WO2023202625A1 - Inhibiteur de fgfr2 et son procédé d'utilisation - Google Patents

Inhibiteur de fgfr2 et son procédé d'utilisation Download PDF

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WO2023202625A1
WO2023202625A1 PCT/CN2023/089242 CN2023089242W WO2023202625A1 WO 2023202625 A1 WO2023202625 A1 WO 2023202625A1 CN 2023089242 W CN2023089242 W CN 2023089242W WO 2023202625 A1 WO2023202625 A1 WO 2023202625A1
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phenyl
fluoro
group
groups
oxy
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PCT/CN2023/089242
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Chinese (zh)
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朱程刚
杨铉
张朝春
汪春牛
王倩文
陈超乐
徐良亮
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深圳福沃药业有限公司
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Publication of WO2023202625A1 publication Critical patent/WO2023202625A1/fr

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    • 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
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to a highly selective FGFR2 inhibitor and its preparation method and application.
  • This article relates to dihydroimidazopyrrolopyrimidines and pharmaceutically acceptable salts thereof, which compounds or salts thereof may be used to treat or prevent diseases or conditions by modulating certain mutant forms of fibroblast growth factor receptors .
  • pharmaceutical compositions comprising the compounds or salts thereof, and methods of using the compounds and salts thereof to treat a variety of diseases mediated by various forms of FGFR2, including intrahepatic cholangiocarcinoma, gastric cancer, and the like.
  • Fibroblast growth factor receptor is a tyrosine kinase receptor that binds to fibroblast growth factor ligands.
  • FGFR is a family of tyrosine kinase receptors composed of an extracellular ligand-binding domain and an intracellular tyrosine kinase domain, including FGFR1, FGFR2, FGFR3 and FGFR4 subtypes.
  • the ligand FGF When the ligand FGF binds, it will lead to receptor dimerization, phosphorylation and changes in intracellular domain conformation, stimulate activation of protein kinase activity, and recruit many intracellular proteins for binding. These protein interactions can help activate a series of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phosphatase C, which are important for cell growth, proliferation, and survival.
  • FGFR Aberrant activation of this pathway, such as overexpression of FGF ligands or through activating mutations in FGFR, can lead to tumor growth, progression, and resistance to conventional cancer therapies, leading to cell proliferation, growth, differentiation, migration, and angiogenesis.
  • genetic changes that can bring about ligand-independent receptor activation include gene amplification.
  • Unregulated FGFR signals are generated through FGFR gene amplification or fusion, FGFR missense mutations, etc., and are expressed by Receptor overexpression caused by dysregulation of epigenetic and/or transcriptional regulatory factors, or upregulation of FGF ligands in the tumor microenvironment.
  • FGFR is expressed in multiple cell types, and therefore, aberrant FGFR signaling is associated with tumor formation, tumor progression, and treatment resistance in multiple tumor types.
  • pan-FGFR inhibitors i.e., inhibitors that non-selectively inhibit FGFR1-4
  • pan-FGFR inhibitors include Erdafitinib, Pemigatinib, etc., but due to their low selectivity for FGFR2, they can cause many FGFR Altered cancer clinical responses, and these inhibitors have dose-limiting on-target toxicities.
  • One of the most important adverse effects of pan-FGFR inhibitors is hyperphosphatemia. Regulation of phosphate reabsorption is mediated by FGFR3 and FGFR1. Therefore, there is a need for a highly selective FGFR2 inhibitor, especially one with weak inhibitory activity against FGFR1, FGFR3 and/or FGFR4 (J. Gattineni et al., Am. J. Physiol.
  • Pan-FGFR inhibitors have been shown to be effective in cancers with FGFR2 gene fusions and FGFR2 amplification and/or FGFR2 activating mutations, however low response rates and duration suggest toxicity limitations. Therefore, there is a need for FGFR2 selective inhibitor compounds that are useful in the treatment of tumors and other disorders.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which has good FGFR inhibitory activity, especially good FGFR2 selectivity, and can be used for the safe and effective treatment of related diseases.
  • R 5 is selected from the following groups: -R 5A -L 5 -R 5B ;
  • R 5A is selected from the following groups:
  • R 5A is selected from C 3-14 cycloalkyl, aryl, C 5-14 heteroaryl, C 3-14 saturated or partially unsaturated heterocycloalkyl, which is optionally substituted by at least one substituent R 5C , C 3-14 heterocycloalkyl and C 5-14 heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • R 5C is selected from hydrogen, halogen (such as -F, -Cl or -Br), cyano, hydroxyl, amino, nitro, alkyl, alkoxy, alkenyl, alkynyl, C 1-3 haloalkyl, C 1-3 haloalkoxy (such as -OCF 3 );
  • R 5B is selected from C 3-14 cycloalkyl, aryl, C 5-14 heteroaryl, C 3-14 saturated or unsaturated heterocycloalkyl, which is optionally substituted by at least one substituent R 5D , C 3-14 Heterocycloalkyl and C 5-14 heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • R 5D is selected from hydrogen, halogen (such as -F, -Cl or -Br), cyano, hydroxyl, amino, nitro, alkyl, alkoxy, alkenyl, alkynyl, C 1-3 haloalkyl, C 1-3 haloalkoxy (such as -OCF 3 );
  • Cy 6 is selected from C 3-14 cycloalkyl, aryl, C 5-14 heteroaryl, saturated or partially unsaturated C 3-14 cycloalkyl, saturated or partially unsaturated C 3-14 hetero Cycloalkyl, C 5-14 heteroaryl, which is optionally substituted by at least one substituent R Cy6 , said C 3-14 cycloalkyl, C 3-14 heterocycloalkyl, C 3-14 hetero Cycloalkyl and C 5-14 heteroaryl respectively contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N, and R Cy6 is selected from hydrogen , Halogen (such as -F, -Cl or -Br), cyano, hydroxyl, amino, nitro, alkyl, alkoxy, alkenyl, alkynyl, C 1-3 haloalkyl, C 1-3 haloalkoxy group (such as -OCF 3 ); wherein the amino, alkyl, al
  • RW is considered a warhead group particularly suitable for covalent binding to sulfhydryl side chains of protein kinases, such as Cys491 of FGFR2.
  • RW is characterized by the ability to covalently bind to a cysteine residue, thereby irreversibly inhibiting a protein kinase.
  • the protein kinase is FGFR.
  • the protein kinase is FGFR2.
  • the protein kinase is FGFR2 and the cysteine residue is Cys491.
  • R W is selected from the following groups: halogen,
  • R WA , R WB , and R WC are independently selected from hydrogen, deuterium, halogen, -CN-, -C(O)R-, -C(O)OR, -C(O)NR 2 , -C(O) N(R)OR, or optionally C 1-6 aliphatic hydrocarbon group (such as C 1-6 alkyl or C 2-6 alkenyl), phenyl, C 3-7 saturated or partially unsaturated heterocycloalkyl and Contains 1, 2 heteroatoms independently selected from -NH-, -O-, -S-, or 1, 2, 3 or 4 heteroatoms independently selected from -NH-, -O-, -S- Heteroaryl, wherein the ring is substituted by w R C groups; or
  • R WA and R WB , R WB and R WC may together with the atoms to which they are attached form a saturated, partially unsaturated ring of C 4-7 , wherein said ring may respectively contain 0, 1 or 2 atoms independently selected from - Heteroatoms or heteroatom groups of NH-, -O-, -S-; wherein the ring is substituted by w R C groups;
  • R WD is selected from halogen or -OS(O) 2 R;
  • R 5C , R 5D , and R 7A are independently selected from RA or RB and are substituted by u R C groups, or two R 5C groups, one R 5C group and one R 5D group, or two The R 5D groups together with the atoms to which they are attached form a C 3-7 saturated, partially unsaturated, or aryl group, wherein the C 3-7 saturated, partially unsaturated, or aryl group contains 0, 1, 2 respectively , 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-; wherein the ring is substituted by w R C groups;
  • R A is independently selected from oxygen, halogen, -CN, -NO 2 , -OR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S( O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O) NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , - N(R)S(O) 2 NR 2 or -N(R)S(O) 2 R;
  • R B is independently selected from C 1-6 aliphatic hydrocarbon group (such as C 1-6 alkyl or C 2-6 alkenyl); phenyl; C 5-6 monocyclic heteroaryl group, the monocyclic heteroaryl group is selected from Contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-; C 8-10 bicyclic heteroaryl, the bicyclic heteroaryl is selected from the group consisting of 1, 2, 3 or 4 independent Heteroatom or heteroatom group selected from -NH-, -O-, -S-; C 3-7 saturated or partially unsaturated cycloalkyl group; C 3-7 saturated or partially unsaturated monoheterocycloalkyl group,
  • the monoheterocyclic alkyl group is selected from the group consisting of 1 or 2 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-; C 7-12 bicyclic heterocycloalkyl group, the bicyclic hetero
  • R C is independently selected from oxygen, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -S(O) 2 F , -OS(O) 2 F , -C(O)R , -C(O)OR , -C(O)NR 2 , -C(O )N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C (O)OR, -N(R)C(O)R, -N(R)C (O)NR 2 , -N(R)C (O)NR 2 ,
  • R is independently selected from hydrogen, or optionally C 1-6 aliphatic hydrocarbon group (such as C 1-6 alkyl or C 2-6 alkenyl); phenyl; C 3-7 saturated or partially unsaturated heterocycloalkyl,
  • the heterocycloalkyl group is selected from the group consisting of 1 or 2 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-; C 5-6 heteroaryl group, the heteroaryl group is selected from the group consisting of 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-;
  • the two R groups When two R groups are attached to the same nitrogen atom, the two R groups together with the nitrogen atoms to which they are attached form a C 4-7 saturated, partially unsaturated heteroaryl group, wherein the heteroaryl group
  • the aryl group contains 0, 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-;
  • n, p, q, r, t, u, v and w are independently selected from 0, 1, 2, 3 or 4.
  • Cy 6 is selected from phenylene, divalent saturated or partially unsaturated C 3-7 monocyclic alkyl; divalent saturated or partially unsaturated Saturated C 8-14 bicycloalkyl; divalent saturated or partially unsaturated C 3-7 monoheterocycloalkyl; the monoheterocycloalkyl contains 1, 2, 3 or 4 independently selected from -N-, -O-, -S- heteroatoms or heteroatom groups; divalent saturated or partially unsaturated C 8-14 biheterocycloalkyl groups; the biheterocycloalkyl groups include 1 and 2 respectively , 3 or 4 heteroatoms or heteroatom groups independently selected from -N-, -O-, -S-; C 5-6 monocyclic heteroaryl, the monocyclic heteroaryl includes 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -N-, -O-, -S-; C 9-10 bicyclic heteroaryl; the
  • Cy 6 is selected from divalent saturated or partially unsaturated C 3-14 cycloalkyl; in addition to -L 6 -R W , Cy 6 is also modified by p R 6 groups Substitution; in some embodiments, Cy 6 is selected from divalent saturated and a partially unsaturated C 3-7 monocyclic alkyl group, or a divalent saturated or partially unsaturated C 8-14 bicyclic alkyl group; in addition to -L 6 -R W , the Cy 6 Substituted by p R 6 groups; Cy 6 is selected from divalent saturated or partially unsaturated C 3-7 monoheterocycloalkyl; in addition to -L 6 -R W , the Cy 6 is also p R 6 groups are substituted; Cy 6 is selected from divalent saturated or partially unsaturated C 8-14 biheterocycloalkyl; in addition to -L 6 -R W , the Cy 6 is also substituted by p R 6 group substitution;
  • Cy 6 is selected from divalent saturated or partially unsaturated C 3-14 heterocycloalkyl groups; the heterocycloalkyl groups respectively contain 1, 2, 3 or 4 independently selected from -N -, -O-, -S- heteroatoms or heteroatom groups; in addition to -L 6 -R W , Cy 6 is also substituted by p R 6 groups; in some embodiments, Cy 6 is selected from From divalent saturated or partially unsaturated C 3-7 monoheterocycloalkyl; the monoheterocycloalkyl contains 1, 2, 3 or 4 independently selected from -N-, -O-, - S- heteroatoms or heteroatom groups; or C 8-14 bicycloalkyl groups; the bicycloalkyl groups respectively contain 1, 2, 3 or 4 hetero atoms independently selected from -N-, -O-, -S- Atoms or heteroatom groups; in addition to -L 6 -R W , Cy 6 is also substituted by p R 6 groups;
  • Cy 6 is selected from divalent saturated or partially unsaturated C 3-7 monoheterocycloalkyl groups; the monoheterocycloalkyl groups respectively contain 1, 2, 3 or 4 independently selected from Heteroatoms or heteroatom groups of -N-, -O-, -S-; in addition to -L 6 -R W , the Cy 6 is also substituted by p R 6 groups; in some embodiments, Cy 6 is selected from divalent saturated or partially unsaturated C 5-6 monoheterocycloalkyl; the monoheterocycloalkyl contains 1 or 2 independently selected from -N-, -O-, -S- Heteroatoms or heteroatom groups; in addition to -L 6 -R W , Cy 6 is also substituted by p R 6 groups; in some embodiments, Cy 6 is selected from pyrrolidinyl or dihydropyrrolidine group; in addition to -L 6 -R W , the Cy 6 is also substituted by p R 6 groups
  • Cy 6 is selected from C 5-14 heteroaryl; the heteroaryl contains 1, 2, 3 or 4 heteroaryls independently selected from -N-, -O-, -S-. atoms or heteroatom groups; in addition to -L 6 -R W , Cy 6 is also substituted by p R 6 groups; in some embodiments, Cy 6 is selected from C 5-6 monocyclic heteroaryl; so The above-mentioned monocyclic heteroaryl groups respectively contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -N-, -O-, -S-; or C 9-10 bicyclic heteroaryl groups, the Bicyclic heteroaryl groups respectively contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -N-, -O-, -S-; in addition to -L 6 -R W , the Cy 6 Also substituted by p R 6 groups;
  • Cy 6 is selected from C 5-6 monocyclic heteroaryl; the monocyclic heteroaryl contains 1, 2, 3 or 4 independently selected from -N-, -O-, - S- heteroatom or heteroatom group; in addition to -L 6 -R W , Cy 6 is also substituted by p R 6 groups; in some embodiments, Cy 6 is selected from C 5-6 monocyclic heterocyclic Aryl; the monocyclic heteroaryl contains 1 or 2 heteroatoms or heteroatom groups independently selected from -N-, -O-, -S-; the Cy 6 except -L 6 -R W In addition, it is also substituted by p R 6 groups; in some embodiments, Cy 6 is selected from C 5 Cyclic heteroaryl; the monocyclic heteroaryl contains 1 or 2 independently selected nitrogen atoms respectively; the Cy 6 , in addition to -L 6 -R W , is also substituted by p R 6 groups;
  • Cy 6 is selected from C 9-10 bicyclic heteroaryl; the bicyclic heteroaryl contains 1, 2, 3 or 4 independently selected from -N-, -O-, -S- Heteroatoms or heteroatom groups; in addition to -L 6 -R W , Cy 6 is also substituted by p R 6 groups; in some embodiments, Cy 6 is selected from C 5-6 C 9-10 bicyclic Heteroaryl; the C 9-10 bicyclic heteroaryl contains 1, 2 or 3 independently selected nitrogen atoms; the Cy 6, in addition to -L 6 -R W , also has p R 6 group substitution;
  • -Cy 6 is selected from:
  • R 6 is independently selected from RA or RB , said R 6 is substituted by q R C groups; or two R 6 groups, one R 6 group and one RL group, one R 6 group And one R WA group, one R 6 group and one R 7a group together with the atoms to which they are connected form a C 4-8 partially unsaturated or aryl group, the C 4-8 partially unsaturated and aryl groups respectively include 0, 1, 2, 3 or 4 heteroatoms or heterogens independently selected from -NH-, -O-, -S- Subgroup; the ring is replaced by r R C groups;
  • two R 6 groups, one R 6 group and one R L group, one R 6 group and one R WA group, one R 6 group and one R 7a group are combined with them
  • the connected atoms together form a C 4-8 partially unsaturated or aryl group, which respectively contains 0, 1 , 2, 3 or 4 independently selected from -NH-, -O- , -S- heteroatom or heteroatom group; the ring is replaced by r R C groups;
  • one R 6 group and one R WA group together with the atom to which they are attached form a C 4-8 partially unsaturated or aryl group, the C 4-8 partially unsaturated and aryl groups respectively containing 0 , 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-; the ring is replaced by r R C groups; one R 6 group and one R The 7a groups together with the atoms to which they are attached form C 4-8 partially unsaturated or aryl groups, which respectively contain 0, 1 , 2, 3 or 4 independently selected from -NH -, -O-, -S- heteroatoms or heteroatom groups; the ring is replaced by r R C groups;
  • one R 6 group and one R 7a group together with the atom to which they are attached form a C 4-8 partially unsaturated or aryl group
  • the C 4-8 partially unsaturated and aryl groups respectively include 0 , 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-; the ring is substituted by r R C groups.
  • one R 6 group and one R 7a group together with the atom to which they are connected form a C 4-8 partially unsaturated ring, and the C 4-8 partially unsaturated ring contains 1 nitrogen atom;
  • Said rings respectively contain 1, 2, or 3 independently selected from halogen, -CN, -O-(C 1-4 alkyl), and -(C 1-4 alkyl); the C 1-4 alkyl Contains any fluorine selected from 1, 2 or 3, respectively.
  • one R 6 group and one R 7a group together with the atom to which they are attached form a C 4-8 partially unsaturated ring. In some embodiments, one R 6 group and one R 7a group together with the atom to which they are attached form a C 4-8 partially unsaturated ring.
  • the C 4-8 partially unsaturated ring contains 1 nitrogen atom;
  • R 5 (such as: -R 5A -L 5 -R 5B ) is selected from:
  • R 5 (such as: -R 5A -L 5 -R 5B ) is selected from:
  • R 5 (such as: -R 5A -L 5 -R 5B ) is selected from:
  • R 5 (such as: -R 5A -L 5 -R 5B ) is selected from:
  • R 5 (such as: -R 5A -L 5 -R 5B ) is selected from:
  • R 5 (such as: -R 5A -L 5 -R 5B ) is selected from:
  • R 5 (such as: -R 5A -L 5 -R 5B ) is selected from:
  • the invention provides compounds of formula I-1, wherein R 5A is selected from the group consisting of aromatic ring groups, aromatic heterocycles, saturated or unsaturated cycloalkyl groups and their substitutes, including and Limited to phenylene, pyridylene, or cyclohexenylene and their substitutes, thus forming compounds of formula II-1, III-1, IV-1 or V-1:
  • the invention provides compounds of formula I-1, wherein R 5A is selected from phenylene, pyridylene, or pyrimidinyl, thus forming formulas VI-1, VII-1 , VIII-1 or IX-1 compounds:
  • the invention provides compounds of formula II-1, III-1, IV-1 or V-1, wherein Cy 6 is selected from phenyl, thus forming formulas X-1, XI Compounds of -1, XII-1 or XIII-1:
  • the invention provides compounds of formula X-1, XI-1, XII-1 or XIII-1:
  • R 5 is selected from
  • R 5B is selected from hydrogen or RB , and the R 5B is substituted by n R 5D groups;
  • R 6 are independently selected from RA or RB , and the R 6 is replaced by q R C ; two R 6 groups, one R 6 group and one R L group are respectively selected from C 4-7 parts. Saturated group or aryl group, the C 4-7 partially unsaturated group or aryl group respectively contains 0, 1, 2, 3 or 4 heteroatoms independently selected from -NH-, -O-, -S- Or a heteroatom group; the ring is replaced by r R C groups;
  • L 5 and L 6 are independently selected from a covalent bond, or C 1-4 divalent saturated or unsaturated, straight or branched hydrocarbon chain, in which one or two methylene units on the chain can be replaced by -CH( R L )-, -C(R L ) 2 -, C 3-5 cycloalkyl, C 3-5 heterocycloalkyl, C 5-6 heteroaryl, -NH-, -N(R L )- , -NHC(O)-, -N(R L )C(O)-, -C(O)NH-, -C(O)N(R L )-, -NHS(O) 2 -, -N (R L )S(O) 2 -, -S(O) 2 NH-, -S(O) 2 N(R L )-, -O-, -C(O)-, -OC(O)- , -C(O)O-, -S-, -
  • R WA , R WB , and R WC are independently selected from hydrogen, deuterium, halogen, -CN-, -C(O)R-, -C(O)OR, -C(O)NR 2 , -C(O) N(R)OR, or optional C 1-6 aliphatic hydrocarbon group (such as C 1-6 alkyl or C 2-6 alkenyl), phenyl, C 3-7 saturated or partially unsaturated heterocycloalkyl,
  • the heterocycloalkyl group contains 1, 2 heteroatoms independently selected from -NH-, -O-, -S-, and C 5-6 heteroaryl group, the heteroaryl group contains 1, 2, 3 or 4 heteroaryl groups independently selected from -NH-, -O-, -S- heteroatoms; or
  • R WA and R WB , R WB and R WC , R WA and RL , or R WC and RL together with the atoms to which they are attached form a saturated, partially unsaturated ring of C 4-7 , which ring respectively contains 0, 1 or 2 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-;
  • R WD is selected from halogen or -OS(O) 2 R;
  • R 5C , R 5D , and R 7A are independently selected from R A or RB , and substituted by u R C substituents;
  • R A is independently selected from oxygen, halogen, -CN, -NO 2 , -OR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S( O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O) NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , - N(R)S(O) 2 NR 2 or -N(R)S(O) 2 R;
  • R B is independently selected from C 1-6 aliphatic hydrocarbon group (such as C 1-6 alkyl or C 2-6 alkenyl); phenyl; C 5-6 monocyclic heteroaryl group, the monocyclic heteroaryl group is selected from Contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-; C 8-10 bicyclic heteroaryl, the bicyclic heteroaryl is selected from the group consisting of 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-; C 3-7 saturated or partially unsaturated cycloalkyl group; C 3-7 saturated or partially unsaturated
  • the monoheterocycloalkyl group is selected from the group consisting of 1 or 2 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-; C 7-12 bicyclic heterocycloalkanes base, the bicyclic heterocycloalkyl group is selected from the group
  • R C is independently selected from oxygen, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -S(O) 2 F , -OS(O) 2 F , -C(O)R , -C(O)OR , -C(O)NR 2 , -C(O )N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C (O)OR, -N(R)C(O)R, -N(R)C (O)NR 2 , -N(R)C (O)NR 2 ,
  • R is independently selected from hydrogen, or optionally C 1-6 aliphatic hydrocarbon group (such as C 1-6 alkyl or C 2-6 alkenyl); phenyl; C 3-7 saturated or partially unsaturated heterocycloalkyl,
  • the heterocycloalkyl group is selected from the group consisting of 1 or 2 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-; C 5-6 heteroaryl group, the heteroaryl group is selected from the group consisting of 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-;
  • R and R together with the nitrogen atom to which they are attached form a C 4-7 saturated, partially unsaturated heteroaryl group, wherein the heteroaryl group contains 0, 1, 2 or 3 independently selected from nitrogen heteroatoms ;
  • Any m, n, p, q, r, t, u, v and w are independently selected from 0, 1, 2, 3 or 4.
  • the invention provides compounds of formula II-1, III-1, IV-1 or V-1, wherein Cy 6 is selected from pyridylene, thus forming formula XIV-1 respectively , compounds of XV-1, XVI-1, XVII-1, XVIII-1, XIX-1, XX-1, or XXI-1:
  • the invention provides compounds of formula II-1, III-1, IV-1 or V-1, wherein Cy 6 is selected from pyrimidinyl, thus forming formula XXII-1 respectively. , XXIII-1, XXIV-1, or XXV-1 compounds:
  • each variable in L 5 , L 6 , R5B , R 5C , R W , R 6 , m and p is as defined in the Examples, classes and subclasses herein.
  • the invention provides formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1, IX-1, X -1, XI-1, XII-1, XIII-1, XIV-1, XV-1, XVI-1, XVII-1, XVIII-1, , XXIII-1, XXIV-1, or XXV-1 compounds, described in Represents the key connecting R 5 , Represents the key connecting Cy 6 .
  • the L 5 is selected from -O-, -C(O)-, -C(O)NH-, or -C(O)N(R L )-; in some more preferred embodiments, the L 5 Selected from -C(O)-;
  • the L 5 is selected from -C(O)NH-; in some more preferred embodiments, the L 5 is selected from -C(O)N(R L )-; more preferably In some embodiments, the L 6 is selected from -NH-, -N(R L )-;
  • the m is selected from 0 or 1; in some more preferred embodiments, the p is selected from 0;
  • the R W is selected from In some more preferred embodiments, the R W is selected from In some other preferred embodiments, the R W is selected from
  • R 5 is
  • the -Cy 6 -L 6 - moiety has a nitrogen atom
  • the R W end is a carbonyl group
  • the present invention provides a compound represented by the following formula XXVI or a pharmaceutically acceptable salt thereof:
  • Cy 6 , L 6 , R WA have the definitions as mentioned above, X is CH or N, and -Cy 6 -L 6 - is partially connected to the nitrogen atom through Partially connected.
  • the -Cy 6 -L 6 - moiety is phenylene amino, pyridylene amino, azetidinyl, azetidinyl optionally substituted by C 1-6 alkyl or halogen , azitidine group, azitidine group, azitidine group, azitidine group, methylene azetidinyl group, methylene azetidinyl group, methylene azepine group Cyclohexyl;
  • R WA is hydrogen or C 1-6 alkyl.
  • the present invention also provides compounds represented by the following formula or pharmaceutically acceptable salts thereof,
  • the present invention also provides a pharmaceutical composition, comprising as an active ingredient a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof or the above-mentioned compositions in the preparation of FGFR inhibitor-related drugs.
  • the FGFR inhibitor-related drug is a drug for solid tumors.
  • aliphatic or "aliphatic group” means a substituted or unsubstituted linear (i.e., unbranched) or branched chain hydrocarbon that is fully saturated or contains one or more unsaturated units. chain, a monocyclic or bicyclic hydrocarbon that is either fully saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as “carbocyclic” or “cycloaliphatic”), which has a linkage to the molecule single connection point for the remainder. Unless otherwise specified, aliphatic groups contain 1 to 6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1 to 5 aliphatic carbon atoms.
  • the aliphatic group contains 1 to 4 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet other embodiments, the aliphatic group contains 1 to 2 aliphatic carbon atoms.
  • cycloaliphatic (or “carbocyclic”) refers to a monocyclic C 3 -C 6 hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic, having a linkage to A single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched chain, substituted or unsubstituted alkyl, alkenyl, alkynyl and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl) Alkyl or (cycloalkyl)alkenyl.
  • alkyl refers to a monovalent aliphatic hydrocarbon group having a straight chain, a branched chain, a monocyclic moiety, or a polycyclic moiety, or a combination thereof, wherein the group is optionally in a straight chain , one or more carbon atoms of the branched chain, monocyclic portion or polycyclic portion, or combinations thereof, are substituted with one or more substituents at each carbon, wherein the one or more substituents are independently C 1 - C 10 alkyl.
  • alkyl examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and similar groups.
  • lower carbon number alkyl refers to a C1-4 straight chain or branched chain alkyl group.
  • exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
  • low carbon number haloalkyl refers to a C1-4 straight or branched chain alkyl group substituted by one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of a base nitrogen; or a heterocyclic Substituted nitrogen, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in pyrrolidinyl substituted on N)).
  • unsaturated means that a moiety has one or more units of unsaturation.
  • C 1-8 saturated or unsaturated, straight or branched divalent hydrocarbon chain
  • C 1-8 or C 1-6 or C 1-4 ) saturated or unsaturated, straight or branched divalent hydrocarbon chain means a straight or branched chain as defined herein.
  • alkylene refers to a divalent alkyl group.
  • Alkylene chain is polymethylene, i.e. -( CH2 ) n- , where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3.
  • Substituted alkylene A chain is a polymethylene in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.
  • alkenylene refers to a divalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene containing at least one double bond in which one or more hydrogen atoms have been replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.
  • halogen means F, Cl, Br or I.
  • aryl used alone or as part of a larger moiety such as “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to a group with a total of five to fourteen ring members.
  • aryl is used interchangeably with the term “aromatic ring”.
  • “aryl” refers to an aromatic ring system that may have one or more substituents, including (but not limited to) phenyl, biphenyl, naphthyl, anthracenyl and the like. group.
  • heteroaryl refers to a 5- to 6-membered group containing one or more heteroatoms (eg, one to three heteroatoms, such as nitrogen, oxygen, and sulfur).
  • Heteroaryl rings can be linked to adjacent groups via carbon or nitrogen.
  • heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, indole, and the like.
  • a 1,2,3,4-tetrahydroquinoline is a heteroaryl ring if its point of attachment is via a benzo ring, for example:
  • heterocyclyl refers to a saturated or partially unsaturated 3 to 10 membered monocyclic or 7 to 14 membered polycyclic ring system, including bridged or fused rings, And its ring system includes one to four heteroatoms, such as nitrogen, oxygen and sulfur. Heterocyclyl rings can be linked to adjacent groups via carbon or nitrogen.
  • partially unsaturated in the context of a ring refers to a monocyclic ring, or a constituent ring within a polycyclic (e.g., bicyclic, tricyclic, etc.) ring system, wherein said constituent ring contains at least one ring other than the ring itself Unsaturations other than those provided, but not aromatic.
  • partially unsaturated rings include, but are not limited to, 3,4-dihydro-2H-pyran, 3-pyrroline, 2-thiazoline, and the like.
  • the partially unsaturated ring it is a polycyclic ring
  • the other constituent rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on the partially unsaturated constituent ring.
  • 1,2,3,4-tetrahydroquinoline is a partially unsaturated ring, provided that the point of attachment is via a piperidinyl ring, for example:
  • saturated in the context of a ring refers to a 3 to 10 membered monocyclic or a 7 to 14 membered polycyclic (e.g., bicyclic, tricyclic, etc.) ring system, wherein the monocyclic ring or as a polycyclic ring
  • monocyclic saturated rings include, but are not limited to, azetidine, oxetane, cyclohexane, and the like.
  • a saturated ring is part of a polycyclic ring system
  • the other constituent rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on the saturated constituent ring.
  • 2-azaspiro[3.4]oct-6-ene is a saturated ring if its point of attachment is via an N-azetidinyl ring, for example:
  • alkylene As used herein, the terms “alkylene”, “arylene”, “cycloalkylene”, “heteroarylene”, “heterocycloalkylene” and other similar terms having the prefix “ylidene-” are Refers to the divalent bonding form of the group modified by the prefix.
  • alkylene is a divalent alkyl group that attaches the group to that to which it is attached.
  • bridged bicyclic refers to any saturated or partially unsaturated bicyclic system having at least one bridge, ie, carbocyclic or heterocyclic.
  • a "bridge” is an unbranched chain of multiple atoms or one atom or a valence bond connecting two bridgeheads, where a "bridgehead” is bonded to three or more backbone atoms (other than hydrogen) Any skeletal atom of a ring system.
  • the bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic groups are well known in the art and include those described below, wherein each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise stated, bridged bicyclic groups are optionally substituted with one or more substituents as set forth for aliphatic groups. Alternatively or additionally, any substitutable nitrogen of the bridging bicyclic group is optionally substituted.
  • Example bridged dual rings include:
  • compounds of the invention may contain "optionally substituted” moieties.
  • substituted means that one or more hydrogens of a specified moiety are replaced with a suitable substituent.
  • a group that is “optionally substituted” may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one selected from the specified When a group is substituted with substituents, the substituents at each position may be the same or different.
  • Combinations of substituents contemplated by this invention are preferably those which result in the formation of stable or chemically feasible compounds.
  • stable means that a compound does not undergo substantial changes when subjected to conditions that permit its production, detection, and (in certain embodiments) its recovery, purification, and use for one or more purposes disclosed herein. change.
  • Suitable monovalent substituents on R ⁇ are independently halogen, -(CH 2 ) 0-2 R ⁇ , -(halo R ⁇ ), -(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR ⁇ , -(CH 2 ) 0 -2 CH(OR ⁇ ) 2 ; -O(halogen R ⁇ ), -CN, -N 3 , -(CH 2 ) 0-2 C(O)R ⁇ , -(CH 2 ) 0-2 C(O)OH, -(CH 2 ) 0-2 C(O)OR ⁇ , -(CH 2 ) 0-2 SR ⁇ , -(CH 2 ) 0-2 SH , -(CH 2 ) 0-2 NH 2 , -(CH 2 ) 0-2 NHR ⁇ , -(CH 2 )
  • Suitable divalent substituents bonded to the ortho-substitutable carbon of the "optionally substituted” group include: -O(CR * 2 ) 2-3O- , wherein each R * appearing alone is selected from hydrogen , a substituted C 1-6 aliphatic group as defined below, or an unsubstituted 5 to 6 membered saturated, partially unsaturated or unsubstituted 5 to 6 membered saturated or partially unsaturated group having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. aromatic ring.
  • Suitable substituents on the aliphatic group of R * include halogen, -R ⁇ , -(halogen R ⁇ ), -OH, -OR ⁇ , -O(halogen R ⁇ ), -CN, -C(O)OH, -C(O)OR ⁇ , -NH 2 , -NHR ⁇ , -NR ⁇ 2 or -NO 2 , where each R ⁇ has not been Substituted or, in the case preceded by "halo" substituted only with one or more halogens and independently is C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or has 0 to 5 to 6 membered saturated, partially unsaturated or aromatic rings with 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.
  • Suitable substituents on the substitutable nitrogen of the "optionally substituted” group include Each of them is independently hydrogen, substituted C 1-6 aliphatic as defined below, unsubstituted -OPh, or unsubstituted 5 having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur to a 6-membered saturated, partially unsaturated or aromatic ring; or regardless of the above definition, two separate Together with intervening atoms, an unsubstituted 3 to 12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring is formed having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.
  • Suitable substituents on the aliphatic group are independently halogen, -R ⁇ , -(halogen R ⁇ ), -OH, -OR ⁇ , -O(halo R ⁇ ), -CN, -C(O )OH, -C(O)OR ⁇ , -NH 2 , -NHR ⁇ , -NR ⁇ 2 or -NO 2 , where each R ⁇ is unsubstituted or, when preceded by "halo", is only substituted by one or Multiple halogen substituted, and independently C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, with 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur 5 to 6-membered saturated, partially unsaturated or aromatic ring.
  • stereoisomers refers to compounds that have the same chemical formula but different structures or optical configurations.
  • stereoisomers refers to and includes isomeric molecules that have the same molecular formula but differ in the positioning of atoms and/or functional groups in space. All stereoisomers of the compounds of the present invention (e.g., those that may exist due to asymmetric carbons on each substituent), including enantiomeric and diastereomeric forms, are encompassed by the present disclosure within the scope. Therefore, unless otherwise stated, single stereochemical isomers as well as mixtures of enantiomeric, diastereomeric and geometric (or conformational) isomers of the compounds of the invention are within the scope of the invention.
  • tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. It should be understood that tautomers encompass both valence tautomers and proton tautomers (also known as proton-transfer tautomers). Valence tautomers include interconversions caused by the reorganization of some bonding electrons. Protic tautomers include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Unless otherwise stated, the present invention All tautomers of the compounds are within the scope of the invention.
  • isotopically substituted refers to the substitution of an atom with its isotope.
  • isotope refers to an atom that has the same atomic number as the atoms predominantly found in nature, but a different mass number (number of neutrons) than the mass number of the atoms predominantly found in nature.
  • a compound having isotopic substitution refers to a compound in which at least one atom contained therein is substituted by its isotope.
  • Atoms that may be substituted by their isotopes include, but are not limited to, hydrogen, carbon, and oxygen. Examples of isotopes of hydrogen atoms include 2 H (also represented as D) and 3 H.
  • isotopes of carbon atoms include 13C and 14C .
  • isotopes of oxygen atoms include 18 O.
  • all isotopic substitutions of the compounds of the invention are within the scope of the invention.
  • Such compounds are suitable for use, for example, as analytical tools, as probes in biological analyses, or as therapeutic agents according to the invention.
  • the warhead portion R W of provided compounds includes one or more deuterium atoms.
  • the term "pharmaceutically acceptable salt” means a salt suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reaction and the like and with reasonable The benefit/risk ratio is commensurate with those of salt.
  • Exemplary pharmaceutically acceptable salts are found, for example, in Berge et al., J. Pharm. Sci. 1977, 66(1), 1; and Gould, P.L., Int. One is incorporated herein by reference in its entirety).
  • Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases.
  • suitable inorganic and organic acids and bases include amino acids with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or by using other methods used in the art (such as ion exchange).
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethane sulfonate, formate, fumarate, glucoheptanate Glycolate, glycerophosphate, gluconate, hemisulfate, enanthate, caproate, hydroiodide, 2-hydroxy-ethane sulfonate, lactobionate, lactate, laurate , Lauryl sulfate, malate, maleate, malonate, methane sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, Palmitate, pamo
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like.
  • other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and salts such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and arylsulfonates. The counter ion forms the amine cation.
  • compositions are also intended to encompass half-salts in which the compound:acid ratio is 2:1 respectively.
  • exemplary half-salts are those derived from acids containing two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, Adipic acid and citric acid.
  • Other exemplary half-salts are those derived from diprotic mineral acids such as sulfuric acid.
  • Preferred exemplary hemi-salts include, but are not limited to, hemi-maleate, hemi-fumarate, and hemi-succinate.
  • the term “about” is used herein to mean approximately, approximately, around, or in the vicinity of. When the term “about” is used in connection with a numerical range, it modifies the range by extending the limits above and below the stated numerical value. In general, the term “about” is used herein to modify numerical values above and below the stated value: upward or downward (higher or lower) 20%.
  • an "effective amount,” “sufficient amount,” or “therapeutically effective amount” is an amount of a compound sufficient to achieve beneficial or desired results, including clinical results.
  • an effective amount may be sufficient, for example, to reduce or ameliorate the severity and/or duration of a disorder associated with FGFR2 signaling or one or more symptoms thereof; to prevent the progression of a condition or symptom associated with a disorder associated with FGFR2 signaling; or to enhance or otherwise improve the preventive or therapeutic effect of another therapy.
  • An effective amount also includes an amount of a compound that avoids or substantially attenuates undesirable side effects.
  • treatment is a means to obtain beneficial or desired results, including clinical results.
  • beneficial or desired clinical results may include (but are not limited to) alleviation or improvement of one or more symptoms or conditions, reduction in the severity of the disease or illness, stabilization of the disease or illness (i.e., no worsening), prevention of the spread of the disease or illness , delay or slowing of the progression of a disease or illness, improvement or alleviation of the state of a disease or illness, and remission (whether partial or total), detectable or undetectable.
  • Treatment may also mean prolongation of survival compared to expected survival without treatment.
  • therapy may be administered after one or more symptoms have developed.
  • therapy may be administered in the absence of symptoms.
  • therapy may be administered to susceptible individuals prior to the onset of symptoms (eg, based on a history of symptoms and/or based on genetic or other predisposing factors). Treatment can also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • in need thereof refers to a need for symptomatic or asymptomatic relief from a condition associated with FGFR2 signaling activity or that may otherwise be relieved by a compound and/or composition of the present disclosure.
  • the compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic and/or enzymatic methods.
  • the intermediate (IB) is obtained by the substitution reaction of the compound of formula (IA) and the compound of formula N-Boc-2-chloroethylamine:
  • Intermediate (IC) is treated with ammonia water to obtain intermediate (ID).
  • Intermediate (ID) undergoes a halogenation reaction to obtain intermediate (IE), and continues to be deprotected under the action of a suitable acid to obtain intermediate (IF):
  • the anhydrous solvent is selected from ethylene glycol dimethyl ether, dimethyl ether, xylene, toluene, N,N-dimethylformamide, dioxane, dichloromethane, methanol, and acetonitrile.
  • the catalyst is selected from methane sulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-Amino-1,1'-biphenyl-2-yl)palladium(II)(BrettPhos Pd G3), tetrakis(triphenylphosphine)palladium(Pd(PPh 3 ) 4 ), [1,1' -Bis(diphenylphosphonium)ferrocene]palladium dichloride (Pd(dppf)Cl2), tris(dibenzylacetone)dipalladium(0)( Pd2 (dba) 3 ), bisdibenzylidene Acetone palladium (0) (Pd (dba) 2 ), [1,1'-bis (di-tert-butylphosphine) ferrocene
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • T 3 P 1-propylphosphonic anhydride
  • Step 3 Synthesis of (2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl-carbamic acid tert-butyl ester
  • Step 4 (2-(4-chloro-5-iodo-(3-fluoro-4-((6-methylpyridin-2-yl)oxo)phenyl)-7H-pyrrolo[2,3- d] Synthesis of pyrimidin-7-yl)ethyl-carbamic acid tert-butyl ester
  • Step 5 (2-(6-bromo-4-chloro-5-iodo-(3-fluoro-4-((6-methylpyridin-2-yl)oxo)phenyl)-7H-pyrrolo Synthesis of [2,3-d]pyrimidin-7-yl)ethyl-carbamic acid tert-butyl ester
  • Step six 4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo[1', Synthesis of tert-butyl 2':1,5]pyrrolo[2,3-d]pyrimidine-6-carboxylate
  • Step 7 4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-imidazo[1',2' :Synthesis of 1,5]pyrrolo[2,3-d]pyrimidine
  • Step 8 (3-(4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo Synthesis of [1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamic acid tert-butyl ester
  • Step 9 6-(3-aminobenzene)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-imidazo[ Synthesis of 1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-amino
  • reaction solution is concentrated and separated and purified through a silica gel column to obtain 6-(3-aminobenzene)-5-(3-fluoro -4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-imidazo[1',2':1,5]pyrrolo[2,3-d ]pyrimidine-4-amino (50 mg, yield 32.3%).
  • Step 10 N-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acrylamide
  • 6-(3-Aminobenzene)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-imidazo[1' ,2':1,5]pyrrolo[2,3-d]pyrimidine-4-amino 50mg, 1.00eq
  • acryloyl chloride 9.86mg, 1.00eq
  • LCMS detects the end of the reaction.
  • Step 2 Synthesis of (2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)carbamic acid tert-butyl ester
  • Step 3 (2-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d] Synthesis of pyrimidin-7-yl)ethyl)carbamic acid tert-butyl ester
  • Step 4 (2-(4-amino-6-bromo-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo Synthesis of [2,3-d]pyrimidin-7-yl)ethyl)carbamic acid tert-butyl ester
  • Step six N-(2-(4-amino-6-bromo-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[ Synthesis of 2,3-d]pyrimidin-7-yl)ethyl)-3-(phenylsulfonyl)propylamine
  • Step seven 1-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo[ Synthesis of 1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)prop-2-en-1-one
  • Step 1 3-((2-(4-amino-6-bromo-5-(3-fluoro-4-((6-methylpyrimidin-2-yl)oxo-phenyl))-7H-pyrrolo Synthesis of [3,2-d]pyrimidin-7-yl)ethyl)amino)tetrahydropyrrole-1-carboxylic acid tert-butyl ester
  • Step 2 3-(4-amino-5-(3-fluoro-4-((6-methylpyrimidin-2-yl)oxo)phenyl)-7,8-2H-6H-imidazo[1 ',2':Synthesis of 1,5]pyrrole[3,2-d]pyrimidin-6-yl)tetrahydropyrrole-1-carboxylic acid tert-butyl ester
  • Step 3 (R)-5-(3-fluoro-4-((6-methylpyrimidin-2-yl)oxo)phenyl)-6-(tetrahydropyrrol-3-yl)-7,8 -2Hydro-6H-imidazo[1',2':1,5]pyrrole[3,2-d]pyrimidin-4-amine, (S)-5-(3-fluoro-4-((6- Methylpyrimidin-2-yl)oxo)phenyl)-6-(tetrahydropyrrol-3-yl)-7,8-2hydro-6H-imidazo[1',2':1,5]pyrrole Synthesis of [3,2-d]pyrimidin-4-amine
  • the organic phase is concentrated and spin-dried to obtain a crude product.
  • the crude product is separated by chirality to obtain (R)- 5-(3-fluoro-4-((6-methylpyrimidin-2-yl)oxo)phenyl)-6-(tetrahydropyrrol-3-yl)-7,8-2hydro-6H-imidazole Para[1',2':1,5]pyrrole[3,2-d]pyrimidin-4-amine (50.0 mg, 107umol, yield 14.6%) and (S)-5-(3-fluoro-4- ((6-methylpyrimidin-2-yl)oxo)phenyl)-6-(tetrahydropyrrol-3-yl)-7,8-2hydro-6H-imidazo[1',2':1 ,5]pyrrole[3,2-d]pyrimidin-4-amine (60.0 mg, 125umol, yield 17.1%).
  • Step 4 (R)-1-(3-(4-amino-5-(3-fluoro-4-((6-methylpyrimidin-2-yl)oxo)phenyl)-7,8-2 Hydro-6H-imidazo[1',2':1,5]pyrrole[3,2-d]pyrimidin-6-yl)tetrahydropyrrol-1-yl)-propyl-2-en-1-one Synthesis
  • Step 5 (S)-1-(3-(4-amino-5-(3-fluoro-4-((6-methylpyrimidin-2-yl)oxo)phenyl))-7,8-2 Hydro-6H-imidazo[1',2':1,5]pyrrole[3,2-d]pyrimidin-6-yl)tetrahydropyrrol-1-yl)-propyl-2-en-1-one Synthesis
  • Step 1 (4-(4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo Synthesis of [1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamic acid tert-butyl ester
  • reaction solution is filtered, and the filtrate is spin-dried and separated and purified through a silica gel column to obtain (4-(4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)) Oxy)phenyl)-7,8-dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)aminotertiary acid Butyl ester (160 mg, yield 35.9%).
  • reaction solution is concentrated and separated and purified through a silica gel column to obtain 6-(4-aminobenzene)-5-(3-fluoro -4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3 -d]pyrimidine-4-amino (100 mg, yield 17.2%).
  • Step 3 N-(4-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acrylamide
  • Step 1 4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(4-methyl-3-nitrobenzene)- Synthesis of 7,8-dihydro-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine
  • Step 2 5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(4-methyl-3-nitrobenzene)-7,8- Synthesis of dihydro-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-amino
  • Step 3 6-(3-amino-4-methylphenyl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8- Synthesis of dihydro-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-amino
  • Step 4 N-(5-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-methylphenyl)acrylamide
  • Step 1 3-((2-(4-amino-6-bromo-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl))7-H-pyrrole Synthesis of tert-butyl[2,3-d]pyrimidin-7-yl)ethyl)amino)azetidine-1-carboxylate
  • Step 2 3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo[ Synthesis of tert-butyl 1',1':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)azetidine-1-carboxylate
  • Step 3 6-(azetidin-3-yl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-di Synthesis of hydrogen-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 4 1-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)azetidin-1-yl)prop-2-en-1-one
  • Step 1 4-(((2-(4-amino-6-bromo-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl))-7H-pyrrole Synthesis of tert-butyl[2,3-d]pyrimidin-7-yl)ethyl)amino)methyl)piperidine-1-carboxylate
  • Step 2 4-(((2-(4-amino-6-bromo-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl))-7H-pyrrole Synthesis of tert-butyl[2,3-d]pyrimidin-7-yl)ethyl)amino)methyl)piperidine-1-carboxylate
  • Step 3 5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(piperidin-4-methylene)-7,8-dihydro Synthesis of -6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-amino
  • Step 4 1-(4-((4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl))-7,8-dihydro-6H -Synthesis of imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)methyl)piperidin-1-yl)prop-2-en-1-one
  • Reverse phase column purification yields 1-(4-((4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl))-7,8-dihydro -6H-Imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)methyl)piperidin-1-yl)prop-2-en-1-one (13.0 mg, yield 97.6%).
  • Step 1 4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(2-nitrophenyl)-7,8- Synthesis of dihydro-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine
  • Step 2 5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(2-nitrophenyl)-7,8-dihydro-6H -Synthesis of imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-amino
  • Step 4 N-(2-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H -Synthesis of imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)acrylamide
  • Step 1 3-((2-(4-amino-6-bromo-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl))-7H-pyrrolo Synthesis of [2,3-d]pyrimidin-7-yl)ethyl)amino)piperidine-1-carboxylic acid tert-butyl ester
  • Step 2 (S)-3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H -Imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylic acid tert-butyl ester and (R)-3-(4-amino -5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo[1',2':1,5 Synthesis of tert-butylpyrrolo[2,3-d]pyrimidin-6-yl)piperidine-1-carboxylate
  • Step 3 (S)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(piperidin-3-yl)-7,8- Synthesis of dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 4 (S)-1-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-di Synthesis of hydrogen-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one
  • Step 1 (R)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(piperidin-3-yl)-7,8- dihydrogen Synthesis of -6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 2 (R)-1-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-di Synthesis of hydrogen-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)piperidin-1-yl)prop-2-en-1-one
  • Step 1 N-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide
  • Step 1 Synthesis of ethyl 2-methyl-2-(4-methylpiperazin-1-yl)propionate
  • Step 4 N-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyanoacetyl
  • Step 5 (E)-N-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-di Hydrogen-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)-2-cyano-4-methyl-4-(4-methyl Synthesis of piperazin-1-yl)-2-enamide
  • the compounds of the examples in Table 1 can be prepared by following steps similar to the route of Preparation Example 1. The difference is that raw materials are replaced in the intermediate steps to obtain the corresponding compounds.
  • reaction solution was added to saturated brine and ethyl acetate.
  • organic phase was dried and concentrated, and purified by flash silica gel column to obtain 7-(2,2-dimethoxy-ethyl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy) )Phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (14.0 g, 21.9 mmol, 66.5% purity, 63.7% yield).
  • NBS 7-(2,2-dimethoxy-ethyl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)) in portions Oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (13.0g, 30.7mmol) in acetonitrile (130mL), the reaction solution was stirred at 20°C for 1 hour, LCMS and TLC Monitor the end of the reaction, add the reaction solution to ethyl acetate, wash the organic phase with saturated brine, dry and concentrate, and then purify and beat through a fast silica gel column to obtain 6-bromo-7-(2,2-dimethoxy-ethyl) )-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (6.00g, 38.9% yield).
  • Step 5 1-((2-(4-amino-6-bromo-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl))-7H-pyrrole Synthesis of [2,3-d]pyrimidin-7-yl)ethyl)amino)cyclopropylcarbonitrile
  • Step six 1-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo Synthesis of [1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)cyclopropylcarbonitrile
  • Step 7 6-(1-(aminomethyl)cyclopropyl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8 -Dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-amino
  • reaction solution is added to saturated brine (50 mL) and ethyl acetate (150 mL).
  • the organic phase is dried and concentrated, and purified by prep-HPLC to obtain 6-(1-(aminomethyl)cyclopropyl).
  • -5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo[1',2':1,5 ]pyrrolo[2,3-d]pyrimidine-4-amino (17.0 mg, 9.52% yield).
  • Step 8 N-((1-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl))-7,8-dihydro- Synthesis of 6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)cyclopropyl)methyl)acrylamide
  • acryloyl chloride (6.09 mg, 67.3umol) was slowly added dropwise to 6-(1-(aminomethyl)cyclopropyl)-5-(3-fluoro-4-((6-methyl) Pyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-amino (15.0 mg, 33.6umol) in tetrahydrofuran (0.1 mL), and the reaction solution was continued to stir at 20°C for 1 hour.
  • LCMS monitors the end of the reaction, adds water to quench, and filters.
  • the filtrate is purified by prep-HPLC to obtain N-((1-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl) )oxy)phenyl)-7,8-dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)cyclopropyl)methyl acrylamide (4.00 mg, 23.4% yield).
  • Step 1 3-(((2-(4-amino-6-bromo-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl))-7H-pyrrole Synthesis of tert-butyl[2,3-d]pyrimidin-7-yl)ethyl)amino)methyl)azetidine-1-carboxylate
  • Step 2 3-((4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo Synthesis of [1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester
  • Step 3 6-(azetidin-3-ylmethyl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8- Synthesis of dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 4 1-(3-((4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl))-7,8-dihydro-6H -Imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)methyl)azetidin-1-yl)prop-2-en-1-one Synthesis
  • Step 1 3-((4-amino-5-(3-fluoro-4-((6-6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of tert-butyl imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)methyl)pyrrolidine-1-carbamate
  • Step 2 (S)-3-((4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro- 6H-Imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester and (R)-3- ((4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo[1',2 ':Synthesis of 1,5]pyrrolo[2,3-d]pyrimidin-6-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 3 (S)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(pyrrolidin-3-yl-methyl)-7 ,Synthesis of 8-dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 4 (S)-1-(3-((4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl))-7,8- Dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)propyl-2-en- Synthesis of 1-ketone
  • Step 3 (R)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(pyrrolidin-3-yl-methyl)-7 ,Synthesis of 8-dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 4 (R)-1-(3-((4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl))-7,8- Dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)propyl-2-en- Synthesis of 1-ketone
  • Step 1 4-chloro-6-(4-fluoro-3-nitrophenyl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl-7 ,Synthesis of 8-dihydro-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine
  • Step 2 5-(4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazole [1 ',2':Synthesis of 1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-fluoroaniline
  • Step 3 6-(3-amino-4-fluoroaniline)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro Synthesis of -6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-amino
  • reaction solution was concentrated and separated and purified through a silica gel column to obtain a red solid 6-(3-amino-4-fluoroaniline)-5-(3-fluoro-4-((6-methylpyridin-2-yl) )oxy)phenyl)-7,8-dihydro-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-amino (60mg, yield 31.2% ).
  • Step 4 N-(5-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)acrylamide
  • Step 1 4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(2-fluoro-5-nitrobenzene)-7 ,Synthesis of 8-dihydro-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine
  • Step 2 3-(4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazole [1 ',2':Synthesis of 1,5]pyrrolo[2,3-d]pyrimidin-6yl)-4-fluoroaniline
  • Step 3 6-(5-amino-2-fluoroaniline)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro Synthesis of -6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-amino
  • reaction solution was concentrated and separated and purified through a silica gel column to obtain a red solid 6-(5-amino-2-fluoroaniline)-5-(3-fluoro-4-((6-methylpyridin-2-yl) )oxy)phenyl)-7,8-dihydro-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-amino (100mg, yield 34.6% ).
  • Step 4 N-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-4-fluoroaniline)acrylamide
  • Step 1 4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazole [1',2 Synthesis of ':1,5]pyrrolo[2,3-d]pyrimidine-6-carboxylic acid tert-butyl ester
  • Step 2 4-acetamido-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo[1 Synthesis of ',2':1,5]pyrrolo[2,3-d]pyrimidine-6-carboxylic acid tert-butyl ester
  • Step 3 N-(5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo[1',2 Synthesis of ':1,5]pyrrolo[2,3-d]pyrimidin-4-yl)acetamide
  • Step 5 (4-(4-acetamido-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro Synthesis of -6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)carbamic acid tert-butyl ester
  • Step 6 N-(6-(2-aminopyridin-4-yl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8 -Synthesis of dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-yl)acetamide
  • Step 8 N-(4-(4-acetamido-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H -Synthesis of imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-3-(phenylsulfonyl)propionamide
  • Step 9 N-(4-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-3-(phenylsulfonyl)propionamide
  • reaction solution is slowly added to ice water to quench, add saturated sodium bicarbonate solution to adjust the pH to 7, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain N-(4 -(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo[1',2 ':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-3-(phenylsulfonyl)propionamide (110 mg, yield 64.3%).
  • Step 10 N-(4-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)acrylamide
  • Step 1 4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(2-methoxy-3-nitrophenyl) Synthesis of -7,8-dihydro-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine
  • Step 2 3-(4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazole [1 ',2':Synthesis of 1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-methoxyaniline
  • Step 3 6-(3-amino-2-methoxyphenyl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8 -Synthesis of dihydro-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-amino
  • Step 4 N-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-methoxyphenyl)acrylamide
  • Step 1 4-chloro-6-(2-fluoro-3-niphenyl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7 ,Synthesis of 8-dihydro-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine
  • Step 2 3-(4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazole [1 ',2':Synthesis of 1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-fluoroaniline
  • Step 3 6-(3-amino-2-fluorophenyl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-di Synthesis of Hydrogen-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-amino
  • reaction solution is concentrated and separated and purified through a silica gel column to obtain 6-(3-amino-2-fluorophenyl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)) Oxy)phenyl)-7,8-dihydro-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-amino (50 mg, crude).
  • Step 4 N-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)acrylamide
  • Step 1 2-(2-(4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-6-nitrophenoxy)-N,N-dimethylethane-1- amine synthesis
  • Step 2 3-(4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo[ Synthesis of 1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-(2-(dimethylamino)ethoxy)aniline
  • Step 3 6-(3-amino-2-(2-(dimethylamino)ethoxy)phenyl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy) Synthesis of phenyl)-7,8-dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 4 N-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-(2-(dimethylamino)ethoxy)phenyl)acrylamide Synthesis
  • Step 1 4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(2-(4-methylpiperazine-1- Synthesis of methyl)-3-nitrophenyl)-7,8-dihydro-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine
  • Step 2 3-(4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazole [1 ',2':Synthesis of 1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-(4-methylpiperazin-1-yl)aniline
  • Step 3 6-(3-amino-2-(4-methylpyridin-1-yl)phenyl)-5-(3-fluoro-4-((6-methylpiperazin-2-yl)oxy) Synthesis of phenyl)-7,8-dihydro-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-aniline
  • Step 4 N-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide
  • Step 1 4-(2-(4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-6-nitrophenyl)morpholine
  • Step 3 3-(4-chloro-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazole [1 ',2':Synthesis of 1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-morpholineaniline
  • Step 4 6-(3-amino-2-phenanlinaniline)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-di Synthesis of Hydrogen-6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-aniline
  • Step 5 N-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-morpholineaniline)acrylamide
  • 6-(3-Amino-2-phenanlinaniline)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro- 6H-imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-aniline (60.0mg, 1.00eq) was dissolved in 3mL tetrahydrofuran, and acryloyl chloride (5.90 mg, 0.6eq) at 20°C for 2 hours. LCMS detects the end of the reaction.
  • the compounds of the examples in Table 2 can be prepared by following steps similar to the route of Preparation Example 27. The difference is that raw materials are replaced in the intermediate steps to obtain the corresponding compounds.
  • Step 2 2- ⁇ [2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxy ⁇ -Synthesis of 4-methylpyrimidine
  • reaction solution is concentrated and separated and purified through a silica gel column to obtain 2- ⁇ [2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboroheterocycle) Pent-2-yl)phenyl]oxy ⁇ -4-methylpyrimidine (5.60 g, yield 96.0%).
  • Step 3 ⁇ [2-(4-amino-5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ pyrrolo[2,3-d]pyrimidine- Synthesis of 7-yl)ethyl]amino ⁇ methanoic acid-2-methylpropan-2-yl ester
  • Step 4 ⁇ [2-(4-amino-6-bromo-5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ pyrrolo[2,3- Synthesis of d]pyrimidin-7-yl)ethyl]amino ⁇ methanoic acid-2-methylpropan-2-yl ester
  • Step five 4-amino-5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -7,8-dihydro-6H-imidazo[2', Synthesis of 3':5,1]pyrrolo[2,3-d]pyrimidine-6-carboxylic acid-2-methylpropan-2-yl ester
  • Step six 4-(N-diacetamido)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidine-6-carbamic acid tert-butyl ester
  • Step 7 N-acetyl-N-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)methoxy)phenyl)-7,8-dihydro-6H-imidazole Synthesis of [1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-yl)acetamide
  • TLC detects that the reaction is complete, adjust the pH to 8 with saturated sodium bicarbonate, extract with ethyl acetate and dry the organic phase to obtain N-acetyl-N-(5-(3-fluoro-4-((4-methylpyrimidine) -2-yl)methoxy)phenyl)-7,8-dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-yl) Acetamide (300 mg, 52% yield).
  • Step 8 N-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(2-methoxy-3-nitrophenyl) Synthesis of -7,8-dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-yl)acetamide
  • reaction solution was reacted at 125°C for 8 hours.
  • TLC and LCMS detected that the reaction was completed, concentrated and mixed the sample, and purified by column chromatography to obtain N-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6- (2-methoxy-3-nitrophenyl)-7,8-dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4- acetamide (150 mg, 40.4% yield).
  • Step 9 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(2-methoxy-3-nitrophenyl)-7, Synthesis of 8-dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 10 6-(3-amino-2-methoxyphenyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7,8 -Synthesis of dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine
  • TLC detects that the reaction is complete, filter through diatomaceous earth, and spin the filtrate to dryness to obtain 6-(3-amino-2-methoxyphenyl)-5-(3-fluoro-4-((4-methylpyrimidine-2- (base)oxy)phenyl)-7,8-dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-amine (80 mg, crude product) .
  • Step 11 N-(3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7,8-dihydro-6H -Synthesis of imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-methoxyphenyl)acetamide
  • Step 2 N-(6-(2-ethoxy-3-nitrophenyl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl) Synthesis of -7,8-dihydro-6H-imidazole[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-yl)acetamide
  • Step 3 (6-(2-ethoxy-3-nitrophenyl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7 ,Synthesis of 8-dihydro-6H-imidazole[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine
  • Step 4 6-(3-amino-2-ethoxyphenyl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7, Synthesis of 8-dihydro-6H-imidazole[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine
  • Step 5 N-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H -Synthesis of imidazole[1',2':1,5]pyrrole[2,3-d]pyrimidin-6-yl)-2-ethoxyphenyl)acrylamide
  • acryloyl chloride (47.7mg, 527umol, 43.0uL) was slowly added dropwise to 6-(3-amino-2-ethoxyphenyl)-5-(3-fluoro-4-((6 -methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazole[1',2':1,5]pyrrole[2,3-d]pyrimidin-4-amine ((270mg, 527umol) in tetrahydrofuran (2mL).
  • the reaction solution was stirred at 20°C for 2 hours.
  • LCMS monitored the end of the reaction.
  • Step 1 N-(6-(2-fluoro-3-nitrophenyl)-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7 ,Synthesis of 8-dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-4-yl)acetamide
  • Step 2 5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(2-((4-methoxyphenyl)(methyl) Synthesis of amino)-3-nitrophenyl)-7,8-dihydro-6H-imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidine-4-amino
  • Step 3 6-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo[ 1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-N1-(4-methoxyphenyl)-N1-methylphenyl-1,2-ethyl Synthesis of amides
  • Step 4 N-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-((4-methoxyphenyl)(methyl)amino)phenyl) Synthesis of acrylamide
  • Step 5 N-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-(methylamino)phenyl)acrylamide
  • Step 1 N-(3-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-methoxyphenyl)methacrylamide
  • Step 1 N-(5- ⁇ 3-fluoro-4-[(6-methylpyridin-2-yl)oxy]phenyl ⁇ -6-(2-methoxy-3-nitrophenyl) Synthesis of -7,8-dihydro-6H-imidazo[2',1':5,1]pyrrolo[2,3-d]pyrimidin-4-yl)acetamide
  • Step 2 5- ⁇ 3-fluoro-4-[(6-methylpyridin-2-yl)oxy]phenyl ⁇ -6-(2-methoxy-3-nitrophenyl)-7, Synthesis of 8-dihydro-6H-imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-4-amine
  • N-(5- ⁇ 3-fluoro-4-[(6-methylpyridin-2-yl)oxy]phenyl ⁇ -6-(2-methoxy-3-nitrophenyl)-7 ,8-dihydro-6H-imidazo[2',1':5,1]pyrrolo[2,3-d]pyrimidin-4-yl)acetamide (200mg, 280umol, 1eq) dissolved in 0.5mL methanol , add potassium carbonate (77.6mg, 561umol, 2eq) and react at 60°C for 1 hour.
  • Step 3 6-(3-amino-2-methoxyphenyl)-5- ⁇ 3-fluoro-4-[(6-methylpyridin-2-yl)oxy]phenyl ⁇ -7,8 -Synthesis of dihydro-6H-imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 4 N-[3-(4-amino-5- ⁇ 3-fluoro-4-[(6-methylpyridin-2-yl)oxy]phenyl ⁇ -7,8-dihydro-6H- Synthesis of imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-6-yl)-2-methoxyphenyl]-2-methylprop-2-enamide
  • Step 1 N-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)methacrylamide
  • Step 1 N-(5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -6-(2-fluoro-3-nitrophenyl)-7 ,Synthesis of 8-dihydro-6H-imidazo[2',1':5,1]pyrrolo[2,3-d]pyrimidin-4-yl)acetamide
  • Step 2 N-[6-(3-amino-2-fluorophenyl)-5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -7, Synthesis of 8-dihydro-6H-imidazo[2',1':5,1]pyrrolo[2,3-d]pyrimidin-4-yl]acetamide
  • N-(5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -6-(2-fluoro-3-nitrophenyl)-7,8 -Dihydro-6H-imidazo[2',1':5,1]pyrrolo[2,3-d]pyrimidin-4-yl)acetamide (500mg, 895umol, 1eq) was dissolved in 5.00mL tetrahydrofuran, Add Pd/C (10%, 1.00g) and react for 3 hours at 25°C and 15Psi in a hydrogen atmosphere.
  • Step 3 4-(4-amino-6-(3-amino-2-fluorophenyl)-7,8-dihydro-6H-imidazo[2',3':5,1]pyrrolo[2 ,Synthesis of 3-d]pyrimidin-5-yl)-2-fluorophenol
  • Step 4 6-(3-amino-2-fluorophenyl)-5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -7,8-di Synthesis of hydrogen-6H-imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 5 N-[3-(4-amino-5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -7,8-dihydro-6H- Synthesis of imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-6-yl)-2-fluorophenyl]prop-2-enamide
  • Step 6 N-[3-(4-amino-5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -7,8-dihydro-6H- Synthesis of imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-6-yl)-2-fluorophenyl]-2-methylprop-2-enamide
  • Step 1 5-((2-(4-amino-6-bromo-5-(3-fluoro-4-(6-(methylpyridin-2-yl)oxy)phenyl))-7H-pyrrolo Synthesis of [2,3-d]pyrimidin-7-yl)ethyl)amino)tetrahydro-2H-pyran-3-yl)carbamic acid tert-butyl ester
  • Step 2 5-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H-imidazo[ Synthesis of 1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-yl)carbamic acid tert-butyl ester
  • Step 4 N-(5-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazo[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-yl)acrylamide
  • Step 1 N-(5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -6-(2-methyl-3-nitrophenyl)- Synthesis of 7,8-dihydro-6H-imidazo[2',1':5,1]pyrrolo[2,3-d]pyrimidin-4-yl)acetamide
  • Step 2 5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -6-(2-methyl-3-nitrophenyl)-7,8 - Synthesis of dihydro-6H-imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-4-amine
  • N-(5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -6-(2-methyl-3-nitrophenyl)-7, 8-Dihydro-6H-imidazo[2',1':5,1]pyrrolo[2,3-d]pyrimidin-4-yl)acetamide (170mg, 306umol, 1eq) was dissolved in 1.00mL methanol , add potassium carbonate (84.7mg, 613umol, 2eq), react at 50°C for 1 hour, after the reaction is detected by LCMS, filter and concentrate to obtain the crude product 5- ⁇ 3-fluoro-4-[(4-methylpyrimidine-2- base)oxy]phenyl ⁇ -6-(2-methyl-3-nitrophenyl)-7,8-dihydro-6H-imidazo[2',3':5,1]pyrrolo[ 2,3-d]pyrimidin-4-amine (150 mg, crude product).
  • Step 3 6-(3-amino-2-methylphenyl)-5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -7,8- Synthesis of dihydro-6H-imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 4 N-[3-(4-amino-5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -7,8-dihydro-6H- Synthesis of imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-6-yl)-2-methylphenyl]prop-2-enamide
  • Step 1 N-(5- ⁇ 3-fluoro-4-[(6-methylpyridin-2-yl)oxy]phenyl ⁇ -6-(2-methyl-3-nitrophenyl)- Synthesis of 7,8-dihydro-6H-imidazo[2',1':5,1]pyrrolo[2,3-d]pyrimidin-4-yl)acetamide
  • the reaction solution is concentrated and separated and purified through a silica gel column to obtain N-(5- ⁇ 3-fluoro-4-[(6-methylpyridin-2-yl)oxy]phenyl ⁇ -6- (2-Methyl-3-nitrophenyl)-7,8-dihydro-6H-imidazo[2',1':5,1]pyrrolo[2,3-d]pyrimidin-4-yl ) Acetamide (250 mg, 451.64umol, yield 94.5%).
  • Step 2 5- ⁇ 3-fluoro-4-[(6-methylpyridin-2-yl)oxy]phenyl ⁇ -6-(2-methyl-3-nitrophenyl)-7,8 -Synthesis of dihydro-6H-imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-4-amine
  • N-(5- ⁇ 3-fluoro-4-[(6-methylpyridin-2-yl)oxy]phenyl ⁇ -6-(2-methyl-3-nitrophenyl)-7, 8-Dihydro-6H-imidazo[2',1':5,1]pyrrolo[2,3-d]pyrimidin-4-yl)acetamide (250mg, 451.64umol, 1eq) was dissolved in 3mL methanol , add potassium carbonate (187.26mg, 1.35mmol, 3eq), react at 50°C for 1 hour, LCMS and TLC detect the end of the reaction, filter and spin dry to obtain 5- ⁇ 3-fluoro-4-[(6-methylpyridine -2-yl)oxy]phenyl ⁇ -6-(2-methyl-3-nitrophenyl)-7,8-dihydro-6H-imidazo[2',3':5,1] Pyrro[2,3-d]pyrimidin-4-amine (231.01 mg, 451.63umol
  • Step 3 6-(3-amino-2-methylphenyl)-5- ⁇ 3-fluoro-4-[(6-methylpyridin-2-yl)oxy]phenyl ⁇ -7,8- Synthesis of dihydro-6H-imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 4 N-[3-(4-amino-5- ⁇ 3-fluoro-4-[(6-methylpyridin-2-yl)oxy]phenyl ⁇ -7,8-dihydro-6H- Synthesis of imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-6-yl)-2-methylphenyl]-2-methylprop-2-enamide
  • 6-(3-Amino-2-methylphenyl)-5- ⁇ 3-fluoro-4-[(6-methylpyridin-2-yl)oxy]phenyl ⁇ -7,8-dihydro -6H-Imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-4-amine (100.00mg, 207.67umol, 1eq) was dissolved in 1mL tetrahydrofuran, and methacryloyl chloride was added (21.71mg, 207.67umol, 20.29uL, 1eq), stirred and reacted at 0°C for 2 hours.
  • Step 1 N-(3-(4-amino-5-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7,8-dihydro-6H- Synthesis of imidazole[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6-yl)-2-phenylmethyl)acrylamide
  • Step 1 N-acetyl-N-(5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -6-(3-nitrophenyl)- Synthesis of 7,8-dihydro-6H-imidazo[2',1':5,1]pyrrolo[2,3-d]pyrimidin-4-yl)acetamide
  • Step 2 5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -6-(3-nitrophenyl)-7,8-dihydro-6H -Synthesis of imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-4-amine
  • N-(5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -6-(3-nitrophenyl)-7,8-dihydro- 6H- Imidazo[2',1':5,1]pyrrolo[2,3-d]pyrimidin-4-yl)acetamide 160 mg, 296 ⁇ mol was dissolved in methanol (2.00 mL), and potassium carbonate (81.8 mg was added , 592 ⁇ mol), reacted for 1 hour at 50°C, and after the reaction was detected by LCMS, extracted with water and ethyl acetate, and the organic phase was dried and concentrated to obtain the crude product 5- ⁇ 3-fluoro-4-[(4-methylpyrimidine-2- base)oxy]phenyl ⁇ -6-(3-nitrophenyl)-7,8-dihydro-6H-imidazo[2',3':5,1]pyrrolo[2,3-d ]pyrimidin-4-amine (150 mg
  • Step 3 6-(3-aminophenyl)-5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -7,8-dihydro-6H- Synthesis of imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 4 N-[3-(4-amino-5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -7,8-dihydro-6H- Synthesis of imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]prop-2-enamide
  • 6-(3-Aminophenyl)-5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -7,8-dihydro-6H-imidazo [2',3':5,1]pyrrolo[2,3-d]pyrimidin-4-amine (55 mg, 117 ⁇ mol) was dissolved in tetrahydrofuran (1.00 mL), and acryloyl chloride (10.6 mg, 117 ⁇ mol) was added at 20°C. ). React for 1 hour at 20°C, and detect the end of the reaction by LCMS.
  • reaction solution was spun to dryness and purified by reverse phase HPLC to obtain N-[3-(4-amino-5- ⁇ 3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl ⁇ -7 ,8-dihydro-6H-imidazo[2',3':5,1]pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]propan-2-enamide (25.0 mg, collected rate 39.9%).
  • the compounds of the examples in Table 3 can be prepared by following steps similar to the route of the aforementioned Preparation Example 1 or 44. The difference is that raw materials are replaced in the intermediate steps to obtain the corresponding compounds.
  • Test Example 1 SNU-16 cell proliferation test
  • the human gastric cancer cell line SNU-16 (ATCC, CRL-5974) is a cell line with FGFR2 gene amplification. SNU-16 cells were cultured in RPMI 1640 medium containing 10% fetal calf serum and placed in a humidified incubator with 5% CO2 for growth at 37°C.
  • Promega's Cell Titer-Glo Luminescent cell Viability Assay Promega The number of viable cells in the culture was determined using the protocol described in Catalog #G7570). 90 ⁇ L of cells (8,000 cells/well) were cultured in growth medium in Corning black transparent bottom 96-well plates and cultured overnight at 37°C in a 5% CO2 humidified incubator. Serially diluted compounds in 100% DMSO were added to the cells using a pipette, and cells were incubated for an additional 72 hours. Add 100 ⁇ L of mixed Cell Titer-Glo reagent to the cells in the 96-well culture plate to lyse the cells and mix gently.
  • IC50 value is determined by calculating the concentration of compound required to obtain 50% inhibition.
  • the human gastric cancer cell line KATO III (ATCC, HTB-103) is a cell line with FGFR2 gene amplification.
  • KATO III cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and grown at 37°C in a humidified incubator with 5% CO2.
  • the number of viable cells in the culture was determined following the protocol described in Promega's Cell Titer-Glo Luminescent cell Viability Assay (Promega catalog #G7570).
  • 90 ⁇ L of cells (8,000 cells/well) were cultured in growth medium in Corning black transparent bottom 96-well plates and cultured overnight at 37°C in a 5% CO2 humidified incubator.
  • Serially diluted compounds in 100% DMSO were added to the cells using a pipette, and cells were incubated for an additional 72 hours.
  • IC50 value is determined by calculating the concentration of compound required to obtain 50% inhibition.
  • Test Example 3 AN3 CA cell proliferation test
  • the human endometrial cancer cell line AN3 CA (ATCC, HTB-111) is an FGFR2 N550K mutant cell line.
  • AN3 CA cells were cultured in MEM medium containing 10% fetal calf serum and placed in a humidified incubator with 5% CO2 for growth at 37°C.
  • the number of viable cells in the culture was determined following the protocol described in Promega's Cell Titer-Glo Luminescent cell Viability Assay (Promega catalog #G7570).
  • 90 ⁇ L of cells (8,000 cells/well) were cultured in growth medium in Corning black transparent bottom 96-well plates and cultured overnight at 37°C in a 5% CO2 humidified incubator.
  • Serially diluted compounds in 100% DMSO were added to the cells using a pipette, and cells were incubated for an additional 72 hours.
  • Mix 100 ⁇ L of Cell Titer-Glo reagent is added to the cells in the 96-well culture plate to lyse the cells and mix gently.
  • IC50 value is determined by calculating the concentration of compound required to obtain 50% inhibition.

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Abstract

La présente invention concerne un inhibiteur de FGFR2 hautement sélectif, son procédé de préparation, son utilisation, une composition pharmaceutique contenant le composé ou un sel de celui-ci, et un procédé de traitement de diverses maladies médiées par FGFR2 sous diverses formes différentes au moyen du composé et du sel de celui-ci, les maladies comprenant le cholangiocarcinome intrahépatique, le cancer gastrique, etc.
PCT/CN2023/089242 2022-04-20 2023-04-19 Inhibiteur de fgfr2 et son procédé d'utilisation WO2023202625A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1259950A (zh) * 1997-03-19 2000-07-12 Basf公司 吡咯并[2,3d]嘧啶类化合物及它们作为酪氨酸激酶抑制剂的用途
CN1326457A (zh) * 1998-09-18 2001-12-12 巴斯福股份公司 作为激酶抑制剂的4－氨基吡咯并嘧啶
US20040043403A1 (en) * 2000-12-20 2004-03-04 Peter Furst Process for determining the biological activity of epidermal growth factor receptor tyrosine kinase inhibitors
CN103582643A (zh) * 2011-04-04 2014-02-12 弗马塞斯有限公司 蛋白激酶抑制剂
CN114126620A (zh) * 2019-05-13 2022-03-01 传达治疗有限公司 Fgfr抑制剂和其使用方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1259950A (zh) * 1997-03-19 2000-07-12 Basf公司 吡咯并[2,3d]嘧啶类化合物及它们作为酪氨酸激酶抑制剂的用途
CN1326457A (zh) * 1998-09-18 2001-12-12 巴斯福股份公司 作为激酶抑制剂的4－氨基吡咯并嘧啶
US20040043403A1 (en) * 2000-12-20 2004-03-04 Peter Furst Process for determining the biological activity of epidermal growth factor receptor tyrosine kinase inhibitors
CN103582643A (zh) * 2011-04-04 2014-02-12 弗马塞斯有限公司 蛋白激酶抑制剂
CN114126620A (zh) * 2019-05-13 2022-03-01 传达治疗有限公司 Fgfr抑制剂和其使用方法

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