WO2024125451A1 - Dérivés de pipérindine-ones, procédés de préparation et utilisations médicinales associés - Google Patents

Dérivés de pipérindine-ones, procédés de préparation et utilisations médicinales associés Download PDF

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WO2024125451A1
WO2024125451A1 PCT/CN2023/137890 CN2023137890W WO2024125451A1 WO 2024125451 A1 WO2024125451 A1 WO 2024125451A1 CN 2023137890 W CN2023137890 W CN 2023137890W WO 2024125451 A1 WO2024125451 A1 WO 2024125451A1
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alkyl
mmol
haloalkyl
alkoxy
equiv
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Hugh Y. Zhu
Jason Rohde
Jianhua TIAN
Allen CHAO
Wei Zhou
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Jiangsu Hansoh Pharmaceutical Group Co., Ltd.
Hansoh Bio Llc
Shanghai Hansoh Biomedical Co., Ltd.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
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    • 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
    • C07D471/10—Spiro-condensed systems
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine, and relates to piperidin-ones derivatives, preparation methods thereof, pharmaceutical compositions comprising the compounds, and medical uses thereof.
  • MK2 Mitogen-activiated protein kinase-activated protein kinase 2
  • TNFa tumor necrosis factor alpha
  • IFNg interleukin 6
  • IFNg interferon gamma
  • MK2 resides in the nucleus of non-stimulated cells and upon stimulation, it translocates to the cytoplasm and phosphorylates and activates tuberin and HSP27. MK2 is also implicated in heart failure, brain ischemic injury, the regulation of stress resistance and the production of TNF-quadrature.
  • diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events as described above. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Accordingly, there is a need for compounds that inhibit the mitogen activated protein kinase activated protein kinase-2 (MK2, MAPKAPK2) .
  • MK2, MAPKAPK2 mitogen activated protein kinase activated protein kinase-2
  • the present invention in one aspect, provides a compound of formula (I) :
  • X 1 , X 2 , X 3 and X 4 a re each independently selected from bond, CH, N, O or S;
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are each independently selected from bond, CH, N, O or S;
  • M 1 , M 2 , M 3 , M 4 , M 5 and M 6 are each independently selected from bond, CH, N, O or S;
  • L is bond, NH, O, S, alkyl, alkoxy, alkyl-N-or -CONH-;
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, hydroxyalkyl, cyano-alkyl, oxo, -CONH 2 , alkenyl-C (O) NH-, alkynyl-NH-, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyal
  • R 2 and R 3 together with the C atom to which they are bound form a heterocyclyl, wherein the heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;
  • t 0, 1, 2 or 3;
  • s 0, 1, 2 or 3.
  • X 1 , X 2 , X 3 or X 4 is selected from heteroatoms N, it has hydrogen substituents to satisfy the valences;
  • the compound of formula (I-0) or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated derivative, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is compound of formula (I) :
  • X 1 , X 2 , X 3 and X 4 are each independently selected from bond, CH, N, NH, O or S;
  • X 1 , X 2 , X 3 or X 4 is selected from heteroatoms N, it has hydrogen substituents to satisfy the valences;
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are each independently selected from bond, CH, N, O or S;
  • M 1 , M 2 , M 3 , M 4 , M 5 and M 6 are each independently selected from bond, CH, N, O or S;
  • L is bond, NH, O, S, alkyl, alkoxy, alkyl-N-or -CONH-;
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, hydroxyalkyl, cyano-alkyl, oxo, -CONH 2 , alkenyl-C (O) NH-, alkynyl-NH-, -C (O) O-alkyl, -C (O) NH-alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino
  • R 2 and R 3 together with the C atom to which they are bound form a heterocyclyl, wherein the heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;
  • t 0, 1, 2 or 3;
  • s 0, 1, 2 or 3.
  • L is bond, NH, O, S, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-N-or -CONH-.
  • L is bond, NH, O, S, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl-N-or -CONH-.
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, oxo, -CONH 2 .
  • R 1 hydrogen, deuterium, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl.
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, oxo, -CONH 2 .
  • R 2 and R 3 are each independently selected from hydrogen, deuterium, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl.
  • R 2 and R 3 together with the C atom to which they are bound form a 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S.
  • R 2 and R 3 together with the C atom to which they are bound form
  • R 4 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, oxo, -CONH 2 ;
  • R 4 is independently selected from the group consisting of hydrogen, deuterium, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, amino, F, Cl or Br.
  • R 5 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 2-6 cyano-alkyl, oxo, -CONH 2 , C 3-6 alkenyl-C (O) NH-, C 2-6 alkynyl-NH-, -C (O) O-C 1-4 alkyl, -C (O) NH-C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O, C 6-10 aryl, 5-7 membered heteroaryl containing 1 or 2 of heteroatoms selected from N or O, wherein each of the alkyl, haloalkyl, hydroxyalkyl, hydroxy
  • R 5 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 2-4 cyano-alkyl, C 2-4 alkoxyalkyl, oxo, -CONH 2 , C 3-6 alkenyl-C (O) NH-, C 2-4 alkynyl-NH-, -C (O) O-C 1-4 alkyl, -C (O) NH-C 1-4 alkyl, more preferably, R 5 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C
  • the compound of formula (I) is compound of formulas (Ia) - (Ig) :
  • X 1 is selected from CH, N, O or S;
  • Y 2 is selected from CH, CR y , N, O or S;
  • M 1 is selected from CH, N, O or S;
  • M 4 is selected from CH, N, O or S;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, oxo, -CONH 2 ; or, R 2 and R 3 together with the C atom to which they are bound form a 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S;
  • R 5 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 2-6 cyano-alkyl, oxo, -CONH 2 , C 3-6 alkenyl-C (O) NH-, C 2-6 alkynyl-NH-, -C (O) O-C 1-6 alkyl, -C (O) NH-C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-O-C 3-6 cycloalkyl, C 1-6 alkyl-O-C 1-6 haloalkyl, deuterated C 1-6 alkyl-O-C 1-6 haloalkyl,
  • R 5 is independently selected from the group consisting of i) hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 2-4 cyano-alkyl, oxo, -CONH 2 , C 3-6 alkenyl-C (O) NH-, C 2-4 alkynyl-NH-, -C (O) O-C 1-4 alkyl, -C (O) NH-C 1-4 alkyl, C 1-3 alkyl-O-C 1-5 alkyl, deuterated C 1-3 alkyl-O-C 1-3 haloalkyl, -C 1-3 alkyl-O-C 3-6 cycloalkyl, C 1-3 alkyl-O-C 1-6 haloalkyl, C 1-3 alkyl,
  • R 6 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl;
  • R 6 is independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, amino, cyano, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 hydroxyalkyl;
  • R 2g , R 3g , R 4g , R 5g are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, deuterated C 1-6 alkyl, deuterated C 2-6 alkenyl, deuterated C 2-6 alkynyl, deuterated C 1-6 haloalkyl, deuterated C 1-6 alkoxy, C 1-6 hydroxyalkyl, oxo, -CONH 2 ;
  • R y is selected from the group consisting of hydrogen, deuterium, F, Cl Br, amino, cyano, nitro, deuterated C 1-6 alkyl, deuterated C 2-6 alkenyl, deuterated C 2-6 alkynyl, deuterated C 1-6 haloalkyl, deuterated C 1-6 alkoxy, C 1-6 hydroxyalkyl, oxo, and -CONH 2 ;
  • t 0, 1, 2 or 3.
  • R 2 and R 3 are each independently selected from hydrogen, deuterium, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl;
  • R 2 and R 3 together with the C atom to which they are bound form
  • the compound of formula (I) is compound of formulas (IIa) or (IIb) :
  • L is NH, O, S, C 1-3 alkylene, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH-or -CONH-;
  • L 1 is O, S or NH
  • Y 2 is selected from CH, N, O or S;
  • M 4 is selected from CH, N, O or S;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, oxo and -CONH 2 ; or, R 2 and R 3 together with the C atom to which they are bound form a C 3-6 cycloalkyl or 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S;
  • R 4 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, oxo and -CONH 2 ;
  • R 5 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O, C 6-10 aryl and 5-7 membered heteroaryl containing 1 or 2 of heteroatoms selected from N or O;
  • R 7 is together with to form a 9-10 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, 9-10 membered heteroaryl containing 1 2, 3 or 4 of heteroatoms selected from N, O or S;
  • R a is independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and C 3-6 cycloalkyl;
  • R b is independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, and 5-6 membered heteroaryl containing 1 or 2 of heteroatoms selected from N, O or S;
  • n 0, 1 or 2;
  • n 0, 1 or 2;
  • t 0, 1 or 2;
  • s 0, 1, 2 or 3.
  • L is NH, O, S,
  • L 1 is O, S or NH
  • Y 2 is selected from CH, N, O or S;
  • M 4 is selected from CH, N, O or S;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 hydroxyalkyl;
  • R 2 and R 3 together with the C atom to which they are bound form a C 3-6 cycloalkyl or 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S;
  • R 4 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, oxo and -CONH 2 ;
  • R 5 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, and C 3-6 cycloalkyl;
  • R a is independently selected from the group consisting of hydrogen, deuterium, C 1-3 alkyl, deuterated C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, and C 3-6 cycloalkyl;
  • R b is independently selected from the group consisting of hydrogen, deuterium, C 1-3 alkyl, deuterated C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, and 5-6 membered heteroaryl containing 1 or 2 of heteroatoms selected from N, O or S.
  • the present invention also provides a process for the preparation of a compound of formula (I) , or a pharmaceutically acceptable salt, comprising the step of reacting a compound of formula (Xa) with a compound of formula (Xb) ,
  • X is OH, SH or NH 2 ;
  • Hal is halogen
  • R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , s, and t are defined as formula (I) .
  • the amount of the compound, tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated derivative, or pharmaceutically acceptable salts thereof is about 0.1-95%by weight of free base; preferably, is about 5-70%, e.g. 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%.
  • above stated pharmaceutical composition is formulated as a tablet, capsule, liquid form or injection form.
  • the amount of the compound, tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated derivative, or pharmaceutically acceptable salts thereof is about 1-1000mg; preferably, is about 1-500mg, more preferably, is about 1mg, 2mg, 3mg, 5mg, 10mg, 20mg, 40mg, 50mg, 60mg, 80mg, 100mg, 200mg, 300mg, 400m or 500mg.
  • the compound, tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated derivative, or pharmaceutically acceptable salts thereof is can be administered by any suitable route of administration, e.g. oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical compositions adapted accordingly.
  • the compound, tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salts is formulated as a soild or liquid form, e.g. syrups, suspension, emulsion, tablets, capsules, powders, granules or lozenges.
  • the present invention also provides a pharmaceutical composition, comprising a therapeutically effective amount of a compound of any formula (I) - (IV) , or tautomer, or deuterated derivative, or pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention relates to a method of inhibiting MK2 kinase, comprising administering to a subject in need thereof an effective amount of a compound of any formula (I) - (IV) , or a pharmaceutical composition comprising the same.
  • the present invention provides a method for treating a disorder mediated by MK2 kinase, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof.
  • diseases include, but are not limited to, immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases and proliferative diseases.
  • the immune, autoimmune or inflammatory diseases is selected from the group consisting of inflammatory bowel diseases, ulcerative colitis, Crohn's disease, multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis, juvenile arthritis, psoriatic arthritis, reactive arthritis, ankylosing spondylitis, cryopyrin associated periodic syndromes, Muckle-Wells syndrome, familial cold auto-inflammatory syndrome, neonatal-onset multisystem inflammatory disease, TNF receptor associated periodic synderome, acute and chronic pancreatitis, atherosclerosis, gout, ankylosing spondylitis, fibrotic disorders, hepatic fibrosis, idiopathic pulmonary fibrosis, nephropathy, sarcoidosis, scleroderma, anaphylaxis, diabetes, diabetes mellitus type 1, diabetes mellitus type 2, diabetic retinopathy, Still's disease, vasculitis, sarcoidos
  • graft vs. host disease allograft rejections, acute allograft rejection, chronic allograft rejection, early transplantation rejection, acute allograft rejection, reperfusion injury, pain, acute pain, chronic pain, neuropathic pain, fibromyalgia, chronic infections, meningitis, encephalitis, myocarditis, gingivitis, post surgical trauma, tissue injury, traumatic brain injury, enterocolitis, sinusitis, uveitis, ocular inflammation, optic neuritis, gastric ulcers, esophagitis, peritonitis, periodontitis, dermatomyositis, gastritis, myositis, polymyalgia, pneumonia and bronchitis.
  • Alkyl refers to a saturated aliphatic hydrocarbon group including C 1 -C 20 straight chain and branched chain groups.
  • an alkyl group is an alkyl having 1 to 12, sometimes preferably 1 to 6, sometimes more preferably 1 to 4, carbon atoms.
  • Representative examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, 2, 2-dimethyl propyl, 1-ethyl propyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 1, 2-trimethylpropyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,
  • an alkyl group is a lower alkyl having 1 to 6 carbon atoms.
  • Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 1, 2-trimethylpropyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, etc.
  • the alkyl group can be substituted or unsubstituted.
  • the substituent group (s) can be substituted at any available connection point, preferably the substituent group (s) is one or more substituents independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.
  • Alkenyl refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, for example, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc., preferably C 2-20 alkenyl, more preferably C 2-12 alkenyl, and most preferably C 2-6 alkenyl.
  • the alkenyl group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.
  • Alkynyl refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl etc., preferably C 2-20 alkynyl, more preferably C 2-12 alkynyl, and most preferably C 2-6 alkynyl.
  • the alkynyl group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • Alkylene refers to a saturated linear or branched aliphatic hydrocarbon group, wherein having 2 residues derived by removing two hydrogen atoms from the same carbon atom of the parent alkane or two different carbon atoms.
  • the straight or branched chain group containing 1 to 20 carbon atoms preferably has 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH 2 -) , 1, 1-ethylene (-CH (CH 3 ) -) , 1, 2-ethylene (-CH 2 CH 2 ) -, 1, 1-propylene (-CH (CH 2 CH 3 ) -) , 1, 2-propylene (-CH 2 CH (CH 3 ) -) , 1, 3-propylene (-CH 2 CH 2 CH 2 -) , 1, 4-butylidene (-CH 2 CH 2 CH 2 CH 2 -) etc.
  • the alkylene group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • Alkenylene refers to an alkylene defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, preferably C 2-20 alkenylene, more preferably C 2-12 alkenylene, and most preferably C 2-6 alkenylene.
  • the alkenylene group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • Alkynylene refers to an alkynyl defined as above that has at least two carbon atoms and at least one carbon-carbon triple bond, preferably C 2-20 alkynylene, more preferably C 2-12 alkynylene, and most preferably C 2-6 alkynylene.
  • alkenylene groups include, but are not limited to, -CH ⁇ CH-, -CH ⁇ CHCH 2 -, -CH ⁇ CHCH 2 CH 2 -, -CH 2 CH ⁇ CHCH 2 -etc.
  • the alkynylene group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • Cycloalkyl refers to a saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably 3 to 8 carbon atoms or 3 to 6 carbon atoms.
  • Representative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.
  • Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring.
  • “Spiro Cycloalkyl” refers to a 5 to 20 membered polycyclic group with rings connected through one common carbon atom (called a spiro atom) , wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system.
  • a spiro cycloalkyl is 6 to 14 membered, and more preferably 7 to 10 membered.
  • a spiro cycloalkyl is divided into mono-spiro cycloalkyl, di-spiro cycloalkyl, or poly-spiro cycloalkyl, and preferably refers to a mono-spiro cycloalkyl or di-spiro cycloalkyl, more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro cycloalkyl.
  • Representative examples of spiro cycloalkyl include, but are not limited to the following substituents:
  • “Fused Cycloalkyl” refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system.
  • a fused cycloalkyl group is 6 to 14 membered, more preferably 7 to 10 membered.
  • fused cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and preferably refers to a bicyclic or tricyclic fused cycloalkyl, more preferably 5-membered/5-membered, or 5-membered/6-membered bicyclic fused cycloalkyl.
  • Representative examples of fused cycloalkyls include, but are not limited to, the following substituents:
  • “Bridged Cycloalkyl” refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein every two rings in the system share two disconnected carbon atoms. The rings can have one or more double bonds, but have no completely conjugated pi-electron system.
  • a bridged cycloalkyl is 6 to 14 membered, and more preferably 7 to 10 membered.
  • bridged cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl.
  • Representative examples of bridged cycloalkyls include, but are not limited to, the following substituents:
  • the cycloalkyl can be fused to the ring of an aryl, heteroaryl or heterocyclic alkyl, wherein the ring bound to the parent structure is cycloalkyl.
  • Representative examples include, but are not limited to indanylacetic, tetrahydronaphthalene, benzocycloheptyl and so on.
  • the cycloalkyl is optionally substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.
  • Heterocyclyl refers to a 3 to 20 membered saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more, sometimes preferably one to five, sometimes more preferably one to three, heteroatoms selected from the group consisting of N, O, and S (O) m (wherein m is 0, 1, or 2) as ring atoms, but excluding -O-O-, -O-S-or -S-S-in the ring, the remaining ring atoms being C.
  • heterocyclyl is a 3 to 12 membered having 1 to 4 heteroatoms; more preferably a 3 to 10 membered having 1 to 3 heteroatoms; more preferably a 4 to 8 membered having 1 to 3 heteroatoms; most preferably a 5 to 6 membered having 1 to 2 heteroatoms.
  • monocyclic heterocyclyls include, but are not limited to, oxetanyl, azabutyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, sulfo-morpholinyl, homopiperazinyl, and so on.
  • Polycyclic heterocyclyl includes the heterocyclyl having a spiro ring, fused ring or bridged ring.
  • “Spiro heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl with rings connected through one common carbon atom (called a spiro atom) , wherein said rings have one or more, sometimes preferably one to five, sometimes more preferably one to three, heteroatoms selected from the group consisting of N, O, and S (O) m (wherein m is 0, 1 or 2) as ring atoms, the remaining ring atoms being C, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system.
  • a spiro heterocyclyl is 6 to 14 membered, and more preferably 7 to 10 membered.
  • spiro heterocyclyl is divided into mono-spiro heterocyclyl, di-spiro heterocyclyl, or poly-spiro heterocyclyl, and preferably refers to mono-spiro heterocyclyl or di-spiro heterocyclyl, more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro heterocyclyl.
  • Representative examples of spiro heterocyclyl include, but are not limited to the following substituents:
  • “Fused Heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of carbon atoms with the other ring, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and wherein said rings have one or more, sometimes preferably one to five, sometimes more preferably one to three, heteroatoms selected from the group consisting of N, O, and S (O) p (wherein p is 0, 1, or 2) as ring atoms, the remaining ring atoms being C.
  • a fused heterocyclyl is 6 to 14 membered, and more preferably 7 to 10 membered.
  • fused heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably refers to bicyclic or tricyclic fused heterocyclyl, more preferably 5-membered/5-membered, or 5-membered/6-membered bicyclic fused heterocyclyl.
  • fused heterocyclyl include, but are not limited to, the following substituents:
  • “Bridged Heterocyclyl” refers to a 5 to 14 membered polycyclic heterocyclic alkyl group, wherein every two rings in the system share two disconnected atoms, the rings can have one or more double bonds, but have no completely conjugated pi-electron system, and the rings have one or more heteroatoms selected from the group consisting of N, O, and S (O) m (wherein m is 0, 1, or 2) as ring atoms, the remaining ring atoms being C.
  • a bridged heterocyclyl is 6 to 14 membered, and more preferably 7 to 10 membered.
  • bridged heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and preferably refers to bicyclic, tricyclic or tetracyclic bridged heterocyclyl, more preferably bicyclic or tricyclic bridged heterocyclyl.
  • Representative examples of bridged heterocyclyl include, but are not limited to, the following substituents:
  • the ring of said heterocyclyl can be fused to the ring of an aryl, heteroaryl or cycloalkyl, wherein the ring bound to the parent structure is heterocyclyl.
  • Representative examples include, but are not limited to the following substituents:
  • the heterocyclyl is optionally substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio, heterocylic alkylthio.
  • Aryl refers to a 6 to 14 membered all-carbon monocyclic ring or a polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group, and has a completely conjugated pi-electron system.
  • aryl is 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl.
  • the aryl can be fused to the ring of heteroaryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is aryl. Representative examples include, but are not limited to, the following substituents:
  • the aryl group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • Heteroaryl refers to an aryl system having 1 to 4 heteroatoms selected from the group consisting of O, S and N as ring atoms and having 5 to 14 annular atoms.
  • a heteroaryl is 5-to 10-membered, more preferably 5-or 6-membered, for example, thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl can be fused with the ring of an aryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is heteroaryl. Representative examples include, but are not limited to, the following substituents:
  • the heteroaryl group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio, heterocylic alkylthio and -NR 9 R 10 .
  • Alkoxy refers to both an -O- (alkyl) and an -O- (unsubstituted cycloalkyl) group, wherein the alkyl is defined as above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxyl can be substituted or unsubstituted.
  • the substituent is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • “Bond” refers to a covalent bond using a sign of “-” .
  • Hydroalkyl refers to an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.
  • Haldroxy refers to an -OH group.
  • Halogen refers to fluoro, chloro, bromo or iodo atoms.
  • Amino refers to a -NH 2 group.
  • Cyano refers to a -CN group.
  • Niro refers to a -NO 2 group.
  • Carboxyl refers to a -C (O) OH group.
  • Alkoxycarbonyl refers to a -C (O) O (alkyl) or (cycloalkyl) group, wherein the alkyl and cycloalkyl are defined as above.
  • deuterated derivative refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom ( “D” ) . It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending on the origin of chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation is small and immaterial as compared to the degree of stable isotopic substitution of deuterated derivatives described herein. Thus, unless otherwise stated, when a reference is made to a “deuterated derivative” of a compound of the invention, at least one hydrogen is replaced with deuterium at well above its natural isotopic abundance (which is typically about 0.015%) .
  • the deuterated derivatives of the invention have an isotopic enrichment factor for each deuterium atom, of at least 3500 (52.5%deuterium incorporation at each designated deuterium) at least 4500, (67.5%deuterium incorporation) , at least 5000 (75%deuterium incorporation) at least 5500 (82.5%deuterium incorporation) , at least 6000 (90%deuterium incorporation) , at lease 6333.3 (95%deuterium incorporation, at least 6466.7 (97%deuterium incorporation, or at least 6600 (99%deuterium incorporation) .
  • heterocyclic group optionally substituted by an alkyl means that an alkyl group can be, but need not be, present, and the description includes the case of the heterocyclic group being substituted with an alkyl and the heterocyclic group being not substituted with an alkyl.
  • “Substituted” refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently substituted with a corresponding number of substituents. It goes without saying that the substituents exist in their only possible chemical position. The person skilled in the art is able to determine if the substitution is possible or impossible without paying excessive efforts by experiment or theory. For example, the combination of amino or hydroxyl group having free hydrogen and carbon atoms having unsaturated bonds (such as olefinic) may be unstable.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • a “pharmaceutical composition” refers to a mixture of one or more of the compounds described in the present invention or physiologically/pharmaceutically acceptable salts or prodrugs thereof and other chemical components such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, which is conducive to the absorption of the active ingredient and thus displaying biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the invention, such salts being safe and effective when used in a mammal and have corresponding biological activity.
  • each compound was identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS) .
  • NMR chemical shifts ( ⁇ ) were given in 10 -6 (ppm) .
  • NMR was determined by Varian Mercury 300 MHz Bruker Avance III 400MHz machine.
  • the solvents used were deuterated-dimethyl sulfoxide (DMSO-d 6 ) , deuterated-chloroform (CDCl 3 ) and deuterated-methanol (CD 3 OD) .
  • HPLC High performance liquid chromatography
  • LCMS Liquid Chromatography Mass Spectrometry
  • the average rates of ATPase inhibition, and the IC 50 values were determined by Victor Nivo multimode plate reader (PerkinElmer, USA) .
  • the thin-layer silica gel plates used in thin-layer chromatography were Yantai Xinnuo silica gel plate.
  • the dimension of the plates used in TLC was 0.15 mm to 0.2 mm, and the dimension of the plates used in thin-layer chromatography for product purification was 0.4 mm to 0.5 mm.
  • the known starting material of the invention can be prepared by the conventional synthesis method in the prior art, or can be purchased from ABCR GmbH &Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc or Dari chemical Company, etc.
  • argon atmosphere or “nitrogen atmosphere” means that a reaction flask was equipped with a balloon having 1 L of argon or nitrogen.
  • hydrogen atmosphere means that a reaction flask was equipped with a balloon having 1 L of hydrogen.
  • Step 1 6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (INT-003)
  • Step 1 2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one: to a solution of 1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one (250 mg, 1.84 mmol, 1.0 equiv) in MTBE (20 mL) was added 4, 4, 4’, 4’, 5, 5, 5’, 5’-octamethyl-2, 2’-bi-1, 3, 2-dioxaborolane (467 mg, 1.84 mmol, 1.1 equiv) , di-mu-methoxobis (1, 5-cyclooctadiene) diiridium (I) (37 mg, 0.055 mmol, 0.03 equiv) and 4, 4'-di-tert-butyl-2, 2'-bipyridine (30 mg, 0.11
  • 2-bromo-3-fluoro-N-methoxy-N-methylisonicotinamide To a solution of 2-bromo-3-fluoropyridine-4-carboxylic acid (3.00 g, 13.6 mmol) in DCM (15 mL) was added HATU (7.76 g, 20.4 mmol) , methoxy (methyl) amine (1.25 g, 20.4 mmol) and DIEA (7.03 g, 5.4 mmol) . The reaction was stirred at 25°C under N 2 for 6 hours. The reaction mixture was concentrated under vacuum and then extracted with EtOAc (15 mLx3) .
  • 2-chloro-4- (1-ethoxyvinyl) pyrimidine A mixture of 2, 4-dichloropyrimidine (2 g, 13.42 mmol, 1.0 equiv) , tributyl (1-ethoxyvinyl) stannane (7.27 g, 20.14 mmol, 1.5 equiv) and Pd (PPh 3 ) 2 Cl 2 (471 mg, 0.67 mmol, 0.05 equiv) in DMF (20 mL) was stirred under N 2 at 80 °C overnight.
  • 2-bromo-1- (2-chloropyrimidin-4-yl) ethan-1-one To a solution of 2-chloro-4- (1-ethoxyvinyl) pyrimidine (1.53 g, 8.29 mmol, 1.0 equiv) in THF (27 mL) and water (3 mL) was added NBS (1.62 g, 9.12 mmol, 1.1 equiv) at room temperature. The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mL ⁇ 3) .
  • tert-butyl 2- (2-hydroxy-4-pyridyl) -4-oxo-spiro [5, 6-dihydro-1H-pyrrolo [3, 2-c] pyridine-7, 3'-piperidine] -1'-carboxylate
  • Int-009 A mixture of tert-butyl 2- (2-chloro-4-pyridyl) -4-oxo-spiro [5, 6-dihydro-1H-pyrrolo [3, 2-c] pyridine-7, 3'-piperidine] -1'-carboxylate (600 mg, 1.44 mmol, 1.0 equiv) , potassium hydroxide (242 mg, 4.32 mmol, 3.0 equiv) , Pd 2 (dba) 3 (131.79 mg, 0.14 mmol, 0.1 equiv) , t-Bu, bippyphos (145.82 mg, 0.29 mmol, 0.2 equiv) in 1, 4-dioxan
  • tert-butyl 2- (2-chloropyridin-4-yl) -4-oxo-1, 4, 6, 7-tetrahydro-5H-pyrrolo [3, 2-c] pyridine-5-carboxylate A solution of 2-bromo-1- (2-chloro-4-pyridyl) ethanone 1 (1.65 g, 7.04 mmol, 1.0 equiv. ) , tert-butyl 2, 4-dioxopiperidine-1-carboxylate (1.5 g, 7.04 mmol, 1.0 equiv. ) , ammonium acetate (2.17 g, 28.16 mmol, 4.0 equiv.
  • Test Method Used Test Method D.
  • 2-bromo-5-fluoro-N-methoxy-N-methylisonicotinamide To a solution of 2-bromo-5-fluoropyridine-4-carboxylic acid (5.00 g, 22.5 mmol) in dichloroethane (50 mL) was added HATU (12.96 g, 33.8 mmol) , DIEA (11.75 g, 90.0 mmol) and N-methoxymethylamine (2.08 g, 33.8 mmol) at 25°C under N2 atmosphere. The resulting mixture was stirred at 25°C for 2 h. The mixture was diluted with water (20 mL) and extracted with DCM (15 mL x 3) .
  • Step 1 Int-007 (3 g, 12.14 mmol, 1 eq) , 2, 4-dichloro-5-iodopyrimidine (2.65 g, 9.71 mmol, 0.8 eq) and NaHCO 3 (3.05 g, 36.42 mmol, 3 eq) in DMF (25 mL) was stirred at 90°C under N 2 for 3 hours.
  • the reaction mixture was directly purified by pre-HPLC (ACN-H2O, 0.1%FA) to afford Int-0016-A (600 mg, 10.1%) as a white solid.
  • LCMS (m/z) [M+H] + calc’d 485.96; found, 486.0.
  • Test Method A Titank C183u 50*2.1mm; Mobile phase: A: 0.1%formic acid in water; B: acetonitrile. Separation method: 0-0.2 min: 5%B, 0.2-2.5 min: 5%B ⁇ 95%B, 2.5-2.6 min: 95%B ⁇ 5%B, 2.6-3.5 min: 5%B. Flow rate: 1 mL/min; Column temperature: 25 °C
  • Test Method B XBRIDGE C18 2.1*50mm, 3.5um; Mobile phase: H 2 O (0.05%TFA) -ACN (0.05%TFA) ACN from 0%to 60%over 7 minutes, 7-8min, ACN from 60%to 100%. Flow rate: 0.8mL/min, Column temperature: 30 °C
  • Test Method C CHIRALPAK IA 4.6*250mm, 5 ⁇ m; Mobile phase: 40%Acetonitrile, H2O (0.1%FA) . Flow rate: 25 mL/min, Column temperature: 30 °C
  • Test Method D XBRIDGE C18 2.1*50mm, 3.5um; Mobile phase: H 2 O (0.05%TFA) , ACN (0.05%TFA) ; 7 min., ACN from 10-100%; Flow rate: 1.0 mL/min; Column temperature: 45°C.
  • Test Method E Gemini 5u C19 150*21.2mm; Mobile phase: H 2 O (0.5%NH 4 OH) , ACN; 10.5 min., ACN from 2-95%; Flow rate: 20 mL/min; Column temperature: 20°C.
  • Test Method F XBRIDGE C18 2.12*150mm, 5um; H 2 O (0.1%FA) -CAN; ACN from 2%to 95%over 16 minutes; Flow rate: 20.0 mL/min; Column temperature 45°C.
  • Step 1 To a solution of 1-1 (580 mg, 2.59 mmol, 1.0 equiv) in DMF (10 mL) was added 2, 4-dichloro-5- (ethoxymethyl) pyrimidine 1-2 (710 mg, 2.59 mmol, 1.0 equiv) and NaHCO 3 (565 mg, 5.17 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred under 100 °C for 2h. The reaction mixture was concentrated. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mL ⁇ 3) . The combined organic phase was washed with brine (50 mL) , dried over Na 2 SO 4 and concentrated to give the crude.
  • Step 2 To a solution of 1-4 (250 mg, 1.84 mmol, 1.0 equiv) in MTBE (20 mL) was added 4, 4, 4’, 4’, 5, 5, 5’, 5’-octamethyl-2, 2’-bi-1, 3, 2-dioxaborolane 1-5 (467 mg, 1.84 mmol, 1.1 equiv) , di-mu-methoxobis (1, 5-cyclooctadiene) diiridium (I) (37 mg, 0.055 mmol, 0.03 equiv) and 4, 4'-di-tert-butyl-2, 2'-bipyridine (30 mg, 0.11 mmol, 0.06 equiv) at room temperature.
  • Step 3 A mixture of compound 1-3 (50 mg, 0.15 mmol, 1.0 equiv) , compound 1-6 (95 mg, 0.36 mmol, 2.5 equiv) , Ad 2 nBuP G3 (11 mg, 14.51 ⁇ mol, 0.1 equiv) and CsOAc (56 mg, 290.20 ⁇ mol, 2.0 equiv) in 1, 4-dioxane (0.5 mL) and water (0.05 mL) was stirred under N 2 at 80 °C overnight. The mixture was diluted with water (10 mL) and extracted with DCM (15 mL ⁇ 3) . The combined organic phase was washed with brine (50 mL) , dried over sodium sulphate and concentrated under reduced pressure. The crude was purified by prep-HPLC to give Example 1 (35 mg, 60%) .
  • Test Method Titank C183u 50*2.1mm; Mobile phase: A: 0.1%formic acid in water; B: acetonitrile. Separation method: 0-0.2 min: 5%B, 0.2-2.5 min: 5%B ⁇ 95%B, 2.5-2.6 min: 95%B ⁇ 5%B, 2.6-3.5 min: 5%B
  • Step 1 to a solution of 4-bromopyridin-2-ol (580 mg, 2.59 mmol, 1.0 equiv) in DMF (10 mL) was added 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (710 mg, 2.59 mmol, 1.0 equiv) and NaHCO 3 (565 mg, 5.17 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred under 100 °C for 2h. The reaction mixture was concentrated. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mL ⁇ 3) . The combined organic phase was washed with brine (50 mL) , dried over Na 2 SO 4 and concentrated to give the crude.
  • Step 2 A mixture of 4-bromopyridin-2-ol : to a solution of 4-bromopyridin-2-ol (50 mg, 0.15 mmol, 1.0 equiv) , Int-005 (95 mg, 0.36 mmol, 2.5 equiv) , Ad 2 nBuP G3 (11 mg, 14.51 ⁇ mol, 0.1 equiv) and CsOAc (56 mg, 290.20 ⁇ mol, 2.0 equiv) in 1, 4-dioxane (0.5 mL) and water (0.05 mL) was stirred under N 2 at 80 °C overnight. The mixture was diluted with water (10 mL) and extracted with DCM (15 mL ⁇ 3) .
  • Step 1 A mixture of Example 212 (60 mg, 150.06 ⁇ mol, 1.0 equiv) , trimethylsilylacetylene (44 mg, 450.19 ⁇ mol, 3.0 equiv) , Pd (PPh 3 ) 4 (35 mg, 30.01 ⁇ mol, 0.2 equiv) , CuI (11 mg, 60.03 ⁇ mol, 0.4 equiv) and TEA (46 mg, 450.19 mmol, 3.0 equiv) in DCM (2 mL) was stirred under N 2 at 50 °C overnight.
  • Step 2 A mixture of Example 212 (100 mg, 316.64 ⁇ mol, 1.0 equiv) , K2CO3 (59 mg, 433.29 ⁇ mol, 2.0 equiv) in MeOH (2 mL) was stirred at room temperature under air until Example 213 was fully consumed. The mixture was purified by prep-HPLC to give Example 214 (8 mg, 10%) .
  • LCMS-ESI (m/z) [M+H] + calc’d for C 21 H 19 N 5 O 3 , 389.42; found, 390.04.
  • Step 1 di-tert-butyl 2- (2- ( (2-chloro-5- (ethoxymethyl) pyrimidin-4-yl) oxy) pyridin-4-yl) -4-oxo-6, 7-dihydro-1H-pyrrolo [3, 2-c] pyridine-1, 5 (4H) -dicarboxylate: A mixture of Example 212 (150 mg, 0.38 mmol, 1.0 equiv. ) , di-tert-butyl dicarbonate (410 mg, 1.88 mmol, 5.0 equiv. ) , DMAP (9.0 mg, 75 ⁇ mol, 0.2 equiv. ) and TEA (230 mg, 2.25 mmol, 6.0 equiv.
  • Step 2 tert-butyl 2- (2-hydroxypyridin-4-yl) -4-oxo-1, 4, 6, 7-tetrahydro-5H-pyrrolo [3, 2-c] pyridine-5-carboxylate: A mixture of di-tert-butyl 2- (2- ( (2-chloro-5- (ethoxymethyl) pyrimidin-4-yl) oxy) pyridin-4-yl) -4-oxo-6, 7-dihydro-1H-pyrrolo [3, 2-c] pyridine-1, 5 (4H) -dicarboxylate (547 mg, 0.91 mmol, 1.0 equiv. ) in NH 3 in MeOH (10 mL, 7 M) was stirred at room temperature overnight.
  • Step 3 tert-butyl 2- (2- ( (5-carbamoyl-2-chloropyrimidin-4-yl) oxy) pyridin-4-yl) -4-oxo-1, 4, 6, 7-tetrahydr o-5H-pyrrolo [3, 2-c] pyridine-5-carboxylate: A mixture of tert-butyl 2- (2-hydroxypyridin-4-yl) -4-oxo-1, 4, 6, 7-tetrahydro-5H-pyrrolo [3, 2-c] pyridine-5-carboxylate (70 mg, 0.21 mmol, 1.0 equiv. ) , NaHCO 3 (36 mg, 0.42 mmol, 2.0 equiv.
  • Step 4 A mixture of tert-butyl 2- (2- ( (5-carbamoyl-2-chloropyrimidin-4-yl) oxy) pyridin-4-yl) -4-oxo-1, 4, 6, 7-tetrahydro-5H-pyrrolo [3, 2-c] pyridine-5-carboxylate (32 mg, 0.07 mmol, 1.0 equiv. ) and 1 N HCl (0.2 mL) in acetonitrile (2.0 mL) was stirred at room temperature for 4 h. The mixture was purified by prep-HPLC to give Example 215 (6.7 mg, 26%) .
  • Step 1 To a mixture of 4, 6-dichloropyrimidine (745 mg, 5.0 mmol, 1.0 equiv) and 4-bromopyridin-2-ol (870 mg, 5.0 mmol, 1.0 equiv) in DMF (40 mL) was added NaHCO 3 (840 mg, 10.0 mmol, 2.0 equiv) . The reaction was stirred at 100°C for 2 h. The reaction was cooled to room temperature, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL ⁇ 3) . The combined organic layers were washed with brine (50 mL) , dried over Na 2 SO 4 and concentrated.
  • NaHCO 3 840 mg, 10.0 mmol, 2.0 equiv
  • Step 2 To a solution of 4- ( (4-bromopyridin-2-yl) oxy) -6-chloropyrimidine (40 mg, 139.61 ⁇ mol, 1.0 equiv) and 2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one (91 mg, 349.03 ⁇ mol, 2.5 equiv) in 1, 4-dioxane (6 mL) and water (0.6 mL) was added Ad 2 nBu-G 3 (10 mg, 13.96 ⁇ mol, 0.1 equiv) and cesium acetate (53 mg, 279.22 ⁇ mol, 2.0 equiv) .
  • Step 1 A solution of 5- (trifluoromethyl) -1H-pyrimidine-2, 4-dione (2.16 g, 12.0 mmol, 1.0 equiv) and acetohydrazide (1.16 g, 15.6 mmol, 1.3 equiv) in 1 M NaOH (48 mL, 48.0 mmol, 4.0 equiv) was stirred at 80°C for 48 h. After cooling the mixture to room temperature, 1 M HCl (50 mL) was added while stirring. The mixture was filtered and the cake was washed with 1 M HCl (50 mL) and water (50 mL ⁇ 4) .
  • Step 2 To a suspension of 5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidine-2, 4 (1H, 3H) -dione (583 mg, 3.00 mmol, 1.0 equiv) in POCl 3 (12 mL) was added DIEA (1.94 g, 15.00 mmol, 2.6 mL, 5.0 equiv) at room temperature. The reaction mixture was stirred at 100°C overnight. The reaction was slowly poured into water (200 mL) and the mixture was extracted with EtOAc (120 mL ⁇ 2) . The combined organic layer was washed with brine (150 mL ⁇ 2) , dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Step 3 A solution of 2-bromo-1- (2-chloro-4-pyridyl) ethanone (1.65 g, 7.04 mmol, 1.0 equiv) , tert-butyl 2, 4-dioxopiperidine-1-carboxylate (1.50 g, 7.04 mmol, 1.0 equiv) , ammonium acetate (2.17 g, 28.16 mmol, 4.0 equiv) in EtOH (60 mL) was stirred at 60°C overnight. Cooled the reaction to room temperature, the mixture was diluted with water (60 mL) and the mixture was filtered.
  • Step 4 2- (2-hydroxypyridin-4-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one:
  • Step 5 2- (2- ( (2-chloro-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) pyrimidin-4-yl) oxy) pyridin-4-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one
  • Example 217 To a solution of 2- (2, 4-dichloropyrimidin-5-yl) -5-methyl-1, 3, 4-oxadiazole (50 mg, 218 ⁇ mol, 1.0 equiv) in NMP (1 mL) was added sodium bicarbonate (55 mg, 654 ⁇ mol, 3.0 equiv) , and the mixture was stirred at room temperature for 30 min.
  • Step 1 To a solution of Int-0013 (400 mg, 0.97 mmol, 1.0 equiv. ) and 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (284 mg, 1.46 mmol, 1.5 equiv. ) in 1, 4-dioxane (20 mL) and water (4 mL) was added Pd (dppf) Cl 2 -DCM (79 mg, 97 ⁇ mol, 0.1 equiv. ) and NaHCO 3 (244 mg, 2.91 mmol, 3.0 equiv. ) . The reaction was stirred at 55°C overnight. The mixture was filtered, and the solution was concentrated.
  • Step 2 To a solution of 4- (4- ( (4-bromopyridin-2-yl) oxy) -2-chloropyrimidin-5-yl) isoxazole (100 mg, 0.28 mmol, 1.0 equiv. ) and 2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one (147 mg, 0.56 mmol, 2.0 equiv.
  • Step 1 A mixture of Int-0013 (300 mg, 728 ⁇ mol, 1.0 equiv. ) , 1-methyl-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (144 mg, 692 ⁇ mol, 0.95 equiv) , Pd (dppf) Cl 2 .
  • DCM 60 mg, 72.8 ⁇ mol, 0.1 equiv.
  • NaHCO 3 184 mg, 2.18 mmol, 3.0 equiv.
  • Step 2 A mixture of 4- ( (4-Bromopyridin-2-yl) oxy) -2-chloro-5- (1-methyl-1H-pyrazol-3-yl) pyrimidine (33 mg, 90 ⁇ mol, 1.0 equiv. ) , 2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one (59 mg, 224 ⁇ mol, 2.5 equiv. ) , Ad 2 nBuP G3 (7 mg, 9 ⁇ mol, 0.1 equiv. ) and CsOAc (35 mg, 180 ⁇ mol, 2.0 equiv.
  • Step 1 To a solution of 4-bromopyridin-2-ol (87 mg, 0.5 mmol, 1 eq. ) in DMF (1 mL) was added 2, 4-dichloro-5-phenylpyrimidine (135 mg, 0.6 mmol, 1.2 eq. ) and sodium bicarbonate (84 mg, 1 mmol, 2 eq. ) . The mixture was stirred at 100 °C for 2 h.
  • Step 2 To a solution of 4- ( (4-bromopyridin-2-yl) oxy) -2-chloro-5-phenylpyrimidine (80 mg, 0.22 mmol, 1 eq. ) in dioxane (2 mL) and H 2 O (0.2 mL) was added Int-005 (144 mg, 0.55 mmol, 2.5 eq. ) , Ad 2 nBuP G3 Pd (16 mg, 0.02 mmol) , CsOAc (84 mg, 0.44 mmol, 2 eq. ) , the reaction was stirred at 80 °C overnight.
  • Step 1 To a solution of Int-0013 (600 mg, 1.46 mmol, 1.0 equiv. ) and pyridin-3-ylboronic acid (269 mg, 2.19 mmol, 1.5 equiv. ) in 1, 4-dioxane (30 mL) and water (6 mL) was added Pd (dppf) Cl 2 -DCM (119 mg, 146 ⁇ mol, 0.1 equiv. ) and NaHCO 3 (368 mg, 4.38 mmol, 3.0 equiv. ) . The reaction was stirred at 55°C overnight. The mixture was filtered and the solution was concentrated.
  • Step 2 To a solution of 4- ( (4-bromopyridin-2-yl) oxy) -2-chloro-5- (pyridin-3-yl) pyrimidine (180 mg, 0.50 mmol, 1.0 equiv. ) and Int-005 (262 mg, 1 mmol, 2.0 equiv. ) in 1, 4-dioxane (10 mL) and water (2 mL) was added Pd (dppf) Cl 2 -DCM (41 mg, 50 ⁇ mol, 0.1 equiv. ) and K 3 PO 4 (318 mg, 1.5 mmol, 3.0 equiv. ) . The reaction was stirred at 65 °C in microwave for 1.5 h.
  • Step 1 To a solution of Int-007 (100 mg, 0.404 mmol) in ACN (3 mL) was added 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (67 mg, 0.323 mmol) and K 2 CO 3 (167 mg, 1.213 mmol) and the mixture was stirred at 60°C for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (5 mLx3) . The combined organic layer was concentrated under vacuum and the residue was purified by pre-HPLC (CAN-H 2 O, 0.1%TFA) to afford Example 222 (2.41 mg, 2%) .
  • Test Method Used Test Method B.
  • Step 1 To a solution of 1, 2-oxazol-4-ylboranediol (500 mg, 4.43 mmol) in 1, 4-dioxane/H 2 O (5 mL) was added 2, 4-dichloro-5-iodopyrimidine (1461 mg, 5.32 mmol) , potassium carbonate (1836 mg, 13.29 mmol) and [1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (321 mg, 0.44 mmol) . The reaction mixture was stirred at 50°C under N2 for 6 hours and then filtered.
  • Step 2 To a solution of 2, 4-dichloro-5- (1, 2-oxazol-4-yl) pyrimidine 3 (55 mg, 0.25 mmol, 1.0 equiv) in DMF (5 mL) was added 2- (3-fluoro-2-hydroxypyridin-4-yl) -1H, 5H, 6H, 7H-pyrrolo [3, 2-c] pyridin-4-one 4 (76 mg, 0.31 mmol) and NaHCO3 (64 mg, 0.76 mmol) . The reaction mixture was stirred at 50°C for 2h under N2. Dilute with water, extract with ethyl acetate (10 mL ⁇ 3) .
  • Step 1 To a solution of 2-bromo-5-fluoropyridine-4-carboxylic acid (5.00 g, 22.5 mmol) in dichloroethane (50 mL) was added HATU (12.96 g, 33.8 mmol) , DIEA (11.75 g, 90.0 mmol) and N-methoxymethylamine (2.08 g, 33.8 mmol) at 25°C under N 2 atmosphere. The resulting mixture was stirred at 25°C for 2 h. The mixture was diluted with water (20 mL) and extracted with DCM (15 mL x 3) . The organic phase was dried over Na 2 SO 4 , filtered and the filtrate was concentrated to give crude product.
  • Step 2 To a solution of 2-bromo-5-fluoro-N-methoxy-N-methylisonicotinamide (4.04 g, 15.3 mmol) in THF (25 mL) was added methyl magnesium bromide (5.48 g, 45.9 mmol) at 25°C under N 2 atmosphere. The resulting mixture was stirred at 25°C for 3 h. The reaction mixture was quenched by saturated aqueous NH 4 Cl solution, diluted with ice water (10 mL) and extracted with EA (15 mL x 3) . The combined organic phase was dried over Na 2 SO 4 , filtered and the filtrate was concentrated to give crude product.
  • Step 3 2-bromo-1- (2-bromo-5-fluoropyridin-4-yl) ethan-1-one: To a solution of 1- (2-bromo-5-fluoropyridin-4-yl) ethan-1-one (2.98 g, 13.3 mmol) in HBr (15 mL, 0.3 mol/L in AcOH) was added Br 2 (3.49 g, 21.28 mmol) at 0°C under N 2 atmosphere and then warmed to room temperature and stirred for 16 h. The reaction mixture was transferred to a mixture of MTBE (15 mL) .
  • Step 4 2- (2-bromo-5-fluoropyridin-4-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one: To a solution of 2-bromo-1- (2-bromo-5-fluoropyridin-4-yl) ethan-1-one (3.1 g, 13.3 mmol) in EtOH (30 mL) was added acetic acid (3.98 g, 53.3 mmol) , ammonium acetate (6.16 g, 79.9 mmol) , 2, 4-piperadinedione (3 g, 26.6 mmol) at 0°C under N 2 atmosphere.
  • Step 5 2- (5-fluoro-2-hydroxypyridin-4-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one: To a solution of 2- (2-bromo-5-fluoropyridin-4-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one (500 mg, 1.59 mmol) in 1, 4-dioxane (10 mL) was added Pd 2 (dba) 3 (85 mg, 0.29 mmol) , t-BuXPhos (127 mg, 0.29 mmol) , KOH (2.5 mL, 2 mol/L in water) at 100°C under N 2 atmosphere in microwave for 1 h.
  • Step 6 To a solution of 2- (5-fluoro-2-hydroxypyridin-4-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-on e (100 mg, 0.4 mmol) in DMF (2 mL) was added NaHCO 3 (102 mg, 1.21 mmol) , 2, 4-dichloro-5-ethoxymethyl-pyrimidine (126 mg, 0.6 mmol) at 25°C under N 2 atmosphere and the mixture was stirred at 25°C for 3 h. The reaction mixture was filtrated, and the filtrate was diluted with water and extracted with EA (4 mL x 3) .
  • Test Method Used Test Method B.
  • Step 1 To a solution of ethyl 2, 4-dichloropyrimidine-5-carboxylate (10.0 g, 45.2 mmol, 1 equiv. ) in MeOH (100 mL) was added sodium methoxide (8.55 g, 158.3 mmol, 3.5 equiv. ) , the reaction was stirred at room temperature overnight. The reaction solvent was removed under reduced pressure and the residual was diluted with EA (100 mL) , the mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo to give methyl 2, 4-dimethoxypyrimidine-5-carboxylate (6.8 g, 34.3 mmol, 75%) as a white solid.
  • LCMS-ESI (m/z) [M+H] + calc’d for C 8 H 10 N 2 O 4 , 199.06; found, 199.03.
  • Step 2 To a solution of methyl 2, 4-dimethoxypyrimidine-5-carboxylate (6.8 g, 34.3 mmol) in anhydrous DCM (200 mL) was added DIBALH (68.6 mL, 68.6 mmol, 2 equiv., 1 M, in hexane) at 0 °C under N 2 , the reaction was stirred at 0 °C for 1 h. Water (2.7 mL) was slowly added into the reaction mixture at 0 °C, followed by 15%NaOH solution (2.7 mL) and water (6.8 mL) , the mixture was stirred at room temperature for 15 min, MgSO 4 was added and the reaction was stirred for another 15 min.
  • DIBALH 68.6 mL, 68.6 mmol, 2 equiv., 1 M, in hexane
  • Step 3 To a solution of (2, 4-dimethoxypyrimidin-5-yl) methanol (3.8 g, 22.3 mmol) in DCM (120 mL) was added Dess-martin Periodinane (14.2 g, 33.5 mmol, 1.5 equiv. ) , the reaction was stirred at room temperature overnight.
  • Step 4 To a solution of hydroxylamine hydrochloride (1.24 g, 17.8 mmol, 1.2 equiv. ) in water (20 mL) was added NaHCO 3 (1.5 g, 17.8 mmol, 1.2 equiv. ) , the mixture was added dropwise into the solution of 2, 4-dimethoxypyrimidine-5-carbaldehyde (2.5 g, 14.8 mmol) in EtOH (40 mL) , the reaction was stirred at room temperature for 2 h.
  • Step 5 To a solution of (E) -2, 4-dimethoxypyrimidine-5-carbaldehyde oxime (2.65 g, 14.4 mmol) in water (50 mL) was added ethynyl (trimethyl) silane (2.13 g, 21.6 mmol, 1.5 equiv. ) , then KCl (1.08 g, 14.4 mmol, 1 equiv. ) was added potion-wise, followed by oxone (13.3 g; 21.6 mmol, 1.5 equiv. ) . The mixture was stirred at room temperature for 12 h.
  • Step 6 To a solution of 3- (2, 4-dimethoxypyrimidin-5-yl) -5- (trimethylsilyl) isoxazole (2.68 g, 9.6 mmol) in MeOH (50 mL) was added K 2 CO 3 (2.0 g, 14.4 mmol, 1.5 equiv. ) . The mixture was stirred at room temperature for 0.5 h.
  • Step 7 To a solution of 3- (2, 4-dimethoxypyrimidin-5-yl) isoxazole (0.66 g, 3.2 mmol) in AcOH (10 mL) was added NaI (1.43 g, 9.6 mmol, 3 equiv. ) . The mixture was stirred at 110 °C for 2 h. The reaction was concentrated and diluted with water (20 mL) . The residual was washed with saturated Na 2 S 2 O 3 (20 mL) , white precipitate was filtered and washed with water to give 3- (2, 4-dimethoxypyrimidin-5-yl) isoxazole (0.37 g, 2.0 mmol, 64%) .
  • LCMS-ESI (m/z) [M+H] + calc’d for C 7 H 5 N 3 O 3 , 180.03; found, 180.06.
  • LCMS-ESI (m/z) [M+H] + calc’d for C 7 H 3 Cl 2 N 3 O, 215.97; found, 216.00.
  • Step 9 To a solution of 3- (2, 4-dichloropyrimidin-5-yl) isoxazole (44 mg, 0.19 mmol) in DMAc (1 mL) was added Int-0012 (50 mg, 0.22 mmol, 1.2 equiv. ) and potassium tert-butoxide (32 mg, 0.29 mmol, 1.5 equiv. ) , the mixture was stirred at 55 °C for 2 h. The mixture was concentrated and purified by flash column to give Example 225 (5.4 mg, 0.012 mmol, 7%) as yellow solid.
  • Step 1 To a solution of 2, 4-dichloro-5- (iodomethyl) pyrimidine (1.00 g, 3.47 mmol) , DIEA (888 mg, 6.94 mmol) in dichloromethane (10 mL) was added piperidine (295 mg, 3.47 mmol) dropwise in DCM (2 mL) at -20 °C. The reaction mixture was stirred at -20°C for 3 h.
  • Step 2 To a solution of 2, 4-dichloro-5- (piperidin-1-ylmethyl) pyrimidine (107 mg, 0.43 mmol) , Int-0012 (100 mg, 0.43 mmol) in DMF (5 mL) was added NaHCO 3 (144 mg, 1.72 mmol) at room temperature. The reaction mixture was stirred at 40°C for 16 h. The reaction mixture was extracted with EA (20 mL*2) , washed with brine (10 mL*3) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the crude. The crude was purified by prep-HPLC to afford product Example 226 (17 mg, yield 17%) , as a yellow solid.
  • Step 1 A mixture of Int-008 (2.0 g, 4.32 mmol, 1.0 equiv) , 2-bromo-1- (2-chloropyrimidin-4-yl) ethan-1-one (1.02 g, 4.32 mmol, 1.0 equiv) and NH 4 OAc (999 mg, 12.96 mmol, 3 equiv) in EtOH (50 mL) was stirred at 60 °C overnight.
  • Step 2 To a solution of tert-butyl 2'- (2-chloropyrimidin-4-yl) -4'-oxo-5'- (2, 4, 6-trimethoxybenzyl) -1', 4', 5', 6'-tetrahydrospiro [piperidine-3, 7'-pyrrolo [3, 2-c] pyridine] -1-carboxylate (1.94 g, 3.24 mmol, 1.0 equiv) in DCM (20 mL) was added TFA (5 mL) , the reaction was stirred at 50 °C for 2 h.
  • Step 3 To a solution of crude 2'- (2-chloropyrimidin-4-yl) -5', 6'-dihydrospiro [piperidine-3, 7'-pyrrolo [3, 2-c] pyridin] -4' (1'H) -one in MeCN (50 mL) was added TEA (5 mL) , DMAP (33 mg, 0.32 mmol, 0.1 equiv) and (Boc) 2 O (1.41 g, 6.48 mmol, 2 equiv) , the reaction was stirred at room temperature overnight.
  • Step 4 A mixture of tert-butyl 2'- (2-chloropyrimidin-4-yl) -4'-oxo-1', 4', 5', 6'-tetrahydrospiro [piperidine-3, 7'-pyrrolo [3, 2-c] pyridine] -1-carboxylate (1.02 g, 2.44 mmol, 1.0 equiv) , N-hydroxyacetamide (549 mg, 7.31 mmol, 3.0 equiv) and K 2 CO 3 (1.68 g, 12.18 mmol, 5.0 equiv) in DMSO (8.1 mL) was stirred at 80 °C under N 2 overnight.
  • Step 5 To a solution of tert-butyl 2'- (2-hydroxypyrimidin-4-yl) -4'-oxo-1', 4', 5', 6'-tetrahydrospiro [piperidine-3, 7'-pyrrolo [3, 2-c] pyridine] -1-carboxylate (200 mg, 0.50 mmol, 1.0 equiv) in DMF (1 mL) was added 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (109 mg, 0.53 mmol, 1.05 equiv) and NaHCO 3 (85 mg, 1.00 mmol, 2.0 equiv) , the reaction mixture was stirred under 100 °C for 2 h.
  • Step 1 To a solution of Int-009 (50 mg, 0.50 mmol, 1.0 equiv) in DMF (2 mL) was added 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (45 mg, 0.25 mmol, 2.0 equiv) and NaHCO 3 (20 mg, 0.25 mmol, 2.0 equiv) , the reaction was stirred under 100 °C for 2 h. The reaction mixture concentrated and purified by prep-HPLC to give Example 228 (16 mg, 22%) . LCMS-ESI (m/z) : [M+H] + calc’d for C 27 H 32 ClN 7 O 5 , 569.06; found, 569.06.
  • Step 1 To a solution of Int-009 (84 mg, 0.21 mmol, 1.0 equiv. ) in DMF (1 mL) was added 2, 4-dichloropyrimidine-5-carboxamide (81 mg, 0.42 mmol, 2.0 equiv. ) and NaHCO 3 (35 mg, 0.42 mmol, 2.0 equiv. ) , the reaction was stirred under 100 °C for 2 h. The reaction mixture concentrated and purified by prep-HPLC to give Example 229 (10 mg, 8%) . LCMS-ESI (m/z) : [M+H] + calc’d for C 26 H 28 ClN 7 O 5 , 554.18; found, 553.98.
  • Step 1 To a solution of Int-0010 (150 mg, 0.23 mmol) in dioxane (1.5 mL) was added 6-chloropicolinamide (55 mg, 0.35 mmol) , Xantphos (27 mg, 0.047 mmol) , Pd 2 (dba) 3 (21 mg, 0.023 mmol) and Cs 2 CO 3 (228 mg, 0.70 mmol) . The reaction mixture was stirred at 100°C under microwave for 1 h.
  • Step2 A solution of tert-butyl 2'- (2- (6-chloropicolinamido) pyridin-4-yl) -4'-oxo-5'- (2, 4, 6-trimethoxybenzyl) -1', 4', 5', 6 '-tetrahydrospiro [piperidine-3, 7'-pyrrolo [3, 2-c] pyridine] -1-carboxylate (110 mg, 0.15 mmol) and anisole (83 mg, 0.77 mmol) in TFA (1 mL) was stirred at 25°C for 30min.
  • Step 1 To a solution of Int-009 (300 mg, 519 ⁇ mol, 1.0 equiv) and 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (128 mg, 623 ⁇ mol, 1.2 equiv) in acetonitrile (10 mL) was added K 2 CO 3 (215 mg, 1.56 mmol) at room temperature. The mixture was stirred at 60°C for 2 h and then filtered.
  • Step 2 To a solution of tert-butyl 2'- (2- ( (2-chloro-5- (ethoxymethyl) pyrimidin-4-yl) oxy) pyridin-4-yl) -4'-oxo-5'- (2, 4, 6-trimethoxybenzyl) -1', 4', 5', 6'-tetrahydrospiro [piperidine-3, 7'-pyrrolo [3, 2-c] pyridine] -1-carboxylate (40 mg, 53.4 ⁇ mol) in Anisole (1 mL) was added TFA (2 mL) at 25°C and stirred at room temperature for 30 min. The reaction mixture was quenched by H 2 O.
  • Step 1 To a solution of Int-007 (700 mg, 1.21 mmol) in acetonitrile (7 mL) was added 2, 4-dichloro-5- ( ( (4-methoxybenzyl) oxy) methyl) pyrimidine (434 mg, 1.45 mmol) and K 2 CO 3 (501mg, 3.62 mmol) at 80 °C under N 2. The resulting mixture was stirred 80 °C for 4 h and then filtered.
  • Step 2a To a solution of tert-butyl 2'- (2- ( (2-chloro-5- ( ( (4-methoxybenzyl) oxy) methyl) pyrimidin-4-yl) oxy) pyridin-4-yl) -4'-oxo-5'- (2, 4, 6-trimethoxybenzyl) -1', 4', 5', 6'-tetrahydrospiro [piperidine-3, 7'-pyrrolo [3 , 2-c] pyridine] -1-carboxylate (45 mg, 0.054 mmol) in TFA (1 mL) was added anisole (30 mg, 0.28 mmol) at room temperature and it was stirred for 1 h.
  • Step 2b To a solution of tert-butyl 2'- (2- ( (4-chloro-5- ( (4-methoxybenzyl) oxy) pyrimidin-2-yl) oxy) pyridin-4-yl) -4'-oxo-5'- (2, 4, 6-trimethoxybenzyl) -1', 4', 5', 6'-tetrahydrospiro [piperidine-3, 7'-pyrrolo [3, 2-c] pyri dine] -1-carboxylate (22 mg, 0.027 mmol) in TFA (1 mL) was added anisole (15 mg, 0.14 mmol) at room temperature and it was stirred for 1 h.
  • Test Method Used Test Method B.
  • Example 232, Retention time 3.31 min;
  • Step 1 To a solution of Int-009 (500 mg, 0.86 mmol) in acetonitrile (5 mL) was added 4, 6-dichloropyrimidine (141 mg, 0.95mmol) and K 2 CO 3 (358 mg, 2.59 mmol) at 80°C under N 2. The resulting mixture was stirred at 80°C for 16 h and then filtered.
  • Step 2 To a solution of tert-butyl 2'- (2- ( (6-chloropyrimidin-4-yl) oxy) pyridin-4-yl) -4'-oxo-5'- (2, 4, 6-trimethoxybenzyl) -1 ', 4', 5', 6'-tetrahydrospiro [piperidine-3, 7'-pyrrolo [3, 2-c] pyridine] -1-carboxylate (100 mg, 0.14 mmol) in TFA (1 mL) was added anisole (78 mg, 0.72 mmol) at room temperature and it was stirred for 1 h.
  • Step 1 To a solution of 2, 4-dichloropyrimidine-5-carbonitrile (77 mg, 0.44 mmol, 1.2 equiv. ) and Int-0012 (85 mg, 0.37 mmol, 1.0 equiv. ) in DMAc (10 mL) was added NaHCO 3 (37 mg, 0.44 mmol, 1.2 equiv. ) . The reaction was stirred at 50 °C for 2 h. The reaction mixture was purified by prep-HPLC to give Example 235 (3.9 mg, 18 ⁇ mol, 5%) . LCMS-ESI (m/z) : [M+H] + calc’d for C 17 H 11 ClN 6 O 2 , 367.06; found, 366.99.
  • Step 1 To a solution of Int-0013 (600 mg, 1.46 mmol, 1.0 equiv. ) and pyridin-4-ylboronic acid (269 mg, 2.19 mmol, 1.5 equiv. ) in 1, 4-dioxane (30 mL) and water (6 mL) was added Pd (dppf) Cl 2 -DCM (119 mg, 146 ⁇ mol, 0.1 equiv. ) and NaHCO 3 (368 mg, 4.38 mmol, 3.0 equiv. ) . The reaction was stirred at 55°C overnight. The mixture was filtered and the solution was concentrated to obtain the crude.
  • Pd (dppf) Cl 2 -DCM 119 mg, 146 ⁇ mol, 0.1 equiv.
  • NaHCO 3 368 mg, 4.38 mmol, 3.0 equiv.
  • Step 2 To a solution of 4- ( (4-bromopyridin-2-yl) oxy) -2-chloro-5- (pyridin-4-yl) pyrimidine (180 mg, 0.50 mmol, 1.0 equiv. ) and 2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one (262 mg, 1 mmol, 2.0 equiv. ) in 1, 4-dioxane (10 mL) and water (2 mL) was added Pd (dppf) Cl 2 -DCM (41 mg, 50 ⁇ mol, 0.1 equiv.
  • Step 1 To a solution of 2-bromo-1- (2-chloropyridin-4-yl) ethanone (10 g, 42.6 mmol) in EtOH (50 mL) was added NH 4 AC (19.7 g, 255.6 mmol) , HOAc (10.23 g, 170.4 mmol) and tert-butyl 2, 4-dioxopiperidine-1-carboxylate (18.17 g, 85.2 mmol) . The resulting mixture was stirred at 80°C under N 2 atmosphere for 16 h. The mixture was diluted with water (200 mL) and filtered.
  • Step 2 To a solution of tert-butyl 2- (2-chloropyridin-4-yl) -4-oxo-1, 4, 6, 7-tetrahydro-5H-pyrrolo [3, 2-c] pyridine-5-carboxylate (4 g, 11.5 mmol) in DMF (25 mL) was added iodomethane (8.14 g, 57.3 mmol) , potassium carbonate (1.93 g, 34.4 mmol) at 25°C under N2 atmosphere for 1 h. The mixture was diluted with water (60 mL) and extracted with EtOAc (30 mL x 3) . The organic layer was washed with brine (40 mL) and concentrated under reduced pressure.
  • Step 3 To a solution of tert-butyl 2- (2-chloropyridin-4-yl) -1-methyl-4-oxo-1, 4, 6, 7-tetrahydro-5H-pyrrolo [3, 2-c] pyridine-5-carboxylate (2.65 g, 7.3 mmol) in AcOH (18 mL) was added H 2 O (6 mL) at 130°Cunder for 120 h.
  • Step 4 To a solution of 2- (2-hydroxypyridin-4-yl) -1-methyl-1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one (300 mg, 1.3 mmol) in DMF (5 mL) was added 2, 4-dichloro-5-iodopyrimidine (539 mg, 1.9 mmol) , NaHCO3 (329 mg, 3.9 mmol) at 25°C under N2 atmosphere and then the mixture was warmed to 90°C and stirred for 16 h. The mixture was diluted with water (15 mL) and extracted with EA (15 mL x 3) . The organic layer was washed with brine (10 mL) and concentrated under reduced pressure.
  • Step 5 A solution of 2- (2- ( (2-chloro-5-iodopyrimidin-4-yl) oxy) pyridin-4-yl) -1-methyl-1, 5, 6, 7-tetrahydro-4 H-pyrrolo [3, 2-c] pyridin-4-one (130 mg, 0.27 mmol) , 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (63 mg, 0.32 mmol) , [1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (20 mg, 0.027 mmol) and potassium phosphate tribasic (172 mg, 0.81 mmol) in 1, 4-dioxane (1.5 mL) and H 2 O (0.15 mL) was stirred at 65°C under N2 atmosphere for 2 h.
  • Test Method Used Test Method D.
  • Step 1 A suspension of Int-009 (300 mg, 0.52 mmol) , 2, 4-dichloro-5-iodopyrimidine (170 mg, 0.62 mmol) and NaHCO 3 (130 mg, 1.5524 mmol) in DMF (5 mL) was stirred under nitrogen at 90°C for 2h. The residue was diluted with EtOAc (20 mL x2) , washed with brine (20 mL) . The organic phase was collected and dried over NaSO 4 and concentrated.
  • Step 2 A suspension of tert-butyl 2'- (2- ( (2-chloro-5-iodopyrimidin-4-yl) oxy) pyridin-4-yl) -4'-oxo-5'- (2, 4, 6-trimethoxybenzyl) -1', 4', 5', 6'-tetrahydrospiro [piperidine-3, 7'-pyrrolo [3, 2-c] pyridine] -1-carboxylate (260 mg, 0.32 mmol) , 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (123 mg, 0.64 mmol) , Pd (dppf) Cl 2 (37 mg, 0.03 mmol) and K 2 CO 3 (220 mg, 1.59 mmol) in dioxane/H 2 O (5 mL) was stirred under nitrogen at 60°C for 2h.
  • Step 3 A solution of tert-butyl 2'- (2- ( (2-chloro-5- (isoxazol-4-yl) pyrimidin-4-yl) oxy) pyridin-4-yl) -4'-oxo-5'- (2, 4, 6-trimethoxybenzyl) -1', 4', 5', 6'-tetrahydrospiro [piperidine-3, 7'-pyrrolo [3, 2-c] pyridine] -1-carboxylate (140 mg, 0.18 mmol) in anisole (3 mL) and TFA (3 mL) was stirred at 25°C for 3h.
  • Step 1 To a solution of Int-0013 (110 mg, 0.23 mmol) in dioxane (6 mL) and water (0.6 mL) was added K 3 PO 4 (100 mg, 0.47 mmol) , 5-methyl-4- (4, 4, 5, 5-tetraMethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (59 mg, 0.28 mmol) and Pd (dppf) Cl 2 (17 mg, 0.023 mmol) . The mixture was stirred at 50°C for 4 h under nitrogen atmosphere.
  • Step 1 To a solution of Int-0013 (100 mg, 0.21 mmol) in 1, 4-dioxane (2 mL) and H2O (0.2 mL) was added 1-Methyl-1H-pyrazole-4-boronic acid (32 mg, 0.25 mmol) , Pd (dppf) Cl 2 (16 mg, 0.02 mmol) and potassium carbonate (89 mg, 0.64 mmol) at 50°C under N2 atmosphere for 2 h. The reaction mixture was filtrated, and the filtrate was concentrated, and the residue was purified by Prep-HPLC to afford Example 240 (27.26 mg, yield 27%) .
  • LCMS (m/z) [M+H] + calc’d 422.1; found, 421.7.
  • Test Method Used Test Method D.
  • Step 1 To a solution of Int-0013 (100 mg, 0.21 mmol) in 1, 4-dioxane (2 mL) and H2O (0.2 mL) was added 2-fluorophenylboronic acid (24 mg, 0.17 mmol) , Pd (dppf) Cl 2 (16 mg, 0.02 mmol) and Potassium carbonate (89 mg, 0.64 mmol) at 50°Cunder N2 atmosphere for 16 h. The reaction mixture was filtrated, and the filtrate was purified by Prep-HPLC to afford Example 241 (15.35 mg, yield 15%) . LCMS (m/z) : [M+H] + calc’d 436.09; found, 436.1.
  • Test Method Used Test Method D.
  • Step 1 To a solution of Int-0013 (90 mg, 0.19 mmol, 1 equiv. ) and 2 (29 mg, 0.21 mmol, 1.1 equiv. ) in dioxane (5 mL) and water (1 mL) was added Pd (PPh 3 ) 4 (22 mg , 0.019 mmol) and K2CO3 (123 mg, 0.58 mmol) at room temperature. The mixture was stirred at 65 °C for 4 h and then filtered. The mixture was filtered, and the filtrate was purified by Prep-HPLC using a gradient of H2O (0.1%FA) /ACN (Flow rate: 20 ml/min; Wavelength: 214 nm/254 nm.
  • Step 1 To a solution of Int-0013 (80 mg, 0.17 mmol, 1 equiv. ) and 2 (38 mg, 0.34 mmol, 2.0 equiv. ) in dioxane (5 mL, 20 V) , was added purified water (1 mL, 2 V) , Pd (dppf) Cl2 (12 mg , 0.017 mmol) and K 3 PO 4 (109 mg, 0.51 mmol) at room temperature in the glove box. The mixture was stirred at 65 °C for 4 h and then filtered.
  • Step 1 To a solution of 2, 4-dichloro-5- (iodomethyl) pyrimidine (1.00 g, 3.50 mmol) , DIEA (1.36 g, 10.50 mmol) in DCM (10 mL) was added morpholine (0.27 g, 3.15 mmol) dropwise in DCM (2 mL) at -20 °C. The reaction mixture was stirred at -20°C for 3 h.
  • Step 2 To a solution of 4- ( (2, 4-dichloropyrimidin-5-yl) methyl) morpholine (130 mg, 0.52 mmol) and 3 (240 mg, 1.05 mmol) in DMF (3 mL) was added NaHCO 3 (53 mg, 0.63 mmol) at room temperature. The reaction mixture was stirred at 90°C for 2 h. The reaction mixture was extracted with EA (20 mL x 3) , washed with brine (10 mL x 3) , dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the crude. The crude was purified by Prep-HPLC to afford Example 244 (4.12 mg, yield 1.7%) .
  • Step 1 To a solution of 1, 3-oxazole (2 g, 0.029 mol, 1.0 equiv) in THF (30 mL) was added n-BuLi (2.5 M, 11.6 mL, 1.0 equiv) at -78°C under N2. The reaction mixture was stirred at -78 °C for 1 h. Then the reaction mixture was added Triisopropyl (trifluoromethylsulfonyloxy) silane (8.89 g, 0.029 mol, 1.0 equiv) . The reaction mixture was stirred at -78 to 25 °C for 16h.
  • Step 2 To a solution of - (triisopropylsilyl) oxazole (2 g, 8.9 mmol, 1.0 equiv) in THF(20 mL) was added n-BuLi (2.5 M, 4.3 mL, 1.2 equiv) at -78°C under N2. The reaction mixture was stirred at -78 °C for 1 h. Then the reaction mixture was added triisopropyl borate (1.96 g, 0.0104 mol, 1.2 equiv) and stirred at -78 °C for 2 h.
  • Step 3 To a solution of Int-0013 (100 mg, 0.21 mmol, 1.0 equiv. ) in dioxane/H 2 O (10 mL) was added (2- (triisopropylsilyl) oxazol-5-yl) boronic acid (86 mg, 0.32 mmol, 1.5 equiv. ) , K 3 PO 4 (136 mg, 0.64 mmol, 3.0 equiv. ) , Pd (dppf) Cl 2 (16 mg, 0.021 mmol, 0.1 equiv. ) at room temperature under N2 atmosphere with balloon and then warmed to 50 °C for 2 h and then filtered.
  • 2- (triisopropylsilyl) oxazol-5-yl) boronic acid 86 mg, 0.32 mmol, 1.5 equiv.
  • K 3 PO 4 136 mg, 0.64 mmol, 3.0 equiv.
  • Pd (dppf) Cl 2
  • Step 4 To a solution of 2- (2- ( (2-chloro-5- (2- (triisopropylsilyl) oxazol-5-yl) pyrimidin-4-yl) oxy) pyridin-4-yl) -1 , 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one (50 mg, 0.089 mmol, 1.0 equiv. ) in DMF (2 mL) was added CsF (27 mg, 0.18 mmol, 2.0 equiv. ) . The reaction mixture was stirred at 25 °C for 2 h and then filtered.
  • Step 1 To a solution of Int-0013 (80 mg, 0.17 mmol, 1 equiv. ) and (3-fluorophenyl) boronic acid (24 mg, 0.17 mmol, 1.0 equiv) in dioxane (5 mL) , was added purified water (1 mL) , Xantphos Pd G3 (16 mg , 0.017 mmol) and K 2 CO 3 (71 mg, 0.51 mmol) at room temperature. The mixture was stirred at 65 °C for 4 h under N 2 atmosphere and then filtered and the filtrate was concentrated .
  • Step 1 To a solution of Int-0013 (70 mg, 0.15 mmol) in dioxane (3 mL) and water (0.3 mL) was added K 2 CO 3 (41 mg, 0.30 mmol) , 2-trifluoromethyl-5-pyridineboric acid (35 mg, 0.18 mmol) and Tetrakis (triphenylphosphine) Palladium (17 mg, 0.015 mmol) . The mixture was stirred at 65°C for 8 h under N 2 atmosphere. The mixture was filtered, and the filtrate was purified by Prep-HPLC using a gradient of H 2 O (0.1%FA) /ACN (Flow rate: 20 ml/min; Wavelength: 214 nm/254 nm.
  • Step 1 To a solution of an isopropylamine (111 mg, 1.89 mmol) and triethylamine (263 mg, 2.60 mmol) in DCM (2 mL) was added dropwise to a stirred suspension of 2, 4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.365 mmol) in DCM (5 mL) at -60 °C under N2. The reaction mixture was stirred at -60°C for 3 hours. The reaction mixture was quenched with water (5 mL) and then extracted with DCM (5 mLx3) .
  • Step 2 To a solution of 2, 4-dichloro-N-isopropylpyrimidine-5-carboxamide (100 mg, 0.43 mmol) , 2- (2-hydroxypyridin-4-yl) -1H, 5H, 6H, 7H-pyrrolo [3, 2-c] pyridin-4-one (117 mg, 0.512 mmol) and NaHCO 3 (179 mg, 2.14 mmol) in DMF (2 mL) was stirred at 90 °C under N2 for 1 hour and then filtered. The filtrate was concentrated in vacuum and the residue was purified by Prep-HPLC to afford Example 248 (10.29 mg, yield 5.31%) .
  • Test Method Used Test Method F.
  • Step 1 To a solution of tert-butyl 2, 4-dioxopiperidine-1-carboxylate (3 g, 0.014 mol) and 1, 4-dibromobutane (4.53 g, 0.021 mol) in THF (50 mL) was added a solution of LiHMDS (1M in THF, 84 mL, 0.084 mol) at -20 °C under N 2 atmosphere with balloon and then warmed to room temperature for 2 h. The reaction mixture was quenched by NH 4 Cl solution and extracted with ethyl acetate.
  • Step 3 To a solution of tert-butyl 2'- (2-chloropyridin-4-yl) -4'-oxo-1', 4'-dihydrospiro [cyclopentane-1, 7'-pyrrolo [3, 2-c] py ridine] -5' (6'H) -carboxylate (300 mg, 0.74 mmol) in AcOH (12 mL) was added water (4 mL) . The mixture was stirred at 130 °C for 3 days.
  • Step 4 To a solution of 2'- (2-hydroxypyridin-4-yl) -5', 6'-dihydrospiro [cyclopentane-1, 7'-pyrrolo [3, 2-c] pyridin] -4' (1'H) -one (150 mg, 0.53 mmol) and 2, 4-dichloro-5-iodopyrimidine (175 mg, 0.764 mmol) in DMF (5 mL) was added NaHCO 3 (133 mg, 1.59 mmol) . The mixture was stirred at 90 °C for 2 h and then filtered.
  • Test Method Used Test Method B.
  • Step 1 To a solution of Int-0013 (80 mg, 0.17 mmol) in dioxane (4 mL) and water (0.4 mL) was added K 2 CO 3 (47 mg, 0.34 mmol) , 3-methylisoxazole-4-boronic acid pinacol ester (40 mg, 0.19 mmol) and Pd (PPh 3 ) 4 (20 mg, 0.017 mmol) . The mixture was stirred at 50°C for 2 h under nitrogen atmosphere. The mixture was filtered, and the filtrate was purified by Prep-HPLC using a gradient of H 2 O (0.1%FA) /ACN (Flow rate: 20 ml/min; Wavelength: 214 nm/254 nm.
  • Step 1 To a solution of 5-bromo-2, 4-dichloro-pyrimidine (1.0 g, 4.39 mmol, 1.0 equiv. ) in MeOH (1.5 mL) and THF (20 mL) was added CH 3 ONa (593 mg, 10.97 mmol, 2.5 equiv. ) at 0°C and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL ⁇ 3) . The combined organic phase was washed with brine (30 mL) , dried over with Na 2 SO 4 and concentrated under reduced pressure.
  • Step 2 A mixture of 5-bromo-2, 4-dimethoxypyrimidine 2 (510 mg, 2.33 mmol, 1.0 equiv. ) , tributyl (oxazol-2-yl) stannane (1.0 g, 2.79 mmol, 1.2 equiv. ) and Pd (PPh 3 ) 2 Cl 2 (82 mg, 116.42 ⁇ mol, 0.05 equiv. ) in DMF (4 mL) was stirred at 90 °C overnight under N 2 . The mixture was diluted with water (30 mL) and extracted with EtOAc (20 ml ⁇ 3) . The combined organic layer was dried over with Na 2 SO 4 and concentrated under reduced pressure.
  • Step 3 To a solution of 2- (2, 4-dimethoxypyrimidin-5-yl) oxazole (350 mg, 1.69 mmol, 1.0 equiv. ) in AcOH (6 mL) was added NaI (759.63 mg, 5.07 mmol, 3.0 equiv. ) , the reaction mixture was stirred at 110°C for 1 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography MeOH and DCM (1: 20) to give 5-oxazol-2-ylpyrimidine-2, 4-diol (250 mg, 83%) . LCMS-ESI (m/z) : [M+H] + calc’d 180.03; found, 180.13.
  • Step 4 To a solution of 5-oxazol-2-ylpyrimidine-2, 4-diol (250 mg, 1.40 mmol, 1.0 equiv. ) in POCl 3 (5 mL) was added DIEA (180 mg, 1.40 mmol, 243.09 ⁇ L, 1.0 equiv. ) , the reaction was stirred at 110°C for 2 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography with petroleum ether and EtOAc (20: 1) to give 2- (2, 4-dichloropyrimidin-5-yl) oxazole (90 mg, 30%) . LCMS-ESI (m/z) : [M+H] + calc’d 215.97; found, 216.07.
  • Step 5 To a solution of Int-0012 (90 mg, 392.6 ⁇ mol, 1.0 equiv. ) in DMF (1 mL) was added 2- (2, 4-dichloropyrimidin-5-yl) oxazole (85 mg, 392.6 ⁇ mol, 1.0 equiv. ) and NaHCO 3 (66 mg, 785.2 ⁇ mol, 2.0 equiv. ) , the reaction mixture was stirred at 100°C for 0.5 h. The reaction mixture was purified by prep-HPLC to give Example 251 (8.4 mg, 5%) . LCMS-ESI (m/z) : [M+H] + calc’d 409.07; found, 408.93.
  • Step 1 To a solution of (2, 4-dimethoxypyrimidin-5-yl) boronic acid (1.39 g, 7.55 mmol, 1.2 equiv. ) in 1, 4-dioxane (50 mL) and water (5 mL) was added 2-bromopyrimidine (1.0 g, 6.29 mmol, 1.0 equiv. ) , Pd (dppf) Cl2 ⁇ DCM (103 mg, 125.80 ⁇ mol, 0.02 equiv. ) and NaHCO 3 (1.59 g, 18.87 mmol, 3.0 equiv. ) , the reaction was stirred at 90°C for 16 h.
  • Step 2 To a solution of 2', 4'-dimethoxy-2, 5'-bipyrimidine (328 mg, 1.50 mmol, 1.0 equiv) and NaI (450 mg, 3.01 mmol, 2.0 equiv) in AcOH (6 mL) was stirred at 110°C for 1 h. The reaction solvent was removed under reduced pressure. The residue was purified by a silica gel column eluting (0-10%MeOH in DCM) to give [2, 5'-bipyrimidine] -2', 4'-diol (267 mg, 93%) .
  • LCMS-ESI (m/z) [M+H] + calc’d 191.16; found, 190.76.
  • Step 3 To a solution of [2, 5'-bipyrimidine] -2', 4'-diol (267 mg, 1.40 mmol, 1.0 equiv. ) in POCl 3 (4 mL) was added DIEA (181 mg, 1.40 mmol, 1.0 equiv. ) , the reaction was stirred at 110°C for 3 h. The reaction solvent was removed under reduced pressure. The residue was purified by a silica gel column eluting (0-20%EA in PE) to give 2', 4'-dichloro-2, 5'-bipyrimidine (150 mg, 47%) .
  • LCMS-ESI (m/z) [M+H] + calc’d 227.05; found, 226.91.
  • Step 4 To a solution of 2', 4'-dichloro-2, 5'-bipyrimidine (110 mg, 1.40 mmol, 1.0 equiv. ) in DMAc (10 mL) was added Int-0012 (122 mg, 532.92 ⁇ mol, 1.1 equiv. ) and t-BuOK (82 mg, 726.71 ⁇ mol, 1.5 equiv. ) , the reaction was stirred at 60°C for 2 h. The residue was purified by prep-HPLC to give Example 252 (2.1 mg, 1%) . LCMS-ESI (m/z) : [M+H] + calc’d 419.83; found, 419.92.
  • Step 1 A solution of 2, 4-dichloro-5-pyrimidinecarbonyl chloride (2 g, 9.5 mmol) in t-BuOH (20 mL) was stirred at 30°C for 16 h under nitrogen atmosphere. When TLC analysis showed that the reaction was completed, the reaction mixture was diluted with EtOAc (30 mL) , and subsequently washed with water (50 mL) , saturated aq. NaHCO3 (40 mL) , brine (40 mL) . The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure.
  • Step 2 To a solution of tert-butyl 2, 4-dichloropyrimidine-5-carboxylate (305 mg, 1.22 mmol) in DMF (5 mL) was added Int-0012 (300 mg, 1.11 mmol) and K 2 CO 3 (307 mg, 2.22 mmol) . The mixture was stirred at 50°C for 2 h under nitrogen atmosphere. The mixture was filtered, and the filtrate was purified by Prep-HPLC using a gradient of H 2 O (0.1%FA) /ACN (Flow rate: 20 ml/min; Wavelength: 214 nm/254 nm.
  • Step 1 To a solution of 2, 4-dichloro-5- (iodomethyl) pyrimidine (1.0 g, 3.5 mmol) in DCM (10 mL) was added pyrrolidine (220 mg, 3.1 mmol) and DIEA (900 mg, 7.0 mmol) at -20°C under N 2 . The reaction mixture was stirred at -20°C for 2 h.
  • Step 2 To a solution of 2, 4-dichloro-5- (pyrrolidin-1-ylmethyl) pyrimidine (150 mg, 0.65 mmol) in DMF (1.5 mL) was added NaHCO 3 (163 mg, 1.9 mmol) and Int-0012 (222 mg, 0.78 mmol) at 50°C under N 2 . The reaction mixture was stirred at 50°C for 2 h .
  • Step 1 To a solution of 2, 4-dichloro-5- (iodomethyl) pyrimidine (500 mg, 1.73 mmol, 1.0 equiv) in DCM (5 mL) , piperidine (147 mg, 1.73 mmol, 1.0 equiv) and DIEA (447 mg, 3.46 mmol, 2.0 equiv) in DCM (3 mL) was added at -20°C under N 2 . The reaction mixture was stirred at -20 °C for 1 h.
  • Step 2 To a solution of 2, 4-dichloro-5- (piperidin-1-ylmethyl) pyrimidine (100 mg, 0.41 mmol, 1.0 equiv. ) in DMF (5 mL) was added Int-0014 (100 mg, 0.41 mmol, 1.0 equiv. ) , NaHCO 3 (102 mg, 1.22 mmol, 3.0 equiv. ) . The reaction mixture was stirred at 90 °C for 2 h. The mixture was filtered, and the filtrate was purified by Prep-HPLC using a gradient of H 2 O (0.1%FA) /ACN (Flow rate: 20 ml/min; Wavelength: 214 nm/254 nm.
  • Step 1 A vial was charged with Int-007 (10 mg, 0.04 mmol, 1.25 eq. ) and dissolved in ACN (1 mL) . To the solution was added 2, 6-dichloropyrimidine-4-carbonitrile (5.6 mg, 0.03 mmol, 1.0 eq. ) and K 2 CO 3 (18 mg, 0.13 mmol, 4.0 eq. ) and the reaction solution warmed to 60°C and stirred for 2 hours. The solution was cooled to room temperature, diluted with EtOAc, washed with brine, dried with MgSO 4 , and concentrated in vacuo.
  • Example 256 (3 mg, 24%yield) .
  • LCMS (m/z) [M+H] + calc’d 384.0; found 385.0.
  • Step 1 A flask was charged with ethyl 4, 4-difluoro-3-oxobutanoate (1.00 g, 6.02 mmol) and urea (0.723 g, 12.04 mmol, 2.0 eq. ) .
  • the flask was pump flushed with Ar, then the solids suspended in PhMe (30 mL, 0.2 M) .
  • the suspension was treated with NaOEt (0.819 g, 12.04 mmol, 2.0 eq. ) , warmed to 130°C and stirred for 48 hours.
  • the solution was cooled to room temperature, concentrated, then triturated with EtOAc overnight.
  • Step 2 A flask was charged with 6- (difluoromethyl) pyrimidine-2, 4-diol (0.975 g, 6.02 mmol) and dissolved with CAN (10 mL, 0.6 M) . The reaction solution was cooled to 0°C, treat with POCl 3 (4.06 g, 26.47 mmol, 4.4 eq. ) and DIPEA (0.660 g, 5.11 mmol, 0.85 eq. ) . The reaction solution was then warmed to 95°C and stirred overnight. Afterward, the solution was cooled to room temperature, quenched with ice-water, extracted with EtOAc, washed with one volume of brine, dried with MgSO 4 , and concentrated.
  • Step 3 A flask was charged with Int-007 (0.020 g, 0.08 mmol) , 2, 4-dichloro-6- (difluoromethyl) pyrimidine (0.016 g, 0.08 mmol, 1.0 eq. ) , K 2 CO 3 (0.045 g, 0.32 mmol, 4.0 eq. ) dissolved in ACN (1 mL, 0.08 M) and warmed to 80°C for 2 hours. The reaction solution was cooled to room temperature, diluted with EtOAc, washed with one volume of brine, dried with MgSO 4 , and concentrated.
  • Step 1 To a solution of 2, 4-dichloropyrimidine-5-carbonyl chloride (2.00 g, 9.46 mmol, 1.2 eq) in DCM (20 mL) at 0 °C was added dimethylamine (355 mg, 7.89 mmol, 1 eq) and triethylamine (798 mg, 7.89 mmol, 1 eq) . The reaction mixture was stirred at 25°C under N 2 for 1 hour. After adding water, the mixture was extracted with DCM (10 mL X2) . The combined organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure.
  • Step 2 A suspension of 2, 4-dichloro-N, N-dimethylpyrimidine-5-carboxamide (140 mg, 0.64 mmol, 1 eq) , Int-0012 (175 mg, 0.76 mmol, 1.2 eq) and sodium bicarbonate (267 mg, 3.18 mmol, 1.5 eq) in DMF (2 mL) was stirred at 90°C under N 2 for 1 hour and then filtered. The filtrate was purified by prep-HPLC to afford product Example 258 (1.30 mg, yield 0.44%) .
  • LCMS (m/z) [M+H] + calc’d 413.11; found, 413.1.
  • Test Method Used Test Method F.
  • Step 1 To a mixture of 2, 3-dichloro-N-methoxy-N-methylisonicotinamide (5.0 g, 0.026 mol, 1.0 equiv. ) in DCM (100 mL) was added HATU (14.83 g, 0.039 mol, 1.5 equiv. ) , DIEA (13.44 g, 0.10 mol, 4 equiv. ) and then N, O-dimethylhydroxylamine hydrochloride (3.82 g, 0.039 mol, 1.5 equiv. ) . The reaction mixture was stirred at 25°Cfor 16 h. Then it was diluted with water (100 mL) and extracted with DCM (200 mL ⁇ 3) .
  • Step 2 To a mixture of 2, 3-dichloro-N-methoxy-N-methylisonicotinamide (7.5 g, 0.032 mol, 1 equiv. ) in THF (100 mL) was slowly add CH 3 MgBr (1M in THF, 36 mL, 0.036 mol, 1.1 eq) at 0°C. The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution. Then it was extracted with ethyl acetate (200 mL ⁇ 3) . The combined organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuum to give crude product.
  • Step 3 To a mixture of 1- (2, 3-dichloropyridin-4-yl) ethan-1-one (2.0 g, 0.011 mol, 1.0 equiv. ) in HBr (30%in AcOH, 30 mL) . Then Br 2 (0.6 mL, 10.8 mmol, 1.0 equiv. ) was add slowly at 0°C. The reaction mixture was stirred at 25°C for 16 h. Methyl tert-butyl ether (30 mL) was added to the reaction solution.
  • Step 4 A mixture of 2-bromo-1- (2, 3-dichloropyridin-4-yl) ethan-1-one (2.0 g, 0.01 mol, 1.0 equiv. ) and piperidine-2, 4-dione (1.67 g, 0.02 mol, 2.0 equiv. ) , AcOH (0.64 g, 0.015 mol, 1.5 equiv. ) , NH 4 OAc (1.32 g, 0.02 mol, 2.0 equiv. ) in EtOH (30 mL) was stirred at 80°C for 16 h.
  • Step 5 To a mixture of 2- (2, 3-dichloropyridin-4-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one (500 mg, 1.6 mmol, 1.0 equiv. ) in 1, 4-dioxane (3 mL) was added Pd 2 (dba) 3 (295 mg, 0.32 mmol, 0.2 equiv. ) , t-BuXPhos (70 mg, 0.15 mmol, 0.1 equiv. ) , KOH (360 mg, 6 mmol, 4 equiv. ) and H 2 O (1 mL) .
  • Step 6 A mixture of 2- (3-chloro-2-hydroxypyridin-4-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-on e (80 mg, 0.28 mmol, 1.0 equiv. ) , 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (50 mg, 0.24 mmol, 0.8 equiv. ) , NaHCO 3 (76 mg, 0.83 mmol, 3.0 equiv. ) in DMF (4 mL) was stirred at 90°C for 2 hours.
  • Test Method Used Test Method B. Retention time 4.61 min.
  • Step 1 To a mixture of pyrrolidin-2-one (176 mg, 2.08 mmol, 1.2 equiv) in THF (10 mL) was add NaH (60%, 103 mg, 2.59 mmol, 1.5 equiv) at 0°C and the resulting mixture was stirred for 10 minutes. Then add 2, 4-dichloro-5- (iodomethyl) pyrimidine (500 mg, 1.73 mmol, 1.0 equiv) was added at 0°C. The resulting mixture was stirred for another 1 hour at 25°C. Acetic acid (1 mL) was added to quench the reaction, then diluted with water (20 mL) and extracted with ethyl acetate (20 mL ⁇ 3) .
  • Step 1 A mixture of 2-bromo-5-methyl-1, 3, 4-thiadiazole 1 (1 g, 5.62 mmol, 1.0 equiv. ) , (2, 4-dimethoxypyrimidin-5-yl) boronic acid (1.24 g, 6.74 mmol, 1.2 equiv. ) , cesium carbonate (3.7 g, 11.24 mmol, 2.0 equiv. ) and Pd (dppf) Cl2 ⁇ CH2Cl2 (459 mg, 560 ⁇ mol, 0.1 equiv. ) in water (4 mL) and 1, 4-dioxane (40 mL) was stirred at 90 °C overnight.
  • Step 2 To a solution of 2- (2, 4-dimethoxypyrimidin-5-yl) -5-methyl-1, 3, 4-thiadiazole (500 mg, 2.1 mmol, 1.0 equiv. ) in acetic acid (10 mL) was added NaI (540 mg, 3.6 mmol, 3.0 equiv. ) . Then the reaction was stirred at 110 °C for 1 h. The reaction was concentrated, and the residue was purified by column chromatography (0-3%MeOH in DCM) to give 5- (5-methyl-1, 3, 4-thiadiazol-2-yl) pyrimidine-2, 4-diol (400 mg, 90%) .
  • LCMS-ESI (m/z) [M+H] + calc’d 211.02; found, 210.98.
  • Step 3 To a solution of 5- (5-methyl-1, 3, 4-thiadiazol-2-yl) pyrimidine-2, 4-diol (400 mg, 1.9 mmol, 1.0 equiv. ) in POCl 3 (5 mL) was added a few drops of DIEA. The solution was stirred at 110 °C for 2 h, then the solution was added dropwise to cold NaHCO 3 aq., the mixture was extracted with EtOAc (50 mL) , washed with water (50 mL) and brine (50 mL) . The organic layer was dried over Na 2 SO 4 and concentrated.
  • Step 4 A mixture of 2- (2, 4-dichloropyrimidin-5-yl) -5-methyl-1, 3, 4-thiadiazole (80 mg, 330 ⁇ mol, 1.0 equiv. ) , 2- (2-hydroxypyridin-4-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one (76 mg, 330 ⁇ mol, 1.0 equiv. ) and NaHCO 3 (28 mg, 330 ⁇ mol, 1.0 equiv. ) in DMAc (5 mL) was stirred at 60 °C for 2 h. The solution was purified by prep-HPLC to give Example 261 (2.2 mg, 2%) .
  • Step 1 To a solution of Int-007 (500 mg, 2.02 mmol, 1.0 equiv. ) in DMF (4 mL) was added 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (417 mg, 2.02 mmol, 1.0 equiv. ) and NaHCO 3 (510 mg, 6.07 mmol, 3.0 equiv. ) . The resulting mixture was stirred at 90°C under N 2 for 3 hours.
  • Test Method Used Test Method B.
  • Step 1 To a solution of 4- (tributylstannyl) -2- (triisopropylsilyl) -1, 3-oxazole (330 mg, 0.64 mmol) in anhydrous ACN (8 mL) was added Int-0013 (100 mg, 0.21 mmol) and bis(triphenylphosphine) palladium (II) chloride (15 mg, 0.021 mmol) . The mixture was stirred at 75°C for 18 hours.
  • Step 2 To a solution of 2- (2- ( (2-chloro-5- (2- (triisopropylsilyl) oxazol-4-yl) pyrimidin-4-yl) oxy) pyridin-4-yl) -1 , 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one (30 mg, 0.053 mmol) in DMF (5 mL) was added CsF (41 mg, 0.27 mmol) . The mixture was stirred at 25°C for 2 h under nitrogen atmosphere.
  • Step 1 To a solution of 5-bromo-2, 4-dimethoxypyrimidine (10 g, 46.12 mmol, 1.0 equiv. ) in THF (100 mL) was added n-BuLi (2.4M in THF, 21.9 mL, 52 mmol, 1.15 equiv. ) at -78°C. The reaction mixture was stirred at -78 °C for 1 h. Then DMF (4.01 g, 55.34 mmol, 1.2 equiv. ) was added to the reaction. The reaction mixture was stirred at -78°C for 1 h. The reaction mixture was quenched by NH 4 Cl solution.
  • Step 2 To a solution of 2, 4-dimethoxypyrimidine-5-carbaldehyde (5.5 g, 33.01 mmol, 1.0 equiv. ) in EtOH (50 mL) was added NH 2 OH . HCl (3.41 g, 49.52 mmol, 1.5 equiv. ) and TEA (4.96 g, 49.52 mmol, 1.5 equiv. ) . The reaction mixture was stirred at 25°C for 3 h and then filtered.
  • Step 3 To a solution of (E) -2, 4-dimethoxypyrimidine-5-carbaldehyde oxime (3.2 g, 17.72 mmol, 1.0 equiv. ) in DMF (20 mL) was added NCS (2.57 g, 19.49 mmol, 1.1 equiv. ) at 0°C. The reaction mixture was stirred at 0°C for 2 h. Then to the reaction was added TMSA (5.16 g, 53.16 mmol, 3.0 equiv. ) in THF (30 mL) and TEA (3.54 g, 35.44 mmol, 2.0 equiv. ) at 0°C.
  • Step 4 To a solution of 3- (2, 4-dimethoxypyrimidin-5-yl) -5- (trimethylsilyl) isoxazole (3.4 g, 12.19 mmol, 1.0 equiv. ) in MeOH (40 mL) was added K 2 CO 3 (2.53 g, 18.28 mmol, 1.5 equiv. ) . The reaction mixture was stirred at 25°C for 1 h. The mixture was extracted with ethyl acetate (50 mL ⁇ 3) . The combined organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuum. The crude was used for the next step without any further purification. The crude product was obtained (2.2 g, yield 81%) . LCMS (m/z) : [M+H] + calc’d 208.06; found, 208.2.
  • Step 5 To a solution of 3- (2, 4-dimethoxypyrimidin-5-yl) isoxazole (1.85 g, 88.95 mmol, 1.0 equiv. ) in DCM (20 mL) was added BBr 3 (1 M in DCM, 35.6 mL, 35.6 mmol, 0.4 equiv. ) at 0°C. The reaction mixture was stirred at 25°C for 1 h. The reaction mixture was quenched by NaHCO 3 solution. The mixture was extracted with ethyl acetate (50 mL ⁇ 3) . The combined organic phase was dried over anhydrous sodium sulfate and then filtered.
  • Step 1 To a suspension of (2, 4-dichloro-5- (iodomethyl) pyrimidine (1 g, 3.46 mmol, 1.0 equiv. ) in DCM (10 mL) was added DIEPA (895 mg, 6.92 mmol, 2.0 equiv. ) and piperidine (295 mg, 3.46 mmol, 1.0 equiv. ) at -20°C under N 2 . The reaction mixture was stirred at -20°C for 1 h.
  • Step 2 To a suspension of 2, 4-dichloro-5- (piperidin-1-ylmethyl) pyrimidine (100 mg, 0.41 mmol, 1.0 equiv. ) and NaHCO 3 (102 mg, 1.22 mmol, 3.0 equiv. ) in DMF (3 mL) was added Int-007 (100 mg, 0.41 mmol, 1.0 equiv. ) . The reaction mixture was stirred at 90°C for 2 h. The mixture was filtered, and the filtrate was purified by prep-HPLC using a gradient of H 2 O (0.1%FA) /ACN (Flow rate: 20 ml/min; Wavelength: 214 nm/254 nm.
  • Step 1 To a suspension of (2, 4-dichloro-5- (iodomethyl) pyrimidine (1 g, 3.46 mmol, 1.0 equiv. ) in DCM (10 mL) was added DIEPA (895 mg, 6.92 mmol, 2.0 equiv. ) and piperidine (295 mg, 3.46 mmol, 1.0 equiv. ) at -20°C under N 2 . The reaction mixture was stirred at -20°C for 1 h.
  • Step 2 To a suspension of 2, 4-dichloro-5- (piperidin-1-ylmethyl) pyrimidine (100 mg, 0.41 mmol, 1.0 equiv. ) and NaHCO 3 (102 mg, 1.22 mmol, 3.0 equiv. ) in DMF (3 mL) was added Int-007 (100 mg, 0.41 mmol, 1.0 equiv. ) . The reaction mixture was stirred at 90°C for 2 h. The mixture was filtered, and the filtrate was purified by prep-HPLC using a gradient of H 2 O (0.1%FA) /ACN (Flow rate: 20 ml/min; Wavelength: 214 nm/254 nm.
  • Step 1 To the mixture of cyclopropanol (500 mg, 8.61 mmol, 1 equiv. ) in DMF (5 mL) was added NaH (413 mg, 60%purity, 10.3 mmol, 1.21 equiv. ) at 0°C under N2 atmosphere for 30 min. Then the mixture was added to the mixture of 2, 4-dichloro-5- (iodomethyl) pyrimidine mixture (1.5 g, 5.2 mmol, 1.61 equiv. ) in DMF (10 mL) at 0°C under N 2 atmosphere. The mixture was stirred at 0°C for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL x 3) .
  • Step 2 A mixture of 2, 4-dichloro-5- (cyclopropoxymethyl) pyrimidine (70 mg, 0.35 mmol, 1 equiv. ) , Int-007 (95 mg, 0.38 mmol) , sodium bicarbonate (80 mg, 0.96 mmol) in DMF (2 mL) was stirred at 90°C under N 2 atmosphere for 1 h. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC to afford Example 267 (11.6 mg, yield 16%) . LCMS (m/z) : [M+H] + calc’d 430.1; found, 430.1.
  • Example 268 A mixture of 2, 4-dichloro-5- (cyclopropoxymethyl) pyrimidine (70 mg, 0.35 mmol, 1 equiv. ) , Int-007 (95 mg, 0.38 mmol) , sodium bicarbonate (80 mg, 0.96 mmol) in DMF (2 mL) was stirred at 90°C under N 2 atmosphere for 1 h. The reaction mixture was filtered, and the filtrate was purified by prep-HPLC to afford Example 268 (19.63 mg, yield 25%) . LCMS (m/z) : [M+H] + calc’d 430.1; found, 430.1.
  • Test Method Used Test Method B.
  • Step 1 To suspension of 2, 2, 2-trifluoroethan-1-ol (300 mg, 2.96 mmol, 1 equivalent) in THF (6 mL) was added NaH (237 mg, 60%, 5.94 mmol, 2 equivalent) at 0°C under N2. The mixture was stirred for 0.5 h and then it was added the mixture into a solution of 2, 4-dichloro-5- (iodomethyl) pyrimidine (1286 mg, 3.56 mmol, 1.2 equivalent) in THF (8 mL) . The mixture was stirred at 0°C for 2 h. The reaction mixture was diluted with NH 4 Cl (20 mL) and extracted with EA (20 mLx3) . The organic phase was dried over anhydrous Na 2 SO 4 .
  • Step 2 To a solution of Int-007 (136 mg, 0.55 mmol, 1 equivalent) in DMF (1 mL) was added 2, 4-dichloro-5- ( (2, 2, 2-trifluoroethoxy) methyl) pyrimidine (240 mg, 0.55 mmol, 1 equivalent) and NaHCO 3 (138 mg, 1.65 mmol, 3 equivalent) . The mixture was stirred at 50°C under N 2 for 2h and then filtered. The filtrate was purified by prep-HPLC using a gradient of H 2 O (0.1%FA) /ACN (Flow rate: 20 ml/min; Wavelength: 214 nm/254 nm.
  • Example 270 To a solution of Int-007 (136 mg, 0.55 mmol, 1 equivalent) in DMF (1 mL) was added 2, 4-dichloro-5- ( (2, 2, 2-trifluoroethoxy) methyl) pyrimidine (240 mg, 0.55 mmol, 1 equivalent) and NaHCO 3 (138 mg, 1.65 mmol, 3 equivalent) . The mixture was stirred at 50°C under N 2 for 2h and then filtered. The filtrate was purified by prep-HPLC using a gradient of H 2 O (0.1%FA) /ACN (Flow rate: 20 ml/min; Wavelength: 214 nm/254 nm.
  • Step 3 To a solution of tert-butyl 2'- (3-fluoro-2-hydroxypyridin-4-yl) -4'-oxo-1', 4'-dihydrospiro [cyclopentane-1, 7'-pyrrolo [3, 2-c] pyridine] -5' (6'H) -carboxylate (170 mg, 0.42 mmol, 1 equiv. ) and 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (87 mg, 0.42 mmol, 1 equiv. ) in DMF (5 mL) was added NaHCO 3 (71 mg, 0.84 mmol, 2 equiv. ) .
  • Step 4 A solution of tert-butyl 2'- (2- ( (4-chloro-5- (ethoxymethyl) pyrimidin-2-yl) oxy) -3-fluoropyridin-4-yl) -4'-oxo-1', 4'-dihydrospiro [cyclopentane-1, 7'-pyrrolo [3, 2-c] pyridine] -5' (6'H) -carboxylate (120 mg, 0.21 mmol, 1 equiv. ) in DCM (10 mL) and TFA (1 mL) was stirred at 25°C for 0.5 h.
  • Test Method Used Test Method B.
  • Step 1 To a solution of 4- ( (4-bromopyridin-2-yl) oxy) -2-chloro-5-iodopyrimidine (148 mg, 0.36 mmol, 1.0 equiv. ) and 4-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3-dioxolan-2-yl) oxazole (90 mg, 0.43 mmol, 1.2 equiv. ) in 1, 4-dioxane (10 mL) and water (2 mL) was added Pd (dppf) Cl2 ⁇ DCM (29 mg, 36 ⁇ mol, 0.1 equiv. ) and K 3 PO 4 (229 mg, 1.08 mmol, 3.0 equiv. ) .
  • Step 2 To a solution of 5- (4- ( (4-bromopyridin-2-yl) oxy) -2-chloropyrimidin-5-yl) -4-methyloxazole (100 mg, 0.27 mmol, 1.0 equiv. ) and Int-005 (141 mg, 0.54 mmol, 2.0 equiv. ) in 1, 4-dioxane (10 mL) and water (2 mL) was added Pd (dppf) Cl2 ⁇ DCM (22 mg, 27 ⁇ mol, 0.1 equiv. ) and K 3 PO 4 (172 mg, 0.81 mmol, 3.0 equiv. ) . The reaction mixture was stirred at 65°C using a microwave reactor for 1.5 h.
  • Step 1 To a solution of 4- ( (4-bromopyridin-2-yl) oxy) -2-chloro-5-iodopyrimidine (395 mg, 0.96 mmol, 1.0 equiv. ) and 2-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3-dioxolan-2-yl) oxazole (240 mg, 1.15 mmol, 1.2 equiv. ) in 1, 4-dioxane (20 mL) and water (4 mL) was added Pd (dppf) Cl2 ⁇ DCM (78 mg, 96 ⁇ mol, 0.1 equiv. ) and K 3 PO 4 (611 mg, 2.88 mmol, 3.0 equiv. ) .
  • Step 2 To a solution of 5- (4- ( (4-bromopyridin-2-yl) oxy) -2-chloropyrimidin-5-yl) -2-methyloxazole (100 mg, 0.27 mmol, 1.0 equiv. ) and Int-005 (141 mg, 0.54 mmol, 2.0 equiv. ) in 1, 4-dioxane (10 mL) and water (2 mL) was added Pd (dppf) Cl2 ⁇ DCM (22 mg, 27 ⁇ mol, 0.1 equiv. ) and K 3 PO 4 (172 mg, 0.81 mmol, 3.0 equiv. ) . The reaction mixture was stirred at 65°C in a microwave reactor for 1.5 h.
  • Step 1 A suspension of 2, 4-dichloro-N-isopropylpyrimidine-5-carboxamide (100 mg, 0.43 mmol, 1 eq) , Int-014 (127 mg, 0.51 mmol, 1.2 eq) and NaHCO 3 (179 mg, 2.14 mmol, 5 eq) in DMF (2 mL) was stirred at 90°C under N 2 for 1 hour and then filtered. The filtrate was purified by prep-HPLC to afford Example 276 (1.15 mg, yield 0.59%) .
  • LCMS (m/z) [M+H] + calc’d 445.11; found, 445.2.
  • Test Method Used Test Method F.
  • Step 1 A suspension of 2, 4-dichloro-N-isopropylpyrimidine-5-carboxamide (100 mg, 0.43 mmol, 1 eq) , Int-007 (127 mg, 0.51 mmol, 1.2 eq) and sodium bicarbonate (179 mg, 2.14 mmol, 5 eq) in DMF (2 mL) was stirred at 90°C under N 2 for 1 hour and then filtered. The filtrate was purified by prep-HPLC to afford Example 277 (3.64 mg, yield 1.71%) . LCMS (m/z) : [M+H] + calc’d 445.11; found, 445.1.
  • Test Method Used Test Method F.
  • Step 1 To a solution of 2, 4-dichloro-5- (iodomethyl) pyrimidine (500 mg, 1.73 mmol, 1 equiv) and piperidin-2-one (206 mg, 2.08 mmol, 1.2 equiv) in THF (20 mL) was added a solution of NaH (138 mg, 60%in oil, 3.46 mmol, 2 equiv) at 0 °C under N 2 atmosphere with balloon. The reaction mixture was stirred at 0°C for 0.5 h. Then the mixture was quenched with 1 mL AcOH and concentrated under vacuum.
  • Step 2 To a solution of 1- ( (2, 4-dichloropyrimidin-5-yl) methyl) piperidin-2-one (200 mg, 0.77 mmol, 1 equiv) and Int-007 (228 mg, 0.92 mmol, 1.2 equiv) in DMF (5 mL) was added NaHCO 3 (194 mg, 2.3 mmol, 3 equiv) . The mixture was stirred at 90°C for 1 h and then filtered. The filtrate was purified by prep-HPLC using a gradient of H 2 O (0.1%FA) /ACN (Flow rate: 20 ml/min; wavelength: 214 nm/254 nm.
  • Test Method Used Test Method B.
  • Step 1 To a solution of Int-007 (100 mg, 0.41 mmol) in DMF (5 mL) was added NaHCO 3 (102 mg, 1.22 mmol) and 4, 6-dichloro-2- (2-methoxyethoxy) pyrimidine (91 mg, 0.41 mmol) . The mixture was stirred at 90°C for 2 h under nitrogen atmosphere. The mixture was filtered, and the filtrate was purified by prep-HPLC using a gradient of H 2 O (0.1%FA) /ACN (Flow rate: 20 ml/min; wavelength: 214 nm/254 nm.
  • Test Method Used Test Method B.
  • Step 3 To a solution of tert-butyl 2'- (3-fluoro-2-hydroxypyridin-4-yl) -4'-oxo-1', 4'-dihydrospiro [cyclopentane-1, 7'-pyrro lo [3, 2-c] pyridine] -5' (6'H) -carboxylate (170 mg, 0.42 mmol, 1 equiv) and 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (87 mg, 0.42 mmol, 1 equiv) in DMF (5 mL) was added NaHCO 3 (71 mg, 0.84 mmol, 2 equiv) . The mixture was stirred at 90°C for 2 h and then filtered.
  • Step 4 A solution of tert-butyl 2'- (2- ( (4-chloro-5- (ethoxymethyl) pyrimidin-2-yl) oxy) -3-fluoropyridin-4-yl) -4'-oxo-1', 4'-dihydrospiro [cyclopentane-1, 7'-pyrrolo [3, 2-c] pyridine] -5' (6'H) -carboxylate (120 mg, 0.21 mmol, 1 equiv. ) in DCM (10 mL) and TFA (1 mL) was stirred at 25°C for 0.5 h.
  • Step 1 To a solution of tert-butyl 2'- (3-fluoro-2-hydroxypyridin-4-yl) -4'-oxo-1', 4'-dihydrospiro [cyclopentane-1, 7'-pyrro lo [3, 2-c] pyridine] -5' (6'H) -carboxylate (170 mg, 0.42 mmol, 1 equiv. ) and 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (87 mg, 0.42 mmol, 1 equiv. ) in DMF (5 mL) was added NaHCO 3 (71 mg, 0.84 mmol, 2 equiv. ) .
  • Step 2 A solution of tert-butyl 2'- (2- ( (4-chloro-5- (ethoxymethyl) pyrimidin-2-yl) oxy) -3-fluoropyridin-4-yl) -4'-oxo-1', 4'-dihydrospiro [cyclopentane-1, 7'-pyrrolo [3, 2-c] pyridine] -5' (6'H) -carboxylate (120 mg, 0.21 mmol, 1 equiv. ) in DCM (10 mL) and TFA (1 mL) was stirred at 25°C for 0.5 h.
  • Step 1 To a solution of tert-butyl 2, 4-dioxopiperidine-1-carboxylate (3 g, 0.014 mol, 1 equiv. ) and iodoethane (4.37 g, 0.028 mol, 2 equiv. ) in THF (50 mL) was added a solution of LiHMDS (70 mL, 1M in THF, 0.07 mol, 5 equiv. ) in THF at -20 °C under N 2 atmosphere with balloon. The mixture was allowed to warm to room temperature and stirred for 2 h.
  • LiHMDS 70 mL, 1M in THF, 0.07 mol, 5 equiv.
  • Step 4 To a solution of 7-ethyl-2- (3-fluoro-2-hydroxypyridin-4-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyrid in-4-one (500 mg, 1.82 mmol, 1 equiv. ) and 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (376 mg, 1.82 mmol, 1 equiv. ) in DMF (5 mL) was added NaHCO 3 (305 mg, 3.63 mmol, 2 equiv. ) . The mixture was stirred at 90°C for 2 h and then filtered.
  • Step 1 To a solution of 7-ethyl-2- (3-fluoro-2-hydroxypyridin-4-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyrid in-4-one (500 mg, 1.82 mmol, 1 equiv. ) and 2, 4-dichloro-5- (ethoxymethyl) pyrimidine (376 mg, 1.82 mmol, 1 equiv. ) in DMF (5 mL) was added NaHCO 3 (305 mg, 3.63 mmol, 2 equiv. ) . The mixture was stirred at 90°C for 2 h and then filtered.
  • Test Method Used Test Method B. Retention time 4.48 min.
  • Step 1 To suspension of 2- (3-fluoro-2-hydroxypyridin-4-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one (100 mg, 0.40 mmol, 1 equiv. ) in DMF (2 mL) was added 2, 4-dichloro-5-iodo pyrimidine (122 mg, 0.45 mmol, 1.1 equivalent) and NaHCO 3 (102 mg, 1.21 mmol, 3 equiv. ) . The mixture was stirred at 90°C for 2 h.
  • Step 2 To a solution of the mixture of 2- (2- ( (2-chloro-5-iodopyrimidin-4-yl) oxy) -3-fluoropyridin-4-yl) -1, 5, 6, 7-tetrahydro-4 H-pyrrolo [3, 2-c] pyridin-4-one and 2- (2- ( (4-chloro-5-iodopyrimidin-2-yl) oxy) -3-fluoropyridin-4-yl) -1, 5, 6, 7-tetrahydro-4 H-pyrrolo [3, 2-c] pyridin-4-one (100 mg, 0.21 mmol, 1 equiv.
  • Example 286 The filtrate was purified by prep-HPLC using a gradient of H 2 O (0.1%FA) /ACN (Flow rate: 20 ml/min; sample injected in DMF, 6.59 min linear gradient from 15%to 28%ACN) to give the mixture of Example 286 and Example 287 After freeze-dried, the mixture was purified by SFC using equal gradient 40%MeOH (0.2%NH 4 OH) /60%CO 2 (flow rate: 12.5/min; 5.19 min) to give Example 287 (0.63 mg, 1%) .
  • LCMS (m/z) [M+H] + calc’d 427.0; found, 426.9.
  • Step 1 To a solution of Int-007 (70 mg, 283 ⁇ mol, 1.0 equiv. ) in DMF (3 mL) was added 2, 4-dichloro-7, 8-dihydro-5H-pyrano [4, 3-d] pyrimidine (70 mg, 340 ⁇ mol, 1.2 equiv. ) and NaHCO 3 (71 mg, 849 ⁇ mol, 3.0 equiv. ) , the reaction mixture was stirred at 100°C for 2 h. The reaction mixture was purified by prep-HPLC to afford Example 288 (50 mg, 43%) . LCMS-ESI (m/z) : [M+H] + calc’d 416.09; found, 416.02.
  • Step 1 To a solution of 1, 3-oxazole (5 g, 72.41 mmol, 1.0 equiv. ) in THF (60 mL) was added n-BuLi (2.5 M in THF, 29 mL, 72.5 mmol, 1.0 equiv. ) at -78°C under N 2 . The reaction mixture was stirred at -78 °C for 1 h. Then to the reaction was added triisopropyl (trifluoromethylsulfonyloxy) -silane (22.18 g, 72.41 mmol, 1.0 equiv. ) . The reaction mixture was warmed to room temperature and stirred for 16h.
  • Step 2 To a solution of 2- (triisopropylsilyl) oxazole (13.3 g, 59.16 mmol, 1.0 equiv. ) in THF (130 mL) was added n-BuLi (2.5 M in THF, 28.3 mL, 70.75 mmol, 1.2 equiv. ) at -78°C under N 2 . The reaction mixture was stirred at -78 °C for 1 h. Then the reaction was added triisopropyl borate (12.98 g, 69.03 mmol, 1.2 equiv. ) . The reaction mixture was stirred at -78 °C for 2 h.
  • Step 3 To a solution of Int-0016-A (250 mg, 0.51 mmol, 1.0 equiv. ) in dioxane/H 2 O (10 mL/1 mL) was added (2- (triisopropylsilyl) oxazol-5-yl) boronic acid (277 mg, 1.03 mmol, 2 equiv. ) , K 2 CO 3 (213 mg, 1.54 mmol, 3.0 equiv. ) , Xantphos-Pd-G3 (49 mg, 0.051 mmol, 0.1 equiv. ) at room temperature under N 2 atmosphere. Then it was warmed to 50°C and stirred for 3 h. The mixture was filtered.
  • Step 4 To a solution of 2- (2- ( (2-chloro-5- (2- (triisopropylsilyl) oxazol-5-yl) pyrimidin-4-yl) oxy) pyridin-4-yl) -1 , 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one (70 mg, 0.12 mmol, 1.0 equiv. ) in DMF (2 mL) was added CsF (36 mg, 0.24 mmol, 2.0 equiv. ) . The reaction mixture was stirred at 25°C for 2 h. Then it was filtered, and the filtrate was concentrated in vacuum.
  • Step 1 To a solution of Int-0017 (100 mg, 0.21 mmol, 1.0 equiv. ) in dioxane/H 2 O (10 mL/1 mL) was added (2- (triisopropylsilyl) oxazol-5-yl) boronic acid (111 mg, 0.41 mmol, 2.0 equiv. ) , K 2 CO 3 (85 mg, 0.62 mmol, 3.0 equiv. ) , Xantphos-Pd-G3 (20 mg,0.021 mmol, 0.1equiv. ) at room temperature under N 2 atmosphere. The mixture was warmed to 50°C and stirred for 3 h and then filtered.
  • (2- (triisopropylsilyl) oxazol-5-yl) boronic acid 111 mg, 0.41 mmol, 2.0 equiv.
  • K 2 CO 3 85 mg, 0.62 mmol, 3.0 equiv.
  • Step 2 To a solution of 2- (2- ( (2-chloro-5- (2- (triisopropylsilyl) oxazol-5-yl) pyrimidin-4-yl) oxy) -5-fluoropyridin-4-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one (40 mg, 0.069 mmol, 1.0 equiv. ) in DMF (2 mL) was added CsF (21 mg, 0.14 mmol, 2.0 equiv. ) . The reaction mixture was stirred at 25°C for 2 h and then filtered.
  • Step 1 A suspension of 2, 4-dichloro-5- (iodomethyl) pyrimidine (500 mg, 1.73 mmol, 1.0 eq) , 1H-pyrazole (106 mg, 1.55 mmol, 0.9 eq) and K 2 CO 3 (239 mg, 1.73 mmol) in ACN (5 mL) was stirred under nitrogen at 85°C for 3h. The mixture was extracted with EA (20 mLx3) . Combined the organic phases and dried over anhydrous sodium sulfate and then filtered.
  • Step 2 A suspension of Int-007 (250 mg, 1.01 mmol, 1.0 eq) , 5- ( (1H-pyrazol-1-yl) methyl) -2, 4-dichloropyrimidine (254 mg, 1.1 mmol, 1.1 eq) and NaHCO 3 (254 mg, 3.03 mmol, 3.0 eq) in DMF (3 mL) was stirred under nitrogen at 90°C for 2h. The mixture was filtered. The filtrate was purified by prep-HPLC using a gradient of H 2 O (0.1%FA) /ACN (Flow rate: 20 ml/min; wavelength: 214 nm/254 nm.
  • Test Method Used Test Method B.
  • Step 1 To a solution of 4- (tributylstannyl) -2- (triisopropylsilyl) -1, 3-oxazole (794 mg, 1.53 mmol, 3 equiv. ) in anhydrous ACN (10 mL) was added Int-0016-A (250 mg, 0.51 mmol, 1 equiv. ) and bis (triphenylphosphine) palladium (II) chloride (37 mg, 0.051 mmol, 0.1 equiv. ) . The mixture was stirred at 85°C for 18 h.
  • Step 1 To a solution of 5-bromo-2, 4-dimethoxypyrimidine (20 g, 91.32 mmol, 1.0 equiv. ) in THF (200 mL) was added n-BuLi (2.5M in THF, 43.8 mL, 109.5 mmol, 1.2 equiv. ) at -78°C. The reaction mixture was stirred at -78 °C for 1 h., then the reaction was added N, N-dimethylformamide (8.01 g, 109.58 mmol, 1.2 equiv. ) , The reaction mixture was stirred at -78°C for another 1 h.
  • n-BuLi 2.5M in THF, 43.8 mL, 109.5 mmol, 1.2 equiv.
  • Step 2 To a solution of 2, 4-dimethoxypyrimidine-5-carbaldehyde (6.65 g, 39.51 mmol, 1.0 equiv. ) in EtOH (70 mL) was added hydroxylamine hydrochloride (4.12 g, 59.26 mmol, 1.5 equiv. ) and TEA (6 g, 59.26 mmol, 1.5 equiv. ) . The reaction mixture was stirred at 25 °C for 3 h and then filtered.
  • Step 3 To a solution of (E) -2, 4-dimethoxypyrimidine-5-carbaldehyde oxime (3 g, 16.41 mmol, 1.0 equiv. ) in DMF (30 mL) was added NCS (4.38 g, 32.82 mmol, 1.1 equiv. ) at 0°C. The reaction mixture was stirred at 0°C for 2 h. Then the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL ⁇ 3) . Combined the organic phases and dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuum and the crude was used for next step without any further purification. The crude product was obtained (3.2 g, yield 70%) . LCMS (m/z) : [M-35] + calc’d 218.03; found, 218.1.
  • Step 4 To a solution of (Z) -N-hydroxy-2, 4-dimethoxypyrimidine-5-carbimidoyl chloride (3.2 g, 14.69 mmol, 1.0 equiv. ) in DMF (30 mL) was added (1E) -1-ethoxyprop-1-ene (2.53 g, 29.38 mmol, 2.0 equiv. ) and NaHCO 3 (2.47 g, 29.38 mmol, 2.0 equiv. ) . The reaction mixture was stirred at 25°C for 16 h. The reaction mixture was quenched with H 2 O. Extracted with ethyl acetate (100 mL ⁇ 3) .
  • LCMS (m/z) [M+H] + calc’d 222.1; found, 222.1.
  • Step 6 To a solution of 3- (2, 4-dimethoxypyrimidin-5-yl) -4-methylisoxazole (1.74 g, 7.86 mmol, 1.0 equiv. ) in DCM (20 mL) was added BBr 3 (7.92 g, 31.44 mmol, 4.0 equiv. ) at 0°C. The reaction mixture was stirred at 25°C for 1 h. The reaction mixture was quenched by NaHCO 3 solution, extracted with ethyl acetate (50 mL ⁇ 3) . Combined the organic phases and dried over anhydrous sodium sulfate and then filtered.
  • Step 1 To a solution of Int-0017 (80 mg, 0.16 mmol, 1.0 equiv. ) in dioxane/H 2 O (10 mL/1 mL) was added 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (39 mg,0.20 mmol, 1.2 equiv. ) , K 2 CO 3 (68 mg, 0.49 mmol, 3.0 equiv. ) , Pd (PPh 3 ) 4 (19 mg,0.016 mmol, 0.1 equiv. ) at room temperature under N 2 atmosphere with balloon and then warmed to 50°C and stirred for 4 h. then filtered.
  • 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole 39 mg,0.20 mmol, 1.2 equiv.
  • K 2 CO 3 68 mg, 0.49 mmol, 3.0 e
  • LCMS (m/z) [M+H] + calc’d 207.0; found, 207.1.
  • Step 3 A suspension of Int-007 (200 mg, 0.81 mmol, 1.0 eq) , 2, 4-dichloro-6- (ethoxymethyl) pyrimidine (184 mg, 0.89 mmol, 1.1 eq) and NaHCO 3 (203 mg, 2.4 mmol, 3.0 eq) in DMF (4 mL) was stirred under nitrogen at 90°C for 2h. Then it was filtered, and the filtrate was purified by prep-HPLC using a gradient of H 2 O (0.1%FA) /ACN (flow rate: 20 ml/min; wavelength: 214 nm/254 nm.
  • Step 1 A suspension of Int-007 (200 mg, 0.81 mmol, 1.0 eq) , 2, 4-dichloro-6- (ethoxymethyl) pyrimidine (184 mg, 0.89 mmol, 1.1 eq) and NaHCO 3 (203 mg, 2.4 mmol, 3.0 eq) in DMF (4 mL) was stirred under nitrogen at 90°C for 2h. Then it was filtered, and the filtrate was purified by prep-HPLC using a gradient of H 2 O (0.1%FA) /ACN (flow rate: 20 ml/min; wavelength: 214 nm/254 nm.
  • Pd (dppf) Cl2 9 mg, 0.012 mmol, 0.1 equiv.
  • K 2 CO 3 34 mg, 0.25 mmol, 2 equiv.
  • Test Method Used Test Method B.
  • Step 1 A mixture of Int-0012 (16.3 mg, 71.11 ⁇ mol, 1.0 equiv. ) , 2, 4-dichloro-6-fluoro-quinazoline (23.15 mg, 106.66 ⁇ mol, 1.5 equiv. ) , and K 2 CO 3 (39.31 mg, 284.43 ⁇ mol, 4.0 equiv. ) in acetonitrile (1 mL) and DMF (1 mL) was stirred at 60 °C for 2 h and room temperature for 16 h. The mixture was diluted with EtOAc and washed with water, dried (Na 2 SO 4 ) , and filtered.
  • Step 1 A suspension of 2, 4-dichloro-5- (iodomethyl) pyrimidine (500 mg, 1.73 mmol, 1.0 eq) , 1H-pyrazole (106 mg, 1.55 mmol, 0.9 eq) and K 2 CO 3 (239 mg, 1.73 mmol) in ACN (5 mL) was stirred under nitrogen at 85°C for 3h. The mixture was extracted with EA (20 mLx3) . Combined the organic phases and dried over anhydrous sodium sulfate and then filtered.
  • Step 2 A suspension of Int-007 (250 mg, 1.01 mmol, 1.0 eq) , 5- ( (1H-pyrazol-1-yl) methyl) -2, 4-dichloropyrimidine (254 mg, 1.1 mmol, 1.1 eq) and NaHCO 3 (254 mg, 3.03 mmol, 3.0 eq) in DMF (3 mL) was stirred under nitrogen at 90°C for 2h. The mixture was filtered. The filtrate was purified by prep-HPLC using a gradient of H 2 O (0.1%FA) /ACN (Flow rate: 20 ml/min; wavelength: 214 nm/254 nm.
  • Test Method Used Test Method B.
  • Step 1 To a solution of (1- (2-methoxyethyl) -1H-pyrazol-4-yl) boronic acid SM1 (251 mg, 1.48 mmol, 1.1 equiv. ) and 5-bromo-2-chloro-4-methoxypyrimidine SM2 (300 mg, 1.34 mmol, 1.0 equiv. ) in 1, 4-dioxane (10 mL) and water (1 mL) was added Pd (dppf) Cl 2 ⁇ DCM (100 mg, 0.13 mmol, 0.1 equiv. ) and Cs 2 CO 3 (875 mg, 2.68 mmol, 2.0 equiv.
  • Step 2 To a solution of 2-chloro-4-methoxy-5- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) pyrimidine (254 mg, 0.94 mmol, 1.0 equiv. ) in AcOH (5.0 mL) was added NaI (425 mg, 2.84 mmol, 3.0 equiv. ) and the reaction was stirred at 110 °C for 2 h, the mixture was concentrated.
  • Step 3 To a solution of 5- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) pyrimidine-2, 4-diol (340 mg, 1.44 mmol, 1.0 equiv. ) in POCl 3 (5.0 mL) was added DIEA (558 mg, 4.32 mmol, 3.0 equiv. ) at 0 °C, the reaction was stirred at 100 °C for 1 h.
  • Step 4 To a solution of Int-007 (18 mg, 0.07 mmol, 1.0 equiv. ) in DMF (2 mL) was added NaHCO 3 (12 mg, 0.15 mmol, 2.0 equiv. ) , the reaction was stirred at 100 °C for 0.5 h, then 2, 4-dichloro-5- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) pyrimidine (20 mg, 0.07 mmol, 1.0 equiv. ) was added and the mixture was stirred at 100 °C for 1.5 h, the mixture was purified by prep-HPLC to give Example 300 (1.6 mg, 3.3 ⁇ mol, 5%) .
  • Step 1 To a round-bottomed flask was added 2, 4-dimethoxy-5- (1-methyl-1H-pyrazol-4-yl) pyrimidine (500 mg, 2.28 mmol, 1.0 equiv. ) , (1-methylpyrazol-4-yl) boronic acid (575 mg, 4.56 mmol, 2.0 equiv. ) , Pd (dppf) Cl 2 ⁇ CH 2 Cl 2 (185 mg, 0.22 mmol, 0.1 equiv. ) and K 2 CO 3 (946 mg, 6.84 mmol, 3 equiv.
  • Step 2 To a solution of 2, 4-dimethoxy-5- (1-methyl-1H-pyrazol-4-yl) pyrimidine (500 mg, 2.27 mmol, 1.0 equiv. ) in AcOH (10 mL) was added NaI (1.02 g, 6.81 mmol, 3 equiv. ) , the mixture was refluxed at 110 °C for 2 h. The solvent was evaporated, and the residue was diluted with sat. Na 2 S 2 O 3 solution (20 mL) , solid was filtered and washed with water (10 mL) to afford 5- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diol (410 mg, 93%) .
  • LCMS-ESI (m/z) [M+H] + calc’d 193.06; found, 193.20.
  • Step 3 To a solution of 5- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diol (390 mg, 2.03 mmol, 1.0 equiv. ) in POCl 3 (5 mL) was added DIEA (1.31 g, 10.15 mmol, 5.0 equiv. ) , the mixture was refluxed at 110 °C for 2 h. Most of the solvent was evaporated, the residue was added dropwise into sat.
  • Step 4 To a solution of Int-003 (100 mg, 0.4 mmol, 1.0 equiv. ) in DMF (0.5 mL) was added NaHCO 3 (68 mg, 0.8 mmol, 2.0 equiv. ) , the mixture was stirred at 100 °C for 30 min, then a solution of 2, 4-dichloro-5- (1-methyl-1H-pyrazol-4-yl) pyrimidine (93 mg, 0.4 mmol, 1.0 equiv. ) in DMF (0.5 mL) and added into the reaction mixture. Then reaction mixture was stirred at 100 °C for another 2 h. The reaction mixture was purified by prep-HPLC to afford Example 301 (50 mg, 29%) as yellow solid.
  • Step 1 To a solution of 5-bromo-2-chloro-4-methoxypyrimidine (150 mg, 0.67 mmol, 1.0 equiv. ) and (1, 3-dimethyl-1H-pyrazol-4-yl) boronic acid (113 mg, 0.80 mmol, 1.2 equiv. ) in 1, 4-dioxane (10 mL) and water (1 mL) was added Pd (dppf) Cl 2 ⁇ DCM (27 mg, 0.03 mmol, 0.05 equiv. ) and Cs 2 CO 3 (256 mg, 1.34 mmol, 2.0 equiv.
  • Step 2 To a solution of 2-chloro-5- (1, 3-dimethyl-1H-pyrazol-4-yl) -4-methoxypyrimidine (117 mg, 0.49 mmol, 1.0 equiv. ) in AcOH (3 mL) was added NaI (220 mg, 1.47 mmol, 3.0 equiv. ) and stirred at 110 °C for 1 h, the mixture was concentrated and dichloromethane (6 mL) was added, stirred for 1 h and filtered to afford 5- (1, 3-dimethyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diol (80 mg, 79%) .
  • LCMS-ESI (m/z) [M+H] + 207.09; found, 207.06.
  • Step 3 To a solution of 5- (1, 3-dimethyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diol (520 mg, 2.50 mmol, 1.0 equiv. ) in POCl 3 (5 mL) was added DIEA (1.6 g, 12.60 mmol, 5.0 equiv.
  • Step 4 To a solution of Int-003 (20 mg, 0.08 mmol, 1.0 equiv. ) in DMF (1.5 mL) was added NaHCO 3 (14 mg, 0.16 mmol, 2.0 equiv. ) and stirred at 100°C for 0.5 h, 2, 4-dichloro-5- (1, 3-dimethyl-1H-pyrazol-4-yl) pyrimidine (20 mg, 0.08 mmol, 1.0 equiv. ) was added and stirred at 100°C for 2 h, the mixture was purified by prep-HPLC to afford Example 302 (2.0 mg, 5%) .
  • LCMS-ESI (m/z) [M+H] + 454.12; found, 454.30.
  • Step 1 To a solution of Example 222 (50 mg, 0.12 mmol, 1.0 equiv. ) in dichloromethane (5 mL) was added trimethylsilylacetylene (59 mg, 0.60 mmol, 5 equiv. ) , Pd (PPh 3 ) 4 (55 mg, 0.05 mmol, 0.4 equiv. ) , CuI (18 mg, 0.09 mmol, 0.8 equiv. ) and TEA (48 mg, 0.48 mmol, 4.0 equiv. ) , the mixture was stirred at 50°C for 24 h under N 2 .
  • Step 2 To a solution of 2- (2- ( (5- (ethoxymethyl) -2- ( (trimethylsilyl) ethynyl) pyrimidin-4-yl) oxy) -3-fluoropyridin-4-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one (136 mg, 0.28 ⁇ mol, 1.0 equiv. ) in MeOH (2.5 mL) was added K 2 CO 3 (78 mg, 0.57 mmol, 2.0 equiv. ) , the mixture was stirred at room temperature for 0.5 h. The mixture was purified by prep-HPLC to afford Example 303 (42 mg, 35%) .
  • Step 1 To a solution of 1- (difluoromethyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (262 mg, 1.07 mmol, 1.2 equiv. ) and 5-bromo-2-chloro-4-methoxypyrimidine (200 mg, 0.90 mmol, 1.0 equiv. ) in 1, 4-dioxane (5.0 mL) and water (0.5 mL) was added Pd (dppf) Cl 2 ⁇ DCM (73 mg, 0.09 mmol, 0.1 equiv. ) and Cs 2 CO 3 (583 mg, 1.79 mmol, 2.0 equiv.
  • Step 2 To a solution of 2-chloro-5- (1- (difluoromethyl) -1H-pyrazol-4-yl) -4-methoxypyrimidine (50 mg, 0.19 mmol, 1.0 equiv. ) in AcOH (1.0 mL) was added NaI (86 mg, 0.57 mmol, 3.0 equiv. ) , the reaction was stirred at 110 °C for 2 h.
  • Step 3 To a solution of 5- (1- (difluoromethyl) -1H-pyrazol-4-yl) pyrimidine-2, 4-diol (67 mg, 0.29 mmol, 1.0 equiv. ) in POCl 3 (1.5 mL) was added DIEA (114 mg, 0.88 mmol, 3.0 equiv.
  • Step 4 To a solution of Int-007 (20 mg, 0.08 mmol, 1.0 equiv. ) in DMF (2.0 mL) was added NaHCO 3 (13 mg, 0.16 mmol, 2.0 equiv. ) and the reaction was stirred at 100 °C for 0.5 h, 2, 4-dichloro-5- (1- (difluoromethyl) -1H-pyrazol-4-yl) pyrimidine (21 mg, 0.08 mmol, 1.0 equiv. ) was added and stirred at 100 °C for 3 h, the mixture was purified by prep-HPLC to give Example 304 (2.0 mg, 4.2 umol, 5%) .
  • Step 1 A vial was charged with 2- [2- (2-chloro-5-iodo-pyrimidin-4-yl) oxy-3-fluoro-4-pyridyl] -1, 5, 6, 7-tetrahydropyrro lo [3, 2-c] pyridin-4-one (20 mg, 41.18 ⁇ mol) , 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (10.38 mg, 49.42 ⁇ mol, 1.2 eq. ) , Pd (dppf) Cl 2 (3.01 mg, 4.12 ⁇ mol, 0.1 eq.
  • Step 1 A mixture of 5-bromo-2, 4-dimethoxy-pyrimidine (1.2 g, 5.48 mmol, 1.0 equiv. ) , 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiazole (2.31 g, 10.96 mmol, 2.0 equiv. ) , K 2 CO 3 (2.27 g, 16.44 mmol, 3.0 equiv. ) , Pd (dppf) Cl 2 ⁇ DCM (895 mg, 1.10 mmol, 0.2 equiv. ) in 1, 4-dioxane (20 mL) and water (4 mL) was stirred at 100 °C for 16 h under nitrogen atmosphere.
  • Step 2 A mixture of 5- (2, 4-dimethoxypyrimidin-5-yl) thiazole (0.19 g, 851.06 ⁇ mol, 1.0 equiv. ) and NaI (383 mg, 2.55 mmol, 3.0 equiv. ) in AcOH (2 mL) was stirred at 110°C for 1 h. The mixture was filtered. The cake was washed with DCM and dried to afford the crude 5-thiazol-5-ylpyrimidine-2, 4-diol (160 mg, 819.68 ⁇ mol) . The crude was used in the next step without further purification. LCMS-ESI (m/z) : [M+H] + calc’d 196.01; found, 196.00.
  • Step 3 To a suspension of 5- (thiazol-5-yl) pyrimidine-2, 4-diol (160 mg, 819.68 ⁇ mol, 1.0 equiv. ) in POCl 3 (3 mL) was added DIEA (0.5 mL) , the reaction was stirred at 110°C for 1 h. The resulting mixture was quenched by sat. NaHCO 3 (aq., 200 mL) , and extracted by EtOAc (80 mL ⁇ 3) . The combined organic layer was washed by brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 4 To a solution of Int-007 (50 mg, 202.25 ⁇ mol, 1.0 equiv. ) and 5- (2, 4-dichloropyrimidin-5-yl) thiazole (51 mg, 222.47 ⁇ mol, 1.1 equiv. ) in DMSO (3 mL) was added K 2 CO 3 (56 mg, 404.49 ⁇ mol, 2.0 equiv. ) and sodium methanesulfinate (0.6 mg, 6.07 ⁇ mol, 0.03 equiv. ) , the mixture was stirred at room temperature for 2 h and purified by prep-HPLC to give Example 306 (7.3 mg, 16.48 ⁇ mol, 8%) .
  • Step 1 To a solution of 2, 6-dimethoxypyrimidine-4-carboxylic acid (2.0 g, 10.87 mmol, 1.0 equiv. ) and N, O-dimethylhydroxylamine hydrochloride (1.27 g, 13.04 mmol, 1.2 equiv. ) in DMF (50 mL) was added triethylamine (3.29 g, 32.61 mmol, 3.0 equiv. ) and HATU (5 g, 13.04 mmol, 1.2 equiv. ) , the reaction mixture was stirred at room temperature overnight. The reaction was diluted with water (100 mL) , extracted with EtOAc (50 mL ⁇ 3) .
  • Step 2 To a solution of N, 2, 6-trimethoxy-N-methylpyrimidine-4-carboxamide (2.5 g, 11.01 mmol, 1.0 equiv. ) in THF (50 mL) was dropwise added diisobutylaluminium hydride (1 M, 33.03 mL, 3.0 equiv. ) at -78°C, the reaction was stirred at -78°C for 3 h. The reaction was diluted with water (100 mL) , extracted with EtOAc (50 mL ⁇ 3) . The combined layers were washed with brine (50 mL) , dried over Na 2 SO 4 .
  • diisobutylaluminium hydride 1 M, 33.03 mL, 3.0 equiv.
  • Step 4 To a solution of 5- (2, 6-dimethoxypyrimidin-4-yl) oxazole (600 mg, 2.9 mmol, 1.0 equiv. ) in HOAc (10 mL) was added sodium iodide (1.3 g, 8.7 mmol, 3.0 equiv. ) , the reaction was stirred at 110°C for 1 h. The mixture was filtered, and the cake was washed with DCM. The solid was dried to give 6- (oxazol-5-yl) pyrimidine-2, 4-diol (600 mg, 100%) . The crude was used in the next step without further purification. LCMS-ESI (m/z) : [M+H] + calc’d 180.03; found, 179.98.
  • Step 5 To a solution of 6- (oxazol-5-yl) pyrimidine-2, 4-diol (200 mg, 1.12 mmol, 1.0 equiv. ) in POCl 3 (5 mL) was added DIPEA (1.5 mL) , the reaction was stirred at 110°C for 1 h. The reaction mixture was cooled to room temperature, then the reaction mixture was added to cold sat. NaHCO 3 aqueous dropwise. The solution was extracted with EtOAc (100 mL ⁇ 3) , washed with brine (100 mL) , dried over Na 2 SO 4 . The mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (0-50%EtOAc in PE) to give 5- (2, 6-dichloropyrimidin-4-yl) oxazole (136 mg, 56%) .
  • Step 6 To a solution of 5- (2, 6-dichloropyrimidin-4-yl) oxazole (100 mg, 0.47 mmol, 1.0 equiv. ) and Int-007 (116 mg, 0.47 mmol, 1.0 equiv. ) in DMSO (3 mL) was added K 2 CO 3 (130 mg, 0.94 mol, 2.0 equiv. ) and sodium methyl sulfinate (1.5 mg, 14 ⁇ mol, 0.03 equiv. ) , the reaction mixture was stirred at room temperature for 2 h. The mixture was filtered, and the filtrate was purified by prep-HPLC to give Example 307 (10.4 mg, 5%) .
  • Step 1 A mixture of tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate (1.48 g, 5.02 mmol, 2.2 equiv. ) , 5-bromo-2, 4-dimethoxypyrimidine (2) (500 mg, 2.28 mmol, 1.0 equiv. ) , K 2 CO 3 (946 mg, 6.85 mmol, 3.0 equiv. ) and Pd (dppf) Cl 2 ⁇ DCM (186 mg, 228 ⁇ mol, 0.1 equiv.
  • Step 2 A mixture of 2, 4-dimethoxy-5- (1H-pyrazol-4-yl) pyrimidine (124 mg, 601 ⁇ mol, 1.0 equiv. ) and NaI (283 mg, 1.89 mmol, 3.0 equiv. ) in HOAc (5 mL) was stirred at 110°C for 1 h. The mixture was concentrated, and the residue was diluted with DCM (10 mL) . The mixture was stirred for 10 min and filtered. The cake was washed by DCM and dried to afford the crude 5- (1H-pyrazol-4-yl) pyrimidine-2, 4-diol as a light-pink solid (242 mg, contained NaI, NaOAc, HOAc, etc. ) . The crude was used in the next step without further purification. LCMS-ESI (m/z) : [M+H] + calc’d for 179.06; found, 179.07.
  • Step 3 To a suspension of 5- (1H-pyrazol-4-yl) pyrimidine-2, 4-diol (222 mg crude, 1.0 equiv. ) in POCl 3 (5 mL) was added DIEA (1 mL) , the reaction was stirred at 100°C for 2 h. The mixture was concentrated and quenched by sat. NaHCO3 (aq, 50 mL) , extracted by EtOAc (50 mL ⁇ 4) . The combined organic layer was washed by brine, dried over Na 2 SO 4 , and concentrated in-vacuo.
  • Step 4 A mixture of Int-007 (52 mg, 210 ⁇ mol, 1.2 equiv. ) and NaHCO 3 (53 mg, 631 ⁇ mol, 3.6 equiv. ) in DMF (3 mL) was stirred at 100°C for 30 min, then a solution of 1- (4- (2, 4-dichloropyrimidin-5-yl) -1H-pyrazol-1-yl) ethan-1-one (45 mg, 175 ⁇ mol, 1.0 equiv. ) in DMF (1 mL) was added and the mixture was stirred at 100°C for 2 h. The mixture was purified by prep-HPLC to afford Example 308 (2 mg, 4.70 ⁇ mol, 2%) .
  • Step 1 To a round-bottomed flask was added 5-bromo-2, 4-dimethoxy-pyrimidine (590 mg, 2.7 mmol, 1.0 equiv. ) , 1, 5-dimethyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (1.2 g, 5.4 mmol, 2.0 equiv. ) , Pd (dppf) Cl 2 ⁇ CH 2 Cl 2 (219 mg, 0.27 mmol, 0.1 equiv. ) and K 2 CO 3 (1.12 g, 8.1 mmol, 3 equiv.
  • Step 2 To a solution of 5- (1, 5-dimethyl-1H-pyrazol-4-yl) -2, 4-dimethoxypyrimidine (600 mg, 2.56 mmol, 1.0 equiv. ) in AcOH (20 mL) was added NaI (1.15 g, 7.68 mmol, 3 equiv. ) , the mixture was refluxed at 110 °C for 2 h. The solvent was evaporated, and the residue was added in to sat. NaHCO 3 (30 mL) and extracted by EtOAc (30 mL ⁇ 3) .
  • Step 3 To a solution of 5- (1, 5-dimethyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diol (600 mg, 2.9 mmol, 1.0 equiv. ) in POCl 3 (10 mL) was added DIEA (1.87 g, 14.5 mmol, 5.0 equiv. ) , the mixture was refluxed at 110 °C for 2 h. Then, most of the solvent was evaporated, the residue was added dropwise into sat.
  • Step 4 To a solution of 2, 4-dichloro-5- (1, 5-dimethyl-1H-pyrazol-4-yl) pyrimidine (170 mg, 0.7 mmol, 1.0 equiv. ) in anhydrous DMSO (2 mL) was added 3-fluoro-4-iodo-pyridin-2-ol (184 mg, 0.77 mmol, 1.1 equiv. ) , NaMeSO 2 (2 mg, 0.02 mg, 0.03 equiv. ) and K 2 CO 3 (193 mg, 1.4 mmol, 2 equiv.
  • Step 5 To a round-bottomed flask was added 2-chloro-5- (1, 5-dimethyl-1H-pyrazol-4-yl) -4- ( (3-fluoro-4-iodopyridin-2-yl) oxy) pyrimidine (110 mg, 0.25 mmol, 1.0 equiv. ) , compound 1-6 (97 mg, 0.37 mmol, 1.5 equiv. ) , Pd (dppf) Cl 2 ⁇ CH 2 Cl 2 (20 mg, 0.025 mmol, 0.1 equiv. ) and K 3 PO 4 (157 mg, 0.75 mmol, 3 equiv.
  • Step 1 To a solution of 2- (2, 4-dichloropyrimidin-5-yl) oxazole Int-0019 (200 mg, 1.02 mmol, 1.0 equiv. ) in DMF (10 mL) was added 3-fluoro-4-iodopyridin-2-ol (243 mg, 1.02 mmol, 1.0 equiv. ) and NaHCO 3 (171 mg, 2.04mol, 2.0 equiv. ) , then the reaction was stirred at 100°C for 2 h.
  • Step 2 To a solution of 2- (2-chloro-4- ( (3-fluoro-4-iodopyridin-2-yl) oxy) pyrimidin-5-yl) oxazole (100 mg, 0.24 mmol, 1.0 equiv. ) and 1-6 (126 mg, 0.48 mmol, 2.0 equiv. ) in 1, 4-dioxane (10 mL) and water (2 mL) was added Pd (dppf) Cl 2 ⁇ DCM (20 mg, 24 ⁇ mol, 0.1 equiv. ) and NaHCO 3 (60 mg, 0.72 mmol, 3.0 equiv. ) , the reaction was stirred at 65°C using a microwave reactor for 1 h.
  • Step 1 To a solution of methyl 2, 4-dichloropyrimidine-5-carboxylate (1.0 g, 4.85 mmol, 1.0 equiv. ) in MeOH (15 mL) at 0°C was added sodium methoxide (786 mg, 14.55 mmol, 3.0 equiv. ) , then the reaction was stirred at 0°C for 2 h. The solution was concentrated. The residue was purified by column chromatography (0-33%EtOAc in PE) to give methyl 2, 4-dimethoxypyrimidine-5-carboxylate (970 mg, 100%) . LCMS-ESI (m/z) : [M+H] + calc’d 199.06; found, 199.02.
  • Step 2 To a solution of methyl 2, 4-dimethoxypyrimidine-5-carboxylate (970 mg, 4.9 mmol, 1.0 equiv. ) in THF (10 mL) and water (10 mL) was added LiOH ⁇ H 2 O (412 mg, 9.8 mmol, 2.0 equiv. ) , then the reaction was stirred at room temperature for 1 h. The pH of the solution was adjusted to 3 with 1 M HCl, then the mixture was extracted with EtOAc (20 mL ⁇ 3) . The combined layers were washed with brine (50 mL) , dried over Na 2 SO 4 .

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Abstract

L'invention concerne un composé de pipéridine-ones de formule (I), son procédé de préparation, des compositions pharmaceutiques comprenant les composés, et les utilisations pharmaceutiques pour le traitement de troubles.
PCT/CN2023/137890 2022-12-11 2023-12-11 Dérivés de pipérindine-ones, procédés de préparation et utilisations médicinales associés WO2024125451A1 (fr)

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