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WO2025031358A1 - Dérivé de phényl-2-aminopyrimidine à substitution n2-3-fluoro-5, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Dérivé de phényl-2-aminopyrimidine à substitution n2-3-fluoro-5, son procédé de préparation et son utilisation pharmaceutique Download PDF

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WO2025031358A1
WO2025031358A1 PCT/CN2024/110108 CN2024110108W WO2025031358A1 WO 2025031358 A1 WO2025031358 A1 WO 2025031358A1 CN 2024110108 W CN2024110108 W CN 2024110108W WO 2025031358 A1 WO2025031358 A1 WO 2025031358A1
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compound
alkyl
acid
boc
reaction
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刘滔
李佳
李学梅
周宇波
王培培
许冉
高越
胡小蓓
阚伟娟
姜凯龙
蓝心艳
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Zhejiang University ZJU
Shanghai Institute of Materia Medica of CAS
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Zhejiang University ZJU
Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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
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    • 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
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the field of medicine, and in particular to an N2-3 -fluoro-5-substituted phenyl-2-aminopyrimidine derivative, an optical isomer, a salt and a preparation method thereof, as well as the use of the derivative as an inhibitor of Fms-like tyrosine kinase 3 (FLT3), interleukin 1 receptor-associated kinase 4 (IRAK4) or a dual-targeted FLT3/IRAK4 inhibitor in anti-tumor, anti-inflammatory and anti-autoimmune disease drugs.
  • FLT3 Fms-like tyrosine kinase 3
  • IRAK4 interleukin 1 receptor-associated kinase 4
  • dual-targeted FLT3/IRAK4 inhibitor in anti-tumor, anti-inflammatory and anti-autoimmune disease drugs.
  • the FLT3 gene is located in the long arm of human chromosome 13, region 1, band 2 (13q12). It is about 100 kb in length and includes 24 exons, 16 of which are highly conserved with the c-KIT gene. It encodes a hematopoietic factor receptor tyrosine kinase, FLT3 kinase. FLT3 is usually expressed in early stem cells and progenitor cells to regulate cell proliferation, survival and differentiation.
  • the FLT3 protein consists of: an extracellular domain composed of 5 immunoglobulin-like structures; a transmembrane domain (TM); a juxtamembrane domain (JM) and two intracellular tyrosine kinase domains (TKDs) connected by a kinase insert domain (KI).
  • TM transmembrane domain
  • JM juxtamembrane domain
  • TKDs tyrosine kinase domains
  • KI kinase insert domain
  • FLT3 exists as a monomer.
  • FLT3 dimerizes and the tyrosine residues in the activation loop are transphosphorylated.
  • Activated FLT3 can induce multiple intracellular signaling pathways, such as PI3K/Akt/mTOR, RAS/RAF/MEK/ERK, and STAT5, leading to the proliferation and differentiation of hematopoietic cells.
  • FLT3-ITD the internal tandem duplication mutation of the JM coding sequence of the FLT3 gene was first demonstrated in AML cells.
  • FLT3-TKD missense point mutations of the D835 residue in the FLT3 kinase domain
  • FLT3-TKD point mutations, deletions, and insertion mutations of surrounding codons
  • FLT3-ITD mutations and FLT3-TKD mutations account for 20% and 10% of AML patients, respectively.
  • the FLT3-D835 mutation is a common target resistance mutation in clinical practice.
  • FLT3-ITD and FLT3-TKD mutations can activate FLT3 and downstream signaling pathways in a ligand-independent manner, leading to the occurrence, development, and poor prognosis of AML.
  • three FLT3 inhibitors have been approved for marketing by the FDA/Japan, and several candidate drugs are in clinical research for AML.
  • midostaurin a multi-kinase inhibitor developed by Novartis, was approved by the FDA in April 2017 for the treatment of adult AML patients with FLT3 mutations.
  • Gilteritinib developed by Astellas was approved by the FDA in 2018 for the treatment of relapsed/refractory adult AML patients.
  • Quizartinib developed by Daiichi Sankyo of Japan was also approved for marketing in Japan in 2019 for the treatment of relapsed/refractory (R/R) AML patients.
  • Treatment with FLT3 inhibitors has greatly improved the survival and prognosis of AML patients.
  • domestic FLT3 inhibitors have also developed rapidly.
  • SKLB-1028 jointly developed by Shijiazhuang Pharmaceutical and Sichuan University, crifotinib besylate developed by Guangdong East Sunshine, and HYML-122 developed by Liu Qingsong's research group have successively entered Phase II and Phase III clinical trials.
  • IRAK4 interleukin 1 receptor-associated kinase 4
  • TLRs upstream toll-like receptor family
  • IL-1R interleukin-1 receptor family
  • IRAK4 is a key node in the signaling pathways of IL-1R and TLR family except TLR3, and can mediate the activation of signaling pathways such as NF- ⁇ B.
  • TLRs and IL-1R can recruit the adaptor protein MyD88.
  • MyD88 protein interacts with the N-terminal death domain of IRAK4 and IRAK2 to promote the assembly of the multimeric helical signaling complex myddosome.
  • the complex is composed of 6 MyD88 molecules, 4 IRAK4 molecules and 4 IRAK2 molecules.
  • IRAK4 recruited to the myddosome complex can activate autophosphorylation and recruit IRAK1.
  • phosphorylation of IRAK4 promotes the recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF6), which subsequently leads to the activation of the NF- ⁇ B signaling pathway and the production of proinflammatory cytokines IL-1, IL-8, IL-33 and chemokines through kinases such as TAK1 and IKK ⁇ .
  • TAK1 and IKK ⁇ tumor necrosis factor receptor-associated factor 6
  • IRAK4-related signaling pathways Abnormal activation of IRAK4-related signaling pathways has been elucidated in a variety of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, gout, and so on. Recent studies have shown that IRAK4 also plays an important role in the pathological processes of a variety of tumors, such as macroglobulinemia, non-Hodgkin's lymphoma, large B-cell lymphoma, myelodysplastic syndrome (MDS), and AML.
  • MDS myelodysplastic syndrome
  • IRAK4 is overexpressed in MDS/AML patients with mutations in the U2AF1 gene and SF3B1 gene, and the use of IRAK4 inhibitors can significantly inhibit the proliferation of tumor cells.
  • IRAK4-related signaling pathways are overactivated, leading to AML disease progression and relapse resistance to FLT3 inhibitors.
  • the use of FLT3/IRAK4 dual-target inhibitors has a significant synergistic anti-tumor effect and can overcome the resistance of FLT3i.
  • IRAK4 inhibitors have entered the clinical research stage, including PF-06650833 developed by Pfizer, BAY-1834845 and BAY-1830839 developed by Bayer, BMS-978299 developed by Bristol-Myers Squibb, R835 developed by Rigel Pharmaceuticals, and MY004 developed by Shanghai Meiyue Company, which are in Phase I/II clinical studies for rheumatoid arthritis, systemic lupus erythematosus, and psoriasis, respectively.
  • Multiple IRAK4 inhibitors have also entered the preclinical research stage.
  • the candidate drug CA-4948 developed by Curis is the only IRAK4/FLT3 inhibitor that has entered Phase II clinical studies for anti-tumor (blood tumors such as myelodysplastic syndrome and acute myeloid leukemia).
  • the object of the present invention is to provide a class of N 2 -3-fluoro-5-substituted phenyl-2-aminopyrimidine derivatives having FLT3 and IRAK4 inhibitory activity and anti-tumor effect, and the compounds have excellent biological activity and improve the molecular diversity and novelty of the compounds; another object of the present invention is to provide a preparation method and application of such N 2 -3-fluoro-5-substituted phenyl-2-aminopyrimidine derivatives.
  • the present invention relates to a compound having a structure shown in general formula (I):
  • X is selected from (CH 2 ) m , NR 4 , O, CO, R 4 is selected from H, C 1-3 alkyl, and the C 1-3 alkyl may be further substituted by hydroxyl or halogen;
  • n is selected from 0, 1, 2, and 3; when m is 0, X does not exist, and R 1 is directly connected to the benzene ring;
  • Y is selected from NR 5 , O, a chemical bond, and R 5 is selected from H, a C 1-3 alkyl group; when Y is a chemical bond, R 2 is directly connected to the pyrimidine ring;
  • R 1 is selected from -C 1-6 alkyl-amino, -C 0-3 alkyl-C 3-10 cycloalkyl, -C 0-3 alkyl-C 3-10 heterocycloalkyl, -C 0-3 alkyl-C 3-10 cycloalkyl-amino, -C 0-3 alkyl-C 3-10 heterocycloalkyl-amino, -C 0-3 alkyl-C 3-10 cycloalkyl-C 1-4 alkyl-amino, -C 0-3 alkyl-C 3-10 heterocycloalkyl-C 1-4 alkyl-amino, and the alkyl, amino, cycloalkyl, and heterocycloalkyl moieties in the above groups may be further independently substituted by 1, 2, 3, or 4 R 6, respectively; and when there are multiple R 6 on the same group, the multiple R 6 are independent of each other and may be the same or different; wherein when the subscript C in the C 0
  • R6 is selected from hydrogen, halogen, hydroxyl, amino, cyano, C1-5 alkyl, C1-5 alkenyl, C1-5 alkynyl, -NHCO- C1-5 alkyl, -NHSO2- C1-5 alkyl, -NHSO- C1-5 alkyl, -CONH- C0-5 alkyl, -SO2NH- C0-5 alkyl, -SONH- C0-5 alkyl, -amino- C1-5 alkyl- C3-5 heterocycloalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, -C1-3 alkyl- C3-6 cycloalkyl, -C1-3 alkyl - C3-6 heterocycloalkyl, -CO- C1-5 alkyl, -SO2 - C1-5 alkyl, -SO- C1-5 alkyl, and the C1-5 alkyl or C3-5 heterocycloalkyl portion may be further substituted by hal
  • R2 is selected from C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C3-10 heterocycloalkyl, and the C1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, C3-10 heterocycloalkyl may be further substituted by hydrogen, deuterium, hydroxyl, amino, nitro, cyano, C1-3 alkoxy, -NHCO- C1-3 alkyl, -NHSO2- C1-3 alkyl, -NHSO- C1-3 alkyl, -CO- C1-3 alkyl, -SO2 - C1-3 alkyl, -SO- C1-3 alkyl, C3-6 cycloalkyl , C3-6 heterocycloalkyl, and the heteroatom is selected from any one or more of N, O, and S;
  • R 2 When R 2 is cyclohexyl, it may be further substituted by amino, hydroxyl, -NHCO-C 1-3 alkyl, -NHSO 2- C 1-3 alkyl, C 3-6 heterocycloalkyl;
  • R3 is selected from hydrogen, cyano, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, carboxamide, nitro, 6-10 membered monocyclic or bicyclic aromatic group, 5-10 membered monocyclic or bicyclic heterocyclic group, wherein the heterocyclic group refers to an aliphatic or aromatic monocyclic or bicyclic system, wherein the aromatic group and the heterocyclic group may be further substituted by C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, hydroxyl, and cyano.
  • X is selected from (CH 2 ) m , NR 4 , O, CO, R 4 is selected from H, C 1-3 alkyl, and the C 1-3 alkyl may be further substituted by hydroxyl or halogen;
  • n 0, 1, 2, 3;
  • R 1 is selected from -C 1-6 alkyl-amino, -C 0-3 alkyl-C 3-10 cycloalkyl, -C 0-3 alkyl-C 3-10 heterocycloalkyl, -C 0-3 alkyl-C 3-10 cycloalkyl-amino, -C 0-3 alkyl-C 3-10 heterocycloalkyl-amino, -C 0-3 alkyl-C 3-10 cycloalkyl-C 1-4 alkyl-amino, -C 0-3 alkyl-C 3-10 heterocycloalkyl-C 1-4 alkyl-amino, in which the alkyl, amino, cycloalkyl and heterocycloalkyl moieties in the above groups may be further independently substituted by 1, 2, 3 or 4 R 6, respectively; and when there are multiple R 6 in the same group, the multiple R 6 are independent of each other and may be the same or different;
  • R6 is selected from hydrogen, halogen, hydroxyl, amino, cyano, C1-5 alkyl, C1-5 alkenyl, C1-5 alkynyl, -NHCO- C1-5 alkyl, -NHSO2- C1-5 alkyl, -NHSO- C1-5 alkyl, -CONH- C0-5 alkyl, -SO2NH- C0-5 alkyl, -SONH- C0-5 alkyl, -amino- C1-5 alkyl- C3-5 heterocycloalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl, -C1-3 alkyl- C3-6 cycloalkyl, -C1-3 alkyl - C3-6 heterocycloalkyl, -CO- C1-5 alkyl, -SO2 - C1-5 alkyl, -SO- C1-5 alkyl, wherein the C1-5 alkyl or C3-5 heterocycloalkyl portion may be further substituted by
  • R3 is selected from hydrogen, cyano, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, carboxamide, nitro, 6-10 membered monocyclic or bicyclic aromatic group, 5-10 membered monocyclic or bicyclic heterocyclic group, wherein the heterocyclic group refers to an aliphatic or aromatic monocyclic or bicyclic system, wherein the aromatic group and the heterocyclic group may be further substituted by C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, halogen, hydroxyl, and cyano.
  • X is NH, O, (CH 2 ) m , CO, m is selected from 0, 1, 2; Y is NH.
  • R 1 is selected from any of the following structures:
  • R 3 is selected from trifluoromethyl, 6-10 membered monocyclic or bicyclic aromatic group, 5-10 membered monocyclic or bicyclic heterocyclic group, wherein aromatic group and heterocyclic group are selected from any of the following structures:
  • the aryl and heterocyclic moieties may be further substituted by C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, halogen, hydroxyl, or cyano.
  • R 3 is trifluoromethyl; X is NH, and Y is NH;
  • alkyl and the alkyl portion of other groups (such as alkoxy, haloalkyl) can be branched or unbranched.
  • cycloalkyl refers to a monocyclic or polycyclic hydrocarbon ring group, generally a 3-10 membered hydrocarbon ring group, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptatrienyl, bornyl, norpinyl, norcaryl, adamantyl, pinanyl, decahydronaphthyl, norbornyl, spiro[4.5]decyl, etc.
  • the cycloalkyl group may be unsubstituted or substituted by one or more suitable substituents.
  • halogen refers to fluorine, chlorine, bromine, iodine and the corresponding hydrides.
  • heterocycloalkyl means that at least one carbon atom in the ring is replaced by at least one heteroatom including nitrogen, oxygen or sulfur. Heterocycloalkyl may have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring group, as long as the ring group is not aromatic due to its presence.
  • heterocyclyl refers to an aliphatic (e.g., a fully or partially saturated heterocycle) or aromatic (e.g., heteroaryl) monocyclic or bicyclic ring system.
  • monocyclic ring systems are any 5-membered or 6-membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • the 5-membered ring has 0-2 double bonds, and the 6-membered ring has 0-3 double bonds.
  • monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazolline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole
  • Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein.
  • Representative examples of bicyclic ring systems include, but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, 1,4-benzodioxane, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, indazole, indole, indolone, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazin
  • the compound of general formula (I) can be selected from the following specific compounds:
  • the present invention provides the above-mentioned N 2 -3-fluoro-5-substituted phenyl-2-aminopyrimidine derivatives and pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salt is an organic acid salt or an inorganic acid salt.
  • the organic acid salt includes formate, acetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, mandelate, citrate, trifluoroacetate, fumarate, oxalate, malate, L-malate, D-malate, lactate, camphorsulfonate, p-toluenesulfonate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, benzoate, tartrate, L-tartrate, D-tartrate, oxalate, succinate, maleate, ascorbate, and amino acid salt.
  • the inorganic acid salt includes hydrochloride, hydrobromide, sulfate, phosphate, nitrate, hydroiodide or perchlorate.
  • the present invention provides a method for preparing the above-mentioned N 2 -3-fluoro-5-substituted phenyl-2-aminopyrimidine derivatives, optical isomers, and salts, which is achieved by the following route:
  • the method comprises: reacting compound (I-1) and compound (I-2) in the presence of Pd 2 (dba) 3 , Xant-phos and Cs 2 CO 3 in an organic solvent at 80° C.-120° C., and treating after the reaction to obtain compound I or a Boc-protected precursor of compound I, wherein the Boc-protected precursor is further treated with an acid to remove the Boc group to obtain compound I.
  • R 1 , R 2 , R 3 and Y are as defined in the general formula (I), and R 1 ' is R 1 or a Boc-protected precursor of R 1 ; the preparation method comprises the following steps:
  • R The precursor compound of 1 - amine compounds (such as morpholine, 1-N-Boc-cis-2,6-dimethylpiperazine, cis-2,6-dimethylmorpholine, N-Boc-piperazine, 4-Boc-aminopiperidine, 4-Boc-aminomethylpiperidine, R-3-Boc-amino-piperidine, S-3-Boc-aminopiperidine, methylpiperazine, ethylpiperazine, isopropylpiperazine, 1-(3-oxetanyl)piperazine, 4-N-Boc-4-N-methylaminopiperidine, 4-N,N-dimethylaminopiperidine, R-3-Boc-aminopyrrole, S-3-Boc-aminopyrrole, 4-methyl-4-N-Boc-aminopiperidine, hydroxyethylpiperazine, cis-1,2,6-trimethylpiperazine, N
  • step (1) after the reaction is completed by TLC detection, the reaction solution is extracted with ethyl acetate and washed with saturated brine, and the solvent is distilled off under reduced pressure, and silica gel column chromatography is performed to finally obtain the compound 2;
  • step (2) after the reaction is completed by TLC detection, the solvent is removed by reduced pressure distillation, and the compound I or the Boc-protected precursor of the compound I is purified by silica gel column chromatography.
  • Route 2
  • R 1 , R 2 , R 3 , and Y are defined as in the general formula (I); R 1 ' is R 1 or a Boc-protected precursor of R 1 ; the preparation method comprises the following steps:
  • an amine compound such as N-methyl-4-aminopiperidine, R-N-Boc-3-aminopiperidine, S-N-Boc-3-aminopiperidine, R-N-Boc-3-aminopyrrole, S-N-Boc-3-aminopyrrole, N-Boc-4-aminopiperidine, N-Boc-4-aminomethylpiperidine, N-Boc-cis-linked diamine, N-Boc-trans-cyclohexanediamine, N,N-dimethylpropylenediamine, etc.) is dissolved in DMSO or DMF, and compound 4, an inorganic base (such as potassium carbonate, cesium carbonate) and sodium iodide/potassium iodide as a catalyst are added at 0-40°C, and the above reaction solution is reacted in a sealed tube at 80-160°C. After the reaction is completed, the compound 5 is obtained by treatment
  • step (1) after the reaction is completed by TLC detection, the reaction solution is extracted with ethyl acetate and washed with saturated brine, and the solvent is distilled off under reduced pressure, and silica gel column chromatography is performed to finally obtain the compound 5;
  • step (2) after the reaction is completed by TLC detection, the solvent is distilled off under reduced pressure, and the compound II or the Boc-protected precursor of the compound II is purified by silica gel column chromatography.
  • R 1 , R 2 , R 3 , and Y are defined as in the general formula (I); R 1 ' is R 1 or a Boc-protected precursor of R 1 ; the preparation method comprises the following steps:
  • amine compounds such as N-methyl-piperazine, N-Boc-ethylenediamine, N-Boc-propylenediamine, N-Boc-butylenediamine, N-Boc-pentanediamine, N-methyl-4-aminopiperidine, R-N-Boc-3-aminopiperidine, S-N-Boc-3-aminopiperidine, R-N-Boc-3-aminopyrrole, S-N-Boc-3-aminopyrrole, N-Boc-4-amino Piperidine, N-Boc-4-aminomethylpiperidine, N-Boc-cis-linked diamine, N-Boc-trans-cyclohexanediamine, N,N-dimethylpropylenediamine, etc.), compound 6, an inorganic base (such as cesium carbonate, potassium carbonate, sodium carbonate), palladium acetate, 1,1'-
  • step (1) after the reaction is completed by TLC detection, the product is filtered, the filtrate is distilled under reduced pressure to remove the solvent, and the product is subjected to silica gel column chromatography to finally obtain the compound 7;
  • step (2) after the reaction is completed by TLC detection, the solvent is distilled off under reduced pressure, and the compound III or the Boc-protected precursor of the compound III is purified by silica gel column chromatography.
  • R 1 , R 2 , R 3 and Y are as defined in the general formula (I), and R 1 ' is R 1 or a Boc-protected precursor of R 1 ; the preparation method comprises the following steps:
  • step (1) after the reaction is completed by TLC detection, the reaction solution is extracted with ethyl acetate and washed with saturated brine, and then the solvent is distilled off under reduced pressure and subjected to silica gel column chromatography to finally obtain the compound 9;
  • step (2) after the reaction is completed by TLC detection, the solvent is distilled off under reduced pressure, and the compound IV or the Boc-protected precursor of the compound IV is purified by silica gel column chromatography.
  • the preparation method of the above N 2 -3-fluoro-5-substituted phenyl-2-aminopyrimidine derivatives comprises the following steps:
  • the raw material 1 is reacted with the corresponding amine under alkaline conditions at 20-100°C overnight to obtain the intermediate 1.
  • the base used is any one of sodium carbonate, potassium carbonate, and cesium carbonate.
  • Raw material 2 reacts with the corresponding amine or alcohol under alkaline conditions or hydrogen extraction reagent conditions to produce intermediate 2.
  • the base used is any one of cesium carbonate and potassium carbonate
  • the reaction solvent is any one of DMF and DMSO
  • the catalyst is any one of sodium iodide and potassium iodide
  • the reaction temperature is 80-160° C.
  • the reaction is carried out in a sealed tube for 2-4 days
  • the hydrogen extraction reagent is any one of sodium hydride, bistrimethylaminosilyl lithium, and bistrimethylaminosilyl sodium
  • the reaction solvent is any one of anhydrous DMF and anhydrous THF
  • the reaction temperature is 60-120° C.
  • the reaction is carried out overnight under the protection of inert gas
  • the raw material 4 reacts with the corresponding amine under the conditions of HOBt, EDCI and DIPEA at 20-60°C to obtain the intermediate 4.
  • the reaction solvent used is any one of dichloromethane and DMF.
  • the raw material 5 is reacted at low temperature in aqueous ammonia for 1 h to obtain the intermediate intermediate 5, the reaction solvent is acetonitrile, and the reaction temperature is an ice bath;
  • Intermediate 5 is reacted with the corresponding amine under alkaline conditions overnight by heating to obtain intermediate 6.
  • the reaction solvent is any one of dioxane, acetonitrile, and methanol.
  • the base used is any one of triethylamine and DIPEA.
  • the reaction temperature is 70-100°C.
  • Step 6 is subjected to Buchwald-Hartwig coupling with any one of intermediates 1, 2, 3, and 4 under inert gas protection and catalytic conditions of base, palladium, and corresponding ligands to directly obtain the compound of formula (1) or obtain the compound of formula (1) by removing the Boc protecting group.
  • the solvent used for the Buchwald-Hartwig coupling is anhydrous dioxane
  • the base is any one of cesium carbonate, potassium carbonate, and sodium carbonate
  • the catalyst is any one of Pd 2 (dba) 3 and Pd(OAc) 2
  • the ligand is any one of Xantphos and BINAP
  • the reaction temperature is 80-120°C;
  • the raw material 6 is reacted with the corresponding amine under alkaline conditions overnight by heating to obtain the intermediate 7.
  • the reaction solvent is any one of dioxane, acetonitrile, and methanol.
  • the base used is any one of triethylamine and DIPEA.
  • the reaction temperature is 70-100°C.
  • intermediate 7 is subjected to Suzuki coupling reaction with boric acid or boric ester compound under alkaline conditions with palladium catalysis to obtain intermediate 8,
  • the base used in the reaction is any one of cesium carbonate, potassium carbonate and sodium carbonate
  • the palladium catalyst used is any one of tetrakis(triphenylphosphine)palladium and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride
  • the reaction solvent is any one of dioxane/water, DMF and ethanol/water
  • the reaction temperature is 70-140°C;
  • the compound of the present invention is dissolved in isopropanol, and an isopropanol, methanol, ethanol or ethyl acetate solution containing 1-1.5 times (1.2 times) equivalents of an organic acid or an inorganic acid is slowly added dropwise at room temperature. After the addition is completed, the reaction solution is stirred at 40-60°C overnight. After the reaction solution is cooled to room temperature, it is filtered, and the solid is washed with ether and dried to obtain the corresponding salt.
  • the present invention provides a key intermediate in the process of preparing the above-mentioned N 2 -3 fluoro-5-substituted phenyl-2-aminopyrimidine derivatives and their optical isomers or pharmaceutically acceptable salts thereof, the structure of which is shown below:
  • the present invention provides a composition comprising a therapeutically effective amount of the above-mentioned N 2 -3-fluoro-5-substituted phenyl-2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof.
  • the composition comprises at least one therapeutically effective amount of an N2-3 -fluoro-5-substituted phenyl-2-aminopyrimidine compound of general formula (I) or a pharmaceutically acceptable salt thereof, and another targeting molecule (preferably a conventional cytotoxic drug, a compound used after chemotherapy, a compound used in stem cell induction maintenance therapy, and a compound used in acute myeloid leukemia), and an optional pharmaceutically acceptable carrier.
  • another targeting molecule preferably a conventional cytotoxic drug, a compound used after chemotherapy, a compound used in stem cell induction maintenance therapy, and a compound used in acute myeloid leukemia
  • the present invention provides a pharmaceutical preparation for treating or preventing diseases related to FLT3, IRAK4, or FLT3/IRAK4, comprising a therapeutically effective amount of the above-mentioned N 2 -3 fluoro-5-substituted phenyl-2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof, and also comprising auxiliary ingredients.
  • the pharmaceutical preparation is a tablet, capsule, powder, granule, ointment, solution, suspension, injection, inhalant, gel, microsphere, or aerosol, etc.
  • the auxiliary ingredients are, for example, cyclodextrin, arginine, or meglumine.
  • the cyclodextrin is selected from ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, (C 1-4 alkyl)- ⁇ -cyclodextrin, (C 1-4 alkyl)- ⁇ -cyclodextrin, (C 1-4 alkyl)- ⁇ -cyclodextrin, (hydroxy-C 1-4 alkyl)- ⁇ -cyclodextrin, (hydroxy-C 1-4 alkyl)- ⁇ -cyclodextrin, (hydroxy-C 1-4 alkyl)- ⁇ -cyclodextrin, (carboxy-C 1-4 alkyl)- ⁇ -cyclodextrin, (carboxy-C 1-4 alkyl)- ⁇ -cyclodextrin, (carboxy-C 1-4 alkyl)- ⁇ -cyclodextrin, (carboxy-C 1-4 alkyl )- ⁇ -cyclodextrin, saccharide ethers of ⁇ -
  • the auxiliary components also include medically acceptable carriers, adjuvants or vehicles.
  • Pharmaceutically acceptable pharmaceutical compositions also include ion exchangers, aluminum oxide, aluminum stearate, egg gelatin; buffer substances include phosphates, glycine, arginine, sorbic acid, etc.
  • the present invention provides the use of N 2 -3-fluoro-5-substituted phenyl-2-aminopyrimidine compounds or pharmaceutically acceptable salts thereof in the preparation of drugs for preventing or treating clinical diseases associated with FLT3 and/or IRAK4.
  • the FLT3-mediated disease is a blood disease, a solid tumor, an autoimmune disease, and a skin disease, such as psoriasis and atopic dermatitis.
  • the hematological disease is selected from acute myeloid leukemia (AML), acute T-cell leukemia, myelodysplastic syndrome, mixed lineage leukemia (MLL), cellular acute leukemia (T-ALL), B-cell acute leukemia (B-ALL), chronic myelomonocytic leukemia (CMML), chronic lymphocytic leukemia, chronic myeloid leukemia, and chronic neutrophilic leukemia.
  • AML acute myeloid leukemia
  • MML mixed lineage leukemia
  • T-ALL cellular acute leukemia
  • B-ALL B-cell acute leukemia
  • CMML chronic myelomonocytic leukemia
  • chronic lymphocytic leukemia chronic myeloid leukemia
  • chronic myeloid leukemia chronic myeloid leukemia
  • chronic neutrophilic leukemia chronic neutrophilic leukemia
  • the IRAK4-mediated disease is a hematological disease (such as non-Hodgkin's lymphoma, B-cell lymphoma, mantle cell lymphoma, myelodysplastic syndrome, plasma cell lymphoma, acute myeloid leukemia), a solid tumor, a skin disease (such as melanoma) or an inflammatory or autoimmune disease.
  • a hematological disease such as non-Hodgkin's lymphoma, B-cell lymphoma, mantle cell lymphoma, myelodysplastic syndrome, plasma cell lymphoma, acute myeloid leukemia
  • a solid tumor such as melanoma
  • a skin disease such as melanoma
  • an inflammatory or autoimmune disease such as non-Hodgkin's lymphoma, B-cell lymphoma, mantle cell lymphoma, myelodysplastic syndrome, plasma cell lymphoma, acute myeloid leukemia
  • the inflammatory or autoimmune disease is selected from ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal keratoconjunctivitis, allergic rhinitis, autoimmune hematopoietic disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and congenital thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Jones syndrome, idiopathic, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontal inflammation, hyaline membrane disease, kidney disease, glomerulopathy, alcoholic liver
  • the present invention provides the use of N2-3 -fluoro-5-substituted phenyl-2-aminopyrimidine compounds or pharmaceutically acceptable salts thereof alone or in combination with one or more other therapeutic agents in clinical diseases related to FLT3 and/or IRAK4.
  • the other therapeutic agents are selected from IDH1 inhibitors, IDH2 inhibitors, BCL-2 inhibitors, hypomethylating agents, and antimetabolites.
  • the compound of the present invention has FLT3 and IRAK4 inhibitory activity, has proliferation inhibitory activity on various tumor cell lines, and is effective against various AML mutations such as internal tandem duplication mutations in the juxtamembrane domain and D835 point mutations in the activation loop in the kinase domain. It can overcome the drug resistance caused by clinical point mutations and can be used in the preparation of anti-tumor drugs.
  • Figure 1 shows the therapeutic effects of compounds 36 and 37 on human acute myeloid leukemia MV-4-11NU/NU mouse transplanted tumors
  • Step 1 Synthesis of 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 1-2)
  • Step 2 Synthesis of tert-butyl ((1S, 4S)-4-((2-amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexyl)carbamate (Intermediate 1-3)
  • intermediate 1-2 (2.14 g, 10.84 mmol) was dissolved in anhydrous methanol (40 mL), and triethylamine (1.65 g, 16.26 mmol) and N-Boc-cis-cyclohexanediamine (1.91 g, 13.55 mol) were added sequentially under stirring.
  • Step 4 N 4 -((1S,4S)-4-aminocyclohexyl)-N 2 -(3-fluoro-5-(morpholinomethyl)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 1)
  • Cyclopropylamine was used to replace N-Boc-1,4-cis-cyclohexanediamine, and N-Boc-piperazine, 1-Boc-(2S,6R)-2,6-dimethylpiperazine, N-Boc-4-aminopiperidine, N-Boc-4-aminomethylpiperidine, (R)-3-Boc-aminopiperidine, (S)-3-Boc-aminopiperidine, 4-N-Boc-4-N-methylaminopiperidine, (R)-3-Boc-aminopyrrolidine, (S)-3-Boc-aminopyrrolidine, 4-methyl-4-N-Boc-aminopiperidine were used to replace morpholine respectively.
  • Step 1 Synthesis of N 4 -cyclopropyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Intermediate 1-6)
  • Step 2 Synthesis of N 2 -(3-fluoro-5-(morpholinomethyl)phenyl)-N 4 -cyclopropyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 2)
  • intermediate 1-6 150 mg, 0.69 mmol
  • intermediate 1-5 (226 mg, 0.83 mmol)
  • tris(dibenzylideneacetone)dipalladium 63 mg, 0.069 mmol
  • 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene 10 mL
  • cesium carbonate 449 mg, 1.38 mmol
  • react at 110 ° C overnight, filter, recover the solvent under reduced pressure to obtain the residue, and purify it by silica gel column chromatography with PE:EA 2:1 as the eluent to obtain a white solid (225 mg, 80%).
  • the synthesis steps refer to Preparation Example 3, using 4-chloro-5-(trifluoromethyl)pyrimidine-2-amine as the starting material, isopropylamine is replaced by isopropylamine, cyclobutylamine, ethylamine, cyclopentylamine, cyclohexylamine, and methylamine, respectively, to synthesize the corresponding intermediates, and then tri(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene catalyzes the intermediate 1-5 to undergo Buchwald-Hartwig reaction to obtain the target compounds 3-7 and 9.
  • Step 1 Synthesis of tert-butyl (1S,4S)-4-((2-amino-5-bromopyrimidin-4-yl)amino)cyclohexyl)carbamate (Intermediate 1-8).
  • Step 2 Synthesis of 6-benzothiazole pinacol boronate (Intermediate 1-10).
  • Step 3 Synthesis of tert-butyl ((1S,4S)-4-((2-amino-5-(benzo[d]thiazol-6-yl)pyrimidin-4-yl)amino)cyclohexyl)carbamate (Intermediate 1-11)
  • Step 4 Synthesis of N 4 -((1S,4S)-4-aminocyclohexyl)-5-(benzo[d]thiazol-6-yl)-N 2 -(3-fluoro-5-(morpholinomethyl)phenyl)pyrimidine-2,4-diamine (Compound 10)
  • Step 1 Synthesis of 5-bromo-N 4 -cyclohexylpyrimidine-2,4-diamine (Intermediate 1-12)
  • intermediate 1-7 500 mg, 2.40 mmol was dissolved in anhydrous methanol (5 mL), and triethylamine (364 mg, 3.60 mmol) and cyclohexylamine (286 mg, 2.88 mol) were added sequentially under stirring.
  • Step 2 Synthesis of 5-(Benzo[d]thiazol-6-yl)-N 4 -cyclohexylpyrimidine-2,4-diamine (Intermediate 1-13)
  • Step 3 Synthesis of 5-(benzo[d]thiazol-6-yl)-N 4 -cyclohexyl-N 2 -(3-fluoro-5-(morpholinomethyl)phenyl)pyrimidine-2,4-diamine (Compound 11)
  • the synthesis steps refer to Preparation Example 6, using 5-bromo-4-chloro-pyrimidine-2-amine as the starting material, and cyclopropylamine instead of cyclohexylamine to synthesize the corresponding intermediate, and then tri(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene catalyzed by Buchwald-Hartwig reaction with intermediate 1-5 to obtain the target compound 12.
  • the above target molecule is shown in Table 3 below.
  • 1-methyl-4-piperidinol (810 mg, 6.22 mmol) was dissolved in 25 mL of anhydrous DMF.
  • 60% sodium hydrogen 300 mg, 7.77 mmol was added to the reaction solution in batches under ice bath conditions.
  • 1-bromo-3,5-difluorobenzene (1 g, 5.18 mmol was added under ice bath conditions.
  • the reaction solution was reacted at 80°C overnight to obtain a light yellow oil (1151 mg, 77%).
  • Step 2 Synthesis of N 4 -cyclopropyl-N 2 -(3-fluoro-5-((1-methylpiperidin-4-yl)oxy)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 33)
  • Step 2 Synthesis of 3-((4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-fluorophenyl)(4-methylpiperazin-1-yl)methanone (Compound 34)
  • Step 2 Synthesis of N 4 -cyclopropyl-N 2 -(3-fluoro-5-(4-methylpiperazin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 35)
  • Step 1 Synthesis of N-(3-bromo-5-fluorophenyl)-1-methylpiperidin-4-amine (Intermediate 1-21)
  • N-methyl-4-aminopiperidine (1g, 8.8mmol), 1-bromo-3,5-difluorobenzene (2.54g, 13.1mmol), cesium carbonate (5.7g, 17.5mmol) and sodium iodide (0.66g, 4.4mmol) were dissolved in 15mL of DMSO, and the mixture was reacted at 120°C in a sealed tube for 3d. The reaction solution was cooled to room temperature, and water and ethyl acetate were added to the reaction solution for extraction 3-4 times.
  • Step 2 Synthesis of N 4 -cyclopropyl-N 2 -(3-fluoro-5-((1-methylpiperidin-4-yl)amino)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 36)
  • Step 1 Synthesis of (R)-tert-butyl 3-((3-bromo-5-fluorophenyl)amino)piperidine-1-carboxylate (Intermediate 1-22)
  • Step 2 Synthesis of (R)-N 4 -cyclopropyl-N 2 -(3-fluoro-5-(piperidin-3-ylamino)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 37)
  • Step 1 Synthesis of tert-butyl (3-((3-bromo-5-fluorophenyl)amino)propyl)carbamate (Intermediate 1-23)
  • Step 2 Synthesis of N 2 -(3-((3-aminopropyl)amino)-5-fluorophenyl)-N 4 -cyclopropyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 43)
  • the synthesis steps refer to Preparation Example 14, using 1,3-dibromo-5-fluorobenzene as the starting material, N-Boc-butylenediamine and N-Boc-pentanediamine are used to replace N-Boc-propylenediamine, respectively, to synthesize the corresponding intermediates, and then tri(dibenzylideneacetone)dipalladium and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene catalyze the intermediates 1-6 to undergo Buchwald-Hartwig reaction, and the resulting compounds are further subjected to trifluoroacetic acid to remove the Boc group to obtain target compounds 46-47.
  • Table 5 The above target molecules are shown in Table 5 below.
  • Step 1 Synthesis of N 4 -isopropyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Intermediate 1-24)
  • Step 2 Synthesis of (R)-N 2 -(3-fluoro-5-(piperidin-3-ylamino)phenyl)-N 4 -isopropyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 49)
  • the synthesis steps refer to Preparation Example 16, using 4-chloro-5-(trifluoromethyl)pyrimidine-2-amine as the starting material, replacing isopropylamine with cyclobutylamine to obtain the corresponding intermediate, and then undergoing Buchwald-Hartwig reaction with intermediate 1-22 in the presence of tri(dibenzylideneacetone)dipalladium and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene as the catalyzer, the obtained compound is further subjected to trifluoroacetic acid to remove the Boc group to obtain the target compound 50, and the above target molecule is shown in Table 6 below.
  • Step 1 Synthesis of 5-bromo-N 4 -cyclopropylpyrimidine-2,4-diamine (Intermediate 1-25)
  • Step 2 Synthesis of N 4 -cyclopropyl-5-(furan-3-yl)pyrimidine-2,4-diamine (Intermediate 1-26)
  • Step 3 Synthesis of (R)-N 4 -cyclopropyl-N 2 -(3-fluoro-5-(piperidin-3-ylamino)phenyl)-5-(furan-3-yl)pyrimidine-2,4-diamine (Compound 51)
  • the synthesis steps refer to Preparation Example 18, with 5-bromo-N 4 -cyclopropylpyrimidine-2,4-diamine as the starting material, 1-methyl-1H-pyrazole-4-boric acid, phenylboric acid and pyridine-4-boric acid respectively replacing 3-furanboric acid to obtain the corresponding intermediates, and then tri(dibenzylideneacetone)dipalladium, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene catalyzed the Buchwald-Hartwig reaction with the intermediate 1-22, and the obtained compounds were further subjected to trifluoroacetic acid to remove the Boc group to obtain the target compounds 52-54.
  • Table 7 The above target molecules are shown in Table 7 below.
  • Dissolve compound 36 in isopropanol and slowly dropwise add isopropanol/methanol/ethanol/ethyl acetate solution containing 1.2 times the equivalent of organic acid or inorganic acid at room temperature. After the dropwise addition is completed, the reaction solution is stirred at 40°C overnight.
  • the synthesis steps refer to Preparation Example 20, using compound 37 as the starting material and reacting with different acids in corresponding solvents to obtain compounds 69-82.
  • the target molecules are described in the following table.
  • Example 22 Kinase activity test
  • the compounds provided by the present invention are tested for their inhibitory activity against FLT3, FLT3-D835Y and IRAK4 kinases.
  • Sample processing Dissolve in DMSO and store at low temperature. The concentration of DMSO in the final system is controlled within the range that does not affect the detection activity.
  • FLT3, FLT3-D835Y and substrate (specific biotin-labeled peptide TKSubstrate) were diluted with HTRF kinase buffer (1.25XKinasebuffer, 6.25mM MgCl 2 , 1.25mM MnCl 2 , 1.25mM DTT), and IRAK4 and substrate were diluted with HTRF kinase buffer (1XKinasebuffer, 5mM MgCl 2 , 1mM MnCl 2 , 1mM DTT).
  • a solvent control group and a blank control group were set up in which DMSO was used to replace the test compound, and 3 replicate wells were set for each sample and each concentration.
  • the activity of the sample was tested under a single concentration condition, such as 10 ⁇ M, for the initial screening.
  • the activity dose dependence i.e., IC50 value
  • the sample concentration was obtained by nonlinear fitting of the sample activity.
  • the software used for calculation was GraphpadPrism8, and the model used for fitting was sigmoidaldose-response (varibleslope). For most inhibitor screening models, the bottom and top of the fitting curve were set to 0 and 100.
  • MV-4-11 human acute myelomonocytic leukemia, expressing FLT3-ITD homozygous mutation
  • Molm-13 human acute myelomonocytic leukemia, FLT3-ITD heterozygous mutation
  • BaF3-FLT3-ITD human acute myelomonocytic engineered cell line, expressing FLT3-ITD homozygous mutation
  • THP-1 human monocytic leukemia, high expression of IRAK4
  • TF-1 human erythroid leukemia, high expression of IRAK4
  • OCY-LY10 diffuseuse large B-cell lymphoma, MyD88 mutation
  • HL-60 human promyelocytic leukemia cells
  • Kasumi-1 human acute myeloblastic leukemia, FLT3 wild type
  • Jurkat acute T-cell leukemia.
  • MTS method was used to determine the antiproliferative activity (IC 50 ) of the test compound against MV-4-11 and other cell lines: cells in the logarithmic growth phase were digested with trypsin, counted, and seeded in a 96-well plate at a density of 1 ⁇ 10 4 cells/well, 100 cells per well, and placed in a 37°C incubator containing 5% CO 2 for overnight culture. Six concentration gradients were set for each test compound, and three sets of replicate wells were set for each concentration. After addition, the cells were cultured for 72 hours, and 20 ⁇ 0 MTS was added.
  • Tables 14 and 15 show that the compounds of the present invention have excellent anti-proliferation activity against THP-1 and TF-1 cells with high expression of IRAK4.
  • Table 17 above shows that the preferred compound 36 has excellent antiproliferative activity against HL-60 and Kasumi-1 cell lines
  • Example 24 MV-4-11 transplanted tumor model
  • NU/NU mice were subcutaneously injected with human MV-4-11 cells, with a cell inoculation amount of 5 ⁇ 10 6 /mouse. After the tumor grew to 100-300 mm 3 , the animals were randomly divided into a 0.5% CMC-Na solvent control group, a cytarabine (AraC) control group and a drug-treated group according to the animal weight and tumor size, with 5 mice in each group. They were treated with 10 mg/kg of compound 36 and 37 daily for one week and then stopped to observe the tumor growth of the mice.
  • CMC-Na solvent control group a cytarabine (AraC) control group
  • RhaC cytarabine
  • the control group was subcutaneously injected with cytarabine (20 mg/kg) 5 times a week for 3 consecutive weeks, and the negative control group (0.5% CMC-Na group) was given an equal amount of solvent for 21 days. During the experiment, the tumor volume was measured twice a week and the mouse weight was weighed. The experimental results are shown in Figure 1
  • compounds 36 and 37 provided by the invention can induce almost complete tumor disappearance in the human acute myeloid leukemia MV-4-11 transplanted tumor model.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Transplantation (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention divulgue un composé tel que représenté dans la formule (I), son procédé de préparation et son utilisation pharmaceutique, comprenant un isomère optique et un sel pharmaceutiquement acceptable de celui-ci. Le composé de la présente invention a une activité inhibitrice de FLT3 et/ou d'IRAK4, a une activité inhibitrice de la prolifération sur diverses souches de cellules leucémiques et souches de cellules associées à IRAK4, et peut être utilisé dans la préparation de médicaments pour lutter contre des maladies sanguines, l'inflammation et des maladies auto-immunes.
PCT/CN2024/110108 2023-08-08 2024-08-06 Dérivé de phényl-2-aminopyrimidine à substitution n2-3-fluoro-5, son procédé de préparation et son utilisation pharmaceutique Pending WO2025031358A1 (fr)

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CN202310989248.4A CN119462522A (zh) 2023-08-08 2023-08-08 N2-3-氟-5-取代苯基-2-氨基嘧啶类衍生物、其制备方法及医药用途
CN202310989248.4 2023-08-08

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010090875A1 (fr) * 2009-01-21 2010-08-12 Rigel Pharmaceuticals, Inc. Dérivés de n2-(3-pyridil ou phényl)-n4-(4-pipéridyl)-2,4-pyrimidinediamine utiles dans le traitement de maladies inflammatoires, auto-immunes ou prolifératives
DE102009001438A1 (de) * 2009-03-10 2010-09-16 Bayer Schering Pharma Aktiengesellschaft Carbonylamino-substituierte Anilino-Pyrimidinderivate als Tyk-Inhibitoren, deren Herstellung und Verwendung als Arzneimittel
DE102009015070A1 (de) * 2009-03-30 2010-10-14 Bayer Schering Pharma Aktiengesellschaft Aminocabonylamino-substituierte Anilino-Pyrimidinderivate als Tyk-Inhibitoren, deren Herstellung und Verwendung als Arzneimittel
WO2014058685A1 (fr) * 2012-10-08 2014-04-17 Merck Sharp & Dohme Corp. Inhibiteurs de l'activité de l'irak4
CN116546986A (zh) * 2020-12-10 2023-08-04 住友制药肿瘤公司 Alk-5抑制剂及其用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010090875A1 (fr) * 2009-01-21 2010-08-12 Rigel Pharmaceuticals, Inc. Dérivés de n2-(3-pyridil ou phényl)-n4-(4-pipéridyl)-2,4-pyrimidinediamine utiles dans le traitement de maladies inflammatoires, auto-immunes ou prolifératives
DE102009001438A1 (de) * 2009-03-10 2010-09-16 Bayer Schering Pharma Aktiengesellschaft Carbonylamino-substituierte Anilino-Pyrimidinderivate als Tyk-Inhibitoren, deren Herstellung und Verwendung als Arzneimittel
DE102009015070A1 (de) * 2009-03-30 2010-10-14 Bayer Schering Pharma Aktiengesellschaft Aminocabonylamino-substituierte Anilino-Pyrimidinderivate als Tyk-Inhibitoren, deren Herstellung und Verwendung als Arzneimittel
WO2014058685A1 (fr) * 2012-10-08 2014-04-17 Merck Sharp & Dohme Corp. Inhibiteurs de l'activité de l'irak4
CN116546986A (zh) * 2020-12-10 2023-08-04 住友制药肿瘤公司 Alk-5抑制剂及其用途

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