WO2020038458A1 - Classe de composé de triazole cyclique fusionné, procédé de préparation et utilisation - Google Patents

Classe de composé de triazole cyclique fusionné, procédé de préparation et utilisation Download PDF

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WO2020038458A1
WO2020038458A1 PCT/CN2019/102214 CN2019102214W WO2020038458A1 WO 2020038458 A1 WO2020038458 A1 WO 2020038458A1 CN 2019102214 W CN2019102214 W CN 2019102214W WO 2020038458 A1 WO2020038458 A1 WO 2020038458A1
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alkyl
hydrogen
membered
group
halogen
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万惠新
潘建峰
马金贵
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如东凌达生物医药科技有限公司
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • 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 medicinal chemistry, and particularly relates to a class of fused ring triazole compounds, a preparation method and uses thereof.
  • Receptor tyrosine kinase activation or gene mutation plays a key role in tumor occurrence, development, invasion and metastasis, and drug resistance, so as to become an important target for the development of anti-tumor drugs.
  • fibroblast growth factor receptor FGFR
  • FGFR fibroblast growth factor receptor
  • FGFRs are highly expressed and abnormally activated in many tumors, and are closely related to the poor prognosis of tumor patients. Therefore, FGFRs are recognized as an important target for antitumor, and the development of FGFR small molecule inhibitors has gradually received more and more attention.
  • FGF19 is a ligand of FGFR4, which is responsible for regulating normal bile secretion and liver cell proliferation in the liver. Its overexpression or overactivation can promote liver cell proliferation and induce liver cancer formation. This has been confirmed in transgenic mice, and knocking out the FGFR4 gene can block the development of hepatocellular carcinoma.
  • the technical problem to be solved by the present invention is to overcome the problems that the existing FGFR inhibitor compounds have a single structure, or have poor target selectivity, or low target inhibitory activity, or have poor pharmacological properties, or are prone to mutation and resistance. , And provides a class of fused ring triazole compounds, preparation method and application.
  • the fused ring triazole compound of the present invention is a new type of specific irreversible inhibitor of FGFR kinase, has good target selectivity, and can be used to treat tumors.
  • the present invention solves the above technical problems through the following technical solutions.
  • the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polycrystal Type or prodrug,
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, acyl, or sulfonyl; preferably from hydrogen, halogen, alkane Radical, or alkoxy;
  • R 5 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, amino, or hydroxyl; preferably from hydrogen, halogen, or alkyl;
  • Y is N and Z is CR 6 , or Y is CR 6 and Z is N;
  • R 6 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkylene- NR 6-1 R 6-2 ; preferably from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 heterocycloalkyl, or alkylene-NR 6-1 R 6-2 ; R 6- 1 and R 6-2 are independently hydrogen or C 1 -C 6 alkyl;
  • M is selected from CR a or N;
  • R a is selected from hydrogen, or halogen;
  • Cy is selected from 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl; preferably from 5-6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
  • R 7 is selected from hydrogen, halogen, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; preferably from hydrogen, Halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl, or 4-8 membered heterocycloalkyl; and one or more groups on R 7 may interact with one or more hydrogens on ring Cy Substitute to form the corresponding fused ring, parallel ring, spiro ring, or bridge ring ring system, the ring system has 0 to 3 heteroatoms including O, N, S; one or more of any of the above groups
  • the hydrogen atom is optionally selected from the group consisting of deuterium, halogen, hydroxy, amino, cyano, sulfone, sulfoxide, C 1 -C 8 alkyl, C 1 -C
  • n is selected from 0-4;
  • R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, nitro, alkyl, sulfone, sulfoxide, or alkylene-NR 8-1 R 8-2 ; any of the above One or more hydrogen atoms on the group are optionally selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, sulfone, sulfoxide, C 1 -C 8 alkyl, C 1- C 8 alkoxy, C 1 -C 8 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl, sulfonyl, 5-8 membered aryl or heteroaryl, 4 -8-membered cycloalkyl or heterocycloalkyl; R 8-1 and R 8-2 are independently hydrogen or C 1 -C 6 alkyl;
  • the heteroaryl group includes 1-3 heteroatoms selected from the group: N, O, P, and S
  • the heterocycloalkyl group includes 1-3 heteroatoms selected from the group: N , O, P, and S.
  • the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer Conformers, solvates, polymorphs or prodrugs,
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, C 1 -C 6 alkyl Oxy, amino, acyl, or sulfonyl; preferably from hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • R 5 is selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, or hydroxyl; preferably from hydrogen, halogen, or C 1 -C 6 alkyl;
  • Y is N and Z is CR 6 , or Y is CR 6 and Z is N;
  • R 6 is selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl, sulfonyl, C 6- C 10 aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, or C 1 -C 6 alkylene-NR 6-1 R 6-2 ; preferably from hydrogen, halo, C 1 -C 6 alkyl, 4-6 membered heterocycloalkyl, or a C 1 -C 6 alkylene group -NR 6-1 R 6-2; R 6- 1 and R 6 -2 is independently hydrogen or C 1 -C 6 alkyl;
  • M is selected from CR a or N;
  • R a is selected from hydrogen, or halogen;
  • Cy is selected from 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl; preferably from 5-6 membered cycloalkyl, 5-6 membered Heterocycloalkyl, 5-8 membered aryl, or 5-6 membered heteroaryl;
  • R 7 is selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl, sulfonyl, C 6 -C 10 aromatic Radical, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, or 4-11 membered heterocycloalkyl; preferably from hydrogen, halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl, Or 4- to 8-membered heterocycloalkyl; and one or more groups on R 7 may be substituted with one or more hydrogens on the ring Cy to form the corresponding rings such as fused rings, fused rings, spiro rings, bridged rings, etc.
  • the ring system has 0 to 3 heteroatoms including O, N, S; the C 1 -C 6 alkyl group is optionally substituted by 1-3 selected from hydroxyl, halogen, C 1 -C 6 alkyl Oxygen, -NR 7-2 R 7-3 , 4-8 membered heterocycloalkyl, or R 7-4 substituted 4-8 membered heterocycloalkyl; R 7-4 is C 1 -C 6 alkyl; R 7-2 and R 7-3 are independently selected from hydrogen or C 1 -C 6 alkyl; said C 6 -C 10 aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, 4-11 membered heterocycloalkyl or optionally independently substituted with 1-3 substituents selected from C 1 -C 6 alkyl, R 7-5 is a substituted C 1 -C 6 alkyl , -NR 7-6 R 7-7 , carbonyl, 3-8 membered cycloalkyl, or 4-8
  • n is selected from 0, 1, 2, 3, or 4;
  • R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, nitro, C 1 -C 6 alkyl, sulfone, sulfoxide, or C 1 -C 6 alkylene-NR 8- 1 R 8-2 ; one or more hydrogen atoms on any of the above groups is optionally selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano, sulfone, sulfoxide , C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl, sulfonyl, 5- 8-membered aryl or heteroaryl, 4-8 membered cycloalkyl or heterocycloalkyl; R 8-1 and R 8-2 are independently hydrogen or C 1 -C 6 alkyl.
  • the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer Conformers, solvates, polymorphs or prodrugs,
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, acyl, sulfonyl; preferably from hydrogen, halogen, alkyl , Alkoxy;
  • R 5 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, amino, hydroxyl, etc .; preferably, hydrogen, halogen, alkyl;
  • Y, Z are each independently selected from N or CR 6 ;
  • R 6 is independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, etc .; preferably from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 heterocycloalkyl, etc .;
  • M is independently selected from CR a or N;
  • R a is independently selected from hydrogen, halogen;
  • Cy is selected from 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl, respectively; preferably from 5-6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ;
  • R 7 is selected from hydrogen, halogen, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, etc .; preferably from hydrogen, Halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, etc .; and one or more groups on R 7 may be linked to one or more hydrogens on ring Cy Substitute to form the corresponding fused ring, parallel ring, spiro ring, bridge ring and other ring systems.
  • the ring system may have 0 to 3 heteroatoms including O, N, S;
  • n is independently selected from 0-4;
  • R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, nitro, alkyl, sulfone, sulfoxide, etc .; one or more hydrogen atoms on any of the above groups may be selected Substitution from the following groups: including but not limited to deuterium, halogen, hydroxy, amino, cyano, sulfone or sulfoxide, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1- C 8 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl or sulfonyl, 5- to 8-membered aryl or heteroaryl, 4- to 8-membered cycloalkyl or heterocycloalkyl ; Wherein the heteroaryl group contains 1-3 heteroatoms selected from the group: N, O, P or S, and the heterocycloalkyl group contains 1-3 heteroatoms selected from the group: N, O
  • the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or solvent thereof Compounds, polymorphs or prodrugs,
  • M is independently selected from CH or N;
  • R 1 and R 2 are independently selected from hydrogen and halogen, preferably from fluorine and chlorine;
  • R 3 and R 4 are independently selected from halogen, alkoxy, alkyl, amino, cycloalkyl, or heterocycloalkyl, and more preferably From fluorine, methoxy;
  • R 5 is selected from hydrogen, halogen, and alkyl; further preferably, hydrogen, fluorine, and methyl;
  • Y, Z are each independently selected from N or CR 6 ;
  • R 6 is independently selected from hydrogen, halogen, C1-C 6 alkyl, preferably from hydrogen;
  • Cy is independently preferably a 4- to 6-membered cycloalkyl or heterocycloalkyl, a 5- to 6-membered aryl or heteroaryl; further preferably a tetrahydrofuran ring, a tetrahydropyran ring, a tetrahydropyrrole ring, piperidine Ring, benzene ring, pyridine ring, pyrazole ring, etc .;
  • R 7 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, cyano, hydroxy, amino, 4- to 8-membered heterocycloalkyl, alkoxy, alkylamino, acyl or sulfonyl, and the like is more preferred. , Fluorine, cyano, amino, C 1 -C 6 alkyl or 4-7 membered heterocycloalkyl, etc .; more preferably hydrogen, fluorine, methyl, piperazinyl, morpholinyl, piperidinyl, Tetrahydropyrrolyl, etc .;
  • n is independently selected from 0-4, preferably from 0-2.
  • R 8 , R 9, and R 10 are independently selected from hydrogen, halogen, alkyl, and cyano; further preferably, they are selected from hydrogen, fluorine, methyl, and the like.
  • the compound has the following general formulae (IA), (IB):
  • each group is defined as described above.
  • a method for preparing a compound of formula I characterized in that the method includes steps a-d:
  • a compound of the general formula (I) is prepared by subjecting a compound of the general formula (D) to a condensation reaction with an acrylic acid or an acryloyl chloride compound in the presence of a base catalyst or a condensation reagent.
  • LG represents a leaving group, such as halogen, sulfone group, sulfoxide group, sulfonate group, etc., and the definitions of other groups are as described above;
  • the steps a), b), c), and d) are each performed in a solvent, and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, and ethyl acetate.
  • the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, and ethyl acetate.
  • the transition metal catalyst is selected from the group consisting of tris (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), tetrakis (triphenylphosphine) palladium (Pd (PPh 3 ) 4 ), acetic acid Palladium, palladium chloride, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, palladium triphenylphosphine acetate, [1,1'-bis (diphenylphosphino) ferrocene] dichloride Palladium, bis (tri-o-phenylmethylphosphine) palladium dichloride, 1,2-bis (diphenylphosphino) ethane palladium dichloride, or a combination thereof; the catalyst ligand is selected from the group consisting of: Tri-tert-butylphosphine, tri-tert-butylphosphine t
  • the condensation reagent is selected from the group consisting of DCC, DIC, CDI, EDCI, HOAt, HOBt, BOP, PyBOP, HATU, TBTU, etc., or a combination thereof.
  • the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, carbonic acid Potassium hydrogen, sodium carbonate, sodium bicarbonate, or a combination thereof;
  • the organic base is selected from the group consisting of pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] Undecyl-7-ene (DBU), lithium hexamethyldisilyl, sodium hexamethyldisilyl, dimethylpyridine, or a combination thereof.
  • the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, trifluoromethanesulfonic acid, or a combination thereof.
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, acyl, sulfonyl; preferably from hydrogen, halogen, alkyl , Alkoxy;
  • R 5 is selected from hydrogen, halogen, cyano, alkyl, alkoxy, amino, hydroxyl, etc .; preferably, hydrogen, halogen, alkyl;
  • Y is N and Z is CR 6 ;
  • Y is CR 6 and Z is N;
  • R 6 is independently selected from hydrogen, halogen, cyano, alkyl, alkoxy, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl and the like; preferably from Hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 heterocycloalkyl, etc .;
  • M is independently selected from CR a or N;
  • R a is independently selected from hydrogen, halogen;
  • Cy is selected from 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl, respectively; preferably from 5-6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ;
  • R 7 is selected from hydrogen, halogen, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, etc .; preferably from hydrogen, Halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, etc .; and one or more groups on R 7 may be linked to one or more hydrogens on ring Cy Substitute to form the corresponding fused ring, parallel ring, spiro ring, bridge ring and other ring systems.
  • the ring system may have 0 to 3 heteroatoms including O, N, S;
  • n is independently selected from 0-4;
  • R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, nitro, alkyl, sulfone, sulfoxide, etc .; one or more hydrogen atoms on any of the above groups may be selected Substitution from the following groups: including but not limited to deuterium, halogen, hydroxy, amino, cyano, sulfone or sulfoxide, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1- C 8 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, acyl or sulfonyl, 5- to 8-membered aryl or heteroaryl, 4- to 8-membered cycloalkyl or heterocycloalkyl .
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 1 and R 2 are independently When it is a halogen, the halogen is preferably fluorine or chlorine.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 3 and R 4 are independently When it is halogen, the halogen is preferably fluorine.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 3 and R 4 are independently When it is an alkoxy group, the alkoxy group is preferably a C 1 -C 6 alkoxy group, and more preferably a C 1 -C 4 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy) , N-butoxy, isobutoxy, sec-butoxy, or tert-butoxy), and methoxy is more preferred.
  • certain groups of the compound represented by the formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 6 is an alkyl group,
  • the alkyl group is preferably a C 1 -C 6 alkyl group, and more preferably a C 1 -C 4 alkyl group (for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Tert-butyl), more preferably methyl.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 6 is -alkylene
  • the alkylene group is preferably a C 1 -C 6 alkylene group, more preferably a C 1 -C 4 alkylene group, and still more preferably a methylene group.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 6-2 and R 6 When -3 is independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is preferably C 1 -C 4 alkyl (for example, methyl, ethyl, propyl, isopropyl, n-butyl , Isobutyl, sec-butyl or tert-butyl), more preferably methyl.
  • certain groups of the compound represented by the formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when Cy is 3-8 membered hetero
  • the 3-8 membered heterocycloalkyl group is preferably a 5-6 membered "heteroatom selected from one or more of N, O, and S, and the number of heteroatoms is 1-3" Heterocycloalkyl, more preferably tetrahydrofuranyl (e.g. ), Tetrahydropyrrolyl (e.g. ), Tetrahydrothienyl (e.g. ), Or tetrahydropyranyl (e.g. ), More preferably tetrahydrofuranyl or tetrahydropyranyl.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when Cy is 5-8 yuan aromatic As the radical, the 5- to 8-membered aryl group is preferably a phenyl group.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when Cy is 5-8 membered hetero
  • the 5- to 8-membered heteroaryl group is preferably a 5- to 6-membered heteroaryl group having "a heteroatom selected from one or more of N, O, and S, and the number of heteroatoms is 1-3" , More preferably pyrazolyl (e.g. ) Or pyridyl (e.g. ), More preferably pyrazolyl.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 7 is alkyl,
  • the alkyl group is preferably a C 1 -C 6 alkyl group, and more preferably a C 1 -C 4 alkyl group (for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Tert-butyl), more preferably methyl, ethyl, n-propyl or isobutyl, and still more preferably methyl.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 7 is heterocycloalkyl
  • the heterocycloalkyl group is preferably a 4- to 11-membered heterocycloalkyl group, and more preferably 5 having a "heteroatom selected from one or more of N, O, or S, and the number of heteroatoms is 1-3.”
  • the 5-7 membered monocyclic heterocycloalkyl group is preferably piperidinyl (e.g. ), Piperazinyl (e.g. ), Or homopiperazinyl (e.g. );
  • the 8-9 membered bicyclic heterocycloalkyl group is preferred
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes):
  • the C 1 -C 8 alkoxy group is preferably a C 1 -C 4 alkoxy group (for example, methoxy, ethoxy , Propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or t-butoxy), more preferably methoxy.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes):
  • said 4-8 membered heterocycloalkyl group is preferably "heteroatom selected from one or more of N, O or S
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes):
  • the C 1 -C 8 alkyl is preferably C 1 -C 4 alkyl (eg methyl, ethyl, propyl , Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), more preferably methyl, ethyl or isopropyl.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes):
  • the 4-8 membered cycloalkyl group is preferably "a heteroatom selected from one or more of N, O or S
  • a 4- to 6-membered cycloalkyl group having 1 to 3 heteroatoms, more preferably a tetrahydropyrrolyl group is preferably "a heteroatom selected from one or more of N, O or S.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): in R 7 , the substitutions described When one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, 4-8 membered heterocycloalkyl group are optionally substituted by C 1 -C 6 alkyl group, C 1 -C 6 alkyl is preferably C 1 -C 4 alkyl (eg methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), more preferably methyl Or ethyl.
  • C 1 -C 6 alkyl is preferably C 1 -C 4 alkyl (eg methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), more preferably methyl Or e
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): in R 7 , the substitutions described When one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, 4-8 membered heterocycloalkyl group are optionally substituted by C 1 -C 6 alkoxy group, C 1 -C 6 alkoxy is preferably C 1 -C 4 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy Or tert-butoxy), more preferably methoxy.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): in R 7 , the substitutions described When one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, 4-8 membered heterocycloalkyl group are optionally substituted by 5-10 membered heteroaryl group, or C 1 -C
  • the 5-10 membered heteroaryl is preferably "a heteroatom selected from one or more of N, O or S, and the number of heteroatoms is 1- 3 "5-6 membered heteroaryl, more preferably pyrazolyl.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): in R 7 , the substitutions described When the one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, 4-8 membered heterocycloalkyl group are optionally substituted by C 1 -C 6 alkyl group, When the heteroaryl group is substituted, the C 1 -C 6 alkyl group is preferably a C 1 -C 4 alkyl group, and more preferably a methyl group.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): in R 7 , the substitutions described When one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, 4-8 membered heterocycloalkyl group are optionally substituted with 3-8 membered cycloalkyl group, the The 3-8 membered cycloalkyl group is preferably a 3-6 membered cycloalkyl group, and more preferably a cyclopropyl group.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes):
  • R 7 when R 7- 2.
  • the C 1 -C 6 alkyl is preferably C 1 -C 4 alkyl (e.g. methyl, ethyl, propyl (Propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), more preferably methyl or ethyl.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 7-5 is C 1
  • the C 1 -C 6 alkoxy is preferably C 1 -C 4 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy Group, isobutoxy, sec-butoxy or tert-butoxy), more preferably methoxy.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 7-5 is 5- In the case of a 10-membered heteroaryl group or a 5- to 10-membered heteroaryl group substituted with R 7-5c , the 5- to 10-membered heteroaryl group is preferably "a heteroatom selected from one or more of N, O or S A 5-6 membered heteroaryl group having 1 to 3 heteroatoms, more preferably a pyrazolyl group.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes):
  • R 7-5 is 3-
  • the 3-8-membered cycloalkyl group is preferably a 3-6-membered cycloalkyl group, and more preferably a cyclopropyl group.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 7-6 , R 7 When -7 , R 7-5a and R 7-5b and R 7-5c are independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is preferably C 1 -C 4 alkyl (for example methyl , Ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), more preferably methyl.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 8 is alkyl,
  • the alkyl group is preferably a C 1 -C 6 alkyl group, and more preferably a C 1 -C 4 alkyl group (for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Tert-butyl), more preferably methyl.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes):
  • the halogen is preferably fluorine.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes):
  • R 8 when the alkyl group is substituted with one or more halogens, the number of said halogens is preferably 1, 2 or 3, and more preferably 3.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 9 and R 10 are independently When it is C 1 -C 6 alkylene-NR 8-1 R 8-2 , the C 1 -C 6 alkylene is preferably C 1 -C 4 alkylene, and more preferably methylene.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): when R 8-1 and R 8 When -2 is independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl is preferably C 1 -C 4 alkyl (for example, methyl, ethyl, propyl, isopropyl, n-butyl , Isobutyl, sec-butyl or tert-butyl), more preferably methyl.
  • R 1 and R 2 are independently selected From fluorine or chlorine.
  • R 3 and R 4 are independently selected Self-fluorine or methoxy, preferably methoxy.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): Y and Z are independently selected from N , -CH-, -C (CH 3 )-, or N or -CH- is preferred.
  • certain groups of the compound represented by formula (I) are defined as follows (undefined groups are as described in any of the previous schemes): M is selected from CH or N.
  • R 7 is selected from H, F, Me, CF 3 , H, F, Me,
  • R 8 is selected from H, F, Cl, CN, Me or CF 3 , preferably H.
  • R 9 and R 10 are independently selected From H, or H is preferred.
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, or alkoxy;
  • R 5 is hydrogen
  • Y is N and Z is CR 6 , or Y is CR 6 and Z is N;
  • R 6 is selected from hydrogen, alkyl, or alkylene-NR 6-1 R 6-2 ;
  • R 6-1 and R 6-2 are independently hydrogen or C 1 -C 6 alkyl;
  • M is selected from CR a or N; R a is hydrogen;
  • Cy is selected from 3-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl;
  • R 7 is selected from hydrogen, halogen, alkyl, or heterocycloalkyl; one or more hydrogen atoms on any of the above groups is optionally selected from the group consisting of halogen, hydroxy, amino, Cyano, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, carbonyl, 5-8 membered aryl or heteroaryl, 3-8 membered cycloalkyl or 4-8 membered heterocycloalkyl; In the substituent, one or more hydrogen atoms on the amino group, C 1 -C 8 alkyl group, and 4- to 8-membered heterocycloalkyl group are optionally substituted by hydroxyl group, cyano group, C 1 -C 6 Alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted amino, 5-10 membered heteroaryl, C 1 -C 6 alkyl substituted 5-10 membered heteroaryl, or 3 -8-membered cycloalky
  • n is selected from 0-4;
  • R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, alkyl, or alkylene-NR 8-1 R 8-2 ; one or more hydrogen atoms on any of the above groups Optionally substituted with halogen; R 8-1 and R 8-2 are independently hydrogen or C 1 -C 6 alkyl.
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, or C 1 -C 6 alkoxy;
  • R 5 is hydrogen
  • Y is N and Z is CR 6 , or Y is CR 6 and Z is N;
  • R 6 is selected from hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkylene-NR 6-1 R 6-2 ;
  • R 6-1 and R 6-2 are independently hydrogen or C 1- C 6 alkyl;
  • M is selected from CR a or N; R a is hydrogen;
  • Cy is selected from 3-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl;
  • R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, or 4-11 membered heterocycloalkyl; said C 1 -C 6 alkyl is optionally selected from 1-3, selected from hydroxyl, halogen, C 1 -C 6 alkoxy, -NR 7-2 R 7-3 , 4-8 membered heterocycloalkyl, or R 7-4 substituted 4-8 membered heterocycloalkyl; R 7-4 is C 1 -C 6 alkyl or C 6 -C 10 aryl; R 7-2 and R 7-3 are independently selected from hydrogen or C 1 -C 6 alkyl; said heterocyclic ring Alkyl is optionally optionally substituted with 1-3 C 1 -C 6 alkyl, R 7-5 substituted C 1 -C 6 alkyl, -NR 7-6 R 7-7 , carbonyl, 3- 8-member ring group, or a 4-8 membered heterocycloalkyl substituents; wherein, R 7- 5 selected from hydroxy
  • n is selected from 0-4;
  • R 8 , R 9 and R 10 are independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, or C 1 -C 6 alkylene-NR 8-1 R 8-2 ; any of the above One or more hydrogen atoms on the group are optionally substituted with halogen; R 8-1 and R 8-2 are independently hydrogen or C 1 -C 6 alkyl.
  • R 1 and R 2 are independently selected from halogen, or C 1 -C 6 alkoxy;
  • R 3 and R 4 are independently selected from halogen, or C 1 -C 6 alkoxy
  • R 5 is hydrogen
  • Y is N, Z is CH, or Y is CH and Z is N;
  • M is selected from CH or N;
  • Cy is selected from 3-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl;
  • R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally selected from 1-3 C 1- C 6 alkyl, R 7-5 substituted C 1 -C 6 alkyl, -NR 7-6 R 7-7 , carbonyl, or a 4- to 8-membered heterocycloalkyl substituent; wherein, R 7-5 is a 3-8 membered cycloalkyl; R 7-6 and R 7-7 are independently C 1 -C 6 alkyl;
  • n is selected from 0, 1 or 2;
  • R 8 is selected from hydrogen, halogen, cyano, or C 1 -C 6 alkyl; said C 1 -C 6 alkyl is optionally substituted with 1-3 halogens;
  • R 9 and R 10 are independently selected from hydrogen, or C 1 -C 6 alkylene-NR 8-1 R 8-2 ; R 8-1 and R 8-2 are independently C 1 -C 6 alkyl.
  • R 1 and R 2 are independently halogen
  • R 3 and R 4 are independently C 1 -C 6 alkoxy
  • R 5 is hydrogen
  • Y is N, Z is CH, or Y is CH and Z is N;
  • M is selected from CH or N;
  • Cy is selected from 3-8 membered heterocycloalkyl, 5-8 membered aryl, or 5-8 membered heteroaryl;
  • R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally selected from 1-3 C 1- C 6 alkyl, R 7-5 substituted C 1 -C 6 alkyl, -NR 7-6 R 7-7 , carbonyl, or a 4- to 8-membered heterocycloalkyl substituent; wherein, R 7-5 is a 3-8 membered cycloalkyl; R 7-6 and R 7-7 are independently C 1 -C 6 alkyl;
  • n is selected from 0, 1 or 2;
  • R 8 is selected from hydrogen, halogen, cyano, or C 1 -C 6 alkyl; said C 1 -C 6 alkyl is optionally substituted with 1-3 halogens;
  • R 9 and R 10 are hydrogen.
  • R 1 and R 2 are independently halogen
  • R 3 and R 4 are independently C 1 -C 6 alkoxy
  • R 5 is hydrogen
  • Y is N, Z is CH, or Y is CH and Z is N;
  • M is selected from CH or N;
  • Cy is selected from a 5-8 membered aryl group, or a 5-8 membered heteroaryl group;
  • R 7 is selected from hydrogen, C 1 -C 6 alkyl, or 4-11 membered heterocycloalkyl; said 4-11 membered heterocycloalkyl is independently optionally selected from 1-3 selected from C 1- C 6 alkyl, R 7-5 substituted C 1 -C 6 alkyl, -NR 7-6 R 7-7 , carbonyl, or a 4- to 8-membered heterocycloalkyl substituent; wherein R 7 -5 is a 3-8 membered cycloalkyl group; R 7-6 and R 7-7 are independently C 1 -C 6 alkyl;
  • n is selected from 0, 1 or 2;
  • R 8 is selected from hydrogen, halogen, or C 1 -C 6 alkyl
  • R 9 and R 10 are hydrogen.
  • R 1 and R 2 are independently halogen
  • R 3 and R 4 are independently C 1 -C 6 alkoxy
  • R 5 is hydrogen
  • Y is N, Z is CH, or Y is CH and Z is N;
  • M is selected from CH or N;
  • Cy is a 5-8 membered aryl group
  • R 7 is selected from hydrogen, or a 4-11 membered heterocycloalkyl group; the 4-11 membered heterocycloalkyl group is independently optionally substituted with 1-3 C 1 -C 6 alkyl groups;
  • n is selected from 0, 1 or 2;
  • R 8 is hydrogen
  • R 9 and R 10 are hydrogen.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , Cy, M, and n are as defined above.
  • the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer Body, solvate, polymorph or prodrug, wherein the compound represented by formula (I) may be any one of the following compounds:
  • the invention also provides a method for preparing a compound represented by formula (I), which comprises steps a-d:
  • the reducing agent is a metal reducing agent hydrogen or sodium thiosulfate
  • LG represents a leaving group conventionally used in such reactions in the art, such as halogen, sulfone, sulfoxide, sulfonate and the like, and the definitions of other groups are as described above.
  • step a) the conditions and operations of step a) are the same as those in the literature.
  • the steps a), b), c), and d) are each performed in a solvent, and each of the solvents is independently selected from water, methanol, ethanol, isopropanol, butanol, ethylene glycol, and ethyl acetate.
  • the transition metal catalyst is selected from tris (dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), tetrakis (triphenylphosphine) palladium (Pd (PPh 3 ) 4 ), palladium acetate, chlorine Palladium, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, palladium triphenylphosphine acetate, [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride, bis One or more of (tri-o-phenylmethylphosphine) palladium dichloride and 1,2-bis (diphenylphosphino) ethane palladium dichloride; the ligand of the transition metal catalyst is selected from tris One or more of tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate
  • the condensation reagent is selected from one or more of DCC, DIC, CDI, EDCI, HOAt, HOBt, BOP, PyBOP, HATU and TBTU.
  • the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, One or more of sodium carbonate and sodium bicarbonate;
  • the organic base is selected from the group consisting of pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0 ]
  • DBU undecyl-7-ene
  • the acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, and trifluoromethanesulfonic acid.
  • the reducing agent is selected from one or more of iron powder, zinc powder, stannous chloride, sodium thiosulfate, sodium sulfite, and hydrogen.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer Body, solvate, polymorph or prodrug, and a pharmaceutically acceptable carrier.
  • the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or A prodrug may be a therapeutically effective amount.
  • the pharmaceutical composition is preferably a pharmaceutical composition for treating tumors, which is composed of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, Tautomers, solvates, polymorphs or prodrugs, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for treating tumors which is composed of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, Tautomers, solvates, polymorphs or prodrugs, and a pharmaceutically acceptable carrier.
  • the invention also provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, poly
  • the medicament is preferably a medicament for preventing and / or treating tumors, or a medicament for diseases related to FGFR kinase.
  • the tumors include, but are not limited to, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, colon cancer, bile duct cancer, brain cancer, and leukemia.
  • the FGFR kinase is preferably FGFR1 and / or FGFR4, and more preferably FGFR4.
  • the invention also provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, poly Use of a crystalline form or a prodrug, or the above pharmaceutical composition in the preparation of an FGFR kinase inhibitor.
  • the FGFR kinase is preferably FGFR1 and / or FGFR4, and more preferably FGFR4.
  • the present invention also provides a method for preventing and / or treating a tumor, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or Enantiomers, diastereomers, tautomers, solvates, polymorphs or prodrugs, or pharmaceutical compositions described above.
  • a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or Enantiomers, diastereomers, tautomers, solvates, polymorphs or prodrugs, or pharmaceutical compositions described above.
  • the manufacturer's instructions for use of the kit can be used, or the reaction and purification can be performed in a manner known in the art or as described in the present invention.
  • the techniques and methods described above can generally be implemented according to conventional methods well known in the art, based on descriptions in several summary and more specific references that are cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituent When a substituent is described by a general chemical formula written from left to right, the substituent also includes a chemically equivalent substituent obtained when the structural formula is written from right to left.
  • substituent -CH2O- is equivalent to -OCH2-.
  • C1-6 alkyl refers to an alkyl group, as defined below, having a total of 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified symbol does not include carbons that may be present in the substituents of the group.
  • halogen refers to fluorine, chlorine, bromine or iodine
  • hydroxy refers to the -OH group
  • hydroxyalkyl refers to an alkane group as defined below substituted with a hydroxyl group (-OH)
  • nitro refers to -NO 2
  • cyano refers to -CN
  • amino refers to -NH 2
  • substituted amino Means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, and heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamido, arane Amino, heteroaralkylamino
  • carbboxy means -COOH.
  • alkyl means only composed of carbon atoms and hydrogen atoms, and no unsaturated A straight or branched hydrocarbon chain group having a bond, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and connected to the rest of the molecule through a single bond.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl.
  • alkenyl means composed of only carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) (More preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group connected to the rest of the molecule through a single bond, such as, but not limited to, vinyl, propenyl, allyl, butane- 1-alkenyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.
  • alkynyl means composed of only carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, A straight or branched hydrocarbon chain group of 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms connected to the rest of the molecule by a single bond, such as, but not limited to, ethynyl , Prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, and the like.
  • cycloalkyl means a stable non-aromatic monocyclic or polycyclic hydrocarbon group composed of only carbon atoms and hydrogen atoms, which may include fused Ring system, bridged ring system or spiro ring system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and which are saturated or unsaturated and may pass through any suitable The carbon atom is connected to the rest of the molecule by a single bond. Unless specifically stated otherwise in this specification, carbon atoms in a cycloalkyl group may be optionally oxidized.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene Acylcycloheptene-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , Fluorenyl, bicyclo [2.2.1] heptyl, 7,7-dimethyl-bicyclo [
  • heterocyclyl also means “heterocycloalkyl”, which means from 2 to 14 carbon atoms and 1 to 6 selected from nitrogen and phosphorus A stable 3- to 20-membered non-aromatic cyclic group consisting of heteroatoms of oxygen, oxygen and sulfur.
  • a heterocyclic group may be a monocyclic, bicyclic, tricyclic, or more cyclic ring system, which may include a fused ring system, a bridged ring system, or a spiro ring system; Nitrogen, carbon or sulfur atoms may be optionally oxidized; nitrogen atoms may be optionally quaternized; and heterocyclic groups may be partially or fully saturated. Heterocyclyl can be attached to the rest of the molecule via a carbon atom or a heteroatom and via a single bond.
  • one or more rings may be an aryl or heteroaryl group as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the group is more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged, or spiro ring group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro [3.5] non Alk-7-yl, 2-oxa-6-aza-spiro [3.3] heptane-6-yl, 2,5-diaza-bicyclo [2.2.1] heptane-2-yl, aza Cyclobutyl, pyranyl, tetrahydropyranyl, thioranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl,
  • aryl means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms.
  • the aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused with a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by a single bond.
  • aryl examples include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl and the like.
  • arylalkyl refers to an alkyl group, as defined above, substituted with an aryl group, as defined above.
  • heteroaryl means having 1 to 15 carbon atoms in the ring (preferably having 1 to 10 carbon atoms) and 1 to 6 selected from nitrogen A 5- to 16-membered conjugated ring system group of a heteroatom of oxygen, oxygen, sulfur, and phosphorus.
  • a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may be fused with a cycloalkyl or heterocyclic group as defined above, provided that the The aryl group is connected to the rest of the molecule via a single bond via an atom on the aromatic ring.
  • the nitrogen, oxygen, sulfur, and phosphorus atoms in the heteroaryl group can be optionally oxidized; the nitrogen atoms can be optionally quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably 1 to 4 members.
  • heteroaryl examples include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benpyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , Purinyl, quinolinyl, isoquinolinyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthroline, phenanthroline, acridine Base, phenazin
  • heteroarylalkyl refers to an alkyl group, as defined above, substituted with a heteroaryl group, as defined above.
  • optionally or “optionally” means that the event or condition described later may or may not occur, and the description includes both the occurrence or non-occurrence of the event or condition.
  • optionally substituted aryl means that the aryl group is substituted or unsubstituted, and the description includes both a substituted aryl group and an unsubstituted aryl group.
  • portion refers to a specific fragment or functional group in a molecule.
  • a chemical moiety is generally considered to be a chemical entity that is embedded or attached to a molecule.
  • a “stereoisomer” refers to a compound that is composed of the same atom and is bonded through the same bond, but has a different three-dimensional structure.
  • the invention will cover various stereoisomers and mixtures thereof.
  • the compound of the present invention contains an olefinic double bond, unless otherwise stated, the compound of the present invention is intended to include E- and Z-geometric isomers.
  • Tautomers refers to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be included within the scope of the invention.
  • the compounds of the invention may contain one or more chiral carbon atoms, and may thus give rise to enantiomers, diastereomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)-or (S)-based on stereochemistry.
  • the invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • the compounds of the present invention can be prepared as racemates, diastereomers or enantiomers as raw materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc .
  • organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , Trifluoroacetate, propionate, hexanoate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate Salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , Cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesul
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic or organic base capable of maintaining the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following salts: primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , Such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin and the like.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine
  • Polymorph refers to different solid crystalline phases produced by certain compounds of the present invention due to the presence of two or more different molecular arrangements in the solid state. Certain compounds of the invention may exist in more than one crystalline form, and the invention is intended to include various crystalline forms and mixtures thereof.
  • solvate refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more solvent molecules.
  • the solvent may be water, and the solvate in this case is a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms.
  • the compounds of the present invention can form true solvates, but in some cases it is also possible to keep only the water or a mixture of water plus a portion of the solvent.
  • the compounds of the present invention can be reacted in a solvent or precipitated or crystallized from the solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
  • the invention also includes prodrugs of the aforementioned compounds.
  • prodrug means a compound that can be converted into a biologically active compound of the present invention under physiological conditions or by solvolysis. Accordingly, the term “prodrug” refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention.
  • the prodrug When administered to an individual in need, the prodrug may not be active, but is transformed in vivo into the active compound of the invention.
  • Prodrugs are usually rapidly transformed in vivo to produce the parent compound of the invention, for example, by hydrolysis in blood.
  • Prodrug compounds generally provide the advantages of solubility, histocompatibility, or sustained release in mammalian organisms.
  • Prodrugs include known amino protecting groups and carboxy protecting groups.
  • prodrug preparation methods can refer to Saulnier, M.G., et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, R.B., et al., J. Med. Chem. 2000, 43, 475.
  • pharmaceutical composition refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
  • the term "pharmaceutically acceptable” refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing undesirable organisms. React or interact in an undesirable manner with any of the components contained in the composition.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government authority as acceptable for human or livestock use. , Diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • tumor and abnormal cell proliferation-related diseases include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cancer, cervical cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.
  • prevention include enabling a patient to reduce the likelihood of the occurrence or worsening of a disease or disorder.
  • treatment and other similar synonyms as used herein include the following meanings:
  • an "effective amount” for use in therapy is an amount of a composition comprising a compound disclosed herein that is required to provide a significant clinically alleviating effect on a condition.
  • An effective amount suitable for any individual case can be determined using techniques such as a dose escalation test.
  • the terms "taking,” “administering,” “administering,” and the like refer to a method capable of delivering a compound or composition to a desired site for a biological effect. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration topical administration and rectal administration.
  • Those skilled in the art are familiar with the application techniques that can be used for the compounds and methods described herein, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current. The ones discussed in Easton, Pa.
  • the compounds and compositions discussed herein are administered orally.
  • the terms “pharmaceutical combination”, “drug combination”, “combination”, “administration of other treatments”, “administration of other therapeutic agents”, etc. refer to a drug treatment obtained by mixing or combining more than one active ingredient, It includes fixed and non-fixed combinations of active ingredients.
  • the term “fixed combination” refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • the term “unfixed combination” refers to the simultaneous, combined, or sequential administration of at least one compound described herein and at least one synergistic formulation to a patient in the form of separate entities. These also apply to cocktail therapies, for example the administration of three or more active ingredients.
  • the intermediate compound functional group may need to be protected by a suitable protecting group.
  • suitable protecting groups include trialkylsilyl or diarylalkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , Tetrahydropyranyl, benzyl and the like.
  • Suitable protecting groups for amino, fluorenyl and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable thiol protecting groups include -C (O) -R "(where R” is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is detailed in Greene, T.W. and P.G.M.Wuts, Protective Groups in Synthesis, (1999), 4th Ed., Wiley.
  • the protective group may also be a polymer resin.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention lies in that the fused ring triazole compound of the present invention is a novel specific irreversible inhibitor of FGFR kinase, has good target selectivity, and can be used for treating tumors.
  • the present inventors prepared a class of compounds having a novel structure represented by Formula I, and found that they have good FGFR kinase inhibitory activity, and the compounds are at extremely low concentrations (can be as low as ⁇ Under 10nmol / L), it has specific and irreversible inhibitory effect on FGFR kinase, and its inhibitory activity is quite excellent, so it can be used to treat related diseases such as tumors caused by FGFR kinase mutation or abnormal expression. Based on the above findings, the inventors have completed the present invention.
  • Step 1 Add 1,3-dimethoxy-5-methylbenzene (30g, 0.20mol) and dichloromethane (900mL) to a dry round bottom flask (1L), and add the solution to the above solution under ice-cooling. Dichlorosulfone (52.5 g, 0.40 mol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight.
  • Step 2 Dissolve 2,4-dichloro-1,5-dimethoxy-3-methylbenzene (31g, 0.14mol) in CCl 4 (600mL) and place in a dry round bottom flask (1000mL) At room temperature, azobisisobutylcyanide (3.0 g, 0.018 mol) and NBS (27.6 g, 0.154 mol) were sequentially added at room temperature. The reaction was carried out at 80 degrees for 3 hours. The reaction was quenched by adding NaHCO 3 aqueous solution, and then extracted with dichloromethane. The organic phase was dried, concentrated, and methyl tert-butyl ether was crystallized to obtain the compound 3-bromomethyl-2,4-dichloro-1. , 5-dimethoxybenzene (30 g, white solid).
  • Step 3 Add the compound 3-bromomethyl-2,4-dichloro-1,5-dimethoxybenzene (30g, 0.1mol) and acetonitrile (500mL) to a dry 1000mL round bottom flask at room temperature. Trimethylsilyl cyanide (12 g, 0.34 mmol) and tetrabutylammonium fluoride (100 mL, 1 mol / L) were added. After stirring at room temperature for 1 h, TLC showed the reaction was over. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried and concentrated. The concentrate was slurried with ethyl acetate to obtain the compound (2,6-dichloro-3,5-dimethoxy-benzene). ) -Acetonitrile (20 g, white solid).
  • Step 4 In a dry 250mL round bottom flask, add (2,6-dichloro-3,5-dimethoxy-phenyl) -acetonitrile (10.4g, 0.028mol) and DMF (100mL) at room temperature. Next, 4-amino-2-methylthio-pyrimidine-5-carbaldehyde (5 g, 0.02 mol) and potassium carbonate (12.25 g, 0.06 mol) were sequentially added, and the reaction was stirred overnight until the reaction was completed. The reaction solution was extracted with ethyl acetate, the organic phase was washed with distilled water and saturated brine, dried and filtered, and concentrated under reduced pressure.
  • Step 1 Dissolve 4- (4-methyl-piperazin-1-yl) -aniline (5g) and triethylamine (5g) in dry ethyl acetate (20mL). Add acetic anhydride (5 mL). After the dropwise addition, the reaction was carried out at room temperature for 3 hours. A solid was precipitated in the reaction solution, filtered under reduced pressure, washed with ethyl acetate, and dried to obtain N- [4- (4-methyl-piperazin-1-yl) -phenyl] -acetamide as a solid (4 g).
  • LC-MS: ESI [M + H] + 234.3.
  • Step 3 Dissolve N- [4- (4-methyl-piperazin-1-yl) -2-nitro-phenyl] -acetamide (2.5g) in methanol (10mL), and add 4N hydrochloric acid The solution (10 mL) was heated at reflux for 1 hour. After the reaction, the reaction solution was diluted with water, and the pH was adjusted to 8-9 with ammonia water under ice-cooling, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4- (4-methyl- Piperazin-1-yl) -2-nitro-aniline.
  • LC-MS: ESI [M + H] + 237.2.
  • Step 1 6- (2,6-dichloro-3,5-dimethoxy-phenyl) -2-methylthio-pyrido [2,3-d] pyrimidin-7-ylamine ( 4g, 10mmol) was dissolved in methanol (300mL), N, N-dimethylformamide dimethyl acetal (2.4g, 20mmol) was added, the temperature was raised to 80 ° C, stirred overnight, concentrated under reduced pressure, ethyl acetate Purified and purified, filtered and dried to obtain compound N '-(6- (2,6-dichloro-3,5-dimethoxy-phenyl) -2- (methylthio) pyridine [2,3-d] pyrimidine -7-yl) -N, N-dimethylformimide (3.6 g, yellow solid) was used directly in the next reaction.
  • LC-MS: ESI [M + H] + 452.1.
  • N '-(6- (2,6-dichloro-3,5-dimethoxy-phenyl) -2- (methylthio) pyridine [2,3-d] pyrimidine-7 -Yl) -N, N-dimethylformimide (2.3g, 5mmol) was dissolved in methanol (50mL), and pyridine (0.8g, 10mmol) and hydroxylammonium hydrochloride (417mg, 6mmol) were sequentially added at room temperature. And stirred at room temperature overnight. The reaction was monitored by LCMS and the reaction was concentrated under reduced pressure.
  • the third step 4- (2,6-dichloro-3,5-dimethoxy-phenyl) -8- (methylthio)-[1,2,4] triazol [1 ', 5 ': 1,6] pyridine
  • pyrimidine 1.1g, 2.6mmol
  • chloroform 100mL
  • m-CPBA 1.6g, 7.8mmol
  • the reaction solution was washed successively with a saturated sodium bicarbonate solution and water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered to obtain the compound 4- (2,6-dichloro-3,5-dimethoxy-phenyl).
  • the third step 6- (2,6-dichloro-3,5-dimethoxyphenyl) -2- (methylthio)-[1,2,4] triazolo [4 ', 3 ': 1,6] pyrido [2,3-d] pyrimidine (1.1 g, 2.6 mmol) was dissolved in chloroform (100 mL), m-CPBA (1.6 g, 7.8 mmol) was added, and the reaction was performed at room temperature for 3 h.
  • Step 1 Add triethylamine (2.5mL, 17.3mmol) to 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (1.6g, 8.64mmol) and DMF under cooling in an ice bath. (15 mL) and tert-butanol (5 mL), DPPA (3.6 g, 12.97 mmol) was then added, and the reaction solution was heated to 80 ° C. and stirred for 4 h. After completion of the reaction, some solvents were removed under reduced pressure and diluted with ethyl acetate.
  • the nitro compound (1 eq.) was dissolved in methanol, and a saturated sodium thiosulfate solution (2 eq.) And a sodium carbonate solution (2 eq.) Were added, followed by stirring at room temperature overnight. After completion of the reaction, ethyl acetate was added for extraction, and the mixture was washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized from ethyl acetate to obtain an amino intermediate.
  • Test method (1) Prepare 1 ⁇ Kinase buffer. (2) Formulation of compound concentration gradient: the test compound test concentration is 10uM starting, 3 times diluted 10 concentrations, duplicate well test, 10 different concentrations of 100 times final concentration in 96-well plate. Compounds of each concentration were then further diluted with a 1 ⁇ Kinase buffer to a 5x final concentration intermediate dilution solution. (3) 5 ⁇ L of the prepared compound solution was added to the compound wells of the 384-well plate, and each concentration was tested in a single well; 5 ⁇ L of 5% DMSO was added to the negative control well and the positive control well. (4) A 2.5-fold final concentration of the kinase solution was prepared with 1 ⁇ Kinase buffer.
  • Inhibition rate (%) (OD negative control well-OD administration well) / OD negative control well x 100%. Analysis of the results. The IC 50 value was obtained by a four-parameter regression method using the software provided with the microplate reader.
  • the majority of embodiments of the present invention provides inhibitory activity IC 50 value is less than the FGFR4 100nM, most of the inhibitory activity of IC 50 of the embodiment is less than 20nM, the inhibitory activity of some embodiments even less than 1nM, show a more Strong enzyme inhibitory activity; and FGFR1 inhibitory activity is weak, the IC 50 of FGFR1 inhibitory activity of most of the compounds of the examples is greater than 20 nM, and some examples are even greater than 1000 nM, showing a higher selectivity of kinase subtypes.
  • Table 1 The specific results are shown in Table 1.
  • Table 1 FGFR kinase inhibitory activity of some example compounds
  • Table 2 Comparison of kinase activity and selectivity of some example compounds and comparative compounds.
  • Test Example 2 Effect of the Example of the Invention on FGFR-Mediated Tumor Cell Proliferation Ability
  • Test method Hep3B cells (ATCC) in logarithmic growth phase were seeded into a 96-well culture plate at an appropriate density, 100 ⁇ L per well. After overnight culture, compounds of different concentrations were added for 72 hours, and a solvent control group was set. (Negative control). Incubate at 37 ° C under 5% CO2. 10 mM compound stock solution was added to the cells, and the effect of the compounds on cell proliferation was 72 hours after the compounds were applied to the cells. (Promega) method, add 30 ⁇ L of CTG reagent to each well, place in a 37 degree incubator for 2-4 hours, read with a full-wavelength microplate microplate reader, Envision, and measure the wavelength at 450 nm.
  • inhibition rate (%) (OD negative control well-OD administration well) / OD negative control well x 100%.
  • IC 50 value was obtained by Graphpad Prism 5 software with four-parameter regression.
  • results Some of the examples 1 to 50 provided by the present invention have inhibitory activity on Hep3B cells.
  • the IC 50 values are all less than 500 nM.
  • the inhibitory activity IC 50 values of some compound compounds are even less than 100 nM.
  • Cell proliferation inhibitory activity The specific results are shown in Table 3:
  • Table 3 Inhibitory activity of some example compounds on Hep3B cell proliferation.
  • Test Example 3 Tests of Example Compounds Not Different in Kinase Inhibition Activity
  • the compounds of the present invention have different kinases such as EGFR, VEGFR, PDGFR, FGFR1-3, RET, MET, Src, Lyn, Syk, MEK, CDK, RAF, ROS, FGFR1, FGFR2, FGFR3, FGFR gated mutants V550L, CSF1R, etc. Inhibitory activity was also tested, and some of the compounds of Examples, such as Example 3, Example 7, Example 11, Example 35, Example 47, etc., showed good FGFR4 kinase selectivity (IC 50 ⁇ 5nM).
  • VEGFR, FGFR3, CDK and other kinases (IC 50 > 500nM) are more than 100 times more selective; while for FGFR1, FGFR2, CSF1R, FGFR4 gated mutant kinases (20nM ⁇ IC 50 ⁇ 400nM) and other selectivity are 10-100 times; in contrast, some embodiments exhibits a higher FGFR1, FGFR2 inhibitory activity (IC 50 ⁇ 50nM), its FGFR4 kinase (IC 50> 1000 nM selectivity) is greater than 100 times, as described in Example 43.
  • Test Example 4 Test of the compound of the Example for inhibiting the proliferation of different tumor cells
  • SRB staining method or CCK8 method or CTG method to test a variety of tumor cells such as BaF3-FGFR4, BaF3-FGFR V550L, HuH-7, JHH-7, MDA-MB-453, DMS114, SNU-16, KG1, UM -UC-14, HCT116, NCI-H716, MCF-7, KATOIII, Colo-205, KMS11, H1581, RT-112, RT-4, OPM-2, NCI-H460, SNU-869, SNU878, CNE, NCI -H2122, NCI-H1299, A204, A427, A549, MG63, Kappars-299, SK-OV-3, U87MG, BT474, LNCAP, A498, KYSE140, HUCC-T1, PANC-1, etc., partial implementation Exemplary compounds such as Example 3, Example 4, Example 7, Example 11, Example 32, Example 34, etc., showed a strong inhibitory activity on the inhibition of the increase in value of different cells, showing
  • Metabolic stability test 150 microliters of liver microsomes (final concentration 0.5mg / mL) were used for metabolic stability incubation.
  • the system contains NADPH (final concentration 1mM), 1 ⁇ M test compound and positive control midazole.
  • negative control atenolol the reaction was stopped with tinidazole-containing acetonitrile at 0min, 5min, 10min, and 30min, vortexed for 10min, centrifuged at 15000rmp for 10min, and 50 ⁇ L of the supernatant was injected in a 96-well plate.
  • the compound's metabolic stability was calculated by measuring the relative decrease of the original drug.
  • DI test Direct inhibition test: 100 ⁇ L of human liver microsomes (final concentration 0.2 mg / mL) were used for direct inhibition incubation. The system contained NADPH (final concentration 1 mM), 10 ⁇ M compound, and positive inhibitor cocktail.
  • Example 3 Some example compounds such as Example 3, Example 4, Example 5, Example 32, etc. have high metabolic stability to microsomes, T 1/2 is greater than 30 min, has no direct inhibitory effect on major metabolic enzymes, and IC 50 is greater than 20uM, showing a good drugability.
  • Test Example 6 Test of Pharmacokinetic Parameters of Compounds of Examples in Rats and Mice in Vivo
  • test compounds Six male SPF-grade SD rats (Shanghai Xipuer-Bikai experimental animals) were divided into two groups, and the test compounds were configured into appropriate solutions or suspensions; one group was administered by intravenous injection (1 mg / kg dose), and the other was administered orally Administration (5 mg / kg dose). Blood was collected via jugular vein puncture, and each sample was collected at about 0.2 mL / time point. Heparin sodium was used for anticoagulation.
  • the time points for blood collection were as follows: before administration and 5, 15, and 30 minutes after administration, 1, 2, 4, 6, 8, and 24h; After collecting blood samples, place them on ice, centrifuge the plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ° C), and store the collected plasma at -80 ° C before analysis. Plasma samples were analyzed by LC-MS / MS.
  • the pharmacokinetic calculation software WinNonlin5.2 non-compartment model was used to calculate the pharmacokinetic parameters AUC0-t, AUC0- ⁇ , MRT0- ⁇ , Cmax, Tmax, T1 of the test product. Parameters such as / 2 and Vd and their average and standard deviation.
  • the bioavailability (F) will be calculated by the following formula.
  • Example 3 Some example compounds such as Example 3, Example 4, Example 5, Example 32, etc. were administered by gavage with Cmax greater than 200 nM, AUC greater than 2000 hr * nM, and F% greater than 15%, showing good drug-making properties. .
  • Test Example 7 Test of Inhibition of Hep3B Xenograft Tumor Growth in Nude Mice by Compounds of Examples
  • the tumor tissue during the vigorous growth period was cut to about 1.5 mm 3 and inoculated subcutaneously in the right armpit of nude mice under sterile conditions.
  • Subcutaneously transplanted tumors in nude mice were measured with vernier calipers. The diameter of the transplanted tumors was measured, and the animals were randomly divided into groups until the average tumor volume reached about 130 mm 3 .
  • the compound of the example (configured with water for injection containing 1% Tween80 to a desired concentration for use) was orally administered daily at a given dose for three consecutive weeks, and the solvent control group was given the same amount of solvent.
  • the diameter of the transplanted tumor was measured twice a week, and the weight of the mice was weighed.
  • Example 3 Example 7 and the like were administered orally for 21 days at a dose of 40 mg / kg, with T / C less than 10%, and some experimental animals.
  • the tumors in the group subsided.

Abstract

L'invention concerne une classe de composés de triazole cycliques fusionnés, un procédé de préparation et une utilisation. L'invention concerne particulièrement un composé de triazole cyclique fusionné tel que représenté par la formule (I), ou son sel pharmaceutiquement acceptable, ou son énantiomère, diastéréoisomère, tautomère, solvate, polymorphe ou promédicament, son procédé de préparation, et une utilisation pharmaceutique de celui-ci. (I)
PCT/CN2019/102214 2018-08-23 2019-08-23 Classe de composé de triazole cyclique fusionné, procédé de préparation et utilisation WO2020038458A1 (fr)

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CN105524048A (zh) * 2014-08-19 2016-04-27 上海海和药物研究开发有限公司 作为fgfr激酶抑制剂的吲唑类化合物及其制备和应用
WO2018004258A1 (fr) * 2016-06-28 2018-01-04 한미약품 주식회사 Nouveau dérivé hétérocyclique et son utilisation
CN109721600A (zh) * 2017-10-30 2019-05-07 如东凌达生物医药科技有限公司 一类含氮稠环化合物及其制备方法和用途

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EP4130004A4 (fr) * 2020-03-27 2024-04-10 Betta Pharmaceuticals Co Ltd Sel et formes cristallines d'inhibiteur de fgfr4 et leurs utilisations
CN114907350A (zh) * 2021-02-10 2022-08-16 上海凌达生物医药有限公司 一类含氮稠环类化合物、制备方法和用途
CN114907350B (zh) * 2021-02-10 2023-12-29 上海凌达生物医药有限公司 一类含氮稠环类化合物、制备方法和用途
WO2024044713A1 (fr) * 2022-08-25 2024-02-29 Enliven Inc. Composés de naphtyridine pour l'inhibition de kinases raf

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