WO2019029541A1 - Inhibiteur de récepteur du facteur de croissance des fibroblastes et son utilisation - Google Patents

Inhibiteur de récepteur du facteur de croissance des fibroblastes et son utilisation Download PDF

Info

Publication number
WO2019029541A1
WO2019029541A1 PCT/CN2018/099242 CN2018099242W WO2019029541A1 WO 2019029541 A1 WO2019029541 A1 WO 2019029541A1 CN 2018099242 W CN2018099242 W CN 2018099242W WO 2019029541 A1 WO2019029541 A1 WO 2019029541A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
group
membered
hydrogen
amino
Prior art date
Application number
PCT/CN2018/099242
Other languages
English (en)
Chinese (zh)
Inventor
吴永谦
Original Assignee
南京药捷安康生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京药捷安康生物科技有限公司 filed Critical 南京药捷安康生物科技有限公司
Publication of WO2019029541A1 publication Critical patent/WO2019029541A1/fr

Links

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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of medicine and relates to an irreversible inhibitor of fibroblast growth factor receptor (FGFR), or a pharmaceutically acceptable salt thereof, a stereoisomer thereof and use thereof.
  • FGFR fibroblast growth factor receptor
  • Tyrosine kinase receptors play an important role in tumor angiogenesis, tumor cell proliferation, migration and infiltration. More than 100 tyrosine kinase inhibitor drugs have been marketed or entered clinical trials. These small molecule tyrosine kinase inhibitors (TKI) play a role in reversible inhibition, which brings some disadvantages: 1 the selectivity is not good enough, 2 the efficacy is not strong enough and lasting, 3 It is easy to cause drug resistance. Therefore, scientists are encouraged to focus their research on the development of irreversible TKI.
  • TKI small tyrosine kinase inhibitors
  • the irreversible TKI is usually modeled by the backbone structure of the reversible TKI, and an electrophilic functional group is attached at a suitable position, and the electrophilic functional group can be associated with a cysteine residue near the ATP binding domain of the tyrosine kinase. (Electron-rich nucleophilic structure) undergoes an electrophilic reaction to form a covalent bond, thereby irreversibly inhibiting kinase activity.
  • irreversible TKI has many unique advantages: 1 irreversible TKI works in a permanent inactivation manner, this way of inhibiting enzyme activity makes its effect stronger and longer, even drug molecules It is completely removed from the circulatory system and its efficacy is maintained.
  • Fibroblast growth factor receptor is an important member of the tyrosine kinase receptor family.
  • FGFR contains four members, namely FGFR-1, FGFR-2, FGFR-3 and FGFR. -4. They are mostly single-chain glycoprotein molecules with molecular masses ranging from 110 to 150 kd, and the structure is divided into extracellular regions, transmembrane regions and intracellular regions.
  • FGFR binds to its ligand fibroblast growth factor (FGF), which dimerizes FGFR and phosphorylates itself, activating downstream signaling pathways such as JAK/STAT pathway, phospholipase The C pathway, phosphatidylinositol-3-kinase PI3K and MAPK signaling pathways play an important role in tumor growth and angiogenesis.
  • FGF ligand fibroblast growth factor
  • Abnormalities of FGFR are closely related to the occurrence of various tumors, such as bladder cancer (including urinary tract epithelial cancer, etc.), breast cancer, cholangiocarcinoma, gastric cancer, ovarian cancer, salivary gland cancer, colorectal cancer, non-small cell lung cancer, small Hepatocellular carcinoma, liver cancer, endometrial cancer, cervical cancer, pancreatic cancer, rhabdomyosarcoma, multiple myeloma, prostate cancer, esophageal cancer, glioma, myelodysplastic syndrome, dwarf syndrome, renal pelvic tumor, chondrosarcoma, Melanoma and the like.
  • bladder cancer including urinary tract epithelial cancer, etc.
  • breast cancer including urinary tract epithelial cancer, etc.
  • cholangiocarcinoma gastric cancer
  • ovarian cancer salivary gland cancer
  • colorectal cancer non-small cell lung cancer
  • non-small cell lung cancer small Hepatocellular carcinoma
  • liver cancer
  • the invention also provides the use of the above FGFR inhibitors.
  • FGFR fibroblast growth factor receptor
  • Warhead 1 and warhead 2 refer to the part capable of forming a covalent bond with a nucleophile, and warhead 1 and warhead 2 are not present at the same time;
  • X is selected from C or N, when X is C, Represents a double bond, when X is N, Represents a single button;
  • R 1 is selected from C 1-6 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, halo C 1-6 alkylene or —(L 1 )n -Cy 1 -(L 2 )t-(Cy 2 )p-; when warhead 1 is absent, R 1 is selected from hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl , halogenated C 1-6 alkyl or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p;
  • R 2 is selected from C 1-6 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, halo C 1-6 alkylene or —(L 3 )q -Cy 3 -; when warhead 2 is absent, R 2 is selected from hydrogen, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo C 1-6 alkyl or -( L 3 )q-Cy 3 ;
  • Cy 1 and Cy 2 are each independently selected from the group consisting of one or more R a substituted or unsubstituted 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3- a 12-membered heterocyclic group, an aryl group or a 5-10 membered heteroaryl group, the ring-forming carbon atom may be optionally oxidized to C(O), and the ring-forming sulfur atom may be optionally oxidized to S(O), S(O). 2 or S(O)(N);
  • Cy 3 is selected from the group consisting of one or more R b substituted or unsubstituted 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group. , aryl or 5-10 membered heteroaryl, the ring-forming carbon atom may be optionally oxidized to C(O), and the ring-forming sulfur atom may be optionally oxidized to S(O), S(O) 2 or S ( O)(N);
  • R a and R b are each independently selected from:
  • R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkylamino C 1-6 alkyl, (C 1-6 alkyl) 2 amino C 1-6 alkyl, halogenated C 1-6 An alkyl group, a halogenated C 2-8 alkenyl group, a C 2-8 alkynyl group, or a 3-12 membered cycloalkyl group optionally substituted by a substituent Q 1 , a 3-12 membered cycloalkenyl group, a 3-12 membered hetero cycloalkyl group, an aryl group or a 5-10 membered heteroaryl, the substituents Q 1 is selected from: hydroxy, amino, cyano, nitro, halogen, carboxyl, amide group, aminocarbonyl, aminosulfonyl, C 1- 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halogenated C
  • R 4 is selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, halogen, carboxyl, amide, aminocarbonyl, aminosulfonyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkane Amino group, (C 1-6 alkyl) 2 amino group, halogenated C 1-6 alkyl group, halogenated C 1-6 alkoxy group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 1- 6 alkylsulfonyl, C 1-6 alkylcarbonylamino, (C 1-6 alkyl) 2 carbonylamino, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1 -6 alkylaminosulfonyl, (C 1-6 alkyl) 2 aminosulfonyl, C 1-6 alkoxy C 1-6 alkoxy, or 3-12 optionally substituted by substituent Q 2 a
  • L 1 , L 2 , and L 3 are each independently a bond, -N(Rc)-, -O-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NH-, -C(O)-, -NHC(O)-, -OC(O)-, C 1-6 alkylene, C 2-8 alkenylene or C 2-8 alkynylene, Rc selected From hydrogen or C 1-6 alkyl;
  • n, t, p, q are each independently 0 or 1;
  • n is an integer from 0 to 5, and when m ⁇ 2, R 4 may be selected from the same or different groups.
  • Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the general formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
  • Warhead 1 and warhead 2 are independently selected from Warhead 1 and warhead 2 do not exist at the same time;
  • R 10 , R 11 , R 12 , R 13 , R 14 , R 15 are each independently selected from hydrogen, halogen, C 1-6 alkyl or halo C 1-6 alkyl;
  • Cy 4 is a divalent group selected from the group consisting of a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-12 membered heterocyclic group, an aryl group or a 5-10 membered heteroaryl group;
  • z is an integer from 0-4;
  • X is selected from C or N, when X is C, Represents a double bond, when X is N, Represents a single button;
  • R 1 is selected from C 1-6 alkylene, halo C 1-6 alkylene or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p-
  • R 1 is selected from hydrogen, C 1-6 alkyl, halogenated C 1-4 alkyl or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 ) p;
  • R 2 is selected from C 1-6 alkylene, halo C 1-6 alkylene or -(L 3 )q-Cy 3 -; when warhead 2 is absent, R 2 is selected from Hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl or -(L 3 )q-Cy 3 ;
  • Cy1 and Cy2 are each independently selected from the group consisting of one or more Ra-substituted or unsubstituted 3-8 membered monoheterocyclic groups, 6-11-membered bridged heterocyclic groups, 7- a 12-membered spiroheterocyclyl group or a 6-11 membered heterocyclic group, an aryl group or a 5-10 membered heteroaryl group, the ring-forming carbon atom may be optionally oxidized to C(O), and the ring-forming sulfur atom may be optionally selected. Oxidized to S(O) or S(O)2;
  • Cy 3 is selected from the group consisting of one or more R b -substituted or unsubstituted 3-8 membered monoheterocyclic groups, 6-11 membered bridged heterocyclic groups, 7-12 membered snails a heterocyclic group or a 6-11 membered heterocyclic group, an aryl group or a 5-10 membered heteroaryl group, the ring-forming carbon atom may be optionally oxidized to C(O), and the ring-forming sulfur atom may be optionally oxidized to S(O) or S(O) 2 ;
  • R a and R b are each independently selected from:
  • amino-carbonyl cyano-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylamino-carbonyl, (C 1-6 alkyl) 2 amino-carbonyl, C 1-6 alkoxy a carbonyl group, a 3-8 membered cycloalkyl-carbonyl group or a 3-8 membered heterocyclyl-carbonyl group;
  • R 3 is selected from hydrogen or C 1-6 alkyl
  • R 4 is selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, halogen, carboxyl, amide, aminocarbonyl, aminosulfonyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkane Amino, (C 1-6 alkyl) 2 amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1- 6 alkylsulfonyl, C 1-6 alkylcarbonylamino, (C 1-6 alkyl) 2 carbonylamino, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1 -6 alkylaminosulfonyl, (C 1-6 alkyl) 2 aminosulfonyl or C 1-6 alkoxy C 1-64 alkoxy;
  • L 1 , L 2 , and L 3 are each independently a bond, -N(R c )-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O). -, -NHC(O)-, -OC(O)- or C 1-6 alkylene, R c is selected from hydrogen or C 1-6 alkylene;
  • n, t, p, q are each independently 0 or 1;
  • n is an integer from 0 to 5, and when m ⁇ 2, R 4 may be selected from the same or different groups;
  • R 1 is -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p-, t and p are 0, and Cy 1 is substituted by one to more R a , or unsubstituted
  • R 2 is -(L 3 )q-Cy 3
  • Cy 3 is substituted with one to more R b or unsubstituted 7- 12-membered spiro heterocyclic group.
  • Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the general formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
  • Warhead 1 and warhead 2 are independently selected from Warhead 1 and warhead 2 do not exist at the same time;
  • R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl
  • X is selected from C or N, when X is C, Represents a double bond, when X is N, Represents a single button;
  • R 1 is selected from C 1-4 alkylene or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p-; when warhead 1 is absent, R 1 Selected from hydrogen, C 1-4 alkyl or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p;
  • R 2 is selected from C 1-4 alkylene, halo C 1-4 alkylene or -(L 3 )q-Cy 3 -; when warhead 2 is absent, R 2 is selected from Hydrogen, C 1-4 alkyl or -(L 3 )q-Cy 3 ;
  • Cy 1 are independently selected from the following group or a divalent group: substituted by one to the plurality of R a, or unsubstituted 3-8 membered monocyclic heterocyclyl, 7-12 membered heterocyclyl spiro Or aryl;
  • Cy 3 is selected from the group consisting of one or more R b substituted or unsubstituted 3-8 membered monoheterocyclyl or 7-12 membered spiroheterocyclyl;
  • R a and R b are each independently hydrogen, C 1-4 alkyl or hydroxy C 1-4 alkyl;
  • R 3 is selected from hydrogen or C 1-4 alkyl
  • R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;
  • L 1 , L 2 , and L 3 are each independently a bond or a C 1-4 alkylene group
  • n is an integer from 0 to 5, and when m ⁇ 2, R 4 may be selected from the same or different groups;
  • R 1 is -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p-, t and p are 0, and Cy 1 is substituted by one to more R a , or unsubstituted
  • R 2 is -(L 3 )q-Cy 3
  • Cy 3 is substituted with one to more R b or unsubstituted 7- 12-membered spiro heterocyclic group.
  • Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the general formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
  • Warhead 1 and warhead 2 are independently selected from Warhead 1 and warhead 2 do not exist at the same time;
  • R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl
  • X is selected from C or N, when X is C, Represents a double bond, when X is N, Represents a single button;
  • R 1 is selected from C 1-4 alkylene or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p-; when warhead 1 is absent, R 1 Selected from hydrogen, C 1-4 alkyl or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p;
  • R 2 is selected from C 1-4 alkylene or -(L 3 )q-Cy 3 -; when warhead 2 is absent, R 2 is selected from hydrogen, C 1-4 alkyl or - (L 3 )q-Cy 3 ;
  • Cy 1 and Cy 2 are each independently selected from the group consisting of one or more R a substituted or unsubstituted 3-8 membered monoheterocyclic group, 6-11 membered bridged heterocyclic group. a 7-12 membered spiroheterocyclyl group or a 6-11 membered heterocyclic group;
  • Cy 3 is selected from the group consisting of one or more R b -substituted or unsubstituted 3-8 membered monoheterocyclic groups, 6-11 membered bridged heterocyclic groups, 7-12 membered snails Heterocyclic group, 6-11 membered heterocyclic group;
  • R a and R b are each independently selected from:
  • L 1 , L 2 , and L 3 are each independently a bond or a C 1-4 alkylene group
  • n, t, p, q are each independently 0 or 1;
  • R 3 is selected from hydrogen or C 1-4 alkyl
  • R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;
  • n is an integer from 0 to 5, and when m ⁇ 2, R 4 may be selected from the same or different groups;
  • R 1 is -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p-, t and p are 0, and Cy 1 is substituted by one to more Ra, or unsubstituted
  • R 2 is -(L 3 )q-Cy 3
  • Cy 3 is substituted with one to more R b or unsubstituted 7-12 membered spiro Ring base.
  • Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the general formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
  • Warhead 1 and warhead 2 are independently selected from Warhead 1 and warhead 2 do not exist at the same time;
  • R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl
  • X is selected from C or N, when X is C, Represents a double bond, when X is N, Represents a single button;
  • R 1 is selected from C 1-4 alkylene or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p-; when warhead 1 is absent, R 1 Selected from hydrogen, C 1-4 alkyl or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p;
  • R 2 is selected from C 1-4 alkylene or -(L 3 )q-Cy 3 -; when warhead 2 is absent, R 2 is selected from hydrogen, C 1-4 alkyl or - (L 3 )q-Cy 3 ;
  • Cy 1 are independently selected from the following groups or a divalent radical: by one to the plurality of R a substituted or unsubstituted 3-8 membered monocyclic or 7-12 membered heterocyclyl spiro-heterocyclyl ;
  • Cy 3 is selected from the group consisting of one or more R b substituted or unsubstituted 3-8 membered monoheterocyclyl or 7-12 membered spiroheterocyclyl;
  • R a is hydrogen or C 1-4 alkylene
  • R b is hydrogen, C 1-4 alkylene or hydroxy C 1-4 alkyl
  • L 1 , L 2 , and L 3 are each independently a bond or a C 1-4 alkylene group
  • n, t, p, q are each independently 0 or 1;
  • R 3 is selected from hydrogen or C 1-4 alkyl
  • R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;
  • n is an integer from 0 to 5, and when m ⁇ 2, R 4 may be selected from the same or different groups;
  • R 1 is -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p-, t and p are 0, and Cy 1 is substituted by one to more Ra, or unsubstituted
  • R 2 is -(L 3 )q-Cy 3
  • Cy 3 is substituted with one to more R b or unsubstituted 7-12 membered spiro Ring base.
  • Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the general formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
  • Warhead 1 and warhead 2 are independently selected from Warhead 1 and warhead 2 do not exist at the same time;
  • R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl
  • X is selected from C or N, when X is C, Represents a double bond, when X is N, Represents a single button;
  • R 1 is selected from C 1-4 alkylene or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p-; when warhead 1 is absent, R 1 Selected from hydrogen, C 1-4 alkyl or -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p;
  • R 2 is selected from C 1-4 alkylene or -(L 3 )q-Cy 3 -; when warhead 2 is absent, R 2 is selected from hydrogen, C 1-4 alkyl or - (L 3 )q-Cy 3 ;
  • Cy 1 and Cy 2 are each independently selected from a monovalent or divalent group of the following structure: substituted with one to more R a or unsubstituted
  • Cy 3 is selected from the group consisting of a monovalent or divalent group such as a structure: one or more R b substituted or unsubstituted
  • R a and R b are each independently selected from hydrogen, C 1-4 alkyl or hydroxy C 1-4 alkyl;
  • L 1 , L 2 , and L 3 are each independently a bond or a C 1-4 alkylene group
  • n, t, p, q are each independently 0 or 1;
  • R 3 is selected from hydrogen or C 1-4 alkyl
  • R 4 is selected from the group consisting of hydrogen, a halogen atom, a C 1-4 alkyl group or a C 1-4 alkoxy group;
  • n is an integer from 0 to 5, and when m ⁇ 2, R 4 may be selected from the same or different groups;
  • R 1 is -(L 1 )n-Cy 1 -(L 2 )t-(Cy 2 )p-, t and p are 0, and Cy 1 is substituted by one to more R a , or unsubstituted of In the case of a divalent group, R 2 is -(L 3 )q-Cy 3 and Cy 3 is substituted by one to more R b or unsubstituted One price base.
  • Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the general formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
  • Warhead 1 is Warhead 2 does not exist;
  • R 12 and R 13 are each independently selected from hydrogen or C 1-4 alkyl
  • X is selected from C or N, when X is C, Represents a double bond, when X is N, Represents a single button;
  • R 1 is -(L 1 ) n -Cy 1 -;
  • Cy 1 is a 7-12 membered spiroheterocyclyl group substituted by one to a plurality of R a , preferably 7-12 members containing an N-spiroheterocyclic group, and any of warhead 1 and Cy 1 is looped. N heteroatoms are connected;
  • L 1 is a bond or a C 1-4 alkylene group
  • R a is selected from hydrogen or C 1-4 alkyl
  • R 2 is selected from hydrogen or C 1-4 alkyl
  • R 3 is selected from hydrogen or C 1-4 alkyl
  • R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;
  • n 0 or 1
  • n is an integer from 0 to 5, and when m ⁇ 2, R 4 may be selected from the same or different groups.
  • Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the general formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
  • Cy 1 is a divalent group of the following structure: substituted by one to more R a or unsubstituted Warhead 1 is attached to any ring-forming N heteroatom in Cy 1 .
  • Another embodiment of the present invention relates to the aforementioned fibroblast growth factor receptor irreversible inhibitor or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, the fibroblast growth factor receptor irreversible inhibitor such as a general formula (IA):
  • Warhead 1 is selected from
  • R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl
  • X is selected from C or N, when X is C, Represents a double bond, when X is N, Represents a single button;
  • R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, halo C 1-4 alkyl or -(L 3 )q-Cy 3 ;
  • Cy1 and Cy2 are each independently selected from a divalent group of a group: one to a plurality of Ra-substituted or unsubstituted 3-8 membered monoheterocyclic groups, 6-11-membered bridged heterocyclic groups, 7-12 a snail heterocyclic group or a 6-11 membered heterocyclic group;
  • Cy 3 is selected from the group consisting of one or more R b substituted, or unsubstituted 3-8 membered monoheterocyclyl, 6-11 membered bridged heterocyclyl, 7-12 membered spiroheterocyclyl or 6 -11 membered heterocyclic group;
  • R 3 is selected from hydrogen or C 1-4 alkyl
  • R 4 is selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, halogen, carboxyl, amide, aminocarbonyl, aminosulfonyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkane Amino, (C 1-4 alkyl) 2 amino, halo C 1-4 alkyl, halo C 1-4 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1- 4 -alkylsulfonyl, C 1-4 alkylcarbonylamino, (C 1-4 alkyl) 2 carbonylamino, C 1-4 alkylaminocarbonyl, (C 1-4 alkyl) 2 aminocarbonyl, C 1 -4 alkylaminosulfonyl, (C 1-4 alkyl) 2 aminosulfonyl or C 1-4 alkoxy C 1-4 alkoxy;
  • L 1 , L 2 , and L 3 are each independently a bond, -N(R c )-, -O-, -S- or C 1-4 alkylene, and R c is selected from hydrogen or C 1-4 alkyl. ;
  • n, t, p, q are each independently 0 or 1;
  • n is an integer from 0 to 5, and when m ⁇ 2, R 4 may be selected from the same or different groups;
  • R 2 is -(L 3 )q-Cy 3 and Cy 3 is a 7-12 membered spiroheterocyclic group substituted with one to more R b or unsubstituted.
  • Another embodiment of the present invention relates to the irreversible fibroblast growth factor receptor represented by the above formula (I-A)
  • Warhead 1 is selected from
  • R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl
  • X is selected from C or N, when X is C, Represents a double bond, when X is N, Represents a single button;
  • R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, halo C 1-4 alkyl or -(L 3 )q-Cy 3 ;
  • Cy1 and Cy2 are each independently selected from a divalent group of a group: one to a plurality of Ra-substituted or unsubstituted 3-8 membered monoheterocyclic groups or 7-12-membered spiroheterocyclic groups;
  • Cy 3 is selected from the group consisting of one or more R b substituted or unsubstituted 3-8 membered monoheterocyclyl or 7-12 membered spiroheterocyclyl;
  • R a , R b are each independently selected from hydrogen, C 1-4 alkyl or hydroxy C 1-4 alkyl;
  • R 3 is selected from hydrogen or C 1-4 alkyl
  • R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;
  • L 1 , L 2 , and L 3 are each independently a bond or a C 1-4 alkylene group
  • n, t, p, q are each independently 0 or 1;
  • n is an integer from 0 to 5, and when m ⁇ 2, R 4 may be selected from the same or different groups;
  • R 2 is -(L 3 )q-Cy 3 and Cy 3 is a 7-12 membered spiroheterocyclic group substituted with one to more R b or unsubstituted.
  • Another embodiment of the present invention relates to the irreversible fibroblast growth factor receptor represented by the above formula (I-A)
  • Warhead 1 is selected from
  • R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl
  • X is selected from C or N, when X is C, Represents a double bond, when X is N, Represents a single button;
  • Cy 1 and Cy 2 are each independently a divalent group selected from the group consisting of one or more R a substituted or unsubstituted 3-8 membered nitrogen-containing monoheterocyclic groups and a 6-11 membered nitrogen-containing bridge. a heterocyclic group or a 7-12 membered nitrogen-containing spiroheterocyclyl;
  • R 2 is selected from hydrogen, C 1-4 alkyl or -(L 3 )q-Cy 3 ;
  • Cy 3 is a 7-12 membered spiroheterocyclic group substituted with one to more R b or unsubstituted;
  • R a , R b , R 3 are each independently selected from hydrogen or C 1-4 alkyl;
  • R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;
  • L 1 , L 2 , and L 3 are each independently a bond or a C 1-4 alkylene group
  • n, t, p, q are each independently 0 or 1;
  • n is an integer from 0 to 5, and when m ⁇ 2, R 4 may be selected from the same or different groups;
  • R 2 is -(L 3 )q -Cy 3 and Cy 3 is a 7-12 membered spiroheterocyclyl group substituted with one to more R b or unsubstituted.
  • Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the above formula (I-A), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
  • Warhead 1 is selected from
  • R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl
  • X is selected from C or N, when X is C, Represents a double bond, when X is N, Represents a single button;
  • Cy 1 and Cy 2 are each independently selected from a divalent group of the following structure: one to a plurality of R a substituted or unsubstituted
  • R 2 is selected from hydrogen, C 1-4 alkyl or -(L 3 )q-Cy 3 ;
  • Cy 3 is a 7-12 membered spiroheterocyclic group substituted with one to more R b or unsubstituted;
  • R a , R b , and R 3 are each independently selected from hydrogen, C 1-4 alkyl;
  • R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;
  • L 1 , L 2 , and L 3 are each independently a bond or a C 1-4 alkylene group
  • n, t, p, q are each independently 0 or 1;
  • n is an integer from 0 to 5, and when m ⁇ 2, R 4 may be selected from the same or different groups;
  • R 2 is -(L 3 )q-Cy 3
  • Cy 3 is a 7-12 membered spiroheterocyclic group substituted with one to more R b or unsubstituted.
  • Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the above formula (I-A), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
  • R 12 and R 13 are each independently selected from hydrogen or C 1-4 alkyl
  • Cy 1 is a divalent group of the following structure: substituted by one to more R a or unsubstituted Warhead 1 is attached to any ring-forming N hetero atom in Cy 1 ;
  • t and p are respectively 0;
  • n 0;
  • R a is selected from hydrogen or C 1-4 alkyl
  • R 2 is selected from hydrogen or C 1-4 alkyl
  • R 3 is selected from hydrogen or C 1-4 alkyl
  • R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;
  • n is an integer from 0 to 5, and when m ⁇ 2, R 4 may be selected from the same or different groups.
  • Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the above formula (I-A), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
  • R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl
  • Cy 1 is a divalent group of the following structure: substituted by one to more R a or unsubstituted Warhead 1 is attached to any ring-forming N hetero atom in Cy 1 ;
  • t and p are respectively 0;
  • R 2 is selected from hydrogen, C 1-4 alkyl or is -(L 3 )q-Cy 3 -;
  • Cy 3 is a monovalent group of the following structure: substituted with one to more R b or unsubstituted
  • n, q are independently 0 or 1;
  • R a , R b are each independently selected from hydrogen or C 1-4 alkyl
  • R 3 is selected from hydrogen or C 1-4 alkyl
  • R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;
  • L 1 , L 3 are each independently a bond, -CH 2 - or -CH 2 -CH 2 -;
  • n is an integer from 0 to 5, and when m ⁇ 2, R 4 may be selected from the same or different groups.
  • Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the above formula (I-A), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
  • R 12 and R 13 are each independently selected from hydrogen or C 1-4 alkyl
  • Cy 1 and Cy 2 are each independently a divalent group of the following structure: optionally substituted by one to more R a , or unsubstituted Warhead 1 is attached to any of the N heteroatoms on the ring in Cy 2 ;
  • n, t are respectively 0;
  • p 1;
  • R a is selected from hydrogen or C 1-4 alkyl
  • R 2 is selected from hydrogen or C 1-4 alkyl
  • R 3 is selected from hydrogen or C 1-4 alkyl
  • R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;
  • n is an integer from 0 to 5, and when m ⁇ 2, R 4 may be selected from the same or different groups.
  • Another embodiment of the present invention relates to the fibroblast growth factor receptor irreversible inhibitor represented by the above formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, which is affected by the fibroblast growth factor
  • the irreversible inhibitor of the body is as shown in the general formula (IB):
  • Warhead 2 is selected from
  • R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen or C 1-4 alkyl;
  • X is selected from C or N, when X is C, Represents a double bond, when X is N, Represents a single button;
  • R 1 is selected from hydrogen or C 1-4 alkyl
  • Cy 3 is a 3-8 membered monomonoheterocyclic group substituted with one to more R b or unsubstituted;
  • R b is selected from:
  • amino-carbonyl cyano-carbonyl, C 1-4 alkyl-carbonyl, C 1-4 alkylamino-carbonyl, (C 1-4 alkyl) 2 amino-carbonyl, C 1-4 alkoxy a carbonyl group, a 3-8 membered cycloalkyl-carbonyl group or a 3-8 membered heterocyclyl-carbonyl group;
  • R 3 is selected from hydrogen or C 1-4 alkyl
  • R 4 is selected from the group consisting of hydrogen, hydroxy, amino, cyano, nitro, halogen, carboxyl, amide, aminocarbonyl, aminosulfonyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkane Amino, (C 1-4 alkyl) 2 amino, halo C 1-4 alkyl, halo C 1-4 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1- 4 -alkylsulfonyl, C 1-4 alkylcarbonylamino, (C 1-4 alkyl) 2 carbonylamino, C 1-4 alkylaminocarbonyl, (C 14 alkyl) 2 aminocarbonyl, C 1-4 An alkylaminosulfonyl group, a (C 1-4 alkyl) 2 aminosulfonyl group or a C 1-4 alkoxy C 1-4 alkoxy group;
  • L 3 is each a bond, -N(R c )-, -O-, -S- or C 1-4 alkyl, and R c is selected from hydrogen or C 1-4 alkyl;
  • q is 0 or 1
  • n is an integer from 0 to 5, and when m ⁇ 2, R 4 may be selected from the same or different groups.
  • Another embodiment of the present invention relates to an irreversible inhibitor of fibroblast growth factor receptor represented by the above formula (I-B) or a pharmaceutically acceptable salt or stereoisomer thereof:
  • R 12 and R 13 are each independently selected from hydrogen or C 1-4 alkyl
  • X is selected from C or N, when X is C, Represents a double bond, when X is N, Represents a single button;
  • R 1 is selected from hydrogen or C 1-4 alkyl
  • Cy 3 is a divalent group of the following structure: substituted by one to more R b or unsubstituted Optimal Warhead 2 is connected to any ring-forming N hetero atom in Cy 3 ;
  • R b is selected from hydrogen, C 1-4 alkyl or hydroxy C 1-4 alkyl, preferably hydroxy C 1-4 alkyl;
  • R 3 is selected from hydrogen or C 1-4 alkyl
  • R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl or C 1-4 alkoxy;
  • n is an integer from 0 to 5, and when m ⁇ 2, R 4 may be selected from the same or different groups.
  • the compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the compounds of Table 1:
  • the present invention also provides a pharmaceutical preparation comprising the aforementioned irreversible inhibitor of fibroblast growth factor receptor, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the pharmaceutical formulation comprises one or more pharmaceutically acceptable carriers.
  • the pharmaceutical carrier of the present invention may be one or more solid or liquid filler or gel materials suitable for human use.
  • the pharmaceutically acceptable carrier preferably has sufficient purity and sufficiently low toxicity and is compatible with the active ingredient of the present invention (an irreversible inhibitor of fibroblast growth factor receptor or a pharmaceutically acceptable salt thereof, a stereoisomer thereof) sexually and not significantly reduce the efficacy of the active ingredients.
  • the pharmaceutically acceptable carrier can be a filler, a binder, a disintegrant, a lubricant, an aqueous solvent or a non-aqueous solvent, and the like.
  • the pharmaceutical preparation of the present invention can be formulated into any pharmaceutically acceptable dosage form, and administered to any patient in need of such treatment by any suitable administration means, for example, by oral, parenteral, rectal or pulmonary administration. Or subject.
  • oral administration it can be formulated into tablets, capsules, pills, granules and the like.
  • parenteral administration it can be prepared as an injection solution, a sterile powder for injection, or the like.
  • the pharmaceutical preparation of the present invention further comprises one or more second therapeutically active agents, wherein the second therapeutically active agent is an antimetabolite, a growth factor inhibitor, Filament classification inhibitors, anti-tumor hormones, alkylating agents, metals, topoisomerase inhibitors, hormonal drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immune checkpoints, or tumor immunotherapy-related antibodies And small molecule drugs.
  • the second therapeutically active agent is an antimetabolite, a growth factor inhibitor, Filament classification inhibitors, anti-tumor hormones, alkylating agents, metals, topoisomerase inhibitors, hormonal drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immune checkpoints, or tumor immunotherapy-related antibodies And small molecule drugs.
  • the present invention also provides the aforementioned fibroblast growth factor receptor irreversible inhibitor or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and the aforementioned pharmaceutical preparation for preparing an FGF (fibroblast growth factor)/FGFR abnormality
  • FGF fibroblast growth factor
  • the FGF/FGFR abnormality-mediated disease is cancer; the cancer includes lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast ductal carcinoma, head and neck cancer, Endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvic cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, Neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, large intestine villus Tumor, melanoma, cell tumor and sarcoma and/or myelodysplastic syndrome.
  • the present invention also provides the aforementioned fibroblast growth factor receptor irreversible inhibitor or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and the use of the aforementioned pharmaceutical preparation for treating a disease.
  • the disease comprises a FGF/FGFR abnormally mediated disease
  • the FGF/FGFR abnormally mediated disease is cancer
  • the cancer comprises lung cancer, squamous cell carcinoma, Bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of the breast, head and neck cancer, endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvic cancer, esophageal cancer, esophageal adenocarcinoma, nerve glue Tumor, prostate, thyroid, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer , pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, large intestine villus adenoma, melanoma, cell tumor and sarcom
  • the present invention also provides a method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of the aforementioned fibroblast growth factor receptor irreversible inhibitor or a pharmaceutically acceptable salt thereof, stereoisomerism Or a pharmaceutical preparation according to the above, wherein the disease comprises a disease mediated by FGF/FGFR abnormality, the disease mediated by the FGF/FGFR abnormality is cancer; the cancer comprises lung cancer, squamous cell carcinoma, Bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of the breast, head and neck cancer, endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvic cancer, esophageal cancer, esophageal adenocarcinoma, nerve glue Tumor, prostate, thyroid, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal strom
  • “Therapeutically effective amount” of the present invention refers to at least mitigate the symptoms of the disorder when administered to a patient is the fibroblast growth factor receptor irreversible inhibitor or a pharmaceutically acceptable salt, stereoisomer And the amount of the aforementioned pharmaceutical preparation.
  • the actual amount comprising a "therapeutically effective amount” will vary depending on a variety of circumstances including, but not limited to, the particular condition being treated, the severity of the condition, the physique and health of the patient, and the route of administration. Skilled medical practitioners can readily determine the appropriate amount using methods known in the medical arts.
  • halogen as used in the present invention means fluorine, chlorine, bromine, iodine or the like, preferably fluorine and chlorine.
  • halo means that any of the hydrogen atoms in the substituent may be substituted by one or more of the same or different halogens.
  • Halogen is as defined above.
  • the "monovalent group” and “divalent group” of the present specification refer to a group formed by the loss of one or two hydrogen atoms.
  • C 1-6 alkyl group as used in the present invention means a straight or branched alkyl group derived from a hydrocarbon having 1 to 6 carbon atoms and removed by a hydrogen atom, such as a methyl group, an ethyl group, a n-propyl group, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, iso-hexyl Base, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-eth
  • C 1-6 alkylene group as used in the present invention means that the aforementioned “C 1-6 alkyl group” further removes a linear or branched divalent alkyl group derived from a hydrogen atom.
  • C 2-8 alkenyl group as used in the present invention means an olefin moiety having 2 to 8 carbon atoms containing a carbon-carbon double bond, and a linear or branched or cyclic alkene group derived from a hydrogen atom, such as a vinyl group.
  • C 2-8 alkenylene group as used in the present invention means that the aforementioned “C 2-8 alkenyl group” further removes a hydrogen atom-derived linear or branched divalent alkene group.
  • the "3-12 membered cycloalkenyl group" of the present invention includes, in the case where it is not particularly specified, all monocyclic rings, fused rings (including fused in the form of a snail, a snail, or a bridge) which may be formed, for example, 3-8-membered monocyclic olefin, 7-11-membered spirocycloolefin, 7-11-membered cycloalkenene, 6-11-membered bridged cycloolefin, and the like.
  • C 2-8 alkynyl group as used in the present invention means an alkyne moiety having 2 to 8 carbon atoms containing a carbon-carbon oxime bond, and a straight or branched alkyne group derived by removing one hydrogen atom, such as ethynyl group, C. Alkynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, and the like.
  • C 2-8 alkynylene group as used in the present invention means that the aforementioned “C 2-8 alkynyl group” further removes a hydrogen atom-derived linear or branched divalent alkyne group.
  • C 1-6 alkylamino group "(C 1-6 alkyl) 2 amino group”, “C 1-6 alkylcarbonylamino group”, and “C 1-6 alkylsulfonylamino group” according to the present invention "C 1-6 alkylaminocarbonyl”", “(C 1-6 alkyl) 2 amino-carbonyl”, “C 1-6 alkoxy-carbonyl”, “C 1-6 alkylsulfonyl””””,”C 1-6 alkylthio", "C 1-6 alkyl-carbonyl”, “3-8 membered cycloalkyl-carbonyl", “3-8 membered heterocyclyl-carbonyl”, respectively C 1-6 alkyl-NH-, (C 1-6 alkyl)(C 1-6 alkyl)N-, C 1-6 alkyl-C(O)-NH-, C 1-6 alkyl -S(O) 2 -NH 2 -, C 1-6 alkyl-NH-C(O)-, (C
  • C 1-6 alkoxy refers to the present invention as hereinbefore defined "C 1-6 alkyl” group linked to the parent molecule through an oxygen atom, i.e., "C 1-6 alkyl -O- "Groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, neopentyloxy and n-hexyloxy.
  • the "C 1-4 alkoxy group” refers to the above-mentioned example having 1 to 4 carbon atoms, that is, a "C 1-4 alkyl-O-" group.
  • the "fused ring” as used in the present invention means a polycyclic ring structure formed by joining two, two or more cyclic structures in a snail, a snail, or a bridge.
  • the parallel ring refers to a fused ring structure formed by two or more ring structures sharing two adjacent ring atoms with each other (ie, sharing one bond).
  • the bridged ring refers to a fused ring structure formed by two or more ring-shaped structures sharing two non-adjacent ring atoms with each other.
  • the spiro ring refers to a fused ring structure formed by two or more ring structures sharing one ring atom with each other.
  • cycloalkyl refers to a 3-12 membered cycloalkyl group which may be a monocyclic, bicyclic, or polycyclic cycloalkyl system (also known as a fused ring system). Unless otherwise specified, all monocyclic, fused rings (including fused in the form of snails, snails, bridges) that may be formed are included.
  • Monocyclic systems are cyclic hydrocarbyl groups containing from 3 to 8 carbon atoms.
  • 3-8 membered monocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl, and the like.
  • the fused ring cycloalkyl group includes a cyclocycloalkyl group, a bridged cycloalkyl group, a spirocycloalkyl group.
  • the cyclocycloalkyl group may be a 6-11 membered cyclocycloalkyl group, a 7-10 membered cyclocycloalkyl group, and representative examples thereof include, but are not limited to, bicyclo [3.1.1] heptane, bicyclo [2.2.1 Heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] decane, bicyclo [3.3.1] decane and bicyclo [4.2.1] decane.
  • the spiro group may be a 7-12 membered spiro group, a 7-11 membered spiro group, examples of which include, but are not limited to:
  • the bridged ring group may be a 6-11 membered bridged ring group and a 7-10 membered bridged ring group, and examples thereof include, but are not limited to:
  • the "3-12 membered heterocyclic group" as used in the present invention means a non-aromatic cyclic group in which at least one ring carbon atom is replaced by a hetero atom selected from O, S, N, preferably 1 to 3 hetero atoms. And including carbon atoms, nitrogen atoms and sulfur atoms can be substituted by oxo.
  • Heterocyclyl means a monocyclic heterocyclic ring, a bicyclic heterocyclic ring system or a polycyclic heterocyclic ring system (also known as a fused ring system), including saturated, partially saturated heterocyclic groups, but excluding aromatic rings. . Unless otherwise specified, all single rings, fused rings (including fused in the form of snails, snails, bridges), saturated, partially saturated, which may be formed, are included.
  • substitutedoheterocyclic group as used in the present invention means that the aforementioned “monoheterocyclic group” further removes a divalent single radical in which at least one ring carbon atom derived from one hydrogen atom is replaced by a hetero atom selected from O, S, N.
  • a cyclic group as used in the present invention means that the aforementioned “monoheterocyclic group” further removes a divalent single radical in which at least one ring carbon atom derived from one hydrogen atom is replaced by a hetero atom selected from O, S, N.
  • the monoheterocyclic group may be a 3-8 membered heterocyclic group, a 3-8 membered saturated heterocyclic group, a 3-6 membered heterocyclic group, a 4-7 membered heterocyclic group, a 5-7 membered heterocyclic group, 5- A 6-membered heterocyclic group, a 5-6 membered oxygen-containing heterocyclic group, a 3-8 membered nitrogen-containing heterocyclic group, a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered saturated heterocyclic group or the like.
  • "3-8"-membered saturated heterocyclic group examples of which include, but are not limited to, aziridine, oxacyclopropane, thietyl, azetidinyl, oxetanyl, sulfur Heterocyclobutane, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2- Thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, pyrrolyl, morpholinyl, 1,4-di An oxacyclohexyl group, a 1,4-oxothianyl group; a "3-8" member partially saturated heterocyclic
  • the fused heterocyclic ring includes a heterocyclic group, a spiroheterocyclic group, a bridged heterocyclic group, and may be saturated, partially saturated or unsaturated, but not aromatic.
  • the fused heterocyclic group is a monocyclic cycloalkyl group, a 5-6 membered monocyclic cycloalkenyl group, a 5-6 membered monocyclic heterocyclic group or a 5-6 membered monocyclic heteroaryl group fused to a benzene ring, 5-6 members.
  • a 5-6 membered monocyclic heterocyclic ring of the group is a monocyclic cycloalkyl group, a 5-6 membered monocyclic cycloalkenyl group, a 5-6 membered monocyclic heterocyclic group or a 5-6 membered monocyclic heteroaryl group fused to a benzene ring, 5-6 members.
  • the heterocyclic group may be 6-11 members and a cyclic group, a 7-10 membered ring group, a 6-10 membered ring group, a 6-12 membered saturated ring group, and representative examples include, but are not limited to: 3-azabicyclo[3.1.0]hexane, 3,6-diazabicyclo[3.2.0]heptyl, 3,8-diazabicyclo[4.2.0]octyl, 3, 7-diazabicyclo[4.2.0]octyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3, 4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydro Benzofuran
  • the spiroheterocyclyl group may be a 6-12 membered spiroheterocyclyl group, a 7-12 membered spiroheterocyclyl group, a 7-12 membered N-containing spiroheterocyclyl group, a 6-12 membered saturated spirocyclic group, and examples thereof include But not limited to:
  • spiroheterocyclyl as used in the present invention means that the aforementioned “spiroheterocyclic group” further removes a divalent snail in which at least one ring carbon atom derived from a hydrogen atom is replaced by a hetero atom selected from O, S, and N.
  • a cyclic group as used in the present invention means that the aforementioned “spiroheterocyclic group” further removes a divalent snail in which at least one ring carbon atom derived from a hydrogen atom is replaced by a hetero atom selected from O, S, and N.
  • the bridged heterocyclic group may be a 6-11 membered bridged heterocyclic group, a 7-11 membered bridged heterocyclic group, and a 6-12 membered saturated bridged ring group, and examples thereof include, but are not limited to:
  • the "aryl group” as used in the present invention means a cyclic aromatic group having 6 to 14 carbon atoms, and includes a 6-8 membered monocyclic aryl group and an 8-14 membered fused ring aryl group, preferably 6-8 members. Monocyclic aryl.
  • the 6-8 membered monocyclic aryl group may be a phenyl group, a pyrazole, a cyclooctadecenyl group or the like.
  • the 8-14 membered fused ring aryl group may be naphthalene, phenanthrene or the like.
  • heteroaryl of the present invention may be a 5-10 membered heteroaryl group, and means an aromatic cyclic group in which at least one ring carbon atom is replaced by a hetero atom selected from O, S, N, preferably 1- 3 heteroatoms, including carbon atoms, sulfur atoms by oxo, such as carbon atoms replaced by C (O), sulfur atoms replaced by S (O), S (O) 2 .
  • the heteroaryl group includes a monoheteroaryl group and a fused heteroaryl group, and includes, unless otherwise specified, all monocyclic, fused ring, wholly aromatic, partially aromatic forms which may be formed.
  • the monoheteroaryl group may be a 5-7 membered heteroaryl group, a 5-6 membered heteroaryl group, and examples thereof include, but are not limited to, furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl , oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl and triazinyl.
  • X
  • One or two groups are optionally substituted.
  • the fused heteroaryl group may be 8-12 membered heteroaryl, 9-10 membered heteroaryl, and examples include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzooxadiazolyl , benzothiadiazolyl, benzothiazolyl, porphyrinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl, anthracene Azyl, fluorenyl, isoquinolyl, naphthyridinyl, fluorenyl, quinolinyl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydro Quinolinyl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, thienopyridin
  • the "pharmaceutically acceptable salt” as used in the present invention means a pharmaceutically acceptable acid or base addition salt or a solvate thereof.
  • Such pharmaceutically acceptable salts include salts of the following acids: hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid. Hydroiodic acid, alkanoic acid (such as acetic acid, HOOC-(CH 2 ) n-COOH (where n is 0 to 4)), and the like.
  • Salts of bases sodium salts, potassium salts, calcium salts, ammonium salts, and the like.
  • a variety of non-toxic pharmaceutically acceptable addition salts are known to those skilled in the art.
  • the "stereoisomer" of the compound of the formula (I) of the present invention means that when an asymmetric carbon atom is present in the compound of the formula (I), (IA), (IB), an enantiomer is produced; when the compound has carbon and carbon In the case of a double bond or a cyclic structure, a cis-trans isomer is produced; when a compound has a ketone or a oxime, a tautomer is produced, and all of the compounds of the formula (I), (IA), (IB) are enantiomerically Constructs, diastereomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are included within the scope of the invention.
  • the "warhead” as used in the present invention refers to a moiety capable of forming a covalent bond with a nucleophile.
  • a “nucleophile” is a substance that is directed to an electrophile to supply an electron pair to form a chemical bond in the reaction.
  • the nucleophile can be an oxygen nucleophile, eg, water or a hydroxyl group; a nitrogen nucleophile, eg, an amine; or a sulfur nucleophile, eg, a sulfhydryl group, such as a cystine residue Sulfhydryl groups in the side chain.
  • warhead refers to a moiety that is reversibly or irreversibly involved in the reaction of a donor (eg, a protein) with a substrate.
  • Warhead can, for example, form a covalent bond with a protein, or can form a stable transition state, or a reversible irreversible alkylating agent.
  • warhead can be a functional group on an inhibitor that can participate in a bond formation reaction, wherein a new covalent bond is formed between a portion of the warhead and a donor (eg, an amino acid residue of a protein).
  • Warhead is an electrophile and the "donor” is a nucleophile, such as a side chain of a cysteine residue. Suitable for the warhead part include but are not limited to the following structure:
  • R 11 , R 12 , R 13 , R 14 and R 15 are each independently selected from hydrogen, halogen, cyano, C 1-4 alkyl, halo C 1-4 alkyl, Cy 4 or optionally substituted. a substituted C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a Cy 4 , a C 2-8 alkenyl group, a C 2-8 alkynyl group, the substituent being selected from the group consisting of a hydroxyl group, an amino group, a carboxyl group, and a cyano group.
  • C 1-4 alkyl C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl a 2 amino group, a C 1-4 alkylcarbonylamino group, a C 1-4 alkylsulfonylamino group, a 3-12 membered heterocyclic group;
  • Cy 4 is selected from a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-12 membered heterocyclic group, an aryl group or a 5-10 membered heteroaryl group.
  • z is an integer from 0-4.
  • the fibroblast growth factor receptor (FGFR) irreversible inhibitor provided by the present invention or a pharmaceutically acceptable salt thereof, stereoisomer thereof has an efficient and highly selective inhibitory effect on the fibroblast growth factor receptor, It can be applied to the treatment of related diseases mediated by FGF/FGFR abnormalities, especially in the treatment of cancer diseases.
  • FGFR fibroblast growth factor receptor
  • NMP N-methylpyrrolidone
  • DIPEA N,N-diisopropylethylamine
  • TLC thin layer chromatography
  • PE:EA petroleum ether Ethyl acetate
  • THF tetrahydrofuran
  • EA ethyl acetate
  • DCM: MeOH means dichloromethane: methanol
  • DCM means dichloro Methane
  • MTBE means methyl tert-butyl ether
  • TFAA means trifluoroacetic anhydride
  • TSA means triethylamine
  • LAN means lithium tetrahydrogenate
  • Boc means uncle Butyloxycarbonyl
  • MsCl is succinyl chloride
  • DEAD diethyl azodicarboxylate
  • Step 1 Synthesis of ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate
  • Step 1 Synthesis of 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester
  • Step 1 Synthesis of 4-(3-hydroxypropyl)piperazine-1-carboxylic acid tert-butyl ester
  • Step 2 Synthesis of 4-(3-((methylsulfonyl)oxy)propyl)piperazine-1-carboxylic acid tert-butyl ester
  • Step 1 Synthesis of ethyl 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-(methylthio)pyrimidine-5-carboxylate
  • EtOAc EtOAc (EtOAc) ((1-(tert-Butoxycarbonyl)azetidin-3-yl)amino)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (7.5 g, yield: 95%).
  • Step 2 Synthesis of tert-butyl 3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)azetidin-1-carboxylate
  • Lithium tetrahydroaluminum (1.2 g, 31.6 mmol, 1.5 eq) was dissolved in THF (50 mL), cooled to 0 ° C, and THF (20 mL) was added to dissolve 4-((1-(tert-butoxycarbonyl) aza Ethyl cyclobutane-3-yl)amino)-2-(methylthio)pyrimidine-5-carboxylate (7.5 g, 20.4 mmol, 1.0 eq), mp.
  • Step 3 Synthesis of tert-butyl 3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)azetidin-1-carboxylate
  • Step 4 3-((5-((3,5-Dimethoxyphenyl)amino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)azetidine- Synthesis of 1-tert-butyl carboxylate
  • Step 5 3-(3-(3,5-Dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine Synthesis of -1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester
  • Step 6 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5-d]pyrimidine-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester
  • Step 7 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimidine Synthesis of [4,5-d]pyrimidine-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester
  • Step 8 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5-d]pyrimidine-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester
  • Step 9 1-(Azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4 Synthesis of dihydropyrimido[4,5-d]pyrimidin-2(1H)-one
  • Step 10 4-(3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydro Synthesis of pyrimido[4,5-d]pyrimidin-1(2H)-yl)azetidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester
  • Step 11 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(1-(piperidin-4-yl)azetidine Synthesis of alk-3-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one hydrochloride
  • Step 12 1-(1-(1-Anoylpiperidin-4-yl)azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxybenzene Synthesis of 7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one
  • Step 2 Synthesis of 2-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester
  • Lithium tetrahydroaluminum (842.5 mg, 22.2 mmol, 1.5 eq) was added to tetrahydrofuran (10 mL) at 0 ° C, and 2-((5-(ethoxycarbonyl))-2-methylsulfonate was slowly added dropwise with stirring.
  • a solution of tert-butyl pyridyl-4-methyl)amino)-7-azaspiro[3.5]decane-7-carboxylate (6.49 g, 14.8 mmol, 1.0 eq) in tetrahydrofuran (30 mL) After 5 ° C or less, the mixture was slowly added to room temperature and stirred overnight.
  • Step 3 Synthesis of 2-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester
  • Step 4 2-((5-((3,5-Dimethoxyphenyl)amino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)-7-aza snail [3.5] Synthesis of tert-butyl decane-7-carboxylate
  • Step 5 2-(3-(3,5-Dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine Synthesis of -1(2H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester
  • Step 6 2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5-d]pyrimidine-1(2H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester
  • Step 7 2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimidine Synthesis of [4,5-d]pyrimidine-1(2H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester
  • Step 8 2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5-d]pyrimidine-1(2H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester
  • Step 9 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(7-azaspiro[3.5]decane-2-yl Synthesis of-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one hydrochloride
  • Step 10 1-(7-Acyryl-7-azaspiro[3.5]decane-2-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7 Synthesis of -(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one
  • EtOAc EtOAc
  • Step 1 2-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidine-8 ( Synthesis of 7H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester
  • 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (726 mg, 2 mmol, 1.0 Eq), tert-butyl 2-hydroxy-7-azaspiro[3.5]decane-7-carboxylate (483 mg, 2 mmol, 1.0 eq) and triphenylphosphine (787 mg, 3 mmol, 1.5 eq) dissolved in tetrahydrofuran ( In 10 mL), diethyl azodicarboxylate (522 mg, 3 mmol, 1.5 eq) was slowly added, and reacted at 25 ° C for 4 h.
  • Step 2 2-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidine-8 Synthesis of (7H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester
  • Step 3 2-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidine-8 ( Synthesis of 7H)-yl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester
  • the reaction solution obtained in the above step was directly added to a methylamine aqueous solution (10 mL), and reacted at 25 ° C for 4 h.
  • the reaction was completed by LC-MS.
  • the reaction mixture was separated, the organic phase was dried and concentrated.
  • Step 4 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(7-azaspiro[3.5]decane-2-yl)pyridine Synthesis of [2,3-d]pyrimidine-8(7H)-one
  • Step 5 8-(7-acryloyl-7-azaspiro[3.5]decane-2-yl)-6-(2-chloro-3,5-dimethoxyphenyl)-2-(A Synthesis of pyridyl[2,3-d]pyrimidin-7(8H)-one
  • Step 1 6-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidine-8 ( Synthesis of 7H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester
  • Step 2 6-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidine-8 Synthesis of (7H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester
  • Step 3 6-(6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidine-8 (7H Synthesis of tert-butyl ester of 2-aminopyridyl[3.3]heptane-2-carboxylic acid:
  • Step 4 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(2-azaspiro[3.3]heptan-6-yl)pyridine Synthesis of [2,3-d]pyrimidin-7(8H)-one trifluoroacetate:
  • Step 5 8-(2-Acryloyl-2-azaspiro[3.3]heptane-6-yl)-6-(2-chloro-3,5-dimethoxyphenyl)-2-(A Synthesis of pyridyl[2,3-d]pyrimidin-7-(8H)-one:
  • Step 1 Synthesis of ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate
  • Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (22.0 g, 94.55 mmol, 1.0 eq) was dissolved in THF (100 mL). Aqueous methylamine solution (100 mL) was added dropwise slowly, the temperature did not exceed 30 ° C, and the reaction was completed at room temperature (25 ° C) overnight and monitored by TLC. The reaction was completely monitored by TLC. The reaction mixture was dried under reduced pressure. Water (50 mL) was added, and the mixture was stirred at room temperature (25 ° C) for 10 min. The reaction mixture was filtered with suction. The filter cake was washed with water (several washings) and the filter cake was dried to give a solid 4 Ethyl (methylamino)-2-(methylthio)pyrimidine-5-carboxylate (16.98 g crude).
  • Lithium tetrahydroaluminum (4.01 g, 105.47 mmol, 1.5 eq) was dissolved in THF (500 mL), cooled to -10 ° C to -5 ° C in an ice salt bath, and 4-(methylamino)-2- was slowly added dropwise.
  • a solution of ethyl methylthio)pyrimidine-5-carboxylate (15.98 mg of crude product, 70.31 mmol, 1.0 eq) in THF (120 mL), and the temperature is controlled from -10 ° C to -5 ° C during the dropwise addition.
  • the reaction was stirred at room temperature (25 ° C), rt (25 ° C) overnight (12h) The reaction was completely monitored by TLC.
  • Step 4 Synthesis of 5-((3,5-dimethoxyphenyl)amino)methyl)-N-methyl-2-(methylthio)pyrimidine-4-amine
  • Step 7 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-methyl-7-(methylsulfonyl)-3,4-dihydropyrimido[4, Synthesis of 5-d]pyrimidine-2(1H)-one
  • Step 8 (2S,4S)-4-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methyl-7-oxo-5,6,7 Synthesis of 8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 9 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino Synthesis of 1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one hydrochloride
  • Step 10 7-(((3S,5S)-1-acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-3-(2,6-dichloro-3,5-di Synthesis of methoxyphenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one
  • Step 1 6-(2-Chloro-3,5-dimethoxyphenyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- Ketone synthesis
  • 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one 600 mg, 1.65 mmol
  • EtOAc EtOAc
  • EtOAc EtOAc
  • the reaction was completed by LC-MS.
  • the reaction mixture was poured into water, extracted with dichloromethane, and the organic phase was combined, dried, concentrated, and the crude was added to dichloromethane to give 6-(2-chloro-3,5-dimethoxyphenyl) 8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (400 mg, yield 60%).
  • Step 3 (2S,4S)-4-((6-(2-Chloro-3,5-dimethoxyphenyl)-8-methyl-7-oxo-7,8-dihydropyridine Synthesis of [2,3-d]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • reaction solution of the above step was added to (2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (230 mg, 1.06 mmol, 1.0 eq) previously dissolved in DMF (5 mL).
  • Triethylamine (537 mg, 5.30 mmol, 3.0 eq) was added and reacted at 50 ° C for 4 h.
  • the reaction was completely monitored by TLC.
  • the reaction mixture was poured into water, extracted with EA, and the organic phases were combined, washed once with water and brine, and dried.
  • Step 4 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-8 Synthesis of -methylpyrido[2,3-d]pyrimidin-7(8H)-one
  • Step 5 2-(((3S,5S)-1-acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-6-(2-chloro-3,5-dimethoxy Synthesis of Phenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one
  • Step 1 Synthesis of 6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one
  • the starting material 6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one 300 mg, 0.825 mmol) , 1.0 eq was added to THF and dissolved by heating. The temperature was lowered to 0 ° C, and THF dissolved mCPBA (318.8 mg, 0.907 mmol, 1.1 eq) was added dropwise. After stirring for 2 h, the reaction was completed by TLC. EtOAc (EtOAc m.) Phenyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (390 mg).
  • Step 2 (2S,4S)-4-((6-(2-Chloro-3,5-dimethoxyphenyl)-7-oxo-7,8-dihydropyrido[2,3- Synthesis of d]pyrimidin-2-yl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • reaction mixture was poured into water (30 mL), DCM (30 mL) was added, and the mixture was stirred.
  • the aqueous phase was extracted with DCM (20 mL).
  • the organic phase was combined and washed with saturated sodium chloride solution (20 mL).
  • Step 3 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)amino)pyridine Synthesis of [2,3-d]pyrimidine-7(8H)-one hydrochloride
  • Step 4 2-(((3S,5S)-1-acryloyl-5-(hydroxymethyl)pyrrolidin-3-yl)amino)-6-(2-chloro-3,5-dimethoxy Synthesis of Phenyl)pyrido[2,3-d]pyrimidin-7(8H)-one
  • Step 2 Synthesis of 6-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester
  • Lithium tetrahydrogen aluminum (2.26 g, 59.7 mmol, 3.0 eq) was added to tetrahydrofuran (50 mL), stirred, cooled to 0 ° C, and 6-((5-(ethoxycarbonyl))-2-(methylsulfonate) was slowly added dropwise with stirring.
  • a solution of tert-butyl pyridyl-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (8.15 g, 19.9 mmol, 1.0 eq) in tetrahydrofuran (30 mL). The reaction was carried out at ° C for 6 hours. TLC showed the reaction was complete.
  • Step 3 Synthesis of 6-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester
  • Step 4 6-((5-((3,5-Dimethoxyphenyl)amino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)-2-azaspiro [3.3] Synthesis of tert-butyl heptane-2-carboxylate
  • Step 5 6-(3-(3,5-Dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine Synthesis of tert-butyl ester of -1(2H)-yl)-2-azaspiro[3.3]heptane-2-carboxylate
  • Step 6 6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylthio)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5-d]pyrimidine-1(2H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester
  • Step 7 6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimidine Synthesis of [4,5-d]pyrimidine-1(2H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester
  • Step 8 6-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5-d]pyrimidine-1(2H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester
  • the mixture was cooled to room temperature, extracted with methylene chloride (150 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, filtered, and the filtrate was concentrated.
  • Step 9 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(2-azaspiro[3.3]heptane-6-yl Synthesis of-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one hydrochloride
  • Step 10 1-(2-Aroyl-2-azaspiro[3.3]heptan-6-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7 Synthesis of -(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one
  • Step 1 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimidine Synthesis of [4,5-d]pyrimidine-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester
  • Step 2 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5-d]pyrimidine-1(2H)-yl)azetidin-1-carboxylic acid tert-butyl ester
  • reaction liquid of the previous step was added to a sealed tube, and the aqueous solution of methylamine (10 mL) was added, and the reaction was carried out at 45 ° C for 2 h.
  • the reaction was completed by LC-MS. Drying over anhydrous sodium sulfate, filtration, EtOAc (EtOAc:EtOAc:EtOAc Oxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)azetidin-1 - tert-butyl carboxylate (470 mg, two-step yield: 69%).
  • Step 3 1-(Azetidin-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4 Synthesis of dihydropyrimido[4,5-d]pyrimidin-2(1H)-one
  • Step 4 3-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4-dihydropyrimido[ Synthesis of 4,5-d]pyrimidine-1(2H)-yl)-[-1,3'-biazetidine]-1'-carboxylic acid tert-butyl ester
  • Butane-1-carboxylic acid tert-butyl ester (198.7 mg, 1.2 mmol, 1.5 eq), stirred for 2 h, added sodium triacetoxyborohydride (492.1 mg, 2.3 mmol, 3.0 eq), stirred for 8 h, TLC monitoring The reaction was completed, the pH of the solution was adjusted to 7-8 with a saturated aqueous solution of sodium bicarbonate, and the mixture was separated, and then extracted with DCM (2 ⁇ 50mL). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 5 1-([1,3'-biazetidine]-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methyl Synthesis of amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one hydrochloride
  • Step 6 1-(1'-acrylo[-1,3'-biazetidine]-3-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl) Synthesis of -7-(methylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one
  • Step 1 Synthesis of 6-(2-chloro-3,5-dimethoxyphenyl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one
  • 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (580 mg, 1.754 mmol.
  • the mixture was dissolved in tetrahydrofuran (15 mL), cooled to 0 ° C, and a solution of 70% of mCPBA (616.3 mg, 1.754 mmol, 1.1 eq) in tetrahydrofuran (2 mL) was added dropwise, and the mixture was stirred at 0 ° C - 5 ° C for 3 h.
  • the reaction was completed by TLC.
  • Step 2 2-((2-oxaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)pyrido[2,3- Synthesis of d]pyrimidin-7(8H)-one
  • Step 3 4-(3-(2-((2-oxaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)- Synthesis of tert-butyl 7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl)propyl)piperazine-1-carboxylate
  • Step 4 2-((2-oxaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)-8-(3-( Synthesis of piperazin-1-yl)propyl)pyrido[2,3-d]pyrimidin-7(8H)one
  • Step 5 2-((2-oxaspiro[3.3]heptan-6-yl)amino)-8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2 Synthesis of -Chloro-3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7(8H)-one
  • Step 1 Synthesis of methyl 2-(3,5-dimethoxyphenyl)acetate
  • reaction solution was added to aqueous methylamine (30 mL)
  • aqueous methylamine (30 mL)
  • the mixture was heated to 50 ° C for 1 hour, and solids were precipitated in the reaction system, filtered, and the filter cake was washed twice with dichloromethane, and dried to give a product (1.9 g, yield: 53%).
  • Step 4 6-(6-(3,5-Dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl Synthesis of 2-Azaspiro[33]heptane-2-carboxylic acid tert-butyl ester
  • Step 5 (6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidine-8 Synthesis of (7H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester
  • Step 7 8-(2-Acryloyl-2-azaspiro[3.3]heptan-6-yl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)- Synthesis of 2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one
  • Step 2 6-(2-Chloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)-8-(4-nitrophenethyl)pyrido[2,3-d] Synthesis of pyrimidine-7(8H)-one
  • Step 2 6-((6-(2-Chloro-3,5-dimethoxyphenyl)-8-(4-nitrophenethyl)-7-oxo-7,8-dihydropyridine Synthesis of [2,3-d]pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester
  • Step 3 2-((2-Azaspiro[3.3]heptan-6-yl)amino)-6-(2-chloro-3,5-dimethoxyphenyl)-8-(4-nitro Synthesis of pyridyl[2,3-d]pyrimidin-7(8H)-one trifluoroacetate
  • Step 4 6-(2-Chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3]heptan-6-yl)amino)-8 Synthesis of (4-nitrophenethyl)pyrido[2,3-d]pyrimidin-7(8H)-one
  • the crude product obtained in the above step was dissolved in methanol (10 mL), and then added to a solution of 37% aqueous formaldehyde (83.8 mg, 1.03 mmol, 2.5 eq), and stirred at room temperature under nitrogen for 1 h. The temperature was lowered to 0 ° C, and sodium triacetoxyborohydride (318.8 mg, 1.24 mmol, 3.0 eq) was added portionwise. The reaction was completed by TLC.
  • EtOAc EtOAc
  • EtOAc EtOAc (2-Chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3]heptan-6-yl)amino)-8-(4-nitro Phenylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, yield: 80%).
  • Step 5 8-(4-Aminophenethyl)-6-(2-chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3] Synthesis of heptane-6-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one
  • Step 6 N-(4-(2-(6-(2-chloro-3,5-dimethoxyphenyl)-2-((2-methyl-2-azaspiro[3.3]heptane-) Synthesis of 6-yl)amino)-7-oxopyrido[2,3-d]pyrimidine-8(7H)-yl)ethyl)phenyl)acrylamide
  • Step 1 6-(7-Amino-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-oxo-3,4-dihydropyrimido[4,5- Synthesis of d]pyrimidine-1(2H)-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester
  • Step 3 1-(2-Aroyl-2-azaspiro[3.3]hept-6-yl)-7-amino-3-(2,6-dichloro-3,5-dimethoxyphenyl Synthesis of-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one
  • Step 1 Synthesis of ethyl 2-(methylthio)-4-((4-nitrophenethyl)amino)pyrimidine-5-carboxylate
  • Lithium tetrahydroaluminum (4.9 g, 129.3 mmol, 1.5 eq) was dissolved in tetrahydrofuran (200.0 mL), and 2-(methylthio)-4-((4-nitrophenethyl) was slowly added dropwise at 0 °C.
  • Step 4 Synthesis of 5-(((3,5-dimethoxyphenyl)amino)methyl)-2-(methylthio)-N-(4-nitrophenyl)pyrimidine-4-amine
  • Step 5 3-(3,5-Dimethoxyphenyl)-7-(methylthio)-1-(4-nitrophenyl)-3,4-dihydropyrimido[4,5- Synthesis of d]pyrimidine-2(1H)-one
  • Step 7 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylsulfonyl)-1-(4-nitrophenyl)-3,4-di Synthesis of Hydropyrimido[4,5-d]pyrimidin-2(1H)-one
  • Step 8 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-1-(4-nitrophenyl)-3,4-dihydro Synthesis of pyrimido[4,5-d]pyrimidin-2(1H)-one
  • Step 9 1-(4-Aminophenethyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-3,4-dihydro Synthesis of pyrimido[4,5-d]pyrimidin-2(1H)-one
  • Step 10 N-(4-(2-(3-(2,6-Dichloro-3,5-dimethoxyphenyl)-7-(methylamino)-2-oxo-3,4 Synthesis of dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)ethyl)phenyl)acrylamide
  • Step 1 Synthesis of methyl 2-(3,5-dimethoxyphenyl)acetate
  • 6-(3,5-Dimethoxyphenyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (4.178 g, 0.0121 mol, 1.0 eq Dissolve in methylamine methanol solution (300mL), after 12 hours at 50 °C, LC-MS detection reaction is complete, add water (200mL), stir for 10min, filter, filter cake washed twice with dichloromethane, bake The product was obtained after drying (2.75 g, yield: 72.7%).
  • Step 5 4-(3-(6-(3,5-Dimethoxyphenyl)-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidine-8 (7H) Synthesis of tert-butyl ester of propyl)piperazine-1-carboxylate
  • Step 5 4-(3-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-7-oxopyridine[2,3-d Synthesis of pyrimidine-8(7H)-yl)propyl)piperazine-1-carboxylic acid tert-butyl ester
  • Step 6 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(3-(piperazin-1-yl)propyl)pyridine And [2,3-d]pyrimidin-7(8H)-one trifluoroacetate
  • Step 7 8-(3-(4-Acrylopiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(A Synthesis of pyridyl[2,3-d]pyrimidin-7(8H)-one
  • 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamino)-8-(3-(piperazin-1-yl)propyl)pyridinium[ 2,3-d]pyrimidin-7(8H)-one trifluoroacetate (4.465 g, 0.00888 mol, 1.0 eq) was dissolved in tetrahydrofuran (50 mL), then added triethylamine (4.452 g, 0.044 mol, 5.0 Eq), acryloyl chloride (1.5 g, 0.0088 mol, 1.0 eq) was added at 0 ° C, and reacted at 0 to 5 ° C for 2 h.
  • the reaction was completed by LC-MS.
  • the reaction mixture was poured into saturated aqueous sodium carbonate (50 mL) and stirred for 20 min.
  • the mixture was extracted with methylene chloride (100 mL ⁇ 3).
  • the organic phase was combined, dried and concentrated.
  • the compounds of the present invention have the following innovations: 1
  • the compound has stronger enzymatic inhibitory activity against each subtype of FGFR, and the cancer cell killing activity due to abnormal FGFR gene is more excellent.
  • the compound is more medicinal in the PK of animals and humans in vivo and in vivo, and can ensure better exposure of animals and humans after administration, thereby facilitating the anti-cancer effect of the drug.
  • 3 The compound exhibited a superior inhibitory effect on the animal pharmacodynamic model, so it was predicted to have a better clinical application effect in the human body.
  • Hep3B is an abnormal cell of hepatocellular carcinoma FGFR, derived from ATCC
  • RT112/84 is an abnormal cell of bladder cancer FGFR, derived from ECACC
  • SNU-16 is an abnormal cell of gastric cancer FGFR, derived from ATCC
  • Test substance The compound of the present invention, the structure of which is shown above.
  • Test equipment EnSpire TM or EnVision TM multifunctional microplate reader.
  • Each strain of cells was inoculated in a 96-well plate and cultured overnight. Different concentrations of compounds (12 dose groups, 3 fold gradient DMSO dilution) were added to give a final concentration of 0.17-30000 nM, and the final DMSO content was 5 ⁇ (v). /v).
  • the negative control wells contained only medium containing 5 DMSO, and the positive control wells were medium containing cells and 5 DMSO. It was tested after incubation at 37 ° C, 5% CO 2 , 95% humidity for 72 h. 30 ⁇ L of Cell titer-Glo TM reagent was added to each well, and after incubation for 30 min at room temperature, the plate reader was used to read the chemiluminescence final data.
  • the cell viability inhibition rate is calculated according to the following formula:
  • the maximum luminescence value was obtained from the positive control well, and the minimum luminescence value was obtained from the negative control well.
  • the compound of the present invention has a good inhibitory activity against the abnormal cell viability of FGFR such as Hep3B, RT112/84, SNU-16, etc., indicating that the compound of the present invention can be used for the treatment of abnormality mediated by FGF/FGFR.
  • Cancers such as liver cancer, stomach cancer, and bladder cancer have very good clinical value.
  • the FAM-labeled peptide substrate P22 is derived from GL Biochem
  • Test substance The compound of the present invention, the structure of which is shown above.
  • Tester Use Caliper EZ Reader TM II drug screening platform.
  • step b) Transfer each compound dilution prepared in step a) to a 384-well plate and dilute with 1 ⁇ kinase buffer (50 mM HEPES, Ph 7.5; 0.0015% Brij-35; 2 mM DTT) to give 5 ⁇ L of 10% DMSO per well. (v/v) Dissolved 5 x compound solution such that the highest final concentration was 10 ⁇ M. The negative control wells were 5 [mu]L of 1X Kinase Buffer containing 10% DMSO.
  • 1 ⁇ kinase buffer 50 mM HEPES, Ph 7.5; 0.0015% Brij-35; 2 mM DTT
  • step 1b Add 10 ⁇ L of 2.5 ⁇ enzyme solution to the 5 ⁇ compound solution in step 1b), and after reacting for 10 min at room temperature, add a total volume of 10 ⁇ L of FAM-labeled peptide substrate previously dissolved in 1 ⁇ kinase buffer, and ATP. After the initiation of the reaction, incubation was carried out for 30 minutes by adding 25 ⁇ L of stop solution (100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% Coating Reagent #3; 50 mM EDTA) to terminate the reaction Caliper reading final data.
  • stop solution 100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% Coating Reagent #3; 50 mM EDTA
  • the pharmacokinetic parameters of the compounds of the present invention in BalbC female nude mice were evaluated, and their bioavailability was examined.
  • Compound 9 was prepared by dispersing 0.5% CMC-Na aqueous solution (containing 0.5% Tween-80) to prepare a suspension.
  • Compound 9 suspension was administered to BalbC nude mice at a dose of 10.0 mg/kg (9 in total, 3 points) The group, 3 in each group, was intragastrically administered (suspension of compound 9), and the time of blood collection was after administration: 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, 30 h.
  • DMA dimethylacetamide
  • EL polyoxyethylene castor oil
  • HP- ⁇ -CD 10% hydroxypropyl- ⁇ -cyclodextrin
  • Plasma samples were centrifuged at 8000 rpm for 6 min at 4 ° C to obtain plasma samples. The plasma must be prepared within 30 min after blood collection and stored in a -80 ° C refrigerator before plasma testing.
  • the samples from 9 mouse individuals were taken out from the -80 °C refrigerator and vortexed at room temperature for 5 min.
  • the 10 ⁇ L plasma samples from different individual mice at each time point were precisely aspirated into a 1.5 mL centrifuge tube (precision extraction). Standard curve plasma 30 ⁇ L); add 200 ⁇ L of 100 ng/mL toluene butyrate in methanol (internal standard working solution), mix; vortex 5 min, centrifuge at 12000 rpm for 5 min; precision soak 50 ⁇ L of supernatant to pre-added 150 ⁇ L per well of water in 96-well plates; vortexed for 5 min for LC-MS/MS measurement with an injection volume of 10 ⁇ L.
  • the compound concentration was measured using AB's Analyst 1.6.3.
  • Microsoft Excel calculates the mean, standard deviation, coefficient of variation and other parameters (Analyst 1.6.3 direct output is not calculated), and the pharmacokinetic parameters are calculated using Pharsight Phoenix 6.1 software NCA.
  • T max po peak time
  • AUC inf iv/po area under the drug-time curve
  • F% bioavailability
  • OBJECTIVE To evaluate the stability of human liver microsomes of compounds of the invention.
  • liver microsomes (20 mg protein/mL) were taken out from the -80 °C refrigerator, placed in a 37 ° C water bath thermostat shaker for 3 min, and thawed for use.
  • Control group (excluding ⁇ -NADPH): 30 ⁇ L of water and 30 ⁇ L of compound working solution (10 ⁇ M) were added to 240 ⁇ L of the incubation solution of step (2), vortexed for 30 s, mixed, and reacted. The total volume was 300 ⁇ L and the sample was duplicated. Incubate into a 37 ° C water bath thermostat and start timing. The sampling time points are 0 min and 60 min.
  • Sample group 70 ⁇ L ⁇ -NADPH solution (10 mM) and 70 ⁇ L of compound working solution (10 ⁇ M) were added to 560 ⁇ L of the mixed solution in step (2), the total volume of the reaction was 700 ⁇ L, vortexed for 30 s, mixed, and duplicated. . Incubate into a 37 ° C water bath thermostat shaker, and start timing. The sampling time point is 0 min, 5 min, 10 min, 20 min, 30 min, 60 min after timing.
  • k is the slope of the logarithm of the remaining amount of the compound versus time
  • Vd is the apparent volume of distribution.
  • R 2 coefficient of determination
  • t 1/2 elimination half-life
  • Cl int intrinsic clearance
  • E h liver extraction rate.
  • Test substance Take about 2 mg of the compound, first prepare a 5 mM stock solution with DMSO, dilute it with DMSO to a 1 mM solution, and finally dilute with water to 50 ⁇ M of the test compound working solution, and set aside.
  • Stop solution Take about 2 mg of the compound tolbutamide, first prepare a 1 mg/mL stock solution with DMSO, and finally dilute to 100 ng/mL stop solution with acetonitrile, and store at 4 ° C until use.
  • the frozen Beagle dog plasma (purchased from Reid Liver Disease Research (Shanghai) Co., Ltd.) was pre-incubated and thawed in a 37 ° C water bath thermostat.
  • test compound working solution 50 ⁇ M was added to 490 ⁇ L of Beagle dog plasma, and the final concentration of the test substance was 1 ⁇ M, and two replicates were used.
  • sample tube at each time point is thawed, mixed, and centrifuged at 12000 rpm for 5 min in a 4 °C centrifuge. .
  • the stability of the compound in plasma was evaluated by the percentage retention of the compound after incubation at each time point, and the concentration of the sample was expressed as the ratio of the peak area of the test compound to the internal standard peak area.
  • C T0 is the concentration of the final solution of the compound at the initial incubation.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un inhibiteur irréversible du récepteur du facteur de croissance des fibroblastes (FGFR) tel que représenté par la formule I, un sel pharmaceutiquement acceptable, un stéréoisomère de celui-ci, et des préparations pharmaceutiques, des compositions pharmaceutiques et des utilisations de ces composés. Lesdits composés ont un effet inhibiteur efficace et hautement sélectif sur FGFR, et peuvent être utilisés pour le traitement de maladies associées induites par une anomalie FGF/FGFR, en particulier pour le traitement de maladies cancéreuses.
PCT/CN2018/099242 2017-08-08 2018-08-07 Inhibiteur de récepteur du facteur de croissance des fibroblastes et son utilisation WO2019029541A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710672089.X 2017-08-08
CN201710672089 2017-08-08

Publications (1)

Publication Number Publication Date
WO2019029541A1 true WO2019029541A1 (fr) 2019-02-14

Family

ID=65272747

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/099242 WO2019029541A1 (fr) 2017-08-08 2018-08-07 Inhibiteur de récepteur du facteur de croissance des fibroblastes et son utilisation

Country Status (3)

Country Link
CN (1) CN109384790B (fr)
TW (1) TWI750403B (fr)
WO (1) WO2019029541A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020139992A1 (fr) * 2018-12-27 2020-07-02 Agios Pharmaceuticals, Inc. Inhibiteurs aza-hétérobicycliques de mat2a et procédés d'utilisation pour le traitement du cancer
WO2021084266A1 (fr) * 2019-10-31 2021-05-06 Cancer Research Technology Limited Hétérocycles bicycliques contenant de l'azote en tant qu'inhibiteurs de kinase inductible par le sel sik2

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI767148B (zh) * 2018-10-10 2022-06-11 美商弗瑪治療公司 抑制脂肪酸合成酶(fasn)
CN113527311B (zh) * 2021-08-23 2022-05-06 中南大学湘雅医院 Fgfr4抑制剂、组合物及其在药物制备中的用途
CN113912602B (zh) * 2021-10-14 2023-05-05 温州医科大学 一种2-氧代-1,2-二氢-1,6-萘啶-7-基类化合物及其制备方法和用途
WO2024109799A1 (fr) * 2022-11-22 2024-05-30 西藏海思科制药有限公司 Dérivé de pyrimidine et son application en médecine

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1809569A (zh) * 2003-04-10 2006-07-26 霍夫曼-拉罗奇有限公司 嘧啶并化合物
WO2014182829A1 (fr) * 2013-05-09 2014-11-13 Principia Biopharma Inc. Dérivés de quinolone à utiliser en tant qu'inhibiteurs de facteur de croissance des fibroblastes
WO2015006492A1 (fr) * 2013-07-09 2015-01-15 Dana-Farber Cancer Institute, Inc. Inhibiteurs de kinase pour le traitement d'une maladie
CN104418860A (zh) * 2013-08-20 2015-03-18 中国科学院广州生物医药与健康研究院 嘧啶并杂环类化合物及其药用组合物和应用
CN105307657A (zh) * 2013-03-15 2016-02-03 西建阿维拉米斯研究公司 杂芳基化合物和其用途
WO2016115412A1 (fr) * 2015-01-18 2016-07-21 Newave Pharmaceutical Llc Inhibiteurs covalents de fgfr -4 à doubles "warheads"
CN106459034A (zh) * 2014-02-07 2017-02-22 普林斯匹亚生物制药公司 作为成纤维细胞生长因子受体抑制剂的喹诺酮衍生物

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1809569A (zh) * 2003-04-10 2006-07-26 霍夫曼-拉罗奇有限公司 嘧啶并化合物
CN105307657A (zh) * 2013-03-15 2016-02-03 西建阿维拉米斯研究公司 杂芳基化合物和其用途
WO2014182829A1 (fr) * 2013-05-09 2014-11-13 Principia Biopharma Inc. Dérivés de quinolone à utiliser en tant qu'inhibiteurs de facteur de croissance des fibroblastes
WO2015006492A1 (fr) * 2013-07-09 2015-01-15 Dana-Farber Cancer Institute, Inc. Inhibiteurs de kinase pour le traitement d'une maladie
CN104418860A (zh) * 2013-08-20 2015-03-18 中国科学院广州生物医药与健康研究院 嘧啶并杂环类化合物及其药用组合物和应用
CN106459034A (zh) * 2014-02-07 2017-02-22 普林斯匹亚生物制药公司 作为成纤维细胞生长因子受体抑制剂的喹诺酮衍生物
WO2016115412A1 (fr) * 2015-01-18 2016-07-21 Newave Pharmaceutical Llc Inhibiteurs covalents de fgfr -4 à doubles "warheads"

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BRAMELD, KEN A.: "Discovery of the Irreversible Covalent FGFR Inhibitor 8-(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6- dichloro-3,5-dimethoxyphen- yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the Treatment of Solid Tumors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 60, no. 15, 30 June 2017 (2017-06-30), XP055675966, ISSN: 0022-2623 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020139992A1 (fr) * 2018-12-27 2020-07-02 Agios Pharmaceuticals, Inc. Inhibiteurs aza-hétérobicycliques de mat2a et procédés d'utilisation pour le traitement du cancer
CN113474347A (zh) * 2018-12-27 2021-10-01 法国施维雅药厂 Mat2a的aza杂双环抑制剂和用于治疗癌症的方法
WO2021084266A1 (fr) * 2019-10-31 2021-05-06 Cancer Research Technology Limited Hétérocycles bicycliques contenant de l'azote en tant qu'inhibiteurs de kinase inductible par le sel sik2

Also Published As

Publication number Publication date
CN109384790A (zh) 2019-02-26
TW201910331A (zh) 2019-03-16
CN109384790B (zh) 2022-05-10
TWI750403B (zh) 2021-12-21

Similar Documents

Publication Publication Date Title
AU2020256431B2 (en) Bicyclic heterocycles as fgfr4 inhibitors
US11958855B2 (en) Aurora kinase inhibitors for inhibiting mitotic progression
TWI750403B (zh) 成纖維細胞生長因子受體抑制劑、含有其的藥物製劑及其用途
EP2215094B1 (fr) Composés hétérocycliques à teneur en n
TW202000669A (zh) 吲唑化合物及其用途
WO2021113479A1 (fr) Hétérocycles tricycliques en tant qu'inhibiteurs de fgfr
TW201811799A (zh) 吡唑并嘧啶化合物及其用途
WO2019062733A1 (fr) Inhibiteur de pde9 et son utilisation
KR20100118989A (ko) 키나제 억제제로서의 피리도[4,3-ｄ]피리미디논 유도체
WO2012167600A1 (fr) Composé de [b]pyridone hétérocyclique, ses intermédiaires, procédé de préparation et utilisations
WO2018108079A1 (fr) Composé inhibiteur multi-kinase, forme cristalline et utilisation associée
WO2020038460A1 (fr) Nouvel inhibiteur de dérivé de quinoléine
TWI818424B (zh) 含氮多環稠環類化合物，其藥物組合物、製備方法和用途
WO2022237676A1 (fr) Préparation et application d'un inhibiteur de la phosphatase shp2
WO2020151636A1 (fr) Inhibiteur de pde9 et son utilisation
WO2020143626A1 (fr) Inhibiteur de pde9 et son utilisation
WO2016050171A1 (fr) Inhibiteur de la kinase du lymphome anaplasique polycyclique
WO2022160931A1 (fr) Dérivé de pyridopyrimidine, son procédé de préparation et son utilisation
JPWO2020111087A1 (ja) 複素環化合物
CN116568689A (zh) 一种作为sos1抑制剂的多环嘧啶类衍生物、其制备方法及用途
CN114437116A (zh) 杂环化合物及其制备方法、药物组合物和应用
CN116669738A (zh) 一种作为sos1抑制剂的嘧啶并吡啶酮类衍生物、其制备方法及用途
WO2021249319A1 (fr) Composé tricyclique, composition pharmaceutique et utilisation de celui-ci
CA3080623A1 (fr) Compose presentant une activite inhibitrice de kinase erk et son utilisation
WO2024061333A1 (fr) Inhibiteur de protéine mutante kras, son procédé de préparation et son utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18843011

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18843011

Country of ref document: EP

Kind code of ref document: A1