 Hz, 1H), 7.42 (s, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.36 - 5.30 (m, 1H), 4.85 (t, J = 5.2 Hz, 1H), 4.38 (dd, J = 10.0, 6.4 Hz, 2H), 3.91 - 3.90 (m, 2H), 3.70 - 3.68 (m, 2H), 3.44 - 3.39 (m, 3H), 3.25 - 3.17 (m, 1H), 2.96 - 2.68 (m, 4H), 2.38 - 2.24 (m, 4H), 2.20 (s, 3H), 2.14 - 2.09 (m, 3H), 1.79 - 1.70 (m, 2H), 1.03 (d, J = 6.4 Hz, 3H).

[0557] 1. Synthesis scheme:

[0558] 2. Experimental section: Compound MX02905 was obtained by following the procedure of Example MX02814, starting from compound 02905-0 and R-1. White solid product (50.0 mg, 25.1% yield).

[0559] ESI-MS m / z calcd for C 25 H 34 N6O3S][M+H] + : 499.2 found: 499.4 [M+H] +

[0560] 1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 2.4 Hz, 1H), 7.66 (dd, J = 8.8, 2.4 Hz, 1H), 7.42 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 5.41 - 5.38 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.40 (dd, J = 10.0, 6.4 Hz, 2H), 3.93 (s, 2H), 3.73 - 3.65 (m, 2H), 3.44 - 3.36 (m, 1H), 3.25 - 3.17 (m, 1H), 2.96 - 2.83 (m, 4H), 2.47 - 2.38 (m, 1H), 2.36 - 2.25 (m, 2H), 2.18 (s, 3H), 2.14 - 2.10 (m, 2H), 1.96 - 1.90 (m, 2H), 1.82 - 1.58 (m, 6H).

[0561] 1. Synthesis scheme:

[0562] 2. Experimental section: Compound MX02906 was obtained following the procedure of example MX02814, starting from compound 02906-0 and R-1. White solid product (23.97 mg, yield 32.7%).

[0563] ESI-MS m / z calcd for C 25 H 34 N8O3S][M+H] + : 527.3; found: 526.9

[0564] 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 2H), 7.43 (s, 1H), 5.35 - 5.30 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.41 - 3.37 (m, 2H), 3.95 - 3.93 (m, 2H), 3.73 - 3.66 (m, 2H), 3.45 - 3.36 (m, 1H), 3.25 - 3.17 (m, 1H), 3.09 - 3.07 (m, 4H), 2.96 - 2.84 (m, 2H), 2.68 - 2.66 (m, 4H), 2.36 - 2.27 (m, 2H), 2.14 - 2.10 (m, 2H), 1.79 - 1.64 (m, 3H), 0.46 - 0.42 (m, 2H), 0.35 - 0.32 (m, 2H).

[0565] 1. Synthesis scheme:

[0566] 2. Experimental Section: Compound 02906-1 and R-1 were used as starting materials to obtain compound MX02907 following the procedure of example MX02814. White solid product (23.46 mg, yield 31.2%).

[0567] ESI-MS m / z calcd for C 26 H 36 N8O3S][M+H] + :541.3; found: 541.0

[0568] 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 2H), 7.43 (s, 1H), 5.35 - 5.30 (m, 1H), 4.85 (t, J = 1.6 Hz, 1H), 4.42 - 4.38 (m, 2H), 3.95 - 3.89 (m, 2H), 3.73 - 3.66 (m, 2H), 3.43 - 3.34 (m, 1H), 3.25 - 3.21 (m, 1H), 3.19 - 3.12 (m, 4H), 2.96 - 2.84 (m, 2H), 2.59 - 2.56 (m, 4H), 2.36 - 2.27 (m, 2H), 2.25 - 2.22 (m, 2H), 2.14 - 2.10 (m, 2H), 1.79 - 1.71 (m, 2H), 0.87 - 0.84 (m, 1H), 0.50 - 0.46 (m, 2H), 0.11 - 0.07 (m, 2H).

[0569] 1. Synthesis scheme:

[0570] 2. Experimental Section: Compound 02906-1 and R-1 were used as starting materials to obtain compound MX02907 following the procedure of example MX02814. White solid product (23.46 mg, yield 31.2%).

[0571] ESI-MS m / z calcd for C 25 H 34 N8O3S][M+H] + :527.3; found: 527.1

[0572] 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 2H), 7.42 (s, 1H), 5.32 - 5.29 (m, 1H), 4.84 (br, 1H), 4.39 (dd, J = 10.0, 6.4 Hz, 2H), 3.93 (s, 2H), 3.69 (s, 2H), 3.43 - 3.36 (m, 3H), 3.26 - 3.19 (m, 3H), 2.96 - 2.85 (m, 2H), 2.81 (d, J = 10.4 Hz, 2H), 2.36 - 2.27 (m, 2H), 2.21 (s, 3H), 2.12 (t, J = 9.2 Hz, 2H), 1.96 - 1.94 (m, 2H), 1.77 - 1.71 (m, 2H), 1.64 (d, J = 7.2 Hz, 2H).

[0573] 1. Synthesis scheme:

[0574] 2. Experimental part: Compound 02909-0 and R1 were used as starting materials, and the operation in Example MX-02814 was referred to, to obtain compound MX02909. White solid product (24.53 mg, yield 47.72%).

[0575] ESI-MS m / z calcd for [C 24 H 34 N8O3S][M+H] + : 515.2; found: 515.4

[0576] 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 2H), 7.43 (s, 1H), 5.34 - 5.31 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.42 - 4.37 (m, 2H), 3.95 - 3.94 (m, 2H), 3.69 - 3.68 (m, 2H), 3.52 - 3.50 (m, 2H), 3.47 - 3.36 (m, 1H), 3.25 - 3.17 (m, 1H), 2.96 - 2.74 (m, 4H), 2.43 - 2.23 (m, 4H), 2.20 (s, 3H), 2.14 - 2.10 (m, 3H), 1.80 - 1.71 (m, 2H), 1.05 (d, J = 6.0 Hz, 3H).

[0577] 1. Synthesis scheme:

[0578] 2. Experimental Part: Compound 02910-0 and R1 were used as starting materials to obtain compound MX02910 following the procedure of example MX-02814. White solid product (13.57 mg, yield 26.40%).

[0579] ESI-MS m / z calcd for [C 24 H 34 N8O3S][M+H] + :515.2; found: 515.2

[0580] 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 2H), 7.43 (s, 1H), 5.34 - 5.31 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.42 - 4.36 (m, 2H), 3.95 - 3.94 (m, 2H), 3.70 - 3.68 (m, 2H), 3.54 - 3.38 (m, 2H), 3.22 - 3.16 (m, 1H), 3.25 - 3.17 (m, 1H), 2.96 - 2.74 (m, 4H), 2.45 - 2.31 (m, 4H), 2.27 - 2.26 (m, 4H), 2.14 - 2.07 (m, 2H), 1.81 - 1.68 (m, 2H), 1.05 (d, J = 6.0 Hz, 3H).

[0581] 1. Synthesis scheme:

[0582] 2. Experimental Part: 02911-0 and R-1 were used as starting materials to obtain compound MX02911 following the procedure of example MX02814. White solid product (50.0 mg, yield 25.1%).

[0583] ESI-MS m / z calcd for [C 24 H 33 N7O3S][M+H] + :500.2 found: 500.4 [M+H] +

[0584] 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 2H), 7.44 (s, 1H), 5.42 - 5.37 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.41 (dd, J = 9.6, 6.4 Hz, 2H), 3.98 (s, 2H), 3.73 - 3.66 (m, 2H), 3.45 - 3.37 (m, 1H), 3.25 - 3.17 (m, 1H), 2.97 - 2.84 (m, 4H), 2.47 - 2.44 (m, 1H), 2.38 - 2.25 (m, 2H), 2.18 (s, 3H), 2.15 - 2.10 (m, 2H), 1.97 - 1.90 (m, 2H), 1.79 - 1.63 (m, 6H).

[0585] 1. Synthesis scheme:

[0586] 2. Experimental section: Compound 02912-0 was used as starting material and the procedure of Example MX02814 was followed to obtain compound MX02912. White solid product (9.34 mg, yield 11.4%).

[0587] ESI-MS m / z calcd for C 25 H 33 N7O3S][M+H] + : 512.2; found: 512.3

[0588] 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 3.2 Hz, 1H), 7.41 (s, 1H), 7.23 (dd, J = 8.8, 2.4 Hz, 1H), 6.81 (d, J = 9.2 Hz, 1H), 5.33 - 5.30 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.39 (dd, J = 9.6, 6.4 Hz, 2H), 3.91 (br, 2H), 3.69 (d, J = 5.2 Hz, 2H), 3.56 (d, J = 5.2 Hz, 2H), 3.45 - 3.37 (m, 3H), 3.25 - 3.17 (m, 3H), 2.96 - 2.84 (m, 2H), 2.40 - 2.28 (m, 3H), 2.12 (t, J = 8.8 Hz, 2H), 1.98 (s, 3H), 1.77 - 1.68 (m, 2H), 1.53 (d, J = 8.0 Hz, 1H).

[0589] 1. Synthesis scheme:

[0590] 2. Experimental Section: Using compound 02913-0 and R1 as raw materials, and following the procedure described in Example MX-02814, compound MX02913 was obtained. The product was a white solid (23.51 mg, yield 45.92%).

[0591] ESI-MS m / z calcd for [C 24 H 32 [N8O3S][M+H] + :513.2; found:513.2

[0592] 1 H NMR(400MHz,DMSO-d6)δ8.16(s,2H),7.45(s,1H),5.34–5.29(m,1H),4.43–4.3 8(m,2H),3.95–3.94(m,2H),3.74–3.67(m,3H),3.62(d,J=5.6Hz,2H),3.47–3.3 7(m,4H),3.33–3.30(m,2H),3.25–3.17(m,1H),2.97–2.84(m,2H),2.38–2.25(m ,2H),2.14–2.10(m,2H),2.04(s,3H),1.79–1.71(m,2H),1.57(d,J=8.4Hz,1H).

[0593] 1. Synthesis scheme:

[0594] 2. Experimental Section: Using compounds 02917-0 and R-1 as raw materials, and following the procedure described in Example MX02711, compound MX02917 was obtained. A white solid product (2.22 mg, yield 8.3%) was obtained.

[0595] ESI-MS m / z calculated value [C] 23 H 29 N5O4S2][M+H] + Measured value: 504.2; Actual value: 504.3

[0596] 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 8.0 Hz, 2H), 8.22 - 8.18 (m, 2H), 8.01 (d, J = 8.4 Hz, 2H), 3.86 - 3.80 (m, 3H), 3.71 - 3.63 (m, 2H), 3.37 - 3.17 (m, 5H), 3.08 - 3.03 (m, 1H), 2.45 - 2.29 (m, 5H), 2.86 - 1.82 (m, 2H), 1.64 (s, 3H), 1.25 - 1.23 (m, 2H).

[0597] 1. Synthesis scheme:

[0598] 2. Experimental section: Compound 02918-0 was used as raw material, and the operation of Example MX02814 was referred to to obtain compound MX02918. White solid product (8.47 mg, yield 15%).

[0599] ESI-MS m / z calcd for C 24 H 31 N7O4S][M+H] + : 514.2; found: 514.3

[0600] 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 2.0 Hz, 1H), 7.75 (dd, J = 8.8, 2.8 Hz, 1H), 7.42 (s, 1H), 6.93 (d, J = 8.8 Hz, 1H), 5.42 (br, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.42 (dd, J = 9.2, 6.4 Hz, 2H), 3.96 (br, 2H), 3.70 - 3.63 (m, 4H), 3.43 - 3.36 (m, 1H), 3.25 - 3.18 (m, 1H), 3.11 (s, 2H), 2.97 - 2.84 (m, 2H), 2.72 (t, J = 5.2 Hz, 2H), 2.36 - 2.28 (m, 5H), 2.12 (t, J = 8.8 Hz, 2H), 1.79 - 1.71 (m, 2H).

[0601] 1. Synthesis scheme:

[0602] 2. Experimental section: Compound 02920-0 was used as raw material, and the operation of Example MX02812 was referred to to obtain compound MX02920. White solid product (17.77 mg, yield 19.3%).

[0603] ESI-MS m / z calcd for C 27 H 37 N7O4S2][M+H] + :588.2; found: 588.1

[0604] 1 H NMR (400 MHz, DMSO-d6) δ 8.94 - 8.93 (m, 1H), 8.20 (dd, J = 8.0, 1.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 4.85 - 4.75 (m, 3H), 3.71 (d, J = 5.6 Hz, 2H), 3.45 - 3.38 (m, 5H), 3.29 - 3.26 (m, 2H), 3.23 - 3.18 (m, 1H), 3.04 - 2.85 (m, 5H), 2.34 - 2.29 (m, 3H), 2.17 - 2.14 (m, 2H), 1.90 - 1.87 (m, 2H), 1.77 - 1.75 (m, 2H), 1.66 - 1.62 (m, 5H), 1.21 (d, J = 8.4 Hz, 1H).

[0605] 1. Synthesis scheme:

[0606] 2. Experimental section:

[0607] Compound MX02924 was obtained as a white solid (13.99 mg, yield 10%) from compound 02924-0 and R-1 following the procedure of example MX02812.

[0608] ESI-MS m / z calcd for C 27 H 39 N7O4S2][M+H] + :590.3; found: 590.2

[0609] 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 2.0 Hz, 1H), 8.13 (dd, J = 8.0, 2.4 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 4.85 - 4.77 (m, 3H), 3.72 - 3.71 (m, 2H), 3.46 - 3.29 (m, 4H), 3.21 - 3.11 (m, 3H), 3.05 - 2.84 (m, 5H), 2.38 - 2.27 (m, 2H), 2.18 - 2.14 (m, 2H), 2.01 (s, 6H), 1.92 - 1.88 (m, 3H), 1.80 - 1.48 (m, 5H).

[0610] 1. Synthesis scheme:

[0611] 2. Experimental part: Compound MX02929 was obtained by using compound 02929-0 and R1 as raw materials, referring to the operation of Example MX-02692. White solid product (14.00 mg, yield 23.21%).

[0612] ESI-MS m / z calcd for [C 28 H 41 N7O4S2][M+H] + : 604.3; found: 604.3

[0613] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 2.0 Hz, 1H), 8.05 (dd, J = 8.0, 2.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.80 - 4.77 (m, 2H), 3.74 - 3.31 (m, 2H), 3.62 - 3.59 (m, 2H), 3.45 - 3.37 (m, 1H), 3.28 - 3.14 (m, 2H), 3.04 - 2.84 (m, 4H), 2.42 - 2.27 (m, 4H), 2.28 - 2.22 (m, 3H), 2.08 (s, 6H), 1.91 - 1.88 (m, 2H), 1.80 - 1.60 (m, 6H), 1.43 - 1.33 (m, 2H).

[0614] 1. Synthesis scheme:

[0615] 2. Experimental part: Compound MX02925 was obtained by using compound 02925-0 and R-1 as raw materials, referring to the operation of Example MX02814. White solid compound (19.29 mg, yield 18%).

[0616] ESI-MS m / z calcd for [C 25 H 35 N7O3S][M+H] + : 514.3; found: 514.2

[0617] 1H NMR (400 MHz, DMSO-d6) δ 7.45 (d, J = 2.8 Hz, 1H), 7.40 (s, 1H), 7.07 (dd, J = 9.2, 3.2 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 5.34 - 5.27 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.38 (dd, J = 9.6, 6.8 Hz, 2H), 3.98 - 3.83 (m, 2H), 3.73 - 3.44 (m, 2H), 3.44 - 3.36 (m, 2H), 3.29 - 3.17 (m, 3H), 3.02 - 2.75 (m, 4H), 2.38 - 2.28 (m, 2H), 2.25 (s, 6H), 2.19 - 2.12 (m, 3H), 1.84 - 1.65 (m, 3H).

[0618] 1. Synthesis scheme:

[0619] 2. Experimental section: Compound MX02926 was obtained following the procedure of example MX02814, starting from compound 02926-0 and R-1. White solid compound (18.78 mg, yield 31%).

[0620] ESI-MS m / z calcd for C 24 H 33 N7O3S][M+H] + : 500.2; found: 500.3

[0621] 1 H NMR (400 MHz, DMSO-d6) δ 7.42 (d, J = 3.2 Hz, 1H), 7.40 (s, 1H), 7.04 (dd, J = 8.8, 2.8 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 5.32 - 5.27 (m, 1H), 4.85 (t, J = 9.8 Hz, 1H), 4.38 (dd, J = 10.0, 6.8 Hz, 2H), 3.95 - 3.85 (m, 2H), 3.70 - 3.68 (m, 2H), 3.44 - 3.35 (m, 2H), 3.31 - 3.15 (m, 4H), 2.96 - 2.84 (m, 3H), 2.38 - 2.25 (m, 5H), 2.14 - 2.03 (m, 3H), 1.80 - 1.68 (m, 4H).

[0622] 1. Synthesis scheme:

[0623] 2. Experimental Section: Compound 02928-0 and R-1 were used as starting materials, following the procedure of Example MX02812 to obtain compound MX02928. White solid product (10.95 mg, yield 7.3%).

[0624] ESI-MS m / z calcd for C 23 H 29 N5O4S2][M+H] + : 504.2; found: 504.2

[0625] 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 8.4 Hz, 2H), 8.21 (s, 1H), 8.04 (d, J = 8.4 Hz, 2H), 4.92 (t, J = 6.0 Hz, 1H), 4.19 (d, J = 5.6 Hz, 2H), 3.83 (dd, J = 5.6, 2.4 Hz, 2H), 3.71 - 3.63 (m, 1H), 3.41 - 3.35 (m, 1H), 3.28 - 3.22 (m, 1H), 3.07 (d, J = 10.0 Hz, 3H), 2.78 (d, J = 10.8 Hz, 2H), 2.41 - 2.33 (m, 7H), 1.94 - 1.82 (m, 4H).

[0626] 1. Synthesis scheme:

[0627] 2. Experimental Section: Compound 02925-1 and R-1 were used as starting materials, following the procedure of Example MX02814 to obtain compound MX02930. White solid product (12.7 mg, yield 15.0%).

[0628] ESI-MS m / z calcd for C 25 H 33 N7O3S][M+H] + : 512.2; found: 512.2

[0629] 1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 2.8 Hz, 1H), 7.44 - 7.41 (m, 2H), 6.77 (d, J = 9.2 Hz, 1H), 5.35 - 5.30 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.40 - 4.36 (m, 2H), 3.91 - 3.89 (m, 2H), 3.70 - 3.68 (m, 2H), 3.44 - 3.36 (m, 1H), 3.25 - 3.17 (m, 1H), 2.99 - 2.85 (m, 8H), 2.35 - 2.09 (m, 5H), 1.79-1.70 (m, 2H), 0.51 - 0.46 (m, 4H).

[0630] 1. Synthesis scheme:

[0631] 2. Experimental section: Compound 02925-1 and R-1 were used as starting materials, and the operation in Example MX02814 was referred to to obtain compound

[0632] MX02935. White solid product (18.91 mg, yield 24.3%).

[0633] ESI-MS m / z calcd for C 23 H 30 N6O4S][M+H] + : 487.2; found: 487.3

[0634] 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 2.8 Hz, 1H), 7.49 (dd, J = 8.8, 2.8 Hz, 1H), 7.42 (s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.34 - 5.32 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.41 - 4.37 (m, 2H), 3.92 - 3.89 (m, 2H), 3.74 - 3.68 (m, 6H), 3.42 - 3.36 (m, 1H), 3.23-3.19 (m, 1H), 3.05 - 3.03 (m, 4H), 2.96 - 2.84 (m, 2H), 2.36 - 2.27 (m, 2H), 2.14 - 2.09 (m, 2H), 1.77 - 1.73 (m, 2H).

[0635] 1. Synthesis scheme:

[0636] 2. Experimental Section: Compound 02942-0 and R-1 were used as starting materials to obtain compound MX02942 following the procedure of Reference Example 02971. White solid compound (12.70 mg, yield 17%).

[0637] ESI-MS m / z calcd for C 28 H 37 N5O3S][M+H] + : 524.3; found: 524.3

[0638] 1 H NMR (400 MHz, DMSO-d6) δ 7.44 (s, 1H), 7.17 - 7.15 (m, 2H), 6.79 - 6.77 (m, 2H), 5.09 - 5.04 (m, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.43 (dd, J = 9.6, 6.0 Hz, 2H), 3.95 - 3.85 (m, 2H), 3.73 - 3.65 (m, 2H), 3.45 - 3.34 (m, 1H), 3.25 - 3.17 (m, 1H), 3.02 - 3.00 (m, 2H), 2.96 - 2.84 (m, 2H), 2.47 - 2.40 (m, 1H), 2.38 - 2.10 (m, 6H), 1.79 - 1.67 (m, 4H), 1.63 - 1.47 (m, 3H), 0.44 - 0.39 (m, 2H), 0.31 - 0.28 (m, 2H).

[0639] 1. Synthesis scheme:

[0640] 2. Experimental Section:

[0641] 2.1

[0642] 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (02946-1)

[0643] To a solution of 4-(4-bromophenyl)morpholine (200 mg, 0.83 mmol) and pinacol borate (420 mg, 1.65 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl2(60 mg, 0.08 mmol) and potassium phosphate (526 mg, 2.48 mmol). The mixture was stirred at 100 °C under nitrogen protection for 8 h. After cooling, the reaction was concentrated. The crude product was purified by column chromatography (EA / PE = 0~55%, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to give the product as a yellow solid (124 mg, yield 51.91%).

[0644] ESI-MS m / z calcd for [C 16 H 24 BNO3][M+H] + :290.2; found: 290.4

[0645] 2.2

[0646] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-morpholinophenyl)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02496)

[0647] To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg, 0.17 mmol) and 4-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (100 mg, 0.35 mmol) in 1,4- dioxane and water (5 mL, v / v = 4:1) was added potassium carbonate (48 mg, 0.35 mmol) and Pd(dppf)Cl2(13 mg, 0.02 mmol). The mixture was stirred at 80 °C under nitrogen protection for 4 h. After the reaction was completed, the mixture was distilled to remove the solvent under reduced pressure. The crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (16.3 mg, yield 22.63%).

[0648] ESI-MS m / z calcd for [C 21 H 26 N4O3S][M+H] + :415.2; found: 415.2

[0649] 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 8.8 Hz, 2H), 7.81 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 4.91 (t, J = 5.6 Hz, 1H), 3.82 - 3.80 (m, 2H), 3.76 - 3.74 (m, 4H), 3.63 - 3.55 (m, 1H), 3.72 - 3.35 (m, 1H), 3.25 - 3.23 (m, 4H), 3.19 - 3.13 (m, 1H), 3.01 - 2.97 (m, 1H), 2.46 - 2.27 (m, 4H), 1.87 - 1.81 (m, 2H).

[0650] 1. Synthesis scheme:

[0651] 2. Experimental section:

[0652] 2.1

[0653] 4-(4-bromophenyl)-2-oxopiperazine-1 -carboxylic acid tert-butyl ester (02950-1 )

[0654] A solution of p-bromoiodobenzene (200 mg, 0.71 mmol) in 1,4-dioxane (5 mL), was added 2-oxopiperazine-1 -carboxylic acid tert-butyl ester (141 mg, 0.71 mmol), Xantphos (41 mg, 0.07 mmol) and Pd2(dba)3(32 mg, 0.04 mmol), Cs2C03(463 mg, 1.42 mmol), the reaction was stirred at 100 °C under nitrogen overnight, after the starting material was consumed, water (30 mL) was added to the mixture, extracted with EA (30 mL) twice, the combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 10, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254), to give the product as a yellow oil (118 mg, yield 46.9%).

[0655] ESI-MS m / z calcd for [C 15 H 19 BrN2O3][M-56+H] + : 299.1 ; found: 299.2

[0656] 2.2

[0657] 2-oxo-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1 - carboxylic acid tert-butyl ester (02950-2)

[0658] To a solution of tert-butyl 4-(4-bromophenyl)-2-oxopiperazine-1 -carboxylate (100 mg, 0.30 mmol) in 1,4-dioxane (5 mL) was added B2Pin2 (140 mg, 0.60 mmol), KOAc (60 mg, 0.60 mmol) and Pd(dppf)Cl2 (12 mg, 0.02 mmol). The mixture was stirred at 100 °C under nitrogen overnight. After the starting material was consumed, the mixture was stirred at 100 °C under nitrogen overnight. After cooling, the reaction was filtered and concentrated under reduced pressure. The crude product was used directly in the next step.

[0659] ESI-MS m / z calcd for [C 21 H 31 BN2O5][M+H] + :403.2; found: 403.4

[0660] 2.3

[0661] (R)-4-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-2-yl)phenyl)-2-oxopiperazine-1 -carboxylic acid tert-butyl ester (MX02950-3)

[0662] To a solution of tert-butyl 2-oxo-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperazine-1 -carboxylate (120 mg, 0.30 mmol) in 1,4-dioxane / water (12.5 mL, v / v = 4 / 1 ) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (86 mg, 0.30 mmol), K2CO3 (83 mg, 0.30 mmol) and Pd(dppf)Cl2 (12 mg, 0.015 mmol). The mixture was heated to 80 °C and stirred under nitrogen for 5 hours. After cooling, it was added to water (10 mL) and extracted with DCM (30 mL) three times. The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 10, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product as a white solid (60 mg, 38.0% yield).

[0663] ESI-MS m / z calcd for [C 26 H 33 [N5O5S][M+H] + :528.2; found:528.3

[0664] 2.4

[0665] ((R)-4-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)piperazin-2-one (MX02950)

[0666] Trifluoroacetic acid (0.2 mL) was added to a solution of (R)-4-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)piperazin-2-one (50 mg, 0.09 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L HCOOH), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give a white solid product (14.98 mg, yield 38.98%).

[0667] ESI-MS m / z calcd for [C 21 H 25 [N5O3S][M+H] + :428.2; found:428.3

[0668] 1 H NMR (400MHz, DMSO-d6) δ8.33(d,J=8.4Hz,2H),8.06(s,1H),7.48(d,J=8.8Hz,2H),4.93(t,J=5.6Hz,1H),3.83–3.68(m, 4H),3.66–3.60(m,3H),3.41–3.35(m,2H),3.27–3.18(m,3H),3.06–3.01(m,1H),2.44–2.32(m,4H),1.86–1.81(m,2H).

[0669] 1. Synthesis scheme:

[0670] 2. Experimental Section:

[0671] 2.1

[0672] (1-(((R)-2-((S)-4-(5-chloropyridin-2-yl)-3-(cyanomethyl)piperazin-1-yl)-5-oxo- 6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl(2,2,2- trichloroacetyl)carbamate (02951-1)

[0673] To a solution of 2-((S)-1-(5-chloropyridin-2-yl)-4-((R)-4-((1- (hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2- yl)piperazin-2-yl)acetonitrile (80 mg, 0.16 mmol) in DCM (3 mL) was added 2,2,2- trichloroacetyl isocyanate (93 mg, 0.49 mmol) at 0 °C. The mixture was stirred under nitrogen protection for 3 hours. After LCMS showed the starting material disappeared, the mixture was concentrated for next step.

[0674] ESI-MS m / z calcd for [C 25 H 26 Cl4N8O4S][M+H] + : 675.1; found: 675.0

[0675] 2.2

[0676] (1-(((R)-2-((S)-4-(5-chloropyridin-2-yl)-3-(cyanomethyl)piperazin-1-yl)-5-oxo- 6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl(2,2,2- trichloroacetyl)carbamate (02951-1)

[0677] To a solution of (1-(((R)-2-((S)-4-(5-chloropyridin-2-yl)-3-(cyanomethyl)piperazin-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl(2,2,2- trichloroacetyl)carbamate (110 mg, 0.16 mmol, crude) in methanol (3 mL) was added potassium carbonate (90 mg, 0.66 mmol) at 0 °C. The mixture was stirred under nitrogen protection for 1 hour. After the reaction was completed, the mixture was distilled under reduced pressure to remove the solvent. 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 the product (12.13 mg, yield 13.93%) as a white solid.

[0678] ESI-MS m / z calcd for [C 23 H 27 ClN8O3S][M+H] + :531.2; found: 531.2

[0679] 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 2.8 Hz, 1H), 7.69 - 7.65 (m, 2H), 6.95 (d, J = 8.8 Hz, 1H), 6.50 - 6.47 (m, 2H), 4.96 - 4.94 (m, 1H), 4.65 - 4.36 (m, 4H), 4.07 - 4.04 (m, 1H), 3.47 - 3.38 (m, 2H), 3.26-3.13 (m, 4H), 3.00 - 2.88 (m, 2H), 2.77 - 2.67 (m, 2H), 2.45 - 2.40 (m, 1H), 2.38 - 2.20 (m, 2H), 1.85-1.81 (m, 2H).

[0680] 1. Synthesis scheme:

[0681] 2. Experimental part: Compound 02957-0 was used as starting material and the procedure of Example MX-02946 was followed to obtain compound MX02957. White solid product (9.43 mg, yield 12.02%).

[0682] ESI-MS m / z calcd for [C 21 H 27 N5O2S][M+H] + :414.2; found: 414.2

[0683] 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 8.8 Hz, 2H), 7.86 (s, 1H), 7.06 (d, J = 8.8 Hz, 2H), 4.91 (t, J = 5.6 Hz, 1H), 3.82 - 3.80 (m, 2H), 3.64 - 3.56 (m, 1H), 3.46 - 3.45 (m, 4H), 3.41 - 3.36 (m, 2H), 3.25 - 3.13 (m, 5H), 3.02 - 2.97 (m, 1H), 2.50 - 2.27 (m, 4H), 1.87 - 1.78 (m, 2H).

[0684] 1. Synthesis scheme:

[0685] 2. Experimental Section:

[0686] 2.1

[0687] 4-(5-chloropyridin-2-yl)piperazine-1 -carboxylic acid tert-butyl ester (02958-1 )

[0688] To a solution of 2-bromo-5-chloropyridine (600 mg, 3.12 mmol) in 1,4-dioxane (10 mL) was added Pd2(dba)3(143 mg, 0.156 mmol), Ruphos (73 mg, 0.156 mmol), t-BuONa (600 mg, 6.24 mmol) and piperazine-1 -carboxylic acid tert-butyl ester (581 mg, 3.12 mol). The mixture was stirred at 100 °C for 5 h. After the starting material was consumed, water (30 mL) was added and extracted with DCM (30 mL) twice. The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 20, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give the product as yellow oil (450 mg, yield 48.4%). ESI-MS m / z calcd for [C 14 H 20 ClN3O2][M-56+H] + : 298.1 ; found: 298.4

[0689] 2.2

[0690] 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1 - carboxylic acid tert-butyl ester (02958-2)

[0691] To a solution of 4-(5-chloropyridin-2-yl)piperazine-1 -carboxylic acid tert-butyl ester (358 mg, 1.2 mmol) in 1,4-dioxane (10 mL) was added B2Pin2(914 mg, 3.6 mmol), KOAc (353 mg 3.6 mmol) and Pd(dppf)CI2(88 mg, 0.12 mmol). The mixture was stirred at 80 °C under nitrogen overnight. After the starting material was consumed, the reaction was cooled and concentrated under reduced pressure. The crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give the product as brown solid (350 mg, yield 74.9%).

[0692] ESI-MS m / z calcd for [C 20 H 32 BN3O4][M+H] + :390.2; found: 390.4

[0693] 2.3

[0694] (R)-4-(5-(4-(((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-2-yl)pyridin-2-yl)piperazin-1-yl)butanoic acid (02958-4)

[0695] To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (144 mg, 0.5 mmol) in 1,4-dioxane / water (12 mL, v / v = 4 / 1) was added tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- yl)piperazine-1-carboxylate (195 mg, 0.5 mmol), K2CO3 (138 mg, 1.0 mmol) and Pd(dppf)Cl2 (37 mg, 0.05 mmol). The mixture was stirred at 100 °C under nitrogen protection for 3 hours. After the starting material was consumed, water (20 mL) was added and extracted with EA (20 mL) for three times. The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by prep-HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to give the product as a white solid (80 mg, yield 31.1%).

[0696] ESI-MS m / z calcd for [C 25 H 34 N6O4S][M+H] + :515.2; found: 515.3

[0697] 2.4

[0698] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(6-(piperazin-1-yl)pyridin-3-yl)- 6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02958)

[0699] To a solution of (R)-tert-butyl 4-(5-(4-(((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo- 6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)piperazin-1 -carboxylate (80.0 mg, 0.155 mmol) in DCM (5.0 mL) was added TFA (0.5 mL) and stirred at room temperature for 3 hours. After the starting material was consumed, the reaction was concentrated under reduced pressure after cooling. The resulting 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 the product as a white solid (16 mg, yield 24.9%).

[0700] ESI-MS m / z calcd for[C 20 H 26 N6O2S][M+H] + :415.2; found: 415.3

[0701] 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 2.4 Hz, 1H), 8.30 (dd, J = 9.2, 2.4 Hz, 1H), 7.91 (s, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.93 (t, J = 6.0 Hz, 1H), 3.83 - 3.76 (m, 2H), 3.63 - 3.53 (m, 5H), 3.36 - 3.28 (m, 2H), 3.19 - 3.13 (m, 1H), 3.02 - 2.97 (m, 1H), 2.78 - 2.75 (m, 4H), 2.43 - 2.25 (m, 4H), 2.86 - 2.78 (m, 2H).

[0702] 1. Synthesis scheme:

[0703] 2. Experimental part:

[0704] 2.1

[0705] 1-(5-chloropyridin-2-yl)-4-cyclopropylpiperazine (02961-1)

[0706] To a solution of 2-bromo-5-chloropyridine (400 mg, 2.1 mmol) in 1,4-dioxane (5 mL) was added 1-cyclopropylpiperazine (265 mg, 2.1 mmol), Ruphos (147 mg, 0.32 mmol) and Pd2(dba)3(96 mg, 0.11 mmol), t-BuONa (302 mg, 3.15 mmol), the reaction was stirred at 100 °C under nitrogen overnight. After the starting material was consumed, water (30 mL) was added to the mixture, which was extracted with EA (30 mL) twice, the combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 10, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product as a white solid (347 mg, yield 69.7%).

[0707] ESI-MS m / z calcd for [C 12 H 16 ClN3][M+H] + :238.2; found: 238.1

[0708] 2.2

[0709] 1-cyclopropyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (02961-2)

[0710] To a solution of 1-(5-chloropyridin-2-yl)-4-cyclopropylpiperazine (150 mg, 0.63 mmol) in 1,4-dioxane (10 mL) was added B2Pin2(321 mg, 1.27 mmol), KOAc (124 mg, 1.27 mmol) and X-Phos (30 mg, 0.06 mmol), Pd(dppf)Cl2(26 mg, 0.03 mmol). The mixture was stirred at 100 °C under nitrogen overnight, after the starting material was consumed, the reaction was filtered after cooling, concentrated under reduced pressure, the crude product was used directly in the next step.

[0711] ESI-MS m / z calcd for [C 18 H 28 BN3O2][M+H] + :330.2; found: 330.4

[0712] 2.3

[0713] (R)-2-(6-(4-cyclopropylpiperazin-1-yl)pyridin-3-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)- 6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02961)

[0714] To a solution of 1-cyclopropyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- yl)piperazine (33 mg, 0.10 mmol) in 1,4-dioxane / water (12.5 mL, v / v = 4 / 1) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (30 mg, 0.10 mmol), K2CO3(28 mg, 0.20 mmol) and Pd(dppf)Cl2(4 mg, 0.005 mmol). The mixture was heated to 80 °C and stirred under nitrogen protection for 8 h. After cooling, added to water (10 mL), and extracted with DCM (30 mL) for three times. The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by prep-HPLC [MeCN / H2O (10 mmol / L HCOOH), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (3.32 mg, yield 7.30%).

[0715] ESI-MS m / z calcd for [C 23 H 30 N6O2S][M+H] + :455.2; found: 455.3

[0716] 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 2.0 Hz, 1H), 8.31 (dd, J = 8.8, 2.4 Hz, 1H), 7.88 (s, 1H), 6.90 (d, J = 8, 8 Hz, 1H), 4.91 (t, J = 5.6 Hz, 1H), 3.80 - 3.79 (m, 2H), 3.62 - 3.35 (m, 5H), 3.25 - 3.19 (m, 1H), 3.17 - 3.13 (m, 1H), 3.02 - 2.97 (m, 1H), 2.67 - 2.61 (m, 4H), 2.44 - 2.29 (m, 4H), 1.86 - 1.80 (m, 2H), 1.66 - 1.64 (m, 1H), 0.45 - 0.44 (m, 2H), 0.43 - 0.37 (m, 2H).

[0717] 1. Synthesis scheme:

[0718] 2. Experimental section:

[0719] 2.1

[0720] 1-((4-bromophenyl)sulfonyl)-4-cyclopropylpiperazine (02962-1)

[0721] To a solution of 4-bromobenzene-1-sulfonyl chloride (500 mg, 1.96 mmol) and TEA (594 mg, 5.87 mmol) in acetone (20 mL) was added 1-cyclopropylpiperazine (296 mg, 2.35 mmol). The mixture was stirred at room temperature for 1.5 hours. Then the reaction was concentrated. The crude product was purified by column chromatography (EA / PE = 0~80%, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to give the product as a white solid (505 mg, yield 74.75%).

[0722] ESI-MS m / z calcd for [C 13 H 17 BrN2O2S][M+H] + : 345.0; found: 345.2

[0723] 2.2

[0724] 1-cyclopropyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperazine (02962-2)

[0725] To a solution of 1-((4-bromophenyl)sulfonyl)-4-cyclopropylpiperazine (500 mg, 1.45 mmol) and pinacol borate (552 mg, 2.17 mmol) in 1,4-dioxane (20 mL) was added Pd(dppf)Cl2(106 mg, 0.14 mmol) and potassium acetate (426 mg, 4.34 mmol). The mixture was stirred at 100 °C under nitrogen protection for 8 hours. After cooling, the reaction was concentrated. The crude product was purified by column chromatography (EA / PE = 0~80%, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to give the product as a yellow solid (141 mg, yield 24.82%).

[0726] ESI-MS m / z calcd for [C 19 H 29 BN2O4S][M+H] +: 393.2; found: 393.4

[0727] 2.3

[0728] (R)-2-(4-((4-cyclopropylpiperazin-1-yl)sulfonyl)phenyl)-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02962)

[0729] To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (60 mg, 0.21 mmol) and 1-cyclopropyl-4-((4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperazine (123 mg, 0.31 mmol) in 1,4-dioxane and water (5 mL, v / v = 4:1), potassium carbonate (72 mg, 0.52 mmol) and Pd(dppf)Cl2(15 mg, 0.02 mmol) were added. The mixture was stirred at 80 °C under nitrogen protection for 4 hours. After the reaction was completed, the mixture was distilled to remove the solvent under reduced pressure. The crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (33.05 mg, yield 32.47%).

[0730] ESI-MS m / z calcd for [C 24 H 31 N5O4S2][M+H] + : 518.2; found: 518.2

[0731] 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 8.4 Hz, 2H), 8.21 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 4.92 (t, J = 5.6 Hz, 1H), 3.83 - 3.78 (m, 2H), 3.71 - 3.62 (m, 1H), 3.43 - 3.35 (m, 1H), 3.29-3.22 (m, 1H), 3.08 - 3.03 (m, 1H), 2.86-2.89 (m, 4H), 2.68 - 2.66 (m, 4H), 2.46 - 2.33 (m, 4H), 1.87 - 1.81 (m, 2H), 1.64 - 1.61 (m, 1H), 0.38 - 0.37 (m, 2H), 0.21 - 0.20 (m, 2H).

[0732] 1. Synthesis scheme:

[0733] 2. Experimental part:

[0734] 2.1

[0735] (4-bromo-3-fluorophenyl)(morpholinyl)methanone (02971-1)

[0736] To a solution of 4-bromo-3-fluorobenzoic acid (2.5 g, 11.47 mmol) and morpholine (998 mg, 11.47 mmol) in DCM (30 mL) was added DMAP (1.4 g, 11.47 mmol) and EDCI (2.2 g, 11.47 mmol). The reaction mixture was stirred at room temperature overnight. After the starting material was consumed, water (50 mL) was added to the mixture, which was extracted twice with EA (50 mL). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 0, silica gel-CS 80 g, 50 mL / min, silica gel, UV 254) to give the product as a yellow solid (2.50 g, yield 76%).

[0737] ESI-MS m / z calcd for [C 11 H 11 BrFNO2][M+H] + :288.0; found:288.1

[0738] 2.2

[0739] (3-fluoro-4-hydroxyphenyl)(morpholinyl)methanone (02917-2)

[0740] To a solution of (4-bromo-3-fluorophenyl)(morpholino)methanone (300 mg, 1.04 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1) was added KOH (110 mg, 2.08 mmol), tBu-Xphos (42 mg, 0.10 mmol) and Pd2(dba)3(91 mg, 0.10 mmol) and the reaction was stirred at 80 °C for 3 h. After the starting material was consumed, water (30 mL) was added to the mixture, which was extracted twice with EA (30 mL), the combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 10, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give the product as a white solid (160 mg, yield 68%).

[0741] ESI-MS m / z calcd for [C 11 H 12 FNO3][M+H] + :226.1; found: 226.4

[0742] 2.3

[0743] 3-(2-Fluoro-4-(morpholine-4-carbonyl)phenoxy)azetidine-1-carboxylic acid tert-butyl ester (02917-3)

[0744] To a solution of (3-fluoro-4-hydroxyphenyl)(morpholino)methanone (80 mg, 0.35 mmol) and 3-(p-toluenesulfonyloxy)azetidine-1-carboxylic acid tert-butyl ester (116 mg, 0.35 mmol) in DMF (4 mL) was added Cs2CO3(232 mg, 0.70 mmol) at room temperature. The mixture was then stirred at 80 °C for 2 h, after which water (20 mL) was added and extracted twice with EA (20 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product as a yellow solid (111 mg, yield 82%).

[0745] ESI-MS m / z calcd for [C 19 H 25 FN2O5][M-56+H] + :325.2; found: 325.1

[0746] 2.4

[0747] (4-(azetidin-3-yloxy)-3-fluorophenyl)(morpholinyl)methanone (02917-4)

[0748] To a solution of tert-butyl 3-(2-fluoro-4-(morpholine-4-carbonyl)phenoxy)azetidine-1- carboxylate (111 mg, 0.29 mmol) in DCM (4 mL) was added TFA (0.4 mL). The reaction mixture was stirred at room temperature for 3 hours under nitrogen protection, after the starting material was consumed, the mixture was concentrated under reduced pressure to give the product as a yellow oil (79 mg, yield 96%).

[0749] ESI-MS m / z calcd for [C 14 H 17 FN2O3][M+H] + :281.1; found: 281.4

[0750] 2.5

[0751] (R)-(3-fluoro-4-((1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-2-yl)azetidin-3-yl)oxy)phenyl)(morpholinyl)methanone (MX02917)

[0752] To a solution of (4-(azetidin-3-yloxy)-3-fluorophenyl)(morpholinyl)methanone (79 mg, 0.28 mmol) in DMF (3 mL) and DIEA (72 mg, 0.56 mmol) was added (R)-2-chloro-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (81 mg, 0.28 mmol). The mixture was stirred at 90 °C for 3 hours, after the starting material was consumed, the mixture was concentrated under reduced pressure to give the crude product which was purified by preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254) to give the product as a white solid (13.91 mg, yield 9%).

[0753] ESI-MS m / z calcd for [C 25 H 30 FN5O5S][M+H] + :532.2; found: 532.2

[0754] 1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 1H), 7.37 (dd, J = 11.6, 2.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.05 (t, J = 8.8 Hz, 1H), 5.25 - 5.21 (m, 1H), 4.86 (s, 1H), 4.48 (dd, J = 10.4, 6.4 Hz, 2H), 4.05 - 3.93 (m, 2H), 3.73 - 3.65 (m, 2H), 3.59 - 3.37 (m, 9H), 3.25 - 3.18 (m, 1H), 2.97 - 2.85 (m, 2H), 2.36 - 2.25 (m, 2H), 2.16 - 2.10 (m, 2H), 1.80 - 1.71 (m, 2H).

[0755] 1. Synthesis scheme:

[0756] 2. Experimental section: Compound 02972-0 and R1 were used as starting materials, and the operation in Example MX-02971 was referred to, to obtain compound MX02972. White solid compound (39.42 mg, yield 43.5%).

[0757] ESI-MS m / z calcd for [C 24 H 30 FN5O6S2][M+H] + :568.2; found: 568.0

[0758] 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (dd, J = 10.4, 2.0 Hz, 1H), 7.55 - 7.52 (m, 2H), 7.25 (t, J = 8.4 Hz, 1H), 5.34 - 5.29 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.51 (dd, J = 10.0, 6.0 Hz, 2H), 4.02 (d, J = 7.6 Hz, 2H), 3.73 - 3.68 (m, 2H), 3.63 (t, J = 4.4 Hz, 4H), 3.46 - 3.38 (m, 1H), 3.25 - 3.18 (m, 1H), 2.97 - 2.85 (m, 6H), 2.38 - 2.25 (m, 2H), 2.14 (t, J = 9.2 Hz, 2H), 1.81 - 1.68 (m, 2H).

[0759] 1. Synthesis scheme:

[0760] 2. Experimental Part: Compound 02975-0 and R1 were used as starting materials to obtain compound MX02975 following the procedure of example MX-02692. White solid product (34.30 mg, yield 23%).

[0761] ESI-MS m / z calcd for [C 27 H 32 FN5O4S][M+H] + :542.2; found: 542.3

[0762] 1 H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.43 (m, 2H), 7.29 - 7.22 (m, 2H), 6.17 (s, 1H), 4.86 (t, J = 5.6 Hz, 1H), 4.57 - 4.44 (m, 2H), 3.98 - 3.95 (m, 2H), 3.78 - 3.71 (m, 2H), 3.68 - 3.50 (m, 6H), 3.48 - 3.35 (m, 5H), 3.25 - 3.18 (m, 1H), 2.98 - 2.84 (m, 2H), 2.41 - 2.28 (m, 2H), 2.22 - 2.16 (m, 2H), 1.82 - 1.73 (m, 2H).

[0763] 1. Synthesis scheme:

[0764] 2. Experimental Part:

[0765] 2.1

[0766] 4-(2-Fluoro-4-(morpholinosulfonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (02976-1)

[0767] To a solution of 4-((4-bromo-3-fluorophenyl)sulfonyl)morpholine (300 mg, 0.93 mmol) in a mixture of 1,4-dioxane and water (5 mL, v / v = 4 / 1) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (430 mg, 1.39 mmol), potassium carbonate (385 mg, 2.79 mmol) and Pd(dppf)Cl2(68 mg, 0.093 mmol). The mixture was stirred at 80 °C under nitrogen protection for 3 h. After the starting material was consumed, water was added and extracted with EA (30 mL) twice. The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 1 ~ 1 / 3, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give the product as yellow oil (362 mg, yield 91.4%).

[0768] ESI-MS m / z calcd for [C 20 H 27 FN2O5S][M+H] + : 427.2; found: 327.3

[0769] 2.2

[0770] 4-((3-Fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl)morpholine (02976-2)

[0771] To a solution of tert-butyl 4-(2-fluoro-4-(morpholinosulfonyl)phenyl)-5,6- dihydropyridine-1(2H)-carboxylate (100 mg, 0.23 mmol) in DCM (2.5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature under nitrogen protection for 1 h. After the starting material was consumed, the mixture was concentrated under reduced pressure to give the crude product which was used directly for the next reaction.

[0772] ESI-MS m / z calcd for [C 15 H 19 FN2O3S][M+H] + : 327.1; found: 327.0

[0773] 2.3

[0774] (R)-2-(4-(2-fluoro-4-(morpholine sulfonyl)phenyl)-5,6-dihydropyridin- 1 (2H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2- d]pyrimidine 5-oxide (MX02976)

[0775] To a solution of 4-((3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl)morpholine (76 mg, 0.23 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)- 6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (67 mg, 0.23 mmol) in DMF (2 mL) was added DIEA (178 mg, 1.38 mmol). The mixture was stirred at 100 °C for 2 h, cooled to room temperature and concentrated. The crude product was purified by preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254) to give compound (46.78 mg, yield 35.2%) as a white solid.

[0776] ESI-MS m / z calcd for[C 26 H 32 FN5O5S2][M+H] + :578.2; found: 578.0

[0777] 1 H NMR (400 MHz, DMSO-d6) d 7.69 (t, J = 7.6 Hz, 1H), 7.58 - 7.54 (m, 2H), 7.44 (s, 1H), 6.29 (s, 1H), 4.86 (t, J = 5.2 Hz, 1H), 4.39 (s, 2H), 3.98 (t, J = 5.2 Hz, 2H), 3.75 (d, J = 4.0 Hz, 2H), 3.63 (t, J = 4.4 Hz, 4H), 3.48 - 3.39 (m, 1H), 3.26 - 3.18 (m, 1H), 2.98 - 2.85 (m, 6H), 2.54 - 2.51 (m, 2H), 2.39 - 2.28 (m, 2H), 2.23 - 2.17 (m, 2H), 1.82 - 1.73 (m, 2H).

[0778] 1. Synthesis scheme:

[0779] 2. Experimental part:

[0780] 2.1 2.1

[0781] 2-bromo-5-cyclopropyloxy-pyrimidine (02985-1)

[0782] A solution of 2-bromo-5-fluoropyrimidine (5.0 g, 28.4 mmol) and cyclopropanol (1.65 g, 28.4 mmol) in THF (30 mL) was added NaH (60%, 1.7 g, 28.4 mmol) at 0 °C, and the reaction was stirred at 0 °C for 2 h. After the starting material was consumed, water (100 mL) was added to the mixture, which was extracted twice with EA (100 mL), and the combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 0, silica gel-CS 80 g, 50 mL / min, silica gel, UV 254) to give the product (150 mg, yield 2.4%) as a yellow solid.

[0783] ESI-MS m / z calcd for [C7H7BrN2O] [M+H] + : 215.0; found: 215.3

[0784] 2.2

[0785] 4-(5-cyclopropyloxy-pyrimidin-2-yl)-5,6-dihydro-pyridine-1(2H)-carboxylic acid tert-butyl ester (02985-2)

[0786] A solution of 2-bromo-5-cyclopropyloxy-pyrimidine (150 mg, 0.70 mmol) in 1,4-dioxane / water (2.5 mL, v / v = 4 / 1) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-pyridine-1(2H)-carboxylic acid tert-butyl ester (220 mg, 0.70 mmol), potassium carbonate (200 mg, 2.10 mmol) and Pd(dppf)Cl2(49 mg, 0.07 mmol), and the reaction was stirred at 90 °C for 5 h. After the starting material was consumed, water (30 mL) was added to the mixture, which was extracted twice with EA (30 mL), and the combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 10, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product (190 mg, yield 85%) as a white solid.

[0787] ESI-MS m / z calcd for [C 17 H 23 N3O3] [M+H] +:318.2; found: 318.4

[0788] 2.3

[0789] 4-(5-cyclopropyloxy-pyrimidin-2-yl)-piperidin-1-yl

[0790] To a solution of tert-butyl 4-(5-cyclopropyloxy-pyrimidin-2-yl)-5,6-dihydro- pyridine-1 (2H)-carboxylate (190 mg, 0.55 mmol) in EtOH (5 mL) was added Pd / C (56 mg) at room temperature. The mixture was stirred under hydrogen atmosphere at room temperature for 3 hours, after the reaction was complete, the reaction was filtered and concentrated to give the product as a yellow solid (160 mg, yield 84%).

[0791] ESI-MS m / z calcd for [C 17 H 25 N3O3][M-56+H] + :264.2; found: 264.4

[0792] 2.4

[0793] 5-cyclopropyloxy-2-(piperidin-4-yl)-pyrimidine

[0794] To a solution of tert-butyl 4-(5-cyclopropyloxy-pyrimidin-2-yl)-piperidin-1-ylcarbamate (80 mg, 0.25 mmol) in DCM (3 mL) was added TFA (0.4 mL). The reaction mixture was stirred at room temperature for 3 hours under nitrogen protection, after the starting material was consumed, the mixture was concentrated under reduced pressure to give the product as a yellow oil (51 mg, yield 93%).

[0795] ESI-MS m / z calcd for [C 12 H 17 N3O][M+H] + :220.1; found: 220.4

[0796] 2.5

[0797] (R)-2-(4-(5-cyclopropyloxy-pyrimidin-2-yl)-piperidin-1-yl)-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (MX02985)

[0798] To a solution of 5-cyclopropoxy-2-(piperidin-4-yl)pyrimidine (51 mg, 0.23 mmol) in DMF (3 mL) and DIEA (59 mg, 0.46 mmol) was added (R)-2-chloro-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (67 mg, 0.23 mmol). The mixture was stirred at 90 °C for 3 h, after consumption of the starting material, the mixture was concentrated under reduced pressure, the resulting 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 the product as a white solid (29.67 mg, 27% yield).

[0799] ESI-MS m / z calcd for[C 23 H 30 N6O3S][M+H] + :471.2; found: 471.3

[0800] 1 H NMR (400 MHz, DMSO-d6) δ 8.56 - 8.55 (m, 2H), 7.33 (s, 1H), 4.84 (t, J = 5.2 Hz, 1H), 4.70 (d, J = 10.4 Hz, 2H), 4.04 - 4.01 (m, 1H), 3.75 - 3.69 (m, 2H), 3.45 - 3.32 (m, 1H), 3.24 - 3.08 (m, 4H), 2.96 - 2.83 (m, 2H), 2.41 - 2.26 (m, 2H), 2.20 - 2.10 (m, 2H), 1.95 - 1.92 (m, 2H), 1.77 - 1.62 (m, 4H), 0.82 - 0.71 (m, 4H).

[0801] 1. Synthesis scheme:

[0802] 2. Experimental part:

[0803] 2.1

[0804] 1-(5-chloropyridin-2-yl)-4-(ethylsulfonyl)piperazine (02996-1)

[0805] To a solution of 2-bromo-5-chloropyridine (385 mg, 2.0 mmol) in 1,4-dioxane (10 mL) was added Pd2(dba)3(92 mg, 0.1 mmol), Ruphos (93 mg, 0.2 mmol), t-BuONa (384 mg, 4.0 mmol) and 1-(ethylsulfonyl)piperazine (356 mg, 2.0 mol). The mixture was stirred at 100 °C for 5 h. After the starting material was consumed, water (30 mL) was added and extracted with DCM (30 mL) twice. The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 20, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give the product as a yellow oil (450 mg, yield 77.6%).

[0806] ESI-MS m / z calcd for [C 11 H 16 ClN3O2S][M+H] + :290.1; found: 290.4

[0807] 2.2

[0808] 1-(ethylsulfonyl)-4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (02996-2)

[0809] To a solution of 1-(5-chloropyridin-2-yl)-4-(ethylsulfonyl)piperazine (145 mg, 0.5 mmol) in 1,4-dioxane (10 mL) was added B2Pin2(381 mg, 1.5 mmol), KOAc (148 mg 1.5 mmol) and Pd(dppf)Cl2(37 mg, 0.05 mmol). The mixture was stirred at 80 °C under nitrogen overnight. After the starting material was consumed, the reaction was cooled and concentrated under reduced pressure. The crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give the product as a brown solid (100 mg, yield 52.5%).

[0810] ESI-MS m / z calcd for [C 17 H 28 BN3O4S][M+H] + :382.2; found: 382.3

[0811] 2.3

[0812] (R)-2-(6-(4-(ethylsulfonyl)piperazin-1-yl)pyridin-3-yl)-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02996)

[0813] To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (75.7 mg, 0.263 mmol) in 1,4-dioxane / water (10 mL, v / v = 4 / 1) was added 1-(ethylsulfonyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-yl)piperazine (100 mg, 0.263 mmol), K2CO3(110 mg, 0.79 mmol) and Pd(dppf)Cl2(22 mg, 0.03 mmol). The mixture was stirred at 100 °C under nitrogen protection for 3 h. After the starting material was consumed, water (20 mL) was added and extracted with EA (20 mL) for three times. The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by prep-HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to give the product as a white solid (58 mg, yield 43.6%).

[0814] ESI-MS m / z calcd for [C 22 H 30 N6O4S2][M+H] + :507.2; found: 507.2

[0815] 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 2.4 Hz, 1H), 8.35 (dd, J = 8.8, 2.0 Hz, 1H), 7.94 (s, 1H), 6.97 (d, J = 8.8 Hz, 1H), 4.92 (t, J = 5.6 Hz, 1H), 3.83 - 3.78 (m, 2H), 3.75 - 3.73 (m, 4H), 3.64 - 3.56 (m, 1H), 3.37 - 3.35 (m, 1H), 3.29 - 3.27 (m, 4H), 3.20 - 3.14 (m, 1H), 3.11 (q, J = 7.2 Hz, 2H), 3.02 - 2.97 (m, 1H), 2.44 - 2.29 (m, 4H), 1.88 - 1.78 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H).

[0816] 1. Synthesis scheme:

[0817] 2. Experimental part:

[0818] 2.1

[0819] 1 -(4-bromophenyl)-4-(ethylsulfonyl)piperazine (02997-1 )

[0820] To a solution of 1 -bromo-4-iodobenzene (1415 mg, 5.0 mmol) in 1,4-dioxane (20 mL) was added Pd2(dba)3 (229 mg, 0.25 mmol), Ruphos (233 mg, 0.5 mmol), t-BuONa (960 mg, 10.0 mmol) and 1 -(ethylsulfonyl)piperazine (892 mg, 5.0 mol). The mixture was stirred at 100 °C for 5 hours. After the starting material was consumed, water (30 mL) was added and extracted with DCM (30 mL) twice. The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 20, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give the product as a yellow oil (300 mg, yield 18.02%).

[0821] ESI-MS m / z calcd for [C 12 H 17 BrN2O2S][M+H] + : 333.0; found: 333.3

[0822] 2.2

[0823] 1 -(Ethylsulfonyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (02997-2)

[0824] To a solution of 1 -(4-bromophenyl)-4-(ethylsulfonyl)piperazine (200 mg, 0.6 mmol) in 1,4-dioxane (15 mL) was added B2Pin2 (457 mg, 1.8 mmol), KOAc (177 mg 1.8 mmol) and Pd(dppf)Cl2(44 mg, 0.06 mmol). The mixture was stirred at 80 °C under nitrogen overnight, after the consumption of the starting material, the reaction was cooled and concentrated under reduced pressure, the crude obtained was purified by column chromatography (EA / PE = 0 / 1 to 1 / 1, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give the product as a brown solid (150 mg, 65.8% yield).

[0825] ESI-MS m / z calcd for [C 18 H 29 BN2O4S][M+H] + : 381.2; found: 381.4

[0826] 2.3

[0827] (R)-2-(4-(4-(Ethylsulfonyl)piperazin-1 -yl)phenyl)-4-((1 -(hydroxymethyl)cyclobutyl)amino)- 6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02997)

[0828] To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (57 mg, 0.2 mmol) in 1,4-dioxane / water (10 mL, v / v = 4 / 1) was added 1-(ethylsulfonyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperazine (150 mg, 0.4 mmol), K2CO3(165 mg, 1.2 mmol) and Pd(dppf)Cl2(29 mg, 0.04 mmol). The mixture was stirred at 100 °C under nitrogen protection for 3 h, after the starting material was consumed, water (20 mL) was added and extracted with EA (20 mL) for three times. The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by prep-HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to give the white solid product (50 mg, yield 49.4%).

[0829] ESI-MS m / z calcd for[C 23 H 31 N5O4S2][M+H] + :506.2; found: 506.2

[0830] 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 8.8 Hz, 2H), 7.87 (s, 1H), 7.05 (d, J = 8.8 Hz, 2H), 4.92 (t, J = 5.6 Hz, 1H), 3.85 - 3.77 (m, 2H), 3.64 - 3.56 (m, 1H), 3.38 - 3.35 (m, 4H), 3.30 - 3.27 (m, 5H), 3.20 - 3.08 (m, 3H), 3.02 - 2.97 (m, 1H), 2.46 - 2.26 (m, 4H), 1.87 - 1.78 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H).

[0831] 1. Synthesis scheme:

[0832] 2. Experimental part: Compound MX02998 was obtained by using compound 02998-0 and R1 as starting materials, following the procedure of Example MX-02814. White solid product (13.02 mg, yield 16%).

[0833] ESI-MS m / z calcd for [C 24 H 33 N7O3S][M+H] + :500.2;found:500.3

[0834] 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 2H), 7.43 (s, 1H), 5.35 - 5.30 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.39 (dd, J = 10.0, 6.8 Hz, 2H), 3.97 - 3.88 (m, 2H), 3.73 - 3.67 (m, 2H), 3.61 - 3.58 (m, 2H), 3.45 - 3.37 (m, 1H), 3.25 - 3.17 (m, 1H), 2.96 - 2.84 (m, 2H), 2.64 (dt, J = 12.4, 2.0 Hz, 2H), 2.38 - 2.25 (m, 2H), 2.14 - 2.10 (m, 2H), 1.82 - 1.68 (m, 4H), 1.52 - 1.44 (m, 1H), 1.28 - 1.18 (m, 2H), 0.94 (d, J = 6.4 Hz, 3H).

[0835] 1. Synthesis scheme:

[0836] 2. Experimental section: Compound MX02999 was obtained starting from compound 02999-0 and R1 following the procedure of example MX-02900. White solid product (9.67 mg, 10% yield).

[0837] ESI-MS m / z calcd for [C 25 H 34 N6O3S][M+H] + :499.2;found:499.3

[0838] 1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 2.8 Hz, 1H), 7.46 (dd, J = 9.2, 3.2 Hz, 1H), 7.42 (s, 1H), 6.76 (d, J = 9.2 Hz, 1H), 5.36 - 5.30 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.38 (dd, J = 9.6, 2.4 Hz, 2H), 3.99 - 3.84 (m, 2H), 3.70 - 3.65 (m, 2H), 3.52 - 3.42 (m, 2H), 3.40 - 3.32 (m, 1H), 3.24 - 3.17 (m, 1H), 2.96 - 2.84 (m, 2H), 2.62 - 2.55 (m, 2H), 2.38 - 2.25 (m, 2H), 2.14 - 2.10 (m, 2H), 1.79 - 1.67 (m, 4H), 1.50 - 1.42 (m, 1H), 1.29 - 1.19 (m, 2H), 0.93 (d, J = 6.8 Hz, 3H).

[0839] 1. Synthesis scheme:

[0840] 2. Experimental section: Compound MX021002 was obtained following the procedure of example MX-02950 starting from compound 021002-0 and R1. White solid product (17 mg, yield 21.90%).

[0841] ESI-MS m / z calcd for [C 23 H 28 N4O4S][M+H] + : 457.2; found: 457.3

[0842] 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 8.8 Hz, 2H), 7.81 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 4.93 - 4.92 (m, 1H), 3.83 - 3.81 (m, 4H), 3.63 - 3.55 (m, 1H), 3.33-3.29 (m, 1H), 3.18 - 3.13 (m, 1H), 3.01 - 2.88 (m, 3H), 2.46-2.26 (m, 5H), 1.91 - 1.81 (m, 4H), 1.66-1.57 (m, 2H).

[0843] 1. Synthesis scheme:

[0844] 2. Experimental section:

[0845] 2.1

[0846] (4-bromo-2-fluorophenyl)(morpholinyl)methanone (021013-1)

[0847] To a solution of 4-bromo-2-fluorobenzoate (200 mg, 0.91 mmol) in DMF (6 mL) was added HATU (416 mg, 1.09 mmol), morpholine (95 mg, 1.09 mmol), TEA (460 mg, 4.55 mmol), the mixture was stirred at room temperature for 6 hours, after the starting material was consumed, water (20 mL) was added to the mixture, and extracted with EA (30 mL) for three times. The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the obtained crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to obtain the product as a white solid (220 mg, yield 84.2%).

[0848] ESI-MS m / z calcd for [C 11 H 11 BrFNO2][M+H] + :288.0; found: 289.9

[0849] 2.2

[0850] (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(morpholinyl)methanone (021013-2)

[0851] To a solution of (4-bromo-2-fluorophenyl)(morpholinyl)methanone (200 mg, 0.70 mmol) in 1,4-dioxane (6 mL) was added B2Pin2 (350 mg, 1.39 mmol), KOAc (140 mg, 1.40 mmol) and Pd(dppf)Cl2 (30 mg, 0.035 mmol). The mixture was stirred at 80 °C under nitrogen protection overnight, after the starting material was consumed, the reaction was cooled and filtered, concentrated under reduced pressure, the crude product was directly used for the next reaction.

[0852] ESI-MS m / z calcd for [C 17 H 23 BFNO4][M+H] + :336.2; found: 336.3

[0853] 2.3

[0854] (R)-(2-fluoro-4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7- dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)(morpholino)methanone (MX021013)

[0855] To a solution of (2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)(morpholino)methanone (60 mg, 0.14 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1) was added (R)-2-chloro-4-((l-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2- d]pyrimidine 5-oxide (40 mg, 0.14 mmol), K2CO3(33 mg, 0.24 mmol) and Pd(dppf)Cl2(5 mg, 0.006 mmol). The mixture was heated to 80 °C and stirred under nitrogen protection for 5 hours. After cooling, added to water (10 mL), and extracted with DCM (10 mL) three times. The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L HCOOH), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (10.30 mg, yield 15.99%).

[0856] ESI-MS m / z calcd for [C 22 H 25 FN4O4S][M+H] + :461.2; found: 460.9

[0857] 1 H NMR (400 MHz, DMSO-d6) δ 8.22 - 8.20 (m, 2H), 8.05 (d, J = 10.8 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 4.94 (t, J = 5.6 Hz, 1H), 3.87 - 3.81 (m, 2H), 3.70 - 3.62 (m, 5H), 3.54 - 3.53 (m, 2H), 3.42 - 3.34 (m, 1H), 3.28 - 3.20 (m, 3H), 3.07 - 3.02 (m, 1H), 2.46 - 2.32 (m, 4H), 1.88 - 1.80 (m, 2H).

[0858] 1. Synthesis scheme:

[0859] 2. Experimental section:

[0860] 2.1

[0861] (4-bromo-2-fluorophenyl)(piperidin-l-yl)methanone (021016-1)

[0862] To a solution of 4-bromo-2-fluorobenzoate (200 mg, 0.91 mmol) in DMF (6 mL) was added HATU (416 mg, 1.09 mmol), piperidine (95 mg, 1.09 mmol), TEA (460 mg, 4.55 mmol), the mixture was stirred at room temperature for 6 hours, after the starting material was consumed, water (20 mL) was added to the mixture, and extracted with EA (30 mL) for three times. The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the obtained crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to obtain the product as a white solid (221 mg, yield 85.2%).

[0863] ESI-MS m / z calcd for [C 12 H 13 BrFNO][M+H] + : 286.0; found: 287.9

[0864] 2.2

[0865] (2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)(piperidin-l- yl)methanone (021016-2)

[0866] To a solution of (4-bromo-2-fluorophenyl)(piperidin-l-yl)methanone (200 mg, 0.70 mmol) in 1,4-dioxane (6 mL) was added B2Pin2 (350 mg, 1.39 mmol), KOAc (140 mg, 1.40 mmol) and Pd(dppf)Cl2(30 mg, 0.035 mmol). The mixture was stirred at 80 °C under nitrogen protection overnight, after the starting material was consumed, the reaction was cooled and filtered, concentrated under reduced pressure, the crude product was directly used for the next reaction.

[0867] ESI-MS m / z calcd for [C 18 H 25 BFNO3][M+H] + : 334.2; found: 334.4

[0868] 2.3

[0869] (R)-(2-Fluoro-4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7- dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)(piperidin-1-yl)methanone (MX021016)

[0870] To a solution of (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(piperidin-1- yl)methanone (46 mg, 0.14 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (40 mg, 0.14 mmol), K2CO3(33 mg, 0.24 mmol) and Pd(dppf)Cl2(5 mg, 0.006 mmol). The mixture was heated to 80 °C and stirred under nitrogen protection for 5 hours. After cooling, added to water (10 mL), and extracted with DCM (10 mL) for three times. The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L HCOOH), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (31.70 mg, yield 49.44%).

[0871] ESI-MS m / z calcd for [C 23 H 27 FN4O3S][M+H] + :459.2; found: 459.0

[0872] 1 H NMR (400 MHz, DMSO-d6) d 8.21 - 8.20 (m, 2H), 8.05 (d, J = 10.8 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 4.94 (t, J = 5.6 Hz, 1H), 3.83 - 3.79 (m, 2H), 3.70 - 3.62 (m, 3H), 3.42 - 3.34 (m, 1H), 3.26 - 3.20 (m, 3H), 3.08 - 3.02 (m, 1H), 2.45 - 2.32 (m, 4H), 1.88 - 1.82 (m, 2H), 1.62 - 1.56 (m, 4H), 1.46 - 1.45 (m, 2H).

[0873] 1. Synthesis scheme:

[0874] 2. Experimental part:

[0875] 2.1

[0876] 4-benzyloxy-3-fluorobenzaldehyde (021018-1)

[0877] To a solution of 3-fluoro-4-hydroxybenzaldehyde (1.4 g, 10.0 mmol) and benzyl bromide (1.7 g, 10.0 mmol) in DMF (15 mL) was added K2CO3(2.6 g, 20.0 mmol) at room temperature. The mixture was then stirred at room temperature for 6 hours, after which water (20 mL) was added and extracted twice with EA (20 mL). The combined organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 0 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the yellow solid product (2.0 g, yield 87.0%).

[0878] ESI-MS m / z calcd for [C 14 H 11 FO2][M+H] + :231.2 found:231.4

[0879] 2.2

[0880] (4-(benzyloxy)-3-fluorophenyl)methanol (021018-2)

[0881] To a solution of 4-benzyloxy-3-fluorobenzaldehyde (1 g, 4.3 mmol) in MeOH (15.0 mL) was added NaBH4(200 mg, 5.2 mmol). The mixture was stirred at room temperature for 2 hours, after which it was filtered with celite and the filtrate was distilled under reduced pressure to give the white solid product (997 mg, yield 99.9%).

[0882] ESI-MS m / z calcd for [C 14 H 13 FO2][M+H] + :233.2; found:215.4

[0883] 2.3

[0884] 1-(benzyloxy)-4-(bromomethyl)-2-fluorobenzene (021018-3)

[0885] To a solution of (4-(benzyloxy)-3-fluorophenyl)methanol (500 mg, 2.2 mmol) in DCM (10 mL) was added CBr4(800 mg, 2.4 mmol) and PPh3(690 mg, 2.6 mmol) and stirred at room temperature for 3 h. The reaction was quenched with water (10 mL) and extracted with EA (10 mL) for three times. The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0~1 / 10, silica gel-CS 12 g, 30 mL / min, UV 254) to give the product as colorless oil (420 mg, yield 64.9%).

[0886] ESI-MS m / z calcd for [C 14 H 12 BrFO][M+H] + :295.0

[0887] 2.4

[0888] 1-(4-(benzyloxy)-3-fluorobenzyl)piperidin-2-one (021018-4)

[0889] To a solution of piperidin-2-one (500 mg, 1.4 mmol) in dry THF (10 mL) was added NaH (60%, 114 mg, 2.8 mmol) at 0 °C. The mixture was stirred at 25 °C for 10 min, then 1-(benzyloxy)-4-(bromomethyl)-2-fluorobenzene (377 mg, 1.4 mmol) was added to the mixture, which was stirred at 25 °C overnight. The pH value of the reaction mixture was adjusted to 6 with 1 N aqueous HC1 solution. It was stirred at room temperature for 5 h. The reaction was quenched with water (10 mL) and extracted with EA (10 mL) for three times. The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (THF / PE = 0~1 / 1 / 1, silica gel-CS 12 g, 30 mL / min, UV 254) to give the product as colorless oil (159 mg, yield 36.3%).

[0890] ESI-MS m / z calcd for [C 19 H 20 FNO2][M+H] + :314.2; found: 314.4.

[0891] 2.5

[0892] 1 -(4-(benzyloxy)-3-fluorobenzyl)piperidin-2-one (021018-5)

[0893] To a solution of 1 -(4-(benzyloxy)-3-fluorobenzyl)piperidin-2-one (150 mg, 0.48 mmol) in MeOH (10.0 mL) was added Pd / C (32 mg). The mixture was stirred at room temperature under hydrogen atmosphere for 6 hours, then filtered with celite, and the filtrate was distilled under reduced pressure to give the product as colorless oil (106 mg, yield 99.0%).

[0894] ESI-MS m / z calcd for [C 12 H 14 FNO2][M+H] + :224.2; found: 224.4

[0895] 2.6

[0896] 3-(2-fluoro-4-((2-oxopiperidin-1-yl)methyl)phenoxy)azetidine-1-carboxylic acid tert-butyl ester

[0897] (021018-6)

[0898] To a solution of 1 -(3-fluoro-4-hydroxybenzyl)piperidin-2-one (100 mg, 0.44 mmol) and 3-(p-tolylsulfonyloxy)azetidine-1-carboxylic acid tert-butyl ester (150 mg, 0.44 mmol) in DMF (5 mL) was added Cs2CO3(290 mg, 0.88 mmol) at room temperature. Then the mixture was stirred at 80 °C for 2 hours, after which water (20 mL) was added and extracted twice with EA (20 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product as yellow solid (123 mg, yield 73.4%).

[0899] ESI-MS m / z calcd for [C 20 H 27 FN2O4][M+H] + :379.2; found: 455.8

[0900] 2.7

[0901] 1 -(4-(azetidin-3-yloxy)-3-fluorobenzyl)piperidin-2-one (021018-7)

[0902] To a solution of tert-butyl 3-(2-fluoro-4-((2-oxopiperidin-1-yl)methyl)phenoxy)azetidine-1-carboxylate (100 mg, 0.26 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.3 mL) under ice bath, the mixture was stirred at room temperature for 2 hours, the mixture was concentrated, the crude product was used directly for the next step.

[0903] ESI-MS m / z calcd for [C 15 H 19 FN2O2][M+H] + :279.1; found: 279.3

[0904] 2.8

[0905] (R)-1-(3-Fluoro-4-((1-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-2-yl)azetidin-3-yl)oxy)benzyl)piperidin-2-one (MX021018)

[0906] To a solution of 1-(4-(azetidin-3-yloxy)-3-fluorobenzyl)piperidin-2-one (56 mg, 0.21 mmol) in DMF (3 mL) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2- d]pyrimidine 5-oxide (60 mg, 0.21 mmol) and DIEA (135 mg, 1.05 mmol). The mixture was stirred at 80 °C under nitrogen protection for 2 hours, after the starting material was consumed, after cooling, added to water (10 mL) and extracted with EA (10 mL) for three times. The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, the obtained crude product was purified by prep-HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (47.82 mg, yield 43.0%).

[0907] ESI-MS m / z calcd for [C 26 H 32 FN5O4S][M+H] + :530.2; found: 529.8

[0908] 1H NMR (400 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.11 (dd, J = 12.0, 1.2 Hz, 1H), 7.02 - 6.94 (m, 2H), 5.17 - 5.12 (m, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.48 - 4.43 (m, 4H), 3.96 - 3.94 (m, 2H), 3.71 - 3.68 (m, 2H), 3.45 - 3.37 (m, 1H), 3.25 - 3.18 (m, 3H), 2.97 - 2.85 (m, 2H), 2.38 - 2.25 (m, 4H), 2.15 - 2.11 (m, 2H), 1.79 - 1.71 (m, 6H).

[0909] 1. Synthesis scheme:

[0910] 2. Experimental section:

[0911] 2.1

[0912] 8-(4-bromobenzoyl)-1-oxa-3,8-diazaspiro[4.5]decane-2-one (021019-1)

[0913] To a solution of 1-oxo-3,8-diazaspiro[4,5]decane-2-one (100 mg, 0.64 mmol) in DMF (5 mL) was added BOP (283 mg, 0.64 mmol), TEA (130 mg, 1.28 mmol) and 4-bromobenzoic acid (129 mg, 0.64 mmol), the reaction was stirred at room temperature overnight. After the starting material was consumed, water (15 mL) was added to the mixture, extracted with EA (10 mL) twice, the combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 2, silica gel-CS 12 g, 20 mL / min, silica gel, UV 254) to give the product as a yellow solid (122 mg, yield 56.2%).

[0914] ESI-MS m / z calcd for [C 14 H 15 BrN2O3][M+1] + : 339.0; found: 339.3

[0915] 2.2

[0916] 8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)-1 -oxa-3,8- diazaspiro[4.5]decane-2-one (021019-2)

[0917] To a solution of 8-(4-bromobenzoyl)-1 -oxa-3,8-diazaspiro[4.5]decane-2-one (122 mg, 0.36 mmol) in 1,4-dioxane (5 mL) was added B2Pin2 (274 mg, 1.08 mmol), KOAc (106 mg, 1.08 mmol) and Pd(dppf)Cl2(30 mg, 0.04 mmol). The mixture was stirred at 100 °C under nitrogen overnight. After the starting material was consumed, the reaction was cooled and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 1, silica gel - CS 20 g, 40 mL / min, silica gel, UV 254) to give the product as a brown solid (200 mg, 42% purity, 60.5% yield).

[0918] ESI-MS m / z calcd for [C 20 H 27 BN2O5][M+H] + :387.2; found: 387.4

[0919] 2.3

[0920] (R)-8-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-2-yl)benzoyl)-1 -oxa-3,8-diazaspiro[4.5]decane-2-one (MX021019)

[0921] To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (47 mg, 0.164 mmol) in 1,4-dioxane / water (12 mL, v / v = 4 / 1) was added 8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)-1-oxa-3,8- diazaspiro[4.5]decane-2-one (150 mg, 42% purity, 0.164 mmol), K2CO3(46 mg, 0.33 mmol) and Pd(dppf)Cl2(22 mg, 0.03 mmol). The mixture was stirred at 100 °C under nitrogen protection for 3 hours, after the starting material was consumed, water (10 mL) was added and extracted with EA (10 mL) for three times. The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by prep-HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to give the product as a white solid (25 mg, yield 29.83%).

[0922] ESI-MS m / z calcd for[C 25 H 29 N5O5S][M+H] + :512.2; found: 512.3

[0923] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 8.4 Hz, 2H), 8.12 (s, 1H), 7.57 - 7.52 (m, 3H), 4.93 (t, J = 6.0 Hz, 1H), 4.02 (br, 1H), 3.84 - 3.80 (m, 2H), 3.69 - 3.61 (m, 1H), 3.45 - 3.36 (m, 4H), 3.28 - 3.20 (m, 3H), 3.06 - 3.02 (m, 1H), 2.43 - 2.32 (m, 4H), 1.86 - 1.79 (m, 6H).

[0924] 1. Synthesis scheme:

[0925] 2. Experimental section:

[0926] 2.1

[0927] 8-(1-(4-bromophenyl)ethyl)-1-oxa-3,8-diazaspiro[4.5]decane-2-one (021020-1)

[0928] To a solution of 1-oxo-3,8-diazaspiro[4,5]decane-2-one (100 mg, 0.64 mmol) and 1-bromo-4-(1-bromoethyl)benzene (170 mg, 0.64 mmol) in DMF (3 mL) was added K2CO3 (180 mg, 12.80 mmol) at room temperature. Then the mixture was stirred at 80 °C for 2 h, after which water (20 mL) was added and extracted twice with EA (20 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product as a yellow solid (202 mg, yield 93.4%).

[0929] ESI-MS m / z calcd for [C 15 H 19 BrN2O2][M+H] + :339.1; found: 339.3

[0930] 2.2

[0931] 8-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1-oxa- 3,8-diazaspiro[4.5]decane-2-one (021020-2)

[0932] To a solution of 8-(1-(4-bromophenyl)ethyl)-1-oxa-3,8-diazaspiro[4,5]decane-2- one (200 mg, 0.60 mmol) in 1,4-dioxane (6 mL) was added B2Pin2 (300 mg, 1.20 mmol), KOAc (120 mg, 1.20 mmol) and Pd(dppf)Cl2 (24 mg, 0.03 mmol). The mixture was stirred at 100 °C under nitrogen protection for 8 h, after the starting material was consumed, the reaction was cooled and filtered, concentrated under reduced pressure, and the crude product was used directly in the next step.

[0933] ESI-MS m / z calcd for [C 21 H 31 BN2O4][M+H] + :387.2; found: 387.3

[0934] 2.3

[0935] 8-(1-(4-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-2-yl)phenyl)ethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one (MX021020)

[0936] To a solution of 8-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1-oxa- 3,8-diazaspiro[4.5]decan-2-one (60 mg, 0.21 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2- d]pyrimidine 5-oxide (60 mg, 0.21 mmol), K2CO3(68 mg, 0.42 mmol) and Pd(dppf)Cl2(9 mg, 0.011 mmol). The mixture was heated to 80 °C and stirred under nitrogen protection for 8 hours. After cooling, added to water (10 mL), and extracted with DCM (10 mL) three times. The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L HCOOH), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (12.64 mg, yield 11.78%).

[0937] ESI-MS m / z calcd for [C 26 H 33 N5O4S][M+H] + :512.2; found: 512.2

[0938] 1 H NMR (400 MHz, DMSO-d6) d 8.27 (d, J = 8.0 Hz, 2H), 8.00 (s, 1H), 7.45 - 7.42 (m, 3H), 4.92 (t, J = 5.6 Hz, 1H), 3.83 - 3.81 (m, 2H), 3.67 - 3.54 (m, 2H), 3.41 - 3.35 (m, 2H), 3.24 - 3.18 (m, 3H), 3.08 - 3.00 (m, 1H), 2.44 - 2.32 (m, 7H), 1.87 - 1.68 (m, 6H), 1.32 (d, J = 6.4 Hz, 3H).

[0939] 1. Synthesis scheme:

[0940] 2. Experimental Section:

[0941] 2.1

[0942] 4-((1-(((R)-2-((S)-4-(5-chloropyrimidin-2-yl)-3-(cyanomethyl)piperazin-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methoxy)-4-oxobutyric acid (MX021052)

[0943] Add 2,5-dihydrofurandione (17 mg, 0.17 mmol), DMAP (21 mg, 0.17 mmol), and TEA (35 mg, 0.34 mmol) to a solution of 2-((S)-1-(5-chloropyrimidin-2-yl)-4-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-2-yl)acetonitrile (77 mg, 0.17 mmol) in DCM (2 mL). The mixture was stirred overnight at room temperature. After the starting material was consumed, the mixture was concentrated by vacuum distillation. The crude product was purified by preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to obtain a white solid product (16.03 mg, yield 17%).

[0944] ESI-MS m / z calcd for [C 25 H 29 ClN8O5S][M+H] + :589.2; found:589.1

[0945] 1 H NMR(400MHz, Methanol-d4)δ8.39(s,2H),5.17–5.15(m,1H),4.80–4.77(m,1H),4.68–4.53(m,4H),3.63–3.54(m,1H),3.49–3 .34(m,4H),3.23–3.16(m,1H),3.13–3.04(m,2H),2.86–2.74(m,2H),2.63–2.55(m,4H),2.44–2.35(m,4H),2.00–1.92(m,2H).

[0946] 1. Synthesis scheme:

[0947] 2. Experimental Section:

[0948] 2.1

[0949] (4-(4-bromophenyl)piperazin-1-yl)(cyclopropyl)methanone (021059-1)

[0950] To a solution of cyclopropyl(piperazin-1-yl)methanone (305 mg, 1.98 mmol) and 1-bromo-4-iodobenzene (560 mg, 1.98 mmol) in 1,4-dioxane (15 mL) was added Pd2(dba)3 (181 mg, 0.20 mmol), Xantphos (114 mg, 0.20 mmol) and cesium carbonate (1.62 g, 4.95 mmol). The mixture was stirred at 80 °C for 16 h. After cooling, the reaction was concentrated. The crude product was purified by column chromatography (EA / PE = 0-35%, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to give the product as a yellow solid (365 mg, 59.63% yield).

[0951] ESI-MS m / z calcd for [C 14 H 17 BrN2O][M+H] + : 309.1; found: 309.0

[0952] 2.2

[0953] Cyclopropyl(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)methanone (021059-2)

[0954] To a solution of (4-(4-bromophenyl)piperazin-1-yl)(cyclopropyl)methanone (345 mg, 1.12 mmol) and pinacolborane (567 mg, 2.23 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl2 (82 mg, 0.11 mmol) and potassium acetate (329 mg, 3.35 mmol). The mixture was stirred at 100 °C under nitrogen for 16 h. After cooling, the reaction was concentrated. The crude product was purified by column chromatography (EA / PE = 0-55%, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to give the product as a yellow solid (181 mg, 45.53% yield).

[0955] ESI-MS m / z calcd for [C 20 H 29 BN2O3][M+H]+ :357.2; found: 357.1

[0956] 2.3

[0957] (R)-cyclopropyl(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxido-6,7- dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)piperazin-1-yl)methanone (MX021059)

[0958] To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (87 mg, 0.30 mmol) and cyclopropyl(4-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)methanone (162 mg, 0.45 mol) in 1,4-dioxane and water (5 mL, v / v = 4:1), potassium carbonate (84 mg, 0.60 mmol) and Pd(dppf)Cl2(22 mg, 0.03 mmol) were added. The mixture was stirred at 80 °C under nitrogen protection for 4 hours. After the reaction was completed, the mixture was distilled to remove the solvent under reduced pressure. The crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (58.04 mg, yield 39.86%).

[0959] ESI-MS m / z calcd for [C 25 H 31 N5O3S][M+H] + :482.2; found: 482.3

[0960] 1 H NMR (400 MHz, DMSO-d6) d 8.20 (d, J = 8.8 Hz, 2H), 7.87 (s, 1H), 7.04 (d, J = 8.8 Hz, 2H), 4.95 - 4.92 (m, 1H), 3.83 - 3.81 (m, 4H), 3.62 - 3.56 (m, 3H), 3.35 - 3.34 (m, 2H), 3.31 - 3.29 (m, 3H), 3.19 - 3.13 (m, 1H), 3.02 - 2.97 (m, 1H), 2.45 - 2.29 (m, 4H), 2.05 - 2.02 (m, 1H), 1.87 - 1.81 (m, 2H), 0.76 - 0.71 (m, 4H).

[0961] 1. Synthesis scheme:

[0962] 2. Experimental part:

[0963] 2.1

[0964] (5-Bromo-lH-indol-2-yl)methanol (021062-1)

[0965] To a solution of 5-bromo-lH-indole-2-carboxylic acid ethyl ester (1.5 g, 5.62 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (469 mg, 12.36 mmol) at 0 °C. The mixture was stirred at room temperature under nitrogen protection for 2 hours. After the starting material was consumed, sodium sulfate decahydrate was added to quench the reaction. The mixture was stirred for 0.5 hours and then filtered. The obtained crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 40 g, 35 mL / min, silica gel, UV 254) to give the product as a yellow solid (1.15 g, yield 91.3%).

[0966] ESI-MS m / z calcd for [C9H8BrNO] [M+H] + : 226.0; found: 226.2

[0967] 2.2

[0968] 8-Bromo-3,4-dihydro-lH-[l,4]oxazino[4,3-a]indole (021062-2)

[0969] To a solution of (5-bromo-lH-indol-2-yl)methanol (300 mg, 1.33 mmol) in dichloromethane (10 mL) was added diphenyl(vinyl)sulfonium trifluoromethanesulfonate (578 mg, 1.60 mmol) and potassium hydroxide (186 mg, 3.33 mmol) at 0 °C. The mixture was stirred at room temperature under nitrogen protection overnight. After the starting material was consumed, the reaction mixture was quenched with water and extracted with EA (30 mL) twice. The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give the product as a white solid (201 mg, yield 60%).

[0970] ESI-MS m / z calcd for [C 11 H 10 BrNO] [M+H] +: 252.0; found: 252.2

[0971] 2.3

[0972] 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1 H- [1,4]oxazino[4,3-a]indole (021062-3)

[0973] To a solution of 8-bromo-3,4-dihydro-1 H-[1,4]oxazino[4,3-a]indole (200 mg, 0.80 mmol) in 1,4-dioxane (5 mL) was added B2Pin2 (403 mg, 1.59 mmol), potassium acetate (156 mg, 1.59 mmol) and Pd(dppf)Cl2(57 mg, 0.08 mmol) at room temperature. The mixture was stirred at 100 °C under nitrogen atmosphere for 8 h. After the starting material was consumed, it was filtered and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give the product as a white solid (206 mg, yield 86%).

[0974] ESI-MS m / z calcd for [C 17 H 22 BNO3][M+H] + : 300.2; found: 300.3

[0975] 2.4

[0976] (R)-2-(3,4-dihydro-1 H-[1,4]oxazino[4,3-a]indol-8-yl)-4-((1 -(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX021062)

[0977] To a mixture of 8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydro-lH- [l,4]oxazino[4,3-a]indole (200 mg, 0.67 mmol) in a mixture of 1,4-dioxane and water (5 mL, v / v = 4 / 1) was added (R)-2-chloro-4-((l-(hydroxymethyl)cyclobutyl)amino)- 6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (192 mg, 0.67 mmol), potassium carbonate (277 mg, 2.01 mmol) and Pd(dppf)Cl2(49 mg, 0.067 mmol) at room temperature. The mixture was stirred at 90 °C under nitrogen atmosphere for 4 h. After the starting material was consumed, water (30 mL) was added and extracted with EA (40 mL) twice. The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by prep-HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to give compound (6.09 mg, yield 2.1%) as a yellow solid.

[0978] ESI-MS m / z calcd for [C 22 H 24 N4O3S][M+H] + :425.2; found: 425.2

[0979] 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.17 (dd, J = 8.8, 1.2 Hz, 1H), 7.89 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 6.36 (s, 1H), 4.95 (s, 3H), 4.13 (s, 4H), 3.86 (dd, J = 17.2, 11.6 Hz, 2H), 3.67 - 3.59 (m, 1H), 3.39 - 3.36 (m, 1H), 3.23 - 3.17 (m, 1H), 3.04 - 2.99 (m, 1H), 2.44 - 2.33 (m, 4H), 1.90 - 1.82 (m, 2H).

[0980] 1. Synthesis scheme:

[0981] 2. Experimental part:

[0982] 2.1

[0983] 2-(piperidin-4-yl)acetonitrile hydrochloride (021068-1)

[0984] To a solution of tert-butyl 4-(cyanomethyl)piperidine-l-carboxylate (1 g, 4.46 mmol) in 1,4-dioxane (10 mL) was added 4 M hydrochloric acid in 1,4-dioxane (10 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated and the crude product was used directly in the next step.

[0985] ESI-MS m / z calcd for [C7H 12 N2][M+H] + : 125.2; found: 125.3

[0986] 2.2

[0987] 2-(l-(4-bromophenyl)piperidin-4-yl)acetonitrile (021068-2)

[0988] To a solution of 2-(piperidin-4-yl)acetonitrile hydrochloride (300 mg, 2.43 mmol) in 1,4-dioxane (6 mL) was added p-bromoiodobenzene (685 mg, 2.42 mmol), Xantphos (140 mg, 0.24 mmol) and Pd2(dba)3(111 mg, 0.12 mmol), Cs2CO3(1.57 g, 4.84 mmol), the reaction was stirred at 100 °C under nitrogen overnight, after the starting material was consumed, water (30 mL) was added to the mixture, extracted with EA (30 mL) twice, the combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 10, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254), to give the product as a white solid (128 mg, yield 19.0%).

[0989] ESI-MS m / z calcd for [C 13 H 15 BrN2][M+H] + : 278.0; found: 281.1

[0990] 2.3

[0991] 2-(l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl)acetonitrile (021068-3)

[0992] To a solution of 2-(1-(4-bromophenyl)piperidin-4-yl)acetonitrile (100 mg, 0.36 mmol) in 1,4-dioxane (2 mL) was added B2Pin2 (183 mg, 0.72 mmol), KOAc (71 mg, 0.72 mmol) and Pd(dppf)Cl2 (15 mg, 0.018 mmol). The mixture was stirred at 100 °C under nitrogen overnight. After the starting material was consumed, the reaction was cooled and filtered. The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step.

[0993] ESI-MS m / z calcd for [C 19 H 27 BN2O2][M+H] + :327.2; found: 327.5

[0994] 2.4

[0995] (R)-2-(1-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-2-yl)phenyl)piperidin-4-yl)acetonitrile (MX021068)

[0996] To a solution of 2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4- yl)acetonitrile (68 mg, 0.21 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (60 mg, 0.21 mmol), K2CO3 (58 mg, 0.42 mmol) and Pd(dppf)Cl2 (9 mg, 0.011 mmol). The mixture was heated to 80 °C and stirred under nitrogen for 3 h. After cooling, it was added to water (10 mL) and extracted with DCM (10 mL) three times. The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by prep-HPLC [MeCN / H2O (10 mmol / L HCOOH), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (5.52 mg, 5.83% yield).

[0997] ESI-MS m / z calcd for [C 24 H 29 N5O2S][M+H] + :452.2; found: 452.2

[0998] 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 8.8 Hz, 2H), 7.81 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 4.92 (t, J = 5.6 Hz, 1H), 3.94 - 3.91 (m, 2H), 3.83 - 3.77 (m, 2H), 3.63 - 3.55 (m, 1H), 3.31 - 3.29 (m, 1H), 3.18 - 3.12 (m, 1H), 3.01 - 2.96 (m, 1H), 2.86 - 2.80 (m, 2H), 2.56 - 2.54 (m, 2H), 2.46 - 2.26 (m, 4H), 1.89 - 1.77 (m, 5H), 1.38 - 1.28 (m, 2H).

[0999] 1. Synthesis scheme:

[1000] 2. Experimental part:

[1001] 2.1

[1002] 4-(4-bromophenyl)thiomorpholine 1,1-dioxide (021069-1)

[1003] To a solution of thiomorpholine 1,1-dioxide (300 mg, 2.22 mmol) in toluene (10 mL) was added 1-bromo-4-iodobenzene (689 mg, 2.44 mmol), sodium tert-butoxide (426 mg, 4.44 mmol), Pd2(dba)3(102 mg, 0.11 mmol) and XantPhos (128 mg, 0.22 mmol). The mixture was stirred at 85 °C under nitrogen overnight, after the starting material was consumed, the mixture was filtered and concentrated, the obtained crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 40 g, 35 mL / min, silica gel, UV 254) to give the product as a white solid (412 mg, yield 64%).

[1004] ESI-MS m / z calcd for [C 10 H 12 BrNO2S][M+H] + : 290.0; found: 290.0

[1005] 2.2

[1006] 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiomorpholine 1,1 -dioxide (021069-2)

[1007] To a solution of 4-(4-bromophenyl)thiomorpholine 1,1 -dioxide (330 mg, 1.14 mmol) in 1,4-dioxane (10 mL) was added pinacol diboronic acid (578 mg, 2.28 mmol), potassium acetate (223 mg, 2.28 mmol) and Pd(dppf)Cl2(78.8 mg, 0.11 mmol). The mixture was stirred at 100 °C under nitrogen overnight. After the starting material was consumed, the reaction mixture was quenched with water and extracted with EA (30 mL) twice. The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 1 ~ 1 / 1, Silica gel-CS 40 g, 40 mL / min, Silica gel, UV 254) to give the product as yellow oil (346 mg, 90% yield).

[1008] ESI-MS m / z calcd for [C 16 H 24 BNO4S][M+H] + :338.2; found: 338.3

[1009] 2.3

[1010] (R)-4-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-2-yl)phenyl)thiomorpholine 1,1 -dioxide (MX021069)

[1011] To 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)thiomorpholine 1,1-dioxide (100 mg, 0.30 mmol) in a mixture solution of 1,4-dioxane and water (5 mL, v / v = 4 / 1) was added (R)-2-chloro-4-((l-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2- d]pyrimidine 5-oxide (86 mg, 0.30 mmol), potassium carbonate (124 mg, 0.90 mmol) and Pd(dppf)Cl2(21.5 mg, 0.03 mmol). The mixture was stirred at 100 °C under nitrogen protection for 3 h. After the starting material was consumed, water (30 mL) was added and extracted with EA (40 mL) twice. The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by prep-HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to give the compound (4.29 mg, yield 3.2%) as a white solid.

[1012] ESI-MS m / z calcd for [C 21 H 26 N4O4S2][M+H] + :463.1; found: 463.0

[1013] 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 8.8 Hz, 2H), 7.87 (s, 1H), 7.12 (d, J = 8.8 Hz, 2H), 4.92 (t, J = 5.2 Hz, 1H), 3.91 (s, 4H), 3.81 (d, J = 5.2 Hz, 2H), 3.64 - 3.56 (m, 1H), 3.20 - 3.18 (m, 1H), 3.14 (s, 4H), 3.02 - 2.97 (m, 2H), 2.44 - 2.26 (m, 4H), 1.85 - 1.77 (m, 2H).

[1014] 1. Synthesis scheme:

[1015] 2. Experimental section:

[1016] 2.1

[1017] 1-(4-bromophenyl)-4-piperidinecarboxylic acid methyl ester (021070-1)

[1018] To a solution of 4-bromo-2-iodobenzoic acid (1.0 g, 3.39 mmol) in 1,4-dioxane (10 mL) was added methyl piperidine-4-carboxylate (485 mg, 3.39 mmol), Xantphos (164 mg, 0.28 mmol) and Pd2(dba)3(129 mg, 0.14 mmol), Cs2CO3(1.8 g, 5.66 mmol), the mixture was stirred at 100 °C under nitrogen overnight. After the starting material was consumed, water (30 mL) was added to the mixture, which was extracted with EA (30 mL) twice. The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 10, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product as a white solid (656 mg, yield 78.0%).

[1019] ESI-MS m / z calcd for [C 13 H 16 BrNO2][M+H] + :298.0; found: 298.2

[1020] 2.2

[1021] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-4-carboxylic acid methyl ester (021070-2)

[1022] To a solution of methyl 1-(4-bromophenyl)-4-piperidinecarboxylate (283 mg, 0.95 mmol) in 1,4-dioxane (10 mL) was added B2Pin2(483 mg, 1.90 mmol), KOAc (186 mg, 1.90 mmol) and Pd(dppf)Cl2(39 mg, 0.05 mmol). The mixture was stirred at 100 °C under nitrogen overnight. After the starting material was consumed, the reaction was cooled and filtered. The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step.

[1023] ESI-MS m / z calcd for [C 19 H 28 BNO4][M+H] + :346.2; found: 346.4

[1024] 2.3

[1025] (R)-1-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-2-yl)phenyl)piperidine-4-carboxylic acid methyl ester (021070-3)

[1026] To a solution of methyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-4- carboxylate (257 mg, 0.74 mmol) in 1,4-dioxane / water (12.5 mL, v / v = 4 / 1) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (214 mg, 0.74 mmol), K2CO3(204 mg, 1.48 mmol) and Pd(dppf)Cl2(30 mg, 0.037 mmol). The mixture was heated to 80 °C and stirred under nitrogen protection for 3 hours. After cooling, added to water (10 mL), and extracted with DCM (10 mL) three times. The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product which was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give the product as a white solid (94 mg, yield 27.0%).

[1027] ESI-MS m / z calcd for [C 24 H 30 N4O4S][M+H] + :471.2; found: 471.1

[1028] 2.4

[1029] (R)-1-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-2-yl)phenyl)piperidine-4-carboxylic acid (021070-4)

[1030] To a solution of (R)-methyl 1-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5- oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)piperidine-4-carboxylate (50 mg, 0.11 mmol) in MeOH (2 mL) was added LiOH.H2O (42 mg, 0.55 mmol) and water (0.5 mL. The mixture was stirred at room temperature for 6 h. The mixture was concentrated and water (10 mL) was added. The mixture was acidified with 1M HC1 to pH = 5. The mixture was extracted with EA (20 mL) twice, the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the product as colorless oil (50 mg, yield 99.7%).

[1031] ESI-MS m / z calcd for [C 23 H 28 N4O4S][M+H] + : 457.2; found: 457.1

[1032] 2.5

[1033] (R)-1-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-2-yl)phenyl)-N,N-dimethylpiperidine-4-carboxamide (MX021070)

[1034] To a solution of (R)-methyl 1-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5- oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)piperidine-4-carboxylate (50 mg, 0.11 mmol) in MeOH (2 mL) was added LiOH.H2O (42 mg, 0.55 mmol) and water (0.5 mL. The mixture was stirred at room temperature for 6 h. The mixture was concentrated and water (10 mL) was added. The mixture was acidified with 1M HC1 to pH = 5. The mixture was extracted with EA (20 mL) twice, the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the product as colorless oil (50 mg, yield 99.7%).

[1035] ESI-MS m / z calcd for [C 25 H 33 N5O3S][M+H] +: 484.2; found: 484.1

[1036] 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 8.8 Hz, 2H), 7.81 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 4.93 (t, J = 5.6 Hz, 1H), 3.93 - 3.90 (m, 2H), 3.82 - 3.63 (m, 2H), 3.61 - 3.51 (m, 2H), 3.19 - 3.12 (m, 1H), 3.06 (s, 3H), 3.01 - 2.96 (m, 1H), 2.92 - 2.83 (m, 3H), 2.81 - 2.80 (m, 3H), 2.43 - 2.29 (m, 4H), 1.87 - 1.81 (m, 2H), 1.71 - 1.59 (m, 4H).

[1037] 1. Synthesis scheme:

[1038] 2. Experimental part:

[1039] 2.1

[1040] 4-(1-(4-bromophenyl)ethyl)morpholine (021071-1)

[1041] To a solution of 1-bromo-4-(1-bromoethyl)benzene (200 mg, 0.76 mmol) and morpholine (66 mg, 0.76 mmol) in DMF (3 mL) was added K2CO3(210 mg, 1.52 mmol) at room temperature. The mixture was then stirred at room temperature for 5 hours, after which water (20 mL) was added and extracted twice with EA (20 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product as a yellow solid (202 mg, yield 98.8%).

[1042] ESI-MS m / z calcd for [C 12 H 16 BrNO][M+H] + : 270.0; found: 270.2

[1043] 2.2

[1044] 4-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)morpholine (021071-2)

[1045] To a solution of 4-(1-(4-bromophenyl)ethyl)morpholine (200 mg, 0.74 mmol) in 1,4-dioxane (2 mL) was added B2Pin2 (377 mg, 1.49 mmol), KOAc (145 mg, 1.48 mmol) and Pd(dppf)Cl2(30 mg, 0.037 mmol). The mixture was stirred at 80 °C under nitrogen protection for 8 h. After the starting material was consumed, the reaction was cooled and filtered. The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step.

[1046] ESI-MS m / z calcd for [C 18 H 28 BNO3][M+H] + :318.2; found:318.4

[1047] 2.3

[1048] (5R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-(1-morpholinoethyl)phenyl)- 6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX021071)

[1049] To a solution of 4-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)morpholine (60 mg, 0.21 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2- d]pyrimidine 5-oxide (60 mg, 0.21 mmol), K2CO3(58 mg, 0.42 mmol) and Pd(dppf)Cl2(9 mg, 0.011 mmol). The mixture was heated to 80 °C and stirred under nitrogen protection for 8 h. After cooling, it was added to water (10 mL) and extracted with DCM (10 mL) for three times. The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by prep-HPLC [MeCN / H2O (10 mmol / L HCOOH), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (11.70 mg, yield 12.61%).

[1050] ESI-MS m / z calcd for [C 23 H 30 N4O3S][M+H] + :443.2;found:443.1

[1051] 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 8.0 Hz, 2H), 8.00 (s, 1H), 7.42 (d, J = 8.4 Hz, 2H), 4.92 (t, J = 5.6 Hz, 1H), 3.82 - 3.81 (m, 2H), 3.65 - 3.53 (m, 5H), 3.43 - 3.35 (m, 2H), 3.24 - 3.17 (m, 1H), 3.05 - 3.00 (m, 1H), 2.46 - 2.27 (m, 8H), 1.87 - 1.81 (m, 2H), 1.30 (d, J = 6.4 Hz, 3H).

[1052] 1. Synthesis scheme:

[1053] 2. Experimental part:

[1054] 2.1

[1055] 7,7-Dimethyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine (021091-1)

[1056] A solution of 7,7-dimethyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[4,5]pyrrolo[1,2-A]pyrazin-1-one (100 mg, 0.49 mmol) in THF (4 mL) was added LiAlH4(74 mg, 1.96 mmol) at room temperature, the reaction was stirred at 60 °C for 4 hours. After the starting material was consumed, 1 N aqueous hydrochloric acid (30 mL) was added to the mixture, extracted with EA (30 mL) twice, the combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254), to obtain yellow solid product (31 mg, yield 33%).

[1057] ESI-MS m / z calcd for [C 12 H 18 N2][M+H] + :191.2;found:191.4

[1058] 2.2

[1059] (R)-2-(7,7-dimethyl-3,4,7,8-tetrahydro-lH-cyclopenta[4,5]pyrrolo[l,2- a]pyrazin-2(6H)-yl)-4-((l-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2- d]pyrimidine 5-oxide (MX021091)

[1060] To a solution of 7,7-dimethyl-2,3,4,6,7,8-hexahydro-lH-cyclopenta[4,5]pyrrolo[l,2- a]pyrazine (31 mg, 0.16 mmol) and (R)-2-chloro-4-((l-(hydroxymethyl)cyclobutyl)amino)- 6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (46 mg, 0.16 mmol) in DMF (2 mL) was added DIEA (42 mg, 0.32 mmol), the mixture was stirred at 100 °C for 3 h. The crude product was purified by preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254) to give compound as a white solid (7.23 mg, 10% yield).

[1061] ESI-MS m / z calcd for [C 23 H 31 N5O2S][M+H] + :442.2; found: 442.2

[1062] 1 H NMR (400 MHz, DMSO-d6) d 7.49 (s, 1H), 5.59 (s, 1H), 4.87 - 4.82 (m, 3H), 4.10 - 4.06 (m, 2H), 3.81 - 3.72 (m, 4H), 3.47 - 3.33 (m, 1H), 3.24 - 3.16 (m, 1H), 2.98 - 2.84 (m, 2H), 2.43 (s, 2H), 2.37 - 2.26 (m, 4H), 2.20 - 2.16 (m, 2H), 1.81 - 1.75 (m, 2H), 1.16 (s, 6H).

[1063] 1. Synthesis scheme:

[1064] 2. Experimental part:

[1065] 2.1

[1066] (4-Bromo-2-fluorophenyl)(1,1-dioxothiomorpholino)methyl ketone (021093-1)

[1067] To a solution of 4-bromo-2-fluorobenzoic acid (300 mg, 1.37 mmol) and thiomorpholine 1,1-dioxide (185 mg, 1.37 mmol) in DMF (5 mL), DIEA (353 mg, 2.74 mmol) and HATU (783 mg, 2.06 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reactants were consumed, water (30 mL) was added, and the mixture was extracted twice with EA (30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0–10%, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give a yellow solid product (406 mg, yield 88%).

[1068] ESI-MS m / z calcd for [C 11 H 11 BrFNO3S][M+H] + :336.0; found:336.0

[1069] 2.2

[1070] (1,1-Dioxothiomorpholino)(2-Fluoro-4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)methyl ketone (021093-2)

[1071] To a solution of (4-bromo-2-fluorophenyl)(1,1-dioxothiomorpholino) methyl ketone (100 mg, 0.30 mmol) in 1,4-dioxane (3 mL), B2Pin2 (152 mg, 0.60 mmol), KOAc (90 mg, 0.90 mmol), and Pd(dppf)Cl2 (21 mg, 0.03 mmol) were added. The mixture was stirred overnight at 90 °C under nitrogen protection. After the starting material was consumed, the reaction solution was cooled and concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography (MeCN / H2O = 1 / 20 to 1 / 1, C-18 column, 20 mL / min, UV 254) to give a brown solid product (88 mg, yield 77%).

[1072] ESI-MS m / z calcd for [C 17 H 23 BFNO5S][M+H] + 384.1; found: 384.3

[1073] 2.3

[1074] (R)-(1,1-dioxothiomorpholinyl)(2-fluoro-4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)methanone (MX021093)

[1075] To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (66 mg, 0.23 mmol) in 1,4-dioxane / water (2.5 mL, v / v = 4 / 1) was added (1,1-dioxothiomorpholinyl)(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)methanone (88 mg, 0.23 mmol), K2CO3(95 mg, 0.69 mmol) and Pd(dppf)Cl2(16 mg, 0.023 mmol). The mixture was stirred at 100 °C under nitrogen protection for 3 hours. After the starting material was consumed, water (20 mL) was added and extracted with EA (20 mL) for three times. The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by prep-HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254) to give the product as a white solid (26.02 mg, yield 22%).

[1076] ESI-MS m / z calcd for [C 22 H 25 FN4O5S2][M+H] + :509.1; found: 509.2

[1077] 1 H NMR (400 MHz, Methol-d4) d 8.30 (dd, J = 8.0, 1.2 Hz, 1H), 8.16 (dd, J = 11.2, 1.2 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 4.86 - 4.85 (m, 1H), 4.31 - 4.21 (m, 2H), 4.01 (dd, J = 17.2, 11.2 Hz, 2H), 3.87 - 3.74 (m, 3H), 3.55 - 3.47 (m, 1H), 3.38 - 3.25 (m, 3H), 3.24 - 3.14 (m, 3H), 2.46 - 2.41 (m, 4H), 2.01 - 1.94 (m, 2H).

[1078] 1. Synthesis scheme:

[1079] 2. Experimental section:

[1080] 2.1

[1081] 4-(4-bromophenyl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (021109-1)

[1082] To a solution of 1-bromo-4-iodobenzene (283 mg, 1.0 mmol) in 1,4-dioxane / H2O (12.0 mL, v / v = 5 / 1) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (309 mg, 1.0 mmol), K2CO3 (276 mg, 2.0 mmol) and Pd(dppf)Cl2 (73 mg, 0.1 mmol), the reaction was stirred at 100 °C under argon protection for 4 hours. After the starting material was consumed, water (30 mL) was added to the mixture, which was extracted with EA (30 mL) twice, the combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the yellow solid product (300.0 mg, yield 88.76%).

[1083] ESI-MS m / z calcd for [C 16 H 20 BrNO2][M-56+1] + :282.1; found:282.2

[1084] 2.2

[1085] 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine (021109-2)

[1086] To a solution of 4-(4-bromophenyl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (300 mg, 0.89 mmol) in DCM (10 mL) was added TFA (1.0 mL). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuum to give the yellow solid product (211 mg, yield 100.0%).

[1087] ESI-MS m / z calcd for [C11 H 12 BrN][M+H] + :240.0; found:240.2

[1088] 2.3

[1089] 5-(2-ethoxy-5-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (021109-3)

[1090] A solution of 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine (211 mg, 0.89 mmol) and cyclopropionyl chloride (93 mg, 0.89 mmol) in acetone (5 mL) was reacted with DIEA (388 mg, 3.0 mmol), and the reaction mixture was stirred at 0 °C for 2 hours. After the starting materials were consumed, water (10 mL) was added to the mixture, and the mixture was extracted twice with EA (10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 to 1 / 10, silica gel-CS 20 g, 40 mL / min, silica gel, UV 254) to give a yellow solid product (210 mg, yield 77.1%).

[1091] ESI-MS m / z calcd for [C 15 H 16 BrNO][M+H] + 306.0; found: 306.4

[1092] 2.4

[1093] Cyclopropyl(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-yl)methyl ketone (021109-4)

[1094] To a solution of 5-(2-ethoxy-5-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1 - methyl-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (200 mg, 0.65 mmol) in 1,4-dioxane (10 mL) was added B2Pin2 (498 mg, 1.96 mmol), KOAc (192 mg, 1.96 mmol) and Pd(dppf)Cl2(52 mg, 0.07 mmol). The mixture was stirred at 100 °C under nitrogen overnight, after the starting material was consumed, the reaction was cooled and concentrated under reduced pressure, the crude product was purified by column chromatography (EA / PE = 0 / 1 to 1 / 1, silica gel - CS 20 g, 40 mL / min, silica gel, UV 254) to give the product as a brown solid (200 mg, 87.16% yield).

[1095] ESI-MS m / z calcd for [C 21 H 28 BNO3][M+H] + :354.2; found: 354.4

[1096] 2.5

[1097] (R)-cyclopropyl(4-(4-(4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7- dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)-5,6-dihydropyridin-1(2H)-yl)methanone (MX021109)

[1098] To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (77 mg, 0.27 mmol) in 1,4-dioxane / water (12 mL, v / v = 4 / 1) was added cyclopropyl(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 5,6-dihydropyridin-1(2H)-yl)methanone (95 mg, 0.27 mmol), K2CO3(75.0 mg, 0.54 mmol) and Pd(dppf)Cl2(22 mg, 0.03 mmol). The mixture was stirred at 85 °C under nitrogen protection for 3 hours, after the starting material was consumed, water (10 mL) was added and extracted with EA (10 mL) for three times. The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by prep-HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to give the product as a white solid (50 mg, yield 38.7%).

[1099] ESI-MS m / z calcd for[C 26 H 30 N4O3S][M+H] + :479.2; found: 479.2

[1100] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.4 Hz, 2H), 8.06 (s, 1H), 7.59 (d, J = 7.2 Hz, 2H), 6.34 (s, 1H), 4.94 (t, J = 5.6 Hz, 1H), 4.42 (s, 1H), 4.15 (s, 1H), 3.91 - 3.87 (m, 1H), 3.85 - 3.79 (m, 2H), 3.70 - 3.60 (m, 2H), 3.40 - 3.35 (m, 1H), 3.20 - 3.30 (m, 1H), 3.24 - 3.18 (m, 1H), 3.05 - 3.00 (m, 1H), 2.63 - 2.58 (m, 1H), 2.46 - 2.32 (m, 4H), 2.10 - 1.97 (m, 1H), 1.88 - 1.80 (m, 2H), 0.77 - 0.741 (m, 4H).

[1101] 1. Synthesis scheme:

[1102] 2. Experimental part:

[1103] 2. 14-(Cyclopropylsulfonyl)piperazine-1 -carboxylic acid tert-butyl ester (021116-1 )

[1104] A solution of cyclopropanesulfonyl chloride (500 mg, 3.57 mmol) and piperazine-1 -carboxylic acid tert-butyl ester (730 mg, 3.90 mmol) in acetone (20 mL) was added TEA (721 mg, 7.14 mmol) and the reaction was stirred at room temperature overnight. After the starting material was consumed, water (30 mL) was added to the mixture, which was extracted twice with EA (30 mL), and the combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 10, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give the product as a yellow solid (869 mg, 84.0% yield).

[1105] ESI-MS m / z calcd for C 12 H 22 N2O4S][M-100+H] + : 291.1 ; found: 191.4

[1106] 2. 2

[1107] 1 -(Cyclopropylsulfonyl)piperazine (021116-3)

[1108] To a solution of tert-butyl 4-(cyclopropylsulfonyl)piperazine-1 -carboxylate (800 mg, 2.76 mmol) in DCM (8 mL) was added trifluoroacetic acid (2 mL) under ice bath. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the crude product was used directly in the next step.

[1109] ESI-MS m / z calcd for [C7H 14 N2O2S][M+H] + : 191.0; found: 191.2

[1110] 2. 3

[1111] 1 -(4-Bromophenyl)-4-(cyclopropylsulfonyl)piperazine (021116-3)

[1112] To a solution of 1-(cyclopropylsulfonyl)piperazine (300 mg, 1.56 mmol) in 1,4-dioxane (10 mL) was added 1-bromo-4-iodobenzene (486 mg, 1.72 mmol), Cs2CO3(1.01 mg, 3.12 mmol), xantphos (90 mg, 0.15 mmol) and Pd2(dba)3(72 mg, 0.08 mmol) and the reaction was stirred at 100 °C under nitrogen overnight. After the starting material was consumed, water (20 mL) was added to the mixture, which was extracted twice with EA (30 mL), the combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product as a yellow oil (148 mg, 27.6% yield).

[1113] ESI-MS m / z calcd for [C 13 H 17 BrN2O2S][M+H] + :345.0; found: 345.1

[1114] 2.4

[1115] 1-(cyclopropylsulfonyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (02116-4)

[1116] To a solution of 1-(4-bromophenyl)-4-(cyclopropylsulfonyl)piperazine (148 mg, 0.44 mmol) in 1,4-dioxane (2 mL) was added B2Pin2(222 mg, 0.88 mmol), KOAc (85 mg, 0.88 mmol) and Pd(dppf)Cl2(18 mg, 0.02 mmol). The mixture was stirred at 80 °C under nitrogen overnight, after the starting material was consumed, the reaction was filtered after cooling, concentrated under reduced pressure and the crude product was used directly in the next step.

[1117] ESI-MS m / z calcd for [C 19 H 29 BN2O4S][M+H] + :393.2; found: 393.3

[1118] 2.5

[1119] (R)-2-(4-(4-(cyclopropylsulfonyl)piperazin-1-yl)phenyl)-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX21116)

[1120] To a solution of 1-(cyclopropylsulfonyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)piperazine (150 mg, 0.38 mmol) in 1,4-dioxane / water (8 mL, v / v = 4 / 1) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (109 mg, 0.38 mmol), K2CO3 (104 mg, 0.76 mmol) and Pd(dppf)Cl2 (16 mg, 0.02 mmol). The mixture was heated to 80 °C and stirred under nitrogen protection for 8 h. After cooling, it was added to water (10 mL) and extracted with DCM (10 mL) for three times. The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by prep-HPLC [MeCN / H2O (10 mmol / L HCOOH), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give the product as a white solid (1.78 mg, yield 1.00%).

[1121] ESI-MS m / z calcd for [C 24 H 31 N5O4S2][M+H]+:518.2; found:518.2

[1122] 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 8.4 Hz, 2H), 7.83 (s, 1H), 7.06 (d, J = 8.8 Hz, 2H), 4.91 (t, J = 5.6 Hz, 1H), 3.82 - 3.80 (m, 2H), 3.62 - 3.56 (m, 1H), 3.41 - 3.37 (m, 6H), 3.21 - 3.13 (m, 1H), 3.02 - 3.97 (m, 1H), 2.67 - 2.62 (m, 2H), 2.64 - 2.29 (m, 6H), 1.87 - 1.81 (m, 2H), 1.00 - 0.93 (m, 4H).

[1123] 1. Synthesis scheme:

[1124] 2. Experimental part:

[1125] 2.1

[1126] 4-(4-bromophenyl-d4)morpholine (021118-1)

[1127] To a solution of 1,4-dibromobenzene-d4(500 mg, 2.08 mmol) and morpholine (200 mg, 2.29 mmol) in toluene (20 mL) was added Pd2(dba)3(95 mg, 0.10 mmol), BINAP (65 mg, 0.10 mmol) and sodium tert-butoxide (501 mg, 5.21 mmol). The mixture was stirred at 110 °C under nitrogen protection for 16 h. After cooling, the reaction was concentrated. The crude product was purified by column chromatography (EA / PE = 0-35%, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to give the product as a white solid (323 mg, yield 62.97%).

[1128] ESI-MS m / z calcd for [C 10 H8D4BrNO][M+H] + :246.0; found: 246.1

[1129] 2.2

[1130] 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-d4)morpholine (021118-2)

[1131] To a solution of 4-(4-bromophenyl-d4)morpholine (323 mg, 1.31 mmol) and pinacolboronate (667 mg, 2.62 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl2(96 mg, 0.13 mmol) and potassium phosphate (836 mg, 3.94 mmol). The mixture was stirred at 100 °C under nitrogen protection for 16 h. After cooling, the reaction was concentrated. The crude product was purified by column chromatography (EA / PE = 0-35%, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to give the product as a yellow solid (214 mg, yield 55.62%).

[1132] ESI-MS m / z calcd for [C 16 H 20 D4BNO3][M+H] + :294.2; found: 294.4

[1133] 2.3

[1134] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-morpholinophenyl-d4)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02496)

[1135] To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (66 mg, 0.23 mmol) and 4-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl-d4)morpholine (101 mg, 0.34 mmol) in 1,4-dioxane and water (5 mL, v / v = 4:1) was added potassium carbonate (63 mg, 0.46 mmol) and Pd(dppf)Cl2(17 mg, 0.02 mmol). The mixture was stirred at 80 °C under nitrogen protection for 4 hours. After the reaction was completed, the mixture was distilled to remove the solvent under reduced pressure. The crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254] to give the product as a brown solid (10.75 mg, yield 11.21%).

[1136] ESI-MS m / z calcd for [C 21 H 22 D4N4O3S][M+H] + :419.2; found: 419.4

[1137] 1 H NMR (400 MHz, DMSO-d6) d 7.86 (s, 1H), 4.94 - 4.91 (m, 1H), 3.81 - 3.80 (m, 2H), 3.78 - 3.71 (m, 4H), 3.63 - 3.55 (m, 1H), 3.34 - 3.29 (m, 1H), 3.27 - 3.23 (m, 4H), 3.19 - 3.12 (m, 1H), 3.02 - 2.96 (m, 1H), 2.46 - 2.24 (m, 4H), 1.88 - 1.78 (m, 2H).

[1138] 1. Synthesis scheme:

[1139] 2. Experimental part:

[1140] 2.1

[1141] 1 -((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutane- carboxylic acid methyl ester (021161-1)

[1142] To a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (1.5 g, 7.28 mmol) in acetonitrile (20 mL) was added 1 -aminocyclobutane carboxylic acid methyl ester hydrochloride (1.33 g, 8.00 mmol) and DIEA (3.76 g, 29.12 mmol) at room temperature. Then the mixture was stirred at 85 °C under nitrogen protection overnight, after the starting material was consumed, water (40 mL) was added to the mixture, and extracted with EA (50 mL) for three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, the obtained crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give the product as yellow oil (471 mg, yield 21.6%).

[1143] ESI-MS m / z calcd for [C 12 H 14 ClN3O2S][M+H] + : 300.1 ; found: 300.0

[1144] 2.2

[1145] (1 -((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methane- d2-ol (021161-2)

[1146] To a solution of 1 -((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutane carboxylic acid methyl ester (450 mg, 1.51 mmol) in tetrahydrofuran (10 mL) was added deuterated lithium aluminum hydride (284 mg, 6.77 mmol) at 0 °C. The mixture was stirred at 0 °C under nitrogen protection for 0.5 hours, after the starting material was consumed, heavy water (30 mL) was added to the mixture, and extracted with EA (40 mL) for three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, the obtained crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 35 mL / min, silica gel, UV 254) to give the product as yellow oil (313 mg, yield 75.9%).

[1147] ESI-MS m / z calcd for [C 11 H 12 D2ClN3OS][M+H]+ : 274.1 ; found: 274.1

[1148] 2.3

[1149] (R)-2-chloro-4-((1-(hydroxymethyl-d2)cyclobutyl)amino)-6,7-dihydrothieno[3,2- d]pyrimidine 5-oxide (021161-3)

[1150] To a solution of (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methane-d2-ol (100 mg, 0.37 mmol) in dichloromethane (2 mL) were added S-1,1 '-bi-2-naphtol (10.5 mg, 0.037 mmol), tetraisopropyl titanate (10.5 mg, 0.037 mmol) and water (13.3 mg, 0.74 mmol) at room temperature. Then the mixture was stirred at room temperature overnight, after the starting material was consumed, t-BuOOH (66.6 mg, 0.74 mmol) was added, then the mixture was stirred at room temperature for 1 h, the reaction was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 9, silica gel - CS 12 g, 30 mL / min, silica gel, UV 254) to give the product as a yellow solid (81 mg, 75.8% yield, ee = 66.54%).

[1151] ESI-MS m / z calcd for [C 11 H 12 D2ClN3O2S][M+H] + : 290.1 ; found: 290.1

[1152] 2.4

[1153] (R)-4-((1-(hydroxymethyl-d2)cyclobutyl)amino)-2-(4-morpholinophenyl)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (MX021161)

[1154] To a mixture of (R)-2-chloro-4-((1-(hydroxymethyl-d2)cyclobutyl)amino)- 6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (60 mg, 0.21 mmol), 4-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (72 mg, 0.25 mmol) and potassium carbonate (87 mg, 0.63 mmol) in water (0.2 mL) and 1,4-dioxane (1 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (17 mg, 0.021 mmol) at room temperature. The reaction mixture was stirred at 80 °C under argon protection for 4 h. After the starting material was consumed, water (20 mL) was added to the mixture and extracted with EA (30 mL) for three times. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 0, silica gel-CS 20 g, 40 mL / min, silica gel, UV 254) to give the product as yellow oil. The yellow oil was purified by SFC chiral resolution to give the product as white solid (17.81 mg, yield 20.4%).

[1155] ESI-MS m / z calcd for [C 21 H 24 D2N4O3S][M+H] + :417.2; found: 417.2

[1156] 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 8.8 Hz, 2H), 7.85 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 4.89 (s, 1H), 3.75 (t, J = 4.4 Hz, 4H), 3.64 - 3.55 (m, 1H), 3.31 - 3.29 (m, 1H), 3.24 (t, J = 4.8 Hz, 4H), 3.19 - 3.13 (m, 1H), 3.02 - 2.97 (m, 1H), 2.42 - 2.26 (m, 4H), 1.87 - 1.78 (m, 2H).

[1157] 1. Synthesis scheme:

[1158] 2. Experimental part:

[1159] 2.1

[1160] (R)-4-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-6,6-dideutero- 2-(4-morpholinophenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (021169-2)

[1161] To a solution of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4- morpholinophenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg, 0.24 mmol) in DCM (3 mL) was added imidazole (32 mg, 0.48 mmol) and TBSCl (36 mg, 0.24 mmol) and the reaction was stirred at room temperature under nitrogen for 2 hours. After the starting material was consumed, water (30 mL) was added to the mixture, which was extracted twice with EA (30 mL), and the combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 10, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product as a yellow solid (125 mg, 98% yield).

[1162] ESI-MS m / z calcd for [C 27 H 40 N4O3SSi][M+H] + : 529.3; found: 529.3

[1163] 2.2

[1164] (R)-4-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-6,6-dideutero- 2-(4-morpholinophenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (021169-2)

[1165] To a solution of (R)-4-((l-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)- 2-(4-morpholinophenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (100 mg, 0.20 mmol) in MeOD (4 mL) was added NaOD (40% in D20, 0.4 mL). The reaction mixture was stirred at 50 °C under nitrogen protection for 4 h. After the starting material was consumed, the reaction was adjusted to pH 6-7 with deuterium hydrochloric acid solution in an ice bath, water (30 mL) was added, and the mixture was extracted with EA (30 mL) three times. The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography [MeCN / H20, X-Select 10 pm 19*250 mm, 20 mL / min, UV 254] to give the product as a yellow solid (41 mg, 41% yield).

[1166] ESI-MS m / z calcd for [C 27 H 38 D2N4O3SSi][M+H] + :531.3; found: 531.3

[1167] 2.3

[1168] (R)-4-((l-(hydroxymethyl)cyclobutyl)amino)-6,6-dideutero-2-(4-morpholinophenyl)- 6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX021169)

[1169] A solution of (R)-4-((l-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)amino)-6,6- dideutero-2-(4-morpholinophenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (41 mg, 0.077 mmol) in HC1 / 1,4-dioxane (0.5 M, 2 mL) was stirred at room temperature for 1 h. After the starting material was consumed, the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (MeCN / H20 (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254) to give the product as a white solid (10.70 mg, 33% yield).

[1170] ESI-MS m / z calcd for [C 21 H 24 D2N4O3S][M+H] + :417.2; found: 417.2

[1171] 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 8.8 Hz, 2H), 7.85 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 4.93 (t, J = 5.6 Hz, 1H), 3.82 - 3.81 (m, 2H), 3.76 - 3.74 (m, 4H), 3.30 (s, 1H), 3.25 - 3.23 (m, 4H), 2.99 - 2.96 (m, 1H), 2.45 - 2.29 (m, 4H), 1.87 - 1.81 (m, 2H).

[1172] 1. Synthesis scheme:

[1173] 2. Experimental section:

[1174] 2.1

[1175] (R)-(1-((2-(4-morpholinophenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4- yl)amino)cyclobutyl)methyl(2,2,2-trichloroacetyl)urea (021170-1)

[1176] To a solution of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4- morpholinophenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (260 mg, 0.63 mmol) in DCM (10 mL) was added 2,2,2-trichloroacetyl isocyanate (236 mg, 1.25 mmol) at 0 °C. The mixture was stirred under nitrogen protection for 3 hours. LCMS showed the starting material disappeared, the mixture was concentrated for the next step.

[1177] ESI-MS m / z calcd for [C 24 H 26 Cl3N5O5S][M+H] + : 602.1; found: 602.1

[1178] 2.2

[1179] (R)-(1-((2-(4-morpholinophenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4- yl)amino)cyclobutyl)methyl carbonate (MX021170)

[1180] To a solution of (R)-(l-((2-(4-morpholinylphenyl)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-4-yl)amino)cyclobutyl)methyl (2,2,2-trichloroacetyl)urea (378 mg, 0.63 mmol, crude) in methanol (8 mL) was added potassium carbonate (347 mg, 2.51 mmol) at 0 °C. The mixture was stirred under nitrogen protection for 2 hours. After the reaction was completed, the reaction mixture was purified by reverse phase column (MeCN / H2O = 0-40%, C-18 CS 80 g, 50 mL / min, C-18, UV 254) to give the crude product. The crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254] to give the white solid product. The white solid product was purified by SFC chiral resolution to give the off-white solid product (92 mg, yield 31.92%).

[1181] ESI-MS m / z calcd for [C 22 H 27 N5O4S][M+H] + :458.2; found: 458.2

[1182] 1 H NMR (400 MHz, DMSO-d6) d 8.21 (d, J = 9.2 Hz, 2H), 8.04 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.50 - 6.48 (m, 2H), 4.48 - 4.42 (m, 2H), 3.76 - 3.74 (m, 4H), 3.65 - 3.57 (m, 1H), 3.37 - 3.33 (m, 1H), 3.26 - 3.15 (m, 5H), 3.03 - 2.98 (m, 1H), 2.46 - 2.33 (m, 4H), 1.95 - 1.85 (m, 2H).

[1183] 1. Synthesis scheme:

[1184] 2. Experimental part:

[1185] 2.1

[1186] (S)-(l-(((R)-2-(4-morpholinylphenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4- yl)amino)cyclobutyl)methyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (021171-1) (S)-(l-(((R)-2-(4-morpholinylphenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4- yl)amino)cyclobutyl)methyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (021171-1)

[1187] A solution of (R)-4-((l-(hydroxymethyl)cyclobutyl)amino)-2-(4- morpholinophenyl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (50 mg, 0.12 mmol) in DCM (3 mL) was added with (S)-2-((tert-butoxycarbonyl)amino)-3- methylbutanoic acid (25 mg, 0.12 mmol), DMAP (29 mg, 0.24 mmol) and DCC (50 mg, 0.24 mmol), the reaction was stirred at room temperature overnight. After the starting material was consumed, water (30 mL) was added to the mixture, which was extracted twice with EA (30 mL), the combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 10, silica gel-CS 12 g, 20 mL / min, silica gel, UV 254) to give the product as a white solid (57 mg, yield 77%).

[1188] ESI-MS m / z calcd for [C 31 H 43 N5O6S][M+H] + :614.3; found: 614.4

[1189] 2.2

[1190] (S)-(l-(((R)-2-(4-morpholinophenyl)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-4-yl)amino)cyclobutyl)methyl 2-((tert-butoxycarbonyl)amino)-3- methylbutanoate (MX021171)

[1191] To a solution of (S)-(l-(((R)-2-(4-morpholinophenyl)-5-oxo-6,7- dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl 2-((tert- butoxycarbonyl)amino)-3-methylbutanoate (57 mg, 0.09 mmol) in DCM (2 mL) was added TFA (0.2 mL). The mixture was stirred at room temperature for 2 hours, after the starting material was consumed, the mixture was concentrated under reduced pressure, the obtained 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 the product as a white solid (20.11 mg, yield 42%).

[1192] ESI-MS m / z calcd for [C 26 H 35 N5O4S][M+H] +: 514.2; found: 514.2

[1193] 1 H NMR (400 MHz, DMSO-d6) δ 8.20 - 8.18 (m, 3H), 3.02 (d, J = 8.8 Hz, 2H), 4.58 (dd, J = 17.6, 10.8 Hz, 2H), 3.76 - 3.74 (m, 4H), 3.63 - 3.57 (m, 1H), 3.31 - 3.29 (m, 2H), 3.26 - 3.23 (m, 4H), 3.21 - 3.11 (m, 2H), 3.03 - 2.98 (m, 1H), 2.46 - 2.36 (m, 2H), 2.34 - 2.30 (m, 3H), 1.95 - 1.84 (m, 3H), 0.83 (d, J = 6.8 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H).

[1194] 1. Synthesis scheme:

[1195] 2. Experimental section:

[1196] 2.1

[1197] (R)-Bis(2-cyanoethyl)((1-((2-(4-morpholinylphenyl-D4)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-4-yl)amino)cyclobutyl)methyl)phosphonate (021178-1)

[1198] To a solution of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4-morpholinylphenyl-D4)- 6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (80 mg, 0.19 mmol) in dimethyl sulfoxide (3 mL) was added bis(2-cyanoethyl)diisopropyl phosphoramidite (104 mg, 0.38 mmol) and 1H-tetrazole (40 mg, 0.57 mmol). The mixture was stirred under nitrogen protection for 16 hours. Then tert-butyl hydroperoxide (70% aqueous solution, 74 mg) was added. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction solution was filtered and purified by reverse phase column chromatography (MeCN / H2O = 0~40%, C-18 CS 40 g, 50 mL / min, C-18, UV 254) to give the product (71 mg, yield 61.43%) as a white solid.

[1199] ESI-MS m / z calcd for [C 27 H 29 D4N6O6PS][M+H] +: 605.2; found: 605.2

[1200] 2.2

[1201] (R)-(1-((2-(4-morpholinylphenyl-D4)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4- yl)amino)cyclobutyl)methyl dihydrogenphosphate (MX021178)

[1202] To a solution of (R)-bis(2-cyanoethyl)((1-((2-(4-morpholinophenyl-d4)-5-oxo-6,7- dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl)phosphonate (65 mg, 0.11 mmol) in methanol (8 mL) was added 33% aqueous ammonia solution (8 mL) at 0 °C. The mixture was stirred at 50 °C under nitrogen protection for 5 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure. The crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L HCOOH), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give the yellow solid product (15.31 mg, yield 28.57%).

[1203] ESI-MS m / z calcd for [C 21 H 23 D4N4O6PS][M+H] + : 499.2; found: 499.0

[1204] 1 H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.61 (m, 1H), 7.25 - 7.17 (m, 2H), 4.10 - 4.04 (m, 2H), 3.75 - 3.73 (m, 4H), 3.65 - 3.35 (m, 5H), 3.28 - 2.97 (m, 3H), 2.67 - 2.61 (m, 2H), 2.32 - 2.15 (m, 2H), 1.87 - 1.81 (m, 2H).

[1205] 1. Synthesis scheme:

[1206] 2. Experimental section:

[1207] 2.1

[1208] (R)-(1-((2-(4-morpholinylphenyl-D4)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4- yl)amino)cyclobutyl)methyl (2,2,2-trichloroacetyl)urea (021179-1)

[1209] To a solution of (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(4- morpholinylphenyl-D4)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (420 mg, 1.0 mmol) in DCM (20 mL) was added 2,2,2-trichloroacetyl isocyanate (283 mg, 1.5 mmol) at 0 °C. The mixture was stirred under nitrogen protection for 3 hours. After LCMS showed the starting material disappeared, the mixture was concentrated for next step.

[1210] ESI-MS m / z calcd for [C 24 H 22 D4Cl3N5O5S][M+H] + :606.1; found:606.0

[1211] 2.2

[1212] (R)-(1-((2-(4-morpholinylphenyl-D4)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4- yl)amino)cyclobutyl)methyl (2,2,2-trichloroacetyl)urea (021179-1)

[1213] To a solution of (R)-(1-((2-(4-morpholinylphenyl-D4)-5-oxo-6,7- dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl (2,2,2- trichloroacetyl)urea (607 mg, 1.0 mmol, crude) in methanol (10 mL) was added potassium carbonate (376 mg, 2.0 mmol) at 0 °C. The mixture was stirred under nitrogen protection for 2 hours. After the reaction was completed, the reaction mixture was purified by reverse phase column (MeCN / H2O = 0~40%, C-18 CS 80 g, 50 mL / min, C-18, UV 254) to get the crude product. The crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L HCOOH), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to get the white solid product. The white solid product was purified by SFC chiral resolution to get the white solid product (32.0 mg, yield 6.93%).

[1214] ESI-MS m / z calcd for [C 22 H27 N5O4S][M+H] + : 462.2; found: 462.2

[1215] 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 6.49 (s, 2H), 4.48 - 4.42 (m, 2H), 3.76 - 3.74 (m, 4H), 3.65 - 3.57 (m, 1H), 3.37 - 3.34 (m, 1H), 3.26 - 3.23 (m, 5H), 3.21 - 3.14 (m, 1H), 3.03 - 2.98 (m, 1H), 2.46 - 2.33 (m, 4H), 1.95 - 1.85 (m, 2H).

[1216] The compounds prepared according to or with reference to the above methods and their mass spectral data are summarized in the following table:

[1217] Table: Example compounds (numbering omits prefix "MX")

[1218] Example 2: PDE4B2 / PDE4D2 enzyme activity inhibition experiment

[1219] The compounds were tested for PDE4B2 / 4D2 enzyme activity inhibition experiment by FP method. The PDE4B2 / PDE4D2 (BPS, Cat: 60042 / 60040) enzyme and substrate (FAM-cyclic AMP) (BPS, Cat: 60200) solutions were prepared in reaction buffer (1x IMAP reaction buffer with 1 mM DTT, containing 0.1% BSA). The final concentrations of PDE4B2, PDE4D2 and FAM-cyclic AMP working therein were 0.0075 nM, 0.1 nM and 100 nM, respectively. The positive control MX02018 (BI1015550) was at a starting concentration of 3 mM for PDE4B2 / PDE4D2, 3-fold dilution, 10 concentration doses. The starting concentration of the test compounds on PDE4B2 / PDE4D2 was 3 mM, 3-fold dilution, 10 concentration doses.

[1220] The test compound stock solution was heated and vortexed sufficiently to mix, prepared into a 300 mM starting concentration working solution, and then 3-fold serially diluted into 10 different concentration final concentration working solutions. This part of the reaction was performed in a dilution Source plate. The diluted compound in 0.05 mL of 100% DMSO in the Source plate was transferred to a 384-well plate (Corning 4514) by acoustic liquid transfer technology (Echo 655), centrifuged at 1000 rpm for 1 min, and the final concentration of DMSO was 1%; 2.5 mL of PDE4B2 / PDE4D2 enzyme solution was transferred to the 384 reaction plate and centrifuged at 1000 rpm for 1 min, and incubated at 25°C for 10 min; 2.5 mL of substrate (FAM-cyclic AMP) solution was transferred to the 384 reaction plate, centrifuged at 1000 rpm for 1 min, and incubated at 25°C for 60 min; 15 mL of binding agent mixture was transferred to the 384 reaction plate and centrifuged at 1000 rpm for 1 min, and incubated at 25°C for 60 min; the FP signal was read using BMG (PHERAstar FSX), and the IC 50 values and nonlinear regression curve fitting were obtained using GraphPad Prism software.

[1221] The activity test results of the compounds in some examples are summarized in the following table:

[1222] Table: Activity test results of the compounds in examples

[1223] Wherein:

[1224] The meanings of the above activity levels are as follows: A+<1 nM; 1 nM≤A≤5 nM; 5<B≤10 nM; 10 nM<C≤20 nM; D represents >20 nM;

[1225] The meaning of the above-mentioned selectivity level is as follows: A represents a ratio > 10; B represents 5 < ratio ≤ 10; C represents 1 < ratio ≤ 5.

[1226] The above experimental results show that the compound of the present disclosure has excellent PDE4B inhibitory activity and excellent PDE 4D / PDE 4B selectivity.

[1227] The above has described exemplary embodiments of the present disclosure. It should be understood that the scope of protection of the present application is not limited to the above-mentioned exemplary embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principles of the present disclosure shall be included in the scope of protection of the present application.

Claims

1. A compound as shown in Formula X below, racemates, stereoisomers, tautomers, isotopically labeled, solvates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs thereof: wherein: X1represents a chemical bond, -O-, -S-, -NR q -, -S(=O)-, -S(=O)2-, -C(=O)-, unsubstituted or optionally substituted alkylene, -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 alkenylene-, -C 2-6 alkynylene-, -C 1-6 alkoxy-; wherein "optionally substituted" means that the group is substituted by 1, 2 or more substituents selected from the group consisting of deuterium, halogen, oxo (=O), thioxo (=S), -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalogenated C 1-6 alkyl (such as -CF3, -CHF2, -CH2F), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-20 cycloalkyl; U represents -(CH2) t - O, S, -NR q - -S(=0)-, -S(=0)2-, or -C(=0)-, wherein t represents 0, 1, 2, or 3; v represents 0, 1, 2, 3, 4 or 5; n represents 1 or 2; m represents 0, 1, 2, 3, 4 or 5; l represents 0, 1, 2, 3, 4 or 5; R q selected from H, C 1-20 alkyl, C 3-20 cycloalkyl, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, each of which can be unsubstituted or substituted successively with 1, 2, or more substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, thioxo, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhaloC 1-6 alkyl (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 and NR 1.2 R 1.3 ; R f , R g , R h , R i are each independently hydrogen or deuterium; ring A is a bond, -C 3-20 cycloalkyl-, -C 3-20 cycloalkenyl-, -3-20 membered heterocycloalkyl-, -5-20 membered heterocycloalkenyl-, -C 6- 20 aryl-, -5-20 membered heteroaryl-, -C 3-20 cycloalkyl and C 6-20 aryl-, -C 3-20 cycloalkyl and 5-20 membered heteroaryl-, -3-20 membered heterocycloalkyl and C 6-20 aryl-, -3-20 membered heterocycloalkyl and 5-20 membered heteroaryl-, -5-20 membered heterocycloalkenyl and C 6-20 aryl-, -5-20 membered heterocycloalkenyl and 5-20 membered heteroaryl-, -C 5-20 cycloalkenyl and C 6-20 aryl-, -C 5-20 cycloalkenyl and 5-20 membered heteroaryl-, -3-20 membered heterocycloalkyl and 5-20 membered heteroaryl and C 3-20 cycloalkyl-; B is a bond, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3-20 membered heterocycloalkyl, 5-20 membered heterocycloalkenyl, C 6-20 aryl, 5-20 membered heteroaryl-, C 3-20 cycloalkyl and C 6-20 aryl, C 3-20 cycloalkyl and 5-20 membered heteroaryl, 3-20 membered heterocycloalkyl and C 6-20 aryl, 3-20 membered heterocycloalkyl and 5-20 membered heteroaryl, 5-20 membered heterocycloalkenyl and C 6-20 aryl, 5-20 membered heterocycloalkenyl and 5-20 membered heteroaryl, C 5-20 cycloalkenyl and C 6-20 aryl, C 5-20 cycloalkenyl and 5-20 membered heteroaryl; R a represents hydrogen, deuterium, halogen, oxo, thioxo, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalogenated C 1-6 alkyl (such as -CF3, -CHF2, -CH2F), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3- to 20-membered heterocycloalkyl, 5- to 20-membered heterocycloalkenyl, C 6-20 aryl, 5- to 20-membered heteroaryl, -C 1-6 alkyl-C 6-20 aryl, C 1-6 alkyl-C 6- 20 aryl-, -C 1-6 alkyl-5- to 20-membered heteroaryl, C 1-6 alkyl-5- to 20-membered heteroaryl-, -C 3-20 cycloalkyl-C 6-20 aryl, C 3-20 cycloalkyl-C 6-20 aryl-, -C 3-20 cycloalkyl-5- to 20-membered heteroaryl, C 3-20 cycloalkyl-5- to 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-SO2R 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 ; wherein each of said groups can be unsubstituted or in turn optionally substituted with 1, 2 or more substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, thioxo, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalo-C 1-6 alkyl (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, thioxo, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalogenated C 1-6 alkyl (such as -CF3, -CHF2, -CH2F), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3- to 20-membered heterocycloalkyl, 5- to 20-membered heterocycloalkenyl, C 6-20 aryl, 5- to 20-membered heteroaryl, -C 1-6 alkyl-C 6-20 aryl, C 1-6 alkyl-C 6- 20 aryl-, -C 1-6 alkyl-5- to 20-membered heteroaryl, C 1-6 alkyl-5- to 20-membered heteroaryl-, -C 3-20 cycloalkyl-C 6-20 aryl, C 3-20 cycloalkyl-C 6-20 aryl-, -C 3-20 cycloalkyl-5- to 20-membered heteroaryl, C 3-20 cycloalkyl-5- to 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-SO2R 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 ; wherein each of said groups can be unsubstituted or in turn optionally substituted with 1, 2 or more substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, thioxo, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalo-C 1-6 alkyl (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl, OR 1.1 and NR 1.2 R 1.3 ; or R a with R b together form a C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3-20 membered heterocycloalkyl, 5-20 membered heterocycloalkenyl, C 6-20 aryl, 5-20 membered heteroaryl, and the aforementioned groups can be unsubstituted or in turn optionally substituted with 1, 2, or more substituents selected from the group consisting of hydrogen, deuterium, halogen, oxo, thia, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalogenated C 1-6 alkyl (e.g. -CF3, -CHF2, -CH2F), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3-20 membered heterocycloalkyl, 5-20 membered heterocycloalkenyl, C 6-20 aryl, 5-20 membered 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, 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-SO2R 1.1 , SO2-R 1.1 , C 1-10 alkyl-SO2R 1.1 or SO2-NR 1.2 R 1.3 , wherein each substituent can be unsubstituted or in turn optionally substituted by 1, 2 or more substituents selected from the group consisting of hydrogen, deuterium, OH, OR 1.1 , halogen, oxo, thioxo, -CN, -OH, -SH, -NH2, -NO2, -CF3, -CHF2, -CH2F, C 1-6 -alkyl, C 6-20- aryl and NR 1.2 R 1.3 ; R c -Y-Z; Y represents a chemical bond, -0-, -S-, -NR q -, -S(=0)-, -S(=0)2-, -C(=0)-, unsubstituted or optionally substituted alkylene, C 1-6 alkylene, -C(=0)-NH-, -C(=0)-NH-C 1-6 alkylene, -C(=0)-NH-, -C 1-6 alkylene, -C 1-6 alkylene, -C 1-6 alkylene, -C 2-6 alkylene, -C 2-6 alkylene, -C 1-6 alkylene, -C 1-6 wherein "optionally substituted" means that the group is substituted by 1, 2 or more substituents selected from the group consisting of deuterium, halogen, oxo, thia, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalogenated C 1-6 alkyl (such as -CF3, -CHF2, -CH2F), C 2-6 alkyl, C 2-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 3-20 alkyl, C each Z is the same or different, independently of each other, hydrogen, deuterium, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, 3-20 membered heterocycloalkyl, 5-20 membered heterocycloalkenyl, C 6-20 aryl, 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-C 6-20 aryl, 3-20 membered heterocycloalkyl-C 6-20 aryl, 3-20 membered heterocycloalkyl-5-20 membered heteroaryl, 3-20 membered heterocycloalkyl-5-20 membered heteroaryl, 5-20 membered heterocycloalkenyl-C 6-20 aryl, 5-20 membered heterocycloalkenyl-C 6-20 aryl, 5-20 membered heterocycloalkenyl-C 5-20 heteroaryl, C 5-20 heterocycloalkenyl-C 5-20 heteroaryl, C 5-20 cycloalkenyl-C 6-20 aryl, C 5-20 cycloalkenyl-C 6-20 aryl, C 5-20 cycloalkenyl-5-20 membered heteroaryl, C 5- 20 cycloalkenyl-5-20 membered heteroaryl, C 3-20 cycloalkyl and C 6-20 aryl, C 3-20 cycloalkyl and C 6-20 aryl, C 3-20 cycloalkyl and 5-20 membered heteroaryl, C 3-20 cycloalkyl and 5-20 membered heteroaryl, 3-20 membered heterocycloalkyl and C 6-20 aryl, 3-20 membered heterocycloalkyl and C 6-20 aryl, 3-20 membered heterocycloalkyl and C 5-20 heteroaryl, 3-20 membered heterocycloalkyl and C 5-20 heteroaryl, 5-20 membered heterocycloalkenyl and C 6-20 aryl, 5-20 membered heterocycloalkenyl and C 6-20 aryl, 5-20 membered heterocycloalkenyl and 5-20 membered heteroaryl, 5-20 membered heterocycloalkenyl and 5-20 membered heteroaryl, C 5-20 cycloalkenyl and C 6-20 aryl, C 5-20 cycloalkenyl and C 6-20 aryl, C 5-20 Cycloalkenyl and 5-20 membered heteroaryl, wherein each C 5- 20 Cycloalkenyl and 5-20 membered heteroaryl, wherein each C 3-20 Cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocycloalkyl, 5-20 membered heterocycloalkenyl, C 6-20 Aryl and 5-20 membered heteroaryl can be independently monocyclic or polycyclic; the above groups can be unsubstituted or each independently optionally substituted at an ortho-, para-, meta- or N, O, S atom with 1, 2 or more substituents selected from the group consisting of deuterium, halogen, oxo, thioxo, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalogenated C 1-6 Alkyl (e.g. -CF3, -CHF2, -CH2F), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-20 Cycloalkyl, C 3-20 Cycloalkenyl, 3-20 membered heterocycloalkyl, 5-20 membered heterocycloalkenyl, C 6-20 Aryl and 5-20 membered heteroaryl, C 1-6 Alkyl-C 6-20 Aryl, C 1-6 Alkyl-5-20 membered heteroaryl, C 3-20 Cycloalkyl-C 6-20 Aryl, C 3-20 Cycloalkyl-5-20 membered heteroaryl, OR 1.1 , COOR 1.1 , C 1-10 Alkyl-COOR 1.1 , COR 1.1 , C 1-10 Alkyl-COR 1.1 , COONR 1.1 , C 1-10 Alkyl-COONR 1.1 , CONOH, C 1-10 Alkyl-CONOH, CO-NR 1.1 , C 1-10 Alkyl-CO-NR 1.1 , CH=CHCOOR 1.1 , CO-NR 1.1 CH2CO-NR 1.1 , CH=CHCO-NR 1.1 , NR 1.2 R 1.3 , C 1-10 Alkyl-NR 1.2 R 1.3 , SR 1.1 , C 1-10 alkyl-SR 1.1 , SOR 1.1 , C 1-10 alkyl-SOR 1.1 , SO2-R 1.1 , C 1-10 alkyl-SO2R 1.1 or SO2-NR 1.2 R 1.3 , and each substituent can be unsubstituted or in turn optionally further substituted by 1, 2 or more substituents selected from hydrogen, deuterium, OH, OR 1.1 , halogen, oxo, thioxo, -CN, -OH, -SH, -NH2, -NO2, mono- or polyhalogenated C 1-6 alkyl (such as -CF3, -CHF2, -CH2F), C 1-6 -alkyl, C 6-20- aryl and NR 1.2 R 1.3 ; R 1.1 is H or is selected from the group consisting of C 1-6- alkyl, C 3-20 -cycloalkyl, C 5-20 -cycloalkenyl, 3- to 20-membered heterocycloalkyl, 5- to 20-membered heterocycloalkenyl, C 6-20- aryl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6 -alkyl, 3- to 20-membered heterocyclo-C 1-6 -alkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl, monocyclic or bicyclic C 6-20 -aryl, 5- to 20-membered heteroaryl and heterocycle, which can be unsubstituted or optionally substituted with a substituent selected from the group consisting of halogen, deuterium, OH, CN, NO2, NH2, oxo (=0), thioxo (=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 are the same or different, independently of each other, H or a radical selected from the group consisting of C 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- to 20-membered heteroaryl-C 1-6- alkyl, monocyclic or bicyclic C 6-20- aryl, monocyclic or bicyclic 3- to 20-membered heterocyclic ring, monocyclic or bicyclic 5- to 20-membered heteroaromatic ring, CO-NH2, CO-NH-CH3, -CO-N(CH3)2, SO2-(C 1-6 -alkyl), SO2-(C 3-10 -cycloalkyl), SO2-(3- to 10-membered heterocycloalkyl), SO2-(C 5-10 -cycloalkenyl), SO2-(5- to 20-membered heterocycloalkenyl), CO-R 1.1 and COOR 1.1 which can be unsubstituted or optionally substituted by 1, 2 or more substituents selected from the group consisting of 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 atom to which they are attached form a 4-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused combination or optionally bridged heterocycle comprising 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O, which heterocycle can be unsubstituted or optionally substituted at an ortho-, para-, or meta- position with 1, 2, or more substituents selected from deuterium, halogen, OH, oxo, thioxo, mono- or polyhalogenated C 1-6 alkyl (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 alcohol, 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 heterocyclyl-C 6-20- -aryl, 3-20 membered heterocycle, 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 ; each R d21 , R d22 are identical or different, independently of one another, selected from the group consisting of a chemical bond, H, deuterium, halogen, OH, CN, NO2, oxo (=0), thioxo (=S), SO, SO2, the following radicals which are unsubstituted or optionally substituted by 1, 2 or more R a , C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-20 aryl, 5- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl, C 1-20 alkyloxy, C 2-20 alkenyloxy, C 2-20 alkynyloxy, C 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C 3-20 cycloalkynyloxy, C 6-20 aryloxy, 5- to 20-membered heteroaryloxy, 3- to 20-membered heterocyclyloxy, C 1-20 alkylthio, C 2-20 alkenylthio, C 2-20 alkynylthio, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 cycloalkynylthio, C 6-20 arythio, 5- to 20-membered heteroarylthio, 3- to 20-membered heterocyclylthio, NH2, -C(O)R 11 , -CH2-C(O)R 11 , -C(O)OR 12 , -CH2C(O)OR 12 , -C(O)NHR 12 , -CH2C(O)NHR 12 , -OC(O)R 13 , -S(O)2R 14 , -S(O)2OR 15 , -OS(O)2R 16 , -P(O)(OR 17 )(OR 18 ); or, when two or more substituents selected from the group consisting of R d21 d22 may form, together with the atom(s) to which they are attached, a C e cycloalkyl group, a C 3-20 cycloalkenyl group, a C 3-20 cycloalkynyl group, a C 3-20 aryl group, a 5-20 membered heteroaryl group, a 3-20 membered heterocyclyl group, which is unsubstituted or optionally substituted by one, two or more R 6-20 ;​ each R e identically or differently, independently of one another, selected from the group consisting of hydrogen, deuterium, halogen, OH, CN, NO2, NH2, SH, oxo (=0), thioxo (=S), methylsulfonyl, ethylsulfonyl, methylsulfonamido, ethylsulfonamido, carboxylic acid group, monohalo- or polyhalo-substituted C 1-6 alkyl (such as CF3, CHF2, CH2F), O-CONH2, O-CONR 1.2 R 1.3 , NR q -CONR 1.2 R 1.3 , NR q -C(O)R 1.1 , NR 1.2 R 1.3 , OR 1.1 , C 1-6 -alkyl-OR 1.1 , C 1-6 -alkyl-O-C 1-6 -alkyl-COOR 1.1 , C 1-6 -alkyl-O-C 1-6 -alkenyl-COOR 1.1 , C 1-6 -alkyl-O-C 1-6 -alkyl-CONR 1.2 R 1.3 , -O-C 1-6 -alkyl-CONR 1.2 R 1.3 , -O-C 1-6 -alkyl-COOR 1.1 , -O-C 1-6 -alkyl-O-CO-C 1-6 -alkyl-NR 1.2 R 1.3 , -O-C 1-6 -alkyl-O-C 1-6 -alkyl-COOR 1.1 , C 1-6 -alkyl-O-PO(ONa)2, C 1-6 -alkyl-O-PO(OH)2, C 1-6 -alkyl-O-PO(OR 1.1 )2, C 1-6 -alkyl-O-C(O)-OR 1.1 , C 1-6 -alkyl-O-C(O)-NR 1.2 R 1.3 , C 1-6 -alkyl-O-C(=O)-C 1-6 -alkyl-(O-C 1-6 -alkyl n , C 1-6 -alkyl-O-C(=O)-C 1-6 -alkyl-COOR 1.1 , C 1-6 -alkyl-O-C(=O)-C 1-6 -alkyl, C 1-6 -alkyl-O-C(=O)-C 3-10 -cycloalkyl, C 1-6 -alkyl-O-C(=O)-3-10 membered heterocycloalkyl, C 1-6 -alkyl-O-C(=O)-C 6-20 aryl, C 1-6 -alkyl-O-C(=O)-5-20 membered heteroaryl, C 1-6 -alkyl-O-C(=O)-C 1-6 -alkenyl-COOR 1.1 , C 1-6 -alkyl-N-C(=O)-C 1-6 -alkyl-COOR 1.1 , C 1-6 -alkyl-N-C(=O)-O-C 1-6 -alkyl-COOR 1.1 , C 1-6 -alkyl-N-C(=O)-N-C 1-6 -alkyl-COOR 1.1 , SR 1.1 , C 1-6 -alkyl-SR 1.1 , SO-R 1.1 , C 1-6 -alk-SOR 1.1 , SO2-R 1.1 , C 1-6 -alkyl-SO2R 1.1 , COOR 1.1 , C 1-6 -alkyl-COOR 1.1 , CH=CHCOOR 1.1 , CO-NR 1.2 R 1.3 , C 1-6 -alkyl-CO-NR 1.2 R 1.3 , CH=CHCO-NR 1.2 R 1.3 , COR 1.1 , C 1-6 -alkyl-COR 1.1 , 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-(mono- or polycyclic-C 6-20- aryl), 3-20 membered heterocyclyl-C 6-20- aryl, 3-20 membered heterocycle, 5-20 membered heteroaryl C 1-3 -alkyl-OR 1.1 , NR 1.2 R 1.3 or C 6-20- aryl; each of which substituents can be unsubstituted or in turn optionally substituted by 1, 2 or more substituents selected from the group consisting of deuterium, OH, CN, C 1-6 -alkyl-CN, C 1-6 -alkyl-NH2, -SH, -NH2, -NHOH, -C 1- 6- alkyl-NHOH, -C 1-6- alkyl-CO-NHOH, -CO-NHOH, -C 1-6- alkyl-NH-CO-NR 1.2 R 1.3 , -NR 1.1 CN, -CHO, guanidino, quaternary ammonium salts, C 2-6 -alkenyl, -O-C 3-8 -cycloalkyl, COOR 1.1 , C 1-6 -alkyl-COOR 1.1 , CONHR 1.1 , C 1-6 -alkyl-CONHR 1.1 , -OR 1.1 , oxo, halogen, monohalo- or polyhalogenated C 1-6 alkyl (such as CF3, CHF2, CH2F), C 1-6 -alkyl, C 6-20- aryl and NR 1.2 R 1.3 ; Each R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 They are selected independently from H, halogens, OH, CN, NO2, oxo (=O), thio (=S), and C, whether the same or different. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, NH2; Heterocyclyl preferably comprises 1, 2, 3 or 4 heteroatoms independently selected from N, S or O in a 3-11 membered saturated or partially saturated monocyclic or bicyclic ring, which bicyclic ring can be any fused or bridged ring, but which is not aromatic; wherein heterocyclyl can be heterocycloalkyl, heterocycloalkenyl or heterocycloalkynyl; for example, heterocycloalkyl represents a 3-11 membered saturated monocyclic or bicyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, which bicyclic ring can be any fused or bridged ring; heterocycloalkenyl represents a 3-11 membered monocyclic or bicyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, comprising 1, 2 or more double bonds, which bicyclic ring can be any fused or bridged ring; heterocycloalkynyl represents a 3-11 membered monocyclic or bicyclic ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O, comprising 1, 2 or more triple bonds, which bicyclic ring can be any optionally fused or optionally bridged ring; Heteroaryl preferably comprises 1, 2, 3 or 4 heteroatoms independently selected from N, S or O in a 5-10 membered monocyclic or bicyclic ring and is aromatic, which bicyclic ring can be any fused ring; "Monocyclic or polycyclic" means monocyclic, bicyclic (e.g. fused, spiro, bridged), tricyclic or more.

2. The compound of formula X as claimed in claim 1, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein ring A is selected from the subunits formed by removing any two H atoms from the following groups, wherein the H atoms may be H atoms on C atoms or N atoms: Preferably, when present, examples of ring A can be selected from the group consisting of the radicals described above, minus two H atoms at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, forming a radical.

3. The compound of claim 1 or 2 of Formula X, racemates, stereoisomers, tautomers, isotopically labeled, solvates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs thereof, wherein ring B is selected from the following groups: wherein, "-" in the structural formula represents a chemical bond to the radical in formula X.

4. The compound of Formula X according to any one of claims 1-3, a racemate, stereoisomer, tautomer, isotopically labeled, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein the compound is selected from the group consisting of the following compounds of Formula X-1: wherein R b , R c , R d21 , R e , R f , R g , R h , R i , I each independently have the definition of any of claims 1 to 3.

5. The compound of claim 1 represented by Formula X, racemates, stereoisomers, tautomers, isotopically labeled, solvates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs thereof, wherein the compound is selected from the following compounds:

6. A method of preparing a compound of Formula X, racemates, stereoisomers, tautomers, isotopically-labeled, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs thereof according to any one of claims 1-5, wherein the method comprises reacting a compound of Formula Al with a compound of Formula Bl to obtain a compound of Formula X: ###00010### Formula Al Formula Bl Formula X ​ wherein, LG is a leaving group, for example Cl, Br or I; R e , R d21 , R d22 , U, R a , R b , R c , R f , R g , R h , R i , A, B, X1independently of one another have the definitions indicated above; and optionally, derivatizing the compound of formula X into a stereoisomer, a tautomer, an isotopically labeled compound, a solvate, a polymorph, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof; wherein, LG is a leaving group, for example Cl, Br or I; Cy, W, R a , R b , R c , R f , R g , R h , R i , R2, R 2’ , m independently of one another have the definitions given in any of claims 1 to 5; Preferably, the reaction is carried out with a protecting group on the compound of formula A1 and / or B1.

7. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound of formula X, a racemate, a stereoisomer, a tautomer, an isotopically labeled compound, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof according to any one of claims 1-5.

8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients; For example, the pharmaceutical composition can further comprise one or more additional therapeutic agents.

9. A method of preventing or treating a disease, comprising administering to a patient in need thereof at least one of the compound of formula X, a racemate, a stereoisomer, a tautomer, an isotopically labeled compound, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof according to any one of claims 1-5. The disease can be a PDE4B-mediated disease, or at least a PDE4-mediated disease.

10. The method of claim 9, wherein the disease comprises, but is not limited to, a disease of the respiratory tract, inflammatory bowel disease, arthritic disease, a disease of the skin, psoriasis and other inflammatory skin diseases, rheumatoid arthritis (RA), a disease of the eye, a disease of the peripheral or central nervous system, a degenerative disorder of the central nervous system, Alzheimer's Disease (AD), Non-alcoholic Steatohepatitis (NASH), Idiopathic Pulmonary Fibrosis (IPF) or associated Pulmonary Hypertension, chronic obstructive pulmonary disease (COPD) or associated Pulmonary Hypertension, hepatic fibrosis (HF), Renal fibrosis, benign prostatic hyperplasia (BPH), Gastroesophageal Reflux disease, Obstructive Sleep apnea, Coronary Artery Disease, Heart Failure (HF), Ischemic Heart Disease, Diabetic related nephropathy, cancer related solid tumors, leukemia and lymphoma and obesity associated metabolic disorders; Preferably, the cancer comprises, but is not limited to, one selected from the group consisting of stomach cancer, bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, cancer of the central nervous system, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gall bladder cancer, gastrointestinal cancer, genital cancer, genitourinary tract cancer, head cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, muscle tissue cancer, neck 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; preferably, the disease foci comprise the respiratory system, the digestive system, the excretory system, and / or the reproductive system, such as the lung, the liver, the kidney, and / or the prostate. Preferably, the cancer comprises, but is not limited to, one selected from the group consisting of stomach cancer, bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, cancer of the central nervous system, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gall bladder cancer, gastrointestinal cancer, genital cancer, genitourinary tract cancer, head cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, muscle tissue cancer, neck 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; preferably, the disease foci comprise the respiratory system, the digestive system, the excretory system, and / or the reproductive system, such as the lung, the liver, the kidney, and / or the prostate.

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