JAK3 inhibitor

Abstract

The invention discloses a JAK3 kinase inhibitor compound and application thereof, and particularly discloses a compound shown as a formula IA, or application of a stereoisomer or pharmaceutically acceptable salt of the compound in preparation of JAK3 kinase inhibitor drugs. A new choice is provided for clinical screening and / or preparation of drugs for treating diseases related to the activity of the JAK3 kinase inhibitor.

Description

Technical Field

[0001] This invention relates to a JAK3 inhibitor and its use in the preparation of pharmaceuticals. Background Technology

[0002] Protein kinases are a class of important enzymes that play a crucial role in regulating various cellular activities through phosphorylation and dephosphorylation. These processes provide rapid and dynamic regulatory mechanisms for the biological functions of most proteins and act as molecular switches in signal transduction pathways, driving diverse regulatory events such as cell division, proliferation, metabolism, transcription, differentiation, and apoptosis. The specific regulatory roles of protein kinases in cells and their defects may lead to the development of a variety of diseases. These diseases include, but are not limited to, cardiovascular diseases, blood cancers, cancer, immune-mediated diseases, and genetic diseases. Therefore, protein kinases hold an extremely important position in the life sciences and medicine; they are not only key regulators of cellular physiological processes but also potential targets for the treatment of various diseases. In particular, the JAK family of protein tyrosine kinases plays a very important role in cytokine signal transduction (Cipak et al., Int. J. Mol. Sci. 2022, 23, 3560; Xin et al., Int. Immunopharmacol. 2020, 80, 106210).

[0003] The activation of the JAK-STAT (signal transducer and activator of transcription) signaling pathway typically begins with cytokines binding to their corresponding receptors, leading to conformational changes in the receptors. This causes JAK molecules associated with the receptors to approach each other and phosphorylate each other. The activated JAKs further phosphorylate STAT proteins, causing them to form dimers and translocate into the cell nucleus, thereby regulating the expression of target genes.

[0004] The first JAK inhibitor was discovered in the early 1990s, and its development has spanned over 30 years. The JAK family (Janus kinases) is a class of non-receptor tyrosine kinases, including JAK1, JAK2, JAK3, and TYK2, which play crucial roles in signal transduction pathways. JAK kinases participate in the signal transduction of various cytokines, such as interferon and interleukins, by binding to cytokine receptors, thereby regulating biological processes such as cell proliferation, differentiation, apoptosis, and immune responses.

[0005] JAK3 (Janus kinase 3) is a member of the JAK family and plays a crucial role in the JAK-STAT signaling pathway. JAK3 is primarily expressed in lymphoid tissues and is a selective regulator of lymphocyte development, playing a key role in the immune system. JAK3 selectively binds to cytokine receptor subunits (common γ-subunit or γc chain), regulating γc cytokine signaling. Due to this selectivity, JAK3 has become a potentially ideal target for the treatment of autoimmune diseases. JAK3 is associated with a variety of diseases, including but not limited to immunodeficiency, hematologic malignancies, and autoimmune diseases.

[0006] Targeted covalent inhibitors (TCIs) are a class of small molecule compounds that can covalently bind to specific target proteins, inhibiting their biological functions through covalent bond formation. They have attracted widespread attention in drug discovery, with over 50 covalent drugs currently on the market and many more candidate drugs under development. TCIs inhibit target proteins through a two-step process. First, they bind to the target protein via non-covalent interactions, and then an electrophilic warhead forms a covalent bond with nucleophilic residues of the target protein. This mechanism can be reversible or irreversible, depending on the stability of the covalent bond. TCIs can improve drug efficacy, prolong target binding time, and exhibit greater selectivity. They can target certain "undruggable" targets, addressing drug resistance issues. The pharmacodynamics (PD) of TCIs is less correlated with pharmacokinetics (PK), exhibiting a longer duration of action. This means they can be used at lower doses and frequencies, reducing off-target effects and toxicity (Abdeldayem et al., Chem. Soc. Rev. 2020, 49, 2617-2687).

[0007] The development of JAK3 inhibitors has shown that several drugs have been discovered, covering multiple indications. For example, Ritlecitinib, an irreversible inhibitor of JAK3, exerts its inhibitory activity by covalently binding to the Cys909 residue in JAK3, exhibiting high selectivity for JAK3. Furthermore, Pfizer's Tofacitinib, an inhibitor of both JAK1 and JAK3, has been approved by the FDA for the treatment of moderate to severe ulcerative colitis and is currently undergoing a phase II clinical trial for type 1 diabetes. In general, although research and drug development on JAK3 as a drug target are progressing rapidly, offering new hope for the treatment of various immune-mediated diseases, these JAK3 inhibitors are not entirely satisfactory in terms of activity or selectivity. Therefore, there remains a need for JAK3 inhibitors with better activity and / or better selectivity. Summary of the Invention

[0008] One object of the present invention is to provide a novel class of JAK inhibitors that can replace existing JAK inhibitors, thereby providing JAK inhibitors with a new class of inhibitors.

[0009] More options are available for the treatment of related diseases.

[0010] This invention provides a compound represented by formula IA, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0011]

[0012] Wherein, ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aromatic ring, and 5-10 membered aromatic heterocyclic ring; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further separated by one, two, three, or four independent R. IA1 replace;

[0013] The R IA1 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, =O, -C 0～2 Alkylene-C(O)R IA2 -C 0～2 Alkylene-C(O)(C 2～6 alkenyl), -C 0～2 Alkylene-C(O)NR IA2 R IA3 -C 0～2 Alkylene-NHC(O)R IA2 -C 0～2 Alkylene-N(C) 1～6 Alkyl)C(O)R IA2 -C 0～2 Alkylene -NHC(O) (3- to 10-membered heterocyclic alkyl groups), -C 0～2 Alkylene-NHC(O) (6-10 membered aromatic rings); wherein the alkylene, alkyl, alkenyl, heterocyclic alkyl, or aromatic ring may be further divided by one, two, three, or four independent R groups. IA4 replace;

[0014] R IA2 R IA3 R IA4 Selected independently from hydrogen and -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 1～6 Alkyl-substituted (3- to 10-membered heterocyclic alkyl), -C 0～2 Alkylene (6- to 10-membered aromatic rings);

[0015] L1 is selected from -NH-C0～4 alkylene-, -C 0～4 Alkylene -NH-, -C 0～2 Alkylene-N(C) 1～6 Alkyl)C(O)-, -C(O)-C 0～4 Alkylene -, -O-, or absent; the alkylene is R IL1 replace;

[0016] The R IL1 Selected from hydrogen, -C(O)NR IL2 R IL3 Among them, R IL2 R IL3 Selected independently from hydrogen and -C 1～6 Alkyl, halogen-substituted C 1～6 alkyl;

[0017] L2 is selected from -NH-C 0～4 alkylene-, -C 0～4 Alkylene -NH-, -C(O)-C 0～4 Alkylene -, -O-, or absent; the alkylene is R IL4 Replace; where R IL4 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 alkyl;

[0018] Ring B is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aromatic ring, 5- to 10-membered aromatic heterocycle, or is absent; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further separated by one, two, three, or four independent R IB1 replace;

[0019] The R IB1 Selected from hydrogen, halogens, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-C(O)R IB2 -C 0～2 Alkylene-C(O)(C 2～6 alkenyl), -C 0～2 Alkylene-NHC(O)R IB2 -C 0～2 Alkylene-C(O)NR IB2 R IB3 -NH-C 0～2 Alkylene-NHC(O)R IB2 -NH-C 0～2 Alkylene-C(O)NHR IB2 -C(O)-C0～2 Alkylene (6- to 10-membered aromatic ring); wherein the alkyl, alkenyl, alkylene, or aromatic ring may be further divided by one, two, three, or four independent R groups. IB4 replace;

[0020] R IB2 R IB3 R IB4 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene -NH2, -C 0～2 Alkylene-NH(C) 1～6 Alkyl), -C 0～2 Alkylene-N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles);

[0021] The C ring is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aromatic ring, 5- to 10-membered aromatic heterocycle, or is absent; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further separated by one, two, three, or four independent R rings. IC1 replace;

[0022] The R IC1 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene-C(O)R IC2 -C 0～2 Alkylene-C(O)(C 2～6 alkenyl), -C 0～2 Alkylene-NHC(O)(C 2～6 alkynyl group), -C 0～2 Alkylene-NHC(O)R IC2 ; wherein alkyl, alkenyl, alkynyl, and alkylene groups may be further bonded by one, two, three, or four independent R groups. IC3 replace;

[0023] R IC2 R IC3 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)O(C) 1～6 alkyl).

[0024] Preferably, ring A is selected from 6-membered aromatic rings, 5-membered heterocyclic alkyl groups, 6-membered heterocyclic alkyl groups, 9-membered heterocyclic alkyl groups, 5-membered aromatic heterocycles, and 9-membered aromatic heterocycles; wherein the heterocyclic alkyl group, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R groups. IA1 replace.

[0025] Preferably, the A ring is selected from... The R IA1 Selected from hydrogen, -C1 alkylene-C(O)NR IA2 R IA3 -C(O)R IA2 -NHC(O) (6-membered heterocyclic alkyl group), -NHC(O)R IA2 -NHC(O)(6-aryl aromatic ring), -C(O)(C 2～4 Alkenyl); wherein the alkylene, alkenyl, heterocyclic alkyl, or aromatic ring may be further divided by one, two, three, or four independent R groups. IA4 replace;

[0026] The R IA2 R IA3 R IA4 Selected independently from hydrogen and -C 1～3 Alkyl, halogen-substituted C 1～3 Alkyl, C 1～3 Alkyl-substituted (6-membered heterocyclic alkyl), - (6-membered aromatic ring);

[0027] Specifically, the A ring is selected from

[0028]

[0029] L1 is selected from -NH-, does not exist,

[0030] The L2 is selected from -NH-, Or it doesn't exist;

[0031] Preferably, the B ring is selected from 6-membered aromatic heterocycles, 5-membered heterocyclic alkyl groups, 6-membered heterocyclic alkyl groups, and 6-membered aromatic rings; wherein the heterocyclic alkyl group, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R rings. IB1 replace;

[0032] Preferably, the B ring is selected from... The R IB1 Selected from hydrogen, -NH(C 1～3 Alkyl), -NH-C2 alkylene-NHC(O)R IB2 -NH-C1 alkylene-C(O)NHR IB2 -C(O)(C 2～4 alkenyl), -C(O)R IB2 -C(O)NR IB2 R IB3 -C(O)-C1 alkylene-(6-membered aromatic ring); wherein the alkyl, alkenyl, alkylene, or aromatic ring may be further divided by one, two, three, or four independent R... IB4 replace;

[0033] R IB2 R IB3 R IB4 Selected independently from hydrogen and -C 1～3 Alkyl, halogen-substituted C 1～3 Alkyl, -(6-membered aromatic ring), -C1 alkylene-N(C 1～3 Alkyl)(C 1～3 alkyl);

[0034] Specifically, the B ring is selected from

[0035] Preferably, the C ring is selected from 6-membered cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, 10-membered heterocycloalkyl, 6-membered aromatic ring, 9-membered aromatic heterocycle, and 10-membered aromatic heterocycle; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocycle may be further divided by one, two, three, or four independent R rings. IC1 replace;

[0036] Preferably, the C-ring is selected from... The R IC1 Selected from -C 0～2 Alkylene-NHC(O)(C 2～4 alkynyl), -C1 alkylene-NHC(O)R IC2 -C(O)R IC2 -C(O)(C 2～6Alkenyl); wherein the alkyl, alkenyl, alkynyl, or alkylene groups may be further bonded by one, two, three, or four independent R groups. IC3 replace;

[0037] R IC2 R IC3 Selected independently from hydrogen and -C 1～3 Alkyl, -C 2～4 alkenyl, -C 2～4 Alkyne- and halogen-substituted C 1～3 Alkyl, halogen-substituted C 2～4 Alkenyl, halogen-substituted C 2～4 Alkyne group, -(6-membered aromatic ring), -(3-membered heterocyclic alkyl group), -C(O)O(C) 1～3 alkyl);

[0038] Specifically, the C ring is selected from

[0039] Preferably, the A ring is selected from... L1 is selected from -NH-, and the B ring is selected from... L2 is selected from non-existent, and the C ring is selected from

[0040] Preferably, the A ring is selected from... L1 is selected from -NH-, and the B ring is selected from... L2 is selected from The C ring is selected from

[0041] Preferably, the A ring is selected from... L1 is selected as not existing, and the B ring is selected as... L2 is selected from -NH-, and the C ring is selected from...

[0042] Preferably, the A ring is selected from... L1 is selected from The B ring is selected from L2 is selected from -NH-, and the C ring is selected from...

[0043] Preferably, the A ring is selected from... L1 is selected from The B ring is selected from L2 is selected from non-existent, and the C ring is selected from

[0044] Preferably, the A ring is selected from... L1 is selected from The B ring is selected from L2 is selected from non-existent, and the C ring is selected from

[0045] Preferably, the A ring is selected from... L1 is selected as not present; the B ring is selected as... L2 is selected from -O-, and the C-ring is selected from...

[0046] Preferably, the A ring is selected from... L1 is selected as not present; the B ring is selected as... L2 is selected from -O-, and the C-ring is selected from...

[0047] Preferably, the A ring is selected from... L1 is selected as not present; the B ring is selected as... L2 is selected from The C ring is selected from

[0048] Preferably, the A ring is selected from... L1 is selected as not present; the B ring is selected as... L2 is selected from The C ring is selected from

[0049] Preferably, the A ring is selected from... L1 is selected as not present; the B ring is selected as... L2 is selected from non-existent, and the C ring is selected from

[0050] As a preferred embodiment, the present invention provides a compound of Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0051]

[0052] in,

[0053] R A1 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2Alkylene (5- to 10-membered aromatic heterocycles);

[0054] R A2 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)R A21 -C 0～2 Alkylene-C(O)NR A21 R A22 -C 0～2 Alkylene-NHC(O)R A21 -C 0～2 Alkylene-C(O)OR A21 -C 0～2 Alkylene-S(O)R A21 -C 0～2 Alkylene-S(O)2R A21 ;

[0055] R A21 R A22 Selected independently from hydrogen and -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles);

[0056] Or, R A1 R A2 The atoms directly bonded to it form 6-10 membered aromatic rings and 5-10 membered aromatic heterocycles; wherein the aromatic rings and aromatic heterocycles can be further bonded by one, two, three or four independent R atoms. A11 replace;

[0057] R A11 Selected from hydrogen, -C1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles);

[0058] R A5 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -NH-C 0～2 Alkylene-C(O)R A51 ; wherein the alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R A52 replace;

[0059] R A51 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles);

[0060] R A52 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles);

[0061] R A6 Selected from

[0062] R A3 Selected from hydrogen, -C 0～2 Alkylene-NHC(O)R A31 -C 0～2 Alkylene-C(O)R A31 ;

[0063] R A31 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkyne, halogen, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles);

[0064] R A4 Selected from -C 0～2 Alkylene-C(O)R A41 ;

[0065] RA41 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles);

[0066] R A61 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkyne, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 alkyl);

[0067] R A62 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkyne, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 alkyl).

[0068] As a preferred option: the R A1 Selected from hydrogen; R A2 Selected from -C 0～2 Alkylene-C(O)NR A21 R A22;R A21 R A22 Selected independently from hydrogen and -C 1～3 alkyl.

[0069] Preferably, the R A2 Selected from

[0070] Preferably, R A1 R A2 The atoms directly bonded to it form a 5-membered aromatic heterocycle; wherein the aromatic heterocycle can be further bonded by one, two, three or four independent R atoms. A11 Replace; R A11 Selected from hydrogen, -C 1～3 Alkyl, halogen-substituted C 1～3 alkyl;

[0071] Furthermore, R A1 R A2 The atoms directly connected to it form

[0072] Preferably, R A5 Selected from hydrogen, -NH2, -NH(C) 1～3 alkyl), -N(C) 1～3 Alkyl)(C 1～3 alkyl), -NH-C 0～2 Alkylene-C(O)R A51 ; wherein the alkylene or alkyl group is further divided by one, two, three, or four independent R groups. A52 replace;

[0073] R A51 Selected from hydrogen, -NH(C 1～3 Alkyl), -C 0～2 Alkylene (6- to 10-membered aromatic rings);

[0074] R A52 Selected from hydrogen, -C 1～3 Alkyl groups, 6-membered aromatic rings;

[0075] Furthermore; R A5 Selected from

[0076] Preferably, R A3 Selected from hydrogen, -C 0～2 Alkylene-NHC(O)R A31 -C 0～2 Alkylene-C(O)R A31 ;

[0077] R A31 Selected from hydrogen, -C 1～3 Alkyl, -C 2～4alkenyl, -C 2～4 Alkyne- and halogen-substituted C 1～4 alkyl.

[0078] Furthermore, R A3 Selected from

[0079] Preferably, R A4 Selected from -C 0～2 Alkylene-C(O)R A41 ;R A41 Selected from hydrogen, -C 1～3 Alkyl, halogen-substituted C 1～3 alkyl.

[0080] Furthermore, R A4 Selected from

[0081] Preferably, R A61 Selected from hydrogen, -C 1～3 Alkyl, -C 2～4 alkenyl, -C 2～4 Alkyne- and halogen-substituted C 1～3 alkyl;

[0082] R A62 Selected from hydrogen, -C 1～3 Alkyl, halogen-substituted C 1～3 alkyl.

[0083] Furthermore, the R A6 Selected from

[0084] This invention provides a compound represented by Formula II, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0085]

[0086] in,

[0087] R B1 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2Alkylene (5- to 10-membered aromatic heterocycles);

[0088] R B2 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)R B21 -C 0～2 Alkylene-C(O)OR B21 ;

[0089] R B21 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5-10 membered aromatic heterocycle); wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... B22 replace;

[0090] R B22 Selected independently from hydrogen and -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl), -C 0～2 Alkylene -NH2, -C 0～2 Alkylene-NH(C) 1～6 Alkyl), -C 0～2 Alkylene-N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles);

[0091] R B3 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycle); wherein, the alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... B31 replace;

[0092] R B31 Selected independently from hydrogen and -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl), -C 0～2 Alkylene -NH2, -C 0～2 Alkylene-NH(C) 1～6 Alkyl), -C 0～2 Alkylene-N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycles).

[0093] Preferably, the compound has the structure shown in formula IIA or IIB:

[0094]

[0095] Among them, R B1 R B3 R B21 R B22 The definition is the same as described above.

[0096] Preferably, the R B1 Selected from -C 1～3 Alkyl group, preferably R B1 Selected from methyl.

[0097] Preferably, R B2 Selected from -C 0～2 Alkylene-C(O)R B21 ;

[0098] R B21 Selected from -C 1～3 Alkyl, -C 2～4 alkenyl, -C 2～4 Alkyne- and halogen-substituted C 1～3 Alkyl, halogen-substituted C 2～4 Alkenyl, halogen-substituted C 2～4 Alkynyl; wherein the alkyl, alkenyl, or alkynyl group may be further influenced by one, two, three, or four independent R groups. B22 replace;

[0099] R B22 Each is independently selected from -C1 alkylene-N(C 1～3 Alkyl)(C 1～3 Alkyl groups and benzene rings.

[0100] Furthermore, R B2 Selected from

[0101] Preferably, R B3 It is selected from 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, and benzene ring.

[0102] Preferably, the present invention provides a compound of Formula III, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0103]

[0104] in,

[0105] R C1 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)R C11 -C 0～2 Alkylene-C(O)NR C11 R C12 -C 0～2 Alkylene-NHC(O)R C11 -C 0～2 Alkylene-C(O)OR C11 -C 0～2 Alkylene-S(O)R C11 -C 0～2 Alkylene-S(O)2R C11 -O (3-10 membered cycloalkyl), -O (3-10 membered heterocycloalkyl), -O (6-10 membered aromatic ring), -O (5-10 membered aromatic heterocycle); wherein, the alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocycle may be further divided by one, two, three, or four independent R C13 replace;

[0106] R C11 R C12 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles);

[0107] R C13 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)(C 1～6 Alkyl), -C 0～2 Alkylene-C(O) (halogen-substituted C) 1～6 alkyl);

[0108] R C2 Selected from -C(O)NR C21 R C22 -O (3-10 membered cycloalkyl), -O (3-10 membered heterocycloalkyl), -O (6-10 membered aromatic ring), -O (5-10 membered aromatic heterocycle); wherein, the cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocycle may be further divided by one, two, three, or four independent R C23 replace;

[0109] R C21 R C22 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles);

[0110] R C23 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)R C24 -C 0～2 Alkylene-C(O)NR C24 R C25 -C 0～2 Alkylene-NHC(O)R C24 -C 0～2 Alkylene-C(O)OR C24 ;

[0111] R C24 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5-10 membered aromatic heterocycle); wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... C25 replace;

[0112] R C25 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)R C26 -C 0～2 Alkylene-NHC(O)R C26 -C 0～2 Alkylene-C(O)OR C26 ;

[0113] R C26 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycles).

[0114] Preferably, the compound has the structure shown in formula IIIA or IIIB:

[0115]

[0116] Among them, R C1 R C23 R C24 The definition is the same as that described in claim 1.

[0117] As a preferred option: the R C1 Selected from -C(O)NR C11 R C12 -O (3- to 10-membered heterocyclic alkyl); wherein the heterocyclic alkyl group may be further divided by one, two, three or four independent R C13 Replace; R C11 R C12 Selected independently from hydrogen and -C 1～3 Alkyl; R C13 Each is independently selected from -C(O) (halogen-substituted C) 1～3 alkyl).

[0118] Preferably, the R C1 Selected from

[0119] Preferably, R C2 Selected from -C(O)NR C21 R C22 -O (3- to 10-membered heterocyclic alkyl); wherein the heterocyclic alkyl group may be further divided by one, two, three or four independent R C23 replace;

[0120] R C21 R C22 Selected independently from hydrogen and -C 1～3 alkyl;

[0121] R C23 Selected from -C(O)R C24 ;

[0122] R C24 Selected from hydrogen, -C 1～3 Alkyl, -C 2～4 alkenyl, -C 2～4 Alkyne- and halogen-substituted C 1～3 Alkyl, 3-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 6-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle; wherein, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further divided by one, two, three or four independent R C25 replace;

[0123] R C25 Selected from hydrogen, -C 1～3 Alkyl, halogen-substituted C 1～3 Alkyl, halogen, benzene ring, -C 0～2 Alkylene-C(O)OR C26 ;

[0124] R C26 Selected independently from hydrogen and -C 1～3 alkyl.

[0125] Specifically, R C2 Selected from

[0126] Preferably, the present invention provides a compound of formula IV, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0127]

[0128] in,

[0129] R D1 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C0～2 Alkylene (5- to 10-membered aromatic heterocycle); wherein, the alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... D11 replace;

[0130] R D11 Selected independently from hydrogen and -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycle); wherein, the alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... D12 replace;

[0131] R D12 Selected independently from hydrogen and -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles);

[0132] R D2 Selected from -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2Alkylene (5- to 10-membered aromatic heterocycle); wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... D21 replace;

[0133] R D21 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)R D22 -C 0～2 Alkylene-C(O)NR D22 R D23 -C 0～2 Alkylene-NHC(O)R D22 -C 0～2 Alkylene-C(O)OR D22 ;

[0134] R D22 R D23 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5-10 membered aromatic heterocycle); wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... D24 replace;

[0135] R D24 Selected independently from hydrogen and -C1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycles).

[0136] As a preferred option: the R D1 Selected from hydrogen, -C 1～3 Alkyl, halogen-substituted C 1～3 Alkyl, 5-membered heterocyclic alkyl, 6-membered heterocyclic alkyl, 9-membered heterocyclic alkyl, 6-membered aromatic ring; wherein, the heterocyclic alkyl or aromatic ring may be further divided by one, two, three, or four independent R D11 replace;

[0137] R D11 Each is independently selected from (6-membered heterocyclic alkyl groups); wherein, the heterocyclic alkyl group may be further separated by one, two, three or four independent R groups. D12 replace;

[0138] R D12 C16 molecules, each independently selected from hydrogen, methyl, ethyl, or halogen-substituted compounds, 1～3 alkyl.

[0139] Specifically, the R D1 Selected from Methyl, ethyl.

[0140] Preferably: R D2 Selected from -(10-membered heterocyclic alkyl), -C2-alkylene-(6-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycle); wherein the heterocyclic alkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... D21 replace;

[0141] R D21 Selected from hydrogen, -C 1～3 Alkyl, halogen-substituted C 1～3 Alkyl, halogen, -C 0～2 Alkylene-NHC(O)R D22 ;

[0142] RD22 Selected from hydrogen, -C 1～3 Alkyl, -C 2～4 alkenyl, -C 2～4 Alkyne- and halogen-substituted C 1～3 Alkyl; wherein the alkyl, alkenyl, or alkynyl group may be further influenced by one, two, three, or four independent R groups. D24 replace;

[0143] R D24 Selected from hydrogen, -C 1～3 Alkyl, halogen-substituted C 1～3 Alkyl groups, benzene rings.

[0144] Specifically, R D2 Selected from

[0145] This invention provides a compound of formula V, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0146]

[0147] in,

[0148] R E1 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkyne group, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles);

[0149] R E2 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)R E22 -C 0～2 Alkylene-C(O)NR E22 R E23 -C 0～2 Alkylene-NHC(O)R E22 -C 0～2 Alkylene-C(O)OR E22 ; wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R E21 replace;

[0150] R E21 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles);

[0151] R E22 R E23 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2Alkylene (5-10 membered aromatic heterocycle); wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... E24 replace;

[0152] R E24 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles);

[0153] R E3 Selected from -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycle); wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... E31 replace;

[0154] R E31 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycles).

[0155] As a preferred option: the RE1 Selected from hydrogen, -C 1～3 Alkyl, halogen-substituted C 1～3 Alkyl, -NH2, -NH(C) 1～3 alkyl), -N(C) 1～3 Alkyl)(C 1～3 alkyl).

[0156] Specifically, the R E1 Selected from

[0157] Preferably, R E2 Selected from -C(O)R E22 ;R E22 Selected from hydrogen, -C 1～3 Alkyl, -C 2～4 alkenyl, -C 2～4 Alkyne- and halogen-substituted C 1～3 Alkyl; wherein the alkyl, alkenyl, or alkynyl group may be further influenced by one, two, three, or four independent R groups. E24 Replace; R E24 Selected from hydrogen, -C 1～3 Alkyl, halogen-substituted C 1～3 Alkyl, halogen, 6-membered aromatic ring.

[0158] Specifically, R E2 Selected from Preferably, R E3 Selected from 5-membered aromatic heterocycles, 6-membered aromatic heterocycles, 9-membered aromatic heterocycles, and 10-membered aromatic heterocycles.

[0159] Specifically, R E3 Selected from

[0160] In some implementations, the compound described in Formula IA is specifically selected from:

[0161]

[0162]

[0163] The present invention also provides the use of the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, in the preparation of medicaments for treating JAK3-mediated diseases.

[0164] Furthermore, the JAK3-mediated diseases are one or more of the following: arthritis, autoimmune diseases or conditions, cancer or tumors, diabetes, eye diseases, conditions or conditions, intestinal inflammation or conditions, neurodegenerative diseases, skin diseases, conditions or conditions, allergic reactions, asthma and other obstructive airway diseases, and transplant rejection.

[0165] The present invention also provides a pharmaceutical composition, which is a formulation prepared by adding pharmaceutically acceptable excipients to the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt.

[0166] The present invention also provides the use of the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, in the preparation of a medicament for treating JAK3-mediated diseases.

[0167] The JAK3-mediated diseases defined in this invention are those in which JAK3 plays a crucial role in the pathogenesis of the disease. The primary function of JAK3 is to coordinate local tissue inflammation, thereby playing a role in various diseases. JAK3-mediated diseases include one or more of the following: inflammation, autoimmune diseases, infectious diseases, cancer, and diseases related to precancerous syndromes.

[0168] “Cancer” or “malignant tumor” refers to any of a variety of diseases characterized by uncontrolled, abnormal proliferation of cells, the ability of affected cells to spread locally or via the bloodstream and lymphatic system to other sites of the body (i.e., metastasis), and any of a number of characteristic structural and / or molecular features. “Cancer cell” refers to cells that have undergone early, intermediate, or late stages of multi-step tumor progression. Cancers include sarcoma, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer, and prostate cancer. In some embodiments, the compound of Formula I is used to treat cancers selected from colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma. In some embodiments, the cancer is selected from melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer. In some embodiments, the cancer treated is metastatic cancer.

[0169] Autoimmune diseases are caused by the body's immune response to substances and tissues that are normally present in the body. Examples of autoimmune diseases include myocarditis, lupus nephritis, primary biliary cirrhosis, psoriasis, type 1 diabetes, Graves' disease, celiac disease, Crohn's disease, autoimmune neutropenia, juvenile arthritis, rheumatoid arthritis, fibromyalgia, Guillain-Barré syndrome, multiple sclerosis, and autoimmune retinopathy. Some embodiments of the present invention relate to the treatment of autoimmune diseases such as psoriasis or multiple sclerosis.

[0170] Inflammatory diseases encompass a variety of conditions characterized by histopathological inflammation. Examples of inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, airway inflammation caused by house dust mites, and interstitial cystitis. There is significant overlap between inflammatory diseases and autoimmune diseases. Some embodiments of the present invention relate to the treatment of the inflammatory disease asthma. The immune system is commonly involved in inflammatory diseases, manifesting in allergic reactions and some myopathies; many immune system disorders lead to abnormal inflammation. JAK3-mediated diseases also include autoimmune inflammatory diseases.

[0171] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0172] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0173] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or groups. Alternatively, it can mean the replacement of the lone pair of electrons on an atom by another atom or group; for example, the lone pair of electrons on a sulfur atom can be replaced by an oxygen atom to form a hydrogen atom.

[0174] "Optional further replacement" means that "replacement" may but does not have to occur, and this statement includes situations in which it may or may not occur.

[0175] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a～b Alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C 1～4 "Alkyl" refers to an alkyl group containing 1 to 4 carbon atoms.

[0176] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C1-6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be substituted by one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. Alkyl groups may also be part of other groups, such as C1-6 alkoxy groups.

[0177] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon group having a specified number of member atoms. C a ~ b Alkylene refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight-chain hydrocarbon groups. For example, the term "propylene" can be exemplified by the following structures:

[0178] Similarly, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures: For example, -C0 to -4 alkylene groups can be C0 alkylene, C1 alkylene (e.g., -CH2-), C2 alkylene (e.g., -CH2CH2-), C3 alkylene, or C4 alkylene; C0 alkylene refers to the absence of a group here, which is connected by a chemical bond. For example, A-C0 alkylene-B refers to AB, that is, the A group and the B group are directly connected by a chemical bond.

[0179] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms and, in some embodiments, 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least one vinyl unsaturated site (>C=C<). For example, C a-b Alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadienyl, etc.

[0180] "Alynyl" refers to a straight-chain monovalent hydrocarbon group or a branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is also intended to include hydrocarbon groups having one triple bond and one double bond. For example, (C2-C6) alkynyl is intended to include ethynyl, propynyl, etc.

[0181] "Halogen" refers to fluorine, chlorine, bromine, or iodine;

[0182] "O" means =O, that is, an oxygen atom replaces two hydrogen atoms simultaneously through a double bond.

[0183] "Halogen-substituted alkyl" refers to an alkyl group in which one or more hydrogen atoms can be replaced by one or more halogen atoms. For example, C 1～4 Halogenated alkyl refers to an alkyl group containing 1 to 4 carbon atoms in which one or more hydrogen atoms are replaced by one or more halogen atoms.

[0184] In this invention, "-OR", "-NRR", etc., refer to the R group being connected to an oxygen atom or a nitrogen atom by a single bond.

[0185] In this invention, the oxygen atom in “-C(O)R”, “-S(O)2R”, etc., is connected to the carbon atom or sulfur atom by a double bond, and the R group is connected to the oxygen atom or sulfur atom by a single bond.

[0186] "Cycloalkyl" and "cycloalkanes" refer to saturated or partially saturated cyclic groups having a carbon atom and no heterocyclic atoms, and having a single or multiple rings (including fused, combined, and fused). For polycyclic systems having aromatic and non-aromatic rings without heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8-tetrahydronaphthalene-5-yl) applies when the connecting point is located on a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups including polycyclic dicycloalkyl ring systems are dicyclohexyl, dicyclopentyl, dicyclooctyl, etc.

[0187] "Heterocyclic", "heterocyclic alkyl", and "heterocyclic alkane" refer to saturated rings or non-aromatic unsaturated cyclic groups containing at least one heteroatom and having a single or multiple rings (including fused, combined, and fused); wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;

[0188] "Spirocyclic group" and "spirocyclic" are used interchangeably, both referring to polycyclic cyclic saturated rings or non-aromatic unsaturated cyclic hydrocarbon groups that share a single carbon atom (called a spiro atom) among their monocyclic rings. For example, "5 to 12-membered spirocyclic group" refers to a spirocyclic ring with 5 to 12 ring atoms. Spirocyclic rings are classified into bispirocyclic or multispirocyclic rings based on the number of rings, with bispirocyclic rings being preferred.

[0189] "Spirocycloiden" and "spirocycloheterocycle" are used interchangeably. They refer to non-aromatic saturated rings or non-aromatic unsaturated ring systems with two monocyclic rings sharing a single carbon atom, consisting of a carbon atom and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. For example, "5- to 12-membered spirocycloheterocycles" refer to spirocycloheterocycles with 5 to 12 ring atoms, of which 1, 2, or 3 ring atoms are heteroatoms.

[0190] "Aryl" and "aromatic ring" are used interchangeably, both referring to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system, such as "C". 6-10 "Aryl" refers to a monocyclic or bicyclic aryl group having 6 to 10 carbon atoms. Non-limiting examples of aryl groups include phenyl, naphthyl, etc.

[0191] The term "aromatic heterocycle" as used in this invention refers to an aromatic unsaturated ring containing at least one heteroatom; where the heteroatom refers to nitrogen, oxygen, sulfur, etc. It typically refers to aromatic monocyclic or bicyclic hydrocarbons containing multiple ring atoms, one or more of which are selected from O, N, and S heteroatoms. Preferably, it contains one to three heteroatoms. Examples of heterocyclic aryl groups include: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothiophene, benzofuranyl, benzothiophene, benzopyranyl, benzothiapyranyl, furanyl, pyrroleyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazole, thiophene, oxadiazolyl, benzimidazole, benzothiazolyl, and benzoxazolyl.

[0192] "Bridged ring or bridged ring group" refers to a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms. Specific examples include, but are not limited to:

[0193] "Bridged heterocyclic group" and "bridged heterocycle" are used interchangeably, referring to a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms, composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. Specific embodiments include, but are not limited to:

[0194] "Fused" refers to a structure in which two or more rings share one or more bonds.

[0195] "Stereoisomers" include enantiomers and diastereomers or mixtures thereof.

[0196] The "deuterated compound" of this invention refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0197] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0198] The terms "salt" and "pharmaceutical salt" refer to acidic and / or basic salts formed by the above-described compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-described compounds or their stereoisomers with an appropriate amount (e.g., equimolar amounts) of an acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.

[0199] In some embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent to prepare a medicament or pharmaceutical composition for regulating cell function or treating disease. If a group of compounds is used, these compounds may be administered to the test subject simultaneously, separately, or sequentially.

[0200] Beneficial effects of the present invention: The present invention provides a series of compounds with novel structures that have significant inhibitory activity against JAK3. As JAK3 inhibitors, they provide new options for the preparation of drugs to treat JAK-mediated diseases (such as autoimmune diseases, neurological diseases, inflammatory diseases, cancer, infectious diseases, etc.).

[0201] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0202] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0203] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0204] Unless otherwise specified in the examples, the reaction is carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature. Room temperature is the optimal reaction temperature, which is 20°C to 30°C. Unless otherwise specified in the examples, M is moles per liter.

[0205] The structure of the compound was determined using nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) were expressed in terms of 10⁻¹⁰. -6 The unit (ppm) is given. NMR determination was performed using a Bruker Avance III 400 and Bruker Avance 600 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (Methol-d4). The internal standard was tetramethylsilane (TMS). LC-MS determination was performed using a Shimadzu LC-MS2020 (ESI) system. HPLC determination was performed using a Shimadzu LB-29A high-performance liquid chromatograph. MPLC (medium-pressure preparative chromatography) was performed using a Gilson GX-281 reversed-phase preparative chromatograph. Thin-layer chromatography used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, with a thickness of 0.4 mm to 0.5 mm for product separation and purification. Column chromatography generally used Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0206] The reagents described in the examples are abbreviated as follows: TCFH: N,N,N',N'-Tetramethylchloromethylammonium hexafluorophosphate; NMI: N-methylimidazolium; DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylamide; THF: Tetrahydrofuran; DMSO: N,N-dimethyl sulfoxide; MeOH: Methanol; DCM: Dichloromethane; NaBH4: Sodium borohydride; TFA: Trifluoroacetic acid; DMT-MM: 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride; TEA: Triethylamine; MeCN: Acetonitrile; EA: Ethyl acetate.

[0207] Synthesis of intermediates: Synthesis of intermediates 1-8

[0208]

[0209] Step 1, Synthesis of Compounds 1-2:

[0210] Compound 1-1 (744.00 mg, 2.96 mmol) and methylamine hydrochloride (275.87 mg, 8.88 mmol) were dissolved in DMF (5 mL) in a 50 mL reaction flask, followed by the addition of TCFH (996.13 mg, 3.55 mmol) and NMI (729.05 mg, 8.88 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was purified directly by MPLC and then lyophilized to give crude compound 1-2 (749.00 mg, 2.83 mmol, 95.70% yield).

[0211] Step 2, Synthesis of Compounds 1-3:

[0212] Compounds 1-2 (749.00 mg, 2.83 mmol), TFA (2 mL), and DCM (5 mL) were added sequentially to a 50 mL reaction flask. The reaction was carried out at room temperature for 30 minutes, and the solvent was evaporated to obtain crude product 1-3 (481.77 mg).

[0213] Step 3, Synthesis of Intermediates 1-5:

[0214] Compounds 1-3 (481.77 mg, 2.93 mmol), 1-4 (440.00 mg, 2.93 mmol), and Na₂CO₃ (224.70 mg, 2.12 mmol) were dissolved in DMSO (5 mL) in a 50 mL reaction flask and stirred at room temperature for 1 hour. After the reaction was complete, the mixture was extracted with saturated sodium chloride solution (10 mL) and ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was purified by MPLC to give compound 1-5 (100.00 mg, 0.36 mmol, 12.29% yield).

[0215] Step 4: Synthesis of intermediates 1-7:

[0216] Compounds 1-5 (100.00 mg, 0.36 mmol), 1-6 (100.00 mg, 0.36 mmol), and DMSO (5 mL) were added sequentially to a 50 mL reaction flask, followed by potassium carbonate (149.00 mg, 1.08 mmol). The reaction solution was reacted at 100 °C for 16 hours. After LCMS analysis showed that compounds 1-5 had reacted completely, extraction was completed with saturated sodium chloride solution (10 mL) and ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was purified by MPLC to obtain compounds 1-7 (150.00 mg, 0.33 mmol, 91.67% yield).

[0217] Step 4: Synthesis of intermediates 1-8:

[0218] Compounds 1-7 (150.00 mg, 0.33 mmol), TFA (2 mL), and DCM (2 mL) were added sequentially to a 50 mL reaction flask. The reaction was carried out at room temperature for 30 minutes, and the solvent was evaporated to obtain crude product 1-8 (70.00 mg).

[0219] Referring to the synthesis methods of intermediates 1-8, intermediates 1-10 can be obtained by replacing compounds 1-6 with the raw materials listed in Table 1 below, while keeping other raw materials and operating methods unchanged.

[0220] Table 1. Intermediates 1-10

[0221]

[0222] Example 1: Synthesis method of compound 1-A of the present invention:

[0223]

[0224] Step 1: Synthesis of Compound 1-A

[0225] In a 50 mL reaction flask, 1-8 (70.00 mg, 196.94 μmol), 1-11 (16.55 mg, 236.33 μmol), TCFH (8.52 mg, 236.33 μmol), and NMI (96 mg, 1.18 mmol) were dissolved in 4 mL of DMF. After stirring at room temperature for 2 hours, the reaction was confirmed to be complete by LC-MS. 1-A (39.60 mg, 95.82 μmol, 48.66% yield, 98.6% purity) was obtained by MPLC purification. LC-MS: C 21 H 25 N7O2,[M+H] + 408.21; found 408.1. 1 ¹H NMR (400MHz, DMSO-d⁶+D₂O) δ 8.25 (s, 1H), 7.50–7.48 (m, 2H), 7.27–7.21 (dd, J = 17.2 Hz, 8.0 Hz, 2H), 4.40–4.31 (dd, J = 19.2 Hz, 14.0 Hz, 2H), 4.00–3.99 (d, J = 6.8 Hz, 1H), 3.34 (s, 2H), 3.09–3.02 (m, 3H), 2.83 (t, J = 10.8 Hz, 1H), 2.55 (s, 3H), 1.73–1.70 (m, 3H), 1.39–1.33 (m, 1H), 1.27–1.15 (m, 1H). Purity > 95%.

[0226] Example 2: Synthesis method of compound 1-B of the present invention:

[0227]

[0228] Step 1: Synthesis of Compound 1-B

[0229] In a 50 mL reaction flask, 1-8 (20.00 mg, 56.27 μmol), 1-12 (10.78 mg, 56.27 μmol), and DIPEA (21.82 mg, 168.81 μmol, 29.40 μL) were dissolved in 3 mL of DMSO. After stirring at room temperature for 2 hours, the reaction was confirmed to be complete by LC-MS. 1-B (6.40 mg, 14.85 μmol, 26.39% yield, 99.5% purity) was obtained by MPLC purification. LC-MS: C 20 H 26 ClN7O2,[M+H] + 432.18; found 432.5. 1 H NMR (600MHz, Methanol-d4) δ8.28(s,1H),7.49(s,2H),7.37-7.35(m,2H),4.47-4.38(m,2H),4.25-3.89(m,2H),3.52( s,2H),3.40(m,1H),3.27-3.12(m,3H),2.73(s,3H),1.97-1.83(m,3H),1.63-1.55(m,1H),1.49-1.40(m,1H).Purity>99%.

[0230] Example 3: Synthesis method of compound 1-C of the present invention:

[0231]

[0232] Step 1: Synthesis of Compound 1-C

[0233] Compounds 1-8 (20.00 mg, 56.27 μmol), 1-13 (4.05 mg, 56.27 μmol), DMT-MM (16.43 mg, 56.27 μmol), and NaHCO3 (14.18 mg, 168.81 μmol) were dissolved in MeCN (2 mL) and H2O (2 mL) in a 50 mL reaction flask and stirred at room temperature for 30 min. After the reaction was complete, the mixture was extracted with EA and water, and the organic phase was dried over Na2SO4 and filtered. The solvent was evaporated to dryness, and the mixture was purified by MPLC to give compound 1-C (1.30 mg, 3.18 μmol, 5.65% yield, 99.9% purity). LC-MS: C 21 H 27 N7O2, [M+H] +410.22; found 410.1. 1 H NMR (600MHz, Methanol-d4) δ8.25(s,1H),7.48(s,2H),7.34-7.33(d,J=7.8Hz,2H),6.38-6.18(m,2H),5.67(m,1H),4.50-4.44(m,2H),3.51(s ,2H),3.28-3.19(m,3H),3.12-3.08(dd,J=12.6Hz,9.6Hz,1H),2.73(s ,3H),1.94-1.85(m,3H),1.60-1.53(m,1H),1.46-1.37(m,1H).Purity>99%.

[0234] Example 4: Synthesis method of compound 1-D of the present invention:

[0235]

[0236] Step 1: Synthesis of Compound 1-D

[0237] Compound 1-10 (50.00 mg, 132.47 μmol) was dissolved in DCM (4 mL) and H₂O (4 mL) in a 50 mL reaction flask. Compound 1-14 (14.96 mg, 132.47 μmol) was dissolved in DCM (4 mL) and then slowly added dropwise to the system containing compound 1-10. The reaction was stirred at room temperature for 30 minutes. After the reaction was complete, the mixture was extracted with EA and water. The organic phase was dried over Na₂SO₄ and filtered. The solvent was evaporated to dryness, and the mixture was purified by MPLC to give compound 1-D (9.30 mg, 20.24 μmol, 15.28% yield, 98.8% purity). LC-MS: C 22 H 24 ClN7O2, [M+H] + 454.17; found 454.5. 1 H NMR (600MHz, Methanol-d4) δ8.26 (s, 1H), 7.45-7.43 (d, J = 8.4Hz, 2H), 7.34-7.22 (m,6H),4.62(s,2H),4.39(s,2H),4.04(s,2H),3.49(s,2H),2.72(s,3H). Purity>95%.

[0238] Example 5: Synthesis method of compound 1-E of the present invention:

[0239]

[0240] Step 1: Synthesis of Compound 1-E

[0241] Compounds 1-10 (20.00 mg, 52.99 μmol), 1-11 (3.71 mg, 52.99 μmol), DMT-MM (46.73 mg, 158.96 μmol), and NaHCO3 (13.35 mg, 158.96 μmol) were dissolved in MeCN (2 mL) and H2O (2 mL) in a 50 mL reaction flask and stirred at room temperature for 30 min. After the reaction was complete, the mixture was extracted with EA and water, and the organic phase was dried over Na2SO4 and filtered. The solvent was evaporated to dryness, and the mixture was purified by MPLC to give compound 1-E (1.00 mg, 2.33 μmol, 4.39% yield, 99.9% purity). LC-MS: C 23 H 23 N7O2, [M+H] + 430.19; found 430.5. 1 H NMR (600MHz, Methanol-d4) δ8.20 (s, 1H), 7.45-7.44 (d, J = 8.4Hz, 2H), 7.33-7.19 (m, 6H) ,4.61(s,2H),4.37(s,2H),4.02(s,1H),3.58(s,1H),3.48(s,2H),2.72(s,3H).Purity>99%.

[0242] Example 6: Synthesis method of compound 1-F of the present invention:

[0243]

[0244] Step 1: Synthesis of compounds 1-17

[0245] At 0 °C, NaHCO3 (182.28 mg, 2.17 mmol) was added to a stirred THF (10 mL) solution of compounds 1-15 (400.00 mg, 2.17 mmol) and 1-16 (319.24 mg, 2.17 mmol) for 30 minutes until the reaction was complete (monitored by LC-MS). The solvent was removed by concentration under reduced pressure, and the product was purified by MPLC to give compound 1-17 (600.00 mg, 2.03 mmol, 93.73% yield).

[0246] Step 2, Synthesis of Compounds 1-18:

[0247] Compound 1-17 (640.0000 mg, 2.17 mmol) and methylamine hydrochloride (145.39 mg, 2.17 mmol) were dissolved in THF (10 mL) at 25 °C. The reaction was carried out for 60 minutes until completion (monitored by LC-MS). The solvent was removed by concentration under reduced pressure, and the product was purified by MPLC to give compound 1-18 (210.00 mg, 724.83 μmol, 33.42% yield).

[0248] Step 3, Synthesis of Compounds 1-20:

[0249] K₂CO₃ (100.03 mg, 724.83 μmol) was added to a stirred DMSO (4 mL) solution of compounds 1-19 (135.00 mg, 724.83 μmol) and 1-18 (210.00 mg, 724.83 μmol) at 100 °C for 8 hours until the reaction was complete (monitored by LC-MS). The solvent was removed by concentration under reduced pressure, and the product was purified by MPLC to give compound 1-20 (53.00 mg, 120.59 μmol, 16.64% yield).

[0250] Step 4, Synthesis of Compounds 1-21:

[0251] TFA (13.75 mg, 120.49 μmol) was added to a DCM (3 mL) solution of compound 1-20 (53.00 mg, 120.59 μmol). The mixture was then stirred at 20 °C for 0.5 h. After 0.5 h, TLC analysis (DCM:MeOH = 10:1) showed that compound 1-20 was completely consumed. The reaction mixture was evaporated, and the residue was ready for use in the next step without further purification.

[0252] Step 5, Synthesis of Compound 1-F:

[0253] At 25 °C, compound 1-12 (22.58 mg, 117.86 μmol) was added to a DCM (3 mL) solution of compound 1-21 (40.00 mg, 117.8 μmol). The mixture was reacted for 30 minutes until the reaction was complete (monitored by LC-MS). The solvent was removed by concentration under reduced pressure, and compound 1-F was purified by MPLC to obtain compound 1-F (3.10 mg, 7.45 μmol, 6.32% yield, 99.9% purity). LC-MS: C 18 H 22 ClN9O, [M+H] + 416.16; found 416.2. 1H NMR (600MHz, Methanol-d4) δ7.84(s,1H),7.53-7.42(m,2H),4.31(s,2H),4.03-3.82(m,4H),3.68(s,4H),2.99(s,3H),2.69(s,3H). Purity>99%.

[0254] Example 7: Synthesis method of compound 1-G of the present invention:

[0255]

[0256] Step 1: Synthesis of compounds 1-23

[0257] NaHCO3 (94.08 mg, 1.12 mmol) was added to a stirred THF (10 mL) solution of compounds 1-15 (206.94 mg, 1.12 mmol) and 1-22 (200.00 mg, 1.12 mmol) at 0 °C and the reaction was carried out for 30 minutes until the reaction was complete (monitored by LC-MS). The solvent was removed by concentration under reduced pressure, and the product was purified by MPLC to give compound 1-23 (360.00 mg, 1.10 mmol, 98.35% yield).

[0258] Step 2, Synthesis of Compounds 1-25

[0259] At 25 °C, Na₂CO₃ (116.60 mg, 1.10 mmol) was added to a stirred THF solution of compounds 1-24 (176.82 mg, 1.10 mmol) and 1-23 (360.00 mg, 1.10 mmol) in 5 mL of THF. The reaction was carried out for 30 minutes until completion (monitored by LC-MS). The solvent was removed by concentration under reduced pressure, and the product was purified by MPLC to give compound 1-25 (210.00 mg, 466.74 μmol, 42.29% yield).

[0260] Step 3, Synthesis of Compounds 1-26

[0261] K₂CO₃ (64.41 mg, 466.74 μmol) was added to a stirred DMSO solution of compounds 1-16 (68.69 mg, 466.74 μmol) and 1-25 (210.00 mg, 466.75 μmol) in 3 mL of DMSO at 100 °C, and the reaction was carried out for 8 hours until the reaction was complete (monitored by LC-MS). The solvent was removed by concentration under reduced pressure, and the solution was purified by MPLC to give compound 1-26 (41.00 mg, 73.13 μmol, 15.67% yield).

[0262] Step 4, Synthesis of Compounds 1-27

[0263] TFA (8.34 mg, 73.33 μmol) was added to a DCM (3 mL) solution of compound 1-26 (41.00 mg, 73.13 μmol). The mixture was then stirred at 20 °C for 0.5 h. After 0.5 h, TLC analysis (DCM:MeOH = 10:1) showed that compound 1-26 was completely consumed. The reaction mixture was evaporated, and the residue was ready for use in the next step without further purification.

[0264] Step 5: Synthesis of Compound 1-G

[0265] At 25 °C, 1-12 (13.73 mg, 71.66 μmol) was added to a 3 mL solution of compound 1-27 (33.00 mg, 71.66 μmol) in DCM. The mixture was reacted for 30 minutes until the reaction was complete (monitored by LC-MS). The solvent was removed by concentration under reduced pressure, and the mixture was purified by MPLC to give compound 1-G (18.40 mg, 34.26 μmol, 47.82% yield, 95.0% purity). LC-MS: C 25 H 29 ClN 10 O2, [M+H] + 537.22; found 537.3. 1 H NMR (600MHz, Methanol-d4) δ8.05-7.70(m,1H),7.57-7.05(m,7H),4.77-4.58(m,1H),4.04(t,J=15. 0Hz, 2H), 3.61-3.41 (m, 4H), 3.20-2.97 (m, 2H), 2.70 (s, 3H), .2.56-2.54 (d, J = 10.2Hz, 3H). Purity > 95%.

[0266] Example 8: Synthesis method of compound 1-H of the present invention:

[0267]

[0268] Step 1: Synthesis of Compounds 1-28

[0269] NaHCO3 (136.92 mg, 1.63 mol) was added to a stirred THF solution of compounds 1-15 (300.00 mg, 1.63 mmol) and 1-19 (302.99 mg, 1.63 mmol) in 6 mL of THF at 0 °C. The reaction was carried out for 30 minutes until completion (monitored by LC-MS). The solvent was removed by concentration under reduced pressure, and the product was purified by MPLC to give compound 1-28 (500.00 mg, 1.50 mmol, 91.97% yield).

[0270] Step 2, Synthesis of Compounds 1-29

[0271] NaHCO3 (126.00 mg, 1.50 mmol) was added to a 5 mL THF solution of compounds 1-16 (220.19 mg, 1.50 mmol) and 1-28 (500.00 mg, 1.50 mmol) under stirring at 25 °C. The reaction was carried out for 3 hours until completion (monitored by LC-MS). The solvent was removed by concentration under reduced pressure, and the product was purified by MPLC to give compound 1-29 (510.00 mg, 1.15 mmol, 76.62% yield).

[0272] Step 3, Synthesis of Compounds 1-31

[0273] K₂CO₃ (237.36 mg, 1.72 mmol) was added to a stirred DMSO solution of compounds 1-30 (200.00 mg, 1.72 mmol) and 1-29 (766.03 mg, 1.72 mmol) in 4 mL of DMSO at 100 °C, and the reaction was carried out for 8 hours until completion (monitored by LC-MS). The solvent was removed by concentration under reduced pressure, and the product was purified by MPLC to give compound 1-31 (276.00 mg, 526.10 μmol, 30.56% yield).

[0274] Step 4, Synthesis of Compounds 1-32

[0275] TFA (59.99 mg, 526.10 μmol) was added to a DCM (3 mL) solution of compound 1-31 (276.00 mg, 526.10 μmol). The mixture was then stirred at 20 °C for 0.5 h. After 0.5 h, TLC analysis (DCM:MeOH = 10:1) showed that compound 1-31 was completely consumed. The reaction mixture was evaporated, and the residue was ready for use in the next step without further purification.

[0276] Step 5: Synthesis of compound 1-H

[0277] At 25 °C, 1-12 (90.26 mg, 471.14 μmol) was added to an 8 mL solution of compound 1-32 (200.00 mg, 471.14 μmol) in DCM. The mixture was reacted for 30 minutes until the reaction was complete (monitored by LC-MS). The solvent was removed by concentration under reduced pressure, and compound 1-H was purified by MPLC to obtain compound 1-H (41.80 mg, 83.24 μmol, 17.67% yield, 99.9% purity). LC-MS: C 22 H 29 ClN 10 O2, [M+H] +501.22; found 501.5. 1 H NMR(600MHz,Methanol-d4)δ8.28-8.22(dd,J=27.0Hz,9.0Hz,1H),8.05-8.04( d,J=7.8Hz,1H),7.82-7.76(dd,J=24.0Hz,8.4Hz,1H),4.40-4.28(m,2H),4.07( dd,J=6.0Hz,4.8Hz,4H),3.97-3.92(d,J=31.2Hz,1H),3.66(m,1H),3.28(s,3H) ,2.76-2.72(m,3H),2.57(s,3H),1.91-1.73(m,2H),1.04-1.01(m,3H).Purity>99%.

[0278] Synthesis of intermediates: Synthesis of intermediates 2-6

[0279]

[0280] Step 1, Synthesis of Compounds 2-3:

[0281] Compound 2-1 (400.00 mg, 2.74 mmol) was dissolved in MeOH (5 mL), followed by the addition of compound 2-2 (170.01 mg, 5.47 mmol). The reaction mixture was stirred at 20 °C for 0.5 h. Then, NaBH4 (310.62 mg, 8.21 mmol) was added, and the mixture was stirred at 20 °C for another 2 h. LCMS analysis showed that compound 2-1 was completely consumed. The reaction mixture was purified by MPLC and lyophilized to give compound 2-3 (380.00 mg, 2.36 mmol, 86.13% yield).

[0282] Step 2, Synthesis of Compounds 2-5:

[0283] NMI (96.76 mg, 1.18 mmol, 1 mL) and TCFH (396.02 mg, 1.41 mmol) were added to a DMF (4 mL) solution of compounds 2-3 (190.00 mg, 1.18 mmol) and 2-4 (290.00 mg, 995.40 μmol). The mixture was then stirred at 20 °C for 1 hour. LCMS analysis showed that compound 2-3 was completely consumed. The reaction mixture was purified by MPLC to give compound 2-5 (417.00 mg, 959.66 μmol, 81.42% yield).

[0284] Step 3, Synthesis of Intermediates 2-6:

[0285] TFA (109.42 mg, 959.66 μmol, 2 mL) was added to a DCM (2 mL) solution of compound 2-5 (417.00 mg, 959.66 μmol). After stirring at 20 °C for 1 hour, LCMS showed that compound 2-5 was completely consumed. The reaction mixture was purified by Prep-HPLC and lyophilized to give compound 2-6 (300.00 mg, 897.09 μmol, 93.48% yield) as a white solid.

[0286] Referring to the synthesis method of intermediate 2-6, intermediate 2-8 can be obtained by replacing compound 2-4 with the raw materials listed in Table 1 below, while keeping other raw materials and operating methods unchanged.

[0287] Table 2. Intermediate 8

[0288]

[0289] Example 9: Synthesis method of compound 2-A of the present invention:

[0290]

[0291] Step 1: Synthesis of Compound 2-A

[0292] DMT-MM (52.88 mg, 179.42 μmol) and DIPEA (371.00 mg, 2.87 mmol) were added to a THF / H₂O (5:1, 6 mL) solution containing compounds 2-6 (50.00 mg, 149.52 μmol) and 2-9 (30.00 mg, 416.31 μmol). The reaction mixture was stirred at 20 °C for 2 hours. LC-MS analysis showed that compound 2-6 was completely consumed. The reaction mixture was purified by Prep-HPLC and lyophilized to give compound 2-A (27.00 mg, 69.50 μmol, 46.49% yield, 99.9% purity). LC-MS: C 23 H 24 N4O2,[M+H] + 389.19; found 389.1. 1 ¹H NMR (600MHz, DMSO-d⁶) δ 13.12–12.90 (m, 1H), 7.99–7.48 (m, 2H), 7.38–7.30 (m, 5H), 7.27–7.06 (m, 2H), 6.73–6.10 (m, 2H), 5.71–5.55 (m, 1H), 5.41–4.65 (m, 3H), 4.26–4.02 (m, 1H), 3.70–3.40 (m, 2H), 2.97–2.88 (m, 3H), 2.47–2.00 (m, 2H). Purity > 99%.

[0293] Example 10: Synthesis method of compound 2-B of the present invention:

[0294]

[0295] Step 1: Synthesis of Compound 2-B

[0296] TEA (72.55 mg, 716.97 μmol) was added to a DMSO (2 mL) solution of compounds 2-6 (17.00 mg, 50.84 μmol) and 2-10 (10.00 mg, 52.20 μmol). The reaction mixture was then stirred at 0 °C for 0.5 h. LC-MS analysis showed that compound 2-6 was completely consumed. The reaction mixture was purified by Prep-HPLC and lyophilized to give a white solid, compound 2-B (1.54 mg, 3.42 μmol, 6.72% yield, 91.2% purity). LC-MS: C 22 H 23 ClN4O2,[M+H] + 411.15; found411.0. 1 ¹H NMR (400MHz, Methanol-d⁴) δ 7.93–7.80 (m, 1H), 7.51–7.48 (m, 1H), 7.40–7.12 (m, 8H), 5.17–5.08 (m, 2H), 4.40–4.17 (m, 3H), 3.81–3.66 (m, 2H), 3.09–3.02 (m, 3H), 2.48–2.27 (m, 1H), 2.22–2.15 (m, 1H), 2.08–2.00 (m, 1H). Purity >90%.

[0297] Example 11, Synthesis method of compound 2-C of the present invention:

[0298]

[0299] Step 1: Synthesis of compound 2-C

[0300] Compounds 2-6 (12.00 mg, 35.88 μmol) and 2-11 (5.32 mg, 35.88 μmol) were dissolved in DMF (2 mL), followed by the addition of TCFH (12.08 mg, 43.06 μmol) and NMI (17.68 mg, 215.30 μmol). The mixture was then stirred at 0 °C for 2 hours. LC-MS analysis showed complete consumption of compound 2-6. The reaction mixture was purified by Prep-HPLC and lyophilized to give a white solid, compound 2-C (4.00 mg, 8.60 μmol, 23.97% yield, 99.9% purity). LC-MS: C29 H 28 N4O2, [M+H] + 465.22; found 465.3. 1 HNMR(400MHz, Methanol-d4)δ8.00-7.78(m,1H),7.62-7.09(m,13),5.91-5.89(d,J=8.4Hz,1H),5.54-5.50(m,1H),5.33-5.22(m,1H),5.17-5.13(m ,1H),4.75-4.70(m,1H),3.98-3.77(m,1H),3.71-3.64(m,1H),3.60-3.44 (m,1H),3.11-2.76(m,3H),2.54-2.29(m,1H),2.27-2.03(m,1H).Purity>99%.

[0301] Example 12, Synthesis method of compound 2-D of the present invention:

[0302]

[0303] Step 1: Synthesis of Compound 2-D

[0304] NMI (51.56 mg, 627.96 μmol) and TCFH (100.68 mg, 358.84 μmol) were added to a DMF (5 mL) solution of compounds 2-6 (100.00 mg, 299.03 μmol) and 2-12 (49.52 mg, 299.03 μmol). The reaction mixture was then stirred at 0 °C for 2 hours. LC-MS analysis showed that compound 2-6 was completely consumed. The reaction mixture was purified by Prep-HPLC and lyophilized to give compound 2-D (15.20 mg, 33.84 μmol, 11.32% yield, 99.2% purity). LC-MS: C 26 H 31 N5O2, [M+H] + 446.25; found 446.3. 1H NMR(600MHz,Methanol-d4)δ7.98-7.81(m,1H),7.62-7.49(m,1H),7.48-7.37( m,1H),7.35-7.22(m,5H),7.21-7.11(m,1H),6.88-6.79(m,1H),6.78-6.37(m,1 H),5.33-5.09(m,2H),4.36-4.19(m,1H),3.99-3.97(m,1H),3.86-3.53(m,3H) ,3.31(s,1H),3.13-3.02(m,3H),2.92-2.79(m,6H),2.60-2.15(m,2H). Purity>99%.

[0305] Example 13, Synthesis method of compound 2-E of the present invention:

[0306]

[0307] Step 1: Synthesis of compound 2-E

[0308] NaHCO3 (27.98 mg, 333.04 μmol) and DMT-MM (49.12 mg, 166.52 μmol) were added to a MeCN (2 mL) / H2O (0.5 mL) solution containing compounds 2-8 (37.80 mg, 111.01 μmol) and 2-9 (8.00 mg, 111.01 μmol, 0.025 mL). The reaction mixture was stirred at room temperature for 2 h, and the reaction process was monitored by LC-MS. After the reaction was completed, the reaction mixture was purified by Prep-HPLC to give compound 2-E (3.60 mg, 9.13 μmol, 8.22% yield, 98.8% purity). LC-MS: C 23 H 30 N4O2, [M+H] + 395.24; found 395.1. 1 H NMR(600MHz, Methanol-d4)δ7.93-7.08(m,4H),6.70-6.13(m,2H),5.78-5.57(m,1H),5.29-4.67(m,3H),4.11-3.96(m,1H),3.36-3.15(m,1 H),3.07-2.98(m,3H),2.32-2.18(m,1H),2.08-1.96(m,1H),1.91-1. 83(m,1H),1.78-1.61(m,5H),1.30(m,1H),1.21-0.88(m,5H).Purity>95%.

[0309] Example 14: Synthesis method of compound 2-F of the present invention:

[0310]

[0311] Step 1: Synthesis of compound 2-F

[0312] In a DMSO (1 mL) solution of compound 2-8 (35.00 mg, 102.80 μmol), DIPEA (74.20 mg, 574.11 μmol, 0.1 mL) and compound 2-10 (20.00 mg, 104.40 μmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS. After the reaction was complete, it was quenched with 1N HCl (0.5 mL), and the reaction solution was concentrated and purified by Prep-HPLC to give compound 2-F (3.80 mg, 9.11 μmol, 8.87% yield, 94.2% purity). LC-MS: C 22 H 29 ClN4O2, [M+H] + 417.20; found 417.2. 1 H NMR(600MHz,Methanol-d4)δ7.84(s,1H),7.92-7.73(m,1H),7.53-7.37(m,2H ),7.22-7.11(m,1H),5.28-4.96(m,2H),4.70-4.68(d,J=14.4Hz,1H),4.38-3. 87(m,3H),3.28(m,1H),3.06-2.98(m,3H),2.30-2.18(m,1H),1.97-1.88(m,1H ),1.76-1.64(m,6H),1.30-1.20(m,4H),1.11-1.00(m,1H),0.96-0.87(m,1H). Purity > 90%.

[0313] Example 15: Synthesis method of compound 2-G of the present invention:

[0314]

[0315] Step 1: Synthesis of Compound 2-G

[0316] NaHCO3 (27.21 mg, 323.98 μmol) and DMT-MM (47.79 mg, 161.99 μmol) were added to a MeCN (2 mL) / H2O (0.5 mL) solution of compounds 2-8 (25.00 mg, 73.43 μmol) and 2-11 (16.00 mg, 107.99 μmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was purified by Prep-HPLC to give compound 2-G (2.50 mg, 5.31 μmol, yield 4.92%, purity 93.1%). LC-MS: C 29 H 34 N4O2, [M+H] + 471.27; found 471.2. 1 H NMR(600MHz, Methanol-d4)δ8.02-7.64(m,2H),7.63-7.07(m,7H),5.93-5.28(m,2H),5.20-5.07(m,1H),4.81(m,2H),3.77-3.59( m,1H),3.16-2.71(m,4H),2.25-2.11(m,1H),1.98-1.76(m,2H),1.71-1.38(m,5H),1.27-1.08(m,4H),0.96-0.81(m,2H).Purity>90%.

[0317] Synthesis of intermediates: Synthesis of intermediates 3-6

[0318]

[0319] Step 1, Synthesis of Compound 3:

[0320] Compound 3-1 (150.00 mg, 335.37 μmol) was dissolved in DMF (3 mL). Then, EDCI (64.00 mg, 335.37 μmol), HOBT (45.30 mg, 335.37 μmol), and DIPEA (130.00 mg, 1006.11 μmol) were added under ice bath conditions. After stirring the reaction mixture for 20 min, compound 3-2 (22.50 mg, 335.37 μmol) was added. The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete as monitored by LC-MS, the reaction mixture was purified by MPLC to give compound 3-3 (143.00 mg, 311.94 μmol, 93.01% yield).

[0321] Step 2, Synthesis of Compounds 3-5:

[0322] Compounds 3-3 (143.00 mg, 311.94 μmol) and 3-4 (85.91 mg, 351.94 μmol) were dissolved in dioxane (8 mL) and H₂O (1 mL), followed by the addition of Pd(dppf)Cl₂ (3.00 mg, 3.12 μmol) and K₂CO₃ (145.70 mg, 1055.82 μmol). The reaction mixture was stirred at 60 °C under nitrogen protection for 16 h. LCMS analysis showed that compound 3-3 was completely consumed. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by chromatographic column (DCM / MeOH 100:1→50:1→10:1) to give a yellow solid compound 3-5 (73.00 mg, 162.03 μmol, 46.04% yield).

[0323] Step 3, Synthesis of intermediates 3-6:

[0324] TFA (55.50 mg, 486.90 μmol) was added to a 2 mL solution of compound 3-5 (73.00 mg, 162.03 μmol) in DCM. After stirring at 20 °C for 1 hour, LCMS showed that compound 3-5 was completely consumed. The reaction mixture was concentrated by rotary evaporation, and the crude product was used directly in subsequent reactions.

[0325] Referring to the synthesis method of intermediate 3-6, intermediate 3-8 can be obtained by replacing compound 3-1 with the raw materials listed in Table 1 below, while keeping other raw materials and operating methods unchanged.

[0326] Table 3. Intermediates 3-8

[0327]

[0328]

[0329] Example 16: Synthesis method of compound 3-A of the present invention:

[0330]

[0331] Step 1: Synthesis of Compound 3-A

[0332] DIPEA (11.06 mg, 85.61 μmol, 14.91 μL) was added to a DMSO (2 mL) solution of compounds 3-6 (30.00 mg, 85.61 μmol) and 3-9 (16.40 mg, 85.61 μmol). The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed as monitored by LC-MS, the solvent was removed by concentration under reduced pressure. The crude product was purified by Prep-HPLC and lyophilized to obtain compound 3-A (7.10 mg, 16.63 μmol, 19.43% yield, 99.2% purity). LC-MS: C 22 H 23 ClN4O3,[M+H] + 427.15; found 427.2. 1 H NMR (600MHz, Methanol-d4) δ8.61-8.55 (m, 2H), 8.24-8.05 (dd, J = 108.0Hz, 3.0Hz, 1H), 7.8 2-7.80(dd,J=8.4Hz,2.4Hz,1H),7.62-7.60(m,1H),7.35-7.30(dd,J=24.0Hz,8.4Hz,1H), 6.78-6.76 (m, 1H), 4.84 (m, 1H), 4.42-4.17 (m, 3H), 3.97-3.80 (m, 1H), 3.75-3.53 (m, 1H), 3.48-3.20 (m, 1H), 2.98-2.94 (d, J = 23.4, 3H), 2.22-1.98 (m, 2H), 1.95-1.58 (m, 2H). Purity > 99%.

[0333] Example 17: Synthesis method of compound 3-B of the present invention:

[0334]

[0335] Step 1: Synthesis of Compound 3-B

[0336] Compounds 3-6 (30.00 mg, 85.61 μmol), 3-10 (9.29 mg, 85.61 μmol), TCFH (24.00 mg, 85.61 μmol), and NMI (21.06 mg, 256.83 μmol) were dissolved in DMF (2 mL). The reaction mixture was stirred at room temperature for 2 hours until the reaction was complete as monitored by LC-MS. The reaction mixture was then purified by Prep-HPLC to give compound 3-B (5.10 mg, 11.57 μmol, 13.51% yield, 99.5% purity). LC-MS: C 23 H 25 ClN4O3,[M+H]+ 441.16; found411.1. 1 H NMR(600MHz, Methanol-d4)δ8.62-8.58(m,2H),8.32-8.09(m,1H),7.85-7.81(m,1H),7.63-7.59(m,1H),7.41-7.30(m,1H),6.74-6.72(m,1H),5.03 -4.97(m,1H),4.80-4.60(m,1H),4.11-3.56(m,3H),3.47-3.38(m,1H),3. 00-2.94(t,J=19.8Hz,3H),2.30-1.69(m,4H),1.63-1.58(m,3H).Purity>99%.

[0337] Example 18: Synthesis method of compound 3-C of the present invention:

[0338]

[0339] Step 1: Synthesis of compound 3-C

[0340] Compounds 3-6 (30.00 mg, 85.61 μmol) and 3-11 (6.17 mg, 85.61 μmol) were dissolved in THF (4 mL). DMT-MM (25.23 mg, 85.61 μmol) and NaHCO3 (21.57 mg, 256.83 μmol) were added at 0 °C. The reaction mixture was then stirred at room temperature for 2 hours until the reaction was complete as monitored by LC-MS. The reaction solution was purified by Prep-HPLC to give compound 3-C (5.70 mg, 14.09 μmol, 16.46% yield, 99.9% purity). LC-MS: C 23 H 24 N4O3, [M+H] + 405.18; found 405.1. 1H NMR(600MHz, Methanol-d4)δ8.60-8.55(m,2H),8.26-8.19(dd,J=37.8Hz,2.4Hz,1H),7.85-7.83(dd,J =8.4Hz,2.4Hz,1H),7.60-7.58(dd,J=9.0Hz,3.6Hz,1H),7.36-7.34(d,J=9.0Hz,1H),6.88-6.61(m,2H ), 6.29-6.17 (m, 1H), 5.83-5.64 (m, 1H), 4.96 (s, 1H), 4.48-4.33 (m, 1H), 4.22-3.96 (m, 1H), 3.73-3.59 (m, 1H), 3.52-3.18 (m, 1H), 2.93-2.92 (d, J=7.8Hz, 3H), 2.17-2.00 (m, 2H), 1.86-1.68 (m, 2H). Purity > 99%.

[0341] Example 19: Synthesis method of compound 3-D of the present invention:

[0342]

[0343] Step 1: Synthesis of compound 3-D

[0344] Compounds 3-6 (30.00 mg, 85.61 μmol) and 3-12 (11.99 mg, 85.61 μmol) were dissolved in MeCN (3 mL) and H₂O (1 mL), followed by the addition of NaHCO₃ (21.57 mg, 256.84 μmol) and DMT-MM (28.87 mg, 102.74 μmol) under ice bath conditions. The reaction mixture was stirred at room temperature for 0.5 hours. LC-MS analysis showed complete consumption of compound 3-6. The reaction mixture was purified by Prep-HPLC and lyophilized to give compound 3-D (10.40 mg, 21.99 μmol, 25.69% yield, 99.9% purity). LC-MS: C 24 H 23 F3N4O3, [M+H] + 473.17; found 473.2. 1H NMR(400MHz,Methanol-d4)δ8.55-8.50(d,J=20.0Hz,2H),8.22-8.08(m,1H) ,7.87-7.80(m,1H),7.59-7.56(t,J=3.6Hz,1H),7.39-6.89(m,2H),6.81-6. 49(m,2H),4.86-4.77(m,1H),4.47-4.25(m,1H),4.19-3.88(m,1H),3.80-3. 47(m,2H),3.22-2.95(m,3H),2.22-2.06(m,2H),1.99-1.58(m,2H).Purity>99%.

[0345] Example 20: Synthesis method of compound 3-E of the present invention:

[0346]

[0347] Step 1: Synthesis of compound 3-E

[0348] Compounds 3-6 (30.00 mg, 85.61 μmol), 3-13 (12.68 mg, 85.61 μmol), HATU (39.00 mg, 102.74 μmol), and DIPEA (33.19 mg, 256.84 μmol, 44.74 μL) were added to anhydrous MeCN (3 mL). The reaction mixture was stirred at 0 °C for 10 min, then heated to room temperature and stirred for 1 h. After the reaction was completed as monitored by LC-MS, the mixture was diluted with water (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to obtain the desired compound 3-E (12.90 mg, 26.39 μmol, 30.82% yield, 98.3% purity). LC-MS: C 29 H 28 N4O3, [M+H] + 481.22; found 481.3. 1H NMR(400MHz, Methanol-d4)δ8.55-8.22(m,2H),8.16-7.85(m,1H),7.70-7.39(m,4H),7.38-7.10(m,4H),6.90-6.69(m,1H),5.91-5.69(m,1H) ,5.48-5.30(m,1H),4.57-4.42(m,1H),3.90-3.53(m,3H),3.52-3.37(m ,1H),3.17-2.61(m,3H),2.22-2.00(m,2H),1.97-1.44(m,2H).Purity>95%.

[0349] Example 21: Synthesis method of compound 3-F of the present invention:

[0350]

[0351] Step 1: Synthesis of compound 3-F

[0352] Compounds 3-6 (30.00 mg, 85.61 μmol), 3-14 (7.54 mg, 85.61 μmol), HATU (39.00 mg, 102.74 μmol), and DIPEA (33.19 mg, 256.84 μmol, 44.74 μL) were added to anhydrous DMF (3 mL). The reaction mixture was stirred at 0 °C for 10 min, then heated to room temperature and stirred for 1 h. After the reaction was completed as monitored by LC-MS, the mixture was diluted with water (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to obtain the desired compound 3-F (2.10 mg, 4.99 μmol, 5.83% yield, 99.9% purity). LC-MS: C 23 H 24 N4O4, [M+H] + 421.18; found 421.1. 1H NMR (600MHz, Methanol-d4) δ8.53-8.50 (d, J = 18.6Hz, 2H), 8.22-8.10 (m, 1H), 7.84-7.81 (m, 1H), 7.58-7.55 (m, 1H), 7.39-7.30 (m, 1H), 6.73-6. 71(dd,J=10.8Hz,3.0Hz,1H),4.42-3.85(m,3H),3.84-3.42(m,3H),3.2 2-3.03(m,1H),3.01-2.86(m,4H),2.22-1.99(m,2H),1.98-1.59(m,2H). Purity >99%.

[0353] Example 22, Synthesis method of compound 3-G of the present invention:

[0354]

[0355] Step 1: Synthesis of compound 3-G

[0356] Compounds 3-6 (30.00 mg, 85.61 μmol) and 3-15 (7.20 mg, 85.61 μmol) were dissolved in MeCN (2 mL) and H₂O (1 mL), followed by the addition of NaHCO₃ (21.57 mg, 256.84 μmol) and DMT-MM (28.87 mg, 102.74 μmol). The reaction mixture was stirred at 0 °C for 0.5 h. LC-MS analysis showed that compound 3-6 was completely consumed. The reaction mixture was purified by Prep-HPLC and lyophilized to give compound 3-G (4.70 mg, 11.15 μmol, 13.02% yield, 98.8% purity). LC-MS: C 24 H 24 N4O3, [M+H] + 417.18; found 471.2. 1 H NMR(400MHz, Methanol-d4)δ8.53-8.48(m,2H),8.27-8.10(m,1H),7.89-7.81(m,1H),7,58-7.55(m,1H),7.40-7.31(m,1H),6.75-6.68(m,1H),4.8 3-4.51(m,1H),4.50-4.28(m,1H),4.27-3.93(m,1H),3.91-3.44(m,2H),3 .00-2.98(d,J=7.6Hz,3H),2.24-1.97(m,4H),1.80-1.61(m,3H).Purity>95%.

[0357] Example 23: Synthesis method of compound 3-H of the present invention:

[0358]

[0359] Step 1: Synthesis of compound 3-H

[0360] Compounds 3-6 (30.00 mg, 85.61 μmol) and 3-16 (9.00 mg, 85.61 μmol) were dissolved in DMF (3 mL), followed by the addition of DIPEA (33.19 mg, 256.84 μmol, 44.74 μL). The reaction mixture was stirred at 80 °C for 18 hours. LC-MS analysis showed that compound 3-6 was completely consumed. The reaction mixture was purified by Prep-HPLC and lyophilized to give compound 3-H (20.93 mg, 51.05 μmol, 59.63% yield, 91.9% purity). LC-MS: C 22 H 23 FN4O3, [M+H] + 411.18; found411.0. 1 H NMR(400MHz, Methanol-d4)δ8.58-8.48(m,2H),8.23-8.06(dd,J=77.2Hz,2.4Hz, 1H),7.84-7.79(m,1H),7.57-7.53(m,1H),7.33-7.31(d,J=8.8Hz,1H),6.72-6.7 0(m,1H),5.28-5.04(m,2H),4.43-4.18(m,1H),3.78-3.34(m,3H),3.27-3.08(m, 1H), 2.97-2.94 (d, J = 13.2Hz, 3H), 2.21-1.93 (m, 2H), 1.88-1.59 (m, 2H). Purity > 90%.

[0361] Example 24: Synthesis method of compound 3-I of the present invention:

[0362]

[0363] Step 1: Synthesis of Compound 3-I

[0364] Compounds 3-6 (40.00 mg, 114.15 μmol) and 3-17 (26.94 mg, 114.15 μmol) were added to a 3 mL DMF solution, followed by the addition of DIPEA (44.26 mg, 342.45 μmol, 59.65 μL). The reaction mixture was stirred at 20 °C for 0.5 h. TLC analysis showed that compound 6 was completely consumed. The reaction mixture was purified by Prep-HPLC to give compound 3-I (7.30 mg, 15.49 μmol, 13.57% yield, 98.2% purity). LC-MS: C 22 H 23 BrN4O3, [M+H] + 471.10; found 470.9. 1 H NMR(400MHz,Methanol-d4)δ8.46-8.42(m,1H),8.25-8.02(m,2H),7.78-7.75(d d,J=8.8Hz,2.4Hz,1H),7.45-7.42(m,1H),7.36-7.24(m,1H),6.63-6.55(m,1H) ,4.80-4.59(m,1H),4.56-4.20(m,1H),4.16-3.96(m,2H),3.95-3.80(m,1H),3. 79-3.38(m,2H),3.00-294(m,3H),2.26-1.98(m,2H),1.95-1.57(m,2H).Purity>95%.

[0365] Example 25: Synthesis method of compound 3-J of the present invention:

[0366]

[0367] Step 1: Synthesis of compound 3-J

[0368] Compounds 3-6 (30.00 mg, 85.61 μmol) and 3-18 (12.34 mg, 85.61 μmol) were dissolved in MeCN (2 mL) and H₂O (1 mL), followed by the addition of DMT-MM (25.23 mg, 85.61 μmol) and NaHCO₃ (21.57 mg, 256.83 μmol). After stirring at room temperature for 0.5 hours, LC-MS analysis showed complete consumption of compound 3-6. The reaction mixture was purified by Prep-HPLC and lyophilized to give compound 3-J (18.20 mg, 38.12 μmol, 44.52% yield, 99.8% purity). LC-MS: C 26 H 28 N4O5, [M+H]+ 477.21; found 477.3. 1 H NMR(400MHz, Methanol-d4)δ8.58-8.52(m,2H),8.23-7.82(m,2H),7.61-7.14(m,3H),6.77-6.42(m,2H),4.84-4.73(m,1H),4.46-4.35(m,1 H),4.30-3.93(m,3H),3.92-3.48(m,2H),2.94(s,3H),2.22-2.16(m, 1H), 2.15-1.82(m,2H), 1.79-1.58(m,1H), 1.36-1.07(m,3H). Purity>99%.

[0369] Example 26: Synthesis method of compound 3-K of the present invention:

[0370]

[0371] Step 1: Synthesis of compound 3-K

[0372] Compounds 3-8 (30.00 mg, 93.06 μmol) and 3-9 (17.83 mg, 93.06 μmol) were added to DMSO (2 mL), followed by TEA (72.55 mg, 716.97 μmol, 100 μL). The reaction mixture was stirred at room temperature for 0.5 h. LC-MS analysis showed that compound 3-8 was completely consumed. The reaction mixture was purified by Prep-HPLC and lyophilized to give compound 3-K (1.10 mg, 2.71 μmol, 2.91% yield, 98.2% purity). LC-MS: C 20 H 19 ClN4O3, [M+H] + 399.11; found 399.4. 1 H NMR (400MHz, Methanol-)

[0373] d4)δ8.47-8.45(dd,J=8.0Hz,1.2Hz,1H),8.37-8.33(m,1H),7.94-7.92(d,J=8.0Hz,1H),7 .88(s,1H),7.48-7.46(dd,J=8.4Hz,1.6Hz,1H),7.35-7.32(dd,J=8.0Hz,5.2Hz,1H),7.04- 7.03(d,J=1.6Hz,1H),5.36-5.33(m,1H),4.83(m,1H),4.60-4.55(m,1H),4.51-4.47(dd,J= 9.6Hz, 3.6Hz, 1H), 4.24-4.20 (dd, J = 12.0Hz, 3.6Hz, 1H), 4.11 (s, 2H), 2.98 (s, 3H). Purity > 95%.

[0374] Synthesis of intermediates: Synthesis of intermediates 4-8

[0375]

[0376] Step 1, Synthesis of Compound 4-2:

[0377] Compound 4-1 (163.00 mg, 996.32 μmol) was dissolved in anhydrous MeOH (5 mL), followed by the addition of formaldehyde (500.00 mg, 5.99 mmol, 500 μL, 36% purity) and NaCNBH3 (188 mg, 2.99 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was concentrated by rotary evaporation. The resulting crude compound 4-2 was used directly in subsequent reactions.

[0378] Step 2, Synthesis of Compound 4-4:

[0379] Compound 4-2 (40.00 mg, 283.35 μmol) and compound 4-3 (70.00 mg, 262.82 μmol) were dissolved in anhydrous DMF (3 mL), followed by the addition of TCFH (96.00 mg, 342.15 μmol) and NMI (206.00 mg, 2.51 mmol, 200 μL). The reaction mixture was stirred at 0 °C for 10 min, then brought to room temperature and stirred for another 0.5 h. After the reaction was completed as monitored by LCMS, the reaction mixture was concentrated by rotary evaporation. The crude product was purified by MPLC to obtain the desired compound 4-4 (100.00 mg, 256.75 μmol, 97.69% yield).

[0380] Step 3, Synthesis of intermediates 4-5:

[0381] TFA (744.50 mg, 6.53 mmol, 0.5 mL) was added to a 2 mL solution of compound 4-4 (100.00 mg, 256.75 μmol) in DCM. After stirring at 20 °C for 1 hour, LC-MS showed complete consumption of compound 4-4. The reaction mixture was concentrated by rotary evaporation, and the crude product was used directly in subsequent reactions.

[0382] Step 4, Synthesis of intermediates 4-7:

[0383] Compounds 4-5 (70.00 mg, 241.90 μmol), 4-6 (71.84 mg, 241.90 μmol), HATU (91.92 mg, 241.90 μmol), and DIPEA (93.62 mg, 725.70 μmol) were added to DCM (5 mL). The reaction mixture was stirred at 0 °C for 10 min, then heated to room temperature and stirred for 1 h. After the reaction was completed by LCMS monitoring, the mixture was diluted with water (20 mL) and extracted with DCM (3 × 10 mL). The organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by MPLC to give compound 4-7 (131.66 mg, 231.79 μmol, 95.82% yield).

[0384] Step 5: Synthesis of intermediates 4-8:

[0385] TFA (744.50 mg, 6.53 mmol, 0.5 mL) was added to a DCM (2 mL) solution of compounds 4-7 (131.66 mg, 231.79 μmol). After stirring at 20 °C for 1 hour, LCMS showed complete consumption of compound 7. The reaction mixture was concentrated by rotary evaporation, and the crude product was purified by MPLC to give compounds 4-8 (106.80 mg, 228.20 μmol, 98.45% yield).

[0386] Example 27: Synthesis method of compound 4-A of the present invention:

[0387]

[0388] Step 1: Synthesis of Compound 4-A

[0389] TEA (217.65 mg, 2.15 mmol, 300 μL) was added to an anhydrous DCM (3 mL) solution of compounds 4-8 (313.25 mg, 669.35 μmol). The reaction mixture was stirred at 0 °C for 10 min. Then, compounds 4-9 (141.90 mg, 1.26 mmol, 100 μL) were added, and the reaction mixture was stirred at 0 °C for another 0.5 h. After the reaction was completed as monitored by LC-MS, the mixture was diluted with water (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC and lyophilized to give compound 4-A (63.45 mg, 116.63 μmol, 17.42% yield, 94.0% purity). LC-MS: C 27 H 34 ClFN6O3,[M+H] + 545.24; found 545.6. 1 HNMR(400MHz,Methanol-d4)δ7.26-7.22(t,J=8.0Hz,1H),7.05-7.00(m,2H),6.21(s,1H),4.57-4 .54(d,J=12.8Hz,1H),4.37-4.35(m,2H),4.09(m,2H),3.95-3.92(d,J=14.0Hz,1H),3.84-3.81(d (J=11.6Hz, 1H), 3.73(m, 1H), 3.50-3.48(d, J=10.4Hz, 1H), 3.18-3.08(m, 1H), 3.00-2.81(m, 6H), 2.80-2.68(m, 2H), 2.67-2.58(m, 1H), 2.36(s, 1H), 2.03-1.83(m, 2H), 1.51-1.22(m, 5H). Purity >90%.

[0390] Example 28: Synthesis method of compound 4-B of the present invention:

[0391]

[0392] Step 1: Synthesis of Compound 4-B

[0393] Compounds 4-8 (15.00 mg, 32.01 μmol) and 4-10 (5.00 mg, 69.38 μmol) were dissolved in THF (3 mL) and H₂O (1 mL). Then, DMT-MM (12.00 mg, 40.71 μmol) and NaHCO₃ (10.00 mg, 94.35 μmol) were added under ice bath conditions. The reaction mixture was stirred at 0 °C for 10 minutes, and then stirred at room temperature for 0.5 hours. After the reaction was complete as monitored by LC-MS, the reaction mixture was diluted with water (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried on anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to obtain the desired compound 4-B (8.00 mg, 14.85 μmol, 46.38% yield, 97.0% purity). LC-MS: C 28 H 35 FN6O3,[M+H] + 523.28; found 523.2. 1 HNMR(600MHz,Methanol-d4)δ7.23(t,J=7.8Hz,1H),7.04-6.99(dd,J=22.2Hz,7.8Hz,2H),6.25(t,J=4.8Hz, 2H),5.68(t,J=4.2Hz,1H),4.58-4.54(m,2H),4.37(s,2H),3.94-3.92(d,J=13.2Hz,1H),3.13-3.09(m,3H),2 0.94 (t, J = 7.8 Hz, 1H), 2.86 (m, 1H), 2.79-2.69 (m, 2H), 2.66-2.61 (m, 1H), 2.50-2.48 (d, J = 9.0 Hz, 2H), 2.37 (s, 3H), 2.00-1.98 (m, 3H), 1.93-1.86 (dd, J = 44.4 Hz, 11.4 Hz, 2H), 1.48-1.42 (m, 1H), 1.30-1.27 (m, 1H). Purity > 95%.

[0394] Example 29: Synthesis method of compound 4-C of the present invention:

[0395]

[0396] Step 1: Synthesis of compound 4-C

[0397] Compounds 4-8 (14.00 mg, 29.88 μmol) and 4-11 (5.00 mg, 59.47 μmol) were dissolved in THF (3 mL) and H₂O (1 mL), followed by the addition of DMT-MM (12.00 mg, 40.71 μmol) and NaHCO₃ (10.00 mg, 94.35 μmol). The mixture was stirred at 0 °C for 10 min. Stirring continued at room temperature for 0.5 h. After the reaction was complete as monitored by LC-MS, the reaction mixture was diluted with water (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to obtain the desired compound 4-C (6.00 mg, 11.11 μmol, 37.19% yield, 99.0% purity). LC-MS: C 29 H 35 FN6O3, [M+H] + 535.28; found 535.2. 1 H NMR(600MHz, Methanol-d4)δ7.23(t,J=7.8Hz,1H),7.03-7.01(d,J=7.8Hz,1H),6.99-6.97(d,J =10.8Hz,1H),6.22(s,1H),4.56-4.54(d,J=13.2Hz,1H),4.30-4.29(d,J=3.0Hz,2H),4.05-3.81 (m, 3H), 3.51-3.49 (d, J = 11.4 Hz, 2H), 3.11-3.07 (m, 1H), 2.96-2.86 (m, 6H), 2.78-2.62 (m, 3H), 2.36 (s, 2H), 1.99-1.91 (m, 5H), 1.87-1.85 (m, 1H), 1.47-1.42 (m, 1H), 1.37-1.28 (m, 1H). Purity > 99%.

[0398] Example 30: Synthesis method of compound 4-D of the present invention:

[0399]

[0400] Step 1: Synthesis of compound 4-D

[0401] Compounds 4-8 (15.00 mg, 32.01 μmol) and 4-12 (10.00 mg, 71.40 μmol) were dissolved in THF (3 mL) and H₂O (1 mL), followed by the addition of DMT-MM (12.00 mg, 40.71 μmol) and NaHCO₃ (10.00 mg, 94.35 μmol) under ice bath conditions. The reaction mixture was stirred at 0 °C for 10 min, and then stirred at room temperature for 0.5 h. After the reaction was completed as monitored by LC-MS, the reaction mixture was diluted with water (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried on anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to obtain the desired compound 4-D (6.00 mg, 9.78 μmol, 30.56% yield, 96.3% purity). LC-MS: C 29 H 34 F4N6O3, [M+H] + 591.26; found 591.2. 1 H NMR(600MHz, Methanol-d4)δ7.25(t,J=8.4Hz,1H),7.06-7.04(d,J=7.8Hz,1H),7.03-7.01(d,J=10.8Hz,1H),6 .79-6.71(m,2H),6.25(s,1H),4.58-4.54(m,1H),4.40(s,2H),3.95-3.92(d,J=13.8Hz,1H),3.15-3.09(m,3H), 2.97-2.93 (m, 2H), 2.90-2.84 (m, 1H), 2.82-2.61 (m, 3H), 2.51-2.50 (d, J = 9.6 Hz, 2H), 2.36 (s, 3H), 2.00-1.99 (m, 3H), 1.94-1.92 (d, J = 12.6 Hz, 1H), 1.88-1.86 (d, J = 13.2 Hz, 1H), 1.48-1.41 (m, 1H), 1.30-1.23 (m, 1H). Purity > 95%.

[0402] Example 31: Synthesis method of compound 4-E of the present invention:

[0403]

[0404] Step 1, Synthesis of Compound 4-13:

[0405] Compound 4-6 (200.00 mg, 672.67 μmol) was dissolved in DCM (2 mL), followed by the addition of TFA (2 mL). The reaction mixture was stirred at room temperature for 5 min. After the reaction was completed as monitored by LCMS, the reaction mixture was concentrated under reduced pressure to obtain the crude product of compound 4-13, which was used directly in subsequent reactions.

[0406] Step 2, Synthesis of Compound 4-14:

[0407] Compound 4-13 (132.00 mg, 669.35 μmol) was added to DCM (3 mL) and H₂O (2 mL), followed by compound 4-9 (141.90 mg, 1.26 mmol, 100 μL) and TEA (217.65 mg, 2.15 mmol, 300 μL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. After the reaction was completed as monitored by LCMS, the reaction mixture was diluted with water (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried on anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product of compound 4-14, which was used directly in subsequent reactions.

[0408] Step 3, Synthesis of Compounds 4-15:

[0409] Compound 4-3 (266.00 mg, 998.73 μmol) was dissolved in anhydrous DCM (5 mL), followed by the addition of TEA (253.93 mg, 2.51 mmol, 350 μL) and Ac₂O (163.05 mg, 1.60 mmol, 150 μL). The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed as monitored by LCMS, the reaction mixture was concentrated under vacuum. The crude product was purified by MPLC to give compound 4-15 (228.00 mg, 739.36 μmol, 74.03% yield).

[0410] Step 4, Synthesis of Compound 4-16:

[0411] Compound 4-15 (227 mg, 736.12 μmol) was added to DCM (2 mL), followed by TFA (744.50 mg, 6.53 mmol, 0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed as monitored by LCMS, the mixture was concentrated under reduced pressure to obtain the crude product of compound 4-16, which was used directly in subsequent reactions.

[0412] Step 5, Synthesis of compound 4-E:

[0413] Compounds 4-14 (90.00 mg, 328.84 μmol), 4-16 (70.00 mg, 336.12 μmol), HATU (127.73 mg, 336.12 μmol), and DIPEA (111.30 mg, 861.17 μmol, 150 μL) were dissolved in anhydrous DMF (3 mL). The reaction mixture was then stirred at room temperature for 0.5 h. After the reaction was completed as monitored by LC-MS, the reaction mixture was diluted with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried on anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to obtain the desired compound 4-E (12.00 mg, 23.64 μmol, 7.03% yield, 91.4% purity). LC-MS: C 22 H 27 ClFN5O3, [M+H] + 464.18; found 464.5. 1 H NMR(400MHz, Methanol-d4)δ7.24(t,J=8.0Hz,1H),7.06-7.00(m,2H),6.18(s ,1H),4.58-4.55(d,J=12.8Hz,1H),4.36(s,2H),4.08(s,2H),3.96-3.93(d,J =20.4Hz,1H),3.18-3.08(m,1H),3.00-2.88(m,3H),2.84-2.61(m,3H),2.13( s,2H),1.97(m,2H),1.50-1.43(m,1H),1.37-1.35(m,1H),1.33-1.27(m,1H). Purity >90%.

[0414] Example 32: Synthesis method of compound 4-F of the present invention:

[0415]

[0416] Step 1, Synthesis of Compound 4-18:

[0417] Compound 4-17 (121.00 mg, 500.59 μmol) was dissolved in anhydrous MeOH (3 mL). Then, formaldehyde (251.22 mg, 3.01 mmol, 251.22 μL) and NaCNBH3 (94.46 mg, 1.50 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed as monitored by LCMS, the reaction mixture was concentrated under vacuum to obtain the crude product of compound 4-18, which was directly used in subsequent reactions.

[0418] Step 2, Synthesis of Compound 4-19:

[0419] Compound 4-18 (110.00 mg, 501.64 μmol), compound 4-3 (133.00 mg, 499.36 μmol), TCFH (155.00 mg, 552.43 μmol), and NMI (309.00 mg, 3.76 mmol, 300 μL) were dissolved in anhydrous DMF (3 mL). The reaction mixture was stirred at room temperature for 0.5 h. After the reaction was completed as monitored by LCMS, the reaction mixture was diluted with water (20 mL) and then extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by MPLC to obtain the desired compound 4-19 (152.00 mg, 325.06 μmol, 64.80% yield).

[0420] Step 3, Synthesis of Compound 4-20:

[0421] Compound 4-19 (152.00 mg, 325.06 μmol) was added to DCM (4 mL), followed by TFA (1.49 g, 13.06 mmol, 1 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed as monitored by LCMS, the mixture was concentrated under reduced pressure. The crude product of compound 4-20 was used directly in subsequent reactions.

[0422] Step 4, Synthesis of Compound 4-22:

[0423] Compounds 4-20 (75.00 mg, 204.09 μmol) and 4-21 (60.00 mg, 204.56 μmol) were dissolved in anhydrous DMF (3 mL), followed by the addition of TCFH (63.00 mg, 224.54 μmol) and NMI (206.00 mg, 2.51 mmol, 200 μL). The reaction mixture was stirred at 0 °C for 10 min, and then stirred at room temperature for 0.5 h. After the reaction was completed as monitored by LCMS, the reaction mixture was diluted with water (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried on anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by MPLC to obtain the desired compound 4-22 (65.00 mg, 101.12 μmol, 49.55% yield).

[0424] Step 5, Synthesis of Compound 4-23:

[0425] Compound 4-22 (30.00 mg, 46.67 μmol) was added to DCM (2 mL), followed by TFA (1.49 g, 13.06 mmol, 1 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS until completion. The mixture was concentrated under reduced pressure. The crude product of compound 4-23 was used directly in subsequent reactions.

[0426] Step 6, Synthesis of Compound 4-F

[0427] Compounds 4-23 (25.00 mg, 46.07 μmol) and 4-24 (10.00 mg, 68.43 μmol) were dissolved in THF (3 mL) and H₂O (1 mL), followed by the addition of DMT-MM (17.00 mg, 57.68 μmol) and NaHCO₃ (10.00 mg, 94.35 μmol). The reaction mixture was stirred at 0 °C for 10 min, and then stirred at room temperature for 2 h. After the reaction was completed as monitored by LC-MS, the desired compound 4-F (12.00 mg, 17.87 μmol, 38.79% yield, 99.9% purity) was purified by Prep-HPLC. LC-MS: C 40 H 42 N₆O₄, [M+H] + 671.33; found 671.3. 1 HNMR(400MHz,DMSO-d6+D2O)δ7.91-7.53(m,4H),7.52-7.39(m,4H),7.38-6.90(m,4H),6.44(s,1H),4.55(m,1H),4.25(m,1H),4.17(m,1H) ),4.10-4.03(m,1H),3.53-3.45(m,1H),3.25-2.87(m,9H),2.37(s,3H),2.24(m,1H),2.03(m,1H),1.90-1.78(m,3H),1.73-1.44(m,5H). Purity >99%.

[0428] Example 33: Synthesis method of compound 4-G of the present invention:

[0429]

[0430] Step 1, Synthesis of Compound 4-25:

[0431] Compounds 4-16 (60.00 mg, 288.10 μmol) and 4-21 (80.00 mg, 272.74 μmol) were dissolved in anhydrous DMF (3 mL), followed by the addition of TCFH (89.00 mg, 317.20 μmol) and NMI (206.00 mg, 2.51 mmol, 200 μL). The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed as monitored by LCMS, the reaction mixture was diluted with water (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by MPLC to give the desired compound 4-25 (68.00 mg, 140.62 μmol, 48.81% yield).

[0432] Step 2, Synthesis of Compound 4-26:

[0433] Compound 4-25 (30.00 mg, 62.04 μmol) was added to DCM (3 mL), followed by TFA (1.49 g, 13.06 mmol, 1 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed as monitored by LCMS, the mixture was concentrated under reduced pressure. The crude product of compound 4-26 was used directly in subsequent reactions.

[0434] Step 3, Synthesis of Compound 4-G

[0435] Compounds 4-26 (23.00 mg, 59.98 μmol) and 4-27 (12.00 mg, 82.11 μmol) were dissolved in THF (3 mL) and H₂O (1 mL), followed by the addition of DMT-MM (22.00 mg, 74.64 μmol) and NaHCO₃ (20 mg, 188.70 μmol). The reaction mixture was stirred at 0 °C for 10 min, and then stirred at room temperature for 2 h. After the reaction was completed as monitored by LC-MS, the desired compound 4-G (6.00 mg, 11.72 μmol, 19.53% yield, 99.9% purity) was purified by Prep-HPLC. LC-MS: C 29 H 29 N5O4, [M+H] + 512.22; found 512.1. 1H NMR(600MHz,DMSO-d6+D2O)δ7.60-7.43(m,5H),7.19-7.17(m,1H),7.10- 7.00(m,1H),6.98-6.95(m,1H),6.28(s,1H),4.54(m,1H),4.27-4.18(m, 1H),4.16-4.04(m,2H),3.51-3.44(m,1H),3.19-3.00(m,2H),2.98-2.81 (m,3H),1.99-1.96(m,4H),1.90-1.75(m,1H),1.58-1.37(m,2H).Purity>99%.

[0436] Synthesis of intermediates: Synthesis of intermediates 5-6

[0437]

[0438] Step 1, Synthesis of Compound 5-3:

[0439] Compound 5-1 (300.00 mg, 719.01 μmol) and compound 5-2 (66.99 mg, 2.16 mmol) were dissolved in DMF (5 mL), followed by the addition of TCFH (31.10 mg, 862.82 μmol) and NMI (353.42 mg, 4.31 mmol). The reaction mixture was stirred at room temperature for 0.5 h. LCMS analysis showed that compound 5-1 was completely consumed. The reaction mixture was purified by MPLC and lyophilized to give compound 5-3 (291.89 mg, 678.38 μmol, 94.35% yield).

[0440] Step 2, Synthesis of Compound 5-5:

[0441] Compound 5-3 (136.00 mg, 316.07 μmol), compound 5-4 (77.15 mg, 316.07 μmol), Pd(dppf)Cl2 (23.00 mg, 31.61 μmol), and K2CO3 (130.85 mg, 948.22 μmol) were added to 1,4-dioxane (10 mL) and water (2 mL). The mixture was then stirred at 80 °C for 16 hours under nitrogen protection. LCMS analysis showed that compound 5-3 was completely consumed. The reaction solution was concentrated, purified by MPLC, and lyophilized to give compound 5-5 (116.80 mg, 278.11 μmol, 87.99% yield).

[0442] Step 3, Synthesis of intermediates 5-6:

[0443] Compound 5-5 (107.00 mg, 254.46 μmol) was dissolved in DCM (2 mL), followed by the addition of TFA (744.50 mg, 6.53 mmol, 0.5 mL). The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed as monitored by LCMS, the reaction mixture was concentrated to obtain crude compound 5-6, which was directly used in subsequent reactions.

[0444] Example 34: Synthesis method of compound 5-A of the present invention:

[0445]

[0446] Step 1: Synthesis of Compound 5-A

[0447] Compounds 5-6 (30.00 mg, 93.64 μmol) and 5-7 (20.00 mg, 104.40 μmol) were dissolved in anhydrous DCM (3 mL). Then, TEA (29.02 mg, 286.79 μmol, 40 μL) was added. The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete as monitored by LC-MS, the reaction mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC to obtain the desired compound 5-A (6.00 mg, 15.10 μmol, 16.13% yield, 99.9% purity). LC-MS: C 21 H 21 ClN4O2,[M+H] + 397.14; found 397.1. 1 H NMR (400MHz, Methanol-d4) δ8.32-8.30 (dd, J=8.0Hz, 1.2Hz, 1H), 8.24-8.23 (m, 1H),7.68-7.65(m,3H),7.36-7.34(d,J=8.0Hz,2H),7.20-7.17(dd,J=8.0Hz,4. 8Hz,1H),4.40-4.26(m,2H),3.95-3.88(m,1H),3.83-3.75(m,1H),3.58-3.47(m ,1H),2.72-2.71(d,J=4.4Hz,3H),2.45-2.39(m,1H),2.30-2.19(m,1H).Purity>99%.

[0448] Example 35: Synthesis method of compound 5-B of the present invention:

[0449]

[0450] Step 1: Synthesis of Compound 5-B

[0451] Compounds 5-6 (30.00 mg, 93.64 μmol) and 5-8 (15.45 mg, 104.40 μmol) were dissolved in MeCN (3 mL) and H₂O (1 mL), followed by the addition of DMT-MM (26.22 mg, 93.64 μmol) and NaHCO₃ (10.00 mg, 94.35 μmol). The reaction mixture was then stirred at room temperature for 0.5 h. LC-MS analysis showed that compound 5-6 was completely consumed. The reaction mixture was concentrated, purified by Prep-HPLC, and lyophilized to give compound 5-B (5.30 mg, 11.73 μmol, 12.53% yield, 99.7% purity). LC-MS: C 28 H 26 N4O2,[M+H] + 451.21; found 451.2. 1 H NMR(600MHz,Methanol-d4)δ8.57-8.56(d,J=7.8Hz,1H),8.34-8.33(d,J=4.2Hz,1H),7.79 -7.76(m,1H),7.71-7.69(d,J=8.4Hz,1H),7.62-7.58(dd,J=23.4Hz,8.4Hz,2H),7.44-7.39 (m, 5H), 7.38-7.28(m, 2H), 5.93-5.80(d, J = 79.2 Hz, 1H), 5.57-5.35(d, J = 136.2 Hz, 1H), 4.48-4.24(m, 1H), 3.72-3.53(m, 3H), 2.76-2.54(d, J = 132 Hz, 3H), 2.33-2.16(m, 2H). Purity > 99%.

[0452] Example 36: Synthesis method of compound 5-C of the present invention:

[0453]

[0454] Step 1: Synthesis of compound 5-C

[0455] Compounds 5-6 (20.00 mg, 62.42 μmol) and 5-9 (6.77 mg, 62.42 μmol) were dissolved in DMF (3 mL), followed by the addition of TCFH (2.70 mg, 74.91 μmol) and NMI (30.71 mg, 374.55 μmol). The reaction mixture was stirred at room temperature for 0.5 h. LC-MS analysis showed that compound 5-6 was completely consumed. After concentrating the reaction mixture, the crude product was purified by Prep-HPLC and lyophilized to give compound 5-C (8.80 mg, 21.40 μmol, 34.27% yield, 99.9% purity). LC-MS: C 22 H 23 ClN4O2, [M+H] + 411.15; found 411.2. 1 H NMR (600MHz, Methanol-d4) δ8.80-8.77(m,1H),8.43-8.42(d,J=4.8Hz,1H),7.89-7.88(m,1 H),7.72-7.69(m,2H),7.55-7.53(dd,J=7.8Hz,5.4Hz,1H),7.43-7.40(m,2H),4.82-4.78(q, J = 6.6 Hz, 1H), 4.41-4.34 (dd, J = 31.2 Hz, 6.6 Hz, 1H), 4.11-3.91 (m, 1H), 3.88-3.69 (m, 1H), 3.55-3.52 (q, J = 7.2 Hz, 1H), 2.72 (s, 3H), 2.47 (m, 1H), 2.24 (m, 1H), 1.64-1.58 (m, 3H). Purity > 99%.

[0456] Example 37: Synthesis method of compound 5-D of the present invention:

[0457]

[0458] Step 1: Synthesis of compound 5-D

[0459] Compounds 5-6 (20.00 mg, 62.42 μmol) and 5-10 (4.50 mg, 62.42 μmol) were dissolved in MeCN (3 mL) and H₂O (1 mL), followed by the addition of DMT-MM (26.22 mg, 93.64 μmol) and NaHCO₃ (10.00 mg, 94.35 μmol). The reaction mixture was then stirred at room temperature for 0.5 h. LC-MS analysis showed that compound 5-6 was completely consumed. The reaction mixture was concentrated, purified by Prep-HPLC, and lyophilized to give compound 5-D (2.00 mg, 4.86 μmol, 7.79% yield, 91.0% purity). LC-MS: C 22 H 22 N4O2, [M+H] + 375.17; found 375.2. 1 H NMR (600MHz, Methanol-d4) δ8.93-8.28(m,2H),7.77-7.67(m,3H),7.41-7.29(m,3H),6.7(dd,J=16.8Hz,10.8Hz,1H),6.32-6.29(m,1H),5.81-5.79( dd,J=16.8Hz,2.4Hz,1H),4.55-4.53(m,1H),4.00-3.88(m,2H),3.63-3.5 1(m,1H),2.75-2.72(m,3H),2.47-2.45(m,1H),2.27-2.09(m,1H).Purity>90%.

[0460] Example 38: Synthesis method of compound 6-A of the present invention:

[0461]

[0462] Step 1: Synthesis of Compound 6-2

[0463] Compound 6-1 (50.00 mg, 232.94 μmol) was added to anhydrous MeOH (2 mL), followed by the addition of TEA (72.55 mg, 716.97 μmol, 100 μL) and (Boc)₂O (56.00 mg, 256.59 μmol). The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was completed as monitored by LCMS, the reaction mixture was diluted with water (60 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with saturated brine, dried on anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product of compound 6-2 was used directly in subsequent reactions.

[0464] Step 2, Synthesis of Compound 6-3

[0465] Compound 6-2 (64.00 mg, 229.96 μmol) was added to anhydrous DMF (2 mL), followed by NaH (27.00 mg, 675.06 μmol, 60% purity). The reaction mixture was stirred at 0 °C for 30 min. Then CH3I (50.00 mg, 352.27 μmol) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was monitored by LCMS, the mixture was diluted with water (20 mL) and quenched. It was then extracted with EA (3 × 50 mL), and the combined organic layers were washed with saturated brine, dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was finally purified by MPLC to give compound 6-3 (59.00 mg, 201.82 μmol, 87.76% yield).

[0466] Step 3, Synthesis of Compound 6-4

[0467] Compound 6-3 (59.00 mg, 201.82 μmol) was dissolved in DCM (3 mL), followed by the addition of TFA (1.49 g, 13.06 mmol, 1 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed as monitored by LCMS, the mixture was concentrated under reduced pressure. The crude product of compound 6-4 was used directly in subsequent reactions.

[0468] Step 1: Synthesis of Compound 6-A

[0469] Compound 6-4 (13.00 mg, 67.63 μmol) was dissolved in anhydrous DCM (2 mL). Then, TEA (21.77 mg, 215.09 μmol, 30 μL) and compound 6-5 (13.00 mg, 67.86 μmol) were added, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was complete as monitored by LC-MS, the reaction mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC to obtain the desired compound 6-A (8.00 mg, 29.18 μmol, 43.14% yield, 98.0% purity). LC-MS: C 11 H 13 ClN4O2,[M+H] + 269.07; found 269.3. 1 HNMR(400MHz,Methanol-d4)δ7.88-7.85(m,1H),7.72-7.63(m,1H),7.06-7.04(d,J=6.0Hz,1H),6.98- 6.97 (d, J=6.0Hz, 1H), 4.20-4.17 (m, 4H), 3.79 (t, J=6.0Hz, 2H), 3.13-3.03 (d, J=43.6Hz, 3H). Purity >95%.

[0470] Experimental Example 1: Detection of JAK3 inhibitory activity

[0471] 1. Experimental instruments and reagents:

[0472]

[0473] 2. Experimental methods:

[0474] The compound powder was dissolved in DMSO to form a 10.00 mM solution. The compound was then serially diluted using an Echo 665 instrument and added to a 384-well reaction plate (Corning, 3824) to make the final concentration of DMSO in the entire reaction system (5 μL) 1%. An equal amount of DMSO was added as a control.

[0475] Dilute JAK3 protein in buffer 20mM HEPES, 0.005% BSA, 2mM DTT, 10mM MgCl2, 0.015% Brij-35, pH 7.5 to twice the desired final concentration (1nM JAK3 WT, 1nM JAK3 C909S). Add 2.5 μL of each solution to a pre-added 384-well plate. Centrifuge at 1000 rpm for 1 minute and incubate for 0 or 60 minutes. Then dilute the substrate Poly(Glu,tyr) (Signalchem, P61-58) and ATP (Promega, 9102) in buffer Poly(Glu,tyr) to twice the desired final concentration (7 μM Poly(Glu,tyr), 20 μM ATP). Add 2.5 μL of each solution to the plate. Poly(Glu,tyr) and ATP mixture was added to a 384-well plate and centrifuged at 1000 rpm for 1 minute. The plate was then incubated on a microplate shaker at 25°C and 280 rpm for 60 minutes. After the reaction, 5 μl of ADP-Glo ​​was added, and the plate was incubated at 25°C and 280 rpm for 40 minutes. Then, 10 μl of Kinase detection reagent was added, and the plate was incubated at 25°C and 280 rpm for 40 minutes. The Luminescence signal in the 384-well plate was read using a microplate reader.

[0476] 3. Data Analysis

[0477] The formula for calculating the percentage of remaining activity at each concentration is as follows:

[0478] Residual viability (%) = 100% × (Luminescence) 化合物组 -Luminescence 空白对照 ) / (Luminescence 阳性对照 -Luminescence blank control)

[0479] Then, the IC was calculated by fitting the dose-effect curve using GraphPad 8.0. 50 value.

[0480] Table 4: Compounds and JAK3 Protein Inhibition Table

[0481] serial number <![CDATA[JAK3 IC 50 (0min)]]> <![CDATA[JAK3 IC 50 (60min)]]> <![CDATA[JAK3 C909S IC 50 (60min)]]> 1-A ++++ ++++ + 1-B +++ ++++ ++ 1-C ++ ++ / 1-D ++++ +++++ ++ 1-E ++++ ++++ ++ 1-F ++++ +++++ + 1-G ++++ +++++ + 1-H ++++ ++++ +

[0482] Table 5: Compounds and JAK3 Protein Inhibition Table

[0483] serial number <![CDATA[JAK3 IC 50 (0min)]]> <![CDATA[JAK3 IC 50 (60min)]]> <![CDATA[JAK3 C909S IC 50 (60min)]]> 3-A ++++ ++++ +++ 3-B +++ +++ / 3-C +++ ++++ ++ 3-D ++ ++ / 3-E +++ +++ / 3-F ++ ++ / 3-G ++ +++ / 3-H ++ ++ / 3-I +++ ++++ / 3-J ++ ++ / 3-K +++ ++++ ++ serial number <![CDATA[JAK3 IC 50 (0min)]]> <![CDATA[JAK3 IC 50 (60min)]]> <![CDATA[JAK3 C909S IC 50 (60min)]]> 4-A ++++ ++++ + 4-B +++ ++++ / 4-C ++ ++ / 4-D ++++ ++++ / 4-E ++++ ++++ + 4-F ++ ++ / 4-G ++ ++ / Table 8: Compounds and JAK3 Protein Inhibition Table

[0484]

[0485] Where + represents IC 50 >100μM, ++ indicates IC 50 >10μM, +++ indicates 10μM>IC 50 >1μM, ++++ means 1μM>IC 50 >1nM, +++++ indicates IC 50 <1nM.

[0486] Where + represents IC 50 >100μM, ++ indicates IC 50 >10μM, +++ indicates 10μM>IC 50 >1μM, ++++ means 1μM>IC 50 >1nM, +++++ indicates IC 50 <1nM.

[0487] Experimental Example 2: Selectivity Detection of the JAK Family

[0488] 1. Experimental Method:

[0489] The compound powder was dissolved in DMSO to form a 10.00 mM solution. The compound was then serially diluted using an Echo 665 instrument and added to a 384-well reaction plate (Corning, 3824) to make the final concentration of DMSO in the entire reaction system (5 μL) 1%. An equal amount of DMSO was added as a control.

[0490] JAK1, JAK2, and TYK2 proteins were diluted in buffer 20 mM HEPES, 0.005% BSA, 2 mM DTT, 10 mM MgCl2, 0.015% Brij-35, pH 7.5 to twice the desired final concentration (10 nM JAK1, 2 nM JAK2, 25 nM TYK2). 2.5 μL of each solution was added to a 384-well plate containing the added compounds. After centrifugation at 1000 rpm for 1 minute and pre-incubation for 60 minutes, the substrate Poly(Glu,tyr) (Signalchem, P61-58) and ATP (Promega, 9102) were diluted in buffer Poly(Glu,tyr) to twice the desired final concentration (7 μM Poly(Glu,tyr), 20 μM ATP). 2.5 μL of each solution was added to the plate. Poly(Glu,tyr) and ATP mixture was added to a 384-well plate and centrifuged at 1000 rpm for 1 minute. The plate was then incubated on a microplate shaker at 25°C and 280 rpm for 60 minutes. After the reaction, 5 μl of ADP-Glo ​​was added, and the plate was incubated at 25°C and 280 rpm for 40 minutes. Then, 10 μl of Kinase detection reagent was added, and the plate was incubated at 25°C and 280 rpm for 40 minutes. The Luminescence signal in the 384-well plate was read using a microplate reader.

[0491] 2. Data Analysis

[0492] The formula for calculating the percentage of remaining activity at each concentration is as follows:

[0493] Residual viability (%) = 100% × (Luminescence) 化合物组 -Luminescence 空白对照 ) / (Luminescence 阳性对照 -Luminescence blank control)

[0494] Then, the IC was calculated by fitting the dose-effect curve using GraphPad 8.0. 50 value.

[0495] Table 9: Compound Selectivity Table

[0496]

[0497]

[0498] Where + represents IC 50 >100μM, ++ indicates IC 50 >10μM, +++ indicates 10μM>IC 50 >1μM, ++++ means 1μM>IC50 >1nM, +++++ indicates IC 50 <1nM.

Claims

1. The compound represented by formula IA, or its stereoisomer, or its pharmaceutically acceptable salt: Wherein, ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aromatic ring, and 5-10 membered aromatic heterocyclic ring; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocyclic ring may be further separated by one, two, three, or four independent R. IA1 replace; The R IA1 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, =O, -C 0～2 Alkylene-C(O)R IA2 -C 0～2 Alkylene-C(O)(C 2～6 alkenyl), -C 0～2 Alkylene-C(O)NR IA2 R IA3 -C 0～2 Alkylene-NHC(O)R IA2 -C 0～2 Alkylene-N(C) 1～6 Alkyl)C(O)R IA2 -C 0～2 Alkylene -NHC(O) (3- to 10-membered heterocyclic alkyl groups), -C 0～2 Alkylene-NHC(O) (6-10 membered aromatic rings); wherein the alkylene, alkyl, alkenyl, heterocyclic alkyl, or aromatic ring may be further divided by one, two, three, or four independent R groups. IA4 replace; R IA2 R IA3 R IA4 Selected independently from hydrogen and -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 1～6 Alkyl-substituted (3- to 10-membered heterocyclic alkyl), -C 0～2 Alkylene (6- to 10-membered aromatic rings); L1 is selected from -NH-C 0～4 alkylene-, -C 0～4 Alkylene -NH-, -C 0～2 Alkylene-N(C) 1～6 Alkyl)C(O)-, -C(O)-C 0～4 Alkylene -, -O-, or absent; the alkylene is R IL1 replace; The R IL1 Selected from hydrogen, -C(O)NR IL2 R IL3 ;in, R IL2 R IL3 Selected independently from hydrogen and -C 1～6 Alkyl, halogen-substituted C 1～6 alkyl; L2 is selected from -NH-C 0～4 alkylene-, -C 0～4 Alkylene -NH-, -C(O)-C 0～4 Alkylene -, -O-, or absent; the alkylene is R IL4 Replace; where R IL4 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 alkyl; Ring B is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aromatic ring, 5- to 10-membered aromatic heterocycle, or is absent; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further separated by one, two, three, or four independent R IB1 replace; The R IB1 Selected from hydrogen, halogens, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-C(O)R IB2 -C 0～2 Alkylene-C(O)(C 2～6 alkenyl), -C 0～2 Alkylene-NHC(O)R IB2 -C 0～2 Alkylene-C(O)NR IB2 R IB3 -NH-C 0～2 Alkylene-NHC(O)R IB2 -NH-C 0～2 Alkylene-C(O)NHR IB2 -C(O)-C 0～2 Alkylene (6- to 10-membered aromatic ring); wherein the alkyl, alkenyl, alkylene, or aromatic ring may be further divided by one, two, three, or four independent R groups. IB4 replace; R IB2 R IB3 R IB4 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene -NH2, -C 0～2 Alkylene-NH(C) 1～6 Alkyl), -C 0～2 Alkylene-N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles); The C ring is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aromatic ring, 5- to 10-membered aromatic heterocycle, or is absent; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further separated by one, two, three, or four independent R rings. IC1 replace; The R IC1 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene-C(O)R IC2 -C 0～2 Alkylene-C(O)(C 2～6 alkenyl), -C 0～2 Alkylene-NHC(O)(C 2～6 alkynyl group), -C 0～2 Alkylene-NHC(O)R IC2 ; wherein alkyl, alkenyl, alkynyl, and alkylene groups may be further bonded by one, two, three, or four independent R groups. IC3 replace; R IC2 R IC3 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)O(C) 1～6 alkyl).

2. The compound according to claim 1, characterized in that: The A ring is selected from 6-membered aromatic rings, 5-membered heterocyclic alkyl rings, 6-membered heterocyclic alkyl rings, 9-membered heterocyclic alkyl rings, 5-membered aromatic heterocycles, and 9-membered aromatic heterocycles; wherein the heterocyclic alkyl ring, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R rings. IA1 replace; Preferably, the A ring is selected from... The R IA1 Selected from hydrogen, -C1 alkylene-C(O)NR IA2 R IA3 -C(O)R IA2 -NHC(O) (6-membered heterocyclic alkyl group), -NHC(O)R IA2 -NHC(O)(6-aryl aromatic ring), -C(O)(C 2～4 Alkenyl); wherein the alkylene, alkenyl, heterocyclic alkyl, or aromatic ring may be further divided by one, two, three, or four independent R groups. IA4 replace; The R IA2 R IA3 R IA4 Selected independently from hydrogen and -C 1～3 Alkyl, halogen-substituted C 1～3 Alkyl, C 1～3 Alkyl-substituted (6-membered heterocyclic alkyl), - (6-membered aromatic ring); Specifically, the A ring is selected from L1 is selected from -NH-, does not exist, The L2 is selected from -NH-, Or it doesn't exist; Preferably, the B ring is selected from 6-membered aromatic heterocycles, 5-membered heterocyclic alkyl groups, 6-membered heterocyclic alkyl groups, and 6-membered aromatic rings; wherein the heterocyclic alkyl group, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R rings. IB1 replace; Preferably, the B ring is selected from... The R IB1 Selected from hydrogen, -NH(C 1～3 Alkyl), -NH-C2 alkylene-NHC(O)R IB2 -NH-C1 alkylene-C(O)NHR IB2 -C(O)(C 2～4 alkenyl), -C(O)R IB2 -C(O)NR IB2 R IB3 -C(O)-C1 alkylene-(6-membered aromatic ring); wherein the alkyl, alkenyl, alkylene, or aromatic ring may be further divided by one, two, three, or four independent R... IB4 replace; R IB2 R IB3 R IB4 Selected independently from hydrogen and -C 1～3 Alkyl, halogen-substituted C 1～3 Alkyl, -(6-membered aromatic ring), -C1 alkylene-N(C 1～3 Alkyl)(C 1～3 alkyl); Specifically, the B ring is selected from Preferably, the C ring is selected from 6-membered cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, 10-membered heterocycloalkyl, 6-membered aromatic ring, 9-membered aromatic heterocycle, and 10-membered aromatic heterocycle; wherein the cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocycle may be further divided by one, two, three, or four independent R rings. IC1 replace; Preferably, the C-ring is selected from... The R IC1 Selected from -C 0～2 Alkylene-NHC(O)(C 2～4 alkynyl), -C1 alkylene-NHC(O)R IC2 -C(O)R IC2 -C(O)(C 2～6 Alkenyl); wherein the alkyl, alkenyl, alkynyl, or alkylene groups may be further bonded by one, two, three, or four independent R groups. IC3 replace; R IC2 R IC3 Selected independently from hydrogen and -C 1～3 Alkyl, -C 2～4 alkenyl, -C 2～4 Alkyne- and halogen-substituted C 1～3 Alkyl, halogen-substituted C 2～4 Alkenyl, halogen-substituted C 2～4 Alkyne group, -(6-membered aromatic ring), -(3-membered heterocyclic alkyl group), -C(O)O(C) 1～3 alkyl); Specifically, the C ring is selected from 3. The compound according to claim 1, characterized in that: The compound has the structure shown in Formula I: in, R A1 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles); R A2 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)R A21 -C 0～2 Alkylene-C(O)NR A21 R A22 -C 0～2 Alkylene-NHC(O)R A21 -C 0～2 Alkylene-C(O)OR A21 -C 0～2 Alkylene-S(O)R A21 -C 0～2 Alkylene-S(O)2R A21 ; R A21 R A22 Selected independently from hydrogen and -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles); Or, R A1 R A2 The atoms directly bonded to it form 6-10 membered aromatic rings and 5-10 membered aromatic heterocycles; wherein the aromatic rings and aromatic heterocycles can be further bonded by one, two, three or four independent R atoms. A11 replace; R A11 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles); R A5 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -NH-C 0～2 Alkylene-C(O)R A51 ; wherein the alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R A52 replace; R A51 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles); R A52 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles); R A6 Selected from R A3 Selected from hydrogen, -C 0～2 Alkylene-NHC(O)R A31 -C 0～2 Alkylene-C(O)R A31 ; R A31 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkyne, halogen, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles); R A4 Selected from -C 0～2 Alkylene-C(O)R A41 ; R A41 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles); R A61 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkyne, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 alkyl); R A62 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkyne, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 alkyl).

4. The compound according to claim 1, characterized in that: The compound has the structure shown in Formula II: in, R B1 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles); R B2 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)R B21 -C 0～2 Alkylene-C(O)OR B21 ; R B21 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5-10 membered aromatic heterocycle); wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... B22 replace; R B22 Selected independently from hydrogen and -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl), -C 0～2 Alkylene -NH2, -C 0～2 Alkylene-NH(C) 1～6 Alkyl), -C 0～2 Alkylene-N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles); R B3 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycle); wherein, the alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... B31 replace; R B31 Selected independently from hydrogen and -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl), -C 0～2 Alkylene -NH2, -C 0～2 Alkylene-NH(C) 1～6 Alkyl), -C 0～2 Alkylene-N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycles).

5. The compound according to claim 1, characterized in that: The compound has the structure shown in Formula III: in, R C1 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)R C11 -C 0～2 Alkylene-C(O)NR C11 R C12 -C 0～2 Alkylene-NHC(O)R C11 -C 0～2 Alkylene-C(O)OR C11 -C 0～2 Alkylene-S(O)R C11 -C 0～2 Alkylene-S(O)2R C11 -O (3-10 membered cycloalkyl), -O (3-10 membered heterocycloalkyl), -O (6-10 membered aromatic ring), -O (5-10 membered aromatic heterocycle); wherein, the alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocycle may be further divided by one, two, three, or four independent R C13 replace; R C11 R C12 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles); R C13 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)(C 1～6 Alkyl), -C 0～2 Alkylene-C(O) (halogen-substituted C) 1～6 alkyl); R C2 Selected from -C(O)NR C21 R C22 -O (3-10 membered cycloalkyl), -O (3-10 membered heterocycloalkyl), -O (6-10 membered aromatic ring), -O (5-10 membered aromatic heterocycle); wherein, the cycloalkyl, heterocycloalkyl, aromatic ring, and aromatic heterocycle may be further divided by one, two, three, or four independent R C23 replace; R C21 R C22 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles); R C23 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)R C24 -C 0～2 Alkylene-C(O)NR C24 R C25 -C 0～2 Alkylene-NHC(O)R C24 -C 0～2 Alkylene-C(O)OR C24 ; R C24 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5-10 membered aromatic heterocycle); wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... C25 replace; R C25 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)R C26 -C 0～2 Alkylene-NHC(O)R C26 -C 0～2 Alkylene-C(O)OR C26 ; R C26 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycles).

6. The compound according to claim 1, characterized in that: The compound has the structure shown in Formula IV: in, R D1 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycle); wherein, the alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... D11 replace; R D11 Selected independently from hydrogen and -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycle); wherein, the alkylene, alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... D12 replace; R D12 Selected independently from hydrogen and -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles); R D2 Selected from -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycle); wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... D21 replace; R D21 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)R D22 -C 0～2 Alkylene-C(O)NR D22 R D23 -C 0～2 Alkylene-NHC(O)R D22 -C 0～2 Alkylene-C(O)OR D22 ; R D22 R D23 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5-10 membered aromatic heterocycle); wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... D24 replace; R D24 Selected independently from hydrogen and -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycles).

7. The compound according to claim 1, characterized in that: The compound has the structure shown in Formula V: in, R E1 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 Alkyne group, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles); R E2 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 alkylene-(5-10 membered aromatic heterocycles), -C 0～2 Alkylene-C(O)R E22 -C 0～2 Alkylene-C(O)NR E22 R E23 -C 0～2 Alkylene-NHC(O)R E22 -C 0～2 Alkylene-C(O)OR E22 ; wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R E21 replace; R E21 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles); R E22 R E23 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, halogen-substituted C 2～6 Alkenyl, halogen-substituted C 2～6 alkynyl group, -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5-10 membered aromatic heterocycle); wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... E24 replace; R E24 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycles); R E3 Selected from -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene (5- to 10-membered aromatic heterocycle); wherein the cycloalkyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further divided by one, two, three, or four independent R... E31 replace; R E31 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted C 1～6 Alkyl, halogen, cyano, nitro, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene (3- to 10-membered cycloalkyl), -C 0～2 Alkylene (3- to 10-membered heterocyclic alkyl), -C 0～2 alkylene-(6- to 10-membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycles).

8. The compound according to claim 1, characterized in that: The compound described in Formula IA is specifically:

9. A pharmaceutical composition comprising a compound as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

10. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating and / or preventing diseases or conditions associated with JAK3, wherein the diseases or conditions associated with JAK3 are selected from one or more of arthritis, autoimmune diseases or conditions, cancer or tumors, diabetes, eye diseases, conditions or illnesses, enteritis or illnesses, neurodegenerative diseases, skin diseases, conditions or illnesses, allergic reactions, asthma and other obstructive airway diseases, and transplant rejection-related diseases.

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