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WO2024114680A1 - Composé hétérocyclique, composition pharmaceutique et application associée - Google Patents

Composé hétérocyclique, composition pharmaceutique et application associée Download PDF

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Publication number
WO2024114680A1
WO2024114680A1 PCT/CN2023/135003 CN2023135003W WO2024114680A1 WO 2024114680 A1 WO2024114680 A1 WO 2024114680A1 CN 2023135003 W CN2023135003 W CN 2023135003W WO 2024114680 A1 WO2024114680 A1 WO 2024114680A1
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Prior art keywords
alkyl
mmol
cycloalkyl
ring
alkoxy
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PCT/CN2023/135003
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English (en)
Chinese (zh)
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WO2024114680A9 (fr
Inventor
陈祥
祝伟
王一鸣
汪涛
李正涛
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Hainan Simcere Zaiming Pharmaceutical Co Ltd
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Hainan Simcere Zaiming Pharmaceutical Co Ltd
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Priority to CN202380079968.5A priority Critical patent/CN120530110A/zh
Publication of WO2024114680A1 publication Critical patent/WO2024114680A1/fr
Publication of WO2024114680A9 publication Critical patent/WO2024114680A9/fr
Anticipated expiration legal-status Critical
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure belongs to the field of medical technology, and specifically relates to heterocyclic compounds of FGFR inhibitors, pharmaceutical compositions and applications thereof.
  • FGFR Fibroblast Growth Factor Receptor
  • FGF Fibroblast growth factor
  • FGFR causes receptor dimerization and then phosphorylates the tyrosine residues in the kinase region to activate the receptor.
  • the activated FGFR further activates downstream RAS/RAF, PI3K/AKT, JAK/STAT and PLC ⁇ signaling pathways, and participates in regulating multiple processes such as cell proliferation, apoptosis, migration, repair of damaged tissues and angiogenesis.
  • FGFR signaling pathway Under normal physiological conditions, the FGFR signaling pathway is strictly regulated and is at a weak activation level. However, its overactivation often leads to the occurrence and development of tumors.
  • the molecular mechanisms of abnormal FGFR activation mainly include 1) gene amplification; 2) gene mutation; 3) gene fusion caused by gene translocation, etc.
  • FGFR2 gene amplification occurs in gastric cancer (5-10%)
  • FGFR2 gene translocation occurs in intrahepatic bile duct cancer (14%)
  • FGFR2 gene mutation occurs in endometrial cancer (12-14%).
  • FGFR3 gene abnormalities are most common in bladder cancer, including gene mutations (60-80% of non-muscle invasive bladder cancer and 15-20% of muscle invasive bladder cancer), gene translocation (3-6%), and gene amplification (the incidence has not been reported); followed by myeloma, 15-20% of myeloma patients have FGFR3 gene translocation. Some of the above FGFR gene abnormalities have been proven to be associated with poor prognosis of patients.
  • the present disclosure provides a compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • X 1 and X 2 are independently selected from N or C;
  • Z is selected from O, S, NH, a bond, OCR 6 R 7 , SCR 6 R 7 , NHCR 6 R 7 or CR 6 R 7 , wherein R 6 and R 7 are each independently selected from H and C 1 -C 6 alkyl;
  • R 1 is selected from H, CN, OH, NH 2 , halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 6 -C 10 aryl or 5-6 membered heteroaryl, and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 6 -C 10 aryl or 5-6 membered heteroaryl is optionally substituted with R 1a ;
  • R 1a is selected from halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 6 -C 10 aryl or 5-6 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 6 -C 10 aryl or 5-6 membered heteroaryl is optionally substituted by R 1b ;
  • R 1b is selected from halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • R 2 is selected from H, CN, OH, NH 2 , halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with R 2a ;
  • R 2a is selected from halogen, OH, NH 2 , C 1 -C 6 alkyl or C 1 -C 6 alkoxy, wherein the OH, NH 2 , C 1 -C 6 alkyl or C 1 -C 6 alkoxy is optionally substituted with halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 6 cycloalkyl;
  • R 3 is selected from H, CN, OH, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • Ring A is selected from C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, wherein the C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl
  • the cyclic group, C 6 -C 10 aryl group or 5-10 membered heteroaryl group is optionally substituted by Ra ;
  • Ring B is selected from a C 6 -C 10 aromatic ring or a 5-10 membered heteroaromatic ring, wherein the C 6 -C 10 aromatic ring or the 5-10 membered heteroaromatic ring is optionally substituted by R b ;
  • Ring C is selected from C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl or C 6 -C 10 aryl, and the C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl or C 6 -C 10 aryl is optionally substituted by R c ;
  • W is selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 4-6 membered heterocyclyl, -S( ⁇ O) 2 -C 1 -C 4 alkyl, -C( ⁇ O)-RT, -C( ⁇ O)CR 4 ⁇ C (R 5 ) 2 , -C( ⁇ O)C ⁇ CR 5 , -NHC( ⁇ O)CR 4 ⁇ C(R 5 ) 2 , -NHC( ⁇ O)C ⁇ CR 5 , -S( ⁇ O)CR 4 ⁇ C(R 5 ) 2 , -S( ⁇ O) 2 CR 4 ⁇ C(R 5 ) 2 , -NHS( ⁇ O)CR 4 ⁇ C(R 5 ) 2 , or -NHS( ⁇ O) 2 CR 4 ⁇ C(R 5 ) 2 ;
  • RT is selected from C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, 4-6 membered heterocyclyl, -N( C1 - C6 alkyl) 2 , C1 - C6 alkyl-CN or C3 - C6 cycloalkyl;
  • R 4 is selected from H, CN, halogen or C 1 -C 6 alkyl
  • each R 5 is independently selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or 4-10 membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R 5a ;
  • R 5a is independently selected from halogen, CN, OH, NH 2 , —NH—C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , C 3 -C 8 cycloalkyl or 4-9 membered heterocyclyl.
  • X 1 and X 2 are independently selected from N or C;
  • Z is selected from O, S, NH or a bond
  • R 1 is selected from H, CN, OH, NH 2 , halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 6 -C 10 aryl or 5-6 membered heteroaryl, and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 6 -C 10 aryl or 5-6 membered heteroaryl is optionally substituted with R 1a ;
  • R 1a is selected from halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 6 -C 10 aryl or 5-6 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 6 -C 10 aryl or 5-6 membered heteroaryl is optionally substituted by R 1b ;
  • R 1b is selected from halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • R 2 is selected from H, CN, OH, NH 2 , halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with R 2a ;
  • R 2a is selected from halogen, OH, NH 2 , C 1 -C 6 alkyl or C 1 -C 6 alkoxy, wherein the OH, NH 2 , C 1 -C 6 alkyl or C 1 -C 6 alkoxy is optionally substituted with halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 6 cycloalkyl;
  • R 3 is selected from H, CN, OH, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • Ring A is selected from C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, wherein the C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl is optionally substituted by Ra ;
  • Ring B is selected from a C 6 -C 10 aromatic ring or a 5-10 membered heteroaromatic ring, wherein the C 6 -C 10 aromatic ring or the 5-10 membered heteroaromatic ring is optionally substituted by R b ;
  • Ring C is selected from C 3 -C 6 cycloalkyl or 4-10 membered heterocyclyl, and the C 3 -C 6 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R c ;
  • W is selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 4-6 membered heterocyclyl, -S( ⁇ O) 2 -C 1 -C 4 alkyl, -C( ⁇ O)-RT, -C( ⁇ O)CR 4 ⁇ C (R 5 ) 2 , -C( ⁇ O)C ⁇ CR 5 , -NHC( ⁇ O)CR 4 ⁇ C(R 5 ) 2 , -NHC( ⁇ O)C ⁇ CR 5 , -S( ⁇ O)CR 4 ⁇ C(R 5 ) 2 , -S( ⁇ O) 2 CR 4 ⁇ C(R 5 ) 2 , -NHS( ⁇ O)CR 4 ⁇ C(R 5 ) 2 , or -NHS( ⁇ O) 2 CR 4 ⁇ C(R 5 ) 2 ;
  • RT is selected from C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, 4-6 membered heterocyclyl or C3 - C6 cycloalkyl;
  • R 4 is selected from H, CN, halogen or C 1 -C 6 alkyl
  • each R 5 is independently selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or 4-10 membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R 5a ;
  • R 5a is independently selected from halogen, CN, OH, NH 2 , —NH—C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , C 3 -C 8 cycloalkyl or 4-9 membered heterocyclyl.
  • X 1 and X 2 are independently selected from N or C;
  • Z is selected from O, S, NH or a bond
  • R 1 is selected from H, CN, OH, NH 2 , halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 6 -C 10 aryl or 5-6 membered heteroaryl, and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 6 -C 10 aryl or 5-6 membered heteroaryl is optionally substituted with R 1a ;
  • R 1a is selected from halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • R 2 is selected from H, CN, OH, NH 2 , halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with R 2a ;
  • R 2a is selected from halogen, OH, NH 2 , C 1 -C 6 alkyl or C 1 -C 6 alkoxy, wherein the OH, NH 2 , C 1 -C 6 alkyl or C 1 -C 6 alkoxy is optionally substituted with halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 6 cycloalkyl;
  • R 3 is selected from H, CN, OH, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • Ring A is selected from C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, wherein the C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl is optionally substituted by Ra ;
  • Ring B is selected from a C 6 -C 10 aromatic ring or a 5-10 membered heteroaromatic ring, wherein the C 6 -C 10 aromatic ring or the 5-10 membered heteroaromatic ring is optionally substituted by R b ;
  • Ring C is selected from C 3 -C 6 cycloalkyl or 4-10 membered heterocyclyl, and the C 3 -C 6 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R c ;
  • R 4 is selected from H, CN, halogen or C 1 -C 6 alkyl
  • each R 5 is independently selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or 4-10 membered heterocyclyl, said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or 4-10 membered heterocyclyl being optionally substituted with R 5a ;
  • R 5a is independently selected from halogen, CN, OH, NH 2 , —NH—C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , C 3 -C 8 cycloalkyl or 4-9 membered heterocyclyl.
  • At least one of X1 or X2 is selected from N.
  • X1 is selected from C and X2 is selected from N.
  • X1 is selected from N, and X2 is selected from C.
  • Z is selected from O, S, NH, a bond, OCR 6 R 7 , SCR 6 R 7 , NHCR 6 R 7 , or CR 6 R 7 , wherein R 6 and R 7 are each independently selected from H and C 1 -C 3 alkyl.
  • Z is selected from O, S, NH, a bond, OCH 2 , SCH 2 , NHCH 2 , or CH 2 .
  • Z is selected from O, S, NH, or a bond.
  • Z is O or OCH2 .
  • Z is selected from O.
  • Z is OCH2 .
  • R 1 is selected from H, CN, OH, NH 2 , halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy or C 3 -C 6 cycloalkyl, and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy or C 3 -C 6 cycloalkyl is optionally substituted with R 1a .
  • R 1 is selected from CN, OH, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or C 3 -C 6 cycloalkyl , which is optionally substituted with R 1a .
  • R 1 is selected from CN, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or C 3 -C 6 cycloalkyl, said C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or C 3 -C 6 cycloalkyl being optionally substituted with R 1a .
  • R 1 is selected from C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl, which is optionally substituted with R 1a .
  • R 1 is selected from C 2 -C 6 alkynyl, which is optionally substituted with R 1a .
  • R 1 is selected from C 2 -C 4 alkynyl, which is optionally substituted with R 1a .
  • R 1a is selected from OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, and the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with R 1b .
  • R 1a is selected from OH, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, and the C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with R 1b .
  • the 4-6 membered heterocyclyl contains 1, 2 or 3 heteroatoms independently selected from N, O or S. In some embodiments, the 4-6 membered heterocyclyl contains 1 O or S atom.
  • the 5-6 membered heteroaryl group contains 1, 2 or 3 heteroatoms independently selected from N, O or S. In some embodiments, the 5-6 membered heteroaryl contains 1 or 2 N atoms.
  • R 1a is selected from OH, -CH 3 , -OCH 3 , cyclopropyl, cyclobutyl, 3-oxetanyl, 2-tetrahydrofuranyl, tetrahydro-2H-thiopyranyl-4-yl, phenyl, 3-pyridyl or 5-pyrimidinyl, and the cyclopropyl, cyclobutyl, 3-oxetanyl, 2-tetrahydrofuranyl, tetrahydro-2H-thiopyranyl-4-yl, phenyl, 3-pyridyl or 5-pyrimidinyl is optionally substituted with R 1b .
  • R 1a is selected from OH, -OCH 3 , cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H-thiopyranyl, phenyl, pyridinyl, or pyrimidinyl, which is optionally substituted with R 1b .
  • R 1a is selected from halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R 1a is selected from OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R 1b is selected from halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R 1b is selected from F, Cl, CH 3 or -OCH 3 .
  • R 1 is selected from -CN, -Cl, -CH 3 , -CH 2 OH,
  • R 1 is In some embodiments, R 1 is In some embodiments, R 1 is
  • R 2 is selected from CN, OH, NH 2 , halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, which is optionally substituted with R 2a .
  • R 2a is selected from halogen, OH, NH 2 , C 1 -C 6 alkyl or C 1 -C 6 alkoxy, wherein the OH, C 1 -C 6 alkyl or C 1 -C 6 alkoxy is optionally substituted with halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 3 -C 6 cycloalkyl.
  • R2 is selected from CH3 , CH2OH , CH2O (cyclopropyl), CF3 , CH2OCH3 , CH2OCF3 , C2H5 , OCH3 , or OH .
  • R2 is selected from CH2OH , methyl , CH2OCH3 , OCH3 , or OH.
  • R 2 is selected from CH 2 OH or methyl.
  • R 2 is selected from CH 2 OH.
  • R3 is selected from H.
  • one of R 2 and R 3 is H.
  • R2 is selected from CH3 , CH2OH , CH2O (cyclopropyl), CF3 , CH2OCH3 , CH2OCF3 , C2H5 , OCH3 , or OH; R3 is H.
  • R2 is CH2OH and R3 is H. In some embodiments, R2 is methyl and R3 is H. In some embodiments, R2 is CH2OCH3 and R3 is H.
  • Ring A is selected from C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl, and the C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl is optionally substituted with Ra .
  • Ring A is selected from C 3 -C 6 cycloalkyl or 5-10 membered heteroaryl, wherein the C 3 -C 6 cycloalkyl or 5-10 membered heteroaryl is optionally substituted with Ra .
  • Ring A is selected from C 3 -C 6 cycloalkyl or 5-6 membered heteroaryl, and the C 3 -C 6 cycloalkyl or 5-6 membered heteroaryl is optionally substituted with Ra .
  • the 5-10 membered heteroaryl and the 5-6 membered heteroaryl each independently contain 1, 2 or 3 heteroatoms independently selected from N, O or S. In some embodiments, the 5-10 membered heteroaryl and the 5-6 membered heteroaryl each independently contain 1 or 2 N atoms.
  • Ring A is selected from cyclopropyl, pyridinyl (including 2-pyridinyl, 3-pyridinyl) or pyrimidinyl (including 2-pyrimidinyl), and the cyclopropyl, pyridinyl or pyrimidinyl is optionally substituted with Ra .
  • Ring A is selected from cyclopropyl or pyridinyl, which is optionally substituted with Ra .
  • Ring A is selected from pyridinyl, which is optionally substituted with Ra .
  • Ra is selected from halogen.
  • Ra is selected from F.
  • Ring A is selected from
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring B is selected from a 5-10 membered heteroaryl ring, which is optionally substituted with R b .
  • Ring B is selected from a 5-6 membered heteroaromatic ring containing 1, 2, or 3 N heteroatoms, which is optionally substituted with R b .
  • Ring B is selected from a triazole ring, which is optionally substituted with R b .
  • Ring B is selected from a 1,2,3-triazole ring, which is optionally substituted with R b .
  • R b is selected from C 1 -C 6 alkyl.
  • R b is selected from CH 3 .
  • Ring B is
  • ring C is selected from C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl or phenyl, and the C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl or phenyl is optionally substituted with R c ;
  • Ring C is selected from C 3 -C 6 cycloalkyl or 4-10 membered heterocyclyl, wherein the C 3 -C 6 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R c .
  • Ring C is selected from 4-10 membered heterocyclyl or phenyl, which is optionally substituted with R c .
  • Ring C is selected from 4-6 membered heterocyclyl or phenyl, which is optionally substituted with R c .
  • Ring C is selected from 4-10 membered heterocyclyl, which is optionally substituted with R c .
  • Ring C is selected from 4-6 membered heterocyclyl, which is optionally substituted with R c .
  • the 4-10 membered heterocyclyl or the 4-6 membered heterocyclyl each contains 1, 2 or 3 heteroatoms independently selected from N, O or S. In some embodiments, the 4-10 membered heterocyclyl or the 4-6 membered heterocyclyl each contains 1, 2 or 3 N atoms.
  • Ring C is selected from Said Optionally substituted with R c .
  • Ring C is selected from piperidinyl, which is optionally substituted with R c .
  • R c is selected from halogen or C 1 -C 6 alkyl.
  • R c is F
  • Ring C is selected from C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl, or C 6 -C 10 aryl.
  • Ring C is selected from C 3 -C 6 cycloalkyl or 4-10 membered heterocyclyl.
  • Ring C is selected from a 4-10 membered heterocyclyl or a C 6 -C 10 aryl.
  • Ring C is selected from 6-9 membered heterocyclyl or phenyl.
  • Ring C is selected from a 4-10 membered heterocyclyl.
  • Ring C is selected from a 4-6 membered heterocyclyl.
  • Ring C is selected from
  • Ring C is selected from
  • W is selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 4-6 membered heterocyclyl, -S( ⁇ O) 2 -C 1 -C 4 alkyl, -C( ⁇ O)N(CH 3 ) 2 , -C( ⁇ O)CH 2 CN, -C( ⁇ O) -RT , or -C( ⁇ O)CR 4 ⁇ C(R 5 ) 2 .
  • RT is selected from C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, 4-6 membered heterocyclyl, or C3 - C6 cycloalkyl.
  • RT is selected from C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, or 4-6 membered heterocyclyl.
  • the 4-6 membered heterocyclyl contains 1, 2 or 3 heteroatoms independently selected from N, O or S.
  • W is selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 4-6 membered heterocyclyl, -S( ⁇ O) 2 -C 1 -C 4 alkyl, -C( ⁇ O) -RT , or C( ⁇ O)CR 4 ⁇ C(R 5 ) 2 .
  • RT is selected from C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, or 4-6 membered heterocyclyl.
  • R 4 is selected from H or CH 3 .
  • each R 5 is independently selected from H or CH 2 N(CH 3 ) 2 .
  • RT is selected from C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, 4-6 membered heterocyclyl, -N( C1 - C6 alkyl) 2 , or C1 - C6 alkyl-CN.
  • RT is selected from C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, or 4-6 membered heterocyclyl.
  • the 4-6 membered heterocyclyl contains 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • RT is selected from CH3 , C2H5 , OCH3 , OC2H5 , CF3 , or
  • W is selected from 3-oxetanyl.
  • W is attached to the N atom of ring C.
  • Ring C is And W is connected to the N atom on the ring C.
  • L is selected from a bond.
  • each R 5 is independently selected from H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, said C 1 -C 6 alkyl or C 1 -C 6 alkoxy being optionally substituted with R 5a .
  • R 5a is independently selected from halogen, CN, OH, NH 2 , -NH-C 1 -C 6 alkyl, or -N(C 1 -C 6 alkyl) 2 .
  • the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (II) or its stereoisomer or its pharmaceutically acceptable salt:
  • Ring A, Ring B, Ring C, R 1 , R 2 , R 3 , Z, L, and W are as defined above.
  • the compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt thereof is selected from the compound represented by formula (III) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • Ring A, Ring B, Ring C, R 1 , R 2 , R 3 , Z, L, and W are as defined above.
  • the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (IV) or its stereoisomer or its pharmaceutically acceptable salt:
  • Ring A, Ring C, R 1 , R 2 , R 3 , R b , X 1 , X 2 and W are as defined above.
  • the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds or their stereoisomers or their pharmaceutically acceptable salts:
  • the present disclosure also provides a pharmaceutical composition, which comprises a compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure relates to the use of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a drug for preventing or treating a disease mediated by FGFR.
  • the present disclosure relates to the use of the compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in preventing or treating diseases mediated by FGFR.
  • the present disclosure relates to a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a disease mediated by FGFR.
  • the present disclosure also relates to a method for preventing or treating a disease mediated by FGFR, which comprises administering to an individual a therapeutically effective amount of a compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, or a pharmaceutical preparation comprising a compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof as described in the present disclosure.
  • the disease mediated by FGFR is selected from cancer.
  • the disease mediated by FGFR is a disease mediated by FGFR2 or FGFR3. More preferably, the disease mediated by FGFR The disease is a disease mediated by FGFR3.
  • the cancer is, for example, a solid tumor. In some embodiments, the cancer is, for example, gastric cancer or bladder cancer.
  • any embodiment of any aspect of the present disclosure can be combined with other embodiments without contradiction.
  • any technical feature can be applied to the technical feature in other embodiments without contradiction.
  • the heterocyclic compound or stereoisomer thereof or pharmaceutically acceptable salt thereof provided by the present disclosure can selectively inhibit FGFR protein, such as FGFR3, and has a killing effect on related tumor cells;
  • the heterocyclic compound or its stereoisomer or its pharmaceutically acceptable salt provided by the present disclosure has good inhibitory activity against FGFR, especially FGFR3. Compared with FGFR1 and/or FGFR2, the heterocyclic compound or its stereoisomer or its pharmaceutically acceptable salt provided by the present disclosure has higher selectivity for FGFR3;
  • the heterocyclic compound or stereoisomer thereof or pharmaceutically acceptable salt thereof provided by the present disclosure has good inhibitory activity on tumor cells (eg, cells JMSU-1, cells SNU16, cells RT112).
  • heterocyclic compound or stereoisomer thereof or pharmaceutically acceptable salt thereof provided by the present disclosure has good pharmacokinetic properties, for example, good plasma clearance rate.
  • the heterocyclic compound or its stereoisomer or its pharmaceutically acceptable salt provided by the present disclosure has good permeability, for example, good permeability to caco2 cells.
  • tautomer refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present disclosure may exhibit tautomerism.
  • Tautomeric compounds may exist in two or more interconvertible species.
  • Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates.
  • the present disclosure includes all tautomeric forms of the compounds.
  • stereoisomer refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.
  • the compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • Specific geometric or stereoisomeric forms may be cis and trans isomers, E-type and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and their mixtures.
  • asymmetric carbon atoms asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of these isomers and their mixtures involved in all substituents are also included within the definition of the compounds of the present invention.
  • the compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group may be unsubstituted (CH 2 CH 3 ), monosubstituted (CH 2 CH 2 F, CH 2 CH 2 Cl, etc.), polysubstituted (CHFCH 2 F, CH 2 CHF 2 , CHFCH 2 Cl, CH 2 CHCl 2 , etc.) or fully substituted (CF 2 CF 3 , CF 2 CCl 3 , CCl 2 CCl 3 , etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or cannot be synthesized will be introduced.
  • any variable eg, Ra , Rb
  • its definition is independent at each occurrence. For example, if a group is substituted with 2 Rb , each Rb has an independent option.
  • the substituent "X” is optionally substituted by a substituent "Y", which means that the substituent "X” is optionally substituted by one or more (e.g., 1, 2, 3 or 4) substituents "Y", and the options for each substituent "Y” are independent of each other.
  • substituent "Y” is optionally substituted by one or more (e.g., 1, 2, 3 or 4) substituents "Y"
  • the options for each substituent "Y” are independent of each other.
  • R 1a means that the C 1 -C 6 alkyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl is optionally substituted by one or more R 1a , and the options for each R 1a are independent.
  • L 1 When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary.
  • L 1 When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary.
  • L 1 When L 1 is selected from “C 1 -C 3 alkylene-O", L 1 can connect ring Q and R 1 from left to right to form “ring QC 1 -C 3 alkylene-OR 1 ", or connect ring Q and R 1 from right to left to form “ring QOC 1 -C 3 alkylene-R 1 ".
  • Cm - Cn herein refers to an integer number of carbon atoms in the range of mn.
  • C1 - C10 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 , which may be linear or branched and generally has 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.
  • C1 - C10 alkyl is understood to mean a linear or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 1 -C 1 -C 1 -C 1 -C 1
  • C 1 -C 3 alkyl may be understood to mean a straight or branched saturated alkyl group having 1, 2 or 3 carbon atoms.
  • the "C 1 -C 10 alkyl” may include a range of "C 1 -C 6 alkyl", “C 1 -C 4 alkyl” or “C 1 -C 3 alkyl”, and the “C 1 -C 6 alkyl” may further include “C 1 -C 4 alkyl” or "C 1 -C 3 alkyl”.
  • haloalkyl refers to monohaloalkyl and polyhaloalkyl, usually having 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.
  • C 1-6 haloalkyl refers to C 1-6 alkyl as defined above substituted by one or more halogens, including but not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl and pentachloroethyl, etc.
  • C 1-6 haloalkyl may further include "C 1-3 haloalkyl”.
  • alkoxy refers to a group generated by the loss of a hydrogen atom from a hydroxyl group of a straight or branched alcohol, which can be understood as “alkyloxy” or “alkyl-O-", and usually has 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.
  • C 1 -C 6 alkoxy can be understood as “C 1 -C 6 alkyloxy” or “C 1 -C 6 alkyl-O-”.
  • the "C 1 -C 6 alkoxy” may further include a "C 1 -C 3 alkoxy".
  • alkenyl refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond, usually having 2 to 10, 2 to 8, 2 to 6, 2 to 4, 2 to 3 carbon atoms.
  • C 2 -C 10 alkenyl is understood to mean a straight-chain or branched unsaturated aliphatic hydrocarbon group having at least one double bond.
  • C2 - C10 alkenyl is preferably " C2 - C6 alkenyl", further preferably “ C2 - C4 alkenyl”, and further preferably C2 or C3 alkenyl. It is understood that when the alkenyl contains more than one double bond, the double bonds may be separated or conjugated with each other.
  • alkenyl examples include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond, and generally having 2 to 10, 2 to 8, 2 to 6, 2 to 4, 2 to 3 carbon atoms.
  • C 2 -C 10 alkynyl may be understood to mean a straight or branched unsaturated hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • C 2 -C 10 alkynyl may include "C 2 -C 6 alkynyl".
  • C 2 -C 10 alkynyl examples include, but are not limited to, ethynyl (-C ⁇ CH 3, -CH 2 C ⁇ CH 3), but-1-ynyl, but-2-ynyl or but-3-ynyl.
  • the "C 2 -C 10 alkynyl group” may include a “C 2 -C 3 alkynyl group", and examples of the “C 2 -C 3 alkynyl group” include ethynyl (-C ⁇ CH), prop-1-ynyl (-C ⁇ CCH 3 ), prop-2-ynyl (-CH 2 C ⁇ CH).
  • cycloalkyl refers to a fully saturated carbocyclic ring in the form of a monocyclic, cyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3-10 ring, a 3-8 ring, a 4-8 ring, a 5-8 ring, a 5-6 ring or a 3-6 ring.
  • C 3 -C 10 cycloalkyl is understood to mean a saturated monocyclic, cyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, etc.
  • C 3 -C 10 cycloalkyl may include "C 3 -C 6 cycloalkyl" or "C 3 -C 8 cycloalkyl".
  • C 3 -C 6 cycloalkyl may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • heterocyclyl refers to a fully saturated or partially saturated (not a heteroaromatic group having aromaticity as a whole) monocyclic, fused, spirocyclic or bridged ring group, which contains 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups (i.e., an atom group containing heteroatoms) in the ring atoms.
  • the heterocyclic ring is typically a 4- to 10-membered, 3- to 10-membered, 3- to 8-membered, 4- to 9-membered, 5- to 8-membered, 5- to 6-membered, 6- to 9-membered, 3- to 7-membered, or 4- to 6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, or nitrogen.
  • the term "3- to 10-membered heterocyclyl” refers to a heterocyclyl having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, and containing 1, 2, 3, 4, or 5 heteroatoms or heteroatoms independently selected from the above-described heteroatoms in its ring atoms.
  • 4- to 10-membered heterocyclyl refers to a heterocyclyl having 4, 5, 6, 7, 8, 9, or 10 ring atoms, and containing 1, 2, 3, 4, or 5 heteroatoms or heteroatoms independently selected from the above-described heteroatoms in its ring atoms.
  • the term "4- to 10-membered heterocyclyl” may contain 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • “4-10 membered heterocyclyl” includes “4-9 membered heterocyclyl”, “6-9 membered heterocyclyl” or “4-6 membered heterocyclyl”, each of which independently contains 1, 2 or 3 heteroatoms independently selected from N, O or S, or each of which independently contains 1, 2 or 3 N atoms.
  • “3-10 membered heterocyclic group” includes “4-7 membered heterocyclic group”, wherein specific examples of 4 membered heterocyclic group include but are not limited to azetidinyl, thietanyl or oxetanyl; specific examples of 5 membered heterocyclic group include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclic group include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, 4H-[1,3,4]thiadiazinyl, Specific examples of 7-member
  • the heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl, Heterocyclic Examples include but are not limited to Optionally, the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7-membered heterocyclic group, and specific examples include but are not limited to dihydroisoquinolinyl and the like.
  • “4-10-membered heterocyclic group” may include “5-10-membered heterocyclic group”, “4-7-membered heterocyclic group”, “5-6-membered heterocyclic group”, “6-8-membered heterocyclic group”, “4-10-membered heterocycloalkyl”, “5-10-membered heterocycloalkyl”, “4-7-membered heterocycloalkyl”, “5-6-membered heterocycloalkyl”, “6-8-membered heterocycloalkyl”, and the like, and “4-7-membered heterocyclic group” may further include "4-6-membered heterocyclic group”, "5-6-membered heterocyclic group”, “4-7-membered heterocycloalkyl”, “4-6-membered heterocycloalkyl”, “5-6-membered heterocycloalkyl”, “5-6-membered heterocycloalkyl”, and the like.
  • some bicyclic heterocyclic groups in the present disclosure partially contain a benz
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group with a conjugated ⁇ electron system.
  • the aryl group may have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms.
  • C 6 -C 20 aryl is understood to mean an aryl group having 6 to 20 carbon atoms.
  • a ring having 6 carbon atoms such as phenyl; or a ring having 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl; or a ring having 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring having 13 carbon atoms (“C 13 aryl”), such as fluorenyl; or a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6 -C 10 aryl is understood to mean an aryl group having 6 to 10 carbon atoms. In particular, it refers to a ring having 6 carbon atoms (“C 6 aryl”), such as phenyl; or a ring having 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl; or a ring having 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • C 6 -C 20 aryl may include "C 6 -C 10 aryl"
  • heteroaryl refers to a monocyclic or fused polycyclic ring system with aromaticity, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system with aromaticity, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C.
  • 5-10 membered heteroaryl is understood to include monocyclic or bicyclic aromatic ring systems: which have 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and which contain 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S.
  • the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or azinyl, in
  • halo or halogen refers to fluorine, chlorine, bromine or iodine.
  • treatment means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease.
  • the invention relates to preventing a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.
  • terapéuticaally effective amount means an amount of a compound of the present disclosure that (i) treats a particular disease, condition or disorder, (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition or disorder described herein.
  • the amount of a compound of the disclosure that constitutes a "therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on his or her knowledge and this disclosure.
  • mammals include mammals and non-mammals.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc.
  • non-human mammals include, but are not limited to, birds and fish, etc.
  • the mammal can be a human.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable acid addition or base addition salts, including salts formed between a compound and an inorganic acid or an organic acid, and salts formed between a compound and an inorganic base or an organic base.
  • composition refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient.
  • the purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • the present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl , etc., respectively.
  • Certain isotopically labeled compounds of the present disclosure can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability.
  • Positron emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present disclosure can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.
  • compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or sugar-coated core.
  • suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.
  • the dosage administered is from 0.01 mg/kg to 200 mg/kg body weight per day, in single or divided doses.
  • the experimental methods used in the following embodiments and test examples are conventional methods; the materials, reagents, etc. used are reagents and materials that can be obtained from commercial channels unless otherwise specified.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the unit of NMR shift is 10 -6 (ppm).
  • the solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 " refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
  • the eluent mentioned below can be a mixed eluent formed by two or more solvents, and the ratio is the volume ratio of each solvent.
  • the elution phase is a mixed solvent of petroleum ether containing 0 to 15% ethyl acetate
  • the volume ratio of ethyl acetate to petroleum ether in the mixed eluent is 0:100 to 15:85.
  • n-BuOH n-butanol
  • NIS N-iodosuccinimide
  • DCM dichloromethane
  • DMF N,N-dimethylformamide
  • THF tetrahydrofuran
  • Xphos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
  • Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium
  • Dioxane dioxane
  • Xphos-Pd G 2 chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II);
  • TFA trifluoroacetic acid
  • DIEA or DIPEA N,N-diisopropylethylamine
  • 2-amino-4,6-dichloropyridine (3.2 g, 20 mmol, 1 eq), chloroacetaldehyde (7.8 g, 40 mmol, 2 eq, 40% aqueous solution) and sodium bicarbonate were added. (5.04g, 60mmol, 3eq) was dissolved in n-butanol (50mL) and stirred at 80°C for 16 hours. The reaction solution was distilled under reduced pressure to remove the solvent, and water (100mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (100mL x 3 times).
  • the obtained residue was purified by silica gel column (eluting phase was a petroleum ether mixed solvent containing 0-15% ethyl acetate) to obtain the title compound 1C (3.2 g, 10.32 mmol, yield: 86%).
  • Step 5 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-3-carbonitrile (1F)
  • Step 6 4-(4-(3-cyano-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (1G)
  • Step 7 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(5-methyl-1-(4-piperidinyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-3-carbonitrile (1H)
  • Step 8 7-(1-acryloylpiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 1)
  • Step 1 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (2B)
  • 6-Bromo-3-chloro-4-methoxypyrazolo[1,5-a]pyridine (Compound 2A, 500 mg, 1.91 mmol, 1.0 eq.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (631 mg, 2.48 mmol, 1.3 eq.) were dissolved in 1,4-dioxane (10 mL) at room temperature.
  • Step 2 tert-Butyl 4-(4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (2C)
  • Step 3 tert-Butyl 4-(4-(3-chloro-4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (2D)
  • Step 4 tert-Butyl 4-(4-(3-chloro-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (2E)
  • Step 5 tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (2F)
  • Step 6 2-((3-chloro-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-1-ol (2G)
  • Step 7 1-(4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 2)
  • Example 3 1-[4-[4-[3-(2-cyclopropylethynyl)-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-1-piperidinyl]prop-2-en-1-one (Compound 3)
  • the filtrate was extracted with ethyl acetate (200 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by vacuum filtration to obtain a concentrate.
  • the concentrate and the filter residue were purified by silica gel column (the elution phase was a petroleum ether mixed solvent containing 30-50% tetrahydrofuran) to obtain the title compound 3B (20 g, 93.88 mmol, yield: 85%).
  • Step 2 6-bromo-4-(2-(tert-butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridine (3C)
  • Step 3 4-(2-(tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-6-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (3D)
  • Step 4 tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (3E)
  • Step 5 2-(5-fluoropyridin-2-yl)-2-((6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethane-1-ol (3F)
  • Step 6 1-(4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (3G)
  • Step 7 1-(4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-iodopyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (3H)
  • Step 8 1-[4-[4-[3-(2-cyclopropylethynyl)-4-[1-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-1-piperidinyl]prop-2-en-1-one (Compound 3)
  • Compound 3 was subjected to chiral separation (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia water); B%: 55%-55%; flow rate: 80 ml/min) to obtain two single-configuration compounds 3-1 and 3-2.
  • DAICEL CHIRALPAK AD 250mm*30mm, 10um
  • mobile phase A: carbon dioxide
  • B ethanol (0.1% ammonia water
  • B% 55%-55%
  • flow rate 80 ml/min
  • Step 2 5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-3-carbonitrile (4C)
  • Step 3 tert-butyl 4-(4-(5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-cyanoimidazolo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (4D)
  • Step 4 5-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-7-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-3-carbonitrile (4E)
  • Step 5 7-(1-(1-acryloylpiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-5-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 4)
  • Step 2 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (5B)
  • Step 3 tert-butyl 4-(4-(5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (5C)
  • Step 4 tert-butyl 4-(4-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-iodoimidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (5D)
  • Step 5 tert-Butyl 4-(4-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (5E)
  • Step 6 tert-Butyl 4-(4-(3-ethynyl-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (5F)
  • Step 7 3-ethynyl-5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine (5G)
  • Step 8 1-(4-(4-(3-ethynyl-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 5)
  • reaction solution was distilled under reduced pressure to remove the solvent, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 5%-70% acetonitrile-water) to obtain the title compound 5 (28 mg, 0.06 mmol, yield: 51%).
  • Example 6 1-(4-(4-(3-(3,3-dimethylbut-1-yn-1-yl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 6)
  • Step 1 1-(4-(4-(3-(3,3-dimethylbut-1-yn-1-yl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 6)
  • Step 2 (R)-1-(4-(4-(3-(3,3-dimethylbut-1-yn-1-yl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one and (S)-1-(4-(4-(3-(3,3-dimethylbut-1-yn-1-yl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 6-1 and Compound 6-2)
  • Compound 6 was separated by chiral separation (column: DAICEL CHIRALCEL OD (250mm*30mm, 10um); mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia water); B%: 40%-40%; flow rate: 80 ml/min) to obtain two single-configuration compounds 6-1 and 6-2.
  • Example 11 1-(4-(4-(3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)-2-methylprop-2-en-1-one (Compound 11)
  • Step 1 tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-iodopyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (11A)
  • Step 2 tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-(cyclopropylethynyl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (11C)
  • Step 3 tert-butyl 4-(4-(3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (11D)
  • Step 4 2-((3-(cyclopropylethynyl)-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethane-1-ol (11E)
  • Step 5 1-(4-(4-(3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)-2-methylprop-2-en-1-one (11)
  • Example 15 (E)-1-(4-(4-(3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one (Compound 15)
  • Example 16 2-(5-fluoropyridin-2-yl)-2-((6-(5-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethane-1-ol (Compound 16)
  • Step 1 tert-Butyl 4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (16B)
  • Step 2 2-(5-fluoropyridin-2-yl)-2-((6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethane-1-ol (16C)
  • Step 3 2-(5-fluoropyridin-2-yl)-2-((6-(5-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethane-1-ol (Compound 16)
  • Example 17 2-((6-(1-(1-ethylpiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethane-1-ol (Compound 17)
  • Example 18 2-(5-fluoropyridin-2-yl)-2-((6-(1-(1-isopropylpiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethane-1-ol (Compound 18)
  • Step 1 tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (19B)
  • Compound 11A (778 mg, 1.0 mmol, 1.0 eq), trimethylethynylsilane (300 mg, 3.0 mmol, 3 eq), bistriphenylphosphine palladium dichloride (70 mg, 0.1 mmol, 0.1 eq), cuprous iodide (19 mg, 0.1 mmol, 0.1 eq), triethylamine (505 mg, 5 mmol, 5 eq) were mixed in tetrahydrofuran (10 mL). The mixture was heated to 60 ° C and stirred for 4 hours under a nitrogen atmosphere.
  • Step 2 tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-ethynylpyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (19C)
  • Step 3 tert-butyl 4-(4-(3-ethynyl-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (19D)
  • Step 4 2-((3-ethynyl-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethane-1-ol (19E)
  • Step 5 2-((3-ethynyl-6-(1-(1-isopropylpiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethane-1-ol (Compound 19)
  • Example 20 1-(4-(4-(3-(cyclopropylethynyl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 20)
  • Step 1 tert-Butyl 4-(4-(3-(cyclopropylethynyl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (Compound 20A)
  • Step 2 3-(cyclopropylethynyl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine (20B)
  • Step 3 1-(4-(4-(3-(cyclopropylethynyl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 20)
  • Example 21 Ethyl 4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (Compound 21)
  • Step 1 5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-7-chloroimidazo[1,2-a]pyridine (22A)
  • Step 2 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (22B)
  • Step 3 4-(4-(5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (22C)
  • reaction solution was spin-dried and the obtained residue was purified by reverse phase column (Phenomenex Luna C18 150*25mm*10um, elution phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 22C (490 mg, 0.75 mmol, yield: 53%).
  • Step 4 4-(4-(5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-iodoimidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (22D)
  • Step 5 4-(4-(5-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (22E)
  • Step 6 2-(5-fluoropyridin-2-yl)-2-((7-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-5-yl)oxy)ethane-1-ol (22F)
  • Step 7 2-(5-fluoropyridin-2-yl)-2-((7-(1-(1-isopropylpiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-5-yl)oxy)ethane-1-ol (22)
  • Example 24 4-(4-(5-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid methyl ester (Compound 24)
  • the product was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, elution phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 25 (10 mg, 0.18 mmol, yield: 15%).
  • Step 1 5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-7-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine (26A)
  • reaction solution was spin-dried and the obtained residue was purified by reverse phase column (Phenomenex Luna C18 150*25mm*10um, elution phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 26A (100 mg, 0.18 mmol, yield: 77%).
  • Step 2 5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-iodo-7-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine (26B)
  • Step 3 2-(5-fluoropyridin-2-yl)-2-((7-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-5-yl)oxy)ethane-1-ol (26)
  • the mixture was stirred at room temperature under nitrogen atmosphere for 3 hours.
  • the mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 26 (10 mg, 0.02 mmol, 28%).
  • the first step is phenylazide (26F)
  • the crude product was purified by silica gel column (the elution phase was a mixed solvent of petroleum ether containing 5-50% ethyl acetate) to obtain the title compound 26G (2.65 g, 11 mmol, yield: 65%).
  • Example 27 2-(5-fluoropyridin-2-yl)-2-((6-(5-methyl-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethane-1-ol (Compound 27)
  • Embodiment 28 is a diagrammatic representation of Embodiment 28:
  • compound 28 was synthesized by replacing raw material 11F with raw material C in the table below.
  • Embodiment 29 is a diagrammatic representation of Embodiment 29.
  • Embodiment 30 is a diagrammatic representation of Embodiment 30.
  • Example 22 The synthetic route and steps of intermediate 22F in Example 22 were adopted, and cyclopropylacetylene was used to replace trimethyl(1-propynyl)silane to synthesize the required intermediate 30A.
  • a synthetic route and steps similar to Example 27 were adopted, and raw material 30A in the table below was used to replace raw material 16C to synthesize compound 30.
  • Embodiment 31 is a diagrammatic representation of Embodiment 31.
  • Embodiment 32 is a diagrammatic representation of Embodiment 32.
  • Compound 33 was subjected to chiral separation (column: DAICEL CHIRALCEL AD (250 mm*30 mm, 10 um); mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia water); B%: 60%-60%; flow rate: 80 ml/min) to obtain two single-configuration compounds 33-1 and 33-2.
  • DAICEL CHIRALCEL AD 250 mm*30 mm, 10 um
  • mobile phase A: carbon dioxide
  • B ethanol (0.1% ammonia water
  • B% 60%-60%
  • flow rate 80 ml/min
  • Step 1 5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-7-(5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine (34A)
  • reaction solution was spin-dried and the obtained residue was purified by reverse phase column (Phenomenex Luna C18 150*25mm*10um, elution phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 34A (120 mg, 0.18 mmol, yield: 90%).
  • Step 2 5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-iodo-7-(5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine (34B)
  • Step 3 2-(5-fluoropyridin-2-yl)-2-((7-(5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-5-yl)oxy)ethane-1-ol (34)
  • the mixture was stirred at room temperature under nitrogen atmosphere for 3 hours.
  • the mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 34 (12 mg, 0.025 mmol, 36%).
  • Step 2 5-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazole-4-carboxylic acid ethyl ester (34C)
  • the first step 3-(4-(5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (35D)
  • reaction solution was spin-dried and the obtained residue was purified by reverse phase column (Phenomenex Luna C18 150*25mm*10um, elution phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 35D (137 mg, 0.25 mmol, yield: 81%).
  • Step 2 3-(4-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-iodoimidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (35E)
  • Step 3 3-(4-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (35F)
  • the mixture was stirred at room temperature under nitrogen atmosphere for 3 hours.
  • the mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 35F (39 mg, 0.067 mmol, 48%).
  • Step 4 7-(1-(8-azabicyclo[3.2.1]octan-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (35G)
  • Step 5 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(5-methyl-1-(8-(oxabutane-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (35)
  • the mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 10-95% acetonitrile) to obtain the title compound 35 (19 mg, 0.036 mmol, yield: 55%).
  • the mixture was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, the elution phase was a water mixed solvent containing 10-80% acetonitrile) to give the title compound 35B (1.33 g, 3.5 mmol, yield: 35%).
  • Step 2 3-(4-Bromo-5-methyl-1H-1,2,3-triazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (35C)
  • the mixture was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, the elution phase was a water mixed solvent containing 20-90% acetonitrile) to give the title compound 35C (233.7 mg, 0.63 mmol, yield: 18%).
  • Example 36 3-(Cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-6-(5-methyl-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine (Compound 36)
  • Step 1 tert-Butyl 4-(4-(3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (36A)
  • Step 2 3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine (36B)
  • Step 3 3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-6-(5-methyl-1-(1-(oxabutane-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine (36)
  • Example 37 4-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-6-(5-methyl-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridine (Compound 37)
  • Step 1 tert-Butyl 4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (37A)
  • the mixture was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, the elution phase was a water mixed solvent containing 5-85% acetonitrile) to give the title compound 37A (47.2 mg, 0.08 mmol, yield: 80%).
  • Step 2 4-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridine (37B)
  • Step 3 4-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-6-(5-methyl-1-(1-(oxabutane-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridine (37)
  • Step 1 tert-butyl 4-(4-(5-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (38A)
  • Step 2 5-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-7-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (38B)
  • Step 3 5-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-7-(5-methyl-1-(1-(oxabutane-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (38)
  • Step 1 7-Chloro-5-(2-(5-fluoropyridin-2-yl)-2-methoxyethoxy)imidazo[1,2-a]pyridine (39A)
  • Step 2 5-(2-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (39B)
  • Step 3 4-(4-(5-(2-(5-fluoropyridin-2-yl)-2-methoxyethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (39C)
  • reaction solution was spin-dried and the obtained residue was purified by reverse phase column (Phenomenex Luna C18 150*25mm*10um, elution phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 39C (674.6 mg, 1.22 mmol, yield: 61%).
  • Step 4 4-(4-(5-(2-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-3-iodoimidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (39D)
  • Step 5 4-(4-(5-(2-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (39E)
  • Step 6 5-(2-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-7-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (39F)
  • Step 7 5-(2-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-7-(5-methyl-1-(1-(oxabutane-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (39)
  • Step 1 2-(2-((tert-Butyldimethylsilyl)oxy)-1-methoxyethyl)-5-fluoropyridine (39-Int)
  • the mixture was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, the elution phase was a water mixed solvent containing 10-95% acetonitrile) to give the title compound 39-Int (7.2 g, 25.2 mmol, yield: 84%).
  • Test Example 1 FGFR enzyme inhibition experiment of the disclosed compounds
  • test samples were dissolved in DMSO to prepare a 10 mM storage solution and stored at -30°C.
  • the enzyme reaction was performed using the enzyme reaction kit produced by Promega (FGFR1Kit Catalog No. V2991, FGFR2Kit Catalog No. V4060, FGFR3Kit Catalog No. VA7459, the reaction substrate was Poly E4Y1) according to the method recommended by the manufacturer.
  • the reaction product was detected using the ADP detection kit produced by Promega (ADP-Glo TM Kinase Assay, Catalog No. V9101).
  • the 5 ⁇ L reaction system contains 0.4ng/ ⁇ L FGFR1 kinase (or 1.4ng/ ⁇ L FGFR2 kinase, or 1ng/ ⁇ L FGFR3 kinase), 0.2 ⁇ g/ ⁇ L Poly E4Y1, 5 ⁇ M ATP (Poly E4Y1 and ATP are both from the enzyme reaction kit) and gradient dilutions (starting concentration 10000nM, 3 ⁇ gradient dilution, 10 concentrations) of the test compound.
  • the final concentration of DMSO in the reaction system is 1%.
  • the reaction is carried out in a 384-well plate (Perkinelmer, Cat. 6007290), and all tests are performed in duplicate. In the above system, ATP is added at the end to start the reaction.
  • Luminescence value represents the amount of ADP generated.
  • the inhibition rate of kinase activity was calculated by high signal (Luminescence value with enzyme added but no test compound), low signal (Luminescence value without enzyme added), and sample signal (Luminescence value with enzyme added and test compound added).
  • the half-maximal inhibitory concentration (IC 50 ) was calculated by XLfit2.0 software (ID Business Solutions Ltd).
  • Inhibition rate (%) ((high Lum-sample Lum)/(high Lum-low Lum)) ⁇ 100%.
  • test results Under the experimental conditions, the compounds of the present disclosure were tested to have good inhibitory activity against FGFR3. Compared with FGFR1 and/or FGFR2, the compounds of the present disclosure have higher selectivity for FGFR3.
  • Test Example 2 Experiment on the inhibition of cell proliferation by the disclosed compounds
  • test samples were dissolved in DMSO to prepare a 10 mM stock solution and stored at -30°C.
  • the compound was diluted in serum-free medium containing 5% DMSO to a concentration 10 times the assay concentration.
  • the cells used in the experiment were purchased from ATCC (American Type Culture Collection, USA, catalog number CRL-5974), JMSU-1 cells were purchased from DSMZ, and RT112 cells were purchased from DSMZ.
  • the culture medium IMDM was purchased from Gibco (Cat. No. 12440-061), the culture medium 1640 was purchased from Gibco (Cat. No. 12634-010), and the serum was purchased from Gibco (Cat. No. 10099-141C).
  • Cell-counting kit-8 (CK04) was purchased from Tongren Chemical Co., Ltd.
  • Luminescent Cell Viability Assay was purchased from Promega (Cat. No. G7570).
  • Cells in the logarithmic growth phase were inoculated in a 96-well cell culture plate with a volume of 100 ⁇ L. Cultured overnight at 37°C in an incubator containing 5% carbon dioxide. The next day, 10 ⁇ L/well gradient dilutions (starting concentration: 5000nM, 3 ⁇ gradient dilutions, 10 concentration points) of the test compound were added, and 10 ⁇ L/well serum-free medium containing 5% DMSO was added to the control group instead of the test compound dilution solution, and the final concentration of DMSO was 0.5%. Incubate in an incubator for 72 hours. Add 10 ⁇ L/well Cell-counting kit-8 reagent (or 50 ⁇ L/well CTG).
  • Inhibition rate (%) [1-([OD 450 ] compound- [OD 450 ] background )/([OD 450 ] cell- [OD 450 ] background )] ⁇ 100%
  • [OD 450 ] compound represents the light absorbance value of the compound-treated wells
  • [OD 450 ] cells represent the light absorption value of the wells with DMSO instead of the compound on day 3;
  • the cell proliferation experiment of the disclosed compounds was determined by the above test, and the measured GI 50 values are shown in Table 2.
  • mice were used as test animals, and the drug concentration in plasma at different times after injection of the test compound was determined by LC/MS/MS. The pharmacokinetic behavior of the compound in mice was studied and its pharmacokinetic characteristics were evaluated.
  • mice BALB/c mice, NMP (N-methylpyrrolidone), and solutol HS15 (polyethylene glycol-15 hydroxystearate) are all commercially available.
  • mice Three healthy female BALB/c mice were taken and administered via the tail vein at a dose of 5 mg/kg.
  • the tail vein administration group used a complete solvent solution of 5% (v/v) NMP + 95% (v/v) solutol HS15 (10%, v/v) in water, and the individual dosage was calculated according to the weight of the mouse.
  • the tail vein administration group underwent orbital blood sampling before and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24h after administration. About 30u L of whole blood was collected at each time point and placed in a 1.5mL centrifuge tube anticoagulated with EDTA-2K, followed by centrifugation at 8000r/min for 5min, and the plasma was removed and stored at -80°C.
  • mice plasma sample Take 10uL of mouse plasma sample, add 150uL acetonitrile solvent (containing internal standard compound verapamil) to precipitate protein, vortex for 5min and centrifuge (14000rpm) for 5min, take the supernatant and dilute it 2 times with water containing 0.1% (v/v) formic acid, and perform quantitative detection on LC-MS/MS system (AB Sciex Triple Quad 6500+).
  • acetonitrile solvent containing internal standard compound verapamil

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Abstract

L'invention concerne une classe de composés hétérocycliques agissant en tant qu'inhibiteurs de FGFR, et spécifiquement un composé représenté par la formule (I) ou un stéréoisomère de celui-ci ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique le comprenant, et une application de celui-ci dans la préparation d'un médicament pour le traitement du cancer.
PCT/CN2023/135003 2022-11-30 2023-11-29 Composé hétérocyclique, composition pharmaceutique et application associée Ceased WO2024114680A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12351581B2 (en) 2023-08-07 2025-07-08 Cogent Biosciences, Inc. Compounds for FGFR inhibition
CN120647648A (zh) * 2024-09-24 2025-09-16 上海辉棵生物医药有限公司 新fgfr3抑制剂化合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107438607A (zh) * 2015-02-20 2017-12-05 因赛特公司 作为fgfr抑制剂的双环杂环
WO2022187443A1 (fr) * 2021-03-04 2022-09-09 Eli Lilly And Company Composés inhibiteurs de fgfr3
WO2023212535A1 (fr) * 2022-04-25 2023-11-02 Eli Lilly And Company Composés inhibiteurs de fgfr2

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107438607A (zh) * 2015-02-20 2017-12-05 因赛特公司 作为fgfr抑制剂的双环杂环
WO2022187443A1 (fr) * 2021-03-04 2022-09-09 Eli Lilly And Company Composés inhibiteurs de fgfr3
WO2023212535A1 (fr) * 2022-04-25 2023-11-02 Eli Lilly And Company Composés inhibiteurs de fgfr2

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12351581B2 (en) 2023-08-07 2025-07-08 Cogent Biosciences, Inc. Compounds for FGFR inhibition
CN120647648A (zh) * 2024-09-24 2025-09-16 上海辉棵生物医药有限公司 新fgfr3抑制剂化合物

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