WO2021000884A1 - 2-氨基嘧啶类化合物及其用途 - Google Patents

2-氨基嘧啶类化合物及其用途 Download PDF

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WO2021000884A1
WO2021000884A1 PCT/CN2020/099683 CN2020099683W WO2021000884A1 WO 2021000884 A1 WO2021000884 A1 WO 2021000884A1 CN 2020099683 W CN2020099683 W CN 2020099683W WO 2021000884 A1 WO2021000884 A1 WO 2021000884A1
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amino
phenyl
pyrimidin
piperazine
morpholin
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PCT/CN2020/099683
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English (en)
French (fr)
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赵燕芳
李颖修
秦铭泽
侯云雷
刘亚婧
宫平
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沈阳药科大学
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Priority to JP2022500082A priority Critical patent/JP2022538493A/ja
Priority to CN202080038720.0A priority patent/CN113891881A/zh
Priority to EP20835339.1A priority patent/EP3998254A4/en
Priority to US17/624,749 priority patent/US20220259196A1/en
Publication of WO2021000884A1 publication Critical patent/WO2021000884A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/50—Three nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular to a series of novel 2-aminopyrimidine compounds and their pharmaceutically acceptable salts, solvates or prodrugs, their preparation methods and pharmaceutical compositions containing the compounds.
  • the invention also relates to the use of such compounds in the preparation of medicines for the treatment and/or prevention of hematological malignancies and other proliferative diseases.
  • Hematological malignancies are tumorous diseases of the blood system caused by disorders of the hematopoietic system, which mainly include leukemia, lymphoma, myelodysplastic syndrome, and multiple myeloma. Because of the abnormal hematopoietic function in patients with malignant hematological diseases, combined with chemotherapy or radiotherapy, the patient's bone marrow hematopoietic and immune function is inhibited, and nosocomial infections are easily combined, which leads to aggravation and death.
  • JAK kinase (janus kinase) is an intracellular non-receptor tyrosine protein kinase, and JAK2 is an important member of the JAK kinase family. JAK2 can form a cell signal transduction pathway with multiple members of the STAT family, such as JAK2-STAT3 and JAK2-STAT5. Under normal physiological conditions, erythropoietin, interleukin, thrombopoietin and other cytokines bind to the receptor to cause homologous or heterologous oligomerization of the receptor, thereby activating the JAK2 kinase coupled to the receptor Autophosphorylation occurs.
  • JAK2 catalyzes the phosphorylation of tyrosine residues on the receptor and forms a "parking site" with surrounding amino acids, allowing the STAT protein containing the SH2 domain to bind to and phosphorylate.
  • Activated STATs can form homologous or heterologous dimers and quickly enter the nucleus to induce gene transcription.
  • the JAK2-STATs signaling pathway is an important pathway of cell signal transduction, and it plays an important role in regulating the normal physiological and pathological responses of the human body. The abnormally elevated activity of JAK2 will make the JAK2-STATs signal pathway regulation abnormal, leading to various malignant diseases.
  • FLT3 is a member of the type III receptor tyrosine kinase family and plays an important role in the proliferation, differentiation and apoptosis of hematopoietic cells and lymphocytes. Mutations in the FLT3 gene can cause abnormal activation of kinases. Without relying on ligands, autophosphorylation occurs, which activates a series of downstream signaling pathways, leading to abnormal proliferation of hematopoietic cells and lymphocytes, leading to a variety of malignant blood diseases. Therefore, inhibition of FLT3 kinase and its mutants is an effective method to treat related blood diseases, especially AML.
  • JAK2/FLT3 kinases The abnormally elevated activity of JAK2 and FLT3 kinases is closely related to the occurrence of hematological malignancies, and the medical needs of MF, lymphoma and AML in hematological malignancies have not been met. Therefore, the research of JAK2/FLT3 inhibitors has become a new field for the treatment of such diseases.
  • JAK2/FLT3 inhibitors there are few related literature reports on JAK2/FLT3 inhibitors, and there are no JAK2/FLT3 small molecule inhibitors approved for marketing.
  • some compounds with outstanding activity and good therapeutic effects are in the preclinical and clinical research stage, such as: Pacritinib( J. Med. Chem., 54 (2011) 4638-4658), Fedratinib (Cancer Cell, 13 (2008) 311-320), Lestaurtinib (Blood, 103 (2004) 3669-3676), etc.
  • Momelotinib reported in the literature by Gilead development of a 2-amino pyrimidines JAK1 and JAK2 kinase inhibitor, IC 50, respectively, and 11nM 18nM.
  • the drug is currently in the clinical phase III research stage for the treatment of myelofibrosis, polycythemia and thrombocytosis.
  • the inventors designed and synthesized a series of 2-aminopyrimidine derivatives on the basis of references, and tested in vitro JAK2 and FLT3 kinase inhibitory activity, and the results showed that they all have inhibitory activity.
  • the present invention relates to 2-aminopyrimidine compounds of general formula I and pharmaceutically acceptable salts, solvates or prodrugs thereof,
  • X and Y are the same or different, and are independently selected from N and CH;
  • Q is NH, CH 2 ;
  • Z is selected from NH, NCH 3 , O or a chemical bond
  • n and n are the same or different, and are integers between 1-3;
  • R 1 and R 2 are the same or different, and are independently selected from hydrogen, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, cyano, amino, nitro Group, or R 1 and R 2 together form a (C 6 -C 10 )aryl group, 5-10 membered heteroaryl group, 4-10 membered heterocyclic group, the heterocyclic group optionally includes 0-3 double bonds ;
  • R 3 is (C 1 -C 6 )alkyl acyl, (C 6 -C 10 ) aryl, 5-10 membered heteroaryl, the aryl or heteroaryl may be optionally 1-3 identical or different Replaced by R 8 ;
  • R 8 is hydroxy, halogen, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl acyl, (C 1 -C 6 )amino Formyl, -NR 5 R 6 , -(CH 2 ) p NR 5 R 6 , -CONR 5 R 6 , -NHCONR 5 R 6 , -O(CH 2 ) p NR 5 R 6 , -SO 2 (CH 2 ) p NR 5 R 6 ⁇ -SO 2 (CH 2 ) p CONR 5 R 6 ;
  • R 5 and R 6 are the same or different, and are each independently selected from hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 6 )alkenyl, ( C 2 -C 6 )alkynyl, (C 1 -C 6 )alkyl acyl, (C 1 -C 6 )alkoxy;
  • R 5 and R 6 together with the nitrogen atom to which they are connected form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group, except for those connected to R 5 and R 6
  • it optionally contains 0-4 heteroatoms selected from N, O and/or S
  • the heterocyclic group optionally includes 0-3 double bonds
  • the heterocyclic group or heteroaryl group optionally Replaced by 0-3 identical or different R 7 ;
  • R 7 is (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl;
  • p is an integer from 0-4;
  • R 4 is (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 6 -C 10 ) aryl, 5-10 membered heteroaryl, (C 6 -C 10 ) aryl Ylmethyl, 5-10 membered heteroarylmethyl, the aryl or heteroaryl is optionally substituted with 1-3 R 9 which are the same or different;
  • R 9 is hydroxy, halogen, halogenated (C 1 -C 6 ) alkyl, halogenated (C 1 -C 6 ) alkoxy, nitro, amino, cyano, (C 1 -C 6 ) alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, (C 1 -C 6) alkoxy, optionally substituted with hydroxy, amino, or halogenated (C 1 -C 6) alkyl Or (C 1 -C 6 ) alkoxy, amino substituted by 1-2 (C 1 -C 6 ) alkyl groups, (C 1 -C 6 ) alkyl amide group, free, salt-forming, ester And amidated carboxyl, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkoxy, (C 1 -C
  • the 2-aminopyrimidine compound of general formula I according to claim 1 and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof are preferred in the present invention
  • Z is selected from NH, NCH 3 or a chemical bond
  • R 1 and R 2 are the same or different, and are independently selected from hydrogen, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, cyano, amino, nitro Group, or R 1 and R 2 together form a (C 6 -C 10 ) aryl group or a 5-10 membered heteroaryl group;
  • R 3 is a (C 6 -C 10 ) aryl group, a 5-10 membered heteroaryl group, and the aryl or heteroaryl group is optionally substituted by 1-3 identical or different R 8 groups.
  • the present invention preferably also relates to compounds of 2-aminopyrimidine compounds of general formula I and their stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
  • n and n are the same or different, and are 1, 2;
  • R 3 is a phenyl group, a 5-6 membered heteroaryl group, and the phenyl group or heteroaryl group is optionally substituted by 1-3 same or different R 8 groups;
  • R 8 is (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl acyl, (C 1 -C 6 )carbamoyl, -NR 5 R 6 , -(CH 2 ) p NR 5 R 6 , -CONR 5 R 6 , -NHCONR 5 R 6 , -O(CH 2 ) p NR 5 R 6 , -SO 2 (CH 2 ) p NR 5 R 6 ;
  • R 5 and R 6 are the same or different, and are each independently selected from hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 4 )alkyl acyl;
  • R 5 and R 6 form together with the nitrogen atom to which they are attached
  • R 4 is a phenyl group, a 5-6 membered heteroaryl group, and the phenyl group or heteroaryl group is optionally substituted with 1 to 3 identical or different R 9 groups.
  • the present invention is more preferably 2-aminopyrimidine compounds of general formula I and their stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
  • Z is NH or a chemical bond
  • R 1 and R 2 are the same or different, and are independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, cyclopropyl, methoxy, trifluoromethyl, cyano, amino, nitro, or R 1 Together with R 2 to form a phenyl group, 5-6 membered heteroaryl group;
  • R 8 is (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl acyl, (C 1 -C 6 )carbamoyl, -NR 5 R 6 , -(CH 2 ) p NR 5 R 6 , -CONR 5 R 6 , -NHCONR 5 R 6 , -O(CH 2 ) p NR 5 R 6 ;
  • R 5 and R 6 are the same or different, and are each independently selected from hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl;
  • R 5 and R 6 form together with the nitrogen atom to which they are attached
  • the present invention is further preferred 2-aminopyrimidine compounds of general formula I and their stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
  • X and Y are N;
  • Z is a chemical bond
  • R 1 and R 2 are the same or different, and are independently selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl, amino, and nitro;
  • R 3 is a phenyl group, and the phenyl group is optionally substituted with 1-3 R 8 which are the same or different;
  • R 8 is -NR 5 R 6 , -(CH 2 ) p NR 5 R 6 , -CONR 5 R 6 , -O(CH 2 ) p NR 5 R 6 ;
  • p is an integer of 1-4;
  • R 4 is phenyl, optionally substituted with 1-3 R 9 which are the same or different.
  • the present invention particularly preferably relates to 2-aminopyrimidine compounds of general formula I and their stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
  • R 2 is hydrogen
  • R 8 is -NR 5 R 6 , -O(CH 2 ) p NR 5 R 6 ;
  • p 2, 3;
  • the present invention particularly preferably also relates to 2-aminopyrimidine compounds of general formula I and their stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
  • R 1 is hydrogen, fluorine, chlorine, methyl, or trifluoromethyl
  • R 5 and R 6 form together with the nitrogen atom to which they are attached
  • the compound of formula I of the present invention can form a pharmaceutically acceptable salt thereof with an acid.
  • 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.
  • the compound of the present invention can significantly inhibit the kinase activity of JAK2 and FLT3, and has a strong inhibitory effect on blood cancer cells with high JAK2 or FLT3 expression.
  • the compound of the present invention has significant anti-tumor activity, so the compound of the present invention can be used to prepare treatment or prevent various hyperplasia Drugs for diseases or malignant blood diseases, such as myelofibrosis, multiple myeloma, polycythemia vera, essential thrombocythemia, acute myeloid leukemia, acute lymphocytic leukemia, etc.
  • diseases or malignant blood diseases such as myelofibrosis, multiple myeloma, polycythemia vera, essential thrombocythemia, acute myeloid leukemia, acute lymphocytic leukemia, etc.
  • the precise amount of the compound of the present invention required to treat proliferative diseases or hematological malignancies will vary from subject to subject, depending on the subject’s type, age and general conditions, the severity of the disease being treated, the specific compound used, and the administration. Mode of medication, such as route and frequency of administration, etc. A person of ordinary skill in the art can determine the appropriate effective amount only by using conventional experimental methods.
  • 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 per day. It is understood that the dosage may vary depending on the needs of the patient, the severity of the proliferative disease or hematological malignancy being treated, and the specific compound used. Moreover, it is understandable that the initial dose administered can be increased beyond the upper limit in order to quickly reach the required blood level, or the initial dose can be less than the optimal value, and the daily dose can be gradually increased during the treatment period, depending on the specific Case. If necessary, the daily dose can also be divided into multiple doses, for example 2-4 times a day.
  • Mammal means human or animal.
  • the amount of the active ingredient, that is, the compound according to the present invention, in the pharmaceutical composition and its unit dosage form can vary, depending on the specific application, the potency of the specific compound and the desired concentration. Generally speaking, the active ingredient content will be between 0.5% and 90%, based on the total weight of the composition.
  • the compound of the present invention and other compounds may be administered simultaneously or at intervals.
  • the compound of the present invention and other compounds may be combined in a single pharmaceutical composition or in separate compositions.
  • R 1 and R 2 are hydrogen or methyl.
  • R 4 , R 8 , m and n are the same as in the claims.
  • reaction solution was concentrated under reduced pressure, 10 mL of water was added to the residue, the pH was adjusted to 5 with 1M hydrochloric acid solution, suction filtration, the filter cake was washed with water (10 mL), and after drying, 2.5 g of white solid was obtained with a yield of 91%.
  • the key intermediate G was synthesized according to the synthesis method 1.1 to 1.5 in Example 1; the key intermediate G was synthesized according to the synthesis method 1.6 in Example 1 using 4-aminobenzamide as the raw material Intermediate H, then synthesized N-(4-carbamoylphenyl)-4-(2- ⁇ [4-(4-methylpiperazin-1-yl)benzene according to the synthesis method of 1.7 in Example 1 Yl]amino ⁇ pyrimidin-4-yl)piperazine-1-carboxamide. The yield was 56%.
  • the key intermediate G was synthesized according to the synthesis method of 1.1 to 1.5 in Example 1; 4-aminoacetophenone was used as the raw material, according to 1.6 in Example 1.
  • the key intermediate G was synthesized according to the synthesis method of 1.1 to 1.5 in Example 1; using 4-aminoacetophenone as the raw material, the key was synthesized according to the synthesis method of 1.6 in Example 1.
  • Intermediate H then synthesized N-(4-acetylphenyl)-4-(2- ⁇ [4-(4-methylpiperidin-1-yl)phenyl] according to the synthesis method of 1.7 in Example 1. Amino ⁇ pyrimidin-4-yl)piperazine-1-carboxamide. The yield was 51%.
  • the key intermediate G was synthesized according to the synthesis method of 1.1 to 1.5 in Example 1; with 4-aminoacetophenone as the raw material, according to 1.6 in Example 1.
  • Synthetic method to synthesize key intermediate H and then synthesize N-(4-acetylphenyl)-4-[2-( ⁇ 4-[2-(morpholin-4-yl) according to the synthetic method of 1.7 in Example 1. )Ethoxy]phenyl ⁇ amino)pyrimidin-4-yl]piperazine-1-carboxamide. The yield was 52%.
  • the key intermediate G was synthesized according to the synthesis method 1.1 to 1.5 in Example 1; 4-aminoacetophenone was used as the raw material, and 1.6 in Example 1.
  • Synthetic method to synthesize key intermediate H and then synthesize N-(4-acetylphenyl)-4-[2-( ⁇ 4-[3-(morpholin-4-yl) according to the synthesis method of 1.7 in Example 1. )Propoxy]phenyl ⁇ amino)pyrimidin-4-yl]piperazine-1-carboxamide. The yield was 41%.
  • the key intermediate G was synthesized according to the synthesis method of 1.3 to 1.5 in Example 1; using 4-cyanoaniline as the raw material, according to 1.6 in Example 1.
  • the key intermediate H was synthesized according to the synthetic method, and N-(4-cyanophenyl)-4-(5-methyl-2- ⁇ [4-(morpholine- 4-yl)phenyl]amino ⁇ pyrimidin-4-yl)piperazine-1-carboxamide. The yield was 70%.
  • the key intermediate G was synthesized according to the synthesis method of 1.3 to 1.5 in Example 1; using 4-cyanoaniline as the raw material, according to 1.6 in Example 1.
  • 4-yl)phenyl]amino ⁇ pyrimidin-4-yl)piperazine-1-carboxamide The yield was 51%.
  • the key intermediate G was synthesized according to the synthesis method of 1.3 to 1.5 in Example 1; 4-aminoacetophenone was used as the raw material, according to the method in Example 1.
  • the synthesis method of 1.6 is used to synthesize the key intermediate H, and the synthesis method of 1.7 in Example 1 is followed to synthesize N-(4-acetylphenyl)-4-(5-methyl-2- ⁇ [4-(morpholine -4-yl)phenyl]amino ⁇ pyrimidin-4-yl)piperazine-1-carboxamide.
  • the yield was 64%.
  • the key intermediate G was synthesized according to the synthesis method 1.3 to 1.5 in Example 1; with 4-aminoacetophenone as the raw material, according to the method in Example 1.
  • the synthesis method of 1.6 is used to synthesize the key intermediate H, and then N-(4-acetylphenyl)-4-(6-methyl-2- ⁇ [4-(morpholine) is synthesized according to the synthesis method of 1.7 in Example 1.
  • -4-yl)phenyl]amino ⁇ pyrimidin-4-yl)piperazine-1-carboxamide The yield was 62%.
  • the key intermediate G was synthesized according to the synthesis method of 1.3 to 1.5 in Example 1; using 4-aminoacetophenone as the raw material, according to the implementation
  • the synthesis method of 1.6 in Example 1 was used to synthesize the key intermediate H, and the synthesis method of 1.7 in Example 1 was followed to synthesize N-(4-acetylphenyl)-4-(2- ⁇ [4-(morpholin- 4-yl)phenyl]amino ⁇ thieno[3,2-d]pyrimidin-4-yl)piperazine-1-carboxamide.
  • the yield is 60%.
  • the key intermediate G was synthesized according to the synthesis method of 1.3 to 1.5 in Example 1; using 4-aminoacetophenone as the raw material, the synthesis method of 1.6 in Example 1 was followed Synthesize key intermediate H, and then synthesize N-(4-acetylphenyl)-4-(2- ⁇ [4-(morpholin-4-yl)phenyl]amino ⁇ according to the synthesis method of 1.7 in Example 1. Quinazolin-4-yl)piperazine-1-carboxamide. The yield was 65%.
  • the key intermediate G was synthesized according to the synthesis method 1.3 to 1.5 in Example 1; 4-aminoacetophenone was used as the raw material, according to Example 1.
  • the yield was 61%.
  • the key intermediate G was synthesized according to the synthesis method of 1.3 to 1.5 in Example 1; 4-aminoacetophenone was used as the raw material, according to the method in Example 1.
  • the synthesis method of 1.6 was used to synthesize the key intermediate H, and the synthesis method of 1.7 in Example 1 was followed to synthesize N-(4-acetylphenyl)-4-(5-nitro-2- ⁇ [4-(morpholine) -4-yl)phenyl]amino ⁇ pyrimidin-4-yl)piperazine-1-carboxamide, followed by synthesis of N-(4-acetylphenyl)-4-( according to the synthesis method of 1.2 in Example 1 5-amino-2- ⁇ [4-(morpholin-4-yl)phenyl]amino ⁇ pyrimidin-4-yl)piperazine-1-carboxamide. The yield is 30%.
  • the key intermediate H was synthesized according to the synthesis method of 1.6 in Example 1, followed by 3-[(2-chloro-5-methylpyrimidin-4-yl)amino]pyrrolidine Hydrochloride (M) was used as the raw material, and the key intermediate N-(4-acetylphenyl)-3-[(2-chloro-5-methylpyrimidine-4) was synthesized according to the synthesis method of 1.7 in Example 1.
  • -Amino]pyrrolidine-1-carboxamide The yield is 60%.
  • N N-(4-acetylphenyl)-3-[(2-chloro-5-methylpyrimidin-4-yl)amino]pyrrolidine-1-carboxamide (N) as the raw material, according to Example 1
  • the synthesis method of 1.4 Synthesis of N-(4-acetylphenyl)-3-[(5-methyl-2- ⁇ [4-(morpholin-4-yl)phenyl]amino ⁇ pyrimidin-4-yl )Amino]pyrrolidine-1-carboxamide. The yield was 81%.
  • the key intermediate H was synthesized according to the synthesis method of 1.6 in Example 1.
  • 5.0 g (26.8 mmol) of tert-butyl 3-aminopyrrolidine-1-carboxylate ( K) and 7.5g (29.5mmol) of intermediate H were added to 50mL 1,4-dioxane, 14.0g (107.2mmol) of N,N-diisopropylethylamine (DIPEA) was added dropwise to the reaction solution, After dripping, the temperature was raised to 80°C to react for 3h.
  • DIPEA N,N-diisopropylethylamine
  • N-(4-acetylphenyl)-3-[(5-) was synthesized according to the synthesis method of 28.1-28.4 in Example 28 Methyl-2- ⁇ [4-(morpholin-4-yl)phenyl]amino ⁇ pyrimidin-4-yl)amino]azetidine-1-carboxamide. The yield was 68%.
  • 1-(4-acetylphenyl)-3-[1-() was synthesized according to the synthesis method of 29.1 ⁇ 29.4 in Example 29 5-methyl-2- ⁇ [4-(morpholin-4-yl)phenyl]amino ⁇ pyrimidin-4-yl)azetidin-3-yl]urea. The yield was 61%.
  • N-(4-acetylphenyl)-4-[(5-methyl-2) was synthesized according to the synthesis method of 28.1 ⁇ 28.4 in Example 28 - ⁇ [4-(morpholin-4-yl)phenyl]amino ⁇ pyrimidin-4-yl)amino]piperidine-1-carboxamide. The yield was 71%.
  • the key intermediate E was synthesized according to the synthesis method 1.1-1.2 in Example 1; using 5-methyl-2,4-dichloropyrimidine as the raw material, according to Synthesize the key intermediate G using the synthesis method of 1.3 to 1.5 in Example 1.
  • 4-aminoacetophenone as the raw material, synthesize the key intermediate H according to the synthesis method of 1.6 in Example 1, and then according to the method in Example 1.
  • the key intermediate E was synthesized according to the synthesis method 1.1-1.2 in Example 1; using 5-methyl-2,4-dichloropyrimidine as the raw material, according to the example Synthesize the key intermediate G using the synthesis method of 1.3 ⁇ 1.5 in 1.
  • 4-aminoacetophenone as the raw material, synthesize the key intermediate H according to the synthesis method of 1.6 in Example 1, and then according to the synthesis of 1.7 in Example 1.
  • the key intermediate E was synthesized according to the synthesis method 1.1 to 1.2 in Example 1; using 5-methyl-2,4-dichloropyrimidine as the raw material, according to Synthesize the key intermediate G using the synthesis method of 1.3 to 1.5 in Example 1.
  • 4-aminoacetophenone as the raw material, synthesize the key intermediate H according to the synthesis method of 1.6 in Example 1, and then according to the method in Example 1.
  • the key intermediate E was synthesized according to the synthesis method 1.1-1.2 in Example 1; 5-methyl-2,4-dichloropyrimidine was used as the raw material, Synthesize the key intermediate G according to the synthesis method of 1.3 to 1.5 in Example 1.
  • 4-aminoacetophenone as the raw material, synthesize the key intermediate H according to the synthesis method of 1.6 in Example 1, and then according to Example 1.
  • the in vitro JAK2 and FLT3 kinase activity test was performed on the compound of the 2-aminopyrimidine backbone of the above formula I (concentration 0.1 ⁇ M) according to the present invention using Mobility Shift Assay.
  • the reference materials Pacritinib and Fedratinib were prepared by our research group.
  • the kinase buffer is composed 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 test compound was diluted with 100% DMSO to 50 times the highest concentration required in the reaction. Transfer the test compound dilution (100 ⁇ L) to the wells of the 96-well plate. Then, by adding 100 mL of DMSO to the two wells as a control group, they were labeled as the source plate. Transfer 10 ⁇ L of compound from the source plate to a new 96-well plate to prepare an intermediate plate.
  • the middle plate add 90 ⁇ L of kinase buffer to each well. Shake the middle plate for 10 minutes, and then copy 5 ⁇ L of each well of the 96-well middle plate as an analysis plate to the 384-well plate. Add the prepared enzyme solution to each well of the 384-well plate, then incubate at room temperature for 10 minutes, and then add 10 ⁇ L of the prepared peptide solution (FAM-labeled peptide and ATP in kinase-based buffer). Incubate the sample at 28°C for 1 h, and then add 25 ⁇ L of buffer. Copy the conversion data from the Caliper program and convert it to the inhibition rate.
  • FAM-labeled peptide and ATP in kinase-based buffer
  • Inhibition rate (%) (max-conversion)/(max-min) ⁇ 100.
  • Example 1 Compound 48.7 21.7 Example 2 Compound 54.3 30.5 Example 3 Compound 53.3 27.4 Example 4 Compound 53.7 30.8 Example 5 Compound 64.4 62.8 Example 6 Compound 76.7 72.3 Example 7 Compound 79.3 84.4 Example 8 Compound 63.7 70.3 Example 10 Compound 76.3 71.2 Example 11 Compound 68.1 35.8 Example 12 Compound 76.0 69.7 Example 13 Compound 73.0 70.8
  • Example 15 Compound 84.0 85.0
  • Example 16 Compound 45.0 69.0
  • Example 17 Compound 53.0 54.0
  • Example 18 Compound 61.7 70.6
  • Example 19 Compound 60.9 70.9
  • Example 20 Compound 88.5 95.2
  • Example 22 Compound 81.8 99.1
  • Example 24 Compound 44.0 68.0
  • Example 26 Compound 74.6 82.5
  • Example 27 Compound 22.8 67.9
  • Example 28 compound 69.3 57.3
  • Example 29 Compound 57.4 75.7
  • Example 31 Compound 21.9 50.0
  • Example 32 Compound 80.5 78.6
  • Example 33 Compound 74.3 97.0 Pacritinib 92.0 96.0 Fedratinib 95.2 88.7
  • the compound of the 2-aminopyrimidine skeleton of the above formula I according to the present invention was tested to inhibit the activity of human erythroleukemia cells HEL and human myeloid monocytic leukemia cells Molm-13 in vitro.
  • the reference materials Pacritinib and Fedratinib were prepared by our research group.
  • Inhibition rate (%) [(A control-A plus medicine)/(A control-A blank)] ⁇ 100
  • IC 50 is the concentration of the drug required to inhibit half of the cell growth. According to the results of drug concentration and inhibition rate, the IC 50 is calculated using GraphPad Prism 5 software through the dose-effect curve.
  • Table 3 shows the test results of human erythroleukemia cells HEL and human myeloid monocytic leukemia cells Molm-13 of some compounds.

Abstract

本发明涉及通式I所示的2-氨基嘧啶类化合物及其药学上可接受的盐、溶剂化物或前药、它们的制备方法以及含有所述化合物的药物组合物，其中取代基R1、R2、R3、R4、X、Y、Z、Q、m、n具有在说明书中给出的含义。本发明还涉及通式Ⅰ的化合物在制备治疗和/或预防恶性血液疾病和其它增生性疾病的药物中的用途。

Description

2-氨基嘧啶类化合物及其用途
本申请要求2019年7月4日提交的发明名称为“2-氨基嘧啶类化合物及其用途”的中国专利申请No.201910598383.X的优先权，将其内容完整并入本文作为参考。
技术领域：
本发明涉及药物化学领域，特别涉及一系列新型的2-氨基嘧啶类化合物及其药学上可接受的盐、溶剂化物或前药，它们的制备方法以及含有所述化合物的药物组合物。本发明还涉及该类化合物用于制备治疗和/或预防恶性血液疾病和其它增生性疾病的药物中的用途。
背景技术：
恶性血液病是造血***障碍引起的血液***肿瘤性疾病，主要包括白血病、淋巴瘤、骨髓增生异常综合症以及多发性骨髓瘤等疾病。由于恶性血液疾病患者造血功能异常，加之化疗或放疗抑制了患者骨髓造血及免疫功能，且易合并医院感染，从而导致病情加重甚至死亡。
JAK激酶(janus kinase)是一种细胞内非受体型酪氨酸蛋白激酶，而JAK2是JAK激酶家族中的重要成员之一。JAK2可与STAT家族的多个成员构成细胞信号转导通路，如JAK2-STAT3和JAK2-STAT5等。正常生理情况下，***、白介素、促血小板生成素等多种细胞因子与受体结合，使受体发生同源或异源的寡聚化，从而激活与受体偶联的JAK2激酶发生自磷酸化。活化的JAK2催化受体上的酪氨酸残基磷酸化并与周围的氨基酸形成“停泊位点”，使含有SH2结构域的STAT蛋白与其结合并发生磷酸化。活化的STATs能形成同源或异源的二聚体并迅速进入细胞核内，诱导基因的转录。JAK2-STATs信号通路是细胞信号转导的重要途径，对调节人体正常的生理和病理反应发挥重要作用。JAK2异常升高的活性会使JAK2-STATs信号通路调控失常，从而导致各种恶性疾病的发生。
FLT3是III型受体酪氨酸激酶家族的成员之一，在造血细胞和淋巴细胞的增殖、分化和凋亡过程中发挥重要作用。FLT3基因突变会导致激酶的异常活化，在不依赖于配体的情况下，发生自身磷酸化，从而激活一系列下游信号通路，导致造血细胞和淋巴细胞异常增殖，引发多种恶性血液疾病。因此，抑制FLT3激酶及其突变体是治疗相关血液疾病特别是AML的有效方法。
JAK2和FLT3激酶的异常升高活性与恶性血液疾病的发生密切相关，且MF、淋巴瘤和AML在恶性血液病中的医疗需求未得到满足。因此，JAK2/FLT3抑制剂的研究成为治疗此类疾病的新领域。
目前针对JAK2/FLT3抑制剂的相关文献报道较少，且没有批准上市的JAK2/FLT3小分子抑制剂，但有些活性突出且治疗效果好的化合物已处于临床前及临床研究阶段，如：Pacritinib(J.Med.Chem.,54(2011)4638-4658)、Fedratinib(Cancer Cell,13(2008)311-320)、Lestaurtinib(Blood,103(2004)3669-3676)等。文献报道的Momelotinib是由吉利德公司开发的一种2-氨基嘧啶类JAK1和JAK2激酶抑制剂，IC 50分别为11nM和18nM。该药目前处于临床Ⅲ期研究阶段，用于治疗骨髓纤维化，红细胞增多症及血小板增多症。
Figure PCTCN2020099683-appb-000001
本发明人在参考文献的基础上，设计并合成了一系列2-氨基嘧啶类衍生物，经体外JAK2和FLT3激酶抑制活性测试，结果表明均具有抑制活性。
发明内容：
本发明涉及通式Ⅰ的2-氨基嘧啶类化合物及其药学上可接受的盐、溶剂化物或其前药，
Figure PCTCN2020099683-appb-000002
其中，
X和Y相同或不同，分别独立地选自N和CH；
Q为NH、CH 2；
Z选自NH、NCH 3、O或一根化学键；
m和n相同或不同，为1-3之间的整数；
R 1和R 2相同或不同，分别独立地选自氢、卤素、(C 1-C 6)烷基、(C 1-C 6)烷氧基、三氟甲基、氰基、氨基、硝基，或R 1和R 2一起形成(C 6-C 10)芳基、5-10元杂芳基、4-10元杂环基，所述杂环基任选包括0-3个双键；
R 3为(C 1-C 6)烷基酰基、(C 6-C 10)芳基、5-10元杂芳基，所述芳基或者杂芳基任选被1-3个相同或不同的R 8取代；
R 8为羟基、卤素、氰基、(C 1-C 6)烷基、(C 1-C 6)烷氧基、(C 1-C 6)烷基酰基、(C 1-C 6)氨基甲酰基、-NR 5R 6、-(CH 2) pNR 5R 6、-CONR 5R 6、-NHCONR 5R 6、-O(CH 2) pNR 5R 6、-SO 2(CH 2) pNR 5R 6、-SO 2(CH 2) pCONR 5R 6；
其中，R 5和R 6相同或不同，分别独立地选自氢、(C 1-C 6)烷基、(C 3-C 7)环烷基、(C 2-C 6)烯基、(C 2-C 6)炔基、(C 1-C 6)烷基酰基、(C 1-C 6)烷氧基；
或R 5和R 6与和它们所连接的氮原子一起形成4-10元杂环基或5-10元杂芳基，所述杂环基或杂芳基除了与R 5和R 6连接的氮原子外，任选含有0-4个选自N、O和/或S的杂原子，所述杂环基任选包括0-3个双键，所述杂环基或杂芳基任选被0-3个相同或不同的R 7取代；
R 7为(C 1-C 6)烷基、(C 3-C 7)环烷基；
p为0-4的整数；
R 4为(C 1-C 6)烷基、(C 3-C 7)环烷基、(C 6-C 10)芳基、5-10元杂芳基、(C 6-C 10)芳基甲基、5-10元杂芳基甲基，所述芳基或者杂芳基任选被1-3个相同或不同的R 9取代；
R 9为羟基、卤素、卤代(C 1-C 6)烷基、卤代(C 1-C 6)烷氧基、硝基、氨基、氰基、(C 1-C 6)烷基、(C 2-C 6)烯基、(C 2-C 6)炔基、(C 1-C 6)烷氧基、任选被羟基、氨基或卤代的(C 1-C 6)烷基或(C 1-C 6)烷氧基、被1-2个(C 1-C 6)烷基取代的氨基、(C 1-C 6)烷基酰胺基、游离的、成盐的、酯化的和酰胺化的羧基、(C 1-C 6)烷基亚磺酰基、(C 1-C 6)烷基磺酰基、(C 1-C 6)烷氧基、(C 1-C 6)烷基、(C 1-C 6)烷基酰基、(C 1-C 6)氨基甲酰基、被1-2个(C 1-C 6)烷基取代的氨基甲酰基、(C 1-C 3)亚烷基二氧基、烯丙基。
本发明优选权利要求1通式Ⅰ的2-氨基嘧啶类化合物及其立体异构体、药学上可接受的盐、溶剂化物或其前药，
其中，
Z选自NH、NCH 3或一根化学键；
R 1和R 2相同或不同，分别独立地选自氢、卤素、(C 1-C 6)烷基、(C 1-C 6)烷氧基、三氟甲基、氰基、氨基、硝基，或R 1和R 2一起形成(C 6-C 10)芳基、5-10元杂芳基；
R 3为(C 6-C 10)芳基、5-10元杂芳基，所述芳基或者杂芳基任选被1-3个相同或不同的R 8取代。
本发明优选还涉及通式Ⅰ的2-氨基嘧啶类化合物的化合物及其立体异构体、药学上可接受的盐、溶剂化物或其前药，
其中，
m和n相同或不同，为1，2；
R 3为苯基、5-6元杂芳基，所述苯基或者杂芳基任选被1-3个相同或不同的R 8取代；
R 8为(C 1-C 6)烷氧基、(C 1-C 6)烷基酰基、(C 1-C 6)氨基甲酰基、-NR 5R 6、-(CH 2) pNR 5R 6、-CONR 5R 6、-NHCONR 5R 6、-O(CH 2) pNR 5R 6、-SO 2(CH 2) pNR 5R 6；
R 5和R 6相同或不同，分别独立地选自氢、(C 1-C 4)烷基、(C 3-C 6)环烷基、(C 1-C 4)烷基酰基；
或R 5和R 6与和它们所连接的氮原子一起形成
Figure PCTCN2020099683-appb-000003
Figure PCTCN2020099683-appb-000004
R 4为苯基、5-6元杂芳基，所述苯基或者杂芳基任选被1-3个相同或不同的R 9取代。
本发明更为优选通式Ⅰ的2-氨基嘧啶类化合物及其立体异构体、药学上可接受的盐、溶剂化物或其前药，
Z为NH或一根化学键；
R 1和R 2相同或不同，分别独立地选自氢、氟、氯、甲基、乙基、环丙基、甲氧基、三氟甲基、氰基、氨基、硝基，或R 1和R 2一起形成苯基、5-6元杂芳基；
R 8为(C 1-C 6)烷氧基、(C 1-C 6)烷基酰基、(C 1-C 6)氨基甲酰基、-NR 5R 6、-(CH 2) pNR 5R 6、-CONR 5R 6、-NHCONR 5R 6、-O(CH 2) pNR 5R 6；
其中，R 5和R 6相同或不同，分别独立地选自氢、(C 1-C 4)烷基、(C 3-C 6)环烷基；
或R 5和R 6与和它们所连接的氮原子一起形成
Figure PCTCN2020099683-appb-000005
Figure PCTCN2020099683-appb-000006
本发明进一步优选通式Ⅰ的2-氨基嘧啶类化合物及其立体异构体、药学上可接受的盐、溶剂化物或其前药，
其中，
Q为NH；
X和Y为N；
Z为一根化学键；
m和n为2；
R 1和R 2相同或不同，分别独立地选自氢、氟、氯、甲基、甲氧基、三氟甲基、氨基、硝基；
R 3为苯基，所述苯基任选被1-3个相同或不同的R 8取代；
R 8为-NR 5R 6、-(CH 2) pNR 5R 6、-CONR 5R 6、-O(CH 2) pNR 5R 6；
p为1-4的整数；
R 4为苯基，任选被1-3个相同或不同的R 9取代。
本发明特别优选涉及通式Ⅰ的2-氨基嘧啶类化合物及其立体异构体、药学上可接受的盐、溶剂化物或其前药，
其中，
R 2为氢；
R 8为-NR 5R 6、-O(CH 2) pNR 5R 6；
p为2，3；
本发明特别优选还涉及通式Ⅰ的2-氨基嘧啶类化合物及其立体异构体、药学上可接受的盐、溶剂化物或其前药，
其中，
R 1为氢、氟、氯、甲基、三氟甲基；
R 5和R 6与和它们所连接的氮原子一起形成
Figure PCTCN2020099683-appb-000007
Figure PCTCN2020099683-appb-000008
本发明特别优选下列通式Ⅰ的2-氨基嘧啶类的化合物及其立体异构体、药学上可接受的盐、溶剂化物或其前药：
N-(4-甲氧基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-三氟甲氧基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-乙基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-苯基-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-甲氧甲酰苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-乙酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-硝基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-氰基-3-氟苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-异丙氧基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-氨基甲酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-甲氨基甲酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-氨基磺酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-乙酰氨基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-甲磺酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-氨基甲酰基苯基)-4-(2-{[4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-乙酰基苯基)-4-[2-({4-[2-(吡咯烷-1-基)乙氧基]苯基}氨基)嘧啶-4-基]哌嗪-1-甲酰胺；
N-(4-乙酰基苯基)-4-(2-{[4-(4-甲基哌啶-1-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-乙酰基苯基)-4-[2-({4-[2-(吗啉-4-基)乙氧基]苯基}氨基)嘧啶-4-基]哌嗪-1-甲酰胺；
N-(4-乙酰基苯基)-4-[2-({4-[3-(吗啉-4-基)丙氧基]苯基}氨基)嘧啶-4-基]哌嗪-1-甲酰胺；
N-(4-氰基苯基)-4-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-氰基苯基)-4-(6-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-乙酰基苯基)-4-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-乙酰基苯基)-4-(6-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-乙酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}噻吩并[3,2-d]嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-乙酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}喹唑啉-4-基)哌嗪-1-甲酰胺；
N-(4-乙酰基苯基)-4-(5-三氟甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-乙酰基苯基)-4-(5-氨基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
N-(4-乙酰基苯基)-3-[(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)氨基]吡咯烷-1-甲酰胺；
N-(4-乙酰基苯基)-4-[(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)氨基]哌啶-1-甲酰胺；
N-(4-乙酰基苯基)-4-[5-甲基-2-({4-[3-(吡咯烷-1-基)丙氧基]苯基}氨基)嘧啶-4-基]哌嗪-1-甲酰胺。
按照本发明所属领域的一些通常方法，本发明通式I的化合物可以与酸形成其药学上可接受的盐。优选的酸为盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘磺酸、三氟乙酸和天冬氨酸。
通过对JAK2和FLT3的酶活性测试发现，本发明化合物具有显著的抑制JAK2和FLT3激酶活性，对JAK2或FLT3高表达的血液癌细胞有较强的抑制作用。
通过体外抑制人红白血病细胞HEL和人髓性单核细胞白血病细胞MV4-11活性试验，我们发现本发明化合物具有显著的抗肿瘤活性，因此本发明化合物可以用于制备治疗或预防各种增生性疾病或恶性血液疾病的药物，如骨髓纤维化、多发性骨髓瘤、真性红细胞增多症、原发性血小板增多症、急性髓细胞白血病、急性淋巴细胞白血病等。
治疗增生性疾病或恶性血液疾病所需的本发明化合物的精确量将因受治疗者而异，依赖于受治疗者的种类、年龄与一般条件、所治疗疾病的严重性、所用特定化合物和给药方式，例如给药的途径和频率等等。本领域普通技术人员仅仅利用常规实验方法即可确定适当的有效量。
化合物的给药量可以从约0.1～100mg/kg体重每天，优选1～50mg/kg体重/天。可以理解的是，剂量可以因患者的需求，所治疗的增生性疾病或恶性血液疾病的严重性和所使用的特定化合物而异。而且，可以理解的是，所给药的最初剂量可以增加超出上限，目的是迅速达到所需血液水平，或者最初剂量可以小于最佳值，每日剂量可以在治疗期间逐渐增加，这依赖于具体的情况。如果需要的话，每日剂量也可以分为多剂量给药，例如每天2-4次。
哺乳动物表示人或动物。
活性成分，也就是根据本发明的化合物在药物组合物及其单位剂型中的量可以各不相同，依赖于特定应用、特定化合物的效力和所需浓度。一般而言，活性成分的含量将 在0.5％～90％之间，按组合物的总重量计。
在联合疗法中，本发明化合物和其它化合物可以被同时或间隔给药，在同时给药时，本发明化合物和其他化合物可以被结合在单一的药物组合物中或者在分开的组合物中。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下述实施例和制备例的范围并不以任何方式限制本发明的范围。
下面的合成路线描述了本发明的通式Ⅰ衍生物的制备，所有的原料都是通过这些示意图中描述的方法、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终化合物都是通过这些示意图中描述的方法或通过与其类似的方法制备的，这些方法是有机化学领域普通技术人员熟知的。这些示意图中应用的全部可变因数如下文的定义或如权利要求中的定义。
按照本发明的通式Ⅰ化合物，在路线A、路线B、路线C和路线D中，以如下化合物为例：R 1和R 2为氢或甲基。取代基R 4、R 8、m、n的定义同权利要求书。
路线A：
Figure PCTCN2020099683-appb-000009
路线A化合物I-i的合成
路线A中，以2,4-二氯嘧啶为起始原料，以碳酸钾作碱和N-Boc哌嗪进行取代反应得到中间体B，继而与R 8取代的苯胺E发生取代反应得到中间体F，继而与三氟乙酸进行脱Boc保护基反应得到中间体G，继而与R 4取代的氨基甲酸苯酯H发生取代反应制得通式I的化合物I-i。
路线B：
Figure PCTCN2020099683-appb-000010
路线B化合物I-ii的合成
路线B中，以5-甲基-2,4-二氯嘧啶(J)为起始原料，以碳酸钾作碱，与Boc保护的中间体K进行亲核取代反应得到中间体L，继而在盐酸甲醇溶液中进行脱Boc保护反应得到中间体M，继而与R 4取代的氨基甲酸苯酯H反应得到中间体N，随后与R 8取代的苯胺E发生取代反应制得通式I的化合物I-ii。
路线C：
Figure PCTCN2020099683-appb-000011
路线C化合物I-iii的合成
路线C中，R 4取代的氨基甲酸苯酯H与Boc保护的中间体K进行加成反应得到中间体O，继而在盐酸甲醇溶液中进行脱Boc保护反应得到中间体P，继而与5-甲基-2,4-二氯嘧啶(J)进行亲核取代反应得到中间体Q，随后与R 8取代的苯胺E发生取代反应制得通式I的化合物I-iii。
路线D：
Figure PCTCN2020099683-appb-000012
路线D化合物I-iv的合成
路线D中，以5-甲基-2,4-二氯嘧啶(J)为起始原料，在DIPEA作碱的条件下与4-哌啶甲酸甲酯发生亲核取代反应得到中间体R，继而与R 8取代的苯胺E反应得到中间体S，继而在NaOH溶液中发生水解反应得到中间体T，随后与R 4取代的胺发生缩合反应制得通式I的化合物I-iv。
具体实施方式：
在以下的实施例中，描绘了制备部分所述化合物的方法。应了解，以下方法及所属领域的普通技术人员已知的其他方法均可以适用于本发明所述的所有化合物的制备。实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用Bruker ARX-400或Bruker ARX-600测定，质谱用Agilent 1100LC/MSD测定；所用试剂均为分析纯或化学纯。
实施例1.N-(4-甲氧基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
1.1. 4-(2-氯嘧啶-4-基)哌嗪-1-甲酸叔丁酯的合成(B)
室温下，将20.0g(134mmol)2,4-二氯嘧啶(A)溶于200mL N,N-二甲基甲酰胺(DMF)中，加入22.0g(161mmol)碳酸钾，冰浴下分批加入26.0g(140mmol)N-Boc-哌嗪，加毕，室温反应2h。反应完毕，向反应液中加入1L水，搅拌，抽滤，100mL水洗滤饼，干燥得到中间体E粗品。柱层析纯化得到白色固体30.0g，收率75％。
1.2. 4-(4-硝基苯基)吗啉的合成(D)
室温下，将20.0g(142mmol)对氟硝基苯(C)溶于200mL乙腈中，向反应液中加入17.2g(170mmol)三乙胺和18.5g(212mmol)吗啉，加毕，升温至80℃反应3h。反应完毕，将反应液冷却至室温，减压浓缩溶剂，向残余物中加入200mL水，室温搅拌20min，抽滤，100mL水洗滤饼，干燥后得到黄色固体26.9g，收率91％。
1.3. 4-(4-氨基苯基)吗啉的合成(E)
将26.9g(129mmol)中间体D和1.34g(5％m/m)10％钯碳加入500mL 90％乙醇溶液中，通入氢气，室温反应5h。反应完毕，抽滤，100mL 90％乙醇洗涤滤饼，减压浓缩滤液得到***固体22.0g，收率96％。
1.4. 4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酸叔丁酯的合成(F)
将5.0g(16.8mmol)中间体C与3.6g(20.2mmol)中间体E加入50mL正丁醇中，室温缓慢滴加5.7g(50.4mmol)三氟乙酸，加毕，升温至120℃反应2h。反应完毕，减压浓缩溶剂，向残余物中加入50mL水，用饱和碳酸氢钠溶液调节pH至8，抽滤，滤饼用水(20mL)洗，干燥后得到蓝白色固体6.9g，收率93％。
1.5. 4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪的合成(G)
室温下，将6.9g(15.6mmol)中间体G加入70mL二氯甲烷中，缓慢滴加70mL三氟乙酸，滴毕，室温反应4h。反应完毕，减压浓缩溶液，向残余物中加入50mL水，用饱和碳酸氢钠溶液调节pH至8，抽滤，滤饼用水(20mL)洗，干燥后得到灰色固体4.1g，收率77％。
1.6.N-(4-甲氧基苯基)氨基甲酸苯酯的合成(H)
室温下，将1.4g(11.2mmol)4-甲氧基苯胺和0.7g(6.7mmol)碳酸钠加入10mL乙酸乙酯-四氢呋喃-水(3:1:1)混合溶液中，冰浴下，滴加1.9g(12.3mmol)氯甲酸苯酯的乙酸乙酯(3mL)溶液，滴毕，室温反应2h。反应完毕，减压浓缩反应液，向残余物中加入10mL水，用1M盐酸溶液调节pH至5，抽滤，滤饼用水(10mL)洗，干燥后得到白色固体2.5g，收率91％。
1.7.N-(4-甲氧基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺(I)的合成
室温下，将0.20g(0.6mmol)中间体G和0.17g(0.7mmol)中间体H加入4mL 1,4-二氧六环中，向反应液中滴加0.30g(2.3mmol)N,N-二异丙基乙胺(DIPEA)，滴毕，升温至80℃反应3h。反应完毕，冷却至室温，减压浓缩溶剂，向残余物中加入10mL水，2.5％NaOH溶液调节pH至10，抽滤，干燥得到粗产品。粗产品经柱层析(二氯甲烷:甲醇＝20:1)纯化后得到白色固体0.15g，收率62％。
实施例2.N-(4-三氟甲氧基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以4-三氟甲氧基苯胺为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-三氟甲氧基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率65％。
实施例3.N-(4-乙基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以4-乙基苯胺为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率57％。
实施例4.N-苯基-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以苯胺为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-苯基-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率64％。
实施例5.N-(4-甲氧甲酰苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以4-氨基苯甲酸甲酯为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-甲氧甲酰苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率64％。
实施例6.N-(4-乙酰苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙酰苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率62％。
实施例7.N-(4-硝基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以4-硝基苯胺为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-硝基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率45％。
实施例8.N-(4-氰基-3-氟苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以4-氰基-3-氟苯胺为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-氰基-3-氟苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率71％。
实施例9.N-(4-异丙氧基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以4-异丙氧基苯胺为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-异丙氧基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率70％。
实施例10.N-(4-氨基甲酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以4-氨基苯甲酰胺为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-氨基甲酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率52％。
实施例11.N-(4-甲氨基甲酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以4-氨基-N-甲基苯甲酰胺为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-甲氨基甲酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率61％。
实施例12.N-(4-氨基磺酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以4-氨基苯磺酰胺为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-氨基磺酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率47％。
实施例13.N-(4-乙酰氨基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以4-氨基乙酰苯胺为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙酰氨基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率53％。
实施例14.N-(4-甲磺酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺 的制备
以4-甲磺酰基苯胺为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-甲磺酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率68％。
实施例15.N-(4-氨基甲酰基苯基)-4-(2-{[4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以N-甲基哌嗪为原料，按照实施例1中的1.1～1.5的合成方法合成关键中间体G；以4-氨基苯甲酰胺为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-氨基甲酰基苯基)-4-(2-{[4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率56％。
实施例16.N-(4-乙酰苯基)-4-[2-({4-[2-(吡咯烷-1-基)乙氧基]苯基}氨基)嘧啶-4-基]哌嗪-1-甲酰胺的制备
以1-(2-羟乙基)吡咯烷为原料，按照实施例1中的1.1～1.5的合成方法合成关键中间体G；以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙酰苯基)-4-[2-({4-[2-(吡咯烷-1-基)乙氧基]苯基}氨基)嘧啶-4-基]哌嗪-1-甲酰胺。收率42％。
实施例17.N-(4-乙酰苯基)-4-(2-{[4-(4-甲基哌啶-1-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以4-甲基哌啶为原料，按照实施例1中的1.1～1.5的合成方法合成关键中间体G；以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙酰苯基)-4-(2-{[4-(4-甲基哌啶-1-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率51％。
实施例18.N-(4-乙酰苯基)-4-[2-({4-[2-(吗啉-4-基)乙氧基]苯基}氨基)嘧啶-4-基]哌嗪-1-甲酰胺的制备
以4-(2-羟乙基)吗啉为原料，按照实施例1中的1.1～1.5的合成方法合成关键中间体G；以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙酰苯基)-4-[2-({4-[2-(吗啉-4-基)乙氧基]苯基}氨基)嘧啶-4-基]哌嗪-1-甲酰胺。收率52％。
实施例19.N-(4-乙酰苯基)-4-[2-({4-[3-(吗啉-4-基)丙氧基]苯基}氨基)嘧啶-4-基]哌嗪-1- 甲酰胺的制备
以4-(3-羟丙基)吗啉为原料，按照实施例1中的1.1～1.5的合成方法合成关键中间体G；以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙酰苯基)-4-[2-({4-[3-(吗啉-4-基)丙氧基]苯基}氨基)嘧啶-4-基]哌嗪-1-甲酰胺。收率41％。
实施例20.N-(4-氰基苯基)-4-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以5-甲基-2,4-二氯嘧啶为原料，按照实施例1中的1.3～1.5的合成方法合成关键中间体G；以4-氰基苯胺为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-氰基苯基)-4-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率70％。
实施例21.N-(4-氰基苯基)-4-(6-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以6-甲基-2,4-二氯嘧啶为原料，按照实施例1中的1.3～1.5的合成方法合成关键中间体G；以4-氰基苯胺为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-氰基苯基)-4-(6-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率51％。
实施例22.N-(4-乙酰基苯基)-4-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以5-甲基-2,4-二氯嘧啶为原料，按照实施例1中的1.3～1.5的合成方法合成关键中间体G；以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙酰基苯基)-4-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率64％。
实施例23.N-(4-乙酰基苯基)-4-(6-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以6-甲基-2,4-二氯嘧啶为原料，按照实施例1中的1.3～1.5的合成方法合成关键中间体G；以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙酰基苯基)-4-(6-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率62％。
实施例24.N-(4-乙酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}噻吩并[3,2-d]嘧啶-4-基)哌嗪-1-甲酰胺的制备
以2,4-二氯噻吩并[3,2-d]嘧啶为原料，按照实施例1中的1.3～1.5的合成方法合成关键中间体G；以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}噻吩并[3,2-d]嘧啶-4-基)哌嗪-1-甲酰胺。收率60％。
实施例25.N-(4-乙酰苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}喹唑啉-4-基)哌嗪-1-甲酰胺的制备
以2,4-二氯喹唑啉为原料，按照实施例1中的1.3～1.5的合成方法合成关键中间体G；以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙酰苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}喹唑啉-4-基)哌嗪-1-甲酰胺。收率65％。
实施例26.N-(4-乙酰苯基)-4-(5-三氟甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以5-三氟甲基-2,4-二氯嘧啶为原料，按照实施例1中的1.3～1.5的合成方法合成关键中间体G；以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙酰苯基)-4-(5-三氟甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率61％。
实施例27.N-(4-乙酰基苯基)-4-(5-氨基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以5-硝基-2,4-二氯嘧啶为原料，按照实施例1中的1.3～1.5的合成方法合成关键中间体G；以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙酰基苯基)-4-(5-硝基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺，随后按照实施例1中的1.2的合成方法合成N-(4-乙酰基苯基)-4-(5-氨基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率30％。
实施例28.N-(4-乙酰基苯基)-3-[(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)氨基]吡咯烷-1-甲酰胺的制备
28.1. 3-[(2-氯-5-甲基嘧啶-4-基)氨基]吡咯烷-1-羧酸叔丁酯的合成(L)
室温下，将20.0g(125mmol)5-甲基-2,4-二氯嘧啶(J)溶于200mL N,N-二甲基甲酰 胺(DMF)中，加入20.5g(150mmol)碳酸钾，冰浴下分批加入26.0g(138mmol)3-氨基吡咯烷-1-羧酸叔丁酯(K)，加毕，室温反应2h。反应完毕，向反应液中加入1L水，搅拌，抽滤，100mL水洗滤饼，干燥得到中间体L粗品。柱层析纯化得到白色固体29.3g，收率75％。
28.2. 3-[(2-氯-5-甲基嘧啶-4-基)氨基]吡咯烷盐酸盐的合成(M)
室温下，将7g(22.4mmol)中间体L加入70mL盐酸甲醇溶液中，室温反应12h。反应完毕，减压浓缩溶液，抽滤，滤饼用乙醇(10mL)洗，干燥后得到灰色固体4.1g，收率86％。
28.3.N-(4-乙酰基苯基)-3-[(2-氯-5-甲基嘧啶-4-基)氨基]吡咯烷-1-甲酰胺的合成(N)
以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H，随后以3-[(2-氯-5-甲基嘧啶-4-基)氨基]吡咯烷盐酸盐(M)为原料，再按照实施例1中的1.7的合成方法合成关键中间体N-(4-乙酰基苯基)-3-[(2-氯-5-甲基嘧啶-4-基)氨基]吡咯烷-1-甲酰胺。收率60％。
28.4.N-(4-乙酰基苯基)-3-[(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)氨基]吡咯烷-1-甲酰胺的合成
以N-(4-乙酰基苯基)-3-[(2-氯-5-甲基嘧啶-4-基)氨基]吡咯烷-1-甲酰胺(N)为原料，按照实施例1中的1.4的合成方法合成N-(4-乙酰基苯基)-3-[(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)氨基]吡咯烷-1-甲酰胺。收率81％。
实施例29. 1-(4-乙酰基苯基)-3-[1-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)吡咯烷-3-基]脲的制备
29.1. 1-(4-乙酰基苯基)-3-(1-叔丁氧羰基吡咯烷-3-基)脲的合成(O)
以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H；室温下，将5.0g(26.8mmol)3-氨基吡咯烷-1-羧酸叔丁酯(K)和7.5g(29.5mmol)中间体H加入50mL 1,4-二氧六环中，向反应液中滴加14.0g(107.2mmol)N,N-二异丙基乙胺(DIPEA)，滴毕，升温至80℃反应3h。反应完毕，冷却至室温，减压浓缩溶剂，向残余物中加入10mL水，2.5％NaOH溶液调节pH至10，抽滤，干燥得到粗产品。粗产品经柱层析(二氯甲烷:甲醇＝20:1)纯化后得到白色固体5.8g，收率62％。
29.2. 1-(4-乙酰基苯基)-3-(吡咯烷-3-基)脲盐酸盐的合成(P)
以中间体O为原料，按照实施例28中的28.2的合成方法合成1-(4-乙酰基苯 基)-3-(吡咯烷-3-基)脲盐酸盐。收率89％。
29.3. 1-(4-乙酰基苯基)-3-[1-(2-氯-5-甲基嘧啶-4-基)吡咯烷-3-基]脲的合成(Q)
以中间体P和5-甲基-2,4-二氯嘧啶为原料，按照实施例1中的1.3的合成方法合成1-(4-乙酰基苯基)-3-[1-(2-氯-5-甲基嘧啶-4-基)吡咯烷-3-基]脲。收率74％。
29.4. 1-(4-乙酰基苯基)-3-[1-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)吡咯烷-3-基]脲的合成
以中间体Q为原料，按照实施例1中的1.4的合成方法合成1-(4-乙酰基苯基)-3-[1-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)吡咯烷-3-基]脲。收率65％。
实施例30.N-(4-乙酰基苯基)-3-[(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)氨基]氮杂环丁烷-1-甲酰胺的制备
以3-氨基氮杂环丁烷-1-羧酸叔丁酯为原料，按照实施例28中的28.1～28.4的合成方法合成N-(4-乙酰基苯基)-3-[(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)氨基]氮杂环丁烷-1-甲酰胺。收率68％。
实施例31. 1-(4-乙酰基苯基)-3-[1-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)氮杂环丁烷-3-基]脲的制备
以3-氨基氮杂环丁烷-1-羧酸叔丁酯为原料，按照实施例29中的29.1～29.4的合成方法合成1-(4-乙酰基苯基)-3-[1-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)氮杂环丁烷-3-基]脲。收率61％。
实施例32.N-(4-乙酰苯基)-4-[(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)氨基]哌啶-1-甲酰胺的制备
以4-氨基哌啶-1-羧酸叔丁酯为原料，按照实施例28中的28.1～28.4的合成方法合成N-(4-乙酰苯基)-4-[(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)氨基]哌啶-1-甲酰胺。收率71％。
实施例33.N-(4-乙酰基苯基)-1-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌啶-4-甲酰胺的制备
33.1. 1-(2-氯-5-甲基嘧啶-4-基)哌啶-4-羧酸乙酯的合成(R)
以2,4-二氯-5-甲基嘧啶(J)和哌啶-4-羧酸乙酯为原料，按照实施例1中的1.3的合成方法合成1-(2-氯-5-甲基嘧啶-4-基)哌啶-4-羧酸乙酯，收率90％。
33.2. 1-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌啶-4-羧酸乙酯的合成(S)
以1-(2-氯-5-甲基嘧啶-4-基)哌啶-4-羧酸乙酯(R)为原料，按照实施例1中的1.4的合成方法合成1-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌啶-4-羧酸乙酯，收率92％。
33.3. 1-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌啶-4-羧酸的合成(T)
室温下，将5.0g(11.8mmol)中间体S溶于50mL甲醇中，向反应液中缓慢滴加10mL(1mol/L)氢氧化钠溶液，加毕，升温至60℃反应2h，反应完毕，将反应液冷却至室温，减压浓缩反应液，向残余物中加入50mL水，用10％盐酸将pH调至3，有大量固体析出，抽滤，水洗滤饼，真空下干燥得浅黄色固体0.63g，收率75％。
33.4.N-(4-乙酰基苯基)-1-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌啶-4-甲酰胺的合成
室温下，将2.0g(5.0mmol)中间体T溶于100mL 1,4-二氧六环中，向反应液中加入0.9g(7.5mmol)N,N-二异丙基乙胺、2.8g(7.5mmol)HATU和0.8g(6.0mmol)4-氨基苯乙酮，加毕，室温反应8h，反应完毕，将反应液冷却至室温，减压浓缩反应液，粗品经柱层析纯化得浅黄色固体N-(4-乙酰基苯基)-1-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌啶-4-甲酰胺，收率55％。
实施例34.N-(4-乙酰基苯基)-4-[5-甲基-2-({4-[3-(吡咯烷-1-基)丙氧基]苯基}氨基)嘧啶-4-基]哌嗪-1-甲酰胺的制备
以1-(3-羟丙基)吡咯烷为原料，按照实施例1中的1.1～1.2的合成方法合成关键中间体E；以5-甲基-2,4-二氯嘧啶为原料，按照实施例1中的1.3～1.5的合成方法合成关键中间体G；以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙酰基苯基)-4-[5-甲基-2-({4-[3-(吡咯烷-1-基)丙氧基]苯基}氨基)嘧啶-4-基]哌嗪-1-甲酰胺。收率45％。
实施例35.N-(4-乙酰基苯基)-4-(5-甲基-2-{[3-氟-4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以2,4-二氟硝基苯为原料，按照实施例1中的1.1～1.2的合成方法合成关键中间体E；以5-甲基-2,4-二氯嘧啶为原料，按照实施例1中的1.3～1.5的合成方法合成关键中间体G；以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙酰基苯基)-4-(5-甲基-2-{[3-氟-4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率61％。
实施例36.N-(4-乙酰基苯基)-4-(5-甲基-2-{[3-乙酰氨基-4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以2-乙酰氨基-4-氟硝基苯为原料，按照实施例1中的1.1～1.2的合成方法合成关键中间体E；以5-甲基-2,4-二氯嘧啶为原料，按照实施例1中的1.3～1.5的合成方法合成关键中间体G；以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙酰基苯基)-4-(5-甲基-2-{[3-乙酰氨基-4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率60％。
实施例37.N-(4-乙酰基苯基)-4-(5-甲基-2-{[3-甲氧基-4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺的制备
以2-甲氧基-4-氟硝基苯为原料，按照实施例1中的1.1～1.2的合成方法合成关键中间体E；以5-甲基-2,4-二氯嘧啶为原料，按照实施例1中的1.3～1.5的合成方法合成关键中间体G；以4-氨基苯乙酮为原料，按照实施例1中的1.6的合成方法合成关键中间体H，再按照实施例1中的1.7的合成方法合成N-(4-乙酰基苯基)-4-(5-甲基-2-{[3-甲氧基-4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺。收率60％。
实施例化合物的结构及 1H-NMR、MS数据见表1。
表1
Figure PCTCN2020099683-appb-000013
Figure PCTCN2020099683-appb-000014
Figure PCTCN2020099683-appb-000015
Figure PCTCN2020099683-appb-000016
Figure PCTCN2020099683-appb-000017
Figure PCTCN2020099683-appb-000018
Figure PCTCN2020099683-appb-000019
Figure PCTCN2020099683-appb-000020
Figure PCTCN2020099683-appb-000021
Figure PCTCN2020099683-appb-000022
对本发明的化合物进行了体外酶活性与细胞抗增殖活性的研究，结果如下
对按照本发明的上式I的2-氨基嘧啶骨架的化合物(浓度0.1μM)用Mobility Shift  Assay进行了体外JAK2和FLT3激酶活性测试。对照品Pacritinib和Fedratinib为本课题组自行制备得到。
激酶缓冲液由50mM的HEPEs(pH7.5)，0.0015％的BRIJ-35组成。停止缓冲液含有100mM HEPES(pH7.5)、0.015％BRIJ-35、0.2％涂层试剂#3和50mM EDTA的混合物。将待测化合物用100％DMSO稀释至反应中所需最高浓度的50倍。将被测化合物稀释液(100μL)转移到96孔板的孔中。然后，通过向两个孔中添加100mL DMSO作为对照组，标记为源板。将10μL化合物从源板转移到新的96孔板上制备中间板。在中间板中，每孔额外添加90μL激酶缓冲液。将中间板摇动10min，然后将96孔中间板上的每孔的5μL作为分析板复制到384孔板上。向384孔板中的每孔加入制备好的酶溶液，然后在室温下培养10分钟，然后添加10μL制备的肽溶液(FAM标记的肽和激酶基缓冲液中的ATP)。将样品在28℃孵育1h，然后加入25μL的缓冲液。从Caliper程序中复制转换数据，并将其转换为抑制率。
抑制率(％)＝(max-conversion)/(max-min)×100。
部分化合物的JAK2和FLT3的体外激酶试验结果见表2。
表2部分化合物的抑制JAK2和FLT3激酶的活性
化合物 0.1μM下JAK2％抑制 0.1μM下FLT3％抑制
实施例1化合物 48.7 21.7
实施例2化合物 54.3 30.5
实施例3化合物 53.3 27.4
实施例4化合物 53.7 30.8
实施例5化合物 64.4 62.8
实施例6化合物 76.7 72.3
实施例7化合物 79.3 84.4
实施例8化合物 63.7 70.3
实施例10化合物 76.3 71.2
实施例11化合物 68.1 35.8
实施例12化合物 76.0 69.7
实施例13化合物 73.0 70.8
实施例15化合物 84.0 85.0
实施例16化合物 45.0 69.0
实施例17化合物 53.0 54.0
实施例18化合物 61.7 70.6
实施例19化合物 60.9 70.9
实施例20化合物 88.5 95.2
实施例22化合物 81.8 99.1
实施例24化合物 44.0 68.0
实施例26化合物 74.6 82.5
实施例27化合物 22.8 67.9
实施例28化合物 69.3 57.3
实施例29化合物 57.4 75.7
实施例31化合物 21.9 50.0
实施例32化合物 80.5 78.6
实施例33化合物 74.3 97.0
Pacritinib 92.0 96.0
Fedratinib 95.2 88.7
对按照本发明的上式I的2-氨基嘧啶骨架的化合物进行了体外抑制人红白血病细胞HEL和人髓性单核细胞白血病细胞Molm-13活性的试验。对照品Pacritinib和Fedratinib为本课题组自行制备得到。
细胞复苏并传代2-3次稳定后，吸取10μL细胞混悬液加入细胞计数板中计数，调整细胞浓度为10×10 4个/mL。96孔板中最***不加细胞液，其余皆加入100μL细胞混悬液，B2-B7孔加入100μL培养基作为对照组，其它孔加入不同浓度的待测试化合物。在培养箱中孵育72h后，向A1孔加入200μL新鲜培养基作为空白组，然后每孔中加入20μL CCK-8溶液，继续孵育4h。96孔板在室温下震荡3min，然后用酶标仪测定在450nm波长下的吸光度，根据以下公式计算细胞生长的抑制率：
抑制率(％)＝[(A对照-A加药)/(A对照-A空白)]×100
IC 50为抑制一半细胞生长时所需要的药物浓度，根据药物浓度和抑制率结果，采用GraphPad Prism 5软件通过量效曲线计算出IC 50。
部分化合物的人红白血病细胞HEL和人髓性单核细胞白血病细胞Molm-13的试验结果见表3。
表3部分化合物的抑制肿瘤细胞增殖活性结果
化合物 HEL IC 50(μM) Molm-13 IC 50(μM)
实施例6化合物 4.3 0.077
实施例20化合物 0.9 0.072
实施例22化合物 0.8 0.042
实施例26化合物 4.6 0.083
实施例32化合物 6.7 0.35
实施例33化合物 1.7 0.062
Pacritinib 1.1 0.023
Fedratinib 0.89 0.068
初步的体外抑制激酶和肿瘤细胞增殖活性果表明，本发明所要保护的通式I的化合物，具有良好的JAK2和FLT3的抑制活性，部分化合物相当或优于阳性对照药Pacritinib和Fedratinib。
以上所述的具体实施例，对本发明的目的、技术方案和有益效果进行了进一步详细说明，应理解的是，以上所述仅为本发明的具体实施例而已，并不用于限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (17)

  1. 通式Ⅰ的2-氨基嘧啶类化合物及其药学上可接受的盐、溶剂化物或其前药，
    Figure PCTCN2020099683-appb-100001
    其中，
    X和Y相同或不同，分别独立地选自N、CH和CHNH；
    Q为NH、CH 2；
    Z选自NH、NCH 3、O或一根化学键；
    m和n相同或不同，为1-3之间的整数；
    R 1和R 2相同或不同，分别独立地选自氢、卤素、(C 1-C 6)烷基、(C 1-C 6)烷氧基、三氟甲基、氰基、氨基、硝基，或R 1和R 2一起形成(C 6-C 10)芳基、5-10元杂芳基、4-10元杂环基，所述杂环基任选包括0-3个双键；
    R 3为(C 1-C 6)烷基酰基、(C 6-C 10)芳基、5-10元杂芳基，所述芳基或者杂芳基任选被1-3个相同或不同的R 8取代；
    R 8为氢、羟基、卤素、氰基、(C 1-C 6)烷基、(C 1-C 6)烷氧基、(C 1-C 6)烷基酰基、(C 1-C 6)氨基甲酰基、-NR 5R 6、-(CH 2) pNR 5R 6、-CONR 5R 6、-NHCONR 5R 6、-O(CH 2) pNR 5R 6、-SO 2(CH 2) pNR 5R 6、-SO 2(CH 2) pCONR 5R 6；
    其中，R 5和R 6相同或不同，分别独立地选自氢、(C 1-C 6)烷基、(C 3-C 7)环烷基、(C 2-C 6)烯基、(C 2-C 6)炔基、(C 1-C 6)烷基酰基、(C 1-C 6)烷氧基；
    或R 5和R 6与和它们所连接的氮原子一起形成4-10元杂环基或5-10元杂芳基，所述杂环基或杂芳基除了与R 5和R 6连接的氮原子外，任选含有0-4个选自N、O和/或S的杂原子，所述杂环基任选包括0-3个双键，所述杂环基或杂芳基任选被0-3个相同或不同的R 7取代；
    R 7为(C 1-C 6)烷基、(C 3-C 7)环烷基；
    p为0-4的整数；
    R 4为(C 1-C 6)烷基、(C 3-C 7)环烷基、(C 6-C 10)芳基、5-10元杂芳基、(C 6-C 10)芳基甲基、5-10元杂芳基甲基，所述芳基或者杂芳基任选被1-3个相同或不同的R 9取代；
    R 9为氢、羟基、卤素、卤代(C 1-C 6)烷基、卤代(C 1-C 6)烷氧基、硝基、氨基、氰基、(C 1-C 6)烷基、(C 2-C 6)烯基、(C 2-C 6)炔基、(C 1-C 6)烷氧基、任选被羟基、氨基或卤代的(C 1-C 6)烷基或(C 1-C 6)烷氧基、被1-2个(C 1-C 6)烷基取代的氨基、(C 1-C 6)烷基酰胺基、游离的、成盐的、酯化的和酰胺化的羧基、(C 1-C 6)烷基亚磺酰基、(C 1-C 6)烷基磺酰基、(C 1-C 6)烷氧基、(C 1-C 6)烷基、(C 1-C 6)烷基酰基、(C 1-C 6)氨基甲酰基、被1-2个(C 1-C 6)烷基取代的氨基甲酰基、(C 1-C 3)亚烷基二氧基、烯丙基。
  2. 权利要求1的通式Ⅰ的2-氨基嘧啶类化合物及其药学上可接受的盐、溶剂化物或其前药，
    其中，
    X和Y相同或不同，分别独立地选自N和CH；
    Z选自NH、NCH 3或一根化学键；
    R 1和R 2相同或不同，分别独立地选自氢、卤素、(C 1-C 6)烷基、(C 1-C 6)烷氧基、三氟甲基、氰基、氨基、硝基，或R 1和R 2一起形成(C 6-C 10)芳基、5-10元杂芳基；
    R 3为(C 6-C 10)芳基、5-10元杂芳基，所述芳基或者杂芳基任选被1-3个相同或不同的R 8取代。
  3. 权利要求2的通式Ⅰ的2-氨基嘧啶类化合物及其药学上可接受的盐、溶剂化物或其前药，
    其中，
    m和n相同或不同，为1，2；
    R 3为苯基、5-6元杂芳基，所述苯基或者杂芳基任选被1-3个相同或不同的R 8取代；
    R 8为(C 1-C 6)烷氧基、(C 1-C 6)烷基酰基、(C 1-C 6)氨基甲酰基、-NR 5R 6、-(CH 2) pNR 5R 6、-CONR 5R 6、-NHCONR 5R 6、-O(CH 2) pNR 5R 6、-SO 2(CH 2) pNR 5R 6；
    R 5和R 6相同或不同，分别独立地选自氢、(C 1-C 4)烷基、(C 3-C 6)环烷基、(C 1-C 4)烷基酰基；
    或R 5和R 6与和它们所连接的氮原子一起形成
    Figure PCTCN2020099683-appb-100002
    Figure PCTCN2020099683-appb-100003
    R 4为苯基、5-6元杂芳基，所述苯基或者杂芳基任选被1-3个相同或不同的R 9取代。
  4. 权利要求3的通式I的2-氨基嘧啶类化合物及其药学上可接受的盐、溶剂化物或其前药，
    其中，
    Z为NH或一根化学键；
    R 1和R 2相同或不同，分别独立地选自氢、氟、氯、甲基、乙基、环丙基、甲氧基、三氟甲基、氰基、氨基、硝基，或R 1和R 2一起形成苯基、5-6元杂芳基；
    R 8为(C 1-C 6)烷氧基、(C 1-C 6)烷基酰基、(C 1-C 6)氨基甲酰基、-NR 5R 6、-(CH 2) pNR 5R 6、-CONR 5R 6、-NHCONR 5R 6、-O(CH 2) pNR 5R 6；
    其中，R 5和R 6相同或不同，分别独立地选自氢、(C 1-C 4)烷基、(C 3-C 6)环烷基；
    或R 5和R 6与和它们所连接的氮原子一起形成
    Figure PCTCN2020099683-appb-100004
    Figure PCTCN2020099683-appb-100005
  5. 权利要求4的通式I的2-氨基嘧啶类化合物及其药学上可接受的盐、溶剂化物或其前药，
    其中，
    Q为NH；
    X和Y为N；
    Z为一根化学键；
    m和n为2；
    R 1和R 2相同或不同，分别独立地选自氢、氟、氯、甲基、甲氧基、三氟甲基、氨基、硝基；
    R 3为苯基，所述苯基任选被1-3个相同或不同的R 8取代；
    R 8为-NR 5R 6、-(CH 2) pNR 5R 6、-CONR 5R 6、-O(CH 2) pNR 5R 6；
    p为1-4的整数；
    R 4为苯基，任选被1-3个相同或不同的R 9取代。
  6. 权利要求5的通式I的2-氨基嘧啶类化合物及其药学上可接受的盐、溶剂化物或其前药，
    其中，
    R 2为氢；
    R 8为-NR 5R 6、-O(CH 2) pNR 5R 6；
    p为2，3；
  7. 权利要求6的通式Ⅰ的2-氨基嘧啶类化合物及其药学上可接受的盐、溶剂化物或其前药，
    其中，
    R 1为氢、氟、氯、甲基、三氟甲基；
    R 5和R 6与和它们所连接的氮原子一起形成
    Figure PCTCN2020099683-appb-100006
    Figure PCTCN2020099683-appb-100007
  8. 下列通式I的2-氨基嘧啶类化合物及其药学上可接受的盐、溶剂化物或其前药：
    N-(4-甲氧基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-三氟甲氧基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-乙基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-苯基-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-甲氧甲酰苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-乙酰苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-硝基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-氰基-3-氟苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-异丙氧基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-氨基甲酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-甲氨基甲酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-氨基磺酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-乙酰氨基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-甲磺酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-氨基甲酰基苯基)-4-(2-{[4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-乙酰基苯基)-4-[2-({4-[2-(吡咯烷-1-基)乙氧基]苯基}氨基)嘧啶-4-基]哌嗪-1-甲酰胺；
    N-(4-乙酰苯基)-4-(2-{[4-(4-甲基哌啶-1-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-乙酰苯基)-4-[2-({4-[2-(吗啉-4-基)乙氧基]苯基}氨基]嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-乙酰基苯基)-4-[2-({4-[3-(吗啉-4-基)丙氧基]苯基}氨基)嘧啶-4-基]哌嗪-1-甲酰 胺；
    N-(4-氰基苯基)-4-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-氰基苯基)-4-(6-甲基2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-乙酰基苯基)-4-(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-乙酰基苯基)-4-(6-甲基2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-乙酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}噻吩并[3,2-d]嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-乙酰基苯基)-4-(2-{[4-(吗啉-4-基)苯基]氨基}喹唑啉-4-基)哌嗪-1-甲酰胺；
    N-(4-乙酰基苯基)-4-(5-三氟甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-乙酰基苯基)-4-(5-氨基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)哌嗪-1-甲酰胺；
    N-(4-乙酰基苯基)-3-[(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)氨基]吡咯烷-1-甲酰胺；
    N-(4-乙酰基苯基)-4-[(5-甲基-2-{[4-(吗啉-4-基)苯基]氨基}嘧啶-4-基)氨基]哌啶-1-甲酰胺；
    N-(4-乙酰基苯基)-4-[5-甲基-2-({4-[3-(吡咯烷-1-基)丙氧基]苯基}氨基)嘧啶-4-基]哌嗪-1-甲酰胺。
  9. 权利要求1至8的通式I化合物，其中所述药学上可接受的盐为与酸形成的盐，所述酸选自：盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘磺酸、三氟乙酸和天冬氨酸。
  10. 权利要求9的通式I化合物，其中所述与酸形成的盐为盐酸盐和甲磺酸盐。
  11. 一种药用组合物，所述组合物含有权利要求1-10任何一项的通式I化合物及其药学上可接受的盐、溶剂化物或其前药。
  12. 权利要求1-10中任何一项的化合物及其药学上可接受的盐、水合物、溶剂化物或前药在制备用于预防或治疗与JAK2激酶抑制剂有关的疾病的药物中的用途。
  13. 权利要求1-10中任何一项的化合物及其药学上可接受的盐、水合物、溶剂化物或前药在制备用于预防或治疗与FLT3激酶抑制剂有关的疾病的药物中的用途。
  14. 权利要求1-10中任何一项的化合物及其药学上可接受的盐、水合物、溶剂化 物或前药在制备用于预防或治疗与JAK2/FLT3双靶点激酶抑制剂有关的疾病的药物中的用途。
  15. 权利要求1-10中任一项所述的通式I化合物及其药学上可接受的盐、水合物、溶剂化物或其前药或权利要求12所述的组合物在制备用于治疗增生性疾病和恶性血液疾病的药物中的应用。
  16. 权利要求15中的应用，其中所述的增生性疾病包含骨髓纤维化、多发性骨髓瘤、真性红细胞增多症、原发性血小板增多症。
  17. 权利要求15中的应用，其中所述的恶性血液疾病包含急性髓细胞白血病、急性淋巴细胞白血病。
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