A diazepine compound, pharmaceutical composition and use thereof

Abstract

The application provides a kind of diazine indole compound, pharmaceutical composition and purposes thereof, belong to the technical field of pharmaceutical chemistry.The application synthesizes a kind of novel structure diazine indole compound, it can efficiently inhibit JAK2 V617F The non-cell factor-dependent proliferation caused by mutation is excellent in affinity with JAK2 JH2 pseudokinase domain, significantly inhibits JAK2 V617F Abnormal activation by allosteric regulation pathway.Compared with the compound disclosed in the prior art, the compound of the application has significantly improved effect in inhibiting the proliferation of Ba / F3 JAK2 V617F Cell, and maintains good JAK2-JH2 affinity;Meanwhile, it has better oral pharmacokinetic characteristics, can realize target effective inhibition with lower dosing dose, reduce dosing load and side effects.The compound of the application can realize high selectivity, high efficiency in treating diseases related to abnormal activation of signal caused by JAK2 functional gain mutation, and has wide application prospect.Formula I.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a diazaindole compound, a pharmaceutical composition, and its uses. Background Technology

[0002] JAK2 is an important non-receptor tyrosine kinase in the human body, participating in the transduction of various cytokines and regulating key processes such as cell proliferation, differentiation, and immune regulation. Abnormal and persistent activation of JAK2 can lead to signaling pathway disorders and is an important cause of various proliferative, inflammatory, and immune diseases. Therefore, JAK2 is a key target for targeted drug development.

[0003] The JAK2 protein contains seven homologous domains, JH1-JH7, among which the JH1 kinase domain and the JH2 pseudokinase domain are the core regions regulating its activity. JH1 (residues 836-1132) is a classical kinase domain, possessing an ATP-binding site and a kinase catalytic active site. It can activate JAK2 kinase through autophosphorylation, mediating the phosphorylation cascade of downstream signaling molecules, and is the main site of action for traditional targeted inhibitors. JH2 (residues 543-824) is a pseudokinase domain without catalytic activity. It does not possess independent kinase catalytic function, but JH2 can inhibit the kinase catalytic activity of JH1 through specific intermolecular interactions with the JH1 domain, preventing abnormal activation of the pathway and maintaining JAK2 signaling homeostasis.

[0004] The V617F mutation in the JH2 domain is the most common pathogenic activating mutation of JAK2. This mutation alters the spatial conformation of JH2, disrupts its inhibitory effect on JH1, and continuously activates JH1 kinase activity, leading to overactivation of the JAK2 signaling pathway and ultimately driving disease development and progression.

[0005] Currently, most mainstream JAK2 inhibitors in clinical practice are ATP-competitive inhibitors targeting JH1. Due to the highly conserved amino acid sequences and extremely high structural similarity of the JH1 kinase domain in various JAK family subtypes (JAK1, JAK2, TYK2, etc.), these drugs struggle to achieve subtype-specific inhibition of JAK2, generally exhibiting broad-spectrum inhibitory effects. While inhibiting JAK2, they interfere with JAK1 / TYK2-mediated normal immune and hematopoietic signaling, leading to hematologic and immunotoxic effects such as anemia, thrombocytopenia, herpes zoster, and pulmonary infections. Some drugs also exhibit significant neurotoxicity and cardiovascular adverse reactions, resulting in limited overall drug safety. Furthermore, long-term use of JH1-targeting inhibitors easily leads to drug resistance mutations in the ATP binding pocket, causing drug binding failure and reduced efficacy, failing to meet long-term treatment needs. The high toxicity, poor specificity, and susceptibility to drug resistance significantly limit the clinical applicability and therapeutic efficacy of existing JAK2 inhibitors. Developing highly selective JAK2 inhibitors with low toxicity and high efficacy is the current research trend.

[0006] Compared to traditional JAK2 kinase domain binding drugs, JH2 allosteric inhibitors have advantages such as high selectivity, low toxicity, and low drug resistance. Therefore, developing novel allosteric compounds targeting the JAK2 JH2 domain is the key to achieving low-toxicity and highly effective targeted therapy, and has important research value and clinical application prospects. Summary of the Invention

[0007] The purpose of this invention is to provide a diazaindole compound, a pharmaceutical composition, and its use.

[0008] This invention provides a compound or a pharmaceutically acceptable form thereof, the structure of which is: Formula I; R1 is selected from , , , , , , , , , , 、Being R 3c The 6-10 aryl groups that are replaced by R 3d Substituted or unsubstituted 5-6 membered heteroaryl groups; R 3a R 3b Independently selected from 0 to 6 R 4a The following groups are substituted: C1-C6 alkyl, 3-6 membered cycloalkyl, -(CH2) n1 -O-(CH2) n2-(CH3) n3 -(CH2) n4 -C(CH3)2O-X, 4~7-membered heterocyclic alkyl, 6~10-membered aryl, 5~10-membered heteroaryl, 5~10-membered spirocyclic alkyl, 6~10-membered bridged cycloalkyl, 6~10-membered heterobridged cycloalkyl, 6~10-membered heterospirocyclic alkyl; n1, n2, n4 are independently selected from integers 0~5, n3 is selected from integers 1~3; X is selected from H, C1~C6 alkyl; R 3c Selected from -SO2R 7a -CONHOR 7a -SO2N(R) 7a R 7b ), -N(R 7a SOR 7b -N(R) 7a COR 7b -NHCON(R) 7a R 7b -COOR 7a -N(R) 7a (CH2) n5 COR 7b -N(R) 7a (CH2) n5 COOR 7b , , , ; R 3d Selected from deuterium, halogen, cyano, amino, and R 3e Substituted or unsubstituted C1-C6 alkyl groups, R 3e Substituted or unsubstituted C1-C6 hydroxyalkyl groups, R 3e Substituted or unsubstituted 3- to 6-membered cycloalkyl groups, R 3e Substituted or unsubstituted 4-7 membered heterocyclic alkyl groups, R 3e Substituted or unsubstituted 6-10 aryl groups, R 3e Substituted or unsubstituted 5-10 aryl groups, R 3e Substituted or unsubstituted 5-10 membered spirocycloalkyl groups, R 3e Substituted or unsubstituted 6- to 10-membered bridged cycloalkyl groups, R 3e Substituted or unsubstituted 6- to 10-membered heterobridged cycloalkyl groups, R 3e Substituted or unsubstituted 6- to 10-membered heterospirocycloalkyl groups; R is selected from hydrogen, deuterium, halogen, cyano, amino, C1-C6 alkyl substituted or unsubstituted with R5, 3-6 membered cycloalkyl substituted or unsubstituted with R5, 4-7 membered heterocycloalkyl substituted or unsubstituted with R5, 6-10 membered aryl substituted or unsubstituted with R5, 5-10 membered heteroaryl substituted or unsubstituted with R5, 5-10 membered spirocycloalkyl substituted or unsubstituted with R5, 6-10 membered bridged cycloalkyl substituted or unsubstituted with R5, 6-10 membered heterobridged cycloalkyl substituted or unsubstituted with R5, and 6-10 membered heterospirocycloalkyl substituted or unsubstituted with R5. Ring B is selected from 3-6 membered cycloalkyl groups substituted or unsubstituted with R6, 4-7 membered heterocycloalkyl groups substituted or unsubstituted with R6, 6-10 membered aryl groups substituted or unsubstituted with R6, 5-10 membered heteroaryl groups substituted or unsubstituted with R6, 5-10 membered spirocycloalkyl groups substituted or unsubstituted with R6, 6-10 membered bridged cycloalkyl groups substituted or unsubstituted with R6, 6-10 membered heterobridged cycloalkyl groups substituted or unsubstituted with R6, and 6-10 membered heterospirocycloalkyl groups substituted or unsubstituted with R6. R 3e R 4a R5 and R6 are independently selected from deuterium, halogens, cyano groups, and -OR groups. 7a -SO2R 7a -N(R) 7a R 7b -COR 7a -CON(R) 7a R 7b ), -CONHOR 7a -SO2N(R) 7a R 7b ), -N(R 7a SOR 7b -N(R) 7a COR 7b -NHCON(R) 7a R 7b -COOR 7a -N(R) 7a (CH2) n5 COR 7b -N(R) 7a (CH2) n5 COOR 7b , , , C1-C6 alkyl groups substituted or unsubstituted with R7, 3-6 membered cycloalkyl groups substituted or unsubstituted with R7, 4-7 membered heterocycloalkyl groups substituted or unsubstituted with R7, 6-10 membered aryl groups substituted or unsubstituted with R7, 5-10 membered heteroaryl groups substituted or unsubstituted with R7, 5-10 membered spirocycloalkyl groups substituted or unsubstituted with R7, 6-10 membered bridged cycloalkyl groups substituted or unsubstituted with R7, 6-10 membered heterobridged cycloalkyl groups substituted or unsubstituted with R7, and 6-10 membered heterospirocycloalkyl groups substituted or unsubstituted with R7. n5 is selected from integers between 0 and 3; R 7a R 7b Independently selected from hydrogen, C1-C6 alkyl groups substituted or unsubstituted with R8, 3-6 membered cycloalkyl groups substituted or unsubstituted with R8, 4-7 membered heterocycloalkyl groups substituted or unsubstituted with R8, 6-10 membered aryl groups substituted or unsubstituted with R8, 5-10 membered heteroaryl groups substituted or unsubstituted with R8, 5-10 membered spirocycloalkyl groups substituted or unsubstituted with R8, 6-10 membered bridged cycloalkyl groups substituted or unsubstituted with R8, 6-10 membered heterobridged cycloalkyl groups substituted or unsubstituted with R8, and 6-10 membered heterospirocycloalkyl groups substituted or unsubstituted with R8; or, R 7a and R 7b The atoms attached to them form the following groups: 4-7 membered heterocyclic alkyl groups substituted or unsubstituted with R9, and 6-10 membered spirocyclic alkyl groups substituted or unsubstituted with R9; R7, R8, and R9 are independently selected from deuterium, halogen, hydroxyl, amino, cyano, C1-C4 alkyl, C1-C4 deuterated alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 deuterated alkoxy, C1-C4 haloalkoxy, 3-4 membered cycloalkyl, and 4-6 membered heterocycloalkyl. R2 is selected from R 2a Substituted or unsubstituted C1-C4 alkyl groups, R 2a Substituted or unsubstituted 3- to 4-membered cycloalkyl groups; R 2a Selected from deuterium or halogens; The heteroatom in the heterocyclic alkyl, heteroaryl, heterobridged cycloalkyl, and heterospirocycloalkyl is selected from at least one of N, O, and S.

[0009] Furthermore, R1 is selected from , , , , , , , , , , 、Being R 3c Substituted phenyl, R3d Substituted or unsubstituted 5-6 membered heteroaryl groups; R 3a R 3b Independently selected from 0 to 3 R 4a The following groups are substituted: C1-C6 alkyl, 3-6 membered cycloalkyl, -(CH2) n1 -O-(CH2) n2 -(CH3) n3 -(CH2) n4 -C(CH3)2O-X, 4-6 membered heterocyclic alkyl, phenyl, 5-6 membered heteroaryl; n1, n2, n4 are independently selected from integers 0-3, n3 is selected from integers 1-3; X is selected from H, C1-C3 alkyl; R 3c Selected from -SO2R 7a -CONHOR 7a -SO2N(R) 7a R 7b ), -N(R 7a SOR 7b -N(R) 7a COR 7b -NHCON(R) 7a R 7b -COOR 7a -N(R) 7a (CH2) n5 COR 7b -N(R) 7a (CH2) n5 COOR 7b , , , ; R 3d Selected from deuterium, halogen, cyano, amino, and R 3e Substituted or unsubstituted C1-C3 alkyl groups, R 3e Substituted or unsubstituted C1~C3 hydroxyalkyl groups, R 3e Substituted or unsubstituted 3- to 6-membered cycloalkyl groups, R 3e Substituted or unsubstituted 4-6 membered heterocyclic alkyl groups, R 3e Substituted or unsubstituted phenyl, R 3e Substituted or unsubstituted 5-6 membered heteroaryl groups; R is selected from hydrogen, deuterium, halogen, cyano, amino, C1-C3 alkyl group substituted or unsubstituted with R5, 3-6 membered cycloalkyl group substituted or unsubstituted with R5, 4-6 membered heterocycloalkyl group substituted or unsubstituted with R5, phenyl group substituted or unsubstituted with R5, and 5-6 membered azaaryl group substituted or unsubstituted with R5. Ring B is selected from 3-6 membered cycloalkyl groups substituted or unsubstituted with R6, 4-6 membered heterocycloalkyl groups substituted or unsubstituted with R6, phenyl groups substituted or unsubstituted with R6, and 5-6 membered heteroaryl groups substituted or unsubstituted with R6. R 3e R 4a R5 and R6 are independently selected from deuterium, halogens, cyano groups, and -OR groups. 7a -SO2R 7a -N(R) 7a R 7b -COR 7a -CON(R) 7a R 7b ), -CONHOR 7a -SO2N(R) 7a R 7b ), -N(R 7a SOR 7b -N(R) 7a COR 7b -NHCON(R) 7a R 7b -COOR 7a -N(R) 7a (CH2) n5 COR 7b -N(R) 7a (CH2) n5 COOR 7b , , , C1-C3 alkyl groups substituted or unsubstituted with R7, 3-6 membered cycloalkyl groups substituted or unsubstituted with R7, 4-6 membered heterocycloalkyl groups substituted or unsubstituted with R7, phenyl groups substituted or unsubstituted with R7, and 5-6 membered heteroaryl groups substituted or unsubstituted with R7. n5 is selected from integers between 0 and 1; R 7a R 7b It is independently selected from hydrogen, C1-C3 alkyl groups substituted or unsubstituted with R8, 3-6 membered cycloalkyl groups substituted or unsubstituted with R8, 4-6 membered heterocycloalkyl groups substituted or unsubstituted with R8, phenyl groups substituted or unsubstituted with R8, and 5-6 membered heteroaryl groups substituted or unsubstituted with R8. R7 and R8 are independently selected from deuterium, halogen, hydroxyl, amino, cyano, C1~C3 alkyl, C1~C3 deuterated alkyl, C1~C3 haloalkyl, C1~C3 hydroxyalkyl, C1~C3 alkoxy, C1~C3 deuterated alkoxy, C1~C3 haloalkoxy, 3~4 membered cycloalkyl, and 4~6 membered heterocycloalkyl. R2 is selected from R 2aSubstituted or unsubstituted C1-C3 alkyl groups, R 2a Substituted or unsubstituted 3- to 4-membered cycloalkyl groups; R 2a Selected from deuterium or halogens; The heterocyclic alkyl, heteroaryl, heterobridged cycloalkyl, and heterospirocycloalkyl groups contain 1 to 3 heteroatoms.

[0010] The structure of the compound is further described as follows: Formula II; R1 and R2 are as described above; R is a 5-membered nitrogen-containing heteroaryl group substituted with 0 to 3 R5 groups; the 5-membered nitrogen-containing heteroaryl group is: ; R5 is selected from deuterium, halogen, cyano, and -OR. 7a C1-C3 alkyl groups substituted with R7 or unsubstituted; R 7a R7 is as described above.

[0011] Furthermore, R1 is selected from , , , 、Being R 3c Substituted phenyl, R 3d Substituted or unsubstituted 5-membered heteroaryl groups; R 3a R 3b Independently selected from 0 to 3 R 4a The following groups are substituted: C1-C5 alkyl, 3-6 membered cycloalkyl, -CH2OCH3, -OCH3, -C(CH3)2OH, -C(CH3)2OCH3, phenyl, 5-6 membered heteroaryl; R 3c Selected from -SO2R 7a ; R 3d Selected from deuterium, halogen, cyano, amino, and R 3e Substituted or unsubstituted C1-C3 alkyl groups, R 3e Substituted or unsubstituted C1-C3 hydroxyalkyl groups; R 3e R 4a Independently selected from deuterium, halogen, cyano, C1-C3 alkyl group substituted or unsubstituted with R7, 3-6 membered cycloalkyl group substituted or unsubstituted with R7, 4-6 membered heterocycloalkyl group substituted or unsubstituted with R7, phenyl group substituted or unsubstituted with R7, and 5-6 membered heteroaryl group substituted or unsubstituted with R7. R 7a R 7bIndependently selected from hydrogen, C1-C3 alkyl groups substituted with R8 or unsubstituted; R7 and R8 are independently selected from deuterium, halogen, hydroxyl, amino, cyano, C1~C3 alkyl, C1~C3 deuterated alkyl, C1~C3 haloalkyl, C1~C3 hydroxyalkyl, C1~C3 alkoxy, C1~C3 deuterated alkoxy, and C1~C3 haloalkoxy. R2 is selected from R 2a Substituted or unsubstituted C1-C3 alkyl groups; R 2a Selected from deuterium or halogens; R can be selected from any of the following structures: , , , .

[0012] Furthermore, the structure of the compound is any one of the following: .

[0013] The present invention also provides a pharmaceutical composition which is prepared by adding a pharmaceutically acceptable excipient or carrier to a compound or a pharmaceutically acceptable form thereof as an active ingredient.

[0014] The present invention also provides the use of the compound or a pharmaceutically acceptable form thereof in the preparation of a JAK2 JH2 allosteric inhibitor; or, in the preparation of a medicament for treating diseases associated with abnormal signal activation caused by JAK2 gain-of-function mutations.

[0015] Furthermore, the JAK2 gain-of-function mutation is the V617F mutation.

[0016] Furthermore, the relevant diseases include immune diseases, inflammatory diseases, solid tumors, and / or hematologic malignancies.

[0017] Further, the immune-related diseases include psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjögren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, polymyositis, dermatomyositis, periarteritis nodosa, mixed connective tissue disease, scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I diabetes, type II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, Addison's disease, aberrant immune response, arthritis, dermatitis and / or radiation dermatitis; the inflammatory-related diseases include inflammatory bowel disease, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome, postoperative or post-traumatic inflammation, lung Inflammation, nephritis, meningitis, cystitis, pharyngitis, gastric mucosal injury, meningitis, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary embolism, silicosis and / or pulmonary sarcoidosis; the solid tumors include lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic lymphoma, lymphoplasmacytic lymphoma, ovarian cancer, breast cancer, prostate cancer, bladder cancer, kidney cancer, esophageal cancer, cervical cancer, pancreatic cancer, colorectal cancer, gastric cancer, non-small cell lung cancer, thyroid cancer. Adenocarcinoma, brain cancer, lymphoma, epidermal hyperplasia, psoriasis, prostate cancer and / or combinations thereof; the hematologic malignancies include acute myeloid leukemia, chronic myeloid leukemia, myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic neutrophilic leukemia, acute undifferentiated cell leukemia, myelodysplastic syndrome, myelodysplastic syndrome, myelofibrosis, multiple myeloma, spinal sarcoma and / or combinations thereof.

[0018] This invention synthesizes a novel class of diaza-indole compounds that can effectively inhibit JAK2. V617F It mediates non-cytokine-dependent proliferation, exhibits a high binding affinity to the JAK2-JH2 pseudokinase domain, and significantly inhibits JAK2-JH2 through allosteric regulation. V617F Mutation-mediated aberrant activation. Experiments have shown that, compared to compounds disclosed in the prior art, the compounds of this invention exhibit greater effectiveness in inhibiting Ba / F3 JAK2. V617F It significantly enhances cell proliferation while maintaining good affinity for JAK2-JH2. Furthermore, the compounds of this invention exhibit better oral pharmacokinetic properties than existing technologies, enabling effective target inhibition at lower doses, reducing dosing load and toxic side effects.

[0019] Furthermore, in vitro experiments have demonstrated that the compounds of this invention can downregulate Ba / F3 JAK2. V617F The compound inhibits the levels of p-JAK2 and p-STAT3 in cells, suppresses the JAK-STAT signaling pathway, induces apoptosis and cell cycle arrest, and inhibits tumor cell proliferation. In vivo experiments have demonstrated that the compound of this invention can effectively treat Ba / F3 JAK2. V617F Driven by malignant tumors.

[0020] The diazaindole compounds of this invention are JAK2-targeting compounds with proven in vivo efficacy, enabling highly selective and efficient prevention and / or treatment of diseases related to abnormal signal activation caused by JAK2 gain-of-function mutations, especially JAK2. V617F Mutation-related diseases have broad application prospects.

[0021] Terminology definition: Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0022] Pharmaceutically acceptable forms include pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope-labeled substances, metabolites, or prodrugs.

[0023] The terms “a,” “an,” “the,” “at least one,” and “one or more” are used interchangeably. For example, a composition of “a” pharmaceutically acceptable excipient can be interpreted as meaning that the composition includes “one or more” pharmaceutically acceptable excipients.

[0024] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. For example, "C1-C8" should be understood as encompassing any subrange and each point value within it, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, etc., as well as C1, C2, C3, C4, C5, C6, etc.; the expression "3~6 yuan" should be understood as encompassing any subrange and each point value within it, such as 3~4 yuan, 3~5 yuan, 3~6 yuan, 4~5 yuan, 4~6 yuan, etc., as well as 3, 4, 5, 6 yuan, etc.

[0025] In this invention, unless otherwise stated, halogen refers to fluorine, chlorine, bromine or iodine.

[0026] In this invention, unless otherwise stated, "alkyl" includes straight-chain or branched monovalent saturated hydrocarbon groups.

[0027] In this invention, unless otherwise stated, "cycloalkyl," "carbocyclic," or "cycloalkylene" refers to a saturated or partially saturated, monocyclic or polycyclic (e.g., bicyclic) non-aromatic hydrocarbon group. Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings, or spirocyclic groups, such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, bicyclic [5.2.0]nonyl, decahydronaphthyl, etc. For example, C3-C12 cycloalkyl refers to a cycloalkyl group having 3 to 12 cyclic carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). The cycloalkyl or cycloalkylene groups in this invention may optionally be substituted by one or more substituents described in this invention.

[0028] In this invention, unless otherwise stated, "haloalkyl" refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by a halogen. For example, the term "C1-C6 haloalkyl" refers to a C1-C6 alkyl group optionally substituted with one or more (e.g., 1-3) halogens. Those skilled in the art will understand that when there is more than one halogen substituent, the halogens can be the same or different, and can be located on the same or different C atoms.

[0029] In this invention, unless otherwise stated, "alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group having at least one C=C double bond.

[0030] In this invention, unless otherwise stated, "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents.

[0031] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include, but are not limited to, isotopes of hydrogen, such as deuterium (…). 2 H), tritium ( 3 H); carbon isotopes (e.g., ... 13 C and 14 C); isotopes of chlorine (such as...) 37 Cl); isotopes of iodine (e.g. 125 I); nitrogen isotopes (such as 13 N and 15 N); isotopes of oxygen (such as N); 17 O and 18 O); phosphorus isotopes (such as O); 32 P); and isotopes of sulfur (such as P); 34S).

[0032] In this invention, "polymorph" refers to different solid crystalline phases resulting from the presence of two or more different molecular arrangements in the solid state of certain compounds of this invention. Some compounds of this invention may exist in more than one crystal form, and this invention aims to include various crystal forms and mixtures thereof. Typically, crystallization produces solvates of the compounds of this invention. The term "solvate" as used in this invention refers to an aggregate comprising one or more molecules of the compound of this invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Therefore, the compounds of this invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and corresponding solvated forms. The compounds of this invention can form true solvates, but in some cases, they may also remain only as indeterminate water or a mixture of water and a portion of indeterminate solvent. The compounds of this invention can react in a solvent or precipitate or crystallize from a solvent. The solvates of the compounds of this invention are also included within the scope of this invention. This invention also covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0033] In this invention, "stereoisomer" refers to an isomer formed due to at least one asymmetric center. Compounds having one or more asymmetric centers can produce racemic mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of this invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). The scope of this invention covers all such isomers or mixtures thereof in any proportion.

[0034] In this invention, pharmaceutically acceptable salts include their acid addition salts and base addition salts. Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts; suitable base addition salts are formed by bases that form pharmaceutically acceptable salts. Methods for preparing pharmaceutically acceptable salts of the compounds of this invention are known to those skilled in the art. "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. These salts can be prepared by methods known in this patent. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. These salts can be prepared by methods known in this patent.

[0035] In this invention, unless otherwise stated, "ester" refers to an ester derived from the compounds described herein, including physiologically hydrolyzable esters (compounds of this invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of this invention may themselves be esters.

[0036] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0037] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form nitrogen oxides because nitrogen requires available lone pairs of electrons to be oxidized. Those skilled in the art will identify nitrogen-containing heterocycles capable of forming nitrogen oxides. They will also recognize that tertiary amines can form nitrogen oxides. Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid, hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and diethylene oxides such as dimethyldiethylene oxide. These methods for preparing nitrogen oxides have been extensively described and reviewed in the literature.

[0038] In this invention, "metabolite" refers to a substance formed in the body upon administration of a compound of the present invention. Metabolites of the compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of the present invention, including compounds obtained by methods that expose the compounds of the present invention to mammals for a time sufficient to produce their metabolites.

[0039] In this invention, a "prodrug" refers to certain derivatives of the compounds of the invention that, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that readily convert in vivo into the desired therapeutically active compounds. The prodrugs of the invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the invention with certain portions known to those skilled in the art as "pro-moiety," such as those described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985).

[0040] In this application, "pharmaceutical composition" refers to a formulation of the compounds of the present invention with a medium generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, promote the absorption of the active ingredient, and thereby exert its bioactivity.

[0041] In this application, "pharmaceuticalally acceptable excipients or carriers" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are permitted by the relevant government regulatory authorities or are acceptable for human or livestock use.

[0042] The term "drug combination" as used in this article refers to a drug obtained by mixing or combining one or more active ingredients, including fixed and non-fixed combinations of active ingredients.

[0043] In this invention, unless otherwise stated, "treatment" means reversing, alleviating, or inhibiting the progression of a disease or condition or one or more symptoms of such a disease or condition, or preventing such a disease or condition or one or more symptoms of such a disease or condition.

[0044] 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.

[0045] 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 embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0046] Figure 1 This is a graph showing the results of a Western blotting experiment detecting the inhibitory effect of the compound from Example 10 on the JAK2 signaling pathway in vitro.

[0047] Figure 2 Flow cytometry is used to detect the effect of compounds on the in vivo induction of Ba / F3 JAK2. V617F The experimental results of apoptosis are shown in the figures: control group, 250 nM compound of Example 10, 500 nM compound of Example 10, 1000 nM compound of Example 10, and 5000 M compound of Example 10.

[0048] Figure 3 The compound induces Ba / F3 JAK2 in vivo.V617F Cell cycle arrest diagrams are shown below: control group, 125 nM compound of Example 10, 250 nM compound of Example 10, 500 nM compound of Example 10, and 2500 nM compound of Example 10.

[0049] Figure 4 The compound treats Ba / F3 JAK2 in the body. V617F Experimental results of driving malignant tumors: A, B, and C are the spleen weight, body weight, and spleen morphology of mice in the model group, the 30 mg / kg Fed group, the 120 mg / kg compound group of Example 10, and the 60 mg / kg compound group of Example 10, respectively. Detailed Implementation

[0050] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0051] HPLC analysis was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfirc C18, 150 x 4.6 mm, 5 μm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18, 150 x 4.5 mm, 5 μm column). Qingdao Ocean GF254 silica gel plates were used for thin-layer chromatography (TLC). The silica gel plate size used for TLC was 0.15 mm to 0.2 mm, while 0.4 mm to 0.5 mm silica gel plates were used for TLC separation and purification. Column chromatography used Qingdao Ocean 100-200 and 200-300 mesh silica gel as the support. Unless otherwise specified in the specific implementation, all reactions were carried out under an argon or nitrogen atmosphere. Hydrogenation reactions were typically performed under vacuum, purged with hydrogen, and repeated three times.

[0052] Example 1: Synthesis and characterization of methyl((1R,3R)-3-(8-(cyclopentynyl)-3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (Ⅰ) (1) Synthesis and characterization of tert-butyl(1R,3R)-3-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate (Ⅰ-2) 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (Ⅰ-1, 5.0 g, 14.80 mmol), tert-butyl((1R,3R)-3-aminocyclopentyl)carbamate (3.26 g, 16.28 mmol), and triethylamine (4.13 mL, 29.61 mmol) were added to 80 mL of acetonitrile and stirred at 80 °C for 1 h. After the reaction was complete as detected by TLC, the solvent was evaporated to obtain the crude product. The crude product was then washed with water, filtered, and dried to obtain the target compound Ⅰ-2 in 94% yield.

[0053] 1 HNMR(400MHz,DMSO)δ8.05-7.98(m,2H),7.70-7.63(m,1H),7.60-7.52(m,3 H),7.47(d,J=4.2Hz,1H),6.99(d,J=7.7Hz,1H),6.83(d,J=4.3Hz,1H),5.25 (d,J=7.7Hz,1H),4.36(q,J=6.6Hz,1H),3.98(q,J=6.9Hz,1H),2.14-2.05(m ,1H),2.01-1.94(m,1H),1.85-1.76(m,2H),1.47-1.44(m,1H),1.38(s,9H). LC-MS calculated for C 23 H 28 N5O6S (M+H) + :m / z=502.2;found 502.2. (2) Synthesis and characterization of tert-butyl((1R,3R)-3-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate (Ⅰ-3) To a mixture of 100 mL methanol and 100 mL water, tert-butyl((1R,3R)-3-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate (Ⅰ-2, 7.0 g, 13.96 mmol), iron powder (7.0 g, 125.35 mmol), and ammonium chloride (7.0 g, 130.84 mmol) were added. The mixture was stirred at 85 °C for 6 hours. After the reaction was confirmed to be complete by TLC, the mixture was filtered through diatomaceous earth, washed and extracted with dichloromethane, the organic layer was concentrated, and the solvent was removed to obtain the crude product. The crude product was purified by column chromatography (eluent volume ratio: dichloromethane:methanol = 20:1) to obtain the target compound Ⅰ-3 in 91% yield.

[0054] LC-MS calculated for C23 H 30 N5O4S(M+H) + :m / z=472.2;found 472.3. (3) Synthesis and characterization of tert-butyl((1R,3R)-3-(2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (Ⅰ-4) tert-butyl((1R,3R)-3-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate (Ⅰ-3, 6.0 g, 12.72 mmol) and 1,1'-carbonyldiimidazole (CDI, 6.18 g, 38.17 mmol) were added to 80 mL of acetonitrile and stirred at 80 °C for 2 hours. After the reaction was confirmed to be complete by TLC, the mixture was concentrated under reduced pressure, and 30 mL of dichloromethane and 20 mL of water were added. The mixture was separated into layers in a separatory funnel. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (eluent volume ratio: petroleum ether: ethyl acetate = 3:1) to obtain the target compound Ⅰ-4 in 79% yield.

[0055] 1 HNMR(400MHz, CDCl3)δ10.02(s,1H),8.23(s,1H),8.19-8.15(m,2H),7.75(d,J=4.1Hz,1H), 7.58-7.51(m,1H),7.50-7.41(m,2H),6.68(d,J=4.2Hz,1H),5.11(p,J=9.0Hz,1H),4.39(s,1 H),2.61(dt,J=13.8,8.6Hz,1H),2.50-2.40(m,1H),2.30(ddd,J=17.9,10.5,6.2Hz,1H),2.1 7(dq,J=8.6,4.6Hz,1H),2.02(ddd,J=13.8,9.2,4.5Hz,1H),1.73-1.62(m,1H),1.47(s,9H). LC-MS calculated for C 24 H 27 N5O5S (M+H) + :m / z=498.18;found 498.18. (4) Synthesis and characterization of tert-butyl((1R,3R)-3-(3-methyl-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (Ⅰ-5) tert-butyl((1R,3R)-3-(2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (I-4, 5.0 g, 10.05 mmol) was dissolved in 60 mL of N,N-dimethylformamide (DMF). After dissolution, the solution was stirred in an ice-water bath. After cooling, sodium hydride (0.36 g, 15.07 mmol) was added. After reacting for 15 min, iodomethane (0.94 mL, 15.07 mmol) was added, and the mixture was then stirred at room temperature for 30 min. After TLC detection showed that the reaction was complete, a large amount of water was added, and a white solid precipitated. The solid was filtered, and the filter cake was dried to give the target compound I-5 in 78% yield.

[0056] 1 HNMR(400MHz, CDCl3)δ8.21-8.16(m,2H),8.09(s,1H),7.77(d,J=4.1Hz,1H),7.56(d,J=7.5H z,1H),7.48(dd,J=8.4,6.9Hz,2H),6.69(d,J=4.2Hz,1H),5.08(q,J=8.9Hz,1H),4.44-4.28(m ,1H),2.58(dt,J=13.8,8.6Hz,1H),2.49-2.39(m,1H),2.30(dq,J=13.1,9.1Hz,1H),2.14(dtd ,J=12.3,7.9,3.7Hz,1H),2.00(ddd,J=13.9,9.2,4.6Hz,1H),1.70-1.61(m,1H),1.45(s,9H). LC-MS calculated for C 25 H 26 D3N5O5S (M+H) + :m / z=515.2;found 515.2. (5) Synthesis and characterization of tert-butyl((1R,3R)-3-(7-bromo-3-methyl-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (Ⅰ-6) tert-butyl((1R,3R)-3-(3-methyl-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (I-5, 4.0 g, 7.82 mmol) was added to 100 mL of tetrahydrofuran (THF) solution. Nitrogen gas was purged three times, and the mixture was stirred at -78 °C for 10 minutes under nitrogen protection. After cooling, diisopropylaminolithium (LDA, 2.0 M in) was added. After stirring for 30 minutes, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (3.31 g, 10.16 mmol) in 10 mL of THF was added, and the reaction was stirred for another 40 minutes. After the reaction was complete as monitored by LC-MS, 100 mL of saturated NH4Cl solution was added, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to remove the solvent, yielding the crude product. The crude product was purified by column chromatography (eluent volume ratio: petroleum ether: ethyl acetate = 2:1) to obtain the target compound I-6 in 76% yield.

[0057] 1 HNMR(400MHz,DMSO)δ8.21(s,1H),8.06-8.03(m,1H),7.74-7.70(m,1H),7.66-7.61(m,4H),7.08(d,J=7.8Hz,1H),5.00(p,J=8.2Hz,1H),4.23 -4.10(m,1H),2.36(dd,J=13.7,7.2Hz,1H),2.21-2.03(m,3H),1.83(ddd,J=13.2,8.9,4.2Hz,1H),1.57(dq,J=13.1,7.4Hz,1H),1.40(s,9H). LC-MS calculated for C 25 H 25 D3BrN5O5S (M+H) + :m / z=593.1,595.1; found 593.2,595.1. (6) Synthesis and characterization of tert-butyl((1R,3R)-3-(3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (Ⅰ-7) To a mixture of 80 mL dioxane and 20 mL water, add tert-butyl((1R,3R)-3-(7-bromo-3-methyl-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (I-6, 3.50 g, 5.93 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (1.85 g, 8.8 mmol). 9 mmol), cesium carbonate (5.79 g, 17.78 mmol), and Pd(Ph3P)4 (1.37 g, 1.18 mmol) were added, and the mixture was purged with nitrogen three times. The mixture was stirred at 102 °C for 3 h under nitrogen protection. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, thus obtaining the crude product. The crude product was purified by column chromatography (eluent volume ratio: petroleum ether: ethyl acetate = 2:1) to obtain the target compound I-7 in 57% yield.

[0058] LC-MS calculated for C 29 H 33 N7O5S (M+H) + :m / z=592.23;found 592.23. (7) Synthesis and characterization of tert-butyl((1R,3R)-3-(8-bromo-3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (I-8) Tert-butyl((1R,3R)-3-(3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (I-7, 2.0 g, 3.38 mmol) was added to anhydrous dichloromethane (DCM) solution and stirred in an ice bath for 10 minutes. After cooling, bromine (0.19 mL, 3.72 mmol) was added and stirred for 15 minutes. After TLC detection of complete reaction, saturated NaHCO3 solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated to remove the solvent and obtain crude product. The crude product was purified by column chromatography (eluent volume ratio: petroleum ether: ethyl acetate = 2:1) to obtain target compound I-8 in 80% yield.

[0059] 1HNMR(400MHz,Chloroform-d)δ8.77(s,1H),7.93(d,J=0.6Hz,1H),7.77-7.72(m,2H),7 .67-7.61(m,1H),7.49-7.43(m,3H),4.58-4.51(m,1H),4.37(d,J=7.5Hz,1H),3.99(ddd dd,J=7.9,5.2,3.6,1.8,0.8Hz,1H),3.92(s,3H),3.55(s,3H),2.15-2.00(m,2H),2.00 -1.89(m,2H),1.87-1.80(m,1H),1.69(ddtd,J=13.5,7.1,5.3,1.8Hz,1H),1.41(s,9H). (8) Synthesis and characterization of 1-((1R,3R)-3-aminocyclopentyl)-8-bromo-3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrole[2,3-b]pyridin-2(1H)-one (Ⅰ-9) 10 mL of trifluoroacetic acid was added to a 30.0 mL solution of tert-butyl((1R,3R)-3-(8-bromo-3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (I-8, 1.80 g, 2.68 mmol) in dichloromethane, and the reaction was stirred for 30 minutes. After the reaction was confirmed to be complete by TLC, the mixture was concentrated, and the concentrate was dissolved in 40 mL of dichloromethane and 20 mL of water. Then, excess saturated NaHCO3 solution was added and the mixture was stirred for another 10 minutes. The mixture was then separated, the organic phase was dried and concentrated, and the solvent was removed to obtain the target compound I-9, which could be used directly for the next reaction without purification.

[0060] LC-MS calculated for C 24 H 24 BrN7O3S (M+H) + :m / z=570.09,572.08;found570.09,572.08. (9) Synthesis and characterization of methyl[(1R,3R)-3-(8-bromo-3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl]carbamate (Ⅰ-10) 1-((1R,3R)-3-aminocyclopentyl)-8-bromo-3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (Ⅰ-9, 1.50 g, 2.63 mmol), triethylamine (0.91 mL, 6.57 mmol), and dimethyl dicarbonate (0.42 mL, 3.94 mmol) were added to 60 mL of dichloromethane solution. The mixture was stirred at room temperature for 10 minutes. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated to remove the solvent, yielding a crude product. The crude product was purified by column chromatography (eluent volume ratio: petroleum ether: ethyl acetate = 3:1) to give the target compound Ⅰ-10 in 70% yield.

[0061] 1 HNMR(400MHz, CDCl3)δ7.72(s,1H),7.57(s,1H),7.35(d,J=7.9Hz,2H),7.21-7. 10(m,2H),7.03(t,J=7.7Hz,2H),6.64(d,J=6.9Hz,1H),5.37-5.14(m,1H),3.70( q,J=6.9Hz,1H),3.46(s,3H),2.98(s,3H),2.85(s,3H),1.88(dt,J=13.8,7.3Hz ,1H),1.66-1.51(m,3H),1.38(ddd,J=13.5,10.0,6.5Hz,1H),1.02-0.89(m,1H). LC-MS calculated for C 26 H 26 BrN7O5S (M+H) + :m / z=628.09,630.09;found628.09,630.09. (10) Synthesis and characterization of methyl[(1R,3R)-3-(8-(cyclopentylethynyl)-3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl]carbamate (Ⅰ) To a mixture of 6 mL dioxane and 2 mL water, add methyl[(1R,3R)-3-(8-bromo-3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl]carbamate (I-10, 100.0 mg, 0.16 mmol), 2-(cyclopentylethynyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborheptanane (52 mg, 0.24 mmol), cesium carbonate (155.2 mg, 0.47 mmol), and Pd(Ph3P)4 (18.4 mg, 0.16 mmol). The reaction mixture was 0.16 mmol of methanol and NaOH (250 mg, 6.36 mmol) purged with nitrogen three times and stirred at 102 °C for 1.5 h under nitrogen protection. After TLC detection of complete reaction, 5 mL of methanol and NaOH (250 mg, 6.36 mmol) were added, and the mixture was stirred at 80 °C for 15 min to remove the protecting group. After TLC detection of complete reaction, saturated sodium chloride solution was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated to remove the solvent, yielding a concentrate. The concentrate was purified by column chromatography (eluent volume ratio: petroleum ether: ethyl acetate = 1:1) to obtain a crude product. The crude product was diluted with a mixed solution of acetonitrile and water (volume ratio: acetonitrile: water = 2:1), and ammonia was added to adjust the pH to 9. Then, Agilent 1260 was used for further analysis. Purification was performed using an Infinity II high-performance preparative liquid chromatograph (Welch Xtimate C18 column, with a 57% gradient elution of acetonitrile and water containing 0.1% ammonia (volume ratio: acetonitrile:water = 10:1), at a flow rate of 40 mL / min) to obtain the target compound I in 8% yield.

[0062] LC-MS calculated for C 27 H 31 N7O3(M+H) + :m / z=502.2;found 502.2. 1HNMR(400MHz,DMSO-d6)δ12.16(s,1H),8.32(s,1H),8.20(s,1H),8.06(s,1H),7.26(d,J=7.1Hz, 1H),6.20-6.10(m,1H),4.40(t,J=7.6Hz,1H),3.93(s,3H),3.53(s,3H),3.38(s,3H),3.06(t,J=7 .5Hz,1H),2.35(ddd,J=13.0,8.1,4.2Hz,1H),2.17(q,J=7.1,6.3Hz,3H),2.09(tt,J=8.1,4.0Hz ,2H),1.95(dd,J=12.7,9.3Hz,1H),1.81-1.75(m,2H),1.73-1.61(m,4H),1.46(d,J=10.9Hz,1H). Example 2: Preparation and characterization of methyl((1R,3R)-3-(3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-8-(thiophen-2-ylethynyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate Referring to Example 1, the only difference is that in step (10), 2-(cyclopentylethynyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborheptanane is replaced with 4,4,5,5-tetramethyl-2-(thiophen-2-ylethynyl)-1,3,2-dioxaborheptanane; yield 9%.

[0063] The structural formula is: .

[0064] LC-MS calculated for C 26 H 25 N7O3S (M+H) + :m / z=516.2;found 516.3. 1HNMR(400MHz,DMSO-d6)δ12.46(s,1H),8.36(s,1H),8.20(s,1H),8.12(s,1H),7.67(dd,J=5.1,1.1Hz ,1H),7.44(dd,J=3.6,1.2Hz,1H),7.17(dd,J=5.2,3.6Hz,1H),7.13(d,J=7.3Hz,1H),6.11-5.93(m,1H ),4.38(h,J=8.2Hz,1H),3.95(s,3H),3.50(s,3H),3.40(s,3H),2.37(ddd,J=12.6,8.3,3.7Hz,1H),2 .27-2.12(m,2H),2.09(dd,J=11.9,6.1Hz,1H),1.94(dt,J=13.5,10.5Hz,1H),1.33(p,J=10.6Hz,1H). Example 3: Preparation and characterization of methyl((1R,3R)-3-(3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-8-(thiophen-2-ylethynyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate Referring to Example 1, the only difference is that in step (10), 2-(cyclopentylethynyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborheptanane is replaced with 2-(3-methoxypropynyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborheptanane; yield 9%.

[0065] The structural formula is: .

[0066] LC-MS calculated for C 25 H 29 N7O4(M+H) + :m / z=492.2;found 492.2. 1HNMR(400MHz,DMSO)δ12.42(s,1H),8.36(s,1H),8.15(s,1H),7.88(s,1H) ,7.28(d,J=6.7Hz,1H),5.56-5.47(m,1H),5.46(s,1H),4.53(s,3H),4.31- 4.22(m,1H),3.49(s,3H),3.37(s,3H),2.62(dt,J=13.5,7.5Hz,1H),2.34- 2.17(m,3H),1.99(ddd,J=13.3,9.8,6.8Hz,1H),1.72(s,6H),1.62(m,1H). 13 CNMR(101MHz,DMSO-d6)δ156.75,152.85,148.95,138.22,131.55,131.27,130.83,126.23,124.64,121.4 9,118.65,113.12,108.23,99.72,71.25,55.93,52.13,51.58,43.08,36.29,32.55,32.48,30.23,27.56. Example 4. Synthesis and characterization of methyl((1R,3R)-3-(8-(((E)-3-hydroxy-3-methylbut-1-en-1-yl)-3-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (II) ; (1) Synthesis and characterization of tert-butyl((1R,3R)-3-(3-(methyl-d3)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (Ⅱ-2) tert-butyl((1R,3R)-3-(2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (II-1, 6.0 g, 12.06 mmol) was dissolved in 50 mL of DMF, sonicated until dissolved, and then stirred in an ice-water bath. After cooling, sodium hydride (0.72 g, 18.10 mmol) was added, and the reaction was carried out for 15 min. Then, deuterated iodomethane (0.97 mL, 15.69 mmol) was added, and the mixture was then transferred to room temperature and stirred for 30 min. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and a white solid precipitated. The solid was filtered, and the filter cake was dried to give the target compound II-2 in 80% yield.

[0067] 1 HNMR(404MHz,Chloroform-d)δ8.78(s,1H),7.84-7.79(m,2H),7.68-7.61(m,1H),7.49-7.43(m,2H),7.39(d,J=7.2Hz,1H),7.34(s,1H),4.61- 4.53(m,1H),4.37(d,J=7.5Hz,1H),4.04-3.95(m,1H),3.54(s,3H),2.1 7-2.03(m,2H),1.99-1.91(m,2H),1.90-1.78(m,1H),1.74-1.66(m,1H). (2) Synthesis and characterization of tert-butyl((1R,3R)-3-(7-bromo-3-(methyl-d3)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (Ⅱ-3) tert-butyl((1R,3R)-3-(3-(methyl-d3)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (II-2, 5.0 g, 8.44 mmol) was added to 110 mL of tetrahydrofuran solution, and then nitrogen was purged three times. The mixture was stirred at -78 °C for 10 minutes under nitrogen protection. After cooling, LDA (2.0 M in THF, 10.55 mL, 21.11 mmol) was injected. After stirring for 30 minutes, a THF solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (4.07 g, 12.66 mmol) (10 mL) was injected. Continue stirring for 40 minutes; after the reaction is complete as monitored by LC-MS, inject 100 mL of saturated NH4Cl solution; extract the mixture with ethyl acetate, dry the organic phase with anhydrous sodium sulfate and concentrate it to remove the solvent to obtain the crude product; purify the crude product by column chromatography (eluent volume ratio: petroleum ether: ethyl acetate = 3:1) to obtain the target compound II-3, with a yield of 79%.

[0068] 1 HNMR(404MHz,Chloroform-d)δ8.78(s,1H),7.77-7.71(m,2H),7.69-7.62(m,1H),7.50-7.44(m,2H),4.62-4.50(m,1H) ,4.37(d,J=7.5Hz,1H),4.05-3.95(m,1H),2.16-2.03(m,2H),1.99-1.89(m,2H),1.88-1.80(m,1H),1.76-1.64(m,1H). (3) Synthesis and characterization of tert-butyl((1R,3R)-3-(3-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (II-4) Add tert-butyl((1R,3R)-3-(7-bromo-3-(methyl-d3)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (II-3, 4.50 g, 7.59 mmol) and 1-(methyl-d3)-4-((4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)ethynyl)-1H-pyrazole (2) to a mixed solvent of 80 mL dioxane and 20 mL water. 32 g (9.87 mmol), cesium carbonate (7.42 g, 22.80 mmol), and Pd(Ph3P)4 (1.75 g, 1.52 mmol) were added, and the mixture was purged with nitrogen three times. The mixture was stirred at 102 °C for 3 h under nitrogen protection. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, thus obtaining the crude product. The crude product was purified by column chromatography (eluent volume ratio: petroleum ether: ethyl acetate = 2:1) to obtain the target compound II-4 in 66% yield.

[0069] 1 HNMR(404MHz,Chloroform-d)δ8.77(s,1H),7.81(s,1H),7.77-7.72(m,2H),7. 68-7.62(m,1H),7.61(s,1H),7.50-7.42(m,2H),4.61-4.51(m,1H),4.37(d,J= 7.5Hz,1H),3.99(ddddd,J=7.9,5.2,3.6,1.9,0.8Hz,1H),2.17-2.05(m,2H),1 .99-1.88(m,2H),1.83(dddd,J=12.8,7.4,4.4,1.7Hz,1H),1.75-1.64(m,1H). (4) Synthesis and characterization of tert-butyl((1R,3R)-3-(8-bromo-3-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (II-5) Tert-butyl((1R,3R)-3-(3-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (II-4, 3.0 g, 5.02 mmol) was added to 80 mL of anhydrous DCM solution and stirred in an ice-water bath for 10 minutes. After cooling, bromine (0.28 mL, 5.52 mmol) was added and stirred for 10 minutes. After the reaction was confirmed to be complete by TLC, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with DCM, and the organic phase was dried and concentrated to remove the solvent and obtain the crude product. The crude product was purified by column chromatography (eluent volume ratio: petroleum ether: ethyl acetate = 2:1) to obtain the target compound II-5, yield: 88%.

[0070] 1 HNMR(400MHz,DMSO)δ7.93(s,1H),7.76(d,J=0.7Hz,1H),7.60(d,J=1.4Hz,1H),7.48–7.42(m, 2H),7.28(d,J=0.8Hz,1H),7.17(dd,J=7.7,1.3Hz,1H),7.11(d,J=7.6Hz,1H),7.04(d,J=0.8H z,1H),6.78(s,1H),5.03(q,J=8.4Hz,1H),4.24-4.09(m,1H),2.38(dt,J=14.7,7.9Hz,1H),2. 23-2.06(m,3H),1.87(ddd,J=13.2,8.9,4.4Hz,1H),1.59(dt,J=11.4,6.3Hz,1H),1.40(s,9H). LCMS calculated for C 29 H 26 D6BrN7O5S (M+H) + :m / z=676.18,672.1422;found676.18,678.18. (5) Synthesis and characterization of 1-((1R,3R)-3-aminocyclopentyl)-8-bromo-3-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (II-6) 10 mL of trifluoroacetic acid was added to a DCM solution (10.0 mL) of tert-butyl((1R,3R)-3-(8-bromo-3-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (II-5, 3.0 g, 4.43 mmol), and the reaction was stirred for 30 minutes. After the reaction was confirmed to be complete by TLC, the mixture was concentrated. The concentrate was dissolved in 40 mL of dichloromethane and 20 mL of water, and then 50 mL of saturated NaHCO3 solution was added and the mixture was stirred for another 10 minutes. The mixture was separated, and the organic phase was dried and concentrated to remove the solvent, yielding the target compound II-6, which could be used directly for the next reaction without purification.

[0071] (6) Synthesis and characterization of methyl((1R,3R)-3-(8-bromo-3-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (II-7) 1-((1R,3R)-3-aminocyclopentyl)-8-bromo-3-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (II-6, 2.56 g, 4.43 mmol), triethylamine (1.22 mL, 8.86 mmol), and dimethyl dicarbonate (0.71 mL, 6.65 mmol) were added to 60 mL of anhydrous dichloromethane solution and stirred at room temperature for 10 minutes. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated to remove the solvent, yielding the crude product. The crude product was purified by column chromatography (eluent volume ratio: petroleum ether: ethyl acetate = 3:1) to give the target compound II-7, 2.0 g.

[0072] 1HNMR(400MHz,DMSO)δ8.27(s,1H),8.10(d,J=0.8Hz,1H),7.91-7.82(m,2H),7.7 7–7.64(m,2H),7.57(dd,J=8.4,7.3Hz,2H),7.18(d,J=7.1Hz,1H),5.91-5.74(m, 1H),4.23(q,J=7.0Hz,1H),3.51(s,3H),2.40(dt,J=13.7,7.2Hz,1H),2.21-2.07 (m,3H),1.90(ddd,J=13.2,10.0,6.3Hz,1H),1.50(ddd,J=12.0,9.5,4.7Hz,1H). LC-MS calculated for C 26 H 20 D6BrN7O5S (M+H) + :m / z=634.13,636.13;found634.13,636.13. (7) Methyl ((1) R ,3 R )-3-(8-(( E )-3-hydroxy-3-methylbut-1-en-1-yl)-3-(methyl- d 3)-7-(1-(methyl- d 3)-1 H -pyrazol-4-yl)-2-oxo-3,6-dihydroimidazo[4,5- d ]pyrrolo[2,3- b ]Pyridine-1(2 H Synthesis of 2-yl)cyclopentyl)carbamate (II) To a mixed solution of 6 mL dioxane and 3 mL water, add methyl((1R,3R)-3-(8-bromo-3-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (II-7, 100.0 mg, 0.16 mmol), (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (66.7 mg, 0.24 mmol), cesium carbonate (154.0 mg, 0.47 mmol), and Pd(Ph3) P)4 (18.2 mg, 0.016 mmol) was purged with nitrogen three times and stirred at 102 °C for 1.5 h under nitrogen protection. After the reaction was complete as determined by TLC, 5 mL of methanol and sodium hydroxide (250 mg, 6.36 mmol) were added, and the mixture was stirred at 80 °C for 15 min to remove the protecting group. After the reaction was complete as determined by TLC, saturated sodium chloride solution was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography to obtain the crude product. The crude product was diluted with a mixture of acetonitrile and water (volume ratio: acetonitrile:water = 2:1), and ammonia was added to adjust the pH to 9. The product was then purified using an Agilent 1260 Infinity II high-performance preparative liquid chromatograph (Welch Xtimate C18 column, with a mixture of acetonitrile and water containing 0.1% ammonia (volume ratio: acetonitrile:water = 10:1), 57% gradient elution, flow rate 40 mL / min) to obtain the target compound II in 7% yield.

[0073] LC-MS calculated for C 25 H 25 D6N7O4(M+H) + :m / z=500.2;found 500.3. 1HNMR(400MHz,DMSO-d6)δ11.77(s,1H),8.09(s,1H),8.03(s,1H),7.92(s,1H),7.19-7.13( m,1H),6.73(d,J=15.9Hz,1H),5.92(d,J=16.0Hz,1H),5.38(d,J=11.7Hz,1H),4.95(s,1H), 4.39-4.31(m,1H),3.52(s,3H),2.35(ddd,J=12.8,7.9,4.6Hz,1H),2.17-2.11(m,2H),2.0 7(d,J=8.2Hz,1H),1.87(ddd,J=13.4,10.5,7.8Hz,1H),1.48(d,J=8.6Hz,1H),1.33(s,6H). Example 5: Preparation and characterization of methyl((1R,3R)-3-(3-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-2-oxo-8-(pyridin-2-ylethynyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate Referring to Example 4, the only difference is that in step (7), (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane is replaced with 2-((4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)ethynyl)pyridine; yield 10%.

[0074] The structural formula is: .

[0075] LC-MS calculated for C 27 H 20 D6N8O3(M+H) + :m / z=517.2;found 517.2. 1HNMR(400MHz,DMSO-d6)δ8.64(d,J=4.9Hz,1H),8.52(s,1H),8.30(s,1H),8.07(s,1H), 7.87(t,J=7.7Hz,1H),7.55(d,J=7.9Hz,1H),7.43-7.34(m,2H),6.21-6.10(m,1H),4.3 8(h,J=7.6Hz,1H),3.49(s,3H),2.49-2.44(m,1H),2.28(ddd,J=15.3,12.0,5.7Hz,1H) ,2.18(dt,J=10.8,5.7Hz,2H),2.03(ddd,J=13.9,10.4,7.2Hz,1H),1.64-1.51(m,1H). Example 6. Preparation and characterization of methyl((1R,3R)-3-(3-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-2-oxo-8-(thiophen-3-ylethynyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate Referring to Example 4, the only difference is that in step (7), (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane is replaced with 4,4,5,5-tetramethyl-2-(thiophene-3-ylethynyl)-1,3,2-dioxaborhexacyclopentane; yield 12%.

[0076] The structural formula is: .

[0077] LC-MS calculated for C 26 H 19 D6N7O3S (M+H) + :m / z=522.2;found 522.2. 1HNMR(400MHz,DMSO-d6)δ8.37(s,1H),8.21(s,1H),8.08(s,1H),7.85(dd,J=2.9,1.3Hz,1H),7.6 8(dd,J=5.0,2.9Hz,1H),7.32(dd,J=5.0,1.2Hz,1H),7.14(d,J=7.3Hz,1H),6.11(dp,J=12.2,4. 0Hz,1H),4.48-4.31(m,1H),3.52(s,3H),2.38(ddd,J=12.7,8.2,3.9Hz,1H),2.16(qd,J=12.3,1 0.1,5.1Hz,2H),2.06(dd,J=12.1,6.2Hz,1H),1.96(dt,J=13.4,10.7Hz,1H),1.32-1.22(m,1H). Example 7. Preparation and characterization of methyl((1R,3R)-3-(3-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-2-oxo-8-(thiophen-2-ylethynyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate Referring to Example 4, the only difference is that in step (7), (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane is replaced with 4,4,5,5-tetramethyl-2-(thiophene-2-ylethynyl)-1,3,2-dioxaborhexacyclopentane; yield 11%.

[0078] The structural formula is: .

[0079] LC-MS calculated for C 26 H 19 D6N7O3S (M+H) + :m / z=522.2;found 522.2. 1HNMR(400MHz,DMSO-d6)δ8.33(s,1H),8.18(s,1H),8.07(s,1H),7.66-7.61 (m,1H),7.40(d,J=3.6Hz,1H),7.19-7.09(m,2H),6.02(qd,J=9.9,8.5,5.8H z,1H),4.39(h,J=8.2Hz,1H),3.50(s,3H),2.37(ddd,J=12.1,8.0,3.6Hz,1H ),2.27-2.05(m,3H),2.02-1.88(m,1H),1.34(qd,J=11.9,11.3,8.2Hz,1H). Example 8. Preparation and characterization of methyl((1R,3R)-3-(3-(methyl-d3)-8-((1-methyl-1H-imidazol-5-yl)ethynyl)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate Referring to Example 4, the only difference is that in step (7), (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane is replaced with 1-methyl-5-((4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)ethynyl)-1H-imidazolium; yield 6%.

[0080] The structural formula is: .

[0081] LC-MS calculated for C 26 H 21 D6N9O3(M+H) + :m / z=520.2;found 520.2. 1HNMR(400MHz,DMSO-d6)δ8.35(s,1H),8.17(s,1H),8.09(s,1H),7.79(s,1H),7.38(s, 1H),7.10(d,J=7.3Hz,1H),6.00(qd,J=8.3,3.8Hz,1H),4.32(h,J=8.3Hz,1H),3.71(s ,3H),3.50(s,3H),2.35(ddd,J=12.7,8.1,3.5Hz,1H),2.11(td,J=9.4,8.9,4.6Hz,2H ),2.01(dt,J=11.0,5.3Hz,1H),1.87(dt,J=13.5,10.4Hz,1H),1.09(t,J=10.4Hz,1H). Example 9, Methyl ((1) R ,3 R )-3-(3-(methyl- d 3)-7-(1-(methyl- d 3)-1 H -pyrazol-4-yl)-8-((5-methylthiophen-2-yl)ethynyl)-2-oxo-3,6-dihydroimidazo[4,5-] d ]pyrrolo[2,3- b ]Pyridine-1(2 H Preparation and characterization of 1-yl)cyclopentyl)carbamate Referring to Example 4, the only difference is that in step (7), (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane is replaced with 4,4,5,5-tetramethyl-2-((5-methylthiophen-2-yl)ethynyl)-1,3,2-dioxaborhexacyclopentane; yield 9%.

[0082] The structural formula is: .

[0083] LC-MS calculated for C 27 H 21 D6N7O3S (M+H) + :m / z=536.2;found 536.2. 1HNMR(400MHz,DMSO-d6)δ8.32(s,1H),8.19(s,1H),8.08(s,1H),7.22(d,J=3.6Hz,1H),7.12 (d,J=7.2Hz,1H),6.86(dd,J=3.6,1.3Hz,1H),6.02(dtd,J=11.9,8.2,3.8Hz,1H),4.39(h,J =8.1Hz,1H),3.52(s,3H),2.50(s,3H),2.37(ddt,J=12.2,7.8,3.9Hz,1H),2.16(dtd,J=33. 2,11.9,10.9,5.2Hz,3H),1.94(ddd,J=13.4,10.8,9.0Hz,1H),1.36(td,J=10.7,7.7Hz,1H). Example 10: Preparation and characterization of methyl((1R,3R)-3-(8-(3-hydroxy-3-methylbutynyl)-3-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate Referring to Example 4, the only difference is that in step (7), (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane is replaced with 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)but-3-yn-2-ol; yield 8%.

[0084] The structural formula is: .

[0085] LC-MS calculated for C 25 H 23 D6N7O4(M+H) + :m / z=498.2;found 498.2. 1HNMR(400MHz,DMSO-d6)δ12.47(s,1H),8.42(s,1H),8.21(s,1H),7.94(s,1H),7.34(d,J=6.8Hz,1H),5.56(q,J=8.2,7.5Hz,1H),4.34 -4.21(m,1H),3.75(s,1H),3.55(s,3H),2.74-2.64(m,1H),2.41-2.27(m,3H),2.09-2.02(m,1H),1.78(s,6H),1.69(d,J=8.2Hz,1H). Example 11: Preparation and characterization of methyl((1R,3R)-3-(8-(cyclopentylethynyl)-3-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate Referring to Example 4, the only difference is that in step (7), (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane is replaced with 2-(cyclopentylethynyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane; yield 9%.

[0086] The structural formula is: .

[0087] LC-MS calculated for C 27 H 25 D6N7O3(M+H) + :m / z=508.2;found 508.3. 1HNMR(400MHz,DMSO-d6)δ8.32(s,1H),8.20(s,1H),8.05(s,1H),7.26(d,J=7.1Hz,1H),6.15(dt d,J=11.9,7.9,3.9Hz,1H),4.39(q,J=7.6,7.1Hz,1H),3.53(s,3H),2.35(ddd,J=12.6,7.9,3.9H z,1H),2.22-2.13(m,3H),2.09(tt,J=7.8,3.8Hz,2H),1.94(dt,J=13.5,10.5Hz,1H),1.82-1.7 4(m,2H),1.75-1.67(m,2H),1.67-1.59(m,2H),1.46(td,J=15.8,8.9Hz,1H),1.33-1.25(m,1H). Example 12. Synthesis and characterization of methyl((1R,3R)-3-(7-(3-methoxy-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-8-(4-(methanesulfonyl)phenyl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate ; (1) Synthesis and characterization of tert-butyl((1R,3R)-3-(7-(3-methoxy-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (Ⅲ-2) Add tert-butyl((1R,3R)-3-(7-bromo-3-(methyl-d3)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (III-1, 3.0 g, 5.05 mmol) and 3-methoxy-1-(methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (1) to a mixed solvent of 80 mL dioxane and 20 mL water. 22 g (7.58 mmol), cesium carbonate (4.94 g, 15.16 mmol), and Pd(Ph3P)4 (1.17 g, 1.01 mmol) were added, and the mixture was purged with nitrogen three times. The mixture was stirred at 102 °C for 3 h under nitrogen protection. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, thus obtaining the crude product. The crude product was purified by column chromatography (eluent volume ratio: petroleum ether: ethyl acetate = 3:1) to obtain the target compound III-2 in 63% yield.

[0088] 1 HNMR(400MHz,Chloroform-d)δ8.76(s,1H),7.78-7.72(m,2H),7.69(s,1H),7.67-7.61(m,1H),7.51-7.42(m,2H),5.02(d,J=8.4Hz,1H),4.57-4.50(m ,1H),4.08-4.00(m,1H),3.69(s,3H),2.19-2.03(m,2H),1.94(dddd,J=13. 1,7.2,5.8,3.3Hz,2H),1.90-1.81(m,1H),1.74-1.64(m,1H),0.67(s,9H). (2) Synthesis and characterization of tert-butyl((1R,3R)-3-(8-bromo-7-(3-methoxy-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (Ⅲ-3) Tert-butyl((1R,3R)-3-(3-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-2-oxo-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (Ⅲ-2, 2.0 g, 3.18 mmol) was added to 80 mL of anhydrous DCM solution and stirred in an ice-water bath for 10 minutes. After cooling, bromine (0.18 mL, 3.50 mmol) was added and stirred for 10 minutes. After the reaction was confirmed to be complete by TLC, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with DCM, and the organic phase was dried and concentrated to remove the solvent to obtain the crude product. The crude product was purified by column chromatography (eluent volume ratio: petroleum ether: ethyl acetate = 2:1) to obtain the target compound Ⅲ-3 in 89% yield.

[0089] 1 HNMR(400MHz,Chloroform-d)δ8.77(s,1H),7.83(s,1H),7.77-7.72(m,2H),7.67-7.61(m,1H),7.50-7.38(m,2H),5.02(d,J=8.4Hz,1H),4 .59-4.47(m,1H),4.11-4.01(m,1H),3.98(s,3H),2.20-2.03(m,2H), 2.00-1.89(m,2H),1.89-1.78(m,1H),1.76-1.64(m,1H),0.67(s,9H). (3) Synthesis and characterization of 1-((1R,3R)-3-aminocyclopentyl)-8-bromo-7-(3-methoxy-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (Ⅲ-4) 10 mL of trifluoroacetic acid was added to a DCM solution (10.0 mL) of tert-butyl((1R,3R)-3-(8-bromo-7-(3-methoxy-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (Ⅲ-3, 2.0 g, 2.83 mmol), and the reaction was stirred for 30 minutes. After the reaction was confirmed to be complete by TLC, the mixture was concentrated, and the concentrate was dissolved in 40 mL of dichloromethane and 20 mL of water. Then, 50 mL of saturated NaHCO3 solution was added and the mixture was stirred for another 10 minutes. The mixture was separated, and the organic phase was dried and concentrated to remove the solvent, yielding the target compound Ⅲ-4, which was used directly for the next reaction without purification.

[0090] (4) Synthesis and characterization of methyl((1R,3R)-3-(8-bromo-7-(3-methoxy-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (Ⅲ-5) 1-((1R,3R)-3-aminocyclopentyl)-8-bromo-3-(methyl-d3)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-6-(benzenesulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (Ⅲ-4, 1.71 g, 2.83 mmol), triethylamine (0.78 mL, 5.66 mmol), and dimethyl dicarbonate (0.40 mL, 3.68 mmol) were added to 60 mL of anhydrous dichloromethane solution and stirred at room temperature for 10 minutes. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated to remove the solvent, yielding the crude product. The crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to give the target compound Ⅲ-5, 1.50 g.

[0091] 1HNMR(400MHz,Chloroform-d)δ8.77(s,1H),7.83(s,1H),7.77-7.72(m,2H),7.67–7.61(m,1H),7.50-7.38(m,2H),5.02(d,J=8.4Hz,1H),4 .59-4.47(m,1H),4.11-4.01(m,1H),3.98(s,3H),3.69(s,3H),2.20- 2.03(m,2H),2.00-1.89(m,2H),1.89-1.78(m,1H),1.76-1.64(m,1H). (5) Synthesis and characterization of methyl((1R,3R)-3-(7-(3-methoxy-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-8-(4-(methylsulfonyl)phenyl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (III) Add methyl((1R,3R)-3-(8-bromo-7-(3-methoxy-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (III-5, 100.0 mg, 0.15 mmol), 4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborhexacyclopentane (66.7 mg, 0.23 mmol), cesium carbonate (154.0 mg, 0.45 mmol), and Pd( Ph3P)4 (18.1 mg, 0.015 mmol) was purged with nitrogen three times and stirred at 102 °C for 1.5 h under nitrogen protection. After the reaction was complete as determined by TLC, 5 mL of methanol and sodium hydroxide (250 mg, 6.33 mmol) were added, and the mixture was stirred at 80 °C for 15 min to remove the protecting group. After the reaction was complete as determined by TLC, saturated sodium chloride solution was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography to obtain the crude product. The crude product was diluted with a mixture of acetonitrile and water (volume ratio: acetonitrile:water = 2:1), and ammonia was added to adjust the pH to 9. The product was then purified using an Agilent 1260 Infinity II high-performance preparative liquid chromatograph (Welch Xtimate C18 column, with a mixture of acetonitrile and water containing 0.1% ammonia (volume ratio: acetonitrile:water = 10:1), 57% gradient elution, flow rate 40 mL / min) to obtain the target compound III in 10% yield.

[0092] LC-MS calculated for C 28 H 25 D6N7O6S (M+H) + :m / z=600.2;found 600.2. 1 HNMR(400MHz,DMSO-d6)δ12.03(s,1H),8.15(s,1H),8.00-7.94(m,2H),7.66(d,J=7.7Hz,2H),7. 11(s,1H),6.80(d,J=7.2Hz,1H),4.05(td,J=10.4,8.9,4.9Hz,1H),3.83-3.74(m,1H),3.66(s,3 H),3.48(s,3H),3.29(s,3H),2.06(tt,J=9.7,3.1Hz,1H),1.97(dq,J=8.2,5.3,4.7Hz,1H),1.81 (dt,J=12.4,6.5Hz,1H),1.43(dt,J=13.3,7.5Hz,1H),1.24-1.15(m,1H),0.59(p,J=11.3Hz,1H). Example 13: Preparation and characterization of methyl((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-8-(p-methanesulfonylphenyl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate Referring to Example 12, the only difference is that in step (1), 3-methoxy-1-(methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole is replaced with 3-fluoro-1-(methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole; yield 9%.

[0093] The structural formula is: .

[0094] LC-MS calculated for C 27 H 22 D6FN7O5S (M+H) + :m / z=588.2;found 588.2. 1HNMR(400MHz,DMSO-d6)δ12.12(s,1H),8.16(s,1H),8.03-7.96(m,2H),7.65(d,J=7.7Hz,2H),7 .60(d,J=2.1Hz,1H),6.81(d,J=7.1Hz,1H),4.04(ddd,J=18.7,9.6,7.0Hz,1H),3.76(qd,J=8.7 ,4.7Hz,1H),3.48(s,3H),3.33(s,3H),2.06(ddd,J=13.4,8.6,4.8Hz,1H),2.00-1.90(m,1H),1 .82(dt,J=12.4,6.4Hz,1H),1.49-1.36(m,1H),1.27-1.12(m,1H),0.59(qd,J=11.8,8.0Hz,1H). Example 14: Preparation and characterization of methyl((1R,3R)-3-(8-(4-(tert-butyl)cyclohex-1-enyl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate Referring to Example 13, the only difference is that in step (5), 4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborane was replaced with 2-(4-(tert-butyl)cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane; yield 13%.

[0095] The structural formula is: .

[0096] LC-MS calculated for C 30 H 32 D6FN7O3(M+H) + :m / z=570.3;found 570.3. 1HNMR(400MHz,DMSO-d6)δ11.65(s,1H),8.06(s,1H),7.82(d,J=16.7Hz,1H),7.31-7.14(m,1H),5.82(d,J=16.2Hz,1H),5.56-4.97(m,1H),4 .33(s,1H),3.51(s,3H),2.54(s,1H),2.41-2.29(m,1H),2.27-2.08(m ,4H),2.05-1.83(m,5H),1.41-1.27(m,2H),1.18(s,1H),0.92(s,9H). Example 15: Preparation and characterization of methyl((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-8-(thiophen-3-ylethynyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate Referring to Example 13, the only difference is that in step (5), 4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborhexacyclopentane is replaced with 4,4,5,5-tetramethyl-2-(thiophene-3-ylethynyl)-1,3,2-dioxaborhexacyclopentane; yield 9%.

[0097] The structural formula is: .

[0098] LC-MS calculated for C 26 H 18 D6FN7O3S (M+H) + :m / z=540.2;found 540.2. 1HNMR(400MHz,DMSO-d6)δ8.18(d,J=2.1Hz,1H),8.11(s,1H),7.75(d,J=2.6Hz,1H),7.64(dd, J=5.0,2.9Hz,1H),7.28-7.20(m,1H),7.15(d,J=7.4Hz,1H),6.12(dtd,J=12.0,8.2,3.7Hz,1H ),4.40(dt,J=13.6,8.1Hz,1H),3.51(s,3H),2.38(ddd,J=12.7,8.3,3.8Hz,1H),2.16(tt,J=1 2.5,5.3Hz,2H),2.07(dd,J=11.5,5.4Hz,1H),1.99-1.92(m,1H),1.28(dd,J=9.2,6.3Hz,1H). Comparative Example 1 is a compound disclosed in patent WO2023178285, with the following structural formula: .

[0099] Comparative Example 2: Preparation and Characterization of Methyl((1R,3R)-3-(3-(methyl-d3)-8-(1-methyl-1H-indolo[6,7-d]pyrazol-6-yl)-7-(1-(methyl-d3)-1H-pyrazol-4-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate Referring to Example 4, the only difference is that in step (7), 4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaboranecyclopentane is replaced with 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentyl)-1H-indoline.

[0100] The structural formula is: .

[0101] 1HNMR(400MHz,Chloroform-d)δ8.70(s,1H),8.24-8.17(m,1H),8.04-7.97(m,2H) ,7.77(d,J=0.6Hz,1H),7.53-7.45(m,1H),5.02(d,J=8.4Hz,1H),4.52(ddddd,J= 8.0,6.1,4.4,1.9,0.8Hz,1H),4.10-3.96(m,1H),3.69(s,3H),2.17-2.06(m,2H) ,1.94(dddd,J=13.1,7.2,5.8,3.3Hz,2H),1.90-1.81(m,1H),1.75-1.62(m,1H). The effects of the compounds of the present invention will be verified through experimental examples below.

[0102] Experiment Example 1: Bioactivity Test 1.1 Experimental Methods (1) Ba / F3 JAK2 V617F Cell viability assay: After collecting and counting cells, they were seeded into 96-well plates at a density of 10,000–15,000 cells per well. After 24 hours, the cells were treated with various concentrations of the test compounds for 72 hours, with an equal volume of dimethyl sulfoxide blank solution added to the control wells. After reaching the treatment time point, 20 μL of 3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide (MTT, 5 mg / mL) was added to each well, and the cells were incubated for another 1–4 hours. After observing a clear blue precipitate produced by MTT under a microscope, the medium containing MTT was discarded. The precipitate was thoroughly dissolved in 50 μL of 20% sodium dodecyl sulfate (SDS) in each well and incubated overnight. The absorbance at 570 nm was measured using a microplate reader. The inhibition rate of each test compound was calculated using the formula: Inhibition rate = 100% - (Absorbance of control wells - Absorbance of experimental wells) / Absorbance of control wells × 100%. After calculating the inhibition rate of each compound concentration on cell proliferation activity, the compound treatment concentration was converted to logarithmic form, and the corresponding inhibition rate was used to fit a dose-response curve using Graphpad Prism 8.0 software, and an IC50 was fitted. 50 value.

[0103] (2) JAK2-JH2 protein affinity test: ① Add 10 μL of the stock solution of the test compound to 40 μL DMSO as the first spot dilution, and dilute 4 times for 10 spots; ② Transfer 50 nL of the test compound solution to a 384 plate, with 2 replicates per column. Centrifuge and wash the 384 plate at 1000 RPM. After blocking, discard the blocking solution, wash 3 times with PBST solution, and pat dry the reaction plate; ③ Add 5 μL JAK2 to each well and incubate at 25℃ for 10 min; ④ Add 5 μL JH2 probe 1 to each well and incubate at 25℃ for 60 min; ⑤ Use BMG to read the FP signal.

[0104] 1.2 Experimental Results As shown in Table 1, the compounds of the present invention affect Ba / F3 JAK2. V617F The cells exhibited a significant inhibitory effect; and its Ba / F3 JAK2 V617F IC 50 The levels were significantly lower than those of compounds in Comparative Examples 1 and 2; this indicates that the compounds of the present invention can effectively inhibit JAK2. V617F It mediates non-cytokine-dependent proliferation and, compared to compounds disclosed in the prior art, exhibits better inhibition of Ba / F3JAK2. V617F It has a significant effect on improving cell proliferation.

[0105] As shown in Table 2, the compounds of this invention exhibit good binding affinity to both the JAK2-JH2 pseudokinase domain and a significant inhibitory effect on JAK2-JH2. This indicates that the target of the compounds of this invention is the JAK2 pseudokinase domain JH2, which differs from traditional ATP-competitive JAK inhibitors that target the JH1 catalytic domain. This invention can inhibit JAK2 through allosteric regulation. V617F Mutation-mediated aberrant activation.

[0106] The above experimental results indicate that the compounds of this invention have the potential to treat diseases mediated by abnormal activation of JAK2.

[0107] Table 1 Results of cell antiproliferative activity assay Table 2 Results of JAK2-JH2 protein affinity test Experiment Example 2: Pharmacokinetic Experiment 2.1 Experimental Methods Three male BALB / c mice (weighing 22–24 g) were used in each group for the study. All animal experiments were conducted in strict accordance with the approved animal husbandry and handling ethics protocols. Mice were administered the drug via gavage at a dose of 5 mg / kg, with the suspension consisting of 0.5% methylcellulose and 0.1% Tween 80. Following oral administration, blood samples were collected at multiple time points from 0 to 24 hours (in rats, the superior vena cava was used as the blood collection site), with K3EDTA anticoagulant pre-added to the blood collection tubes. Plasma was separated by centrifugation and stored at -80°C for later analysis. Plasma samples were pretreated and then quantitatively analyzed using liquid chromatography-tandem mass spectrometry (LC-MS / MS). WinNonlin version 5.2 software was used to calculate the pharmacokinetic parameters using a non-compartmental model.

[0108] 2.2 Experimental Results As shown in Table 3, compared with Comparative Example 1, the compound of Example 10 has a significantly increased AUC, which significantly improves the in vivo drug exposure level and has better oral pharmacokinetic characteristics; it can achieve effective target inhibition with a lower dose, reducing the dosing load and toxic side effects.

[0109] Table 3 Pharmacokinetic parameters Experiment 3: Inhibition of the JAK2 signaling pathway in vitro 3.1 Experimental Methods Western Blot experiment: (1) Preparation of protein samples: Ba / F3 JAK2 V617FAfter cell line treatment, cell slurry was collected, centrifuged at 300g for 5 min, and the supernatant was discarded. The precipitate was the cell sample required for the experiment. The cell sample was washed twice with pre-cooled PBS. A strong lysis buffer (PMSF, Cocktail, and RIPA lysis buffer, volume ratio PMSF:Cocktail:RIPA = 1:1:100) was prepared by mixing PMSF solution, phosphatase inhibitor Cocktail, and RIPA lysis buffer. The cell sample was lysed with this strong lysis buffer, vortexing every 5 min for a total of 30 min. To ensure complete cell lysis, the cells were sonicated 5 times, 3 s each time with a 9 s interval. The sonicated samples were placed in a water bath at 95℃ or above for 10 min to inactivate and fully lyse the proteins. After centrifugation at 13000 rpm for 15 min at 4℃, the supernatant was transferred to a new 1.5 mL EP tube, and the protein concentration was determined using the Bradford method. After quantifying each sample to the same concentration with RIPA, 5× Loading solution was added. The buffer was placed in a 100℃ metal bath for 10 min to completely denature the protein. Then it was sealed and frozen at -20℃. The sample preparation was completed. (2) Electrophoresis and transfer: SDS-PAGE gel electrophoresis was performed using a 7.5% or 10% gradient gel. Electrophoresis was performed under a constant voltage of 120V. When the electrophoretic band reached the end of the gel, the electrophoresis was stopped. The gel was placed in the pre-cooled transfer solution. After cutting off the edge of the gel, it was placed on the transfer clamp. A PVDF membrane with a protein pore size of 0.2μm or 0.45μm was cut and soaked in methanol for about 30s. The activated PVDF membrane was tightly attached to the separated SDS-PAGE gel, and the air bubbles between them were removed. For target proteins with a molecular weight <50 kD, a PVDF membrane with a protein pore size of 0.2 μm was selected and the membrane was transferred at a constant current of 350 mA for 60 min; for target proteins with a molecular weight >50 kD, a PVDF membrane with a protein pore size of 0.45 μm was selected and the membrane was transferred at a constant current of 300 mA for 100~120 min; (3) Blocking, incubation of primary and secondary antibodies and development: After blocking the PVDF membrane in PBS / T buffer containing 5% skim milk for 1 h, it was briefly washed in PBS / T and incubated with primary antibody overnight at 4℃. The next day, it was washed 3 times with PBS / T for 10 min each time; then the secondary antibody was incubated at room temperature for 1 h, and the membrane was washed several times with PBS / T, with the buffer changed intermittently, for a total washing time of 45 min; after washing, ECL chemiluminescent substrate was added, the membrane was developed, and the gray values ​​of the bands in the western blot experiment were analyzed using ImageJ software for quantitative analysis.

[0110] 3.2 Experimental Results like Figure 1 As shown, the compound in Example 10 significantly downregulated Ba / F3 JAK2. V617F The phosphorylation levels of p-JAK2 and p-STAT3 in cells indicate their role in the action of Ba / F3 JAK2.V617F After cellularization, it participates in the JAK-STAT signaling pathway.

[0111] Experimental Example 4: In vivo induction of Ba / F3 JAK2 V617F Apoptosis 4.1 Experimental Methods Flow cytometry detection of apoptosis: The compound from Example 10 was used to treat Ba / F3 JAK2 cells at concentrations of 0.25 μM, 0.5 μM, 1 μM, and 5 μM. V617F Cell lines were treated for 48 hours. The apoptosis double staining kit was used according to the instructions: culture medium was collected and centrifuged at 2000 rpm for 5 minutes. Cells were washed once with binding buffer, resuspended in 100 μL of binding buffer, and each sample was incubated with 5 μL Annexin V and 5 μL PI staining solution for 15 minutes in the dark. Samples were analyzed within 1 hour, and the flow cytometry results were analyzed using FlowJo software.

[0112] 4.2 Experimental Results like Figure 2 As shown, compared with the control group, the compound of Example 10 showed better performance on Ba / F3 JAK2. V617F After cells, Ba / F3 JAK2 V617F The apoptosis rate of cells was significantly increased.

[0113] Experimental Example 5: In vivo induction of Ba / F3 JAK2 V617F Cell cycle arrest 5.1 Experimental Methods The compound from Example 10 was used to treat Ba / F3 JAK2 at concentrations of 0.125 μM, 0.25 μM, 0.5 μM, and 2.5 μM. V617F Cells were treated for 24 hours. Cell culture medium was collected, centrifuged at 1500 rpm for 3 min, washed once with PBS, fixed with pre-cooled 75% ethanol, and stored at 4°C overnight. The next day, cells were washed twice with PBS, stained with Propidium Iodide (PI) in the dark for 10 min, and then flow cytometry was performed. The flow cytometry results were analyzed using ModFit LT software.

[0114] 5.2 Experimental Results like Figure 3 As shown, compared with the control group, the proportion of cells in G0 / G1 and G2M phases was significantly increased and the proportion of cells in S phase was significantly decreased after treatment with the compound of Example 10, indicating that the compound of Example 10 can induce cell cycle arrest and inhibit Ba / F3JAK2. V617F Cell proliferation.

[0115] In vivo therapeutic studies of the compounds in Experimental Example 6 and Example 10 6.1 Experimental Methods Ba / F3 JAK2 V617F Driven malignant tumor mouse model: Routine culture of Ba / F3 JAK2 V617F Cells, 200 μL, were transplanted into immunodeficient mice BALB / c-nude via tail vein injection. Ba / F3 JAK2 V617F The inoculation dose for driving the malignant tumor mouse model was 3.0 × 10⁻⁶. 6 / mouse, batch induction modeling; after successful modeling, drug administration began on the fourth day and continued for 24 days, divided into 4 groups: 3 mice in the Fedratinib positive control group and 5 mice in the compound group of Example 10; at the end of the experiment, all mice were euthanized, and the spleen and liver were collected and weighed. The 5-6 week old Balb / C mice used in the experiment were purchased from Beijing Huafake Biotechnology Co., Ltd. All animal experiments followed the guidelines for the care and use of laboratory animals, and all mouse experimental protocols were approved by the Animal Care and Use Committee of Sichuan University (Chengdu, Sichuan, China).

[0116] The calculation method for the recovery of spleen weight ratio is: (spleen weight of the treatment group - spleen weight of the model group) / spleen weight of the model group.

[0117] 6.2 Experimental Results As shown in Table 4 and Figure 4 As shown, the compound of Example 10 is effective in treating Ba / F3 JAK2. V617F It drives malignant tumors and has similar effects to the marketed drug Fedratinib.

[0118] Table 4. Treatment results of Example 10 for myelofibrosis. In summary, this invention synthesizes a novel class of diaza-indole compounds that can effectively inhibit JAK2. V617F It mediates non-cytokine-dependent proliferation, exhibits a high binding affinity to the JAK2-JH2 pseudokinase domain, and significantly inhibits JAK2-JH2 through allosteric regulation. V617F Mutation-mediated aberrant activation. Notably, the Ba / F3 JAK2 compounds of this invention... V617F IC 50 All values ​​were ≤300 nM, significantly lower than those of compounds in Comparative Examples 1 and 2 (567.9 nM / 569 nM), demonstrating that the compounds of the present invention, compared to compounds disclosed in the prior art, are more effective in inhibiting Ba / F3 JAK2. V617FIt significantly enhanced cell proliferation while maintaining good affinity for JAK2-JH2. Furthermore, compared to the compound in Comparative Example 1, the compound of Example 10 of this invention exhibited a significantly increased AUC, markedly improved in vivo drug exposure, and better oral pharmacokinetic characteristics, enabling effective target inhibition at lower doses and reducing dosing load and toxic side effects. In addition, the compound of Example 10 downregulated Ba / F3 JAK2. V617F The compound lowered the levels of p-JAK2 and p-STAT3 in cells, inhibited the JAK-STAT signaling pathway, induced apoptosis, triggered cell cycle arrest, and inhibited tumor cell proliferation. In vivo experiments showed that the compound in Example 10 was effective in treating Ba / F3 JAK2. V617F Driven by malignant tumors, its efficacy is comparable to Fedratinib. Experimental results show that the compounds of this invention can achieve highly selective and efficient treatment of diseases related to abnormal signal activation induced by JAK2 gain-of-function mutations, especially JAK2. V617F Mutation-related diseases.

Claims

1. A compound or a pharmaceutically acceptable form thereof, characterized in that, The structure of the compound is as follows: Formula I; R1 is selected from , , , , , , , , , , 、Being R 3c The 6-10 aryl groups that are replaced by R 3d Substituted or unsubstituted 5-6 membered heteroaryl groups; R 3a R 3b Independently selected from 0 to 6 R 4a The following groups are substituted: C1-C6 alkyl, 3-6 membered cycloalkyl, -(CH2) n1 -O-(CH2) n2 -(CH3) n3 -(CH2) n4 -C(CH3)2O-X, 4~7-membered heterocyclic alkyl, 6~10-membered aryl, 5~10-membered heteroaryl, 5~10-membered spirocyclic alkyl, 6~10-membered bridged cycloalkyl, 6~10-membered heterobridged cycloalkyl, 6~10-membered heterospirocyclic alkyl; n1, n2, n4 are independently selected from integers 0~5, n3 is selected from integers 1~3; X is selected from H, C1~C6 alkyl; R 3c Selected from -SO2R 7a -CONHOR 7a -SO2N(R) 7a R 7b ), -N(R 7a SOR 7b -N(R) 7a COR 7b -NHCON(R) 7a R 7b -COOR 7a -N(R) 7a (CH2) n5 COR 7b -N(R) 7a (CH2) n5 COOR 7b , , , ; R 3d Selected from deuterium, halogen, cyano, amino, and R 3e Substituted or unsubstituted C1-C6 alkyl groups, R 3e Substituted or unsubstituted C1-C6 hydroxyalkyl groups, R 3e Substituted or unsubstituted 3- to 6-membered cycloalkyl groups, R 3e Substituted or unsubstituted 4-7 membered heterocyclic alkyl groups, R 3e Substituted or unsubstituted 6-10 aryl groups, R 3e Substituted or unsubstituted 5-10 aryl groups, R 3e Substituted or unsubstituted 5-10 membered spirocycloalkyl groups, R 3e Substituted or unsubstituted 6- to 10-membered bridged cycloalkyl groups, R 3e Substituted or unsubstituted 6- to 10-membered heterobridged cycloalkyl groups, R 3e Substituted or unsubstituted 6- to 10-membered heterospirocycloalkyl groups; R is selected from hydrogen, deuterium, halogen, cyano, amino, C1-C6 alkyl substituted or unsubstituted with R5, 3-6 membered cycloalkyl substituted or unsubstituted with R5, 4-7 membered heterocycloalkyl substituted or unsubstituted with R5, 6-10 membered aryl substituted or unsubstituted with R5, 5-10 membered heteroaryl substituted or unsubstituted with R5, 5-10 membered spirocycloalkyl substituted or unsubstituted with R5, 6-10 membered bridged cycloalkyl substituted or unsubstituted with R5, 6-10 membered heterobridged cycloalkyl substituted or unsubstituted with R5, and 6-10 membered heterospirocycloalkyl substituted or unsubstituted with R5. Ring B is selected from 3-6 membered cycloalkyl groups substituted or unsubstituted with R6, 4-7 membered heterocycloalkyl groups substituted or unsubstituted with R6, 6-10 membered aryl groups substituted or unsubstituted with R6, 5-10 membered heteroaryl groups substituted or unsubstituted with R6, 5-10 membered spirocycloalkyl groups substituted or unsubstituted with R6, 6-10 membered bridged cycloalkyl groups substituted or unsubstituted with R6, 6-10 membered heterobridged cycloalkyl groups substituted or unsubstituted with R6, and 6-10 membered heterospirocycloalkyl groups substituted or unsubstituted with R6. R 3e R 4a R5 and R6 are independently selected from deuterium, halogens, cyano groups, and -OR groups. 7a -SO2R 7a -N(R) 7a R 7b -COR 7a -CON(R) 7a R 7b ), -CONHOR 7a -SO2N(R) 7a R 7b ), -N(R 7a SOR 7b -N(R) 7a COR 7b -NHCON(R) 7a R 7b -COOR 7a -N(R) 7a (CH2) n5 COR 7b -N(R) 7a (CH2) n5 COOR 7b , , , C1-C6 alkyl groups substituted or unsubstituted with R7, 3-6 membered cycloalkyl groups substituted or unsubstituted with R7, 4-7 membered heterocycloalkyl groups substituted or unsubstituted with R7, 6-10 membered aryl groups substituted or unsubstituted with R7, 5-10 membered heteroaryl groups substituted or unsubstituted with R7, 5-10 membered spirocycloalkyl groups substituted or unsubstituted with R7, 6-10 membered bridged cycloalkyl groups substituted or unsubstituted with R7, 6-10 membered heterobridged cycloalkyl groups substituted or unsubstituted with R7, and 6-10 membered heterospirocycloalkyl groups substituted or unsubstituted with R7. n5 is selected from integers between 0 and 3; R 7a R 7b Independently selected from hydrogen, C1-C6 alkyl groups substituted or unsubstituted with R8, 3-6 membered cycloalkyl groups substituted or unsubstituted with R8, 4-7 membered heterocycloalkyl groups substituted or unsubstituted with R8, 6-10 membered aryl groups substituted or unsubstituted with R8, 5-10 membered heteroaryl groups substituted or unsubstituted with R8, 5-10 membered spirocycloalkyl groups substituted or unsubstituted with R8, 6-10 membered bridged cycloalkyl groups substituted or unsubstituted with R8, 6-10 membered heterobridged cycloalkyl groups substituted or unsubstituted with R8, and 6-10 membered heterospirocycloalkyl groups substituted or unsubstituted with R8; or, R 7a and R 7b The atoms attached to them form the following groups: 4-7 membered heterocyclic alkyl groups substituted or unsubstituted with R9, and 6-10 membered spirocyclic alkyl groups substituted or unsubstituted with R9; R7, R8, and R9 are independently selected from deuterium, halogen, hydroxyl, amino, cyano, C1-C4 alkyl, C1-C4 deuterated alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 deuterated alkoxy, C1-C4 haloalkoxy, 3-4 membered cycloalkyl, and 4-6 membered heterocycloalkyl. R2 is selected from R 2a Substituted or unsubstituted C1-C4 alkyl groups, R 2a Substituted or unsubstituted 3- to 4-membered cycloalkyl groups; R 2a Selected from deuterium or halogens; The heteroatom in the heterocyclic alkyl, heteroaryl, heterobridged cycloalkyl, and heterospirocycloalkyl is selected from at least one of N, O, and S.

2. The compound according to claim 1, or a pharmaceutically acceptable form thereof, characterized in that, R1 is selected from , , , , , , , , , , 、Being R 3c Substituted phenyl, R 3d Substituted or unsubstituted 5-6 membered heteroaryl groups; R 3a R 3b Independently selected from 0 to 3 R 4a The following groups are substituted: C1-C6 alkyl, 3-6 membered cycloalkyl, -(CH2) n1 -O-(CH2) n2 -(CH3) n3 -(CH2) n4 -C(CH3)2O-X, 4-6 membered heterocyclic alkyl, phenyl, 5-6 membered heteroaryl; n1, n2, n4 are independently selected from integers 0-3, n3 is selected from integers 1-3; X is selected from H, C1-C3 alkyl; R 3c Selected from -SO2R 7a -CONHOR 7a -SO2N(R) 7a R 7b ), -N(R 7a SOR 7b -N(R) 7a COR 7b -NHCON(R) 7a R 7b -COOR 7a -N(R) 7a (CH2) n5 COR 7b -N(R) 7a (CH2) n5 COOR 7b , , , ; R 3d Selected from deuterium, halogen, cyano, amino, and R 3e Substituted or unsubstituted C1-C3 alkyl groups, R 3e Substituted or unsubstituted C1~C3 hydroxyalkyl groups, R 3e Substituted or unsubstituted 3- to 6-membered cycloalkyl groups, R 3e Substituted or unsubstituted 4-6 membered heterocyclic alkyl groups, R 3e Substituted or unsubstituted phenyl, R 3e Substituted or unsubstituted 5-6 membered heteroaryl groups; R is selected from hydrogen, deuterium, halogen, cyano, amino, C1-C3 alkyl group substituted or unsubstituted with R5, 3-6 membered cycloalkyl group substituted or unsubstituted with R5, 4-6 membered heterocycloalkyl group substituted or unsubstituted with R5, phenyl group substituted or unsubstituted with R5, and 5-6 membered azaaryl group substituted or unsubstituted with R5. Ring B is selected from 3-6 membered cycloalkyl groups substituted or unsubstituted with R6, 4-6 membered heterocycloalkyl groups substituted or unsubstituted with R6, phenyl groups substituted or unsubstituted with R6, and 5-6 membered heteroaryl groups substituted or unsubstituted with R6. R 3e R 4a R5 and R6 are independently selected from deuterium, halogens, cyano groups, and -OR groups. 7a -SO2R 7a -N(R) 7a R 7b -COR 7a -CON(R) 7a R 7b ), -CONHOR 7a -SO2N(R) 7a R 7b ), -N(R 7a SOR 7b -N(R) 7a COR 7b -NHCON(R) 7a R 7b -COOR 7a -N(R) 7a (CH2) n5 COR 7b -N(R) 7a (CH2) n5 COOR 7b , , , C1-C3 alkyl groups substituted or unsubstituted with R7, 3-6 membered cycloalkyl groups substituted or unsubstituted with R7, 4-6 membered heterocycloalkyl groups substituted or unsubstituted with R7, phenyl groups substituted or unsubstituted with R7, and 5-6 membered heteroaryl groups substituted or unsubstituted with R7. n5 is selected from integers between 0 and 1; R 7a R 7b It is independently selected from hydrogen, C1-C3 alkyl groups substituted or unsubstituted with R8, 3-6 membered cycloalkyl groups substituted or unsubstituted with R8, 4-6 membered heterocycloalkyl groups substituted or unsubstituted with R8, phenyl groups substituted or unsubstituted with R8, and 5-6 membered heteroaryl groups substituted or unsubstituted with R8. R7 and R8 are independently selected from deuterium, halogen, hydroxyl, amino, cyano, C1~C3 alkyl, C1~C3 deuterated alkyl, C1~C3 haloalkyl, C1~C3 hydroxyalkyl, C1~C3 alkoxy, C1~C3 deuterated alkoxy, C1~C3 haloalkoxy, 3~4 membered cycloalkyl, and 4~6 membered heterocycloalkyl. R2 is selected from R 2a Substituted or unsubstituted C1-C3 alkyl groups, R 2a Substituted or unsubstituted 3- to 4-membered cycloalkyl groups; R 2a Selected from deuterium or halogens; The heterocyclic alkyl, heteroaryl, heterobridged cycloalkyl, and heterospirocycloalkyl groups contain 1 to 3 heteroatoms.

3. The compound according to claim 2, or a pharmaceutically acceptable form thereof, characterized in that, The structure of the compound is as follows: Formula II; R1 and R2 are as described in claim 2; R is a 5-membered nitrogen-containing heteroaryl group substituted with 0 to 3 R5 groups; the 5-membered nitrogen-containing heteroaryl group is: ; R5 is selected from deuterium, halogen, cyano, and -OR. 7a C1-C3 alkyl groups substituted with R7 or unsubstituted; R 7a R7 is as described in claim 2.

4. The compound according to claim 3, or a pharmaceutically acceptable form thereof, characterized in that, R1 is selected from , , , 、Being R 3c Substituted phenyl, R 3d Substituted or unsubstituted 5-membered heteroaryl groups; R 3a R 3b Independently selected from 0 to 3 R 4a The following groups are substituted: C1-C5 alkyl, 3-6 membered cycloalkyl, -CH2OCH3, -OCH3, -C(CH3)2OH, -C(CH3)2OCH3, phenyl, 5-6 membered heteroaryl; R 3c Selected from -SO2R 7a ; R 3d Selected from deuterium, halogen, cyano, amino, and R 3e Substituted or unsubstituted C1-C3 alkyl groups, R 3e Substituted or unsubstituted C1-C3 hydroxyalkyl groups; R 3e R 4a Independently selected from deuterium, halogen, cyano, C1-C3 alkyl group substituted or unsubstituted with R7, 3-6 membered cycloalkyl group substituted or unsubstituted with R7, 4-6 membered heterocycloalkyl group substituted or unsubstituted with R7, phenyl group substituted or unsubstituted with R7, and 5-6 membered heteroaryl group substituted or unsubstituted with R7. R 7a R 7b Independently selected from hydrogen, C1-C3 alkyl groups substituted with R8 or unsubstituted; R7 and R8 are independently selected from deuterium, halogen, hydroxyl, amino, cyano, C1~C3 alkyl, C1~C3 deuterated alkyl, C1~C3 haloalkyl, C1~C3 hydroxyalkyl, C1~C3 alkoxy, C1~C3 deuterated alkoxy, and C1~C3 haloalkoxy. R2 is selected from R 2a Substituted or unsubstituted C1-C3 alkyl groups; R 2a Selected from deuterium or halogens; R can be selected from any of the following structures: , , , .

5. The compound according to claim 4, or a pharmaceutically acceptable form thereof, characterized in that, The structure of the compound is any one of the following: 。 6. A pharmaceutical composition, characterized in that, It is prepared by adding a pharmaceutically acceptable excipient or carrier to the compound described in any one of claims 1 to 5 or its pharmaceutically acceptable form as the active ingredient.

7. Use of the compound of any one of claims 1 to 5 or in a pharmaceutically acceptable form thereof in the preparation of a JAK2 JH2 allosteric inhibitor; or, in the preparation of a medicament for treating diseases associated with abnormal signal activation caused by JAK2 gain-of-function mutations.

8. The use according to claim 7, characterized in that, The gain-of-function mutation of JAK2 is the V617F mutation.

9. The use according to claim 7, characterized in that, The relevant diseases include immune diseases, inflammatory diseases, solid tumors and / or hematologic malignancies.

10. The use according to claim 9, characterized in that, The immune-related diseases include psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjögren's syndrome, Behçet's disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, polymyositis, dermatomyositis, periarteritis nodosa, mixed connective tissue disease, scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I diabetes, type II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, Addison's disease, aberrant immune response, arthritis, dermatitis and / or radiation dermatitis; the inflammatory-related diseases include inflammatory bowel disease, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome, postoperative or post-traumatic inflammation, pneumonia. Nephritis, meningitis, cystitis, pharyngitis, gastric mucosal injury, meningitis, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary embolism, silicosis and / or pulmonary sarcoidosis; the solid tumors include lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic lymphoma, lymphoplasmacytic lymphoma, ovarian cancer, breast cancer, prostate cancer, bladder cancer, kidney cancer, esophageal cancer, cervical cancer, pancreatic cancer, colorectal cancer, gastric cancer, non-small cell lung cancer, thyroid cancer. Cancer, brain cancer, lymphoma, epidermal hyperplasia, psoriasis, prostate cancer and / or combinations thereof; the hematologic malignancies include acute myeloid leukemia, chronic myeloid leukemia, myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic neutrophilic leukemia, acute undifferentiated cell leukemia, myelodysplastic syndrome, myelodysplastic syndrome, myelofibrosis, multiple myeloma, spinal sarcoma and / or combinations thereof.

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