2-Aminopyrimidine compounds and their uses

Abstract

The present invention relates to 2-aminopyrimidine compounds of general formula I, and pharmaceutically acceptable salts, solvates or prodrugs thereof, methods for their preparation, and pharmaceutical compositions containing said compounds, wherein R 1 , R 2 , Ar, X, Y, Z, m, and n have the meanings given in the specification. The present invention also relates to the use of the compounds of general formula I in the preparation of medicaments for the treatment and / or prevention of malignant blood diseases and inflammatory bowel diseases.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly to a 2-aminopyrimidine compound and its use in the preparation of a medicament for treating and / or preventing malignant blood diseases and other proliferative diseases. Background Art

[0002] Hematological malignancies are a group of malignant clonal diseases originating from the hematopoietic system, mainly including myelodysplastic syndromes, myeloproliferative diseases, malignant lymphomas, leukemia, etc. Among them, the main feature of acute myeloid leukemia (AML) is the differentiation arrest of primitive progenitors and immature myeloid cells in the bone marrow and peripheral blood, resulting in abnormal proliferation and accumulation of primitive myeloid cells at different differentiation stages, while the production of red blood cells, platelets and white blood cells with normal functions decreases sharply. AML occurs commonly in all age groups, especially in the elderly (>60 years old). In recent years, the overall incidence has shown an upward trend and a tendency to be younger.

[0003] The Janus kinases (JAKs) / signal transducer and activator of transcription (STAT) signaling pathway is the downstream pathway of the signal transduction of numerous cytokines, and is widely involved in processes such as cell proliferation, differentiation, apoptosis and inflammation. The activation of this pathway is closely related to the occurrence and development of various diseases, especially hematological malignancies and inflammation. JAKs include four subtypes: JAK1, JAK2, JAK3 and TYK2. Among them, JAK2 can alone mediate cytokines such as erythropoietin (EPO), and the latter forms a signal transduction pathway with downstream STAT5, playing an important role in the processes of bone marrow, red blood cell and platelet production. When the level of JAK2 in the human body increases or mutates (common JAK2-V617F mutation), it will cause overactivation of the JAK2-STAT5 pathway, thus leading to the occurrence of malignant blood tumors.

[0004] Inflammatory bowel disease (IBD) is a chronic inflammatory disease with a prevalence of approximately 0.3%, affecting the small intestine, colon, and rectum, and including two types: ulcerative colitis and Crohn's disease. In IBD, IL-6, IL-12, and IL-23 are important drivers of disease activity. Among these inflammatory factors, IL-6 signal transduction occurs through the JAK1 / JAK2 / TYK2-STAT3 pathway, and IL-12 and IL-23 signal transduction depends on the JAK2 / TYK2-STAT4 pathway. Therefore, the JAK / STAT pathway signal transduction pathway is one of the main targets for treating IBD.

[0005] FMS-like tyrosine kinase 3 (FLT3) is an important type III receptor tyrosine kinase that plays an important role in the proliferation, survival, and differentiation of multipotent hematopoietic stem cells. FLT3 is highly expressed in the tumor cells of nearly 90% of AML patients, and approximately 30% of AML patients have mutations in the FLT3 gene. With the development of such inhibitors, point mutations in the FLT3 kinase domain (FLT3-TKD, mainly secondary mutations at residues F691 and D835) have become the main cause of clinical acquired resistance to FLT3 inhibitors. Therefore, inhibiting FLT3 and its mutants is an effective method for treating related blood diseases, especially AML.

[0006] The abnormal activation of JAK2 and FLT3 is closely related to the occurrence of malignant blood diseases, and the two have a mutually promoting effect. Therefore, selective JAK2 / FLT3 dual inhibitors can synergistically downregulate the content of p-STAT5, more effectively control the development process of AML, overcome the problem of acquired resistance faced by single inhibition of FLT3, and reduce the occurrence of adverse reactions, which is a new field for treating such diseases.

[0007] Currently, the approved JAK2 / FLT3 small molecule inhibitors on the market are Pacritinib and Fedratinib. Among them, Fedratinib is a JAK2 / FLT3 dual inhibitor developed by Impact Biomedicines, with IC 50 values for FLT3 and JAK2 of 15 nM and 3 nM, respectively, and was approved by the FDA in August 2019 for the treatment of adult patients with moderate or high-risk primary or acquired (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis.

[0008]

[0009] Based on previous research, the present inventors designed and synthesized a series of compounds with improved selectivity and high inhibitory activity. Summary of the Invention

[0010] The object of the present invention is a 2-aminopyrimidine compound and its use in the preparation of a drug for treating and / or preventing malignant blood diseases and other proliferative diseases.

[0011] To achieve the above object, the technical solution adopted by the present invention is:

[0012] A 2-aminopyrimidine compound, which is a 2-aminopyrimidine compound of general formula I, its pharmaceutically acceptable salt, solvate or prodrug,

[0013]

[0014] Wherein,

[0015] R 1 independently selected from hydrogen, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl;

[0016] Ar is a (C6-C 10 ) aryl, 5-10 membered heteroaryl, and the aryl or heteroaryl is optionally substituted by 1-3 identical or different R 3 substituents;

[0017] R 3 is hydroxy, halogen, nitro, amino, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkyl or (C1-C6) alkoxy optionally substituted by hydroxy or amino or halogen, amino substituted by 1-2 (C1-C6) alkyls, (C1-C6) alkylamide group, free or salt-forming or esterified or amidated carboxyl group, (C1-C6) alkylsulfinyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylacyl, carbamoyl substituted by 1-2 (C1-C6) alkyls, (C1-C3) alkylenedioxy, (C6-C 10 ) aryl, (C3-C 10 ) cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group;

[0018] m and n are each independently an integer between 1 and 3;

[0019] Y and Z are each independently selected from N or CH;

[0020] X is N or CH;

[0021] When X is CH, R 2 is -NR 4 R 5, when X is N, R 2 is a 4- to 10-membered heterocyclic group;

[0022] R 4 and R 5 are the same or different and are each independently selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkylacyl, (C1-C6)alkyl optionally substituted with hydroxy, amino or halogen; or R 4 and R 5 together with the N atom to which they are attached form a 4- to 10-membered heterocyclic group or a 5- to 10-membered heteroaryl group;

[0023] The aforementioned R 2 , R 4 and R 5 the heterocyclic group or heteroaryl group in is optionally substituted with 0-3 identical or different R 6 ; the heterocyclic group or heteroaryl group optionally contains 1-4 identical or different heteroatoms selected from N, O, S, wherein the heterocyclic group optionally includes 0-2 carbon-carbon double bonds or carbon-carbon triple bonds;

[0024] R 6 is oxo, halogen, (C1-C6)alkyl or (C1-C6)alkylacyl.

[0025] Preferably, the 2-aminopyrimidine compound of formula I and its pharmaceutically acceptable salt, solvate or prodrug,

[0026] wherein,

[0027] R 1 are independently selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl;

[0028] Ar is a (C6-C 10 )aryl, 5- or 6-membered heteroaryl, and the aryl or heteroaryl is optionally substituted with 1-3 identical or different R 3 ;

[0029] R 3 is hydroxy, halogen, nitro, amino, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkyl or (C1-C4)alkoxy optionally substituted with hydroxy, amino or halogen, amino substituted with 1-2 (C1-C4)alkyls, (C1-C4)alkylamide group, free or salt-formed or esterified or amidated carboxyl group, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylacyl, carbamoyl group substituted with 1-2 (C1-C4)alkyls, (C1-C3)alkylenedioxy, (C6-C 10aryl, (C3-C7) cycloalkyl, 5- or 6-membered heteroaryl, 4- to 6-membered heterocyclic group;

[0030] m and n are each independently an integer between 1 and 3;

[0031] Y and Z are each independently selected from N or CH;

[0032] X is N or CH;

[0033] R 2 is -NR 4 R 5 , 4- to 6-membered heterocyclic group or 5- or 6-membered heteroaryl, and when X is N, R 2 is not NR 4 R 5 ;

[0034] R 4 and R 5 are the same or different and are each independently selected from hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkylcarbonyl, (C1-C4) alkyl optionally substituted with hydroxy, amino or halogen; or R 4 and R 5 together with the N atom to which they are attached form a 4- to 6-membered heterocyclic group;

[0035] The aforementioned R 2 , R 4 and R 5 in the heterocyclic group are optionally substituted with 0 to 3 identical or different R 6 ; the heterocyclic group optionally contains 1 to 4 identical or different heteroatoms selected from N, O, S, and optionally includes 0 to 2 carbon-carbon double bonds or carbon-carbon triple bonds;

[0036] R 6 is oxo, halogen, (C1-C6) alkyl, (C1-C6) alkylcarbonyl.

[0037] Preferably, the 2-aminopyrimidine compound of general formula I and its pharmaceutically acceptable salt, solvate or prodrug,

[0038] wherein,

[0039] R 1 are each independently selected from hydrogen, halogen, (C1-C4) alkyl, trifluoromethyl;

[0040] Ar is (C6-C 10 ) aryl, 5- or 6-membered heteroaryl, and the aryl or heteroaryl is optionally substituted with 1 to 3 identical or different R 3 ;

[0041] R 3is hydroxy, halogen, nitro, amino, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkyl or (C1-C4)alkoxy optionally substituted with hydroxy or amino or halogen, amino substituted with 1-2 (C1-C4)alkyls, (C1-C4)alkylamido, carboxyl in free form or in salt form or esterified or amidated form, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylacyl, carbamoyl substituted with 1-2 (C1-C4)alkyls, (C3-C6)alkylenedioxy, (C3-C6)cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclic group;

[0042] m and n are each independently 1 or 2;

[0043] Y and Z are each independently selected from N or CH;

[0044] X is CH;

[0045] R 2 is -NR 4 R 5 ;

[0046] R 4 and R 5 are the same or different and are each independently selected from hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl, (C1-C4)alkylacyl, (C1-C4)alkyl optionally substituted with hydroxy, amino or halogen; or R 4 and R 5 together with the N atom to which they are attached form a 4-6 membered heterocyclic group;

[0047] The aforementioned R 2 、R 4 and R 5 in the heterocyclic group are optionally substituted with 0-3 identical or different R 6 ; the heterocyclic group optionally contains 1-4 identical or different heteroatoms selected from N, O, S and optionally includes 0-2 carbon-carbon double bonds or carbon-carbon triple bonds;

[0048] R 6 is oxo, halogen, (C1-C4)alkyl, (C1-C4)alkylacyl.

[0049] More preferably, the 2-aminopyrimidine compounds of formula I and their pharmaceutically acceptable salts, solvates or prodrugs,

[0050] wherein, X is C;

[0051] m and n are the same or different and are 1 or 2;

[0052] R 1Independently selected from hydrogen, halogen, (C1-C4)alkyl, trifluoromethyl;

[0053] Ar is (C6-C 10 )aryl, 5- or 6-membered heteroaryl, and said aryl or heteroaryl is optionally substituted by 1-3 identical or different R 3 substituents;

[0054] R 3 is hydroxy, halogen, nitro, amino, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkyl or (C1-C4)alkoxy optionally substituted by hydroxy, amino or halogen, amino substituted by 1-2 (C1-C4)alkyl groups, (C1-C4)alkylamido, free or salt-forming or esterified or amidated carboxy, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylcarbonyl, carbamoyl substituted by 1-2 (C1-C4)alkyl groups, (C1-C3)alkylenedioxy, (C3-C6)cycloalkyl, 5- or 6-membered heteroaryl, 4- to 6-membered heterocyclic group;

[0055] Y and Z are each independently selected from N or CH;

[0056] R 4 and R 5 are the same or different and are each independently selected from (C1-C4)alkyl, (C1-C4)alkyl optionally substituted by hydroxy; or R 4 and R 5 together with the N atom to which they are attached form a 4- to 6-membered heterocyclic group;

[0057] said heterocyclic group is optionally substituted by 0-3 identical or different R 6 substituents; the heterocyclic group optionally contains 1-4 identical or different heteroatoms selected from N, O, S and optionally includes 0-2 carbon-carbon double bonds or carbon-carbon triple bonds;

[0058] R 6 is oxo, halogen, (C1-C4)alkyl, (C1-C4)alkylcarbonyl.

[0059] More preferably, the 2-aminopyrimidine compounds of formula I and their pharmaceutically acceptable salts, solvates or prodrugs,

[0060] R 1 are each independently selected from hydrogen, halogen, (C1-C4)alkyl;

[0061] X is C;

[0062] m and n are the same or different and are 1 or 2;

[0063] Ar is phenyl, and said phenyl is optionally substituted by 1-3 identical or different Rs 3 substituted;

[0064] R 3 is hydroxyl, halogen, nitro, amino, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkyl or (C1-C4)alkoxy optionally substituted by hydroxyl, amino or halogen, amino substituted by 1-2 (C1-C4)alkyls, (C1-C4)alkylamido, free, salt-forming, esterified and amidated carboxyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylacyl, (C1-C4)alkylcarbamoyl, carbamoyl substituted by 1-2 (C1-C4)alkyls, (C1-C3)alkylenedioxy, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl;

[0065] Y and Z are CH;

[0066] R 4 and R 5 are the same or different and are each independently selected from (C1-C4)alkyl, (C1-C4)alkyl optionally substituted by hydroxyl; or R 4 and R 5 together with the N atom to which they are attached form

[0067] More preferably, 2-aminopyrimidine compounds of general formula I and their pharmaceutically acceptable salts, solvates or prodrugs thereof:

[0068] N-(4-acetylphenyl)-4-[5-chloro-2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0069] N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0070] N-(4-acetylphenyl)-4-[2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0071] N-(4-acetylphenyl)-4-[5-chloro-2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0072] N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0073] N-(4-acetylphenyl)-4-[2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0074] N-(4-acetylphenyl)-4-[5-chloro-2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0075] N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0076] N-(4-acetylphenyl)-4-[2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0077] N-(4-acetylphenyl)-4-[5-chloro-2-({4-[4-(piperidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0078] N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(piperidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0079] N-(4-acetylphenyl)-4-[2-({4-[4-(piperidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0080] N-(4-acetylphenyl)-4-[5-chloro-2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0081] N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0082] N-(4-acetylphenyl)-4-[2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0083] N-(4-Acetylphenyl)-4-{5-chloro-2-[(4-{4-[(2-hydroxyethyl)(methyl)amino]piperidin-1-yl}phenyl)amino]pyrimidin-4-yl}piperazine-1-carboxamide;

[0084] N-(4-Acetylphenyl)-4-{5-chloro-2-[(4-{4-[(methyl)(propyl)amino]piperidin-1-yl}phenyl)amino]pyrimidin-4-yl}piperazine-1-carboxamide;

[0085] N-(4-Acetylphenyl)-4-{5-chloro-2-({4-[3-(morpholin-4-yl)pyrrolidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0086] N-(4-Acetylphenyl)-4-{5-chloro-2-[(4-{3-[(2-hydroxyethyl)(methyl)amino]pyrrolidin-1-yl}phenyl)amino]pyrimidin-4-yl}piperazine-1-carboxamide;

[0087] N-[4-(1,3,4-Oxadiazol-2-yl)phenyl]-4-[5-methyl-2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0088] N-[4-(1,3,4-Oxadiazol-2-yl)phenyl]-4-[2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0089] N-[4-(1,3,4-Oxadiazol-2-yl)phenyl]-4-[5-methyl-2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0090] N-[4-(1,3,4-Oxadiazol-2-yl)phenyl]-4-[5-methyl-2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0091] N-[4-(1,3,4-Oxadiazol-2-yl)phenyl]-4-[2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0092] N-[4-(1,3,4-Oxadiazol-2-yl)phenyl]-4-[2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0093] N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[5-methyl-2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0094] N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide;

[0095] According to some common methods in the field to which the present invention pertains, the compounds of general formula I of the present invention can form their pharmaceutically acceptable salts with acids. Preferred acids are hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid and aspartic acid.

[0096] The present invention also includes prodrugs of the derivatives of the present invention. The prodrugs of the derivatives of the present invention are derivatives of general formula I, which may themselves have weak activity or even no activity, but after administration, they are converted into the corresponding bioactive forms under physiological conditions (such as by metabolism, solvolysis or other means).

[0097] Unless otherwise indicated, the term "halogen" as used in the present invention refers to fluorine, chlorine or bromine; "alkyl" refers to straight-chain or branched-chain alkyl; "cycloalkyl" refers to substituted or unsubstituted cycloalkyl; "alkoxy" refers to straight-chain or branched-chain alkoxy; "alkenyl" refers to straight-chain or branched-chain alkenyl; "alkynyl" refers to straight-chain or branched-chain alkynyl; "aryl" refers to phenyl without substituents or with substituents; "heteroaryl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, and the ring system is aromatic, such as imidazolyl, pyridyl, pyrazolyl, furyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, etc.; "saturated or partially saturated heterocyclic group" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl and thiazolinyl, etc.

[0098] The present invention also includes pharmaceutical compositions, which comprise the compounds of general formula I and their pharmaceutically acceptable salts and / or solvates as active ingredients and pharmaceutically acceptable carriers; the compounds of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.

[0099] The carriers for the pharmaceutical compositions of the present invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, colorants-free, flavoring agents, etc. for oral preparations; preservatives, solubilizing agents, stabilizers, etc. for injectable preparations; matrices, diluents, lubricants, preservatives, etc. for topical preparations. The pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0100] Through the enzyme activity tests of JAK2, JAK3 and FLT3, it was found that the compounds of the present invention have significant inhibitory activities on JAK2 and FLT3, have strong inhibitory effects on blood cancer cells with high expression of JAK2 or FLT3, and some compounds have improved selectivity.

[0101] Through the in vitro inhibitory activity tests on human erythroleukemia cells HEL and human myelomonocytic leukemia cells MV4-11, we found that the compounds of the present invention have significant anti-tumor activities. Therefore, the compounds of the present invention can be used to prepare drugs for treating or preventing various proliferative diseases or malignant blood diseases, such as myelofibrosis, multiple myeloma, polycythemia vera, essential thrombocythemia, acute myeloid leukemia, acute lymphoblastic leukemia, etc.

[0102] The precise amount of the compounds of the present invention required for treating inflammatory bowel disease or malignant blood diseases will vary depending on the subject being treated, depending on the type, age and general condition of the subject being treated, the severity of the disease being treated, the specific compound used and the mode of administration, such as the route and frequency of administration, etc. A person of ordinary skill in the art can determine an appropriate effective amount using only routine experimental methods.

[0103] The said hematological malignancies include: leukemia, myelodysplastic syndrome, malignant lymphoma, multiple myeloma, myeloproliferative diseases.

[0104] The said leukemia includes: acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia and chronic myeloid leukemia.

[0105] The said myeloproliferative diseases include: polycythemia vera, chronic myelogenous leukemia, essential thrombocythemia and myelofibrosis.

[0106] The said inflammatory bowel disease includes: ulcerative colitis and Crohn's disease.

[0107] The dosage of the compound can be from about 0.1 to 100 mg / kg body weight per day, preferably 1 to 50 mg / kg body weight / day. It is understood that the dosage can vary depending on the needs of the patient, the severity of the proliferative or malignant hematological disease being treated, and the specific compound used. Also, it is understood that the initial dosage administered can be increased beyond the upper limit in order to rapidly achieve the desired blood level, or the initial dosage can be less than the optimal value and the daily dosage can be gradually increased during treatment, depending on the specific circumstances. If desired, the daily dosage can also be divided into multiple doses, for example 2 - 4 times a day.

[0108] Mammal means a human or an animal.

[0109] The amount of the active ingredient, i.e., the compound according to the present invention, in the pharmaceutical composition and its unit dosage forms can vary and depends on the specific application, the potency of the specific compound, and the desired concentration. Generally, the content of the active ingredient will be between 0.5% and 90%, based on the total weight of the composition.

[0110] In combination therapy, the compound of the present invention and other compounds can be administered simultaneously or at intervals. When administered simultaneously, the compound of the present invention and other compounds can be combined in a single pharmaceutical composition or in separate compositions.

[0111] The examples and preparation examples provided below further illustrate and exemplify the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparation examples does not limit the scope of the present invention in any way.

[0112] The following synthetic routes describe the preparation of the derivatives of general formula I of the present invention. All starting materials are prepared by the methods described in these schemes, by methods well-known to those of ordinary skill in the art of organic chemistry, or are commercially available. All final compounds of the present invention are prepared by the methods described in these schemes or by methods similar thereto, which are well-known to those of ordinary skill in the art of organic chemistry. All variable factors applied in these schemes are defined as below or as defined in the claims.

[0113] According to the derivative of general formula I of the present invention, in this synthetic route, the following compound is taken as an example: substituent R 1 、R 4 、R 5 、Y, Z, m, n, Ar are defined as in the claims.

[0114]

[0115] Synthesis of Compound I-i in Route A

[0116] In Route A, aniline A undergoes a condensation reaction with phenyl chloroformate to obtain intermediate B; intermediate C undergoes reductive amination with a small molecule amine to obtain intermediate D, which is then deprotected by Boc, substituted, and reduced to obtain intermediate H; intermediate I undergoes a substitution reaction with N-Boc piperazine to obtain intermediate J, and intermediate H and intermediate J then undergo nucleophilic substitution, deprotection by Boc, and urea formation to obtain the target compound I-i.

[0117]

[0118] Synthesis of Compound I-ii in Route B

[0119] In Route B, aniline A undergoes a condensation reaction with phenyl chloroformate to obtain intermediate B; intermediate M undergoes reductive amination with a small molecule amine to obtain intermediate N, which is then deprotected by Boc, substituted, and reduced to obtain intermediate Q; intermediate I undergoes a substitution reaction with N-Boc piperazine to obtain intermediate J, and intermediate Q and intermediate J then undergo nucleophilic substitution, deprotection by Boc, and urea formation to obtain the target compound I-ii. Detailed implementation mode

[0120] In the following examples, methods for preparing some of the described compounds are depicted. It should be understood that the following methods and other methods known to those of ordinary skill in the art can be applied to the preparation of all compounds described in the present invention. The examples are intended to illustrate rather than limit the scope of the present invention. The 1H NMR spectra of the compounds were measured using a Bruker ARX-600, and the mass spectra were measured using an Agilent 1100 LC / MSD; the reagents used were all of analytical grade or chemical pure grade. According to the method of Example 1, the compounds of Examples 1-35 were prepared using intermediate L or intermediate S as raw materials and reacting with various substituted phenyl carbamates B.

[0121] Example 1. Preparation of N-(4-acetylphenyl)-4-[5-chloro-2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0122] 1.1. Synthesis of tert-butyl 4-(morpholin-4-yl)piperidine-1-carboxylate (D)

[0123] At room temperature, N-Boc-4-piperidone (2.0 g, 10.04 mmol), morpholine (1.05 g, 12.05 mmol) and acetic acid (0.72 g, 12.05 mmol) were dissolved in methanol (20 mL). After stirring for 4 h, sodium cyanoborohydride (1.89 g, 30.12 mmol) was added and the reaction continued for 6 h. After the reaction was completed, 10% aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction. The organic solvent was evaporated under reduced pressure. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were collected, and the organic solvent was evaporated under reduced pressure to obtain 2.0 g of a yellow oil, with a yield of 74.1%.

[0124] 1.2. Synthesis of 4-(piperidin-4-yl)morpholine (E)

[0125] At room temperature, intermediate D (2.0 g, 7.41 mmol) was dissolved in 1,4-dioxane (10 mL). Hydrochloric acid solution in 1,4-dioxane (10 mL) was slowly added. After the addition was complete, the reaction was carried out at room temperature for 4 h. After the reaction was completed, filtration was performed by suction, and the filter cake was washed with a small amount of 1,4-dioxane (2 mL) and dried to obtain 1.1 g of a white solid, with a yield of 87.3%.

[0126] 1.3. 4-[1-(4-Nitrophenyl)piperidin-4-yl]morpholine (G)

[0127] At room temperature, intermediate E (1 g, 4.84 mmol), p-fluoronitrobenzene (0.72 g, 5.08 mmol) and anhydrous potassium carbonate (2.0 g, 14.52 mmol) were dissolved in DMSO (10 mL). The temperature was raised to 80 °C and the reaction was carried out for 4 h. After the reaction was completed, water (20 mL) was added. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were collected. The organic phase was washed with an aqueous lithium chloride solution (20 mL × 3). The organic solvent was evaporated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to obtain 1.0 g of a yellow solid, with a yield of 71.4%.

[0128] 1.4. 4-[4-(Morpholin-4-yl)piperidin-1-yl]aniline (H)

[0129] At room temperature, under a hydrogen atmosphere, intermediate G (1.0 g, 3.44 mmol) and 55% palladium on carbon (0.1 g) were dissolved in anhydrous ethanol (10 mL). The reaction was carried out at room temperature for 6 h. After the reaction was completed, filtration was performed by suction through diatomaceous earth. The filter cake was washed with ethanol (20 mL). The filtrate was collected and the organic solvent was evaporated under reduced pressure and dried to obtain 0.6 g of a brown solid, with a yield of 67.4%.

[0130] 1.5. Synthesis of tert-butyl 4-(2,4,5-trichloropyrimidin-4-yl)piperazine-1-carboxylate (J)

[0131] At room temperature, 2,4,5-trichloropyrimidine (20.0 g, 110 mmol) was dissolved in DMF (200 mL), potassium carbonate (19.0 g, 132 mmol) was added, and N-Boc-piperazine (21.5 g, 115.5 mmol) was added in batches. After the addition, the reaction was carried out at room temperature for 2 h. After the reaction was completed, water (1 L) was added to the reaction solution, stirred, filtered by suction, the filter cake was washed with water (100 mL), and dried to obtain 30.0 g of a white solid with a yield of 82.2%.

[0132] 1.6. Synthesis of tert-butyl 4-[5-chloro-2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxylate (K)

[0133] At room temperature, intermediate J (0.5 g, 1.92 mmol) and intermediate H (0.67 g, 2.02 mmol) were dissolved in isopropanol (5 mL), trifluoroacetic acid (0.66 g, 5.76 mmol) was added, and the temperature was raised to 85 °C for reaction for 6 h. After the reaction was completed, the solvent was concentrated under reduced pressure. Water (10 mL) was added to the residue, the pH was adjusted to 8 with saturated sodium bicarbonate solution, filtered by suction, the filter cake was washed with water (20 mL), and dried to obtain 0.7 g of a white solid with a yield of 66%.

[0134] 1.7. Synthesis of N-(4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl)-5-chloro-4-(piperazin-1-yl)pyrimidin-2-amine (L)

[0135] At room temperature, intermediate K (0.7 g, 1.26 mmol) was added to 7 mL of dichloromethane, 7 mL of trifluoroacetic acid was slowly added dropwise. After the addition, the reaction was carried out at room temperature for 4 h. After the reaction was completed, the solution was concentrated under reduced pressure. Water (5 mL) was added to the residue, the pH was adjusted to 10 with 20% sodium hydroxide solution, filtered by suction, the filter cake was washed with water (20 mL), and dried to obtain 0.5 g of a gray solid with a yield of 87.7%.

[0136] 1.8. Synthesis of phenyl N-(4-acetylphenyl)carbamate (B)

[0137] At room temperature, 4-aminoacetophenone (20 g, 148 mmol) and sodium carbonate (9.42 g, 88.8 mmol) were added to a mixed solution of ethyl acetate - tetrahydrofuran - water (3:1:1, 200 mL). Under an ice bath, phenyl chloroformate (27.7 g, 178 mmol) was added dropwise. After the addition, the reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. Water (100 mL) was added to the residue, the pH was adjusted to 5 with 1M hydrochloric acid solution, filtered by suction, the filter cake was washed with water (100 mL), and dried to obtain 30 g of a white solid with a yield of 81.1%.

[0138] 1.9. Synthesis of N-(4-acetylphenyl)-4-[5-chloro-2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide (Ⅰ)

[0139] At room temperature, intermediate L (0.2 g, 0.44 mmol), DIPEA (0.07 g, 0.53 mmol) and intermediate B (0.13 g, 0.53 mmol) were added to 1,4-dioxane (2 mL), and the temperature was raised to 80 °C for reaction for 4 h. After the reaction was completed, it was cooled to room temperature, the solvent was concentrated under reduced pressure, water (5 mL) was added to the residue, and the pH was adjusted to 10 with 5% NaOH solution, then filtered by suction and dried to obtain the crude product. The crude product was purified by column chromatography (methylene chloride:methanol = 20:1) to obtain 0.15 g of white solid, with a yield of 55.6%.

[0140] Example 2. Preparation of N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0141] Using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis method in 1.5 - 1.7 of Example 1, and then N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method in 1.9 of Example 1. The yield was 61.2%.

[0142] Example 3. Preparation of N-(4-acetylphenyl)-4-[2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0143] Using 2,4-dichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis method in 1.5 - 1.7 of Example 1, and then N-(4-acetylphenyl)-4-[2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method in 1.9 of Example 1. The yield was 58.7%.

[0144] Example 4. Preparation of N-(4-acetylphenyl)-4-[5-chloro-2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0145] Using N-methylpiperazine, N-Boc-4-piperidone, and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4,5-trichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, N-(4-acetylphenyl)-4-[5-chloro-2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 62.7%.

[0146] Example 5. Preparation of N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0147] Using N-methylpiperazine, N-Boc-4-piperidone, and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 65.1%.

[0148] Example 6. Preparation of N-(4-acetylphenyl)-4-[2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0149] Using N-methylpiperazine, N-Boc-4-piperidone, and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4-dichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, N-(4-acetylphenyl)-4-[2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 56.5%.

[0150] Example 7. Preparation of N-(4-acetylphenyl)-4-[5-chloro-2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0151] Using pyrrolidine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4,5-trichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, N-(4-acetylphenyl)-4-[2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 63.5%.

[0152] Example 8. Preparation of N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0153] Using pyrrolidine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 68.1%.

[0154] Example 9. Preparation of N-(4-acetylphenyl)-4-[2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0155] Using pyrrolidine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4-dichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, N-(4-acetylphenyl)-4-[2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 70.4%.

[0156] Example 10. Preparation of N-(4-acetylphenyl)-4-[5-chloro-2-({4-[4-(piperidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0157] Using piperidine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods in 1.1 - 1.4 of Example 1. Then, using 2,4,5-trichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods in 1.5 - 1.7 of Example 1. Finally, N-(4-acetylphenyl)-4-[2-({4-[4-(piperidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method in 1.9 of Example 1. The yield was 56.2%. Example 11. Preparation of N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(piperidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0158] Using piperidine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods in 1.1 - 1.4 of Example 1. Then, using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods in 1.5 - 1.7 of Example 1. Finally, N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(piperidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method in 1.9 of Example 1. The yield was 68.7%.

[0159] Example 12. Preparation of N-(4-acetylphenyl)-4-[2-({4-[4-(piperidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0160] Using piperidine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods in 1.1 - 1.4 of Example 1. Then, using 2,4-dichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods in 1.5 - 1.7 of Example 1. Finally, N-(4-acetylphenyl)-4-[2-({4-[4-(piperidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method in 1.9 of Example 1. The yield was 64.5%. Example 13. Preparation of N-(4-acetylphenyl)-4-[5-chloro-2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0161] Using N-ethylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1-1.4 in Example 1. Then, using 2,4,5-trichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5-1.7 in Example 1. Finally, N-(4-acetylphenyl)-4-[2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 69.1%.

[0162] Example 14. Preparation of N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0163] Using N-ethylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1-1.4 in Example 1. Then, using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5-1.7 in Example 1. Finally, N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 74.2%.

[0164] Example 15. Preparation of N-(4-acetylphenyl)-4-[2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0165] Using N-ethylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1-1.4 in Example 1. Then, using 2,4-dichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5-1.7 in Example 1. Finally, N-(4-acetylphenyl)-4-[2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 70.5%.

[0166] Example 16. Preparation of N-(4-acetylphenyl)-4-{5-chloro-2-[(4-{4-[(2-hydroxyethyl)(methyl)amino]piperidin-1-yl}phenyl)amino]pyrimidin-4-yl}piperazine-1-carboxamide

[0167] Using N-methylethanolamine, N-Boc-4-piperidone, and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis method in 1.1 - 1.4 of Example 1. Then, using 2,4,5-trichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis method in 1.5 - 1.7 of Example 1. Finally, N-(4-acetylphenyl)-4-{2-[(4-{4-[(2-hydroxyethyl)(methyl)amino]piperidin-1-yl}phenyl)amino]pyrimidin-4-yl}piperazine-1-carboxamide was synthesized according to the synthesis method in 1.9 of Example 1. The yield was 57.8%.

[0168] Example 17. Preparation of N-(4-acetylphenyl)-4-{5-chloro-2-[(4-{4-[(methyl)(propyl)amino]piperidin-1-yl}phenyl)amino]pyrimidin-4-yl}piperazine-1-carboxamide

[0169] Using N-methylpropylamine, N-Boc-4-piperidone, and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis method in 1.1 - 1.4 of Example 1. Then, using 2,4,5-trichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis method in 1.5 - 1.7 of Example 1. Finally, N-(4-acetylphenyl)-4-{2-[(4-{4-[(methyl)(propyl)amino]piperidin-1-yl}phenyl)amino]pyrimidin-4-yl}piperazine-1-carboxamide was synthesized according to the synthesis method in 1.9 of Example 1. The yield was 57.5%.

[0170] Example 18. Preparation of N-(4-acetylphenyl)-4-{5-chloro-2-({4-[3-(morpholin-4-yl)pyrrolidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0171] Using morpholine, N-Boc-3-pyrrolidone, and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis method in 1.1 - 1.4 of Example 1. Then, using 2,4,5-trichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis method in 1.5 - 1.7 of Example 1. Finally, N-(4-acetylphenyl)-4-{5-chloro-2-({4-[3-(morpholin-4-yl)pyrrolidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method in 1.9 of Example 1. The yield was 62.5%.

[0172] Example 19. Preparation of N-(4-acetylphenyl)-4-{5-chloro-2-[(4-{3-[(2-hydroxyethyl)(methyl)amino]pyrrolidin-1-yl}phenyl)amino]pyrimidin-4-yl}piperazine-1-carboxamide

[0173] Using N-methylethanolamine, N-Boc-3-pyrrolidone, and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis method in 1.1 - 1.4 of Example 1. Then, using 2,4,5-trichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis method in 1.5 - 1.7 of Example 1. Finally, N-(4-acetylphenyl)-4-{5-chloro-2-[(4-{3-[(2-hydroxyethyl)(methyl)amino]pyrrolidin-1-yl}phenyl)amino]pyrimidin-4-yl}piperazine-1-carboxamide was synthesized according to the synthesis method in 1.9 of Example 1. The yield was 66.5%.

[0174] Example 20. Preparation of N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[5-methyl-2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0175] Using N-methylpiperazine, N-Boc-4-piperidone, and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis method in 1.1 - 1.4 of Example 1. Then, using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis method in 1.5 - 1.7 of Example 1. Finally, using phenyl [4-(1,3,4-oxadiazol-2-yl)phenyl]carbamate as the raw material, N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[5-methyl-2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method in 1.9 of Example 1. The yield was 53.6%. Example 21. Preparation of N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0176] Using N-methylpiperazine, N-Boc-4-piperidone, and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis method in 1.1 - 1.4 of Example 1. Then, using 2,4-dichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis method in 1.5 - 1.7 of Example 1. Finally, using phenyl [4-(1,3,4-oxadiazol-2-yl)phenyl]carbamate as the raw material, N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method in 1.9 of Example 1. The yield was 56.7%.

[0177] Preparation of Example 22. N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[5-methyl-2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0178] Using pyrrolidine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, using phenyl [4-(1,3,4-oxadiazol-2-yl)phenyl]carbamate as the raw material, N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[5-methyl-2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 70.4%.

[0179] Preparation of Example 23. N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[5-methyl-2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0180] Using N-ethylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, using phenyl [4-(1,3,4-oxadiazol-2-yl)phenyl]carbamate as the raw material, N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[5-methyl-2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 62.1%.

[0181] Preparation of Example 24. N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0182] Using N-ethylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis method in 1.1 - 1.4 of Example 1. Then, using 2,4-dichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis method in 1.5 - 1.7 of Example 1. Finally, using phenyl [4-(1,3,4-oxadiazol-2-yl)phenyl]carbamate as the raw material, N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method in 1.9 of Example 1. The yield was 64.3%.

[0183] Example 25. Preparation of N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0184] Using pyrrolidine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis method in 1.1 - 1.4 of Example 1. Then, using 2,4-dichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis method in 1.5 - 1.7 of Example 1. Finally, using phenyl [4-(1,3,4-oxadiazol-2-yl)phenyl]carbamate as the raw material, N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method in 1.9 of Example 1. The yield was 54.2%.

[0185] Example 26. Preparation of N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[5-methyl-2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0186] Using morpholine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis method in 1.1 - 1.4 of Example 1. Then, using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis method in 1.5 - 1.7 of Example 1. Finally, using phenyl [4-(1,3,4-oxadiazol-2-yl)phenyl]carbamate as the raw material, N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[5-methyl-2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method in 1.9 of Example 1. The yield was 61.3%.

[0187] Example 27. Preparation of N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0188] Using morpholine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4-dichloropyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, using phenyl [4-(1,3,4-oxadiazol-2-yl)phenyl]carbamate as the raw material, N-[4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 51.8%.

[0189] Example 28. Preparation of N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(4-acetylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0190] Using acetylpiperazine, N-Boc-4-piperidone and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(4-acetylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 45.7%.

[0191] Example 29. Preparation of N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(thiomorpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0192] Using thiomorpholine, N-Boc-4-piperidone, and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(thiomorpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 53.1%.

[0193] Example 30. Preparation of N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(1-oxothiomorpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0194] Using 1-oxothiomorpholine, N-Boc-4-piperidone, and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(1-oxothiomorpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 56.4%.

[0195] Example 31. Preparation of N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(1,2-dioxothiomorpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0196] Using 1,2-dioxothiomorpholine, N-Boc-4-piperidone, and p-fluoronitrobenzene as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(1,2-dioxothiomorpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 52.5%.

[0197] Example 32. Preparation of N-(4-acetylphenyl)-4-[5-methyl-2-({5-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0198] Using N-methylpiperazine, N-Boc-4-piperidone and 5-fluoro-2-nitropyridine as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, N-(4-acetylphenyl)-4-[5-methyl-2-({5-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 48.1%.

[0199] Example 33. Preparation of N-(4-acetylphenyl)-4-[5-methyl-2-({6-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]pyridin-3-yl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0200] Using N-methylpiperazine, N-Boc-4-piperidone and 2-fluoro-5-nitropyridine as raw materials, the key intermediate H was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate L was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, N-(4-acetylphenyl)-4-[5-methyl-2-({6-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]pyridin-3-yl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 45.4%.

[0201] Example 34. Preparation of N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0202] Using N-methylpiperidone, N-Boc-piperazine and p-fluoronitrobenzene as raw materials, the key intermediate Q was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate S was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, N-(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 67.8%.

[0203] Preparation of Example 35. N-(4-Acetylphenyl)-4-[5-methyl-2-({4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide

[0204] Using oxetanone, N-Boc-piperazine and p-fluoronitrobenzene as raw materials, the key intermediate Q was synthesized according to the synthesis methods of 1.1 - 1.4 in Example 1. Then, using 2,4-dichloro-5-methylpyrimidine as the raw material, the key intermediate S was synthesized according to the synthesis methods of 1.5 - 1.7 in Example 1. Finally, N-(4-Acetylphenyl)-4-[5-methyl-2-({4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide was synthesized according to the synthesis method of 1.9 in Example 1. The yield was 55.5%.

[0205] The structure of the example compound and 1 The 1H-NMR and MS data are shown in the following table.

[0206] Table 1 The structure of the example compound and 1 1H-NMR and MS data

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213] Studies on the in vitro enzyme activity and cell anti-proliferation activity of some compounds prepared by the present invention were carried out, and the results are as follows

[0214] The in vitro JAK2, JAK3 and FLT3 kinase activities of the compounds with the 2-aminopyrimidine skeleton of the general formula I according to the present invention were tested by Mobility Shift Assay.

[0215] The kinase buffer consists of 50 mM HEPES (pH 7.5) and 0.0015% BRIJ-35. The stop buffer contains a mixture of 100 mM HEPES (pH 7.5), 0.015% BRIJ-35, 0.2% coating reagent #3, and 50 mM EDTA. The starting concentration of the compound was set to 100 nM (JAK2 and FLT3) or 1000 nM (JAK3), and the test compound was diluted with 100% DMSO to 50 times the highest concentration required in the reaction. Transfer 100 μL of the diluted test compound into the wells of a 96-well plate. Then, add 100 μL of DMSO to two wells as a control group and label it as the source plate. Transfer 10 μL of the compound from the source plate to a new 96-well plate to prepare an intermediate plate. In the intermediate plate, add an additional 90 μL of kinase buffer to each well. Shake the intermediate plate for 10 min, and then transfer 5 μL from each well of the 96-well intermediate plate to a 384-well plate as an assay plate. Add 10 μL of the prepared enzyme solution to each well in the 384-well plate, incubate at room temperature for 10 min, and then add 10 μL of the prepared peptide solution (FAM-labeled peptide and ATP in kinase base buffer). Incubate the samples at 28 °C for 1 h, and then add 30 μL of the stop buffer. Copy the conversion data from the Caliper program and convert it to the inhibition rate.

[0216] Inhibition rate (%) = (max - conversion) / (max - min) × 100.

[0217] Use XLfit excel to fit the data to obtain the IC 50 value. Y = Bottom + (Top - Bottom) / (1 + (IC 50 / X)^HillSlope)

[0218] The in vitro kinase test results of some compounds are shown in Table 2 - 3.

[0219] Table 2

[0220]

[0221] a Not determined.

[0222] Table 3

[0223]

[0224]

[0225] Furthermore, the compounds with a 2-aminopyrimidine skeleton described above were selected for in vitro tests on the activities of inhibiting human erythroleukemia cells HEL and human myelomonocytic leukemia cells MV4-11.

[0226] After the cells were resuscitated and passaged 2-3 times until stable, 10 μL of the cell suspension was aspirated and added to a cell counting chamber for counting, and the cell concentration was adjusted to 5×10 4 cells / mL. Using a Matrix 12 pipettor, 100 μL of the cell suspension or culture medium was placed into a 96-well plate. The remaining wells were filled with 200 μL of PBS, and then different concentrations of the test compound were added to the 96-well plate. After incubating in an incubator for 72 h, 22 μL of Alamar-Blue solution was added to the 96-well plate, and incubation was continued for 4 h. The 96-well plate was shaken at room temperature for 10 seconds, and then the absorbance at a wavelength of 530 / 590 nm was measured using a microplate reader. The inhibition rate of cell growth was calculated according to the following formula:

[0227] Inhibition rate (%) = [(Acontrol - Atreated) / (Acontrol - Ablank)]×100

[0228] IC 50 is the drug concentration required to inhibit the growth of half of the cells. According to the drug concentration and inhibition rate results, the IC 50 .

[0229] The test results of some compounds on human erythroleukemia cells HEL and human acute monocytic leukemia cells MV4-11 are shown in Table 4.

[0230] Table 4

[0231] Example <![CDATA[HEL IC 50 (nM)]]> <![CDATA[MV4-11 IC 50 (nM)]]> Compound of Example 1 567 6.8 Compound of Example 5 644 9.43 Compound of Example 6 1955 22.9 Compound of Example 8 1105 6.08 Compound of Example 14 1468 7.87 Compound of Example 15 3206 15.4 Fedratinib 1425 79

[0232] The preliminary in vitro kinase test results show that the compounds of general formula I to be protected by the present invention have good inhibitory activities against JAK2, FLT3 and their mutant enzymes. The selectivity of some compounds for JAK3 is improved, and some compounds have inhibitory activities against JAK1 and TYK2. At the same time, some compounds are equivalent to or superior to the positive control drug Fedratinib. The preliminary cell activity test results show that the compounds of general formula I to be protected by the present invention have good cell activities, and some compounds are equivalent to the positive control drug Fedratinib.

Claims

1. A 2-aminopyrimidine compound, characterized in that: The compound is a 2-aminopyrimidine compound of general formula I and its pharmaceutically acceptable salts, wherein, R 1 independently selected from hydrogen, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl; Ar is phenyl, and the phenyl is optionally substituted by 1-3 identical or different Rs 3 substituted; R 3 is (C1-C6) alkyl acyl, 5-10 membered heteroaryl; m and n are each independently an integer between 1 and 2; Y and Z are each independently selected from N or CH; X is N or CH; When X is CH, R 2 is -NR 4 R 5 , when X is N, R 2 is a 4- to 10-membered heterocyclic group; R 4 and R 5 are the same or different and are each independently selected from (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C6) alkyl optionally substituted with a hydroxyl group; or R 4 and R 5 together with the N atom to which they are attached form a 4- to 10-membered heterocyclic group; The aforementioned R 2 , R 4 and R 5 the heterocyclic group in which is optionally substituted by 0-3 identical or different R 6 ; the heterocyclic group optionally contains 1-4 identical or different heteroatoms selected from N, O, and S; R 6 is oxo, (C1-C6) alkyl or (C1-C6) alkyl acyl group.

2. The 2-aminopyrimidine compound according to claim 1, characterized in that: The 2-aminopyrimidine compound of general formula I and its pharmaceutically acceptable salts, wherein, R 1 independently selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl; Ar is phenyl, which is optionally substituted by 1-3 identical or different R 3 substituents; R 3 is (C1-C4) alkyl acyl, 5-6 membered heteroaryl; m and n are each independently an integer between 1 and 2; Y and Z are each independently selected from N or CH; X is N or CH; When X is CH, R 2 is -NR 4 R 5 , when X is N, R 2 is a 4- to 10-membered heterocyclic group; R 4 and R 5 are the same or different and are each independently selected from (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkyl optionally substituted with a hydroxyl group; or R 4 and R 5 together with the N atom to which they are attached form a 4- to 6-membered heterocyclic group; The aforementioned R 2 , R 4 and R 5 The heterocyclic group in R 6 is optionally substituted with 0-3 identical or different R 6 ; the heterocyclic group optionally contains 1-4 identical or different heteroatoms selected from N, O, and S; R 6 is oxo, (C1-C6)alkyl, (C1-C6)alkylacyl.

3. The 2-aminopyrimidine compound according to claim 2, characterized in that: The 2-aminopyrimidine compound of general formula I and its pharmaceutically acceptable salts, wherein, R 1 independently selected from hydrogen, halogen, (C1-C4)alkyl, trifluoromethyl; Ar is phenyl, which is optionally substituted by 1-3 identical or different Rs 3 substituted; R 3 is (C1-C4) alkyl acyl, 5-6 membered heteroaryl; m and n are each independently 1 or 2; Y and Z are each independently selected from N or CH; X is CH; R 2 is - NR 4 R 5 ; R 4 and R 5 are the same or different and are each independently selected from (C1-C4) alkyl, (C3-C6) cycloalkyl, (C1-C4) alkyl optionally substituted with a hydroxyl group; or R 4 and R 5 together with the N atom to which they are attached form a 4-6 membered heterocyclic group; The aforementioned R 2 , R 4 and R 5 the heterocyclic group in which is optionally substituted by 0-3 identical or different R 6 ; the heterocyclic group optionally contains 1-4 identical or different heteroatoms selected from N, O, S; R 6 is oxo, (C1-C4) alkyl, (C1-C4) alkyl acyl.

4. The 2-aminopyrimidine compound according to claim 3, wherein: The 2-aminopyrimidine compound of general formula I and its pharmaceutically acceptable salts, wherein X is C; m and n are the same or different, being 1 or 2; R 1 independently selected from hydrogen, halogen, (C1-C4)alkyl, trifluoromethyl; Ar is phenyl, and the phenyl is optionally substituted by 1-3 identical or different R 3 substituents; R 3 is (C1-C4) alkyl acyl, 5- or 6-membered heteroaryl; Y and Z are each independently selected from N or CH; R 4 and R 5 are the same or different and are each independently selected from (C1-C4) alkyl, (C1-C4) alkyl optionally substituted with a hydroxyl group; or R 4 and R 5 together with the N atom to which they are attached form a 4-6 membered heterocyclic group; The heterocyclic group is optionally substituted with 0-3 identical or different Rs 6 ; the heterocyclic group optionally contains 1-4 identical or different heteroatoms selected from N, O, and S; R 6 is oxo, (C1-C4) alkyl, (C1-C4) alkyl acyl.

5. The 2-aminopyrimidine compound according to claim 4, wherein: The 2-aminopyrimidine compound of general formula I and its pharmaceutically acceptable salts, wherein, R 1 independently selected from hydrogen, halogen, (C1-C4) alkyl; Ar is phenyl, and said phenyl is optionally substituted by 1-3 identical or different R 3 substituents; X is C; m and n are the same or different, being 1 or 2; R 3 is (C1-C4) alkyl acyl, oxadiazolyl; Y and Z are CH; R 4 and R 5 are the same or different and are each independently selected from (C1-C4) alkyl, (C1-C4) alkyl optionally substituted with hydroxy; or R 4 and R 5 together with the N atom to which they are attached form , , , , , , , or .

6. A 2-aminopyrimidine compound and a pharmaceutically acceptable salt thereof, wherein: N -(4-acetylphenyl)-4-[5-chloro-2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -(4-acetylphenyl)-4-[2-({4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -(4-acetylphenyl)-4-[5-chloro-2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -(4-acetylphenyl)-4-[2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -(4-acetylphenyl)-4-[5-chloro-2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -(4-acetylphenyl)-4-[2-({4-[4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -(4-acetylphenyl)-4-[5-chloro-2-({4-[4-(piperidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(piperidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -(4-acetylphenyl)-4-[2-({4-[4-(piperidin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -(4-acetylphenyl)-4-[5-methyl-2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -(4-acetylphenyl)-4-[2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -(4-acetylphenyl)-4-{5-chloro-2-({4-[3-(morpholin-4-yl)pyrrolidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[5-methyl-2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[2-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[5-methyl-2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide; N -4-(1,3,4-oxadiazol-2-yl)phenyl]-4-[2-({4-[4-(4-ethylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrimidin-4-yl]piperazine-1-carboxamide.

7. The 2-aminopyrimidine compound according to any one of claims 1-6, characterized in that: The compound salt is a salt formed with an acid, and the acid is: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid or aspartic acid.

8. A pharmaceutical composition, characterized in that: The composition contains the compound of general formula I and its pharmaceutically acceptable salts according to any one of claims 1-7.

9. An application of the compound according to any one of claims 1-7, characterized in that: Use of the compound according to any one of claims 1-7 and its pharmaceutically acceptable salts in the preparation of a drug for preventing or treating diseases related to JAK2 / FLT3 dual kinase inhibitors.

10. The application according to any one of claim 9, characterized in that: The diseases are: inflammatory bowel disease and hematological malignancies.

11. The application according to claim 10, characterized in that: The hematological malignancies are: leukemia, myelodysplastic syndrome, malignant lymphoma, multiple myeloma, myeloproliferative diseases.

12. The application according to claim 11, characterized in that: The leukemia is: acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia and chronic myeloid leukemia.

13. The application according to claim 11, characterized in that: The myeloproliferative diseases are: polycythemia vera, chronic myelogenous leukemia, essential thrombocythemia and myelofibrosis.

14. The application according to claim 10, characterized in that: The inflammatory bowel disease is: ulcerative colitis and Crohn's disease.

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