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WO2024131265A1 - COMPOSÉ POUR TRAITER DES MALADIES MÉDIÉES PAR PI3Kγ ET SON UTILISATION - Google Patents

COMPOSÉ POUR TRAITER DES MALADIES MÉDIÉES PAR PI3Kγ ET SON UTILISATION Download PDF

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WO2024131265A1
WO2024131265A1 PCT/CN2023/126472 CN2023126472W WO2024131265A1 WO 2024131265 A1 WO2024131265 A1 WO 2024131265A1 CN 2023126472 W CN2023126472 W CN 2023126472W WO 2024131265 A1 WO2024131265 A1 WO 2024131265A1
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alkyl
cancer
amino
optionally substituted
dimethoxypyridin
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Chinese (zh)
Inventor
刘青松
刘静
梁小飞
王纯
邓茂青
王傲莉
王蓓蕾
齐紫平
邹凤鸣
刘青旺
亓爽
王俊杰
沈丽娟
刘娟
梁华民
王黎
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Hefei Institutes of Physical Science of CAS
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Hefei Institutes of Physical Science of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicine, and in particular to compounds for treating cancer, inflammatory diseases or autoimmune diseases and uses thereof.
  • Phosphatidylinositol-3-kinase plays an important role in cell growth, development, division, differentiation and apoptosis, and is closely related to the occurrence and development of tumors. According to the different structures and substrate specificities, PI3K can be divided into three types: type I, type II and type III. Among them, type I PI3K is the most intensively studied and widely studied subtype, and it is also most closely related to tumors, while type I PI3K is divided into type IA and type IB.
  • the catalytic subunits of type IA PI3K include three proteins, p110 ⁇ , p110 ⁇ , and p110 ⁇ , while type I PI3K has only one catalytic subunit, p110 ⁇ . According to the different catalytic subunits, these PI3Ks are called PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ , respectively. In terms of expression, PI3K ⁇ and PI3K ⁇ are expressed in a variety of cells, while PI3K ⁇ is only expressed in the immune system. p110 ⁇ plays an important role in the tumor microenvironment, so the development of targeted p110 ⁇ inhibitors will become a research hotspot in the future.
  • the PI3K ⁇ signaling pathway of macrophages promotes immunosuppression by inhibiting the activation of T cells. Inhibition of PI3K ⁇ can activate immune responses and significantly inhibit the growth of transplanted tumors. Preclinical studies have shown that PI3K ⁇ plays a very important role in maintaining the immunosuppressive state of tumor-associated macrophages in the tumor microenvironment. Eganelisib, which targets PI3K ⁇ , can reprogram key immunosuppressive macrophages (M2) in the tumor microenvironment to anti-tumor macrophages (M1), downregulate immunosuppression, increase immune activity, and ultimately lead to the activation and proliferation of cytotoxic T cells.
  • M2 immunosuppressive macrophages
  • M1 anti-tumor macrophages
  • PI3K ⁇ may be an important therapeutic agent in oncology (Schmid et al., Cancer Cell, 2011, 19, 715-27).
  • PI3K ⁇ has been shown to have tumor-specific high accumulation in human pancreatic ductal adenocarcinoma (PDAC), indicating a role for PI3K ⁇ in pancreatic cancer (Edling et al., Human Cancer Biology, 2010, 16(2), 4928-37).
  • PI3K ⁇ inhibitors can change the balance of these immunosuppressive cells and promote the activation of anti-tumor immunity.
  • PI3K ⁇ has become a very attractive drug target, but there is still a need to develop safer and more effective PI3K ⁇ inhibitors for the prevention and/or treatment of cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction or neurological diseases.
  • the present disclosure provides a PI3K ⁇ kinase inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable an acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug,
  • X is selected from CH or N;
  • R 1 is selected from C1-6 alkoxy, halogen, C1-6 haloalkyl, or C1-6 haloalkoxy;
  • R2 is selected from H, Heteroaryl, heteroarylC1-6alkyl, C2-6dialkylaminosulfonyl, or dihydropyran-4-yl;
  • R3 is selected from H, halogen, or C1-6 alkoxy
  • n and p are each 0 or 1;
  • R4 and R5 are each independently selected from H, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C3-6 cycloalkylC1-6 hydroxyalkyl, C1-6 alkoxyC1-6 alkyl, C3-6 cycloalkylC1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, C1-6 aminoalkyl optionally substituted with an amino protecting group, C3-6 cycloalkyl, 4-8 membered heterocyclyl, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl, or heteroarylaminoC1-6 alkyl,
  • R6 and R7 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy C1-6 alkyl, C2-6 dialkylamino C1-6 alkyl, amino protecting group, aminoacyl C1-6 alkyl, C1-6 alkylaminoacyl C1-6 alkyl, or 4-8 membered heterocyclyl C1-6 alkyl,
  • R 8 is selected from C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, phenyl, phenoxy, phenylC1-6 alkyl, phenylC1-6 alkoxy, heteroaryl, heteroarylC1-6 alkyl, 4-8 membered heterocyclyl, or 4-8 membered heterocyclylC1-6 alkyl;
  • R 9 is selected from H or methyl
  • R 10 is selected from 1-methyl-pyrrolidin-3-yl, tetrahydrofuran-3-yl, or pyrrolidin-2-one-5-ylmethyl;
  • C3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, and heteroaryl are each optionally substituted by 1-3 substituents independently selected from the following: hydroxy, oxo, aminoacyl, sulfamoyl, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino protecting group, amino optionally substituted by amino protecting group, C2-6 dialkylamino, C2-6 alkanoyl, C2-6 haloalkanoyl, C1-6 alkylsulfonyl, 4-8 membered heterocyclyl, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl, heteroarylC1-6 alkylaminoacyl, or C1-6 alkoxyC1-6 alkylaminoacyl, or two adjacent substituents together form a 4-6 membered fused heterocyclyl.
  • the present disclosure relates to a PI3K ⁇ kinase inhibitor, which is a compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug thereof,
  • R 1 is selected from C1-6 alkoxy, halogen, C1-6 haloalkyl, or C1-6 haloalkoxy;
  • R2 is selected from H, Heteroaryl, heteroarylC1-6alkyl, C2-6dialkylaminosulfonyl, or dihydropyran-4-yl;
  • R3 is selected from H, halogen, or C1-6 alkoxy
  • n and p are each 0 or 1;
  • R4 and R5 are each independently selected from H, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C3-6 cycloalkylC1-6 hydroxyalkyl, C1-6 alkoxyC1-6 alkyl, C3-6 cycloalkylC1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, C1-6 aminoalkyl optionally substituted with an amino protecting group, C3-6 cycloalkyl, 4-8 membered heterocyclyl, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl, or heteroarylaminoC1-6 alkyl,
  • R6 and R7 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy C1-6 alkyl, C2-6 dialkylamino C1-6 alkyl, amino protecting group, aminoacyl C1-6 alkyl, C1-6 alkylaminoacyl C1-6 alkyl, or 4-8 membered heterocyclyl C1-6 alkyl,
  • R 8 is selected from C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, phenyl, phenoxy, phenylC1-6 alkyl, phenylC1-6 alkoxy, heteroaryl, heteroarylC1-6 alkyl, 4-8 membered heterocyclyl, or 4-8 membered heterocyclylC1-6 alkyl;
  • R 9 is selected from H or methyl
  • R 10 is selected from 1-methyl-pyrrolidin-3-yl, tetrahydrofuran-3-yl, or pyrrolidin-2-one-5-ylmethyl;
  • C3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, and heteroaryl are each optionally substituted by 1-3 substituents independently selected from the following: hydroxy, oxo, aminoacyl, sulfamoyl, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino protecting group, amino optionally substituted by amino protecting group, C2-6 dialkylamino, C2-6 alkanoyl, C2-6 haloalkanoyl, C1-6 alkylsulfonyl, 4-8 membered heterocyclyl, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl, heteroarylC1-6 alkylaminoacyl, or C1-6 alkoxyC1-6 alkylaminoacyl, or two adjacent substituents together form a 4-6 membered fused heterocyclyl.
  • the heterocyclic group is selected from azetidinyl (e.g., azetidin-3-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl), azepanyl (e.g., azepan-3-yl), piperazinyl (e.g., piperazin-1-yl), diazepanyl (e.g., 1,4-diazepan-1-yl), tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl, tetrahydrofuran-3-yl), tetrahydropyranyl (e.g., tetrahydrofuran-2-yl,
  • R 1 is selected from methoxy, fluorine, trifluoromethyl, or difluoromethoxy; more preferably methoxy.
  • R 3 is selected from H, fluoro, or methoxy; more preferably H.
  • R 2 is selected from Heteroaryl optionally substituted by 1-3 independently selected Ra, preferably pyrazolyl or pyridinyl; heteroaryl C1-6 alkyl optionally substituted by 1-3 independently selected Ra, preferably imidazolylmethyl; C2-6 dialkylaminosulfonyl, preferably diethylaminosulfonyl; or dihydropyran-4-yl;
  • R2 is more preferably selected from pyrazol-4-yl optionally substituted by 1-3 independently R a; or imidazol-1-ylmethyl optionally substituted by 1-3 independently R a;
  • each Ra is independently selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, 4-8 membered heterocyclyl; more preferably, each Ra is independently selected from methyl, ethyl, isopropyl, difluoromethyl, 2-hydroxy-2-methylpropyl, tetrahydropyran-4-yl, morpholin-4-yl; most preferably, each Ra is independently selected from methyl, or 2-hydroxy-2-methylpropyl.
  • R2 is
  • m is 0 or 1, more preferably 0;
  • R4 and R5 are each independently selected from H, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C3-6 cycloalkylC1-6 hydroxyalkyl, C1-6 alkoxyC1-6 alkyl, C3-6 cycloalkylC1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, C1-6 aminoalkyl optionally substituted with an amino protecting group, C3-6 cycloalkyl optionally substituted with 1-3 independently Rb, 4-8 membered heterocyclyl optionally substituted with 1-3 independently Rb, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl optionally substituted with 1-3 independently Rb, heteroarylaminoC1-6 alkyl, or R4, R5 together with the N to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-3 independently Rb; more preferably, R4 and R5 are each independently selected from H, C1-6 alkyl, C ...3-6
  • Each Rb is independently selected from hydroxy, oxo, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C2-6 dialkylamino, C2-6 alkanoyl, C1-6 alkylsulfonyl, an amino protecting group, a 4-8 membered heterocyclyl, or a heteroaryl; more preferably, each Rb is independently selected from hydroxy, oxo, fluoro, methyl, ethyl, isopropyl, isobutyl, hydroxymethyl, ethoxy, dimethylamino, acetyl, ethylsulfonyl, Boc, pyrrolidinyl, morpholinyl, or pyridinyl; most preferably, each Rb is independently selected from hydroxy, oxo, methyl, ethyl, isopropyl, isobutyl, hydroxymethyl, dimethylamino, acetyl, ethy
  • R2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 6 and R 7 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, an amino protecting group, aminoacylC1-6 alkyl, C1-6 alkylaminoacylC1-6 alkyl, or a 4-8 membered heterocyclylC1-6 alkyl, or R 6 , R 7 together with the N to which they are attached form a 4-8 membered heterocyclyl optionally substituted by 1-3 independently R c; more preferably, R 6 and R 7 are each independently selected from H, ethyl, propyl, isopropyl, 2-fluoroethyl, 2,2-difluoroethyl, methoxyethyl, methoxypropyl, ethoxyethyl, dimethylaminoethyl, Boc, aminoacylmethyl, methylaminoacylmethyl, or 2-morpholinoethyl, or R
  • Each Rc is independently selected from hydroxy, oxo, aminoacyl, halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 dialkylamino, amino optionally substituted with an amino protecting group, heteroarylC1-6 alkylaminoacyl, or C1-6 alkoxyC1-6 alkylaminoacyl; more preferably, each Rc is independently selected from hydroxy, oxo, aminoacyl, fluoro, methyl, difluoromethyl, dimethylamino, Boc-amino, amino, 1,2,4-triazolylethylaminoacyl, or methoxyethylaminoacyl; most preferably, each Rc is independently selected from oxo, aminoacyl, methyl, dimethylamino, Boc-amino, 1,2,4-triazol-1-ylethylaminoacyl, or methoxyethylaminoacyl.
  • R2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • n is 0 or 1, more preferably 1;
  • R 9 is selected from H or methyl; preferably, R 9 is H;
  • R8 is selected from C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, phenyl optionally substituted by 1-3 independently Rd, phenoxy, phenylC1-6 alkyl optionally substituted by 1-3 independently Rd, phenylC1-6 alkoxy, heteroaryl optionally substituted by 1-3 independently Rd, heteroarylC1-6 alkyl optionally substituted by 1-3 independently Rd, 4-8 membered heterocyclyl optionally substituted by 1-3 independently Rd, or 4-8 membered heterocyclylC1-6 alkyl optionally substituted by 1-3 independently Rd; preferably, R 8 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, diflu
  • Each Rd is independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino protecting group, C2-6 haloalkanoyl, sulfamoyl, or 4-8 membered heterocyclyl C1-6 alkyl, or two adjacent Rd together form a 4-6 membered fused heterocyclyl; preferably, each Rd is independently selected from fluorine, methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, Boc, trifluoropropionyl, sulfamoyl, or morpholineethyl, or two adjacent Rd together form a dioxolane or dioxanyl; more preferably, each Rd is independently selected from methyl, methoxy, Boc, sulfamoyl, or morpholineethyl.
  • the present disclosure provides a PI3K ⁇ kinase inhibitor selected from the following compounds or pharmaceutically acceptable salts, solvates, polymorphs, esters, acids, isomers, metabolites or prodrugs thereof:
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned PI3K ⁇ kinase inhibitor, and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure relates to the use of the aforementioned PI3K ⁇ kinase inhibitor in the preparation of a medicament for treating a PI3K ⁇ -mediated disease selected from cancer, inflammatory disease or autoimmune disease.
  • the cancer is selected from solid tumors or blood cancers, and the solid tumors are preferably selected from: head and neck cancer, nasal cancer, paranasal sinus cancer, nasopharyngeal cancer, oral cancer, oropharyngeal cancer, laryngeal cancer, hypopharyngeal cancer, salivary gland cancer, paraganglioma, pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), gastric cancer, gastrointestinal cancer (e.g., carcinoid or stromal cancer), skin cancer, esophageal cancer, uterine cancer, endometrial cancer, liver cancer, hepatocellular carcinoma, bile duct cancer, bone cancer, gastrointestinal cancer
  • the present invention adopts conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology within the technical scope of the art.
  • mass spectrometry NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology
  • specific definitions are provided, the nomenclature and laboratory operations and techniques related to chemical processes such as analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are known to those skilled in the art.
  • the aforementioned techniques and steps can be implemented by conventional methods well known in the art and described in various general and more specific literatures, which are cited and discussed in this specification.
  • alkyl refers to an aliphatic hydrocarbon group, which can be a branched or straight chain alkyl. According to the structure, the alkyl can be a monovalent group or a divalent group (i.e., an alkylidene group). In the present invention, the alkyl is preferably an alkyl having 1 to 8 carbon atoms, more preferably a "low alkyl” having 1 to 6 carbon atoms, and even more preferably an alkyl having 1 to 4 carbon atoms. Typical alkyls include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.
  • alkyl includes the alkyl of all possible configurations and conformations, such as the "propyl” mentioned herein includes n-propyl and isopropyl, "butyl” includes n-butyl, isobutyl and tert-butyl, and "pentyl” includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and penta-3-yl, etc.
  • alkoxy refers to -O-alkyl, wherein alkyl is as defined herein.
  • Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • alkoxyalkyl means an alkyl group, as defined herein, substituted with an alkoxy group, as defined herein.
  • cycloalkyl refers to a monocyclic or polycyclic radical containing only carbon and hydrogen. Cycloalkyl includes a group having 3-12 ring atoms. According to the structure, cycloalkyl can be a monovalent group or a divalent group (e.g., cycloalkylidene). In the present invention, cycloalkyl is preferably a cycloalkyl having 3-8 carbon atoms, more preferably a "low cycloalkyl" having 3-6 carbon atoms.
  • cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and adamantyl.
  • alkyl (cycloalkyl) or "cycloalkylalkyl” refers to an alkyl group, as defined herein, substituted with a cycloalkyl group, as defined herein.
  • Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
  • aromatic refers to a planar ring with a delocalized ⁇ electron system and containing 4n+2 ⁇ electrons, where n is an integer.
  • the aromatic ring can be composed of five, six, seven, eight, nine or more than nine atoms.
  • the aromatic group can be optionally substituted.
  • aromatic includes carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine).
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.
  • aryl as used herein means that each of the atoms constituting the ring in the aromatic ring is a carbon atom.
  • the aryl ring can be composed of five, six, seven, eight, nine or more than nine atoms.
  • the aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl.
  • the aryl group can be a monovalent group or a divalent group (i.e., an arylene group).
  • aryloxy refers to an -O-aryl group wherein aryl is as defined herein.
  • heteroaryl refers to an aromatic group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • An N-containing “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms in the ring is a nitrogen atom.
  • heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, and furopyri
  • alkyl (aryl) or “aralkyl” refers to an alkyl group, as defined herein, substituted with an aryl group, as defined herein.
  • alkyl (aryl) groups include benzyl, phenethyl, and the like.
  • alkyl(heteroaryl) or “heteroarylalkyl” means an alkyl group, as defined herein, substituted with a heteroaryl group, as defined herein.
  • heteroalkyl refers to an alkyl group as defined herein where one or more of the backbone chain atoms is a heteroatom, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or a combination thereof.
  • the heteroatom(s) may be located at any position within the heteroalkyl group or at a position where the heteroalkyl group is attached to the rest of the molecule.
  • heterocycloalkyl or “heterocyclic group” as used herein refers to a non-aromatic ring in which one or more atoms constituting the ring are heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heterocycloalkyl ring can be a monocyclic or polycyclic ring consisting of three, four, five, six, seven, eight, nine or more atoms.
  • the heterocycloalkyl ring can be optionally substituted.
  • heterocycloalkyls include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimides, cyclic carbamates, tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1,3-dioxins, 1,3-dioxanes, 1,4-dioxins, 1,4-dioxanes, piperazines, 1,3-oxathiacyclohexanes, 1,4-oxathiacyclohexanes, 1,4-oxathiacyclohexanes, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbital Acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5
  • alkyl(heterocycloalkyl) or “heterocycloalkylalkyl” means an alkyl group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.
  • alkoxy(heterocycloalkyl) or “heterocycloalkylalkoxy” means an alkoxy group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • haloalkyl examples include structures of alkyl, alkoxy or heteroalkyl, wherein at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same or different from each other.
  • hydroxy refers to an -OH group.
  • cyano refers to a -CN group.
  • ester group refers to a chemical moiety having the formula -COOR, wherein R is selected from the group consisting of alkyl, cycloalkyl, aromatic
  • R is selected from the group consisting of alkyl, cycloalkyl, aromatic
  • the invention also includes aryl, heteroaryl (attached through a ring carbon), and heterocyclyl (attached through a ring carbon).
  • amino refers to a -NH2 group.
  • aminoacyl refers to a -CO- NH2 group.
  • alkylaminoacyl means a -CO-NH-R group wherein R is alkyl as defined herein.
  • amido or “amido” refers to -NR-CO-R', wherein R and R' are each independently hydrogen, alkyl, aryl or heteroaryl.
  • alkylamino refers to an amino substituent further substituted with one or two alkyl groups, specifically the group -NRR', wherein R and R' are each independently selected from hydrogen or lower alkyl, provided that -NRR' is not -NH2 .
  • Alkylamino includes groups of compounds wherein the nitrogen of -NH2 is attached to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like.
  • Dialkylamino includes groups wherein the nitrogen of -NH2 is attached to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.
  • arylamino and diarylamino refer to amino substituents further substituted with one or two aryl groups, specifically to the group -NRR', wherein R and R' are each independently selected from hydrogen, lower alkyl, or aryl, wherein N is attached to at least one or two aryl groups, respectively.
  • cycloalkylamino refers to an amino substituent further substituted with one or two cycloalkyl groups as defined herein.
  • heteroalkylamino refers to an amino substituent further substituted with one or two heteroalkyl groups as defined herein.
  • aralkylamino herein refers to the group -NRR' wherein R is lower aralkyl and R' is hydrogen, lower alkyl, aryl or lower aralkyl.
  • heteroarylamino refers to an amino substituent further substituted with one or two heteroaryl groups as defined herein.
  • heterocycloalkylamino means an amino group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.
  • alkylaminoalkyl means an alkyl group, as defined herein, substituted with an alkylamino group, as defined herein.
  • aminoalkyl refers to an alkyl substituent further substituted with one or more amino groups.
  • aminoalkoxy refers to an alkoxy substituent further substituted with one or more amino groups.
  • hydroxyalkyl or "hydroxyalkyl” refers to an alkyl substituent further substituted with one or more hydroxy groups.
  • cyanoalkyl refers to an alkyl substituent further substituted with one or more cyano groups.
  • acyl refers to a monovalent atomic group remaining after removing the hydroxyl group from an organic or inorganic oxygen-containing acid, and has the general formula R-M(O)-, where M is usually C.
  • alkanoyl or “alkylcarbonyl” refers to a carbonyl group further substituted with an alkyl group.
  • Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, hexanoyl, and the like.
  • arylcarbonyl means a carbonyl group, as defined herein, substituted with an aryl group, as defined herein.
  • alkoxycarbonyl refers to a carbonyl group further substituted with an alkoxy group.
  • heterocycloalkylcarbonyl refers to a carbonyl group further substituted with a heterocycloalkyl group.
  • alkylaminocarbonyl refers to a carbonyl group, as defined herein, substituted with an alkylamino, cycloalkylamino, arylamino, aralkylamino, or heteroarylamino group, as defined herein respectively.
  • alkylcarbonylalkyl or “alkanoylalkyl” refers to an alkyl group further substituted with an alkylcarbonyl group.
  • alkylcarbonylalkoxy or “alkanoylalkoxy” refers to an alkoxy group further substituted with an alkylcarbonyl group.
  • heterocycloalkylcarbonylalkyl refers to an alkyl group further substituted with a heterocycloalkylcarbonyl group.
  • alkylaminosulfone means a sulfone group, as defined herein, substituted with an alkylamino group, as defined herein.
  • the term “optionally” refers to one or more events described later that may or may not occur, and includes both events that occur and events that do not occur.
  • the term “optionally substituted” or “substituted” refers to that the group mentioned can be substituted by one or more additional groups, and the additional groups are each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic radical, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methylsulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc.
  • the amino protecting group is preferably selected from pivaloyl, tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl, etc.
  • pharmaceutically acceptable forms include, but are not limited to, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, esters, acids, isomers, metabolites, prodrugs, and isotopically labeled derivatives of the disclosed compounds.
  • the pharmaceutically acceptable salts of the compounds provided herein include salts derived from suitable inorganic and organic acids and bases.
  • suitable inorganic and organic acids and bases include salts derived from suitable inorganic and organic acids and bases.
  • pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or by using other methods used in the art such as ion exchange formed amino salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionic acid Salt, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, naphthalene-m,n-disulfonate, nicotinate
  • Solvate or “solvate” refers to a solvent addition form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate. "Hydrate” is formed by the combination of one or more water molecules with one molecule of the substance, wherein the water remains in its molecular state as H2O .
  • the “metabolites” of the compounds disclosed herein are derivatives of the compounds formed when the compounds are metabolized.
  • active metabolite refers to biologically active derivatives of the compounds formed when the compounds are metabolized.
  • metabolized refers to the sum of processes by which a particular substance is changed by an organism (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Therefore, enzymes can produce specific structural changes into compounds.
  • cytochrome P450 catalyzes various oxidation and reduction reactions
  • diphosphoglucosyltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups.
  • the metabolites of the compounds disclosed herein can be identified by administering the compounds to a host and analyzing tissue samples from the host, or by incubating the compounds with hepatocytes in vitro and analyzing the resulting compounds. Both methods are known in the art.
  • the metabolites of the compounds are formed by oxidation processes and correspond to the corresponding hydroxyl-containing compounds.
  • the compound is metabolized to a pharmaceutically active metabolite.
  • Effective amount refers to the amount of a drug or pharmaceutical preparation that will elicit a biological or medical response in a tissue, system, animal or human being, such as that being studied by a researcher or physician.
  • therapeutically effective amount refers to any amount that results in improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduced rate of progression of a disease or disorder, compared to a corresponding subject not receiving that amount. Also included within the scope of the term is an amount that is effective to enhance normal physiological function.
  • the term “treat” refers to the alleviation of at least one symptom of a disease, disorder, or condition.
  • the term includes administering and/or applying one or more compounds described herein to a subject to provide management or treatment of a condition.
  • Treatment for the purposes of this disclosure may, but need not, provide a cure; rather, it is meant that “treatment” may be a form of management of a condition.
  • treatment includes partial or complete destruction of the harmful proliferating cells, but with minimal destructive effects on normal cells.
  • the desired treatment mechanism for harmful rapidly proliferating cells (including cancer cells) at the cellular level is apoptosis.
  • prevention includes co-preventing or slowing the onset of clinically significant disease development or preventing or slowing the onset of a preclinically significant disease stage in an at-risk individual. This includes prophylactic treatment of an individual at risk of developing a disease.
  • subject or “patient” includes organisms that can suffer from a disorder or a disorder associated with reduced or insufficient programmed cell death (apoptosis) or can otherwise benefit from the administration of the compounds of the invention, such as humans and non-human animals.
  • Preferred humans include human patients suffering from or prone to suffering from a disorder or related condition as described herein.
  • non-human animal includes vertebrates, such as mammals, such as non-human primates, sheep, cattle, dogs, cats, and rodents such as mice, as well as non-mammals, such as chickens, amphibians, reptiles, etc.
  • IC50 refers to the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximal effect in an assay measuring the effect.
  • EC50 refers to the dose, concentration or amount of a test compound which elicits a dose-dependent response that elicits 50% of the maximal expression of a specific response induced, stimulated or potentiated by the particular test compound.
  • the present disclosure relates to a PI3K ⁇ kinase inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug thereof,
  • X is selected from CH or N;
  • R 1 is selected from C1-6 alkoxy, halogen, C1-6 haloalkyl, or C1-6 haloalkoxy;
  • R2 is selected from H, Heteroaryl, heteroarylC1-6alkyl, C2-6dialkylaminosulfonyl, or dihydropyran-4-yl;
  • R3 is selected from H, halogen, or C1-6 alkoxy
  • n and p are each 0 or 1;
  • R4 and R5 are each independently selected from H, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C3-6 cycloalkylC1-6 hydroxyalkyl, C1-6 alkoxyC1-6 alkyl, C3-6 cycloalkylC1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, C1-6 aminoalkyl optionally substituted with an amino protecting group, C3-6 cycloalkyl, 4-8 membered heterocyclyl, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl, or heteroarylaminoC1-6 alkyl,
  • R6 and R7 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy C1-6 alkyl, C2-6 dialkylamino C1-6 alkyl, amino protecting group, aminoacyl C1-6 alkyl, C1-6 alkylaminoacyl C1-6 alkyl, or 4-8 membered heterocyclyl C1-6 alkyl,
  • R 8 is selected from C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, phenyl, phenoxy, phenylC1-6 alkyl, phenylC1-6 alkoxy, heteroaryl, heteroarylC1-6 alkyl, 4-8 membered heterocyclyl, or 4-8 membered heterocyclylC1-6 alkyl;
  • R 9 is selected from H or methyl
  • R 10 is selected from 1-methyl-pyrrolidin-3-yl, tetrahydrofuran-3-yl, or pyrrolidin-2-one-5-ylmethyl;
  • C3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, and heteroaryl are each optionally substituted by 1-3 substituents independently selected from the following: hydroxy, oxo, aminoacyl, sulfamoyl, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino protecting group, amino optionally substituted by amino protecting group, C2-6 dialkylamino, C2-6 alkanoyl, C2-6 haloalkanoyl, C1-6 alkylsulfonyl, 4-8 membered heterocyclyl, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl, heteroarylC1-6 alkylaminoacyl, or C1-6 alkoxyC1-6 alkylaminoacyl, or two adjacent substituents together form a 4-6 membered fused heterocyclyl.
  • the present disclosure relates to a PI3K ⁇ kinase inhibitor, which is a compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug thereof,
  • R 1 is selected from C1-6 alkoxy, halogen, C1-6 haloalkyl, or C1-6 haloalkoxy;
  • R2 is selected from H, Heteroaryl, heteroarylC1-6alkyl, C2-6dialkylaminosulfonyl, or dihydropyran-4-yl;
  • R3 is selected from H, halogen, or C1-6 alkoxy
  • n and p are each 0 or 1;
  • R4 and R5 are each independently selected from H, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C3-6 cycloalkylC1-6 hydroxyalkyl, C1-6 alkoxyC1-6 alkyl, C3-6 cycloalkylC1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, C1-6 aminoalkyl optionally substituted with an amino protecting group, C3-6 cycloalkyl, 4-8 membered heterocyclyl, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl, or heteroarylaminoC1-6 alkyl,
  • R6 and R7 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy C1-6 alkyl, C2-6 dialkylamino C1-6 alkyl, amino protecting group, aminoacyl C1-6 alkyl, C1-6 alkylaminoacyl C1-6 alkyl, or 4-8 membered heterocyclyl C1-6 alkyl,
  • R 8 is selected from C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, phenyl, phenoxy, phenylC1-6 alkyl, phenylC1-6 alkoxy, heteroaryl, heteroarylC1-6 alkyl, 4-8 membered heterocyclyl, or 4-8 membered heterocyclylC1-6 alkyl;
  • R 9 is selected from H or methyl
  • R 10 is selected from 1-methyl-pyrrolidin-3-yl, tetrahydrofuran-3-yl, or pyrrolidin-2-one-5-ylmethyl;
  • C3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, and heteroaryl are each optionally substituted by 1-3 substituents independently selected from the following: hydroxy, oxo, aminoacyl, sulfamoyl, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino protecting group, amino optionally substituted by amino protecting group, C2-6 dialkylamino, C2-6 alkanoyl, C2-6 haloalkanoyl, C1-6 alkylsulfonyl, 4-8 membered heterocyclyl, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl, heteroarylC1-6 alkylaminoacyl, or C1-6 alkoxyC1-6 alkylaminoacyl, or two adjacent substituents together form a 4-6 membered fused heterocyclyl.
  • the heterocyclic group is selected from azetidinyl (e.g., azetidin-3-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl), azepanyl (e.g., azepan-3-yl), piperazinyl (e.g., piperazin-1-yl), diazepanyl (e.g., 1,4-diazepan-1-yl), tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl, tetrahydrofuran-3-yl), tetrahydropyranyl (e.g., tetrahydrofuran-2-yl,
  • R 1 is selected from methoxy, fluorine, trifluoromethyl, or difluoromethoxy; more preferably methoxy.
  • R 3 is selected from H, fluoro, or methoxy; more preferably H.
  • R 2 is selected from Heteroaryl optionally substituted by 1-3 independently selected Ra, preferably pyrazolyl or pyridinyl; heteroaryl C1-6 alkyl optionally substituted by 1-3 independently selected Ra, preferably imidazolylmethyl; C2-6 dialkylaminosulfonyl, preferably diethylaminosulfonyl; or dihydropyran-4-yl;
  • R2 is more preferably selected from pyrazol-4-yl optionally substituted by 1-3 independently R a; or imidazol-1-ylmethyl optionally substituted by 1-3 independently R a;
  • each Ra is independently selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, 4-8 membered heterocyclyl; more preferably, each Ra is independently selected from methyl, ethyl, isopropyl, difluoromethyl, 2-hydroxy-2-methylpropyl, tetrahydropyran-4-yl, morpholin-4-yl; most preferably, each Ra is independently selected from methyl, or 2-hydroxy-2-methylpropyl.
  • R2 is
  • m is 0 or 1, more preferably 0;
  • R4 and R5 are each independently selected from H, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C3-6 cycloalkylC1-6 hydroxyalkyl, C1-6 alkoxyC1-6 alkyl, C3-6 cycloalkylC1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, C1-6 aminoalkyl optionally substituted with an amino protecting group, C3-6 cycloalkyl optionally substituted with 1-3 independently Rb, 4-8 membered heterocyclyl optionally substituted with 1-3 independently Rb, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl optionally substituted with 1-3 independently Rb, heteroarylaminoC1-6 alkyl, or R4, R5 together with the N to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-3 independently Rb; more preferably, R4 and R5 are each independently selected from H, C1-6 alkyl, C ...3-6
  • Each Rb is independently selected from hydroxy, oxo, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C2-6 dialkylamino, C2-6 alkanoyl, C1-6 alkylsulfonyl, an amino protecting group, a 4-8 membered heterocyclyl, or a heteroaryl; more preferably, each Rb is independently selected from hydroxy, oxo, fluoro, methyl, ethyl, isopropyl, isobutyl, hydroxymethyl, ethoxy, dimethylamino, acetyl, ethylsulfonyl, Boc, pyrrolidinyl, morpholinyl, or pyridinyl; most preferably, each Rb is independently selected from hydroxy, oxo, methyl, ethyl, isopropyl, isobutyl, hydroxymethyl, dimethylamino, acetyl, ethy
  • R2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 6 and R 7 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, an amino protecting group, aminoacylC1-6 alkyl, C1-6 alkylaminoacylC1-6 alkyl, or a 4-8 membered heterocyclylC1-6 alkyl, or R 6 , R 7 together with the N to which they are attached form a 4-8 membered heterocyclyl optionally substituted by 1-3 independently R c; more preferably, R 6 and R 7 are each independently selected from H, ethyl, propyl, isopropyl, 2-fluoroethyl, 2,2-difluoroethyl, methoxyethyl, methoxypropyl, ethoxyethyl, dimethylaminoethyl, Boc, aminoacylmethyl, methylaminoacylmethyl, or 2-morpholinoethyl, or R
  • Each Rc is independently selected from hydroxy, oxo, aminoacyl, halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 dialkylamino, amino optionally substituted with an amino protecting group, heteroarylC1-6 alkylaminoacyl, or C1-6 alkoxyC1-6 alkylaminoacyl; more preferably, each Rc is independently selected from hydroxy, oxo, aminoacyl, fluoro, methyl, difluoromethyl, dimethylamino, Boc-amino, amino, 1,2,4-triazolylethylaminoacyl, or methoxyethylaminoacyl; most preferably, each Rc is independently selected from oxo, aminoacyl, methyl, dimethylamino, Boc-amino, 1,2,4-triazol-1-ylethylaminoacyl, or methoxyethylaminoacyl.
  • R2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • n is 0 or 1, more preferably 1;
  • R 9 is selected from H or methyl; preferably, R 9 is H;
  • R8 is selected from C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, phenyl optionally substituted by 1-3 independently Rd, phenoxy, phenylC1-6 alkyl optionally substituted by 1-3 independently Rd, phenylC1-6 alkoxy, heteroaryl optionally substituted by 1-3 independently Rd, heteroarylC1-6 alkyl optionally substituted by 1-3 independently Rd, 4-8 membered heterocyclyl optionally substituted by 1-3 independently Rd, or 4-8 membered heterocyclylC1-6 alkyl optionally substituted by 1-3 independently Rd; preferably, R 8 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, diflu
  • Each Rd is independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino protecting group, C2-6 haloalkanoyl, sulfamoyl, or 4-8 membered heterocyclyl C1-6 alkyl, or two adjacent Rd together form a 4-6 membered fused heterocyclyl; preferably, each Rd is independently selected from fluorine, methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, Boc, trifluoropropionyl, sulfamoyl, or morpholineethyl, or two adjacent Rd together form a dioxolane or dioxanyl; more preferably, each Rd is independently selected from methyl, methoxy, Boc, sulfamoyl, or morpholineethyl.
  • the compounds described herein can be made and/or used as pharmaceutically acceptable salts.
  • Types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, or the like; or with an organic acid, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic
  • the corresponding counter ions of the pharmaceutically acceptable salts can be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.
  • the salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization.
  • Screening and characterizing pharmaceutically acceptable salts, polymorphs and/or solvates can be accomplished using a variety of techniques, including but not limited to thermal analysis, X-ray diffraction, spectrum, microscopy, elemental analysis.
  • the various spectral techniques used include but are not limited to Raman, FTIR, UVIS and NMR (liquid and solid state).
  • Various microscopic techniques include but are not limited to IR microscopy and Raman (Raman) microscopy.
  • the PI3K ⁇ kinase inhibitors disclosed herein can be used in drugs for treating PI3K ⁇ -mediated diseases selected from cancer, inflammatory diseases or autoimmune diseases, and the disorders treated by the methods or compounds disclosed herein are cancer, inflammatory diseases or autoimmune diseases.
  • the cancer is selected from one or more of the following: blood cancer or solid tumors.
  • the inflammatory disease or autoimmune disease is selected from one or more of the following: asthma, emphysema, allergy, dermatitis, arthritis, psoriasis, lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, eczema, scleroderma, Crohn's disease or multiple sclerosis.
  • the solid tumor treated using the methods or compounds disclosed herein is a cancer or tumor selected from one or more of the following: head and neck cancer, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, oral cancer, oropharyngeal cancer, laryngeal cancer, hypopharyngeal cancer, salivary gland cancer, paraganglioma, pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), gastric cancer, gastrointestinal cancer (e.g., carcinoid or stromal cancer), skin cancer, esophageal cancer, uterine cancer, endometrial cancer, liver cancer, hepatocellular carcinoma, bile duct cancer, bone cancer, gastrointestinal cancer, intestinal cancer, colon cancer, rectal cancer, Ovarian cancer, prostate cancer, breast cancer (e.g., triple-negative breast cancer), central nervous system tumors, brain cancer, lung cancer (e.g., non-
  • the blood cancer is a cancer selected from one or more of the following: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), myeloproliferative disorders, mast cell cancer, Hodgkin's disease, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, human lymphotropic virus type 1 (HTLV-1) leukemia/lymphoma, AIDS-related lymphoma, adult T-cell lymphoma, acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia, B-cell acute lymphocytic leukemia, chronic lymphocytic leukemia or multiple myeloma (MM).
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • MDS myelodysplastic syndrome
  • myeloproliferative disorders mast cell cancer
  • Hodgkin's disease non-Hodgkin's lymphom
  • the cancer is a leukemia or lymphoma.
  • the leukemia is B-cell acute lymphoblastic leukemia (B-ALL), acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic myeloid leukemia, hairy cell leukemia, myeloproliferative disorder, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), or mast cell cancer.
  • B-ALL B-cell acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • MDS myelodysplastic syndrome
  • the lymphoma is diffuse large B-cell lymphoma, B-cell lymphoblastoid lymphoma, small non-cleaved cell lymphoma or Burkitt's lymphoma, human lymphotropic virus type I (HTLV-1) leukemia/lymphoma, adult T-cell lymphoma, Hodgkin's disease or non-Hodgkin's lymphoma or its metastatic lesions.
  • the disorder treated by the methods or compounds disclosed herein is an inflammatory disease or an autoimmune disease.
  • the inflammatory disease or autoimmune disease is asthma, emphysema, allergy, dermatitis, arthritis (e.g., rheumatoid arthritis), psoriasis, lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, eczema, scleroderma, Crohn's disease, or multiple sclerosis.
  • the disorder is rheumatoid arthritis.
  • the disorder is rheumatoid arthritis and the amount of the compound is effective to improve one or more symptoms associated with rheumatoid arthritis, wherein the symptoms associated with rheumatoid arthritis are independently reduced joint swelling, reduced serum anti-collagen levels, reduced joint pathology, reduced bone resorption, reduced cartilage destruction, reduced pannus and/or reduced inflammation.
  • the disorder treated by the methods or compounds disclosed herein is a respiratory disease.
  • the respiratory disease is asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, or bronchiectasis.
  • COPD chronic obstructive pulmonary disease
  • chronic bronchitis chronic bronchitis
  • emphysema emphysema
  • bronchiectasis bronchiectasis.
  • the disorder is asthma.
  • a medicament comprising a compound of the present invention may be administered to a patient by at least one of injection, oral administration, inhalation, rectal administration, and transdermal administration.
  • the amount of a given medicament depends on a number of factors, such as the specific dosing regimen, the type of disease or condition, and its severity.
  • the specific surrounding conditions include, for example, specific drugs, routes of administration, diseases for treatment, and patients or hosts for treatment, but, according to specific surrounding conditions, including, for example, specific drugs, routes of administration, diseases for treatment, and patients or hosts for treatment, the dosage can be determined by methods known in the art.
  • the dosage is typically in the range of 0.02-5000mg/day, for example, about 1-1500mg/day.
  • the required dosage can be conveniently expressed as a dose, or a dose administered simultaneously (or in a short time) or in a divided dose at appropriate intervals, for example, two, three, four, or more divided doses per day. It will be appreciated by those skilled in the art that, although the above-mentioned dosage range is given, the specific effective amount can be appropriately adjusted according to the patient's situation and in conjunction with the physician's diagnosis.
  • a compound as described herein in any one of the compounds is administered to a subject at a dosage (e.g., a therapeutically effective dose) of about 2 mg, 1-3 mg, 1-5 mg, 1-10 mg, 0.5-20 mg, or 0.1-50 mg.
  • the dosage e.g., a therapeutically effective dose
  • the dosage is about 2 mg, 1-3 mg, 1-5 mg, 1-10 mg, 0.5-20 mg, 0.1-50 mg, 0.1-75 mg, 0.5-75 mg, 1-75 mg, 0.1-100 mg, 0.5-100 mg, or 1-100 mg.
  • the dosage is about 1-10 mg.
  • the dosage is about 1-50 mg.
  • the dosage is about 1-100 mg.
  • the compounds disclosed herein, including salts thereof, can be prepared using known organic synthesis techniques, and can be synthesized according to any of a variety of possible synthetic routes.
  • reaction can be monitored according to any suitable method known in the art, such as NMR, LC-MS and TLC.
  • Compounds can be purified by a variety of methods including HPLC and normal phase silica chromatography.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the crude product was obtained by vacuum distillation of the organic phase, and the crude product was purified by silica gel column chromatography.
  • the yellow product after precipitation is 5-(5,6-dimethoxypyridin-3-yl)-N-(pyridin-2-yl)pyrazolo[1,5-A]pyrimidin-2-amine.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(pyrrolidin-1-yl)methanone.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(2-methoxyethyl)pyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)pyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N,N-diethylpyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(2-(dimethylamino)ethyl)pyridine-2-amide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-isopropylpyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(2-hydroxy-2-methylpropyl)pyridine-2-amide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(2-(dimethylamino)ethyl)-N-ethylpyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-ethyl-N-methylpyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N,N-diisopropylpyridine-2-amide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-methyl-N-propylpyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-ethyl-N-propylpyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(2-(dimethylamino)ethyl)-N-methylpyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N,N-dimethylpyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N,N-dipropylpyridine-2-amide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, tert-butyl (2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-ethylpyridine-2-amide)carbamate.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N,N-bis(2-hydroxyethyl)pyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-ethyl-N-(2-hydroxyethyl)picolinyl-2-amine.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, and then washed with Dry over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(1-methyl-2-oxopyrrolidin-3-yl)pyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(3-(dimethylamino)pyrrolidin-1-yl)methanone.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(piperazine-1-yl)methanone.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 1-(4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)piperazin-1-yl)ethan-1-one.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(4-(ethylsulfonyl)piperazine-1-yl)methanone.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography to obtain a yellow product (R)-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(morpholinyl)methanone.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-isopropylmorpholinyl)methanone.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-acyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(3,4-dimethylpiperazin-1-yl)methanone.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-isobutylpyrrolidin-1-yl)methanone.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(piperidin-1-yl)methanone.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(tetrahydro-2H-pyran-4-yl)pyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was purified by silica gel column chromatography to obtain a yellow product [1,3'-bipyrrolidine]-1'-yl (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl Ketone.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(4-methylpiperazin-1-yl)methanone.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)pyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(4-ethylpiperazine-1-yl)methanone.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(3-ethoxypyrrolidin-1-yl)methanone.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(2-hydroxycyclopentyl)pyridine-2-amide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)-6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-amide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-acyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (1,4-diazepan-1-yl)(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methanone.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product (4,4-difluoropiperidin-1-yl)(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methanone.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(3-methylpiperazin-1-yl)methanone.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(1R,4R)-4-morpholinocyclohexyl)pyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(1R,4R)-4-hydroxycyclohexyl)pyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(1S,4S)-4-hydroxycyclohexyl)pyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product (R)-N-(1-cyclopropyl-2-hydroxyethyl)-6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-N-(1-cyclopropyl-2-hydroxyethyl)-6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-amide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(1S,4S)-4-hydroxy-4-methylcyclohexyl)pyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(1R,4R)-4-hydroxy-4-methylcyclohexyl)pyridine-2-amide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2- yl )amino)-N-(1S,3S)-3-hydroxycyclopentyl)pyridine-2-amide.
  • the reaction mixture was stirred for three times and the organic phases were combined.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(2-(pyridin-2-ylamino)ethyl)pyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(5-methylisoxazol-3-yl)pyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(pyridin-3-yl)pyridine-2-amide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(4-(pyridin-2-yl)piperazine-1-yl)methanone.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-N,N-dimethylacetamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)-N,N-diethylacetamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)-1-(pyrrolidin-1-yl)ethan-1-one.
  • the reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 . The organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was purified by silica gel column chromatography to obtain a yellow product (R)-(1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester.
  • the mixed solution is extracted three times with 20 mL of ethyl acetate, and the organic phases are combined.
  • the organic phase is washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4.
  • the organic phase is distilled under reduced pressure to obtain a crude product, and the crude product is chromatographed on a silica gel column to obtain a yellow product (R)-N-(6-(3-aminopyrrolidin-1-yl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine.
  • the crude product was purified by silica gel column chromatography to obtain a yellow product (S)-5-(5,6-dimethoxypyridin-3-yl)-N-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)pyrazolo[1,5-A]pyrimidin-2-amine.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidine-2-carboxamide.
  • the reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the reaction was neutralized with 20 mL of water.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was chromatographed on a silica gel column to obtain a yellow product N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-N6-(2-morpholinoethyl)-pyridine-2,6-diamine.
  • the reaction system was then reacted at 120°C for 14 hours. After the reaction was completed, the reaction was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(tert-butyloxycarbonyl)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)glycine.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(2-amino-2-oxoethyl)-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)carbamic acid tert-butyl ester.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-N-(2-(methylamino)-2-oxoethyl)carbamic acid tert-butyl ester.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the crude product was obtained by distillation of the organic phase under reduced pressure, and the yellow product 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)amino)acetamide was obtained after silica gel column chromatography.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)amino)-N-methylacetamide.
  • the reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 . The organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was purified by silica gel column chromatography to obtain a yellow product 1-(4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol.
  • the reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phase was combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the reaction was neutralized with 20 mL of water.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phases were respectively 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine.
  • the reaction was neutralized with 20 mL of water.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(4,4-difluoropiperidin-1-yl)methyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine.
  • Example 104 Synthesis of 1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-methylimidazolin-2-one Compound 104
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)picolinic acid methyl ester.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)-N,N-diethylpyridineamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, methyl 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)picolinate.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)-N,N-diethylpyridineamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, methyl 6-(6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)aminopicolinate.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)amino)-N,N-diethylpicolinamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, methyl 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)aminopicolinate.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N,N-diethylpicolinamide.
  • Example 111 Synthesis of 1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyridin-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one Compound 111
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, methyl 6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)aminopicolinate.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product (6-(5-(5-fluoro -6-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(2-(dimethylamino)ethyl)-N-ethyl-6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)picolinamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 4-(6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridinoyl)piperazine-1-carboxylic acid tert-butyl ester.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4.
  • the crude product was obtained by vacuum distillation of the organic phase, and the yellow product (6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(piperazine-1-yl)methanone was obtained after silica gel column chromatography.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)aminopicolinic acid methyl ester.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N,N-diethylpicolinamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(2-(dimethylamino)ethyl)-N-ethylpicolinamide.
  • the organic phase was washed with 20mL of water and 20mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 4-(6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridinoyl)piperazine-1-carboxylic acid tert-butyl ester.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product (6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(piperazine-1-yl)methanone.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, 4-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridinoyl)piperazine-1-carboxylic acid tert-butyl ester.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(piperazin-1-yl)methanone.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4.
  • the crude product was obtained by vacuum distillation of the organic phase, and the yellow product N-(6-(1-aminoethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-amine was obtained after silica gel column chromatography. MS m/z(ESI):392.18[M+H] + .
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)ethyl)-2,6-difluorobenzamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)ethyl)-4-methoxybenzamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4.
  • the crude product was obtained by vacuum distillation of the organic phase, and the yellow product N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-amine was obtained after silica gel column chromatography. MS m/z(ESI):378.17[M+H] + .
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-phenylpropanamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin - 3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(thiophen-2-yl)acetamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-1-methyl-1H-imidazole-4-carboxamide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(4-fluorophenyl)acetamide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4.
  • the crude product was obtained by distillation of the organic phase under reduced pressure.
  • the crude product was subjected to silica gel column chromatography to obtain the yellow product N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine. [1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)benzamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin- 2 -yl)amino)pyridin-2-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)propanamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-2-(6-methoxypyridin-3-yl)acetamide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)furan-2-carboxamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)thiophene-2-carboxamide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-2-(thiophen-3-yl)acetamide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-tert-butyl 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively. Then it was dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidine-2-carboxamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-1-(3,3,3-trifluoropropionyl)pyrrolidine-2-carboxamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product (S)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-1-(2-morpholineethyl)pyrrolidine-2-carboxamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, tert-butyl 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)piperidine-1-carboxylate.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then Then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-2-carboxamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, tert-butyl 3-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)piperidine-1-carboxylate.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4.
  • the crude product was obtained by vacuum distillation of the organic phase, and the yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-3-carboxamide was obtained after silica gel column chromatography.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)acetamide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)propionamide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)butanamide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)isobutyramide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)pivalamide after silica gel column chromatography.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)cyclopropanecarboxamide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)cyclobutanecarboxamide.
  • the reaction system was reacted at 120°C for 14 hours, and the reaction was terminated. Afterwards, the reaction was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4.
  • the crude product was obtained by vacuum distillation of the organic phase, and the yellow product N2-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)pyridine-2,6-diamine was obtained after silica gel column chromatography.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-tert-butyl 2-(6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the crude product was obtained by distillation of the organic phase under reduced pressure, and the crude product was purified by silica gel column chromatography After precipitation, the yellow product (S)-N-(6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidine-2-carboxamide was obtained.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4.
  • the crude product was obtained by vacuum distillation of the organic phase, and the yellow product N2-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine was obtained after silica gel column chromatography. MS m/z(ESI):400.13[M+H] + .
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-((6-((5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2,3-dihydrobenzo[B][1,4]dioxin-5-carboxamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)benzo[D][1,3]dioxole-4-carboxamide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)acetamide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)propionamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)pivalamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, methyl ((6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamate.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-methoxyacetamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2,2-difluoroacetamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3,3-difluoropropionamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-fluoropropionamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2,2,2-trifluoroacetamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(dimethylamino)acetamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4.
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was chromatographed on a silica gel column to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)cyclopropanecarboxamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)cyclobutanecarboxamide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)cyclopentanecarboxamide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)cyclohexanecarboxamide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)tetrahydrofuran-2-carboxamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin - 3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-morpholineacetamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)piperidine-3-carboxamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(4-methylpiperazin-1-yl)acetamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-1-methylpiperidine-4-carboxamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, tert-butyl 3-((6-((5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)azetidine-1-carboxylate.
  • the mixed solution is extracted three times with 20 mL of ethyl acetate, and the organic phases are combined.
  • the organic phase is washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na 2 SO 4.
  • the organic phase is distilled under reduced pressure to obtain a crude product.
  • the crude product is chromatographed on a silica gel column to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)azetidine-3-carboxamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, tert-butyl 4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)piperidine-1-carboxylate.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-(piperidin-1-yl)propanamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-( ... pyridin-1-yl)acetamide.
  • the organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)benzamide.

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Abstract

L'invention concerne un inhibiteur de kinase PI3Kγ et son utilisation dans un médicament pour traiter des maladies associées à l'activité de la kinase PI3Kγ et de voies de signalisation associées. L'inhibiteur de kinase PI3Kγ est un composé de formule (I) ou un sel, solvate, polymorphe, ester, acide, métabolite ou promédicament pharmaceutiquement acceptable de celui-ci, R1, R2, R3, X, A et B étant tels que définis dans la description.
PCT/CN2023/126472 2022-12-23 2023-10-25 COMPOSÉ POUR TRAITER DES MALADIES MÉDIÉES PAR PI3Kγ ET SON UTILISATION Ceased WO2024131265A1 (fr)

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CN202211660839.9A CN118239953A (zh) 2022-12-23 2022-12-23 用于治疗PI3Kγ介导的疾病的化合物及其用途
CN202211660839.9 2022-12-23

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WO2024131265A1 true WO2024131265A1 (fr) 2024-06-27

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WO2009010530A1 (fr) * 2007-07-18 2009-01-22 Novartis Ag Composés hétéroaryliques bicycliques et leur utilisation comme inhibiteurs de kinase
WO2010125799A1 (fr) * 2009-04-27 2010-11-04 塩野義製薬株式会社 Dérivé d'urée présentant une activité inhibitrice de la pi3k
CN103298792A (zh) * 2010-11-19 2013-09-11 利亘制药公司 杂环胺及其用途
US20190047980A1 (en) * 2015-12-18 2019-02-14 Bayer Pharma Aktiengesellschaft Heteroarylbenzimidazole compounds

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009010530A1 (fr) * 2007-07-18 2009-01-22 Novartis Ag Composés hétéroaryliques bicycliques et leur utilisation comme inhibiteurs de kinase
US20100197682A1 (en) * 2007-07-18 2010-08-05 Novartis Ag Organic Compounds
WO2010125799A1 (fr) * 2009-04-27 2010-11-04 塩野義製薬株式会社 Dérivé d'urée présentant une activité inhibitrice de la pi3k
CN103298792A (zh) * 2010-11-19 2013-09-11 利亘制药公司 杂环胺及其用途
US20190047980A1 (en) * 2015-12-18 2019-02-14 Bayer Pharma Aktiengesellschaft Heteroarylbenzimidazole compounds

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