Pyrimidine derivative, pharmaceutical composition thereof and use thereof

Abstract

The present disclosure relates to a pyrimidine derivative, a pharmaceutical composition thereof and a use thereof, and specifically provides a compound represented by the following formula H, and a racemate, a stereoisomer, a tautomer, an isotopic marker, a solvate, a polymorph, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof.

Description

Pyrimidine derivatives, pharmaceutical compositions thereof and uses thereof

[0001] This application claims the priority benefit of the following prior application filed by the applicant with the China National Intellectual Property Office: the patent application for invention with the application number 202411248808.1 and the invention name "Pyrimidine derivatives, pharmaceutical compositions thereof and uses thereof", which was filed on September 6, 2024. The entire contents of the above-mentioned prior application are incorporated herein by reference. TECHNICAL FIELD

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

[0003] Phosphodiesterase (PDE) is a very important class of disease treatment targets, and its inhibitors can be used for the treatment of various diseases. PDE, as the only family of enzymes in the body that hydrolyzes the important second messenger cAMP and cGMP in cells, is composed of 11 subfamilies (PDE1-11). Drugs with inhibitory activity against PDE can treat a variety of diseases. For example:

[0004] PDE1 is known to have three subtypes: PDE1A, PDE1B and PDE1C, among which PDE1A and PDE1B have stronger cGMP hydrolysis ability, while PDE1C has no significant difference in cAMP and cGMP hydrolysis ability. PDE1A is mainly distributed in vascular smooth muscle cells and can regulate the tone of smooth muscle, PDE1B is mainly distributed in the nervous system and is involved in physiological activities such as learning and memory, immune regulation, etc., while PDE1C is mainly distributed in the brain and smooth muscle cells and may be involved in the proliferation of vascular smooth muscle cells and signal transmission in the central nervous system.

[0005] PDE2 has one subtype PDE2A. PDE2 is expressed in many tissues and cells, such as the central nervous system, platelets, cardiomyocytes, endothelial cells, etc. PDE2 plays an important role in regulating myocardial contraction, improving cognitive function and long-term memory.

[0006] PDE3 has two gene subtypes PDE3A and PDE3B, which are located on chromosomes 11 and 12, respectively. PDE3A is mainly distributed in the heart, platelets, vascular smooth muscle and oocytes, and has the effects of regulating myocardial contractility, platelet aggregation, vascular smooth muscle contraction, oocyte maturation and renin release, etc. PDE3B is mainly distributed in adipocytes, hepatocytes, spermatocytes and pancreas, and mainly participates in the regulation of insulin, insulin-like growth factor and leptin signaling, and plays an important role in metabolic diseases such as obesity and diabetes.

[0007] 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. It can be seen that 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. Inhibition of PDE4B can lead to an increase in intracellular cAMP levels, which in turn activates protein kinase A (PKA) and cAMP-dependent exchange protein (EPAC), reduces the synthesis and release of pro-inflammatory cytokines, and increases the synthesis of anti-inflammatory cytokines.

[0008] 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.

[0009] PDE5 has only one isoform, PDE5A, which is mainly distributed in the lung, pancreas, brain, corpus cavernosum, vascular smooth muscle cells, platelets, skeletal muscle cells and myocardial cells. PDE5 can well regulate the contractility of vascular smooth muscle, especially the contractility of penile and pulmonary vascular smooth muscle. PDE5 can also participate in platelet aggregation through the NO-cGMP signaling pathway, and PDE5 may also play an important role in cGMP signaling in the brain.

[0010] Targeted drugs are a class of drugs designed to target pathogenic factors (such as protein molecules or gene fragments, etc.) with specific inhibitory activity. The unique mechanism of action and therapeutic advantages of targeted drugs are of great significance to the treatment of diseases, the reduction of side effects and the improvement of the quality of life of patients. Targeted drugs, while exerting unique therapeutic advantages and bringing great clinical benefits, also have limitations such as high price, narrow application range, easy drug resistance and certain toxic side effects. These limitations also require researchers to develop new targeted drugs or new technologies, among which the development of dual-target drugs or multi-target drugs, especially dual-target or multi-target drugs with synergistic effects, will have remarkable advantages in improving efficacy and reducing drug resistance. SUMMARY

[0011] To solve the above technical problems, the present disclosure provides a compound as shown in the following formula H, a racemate, a stereoisomer, a tautomer, an isotopically labeled substance, a solvate, a polymorph, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof:

[0012] wherein:

[0013] X1represents a chemical bond, C 1-20 alkylene, O, S, NR q , S(=O), S(=O)2or C(=O);

[0014] X2represents a chemical bond, C 1-20 alkylene, O, S, NR q , S(=O), S(=O)2or C(=O);

[0015] U represents -(CH2) t , O, S, NR q , S(=O), S(=O)2or C(=O), wherein t represents 0, 1, 2 or 3;

[0016] 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 2-20 alkenyloxy, C 2-20 alkynyloxy, C 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C 3-20 cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 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, 5-20 membered heteroarylthio, 3-20 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)R 42 -C(O)OR 43 -OC(O)R 44 -S(O)2R 45 -S(O)2OR 46 -OS(O)2R 47 -P(O)(OR 48 )(OR a );

[0017] v represents 0, 1, 2, 3, 4 or 5;

[0018] R d4 represents H or -X-R3;

[0019] X represents CH2, O, S, NH, -S(O)-, -S(O)2- or -C(O)-;

[0020] R3represents H, halogen, OH, CN, -CH2CF3, -NHR d4 , unsubstituted or optionally substituted by 1, 2 or more R 1-20 alkyl, -C(O)R 61 , -C(O)OR 62 , -OC(O)R 63 , NH2;

[0021] R b represents H or -Y-R4;

[0022] Y represents CH2, O, S, NH, -S(O)-, -S(O)2- or -C(O)-;

[0023] R4represents H, halogen, OH, CN, -CH2CF3, -NHR d4 , unsubstituted or optionally substituted by 1, 2 or more R d5 alkyl, -C(O)R 1-20 , -C(O)OR 61 , -OC(O)R 62 , NH2;

[0024] with the proviso that R 63 , R a are not simultaneously H;

[0025] or, R b , R a together with the atom to which they are attached form unsubstituted or optionally substituted by 1, 2 or more R b alkyl, -C(O)R d6 , -C(O)OR 5-20 , -OC(O)R , NH2;

[0026] Each R d21 R d22 R d4 R d5 R d6 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 );

[0027] Alternatively, when two or more R-selected groups are present on the same group. d22 R d4 Rd5 , R d6 When two substituents of the substituents of R e , C 3-20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;

[0028] R c represents hydrogen, mono- or polycyclic C 6-20 -aryl, mono- or polycyclic C 6-20 -aryl and 4-12 membered cycloalkyl, mono- or polycyclic C 6-20 -aryl and 4-10 membered heterocycloalkyl, mono- or polycyclic 5-20 membered heteroaryl, mono- or polycyclic 5-20 membered heteroaryl and 4-12 membered cycloalkyl, mono- or polycyclic 5-20 membered heteroaryl and 4-10 membered heterocycloalkyl, for example C 4-10 cycloalkyl and C 6-20 aryl-, C 4-10 cycloalkenyl and C 6-20 aryl-, 4-10 membered heterocycloalkyl and C 6-20 aryl-, 4-10 membered heterocycloalkenyl and C 6-20 aryl-, C 4-10 cycloalkyl-C 6-20 aryl-, C 4- 10 cycloalkenyl-C 6-20 aryl-, 4-10 membered heterocycloalkyl-C 6-20 aryl-, 4-10 membered heterocycloalkenyl-C 6-20 aryl-, 5-20 membered heteroaryl, C 4-10 cycloalkyl and 5-20 membered heteroaryl-, C 4-10 cycloalkenyl and 5-20 membered heteroaryl-, 4-10 membered heterocycloalkyl and 5-20 membered heteroaryl-, 4-10 membered heterocycloalkenyl and 5-20 membered heteroaryl-, C 4-10 cycloalkyl-5-20 membered heteroaryl-, C 4-10 cycloalkenyl-5-20 membered heteroaryl-, 4-10 membered heterocycloalkyl-5-20 membered heteroaryl-, 4-10 membered heterocycloalkenyl-5-20 membered heteroaryl-; or, R c is selected from 5-20 membered heteroaryl-O-C 6-20 aryl-, 5-20 membered heteroaryl-NH-C 6-20 aryl-, 5-20 membered heteroaryl-S-C 6-20 aryl-, 5-20 membered heteroaryl-CH2-C 6-20aryl-, each of the above ring systems can optionally be substituted at the ortho-, para- or meta- position, each independently optionally substituted with 1, 2 or more substituents selected from the group consisting of halogen, hydroxy, CN, NO2, NH2, or with 1, 2 or more substituents selected from the group consisting of OR 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 , NR 1.2 R 1.3 , CH2-NR 1.2 R 1.3 , CH2CH2-NR 1.2 R 1.3 , C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 1.1 , C 3-10 -cycloalkyl, C 3-10 -cycloalkenyl, 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-CH2CH3and SO2-NR 1.2 R 1.3 substituents;

[0029] Alternatively, R c is selected from the group consisting of heterocyclyl and heteroaryl, which can optionally be substituted at the ortho-, para- or meta- position, each independently optionally substituted with 1, 2 or more groups selected from the group consisting of halogen, OH, oxo, CF3, CHF2and CH2F, or with 1, 2 or more substituents selected from the group consisting of 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, 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 1.1 and NR 1.2 R 1.3 , which can be independently optionally substituted with 1, 2, or more substituents selected from the group consisting of OH, OR 1.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- alkyl, C 6-10- aryl, and NR 1.2 R 1.3 ;

[0030] heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O;

[0031] Heteroaryl is a 5-10 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 the heteroaryl group is selected from 5-membered monocyclic heteroaryl, 5-membered heteroarylbiphenyl, 5-membered heteroarylbicyclo-5-10 membered heteroaryl, 5-membered heteroarylbicyclo-4-12 membered cycloalkyl, 5-membered heteroarylbicyclo-4-12 membered cycloalkenyl, 5-membered heteroarylbicyclo-4-12 membered heterocycloalkyl, 5-membered heteroarylbicyclo-4-12 membered heterocycloalkenyl, 6-membered heteroarylbiphenyl, 6-membered heteroarylbicyclo-5-10 membered heteroaryl, 6-membered heteroarylbicyclo-6-membered heteroaryl, 6-membered heteroarylbicyclo-4-7 membered cycloalkyl, 6-membered heteroarylbicyclo-4-12 membered cycloalkenyl, 6-membered heteroarylbicyclo-4-12 membered heterocycloalkyl, 6-membered heteroarylbicyclo-4-12 membered heterocycloalkenyl;

[0032] each R 1.1 identical or different, independently of one another, denote H or are selected from the group consisting of C 1-6- alkyl, C 1-6- alkyl alcohol, C 1-3 haloalkyl, mono- or bicyclic, -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 heterocyclo-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 heterocyclo, which can optionally be substituted by OH, O-(C 1-3 alkyl), halogen, C 1-10- alkyl and C 5-10 aryl substituents;

[0033] each R 1.2 and R 1.3 identical or different, independently of one another, denote H or are selected from the group consisting of C 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- alkyl, mono- or bicyclic C 6-20- aryl, 3-10 membered heterocyclo, heteroarylo, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 alkyl), CO-R 1.1and COOR 1.1 groups, which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- -aryl and COOR 1.1 groups.

[0034] each R e is, 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 are the following groups: 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)(OR47 (OR) 48 );

[0035] 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;

[0036] 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 );

[0037] Alternatively, when two or more R-selected groups are present on the same group. f 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. g 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;

[0038] Each R g They are selected independently from H, halogens, OH, CN, NO2, oxo (=O), thio (=S), and C, whether they are the same or different. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, NH2;

[0039] 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 They are selected independently from H, halogens, OH, CN, NO2, oxo (=O), thio (=S), and C, whether they are the same or different. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, NH2;

[0040] R h Represents a single- or multi-cyclic C 6-20-aryl, a mono- or polycyclic C 6-20 -aryl 4-12-membered cycloalkyl or a mono- or polycyclic C6-20-aryl 4-12-membered cycloalkenyl group, wherein the above groups may be independently and optionally substituted at the ortho, para, or meta positions of any cyclic group by one, two, or more independent groups of fluorine, chlorine, bromine, hydroxyl, CN, NH2, or by one, two, or more groups selected from OR 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 ,NR 1.2 R 1.3 CH2-NR 1.2 R 1.3 ,CH2CH2-NR 1.2 R 1.3 C 3-10 -cycloalkyl, C 3- 10 -cycloalkenyl, C 1-3 -alkyl-(monocyclic or polycyclic-C) 6-20- aryl), 3-20 membered heterocyclic-C 6-20- Aryl, 3-20 membered heterocyclic group, C 1-6 -alkyl, C 1-3 -Fluoroalkyl, C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 1.1 CF3, CHF2, CH2F, C 6-20- Aryl-C 1-6 -alkyl, 3-10 membered heterocyclic -C 1-6 -alkyl, 5-20-membered heteroaryl-C 1-6- Alkyl, C 6-10 -Aryl, SO2-CH3, SO2-CH2CH3 and SO2-NR 1.2 R 1.3 The substituents may be independently and optionally replaced by one, two or more molecules selected from OH, OR 1.1 CF3, CHF2, CH2F, oxidized, halogenated, CF3, CHF2, CH2F, C 1-6-alkyl, C 6-10- aryl and NR 1.2 R 1.3 , or

[0041] R h represents a group selected from heterocycle or heteroaryl, which is optionally substituted in the ortho-, para- or meta-position, each independently, by 1, 2 or more groups of halogen, OH, oxo, CF3, CHF2and CH2F, or by 1, 2 or more groups selected from OR 1.1 , C 1- 3-alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 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 , 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 heterocycloalkenyl-C 6-20-aryl, 3-10 membered heterocyclyl, 5-20 membered heteroaryl C 1-3 -alkyl-OR 1.1 and NR 1.2 R 1.3 substituted with 1, 2 or more substituents selected from the group consisting of OH, OR 1.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- -alkyl, C 6-20- -aryl and NR 1.2 R 1.3 ;

[0042] heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

[0043] heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

[0044] R 1.1 is H or is selected from the group consisting of C 1-6- -alkyl, C 1-6- -alkyl alcohol, C 1-3 -haloalkyl, C 3-11 -monocyclic or bicyclic heterocyclyl, -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 heterocyclyl-C 1-6 -alkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl, C 3-10 -cycloalkenyl-C 1-6 -alkyl, monocyclic or bicyclic C 6-20- aryl, 5-20 membered heteroaryl and heterocycle, which can optionally be substituted with a group selected from OH, O-(C 1-3 -alkyl), halogen, C 1-10- -alkyl and C 6-20- -aryl;

[0045] R 1.2 and R 1.3 independently of each other represent H or are selected from the group consisting of C 1-6- -alkyl, monocyclic or bicyclic C 3-10- -cycloalkyl, monocyclic 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 1.1 and COOR 1.1 groups, which can optionally be substituted with 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 1.1 groups.

[0046] 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;

[0047] 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;

[0048] 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.

[0049] L represents a bond, C 2-20 alkynyl or Cy; wherein L can be attached to X1or R c at any site;

[0050] Cy represents a bond, 3-20 membered heterocycloalkyl, C 6-20 aryl, 5-20 membered heteroaryl, wherein the 3-20 membered heterocycloalkyl, C 6-20 aryl, 5-20 membered heteroaryl can optionally be fused to a 4-12 membered cycloalkyl or 4-12 membered cycloalkenyl, 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 H via its N atom or a C atom;

[0051] 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 cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.2 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.2 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.2 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 3-10 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 3-10 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 - aryl and a 4- to 12-membered cycloalkyl or 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 cycloalkyl or a mono- or polycyclic C 1-6 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1- - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 6-20- - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-6 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-6 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-6- - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 6-10 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.2 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-6 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 6-10-aryl and NR 1.2 R 1.3 substituted by one or more substituents selected from the group consisting of halogen, OH, oxo, CF3, CHF2, CH2F, CN, NH2, NHR

[0052] 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 1.1 , C 1- 3-alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 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 , 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 1.1 and NR 1.2 R1.3 The substituents are replaced by substituents, which may be independently and optionally selected from OH, OR 1.1 Oxide, halogen, CF3, CHF2, CH2F, C 1-6- Alkyl, C 6-20- Aryl and NR 1.2 R 1.3 One, two or more substituents are substituted;

[0053] 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.

[0054] 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, 6-membered heteroaryl-4-12-membered heterocycloalkenyl;

[0055] Heterocyclic hydrocarbon groups can be saturated or partially saturated;

[0056] R 1.1 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;

[0057] R 1.2 and R 1.3 independently of one another denote H or a group selected from C 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 1.1 and COOR 1.1 which can be optionally substituted with 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 1.1 .

[0058] According to embodiments of the present disclosure, examples of L can be selected from the following groups:

[0059] According to embodiments of the present disclosure, each R d21 , R d22 are identical or different, independently of one another, denote hydrogen, halogen, cyano, hydroxyl, CF3, C 1-6 -alkyl, C 1-3 -fluoroalkyl, CHF2, CH2F, SO2-CH3, SO2-CH2CH3, SO2-NR 1.2 R 1.3 , C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2or C 1-3 -alkyl-NHR 1.1 which can be independently optionally substituted with 1, 2 or more substituents selected from OH, OR 1.1 , CF3, CHF2, CH2F, oxo, CF3, CHF2, CH2F, C 1-6 -alkyl, C 6-20- aryl and NR 1.2 R 1.3 ;

[0060] According to embodiments of the present disclosure, each R d6identically or differently, independently of one another, H, F, Me, C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 1.1 , C 1-6- alkyl, C 2-6- alkenyl, C 2-6- alkynyl, a mono- or polycyclic C 6-20- aryl, a mono- or polycyclic C 6-20 -aryl and a 4- to 12-membered annulated cycloalkyl, a mono- or polycyclic C 6-20 -aryl and a 4- to 12-membered annulated cycloalkenyl, a mono- or polycyclic C6-20-heteroaryl and a 4- to 12-membered annulated cycloalkyl, a mono- or polycyclic C6-20-heteroaryl and a 4- to 12-membered annulated cycloalkenyl, C 6-10 -aryl-C 1-6 -alkyl, C 5-10 -heteroaryl-C 1-6 -alkyl, C 3-10 -heterocycle and C 5-10 -heterocyclyl, -NR’R”, fluorine, C 1-6- fluoroalkyl and C 1-6- fluoroalkoxy, wherein R’ and R” are independently selected from H and C 1-6- alkyl; which radicals can in each case optionally be substituted by 1, 2 or more substituents selected from the group consisting of OH, oxo, halogen, C 1-6- alkyl and O-C 1-6- alkyl; or,

[0061] each R d6 identically or differently, independently of one another, H, F, Me, C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 1.1 , C 1-6- alkyl, C 2-6- alkenyl, C 2-6- alkynyl, C 6-10- aryl, C 6-10 -aryl-C 1-6 -alkyl, C 5-10 -heteroaryl-C 1-6 -alkyl, C 3-10 -heterocycle and C 5-10 -heterocyclyl, -NR’R”, fluorine, C1-6- fluoroalkyl and C 1- 6- fluoroalkoxy, wherein R' and R" are independently selected from H and C 1-6- alkyl; which radicals are in each case optionally substituted by 1, 2 or more substituents selected from the group consisting of OH, oxo, halogen, C 1-6- alkyl and O-C 1-6- alkyl.

[0062] or two R d6 together with the atom to which they are attached form a 3-11 membered, monocyclic or bicyclic, optionally fused combination or optionally bridged cycloalkyl or cycloalkenyl, or a 3-11 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 is unsubstituted or optionally substituted at the ortho-, para- or meta-position by 1, 2 or more substituents selected from the group consisting of halogen, OH, oxo, 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, 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-C6-20- Aryl), 3-10 membered heterocyclic group -C 6-20- Aryl, 3-10 heterocyclic, 5-20 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 ;

[0063] R 1.1 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, mono- or bicyclic -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;

[0064] R 1.2 and R 1.3 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 heterocyclic group, heteroaryl group, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 1.1 and COOR 1.1 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 COOR 1.1 replace.

[0065] According to embodiments of the present disclosure, the compound represented by Formula H, a racemate, a stereoisomer, a tautomer, an isotopically labeled material, a solvate, a polymorph, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof can be selected from the following compounds of Formula I, II, or III, a racemate, a stereoisomer, a tautomer, an isotopically labeled material, a solvate, a polymorph, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof:

[0066] wherein the groups in the above Formula I, II, and III can independently have the definitions in the context of the present disclosure.

[0067] According to embodiments of the present disclosure, the compound of Formula I has the following definitions:

[0068] wherein:

[0069] X1represents a bond, C 1-20 alkylene, O, S, NR q , S(=O), S(=O)2, or C(=O);

[0070] U represents -(CH2) t , O, S, NR q , S(=O), S(=O)2, or C(=O), wherein t represents 0, 1, 2, or 3;

[0071] 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 2-20 alkenyloxy, C 2-20 alkynyloxy, C 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C 3-20 cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 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, C6-20 Arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclic thio, C 1-8 -hexaalkylene 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 );

[0072] v represents 0, 1, 2, 3, 4 or 5;

[0073] R a Represents H or -X-R3;

[0074] X represents CH2, O, S, NH, -S(O)-, -S(O)2- or -C(O)-;

[0075] R3 represents H, halogen, OH, CN, -CH2CF3, -NHR d4 No substitution or optional use by 1, 2 or more R d4 The following groups are substituted: C 1-20 Alkyl, -C(O)R 61 -C(O)OR 62 -OC(O)R 63 NH2;

[0076] R b Represents H or -Y-R4;

[0077] Y represents CH2, O, S, NH, -S(O)-, -S(O)2- or -C(O)-;

[0078] R4 represents H, halogen, OH, CN, -CH2CF3, -NHR d4 No substitution or optional use by 1, 2 or more R d5 The following groups are substituted: C 1-20 Alkyl, -C(O)R 61 -C(O)OR 62 -OC(O)R 63 NH2;

[0079] The condition is R a R b Not both H;

[0080] Or, R a R b Together with the atoms they are attached to, they form unsubstituted or optionally substituted with one, two or more R atoms. d6 The following groups are substituted: C 5-20 Cycloalkenyl, 3-20 membered heterocyclic, 5-20 membered heteroaryl, 6-20 membered aryl;

[0081] Each R d21 R d22 R d4 R d5 R d6 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 );

[0082] or, when there are two or more substituents selected from R d21 , R d22 , R d4 , R d5 , R d6 on the same group, said two substituents can form, together with the atom(s) to which they are attached, a group selected from C e cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 3-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, which is unsubstituted or optionally substituted with 1, 2 or more R 6-20 ;

[0083] each R d21 , R d22 is the same or different, independently of each other, selected from H, halogen, OH, CN, NO2, oxo (=0), thioxo (=S), SO, SO2, a group selected from C e alkyl, C 1-20 alkenyl, C 2-20 alkynyl, C 2-20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 3-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, which is unsubstituted or optionally substituted with 1, 2 or more R 6-20 ; 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, 5-20 membered heteroaryloxy, 3-20 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, 5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH2, -C(O)R 31 , -CH2-C(O)R 31 , -C(O)OR 32 ;-CH2C(O)OR 32 -CH2C(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 );

[0084] or, when there are two or more substituents selected from R d21 , R d22 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, which is unsubstituted or optionally substituted by 1, 2 or more R e ; C 3-20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;

[0085] each R e is the same or different, independently of each other, selected from 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 is unsubstituted or optionally substituted by 1, 2 or more R f ; 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 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C 3-20 cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C 1-20 alkylthio, C 2-20 alkenylthio, C2-20 alkynylthio, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 cycloalkynylthio, C 6-20 arylthio, 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 );

[0086] or, when there are two or more substituents selected from R e 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 groups, which are unsubstituted or optionally substituted by 1, 2 or more R f ; 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;

[0087] each R f is the same or different, independently from each other, selected from the group consisting of H, halogen, OH, CN, NO2, oxo (=0), thioxo (=S), the following groups, which are unsubstituted or optionally substituted by 1, 2 or more R g ; 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 6-20aryloxy, 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 arylthio, 5- to 20-membered heteroarylthio, 3- to 20-membered heterocyclylthio, 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 );

[0088] 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 groups, which are optionally substituted by 1, 2 or more R g ; 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;

[0089] each R g is the same or different, independently of one another, selected from the group consisting of H, halogen, OH, CN, NO2, oxo (=O), 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- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl, NH2;

[0090] each R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 41 , R 42 , R43 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 They are selected independently from H, halogens, OH, CN, NO2, oxo (=O), thio (=S), and C, whether they are the same or different. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, NH2;

[0091] R c Indicates hydrogen, mono- or polycyclic C 6-20 -Aryl, mono- or polycyclic C 6-20 -Aryl 4-12 membered ring hydrocarbon group, mono- or polycyclic C 6-20 -aryl 4-10-membered heterocyclic hydrocarbon group, mono- or polycyclic 5-20-membered heteroaryl, mono- or polycyclic 5-20-membered heteroaryl 4-12-membered ring hydrocarbon group, mono- or polycyclic 5-20-membered heteroaryl 4-10-membered heterocyclic hydrocarbon group, for example C 4-10 cycloalkyl-C 6-20 Aryl, C 4-10 cycloalkenyl-C 6-20 Aryl, 4-10 membered heterocyclic alkyl benzo[C] 6-20 Aryl, 4-10 membered heterocyclic alkenyl benzo[C] 6-20 Aryl, C 4-10 cycloalkyl-C 6-20 Aryl, C 4-10 Cycloalkenyl-C 6-20 Aryl, 4-10 membered heterocyclic alkyl-C 6-20 Aryl, 4-10 membered heterocyclic alkenyl-C 6-20 Aryl-, 5-20 heteroaryl, C 4-10 Cycloalkyl 5-20-membered heteroaryl, C 4-10 Cycloalkenyl 5-20 quinone heteroaryl, 4-10 quinone heterocycloalkyl 5-20 quinone heteroaryl, 4-10 quinone heterocycloalkenyl 5-20 quinone heteroaryl, C 4-10 Cycloalkyl-5-20-membered heteroaryl, C 4-10Cycloalkenyl-5-20 membered heteroaryl, 4-10 membered heterocycloalkyl-5-20 membered heteroaryl, 4-10 membered heterocycloalkenyl-5-20 membered heteroaryl; or, R c selected from 5-20 membered heteroaryl-O-C 6-20 aryl, 5-20 membered heteroaryl-NH-C 6-20 aryl, 5-20 membered heteroaryl-S-C 6-20 aryl, 5-20 membered heteroaryl-CH2-C 6-20 aryl; each ring system in the above groups can optionally be substituted at the ortho-, para- or meta-positions, each independently, with 1, 2 or more substituents selected from halogen, hydroxy, CN, NO2, NH2, or with 1, 2 or more substituents selected from OR 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 , NR 1.2 R 1.3 , CH2-NR 1.2 R 1.3 , CH2CH2-NR 1.2 R 1.3 , C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 1.1 , C 3-10 -cycloalkyl, C 3-10 -cycloalkenyl, 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-CH2CH3and SO2-NR 1.2 R1.3 Substituents of the substituents;

[0092] Or, R c A group selected from heterocyclic and heteroaryl groups, which may optionally be independently and independently substituted at the ortho, para, or meta positions by one, two, or more groups selected from halogens, OH, oxo, CF3, CHF2, and CH2F, or by one, two, or more groups selected from OR 1.1 C 1-3 -alkyl-OR 1.1 SR 1.1 C 1-3 -alkyl-SR 1.1 SO-R 1.1 C 1-3 -alkyl-SOR 1.1 SO2-R 1.1 C 1-3 -alkyl-SO2R 1.1 COOR 1.1 CH2COOR 1.1 CH2CH2COOR 1.1 CH = CHCOOR 1.1 CO-NR 1.1 CH2CO-NR 1.1 ,CH2CH2CO-NR 1.1 ,CH=CHCO-NR 1.1 ,COR 1.1 CH2COR 1.1 C 1-6 -alkyl alcohols, 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-(monocyclic or polycyclic-C) 6-20- Aryl), 3-10 membered heterocyclic group -C 6-20- Aryl, 3-10 heterocyclic, 5-20 heteroaryl C 1-3 -alkyl-OR 1.1 and NR 1.2 R 1.3 It can also be independently and arbitrarily converted by OH and OR. 1.1 Oxide, halogen, CF3, CHF2, CH2F, C 1-6- Alkyl, C 6-10- Aryl and NR 1.2 R 1.3substituted with 1, 2 or more substituents selected from the group consisting of

[0093] heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

[0094] heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; in some embodiments heteroaryl is selected from the group consisting of 5 membered monocyclic heteroaryl, 5 membered heteroarylene benzene, 5 membered heteroarylene 5-10 membered heteroaryl, 5 membered heteroarylene 4-12 membered cycloalkyl, 5 membered heteroarylene 4-12 membered cycloalkenyl, 5 membered heteroarylene 4-12 membered heterocycloalkyl, 5 membered heteroarylene 4-12 membered heterocycloalkenyl, 6 membered heteroarylene benzene, 6 membered heteroarylene 5-10 membered heteroaryl, 6 membered heteroarylene 6 membered heteroaryl, 6 membered heteroarylene 47 membered cycloalkyl, 6 membered heteroarylene 4-12 membered cycloalkenyl, 6 membered heteroarylene 4-12 membered heterocycloalkyl, 6 membered heteroarylene 4-12 membered heterocycloalkenyl;

[0095] each R 1.1 identical or different, independently of one another, denote H or are selected from the group consisting of C 1-6- alkyl, C 1-6- alkyl alcohol, C 1-3 haloalkyl, mono- or bicyclic, -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 heterocycle-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 heterocycle, which can optionally be substituted with OH, O-(C 1-3 alkyl), halogen, C 1-10- alkyl and C 5-10 aryl substituents;

[0096] each R 1.2 and R 1.3 identical or different, independently of one another, denote H or are selected from the group consisting of C 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- alkyl, mono- or polycyclo 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 1.1 and COOR 1.1 , which can optionally be substituted with 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 1.1 .

[0097] L represents a bond, C 2-20 alkynyl or Cy; wherein L can be attached to X1or the phenyl ring at any position;

[0098] Cy represents a bond, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, wherein said 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl can optionally be fused to a 4-12 membered cycloalkyl or cycloalkenyl, with the proviso that when said heterocyclyl contains a N atom, said heterocyclyl can be bonded to the carbon atom in the 2-position of the pyrimidine ring in Formula I via its N atom or C atom;

[0099] L represents alkynyl; a mono- or polycyclo C 6-20- aryl, a mono- or polycyclo C 6-20 -aryl and a 4-12 membered cycloalkyl or a mono- or polycyclo C 6-20 -aryl and a 4-12 membered cycloalkenyl, which can be independently at the ortho, para or meta position optionally substituted with 1, 2 or more groups independently selected from fluoro, chloro, bromo, hydroxy, CN, NH2, or 1, 2 or more groups selected from OR 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 , NR 1.2 R 1.3 , CH2-NR 1.2 R 1.3 , CH2CH2-NR 1.2 R 1.3 , C 3-10 -cycloalkyl, C 3-10 -cycloalkenyl, C1-3 -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, C 1- 3-alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 1.1 , 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-CH2CH3, and SO2-NR 1.2 R 1.3 substituted with 1, 2, or more substituents selected from the group consisting of OH, OR 1.1 , CF3, CHF2, CH2F, oxo, halogen, CF3, CHF2, CH2F, C 1-6 -alkyl, C 6-10- aryl and NR 1.2 R 1.3 substituted with 1, 2, or more substituents selected from the group consisting of OH, OR

[0100] L represents a group selected from heterocyclyl or heteroaryl, each independently optionally substituted at the ortho, para, or meta position with 1, 2, or more groups of halogen, OH, oxo, CF3, CHF2, and CH2F, or 1, 2, or more substituents selected from the group consisting of OR 1.1 , C 1- 3-alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 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 , C1-3 -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 , 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 1.1 and NR 1.2 R 1.3 substituted, which substituents can in turn be independently optionally substituted with 1, 2 or more substituents selected from OH, OR 1.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- alkyl, C 6-20- aryl and NR 1.2 R 1.3 ;

[0101] heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

[0102] Heteroaryl is a 5-10 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 heteroarylbiphenyl, 5-membered heteroarylheteroaryl, 5-membered heteroarylbicyclic C

[0103] R 1.1 is H or is selected from C 1-6- alkyl, C 1-6- alkyl alcohol, C 1-3 -haloalkyl, C 3-11 -monocyclic or bicyclic heterocyclyl, -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 heterocyclyl-C 1-6 -alkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl, C 3-10 -cycloalkenyl-C 1-6 -alkyl, monocyclic or bicyclic C 6-20- aryl, 5-20 membered heteroaryl and heterocyclyl, which can optionally be substituted with a group selected from OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 6-20- aryl;

[0104] R 1.2 and R 1.3 independently of one another represent H or are selected from C 1-6- alkyl, monocyclic or bicyclic C 3-10- cycloalkyl, monocyclic or bicyclic C 3-10- cycloalkenyl, C 6-20- aryl-C 1-6 -alkyl, 5-20 membered heteroaryl-C 1-6 alkylene, monocyclic 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 1.1 and COOR1.1 groups, which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- -aryl and COOR 1.1 groups.

[0105] According to embodiments of the present disclosure, the compound of formula II has the following definition:

[0106] wherein:

[0107] X1represents a bond, C 1-20 alkylene, O, S, NR q , S(=0), S(=0)2or C(=0);

[0108] X2represents a bond, C 1-20 alkylene, S(=0), S(=0)2or C(=0);

[0109] X3represents a bond, C 1-20 alkylene, O, S, NR q , S(=0), S(=0)2or C(=0);

[0110] U represents -(CH2) t -, O, S, NR q , S(=0), S(=0)2or C(=0), wherein t represents 0, 1, 2 or 3;

[0111] 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- 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, C6-20 Arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclic thio, C 1-8 -hexaalkylene 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 );

[0112] v represents 0, 1, 2, 3, 4 or 5;

[0113] R a Represents H or -X-R3;

[0114] X represents CH2, O, S, NH, -S(O)-, -S(O)2- or -C(O)-;

[0115] R3 represents H, halogen, OH, CN, -CH2CF3, -NHR d4 No substitution or optional use by 1, 2 or more R d4 The following groups are substituted: C 1-20 Alkyl, -C(O)R 61 -C(O)OR 62 -OC(O)R 63 NH2;

[0116] R b Represents H or -Y-R4;

[0117] Y represents CH2, O, S, NH, -S(O)-, -S(O)2- or -C(O)-;

[0118] R4 represents H, halogen, OH, CN, -CH2CF3, -NHR d4 No substitution or optional use by 1, 2 or more R d5 The following groups are substituted: C 1-20 Alkyl, -C(O)R 61 -C(O)OR 62 -OC(O)R 63 NH2;

[0119] The condition is R a R b Not both H;

[0120] or R a , R b together with the atom to which they are attached form the following groups, which are unsubstituted or optionally substituted by 1, 2 or more R d6 C 5-20 cycloalkenyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, 6-20 membered aryl;

[0121] each R d21 , R d22 , R d4 , R d5 , R d6 are the same or different, independently of each other, selected from the group consisting of H, halogen, OH, CN, NO2, oxo (=0), thioxo (=S), SO, SO2, the following groups, which are unsubstituted or optionally substituted by 1, 2 or more R e 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 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C 3-20 cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 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, 5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, 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 )2;

[0122] or, when there are two or more substituents selected from R d21 , R d22 , R d4 , R d5 , R d6 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, which is unsubstituted or optionally substituted by 1, 2 or more R e 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;

[0123] each R d21 , R d22 is the same or different, independently of one another, selected from the group consisting of H, halogen, OH, CN, NO2, oxo (=0), thioxo (=S), SO, SO2, a group selected from the following list, which is unsubstituted or optionally substituted by 1, 2 or more R e 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 31 , -CH2-C(O)R 31 , -C(O)OR 32 ;-CH2C(O)OR 32 -CH2C(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 );

[0124] or, when there are two or more substituents selected from R d21 , R d22 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, which is unsubstituted or optionally substituted by 1, 2 or more R e ; C 3-20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;

[0125] each R e is the same or different, independently of each other, selected from the group consisting of H, halogen, OH, CN, NO2, NH2, oxo (=O), thioxo (=S), O-CONH2, O-CONHR f , NRq-CONHR f , NRq-C(O)R f , NH R f which is unsubstituted or optionally substituted by 1, 2 or more R f ; 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 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C 3-20 cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C 1-20 alkylthio, C 2-20 alkenylthio, C2-20 alkynyl thioyl, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 Cycloalkynylthio, C 6-20 Arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclic thio, C 1-8 -hexaalkylene 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 );

[0126] 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;

[0127] 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 6-20aryloxy, 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 arylthio, 5- to 20-membered heteroarylthio, 3- to 20-membered heterocyclylthio, 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 );

[0128] 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 groups, which are optionally substituted by 1, 2 or more R g ; 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;

[0129] each R g is the same or different, independently of one another, selected from the group consisting of H, halogen, OH, CN, NO2, oxo (=O), 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- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl, NH2;

[0130] each R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 41 , R 42 , R43 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 R 1-20 R 2-20 R 2-20 R 3-20 R 3-20 R 3-20 R 6-20 R

[0131] L represents a bond, C 2-20 alkenyl, C 6-20 alkynyl, or Cy; wherein L can be attached to X1or the phenyl ring (for the same reason) at any position;

[0132] Cy represents a bond, 3-20 membered heterocyclyl, C 6-20 aryl, 5-20 membered heteroaryl, which can be optionally fused to a 4-12 membered cycloalkyl or cycloalkenyl, provided that when the heterocyclyl contains an N atom, the heterocyclyl can be bonded to the carbon atom at the 2-position of the pyrimidine ring in Formula II through its N atom or a C atom;

[0133] L represents alkynyl; 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 be optionally substituted at the ortho-, para- or meta-positions, each independently, with 1, 2 or more groups independently selected from fluoro, chloro, bromo, hydroxyl, CN, NH2, or 1, 2 or more groups selected from OR 2.1 , COOR 2.1 , CH2COOR 2.1 , CH2CH2COOR 2.1 , CH=CHCOOR 2.1 , CO-NR 2.1 , CH2CO-NR 2.1 , CH2CH2CO-NR2.1 CH=CHCO-NR 2.1 NR 2.2 R 2.3 CH2-NR 2.2 R 2.3 CH2CH2-NR 2.2 R 2.3 C 3-10 -cycloalkyl, C 3-10 -cycloalkenyl, 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, C 1- 3-alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 1.1 , 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 2.2 R 2.3 substituted with 1, 2 or more substituents selected from the group consisting of OH, OR 2.1 , CF3, CHF2, CH2F, oxo, halogen, CF3, CHF2, CH2F, C 1-6 -alkyl, C 6-10- aryl and NR 2.2 R 2.3 , or,

[0134] L represents a group selected from heterocyclyl or heteroaryl, each independently optionally substituted at the ortho, para or meta position with 1, 2 or more groups of halogen, OH, oxo, CF3, CHF2and CH2F, or with 1, 2 or more substituents selected from the group consisting of OR 2.1 , C 1- 3-alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 2.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR2.1 , C 1-3 -alkyl-OR 2.1 , SR 2.1 , C 1-3 -alkyl-SR 2.1 , SO-R 2.1 , C 1-3 -alkyl-SOR 2.1 , SO2-R 2.1 , C 1-3 -alkyl-SO2R 2.1 , COOR 2.1 , CH2COOR 2.1 , CH2CH2COOR 2.1 , CH=CHCOOR 2.1 , CO-NR 2.1 CH2CO-NR 2.1 , CH2CH2CO-NR 2.1 , CH=CHCO-NR 2.1 , COR 2.1 , CH2COR 2.1 , 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 2.1 and NR 2.2 R 2.3 substituted, which substituents can in turn be independently optionally substituted with 1, 2 or more substituents selected from OH, OR 2.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- alkyl, C 6-20- aryl and NR 2.2 R 2.3 ;

[0135] heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

[0136] 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, 6-membered heteroaryl-4-12-membered heterocycloalkenyl;

[0137] R 2.1 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;

[0138] R 2.2 and R 2.3 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 Alkylene, 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 2.1 and COOR 2.1groups, which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 2.1 substituted.

[0139] R1represents hydrogen, a mono- or polycyclic C 6-20 -aryl, which can optionally be substituted in the ortho, para or meta position, each independently by 1, 2 or more substituents selected from the group consisting of OH, halogen, CN, NO2, NH2, or by 1, 2 or more substituents selected from the group consisting of OR 2.1 , COOR 2.1 CH2COOR 2.1 , CH2CH2COOR 2.1 , CH=CHCOOR 2.1 , CO-NR 2.1 CH2CO-NR 2.1 , CH2CH2CO-NR 2.1 , CH=CHCO-NR 2.1 , NR 2.2 R 2.3 , CH2-NR 2.2 R 2.3 , CH2CH2-NR 2.2 R 2.3 , C 3-10 -cycloalkyl, 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, CF3, CHF2, CH2F, C 6-20- aryl-C 1-6 -alkyl, 3-20 membered heterocyclyl-C 1-6 -alkyl, 5-20 membered heteroaryl-C 1-6- alkyl, C 6-20- aryl, SO2-CH3, SO2-CH2CH3and SO2-NR 2.2 R 2.3 which can independently optionally be substituted by 1, 2 or more substituents selected from the group consisting of OH, OR 2.1 , CF3, CHF2, CH2F, oxo, halogen, CF3, CHF2, CH2F, C 1-6 -alkyl, C 6-20- aryl and NR 2.2 R 2.3 substituents;

[0140] R1represents a group selected from the group consisting of a heterocycle and a heteroaryl, which can be optionally substituted at the ortho-, para- or meta-positions, 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 2.1 , C 1-3 -alkyl-OR 2.1 , SR 2.1 , C 1-3 -alkyl-SR 2.1 , SO-R 2.1 , C 1-3 -alkyl-SOR 2.1 , SO2-R 2.1 , C 1-3 -alkyl-SO2R 2.1 , COOR 2.1 , CH2COOR 2.1 , CH2CH2COOR 2.1 , CH=CHCOOR 2.1 , CO-NR 2.1 CH2CO-NR 2.1 , CH2CH2CO-NR 2.1 , CH=CHCO-NR 2.1 , COR 2.1 , CH2COR 2.1 , 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), 3-20 membered heterocyclyl-C 6-20- aryl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl C 1-3 -alkyl-OR 2.1 and NR 2.2 R 2.3 , which in turn can be independently optionally substituted with 1, 2 or more substituents of OH, OR 2.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- alkyl, C 6-20- aryl and NR 2.2 R 2.3 ;

[0141] Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

[0142] Heteroaromatic ring is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

[0143] R 2.1 is H or is a radical selected from the group consisting of C 1-6- alkyl, C 1-6- alkenyl, 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, 3-20 membered heterocyclyl-C 1-6 -alkyl, C 3-10 cycloalkyl-C 1-6 -alkyl, mono- or bicyclic C 6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which can optionally be substituted by OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 6-20- aryl substituents,

[0144] R 2.2 and R 2.3 independently of one another represent H or a radical selected from the group consisting of C 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, 3-20 membered heterocyclyl, heteroaromatic ring, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 2.1 and COOR 2.1 which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 1.1 , R2 represents hydrogen, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4alkynyl, C 3-8cycloalkyl, 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, Si, OH, CN, NO2, NH2, oxo (=0), thioxo (=S), O-CONH2, O-CONHR q , NRq-CONHR f , NRq-C(O)R f , R f unsubstituted or optionally substituted by 1, 2 or more R f substituents: 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 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C 3-20 cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 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 arylthio, 5-20 membered heteroarylthio, 3-20 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 );

[0145] R2represents a mono- or polycyclic C 6-20- aryl, optionally substituted at each occurrence independently at the ortho-, para- or meta-position by 1, 2, or more substituents selected from the group consisting of halogen, hydroxy, CN, NO2, NH2, or by 1, 2, or more substituents selected from the group consisting of OR 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 , NR 1.2 R 1.3 , CH2-NR 1.2 R 1.3 , CH2CH2-NR 1.2 R 1.3 , C 3-10 - cycloalkyl, C 1-3 - alkyl-(mono- or polycyclic-C 6-20 - aryl), 3- to 20-membered heterocyclyl-C 6-20 - aryl, 3- to 20-membered heterocyclyl, C 1-6 - alkyl, C 1-3 - fluoroalkyl, CF3, CHF2, CH2F, C 6-20- aryl-C 1-6 - alkyl, 3- to 20-membered heterocyclyl-C 1-6 - alkyl, 5- to 20-membered heteroaryl-C 1-6- alkyl, C 6-20- aryl, SO2-CH3, SO2-CH2CH3and SO2-NR 1.2 R 1.3 , which can be independently optionally substituted with 1, 2, or more substituents selected from the group consisting of OH, OR 1.1 , CF3, CHF2, CH2F, oxo, halogen, CF3, CHF2, CH2F, C 1-6 - alkyl, C 6-20- aryl and NR 1.2 R 1.3 ;

[0146] Alternatively, R2represents a group selected from heterocyclyl and heteroaryl, which can be optionally substituted at each occurrence independently at the ortho-, para- or meta-position by 1, 2, or more groups selected from halogen, OH, oxo, CF3, CHF2and CH2F, or by 1, 2, or more substituents selected from the group consisting of OR 2.1 , C 1-3 - alkyl-OR 2.1 , SR 2.1 , C1-3 -alkyl-SR 2.1 ,SO-R 2.1 ,C 1-3 -alkyl-SOR 2.1 ,SO2-R 2.1 ,C 1-3 -alkyl-SO2R 2.1 ,COOR 2.1 ,CH2COOR 2.1 ,CH2CH2COOR 2.1 ,CH=CHCOOR 2.1 ,CO-NR 2.1 CH2CO-NR 2.1 ,CH2CH2CO-NR 2.1 ,CH=CHCO-NR 2.1 ,COR 2.1 ,CH2COR 2.1 ,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), 3-20 membered heterocyclyl-C 6-20- aryl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl C 1-3 -alkyl-OR 2.1 and NR 2.2 R 2.3 , which can be independently optionally substituted with 1, 2 or more substituents selected from the group consisting of OH, OR 2.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- alkyl, C 6-20- aryl and NR 2.2 R 2.3 ;

[0147] heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

[0148] heteroaryl ring is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

[0149] R 2.1 is H or is selected from C 1-6-alkyl, C 1-6- alkyl alcohol, C 1-3 haloalkyl, mono- or bicyclic, -C 3-10 cycloalkyl, 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, mono- or bicyclic C 6-20 aryl, 5- to 20-membered heteroaryl and heterocyclo, which can optionally be substituted by OH, O-(C 1-3 alkyl), halogen, C 1-10- alkyl and C 6-20- aryl substituents,

[0150] R 2.2 and R 2.3 independently of one another denote H or a group selected from C 1-6- alkyl, mono- or bicyclic C 3-10- cycloalkyl, C 6-20- aryl-C 1-6 alkyl, 5- to 20-membered heteroaryl-C 1-6- alkyl, mono- or bicyclic C 6-20- aryl, 3- to 20-membered heterocyclo, heteroarylo, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 alkyl), CO-R 2.1 and COOR 2.1 which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 alkyl, C 6-20- aryl and COOR 2.1 .

[0151] R3denotes H, C 1-6 alkyl, F, chlorine, bromine, hydroxyl, -CN, -CH2CN, -CH2COOR, -COOR, -CO-NH(CH3) C 1- 3-fluoroalkyl, (C 1-6 alkyl)-OH, (C 1-6 alkyl)-OCH3, (C 1-6 alkyl)-NH2, (C 1-6 alkyl)-N(C 1-3 alkyl) or (C 1-6 alkyl)-NH;

[0152] R 3’ denotes H, F, Me, C 1-6- alkyl, C2-6- alkenyl, C 2-6- alkynyl group, C 6-20- Aryl, C 6-20- Aryl-C 1-6 -alkyl, C 5-10 -heteroaryl-C 1-6 -alkyl, C 3-10 - Heterocyclic compounds and C 5-10 -heterocyclic group, -NR'R", fluorine, C 1-6- fluoroalkyl and C 1-6- Fluoroalkoxy, wherein R' and R" are independently selected from H and C. 1-6- Alkyl group; in each case, the group may optionally be selected from one, two or more groups selected from OH, oxo, halogen, C 1-6- Alkyl and OC 1-6- Alkyl groups.

[0153] Or, R3 and R 3’ Together they represent oxo, methylene, ethylene, and propylene, which may optionally be selected from -CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2 and O-(C 1-3 Substituents in (-alkyl);

[0154] R4 represents H and C. 1-6 -alkyl, F, chlorine, bromine, hydroxyl, -CN, -CH2CN, -CH2COOR, -COOR, -CO-NH(CH3)C 1- 3-Fluoroalkyl, (C 1-6 -alkyl)-OH, (C 1-6 -alkyl)-OCH3, (C 1-6 -alkyl)-NH2, (C 1-6 -alkyl)-N(C 1-3 -alkyl) or (C 1-6 -alkyl)-NH;

[0155] R 4’ Representing H, F, Me, C 1-6- Alkyl, C 2-6- alkenyl, C 2-6- alkynyl group, C 6-20- Aryl, C 6-20- Aryl-C 1-6 -alkyl, C 5-10 -heteroaryl-C 1-6 -alkyl, C 3-10 - Heterocyclic compounds and C 5-10 -heterocyclic group, -NR'R", fluorine, C 1-6- fluoroalkyl and C1-6- fluoroalkoxy, wherein R' and R" are independently selected from H and C 1-6- alkyl; which group is optionally in each case mono-, di- or poly-substituted by radicals selected from the group consisting of OH, oxo, halogen, C 1-6- alkyl and O-C 1-6- alkyl.

[0156] or R4 and R 4’ together represent oxo, methylene, ethene and propene, which can optionally be substituted by radicals selected from the group consisting of -CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2and O-(C 1-3- alkyl);

[0157] R5, R6independently represent H, F, C 1-6 -alkyl, C 1-3 -fluoroalkyl, C 1-6 -alkyl-OH, C 1-6 -alkenyl-OCH3, C 1-6 -alkyl-NH2, C 1-6 -alkynyl-NH(C 1-3 -alkyl) and C 1-6 -alkyl-N(C 1-3 -alkyl)2;

[0158] or R1 and R3 together form a saturated or partially saturated 5- or 7-membered heterocyclic radical containing 1, 2 or more nitrogen atoms, which can optionally be substituted by radicals selected from the group consisting of -CH3, -CH2CH3, -CH2CH2CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2and O-(C 1-3- alkyl),

[0159] or R3 and R6 together form a methylene, ethene and propene bridged ring, which can optionally be substituted by radicals selected from the group consisting of -CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2and O-(C 1-3 alkyl);

[0160] or R3 and R5 together form a methylene, ethene and propene bridged ring, which can optionally be substituted by radicals selected from the group consisting of -CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C1-3 -alkyl), -N(C 1-3 -alkyl)2and O-(C 1-3 alkyl) groups;

[0161] R3and R4together form a methylene, ethene and propene bridged ring, which can optionally be substituted with groups selected from -CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2and O-(C 1-3 alkyl) groups;

[0162] R4and R6together form a methylene, ethene and propene bridged ring, which can optionally be substituted with groups selected from -CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2and O-(C 1-3 alkyl) groups;

[0163] R3and R1together form a C 1-6 -alkyl, C 2-10 -alkenyl bridged ring, which can optionally be substituted with groups selected from -CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2and O-(C 1-3 alkyl) groups.

[0164] According to embodiments of the present disclosure, the compound of formula III has the following definition:

[0165] wherein

[0166] X1represents a bond, C 1-20 alkylene, O, S, NR q , S(=O), S(=O)2or C(=O);

[0167] U represents -(CH2) t -, O, S, NR q , S(=O), S(=O)2or C(=O), wherein t represents 0, 1, 2 or 3;

[0168] R q is selected from H, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-20 cycloalkyl, C 3-20Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 1-20 Alkyloxy, C 2-20 alkenyloxy group, C 2-20 alkynyloxy group, C 3-20 Cycloalkyloxy, C 3-20 Cycloalkenyloxy, C 3-20 Cycloalkynyloxy group, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, C 1-20 Alkyl thio, C 2-20 alkenyl thio, C 2-20 alkynyl thioyl, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 Cycloalkynylthio, C 6-20 Arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclic thio, C 1-8 -hexaalkylene 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 );

[0169] v represents 0, 1, 2, 3, 4 or 5;

[0170] R a Represents H or -X-R3;

[0171] X represents CH2, O, S, NH, -S(O)-, -S(O)2- or -C(O)-;

[0172] R3 represents H, halogen, OH, CN, -CH2CF3, -NHR d4 No substitution or optional use by 1, 2 or more R d4 The following groups are substituted: C 1-20 Alkyl, -C(O)R 61 -C(O)OR 62 -OC(O)R 63 NH2;

[0173] R brepresents H or -Y-R4;

[0174] Y represents CH2, O, S, NH, -S(O)-, -S(O)2- or -C(O)-;

[0175] R4represents H, halogen, OH, CN, -CH2CF3, -NHR d4 , unsubstituted or optionally substituted by 1, 2 or more R d5 substituents, C 1-20 alkyl, -C(O)R 61 , -C(O)OR 62 , -OC(O)R 63 , NH2;

[0176] with the proviso that R a , R b are not simultaneously H;

[0177] or, R a , R b together with the atom to which they are attached form unsubstituted or optionally substituted by 1, 2 or more R d6 substituents, C 5-20 cycloalkenyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, 6-20 membered aryl;

[0178] each R d21 , R d22 , R d4 , R d5 , R d6 are the same or different, independently of each other, selected from H, halogen, OH, CN, NO2, oxo (=O), thioxo (=S), SO, SO2, unsubstituted or optionally substituted by 1, 2 or more R e substituents, 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 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C 3-20 cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C 1-20 alkylthio, C2-20 alkenylthio, C 2-20 alkynylthio, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 cycloalkynylthio, C 6-20 arylthio, 5- to 20-membered heteroarylthio, 3- to 20-membered heterocyclylthio, 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 );

[0179] or, when there are two or more substituents selected from R d21 , R d22 , R d4 , R d5 , R d6 on the same group, said two substituents can form, together with the atom(s) to which they are attached, the following groups, which are unsubstituted or optionally substituted by 1, 2 or more R e 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;

[0180] each R d21 , R d22 is the same or different, independently of each other, selected from the group consisting of H, halogen, OH, CN, NO2, oxo (=O), thioxo (=S), SO, SO2, the following groups, which are unsubstituted or optionally substituted by 1, 2 or more R e 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, C2-20 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 );

[0181] 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;

[0182] Each R e They may be the same or different, and are independently selected from H, halogens, OH, CN, NO2, NH2, oxo (=O), thio (=S), O-CONH2, O-CONHR f NRq-CONHR f NRq-C(O)R f NH R f No substitution or optional use by 1, 2 or more R f The following groups are substituted: C 1-20Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3- 20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, C 1-20 Alkyloxy, C 2-20 alkenyloxy group, C 2-20 alkynyloxy group, C 3-20 Cycloalkyloxy, C 3-20 Cycloalkenyloxy, C 3-20 Cycloalkynyloxy group, C 6-20 aryloxy group, 5-20 membered heteroaryloxy group, 3-20 membered heterocyclic oxy group, C 1-20 Alkyl thio, C 2-20 alkenyl thio, C 2-20 alkynyl thioyl, C 3-20 cycloalkylthio, C 3-20 cycloalkenylthio, C 3-20 Cycloalkynylthio, C 6-20 Arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclic thio, C 1-8 -hexaalkylene 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 );

[0183] 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;

[0184] Each R fidentically or differently, independently of one another, selected from H, halogen, OH, CN, N02, oxo (=0), thioxo (=S), unsubstituted or optionally substituted by 1, 2 or more R g substituted 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 arylthio, 5- to 20-membered heteroarylthio, 3- to 20-membered heterocyclylthio, NH2, -C(0)R 51 , -C(0)OR 52 , -OC(0)R 53 , -S(0)2R 54 , -S(0)2OR 55 , -OS(0)2R 56 , -P(0)(OR 57 )(OR 58 );

[0185] 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, the following groups, which are unsubstituted or optionally substituted by 1, 2 or more R g substituted 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;

[0186] each R gthe same or different, independently of one another, are 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- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl, NH2;

[0187] 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 the same or different, independently of one another, are 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- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl, NH2;

[0188] L represents a bond, C 2-20 alkynyl or Cy; wherein L can be attached to X1or the phenyl ring (same above) at any position;

[0189] Cy represents a bond, 3- to 20-membered heterocyclyl, C 6-20 aryl, 5- to 20-membered heteroaryl, wherein the 3- to 20-membered heterocyclyl, C 6-20The aryl, 5-20 membered heteroaryl can optionally be fused with a 4-12 membered cycloalkyl or 4-12 membered cycloalkenyl, provided that when the heterocyclyl contains an N atom, the heterocyclyl can be bonded through its N atom or C atom to the carbon atom at the 2-position of the pyrimidine ring in Formula III;

[0190] L represents alkynyl; 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 be independently at the ortho, para or meta position optionally substituted with 1, 2 or more groups independently selected from fluoro, chloro, bromo, hydroxy, CN, NH2, or 1, 2 or more groups selected from OR 3.1 , COOR 3.1 , CH2COOR 3.1 , CH2CH2COOR 3.1 , CH=CHCOOR 3.1 , CO-NR 3.1 , CH2CO-NR 3.1 , CH2CH2CO-NR 3.1 , CH=CHCO-NR 3.1 , NR 3.2 R 3.3 , CH2-NR 3.2 R 3.3 , CH2CH2-NR 3.2 R 3.3 , 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, C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 1.1 , 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 3.2 R3.3 substituted with 1, 2 or more groups selected from OH, OR 3.1 , CF3, CHF2, CH2F, oxo, halogen, CF3, CHF2, CH2F, C 1-6 -alkyl, C 6-10- -aryl and NR 3.2 R 3.3 , or,

[0191] L represents a group selected from heterocycle or heteroaryl, which is in ortho, para or meta position each independently optionally substituted with 1, 2 or more groups of halogen, OH, oxo, CF3, CHF2and CH2F, or with 1, 2 or more groups selected from OR 3.1 , C 1- 3-alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 3.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 3.1 , C 1-3 -alkyl-OR 3.1 , SR 3.1 , C 1-3 -alkyl-SR 3.1 , SO-R 3.1 , C 1-3 -alkyl-SOR 3.1 , SO2-R 3.1 , C 1-3 -alkyl-SO2R 3.1 , COOR 3.1 , CH2COOR 3.1 , CH2CH2COOR 3.1 , CH=CHCOOR 3.1 , CO-NR 3.1 CH2CO-NR 3.1 , CH2CH2CO-NR 3.1 , CH=CHCO-NR 3.1 , COR 3.1 , CH2COR 3.1 , 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, 5-20 membered heteroaryl C 6-20- aryl, 3-10 membered heterocyclyl, 5-20 membered heteroaryl C 1-3 -alkyl-OR 3.1 and NR 3.2 R 3.3 substituted with 1, 2, or more substituents independently selected from OH, OR 3.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- alkyl, C 6-20- aryl, and NR 3.2 R 3.3 ;

[0192] heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring comprising 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O;

[0193] heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl 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 heteroarylbiphenyl, 5 membered heteroarylbis-5-10 membered heteroaryl, 5 membered heteroarylbis-4-12 membered cycloalkyl, 5 membered heteroarylbis-4-12 membered heterocycloalkyl, 6 membered heteroarylbiphenyl, 6 membered heteroarylbis-5-10 membered heteroaryl, 6 membered heteroarylbis-6 membered heteroaryl, 6 membered heteroarylbis-4-12 membered cycloalkyl, 6 membered heteroarylbis-4-12 membered heterocycloalkyl;

[0194] R 3.1 is H or is selected from C 1-6- alkyl, C 1-6- alkyl alcohol, C 1-3 -haloalkyl, C 3-11 -monocyclic or bicyclic heterocyclyl, -C 3-10 -cycloalkyl, C 6-20- aryl-C 1-6 -alkyl, 5-20 membered heteroaryl-C 1-6 -alkyl, 3-10 membered heterocyclyl-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 optionally substituted with a group selected from OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl, and C 6-20- aryl;

[0195] R 3.2 and R 3.3 independently of one another represent H or are selected from C1-6- Alkyl, mono- or bicyclic C 3-10- cycloalkyl, 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 heterocyclic group, heteroaryl group, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 3.1 and COOR 3.1 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 COOR 3.1 replace.

[0196] R1 represents hydrogen, a mono- or polycyclic carbon atom. 6-20 -Aryl group, which may be independently and optionally substituted at the ortho, para, or meta positions with one, two, or more substituents of halogen, hydroxyl, CN, NO2, or NH2, or with one, two, or more substituents selected from OR 3.1 COOR 3.1 CH2COOR 3.1 CH2CH2COOR 3.1 CH = CHCOOR 3.1 CO-NR 3.1 CH2CO-NR 3.1 ,CH2CH2CO-NR 3.1 ,CH=CHCO-NR 3.1 ,NR 3.2 R 3.3 CH2-NR 3.2 R 3.3 ,CH2CH2-NR 3.2 R 3.3 C 3-10 -cycloalkyl, C 1-3 -alkyl-(monocyclic or polycyclic-C) 6-20 -aryl), 3-20 membered heterocyclic-C 6-20 -Aryl, 3-20 membered heterocyclic group, C 1-6 -alkyl, C 1-3 -Fluoroalkyl, CF3, CHF2, CH2F, C 6-20- Aryl-C 1-6 -alkyl, 3-20 membered heterocyclic -C 1-6 -alkyl, 5-20-membered heteroaryl-C 1-6- Alkyl, C 6-20-aryl, SO2-CH3, SO2-CH2CH3, and SO2-NR 3.2 R 3.3 which can be independently optionally substituted with 1, 2, or more substituents selected from the group consisting of OH, OR 3.1 , CF3, CHF2, CH2F, oxo, halogen, C 1-6 -alkyl, C 6-20- -aryl, and NR 3.2 R 3.3 ;

[0197] Alternatively, R1represents C 1-10 -alkyl, C 3-10 -cycloalkyl, C 1-3 -methylene-C 3-10 -cycloalkyl, C 1-3 -methylene-C 2-6 -alkenyl, C 1- 3-methylene-C 5-10 -cycloalkenyl, C 1-3 -methylene-C 5-10 -heterocycloalkenyl, optionally substituted with 1, 2, or more substituents selected from the group consisting of halogen, hydroxyl, CN, NO2, NH2, CF3, or with 1, 2, or more substituents selected from the group consisting of OR 3.1 , COOR 3.1 CH2COOR 3.1 , CH2CH2COOR 3.1 , CH=CHCOOR 3.1 , CO-NR 3.1 CH2CO-NR 3.1 , CH2CH2CO-NR 3.1 , CH=CHCO-NR 3.1 , NR 3.2 R 3.3 , CH2-NR 3.2 R 3.3 , CH2CH2-NR 3.2 R 3.3 , C 3-10 -cycloalkyl, 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, CF3, CHF2, CH2F, C 6-20- -aryl-C 1- 6-alkyl, 3-20 membered heterocyclyl-C 1-6 -alkyl, 5-20 membered heteroaryl-C 1-6- alkyl, C6-20- aryl, SO2-CH3, SO2-CH2CH3, and SO2-NR 3.2 R 3.3 which can be independently optionally substituted with 1, 2, or more groups selected from OH, OR 3.1 , CF3, CHF2, CH2F, oxo, halogen, C 1-6 -alkyl, C 6-20- aryl, and NR 3.2 R 3.3 ;

[0198] Alternatively, R1represents a group selected from 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, CHF2, and CH2F, or with 1, 2, or more groups selected from OR 3.1 , C 1-3 -alkyl-OR 3.1 , SR 3.1 , C 1-3 -alkyl-SR 3.1 , SO-R 3.1 , C 1-3 -alkyl-SOR 3.1 , SO2-R 3.1 , C 1-3 -alkyl-SO2R 3.1 , COOR 3.1 , CH2COOR 3.1 , CH2CH2COOR 3.1 , CH=CHCOOR 3.1 , CO-NR 3.1 CH2CO-NR 3.1 , CH2CH2CO-NR 3.1 , CH=CHCO-NR 3.1 , COR 3.1 , CH2COR 3.1 , 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), 3-20 membered heterocyclyl-C 6-20- aryl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl C 1-3 -alkyl-OR3.1 and NR 3.2 R 3.3 , which can be independently optionally substituted with OH, OR 3.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- alkyl, C 6-20- aryl and NR 3.2 R 3.3 , 1, 2 or more substituents;

[0199] heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

[0200] heteroaryl ring is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

[0201] R 3.1 is H or is selected from C 1-6- alkyl, C 1-6- alkyl alcohol, 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, 3-20 membered heterocyclo-C 1-6 -alkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl, mono or bicyclic C 6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which can be optionally substituted with OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 6-20- aryl substituents,

[0202] R 3.2 and R 3.3 independently of one another represent H or are selected from C 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, 3-20 membered heterocyclo, heteroarylo, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 3.1 and COOR 3.1groups, which can optionally be substituted with 1, 2 or more substituents selected from the group consisting of OH, OR 1-6 -alkyl, C 6-20- -aryl, and COOR 3.1 ,

[0203] R2represents hydrogen, a mono- or polycyclic C 6-20 -aryl, optionally substituted at each of the ortho, para or meta positions independently of one another with 1, 2 or more substituents selected from the group consisting of halogen, hydroxy, CN, NO2, NH2, or with 1, 2 or more substituents selected from the group consisting of OR 3.1 , COOR 3.1 CH2COOR 3.1 , CH2CH2COOR 3.1 , CH=CHCOOR 3.1 , CO-NR 3.1 CH2CO-NR 3.1 , CH2CH2CO-NR 3.1 , CH=CHCO-NR 3.1 , NR 3.2 R 3.3 , CH2-NR 3.2 R 3.3 , CH2CH2-NR 3.2 R 3.3 , C 3-10 -cycloalkyl, C 1-3 -alkyl-(mono- or polycyclic-C 6-20 -aryl), 3- to 20-membered heterocyclyl-C 6-20 -aryl, 3- to 20-membered heterocyclyl, C 1-6 -alkyl, C 1-3 -fluoroalkyl, CF3, CHF2, CH2F, C 6-20- -aryl-C 1-6 -alkyl, 3- to 20-membered heterocyclyl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6- alkyl, C 6-20- -aryl, SO2-CH3, SO2-CH2CH3and SO2-NR 3.2 R 3.3 which can be independently optionally substituted with 1, 2 or more substituents selected from the group consisting of OH, OR 3.1 , CF3, CHF2, CH2F, oxo, halogen, C 1-6 -alkyl, C 6-20- -aryl, and NR 3.2 R 3.3 ;

[0204] Alternatively, R2represents C 1-10 -alkyl, C 3-10 -cycloalkyl, C1-3 Methylene-C 3-10 -Cycloalkyl, C 1-3 Methylene-C 2-6 -Alkenyl, C 1- 3-methylene-C 5-10 -cycloalkenyl, C 1-3 Methylene-C 5-10 - Heterocyclic alkenyl group, which may be substituted by one, two or more halogen, hydroxyl, CN, NO2, NH2, CF3 substituents, or by one, two or more substituents selected from OR 3.1 COOR 3.1 CH2COOR 3.1 CH2CH2COOR 3.1 CH = CHCOOR 3.1 CO-NR 3.1 CH2CO-NR 3.1 ,CH2CH2CO-NR 3.1 ,CH=CHCO-NR 3.1 ,NR 3.2 R 3.3 CH2-NR 3.2 R 3.3 ,CH2CH2-NR 3.2 R 3.3 C 3-10 -cycloalkyl, C 1-3 -alkyl-(monocyclic or polycyclic-C) 6-20 -aryl), 3-20 membered heterocyclic-C 6-20 -Aryl, 3-20 membered heterocyclic group, C 1-6 -alkyl, C 1-3 -Fluoroalkyl, CF3, CHF2, CH2F, C 6-20- Aryl-C 1- 6-alkyl, 3-20 membered heterocyclic -C 1-6 -alkyl, 5-20-membered heteroaryl-C 1-6- Alkyl, C 6-20- Aryl, SO2-CH3, SO2-CH2CH3 and SO2-NR 3.2 R 3.3 It can be independently and optionally selected by one, two or more from OH, OR 3.1 CF3, CHF2, CH2F, oxidized, halogenated, C 1-6 -alkyl, C 6-20- Aryl and NR 3.2 R 3.3 The substituents in it are replaced;

[0205] Alternatively, R2 represents a group selected from heterocyclic and heteroaryl groups, which may optionally be independently substituted at the ortho, para, or meta positions by one, two, or more halogen, OH, oxo, CF3, CHF2, and CH2F groups, or by one, two, or more groups selected from OR. 3.1 C 1-3 -alkyl-OR 3.1 SR 3.1 C 1-3 -alkyl-SR 3.1 SO-R 3.1 C 1-3 -alkyl-SOR 3.1 SO2-R 3.1 C 1-3 -alkyl-SO2R 3.1 COOR 3.1 CH2COOR 3.1 CH2CH2COOR 3.1 CH = CHCOOR 3.1 CO-NR 3.1 CH2CO-NR 3.1 ,CH2CH2CO-NR 3.1 ,CH=CHCO-NR 3.1 ,COR 3.1 CH2COR 3.1 C 1-6 -alkyl alcohols, 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-(monocyclic or polycyclic-C) 6-20- Aryl), 3-20 membered heterocyclic group -C 6-20- Aryl, 3-20 membered heterocyclic, 5-20 membered heteroaryl C 1-3 -alkyl-OR 3.1 and NR 3.2 R 3.3 It can also be independently and arbitrarily converted by OH and OR. 3.1 Oxide, halogen, CF3, CHF2, CH2F, C 1-6- Alkyl, C 6-20- Aryl and NR 3.2 R 3.3 One, two or more substituents are substituted;

[0206] Heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

[0207] Heteroaromatic ring is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O;

[0208] R 3.1 is H or is a group selected from C 1-6- alkyl, C 1-6- alkyl alcohol, 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, 3-20 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 heterocycle, which can optionally be substituted by OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 6-20- aryl substituents,

[0209] R 3.2 and R 3.3 independently of one another represent H or a group selected from C 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, 3-20 membered heterocyclic, heteroaromatic, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 3.1 and COOR 3.1 which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 3.1 ,

[0210] R5represents H, F, chlorine, bromine, hydroxyl, -CN, -CH2CN, -CH2COOR 3.1 , -COOR 3.1 , -CO-NH(CH3)C 1- 3-fluoroalkyl, -(C1-6 -alkyl)-OCH3, -(C 1-6 -alkyl)-S(=O)2-(C 1-6 -alkyl), -S(=O)2-(C 1-6 -alkyl), -(C 1-6 -alkyl)-NH2, -(C 1-6 -alkyl)-N(C 1-3 -alkyl) or (C 1-6 -alkyl)-NH,

[0211] R5represents C 1-10 -alkyl, C 3-10 -cycloalkyl, C 1-3 -methylene-C 3-10 -cycloalkyl, C 1-3 -methylene-C 2-6 -alkenyl, C 1-3 -methylene-C 5-10 -cycloalkenyl, C 1-3 -methylene-C 5-10 -heterocycloalkenyl, optionally substituted with 1, 2 or more halogen, hydroxy, CN, NO2, NH2, CF3, C 1-3 -alkyl-SO2-CH3, C 1-3 -alkyl-SO2-CH2CH3and C 1-3 -alkyl-SO2-NR 3.2 R 3.3 substituted with 1, 2 or more substituents selected from the group consisting of OR 3.1 , COOR 3.1 CH2COOR 3.1 , CH2CH2COOR 3.1 , CH=CHCOOR 3.1 , CO-NR 3.1 CH2CO-NR 3.1 , CH2CH2CO-NR 3.1 , CH=CHCO-NR 3.1 , NR 3.2 R 3.3 , CH2-NR 3.2 R 3.3 , CH2CH2-NR 3.2 R 3.3 , C 3-10 -cycloalkyl, 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 1-3fluoroalkyl, CF3, CHF2, CH2F, C 6-20- aryl-C 1-6 alkyl, 3-20 membered heterocyclo-C 1-6 alkyl, 5-20 membered heteroaryl-C 1-6- alkyl and C 6-20- aryl, which can be independently optionally substituted with 1, 2 or more substituents selected from the group consisting of OH, OR 3.1 , CF3, CHF2, CH2F, oxo, halogen, C 1-6 -alkyl, C 6-20- aryl and NR 3.2 R 3.3 in the substituents;

[0212] R 5’ denotes H, F, Me, C 1-6- alkyl, C 2-6- alkenyl, C 2-6- alkynyl, C 6-20- aryl, C 6-20- aryl-C 1-6 -alkyl, C 5-10 -heteroaryl-C 1-6 -alkyl, C 3-10 -heterocyclo and C 5-10 -heterocyclyl, -NR'R", fluoro, C 1-6- fluoroalkyl and C 1-6- fluoroalkoxy, wherein R' and R" are independently selected from H and C 1-6- alkyl; which groups can in each case optionally be substituted with 1, 2 or more substituents selected from OH, oxo, halogen, C 1-6- alkyl and O-C 1-6- alkyl.

[0213] or R5and R 5’ together denote oxo, methylene, ethene and propene, which can optionally be substituted with substituents selected from -CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2and O-(C 1-3 -alkyl);

[0214] R 3.1 is H or is selected from C 1-6- alkyl, C 1-6- alkyl alcohol, 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, 3-20 membered heterocyclo-C 1-6 - alkyl, C 3-10 - cycloalkyl-C 1-6 - alkyl, mono- or bicyclic C 6-20 - aryl, 5-20 membered heteroaryl and heterocyclo, which can be optionally substituted with OH, O-(C 1-3 - alkyl), halogen, C 1-10- - alkyl and C 6-20- - aryl substituents,

[0215] R 3.2 and R 3.3 independently of one another denote H or a group selected from C 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, 3-20 membered heterocyclo, heteroarylo, CO-NH2, CO-NH - - CH3, -CO-N(CH3)2, SO2-(C 1-3 - alkyl), CO-R 3.1 and COOR 3.1 which can be optionally substituted with 1, 2 or more OH, halogen, C 1-6 - alkyl, C 6-20- - aryl and COOR 3.1 .

[0216] According to embodiments of the present disclosure, when a substituent is described as a ring structure, the ring described is to be understood as encompassing saturated or unsaturated structures, unless otherwise specified. For example, monocyclic or bicyclic is to be understood as encompassing saturated or unsaturated monocyclic or bicyclic groups. As another example, heterocyclo is to be understood as encompassing saturated heterocyclo (also referred to as heterocycloalkyl) and unsaturated heterocyclo.

[0217] According to embodiments of the present disclosure, the compounds of formula H can be selected from the following compounds (numbering omits the prefix MX):

[0218] According to alternative embodiments of the present disclosure, the compound represented by Formula H does not include the following compounds:

[0219] According to embodiments of the present disclosure, the compound represented by Formula H, a racemate, stereoisomer, tautomer, isotopically-labeled, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug thereof has at least superior inhibitory activity against PDE4.

[0220] According to embodiments of the present disclosure, the compound represented by Formula I, II, III, a racemate, stereoisomer, tautomer, isotopically-labeled, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug thereof can have inhibitory activity against PDE4 and also inhibitory activity against at least one (e.g., 1, 2, 3, or 4) selected from PDE1, PDE2, PDE3, and PDE5.

[0221] According to embodiments of the present disclosure, the compound represented by Formula I, a racemate, stereoisomer, tautomer, isotopically-labeled, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug thereof can have inhibitory activity against PDE4 and also inhibitory activity against at least PDE3.

[0222] According to embodiments of the present disclosure, the compound represented by Formula II, a racemate, stereoisomer, tautomer, isotopically-labeled, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug thereof can have inhibitory activity against PDE4 and also inhibitory activity against at least PDE5.

[0223] According to embodiments of the present disclosure, the compound represented by Formula III, a racemate, stereoisomer, tautomer, isotopically-labeled, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug thereof can have inhibitory activity against PDE4 and also inhibitory activity against at least PDE1 and PDE2.

[0224] The present disclosure also provides a method of preparing a compound represented by Formula H, 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 A with a compound of Formula B to obtain a compound of Formula H:

[0225] wherein LG is a leaving group, for example, Cl, Br, or I;

[0226] X1, X2, U, v, R a , R bR c R d21 R d22 R c R h L independently of one another have the definitions indicated above.

[0227] According to embodiments of the present disclosure, the reaction can be carried out, if necessary, with a protecting group provided on the compound of Formula A, the compound of Formula B. For example, the protecting group can be selected from an amino protecting group, a hydroxyl protecting group, 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.

[0228] According to embodiments of the present disclosure, the preparation method can be carried out in the presence of a solvent, such as an organic solvent. For example, the organic solvent can be selected from at least one of the following: alcohols, such as methanol, ethanol, isopropanol, n-butanol; ethers, such as ethyl propyl ether, n-butyl ether, anisole, 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.

[0229] The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds represented by Formula H (e.g., any one of the compounds represented by Formulas I to III), a racemate, a stereoisomer, a tautomer, an isotopically-labeled, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof.

[0230] According to embodiments of the present disclosure, the pharmaceutical composition can further include one or more pharmaceutically acceptable excipients.

[0231] According to embodiments of the present disclosure, the pharmaceutical composition can further include one or more additional therapeutic agents.

[0232] The present disclosure also provides use of at least one of the compounds of Formula H (e.g., any one of the compounds of Formulae I-III), racemates, stereoisomers, tautomers, isotopically-labeled, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds thereof, in the manufacture of a medicament.

[0233] The medicament can be used for preventing or treating a disease mediated at least by PDE4.

[0234] For example, the disease mediated at least by PDE4 is selected from a disease mediated by PDE4, or a disease mediated by at least one (e.g., 1, 2, 3, or 4) of PDE1, PDE2, PDE3, and PDE5.

[0235] For example, the medicament can be used for preventing or treating a disease mediated by PDE4 and at least one (e.g., 1, 2, 3, or 4) of PDE1, PDE2, PDE3, and PDE5.

[0236] According to embodiments of the present disclosure, the PDE4 is selected from PDE4A, PDE4B (e.g., PDE4B2), PDE4C, and PDE4D (e.g., PDE4D2).

[0237] According to embodiments of the present disclosure, the PDE1 is selected from PDE1A, PDE1B, and PDE1C.

[0238] According to embodiments of the present disclosure, the PDE2 is selected from PDE2A.

[0239] According to embodiments of the present disclosure, the PDE3 is selected from PDE3A and PDE3B.

[0240] According to embodiments of the present disclosure, the PDE5 is selected from PDE5A.

[0241] The present disclosure also provides a method for preventing or treating a disease mediated at least by PDE4, comprising administering to a patient in need thereof at least one of the compounds of Formula H (e.g., any one of the compounds of Formulae I-III), racemates, stereoisomers, tautomers, isotopically-labeled, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds thereof.

[0242] According to embodiments of the present disclosure, the disease mediated at least by PDE4 is selected from a disease mediated by PDE4 or a disease mediated by PDE4 and at least one (e.g., 1, 2, 3, or 4) of PDE1, PDE2, PDE3, and PDE5.

[0243] According to embodiments of the application, the disease includes, but is not limited to, a disease of the respiratory tract, inflammatory bowel disease, arthritic disease, skin inflammatory disease, eye inflammatory disease, disease of the peripheral or central nervous system, degenerative disorder 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 and Coronary Artery Disease or cancer.

[0244] According to embodiments of the application, the cancer includes, 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.

[0245] As pharmaceuticals, the compounds of the disclosure can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner widely known in the art of pharmaceuticals, 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., by 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. Parenteral administration can be by single doses or by continuous infusion pumps, e.g., continuous perfusion pumps. 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.

[0246] In making the compositions of the 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 serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or 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.

[0247] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, 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 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

[0248] The compositions can be formulated in unit dosage form for ease of administration and uniformity of dosage. Each unit dosage will contain dosages of from about 5 to 1000 mg, more usually about 100 to 500 mg, of active ingredient. The term "unit dosage form" refers to physically discrete units suitable for single administration of a predetermined dosage of an active ingredient which is calculated to produce the desired therapeutic effect.

[0249] The amount of active compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered; the age, weight, and response of the individual patient; the severity of the patient's symptoms; and the like.

[0250] 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 uniformly in the composition so that the composition can be subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0251] 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 phase, as in galenical dosage form with which the administration of the active ingredient is prolonged. For example, a tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in turn compressed, enteric-coated, or otherwise compounded. The inner dosage component can contain a quantity of active ingredient, while the outer component can contain a quantity of inactive ingredient. The inner and outer components can both contain active ingredients. A tablet or pill can also comprise an agent for delaying release of the active ingredient, or an agent for decreasing the bioavailability of the active ingredient when it comes in contact with the stomach fluid, or a combination of both.

[0252] Liquid forms in which a compound and composition of the present disclosure can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, 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.

[0253] Compositions intended for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and must be administered as a solution or a suspension. The liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described above. In certain embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. The compositions can be nebulized and delivered with an inert carrier gas from a nebulizer or a face mask or tracheal intubation. Compositions can be administered by inhalation or insufflation, to the lungs or nasal membranes by nebulization with an aerosolizer or insufflator.

[0254] The amount of a compound or composition administered to a patient will vary depending upon the pharmaceutical administered, the purpose for administration, e.g., prophylactic or therapeutic; the state of the patient, the mode of administration, etc. In therapeutic applications, an amount adequate to treat or at least partially arrest symptoms of disease and its complications can be administered to a patient already suffering from the disease. Effective dosages should be decided in accordance with the disease state, age, and weight of the patient, and the judgment of the attending physician, taking into account factors like severity of the disease, the stage of the disease, and the general state of the patient, etc.

[0255] The compositions administered to a patient can be in the form of the above-described pharmaceutical compositions. These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered. Aqueous solutions can be packaged in unit-dose or multi-dose containers, or freeze-dried. The compositions can be formulated to be immediate or modified release. The pH of the compound preparations is generally between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It is understood, that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0256] Therapeutic dosages of the compounds of the present disclosure can vary according to, for example, the particular use for which the compound is employed, the manner of administration, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present disclosure in a pharmaceutical composition can not be fixed, but can vary with a variety of factors, including the dosage, chemical properties (e.g., hydrophobicity) and the route of administration. For example, a compound of the present disclosure can be provided in an aqueous physiological buffer solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosages range from about 1 μg / kg to about 1 g / kg body weight per day. In certain embodiments, the dosage ranges from about 0.01 mg / kg to about 100 mg / kg body weight per day. The dosage will likely depend on such variables as the type and extent of progression of the disease or disorder, the general health and age of the patient, the relative biological efficacy of the compound selected, the formulation of the excipient, and the route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. Beneficial Effects

[0257] Without wishing to be bound by theory, the inventors have found that the compounds of the present disclosure, due to their superior PDE4 inhibitory activity, or further superior inhibitory activity against other PDE subfamilies (e.g. PDE1, PDE2, PDE3 and / or PDE5), will be helpful in developing single- or multi-specific targeted drugs for different patient populations, which will be particularly advantageous for improving therapeutic efficacy and / or reducing side effects, improving patient compliance and quality of life. For example, the compounds can be used for the prevention or treatment of respiratory inflammatory diseases, inflammatory bowel diseases, arthritic diseases, skin inflammatory diseases, eye 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 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 and Coronary Artery Disease or cancer.

[0258] Definitions and explanations of terms

[0259] Unless otherwise indicated, the definitions of groups and terms recited in the specification and claims hereof, including definitions of terms incorporated by reference, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, etc., can be combined and / or combined with each other in any manner. The group definitions and compound structures after such combinations and combinations should be understood to be within the scope recited in the specification and / or claims.

[0260] Unless otherwise indicated, the numerical values in the description and the claims are to be understood as approximations, such that the numerical values are understood to be at least the recited, specific integer value. For example, the numerical range "1-20" is understood to include every integer value between and including 1 and 20, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. Furthermore, when certain numerical ranges are described as "a number," it is understood that the two endpoints of that range, every integer within that range, and every fraction within that range are recited. For example, "a number from 0 to 10" is understood to recite not only every integer from 0 to 10, but also every fraction of those integers, such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and so on.

[0261] It is to be understood that when referring to 1, 2, or more in the description herein, "more" is to be understood as meaning greater than 2, such as an integer of 3 or more, for example 3, 4, 5, 6, 7, 8, 9, or 10.

[0262] The term "halogen" denotes fluorine, chlorine, bromine, and iodine.

[0263] The term "C 1-20 "alkyl" is to be understood as preferably denoting a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, preferably "C 1-10 "alkyl" denotes a straight-chain and branched alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, preferably "C 1-6 "alkyl" denotes a straight-chain and branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, and the like or isomers thereof.

[0264] The term "C 2-20 "alkenyl" is to be understood as preferably denoting a straight-chain or branched monovalent 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" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one, two or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., C...). 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C24, C34, C4 ... 2-3 Alkenyl). It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pentyl-1-enyl, (Z)-pentyl-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl 2-Methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0265] Term "C" 2-20 "Alkyne group" should be understood as representing a straight-chain or branched monovalent hydrocarbon group containing one, two, or more triple bonds and having 2 to 20 carbon atoms, preferably "C". 2-10 "Alkyne group". The term "C" 2-10 "Alkyne" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one, two or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., "C"). 2-6 The alkynyl group ("C") has 2 or 3 carbon atoms ("C") 2-3alkynyl 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.

[0266] The term "C 3-20 Cycloalkyl" is understood to mean a saturated, monovalent, monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C 3-10 Cycloalkyl". The term "C 3-10 Cycloalkyl" is understood to mean a saturated, monovalent, monocyclic, bicyclic (e.g. bridged, spirocyclic) or tricyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The C 3-10 Cycloalkyl" can be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as camphyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.4]octyl, or a tricyclic hydrocarbon group such as adamantyl.

[0267] The term "C 3-20 Cycloalkyl" is understood to mean a saturated, monovalent, monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C 3-20 Cycloalkyl" is understood to mean a saturated, monovalent, monocyclic, bicyclic (e.g. bridged, spirocyclic) or tricyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The C 3-20"Cycloalkenyl" groups can also be referred to as "C 3-20 "Cycloalkyl" groups can also be referred to as "C 3-20 "Cycloalkyl" groups can also be referred to as "C 3-20 "Cycloalkyl" groups can also be referred to as "C

[0268] 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;

[0269] 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.

[0270] 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 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.

[0271] Unless otherwise defined, in the context of the compounds described in the present disclosure, when some substituents are defined as two groups connected (such as 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), the position of the bond in the described compound is not particularly limited, for example, it can be that group 1 is bonded to the connecting position in the described compound, or it can be that group 2 is bonded to the connecting position in the described compound, as long as the above bond conforms to the valence theory. Also, the connecting position between the two groups (such as group 1 and group 2) is not particularly limited, as long as the above connection conforms to the valence theory.

[0272] For the purpose of illustrative rather than limiting, for example, 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, 5-20 membered heteroaryl C 1-3 -alkyl-OR1.1 , 3-20 membered heterocycloalkyl-C 1-6 -alkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl and the like, which can represent 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 heterocycloalkyl-C 6-20- aryl-, 5-20 membered heteroaryl C 1-3 -alkyl-OR 1.1 -, 3-20 membered heterocycloalkyl-C 1-6 -alkyl-, C 3-10 -cycloalkyl-C 1-6 -alkyl-, which can also represent -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 heterocycloalkyl-C 6-20- aryl, -5-20 membered heteroaryl C 1- 3-alkyl-OR 1.1 -, 3-20 membered heterocycloalkyl-C 1-6 -alkyl, -C 3-10 -cycloalkyl-C 1-6 -alkyl.

[0273] For example, for monocyclic or polycyclic C 6-20 -aryl and 4-12 membered cycloalkyl, monocyclic or polycyclic C 6-20 -aryl and 4-10 membered heterocycloalkyl, monocyclic or polycyclic 5-20 membered heteroaryl, monocyclic or polycyclic 5-20 membered heteroaryl and 4-12 membered cycloalkyl, monocyclic or polycyclic 5-20 membered heteroaryl and 4-10 membered heterocycloalkyl, for example C 4-10 cycloalkyl and C 6-20 aryl, C 4-10 cycloalkenyl and C 6-20 aryl, 4-10 membered heterocycloalkyl and C 6-20 aryl, 4-10 membered heterocycloalkenyl and C 6-20 aryl, C 4-10 cycloalkyl-C 6-20 aryl, C 4-10 cycloalkenyl-C 6-20 aryl, 4-10 membered heterocycloalkyl-C 6-20 aryl, 4-10 membered heterocycloalkenyl-C 6-20 aryl-, 5-20 membered heteroaryl, C4-10 Cycloalkyl and 5-20 membered heteroaryl, C 4-10 Cycloalkenyl and 5-20 membered heteroaryl, 4-10 membered heterocycloalkyl and 5-20 membered heteroaryl, 4-10 membered heterocycloalkenyl and 5-20 membered heteroaryl, C 4-10 Cycloalkyl and 5-20 membered heteroaryl, C 4-10 Cycloalkenyl and 5-20 membered heteroaryl, 4-10 membered heterocycloalkyl and 5-20 membered heteroaryl, 4-10 membered heterocycloalkenyl and 5-20 membered heteroaryl; or, 5-20 membered heteroaryl-O-C 6-20 Aryl and 5-20 membered heteroaryl-NH-C 6-20 Aryl and 5-20 membered heteroaryl-S-C 6-20 Aryl and 5-20 membered heteroaryl-CH2-C 6-20 Aryl, which can mean that either side of the group is bonded to the linking position in the compound.

[0274] It should be understood that when referring to the "group 1 - group 2" format above, if a chemical bond "-" is added to the left of group 1 or to the right of group 2, it means that the connecting position in the compound has been determined and that the bonded position in the compound is the corresponding group to which the chemical bond has been added. Thus, for the definition of "group 1 - group 2" or "group 1 and group 2" in the context of this specification, it should be understood that it recites the definition of an arbitrary bondable position on group 1 with the addition of "-" representing the connecting site, and the definition of an arbitrary bondable position on group 2 with the addition of "-" representing the connecting site.

[0275] The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

[0276] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0277] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0278] Unless otherwise specified, heterocyclyl, 5-20 membered heteroaryl or heteroarylene includes all possible isomeric forms thereof, e.g. positional isomers. Thus, for some illustrative, non-limiting examples, forms substituted or bonded to other groups at the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) thereof can be included, including pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-yl and pyridin-4-ylene; thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

[0279] The term "oxo (=0)" means that a hydrogen or a lone pair of electrons on a non- oxygen atom is replaced by oxygen, for example, after being oxo after being oxo

[0280] The definition of the term "alkyl" also applies to C 1-6 The definition of the term "alkyl" also applies to C 1-6 The definition of the term "alkyl" also applies to C 3-8 The definition of the term "alkyl" also applies to C 1-6 The definition of the term "alkyl" also applies to C

[0281] In the context of the present disclosure, a "-", a "--", a "---" or a "----" in a substituent is intended to mark the chemical bond by which the substituent is used for connection;

[0282] It will be appreciated by persons skilled in the art that the compounds of formula I can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (for example, a carboxyl group) and a basic center (for example, an amino group), they can also form inner salts.

[0283] The compounds of the present disclosure can exist in the form of solvates (such as hydrates), wherein the compound of the present disclosure contains a polar solvent, in particular, for example, water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of polar solvent, in particular, water, can be present in stoichiometric or non-stoichiometric ratios.

[0284] The term "pharmaceutically acceptable" as used herein means a material (such as a carrier or diluent), which does not affect the biological activity or properties of the compounds of the present application, and is relatively nontoxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0285] It will be appreciated by persons skilled in the art that the compounds of the present 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 (for example, a carboxyl group) and a basic center (for example, an amino group), they can also form inner salts.

[0286] ​The term "tautomer" refers to isomeric forms of a functional group resulting from the movement of a molecule's atom between two positions. The compounds of the present disclosure can exhibit tautomerism. Compounds that tautomerize can exist in two or more interconvertible forms. Proton-shift tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present disclosure includes all tautomeric forms of the compounds.

[0287] Depending on their molecular structure, the compounds of the present disclosure can be chiral and, therefore, various enantiomeric forms can exist. The compounds can thus exist in racemic or optically active forms. The compounds of the present disclosure encompass the isomers in which each chiral carbon has the R or S configuration or a mixture thereof, a racemate. The compounds of the present disclosure, or, alternatively, the intermediates, can be separated into the individual enantiomeric compounds either by physical methods or by synthesis in enantiomeric form. In the case of racemic amines, the diastereomeric amines are prepared from the mixture by reaction with an optically active resolving agent. 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, for example N-benzoylproline or N-benzenesulfonylproline, or the various optically active camphorsulfonic acids. Enantiomeric separation can also be advantageously performed by chromatography using an optically active stationary phase, for example, on silica gel with bound dinitrobenzoylphenylglycine, cellulose tris acetate or other carbohydrate derivatives or chiral derivatizing reagents followed by elution with a mixture of solvents, for example, hexane / isopropanol / acetonitrile. The corresponding stable isomers can be isolated according to known methods, for example, by extraction, filtration or column chromatography.

[0288] An "isotope" is any of the atoms of an element that has the same atomic number but a different mass number. Examples of isotopes suitable for incorporation into the compounds of the present application are hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, for example, but not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 31 P, 32 P, 35 S, 18 F and 36C1. Isotopically-labeled compounds of the present 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-labeled reagent in place of the non- isotopically labeled reagent. Such compounds are useful in, e.g., determination of biological activity. In the case of stable isotopes, such compounds are useful in providing improved methods of treatment.

[0289] The term "prodrug" means a compound which can be converted under physiological conditions or by solvo lysis to provide a compound of the present disclosure having the biological activity. A prodrug of the present disclosure is prepared by modifying functional groups in the compound in such a way that its activity is retained in the modification or is improved in vivo. Prodrugs include compounds of the present disclosure wherein one or more hydroxyl or amino groups are bonded to any group that, when administered to a mammalian subject, is cleaved to form the free hydroxyl or amino group.

[0290] The term "patient" means any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

[0291] The term "therapeutically effective amount" means an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response that a researcher, veterinarian, medical doctor or other clinical professional is seeking in an organized, systemic, animal, individual or human, and includes one or more of the following: (1) preventing the disease: e.g., preventing a disease, disorder or condition from occurring in an individual that is predisposed or susceptible to the disease, but has not yet been experienced or displayed the pathology or symptomatology of the disease; (2) inhibiting the disease: e.g., arresting the development of a disease, disorder or condition (i.e., retarding the further development of a pathology and / or symptomatology) in an individual that is experiencing or has experienced the pathology or symptomatology of the disease; (3) relieving the disease: e.g., causing the regression of a disease, disorder or condition (i.e., reversing a pathology and / or symptomatology) in an individual that is experiencing or has experienced the pathology or symptomatology of the disease. DETAILED DESCRIPTION

[0292] The technical solutions of the present disclosure will be further described in detail below in combination 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.

[0293] Unless otherwise indicated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0294] Table of Abbreviations

[0295] DMF: N,N-dimethylformamide

[0296] DCM: dichloromethane

[0297] DIEA: N,N-diisopropylethylamine

[0298] TEA: triethylamine

[0299] PE: petroleum ether

[0300] EA: ethyl acetate

[0301] MeCN: acetonitrile

[0302] Et20: diethyl ether

[0303] DMSO: dimethyl sulfoxide

[0304] EtOAc: ethyl acetate

[0305] THF: tetrahydrofuran

[0306] TFA: trifluoroacetic acid

[0307] AcOH: acetic acid

[0308] MeOH: methanol

[0309] EtOH: ethanol

[0310] NaH: sodium hydride

[0311] MeI: methyl iodide

[0312] EtI: ethyl iodide

[0313] HFP: 1,1,1,3,3,3-hexafluoro-2-propanol

[0314] DHP: 3,4-dihydro-2H-pyran

[0315] PPTS: 4-methylphenylsulfonic acid pyridinium

[0316] PPh3: triphenylphosphine

[0317] DEAD: diethyl azodicarboxylate

[0318] MsCl: methylsulfonyl chloride

[0319] TMSOTf: trimethylsilyl trifluoromethanesulfonate

[0320] m-CPBA: meta-chloroperoxybenzoic acid

[0321] Boc: tert-butoxycarbonyl

[0322] Analytical methods:

[0323] 1. Nuclear magnetic resonance (NMR) spectra were recorded on a 400 MHz Bruker AVANCE SH 500 instrument. Chemical shifts are reported in ppm with deuterium lock residual solvent as 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.

[0324] 2. Purity analysis of samples was performed on a Waters HPLC / Waters MS system.

[0325] Chromatography conditions 1:

[0326] Column Waters X-Bridge-C18 50mm*4.6mm*3.5μm

[0327] Column temperature 40 °C.

[0328] Sample temperature: room temperature

[0329] Detection UV 214 nm, UV 254 nm

[0330] Flow rate: 2 mL / min: 2 mL / min.

[0331] Mobile phase A: water (0.05% TFA) B: MeCN

[0332] Mobile phase B: MeCN (0.05% TFA)

[0333] Gradient program: B from 5% to 100% for 1.6 min, 100% for 1.4 min.

[0334] Chromatography conditions 2:

[0335] Column: Waters X Brdige C18 Waters X Brdige C18: 4.6mm*50mm*3.5μm

[0336] Column temperature 40 °C.

[0337] Sample temperature: room temperature

[0338] Detection UV 214 nm, UV 254 nm

[0339] Flow rate: 2 mL / min: 2 mL / min.

[0340] Mobile phase A: water (0.01 mol / L NH4HCO3) B: MeCN

[0341] Mobile phase B: MeCN

[0342] Gradient program: B from 5% to 100% in 1.6 min, 100% for 1.4 min.

[0343] 3. Preparative HPLC was performed on Gilson 281.

[0344] Flow rate: 20 mL / min: 20 mL / min.

[0345] Column: X-Select 10 pm 19 X-Select 10 pm 19 * 250 mm column

[0346] Wavelength: 254 nM or 214 nM

[0347] Solvent A water (10 mM NH4HCO3) and solvent B MeCN.

[0348] Example 1 : Synthesis

[0349] 1. Synthesis scheme:

[0350] 2. Experimental part:

[0351] 2.1

[0352] 6-(4-hydroxyphenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (02437-1)

[0353] To a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (500 mg, 2.461 mmol) in water (5 mL) was added sulfuric acid (1 g, 10.20 mmol) at 0 °C, the mixture was stirred at 0 °C, an aqueous solution of sodium nitrite (190 mg, 2.75 mmol) in water (5 mL) was slowly added dropwise into the reaction, stirring was continued for 20 minutes, the mixture was slowly warmed to 90 °C in 20 minutes. The mixture was poured into water (30 mL), filtered and dried 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 dark brown solid product (220 mg, yield 43.82%).

[0354] ESI-MS m / z calcd for [C 11 H 12 N2O2][M+H] + : 205.0; found: 205.0

[0355] 2.2

[0356] 3-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenoxy)azetidine-1 - carboxylate tert-butyl ester (02437-2)

[0357] To a solution of 6-(4-hydroxyphenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (220 mg, 1.07 mmol) and 3-(p-tolylsulfonyloxy)azetidine-1 -carboxylic acid tert-butyl ester (350 mg, 1.07 mmol) in DMF (10 mL) was added K2CO3(442 mg, 3.21 mmol) with KI (35.52 mg, 0.214 mmol) at 0 °C. The mixture was stirred at 80 °C for 6 h, then the mixture was poured into water (50 mL) and extracted with EA (30 mL) twice. The combined organic phase 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 = 0~80%, silica gel-CS 12 g, 20 mL / min, UV 254) to give the product as a white solid (208 mg, yield 53.74%).

[0358] ESI-MS m / z calcd for C 19 H 25 N3O4][M+H] + : 360.2; found: 360.4

[0359] 2.3

[0360] 6-(4-(azetidin-3-yloxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (02437-3)

[0361] To a solution of 3-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenoxy)azetidine-1 - carboxylic acid tert-butyl ester (70 mg, 2.508 mmol) in DCM (5 mL) was added TFA (0.5 mL). The mixture was stirred at 25 °C for 2 h, the solvent was removed by distillation under reduced pressure, and the obtained white solid crude product (87 mg) was used directly for the next reaction.

[0362] ESI-MS m / z calcd for C 14 H 17 N3O2][M+H] + : 260.2; found: 260.0

[0363] 2.4

[0364] 6-(4-((1-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-2-yl)azetidin-3-yl)oxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (MX02437-rac)

[0365] To a solution of 6-(4-(azetidin-3-yloxy)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (87 mg, 0.335 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (96.35 mg, 0.335 mmol) in DMF (5 mL) was added DIEA (43.29 mg, 1.340 mmol). The mixture was stirred at 90 °C for 3 h, cooled to rt 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 product as a white solid (40.89 mg, 23.92% yield).

[0366] ESI-MS m / z calcd for [C 25 H 30 N6O4S][M+H] + : 511.2; found: 511.3

[0367] 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 7.75 (d, J = 9.2, 2H), 7.47 (s, 1H), 6.94 (d, J = 8.8, 2H), 5.20 - 5.15 (m, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.49 - 4.45 (m, 2H), 4.02 - 3.87 (m, 2H), 3.70 - 3.67 (m, 2H), 3.45 - 3.36 (m, 2H), 3.27 - 3.18 (m, 1H), 2.97 - 2.85 (m, 2H), 2.70 - 2.64 (m, 1H), 2.38 - 2.22 (m, 3H), 2.15 - 2.10 (m, 2H), 1.82 - 1.67 (m, 2H), 1.07 (d, J = 7.2 H, 3H).

[0368] 2.5 (S)-6-(4-((1-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7- dihydrothieno[3,2-d]pyrimidin-2-yl)azetidin-3-yl)oxy)phenyl)-5-methyl-4,5- dihydridiazin-3(2H)-one & (R)-6-(4-((1-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7- dihydrothieno[3,2-d]pyrimidin-2-yl)azetidin-3-yl)oxy)phenyl)-5-methyl-4,5- dihydridiazin-3(2H)-one

[0369] The racemic compound MX02437-rac (40 mg) was resolved by preparative chiral HPLC (A = CO2 co-solvent B = MEOH / ACN, SFC-80 (Waters) - DAICEL AS-H (30*250 mm 5 pm), 100 bar, 45 mL / min, UV 215 nm) to give the leading product (13.17 mg) and the trailing product (15.5 mg).

[0370] MX02437-P1 : ESI-MS m / z calcd for [C 25 H 30 N6O4S][M+H] + : 511.2; found: 511.3

[0371] 1 H NMR (400 MHz, DMSO-d6) d 10.87 (s, 1H), 7.75 (d, J = 9.2, 2H), 7.47 (s, 1H), 6.94 (d, J = 8.8, 2H), 5.20 - 5.15 (m, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.49 - 4.45 (m, 2H), 4.02 - 3.87 (m, 2H), 3.70 - 3.67 (m, 2H), 3.45 - 3.36 (m, 2H), 3.27 - 3.18 (m, 1H), 2.97 - 2.85 (m, 2H), 2.70 - 2.64 (m, 1H), 2.38 - 2.22 (m, 3H), 2.15 - 2.10 (m, 2H), 1.82 - 1.67 (m, 2H), 1.07 (d, J = 7.2 H, 3H).

[0372] MX02437-P2: ESI-MS m / z calcd for [C 25 H 30 N6O4S][M+H] + : 511.2; found: 511.3

[0373] 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 7.75 (d, J = 9.2, 2H), 7.47 (s, 1H), 6.94 (d, J = 8.8, 2H), 5.20 - 5.15 (m, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.49 - 4.45 (m, 2H), 4.02 - 3.87 (m, 2H), 3.70 - 3.67 (m, 2H), 3.45 - 3.36 (m, 2H), 3.27 - 3.18 (m, 1H), 2.97 - 2.85 (m, 2H), 2.70 - 2.64 (m, 1H), 2.38 - 2.22 (m, 3H), 2.15 - 2.10 (m, 2H), 1.82 - 1.67 (m, 2H), 1.07 (d, J = 7.2 H, 3H).

[0374] 1. Synthesis scheme:

[0375] 2. Experimental section:

[0376] 2.1

[0377] 3-bromo-4-ethoxybenzene-1-sulfonyl chloride (02618-1)

[0378] To a solution of 1-bromo-2-ethoxybenzene (1 g, 5.00 mmol) in DCM (10 mL) was added chlorosulfonic acid (2 mL) slowly at -5 °C. Then the mixture was stirred at room temperature for 2 hours, after the starting material was consumed, ice water (50 mL) was added, extracted with DCM (50 mL) twice. The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the product as yellow oil (1.31 g, yield 88%).

[0379] ESI-MS m / z calcd for [C8H8BrClO3S] [M+H] 298.9; found 298.8 + :298.9; found 298.8

[0380] 2.2

[0381] 1-((3-bromo-4-ethoxyphenyl)sulfonyl)-4-methylpiperazine (02618-2)

[0382] To a solution of 3-bromo-4-ethoxybenzene-1-sulfonyl chloride (1.31 g, 4.38 mmol) and 1-methylpiperazine (438 mg, 4.38 mmol) in acetone (15 mL) was added TEA (885 mg, 8.76 mmol) and the reaction was stirred at room temperature for 3 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 layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and 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 (1.37 g, 87% yield).

[0383] ESI-MS m / z calcd for C 13 H 19 BrN2O3S][M+H] + :363.0; found: 362.8

[0384] 2.3

[0385] 2-Ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenol (02618-3)

[0386] To a solution of 1-((3-bromo-4-ethoxyphenyl)sulfonyl)-4-methylpiperazine (200 mg, 0.55 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1) was added KOH (62 mg, 1.10 mmol), tBu-Xphos (23 mg, 0.055 mmol) and Pd2(dba)3(50 mg, 0.055 mmol), and the reaction was stirred at 80 °C under microwave conditions for 1 hour. 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, and 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 (131 mg, 79% yield).

[0387] ESI-MS m / z calcd for C 13 H 20 N2O4S][M+H] + :301.1; found: 300.9

[0388] 2.4

[0389] 3-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenoxy)azetidine-1-carboxylic acid tert-butyl ester (02618-4)

[0390] To a solution of 2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenol (70 mg, 0.23 mmol) and 3-(p-tolylsulfonyloxy)azetidine-1-carboxylic acid tert-butyl ester (76 mg, 0.23 mmol) in DMF (3 mL) was added Cs2CO3(152 mg, 0.47 mmol) at room temperature. The mixture was then 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 a yellow solid (98 mg, 92% yield).

[0391] ESI-MS m / z calcd for C 21 H 33 N3O6S][M+H] + : 456.2; found: 455.8

[0392] 2.5

[0393] (R)-2-(3-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02618)

[0394] A solution of tert-butyl 3-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenoxy)azetidine-1-carboxylate (30 mg, 0.06 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2- d]pyrimidine 5-oxide (19 mg, 0.06 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 with DCM (10 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 prep-HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 pm 19*250 mm, 20 mL / min, UV 254) to give the compound (12.05 mg, 30% yield) as a white solid.

[0395] ESI-MS m / z calcd for C 27 H 38 N6O6S2][M+H] + :607.2; found: 606.7

[0396] 1 H NMR (400 MHz, DMSO-d6) d 7.48 (s, 1H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 5.23 - 5.18 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.44 (dd, J = 10.0, 6.4 Hz, 2H), 4.15 (q, J = 6.8 Hz, 2H), 4.05 - 3.85 (m, 2H), 3.72 - 3.65 (m, 2H), 3.46 - 3.35 (m, 1H), 3.25 - 3.18 (m, 1H), 2.98 - 2.85 (m, 6H), 2.39 - 2.26 (m, 6H), 2.15 (s, 3H), 2.14 - 2.08 (m, 2H), 1.82 - 1.67 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H).

[0397] 1. Synthesis scheme:

[0398] 2. Experimental part:

[0399] 2.1

[0400] (R)-6-(4-bromophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (02651-1)

[0401] To a solution of (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (500 mg, 2.45 mmol) in MeCN (10 mL) were added copper bromide (550 mg, 2.45 mmol) and tert-butyl nitrite (375 mg, 3.67 mmol) at room temperature. The mixture was then stirred at room temperature overnight, ice water (50 mL) was added, and it was extracted twice with EA (50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and 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 yellow solid (370 mg, 56% yield).

[0402] ESI-MS m / z calcd for C 11 H 11 BrN2O][M+H] + :267.0; found: 267.1

[0403] 2.2

[0404] 5-(4-((R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (02651-2)

[0405] To a solution of (R)-6-(4-bromophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (100 mg, 0.37 mmol) in toluene (3 mL) were added tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (79 mg, 0.37 mmol), t-BuONa (72 mg, 0.75 mmol), BINAP (25 mg, 0.04 mmol) and Pd2(dba)3 (36 mg, 0.04 mmol), and the reaction was stirred at 110 °C under argon 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 layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and 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 solid (25 mg, 17% yield).

[0406] ESI-MS m / z calculated value [C] 22 H 30 N4O3][M+H + 399.2; Measured value: 398.9

[0407] 2.3

[0408] (5R)-6-(4-(5-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)phenyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (MX02651)

[0409] A solution of 5-(4-((R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylic acid tert-butyl ester (25 mg, 0.06 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (18 mg, 0.06 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, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to give a white solid compound (2.15 mg, yield 6%).

[0410] ESI-MS m / z calculated value [C] 28 H 35 [N7O3S][M+H] + Measured value: 550.3; Actual value: 549.7

[0411] 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.27 (s, 1H), 6.58 (d, J = 9.2 Hz, 2H), 4.83 (t, J = 5.6 Hz, 1H), 3.82 - 3.76 (m, 2H), 3.72 (d, J = 5.6 Hz, 2H), 3.60 - 3.51 (m, 2H), 3.48 - 3.33 (m, 4H), 3.06 - 3.38 (m, 5H), 2.94 - 2.82 (m, 2H), 2.67 - 2.59 (m, 1H), 2.42 - 2.28 (m, 2H), 2.20 - 2.12 (m, 3H), 1.81 - 1.71 (m, 2H), 1.03 (d, J = 7.2 Hz, 3H).

[0412] 1. Synthesis scheme:

[0413] 2. Experimental section:

[0414] 2.1

[0415] (R)-4-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-5,6- dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (02652-1)

[0416] A solution of (R)-6-(4-bromophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (70 mg, 0.26 mmol) in 1,4-dioxane / H2O (2.4 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 (99 mg, 0.32 mmol), potassium carbonate (76 mg, 0.78 mmol) and Pd(dppf)Cl2(18 mg, 0.026 mmol), the reaction was stirred at 90 °C under argon protection for 3 hours. 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 (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product (89 mg, yield 92%) as a yellow solid.

[0417] ESI-MS m / z calcd for C 21 H 27 N3O3][M+H] +370.2; Measured value: 369.9

[0418] 2.2

[0419] (R)-6-(4-(1-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (MX02652)

[0420] A solution of (R)-4-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (40 mg, 0.10 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (29 mg, 0.10 mmol) in HFP (2 mL) was stirred in a microwave at 120 °C for 2 hours. Then water (10 mL) was added to the mixture, and the mixture was extracted twice with DCM (10 mL). The combined organic layers were washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to give a white solid compound (10.11 mg, yield 18%).

[0421] ESI-MS m / z calculated value [C] 27 H 32 [N6O3S][M+H] + Measured value: 521.2; Actual value: 520.6

[0422] 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.39 (s, 1H), 6.40 - 6.36 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.38 - 4.36 (m, 2H), 3.99 (t, J = 5.2 Hz, 2H), 3.97 - 3.75 (m, 2H), 3.47 - 3.35 (m, 2H), 3.30 - 3.18 (m, 1H), 2.98 - 2.84 (m, 2H), 2.73 - 2.67 (m, 1H), 2.68 - 2.66 (m, 2H), 2.43 - 2.18 (m, 5H), 1.84 - 1.73 (m, 2H), 1.07 (d, J = 7.2 Hz, 3H).

[0423] 1. Synthesis scheme:

[0424] 2. Experimental section: Compound 02680-0 and R-1 were used as starting materials, and the operation in Example MX-02681 was referred to, to obtain compound MX02680. White solid product (13.30 mg, yield 11.2%).

[0425] ESI-MS m / z calcd for C 27 H 36 N8O4S][M+H] + : 569.2; found: 569.3

[0426] 1 H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.28 (s, 1H), 4.83 (t, J = 5.6 Hz, 1H), 4.61 - 4.58 (m, 2H), 4.11 (d, J = 7.2 Hz, 2H), 3.79 (d, J = 6.8 Hz, 1H), 3.73 - 3.66 (m, 2H), 3.43 (s, 3H), 3.42 - 3.35 (m, 2H), 3.24 - 3.18 (m, 1H), 2.93 - 2.79 (m, 4H), 2.39 - 2.25 (m, 2H), 2.17 - 2.10 (m, 2H), 2.07 - 2.01 (m, 1H), 1.80 - 1.69 (m, 2H), 1.61 - 1.58 (m, 2H), 1.34 - 1.28 (m, 1H), 1.16 - 1.07 (m, 2H), 0.52 - 0.46 (m, 2H), 0.44 - 0.39 (m, 2H),

[0427] 1. Synthesis scheme:

[0428] 2. Experimental Section:

[0429] 2.1

[0430] 7-(Cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (02681-1)

[0431] To a solution of 3-methylxanthine (1.5 g, 9.04 mmol) in DMSO (15.0 mL) was added NaH (396 mg, 9.9 mmol) at 0 °C, then (bromomethyl)cyclopropane (1.58 g, 11.75 mmol) was added, and the mixture was stirred at room temperature overnight. After the starting material was consumed, the solid was separated by filtration, and the filter cake was washed with water three times and methanol three times to give the product as a yellow solid (1.1 g, yield 55.3%).

[0432] ESI-MS m / z calcd for C 10 H 12 N4O2][M+H] + :221.1; found:221.2

[0433] 2.2

[0434] 1-(4-Bromobenzyl)-7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (02681-2)

[0435] To a solution of 7-(cyclopropylmethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (200 mg, 0.91 mmol) in DMF (5.0 mL) was added 1-bromo-4-(bromomethyl)benzene (271 mg, 1.09 mmol) and Cs2CO3(593 mg, 1.82 mmol), TBAI (33 mg, 0.09 mmol) at room temperature, and the mixture was stirred at 50 °C for 2 h. After the starting material was consumed, water (10 mL) was added, and the mixture was 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 20 g, 30 mL / min, silica gel, UV 254) to give the product as a yellow oil (322 mg, yield 91.2%).

[0436] ESI-MS m / z calcd for C 17 H 17 BrN4O2][M+H] +: 389.0; found: 388.7

[0437] 2.3

[0438] 7-(Cyclopropylmethyl)-3-methyl-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)-lH-purine-2,6(3H,7H)-dione (02680-2)

[0439] To a solution of l-(4-bromobenzyl)-7-(cyclopropylmethyl)-3-methyl-lH-purine-2,6(3H,7H)-dione (200 mg, 0.68 mmol) in 1,4-dioxane (2 mL) was added B2Pin2 (353 mg, 1.39 mmol), KOAc (200 mg, 2.04 mmol) and Pd(dppf)Cl2(55 mg, 0.07 mmol). The mixture was stirred at 80 °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.

[0440] ESI-MS m / z calcd for C 23 H 29 BN4O4][M+H] + : 437.2; found: 436.8

[0441] 2.4

[0442] (R)-7-(Cyclopropylmethyl)-l-(4-(4-((l-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7- dihydrothieno[3,2-d]pyrimidin-2-yl)benzyl)-3-methyl-lH-purine-2,6(3H,7H)-dione (MX02681)

[0443] To a solution of 7-(cyclopropylmethyl)-3-methyl-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)-lH-purine-2,6(3H,7H)-dione (14 mg, 0.05 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1) were added (R)-2-chloro-4-((l-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2- d]pyrimidine 5-oxide (20 mg, 0.05 mmol), K2CO3(14 mg, 0.10 mmol) and Pd(dppf)Cl2(4 mg, 0.005 mmol). 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 (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 (5.22 mg, yield 18.6%).

[0444] ESI-MS m / z calcd for C 28 H 31 N7O4S][M+H]+: 562.2; found: 562.4

[0445] 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 8.4 Hz, 2H), 8.17 (s, 1H), 8.03 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 5.13 (s, 2H), 4.92 (t, J = 5.6 Hz, 1H), 4.12 (d, J = 7.2 Hz, 2H), 3.82 - 3.78 (m, 2H), 3.65 - 3.59 (m, 1H), 3.45 (s, 3H), 3.23 - 3.17 (m, 1H), 3.04 - 3.00 (m, 1H), 2.40 - 2.30 (m, 5H), 1.85 - 1.78 (m, 2H), 1.36 - 1.32 (m, 1H), 0.53 - 0.48 (m, 2H), 0.42 - 0.40 (m, 2H).

[0446] 1. Synthesis scheme:

[0447] 2. Experimental Part: Compound 02682-0 and R-1 were used as starting materials to obtain compound MX02682 following the procedure of example MX-02681. White solid product (42.0 mg, 38.4% yield).

[0448] ESI-MS m / z calcd for C 25 H 27 N7O4S][M+H] + :522.2; found: 522.2

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 8.4 Hz, 2H), 8.06 (s, 1H), 8.01 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 5.12 (s, 2H), 4.90 (t, J = 5.6 Hz, 1H), 3.90 (s, 3H), 3.83 - 3.77 (m, 2H), 3.66 - 3.59 (m, 1H), 3.44 (s, 3H), 3.39 - 3.33 (m, 1H), 3.29 - 3.17 (m, 1H), 3.04 - 3.00 (m, 1H), 2.43 - 2.28 (m, 4H), 1.86 - 1.76 (m, 2H).

[0450] 1. Synthesis scheme:

[0451] 2. Experimental Part:

[0452] 2.1

[0453] 4-(2-Ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5,6-dihydropyridine-1(2H)- carboxylic acid tert-butyl ester (02686-1)

[0454] 1 -((3-bromo-4-ethoxyphenyl)sulfonyl)-4-methylpiperazine (129 mg, 0.36 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (143 mg, 0.46 mmol), Pd(dppf)CI2(29 mg, 0.04 mmol), K2CO3(148 mg, 1.07 mmol) and water (1 mL) in 1,4-dioxane (4 mL) was stirred at 85 °C under argon protection for 4 h. 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 ~ 1 / 0, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to give the product as a white solid (103 mg, yield 62.1 %).

[0455] ESI-MS m / z calcd for C 23 H 35 N3O5S][M+H] + :466.2; found: 465.8

[0456] 2.2

[0457] 1 -((4-ethoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl)-4-methylpiperazine (02686-2)

[0458] To a solution of tert-butyl 4-(2-ethoxy-5-((4-methylpiperazin-1 -yl)sulfonyl)phenyl)- 5,6-dihydropyridine-1 (2H)-carboxylate (55 mg, 0.12 mmol) in DCM (3 mL) was added TFA (0.5 mL) and stirred at room temperature overnight. After the reaction was completed, the mixture was distilled under reduced pressure to remove the solvent, and the crude product was used directly for the next reaction.

[0459] ESI-MS m / z calcd for C 18 H 27 N3O3S][M+H] + :366.2; found: 365.8

[0460] 2.3

[0461] (R)-2-(4-(2-ethoxy-5-((4-methylpiperazin-1 -yl)sulfonyl)phenyl)-5,6-dihydropyridin- 1 (2H)-yl)-4-((1 -(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5- oxide (MX02686)

[0462] To a solution of 1-((4-ethoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl)-4- methylpiperazine (43.2 mg, 0.12 mmol) in DMF (2 mL) was added (R)-2-chloro-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (34 mg, 0.12 mmol) and DIEA (122 mg, 0.94 mmol). The mixture was stirred at 85 °C under nitrogen protection for 2 hours, after the starting material was consumed, 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 (19.35 mg, yield 26.56%).

[0463] ESI-MS m / z calcd for C 29 H 40 N6O5S2][M+H] + :617.3; found: 617.0

[0464] 1 H NMR (400 MHz, DMSO-d6) d 7.62 - 7.59 (m, 1H), 7.43 - 7.40 (m, 2H), 7.21 (d, J = 8.8 Hz, 1H), 5.97 (s, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.36 - 4.29 (m, 2H), 4.15 (q, J = 6.8 Hz, 2H), 3.94 - 3.92 (m, 2H), 3.74 (d, J = 5.6 Hz, 2H), 3.47 - 3.33 (m, 3H), 3.25 - 3.18 (m, 1H), 2.98 - 2.81 (m, 6H), 2.42 - 2.28 (m, 6H), 2.21 - 2.13 (m, 5H), 1.81 - 1.74 (m, 2H), 1.35 (t, J = 6.8 Hz, 3H).

[0465] 1. Synthesis scheme:

[0466] 2. Experimental part:

[0467] 2.1

[0468] 5-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (02687-1)

[0469] To a solution of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (87.7 mg, 0.41 mmol) and l-((3-bromo-4-ethoxyphenyl)sulfonyl)-4-methylpiperazine (100 mg, 0.28 mmol) in toluene (10 mL) was added Pd2(dba)3(28.2 mg, 0.03 mmol), BINAP (25.7 mg, 0.04 mmol), t-BuOK (92.7 mg, 0.83 mmol) and TEA (83.6 mg, 0.83 mmol). The mixture was stirred at 105 °C under nitrogen protection for 16 h. After cooling to room temperature, the reaction mixture was quenched with water 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 and concentrated. The obtained crude product was purified by column chromatography (MeOH / DCM = 0~1 / 10, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product (92 mg, yield 67.56%) as yellow syrup.

[0470] ESI-MS m / z calcd for C 24 H 38 N4O5S][M+H] + :495.3; found: 495.0

[0471] 2.2

[0472] 2-(2-ethoxy-5-((4-methylpiperazin-l-yl)sulfonyl)phenyl)octahydropyrrolo[3,4- c]pyrrole (02686-2)

[0473] To a solution of tert-butyl 5-(2-ethoxy-5-((4-methylpiperazin-l-yl)sulfonyl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (45 mg, 0.09 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 mL) and stirred at room temperature overnight. After the reaction was completed, the solvent was removed by distillation under reduced pressure and the crude product was used directly for the next step.

[0474] ESI-MS m / z calcd for C 19 H 30 N4O3S][M+H] + :395.2; found: 395.0

[0475] 2.3

[0476] (5R)-2-(5-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2- d]pyrimidine 5-oxide (MX02687)

[0477] To a solution of 2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)octahydropyrrolo[3,4- c]pyrrole (35.9 mg, 0.09 mmol) in DMF (2 mL) was added (R)-2-chloro-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (26.2 mg, 0.09 mmol) and DIEA (70.5 mg, 0.55 mmol). The mixture was stirred at 85 °C under nitrogen protection for 2 hours, after the starting material was consumed, the mixture was concentrated under reduced pressure to remove the solvent, the obtained 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 (15.13 mg, yield 25.75%).

[0478] ESI-MS m / z calcd for C 30 H 43 N7O5S2][M+H] + :646.3; found: 646.0

[0479] 1 H NMR (400 MHz, DMSO-d6) d 7.27 (s, 1H), 7.13 - 7.05 (m, 2H), 6.84 (s, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.09 (q, J = 6.8 Hz, 2H), 3.82 - 3.72 (m, 4H), 3.47 - 3.30 (m, 7H), 3.21 - 3.18 (m, 1H), 3.03 (s, 2H), 2.87 - 2.84 (m, 6H), 2.40 - 2.33 (m, 6H), 2.17 - 2.12 (m, 5H), 1.78 - 1.74 (m, 2H), 1.37 (t, J = 6.8 Hz, 3H).

[0480] 1. Synthesis scheme:

[0481] 2. Experimental Part: Compound 02690-0 and R-1 were used as starting materials to obtain compound MX02690 following the procedure described in example MX-02686. White solid product (27.2 mg, yield 37.2%).

[0482] ESI-MS m / z calcd for C 27 H 35 FN6O4S2][M+H] + :591.2; found: 590.8

[0483] 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (t, J = 8.0 Hz, 1H), 7.57 - 7.53 (m, 2H), 7.43 (s, 1H), 6.28 (s, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.39 (s, 2H), 3.98 (t, J = 5.6 Hz, 2H), 3.75 (d, J = 5.6 Hz, 2H), 3.46 - 3.41 (m, 1H), 3.24 - 3.20 (m, 1H), 2.98 - 2.88 (m, 6H), 2.53 - 2.51 (m, 2H), 2.39 - 2.31 (m, 6H), 2.22 - 2.14 (m, 5H), 1.81 - 1.77 (m, 2H).

[0484] 1. Synthesis scheme:

[0485] 2. Experimental Part: Compound 02691-0 and R-1 were used as starting materials to obtain compound MX02691 following the procedure described in example MX-02686. White solid product (6.04 mg, yield 7.5%).

[0486] ESI-MS m / z calcd for C 26 H 35 N7O4S2][M+H] + :574.2; found: 574.0

[0487] 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 2.0 Hz, 1H), 8.10 (dd, J = 8.4, 2.0 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.05 (s, 1H), 4.85 (t, J = 5.2 Hz, 1H), 4.46 - 4.45 (m, 2H), 4.00 - 3.98 (m, 2H), 3.76 - 3.74 (m, 2H), 3.47 - 3.39 (m, 1H), 3.26 - 3.18 (m, 1H), 2.98 - 2.84 (m, 6H), 2.67 - 2.65 (m, 2H), 2.40 - 2.30 (m, 6H), 2.23 - 2.18 (m, 2H), 2.14 (s, 3H), 1.83 - 1.76 (m, 2H).

[0488] 1. Synthesis scheme:

[0489] 2. Experimental section: Compound 02700-0 and R-1 were used as starting materials, and the procedure of Example MX-02686 was followed to obtain compound MX02700. White solid product (24.97 mg, yield 28.10%).

[0490] ESI-MS m / z calcd for C 27 H 37 N7O4S2][M+H] + : 588.2; Found: 588.0

[0491] 1 H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 2.0 Hz, 1H), 8.09 (dd, J = 8.4, 2.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.05 (s, 1H), 4.85 (t, J = 6.0 Hz, 1H), 4.46 (s, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.75 (d, J = 5.6 Hz, 2H), 3.46 - 3.41 (m, 1H), 3.24 - 3.21 (m, 1H), 2.98 - 2.84 (m, 6H), 2.68-2.66 (m, 2H), 2.42 - 2.27 (m, 8H), 2.24 - 2.18 (m, 2H), 1.81 - 1.78 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[0492] 1. Synthesis scheme:

[0493] 2. Experimental section:

[0494] 2.1

[0495] tert-Butyl ((1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclopentyl)methyl)carbamate (02705-2)

[0496] To a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (4.55 g, 22 mmol) in DMF (40 mL) was added tert-butyl ((1-aminocyclopentyl)methyl)carbamate (2.2 g, 11 mmol) and DIEA (8.52 g, 65.9 mmol). After the mixture was stirred at 80 °C for 16 h, the solvent was removed under reduced pressure, water (50 mL) was added, and the mixture was extracted with DCM (50 mL) three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 0, silica gel-CS 40 g, 50 mL / min, silica gel, UV 254) to give the product as a yellow solid (2.4 g, 58.91% yield).

[0497] ESI-MS m / z calcd for C 16 H 23 ClN4O2S][M+H] + : 371.1; found: 371.0

[0498] 2.2

[0499] tert-Butyl ((1-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclopentyl)methyl)carbamate (02705-2)

[0500] To a solution of tert-butyl ((1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4- yl)amino)cyclobutyl)methyl)carbamate (2.4 g, 6.47 mmol) and S-1,1 '-bi-2-naphthol (185 mg, 0.65 mmol) in DCM (50 mL) were added titanium tetraisopropoxide (184 mg, 0.65 mmol) and water (233 mg, 12.94 mmol). After the mixture was stirred at room temperature for 16 hours, 70% aqueous tert-butyl hydroperoxide (1.25 g, 9.71 mmol) was added in one portion, and then the mixture was stirred at room temperature for 2 hours before water (50 mL) was added and extracted with DCM (50 mL) three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH = 1 / 0 ~ 10 / 1, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give the product as a yellow solid (1.78 g, yield 71.10%).

[0501] ESI-MS m / z calcd for C 16 H 23 ClN4O3S][M+H] + :387.1; found: 387.0

[0502] 2.3

[0503] ((1-(((R)-2-(4-(4-((R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-5,6- dihydropyridin-1 (2H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl)tert- butyl carbamate (02705-3)

[0504] To a solution of tert-butyl ((R)-(1-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4- yl)amino)cyclobutyl)methyl)carbamate (280 mg, 0.72 mmol) in DMF (8 mL) were added (R)-5- methyl-6-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4,5-dihydropyridazin-3(2H)-one (253 mg, 0.94 mmol) and DIEA (561 mg, 4.34 mmol). The mixture was stirred at 85 °C under nitrogen protection for 2 hours, and then the mixture was concentrated under reduced pressure to remove the solvent after the starting material was consumed. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 20, silica gel-CS 40 g, 50 mL / min, silica gel, UV 254) to give the product as a yellow solid (245 mg, yield 54.62%).

[0505] ESI-MS m / z calculated value [C] 32 H 41 [N7O4S][M+H] + :620.3; Measured value: 620.0

[0506] 2.4

[0507] (R)-6-(4-(1-((R)-4-((1-(aminomethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (MX02705)

[0508] TFA (1 mL) was added to a solution of ((1-(((R)-2-(4-(4-(((R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-5,6-dihydropyridin-1(2H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl)carbamate tert-carbamate (245 mg, 0.40 mmol) in DCM (8 mL), and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation of the mixture. The crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give a white solid product (91.8 mg, yield 44.69%).

[0509] ESI-MS m / z calculated value [C] 27 H 33 [N7O2S][M+H] + :520.2; found:520.0

[0510] 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.44 (s, 1H), 6.38 (s, 1H), 4.38 - 4.36 (m, 2H), 3.99 (t, J = 5.6 Hz, 2H), 3.46 - 3.39 (m, 2H), 3.27 - 3.22 (m, 1H), 2.98 - 2.94 (m, 3H), 2.89 - 2.86 (m, 1H), 2.72 - 2.67 (m, 3H), 2.54 - 2.51 (m, 2H), 2.38 - 2.33 (m, 2H), 2.26 - 2.18 (m, 1H), 2.16 - 2.13 (m, 2H), 1.81 - 1.77 (m, 2H), 1.07 (d, J = 7.2 Hz, 3H).

[0511] 1. Synthesis scheme:

[0512] 2. Experimental section:

[0513] 2.1

[0514] ((1-(((R)-2-(4-((R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-5-oxo- 6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl)carbamic acid tert-butyl ester (MX02706-1)

[0515] Tert-butyl ((1-(((R)-2-(4-((R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)- 5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl)carbamate (250 mg, 0.65 mmol), (R)-5-methyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 4,5-dihydropyridazin-3(2H)-one (305 mg, 0.97 mmol), Pd(dppf)Cl2(47 mg, 0.06 mmol), K2CO3(268 mg, 1.94 mmol) and water (4 mL) in 1,4-dioxane (16 mL) were stirred at 90 °C under argon protection for 5 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent, and the crude product was purified by column chromatography (MeOH / DCM = 0-10%, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to obtain the product as a white solid (221 mg, yield 63.49%).

[0516] ESI-MS m / z calcd for C 27H 34 N6O4S][M+H] + :539.2; Measured value: 538.8

[0517] 2.2

[0518] (R)-6-(4-((R)-4-((1-(aminomethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one(MX02705)

[0519] To a solution of tert-butyl carbamate (230 mg, 0.43 mmol) in dichloromethane (8 mL), trifluoroacetic acid (1 mL) was added and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed by vacuum distillation. The crude product was purified by preparative HPLC [MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254] to give a white solid product (71.55 mg, yield 38.21%).

[0520] ESI-MS m / z calculated value [C] 22 H 26 N6O2S][M+H] + :439.2; Measured value: 439.0

[0521] 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.42–7.91(m,5H),3.66–3.62(m,1H),3.47–3.36(m,2H),3.26–3.22 (m,1H),3.06–3.01(m,3H),2.77–2.71(m,1H),2.47–2.25(m,6H),1.87–1.80(m,3H),1.11(d,J=7.2Hz,3H).

[0522] 1. Synthesis scheme:

[0523] 2. Experimental Part: Compound 02707-0 and R-1 were used as starting materials to obtain compound MX02707 following the procedure of example MX-02686. White solid product (31.28 mg, yield 36.09%).

[0524] ESI-MS m / z calcd for C 28 H 37 FN6O4S2][M+H] + : 605.2; found: 604.8

[0525] 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (t, J = 8.0 Hz, 1H), 7.56 - 7.53 (m, 2H), 7.40 (s, 1H), 6.28 (s, 1H), 4.84 (t, J = 6.0 Hz, 1H), 4.39 (s, 2H), 3.98 (t, J = 5.6 Hz, 2H), 3.74 (d, J = 6.0 Hz, 2H), 3.47 - 3.39 (m, 1H), 3.29 - 3.19 (m, 1H), 2.98 - 2.85 (m, 6H), 2.53 - 2.52 (m, 2H), 2.42 - 2.27 (m, 8H), 2.23 - 2.16 (m, 2H), 1.81 - 1.75 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H).

[0526] 1. Synthesis scheme:

[0527] 2. Experimental Part: Compound 02709-0 was used as starting material to obtain compound MX02709 following the procedure of example MX-02770. White solid product (10.64 mg, yield 16%).

[0528] ESI-MS m / z calcd for C 24 H 33 N5O5S2][M+H] + : 536.2; found: 536.2

[0529] 1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.75 (dd, J = 8.8, 2.4 Hz, 1H), 7.35 (d, J = 9.2 Hz, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.20 (q, J = 6.8 Hz, 2H), 3.76 - 3.72 (m, 2H), 3.69 - 3.57 (m, 1H), 3.41 - 3.36 (m, 1H), 3.23 - 3.16 (m, 1H), 3.06 - 3.01 (m, 1H), 2.94 - 2.83 (m, 4H), 2.44 - 2.27 (m, 6H), 2.18 - 2.16 (m, 2H), 2.13 (s, 3H), 1.80 - 1.69 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H).

[0530] 1. Synthesis scheme:

[0531] 2. Experimental section: Compound 02714-0 was used as starting material and the procedure of Example MX-02618 was followed to obtain compound MX02714. White solid product (41.57 mg, 37% yield).

[0532] ESI-MS m / z calcd for C 27 H 38 N6O6S2][M+H] + : 607.2; found: 607.3

[0533] 1 H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 1H), 7.28 (dd, J = 8.4, 2.0 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 5.21 - 5.16 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.48 (dd, J = 10.0, 6.4 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.97 - 3.91 (m, 2H), 3.74 - 3.66 (m, 2H), 3.45 - 3.37 (m, 1H), 3.25 - 3.18 (m, 1H), 2.97 - 2.81 (m, 6H), 2.36 - 2.25 (m, 6H), 2.14 - 2.08 (m, 5H), 1.82 - 1.68 (m, 2H), 1.36 (t, J = 6.8 Hz, 3H).

[0534] 1. Synthesis scheme:

[0535] 2. Experimental section: Compound 02715-0 and R-1 were used as starting materials, following the procedure of example MX-02687 to obtain compound MX02715. White solid product (23.33 mg, yield 37.7%).

[0536] ESI-MS m / z calcd for C 28 H 41 N7O5S2][M+H] + :620.3; found: 619.8

[0537] 1 H NMR (400 MHz, DMSO-d6) δ 7.42 (s, 1H), 7.33 (dd, J = 8.4, 2.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.89 (s, 4H), 3.73 (d, J = 5.6 Hz, 2H), 3.46 - 3.38 (m, 1H), 3.25 - 3.18 (m, 1H), 3.07 - 3.05 (m, 4H), 2.96 - 2.84 (m, 6H), 2.39 - 2.26 (m, 6H), 2.22 - 2.16 (m, 2H), 2.12 (s, 3H), 1.81 - 1.71 (m, 2H), 1.41 (t, J = 6.8 Hz, 3H).

[0538] 1. Synthesis scheme:

[0539] 2. Experimental section: Compound 02716-0 and R-2 were used as starting materials, following the procedure of example MX-02686 to obtain compound MX02716. White solid compound (13.82 mg, yield 22.4%).

[0540] ESI-MS m / z calcd for C 29 H 42 N6O5S2][M+H] + :619.3; found: 619.3

[0541] 1H NMR (400 MHz, DMSO-d6) δ 7.53 (dd, J = 8.4, 2.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.33 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 4.83 (t, J = 5.6 Hz, 3H), 4.17 (q, J = 6.8 Hz, 2H), 3.72 (d, J = 5.6 Hz, 2H), 3.44 - 3.37 (m, 1H), 3.25 - 3.17 (m, 2H), 2.98 - 2.81 (m, 8H), 2.37 - 2.32 (m, 6H), 2.18 - 2.14 (m, 2H), 2.11 (s, 3H), 1.83 - 1.70 (m, 4H), 1.57 - 1.47 (m, 2H), 1.37 (t, J = 6.8 Hz, 3H).

[0542] 1. Experimental Section:

[0543] 2. Experimental Section: Compound 02717-0 and R-1 were used as starting materials, and the procedure of Example MX-02618 was followed to obtain compound MX02717. White solid product (7.65 mg, yield 12.34%).

[0544] ESI-MS m / z calcd for [C 28 H 40 N6O6S2][M+H] + :621.1; found: 621.3

[0545] 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.44 (s, 1H), 7.40 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 4.17 - 4.07 (m, 6H), 3.72 - 3.66 (m, 2H), 3.23 - 3.17 (m, 1H), 3.07 - 2.81 (m, 7H), 2.40 - 2.26 (m, 6H), 2.13 - 2.08 (m, 5H), 1.80 - 1.70 (m, 2H), 1.60 (s, 3H), 1.37 (t, J = 6.8 Hz, 3H).

[0546] 1. Synthetic Scheme:

[0547] 2. Experimental Section: Using compounds 02719-0 and R-1 as raw materials, and following the procedure described in Example MX-02687, compound MX02719 was obtained. The product was a white solid (12.59 mg, yield 17%).

[0548] ESI-MS m / z calculated value [C] 29 H 43 N7O5S2][M+H] + Measured value: 634.3; Actual value: 634.3

[0549] 1 H NMR(400MHz, DMSO-d6)δ7.42(s,1H),7.33(dd,J=8.8,2.4Hz,1H),7.16(d,J=8.8Hz,1H), 7.08(d,J=2.0Hz,1H),4.84(t,J=2.0Hz,1H),4.16(q,J=6.8Hz,2H),3.93–3.85(m,4H),3. 75–3.71(m,2H),3.46–3.38(m,1H),3.25–3.18(m,1H),3.08–3.05(m,4H),2.96–2.83(m, 6H), 2.49–2.17(m,10H),1.81–1.74(m,2H),1.41(t,J=6.8Hz,3H), 0.92(t,J=6.8Hz,3H).

[0550] 1. Synthesis scheme:

[0551] 2. Experimental Section:

[0552] 2.1

[0553] (R)-(1-((2-(3-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenoxy)azacyclobutane-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl)tert-butyl carbamate (02721-1)

[0554] To a solution of 1-((3-(azetidin-3-yloxy)-4-ethoxyphenyl)sulfonyl)-4- methylpiperazine (80 mg, 0.22 mmol) in DMF (3 mL) and DIEA (57 mg, 0.44 mmol) was added (R)-(1-((2-chloro-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl)carbamic acid tert-butyl ester (85 mg, 0.22 mmol). The mixture was stirred at 90 °C for 2 hours, then the mixture was distilled under reduced pressure to remove the solvent. Water (20 mL) was added, and extracted with EA (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 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product as a yellow solid (54 mg, yield 34%).

[0555] ESI-MS m / z calcd for C 32 H 47 N7O7S2][M+H] + :706.3; Found: 706.3

[0556] 2.2

[0557] (R)-4-((1-(Aminomethyl)cyclobutyl)amino)-2-(3-(2-ethoxy-5-((4- methylpiperazin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-6,7-dihydrothieno[3,2- d]pyrimidine 5-oxide (MX02721)

[0558] To a solution of (R)-(1-((2-(3-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl)carbamic acid tert-butyl ester (27 mg, 0.04 mmol) in DCM (2 mL) was added TFA (0.2 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 remove the solvent, the obtained 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 (13.66 mg, yield 59%).

[0559] ESI-MS m / z calcd for C 27 H 39N7O5S2][M+H] + : 606.3; Found: 606.3

[0560] 1 H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 1H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 5.22 - 5.17 (m, 1H), 4.46 - 4.42 (m, 2H), 4.15 (q, J = 6.8 Hz, 2H), 4.18 - 4.13 (m, 2H), 3.45 - 3.37 (m, 2H), 3.27 - 3.19 (m, 2H), 2.98 - 2.85 (m, 8H), 2.45 - 2.28 (m, 6H), 2.15 (s, 3H), 2.06 - 2.00 (m, 2H), 1.82 - 1.65 (m, 2H), 1.37 (t, J = 6.8 Hz, 3H).

[0561] 1. Synthesis scheme:

[0562] 2. Experimental part:

[0563] 2.1

[0564] (R)-4-((3,3-difluoro-l-(hydroxymethyl)cyclobutyl)amino)-2-(3-(2-ethoxy-5-((4- methylpiperazin-l-yl)sulfonyl)phenoxy)azetidin-l-yl)-6,7-dihydrothieno[3,2- d]pyrimidine 5-oxide (MX02722)

[0565] To a solution of l-((3-(azetidin-3-yloxy)-4-ethoxyphenyl)sulfonyl)-4- methylpiperazine (50 mg, 0.14 mmol) in DMF (3 mL) and DIEA (36 mg, 0.28 mmol) was added (R)-2-chloro-4-((3,3-difluoro-l-(hydroxymethyl)cyclobutyl)amino)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (45 mg, 0.14 mmol). The mixture was stirred at 90 °C for 2 hours, after consumption of the starting material, the mixture was concentrated under reduced pressure to give the crude product which 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 (25.22 mg, yield 28%).

[0566] ESI-MS m / z calcd for C 27 H 36 F2N6O6S2][M+H] + :643.2; found: 643.2

[0567] 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 5.23 - 5.12 (m, 1H), 5.13 (t, J = 6.0 Hz, 1H), 4.47 - 4.43 (m, 2H), 4.16 (q, J = 6.8 Hz, 2H), 4.19 - 4.13 (m, 2H), 3.67 - 3.63 (m, 2H), 3.48 - 3.40 (m, 1H), 3.25 - 3.17 (m, 1H), 3.00 - 2.76 (m, 10H), 2.37 - 2.32 (m, 4H), 2.14 (s, 3H), 1.38 (t, J = 6.8 Hz, 3H).

[0568] 1. Synthesis scheme:

[0569] 2. Experimental part:

[0570] 2.1

[0571] (R)-4-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)piperidine-1 - carboxylic acid tert-butyl ester (02724-1 )

[0572] To a solution of (R)-tert-butyl 4-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3- yl)phenyl)piperidine-1 -carboxylate (100 mg, 0.27 mmol) in methanol (10 mL) was added palladium on carbon (20 mg). The reaction was replaced with hydrogen and reacted under hydrogen protection for 4 hours. After the reaction was completed, the mixture was filtered and the solvent was removed under reduced pressure to obtain a white solid product (100 mg, yield 99.5%).

[0573] ESI-MS m / z calcd for C 21 H 29 N3O3][M+H] + :372.2; found: 372.2

[0574] 2.2

[0575] (R)-5-methyl-6-(4-(piperidin-4-yl)phenyl)-4,5-dihydropyridazin-3(2H)-one (02724-2)

[0576] To a solution of (R)-tert-butyl 4-(4-(4-methyl-6-oxo-l,4,5,6-tetrahydropyridazin-3- yl)phenyl)piperidine-l-carboxylate (100 mg, 0.27 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 mL) and stirred at room temperature overnight. After the reaction was completed, the mixture was distilled under reduced pressure to remove the solvent, and the crude product was directly used for the next reaction.

[0577] ESI-MS m / z calcd for C 16 H 21 N3O][M+H] + :272.2; found: 272.2

[0578] 2.3

[0579] (R)-6-(4-(l-((R)-4-((l-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7- dihydrothieno[3,2-d]pyrimidin-2-yl)piperidin-4-yl)phenyl)-5-methyl-4,5- dihydropyridazin-3(2H)-one (MX02724)

[0580] To a solution of (R)-5-methyl-6-(4-(piperidin-4-yl)phenyl)-4,5-dihydropyridazin-3(2H)- one (72 mg, 0.27 mmol) in DMF (2 mL) was added (R)-2-chloro-4-((l- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (51 mg, 0.18 mmol) and DIEA (137 mg, 1.06 mmol). The mixture was stirred at 85 °C under nitrogen protection for 2 hours. After the starting material was consumed, the mixture was concentrated under reduced pressure to remove the solvent, and the obtained 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 (25.04 mg, yield 27.03%).

[0581] ESI-MS m / z calcd for C 27 H 34 N6O3S][M+H] + :523..2; found: 522.9

[0582] 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.34 - 7.30 (m, 3H), 4.85 - 4.80 (m, 3H), 3.72 (d, J = 5.6 Hz, 2H), 3.43 - 3.35 (m, 2H), 3.23 - 3.19 (m, 1H), 2.98 - 2.84 (m, 5H), 2.69 - 2.63 (m, 1H), 2.38 - 2.30 (m, 2H), 2.24 - 2.14 (m, 3H), 1.84 - 1.73 (m, 4H), 1.55 - 1.51 (m, 2H), 1.06 (d, J = 7.2 Hz, 3H).

[0583] 1. Synthesis scheme:

[0584] 2. Experimental part: Compound MX02727 was obtained following the procedure of example MX02706, using 02727-0 and R-1 as starting materials. White solid product (32.0 mg, yield 43.7%).

[0585] ESI-MS m / z Calcd for C 22 H 23 F2N5O3S][M+H] + : 476.1 Found: 476.3

[0586] 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.55 (s, 1H), 8.37 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 5.25 (t, J = 5.6 Hz, 1H), 3.84 - 3.75 (m, 2H), 3.73 - 3.65 (m, 1H), 3.47 - 3.36 (m, 2H), 3.30 - 3.23 (m, 1H), 3.10 - 2.95 (m, 5H), 2.77 - 2.71 (m, 1H), 2.28 (d, J = 16.8 Hz, 1H), 1.12 (d, J = 7.2 Hz, 3H).

[0587] 1. Synthesis scheme:

[0588] 2. Experimental part: Compound MX02728 was obtained following the procedure of example MX-02618, using compound 02728-0 as starting material. White solid product (49.94 mg, yield 49.50%).

[0589] ESI-MS m / z Calcd for C25 H 33 FN6O5S2][M+H] + :581.2; found: 581.3

[0590] 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (dd, J = 10.4, 2.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.24 (t, J = 8.4 Hz, 1H), 5.31 - 5.28 (m, 1H), 4.83 (t, J = 5.6 Hz, 1H), 4.52 - 4.48 (m, 2H), 4.02 - 3.97 (m, 2H), 3.74 - 3.67 (m, 2H), 3.46 - 3.37 (m, 1H), 3.29 - 3.18 (m, 1H), 2.97 - 2.85 (m, 6H), 2.41 - 2.24 (m, 6H), 2.14 - 2.11 (m, 5H), 1.83 - 1.68 (m, 2H).

[0591] 1. Synthesis scheme:

[0592] 2. Experimental section: Compound MX02748 was obtained from compound 02748-0 and R-1 following the procedure of example MX-02618. White solid product (15.63 mg, yield 33%).

[0593] ESI-MS m / z calcd for [C 26 H 36 N6O6S2][M+H] + :593.2; found: 593.3

[0594] 1H NMR (400 MHz, DMSO-d6) δ 7.46 (s, 1H), 7.34 (dd, J = 8.4, 1.6 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 1.6 Hz, 1H), 5.22 - 5.17 (m, 1H), 4.85 (t, J = 5.2 Hz, 1H), 4.44 (dd, J = 9.6, 6.0 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.96 (br, 2H), 3.69 (d, J = 4.0 Hz, 2H), 3.44 - 3.37 (m, 1H), 3.26 - 3.18 (m, 1H), 2.98 - 2.85 (m, 2H), 2.74 (dd, J = 18.0, 4.4 Hz, 8H), 2.37 - 2.29 (m, 2H), 2.11 (t, J = 9.2 Hz, 2H), 1.79 - 1.66 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H).

[0595] 1. Synthesis scheme:

[0596] 2. Experimental section: Compound 02749-0 and R-1 were used as starting materials, following the procedure of Example MX-02618 to obtain compound MX02749. White solid product (75.44 mg, 76% yield).

[0597] ESI-MS m / z calcd for C 25 H 34 N6O5S2][M+H] + : 563.2; found: 563.2

[0598] 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (t, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = 8.4, 2.4 Hz, 1H), 7.10 (t, J = 2.0 Hz, 1H), 5.28 - 5.23 (m, 1H), 4.85 (t, J = 6.0 Hz, 1H), 4.47 (dd, J = 10.0, 1.6 Hz, 2H), 4.08 - 3.85 (m, 2H), 3.73 - 3.65 (m, 2H), 3.45 - 3.37 (m, 1H), 3.25 - 3.18 (m, 1H), 2.97 - 2.85 (m, 6H), 2.35 - 2.25 (m, 6H), 2.14 - 2.09 (m, 5H), 1.82 - 1.65 (m, 2H).

[0599] 1. Synthesis scheme:

[0600] 2. Experimental section:

[0601] 2.1

[0602] (R)-2-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenoxy)-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02760)

[0603] To a solution of 2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenol (50 mg, 0.17 mmol) in MeCN (4 mL) was added (R)-2-chloro-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (48 mg, 0.17 mmol), CS2CO3 (82 mg, 0.25 mmol) and DABCO (2 mg, 0.017 mmol) at room temperature. The mixture was stirred at 50 °C for 2 h. After the starting material was consumed, the reaction was adjusted to pH 6 with 1 N dilute hydrochloric acid, then 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 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 (12.04 mg, yield 13%).

[0604] ESI-MS m / z calcd for C 24 H 33 N5O6S2][M+H] + : 552.2; found: 552.3

[0605] 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 4.79 (t, J = 4.8 Hz, 1H), 4.11 (q, J = 6.8 Hz, 2H), 3.59 - 3.51 (m, 1H), 3.38 - 3.32 (m, 3H), 3.13 - 3.06 (m, 1H), 3.02 - 2.97 (m, 1H), 2.92 - 2.82 (m, 4H), 2.41 - 2.32 (m, 4H), 2.15 (s, 3H), 2.06 - 1.94 (m, 2H), 1.61 - 1.57 (m, 2H), 1.52 - 1.45 (m, 2H), 1.22 (t, J = 6.8 Hz, 3H).

[0606] 1. Synthesis scheme:

[0607] 2. Experimental part: Compound 02765-0 and R-1 were used as starting materials, and the operation in Example MX-02618 was referred to, to obtain compound MX02765. White solid product (39.22 mg, yield 44.00%).

[0608] ESI-MS m / z calcd for C 26 H 35 FN6O6S2][M+H] + : 611.2; found: 611.2

[0609] 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (dd, J = 10.4, 2.4 Hz, 1H), 7.53 (dd, J = 8.8, 1.2 Hz, 1H), 7.49 (s, 1H), 7.24 (t, J = 8.4 Hz, 1H), 5.32 - 5.29 (m, 1H), 4.83 (t, J = 5.6 Hz, 1H), 4.53 - 4.49 (m, 2H), 4.36 (t, J = 5.6 Hz, 1H), 4.03 - 4.01 (m, 2H), 3.72 - 3.69 (m, 2H), 3.46 - 3.37 (m, 3H), 3.26 - 3.18 (m, 1H), 2.97 - 2.85 (m, 6H), 2.51 - 2.47 (m, 3H), 2.38 - 2.28 (m, 4H), 2.16 - 2.11 (m, 2H), 1.80 - 1.70 (m, 2H), 0.95 (s, 1H).

[0610] 1. Synthesis scheme:

[0611] 2. Experimental section:

[0612] 2.1

[0613] 2-(4-((3-bromo-4-ethoxyphenyl)sulfonyl)piperazin-1-yl)ethanol (02770-1)

[0614] To a solution of 3-bromo-4-ethoxybenzene-1-sulfonyl chloride (200 mg, 0.66 mmol) in acetone (3 mL) and TEA (136 mg, 1.32 mmol) was added 2-(piperazin-1-yl)ethanol (86 mg, 0.66 mmol). The reaction mixture was stirred at room temperature for 1 h, then the mixture was distilled under reduced pressure to remove the solvent. Water (30 mL) was added and 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 = 0-50%, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product as a yellow oil (170 mg, yield 65%).

[0615] ESI-MS m / z calcd for [C 14 H 21 BrN2O4S][M+H] + :393.0; found:393.3

[0616] 2.2

[0617] (2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)boronic acid (02770-2)

[0618] To a solution of 2-(4-((3-bromo-4-ethoxyphenyl)sulfonyl)piperazin-1-yl)ethanol (150 mg, 0.38 mmol) in 1,4-dioxane (4 mL) was added B2Pin2 (193 mg, 0.76 mmol), KOAc (112 mg, 1.14 mmol) and Pd(dppf)Cl2.DCM (26 mg, 0.038 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 to give the crude product which was purified by reverse phase column (MeCN / H2O = 1 / 20-1 / 1, C-18 column, 20 mL / min, UV 254) to give the product as a brown solid (72 mg, yield 52%).

[0619] ESI-MS m / z calcd for [C 14 H 23 BN2O6S][M+H] + :359.1; found: 359.2

[0620] 2.3

[0621] (R)-2-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02770)

[0622] To a solution of (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7- dihydrothieno[3,2-d]pyrimidine 5-oxide (40 mg, 0.14 mmol) in 1,4-dioxane / water (2.5 mL, v / v = 4 / 1) was added (2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)boronic acid (50 mg, 0.14 mmol), K2CO3(40 mg, 0.42 mmol) and Pd(dppf)Cl2.DCM (10 mg, 0.014 mmol). The mixture was stirred at 90 °C under nitrogen protection for 3 hours. After the starting material was consumed, water (20 mL) was added and 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 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 (15.86 mg, yield 14%).

[0623] ESI-MS m / z calcd for [C 25 H 35 N5O6S2][M+H] + :566.2; found: 566.2

[0624] 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.75 (dd, J = 8.8, 2.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 4.84 (t, J = 6.0 Hz, 1H), 4.35 (t, J = 5.6 Hz, 1H), 4.20 (q, J = 6.8 Hz, 2H), 3.73 - 3.72 (m, 2H), 3.65 - 3.57 (m, 1H), 3.43 - 3.34 (m, 3H), 3.23 - 3.16 (m, 1H), 3.06 - 3.01 (m, 1H), 2.92 - 2.80 (m, 4H), 2.50 - 2.45 (m, 4H), 2.40 - 2.32 (m, 4H), 2.29 - 2.14 (m, 2H), 1.81 - 1.72 (m, 2H), 1.32 (t, J = 6.8 Hz, 3H).

[0625] 1. Synthesis scheme:

[0626] 2. Experimental section:

[0627] 2.1

[0628] 2-(4-((4-Fluoro-3-nitrophenyl)sulfonyl)piperazin-1-yl)ethanol (02771-1)

[0629] To a solution of 4-fluoro-3-nitrobenzene-1-sulfonyl chloride (500 mg, 2.09 mmol) in acetone (10 mL) was added 2-(piperazin-1-yl)ethanol (272 mg, 2.09 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then the mixture was distilled under reduced pressure to remove the solvent. Water (30 mL) 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, filtered and concentrated to give the product as a yellow oil (680 mg, yield 98%).

[0630] ESI-MS m / z calcd for [C 12 H 16 FN3O5S][M+H] + : 334.1; found: 334.1

[0631] 2.2

[0632] 2-(4-((4-Fluoro-3-nitrophenyl)sulfonyl)piperazin-1-yl)ethanol (02771-1)

[0633] To a solution of 2-(4-((4-fluoro-3-nitrophenyl)sulfonyl)piperazin-1-yl)ethanol (600 mg, 1.80 mmol) in ethanol (15 mL) was added NaH (60%, 144 mg, 3.60 mmol). The reaction mixture was stirred at room temperature for 1 h, then the mixture was distilled under reduced pressure to remove the solvent. Water (30 mL) 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, filtered and concentrated to give the product as a yellow oil (552 mg, yield 85%).

[0634] ESI-MS m / z calcd for [C 14 H 21 N3O6S][M+H] + : 360.1; found: 360.2

[0635] 2.3

[0636] 2-(4-((3-amino-4-ethoxyphenyl)sulfonyl)piperazin-1-yl)ethanol (02771-3)

[0637] To a solution of 2-(4-((4-ethoxy-3-nitrophenyl)sulfonyl)piperazin-1-yl)ethanol (500 mg, 1.40 mmol) in EtOH (10 mL) was added Pd / C (100 mg). The reaction mixture was stirred at room temperature for 2 h under hydrogen atmosphere, then filtered to remove Pd / C with celite, and the filtrate was concentrated under reduced pressure to give the product as a colorless oil (338 mg, yield 85%).

[0638] ESI-MS m / z calcd for [C 14 H 23 N3O4S][M+H] + : 330.1; found: 330.3

[0639] 2.4

[0640] (R)-2-((2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)phenyl)amino)-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02771)

[0641] To a solution of (R)-2-chloro-4-((l-(hydroxymethyl)cyclobutyl)amino)- 6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (65 mg, 0.30 mmol) in 1,4-dioxane (4 mL) was added 2-(4-((3-amino-4-ethoxyphenyl)sulfonyl)piperazin-l-yl)ethanol (110 mg, 0.30 mmol), t-BuONa (60 mg, 0.60 mmol), Ruphos (15 mg, 0.03 mmol) and Pd2(dba)3(14 mg, 0.03 mmol). The mixture was stirred at 100 °C under nitrogen overnight. 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 product as a white solid (16.34 mg, 9% yield).

[0642] ESI-MS m / z calcd for [C 25 H 36 N6O6S2][M+H] + :581.2; found: 581.3

[0643] 1 H NMR (400 MHz, DMSO-d6) δ 8.22 - 8.15 (m, 2H), 7.62 (s, 1H), 7.42 (dd, J = 8.4, 2.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 4.71 (t, J = 5.6 Hz, 1H), 4.36 (t, J = 5.6 Hz, 1H), 4.20 (q, J = 6.8 Hz, 2H), 3.72 - 3.70 (m, 2H), 3.51 - 3.39 (m, 3H), 3.29 - 3.24 (m, 1H), 3.02 - 2.86 (m, 6H), 2.51 - 2.47 (m, 4H), 2.35 (t, J = 6.0 Hz, 2H), 2.26 - 2.11 (m, 4H), 1.67 - 1.63 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H).

[0644] 1. Synthesis scheme:

[0645] 2. Experimental section:

[0646] 2.1

[0647] (1-(((R)-2-(4-((R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-5- oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl(2,2,2- trichloroacetyl)carbamate (02776-1)

[0648] To a solution of (R)-6-(4-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo- 6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)- one (55 mg, 0.13 mmol) in DCM (15 mL) was added 2,2,2-trichloroacetyl isocyanate (95 mg, 0.50 mmol) at 0 °C. The mixture was stirred at room temperature for 3 hours. When the starting material disappeared, the mixture was concentrated for the next step.

[0649] ESI-MS m / z calcd for C 23 H 26 N6O4S][M+H] + :483.2; found: 483.3

[0650] 2.2

[0651] (1-(((R)-2-(4-((R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-5- oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methylcarbamate (MX02776)

[0652] To a solution of (1-(((R)-2-(4-((R)-4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3- yl)phenyl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methyl(2,2,2- trichloroacetyl)carbamate (71 mg, 0.13 mmol) in MeOH (6 mL) was added K2CO3 (86 mg, 0.63 mmol) at room temperature. After the mixture was stirred at room temperature for two hours, the reaction was filtered 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 product as a white solid (14.31 mg, yield 23.70%).

[0653] ESI-MS m / z calcd for C 23H 26 N6O4S][M+H] + :483.2; Found: 483.3

[0654] 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.39 (d, J = 8.4 Hz, 2H), 8.28 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 6.50 (s, 2H), 4.51 - 4.46 (m, 2H), 3.69 - 3.64 (m, 1H), 3.47 - 3.36 (m, 2H), 3.27 - 3.23 (m, 1H), 3.07 - 3.02 (m, 1H), 2.77 - 2.71 (m, 1H), 2.44 - 2.25 (m, 5H), 1.93 - 1.86 (m, 2H), 1.11 (d, J = 7.2 Hz, 3H).

[0655] 1. Synthesis scheme:

[0656] 2. Experimental part: Compound 02778-0 and R-1 were used as starting materials, and the operation of Example MX-02618 was referred to, to obtain compound MX02778. White solid product (32.06 mg, yield 29.72%).

[0657] ESI-MS m / z calcd for C 28 H 40 N6O6S2][M+H] + :621.3; Found: 621.3

[0658] 1H NMR (400 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.35 (dd, J = 8.4, 1.6 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 1.6 Hz, 1H), 5.21 - 5.20 (m, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.46 - 4.42 (m, 2H), 4.16 (q, J = 6.8 Hz, 2H), 3.96 - 3.94 (m, 2H), 3.69 - 3.68 (m, 2H), 3.43 - 3.37 (m, 3H), 3.23 - 3.20 (m, 1H), 2.97 - 2.86 (m, 2H), 2.74 - 2.71 (m, 1H), 2.35 - 2.27 (m, 3H), 2.18 - 2.06 (m, 7H), 1.98 - 1.95 (m, 1H), 1.76 - 1.71 (m, 2H), 1.37 (t, J = 6.8 Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H).

[0659] 1. Synthesis scheme:

[0660] 2. Experimental section: Compound 02781-0 and R-1 were used as starting materials to obtain compound MX02781 following the procedure of example MX-02618. White solid product (13.55 mg, yield 45%).

[0661] ESI-MS m / z calcd for C 28 H 38 N6O6S2][M+H] + : 619.2; found: 619.2

[0662] 1H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.43 (m, 2H), 7.20 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 5.20 - 5.18 (m, 1H), 4.83 (t, J = 5.6 Hz, 1H), 4.46 - 4.39 (m, 2H), 4.13 (q, J = 6.8 Hz, 2H), 4.15 - 3.88 (m, 2H), 3.73 - 3.65 (m, 2H), 3.45 - 3.37 (m, 2H), 3.28 - 3.18 (m, 1H), 2.97 - 2.80 (m, 4H), 2.46 - 2.25 (m, 4H), 2.21 (s, 3H), 2.13 - 2.06 (m, 2H), 1.91 - 1.86 (m, 1H), 1.81 - 1.67 (m, 2H), 1.37 (t, J = 6.8 Hz, 3H), 0.38 - 0.34 (m, 1H), 0.20 - 0.15 (m, 1H).

[0663] 1. Synthesis scheme:

[0664] 2. Experimental section: Compound 02785-0 and R-1 were used as starting materials, and the procedure of Example MX02681 was followed to obtain compound MX02785. White solid product (4.99 mg, yield 5.8%).

[0665] ESI-MS m / z calcd for C 28 H 30 FN7O4S][M+H] + :580.2; Found: 580.3

[0666] 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.11 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 12.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 5.16 (d, J = 7.2 Hz, 2H), 4.92 (t, J = 5.6 Hz, 1H), 4.12 (d, J = 7.2 Hz, 2H), 3.79 - 3.77 (m, 2H), 3.68 - 3.59 (m, 1H), 3.46 (s, 3H), 3.25 - 3.10 (m, 1H), 3.05 - 3.00 (m, 1H), 2.43 - 2.29 (m, 5H), 1.85 - 1.79 (m, 2H), 1.36 - 1.30 (m, 1H), 0.53 - 0.47 (m, 2H), 0.43 - 0.40 (m, 2H).

[0667] 1. Synthesis scheme:

[0668] 2. Experimental part: Compound 02788-0 was used as starting material and the procedure of Example MX-02681 was followed to obtain compound MX02788. White solid product (13.67 mg, yield 19%).

[0669] ESI-MS m / z calcd for C 29 H 33 N7O4S][M+H] + :576.2; found: 576.3

[0670] 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 8.4 Hz, 2H), 8.14 (s, 1H), 7.98 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 6.28 - 6.23 (m, 1H), 4.90 (t, J = 5.6 Hz, 1H), 4.10 (d, J = 6.4 Hz, 2H), 3.84 - 3.79 (m, 2H), 3.76 - 3.58 (m, 1H), 3.40 - 3.34 (m, 4H), 3.23 - 3.17 (m, 1H), 3.04 - 2.99 (m, 1H), 2.45 - 2.28 (m, 4H), 1.84 - 1.76 (m, 5H), 1.18 - 1.12 (m, 1H), 0.51 - 0.40 (m, 4H).

[0671] 1. Synthesis scheme:

[0672] 2. Experimental part: Compound 02808-0 and R-1 were used as starting materials and the procedure of Example MX02687 was followed to obtain compound MX02808. White solid compound (5.06 mg, yield 17%).

[0673] ESI-MS m / z calcd for C 29 H 42 N8O4S2][M+H] + :631.3; found: 631.4

[0674] 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 2.4 Hz, 1H), 7.87 (dd, J = 8.8, 2.4 Hz, 1H), 7.48 (t, J = 5.6 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.23 (d, J = 9.2 Hz, 1H), 4.83 (t, J = 5.6 Hz, 1H), 4.12 - 3.94 (m, 2H), 3.87 - 3.67 (m, 5H), 3.45 - 3.37 (m, 1H), 3.26 - 3.17 (m, 1H), 2.94 - 2.70 (m, 5H), 2.34 - 2.14 (m, 5H), 2.09 (s, 3H), 2.00 - 1.93 (m, 2H), 1.78 - 1.62 (m, 4H), 1.56 - 1.49 (m, 2H), 1.31 - 1.19 (m, 2H), 1.07 - 0.93 (m, 4H).

[0675] 1. Synthesis scheme:

[0676] 2. Experimental section: Compound 02834-0 and R-1 were used as starting materials, and the procedure of Example MX-02771 was followed to obtain compound MX02834. White solid product (18.60 mg, yield 10.50%).

[0677] ESI-MS m / z calcd for [C 26 H 36 N6O5S2][M+H] + :577.2; found:577.2

[0678] 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 2.4 Hz, 1H), 7.87 (dd, J = 8.8, 2.4 Hz, 1H), 7.48 (t, J = 5.6 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.23 (d, J = 9.2 Hz, 1H), 4.83 (t, J = 5.6 Hz, 1H), 4.12 - 3.94 (m, 2H), 3.87 - 3.67 (m, 5H), 3.45 - 3.37 (m, 1H), 3.26 - 3.17 (m, 1H), 2.94 - 2.70 (m, 5H), 2.34 - 2.14 (m, 5H), 2.09 (s, 3H), 2.00 - 1.93 (m, 2H), 1.78 - 1.62 (m, 4H), 1.56 - 1.49 (m, 2H), 1.31 - 1.19 (m, 2H), 1.07 - 0.93 (m, 4H).

[0679] 1. Synthesis scheme:

[0680] 2. Experimental section: Compound 02836-0 and R-1 were used as starting materials to obtain compound MX02836 following the procedure of example MX-02770. White solid product (18.96 mg, yield 19.39%).

[0681] ESI-MS m / z calcd for [C 27 H 37 N5O5S2][M+H] + :576.2; found: 576.3

[0682] 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.76 (dd, J = 8.8, 6.4 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.21 (q, J = 6.8 Hz, 2H), 3.76 - 3.69 (m, 2H), 3.64 - 3.58 (m, 1H), 3.42 - 3.36 (m, 1H), 3.34 - 3.33 (m, 2H), 3.23 - 3.17 (m, 1H), 3.09 - 3.01 (m, 1H), 2.88 - 2.86 (m, 4H), 2.51 - 2.50 (m, 2H), 2.40 - 2.27 (m, 2H), 2.18 - 2.14 (m, 4H), 1.80 - 1.68 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H), 0.74 - 0.70 (m, 1H), 0.43 - 0.38 (m, 2H), 0.04 - 0.01 (m, 2H).

[0683] 1. Synthesis scheme:

[0684] 2. Experimental section: Compound 02838-0 was used as starting material to obtain compound MX02838 following the procedure of example MX-02770. White solid product (2.77 mg, yield 2.2%).

[0685] ESI-MS m / z calcd for [C 26 H 37 N5O5S2][M+H] + :564.2; found: 564.2

[0686] 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.90 (d, J = 2.8 Hz, 1H), 7.80 (dd, J = 8.8, 2.4 Hz, 1H), 7.49 (t, J = 5.2 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.18 (q, J = 6.8 Hz, 2H), 3.73 - 3.71 (m, 2H), 3.65 - 3.57 (m, 1H), 3.42 - 3.34 (m, 1H), 3.25 - 3.16 (m, 1H), 3.06 - 3.01 (m, 1H), 2.88 - 2.82 (m, 1H), 2.80 - 2.70 (m, 2H), 2.43 - 2.38 (m, 2H), 2.18 - 2.11 (m, 2H), 2.08 (s, 3H), 2.00 - 1.93 (m, 2H), 1.80 - 1.61 (m, 4H), 1.56 - 1.48 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H), 1.27 - 1.18 (m, 2H).

[0687] 1. Synthesis scheme:

[0688] 2. Experimental section: Compound MX02839 was obtained starting from compound 02839-0 and R-1 following the procedure of example MX02686. White solid compound (11.03 mg, yield 8.2%).

[0689] ESI-MS m / z calcd for C 29 H 39 N7O4S2][M+H] + : 614.3; found: 614.2

[0690] 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 2.4 Hz, 1H), 8.09 (dd, J = 8.4, 2.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.05 (s, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.47 (s, 2H), 3.99 (t, J = 4.4 Hz, 2H), 3.75 (d, J = 4.4 Hz, 2H), 3.48 - 3.39 (m, 1H), 3.26 - 3.18 (m, 1H), 2.99 - 2.95 (m, 5H), 2.89 - 2.84 (m, 1H), 2.67 (s, 2H), 2.51 - 2.50 (m, 4H), 2.43 - 2.30 (m, 2H), 2.23 - 2.18 (m, 2H), 2.16 (d, J = 6.8 Hz, 2H), 1.84 - 1.73 (m, 2H), 0.77 - 0.70 (m, 1H), 0.43 - 0.39 (m, 2H), 0.04 - 0.02 (m, 2H).

[0691] 1. Synthesis scheme:

[0692] 2. Experimental section: Compound 02840-0 and R-1 were used as starting materials, following the procedure of Example MX02686 to obtain compound MX02840. White solid product (18.73 mg, yield 22.1%).

[0693] ESI-MS m / z calcd for C 25 H 33 N7O4S2][M+H] + :560.2; Found: 560.3

[0694] 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 2.0 Hz, 1H), 8.11 (dd, J = 8.4, 2.4 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.45 (s, 1H), 7.08 - 7.06 (m, 1H), 5.51 - 5.10 (m, 1H), 4.88 - 4.86 (m, 1H), 4.47 - 4.45 (m, 2H), 4.00 - 3.98 (m, 2H), 3.765 - 3.75 (m, 2H), 3.47 - 3.41 (m, 1H), 3.25 - 3.18 (m, 1H), 2.99 - 2.85 (m, 10H), 2.68 - 2.66 (m, 2H), 2.40 - 2.29 (m, 2H), 2.23 - 2.19 (m, 2H), 1.83 - 1.76 (m, 2H).

[0695] 1. Synthesis scheme:

[0696] 2. Experimental part: Compound 02843-0 was used as starting material and the procedure of Example MX-02618 was followed to obtain compound MX02843. White solid compound (64.52 mg, yield 48%).

[0697] ESI-MS m / z calcd for [C 27 H 35 D3N6O6S2][M+H] + : 610.3; found: 610.3

[0698] 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.35 (dd, J = 8.8, 2.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 1.6 Hz, 1H), 5.20 - 5.18 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.44 (dd, J = 10.0, 6.4 Hz, 2H), 4.16 (q, J = 6.8 Hz, 2H), 4.10 - 3.85 (m, 2H), 3.72 - 3.65 (m, 2H), 3.46 - 3.37 (m, 1H), 3.25 - 3.18 (m, 1H), 2.98 - 2.87 (m, 6H), 2.39 - 2.26 (m, 6H), 2.13 - 2.08 (m, 2H), 1.79 - 1.67 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H).

[0699] 1. Synthesis scheme:

[0700] 2. Experimental part: Compound 02846-0 and R-1 were used as starting materials and the procedure of Example MX02681 was followed to obtain compound MX02846. White solid product (7.57 mg, yield 15.5%).

[0701] ESI-MS m / z calcd for [C 27 H 30 N8O4S][M+H] + : 563.2; found: 563.3

[0702] 1H NMR (400 MHz, DMSO-d6) δ 9.26 (d, J = 1.6 Hz, 1H), 8.51 (dd, J = 8.4, 2.0 Hz, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 5.25 (s, 2H), 4.92 (t, J = 6.0 Hz, 1H), 4.12 (d, J = 7.2 Hz, 2H), 3.81 - 3.76 (m, 2H), 3.64 - 3.60 (m, 1H), 3.46 (s, 3H), 3.40 - 3.34 (m, 1H), 3.25 - 3.19 (m, 1H), 3.05 - 3.01 (m, 1H), 2.39 - 2.29 (m, 4H), 1.82 - 1.78 (m, 2H), 1.31 - 1.31 (m, 1H), 0.53 - 0.48 (m, 2H), 0.42 - 0.39 (m, 2H).

[0703] 1. Synthesis scheme:

[0704] 2. Experimental section: Compound MX02849 was obtained following the procedure of example MX02716, starting from 02849-0 and R-1. White solid product (45.0 mg, yield 43.9%).

[0705] ESI-MS m / z calcd for C 27 H 39 N7O5S2][M+H] + :606.2 Found: 606.3 [M+H] +

[0706] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 2.0 Hz, 1H), 8.05 (dd, J = 8.0, 2.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.80 - 4.77 (m, 2H), 4.36 (t, J = 5.2 Hz, 1H), 3.75 - 3.68 (m, 2H), 3.46 - 3.37 (m, 3H), 3.28 - 3.15 (m, 2H), 3.04 - 2.84 (m, 8H), 2.48 - 2.47 (m, 4H), 2.37 - 2.29 (m, 4H), 2.18 - 2.14 (m, 2H), 1.92 - 1.89 (m, 2H), 1.79 - 1.64 (m, 4H).

[0707] 1. Synthesis scheme:

[0708] 2. Experimental section: Compound MX02922 was obtained by using compound 02922-0 and R-1 as starting materials, following the procedure of example MX-02618. White solid compound (50 mg, yield 30%).

[0709] ESI-MS m / z calcd for [C 28 H 40 N6O6S2][M+H] + :621.2; found: 621.3

[0710] 1 H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.42 (m, 2H), 7.23 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 5.24 - 5.19 (m, 1H), 4.84 (t, J = 5.6 Hz, 1H), 4.44 (dd, J = 9.6, 6.4 Hz, 2H), 4.15 (q, J = 6.8 Hz, 2H), 3.90 - 3.96 (m, 2H), 3.73 - 3.65 (m, 2H), 3.45 - 3.34 (m, 2H), 3.29 - 3.18 (m, 2H), 3.12 - 3.06 (m, 1H), 2.97 - 2.80 (m, 3H), 2.50 - 2.40 (m, 1H), 2.39 - 2.26 (m, 2H), 2.13 - 2.09 (m, 2H), 2.04 (s, 6H), 1.93 - 1.85 (m, 1H), 1.79 - 1.67 (m, 2H), 1.52 - 1.47 (m, 1H), 1.37 (t, J = 7.2 Hz, 3H).

[0711] 1. Synthesis scheme:

[0712] 2. Experimental section: Compound MX02923 was obtained by using compound 02923-0 and R-1 as starting materials, following the procedure of example MX-02618. White solid product (10.53 mg, yield 16.61%).

[0713] ESI-MS m / z calcd for [C 29 H 42 N6O6S2][M+H] + :635.3; found: 635.3

[0714] 1H NMR (400 MHz, DMSO-d6) δ 7.45 (s, 1H), 7.35 (dd, J = 8.8, 2.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 5.21 - 4.86 (m, 1H), 4.86 (t, J = 5.6 Hz, 1H), 4.46 - 4.42 (m, 2H), 4.14 (q, J = 6.8 Hz, 2H), 3.96 - 3.95 (m, 2H), 3.72 - 3.66 (m, 2H), 3.59 - 3.56 (m, 2H), 3.45 - 3.37 (m, 1H), 3.26 - 3.18 (m, 1H), 2.97 - 2.85 (m, 2H), 2.34 - 2.26 (m, 4H), 2.08 - 2.02 (m, 9H), 1.79 - 1.67 (m, 4H), 1.44 - 1.35 (m, 5H).

[0715] 1. Synthesis scheme:

[0716] 2. Experimental section: Compound MX02938 was obtained following the procedure of example MX02618, starting from 02938-0 and R-1. White solid product (40.0 mg, yield 44.57%).

[0717] ESI-MS m / z calcd for C 24 H 30 FN5O6S2][M+H] + : 568.2 Found: 568.2

[0718] 1 H NMR (400 MHz, DMSO-d6) δ 7.61 - 7.56 (m, 1H), 7.48 (s, 1H), 7.43 - 7.40 (m, 1H), 7.17 (dd, J = 8.0, 2.0 Hz, 1H), 5.40 - 5.35 (m, 1H), 4.84 (t, J = 6.0 Hz, 1H), 4.47 (dd, J = 10.0, 6.4 Hz, 2H), 4.10 - 3.94 (m, 2H), 3.73 - 3.59 (m, 6H), 3.46 - 3.37 (m, 1H), 3.26 - 3.18 (m, 1H), 2.97 - 2.85 (m, 6H), 2.39 - 2.26 (m, 2H), 2.13 - 2.06 (m, 2H), 1.81 - 1.67 (m, 2H).

[0719] 1. Synthesis scheme:

[0720] 2. Experimental section:

[0721] 2.1

[0722] 4-((3-bromo-4-ethoxyphenyl)sulfonyl)morpholine (02952-1)

[0723] A solution of 3-bromo-4-ethoxybenzene-1-sulfonyl chloride (100 mg, 0.27 mmol) and morpholine (23 mg, 0.27 mmol) in acetone (5 mL) was added TEA (54 mg, 0.53 mmol) and the reaction was stirred at room temperature for 3 hours. 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 (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and 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 (94 mg, yield 99.8%).

[0724] ESI-MS m / z calcd for [C 12 H 16 BrNO4S][M+H] + : 350.0; found: 350.2

[0725] 2.2

[0726] 2-ethoxy-5-(morpholinosulfonyl)phenol (02952-2)

[0727] A solution of 4-((3-bromo-4-ethoxyphenyl)sulfonyl)morpholine (90 mg, 0.26 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1) was added KOH (22 mg, 0.39 mmol), tBu-Xphos (13 mg, 0.03 mmol) and Pd2(dba)3(12 mg, 0.01 mmol), and the reaction was stirred at 80 °C for 3 hours. 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, and 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 (74 mg, yield 99.2%).

[0728] ESI-MS m / z calcd for [C 12 H 17NO5S][M+H] + :288.1; found: 288.2

[0729] 2.3

[0730] 3-(2-ethoxy-5-(morpholinosulfonyl)phenoxy)azetidine-1 -carboxylic acid tert-butyl ester (02952-3)

[0731] To a solution of 2-ethoxy-5-(morpholinosulfonyl)phenol (70 mg, 0.24 mmol) and 3-(p-toluenesulfonyloxy)azetidine-1 -carboxylic acid tert-butyl ester (80 mg, 0.24 mmol) in DMF (3 mL) was added Cs2C03(156 mg, 0.48 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 oil (106 mg, yield 99.9%).

[0732] ESI-MS m / z calcd for [C 20 H 30 N2O7S][M-56+H] + :387.2; found: 387.2

[0733] 2.4

[0734] 4-((3-(azetidin-3-yloxy)-4-ethoxyphenyl)sulfonyl)morpholine (02952-4)

[0735] To a solution of 3-(2-ethoxy-5-(morpholinosulfonyl)phenoxy)azetidine-1 -carboxylic acid tert-butyl ester (100 mg, 0.23 mmol) in DCM (2 mL) was added trifluoroacetic acid (0.2 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated and the crude product was used directly for the next reaction.

[0736] ESI-MS m / z calcd for [C 15 H 22 N2O5S][M+H] + :343.2; found: 343.3

[0737] 2.5

[0738] (R)-2-(3-(2-ethoxy-5-(morpholine-sulfonyl)phenoxy)azetidin-1-yl)-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02952)

[0739] To a solution of 4-((3-(azetidin-3-yloxy)-4-ethoxyphenyl)sulfonyl)morpholine (34 mg, 0.10 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 (26 mg, 0.20 mmol). The mixture was stirred at 80 °C under nitrogen protection for 2 h, 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 (17.57 mg, yield 29.63%).

[0740] ESI-MS m / z calcd for [C 26 H 35 N5O7S2][M+H] + :594.2; found: 594.3

[0741] 1 H NMR (400 MHz, DMSO-d6) d 7.51 (s, 1H), 7.36 (dd, J = 8.8, 2.4 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 5.23 - 5.19 (m, 1H), 4.86 (t, J = 5.6 Hz, 1H), 4.46 - 4.42 (m, 2H), 4.19 - 4.14 (m, 2H), 4.01 - 3.96 (m, 2H), 3.72 - 3.66 (m, 2H), 3.64 - 3.62 (m, 4H), 3.45 - 3.37 (m, 1H), 3.25 - 3.17 (m, 1H), 2.97 - 2.85 (m, 6H), 2.36 - 2.25 (m, 2H), 2.13 - 2.08 (m, 2H), 1.78 - 1.66 (m, 2H), 1.38 (t, J = 6.8 Hz, 3H).

[0742] 1. Synthesis scheme:

[0743] 2. Experimental section:

[0744] 2.1

[0745] (R)-6-(4-bromophenyl)-2,5-dimethyl-4,5-dihydropyridazin-3(2H)-one (02967-1)

[0746] To a solution of (R)-6-(4-bromophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (200 mg, 0.75 mmol) in dry THF (10 mL) was added NaH (60%, 36 mg, 0.91 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min, then iodomethane (210 mg, 1.5 mmol) was added to the mixture, the mixture was stirred at 25 °C for 2 h, the pH value of the reaction mixture was adjusted to 6 with 1 N aqueous HC1. Stirring at room temperature for 2 h. The reaction was quenched with water (10 mL) and extracted with EA (10 mL) three times. 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 (EA / PE = 0~1 / 1 / 1, silica gel-CS 12 g, 30 mL / min, UV 254) to give the product as colorless oil (209 mg, yield 99.5%).

[0747] ESI-MS m / z calcd for [C 12 H 13 BrN2O][M+H] + :281.2; found: 218.2

[0748] 2.2

[0749] (R)-2,5-dimethyl-6-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-4,5- dihydropyridazin-3(2H)-one (02967-2)

[0750] To a solution of (R)-6-(4-bromophenyl)-2,5-dimethyl-4,5-dihydropyridazin-3(2H)-one (120 mg, 0.42 mmol) in 1,4-dioxane (2 mL) was added B2Pin2 (214 mg, 0.84 mmol), KOAc (82 mg, 0.84 mmol) and Pd(dppf)Cl2 (17 mg, 0.02 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 purified by column chromatography (EA / PE = 0~1 / 1 / 1, silica gel-CS 12 g, 30 mL / min, UV 254) to give the product as colorless oil (135 mg, yield 98.5%).

[0751] ESI-MS m / z calcd for [C 18 H 25 BN2O3][M+H] + :329.2; found: 329.4

[0752] 2.3

[0753] (R)-6-(4-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-2-yl)phenyl)-2,5-dimethyl-4,5-dihydropyridazin-3(2H)-one (MX02967)

[0754] To a solution of (R)-2,5-dimethyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 4,5-dihydropyridazin-3(2H)-one (69 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 (16 mg, 0.02 mmol). The mixture was heated to 90 °C and stirred under nitrogen for 5 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 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 white solid (7.35 mg, yield 7.73%).

[0755] ESI-MS m / z calcd for [C 23 H 27 N5O3S][M+H] + :454.2;found:454.0

[0756] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 8.4 Hz, 2H), 8.06 (s, 1H), 7.95 (d, J = 8.8 Hz, 2H), 4.92 (t, J = 5.6 Hz, 1H), 3.84 - 3.82 (m, 2H), 3.68 - 3.61 (m, 2H), 3.51 - 3.39 (m, 1H), 3.36 (s, 3H), 3.27 - 3.22 (m, 1H), 3.06 - 3.02 (m, 1H), 2.81 - 2.75 (m, 1H), 2.44 - 2.34 (m, 5H), 1.88 - 1.82 (m, 2H), 1.11 (d, J = 7.2 Hz, 3H).

[0757] 1. Synthesis scheme:

[0758] 2. Experimental part: Compound MX02982 was obtained from compound 02982-0 and R-1 as starting materials, following the procedure of Example MX-02618. White solid product (30.0 mg, yield 35.17%).

[0759] ESI-MS m / z calcd for [C 28 H 39 N5O6S2][M+H] + :606.2;found:606.2

[0760] 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 1H), 7.34 (dd, J = 8.4, 2.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 5.22 - 5.17 (m, 1H), 4.86 (t, J = 5.6 Hz, 1H), 4.47 - 4.40 (m, 2H), 4.14 (q, J = 6.8 Hz, 2H), 4.03 - 3.87 (m, 2H), 3.72 - 3.64 (m, 2H), 3.60 - 3.59 (m, 2H), 3.46 - 3.37 (m, 1H), 3.25 - 3.17 (m, 1H), 2.98 - 2.85 (m, 2H), 2.38 - 2.25 (m, 2H), 2.18 - 2.07 (m, 4H), 1.79 - 1.63 (m, 4H), 1.37 (t, J = 6.8 Hz, 3H), 1.33 - 1.24 (m, 1H), 1.19 - 1.09 (m, 2H), 0.86 (d, J = 6.4 Hz, 3H).

[0761] 1. Synthesis scheme:

[0762] 2. Experimental part: Compound MX02983 was obtained from compound 02983-0 and R-1 as starting materials, following the procedure of Example MX-02618. White solid product (44.80 mg, yield 54.15%).

[0763] ESI-MS m / z calcd for [C 27 H 37 N5O6S2][M+H] + :592.2; found: 592.3

[0764] 1H NMR (400 MHz, DMSO-d6) δ 7.48 (s, 1H), 7.34 (dd, J = 8.8, 2.0 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 5.22 - 5.17 (m, 1H), 4.84 (t, J = 6.0 Hz, 1H), 4.46 - 4.42 (m, 2H), 4.16 (d, J = 7.2 Hz, 2H), 3.95 - 3.94 (m, 2H), 3.72 - 3.64 (m, 2H), 3.46 - 3.37 (m, 1H), 3.26 - 3.18 (m, 1H), 2.98 - 2.85 (m, 6H), 2.39 - 2.26 (m, 2H), 2.12 - 2.07 (m, 2H), 1.81 - 1.65 (m, 2H), 1.54 - 1.53 (m, 4H), 1.38 (m, 5H).

[0765] 1. Synthesis scheme:

[0766] 2. Experimental part: Compound MX02989 was obtained from compound 02989-0 and R-1 following the procedure of example MX-02618. White solid product (58.0 mg, yield 33.07%).

[0767] ESI-MS m / z calcd for [C 28 H 39 N5O7S2][M+H] + : 622.2; found: 622.2

[0768] 1H NMR (400 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 5.22 - 5.17 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.46 - 4.42 (m, 2H), 4.15 (q, J = 6.8 Hz, 2H), 3.954 - 3.879 (m, 2H), 3.73 - 3.65 (m, 2H), 3.46 - 3.37 (m, 1H), 3.26 - 3.18 (m, 2H), 3.16 (s, 3H), 3.10 - 3.07 (m, 2H), 2.97 - 2.85 (m, 2H), 2.77 - 2.72 (m, 2H), 2.39 - 2.26 (m, 2H), 2.13 - 2.08 (m, 2H), 1.85 - 1.67 (m, 4H), 1.53 - 1.50 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H).

[0769] 1. Synthesis scheme:

[0770] 2. Experimental part:

[0771] 2.1

[0772] 1-((3-bromo-4-ethoxyphenyl)sulfonyl)-3-methoxyazetidine (02990-1)

[0773] A solution of 3-bromo-4-ethoxybenzene-1-sulfonyl chloride (200 mg, 0.67 mmol) and 3-methoxyazetidine (58 mg, 0.67 mmol) in acetone (5 mL) was added TEA (135 mg, 1.34 mmol) and the reaction was stirred at room temperature for 3 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 layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and 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 obtain the yellow solid product (211 mg, yield 90%).

[0774] ESI-MS m / z calcd for [C 12 H 16 BrNO4S][M+H] + : 350.0; found: 350.0

[0775] 2.2

[0776] 2-ethoxy-5-((3-methoxyazetidin-l-yl)sulfonyl)phenol (02990-2)

[0777] To a solution of l-((3-bromo-4-ethoxyphenyl)sulfonyl)-3-methoxyazetidine (211 mg, 0.60 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1) was added KOH (67 mg, 1.20 mmol), tBu-Xphos (25 mg, 0.06 mmol) and Pd2(dba)3(55 mg, 0.06 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 20 g, 20 mL / min, silica gel, UV 254) to give the product as a yellow solid (141 mg, 81% yield).

[0778] ESI-MS m / z calcd for [C 12 H 17 NO5S][M+H] + :288.1; found:288.4

[0779] 2.3

[0780] 3-(2-ethoxy-5-((3-methoxyazetidin-l-yl)sulfonyl)phenoxy)azetidine-l- carboxylic acid tert-butyl ester (02990-3)

[0781] To a solution of 2-ethoxy-5-((3-methoxyazetidin-l-yl)sulfonyl)phenol (141 mg, 0.49 mmol) and 3-(p-tolylsulfonyloxy)azetidine-l-carboxylic acid tert-butyl ester (160 mg, 0.49 mmol) in DMF (4 mL) was added Cs2CO3(319 mg, 0.98 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 (172 mg, 79% yield).

[0782] ESI-MS m / z calcd for [C 20 H 30 N2O7S][M-56+H] + :387.2; found: 387.3

[0783] 2.4

[0784] 1-((3-(azetidin-3-yloxy)-4-ethoxyphenyl)sulfonyl)-3-methoxyazetidine (02990-4)

[0785] To a solution of tert-butyl 3-(2-ethoxy-5-((3-methoxyazetidin-l- yl)sulfonyl)phenoxy)azetidine-l-carboxylate (62 mg, 0.14 mmol) in DCM (3 mL) was added TFA (0.5 mL). The mixture was then stirred at room temperature for 1 h, and the reaction was concentrated under vacuum to give the product as a yellow oil (45 mg, 94% yield).

[0786] ESI-MS m / z calcd for [C 15 H 22 N2O5S][M+H] + :343.1; found: 343.3

[0787] 2.5

[0788] (R)-2-(3-(2-ethoxy-5-((3-methoxyazetidin-l-yl)sulfonyl)phenoxy)azetidin-l- yl)-4-((l-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX02990)

[0789] To a solution of 1-((3-(azetidin-3-yloxy)-4-ethoxyphenyl)sulfonyl)-3- methoxyazetidine (45 mg, 0.13 mmol) and (R)-2-chloro-4-((l- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (38 mg, 0.13 mmol) in DMF (2 mL) was added DIEA (34 mg, 0.26 mmol), and the mixture was stirred at 90 °C for 2 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 the compound as a white solid (47.20 mg, 60% yield).

[0790] ESI-MS m / z calcd for [C 26 H 35 N5O7S2][M+H] + :594.2;found:594.2

[0791] 1 H NMR (400 MHz, DMSO-d6) δ 7.46 (s, 1H), 7.44 (dd, J = 8.4, 2.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 5.27 - 5.22 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.44 (dd, J = 10.0, 6.4 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 4.04 - 3.96 (m, 3H), 3.91 - 3.88 (m, 2H), 3.73 - 3.65 (m, 2H), 3.45 - 3.37 (m, 3H), 3.25 - 3.18 (m, 1H), 3.07 (s, 3H), 2.97 - 2.85 (m, 2H), 2.39 - 2.26 (m, 2H), 2.13 - 2.08 (m, 2H), 1.82 - 1.67 (m, 2H), 1.39 (t, J = 7.2 Hz, 3H).

[0792] 1. Synthesis scheme:

[0793] 2. Experimental part: Compound MX021003 was obtained from compound 021003-0 and R-1 as starting materials, following the procedure of Example MX-02967. White solid product (5.80 mg, yield 9%).

[0794] ESI-MS m / z calcd for [C 22 H 23 N5O4S][M+H] + :454.2;found:454.2

[0795] 1H NMR (400 MHz, DMSO-d6) δ 12.40 (br s, 1H), 11.08 (s, 1H), 9.00 (s, 1H), 8.38 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H), 3.71 - 3.64 (m, 1H), 3.49 - 3.36 (m, 2H), 3.30 - 3.23 (m, 1H), 3.10 - 3.05 (m, 1H), 2.76 - 2.67 (m, 3H), 2.44 - 2.39 (m, 2H), 2.29 - 2.25 (m, 1H), 2.03 - 1.94 (m, 2H), 1.11 (d, J = 7.2 Hz, 3H).

[0796] 1. Synthesis scheme:

[0797] 2. Experimental section: Compound MX021004 was obtained following the procedure of example MX-02967, starting from compound 021004-0 and R-1. White solid product (4.87 mg, 7% yield).

[0798] ESI-MS m / z calcd for [C 21 H 23 N5O4S][M+H] + : 442.2; found: 442.2

[0799] 1 H NMR (400 MHz, DMSO-d6) δ 12.38 (br s, 1H), 11.08 (s, 1H), 8.40 - 8.38 (m, 3H), 7.90 (d, J = 8.8 Hz, 2H), 3.71 - 3.63 (m, 1H), 3.50 - 3.38 (m, 2H), 3.29 - 3.23 (m, 1H), 3.09 - 3.04 (m, 1H), 2.77 - 2.71 (m, 1H), 2.29 - 2.25 (m, 1H), 1.59 (d, J = 10.4 Hz, 6H), 1.11 (d, J = 7.6 Hz, 3H).

[0800] 1. Synthesis scheme:

[0801] 2. Experimental section:

[0802] 2.1

[0803] (R)-6-(4-bromophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (02652-1)

[0804] To a solution of (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (2.5 g, 12.31 mmol) in MeCN (30 mL) was added tert-butyl nitrite (1.52 g, 14.77 mmol) and cuprous bromide (3.16 g, 13.54 mmol) at room temperature. The mixture was stirred at room temperature under nitrogen protection overnight. After the starting material was consumed, water (50 mL) was added to the mixture, which was extracted with EA (70 mL) for three times. The combined organic layer was washed with saturated brine (80 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 / 5, silica gel-CS 40 g, 35 mL / min, silica gel, UV 254) to give the product as a white solid (2.2 g, yield 67.3%).

[0805] ESI-MS m / z calcd for [C 11 H 11 BrN2O][M+H] + :267.0; found: 267.1

[0806] 2.2

[0807] (R)-4-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-5,6- dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (02652-2)

[0808] To a solution of (R)-6-(4-bromophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (1.8 g, 6.77 mmol) in a mixture of 1,4-dioxane and water (20 mL, v / v = 4 / 1) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-1(2H)-carboxylate (3.14 g, 10.15 mmol), potassium carbonate (2.8 g, 20.31 mmol) and Pd(dppf)Cl2(490 mg, 0.67 mmol) at room temperature. The mixture was stirred at 90 °C under nitrogen protection for 3 hours. After the starting material was consumed, water was added, which was extracted with EA (50 mL) for two times. The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give the product as a yellow oil (2.2 g, yield 88.1%).

[0809] ESI-MS m / z calcd for [C 21 H 27 N3O3][M+H] + :370.2; found: 370.0

[0810] 2.3

[0811] (R)-5-methyl-6-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4,5-dihydropyridazin- 3(2H)-one (02652-3)

[0812] To a solution of (R)-tert-butyl 4-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3- yl)phenyl)-5,6-dihydropyridine-1 (2H)-carboxylate (800 mg, 2.17 mmol) in DCM (10 mL) was added TFA (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h under nitrogen protection, after the starting material was consumed, the mixture was concentrated by distillation under reduced pressure to give the crude product which was used directly for the next reaction.

[0813] ESI-MS m / z calcd for [C 16 H 19 N3O][M+H] + :270.2; found: 270.4

[0814] 2.4

[0815] (R)-6-(4-(1-((R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-5-oxo-6,7- dihydrothieno[3,2-d]pyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-5- methyl-4,5-dihydropyridazin-3(2H)-one (MX02652)

[0816] To a solution of (R)-5-methyl-6-(4-(l,2,3,6-tetrahydropyridin-4-yl)phenyl)- 4,5-dihydropyridazin-3(2H)-one (583 mg, 2.17 mmol) and (R)-2-chloro-4-((l- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (622 mg, 2.17 mmol) in DMF (7 mL) was added DIEA (1.68 g, 13.02 mmol). The mixture was stirred at 90 °C for 2 hours, after the starting material was consumed, cooled to room temperature and concentrated. The crude product was purified by column chromatography on silica gel (MeOH / DCM = 0 / 1 ~ 1 / 9, silica gel-CS 40 g, 30 mL / min, silica gel, UV 254) to give the product as yellow oil (886 mg, yield 78.5%).

[0817] ESI-MS m / z calcd for [C 27 H 32 N6O3S][M+H] + :521.2; found: 520.8

[0818] 2.5

[0819] 4-((l-(((R)-2-(4-(4-((R)-4-methyl-6-oxo-l,4,5,6-tetrahydropyridazin-3-yl)phenyl)- 5,6-dihydropyridin-l(2H)-yl)-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino) cyclobutyl)methoxy)-4-oxobutanoic acid (MX021029)

[0820] To a solution of 2,5-dihydrofuran dione (10 mg, 0.10 mmol) in dichloromethane (2 mL) was added (R)-6-(4-(l-((R)-4-((l-(hydroxymethyl)cyclobutyl)amino)-5- oxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)phenyl)-5- methyl-4,5-dihydropyridazin-3(2H)-one (62 mg, 0.12 mmol), triethylamine (18 mg, 0.18 mmol) and DMAP (0.61 mg, 0.005 mmol) at room temperature. The mixture was stirred at room temperature overnight, after the starting material was consumed, 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 white solid (29.11 mg, yield 47.0%).

[0821] ESI-MS m / z calcd for[C 31 H 36 N6O6S][M+H] + :621.2; found: 621.2

[0822] 1 H NMR (400 MHz, DMSO-d6) δ 12.04 (br, 1H), 10.95 (s, 1H), 7.77 (d, J = 9.2 Hz, 3H), 7.52 (d, J = 8.4 Hz, 2H), 6.37 (s, 1H), 4.50 (dd, J = 14.8, 11.2 Hz, 2H), 4.36 (s, 2H), 3.98 (s, 2H), 3.48 - 3.38 (m, 2H), 3.26 - 3.19 (m, 1H), 2.99 - 2.89 (m, 2H), 2.69 (dd, J = 16.8, 6.8 Hz, 1H), 2.54 - 2.51 (m, 5H), 2.41 - 2.22 (m, 6H), 1.89 - 1.81 (m, 2H), 1.08 (d, J = 7.6 Hz, 3H).

[0823] 1. Synthesis scheme:

[0824] 2. Experimental part:

[0825] 2.1

[0826] 3-((2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)amino)azetidine-1-carboxylic acid tert-butyl ester (021072-1)

[0827] A solution of 1-((3-bromo-4-ethoxyphenyl)sulfonyl)-4-methylpiperazine (100 mg, 0.28 mmol) in toluene (5 mL) was added 3-aminoazetidine-1-carboxylic acid tert-butyl ester (48 mg, 0.28 mmol), sodium tert-butoxide (54 mg, 0.56 mmol), BINAP (19 mg, 0.03 mmol) and Pd2(dba)3(34 mg, 0.03 mmol), the reaction was stirred at 100 °C under argon 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 (47 mg, yield 38%) as a yellow solid.

[0828] ESI-MS m / z calcd for [C 21 H 34 N4O5S][M+H] + :455.2; found: 455.3

[0829] 2.2

[0830] N-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)azetidin-3-amine (021072-2)

[0831] To a solution of tert-butyl 3-((2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)amino)azetidine-1-carboxylate (47 mg, 0.10 mmol) in DCM (2 mL) was added TFA (0.5 mL). The mixture was then stirred at room temperature for 1 hour, and the reaction was concentrated under vacuum to give the product as a yellow oil (34 mg, 93% yield).

[0832] ESI-MS m / z calcd for [C 16 H 26 N4O3S][M+H] + :355.2; found: 355.3

[0833] 2.3

[0834] (R)-2-(3-((2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)amino)azetidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX021072)

[0835] To a solution of N-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)azetidin-3-amine (34 mg, 0.10 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (29 mg, 0.10 mmol) in DMF (2 mL) was added DIEA (28 mg, 0.20 mmol), and the mixture was stirred at 90 °C for 2 hours. 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 (47.56 mg, 82% yield).

[0836] ESI-MS m / z calcd for [C 27 H 39 N7O5S2][M+H] + :606.3; found: 606.3

[0837] 1 H NMR (400 MHz, DMSO-d6) δ 7.42 (s, 1H), 7.04 - 6.98 (m, 2H), 6.54 (d, J = 1.2 Hz, 1H), 6.03 (d, J = 1.2 Hz, 1H), 4.89 (t, J = 5.2 Hz, 1H), 4.40 - 4.30 (m, 3H), 4.14 (q, J = 7.2 Hz, 2H), 4.00 - 3.86 (m, 2H), 3.69 - 3.68 (m, 2H), 3.43 - 3.36 (m, 1H), 3.24 - 3.17 (m, 1H), 2.96 - 2.84 (m, 6H), 2.40 - 2.27 (m, 6H), 2.14 (s, 3H), 2.11 - 2.08 (m, 2H), 1.79 - 1.69 (m, 2H), 1.40 (t, J = 6.8 Hz, 3H).

[0838] 1. Synthesis scheme:

[0839] 2. Experimental part: Compound 021170-0 was used as starting material and the procedure of Example MX-02618 was followed to obtain compound MX021177. White solid product (40.0 mg, yield 30%).

[0840] ESI-MS m / z calcd for [C 28 H 40 N6O6S2][M+H] + :621.3; found: 621.3

[0841] 1H NMR (400 MHz, DMSO-d6) δ 7.45 (s, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.52 - 6.46 (m, 2H), 5.12 - 5.05 (m, 1H), 4.86 (t, J = 5.6 Hz, 1H), 4.50 - 4.38 (m, 2H), 3.98 - 3.82 (m, 4H), 3.74 - 3.70 (m, 2H), 3.45 - 3.37 (m, 1H), 3.31 - 3.29 (m, 4H), 3.25 - 3.18 (m, 1H), 3.13 - 3.08 (m, 6H), 2.97 - 2.84 (m, 2H), 2.40 - 2.26 (m, 2H), 2.15 - 2.11 (m, 2H), 1.80 - 1.68 (m, 2H), 1.29 (t, J = 6.8 Hz, 3H), 1.24 (t, J = 7.6 Hz, 3H).

[0842] 1. Synthesis scheme:

[0843] 2. Experimental part:

[0844] 2.1

[0845] N-(2-bromophenyl)acetamide (03178-1)

[0846] A solution of 2-bromoaniline (3.0 g, 17.5 mmol) in acetic anhydride (15 mL) was stirred at 80 °C for 1 h. After the starting material was consumed, water (50 mL) was added to the mixture, which was extracted with EA (50 mL) 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 / 1, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give the product as a yellow solid (2.51 g, yield 67%).

[0847] ESI-MS m / z calcd for [C8H8BrNO] [M+H]: 214.0; found: 214.1 + :214.0;found:214.1

[0848] 2.2

[0849] 4-acetamido-3-bromobenzene-1-sulfonyl chloride (03178-2)

[0850] A solution of N-(2-bromophenyl)acetamide (2.0 g, 9.34 mmol) in chlorosulfonic acid (15 mL) was stirred at 80 °C for 4 h. After the starting material was consumed, ice water (50 mL) was added to the mixture, which was extracted with EA (50 mL) three times. The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product as brown oil (2.10 g, yield 72%).

[0851] ESI-MS m / z calcd for [C8H7BrClNO3S] [M+H] + : 311.9; found: 312.0

[0852] 2.3

[0853] N-(2-bromo-4-((3-methoxypiperazin-1-yl)sulfonyl)phenyl)acetamide (03178-3)

[0854] A solution of 4-acetamido-3-bromobenzene-1-sulfonyl chloride (2.0 g, 6.41 mmol) in acetone (15 mL) was added with 3-methoxypiperazine (641 mg, 6.41 mmol) and TEA (1.28 g, 12.82 mmol), and the reaction was stirred at room temperature for 2 h. After the starting material was consumed, water (50 mL) was added to the mixture, which was extracted with EA (50 mL) three times. 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 / 1, silica gel-CS 40 g, 40 mL / min, silica gel, UV 254) to give the product as yellow oil (1.01 g, yield 43%).

[0855] ESI-MS m / z calcd for [C 12 H 15 BrN2O4S] [M+H] + : 363.0; found: 363.2

[0856] 2.4

[0857] N-(2-bromo-4-((3-methoxypiperazin-1-yl)sulfonyl)phenyl)-N-ethylacetamide (03178-4)

[0858] To a solution of N-(2-bromo-4-((3-methoxypiperazin-1-yl)sulfonyl)phenyl)acetamide (950 mg, 2.62 mmol) in DMF (10 mL) was added iodoethane (408 mg, 2.62 mmol) and potassium carbonate (717 mg, 5.24 mmol) and the reaction was stirred at 80 °C for 2 h. After the starting material was consumed, water (40 mL) was added to the mixture, which was extracted with EA (40 mL) three times. The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give the product as a yellow solid (860 mg, 80% yield).

[0859] ESI-MS m / z calcd for [C 14 H 19 BrN2O4S][M+H] + :391.0; found: 391.2

[0860] 2.5

[0861] 2-Bromo-N-ethyl-4-((3-methoxypiperazin-1-yl)sulfonyl)aniline (03178-5)

[0862] To a solution of N-(2-bromo-4-((3-methoxypiperazin-1-yl)sulfonyl)phenyl)-N- ethylacetamide (840 mg, 2.15 mmol) in ethanol / water (12.5 mL, v / v = 4 / 1) was added potassium hydroxide (241 mg, 4.30 mmol) and the reaction was stirred at 80 °C overnight. After the starting material was consumed, water (40 mL) was added to the mixture, which was extracted with EA (40 mL) three times. The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 30 mL / min, silica gel, UV 254) to give the product as a yellow solid (710 mg, 95% yield).

[0863] ESI-MS m / z calcd for [C 12 H 17 BrN2O3S][M+H] + :349.0; found: 349.1

[0864] 2.6

[0865] 2-(Ethylamino)-5-((3-methoxypiperazin-1-yl)sulfonyl)phenol (03178-6)

[0866] A solution of 2-bromo-N-ethyl-4-((3-methoxypiperazin-l-yl)sulfonyl)aniline (700 mg, 2.01 mmol) in 1,4-dioxane / water (12.5 mL, v / v = 4 / 1) was added KOH (225 mg, 4.02 mmol), tBu-Xphos (85 mg, 0.20 mmol) and Pd2(dba)3(183 mg, 0.20 mmol) and the reaction was stirred at 80 °C for 3 h. After the consumption of the starting material, water (50 mL) was added to the mixture, which was extracted twice with EA (50 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 / 1 ~ 1 / 10, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product as a yellow solid (480 mg, 83% yield).

[0867] ESI-MS m / z calcd for [C 12 H 18 N2O4S][M+H] + : 287.1; found: 287.0

[0868] 2.7

[0869] tert-Butyl 3-(2-(ethylamino)-5-((3-methoxypiperazin-l-yl)sulfonyl)phenoxy)piperazine-l- carboxylate (03178-7)

[0870] To a solution of 2-(ethylamino)-5-((3-methoxypiperazin-l-yl)sulfonyl)phenol (240 mg, 0.84 mmol) and tert-butyl 3-(p-toluenesulfonyloxy)azetidine-l-carboxylate (275 mg, 0.84 mmol) in DMF (4 mL) was added Cs2CO3(548 mg, 1.68 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 phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 1, silica gel-CS 20 g, 20 mL / min, silica gel, UV 254) to give the product as a yellow solid (188 mg, 51% yield).

[0871] ESI-MS m / z calcd for [C 20 H 31 N3O6S][M-56+H]+ :386.2; found: 386.1

[0872] 2.8

[0873] 2-(piperazin-3-yloxy)-N-ethyl-4-((3-methoxypiperazin-1-yl)sulfonyl)aniline (03178-8)

[0874] To a solution of tert-butyl 3-(2-(ethylamino)-5-((3-methoxypiperazin-1- yl)sulfonyl)phenoxy)piperazine-1-carboxylate (188 mg, 0.43 mmol) in DCM (5 mL) was added TFA (1 mL). The mixture was then stirred at room temperature for 1 hour, and the reaction was concentrated under vacuum to give the product as a yellow oil (140 mg, yield 96%).

[0875] ESI-MS m / z calcd for [C 15 H 23 N3O4S][M+H] + :342.1; found: 342.1

[0876] 2.9

[0877] (R)-2-(3-(2-(ethylamino)-5-((3-methoxypiperazin-1-yl)sulfonyl)phenoxy)piperazin-1- yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5- oxide (MX03178)

[0878] A solution of 2-(piperazin-3-yloxy)-N-ethyl-4-((3-methoxypiperazin-1-yl)sulfonyl)aniline (140 mg, 0.41 mmol) and (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)- 6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (118 mg, 0.41 mmol) in DMF (3 mL) was added DIEA (106 mg, 0.82 mmol), and the mixture was stirred at 90 °C for 2 hours. 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 (64.06 mg, yield 25%).

[0879] ESI-MS m / z calcd for [C 26 H 36 N6O6S2][M+H]+ : 593.2; found: 592.9

[0880] 1 H NMR (400 MHz, DMSO-d6) δ 7.48 (s, 1H), 7.28 (dd, J = 8.0, 1.2 Hz, 1H), 6.79 (d, J = 1.2 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.14 (t, J = 4.8 Hz, 1H), 5.27 - 5.20 (m, 1H), 4.86 (t, J = 5.6 Hz, 1H), 4.50 - 4.42 (m, 2H), 4.06 - 3.97 (m, 3H), 3.85 - 3.81 (m, 2H), 3.73 - 3.66 (m, 2H), 3.45 - 3.37 (m, 3H), 3.30 - 3.17 (m, 3H), 3.07 (s, 3H), 2.97 - 2.85 (m, 2H), 2.40 - 2.27 (m, 2H), 2.13 - 2.08 (m, 2H), 1.79 - 1.67 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H).

[0881] 1. Synthesis scheme:

[0882] 2. Experimental part:

[0883] 2.1

[0884] 1-bromo-2-cyclopropoxybenzene (03196-1)

[0885] To a solution of 2-bromophenol (6.0 g, 34.68 mmol) in DMF (40 mL) was added K2CO3(9.59 g, 69.36 mmol) and bromocyclopropane (12.59 g, 104.04 mmol). The mixture was stirred at 140 °C for 24 hours under nitrogen protection. After the reaction was concentrated, the residue was dissolved in diethyl ether (100 mL), the mixture was washed with water (50 mL) and brine (50 mL) respectively. The organic phase was dried with Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0-50%, silica gel-CS 80 g, 50 mL / min, silica gel, UV 254) to give the product as colorless oil (4.1 g, yield 55.49%).

[0886] 2.2

[0887] 3-bromo-4-cyclopropoxybenzenesulfonic acid (03196-2)

[0888] To a solution of 1-bromo-2-cyclopropoxybenzene (2.5 g, 11.73 mmol) in DCM (15 mL) was added chlorosulfonic acid (2.05 g, 17.60 mmol) at -20 °C. The mixture was stirred under nitrogen protection for 5 min. After the reaction was quenched with ice water (50 mL) and washed with MTBE (30 mL) to remove small polar impurities. Then NH4Cl was added to the aqueous phase and extracted with EA (50 mL x 3). The organic phase was dried over Na2SO4, filtered and concentrated to give the white solid product (1.6 g, yield 46.52%).

[0889] ESI-MS m / z calcd for [C9H9BrO4S][M+18] + : 311.9; found: 312.0.

[0890] 2.3

[0891] 3-bromo-4-cyclopropoxybenzene-1-sulfonyl chloride (03196-3)

[0892] 3-bromo-4-cyclopropoxybenzene-1-sulfonyl chloride (03196-3)

[0893] 2.4

[0894] 1-((3-bromo-4-cyclopropoxyphenyl)sulfonyl)-4-methylpiperazine (03196-4)

[0895] To a solution of 3-bromo-4-cyclopropoxybenzene-1-sulfonyl chloride (0.6 g, 1.93 mmol) and triethylamine (390 mg, 3.85 mmol) in acetone (10 mL) was added 1-methylpiperazine (289 mg, 2.89 mmol). The reaction was stirred at room temperature for 3 h. Then the reaction was concentrated and the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 10, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to give the yellow solid product (406 mg, yield 56.18%).

[0896] ESI-MS m / z calcd for [C 14 H 19 BrN2O3S][M+H] +: 375.0; found: 374.9

[0897] 2.5

[0898] 2-cyclopropoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenol (03196-5)

[0899] A solution of 1-((3-bromo-4-cyclopropoxyphenyl)sulfonyl)-4-methylpiperazine (220 mg, 0.56 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1) was added Pd2(dba)3(51 mg, 0.06 mmol), KOH (63 mg, 1.12 mmol) and tBuXphos (24 mg, 0.06 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), 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 as a yellow solid (155 mg, 88.67% yield).

[0900] ESI-MS m / z calcd for [C 14 H 20 N2O4S][M+H] + : 313.1; found: 313.0.

[0901] 2.6

[0902] tert-butyl 3-(2-cyclopropoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenoxy)piperazine-1- carboxylate (03196-6)

[0903] To a solution of 2-cyclopropoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenol (140 mg, 0.45 mmol) in DMF (3 mL) were added tert-butyl 3-(p-tolylsulfonyloxy)piperazine-1-carboxylate (161 mg, 0.49 mmol) and cesium carbonate (292 mg, 0.90 mmol) at room temperature. Then the mixture was stirred at 80 °C for 2 h, after which water (20 mL) was added 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 (133 mg, yield 63.47%).

[0904] ESI-MS m / z calcd for [C 22 H 33 N3O6S][M+H] + :468.2; found: 468.0

[0905] 2.7

[0906] 1-((3-(Piperazin-3-yloxy)-4-cyclopropoxyphenyl)sulfonyl)-4-methylpiperazine (03196-7)

[0907] To a solution of tert-butyl 3-(2-cyclopropoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenoxy)piperazine-1-carboxylate (120 mg, 0.26 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at room temperature for 16 h. The mixture was concentrated and the crude product was used directly in the next step.

[0908] ESI-MS m / z calcd for [C 17 H 25 N3O4S][M+H] + :368.2; found: 368.2

[0909] 2.8

[0910] (R)-2-(3-(2-Cyclopropoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenoxy)piperazin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (MX03196)

[0911] To a solution of 1-((3-(piperazin-3-yloxy)-4- cyclopropoxyphenyl)sulfonyl)-4-methylpiperazine (94 mg, 0.26 mmol) in DMF (4 mL) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2- d]pyrimidine 5-oxide (74 mg, 0.26 mmol) and DIEA (166 mg, 1.28 mmol). The mixture was stirred at 80 °C under nitrogen protection for 2 hours, and the reaction was concentrated after cooling. 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 (133.27 mg, 83.92% yield).

[0912] ESI-MS m / z calcd for [C 28 H 38 N6O6S2][M+H] + :619.2; found:618.9

[0913] 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.40 (dd, J = 8.4, 2.0 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 5.20 - 5.18 (m, 1H), 4.86 - 4.85 (m, 1H), 4.44 - 4.40 (m, 2H), 3.98 - 3.94 (m, 3H), 3.69 - 3.67 (m, 2H), 3.43 - 3.37 (m, 1H), 3.23 - 3.20 (m, 1H), 2.97 - 2.85 (m, 6H), 2.36 - 2.28 (m, 6H), 2.15 - 2.07 (m, 5H), 1.79 - 1.69 (m, 2H), 0.85 - 0.74 (m, 4H).

[0914] 1. Synthesis scheme:

[0915] 2. Experimental part:

[0916] 2.1

[0917] 1-[(3-bromo-4-cyclopropoxyphenyl)sulfonyl]-3-methoxyazetidine (03198-1)

[0918] To a solution of 3-bromo-4-cyclopropyloxybenzene-1-sulfonyl chloride (0.6 g, 1.93 mmol) and triethylamine (390 mg, 3.85 mmol) in acetone (10 mL) was added 3-methoxyazetidine hydrochloride (357 mg, 2.89 mmol). The reaction was stirred at room temperature for 3 h. Then the reaction was concentrated, and the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 10, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to give the product as a yellow solid (393 mg, yield 56.34%).

[0919] ESI-MS m / z calcd for [C 13 H 16 BrNO4S][M+H] + :362.0; found: 362.0

[0920] 2.2

[0921] 2-cyclopropyloxy-5-((3-methoxyazetidin-1-yl)sulfonyl)phenol (03198-2)

[0922] To a solution of 1-((3-bromo-4-cyclopropyloxyphenyl)sulfonyl)-3-methoxyazetidine (200 mg, 0.55 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1) was added Pd2(dba)3 (51 mg, 0.06 mmol), KOH (62 mg, 1.10 mmol) and tBuXphos (23 mg, 0.06 mmol). 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 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 solid (151 mg, yield 91.36%).

[0923] ESI-MS m / z calcd for [C 13 H 17 NO5S][M+H] + :300.1; found: 300.0.

[0924] 2.3

[0925] tert-butyl 3-(2-cyclopropoxy-5-((3-methoxyazetidin-l-yl)sulfonyl)phenoxy)azetidine- 1-carboxylate (03198-3)

[0926] To a solution of 2-cyclopropoxy-5-((3-methoxyazetidin-l-yl)sulfonyl)phenol (131 mg, 0.44 mmol) in DMF (5 mL) were added tert-butyl 3-(p-toluenesulfonyloxy)azetidine-l- carboxylate (158 mg, 0.48 mmol) and cesium carbonate (285 mg, 0.88 mmol) at room temperature. The mixture was then 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 a yellow solid (125 mg, yield 62.84%).

[0927] ESI-MS m / z calcd for [C 21 H 30 N2O7S][M-55] + :399.2; found: 399.0

[0928] 2.4

[0929] 1-((3-(azetidine-3-carbonyl)-4-cyclopropoxyphenyl)sulfonyl)-3-methoxyazetidine (03198-4)

[0930] To a solution of tert-butyl 3-(2-cyclopropoxy-5-((3-methoxyazetidin-l-yl)sulfonyl)phenoxy)azetidine-l-carboxylate (110 mg, 0.24 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated and the crude product was used directly in the next step.

[0931] ESI-MS m / z calcd for [C 16 H 22 N2O5S][M+H] + :355.1; found: 355.0

[0932] 2.5

[0933] (R)-2-(3-(2-cyclopropoxy-5-((3-methoxyazetidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (MX03198)

[0934] To a solution of 1-((3-(azetidine-3-carbonyl)-4-cyclopropoxyphenyl)sulfonyl)-3- methoxyazetidine (86 mg, 0.24 mmol) in DMF (4 mL) was added (R)-2-chloro-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (70 mg, 0.24 mmol) and DIEA (156 mg, 1.21 mmol). The mixture was stirred at 80 °C under nitrogen protection for 2 hours, and the reaction was concentrated after cooling. 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 an off-white solid (91.56 mg, yield 62.14%).

[0935] ESI-MS m / z calcd for [C 27 H 35 N5O7S2][M+H] + :606.2; found: 605.8

[0936] 1 H NMR (400 MHz, DMSO-d6) d 7.57 (d, J = 8.4 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.04 (d, J = 2.0 Hz, 1H), 5.24 - 5.21 (m, 1H), 4.85 (t, J = 5.6 Hz, 1H), 4.86 - 4.83 (m, 2H), 4.05 - 3.89 (m, 6H), 3.72 - 3.65 (m, 2H), 3.46 - 3.37 (m, 3H), 3.25 - 3.21 (m, 1H), 3.08 (s, 3H), 2.97 - 2.86 (m, 2H), 2.39 - 2.29 (m, 2H), 2.13 - 2.08 (m, 2H), 1.81 - 1.67 (m, 2H), 0.88 - 0.76 (m, 4H).

[0937] 1. Synthesis scheme:

[0938] 2. Experimental part:

[0939] 2.1

[0940] tert-Butyl 3-((2-cyclopropoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)amino)azacyclobutane-1-carboxylic acid ester (03200-1)

[0941] To a solution of 1-((3-bromo-4-cyclopropoxyphenyl)sulfonyl)-4-methylpiperazine (160 mg, 0.43 mmol) in toluene (5 mL), tert-butyl-3-aminoazacyclobutane-1-carboxylic acid ester (147 mg, 0.85 mmol), Pd2(dba)3 (39 mg, 0.04 mmol), BINAP (27 mg, 0.04 mmol), and sodium tert-butyl (123 mg, 1.28 mmol) were added. The mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction solution was cooled and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0–5%, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to give a yellow solid product (153 mg, yield 76.91%).

[0942] ESI-MS m / z calcd for [C 22 H 34 [N4O5S][M+H] + 467.2; found: 467.0

[0943] 2.2

[0944] N-(2-Cyclopropoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)azacyclobutane-3-amine (03200-2)

[0945] Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl 3-((2-cyclopropoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)amino)azacyclobutane-1-carboxylic acid ester (133 mg, 0.29 mmol) in DCM (3 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.

[0946] ESI-MS m / z calcd for [C 17 H 26 N4O3S][M+H + :367.2; found:367.2

[0947] 2.3

[0948] (R)-2-(3-((2-cyclopropoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)amino)azetidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (MX03200)

[0949] To a solution of N-(2-cyclopropoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)azetidin-3-amine (107 mg, 0.29 mmol) in DMF (4 mL) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (70 mg, 0.24 mmol) and DIEA (157 mg, 1.22 mmol). The mixture was stirred at 80 °C under nitrogen protection for 2 hours, and the reaction was concentrated after cooling. 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 (116.36 mg, yield 77.43%).

[0950] ESI-MS m / z calcd for [C 28 H 39 N7O5S2][M+H] + :618.3; found: 618.0

[0951] 1 H NMR (400 MHz, DMSO-d6) d 7.41 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.04 (dd, J = 8.0, 2.0 Hz, 1H), 6.53 (d, J = 2.0 Hz, 1H), 6.03 - 6.02 (m, 1H), 4.89 - 4.87 (m, 1H), 4.34 - 4.31 (m, 3H), 3.98 - 3.84 (m, 3H), 3.68 - 3.67 (m, 2H), 3.42 - 3.38 (m, 1H), 3.22 - 3.19 (m, 1H), 2.96 - 2.84 (m, 6H), 2.35 - 2.29 (m, 6H), 2.14 - 2.07 (m, 5H), 1.76 - 1.69 (m, 2H), 0.83 - 0.76 (m, 4H).

[0952] 1. Synthesis scheme:

[0953] 2. Experimental part:

[0954] 2.1

[0955] tert-butyl 3-((2-cyclopropoxy-5-((3-methoxyazetidin-l-yl)sulfonyl)phenyl)amino)azetidine-l-carboxylate (03202-1)

[0956] To a solution of l-((3-bromo-4-cyclopropoxyphenyl)sulfonyl)-3-methoxyazetidine (150 mg, 0.413 mmol) in toluene (5 mL) was added tert-butyl 3-aminoazetidine-l-carboxylate (143 mg, 0.83 mmol), Pd2(dba)3(38 mg, 0.04 mmol), BINAP (26 mg, 0.04 mmol) and sodium tert-butoxide (119 mg, 1.24 mmol). The mixture was stirred at 100 °C for 16 h under nitrogen protection. The reaction was cooled down and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0-5%, silica gel-CS 20 g, 25 mL / min, silica gel, UV 254) to give the product as a yellow solid (122 mg, 64.96% yield).

[0957] ESI-MS m / z calcd for [C 21 H 31 N3O6S][M-55] + :398.2; found:398.0

[0958] 2.2

[0959] N-(2-cyclopropoxy-5-((3-methoxyazetidin-l-yl)sulfonyl)phenyl)azetidin-3-amine (03202-2)

[0960] To a solution of tert-butyl 3-((2-cyclopropoxy-5-((3-methoxyazetidin-l-yl)sulfonyl)phenyl)amino)azetidine-l-carboxylate (110 mg, 0.24 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at room temperature for 16 h. The mixture was concentrated and the crude product was used directly in the next step.

[0961] ESI-MS m / z calcd for [C 16 H 23 N3O4S][M+H] + :354.1; found:354.2

[0962] 2.3

[0963] (R)-2-(3-((2-cyclopropoxy-5-((3-methoxyazetidin-l-yl)sulfonyl)phenyl)amino)azetidin-l-yl)-4-((l-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine-5-oxide (MX03202)

[0964] To a solution of N-(2-cyclopropoxy-5-((3-methoxyazetidin-l-yl)sulfonyl)phenyl)azetidin-3-amine (85 mg, 0.24 mmol) in DMF (4 mL) was added (R)-2-chloro-4-((l-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (60 mg, 0.21 mmol) and DIEA (135 mg, 1.04 mmol). The mixture was stirred at 80 °C under nitrogen protection for 2 hours, and the reaction was concentrated after cooling. 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 an off-white solid (75.81 mg, 60.12% yield).

[0965] ESI-MS m / z calcd for [C 27 H 36 N6O6S2][M+H] + : 605.2; found: 604.9

[0966] 1 H NMR (400 MHz, DMSO-d6) δ 7.38 - 7.35 (m, 2H), 7.11 (dd, J = 8.4, 2.0 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H), 6.07 - 6.05 (m, 1H), 4.88 - 4.86 (m, 1H), 4.34 - 4.31 (m, 3H), 4.03 - 3.85 (m, 6H), 3.69 - 3.68 (m, 2H), 3.44 - 3.38 (m, 3H), 3.24 - 3.17 (m, 1H), 3.07 (s, 3H), 2.95 - 2.84 (m, 2H), 2.38 - 2.28 (m, 2H), 2.12 - 2.07 (m, 2H), 1.79 - 1.69 (m, 2H), 0.85 - 0.78 (m, 4H).

[0967] 1. Synthesis scheme:

[0968] 2. Experimental part:

[0969] 2.1

[0970] 1-bromo-2-(2,2,2-trifluoroethoxy)benzene (03203-1)

[0971] To a solution of 2-bromophenol (2 g, 11.56 mmol) in DMF (20 mL) was added potassium carbonate (3.2 g, 23.12 mmol). The mixture was then stirred at 0 °C for ten minutes, after which 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.22 g, 13.87 mmol) was added. The mixture was allowed to warm to room temperature and stirred under nitrogen overnight. After consumption of the starting material, the mixture was cooled and added to water (30 mL) and extracted three times with EA (60 mL). 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 column chromatography (EA / PE = 0 / 10 to 1 / 10, silica gel-CS 40 g, 30 mL / min, silica gel, UV 254) to give the product as a colorless oil (2.67 g, yield 91%).

[0972] 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (dd, J = 8.0, 1.6 Hz, 1H), 7.42 - 7.37 (m, 1H), 7.25 (dd, J = 8.4, 1.2 Hz, 1H), 7.25 (dt, J = 7.6, 1.2 Hz, 1H), 4.86 (q, J = 8.8 Hz, 2H).

[0973] 2.2

[0974] 3-bromo-4-(2,2,2-trifluoroethoxy)benzene-1-sulfonyl chloride (03203-2)

[0975] To a solution of 1-bromo-2-(2,2,2-trifluoroethoxy)benzene (1 g, 3.92 mmol) in DCM (10 mL) was added chlorosulfonic acid (5 mL) slowly at -5 °C. The mixture was then stirred at -5 °C for ten minutes, after which the mixture was allowed to warm to room temperature and stirred under nitrogen for 2 hours. After consumption of the starting material, the mixture was cooled and added to ice water (25 mL) and extracted three times with DCM (30 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product as a yellow oil (1.44 g, yield: crude).

[0976] 2.3

[0977] 1-(3-bromo-4-(2,2,2-trifluoroethoxy)phenyl)sulfonyl-4-methylpiperazine (03203-3)

[0978] A solution of 3-bromo-4-(2,2,2-trifluoroethoxy)benzene-1-sulfonyl chloride (670 mg, 1.90 mmol) and N-methylpiperazine (190 mg, 1.90 mmol) in acetone (10 mL) was added TEA (384 mg, 3.80 mmol) and the reaction was stirred at room temperature for 3 hours. 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 layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 10, silica gel-CS 12 g, 40 mL / min, silica gel, UV 254) to give the product as a yellow solid (600 mg, yield 76%).

[0979] ESI-MS m / z calcd for [C 13 H 16 BrF3N2O3S][M+H] + : 417.0; found: 417.0

[0980] 2.4

[0981] 5-((4-methylpiperazin-1-yl)sulfonyl)-2-(2,2,2-trifluoroethoxy)phenol (03203-4)

[0982] A solution of 1-(3-bromo-4-(2,2,2-trifluoroethoxy)phenyl)sulfonyl-4-methylpiperazine (216 mg, 0.52 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1) was added KOH (58 mg, 1.04 mmol), tBu-Xphos (22 mg, 0.052 mmol) and Pd2(dba)3(48 mg, 0.052 mmol), and the reaction was stirred at 80°C for 4 hours. 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 layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 10, silica gel-CS 12 g, 25 mL / min, silica gel, UV 254) to give the product as a yellow solid (153 mg, yield 83%).

[0983] ESI-MS m / z calcd for [C 13 H 17 F3N2O4S][M+H] +: 355.1 ; found: 355.3

[0984] 2.5

[0985] 3-(5-((4-methylpiperazin-1-yl)sulfonyl)-2-(2,2,2-trifluoroethoxy)phenoxy)azetidine-1 - carboxylic acid tert-butyl ester (03203-5)

[0986] To a solution of 5-((4-methylpiperazin-1-yl)sulfonyl)-2-(2,2,2- trifluoroethoxy)phenol (153 mg, 0.43 mmol) and 3-(p-tolylsulfonyloxy)azetidine-1- carboxylic acid tert-butyl ester (163 mg, 0.50 mmol) in DMF (5 mL) was added Cs2CO3(282 mg, 0.86 mmol) at room temperature. Then the mixture was stirred at 85 °C for 10 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 / 10 ~ 1 / 10, silica gel-CS 12 g, 25 mL / min, silica gel, UV 254) to give the product as a yellow solid (167 mg, yield 76%).

[0987] ESI-MS m / z calcd for [C 21 H 30 F3N3O6S][M+H] + : 510.2; found: 510.2

[0988] 2.6

[0989] 1-((3-(azetidin-3-yl0-4-(2,2,2-trifluoroethoxy)phenyl)sulfonyl)-4- methylpiperazine (03203-6)

[0990] To a solution of 3-(5-((4-methylpiperazin-1-yl)sulfonyl)-2-(2,2,2- trifluoroethoxy)phenoxy)azetidine-1 -carboxylic acid tert-butyl ester (150 mg, 0.29 mmol) in DCM (3.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at room temperature for 1 h under nitrogen protection, after the starting material was consumed, the mixture was concentrated under reduced pressure, adjusted to pH = 9.0 with saturated aqueous sodium bicarbonate solution, extracted with DCM:i-PrOH (5:1, 45 mL) three times. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the product as a yellow oil (100 mg, yield 75%).

[0991] ESI-MS m / z calcd for [C 16 H 22 F3N3O4S][M+H] + :410.1 ; found: 410.3

[0992] 2.7

[0993] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3-(5-((4-methylpiperazin-1-yl)sulfonyl)-2-(2,2,2- trifluoroethoxy)phenoxy)azetidin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX03203)

[0994] To a solution of 1-((3-(azetidin-3-yloxy)-4-(2,2,2-trifluoroethoxy)phenyl)sulfonyl)-4- methylpiperazine (30 mg, 0.073 mmol) in DMF (2 mL) and DIEA (14 mg, 0.11 mmol) was added (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (21 mg, 0.073 mmol). The mixture was stirred at 85 °C for 2 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 pm 19*250 mm, 20 mL / min, UV 254) to give the product as a white solid (28.90 mg, 60% yield).

[0995] ESI-MS m / z calcd for [C 27 H 35 F3N6O6S2][M+H] + :661.2 ; found: 661.3

[0996] 1H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 1H), 7.39 (s, 2H), 7.02 (s, 1H), 5.28 - 5.24 (m, 1H), 4.91 (q, J = 8.8 Hz, 2H), 4.88 - 4.82 (m, 1H), 4.45 (dd, J = 9.6, 6.4 Hz, 2H), 3.97 (brs, 2H), 3.69 (s, 2H), 3.46 - 3.39 (m, 1H), 3.25 - 3.16 (m, 1H), 2.98 - 2.93 (m, 1H), 2.90 - 2.85 (m, 5H), 2.36 - 2.25 (m, 6H), 2.15 (s, 3H), 2.11 - 2.08 (m, 2H), 1.79 - 1.69 (m, 2H).

[0997] 1. Synthesis scheme:

[0998] 2. Experimental section:

[0999] 2.1

[1000] 1-((3-bromo-4-(2,2,2-trifluoroethoxy)phenyl)sulfonyl)-3-methoxyazetidine (03204-1)

[1001] A solution of 3-bromo-4-(2,2,2-trifluoroethoxy)benzenesulfonyl chloride (670 mg, 1.90 mmol) and 3-methoxy-azetidine (165 mg, 1.90 mmol) in acetone (10 mL) was added TEA (384 mg, 3.80 mmol) and the reaction was stirred at room temperature for 3 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 layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 1 / 10, silica gel-CS 12 g, 30 mL / min, silica gel, UV 254) to give the product as a yellow solid (700 mg, yield 91%).

[1002] ESI-MS m / z calcd for [C 12 H 13 BrF3NO4S][M+H] + :404.0; found:404.0

[1003] 2.2

[1004] 5-((3-methoxyazetidin-l-yl)sulfonyl)-2-(2,2,2-trifluoroethoxy)phenol (03204-2)

[1005] A solution of l-((3-bromo-4-(2,2,2-trifluoroethoxy)phenyl)sulfonyl)-3- methoxyazetidine (200 mg, 0.50 mmol) in 1,4-dioxane / water (5 mL, v / v = 4 / 1) was added KOH (56 mg, 1.00 mmol), tBu-Xphos (21 mg, 0.05 mmol) and Pd2(dba)3(46 mg, 0.05 mmol) and the reaction was stirred at 80 °C for 4 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 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 ~ 2 / 3, silica gel-CS 12 g, 25 mL / min, silica gel, UV 254) to give the product (156 mg, 92% yield) as a yellow solid.

[1006] ESI-MS m / z calcd for [C 12 H 14 F3NO5S][M+H] + :342.1; found: 342.2

[1007] 2.3

[1008] 3-(5-((3-methoxyazetidin-l-yl)sulfonyl)-2-(2,2,2-trifluoroethoxy)phenoxy)azetidine- 1-carboxylic acid tert-butyl ester (03204-3)

[1009] To a solution of 5-((3-methoxyazetidin-l-yl)sulfonyl)-2-(2,2,2- trifluoroethoxy)phenol (130 mg, 0.38 mmol) and 3-(p-tolylsulfonyloxy)azetidine-l- carboxylic acid tert-butyl ester (163 mg, 0.49 mmol) in DMF (5 mL) was added Cs2CO3(248 mg, 0.76 mmol) at room temperature. The mixture was then stirred at 85 °C for 10 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 / 10 ~ 1 / 10, silica gel-CS 12 g, 25 mL / min, silica gel, UV 254) to give the product (194 mg, 89% yield) as a yellow oil.

[1010] ESI-MS m / z calcd for [C 21 H 30 F3N3O6S][M+H-56 + 444.1; found: 441.2

[1011] 2.4

[1012] 1-((3-(azacyclobutane-3-oxy)-4-(2,2,2-trifluoroethoxy)phenyl)sulfonyl)-3-methoxyazacyclobutane(03204-4)

[1013] TFA (1.0 mL) was added to a solution of tert-butyl 3-(5-((3-methoxyazirobutyl-1-yl)sulfonyl)-2-(2,2,2-trifluoroethoxy)phenoxy)azirobutyl-1-carboxylic acid (3.0 mL). The reaction mixture was stirred at room temperature for 1 hour under nitrogen protection. After the starting material was consumed, the mixture was concentrated by vacuum distillation, and the pH was adjusted to 9.0 with saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with DCM:i-PrOH (5:1, 60 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated to give a yellow oily product (150 mg, 97% yield).

[1014] ESI-MS m / z calcd for [C 15 H 19 F3N2O5S][M+H] + :397.1; found:397.2

[1015] 2.5

[1016] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3-(5-((3-methoxyazinobutyl-1-yl)sulfonyl)-2-(2,2,2-trifluoroethoxy)phenoxy)azinobutyl-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX03204)

[1017] To a solution of 1-((3-(azetidin-3-yloxy)-4-(2,2,2- trifluoroethoxy)phenyl)sulfonyl)-3-methoxyazetidine (25 mg, 0.063 mmol) in DMF (2 mL) and DIEA (12 mg, 0.11 mmol) was added (R)-2-chloro-4-((1- (hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (18 mg, 0.063 mmol). The mixture was stirred at 85 °C for 2 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 pm 19*250 mm, 20 mL / min, UV 254) to give the product as a white solid (32.80 mg, 80% yield).

[1018] ESI-MS m / z calcd for [C 26 H 32 F3N5O7S2][M+H] + :648.2; found: 648.3

[1019] 1 H NMR (400 MHz, DMSO-d6) d 7.49 - 7.47 (m, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 5.28 - 5.24 (m, 1H), 4.94 (q, J = 8.4 Hz, 2H), 4.85 (t, J = 5.6 Hz, 1H), 4.45 (dd, J = 9.6, 6.0 Hz, 2H), 4.05 - 3.98 (m, 3H), 3.92 (t, J = 8.0 Hz, 2H), 3.69 (d, J = 3.6 Hz, 2H), 3.46 - 3.41 (m, 2H), 3.41 - 3.37 (m, 1H), 3.25 - 3.18 (m, 1H), 3.07 (s, 3H), 2.97 - 2.85 (m, 2H), 2.37 - 2.26 (m, 2H), 2.13 - 2.09 (m, 2H), 1.79 - 1.69 (m, 2H).

[1020] 1. Synthesis scheme:

[1021] 2. Experimental part:

[1022] 2.1

[1023] 3-((5-((4-methylpiperazin-1-yl)sulfonyl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)azetidine-1 - carboxylic acid tert-butyl ester (03205-1 )

[1024] To a solution of 1 -(3-bromo-4-(2,2,2-trifluoroethoxy)phenyl)sulfonyl-4- methylpiperazine (60 mg, 0.17 mmol) and 1 -tert-butoxycarbonyl-3-aminocyclobutane (32 mg, 0.19 mmol) in toluene (5 mL) was added potassium tert-butoxide (38 mg, 0.34 mmol), BINAP (11 mg, 0.017 mmol) and Pd2(dba)3(8 mg, 0.009 mmol) and the reaction was stirred at 90 °C for 16 h. After the starting material was consumed, water (20 mL) was added to the mixture, which was extracted twice with EA (20 mL), the combined organic layers were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by column chromatography (MeOH / DCM = 0 / 1 ~ 15 / 85, silica gel-CS 12 g, 25 mL / min, silica gel, UV 254) to give the product as a yellow oil (46 mg, 63% yield).

[1025] ESI-MS m / z calcd for [C 21 H 31 F3N4O5S][M+H] + :509.2; found: 509.3

[1026] 2.2

[1027] N-(5-((4-methylpiperazin-1-yl)sulfonyl)-2-(2,2,2-trifluoroethoxy)phenyl)azetidine-3- amine (03205-2)

[1028] To a solution of 3-((5-((4-methylpiperazin-1-yl)sulfonyl)-2-(2,2,2- trifluoroethoxy)phenyl)amino)azetidine-1 -carboxylic acid tert-butyl ester (46 mg, 0.09 mmol) in DCM (3.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at room temperature for 1 h under nitrogen protection, after the starting material was consumed, the mixture was concentrated under reduced pressure, the pH was adjusted to 9.0 with saturated aqueous sodium bicarbonate solution, extracted with DCM:i-PrOH (5:1, 45 mL) three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the product as a yellow oil (22 mg, 60% yield).

[1029] ESI-MS m / z calcd for [C 16H 23 F3N4O3S][M+H] + :409.1; found:408.9

[1030] 2.3

[1031] (R)-4-((1-(hydroxymethyl)cyclobutyl)amino)-2-(3-((5-((4-methylpiperazin-1-yl)sulfonyl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)azacyclobutane-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (MX03205)

[1032] Add (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothiopheno[3,2-d]pyrimidine 5-oxide (16 mg, 0.054 mmol) to a solution of N-(5-((4-methylpiperazin-1-yl)sulfonyl)-2-(2,2,2-trifluoroethoxy)phenyl)azacyclobutane-3-amine (22 mg, 0.054 mmol) in DMF (1.5 mL) and DIEA (10 mg, 0.081 mmol). The mixture was stirred at 85°C for 2 hours. After the starting material was consumed, the mixture was concentrated by vacuum distillation. The crude product was purified by preparative HPLC (MeCN / H2O (10 mmol / L NH4HCO3), X-Select 10 μm 19*250 mm, 20 mL / min, UV 254) to obtain a white solid product (6.36 mg, yield 18%).

[1033] ESI-MS m / z calcd for [C 27 H 36 F3N7O5S2][M+H] + :660.2; found:660.0

[1034] 1H NMR (400 MHz, DMSO-d6) δ 7.39 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.02 (dd, J = 8.4, 2.0 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 6.11 (d, J = 4.8 Hz, 1H), 4.91 - 4.84 (m, 3H), 4.38 - 4.32 (m, 3H), 4.00 - 3.88 (m, 2H), 3.69 (d, J = 5.6 Hz, 2H), 3.44 - 3.36 (m, 1H), 3.25 - 3.17 (m, 1H), 2.96 - 2.86 (m, 6H), 2.40 - 2.28 (m, 6H), 2.14 - 2.08 (m, 5H), 1.79 - 1.67 (m, 2H).

[1035] 1. Synthesis scheme:

[1036] 2. Experimental part:

[1037] 2.1

[1038] tert-Butyl 3-((5-((3-methoxyazetidin-1-yl)sulfonyl)-2-(2,2,2- trifluoroethoxy)phenyl)amino)azetidine-1-carboxylate (03206-1)

[1039] A solution of 1-((3-bromo-4-(2,2,2-trifluoroethoxy)phenyl)sulfonyl)-3- methoxyazetidine (60 mg, 0.18 mmol) and 1-tert-butoxycarbonyl-3- aminocyclobutane (32 mg, 0.19 mmol) in toluene (5 mL) was added potassium tert-butoxide (38 mg, 0.34 mmol), BINAP (11 mg, 0.017 mmol) and Pd2(dba)3(8 mg, 0.01 mmol) and the reaction was stirred at 90 °C for 16 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 layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (EA / PE = 0 / 1 ~ 1 / 1, silica gel-CS 12 g, 25 mL / min, silica gel, UV 254) to give the product (43 mg, yield 58%) as a yellow oil.

[1040] ESI-MS m / z calcd for [C 20 H 28 F3N3O6S][M+H-56] + : 440.2; found: 440.2

[1041] 2.2

[1042] N-(5-((3-methoxyazetidin-l-yl)sulfonyl)-2-(2,2,2-trifluoroethoxy)phenyl)azetidin-3- amine (03206-2)

[1043] To a solution of tert-butyl 3-((5-((3-methoxyazetidin-l-yl)sulfonyl)-2-(2,2,2- trifluoroethoxy)phenyl)amino)azetidine-l-carboxylate (43 mg, 0.09 mmol) in DCM (3.0 mL) was added TFA (1.0 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, adjusted to pH = 9.0 with saturated aqueous sodium bicarbonate solution, extracted with DCM:i-PrOH (5: 1, 60 mL) three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the product as a yellow oil (18 mg, 53% yield).

[1044] ESI-MS m / z calcd for [C 15 H 20 F3N3O4S][M+H] + :396.1; found:396.0

[1045] 2.3

[1046] (R)-4-((l-(hydroxymethyl)cyclobutyl)amino)-2-(3-((5-((3-methoxyazetidin-l- yl)sulfonyl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)azetidin-l-yl)-6,7-dihydrothieno[3,2- d]pyrimidine 5-oxide (MX03206)

[1047] To a solution of N-(5-((3-methoxyazetidin-l-yl)sulfonyl)-2-(2,2,2- trifluoroethoxy)phenyl)azetidin...

Claims

1. A compound as shown in Formula H below, racemates, stereoisomers, tautomers, isotopically labeled, solvates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs thereof: wherein: X1represents a bond, C 1-20 alkylene, O, S, NR q , S(=O), S(=O)2or C(=O); X2represents a bond, C 1-20 alkylene, O, S, NR q , S(=O), S(=O)2or C(=O); U represents -(CH2) t -, O, S, NR q , S(=O), S(=O)2or C(=O), wherein t represents 0, 1, 2 or 3; R q 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 2-20 alkenyloxy, C 2-20 alkynyloxy, C 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C 3-20 cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 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 arylthio, 5-20 membered heteroarylthio, 3-20 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 ); v represents 0, 1, 2, 3, 4 or 5; R a represents H or -X-R3; X represents CH2, O, S, NH, -S(O)-, -S(O)2- or -C(O)-; R3represents H, halogen, OH, CN, -CH2CF3, -NHR d4 , unsubstituted or optionally substituted by 1, 2 or more R d4 substituents selected from the group consisting of C 1-20 alkyl, -C(O)R 61 , -C(O)OR 62 , -OC(O)R 63 , NH2; R b represents H or -Y-R4; Y represents CH2, O, S, NH, -S(O)-, -S(O)2- or -C(O)-; R4represents H, halogen, OH, CN, -CH2CF3, -NHR d4 , unsubstituted or optionally substituted by 1, 2 or more R d5 substituted C 1-20 alkyl, -C(O)R 61 , -C(O)OR 62 , -OC(O)R 63 , NH2; provided that R a , R b are not simultaneously H; or R a , R b together with the atom to which they are attached form the following groups, which are unsubstituted or optionally substituted by 1, 2 or more R d6 C 5-20 cycloalkenyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, 6-20 membered aryl; each R d21 , R d22 , R d4 , R d5 , R d6 are identical or different, independently of one another, selected from the group consisting of H, halogen, OH, CN, NO2, oxo (=0), thioxo (=S), SO, SO2, non-substituted or optionally substituted with 1, 2 or more R e , 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 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 ); or, when there are two or more substituents selected from R d22 , R d4 , R d5 , R d6 on the same group, said two substituents can form, together with the atom(s) to which they are attached, a C 3-20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl group, optionally substituted with 1, 2 or more R e ; R c represents hydrogen, mono- or polycyclic C 6-20 -aryl, mono- or polycyclic C 6-20 -aryl and 4-12 membered cycloalkyl, mono- or polycyclic C 6-20 -aryl and 4-10 membered heterocycloalkyl, mono- or polycyclic 5-20 membered heteroaryl, mono- or polycyclic 5-20 membered heteroaryl and 4-12 membered cycloalkyl, mono- or polycyclic 5-20 membered heteroaryl and 4-10 membered heterocycloalkyl, for example C 4-10 cycloalkyl and C 6-20 aryl-, C 4-10 cycloalkenyl and C 6- 20 aryl-, 4-10 membered heterocycloalkyl and C 6-20 aryl-, 4-10 membered heterocycloalkenyl and C 6-20 aryl-, C 4-10 cycloalkyl-C 6-20 aryl-, C 4-10 cycloalkenyl-C 6-20 aryl-, 4-10 membered heterocycloalkyl-C 6-20 aryl-, 4-10 membered heterocycloalkenyl-C 6-20 aryl-, 5-20 membered heteroaryl, C 4-10 cycloalkyl and C 4-10 cycloalkenyl and C 4-10 cycloalkyl-5-20 membered heteroaryl-, C 4-10 cycloalkenyl-5-20 membered heteroaryl-, 4-10 membered heterocycloalkyl-5-20 membered heteroaryl-, 4-10 membered heterocycloalkenyl-5-20 membered heteroaryl-; or, R c is selected from 5-20 membered heteroaryl-O-C 6-20 aryl-, 5-20 membered heteroaryl-NH-C 6-20 aryl-, 5-20 membered heteroaryl-S-C 6-20 aryl-, 5-20 membered heteroaryl-CH2-C 6-20 aryl-; each ring system in the above radicals can optionally be substituted in the ortho, para or meta position, independently of one another, by 1, 2 or more substituents selected from halogen, hydroxyl, CN, NO2, NH2, or by 1, 2 or more substituents selected from OR 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 NR 1.2 R 1.3 CH2-NR 1.2 R 1.3 CH2CH2-NR 1.2 R 1.3 C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 1.1 , C 3-10 -cycloalkyl, C 3-10 -cycloalkenyl, 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-CH2CH3and SO2-NR 1.2 R 1.3 substituted; or R c is selected from the group consisting of heterocycle and heteroaryl, which can be optionally substituted at the ortho-, para- or meta-positions, each independently, with 1, 2 or more groups selected from halogen, OH, oxo, CF3, CHF2and CH2F, or with 1, 2 or more groups selected from 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, 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 1.1 and NR 1.2 R 1.3 , which in turn can be independently optionally substituted with 1, 2 or more substituents from the group consisting of OH, OR 1.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- alkyl, C 6-10- aryl and NR 1.2 R 1.3 ; heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused ring or optionally bridged ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; each R 1.1 identically or differently, independently of one another, H or selected from C 1-6- alkyl, C 1-6- alkyl alcohol, C 1-3 haloalkyl, mono- or bicyclic, -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 heterocyclo-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 heterocyclo, which can optionally be substituted with OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 5-10 aryl substituents; each R 1.2 and R 1.3 identically or differently, independently of one another, denote H or a radical selected from the group consisting of C 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- to 20-membered heteroaryl-C 1-6- alkyl, mono- or bicyclic C 6-20- aryl, 3- to 10-membered heterocyclyl, heteroarylyl, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 1.1 and COOR 1.1 which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 1.1 ; each R e is independently selected from H, halogen, OH, CN, N02, NH2, oxo (=0), thioxo (=S), O-CONH2, O-CONHR f , NRq-CONHR f , NRq-C(O)R f , NH R f is unsubstituted or optionally substituted by 1, 2 or more R f is selected from the following groups, which are unsubstituted or optionally substituted by 1, 2 or more R 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 ); or, when two or more substituents selected from the group consisting of R e may be present on the same group, said two substituents can form, together with the atom(s) to which they are attached, a group selected from the group consisting of C f alkyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl; each R is independently selected from the group consisting of H, halogen, OH, CN, N02, oxo (=0), thioxo (=S), unsubstituted or optionally substituted with 1, 2 or more R f identical or different, independently of one another, selected from the group consisting of H, halogen, OH, CN, N02, oxo (=0), thioxo (=S), unsubstituted or optionally substituted with 1, 2 or more R g substituted with 1, 2 or more R 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 arylthio, 5- to 20-membered heteroarylthio, 3- to 20-membered heterocyclylthio, NH2, -C(0)R 51 , -C(0)OR 52 , -OC(0)R 53 , -S(0)2R 54 , -S(0)2OR 55 , -OS(0)2R 56 , -P(0)(OR 57 )(OR 58 ); Alternatively, when two or more R-selected groups are present on the same group. f 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. g The following groups are substituted: C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic; Each R g They are selected independently from H, halogens, OH, CN, NO2, oxo (=O), thio (=S), and C, whether they are the same or different. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, NH2; Each R 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 they are the same or different. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, NH2; R h represents 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 C6-20- aryl and a 4- to 12-membered cycloalkenyl, each of which is optionally substituted in each of the cyclic groups in the ortho, para or meta position independently by one, two or more groups selected from the group consisting of F, CI, Br, OH, CN, NH2, or by one, two or more groups selected from the group consisting of OR 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 , NR 1.2 R 1.3 , CH2-NR 1.2 R 1.3 , CH2CH2-NR 1.2 R 1.3 , C 3-10 -cycloalkyl, C 3-10 -cycloalkenyl, C 1-3 -alkyl-(mono- or polycyclic-C 6-20- aryl), 3- to 20-membered heterocyclyl-C 6-20- aryl, 3- to 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 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 1.1 , 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 1.2 R 1.3 , which are optionally independently substituted by one, two or more groups selected from the group consisting of OH, OR 1.1 , CF3, CHF2, CH2F, oxo, halo, CF3, CHF2, CH2F, C 1-6 - alkyl, C 6-10- aryl and NR 1.2 R 1.3 or, alternatively, R h represents a group selected from heterocycle or heteroaryl, which is optionally substituted in the ortho-, para- or meta-position, each independently by 1, 2 or more groups of halogen, OH, oxo, CF3, CHF2and CH2F, or by 1, 2 or more groups selected from OR 1.1 , C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 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 , 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 heterocycloalkenyl-C 6-20- aryl, 3-10 membered heterocyclyl, 5-20 membered heteroaryl C 1- 3-alkyl-OR 1.1 and NR 1.2 R 1.3 , which in turn can be independently optionally substituted by groups selected from OH, OR 1.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- alkyl, C 6-20- aryl and NR 1.2 R 1.3 substituted with 1, 2 or more substituents from the group consisting of heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused ring or optionally bridged ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; R 1.1 is H or is selected from the group consisting of C 1-6- alkyl, C 1-6- alkyl alcohol, C 1-3 -haloalkyl, C 3-11 -monocyclic or bicyclic heterocyclyl, -C 3-10 -cycloalkyl, -C 3-10 -cycloalkenyl, C 6-20- aryl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6 -alkyl, 3- to 10-membered heterocyclyl-C 1-6 -alkyl, C 3- 10 -cycloalkyl-C 1-6 -alkyl, C 3-10 -cycloalkenyl-C 1-6 -alkyl, monocyclic or bicyclic C 6-20- aryl, 5- to 20-membered heteroaryl and heterocyclyl, which can optionally be substituted by a group selected from the group consisting of OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 6-20- aryl; R 1.2 and R 1.3 independently of one another denote H or a radical selected from the group consisting of C 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- to 20-membered heteroaryl-C 1-6 alkylene, mono- or bicyclic C 6-20- aryl, 3- to 10-membered heterocyclyl, heteroarylyl, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 1.1 and COOR 1.1 which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 1.1 ; the 3-20 membered heterocyclyl represents a saturated or unsaturated non-aromatic ring or ring system, for example a 4-, 5-, 6- or 7-membered monocyclic group, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic (e.g. fused, bridged, spirocyclic) ring or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms independently selected from O, S and N, wherein N and S can also be optionally oxidized to various oxidation states to form a nitro oxide, -S(O)- or -S(O)2- state; The C 6-20 Aryl represents a monovalent aromatic or partially aromatic, monocyclic, bicyclic (e.g., fused, bridged, spirocyclic) or tricyclic hydrocarbon ring having from 6 to 20 carbon atoms, which can be a single aromatic ring or multiple aromatic rings that are fused together; 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; L represents a chemical bond, C 2-20 alkynyl or Cy; wherein L can be attached to X1or R c linkage; Cy represents a chemical bond, 3-20 membered heterocycloalkyl, C 6-20 aryl, 5-20 membered heteroaryl, wherein the 3-20 membered heterocycloalkyl, C 6-20 aryl, 5-20 membered heteroaryl can optionally be fused with a 4-12 membered cycloalkyl or 4-12 membered cycloalkenyl, with the proviso that when the heterocyclyl group contains an N atom, the heterocyclyl group can be bonded through its N atom or C atom to the carbon atom at the 2-position of the pyrimidine ring in Formula H; 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 cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.2 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.2 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.2 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 3-10 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 3-10 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 - aryl and a 4- to 12-membered cycloalkyl or 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 cycloalkyl or a mono- or polycyclic C 1-6 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 6-20- - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-6 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-6 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-6- - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 6-10 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.2 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.3 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 - aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-6 - alkyl, C 6-10- aryl and NR 1.2 R 1.3 substituted by one or more substituents selected from the group consisting of halogen, CN, alkyl, C alkenyl, C L represents a group selected from a heterocycle or a heteroaryl group, which is optionally substituted in the ortho-, para- or meta-position, each independently by 1, 2 or more groups of halogen, OH, oxo, CF3, CHF2and CH2F, or by 1, 2 or more groups selected from OR 1.1 , C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 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 , 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 1.1 and NR 1.2 R 1.3 , which substituents can in turn be independently optionally substituted by groups selected from OH, OR 1.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- alkyl, C 6-20- aryl and NR 1.2 R 1.3 one, two or more substituents from the group consisting of alkyl, C heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused ring or optionally bridged ring comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; for example, L is selected from 5-membered monocyclic heteroaryl, 5-membered heteroarylbiphenyl, 5-membered heteroarylheteroaryl, 5-membered heteroarylcycloalkyl, 5-membered heteroarylcycloalkenyl, 5-membered heteroarylheterocycloalkyl, 5-membered heteroarylheterocycloalkenyl, 6-membered heteroarylbiphenyl, 6-membered heteroarylheteroaryl, 6-membered heteroarylcycloalkyl, 6-membered heteroarylcycloalkenyl, 6-membered heteroarylheterocycloalkyl, 6-membered heteroarylheterocycloalkenyl; heterocycloalkyl can be saturated or partially saturated; R 1.1 is H or is selected from the group consisting of C 1-6- alkyl, C 1-6- alkyl alcohol, C 1-3 -haloalkyl, C 3-11 -monocyclic or bicyclic heterocyclyl, -C 3-10 -cycloalkyl, -C 3-10 -cycloalkenyl, C 6-20- aryl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6 -alkyl, 3- to 10-membered heterocyclyl-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- to 20-membered heteroaryl and heterocyclyl, which can optionally be substituted by a group selected from the group consisting of OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 6-20- aryl; R 1.2 and R 1.3 independently of one another denote H or a radical selected from the group consisting of C 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- to 20-membered heteroaryl-C 1-6 alkylene, mono- or bicyclic C 6-20- aryl, 3- to 10-membered heterocyclyl, heteroarylyl, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 1.1 and COOR 1.1 which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 1.1 ; with the proviso that the compound does not include the following compounds:

2. The compound according to claim 1, racemate, stereoisomer, tautomer, isotopically labeled, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: L is selected from the group consisting of: and / or each R d21 , R d22 identically or differently, independently of one another, denote hydrogen, halogen, cyano, hydroxyl, CF3, C 1-6 -alkyl, C 1-3 -fluoroalkyl, CHF2, CH2F, SO2-CH3, SO2-CH2CH3, SO2-NR 1.2 R 1.3 , C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2or C 1-3 -alkyl-NHR 1.1 , which can be independently optionally substituted with 1, 2 or more substituents selected from the group consisting of OH, OR 1.1 , CF3, CHF2, CH2F, oxo, CF3, CHF2, CH2F, C 1-6 -alkyl, C 6-20- aryl and NR 1.2 R 1.3 substituents; and / or each R d6 identically or differently, independently of one another, H, F, Me, C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 1.1 , C 1-6- alkyl, C 2-6- alkenyl, C 2-6- alkynyl, a mono- or polycyclic C 6-20- aryl, a mono- or polycyclic C 6-20 -aryl and 4- to 12-membered cycloalkyl, a mono- or polycyclic C 6-20 -aryl and 4- to 12-membered cycloalkenyl, a mono- or polycyclic C6-20-heteroaryl and 4- to 12-membered cycloalkyl, a mono- or polycyclic C6-20-heteroaryl and 4- to 12-membered cycloalkenyl, C 6-10 -aryl-C 1-6 -alkyl, C 5-10 -heteroaryl-C 1-6 -alkyl, C 3-10 -heterocycle and C 5-10 -heterocyclyl, -NR’R”, fluorine, C 1-6- fluoroalkyl and C 1-6- fluoroalkoxy, wherein R’ and R” are independently selected from H and C 1-6- alkyl; the radicals in each case being optionally substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C 1-6- alkyl and O-C 1-6- alkyl; or, each R d6 identically or differently, independently of one another, denote H, F, Me, C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 1.1 , C 1-6- alkyl, C 2-6- alkenyl, C 2-6- alkynyl, C 6-10- aryl, C 6- 10 -aryl-C 1-6 -alkyl, C 5-10 -heteroaryl-C 1-6 -alkyl, C 3-10 -heterocycle and C 5-10 -heterocyclyl, -NR'R", fluorine, C 1-6- fluoroalkyl and C 1-6- fluoroalkoxy, wherein R' and R" are independently selected from H and C 1-6- alkyl; the radicals in each case can optionally be substituted by 1, 2 or more substituents selected from OH, oxo, halogen, C 1-6- alkyl and O-C 1-6- alkyl; or two R d6 , together with the atom to which they are attached, form a 3-11 membered, monocyclic or bicyclic, optionally fused combination or optionally bridged cycloalkyl or cycloalkenyl, or a 3-11 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 is unsubstituted or optionally substituted at the ortho-, para- or meta- position(s) by 1, 2 or more substituents selected from halogen, OH, oxo, 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, 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 1.1 , NR 1.2 R 1.3 , C 6-20- aryl and NR 1.2 R 1.3 ; R 1.1 is H or is a radical selected from the group consisting of C 1-6- alkyl, C 1-6- alkyl alcohol, C 1-3 -haloalkyl, mono- or bicyclic-C 3-10 -cycloalkyl, mono- or bicyclic-C 3-10 -cycloalkenyl, C 6-20- aryl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6 -alkyl, 3- to 10-membered heterocyclo-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- to 20-membered heteroaryl and heterocyclo, which can optionally be substituted by radicals selected from the group consisting of OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 6-20- aryl; R 1.2 and R 1.3 independently of one another denote H or a radical selected from the group consisting of C 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- to 20-membered heteroaryl-C 1-6 alkylene, mono- or bicyclic C 6-20- aryl, 3- to 10-membered heterocyclo, heteroarylo, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 1.1 and COOR 1.1 which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 1.1 .

3. The compound, racemate, stereoisomer, tautomer, isotopically labeled, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug thereof according to claim 1 or 2, wherein the compound is selected from the following compounds of formula I, II or III: wherein, The groups in the above formulae I, II and III independently have the definitions according to claim 1 or 2.

4. The compound, racemate, stereoisomer, tautomer, isotopically labeled, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug thereof according to claim 3, wherein the compound of Formula I has the following definition: wherein: X1represents a bond, C 1-20 alkylene, O, S, NR q , S(=O), S(=O)2or C(=O); U represents -(CH2) t - O, S, NR q , S(=0), S(=0)2or C(=0), wherein t represents 0, 1, 2 or 3; R q 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 2-20 alkenyloxy, C 2-20 alkynyloxy, C 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C 3-20 cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 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 arylthio, 5-20 membered heteroarylthio, 3-20 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 ); v represents 0, 1, 2, 3, 4 or 5; R a represents H or -X-R3; X represents CH2, O, S, NH, -S(O)-, -S(O)2- or -C(O)-; R3represents H, halogen, OH, CN, -CH2CF3, -NHR d4 , or the following groups, which are unsubstituted or optionally substituted by 1, 2 or more R d4 alkyl, -C(O)R 1-20 , -C(O)OR 61 , -OC(O)R 62 , -OC(O)R 63 , NH2; R b represents H or -Y-R4; Y represents CH2, O, S, NH, -S(O)-, -S(O)2- or -C(O)-; R4represents H, halogen, OH, CN, -CH2CF3, -NHR d4 , or the following groups, which are unsubstituted or optionally substituted by 1, 2 or more R d5 substituents: C 1-20 alkyl, -C(O)R 61 , -C(O)OR 62 , -OC(O)R 63 , NH2; provided that R a , R b are not simultaneously H; or R a , R b together with the atom to which they are attached form the following groups, which are unsubstituted or optionally substituted by 1, 2 or more R d6 C 5-20 cycloalkenyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, 6-20 membered aryl; each R d21 , R d22 , R d4 , R d5 , R d6 are identical or different, independently of one another, selected from the group consisting of H, halogen, OH, CN, N02, oxo (=0), thioxo (=S), SO, S02, unsubstituted or optionally substituted with 1, 2 or more R e 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(0)R 31 , -CH2-C(0)R 31 , -C(0)OR 32 , -CH2C(0)OR 32 , -C(0)NHR 32 , -CH2C(0)NHR 32 , -OC(0)R 33 , -S(0)2R 34 , -S(0)2OR 35 , -OS(0)2R 36 , -P(0)(OR 37 )(OR 38 ); Alternatively, when two or more R-selected groups are present on the same group. d21 R d22 R d4 R d5 R d6 When substituents are present, the two substituents can form an unsubstituted or optionally substituted group with one, two or more R atoms together with the atoms they are attached to. e The following groups are substituted: C 3- 20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic; Each R d21 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 ); 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; each R e is independently selected from H, halogen, OH, CN, N02, NH2, oxo (=0), thioxo (=S), O-CONH2, O-CONHR f , NRq-CONHR f , NRq-C(O)R f , NH R f is unsubstituted or optionally substituted by 1, 2 or more R f is selected from the following groups, which are unsubstituted or optionally substituted by 1, 2 or more R 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 ); or, when two or more substituents selected from the group consisting of R e f 3-20 3-20 3-20 6-20 may form, together with the atom to which they are attached, a group selected from the group consisting of Calkyl, Ccycloalkyl, Ccycloalkenyl, Ccycloalkynyl, Caryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl; each R is independently selected from the group consisting of H, halogen, OH, CN, N02, oxo (=0), thioxo (=S), unsubstituted or optionally substituted with 1, 2 or more R f identical or different, independently of one another, selected from the group consisting of H, halogen, OH, CN, N02, oxo (=0), thioxo (=S), unsubstituted or optionally substituted with 1, 2 or more R g substituted with 1, 2 or more R 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 arylthio, 5- to 20-membered heteroarylthio, 3- to 20-membered heterocyclylthio, NH2, -C(0)R 51 , -C(0)OR 52 , -OC(0)R 53 , -S(0)2R 54 , -S(0)2OR 55 , -OS(0)2R 56 , -P(0)(OR 57 )(OR 58 ); or, when two or more substituents selected from the group consisting of R f may be taken together with the atom(s) to which they are attached to form the following groups, which are unsubstituted or optionally substituted by 1, 2, or more R g ; C 3-20 ycloalkyl, C 3-20 ycloalkenyl, C 3-20 ycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl; Each R g They are selected independently from H, halogens, OH, CN, NO2, oxo (=O), thio (=S), and C, whether they are the same or different. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, NH2; Each R 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 They are selected independently from H, halogens, OH, CN, NO2, oxo (=O), thio (=S), and C, whether they are the same or different. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3- 20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, NH2; R c represents hydrogen, mono- or polycyclic C 6-20 - aryl, mono- or polycyclic C 6-20 - aryl and 4-12 membered cycloalkyl, mono- or polycyclic C 6-20 - aryl and 4-10 membered heterocycloalkyl, mono- or polycyclic 5-20 membered heteroaryl, mono- or polycyclic 5-20 membered heteroaryl and 4-12 membered cycloalkyl, mono- or polycyclic 5-20 membered heteroaryl and 4-10 membered heterocycloalkyl, for example C 4-10 cycloalkyl and C 6-20 aryl, C 4-10 cycloalkenyl and C 6- 20 aryl, 4-10 membered heterocycloalkyl and C 6-20 aryl, 4-10 membered heterocycloalkenyl and C 6-20 aryl, C 4-10 cycloalkyl-C 6-20 aryl, C 4-10 cycloalkenyl-C 6-20 aryl, 4-10 membered heterocycloalkyl-C 6-20 aryl, 4-10 membered heterocycloalkenyl-C 6-20 aryl-, 5-20 membered heteroaryl, C 4-10 cycloalkyl and 5-20 membered heteroaryl, C 4-10 cycloalkenyl and 5-20 membered heteroaryl, 4-10 membered heterocycloalkyl and 5-20 membered heteroaryl, 4-10 membered heterocycloalkenyl and 5-20 membered heteroaryl, C 4-10 cycloalkyl-5-20 membered heteroaryl, C 4-10 cycloalkenyl-5-20 membered heteroaryl, 4-10 membered heterocycloalkyl-5-20 membered heteroaryl, 4-10 membered heterocycloalkenyl-5-20 membered heteroaryl; or, R c is selected from 5-20 membered heteroaryl-O-C 6-20 aryl, 5-20 membered heteroaryl-NH-C 6-20 aryl, 5-20 membered heteroaryl-S-C 6-20 aryl, 5-20 membered heteroaryl-CH2-C 6-20 aryl; each ring system in the above groups can optionally be substituted in the ortho, para or meta position, independently of one another, by 1, 2 or more substituents selected from halogen, hydroxyl, CN, NO2, NH2, or by 1, 2 or more substituents selected from OR 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 CH2=CHCO-NR 1.1 R 1.2 R 1.3 CH2-NR 1.2 R 1.3 CH2CH2-NR 1.2 R 1.3 C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 1.1 , C 3-10 -cycloalkyl, C 3-10 -cycloalkenyl, 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-CH2CH3and SO2-NR 1.2 R 1.3 substituted; or R c is selected from the group consisting of heterocycle and heteroaryl, which can be optionally substituted at the ortho-, para- or meta- position, each independently, with 1, 2 or more groups selected from halogen, OH, oxo, CF3, CHF2and CH2F, or with 1, 2 or more groups selected from 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, 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 1.1 and NR 1.2 R 1.3 , which in turn can be independently optionally substituted with 1, 2 or more substituents from the group consisting of OH, OR 1.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- alkyl, C 6-10- aryl and NR 1.2 R 1.3 ; heterocycloalkyl can be saturated or partially saturated; heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; for example, L is selected from 5-membered monocyclic heteroaryl, 5-membered heteroarylbiphenyl, 5-membered heteroarylheteroaryl, 5-membered heteroarylcycloalkyl, 5-membered heteroarylcycloalkenyl, 5-membered heteroarylheterocycloalkyl, 5-membered heteroarylheterocycloalkenyl, 6-membered heteroarylbiphenyl, 6-membered heteroarylheteroaryl, 6-membered heteroarylcycloalkyl, 6-membered heteroarylcycloalkenyl, 6-membered heteroarylheterocycloalkyl, 6-membered heteroarylheterocycloalkenyl; each R 1.1 identically or differently, independently of one another, H or selected from the group consisting of C 1-6- alkyl, C 1-6- alkyl alcohol, C 1-3 haloalkyl, mono- or bicyclic, -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 heterocyclo-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 heterocyclo, which can optionally be substituted with OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 5-10 aryl substituents; each R 1.2 and R 1.3 identically or differently, independently of one another, denote H or a radical selected from the group consisting of C 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- to 20-membered heteroaryl-C 1-6- alkyl, mono- or bicyclic C 6-20- aryl, 3- to 10-membered heterocyclyl, heteroarylyl, CO-NH2, CO-NH-CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 1.1 and COOR 1.1 which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 1.1 ; L represents a chemical bond, C 2-20 alkynyl or Cy; wherein L can be attached to X1or the phenyl ring at any position; Cy represents a chemical 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 with a 4-12 membered cycloalkyl or cycloalkenyl group, with the proviso that when the heterocyclyl group contains an N atom, the heterocyclyl group can be bonded to the carbon atom at the 2-position of the pyrimidine ring in Formula I through its N atom or a C atom; 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 cycloalkyl or a mono- or polycyclic C 1.1 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.2 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.3 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.2 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.3 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.2 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.3 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 3-10 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 3-10 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 -aryl and a 4- to 12-membered cycloalkyl or 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 cycloalkyl or a mono- or polycyclic C 1-6 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-3 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 6-20- -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-6 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-6 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-6- -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 6-10 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.2 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.3 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1.1 -aryl and a 4- to 12-membered cycloalkyl or a mono- or polycyclic C 1-6 - alkyl, C 6-10- aryl and NR 1.2 R 1.3 substituted by one or more substituents selected from the group consisting of halogen, CN, alkyl, C alkoxy, aryl, aryloxy, arylalkyl, arylalkyloxy, heteroaryl, heteroarylalk L represents a group selected from a heterocycle or a heteroaryl group, which is optionally substituted in the ortho-, para- or meta-position, each independently by 1, 2 or more groups of halogen, OH, oxo, CF3, CHF2and CH2F, or by 1, 2 or more groups selected from OR 1.1 , C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 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 , 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 1.1 and NR 1.2 R 1.3 , which substituents can in turn be independently optionally substituted by groups selected from OH, OR 1.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- alkyl, C 6-20- aryl and NR 1.2 R 1.3 one, two or more substituents from the group consisting of alkyl, C heterocycloalkyl can be saturated or partially saturated; heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, S or O; for example, L is selected from 5-membered monocyclic heteroaryl, 5-membered heteroarylbiphenyl, 5-membered heteroarylheteroaryl, 5-membered heteroarylcycloalkyl, 5-membered heteroarylcycloalkenyl, 5-membered heteroarylheterocycloalkyl, 5-membered heteroarylheterocycloalkenyl, 6-membered heteroarylbiphenyl, 6-membered heteroarylheteroaryl, 6-membered heteroarylcycloalkyl, 6-membered heteroarylcycloalkenyl, 6-membered heteroarylheterocycloalkyl, 6-membered heteroarylheterocycloalkenyl; heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group including 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O; for example, L is selected from a 5-membered monocyclic heteroaryl group, a 5-membered heteroarylbiphenyl group, a 5-membered heteroarylheteroaryl group, a 5-membered heteroarylcycloalkyl group, a 5-membered heteroarylcycloalkenyl group, a 5-membered heteroarylheterocycloalkyl group, a 5-membered heteroarylheterocycloalkenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylheteroaryl group, a 6-membered heteroarylheteroaryl group, a 6-membered heteroarylcycloalkyl group, a 6-membered heteroarylcycloalkenyl group, a 6-membered heteroarylheterocycloalkyl group, a 6-membered heteroarylheterocycloalkenyl group; R 1.1 is H or is selected from the group consisting of C 1-6- alkyl, C 1-6- alkyl alcohol, C 1-3 -haloalkyl, C 3-11 -monocyclic or bicyclic heterocyclyl, -C 3-10 -cycloalkyl, -C 3-10 -cycloalkenyl, C 6-20- aryl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6 -alkyl, 3- to 10-membered heterocyclyl-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- to 20-membered heteroaryl and heterocyclyl, which can optionally be substituted by a group selected from the group consisting of OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 6-20- aryl; R 1.2 and R 1.3 independently of one another denote H or a radical selected from the group consisting of C 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- to 20-membered heteroaryl-C 1-6 alkylene, mono- or bicyclic C 6-20- aryl, 3- to 10-membered heterocyclyl, heteroarylyl, CO-NH2, CO-NH-CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 1.1 and COOR 1.1 which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 1.1 .

5. The compound according to claim 3, its racemic mixture, stereoisomer, tautomer, isotope label, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug, wherein the compound of formula II has the following definition: wherein: X1represents a bond, C 1-20 alkylene, O, S, NR q , S(=O), S(=O)2or C(=O); X2represents a bond, C 1-20 alkylene, S(=0), S(=0)2or C(=0); X3represents a bond, C 1-20 alkylene, O, S, NR q , S(=O), S(=O)2or C(=O); U represents -(CH2) t -, O, S, NR q , S(=O), S(=O)2or C(=O), wherein t represents 0, 1, 2 or 3; R q 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 2-20 alkenyloxy, C 2-20 alkynyloxy, C 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C 3-20 cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 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 arylthio, 5-20 membered heteroarylthio, 3-20 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 ); v represents 0, 1, 2, 3, 4, or 5; R a represents H or -X-R3; X represents CH2, O, S, NH, -S(O)-, -S(O)2-, or -C(O)-; R3 represents H, halogen, OH, CN, -CH2CF3, -NHR d4 No substitution or optional use by 1, 2 or more R d4 The following groups are substituted: C 1-20 Alkyl, -C(O)R 61 -C(O)OR 62 -OC(O)R 63 NH2; R b represents H or -Y-R4; Y represents CH2, O, S, NH, -S(O)-, -S(O)2-, or -C(O)-; R4represents H, halogen, OH, CN, -CH2CF3, -NHR d4 , or the following groups, which are unsubstituted or optionally substituted by 1, 2 or more R d5 alkyl, -C(O)R 1-20 , -C(O)OR 61 , -OC(O)R 62 , -NHC(O)R 63 , NH2; provided that R a , R b are not simultaneously H; or R a , R b together with the atom to which they are attached form the following groups, which are unsubstituted or optionally substituted by 1, 2 or more R d6 C 5-20 cycloalkenyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, 6-20 membered aryl; each R d21 , R d22 , R d4 , R d5 , R d6 are identical or different, independently of one another, selected from the group consisting of H, halogen, OH, CN, NO2, oxo (=0), thioxo (=S), SO, SO2, unsubstituted or optionally substituted with 1, 2 or more R e ; 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 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 ); or, when there are two or more substituents selected from R d21 , R d22 , R d4 , R d5 , R d6 on the same group, said two substituents can form, together with the atom(s) to which they are attached, a group selected from C e 3- 20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;​ each R d21 , R d22 are independently of one another selected from the group consisting of H, halogen, OH, CN, N02, oxo (=0), thioxo (=S), SO, S02, unsubstituted or optionally substituted with 1, 2 or more R e substituents: 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(0)R 31 , -CH2-C(0)R 31 , -C(0)OR 32 , -CH2C(0)OR 32 , -C(0)NHR 32 , -CH2C(0)NHR 32 , -OC(0)R 33 , -S(0)2R 34 , -S(0)2OR 35 , -OS(0)2R 36 , -P(0)(OR 37 )(OR 38 ); 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; each R e is independently selected from H, halogen, OH, CN, N02, NH2, oxo (=0), thioxo (=S), O-CONH2, O-CONHR f , NRq-CONHR f , NRq-C(O)R f , NH R f is unsubstituted or optionally substituted with 1, 2, or more R f is selected from the following groups, which are unsubstituted or optionally substituted with 1, 2, or more R 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 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C 3-20 cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 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, 5-20 membered heteroarylthio, 3-20 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 ); 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; each R is independently selected from the group consisting of H, halogen, OH, CN, N02, oxo (=0), thioxo (=S), unsubstituted or optionally substituted with 1, 2 or more R f identically or differently, independently of one another, selected from the group consisting of H, halogen, OH, CN, N02, oxo (=0), thioxo (=S), unsubstituted or optionally substituted with 1, 2 or more R g substituted with 1, 2 or more R 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 arylthio, 5- to 20-membered heteroarylthio, 3- to 20-membered heterocyclylthio, NH2, -C(0)R 51 , -C(0)OR 52 , -OC(0)R 53 , -S(0)2R 54 , -S(0)2OR 55 , -OS(0)2R 56 , -P(0)(OR 57 )(OR 58 ); or, when two or more substituents selected from the group consisting of R f g 3-20 Cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;​​ Each R g They are selected independently from H, halogens, OH, CN, NO2, oxo (=O), thio (=S), and C, whether they are the same or different. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, NH2; Each R 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 They are selected independently from H, halogens, OH, CN, NO2, oxo (=O), thio (=S), and C, whether they are the same or different. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3- 20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, NH2; L represents a chemical bond, C 2-20 alkynyl or Cy; wherein L can be attached to X1or the phenyl ring (for the same reason) at any position; Cy represents a chemical 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 with a 4-12 membered cycloalkyl or cycloalkenyl group, provided that when the heterocyclyl group contains an N atom, the heterocyclyl group can be bonded through its N atom or a C atom to the carbon atom in the 2-position of the pyrimidine ring in Formula II; 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, which can each independently be 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 2.1 , COOR 2.1 , CH2COOR 2.1 , CH2CH2COOR 2.1 , CH=CHCOOR 2.1 , CO-NR 2.1 , CH2CO-NR 2.1 , CH2CH2CO-NR 2.1 , CH=CHCO-NR 2.1 , NR 2.2 R 2.3 , CH2-NR 2.2 R 2.3 , CH2CH2-NR 2.2 R 2.3 , 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 1.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 1.1 , 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 2.2 R 2.3 , which can each independently be optionally substituted by 1, 2 or more groups selected from OH, OR 2.1 , CF3, CHF2, CH2F, oxo, halogen, CF3, CHF2, CH2F, C 1-6 - alkyl, C 6-10- aryl and NR 2.2 R 2.3 or, alternatively, L represents a group selected from a heterocycle or a heteroaryl group, which is optionally substituted in the ortho-, para- or meta-position, each independently by 1, 2 or more groups of halogen, OH, oxo, CF3, CHF2and CH2F, or by 1, 2 or more groups selected from OR 2.1 , C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 2.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 2.1 , C 1-3 -alkyl-OR 2.1 , SR 2.1 , C 1-3 -alkyl-SR 2.1 , SO-R 2.1 , C 1-3 -alkyl-SOR 2.1 , SO2-R 2.1 , C 1-3 -alkyl-SO2R 2.1 , COOR 2.1 , CH2COOR 2.1 , CH2CH2COOR 2.1 , CH=CHCOOR 2.1 , CO-NR 2.1 CH2CO-NR 2.1 , CH2CH2CO-NR 2.1 , CH=CHCO-NR 2.1 , COR 2.1 , CH2COR 2.1 , 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 2.1 and NR 2.2 R 2.3 , which substituents can in turn be independently optionally substituted by groups selected from OH, OR 2.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- alkyl, C 6-20- aryl and NR 2.2 R 2.3 one, two or more substituents from the group consisting of alkyl, C heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring including 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O; heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group including 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O; for example, L is selected from a 5-membered monocyclic heteroaryl group, a 5-membered heteroarylbiphenyl group, a 5-membered heteroarylheteroaryl group, a 5-membered heteroarylcycloalkyl group, a 5-membered heteroarylcycloalkenyl group, a 5-membered heteroarylheterocycloalkyl group, a 5-membered heteroarylheterocycloalkenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylheteroaryl group, a 6-membered heteroarylheteroaryl group, a 6-membered heteroarylcycloalkyl group, a 6-membered heteroarylcycloalkenyl group, a 6-membered heteroarylheterocycloalkyl group, a 6-membered heteroarylheterocycloalkenyl group; R 2.1 is H or is selected from the group consisting of C 1-6- alkyl, C 1-6- alkyl alcohol, C 1-3 -haloalkyl, C 3-11 -monocyclic or bicyclic heterocyclyl, -C 3-10 -cycloalkyl, -C 3-10 -cycloalkenyl, C 6-20- aryl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6 -alkyl, 3- to 10-membered heterocyclyl-C 1-6 -alkyl, C 3- 10 -cycloalkyl-C 1-6 -alkyl, C 3-10 -cycloalkenyl-C 1-6 -alkyl, monocyclic or bicyclic C 6-20- aryl, 5- to 20-membered heteroaryl and heterocyclyl, which can optionally be substituted by a group selected from the group consisting of OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 6-20- aryl; R 2.2 and R 2.3 independently of one another denote H or a radical selected from the group consisting of C 1-6- alkyl, mono- or bicyclic C 3-10- cycloalkyl, C 6-20- aryl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6 alkylene, mono- or bicyclic C 6-20- aryl, 3- to 10-membered heterocyclyl, heteroarylyl, CO-NH2, CO-NH-CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 2.1 and COOR 2.1 which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 2.1 ; R1represents hydrogen, a mono- or polycyclic C 6-20 -aryl, optionally substituted at each occurrence in the ortho-, para- or meta- position independently with one, two or more halogen, hydroxy, CN, NO2, NH2substituents, or with one, two or more substituents selected from the group consisting of OR 2.1 , COOR 2.1 , CH2COOR 2.1 , CH2CH2COOR 2.1 , CH=CHCOOR 2.1 , CO-NR 2.1 , CH2CO-NR 2.1 , CH2CH2CO-NR 2.1 , CH=CHCO-NR 2.1 , NR 2.2 R 2.3 , CH2-NR 2.2 R 2.3 , CH2CH2-NR 2.2 R 2.3 , C 3-10 -cycloalkyl, 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, CF3, CHF2, CH2F, C 6-20- -aryl-C 1-6 -alkyl, 3-20 membered heterocyclyl-C 1-6 -alkyl, 5-20 membered heteroaryl-C 1-6- -alkyl, C 6-20- -aryl, SO2-CH3, SO2-CH2CH3and SO2-NR 2.2 R 2.3 , which can be independently optionally substituted with one, two or more substituents selected from the group consisting of OH, OR 2.1 , CF3, CHF2, CH2F, oxo, halogen, CF3, CHF2, CH2F, C 1-6 -alkyl, C 6-20- -aryl and NR 2.2 R 2.3 ; R1represents a group selected from the group consisting of a heterocycle and a heteroaryl, which can be optionally substituted at the ortho-, para- or meta-positions, 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 2.1 , C 1-3 -alkyl-OR 2.1 , SR 2.1 , C 1-3 -alkyl-SR 2.1 , SO-R 2.1 , C 1-3 -alkyl-SOR 2.1 , SO2-R 2.1 , C 1-3 -alkyl-SO2R 2.1 , COOR 2.1 , CH2COOR 2.1 , CH2CH2COOR 2.1 , CH=CHCOOR 2.1 , CO-NR 2.1 CH2CO-NR 2.1 , CH2CH2CO-NR 2.1 , CH=CHCO-NR 2.1 , COR 2.1 , CH2COR 2.1 , 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), 3-20 membered heterocyclyl-C 6-20- -aryl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl C 1-3 -alkyl-OR 2.1 and NR 2.2 R 2.3 , which in turn can be independently optionally substituted with 1, 2 or more substituents of OH, OR 2.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- -alkyl, C 6-20- -aryl and NR 2.2 R 2.3 ; heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring including 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O; heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group including 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O; R 2.1 is H or is selected from the group consisting of C 1-6- alkyl, C 1-6- alkyl alcohol, 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, 3-20 membered heterocyclo-C 1-6 -alkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl, mono or bicyclic C 6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which can optionally be substituted with OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 6-20- aryl substituents, R 2.2 and R 2.3 independently of one another H or a radical selected from the group consisting of C 1-6- alkyl, mono- or bicyclic C 3-10- cycloalkyl, C 6-20- aryl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6- alkyl, mono- or bicyclic C 6-20- aryl, 3- to 20-membered heterocyclyl, heteroarylyl, CO-NH2, CO-NH-CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 2.1 and COOR 2.1 , which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 1.1 , R2denotes hydrogen, halogen, cyano, C 1-4 alkyl, C 2- 4alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 4- to 10-membered heterocycloalkyl containing 1 -3 heteroatoms selected from the group consisting of N, S, O, Si, OH, CN, NO2, NH2, oxo (=0), thioxo (=S), O-CONH2, O-CONHR q , NRq-CONHR f , NRq-C(O)R f , R f unsubstituted or optionally substituted by 1, 2 or more R f , 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 cycloalkenylsulfinyl, C 3-20 cycloalkynylsulfinyl, C 6-20 arylsulfinyl, 5-20 membered heteroarylsulfinyl, 3-20 membered heterocyclylsulfinyl, 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 ); R2represents a mono- or polycyclic C 6-20 -aryl, optionally substituted at each occurrence in the ortho-, para- or meta-position independently from each other with one, two or more substituents selected from the group consisting of halogen, hydroxyl, CN, NO2, NH2, or with one, two or more substituents selected from the group consisting of OR 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 , NR 1.2 R 1.3 , CH2-NR 1.2 R 1.3 , CH2CH2-NR 1.2 R 1.3 , C 3-10 -cycloalkyl, C 1-3 -alkyl-(mono- or polycyclic-C 6-20 -aryl), 3- to 20-membered heterocyclyl-C 6-20 -aryl, 3- to 20-membered heterocyclyl, C 1-6 -alkyl, C 1-3 -fluoroalkyl, CF3, CHF2, CH2F, C 6-20- -aryl-C 1-6 -alkyl, 3- to 20-membered heterocyclyl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6- -alkyl, C 6-20- -aryl, SO2-CH3, SO2-CH2CH3and SO2-NR 1.2 R 1.3 , which can be independently optionally substituted with one, two or more substituents selected from the group consisting of OH, OR 1.1 , CF3, CHF2, CH2F, oxo, halogen, CF3, CHF2, CH2F, C 1-6 -alkyl, C 6-20- -aryl and NR 1.2 R 1.3 ; R2represents a group selected from heterocycle and heteroaryl, which can be optionally substituted at the ortho-, para- or meta-positions, each independently optionally with 1, 2 or more groups of halo, OH, oxo, CF3, CHF2and CH2F, or with 1, 2 or more groups selected from OR 2.1 , C 1-3 -alkyl-OR 2.1 , SR 2.1 , C 1-3 -alkyl-SR 2.1 , SO-R 2.1 , C 1-3 -alkyl-SOR 2.1 , SO2-R 2.1 , C 1-3 -alkyl-SO2R 2.1 , COOR 2.1 , CH2COOR 2.1 , CH2CH2COOR 2.1 , CH=CHCOOR 2.1 , CO-NR 2.1 CH2CO-NR 2.1 , CH2CH2CO-NR 2.1 , CH=CHCO-NR 2.1 , COR 2.1 , CH2COR 2.1 , 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), 3-20 membered heterocyclyl-C 6-20- -aryl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl C 1-3 -alkyl-OR 2.1 and NR 2.2 R 2.3 , which in turn can be independently optionally substituted with 1, 2 or more substituents of OH, OR 2.1 , oxo, halo, CF3, CHF2, CH2F, C 1-6- -alkyl, C 6-20- -aryl and NR 2.2 R 2.3 ; heterocycle represents a 3-11 membered, monocyclic or bicyclic, saturated or partially saturated, optionally fused or optionally bridged ring including 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O; heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group including 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O; R 2.1 is H or is selected from the group consisting of C 1-6- alkyl, C 1-6- alkyl alcohol, C 1-3 -haloalkyl, mono- or bicyclic, -C 3-10 -cycloalkyl, 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, mono- or bicyclic C 6-20 -aryl, 5- to 20-membered heteroaryl and heterocyclo, which can optionally be substituted by OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 6-20- aryl substituents, R 2.2 and R 2.3 independently of one another denote H or a radical selected from the group consisting of C 1-6- alkyl, mono- or bicyclic C 3-10- cycloalkyl, C 6-20- aryl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6- alkyl, mono- or bicyclic C 6-20- aryl, 3- to 20-membered heterocyclyl, heteroarylyl, CO-NH2, CO-NH-CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 2.1 and COOR 2.1 , which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 2.1 . R3represents H, C 1-6 -alkyl, F, chlorine, bromine, hydroxy, -CN, -CH2CN, -CH2COOR, -COOR, -CO-NH(CH3)C 1- 3-fluoroalkyl, (C 1-6 -alkyl)-OH, (C 1-6 -alkyl)-OCH3, (C 1-6 -alkyl)-NH2, (C 1-6 -alkyl)-N(C 1-3 -alkyl) or (C 1-6 -alkyl)-NH; R 3’ represents H, F, Me, C 1-6- alkyl, C 2-6- alkenyl, C 2-6- alkynyl, C 6-20- aryl, C 6-20- aryl-C 1-6 -alkyl, C 5- 10 -heteroaryl-C 1-6 -alkyl, C 3-10 -heterocycle and C 5-10 -heterocyclyl, -NR'R", F, C 1-6- fluoroalkyl and C 1-6- fluoroalkoxy, wherein R' and R" are independently selected from H and C 1-6- alkyl; which groups can in each case optionally be substituted by 1, 2 or more radicals selected from OH, oxo, halogen, C 1-6- alkyl and O-C 1-6- alkyl; Or, R3 and R 3’ Together they represent oxo, methylene, ethylene, and propylene, which may optionally be selected from -CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2 and O-(C 1-3 Substituents in (-alkyl); R4represents H, C 1-6 -alkyl, F, chlorine, bromine, hydroxy, -CN, -CH2CN, -CH2COOR, -COOR, -CO-NH(CH3)C 1- 3-fluoroalkyl, (C 1-6 -alkyl)-OH, (C 1-6 -alkyl)-OCH3, (C 1-6 -alkyl)-NH2, (C 1-6 -alkyl)-N(C 1-3 -alkyl) or (C 1-6 -alkyl)-NH; R 4’ represents H, F, Me, C 1-6- alkyl, C 2-6- alkenyl, C 2-6- alkynyl, C 6-20- aryl, C 6-20- aryl-C 1-6 -alkyl, C 5- 10 -heteroaryl-C 1-6 -alkyl, C 3-10 -heterocycle and C 5-10 -heterocyclyl, -NR'R", F, C 1-6- fluoroalkyl and C 1-6- fluoroalkoxy, wherein R' and R" are independently selected from H and C 1-6- alkyl; which groups can in each case optionally be substituted by 1, 2 or more radicals selected from OH, oxo, halogen, C 1-6- alkyl and O-C 1-6- alkyl; or R4and R 4’ together represent oxo, methylene, ethene and propene, which can optionally be substituted with substituents selected from -CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2and O-(C 1-3- alkyl); R5, R6independently represent H, F, C 1-6 - alkyl, C 1-3 - fluoroalkyl, C 1-6 - alkyl-OH, C 1-6 - alkenyl-OCH3, C 1-6 - alkyl-NH2, C 1-6 - alkynyl-NH(C 1-3 - alkyl) and C 1-6 - alkyl-N(C 1-3 - alkyl)2; or R1and R3together form a saturated or partially saturated 5- or 7-membered heterocyclic group containing 1, 2 or more nitrogen atoms, which can optionally be substituted with a group selected from -CH3, -CH2CH3, -CH2CH2CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2and O-(C 1-3- alkyl), or R3and R6together form a methylene, ethene and propene bridged ring which can be optionally substituted with a group selected from -CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2and O-(C 1-3 alkyl); or R3and R5together form a methylene, ethene and propene bridged ring which can be optionally substituted with a group selected from -CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2and O-(C 1-3 alkyl); or R3and R4together form a methylene, ethene and propene bridged ring which can be optionally substituted with a group selected from -CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2and O-(C 1-3 alkyl); or R4and R6together form a methylene, ethene and propene bridged ring which can be optionally substituted with a group selected from -CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2and O-(C 1-3 alkyl); or R3and R1together form a C 1-6 -alkyl, C 2-10 -alkenyl bridge, which can optionally be substituted with a group selected from -CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2and O-(C 1-3 alkyl).

6. The compound, racemate, stereoisomer, tautomer, isotopically labeled, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug thereof according to claim 3, wherein the compound of Formula III is defined as follows: ###0003### Formula III ​ wherein X1represents a bond, C 1-20 alkylene, O, S, NR q , S(=O), S(=O)2or C(=O); U represents -(CH2) t -, O, S, NR q , S(=O), S(=O)2or C(=O), wherein t represents 0, 1, 2 or 3; R q 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 2-20 alkenyloxy, C 2-20 alkynyloxy, C 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C 3-20 cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 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, 5-20 membered heteroarylthio, 3-20 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 ); v represents 0, 1, 2, 3, 4, or 5; R a represents H or -X-R3; X represents CH2, O, S, NH, -S(O)-, -S(O)2-, or -C(O)-; R3represents H, halogen, OH, CN, -CH2CF3, -NHR d4 , unsubstituted or optionally substituted by 1, 2 or more R d4 substituted C 1-20 alkyl, -C(O)R 61 , -C(O)OR 62 , -OC(O)R 63 , NH2; R b represents H or -Y-R4; Y represents CH2, O, S, NH, -S(O)-, -S(O)2-, or -C(O)-; R4represents H, halogen, OH, CN, -CH2CF3, -NHR d4 , unsubstituted or optionally substituted by 1, 2 or more R d5 substituents selected from the group consisting of C 1-20 alkyl, -C(O)R 61 , -C(O)OR 62 , -OC(O)R 63 , NH2; provided that R a , R b are not simultaneously H; or R a , R b together with the atom to which they are attached form the following groups, which are unsubstituted or optionally substituted by 1, 2 or more R d6 C 5-20 cycloalkenyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, 6-20 membered aryl; each R d21 , R d22 , R d4 , R d5 , R d6 are identical or different and independently of each other selected from the group consisting of H, halogen, OH, CN, N02, oxo (=0), thioxo (=S), SO, S02, unsubstituted or optionally substituted with 1, 2 or more R e , 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(0)R 31 , -CH2-C(0)R 31 , -C(0)OR 32 , -CH2C(0)OR 32 , -C(0)NHR 32 , -CH2C(0)NHR 32 , -OC(0)R 33 , -S(0)2R 34 , -S(0)2OR 35 , -OS(0)2R 36 , -P(0)(OR 37 )(OR 38 ); or, when there are two or more substituents selected from R d21 , R d22 , R d4 , R d5 , R d6 on the same group, said two substituents can form, together with the atom(s) to which they are attached, a group selected from C e 3- 20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;​ 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 ); 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; each R e is independently selected from H, halogen, OH, CN, N02, NH2, oxo (=0), thioxo (=S), O-CONH2, O-CONHR f , NRq-CONHR f , NRq-C(O)R f , NH R f is unsubstituted or optionally substituted with 1, 2, or more R f is selected from the following groups, which are unsubstituted or optionally substituted with 1, 2, or more R 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 3-20 cycloalkyloxy, C 3-20 cycloalkenyloxy, C 3-20 cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 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, 5-20 membered heteroarylthio, 3-20 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 ); or, when two or more substituents selected from the group consisting of R e f 3-20 Cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;​​ 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 ); or, when two or more substituents selected from the group consisting of R f are present on the same group, said two substituents can form, together with the atom to which they are attached, a group selected from the group consisting of C g alkyl, C 3-20 cycloalkyl, C 3-20 cycloalkenyl, C 3-20 cycloalkynyl, C 6-20 aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl; Each R g They are selected independently from H, halogens, OH, CN, NO2, oxo (=O), thio (=S), and C, whether they are the same or different. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3-20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, NH2; Each R 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 They are selected independently from H, halogens, OH, CN, NO2, oxo (=O), thio (=S), and C, whether they are the same or different. 1-20 Alkyl, C 2-20 alkenyl, C 2-20 alkynyl group, C 3-20 cycloalkyl, C 3-20 Cycloalkenyl, C 3- 20 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic, NH2; L represents a chemical bond, C 2-20 alkynyl or Cy; wherein, L can be attached to X1or the phenyl ring (above) at any position; Cy represents a chemical 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 with a 4-12 membered cycloalkyl or 4-12 membered cycloalkenyl, provided that when the heterocyclyl contains an N atom, the heterocyclyl can be bonded through its N atom or a C atom to the carbon atom at the 2-position of the pyrimidine ring in Formula III; L represents an alkynyl group; a mono- or polycyclic C 6-20- aryl, a mono- or polycyclic C 6-20 -aryl 4-12 membered cycloalkyl or a mono- or polycyclic C 6-20 -aryl 4-12 membered cycloalkenyl groups, which may be independently substituted at the ortho, para, or meta positions by one, two, or more independent groups substituted with fluorine, chlorine, bromine, hydroxyl, CN, or NH2, or by one, two, or more groups selected from OR 3.1 COOR 3.1 CH2COOR 3.1 CH2CH2COOR 3.1 CH = CHCOOR 3.1 CO-NR 3.1 CH2CO-NR 3.1 ,CH2CH2CO-NR 3.1 ,CH=CHCO-NR 3.1 ,NR 3.2 R 3.3 CH2-NR 3.2 R 3.3 ,CH2CH2-NR 3.2 R 3.3 C 3-10 -cycloalkyl, C 1-3 -alkyl-(monocyclic or polycyclic-C) 6-20- aryl), 3-10 membered heterocyclic-C 6-20- Aryl, 3-10 membered heterocyclic group, C 1-6 -alkyl, C 1-3 -Fluoroalkyl, C 1- 3-alkyl-CN,C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 1.1 C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 1.1 CF3, CHF2, CH2F, C 6-20- Aryl-C 1-6 -alkyl, 3-10 membered heterocyclic -C 1-6 -alkyl, 5-20-membered heteroaryl-C 1-6- Alkyl, C 6-10 -Aryl, SO2-CH3, SO2-CH2CH3 and SO2-NR 3.2 R 3.3 The substituents may be independently and optionally replaced by one, two or more molecules selected from OH, OR 3.1 CF3, CHF2, CH2F, oxidized, halogenated, CF3, CHF2, CH2F, C 1-6 -alkyl, C 6-10- aryl and NR 3.2 R 3.3 substituted by one or more substituents selected from the group consisting of L represents a group selected from a heterocycle or a heteroaryl group, which is optionally substituted in ortho, para or meta position, each independently by 1, 2 or more groups of halogen, OH, oxo, CF3, CHF2and CH2F, or by 1, 2 or more groups selected from OR 3.1 , C 1-3 -alkyl-CN, C 1-3 -alkyl-OH, C 1-3 -alkyl-OR 3.1 , C 1-3 -alkyl-NH2, C 1-3 -alkyl-NHR 3.1 , C 1-3 -alkyl-OR 3.1 , SR 3.1 , C 1-3 -alkyl-SR 3.1 , SO-R 3.1 , C 1-3 -alkyl-SOR 3.1 , SO2-R 3.1 , C 1-3 -alkyl-SO2R 3.1 , COOR 3.1 , CH2COOR 3.1 , CH2CH2COOR 3.1 , CH=CHCOOR 3.1 , CO-NR 3.1 CH2CO-NR 3.1 , CH2CH2CO-NR 3.1 , CH=CHCO-NR 3.1 , COR 3.1 , CH2COR 3.1 , 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 3.1 and NR 3.2 R 3.3 , which substituents can in turn be independently optionally substituted by groups selected from OH, OR 3.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- -alkyl, C 6-20- Aryl and NR 3.2 R 3.3 One, two or more substituents are substituted; heteroaryl is a 5-10 membered, monocyclic or bicyclic, optionally fused heteroaryl group including 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O; for example, L is selected from a 5-membered monocyclic heteroaryl group, a 5-membered heteroarylbiphenyl group, a 5-membered heteroarylbiphenyl group, a 5-membered heteroarylbiphenyl group, a 5-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6-membered heteroarylbiphenyl group, a 6 ​ R 3.1 is H or is selected from C 1-6- alkyl, C 1-6- alkyl alcohol, C 1-3 -haloalkyl, C 3-11 -monocyclic or bicyclic heterocyclyl, -C 3-10 -cycloalkyl, C 6-20- aryl-C 1-6 -alkyl, 5-20 membered heteroaryl-C 1-6 -alkyl, 3-10 membered heterocyclo-C 1-6 -alkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl, mono or bicyclic C 6-20- aryl, 5-20 membered heteroaryl and heterocycle, which can optionally be substituted with a group selected from OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 6-20- aryl; R 3.2 and R 3.3 independently of one another denote H or a radical selected from the group consisting of C 1-6- alkyl, mono- or bicyclic C 3-10- cycloalkyl, C 6-20- aryl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6 alkylene, mono- or bicyclic C 6-20- aryl, 3- to 10-membered heterocyclyl, heteroarylyl, CO-NH2, CO-NH-CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 3.1 and COOR 3.1 which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 3.1 ; R1represents hydrogen, a mono- or polycyclic C 6-20 -aryl, optionally substituted at each occurrence independently in the ortho-, para- or meta-position by 1, 2 or more substituents selected from the group consisting of halogen, hydroxy, CN, NO2, NH2, or by 1, 2 or more substituents selected from the group consisting of OR 3.1 , COOR 3.1 , CH2COOR 3.1 , CH2CH2COOR 3.1 , CH=CHCOOR 3.1 , CO-NR 3.1 , CH2CO-NR 3.1 , CH2CH2CO-NR 3.1 , CH=CHCO-NR 3.1 , NR 3.2 R 3.3 , CH2-NR 3.2 R 3.3 , CH2CH2-NR 3.2 R 3.3 , C 3-10 -cycloalkyl, C 1-3 -alkyl-(mono- or polycyclic-C 6-20 -aryl), 3- to 20-membered heterocyclyl-C 6-20 -aryl, 3- to 20-membered heterocyclyl, C 1-6 -alkyl, C 1-3 -fluoroalkyl, CF3, CHF2, CH2F, C 6-20- -aryl-C 1-6 -alkyl, 3- to 20-membered heterocyclyl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6- -alkyl, C 6-20- -aryl, SO2-CH3, SO2-CH2CH3and SO2-NR 3.2 R 3.3 , which can be independently optionally substituted by 1, 2 or more substituents selected from the group consisting of OH, OR 3.1 , CF3, CHF2, CH2F, oxo, halogen, C 1-6 -alkyl, C 6-20- -aryl and NR 3.2 R 3.3 ; or R1represents C 1-10 -alkyl, C 3-10 -alkyl, C 1-3 -methylene-C 3-10 -alkyl, C 1-3 -methylene-C 2-6 -alkyl, C 1-3 -methylene-C 5-10 -alkyl, C 1-3 -methylene-C 5-10 -heterocycloalkenyl, optionally substituted with 1, 2 or more substituents selected from the group consisting of halogen, hydroxy, CN, NO2, NH2, CF3, or with 1, 2 or more substituents selected from the group consisting of OR 3.1 , COOR 3.1 CH2COOR 3.1 , CH2CH2COOR 3.1 , CH=CHCOOR 3.1 , CO-NR 3.1 CH2CO-NR 3.1 , CH2CH2CO-NR 3.1 , CH=CHCO-NR 3.1 , NR 3.2 R 3.3 , CH2-NR 3.2 R 3.3 , CH2CH2-NR 3.2 R 3.3 , C 3-10 -cycloalkyl, 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, CF3, CHF2, CH2F, C 6-20- -aryl-C 1-6 -alkyl, 3-20 membered heterocyclyl-C 1-6 -alkyl, 5-20 membered heteroaryl-C 1-6- -alkyl, C 6-20- -aryl, SO2-CH3, SO2-CH2CH3and SO2-NR 3.2 R 3.3 , which can be independently optionally substituted with 1, 2 or more substituents selected from the group consisting of OH, OR 3.1 , CF3, CHF2, CH2F, oxo, halogen, C 1-6 -alkyl, C 6-20- -aryl and NR 3.2 R 3.3 ; R1represents a group selected from the group consisting of a heterocycle and a heteroaryl, which can be optionally substituted at the ortho-, para- or meta-positions, 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 3.1 , C 1-3 -alkyl-OR 3.1 , SR 3.1 , C 1-3 -alkyl-SR 3.1 , SO-R 3.1 , C 1-3 -alkyl-SOR 3.1 , SO2-R 3.1 , C 1-3 -alkyl-SO2R 3.1 , COOR 3.1 , CH2COOR 3.1 , CH2CH2COOR 3.1 , CH=CHCOOR 3.1 , CO-NR 3.1 CH2CO-NR 3.1 , CH2CH2CO-NR 3.1 , CH=CHCO-NR 3.1 , COR 3.1 , CH2COR 3.1 , 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), 3-20 membered heterocyclyl-C 6-20- -aryl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl C 1-3 -alkyl-OR 3.1 and NR 3.2 R 3.3 , which in turn can be independently optionally substituted with 1, 2 or more substituents of OH, OR 3.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- -alkyl, C 6-20- -aryl and NR 3.2 R 3.3 ; ​ ​ R 3.1 is H or is selected from the group consisting of C 1-6- alkyl, C 1-6- alkyl alcohol, C 1-3 -haloalkyl, mono- or bicyclic, -C 3-10 -cycloalkyl, 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, mono- or bicyclic C 6-20 -aryl, 5- to 20-membered heteroaryl and heterocyclo, which can optionally be substituted by OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 6-20- aryl substituents, R 3.2 and R 3.3 independently of one another denote H or a radical selected from the group consisting of C 1-6- alkyl, mono- or bicyclic C 3-10- cycloalkyl, C 6-20- aryl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6- alkyl, mono- or bicyclic C 6-20- aryl, 3- to 20-membered heterocyclyl, heteroarylyl, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 3.1 and COOR 3.1 which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 3.1 , R2represents hydrogen, a mono- or polycyclic C 6-20 -aryl, optionally substituted at each occurrence in the ortho-, para- or meta-position independently from each other with one, two or more substituents selected from the group consisting of halogen, hydroxyl, CN, NO2, NH2, or with one, two or more substituents selected from the group consisting of OR 3.1 , COOR 3.1 , CH2COOR 3.1 , CH2CH2COOR 3.1 , CH=CHCOOR 3.1 , CO-NR 3.1 , CH2CO-NR 3.1 , CH2CH2CO-NR 3.1 , CH=CHCO-NR 3.1 , NR 3.2 R 3.3 , CH2-NR 3.2 R 3.3 , CH2CH2-NR 3.2 R 3.3 , C 3-10 -cycloalkyl, C 1-3 -alkyl-(mono- or polycyclic-C 6-20 -aryl), 3- to 20-membered heterocyclyl-C 6-20 -aryl, 3- to 20-membered heterocyclyl, C 1-6 -alkyl, C 1-3 -fluoroalkyl, CF3, CHF2, CH2F, C 6-20- -aryl-C 1-6 -alkyl, 3- to 20-membered heterocyclyl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6- alkyl, C 6-20- aryl, SO2-CH3, SO2-CH2CH3and SO2-NR 3.2 R 3.3 , which can be independently optionally substituted with one, two or more substituents selected from the group consisting of OH, OR 3.1 , CF3, CHF2, CH2F, oxo, halogen, C 1-6 -alkyl, C 6-20- aryl and NR 3.2 R 3.3 ; or R2represents C 1-10 -alkyl, C 3-10 -cycloalkyl, C 1-3 -methylene-C 3-10 -cycloalkyl, C 1-3 -methylene-C 2-6 -alkenyl, C 1-3 -methylene-C 5-10 -cycloalkenyl, C 1-3 -methylene-C 5-10 -heterocycloalkenyl, optionally substituted with 1, 2 or more substituents selected from the group consisting of halogen, hydroxy, CN, NO2, NH2, CF3, or with 1, 2 or more substituents selected from the group consisting of OR 3.1 , COOR 3.1 CH2COOR 3.1 , CH2CH2COOR 3.1 , CH=CHCOOR 3.1 , CO-NR 3.1 CH2CO-NR 3.1 , CH2CH2CO-NR 3.1 , CH=CHCO-NR 3.1 , NR 3.2 R 3.3 , CH2-NR 3.2 R 3.3 , CH2CH2-NR 3.2 R 3.3 , C 3-10 -cycloalkyl, C 1-3 -alkyl-(mono- or polycyclic-C 6-20 -aryl), 3- to 20-membered heterocyclyl-C 6-20 -aryl, 3- to 20-membered heterocyclyl, C 1-6 -alkyl, C 1-3 -fluoroalkyl, CF3, CHF2, CH2F, C 6-20- -aryl-C 1-6 -alkyl, 3- to 20-membered heterocyclyl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6- alkyl, C 6-20- -aryl, SO2-CH3, SO2-CH2CH3and SO2-NR 3.2 R 3.3 , which can be independently optionally substituted with 1, 2 or more substituents selected from the group consisting of OH, OR 3.1 , CF3, CHF2, CH2F, oxo, halogen, C 1-6 -alkyl, C 6-20- -aryl and NR 3.2 R 3.3 ; R2represents a group selected from the group consisting of heterocycle and heteroaryl, which can be optionally substituted at the ortho-, para- or meta-positions, 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 3.1 , C 1-3 -alkyl-OR 3.1 , SR 3.1 , C 1-3 -alkyl-SR 3.1 , SO-R 3.1 , C 1-3 -alkyl-SOR 3.1 , SO2-R 3.1 , C 1-3 -alkyl-SO2R 3.1 , COOR 3.1 , CH2COOR 3.1 , CH2CH2COOR 3.1 , CH=CHCOOR 3.1 , CO-NR 3.1 CH2CO-NR 3.1 , CH2CH2CO-NR 3.1 , CH=CHCO-NR 3.1 , COR 3.1 , CH2COR 3.1 , 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), 3-20 membered heterocyclyl-C 6-20- -aryl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl C 1-3 -alkyl-OR 3.1 and NR 3.2 R 3.3 , which in turn can be independently optionally substituted with 1, 2 or more substituents of OH, OR 3.1 , oxo, halogen, CF3, CHF2, CH2F, C 1-6- -alkyl, C 6-20- -aryl and NR 3.2 R 3.3 ; ​ ​ R 3.1 is H or is selected from the group consisting of C 1-6- alkyl, C 1-6- alkyl alcohol, 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, 3-20 membered heterocyclo-C 1-6 -alkyl, C 3-10 -cycloalkyl-C 1-6 -alkyl, mono or bicyclic C 6-20 -aryl, 5-20 membered heteroaryl and heterocycle, which can optionally be substituted with OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 6-20- aryl substituents, R 3.2 and R 3.3 independently of one another denote H or a radical selected from the group consisting of C 1-6- alkyl, mono- or bicyclic C 3-10- cycloalkyl, C 6-20- aryl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6- alkyl, mono- or bicyclic C 6-20- aryl, 3- to 20-membered heterocyclyl, heteroarylyl, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 3.1 and COOR 3.1 which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 3.1 , R5represents H, F, chloro, bromo, hydroxy, -CN, -CH2CN, -CH2COOR 3.1 , -COOR 3.1 , -CO-NH(CH3)C 1- 3-fluoroalkyl, -(C 1-6 -alkyl)-OCH3, -(C 1-6 -alkyl)-S(=O)2-(C 1-6 -alkyl), -S(=O)2-(C 1-6 -alkyl), -(C 1-6 -alkyl)-NH2, -(C 1-6 -alkyl)-N(C 1-3 -alkyl) or (C 1-6 -alkyl)-NH, R5represents C 1-10 -alkyl, C 3-10 -cycloalkyl, C 1-3 -methylene-C 3-10 -cycloalkyl, C 1-3 -methylene-C 2-6 -alkenyl, C 1-3 -methylene-C 5-10 -cycloalkenyl, C 1-3 -methylene-C 5-10 -heterocycloalkenyl, optionally substituted with 1, 2 or more halogen, hydroxy, CN, NO2, NH2, CF3, C 1-3 -alkyl-SO2-CH3, C 1-3 -alkyl-SO2-CH2CH3and C 1-3 -alkyl-SO2-NR 3.2 R 3.3 substituted with 1, 2 or more substituents selected from the group consisting of OR 3.1 , COOR 3.1 CH2COOR 3.1 , CH2CH2COOR 3.1 , CH=CHCOOR 3.1 , CO-NR 3.1 CH2CO-NR 3.1 , CH2CH2CO-NR 3.1 , CH=CHCO-NR 3.1 , NR 3.2 R 3.3 , CH2-NR 3.2 R 3.3 , CH2CH2-NR 3.2 R 3.3 , C 3-10 -cycloalkyl, C 1-3 -alkyl-(mono- or polycyclic-C 6-20 -aryl), 3- to 20-membered heterocyclyl-C 6- 20 -aryl, 3- to 20-membered heterocyclyl, C 1-6 -alkyl, C 1-3 -fluoroalkyl, CF3, CHF2, CH2F, C 6-20- -aryl-C 1-6 -alkyl, 3- to 20-membered heterocyclyl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6- alkyl and C 6-20- -aryl, which can be independently optionally substituted with 1, 2 or more substituents selected from the group consisting of OH, OR 3.1 , CF3, CHF2, CH2F, oxo, halogen, C 1-6 -alkyl, C 6-20- aryl and NR 3.2 R 3.3 substituted by one or more substituents selected from the group consisting of R 5’ represents H, F, Me, C 1-6- alkyl, C 2-6- alkenyl, C 2-6- alkynyl, C 6-20- aryl, C 6-20- aryl-C 1-6 -alkyl, C 5- 10 -heteroaryl-C 1-6 -alkyl, C 3-10 -heterocycle and C 5-10 -heterocyclyl, -NR’R”, fluorine, C 1-6- fluoroalkyl and C 1-6- fluoroalkoxy, wherein R’ and R” are independently selected from H and C 1-6- alkyl; which groups can in each case be optionally substituted by 1, 2 or more radicals selected from OH, oxo, halogen, C 1-6- alkyl and O-C 1-6- alkyl; or R5and R 5’ together represent oxo, methylene, ethene and propene, which can optionally be substituted with substituents selected from -CH3, -OH, -F, -CF3, -CHF2, -CH2F, -NH2, -NH(C 1-3 -alkyl), -N(C 1-3 -alkyl)2and O-(C 1-3 -alkyl); R 3.1 is H or is selected from the group consisting of C 1-6- alkyl, C 1-6- alkyl alcohol, C 1-3 -haloalkyl, mono- or bicyclic, -C 3-10 -cycloalkyl, 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, mono- or bicyclic C 6-20 -aryl, 5- to 20-membered heteroaryl and heterocyclo, which can optionally be substituted by OH, O-(C 1-3 -alkyl), halogen, C 1-10- alkyl and C 6-20- aryl substituents, R 3.2 and R 3.3 independently of one another denote H or a radical selected from the group consisting of C 1-6- alkyl, mono- or bicyclic C 3-10- cycloalkyl, C 6-20- aryl-C 1-6 -alkyl, 5- to 20-membered heteroaryl-C 1-6- alkyl, mono- or bicyclic C 6-20- aryl, 3- to 20-membered heterocyclyl, heteroarylyl, CO-NH2, CO-NH - CH3, -CO-N(CH3)2, SO2-(C 1-3 -alkyl), CO-R 3.1 and COOR 3.1 which can optionally be substituted by 1, 2 or more OH, halogen, C 1-6 -alkyl, C 6-20- aryl and COOR 3.1 .

7. A method of making the compound of claim 1, racemates, stereoisomers, tautomers, isotopically labeled, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs thereof, wherein the compound is selected from the following compounds:

8. A method of making a compound of any one of claims 1-7, racemate, stereoisomer, tautomer, isotopically labeled, solvate, polymorph, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein the method of making comprises reacting a compound of Formula A: ###00033### Formula A with a compound of Formula B: ###00034### Formula B to obtain a compound of Formula H: ###00035### Formula H. ​ wherein ​ X1, X2, U, v, R a , R b , R c , R d21 , R d22 , R c , R h , L independently of one another have the definitions according to any of claims 1 to 7. ​ ​ 10. A method of preventing or treating a disease mediated by at least PDE4 mediated diseases comprising administering to a patient in need thereof at least one compound selected from the group consisting of the compound of any one of claims 1-7 and the following compounds, racemates, stereoisomers, tautomers, isotopically-labeled, solvates, polymorphs, metabolites, pharmaceutically acceptable salts, or prodrugs thereof: ​ ​ ​ ​ ​ ​ For example, the disease includes, but is not limited to, respiratory inflammatory diseases, inflammatory bowel diseases, arthritic diseases, skin inflammatory diseases, eye 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 associated Pulmonary Hypertension, chronic obstructive pulmonary disease (COPD) or associated Pulmonary Hypertension, benign prostatic hyperplasia (BPH), Gastroesophageal Reflux disease, Obstructive Sleep apnea and Coronary Artery Disease or cancer. For example, the disease includes, but is not limited to, respiratory inflammatory diseases, inflammatory bowel diseases, arthritic diseases, skin inflammatory diseases, eye 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 associated Pulmonary Hypertension, chronic obstructive pulmonary disease (COPD) or associated Pulmonary Hypertension, benign prostatic hyperplasia (BPH), Gastroesophageal Reflux disease, Obstructive Sleep apnea and Coronary Artery Disease or cancer.

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