WO2019085894A1 - Composé cyclique fusionné contenant de l'azote, son procédé de préparation et son utilisation - Google Patents

Composé cyclique fusionné contenant de l'azote, son procédé de préparation et son utilisation Download PDF

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WO2019085894A1
WO2019085894A1 PCT/CN2018/112660 CN2018112660W WO2019085894A1 WO 2019085894 A1 WO2019085894 A1 WO 2019085894A1 CN 2018112660 W CN2018112660 W CN 2018112660W WO 2019085894 A1 WO2019085894 A1 WO 2019085894A1
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group
alkyl
hydrogen
membered
ring
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王慧
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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
    • A61K31/44—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 or sparfloxacin
    • 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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention belongs to the field of medicinal chemistry, and particularly relates to a nitrogen-containing fused ring compound, a preparation method thereof and use thereof.
  • FGFR fibroblast growth factor receptor
  • FGF19 is a ligand of FGFR4, which is responsible for regulating normal bile secretion and hepatocyte proliferation in the liver. Overexpression or overactivation can promote hepatocyte proliferation and induce liver cancer formation. This has been demonstrated in transgenic mice that knockdown of the FGFR4 gene blocks the production of hepatocellular carcinoma.
  • FGFR inhibitors such as BGJ398, AZD4547, AP24534, and BLU9931 are ubiquitous or have poor target selectivity, or low target inhibitory activity, or poor pharmacokinetic properties of the compound, or are prone to mutation resistance.
  • the clinical application of FGFR inhibitors is blocked. Therefore, the discovery and search for novel compounds with high selectivity, high activity, resistance to drug resistance and high drug-forming properties of FGFR has become a hot topic.
  • the technical problem to be solved by the present invention is to overcome the ubiquitous or poor target selectivity of the existing FGFR inhibitor compounds in the prior art, or the target inhibition activity is not high, or the compound pharmacokinetic properties are poor, or easy to produce resistance.
  • the invention provides a kind of nitrogen-containing fused-ring compound, a preparation method and use thereof, and the nitrogen-containing fused-ring compound of the invention belongs to a novel irreversible inhibitor of specific FGFR kinase, which can be used for treating abnormality of FGFR kinase.
  • Related diseases such as tumors.
  • the present invention solves the above technical problems by the following technical solutions.
  • the present invention provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, or a plurality thereof Crystal form or prodrug,
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino; preferably from hydrogen, halogen, alkyl, alkoxy;
  • R 5 is independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkoxy, amino, hydroxy, and the like; preferably from hydrogen, halogen, alkyl;
  • R 6 is independently selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, alkoxy, alkylamino, alkenyl, alkynyl, acyl, sulfonyl, 5-8 membered aryl or heteroaryl a 3-8 membered cycloalkyl or heterocycloalkyl group; preferably from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocycloalkyl, and the like;
  • M is independently selected from CRa or N;
  • Ra is independently selected from hydrogen, halogen;
  • Cy is each selected from a 3-8 membered cycloalkyl or heterocycloalkyl group, a 4-8 membered aryl group or a heteroaryl group; preferably a 5-6 membered cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group. ;
  • R 7 is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, acyl, sulfonyl, aryl, heteroaryl, cycloalkyl, a heterocycloalkyl group or the like; preferably from hydrogen, halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, and the like;
  • R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, sulfone, sulfoxide, trifluoromethyl, etc.; preferably from hydrogen, halogen;
  • One or more hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of, but not limited to, hydrazine, 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, C 2 -C 6 acyl or sulfonyl, 5 -8 membered aryl or heteroaryl, 4-8 membered cycloalkyl or heterocycloalkyl; wherein said heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, P or S, the heterocycloalkyl group contains 1-3 heteroatoms selected from the group consisting of N, O, P or S.
  • the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, or a plurality thereof a crystal form or a prodrug, wherein
  • M is independently selected from CH or N;
  • R 1 and R 2 are independently preferably selected from hydrogen, halogen, preferably from fluorine or chlorine;
  • R 3 and R 4 are independently selected from halogen, alkoxy, alkyl, amino, cycloalkyl or heterocycloalkyl, further preferably From fluorine, methoxy;
  • R 5 is independently selected from the group consisting of hydrogen, halogen, alkyl; further preferably from hydrogen, fluorine, methyl;
  • R 6 is preferably selected from hydrogen, halogen, C 1 -C 6 alkyl, and the hydrogen atom on the C 1 -C 6 alkyl group may be a 3-8 membered cycloalkyl or heterocycloalkyl group, a 5-8 membered aryl group.
  • R 7 is independently selected from the group consisting of hydrogen, halogen, alkyl, cyano, hydroxy, amino, heterocycloalkyl, alkoxy, alkylamino, acyl or sulfonyl, and the like, further preferably from hydrogen, fluorine, cyano, amino Or an alkyl or heterocycloalkyl group; more preferably hydrogen, fluorine, methyl, ethyl, piperazine ring, morpholine ring, piperidine ring, pyrrolidine, etc.;
  • R 8 , R 9 and R 10 are independently selected from hydrogen, halogen; further preferably from hydrogen, fluorine;
  • Cy is preferably a 5- to 6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; further preferably a tetrahydrofuran ring, a tetrahydropyran ring, a tetrahydropyrrole ring, a piperidine ring, a benzene ring, or a pyridine. Ring or pyrazole ring and the like.
  • the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, a polymorph or prodrug wherein the compound of formula (I) has the formula:
  • Cy is preferably selected from the group consisting of tetrahydrofuran ring, tetrahydropyran ring, tetrahydropyrrole ring, piperidine ring, benzene ring, pyridine ring or pyrazole ring; and R 6 is preferably selected from hydrogen, fluorine, methyl, ethyl or propyl.
  • the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, a polymorph or prodrug wherein the compound of formula (I) has the formula:
  • Cy and R 7 are as defined above, and m is preferably from 1-3.
  • the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, a polymorph or prodrug, wherein the compound of formula (I) is any one of the following compounds:
  • the present invention provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, or a plurality thereof Crystal form or prodrug,
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 1 -C 6 Alkoxy, 3-8 membered heterocycloalkoxy, or amino; each independently preferably selected from hydrogen, halogen, 3-8 membered cycloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy base;
  • R 5 is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino or hydroxy;
  • M is selected from CR a or N; wherein R a is selected from hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • Cy is selected from a 3-8 membered cycloalkyl group (preferably a 5-6 membered cycloalkyl group) or a 3-8 membered heterocycloalkyl group (preferably a 5-6 membered heterocycloalkyl group), a 6-10 membered aryl group or a 5- a 10-membered heteroaryl group (preferably a 5-8 membered heteroaryl group);
  • fluoroacryloyl group said 6-10 membered Groups, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, and 3-8 membered heterocycloalkyl or substituted each independently selected from hydrogen, C 1 -C 6 alkyl group, acryloyl group and acrylamide Substituting one or more substituents; z, o, m, n are each independently selected from any of 0-5;
  • R 8 is selected from the group consisting of hydrogen, halogen, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkyl-SO 2 -, C 1 -C 6 alkyl-SO-, or C 1 -C 6 haloalkyl;
  • R 6 and R 8 are not hydrogen at the same time
  • R 7 is selected from the group consisting of hydrogen, halogen, cyano, cyanoethyl, 2,3-dihydroxypropyl, O(R h )-C 1 -C 6 alkyl, N(R i )(R j )-( CH 2 ) p -, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-SO 2 - , C 1 -C 6 alkyl-SO-, 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, or 3-8 membered heterocycloalkyl; wherein, R h , R i and R j are each independently selected from hydrogen, C 1 -C 6 alkyl, or dimethylaminoethyl, and p is selected from any integer from 0 to 5; or,
  • R 9 and R 10 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkyl-SO 2 -, C 1 -C 6 alkyl-SO- , N(R c )(R d )-(CH 2 )x-; or, R 9 and R 10 together form a 5-7 membered nitrogen-containing heterocycloalkyl group substituted by a C 1 -C 6 alkyl group; Wherein R c and R d are each independently selected from hydrogen or C 1 -C 6 alkyl, and x is selected from any of 0-5;
  • Each ring system described in the above definition may be a monocyclic ring, a fused ring, a fused ring, a bridged ring or a spiro ring; the heteroaryl group may be partially oxidized (oxo) and/or reduced (partially saturated).
  • the heteroaryl group comprises 1-3 heteroatoms selected from the group consisting of N, O, P and S, the heterocycloalkyl group comprising 1-3 heteroatoms selected from the group consisting of: N, O, P and S.
  • the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, or a plurality thereof Crystal form or prodrug,
  • R 1 and R 2 are each independently preferably selected from hydrogen or halogen (for example fluorine or chlorine), further each independently preferably selected from fluorine or chlorine;
  • R 3 and R 4 are each independently preferably selected from halogen (for example fluorine or chlorine), 3-8 membered cycloalkyl (for example cyclopropyl) or C 1 -C 6 alkoxy (for example methoxy), further each. Independently preferably selected from the group consisting of fluorine, chlorine, methoxy or cyclopropyl;
  • R 5 is preferably selected from hydrogen, halogen or C 1 -C 6 alkyl; further preferably selected from hydrogen, fluorine or methyl;
  • M is preferably selected from CH or N;
  • Cy is preferably selected from a 5-6 membered cycloalkyl group (further preferably a 4-6 membered cycloalkyl group), a 5-6 membered heterocycloalkyl group (further preferably a 4-6 membered heterocycloalkyl group), a 6 membered aryl group or a 5-8 membered heteroaryl group; more preferably selected from the group consisting of a tetrahydrofuran ring, a tetrahydropyran ring, a tetrahydropyrrole ring, a piperidine ring, a benzene ring, a pyridine ring, a pyrazole ring, and a 2,3-dihydrobenzofuran.
  • Cy is further oxidized, said oxidation occurring at the ring heteroatom (eg And; the connection site of Cy with other structural fragments (two nitrogen atoms) on the mother nucleus is in an ortho relationship;
  • R 6 is preferably selected from the group consisting of hydrogen, halogen (e.g., fluorine), C 1 -C 6 alkyl (e.g., methyl, ethyl, n-propyl or isopropyl), C 1 -C 6 deuterated alkyl (e.g., -CD).
  • halogen e.g., fluorine
  • C 1 -C 6 alkyl e.g., methyl, ethyl, n-propyl or isopropyl
  • C 1 -C 6 deuterated alkyl e.g., -CD
  • R 6 is N(R e )(R f )-(CH 2 ) y -
  • R e and R f are each independent
  • it is selected from hydrogen, C 1 -C 6 alkyl (for example methyl, ethyl, n-propyl or isopropyl) or tetrahydropyrrolidinyl, said tetrahydropyrrolidinyl group preferably being selected from hydrogen a substituent of a C 1 -C 6 alkyl group (for example, methyl, ethyl, n-propyl or isopropyl), an acryloyl group or a fluoroacryloyl group; y is preferably selected from 0, 1, 2 or 3;
  • the N(R e )(R f )-(CH 2 ) y - is further preferably N(CH 3 ) 2 -CH
  • R 6 is N(R e )(R f )-(CH 2 ) y -
  • R e and R f are preferably The nitrogen atom to be bonded together constitutes a tetrahydropyrrole ring or a piperazine ring, which is substituted by one or two or three substituents selected from hydrogen, C 1 - C 6 alkyl (for example methyl), acryloyl or fluoroacryloyl;
  • y is preferably selected from 0, 1, 2 or 3; said N(R e )(R f )-(CH 2 ) y - further Preferred
  • R 6 is O(R g )-C 1 -C 6 alkylene
  • the O(R g )-C 1 -C 6 alkylene group is preferably CH 3 OCH 2 -, CH 3 OCH 2 CH 2 -, HOCH 2 -, HO(CH 2 ) 3 -,
  • R 6 is 6-10 membered aryl-(CH 2 ) z -, in the 6-10 membered aryl-(CH 2 ) z -, z is preferably selected from 0, 1 or 2, 6-10
  • the aryl group is preferably a phenyl group; the 6-10 membered aryl group is preferably substituted with one acrylamide group; and R 6 is further preferably
  • R 6 is a 5-10 membered heteroaryl-(CH 2 ) o -, wherein the 5-10 membered heteroaryl-(CH 2 ) o -, o is preferably from 0, 1 or 2 , 5-
  • the 10-membered heteroaryl group is preferably a pyridyl group; the 5-10 membered heteroaryl group is preferably substituted with one acrylamide group; and R 6 is further preferably
  • R 6 is a 3-8 membered cycloalkyl-(CH 2 ) m -, in the 3-8 membered cycloalkyl-(CH 2 ) m -, m is preferably from 0, 1, or 2,3-
  • the 8-membered cycloalkyl group is preferably a cyclopropyl group or a cyclopentyl group; and R 6 is further preferably
  • R 6 is a 3-8 membered heterocycloalkyl-(CH 2 ) n -, wherein the 3-8 membered heterocycloalkyl-(CH 2 ) n -, n is preferably from 0, 1 or 2,
  • the 3-8 membered heterocycloalkyl group is preferably piperidinyl or oxetanyl; the 3-8 membered heterocycloalkyl group is preferably a C 1 -C 6 alkyl group (e.g., methyl) or acryloyl group. Substituted; R 6 is further preferably
  • R 7 is preferably selected from the group consisting of hydrogen, halogen (e.g., fluorine), cyano, cyanoethyl, 2,3-dihydroxypropyl, C 1 -C 6 alkyl (e.g., methyl, ethyl, n-propyl or iso) Propyl), C 1 -C 6 alkoxy (eg methoxy, ethoxy, n-propoxy or isopropoxy), O(R h )-C 1 -C 6 alkyl, N(R i ) (R j )-(CH 2 ) p —, or a 3-8 membered heterocycloalkyl; wherein, R h , R i and R j are each independently selected from hydrogen, C 1 -C 6 alkyl (eg Methyl, ethyl, n-propyl or isopropyl), or dimethylaminoethyl; p is selected from 0, 2, 3, 4
  • R 7 is O (R h) -C 1 -C 6 alkylene group
  • the O (R h) -C 1 -C 6 alkyl group in R h is preferably hydrogen, methyl, ethyl, n a propyl or isopropyl group, preferably a C 1 -C 6 alkylene group is -C(CH 2 ) 2 -CH 2 - or -CH 2 -CH 2 -;
  • R i and R j in the N(R i )(R j )-(CH 2 ) p - are preferably each Independently hydrogen, methyl, ethyl, n-propyl, isopropyl or dimethylaminoethyl (eg, -N(R i )(R j ) is -N(CH 2 )CH 2 CH 3 ,- N(CH 3 ) 2 , or -N(CH 2 )CH 2 CH 2 N(CH 3 ) 2 ), p is selected from 0, 1 , 2 , 3, 4 or 5;
  • R 7 is hydrogen, C 1 -C 6 alkyl (eg methyl, ethyl or propyl), cyano-C 1 -C 6 alkyl (cyanoethyl), C 1 -C 6 alkoxy -C 1 -C 6 alkyl (eg methoxyethyl), pyrazolyl-C 1 -C 6 alkyl (eg N-methylpyrazolylene), tetrahydropyrrolyl, dimethyl
  • the 3-8 membered heterocycloalkyl group is substituted with one or more substituents of the aminoethyl, oxetanyl and dimethylamino groups, one or more of the ones described above are preferably one, two or Three; the substituents may be the same or different; the 3-8 membered heterocycloalkyl group is preferably: piperazinyl (for example ), tetrahydropiperidinyl (for example) ), tetrahydropyrrolidinyl (for
  • R 8 is preferably hydrogen, cyano, halogen (such as fluorine) or C 1 -C 6 alkyl (such as methyl);
  • R 9 and R 10 are each independently preferably selected from hydrogen, halogen (for example fluorine), or N(R c )(R d )-(CH 2 )x-, wherein x is preferably 0, 1, 2 or 3, R c and R d are each independently preferably selected from hydrogen or methyl (for example, said N(R c )(R d )-(CH 2 )x- is dimethylaminomethylene); or, R 9 And R 10 together constitute N-methylazetidyl;
  • R 6 and R 8 are not hydrogen at the same time
  • Cy When Cy is a saturated 4-6 membered heterocycloalkyl group, Cy forms two chiral carbon-nitrogen bonds with other structural segments on the mother nucleus, namely two nitrogen atoms.
  • the compound of the formula (I) as described in the present invention includes a racemic compound or any of its chiral compounds; when it is a chiral compound, preferably two of them are The carbon-nitrogen bond is in a cis configuration.
  • the present invention is a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, or a plurality thereof a crystal form or a prodrug, wherein the compound represented by the formula (I) has the following formula:
  • X is preferably fluorine or chlorine
  • M is preferably CH or N
  • Cy is preferably selected from the group consisting of a tetrahydrofuran ring, a tetrahydropyran ring, a tetrahydropyrrole ring, a piperidine ring, a benzene ring, a pyridine ring, a pyrazole ring, a 2,3-dihydrobenzofuran ring, and a 2,3-dihydroanthracene.
  • R 6 is preferably selected from the group consisting of hydrogen, fluorine, methyl, ethyl, n-propyl, isopropyl, -CD 3 , -CH 2 F, -CHF 2 , CH 3 SO 2 -CH 2 CH 2 CH 2 -, N (CH 3 ) 2 -CH 2 -, N(CH 3 ) 2 -CH 2 CH 2 -, N(CH 3 ) 2 -CH 2 CH 2 CH 2 -, CH 3 OCH 2 -, CH 3 OCH 2 CH 2 -, HOCH 2 -, HO(CH 2 ) 3 -,
  • R 7 is preferably selected from the group consisting of hydrogen, fluorine, cyano, cyanoethyl, 2,3-dihydroxypropyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyl Oxyl, isopropoxy, HO-C(CH 2 ) 2 -CH 2 -, CH 3 O-CH 2 -CH 2 -, -N(CH 2 )CH 2 CH 3 , -CH 2 -N(CH 3 ) 2 , -N(CH 2 )CH 2 CH 2 N(CH 3 ) 2
  • R 8 is preferably selected from the group consisting of hydrogen, cyano, fluoro or methyl
  • R 6 and R 8 are not hydrogen at the same time
  • R 9 and R 10 are each independently preferably selected from hydrogen, fluorine, or dimethylaminomethylene; or, R 9 and R 10 together form an N-methylazetidyl group.
  • the present invention is a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, or a plurality thereof a crystal form or a prodrug, wherein the compound represented by the formula (I) has the following formula:
  • R 6 , Cy, R 7 and R 8 are as defined above, and q is selected from 1, 2 or 3.
  • the present invention is a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, or a plurality thereof a crystal form or a prodrug, wherein the compound represented by the formula (I) is any one of the following compounds:
  • the present invention provides a method for producing a compound represented by the formula (I), which comprises the steps of:
  • a compound of the formula (B) is obtained by subjecting a compound of the formula (A) to an ⁇ -haloaldehyde or a halogenated ketone or an equivalent thereof in the presence of an acid or a base to prepare a compound of the formula (B);
  • a compound of the formula (I) is condensed with an acrylic acid or an acryloyl chloride compound in the presence of a base or a condensing reagent to prepare a compound of the formula (I);
  • LG represents a leaving group conventionally used in such reactions in the art, such as a halogen, a sulfone group, a sulfoxide group, a sulfonate group, etc., and the other groups are as defined above;
  • the steps a), b), c), d) are each carried out in a solvent, and the solvents are each independently selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, and B.
  • the solvents are each independently selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, and B.
  • 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 ), palladium acetate, chlorine Palladium, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, palladium triphenylphosphine acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, double One or more of (tri-o-phenylmethylphosphine)palladium dichloride, and 1,2-bis(diphenylphosphino)ethanepalladium dichloride;
  • the catalyst ligand is selected from the group consisting of tri-tert-butyl One or more of a phosphine, a tri-tert-butylphosphin
  • the condensation reagent is selected from one or more of DCC, DIC, CDI, EDCI, HOAt, HOBt, BOP, PyBOP, HATU, and TBTU;
  • the base comprises an organic base and/or an inorganic base; wherein the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium t-butoxide, sodium t-butoxide, potassium fluoride One or more of cesium fluoride, potassium phosphate, potassium carbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate; the organic base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropyl B Amine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), hexamethyldisilazide, hexamethyldisilazide, and lutidine One or more;
  • the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium t-butoxide, sodium t-butoxide, potassium fluoride One or
  • the acid is selected from one or more of the group consisting 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 the group consisting of iron powder, zinc powder, stannous chloride, sodium thiosulfate, sodium sulfite, and hydrogen.
  • the compound of the above formula (A) and the respective reagents involved in the above production method are commercially available or can be prepared by a person skilled in the art with reference to a synthesis method in the prior art.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, a diastereomer Isomer, tautomer, solvate, polymorph or prodrug, and at least one pharmaceutical excipient.
  • the present invention provides a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereomer thereof, a tautomer thereof, The use of a solvate, polymorph or prodrug, or a pharmaceutical composition as described above for the preparation of a FGFR kinase inhibitor.
  • the present invention provides a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereomer thereof, a tautomer thereof,
  • a solvate, polymorph or prodrug, or a pharmaceutical composition as described above for the manufacture of a medicament for the prevention and/or treatment of a disease associated with the activity or expression of a protein kinase, in particular a FGFR kinase, in particular for the preparation of prophylaxis and/or Application in the treatment of anti-tumor drugs.
  • the tumor includes, but is not limited to, one or more of the following: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, stomach cancer, intestinal cancer, Cholangiocarcinoma, brain cancer, leukemia, lymphoma, nasopharyngeal carcinoma, bladder cancer, pancreatic cancer, etc., especially liver cancer or cholangiocarcinoma.
  • the present invention provides a method for preventing and/or treating a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable compound thereof a salt, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof.
  • reaction can be carried out and purified using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification.
  • group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • substituent -CH 2 O- is equivalent to -OCH 2 -.
  • C1-6 alkyl refers to an alkyl group as defined below having a total of from 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
  • halogen means fluorine, chlorine, bromine or iodine
  • hydroxy means an -OH group
  • hydroxyalkyl means an alkane as defined below which is substituted by a hydroxy group (-OH).
  • nitro means -NO 2
  • cyano means -CN
  • amino means -NH 2
  • substituted amino Amino group substituted by one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamido, aralkyl Alkylamino, heteroarylalkylamino
  • carboxy means -COOH.
  • alkyl group means consisting only of carbon atoms and hydrogen atoms, and is not unsaturated.
  • a bond a straight or branched hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and attached to the remainder of the molecule by a single bond.
  • alkyl groups 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, decyl and decyl.
  • alkenyl as a group or part of another group means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) And more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group attached to the remainder of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, butyl- 1-Alkenyl, but-2-enyl, pent-1-enyl, pentane-1,4-dienyl and the like.
  • alkynyl as a group or part of another group means consisting solely of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, 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 bonded to the remainder of the molecule by a single bond, such as, but not limited to, an ethynyl group , prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl and the like.
  • cycloalkyl as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, which may include condensing a ring system, a bridged ring system or a spiro ring system having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be suitably employed
  • the carbon atom is connected to the rest of the molecule by a single bond.
  • a carbon atom in a cycloalkyl group may be optionally oxidized.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene And cyclohepten-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[2.2.1]hept
  • heterocyclyl as a group or part of another group means consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, phosphorus, 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;
  • the nitrogen, carbon or sulfur atom may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated.
  • the heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a hetero atom and through a single bond.
  • one or more of the rings may be an aryl or heteroaryl group as defined hereinafter, 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 spiro group containing from 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]fluorene.
  • Alkan-7-yl 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutane, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazolinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indanyl, octahydroindenyl, octahydroisodecyl, pyrrolidinyl, pyrazolidinyl , phthalimido and the like.
  • aryl as a group or part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms.
  • an aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to 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 groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, anthracenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazine-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 as a group or part of another group means having from 1 to 15 carbon atoms (preferably having from 1 to 10 carbon atoms) and from 1 to 6 selected from nitrogen in the ring. a 5- to 16-membered conjugated ring system of a hetero atom of oxygen and sulfur. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that The aryl group is attached to the remainder of the molecule via a single bond through an atom on the aromatic ring.
  • the nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably from 1 to 4 selected
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, fluorenyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, isodecyl, oxazolyl, isoxazolyl , fluorenyl, quinolyl, isoquinolyl, diaza naphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, oxazolyl, porphyrin, phenanthryl, phenanthroline, acridine Base, phenazinyl
  • heteroarylalkyl refers to an alkyl group as defined above which is substituted by a heteroaryl group as defined above.
  • optionally or “optionally” means that the subsequently described event or condition may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or condition.
  • optionally substituted aryl means that the aryl group is substituted or unsubstituted, and the description includes both the substituted aryl group and the unsubstituted aryl group.
  • a chemical moiety refers to a particular 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.
  • Stepoisomer refers to a compound composed of the same atoms bonded by the same bond but having a different three-dimensional structure.
  • the invention will cover various stereoisomers and mixtures thereof.
  • the compounds of the present invention are intended to include E- and Z-geometric isomers unless otherwise stated.
  • Tautomer refers to an isomer 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 embraced within the scope of the invention.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may contain one or more chiral carbon atoms, and thus may 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 racemic and optically pure forms thereof.
  • the preparation of the compounds of the invention may employ racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as by crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without any other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, hexanoate, octoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, hexane Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, me
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic or organic base which is capable of retaining the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, 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 amines, secondary amines and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins.
  • ammonia isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclo Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, hydrazine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, and the like.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • Polymorph refers to a different solid crystalline phase of certain compounds of the invention resulting from the presence of two or more different molecular arrangements in a solid state. Certain compounds of the invention may exist in more than one crystal form, and the invention is intended to include various crystal forms and mixtures thereof.
  • solvate refers to an aggregate comprising one or more molecules of the compound of the 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 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 invention may form true solvates, but in some cases, it is also possible to retain only a defined amount of water or a mixture of water plus a portion of the indefinite solvent.
  • the compound of the present invention can be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
  • the invention also includes prodrugs of the above compounds.
  • prodrug means a compound which can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis.
  • prodrug refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention.
  • Prodrugs may be inactive when administered to an individual in need thereof, but are converted in vivo to the active compound of the invention.
  • Prodrugs are typically rapidly converted in vivo to produce the parent compound of the invention, for example by hydrolysis in blood.
  • Prodrug compounds generally provide the advantage of solubility, tissue compatibility or sustained release in mammalian organisms.
  • Prodrugs include known amino protecting groups and carboxy protecting groups.
  • pharmaceutical composition refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human.
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, thereby facilitating the absorption of the active ingredient and thereby exerting biological activity.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts 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 authorities for acceptable use by humans or livestock. , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • tumor 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 cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.
  • preventing include the possibility of reducing the occurrence or progression of a disease or condition by a patient.
  • treatment and other similar synonyms as used herein includes the following meanings:
  • an "effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system.
  • an "effective amount” for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
  • An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
  • administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injections including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • the techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those discussed in Pa.
  • the compounds and compositions discussed herein are administered orally.
  • pharmaceutical combination means a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, It includes both fixed and unfixed combinations of active ingredients.
  • 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.
  • unfixed combination refers to the simultaneous administration, combination or sequential administration of at least one of the compounds described herein and at least one synergistic formulation to the patient in the form of separate entities. These are also applied to cocktail therapy, for example the administration of three or more active ingredients.
  • the intermediate compound functional groups may need to be protected by a suitable protecting group.
  • suitable protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable mercapto protecting groups include -C(O)-R" (wherein 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 described in detail in Greene, T. W. and P. G. M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • the present inventors prepared a novel compound of the formula (I) and found that it has a good FGFR kinase inhibitory activity, and the compound is at a very low concentration (low At 10 nM), it produces specific irreversible inhibition of FGFR kinase, and has excellent cell proliferation inhibitory activity against FGFR (less than 10 nM), so it can be used to treat the abnormality caused by abnormal FGFR kinase mutation or expression. Diseases such as tumors. Based on the above findings, the inventors completed the present invention.
  • the methylsulfonate intermediate (1 eq.) and the starting amine (2 eq.) were dissolved in anhydrous N,N-dimethylformamide, and potassium t-butoxide (2 eq.) was added, followed by microwave heating to 100 ° C for 2 hours. . After completion of the reaction, the mixture was extracted with methylene chloride. The organic phase was washed with saturated sodium hydrogen sulfate and water, dried over anhydrous sodium sulfate, filtered,
  • the chloroaryl intermediate (1 eq.) and the starting amine (2 eq.) were dissolved in anhydrous N,N-dimethylformamide, nitrogen was bubbled for ten minutes, and Pd 2 (dba) 3 was added in sequence under nitrogen atmosphere. (0.1 eq.), XantPhos (0.2 eq.) and cesium carbonate (2 eq.).
  • the mixture was heated to 100 ° C for 1 hour in a microwave. After completion of the reaction, the mixture was extracted with methylene chloride. The organic phase was washed sequentially with saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate.
  • the nitro compound (1 eq.) was dissolved in methanol, and saturated sodium thiosulfate (2 eq.) and sodium carbonate (2 eq.). After completion of the reaction, the mixture was combined with EtOAc EtOAc.
  • the first step 1,3-dimethoxy-5-methylbenzene (30 g, 0.20 mol) and dichloromethane (900 mL) were added to a dry round bottom flask (1 L) and cooled to the above solution in an ice bath. Disulfone chloride (52.5 g, 0.40 mol) was added dropwise, and the mixture was added dropwise and stirred at room temperature overnight.
  • the second step 2,4-dichloro-1,5-dimethoxy-3-methylbenzene (31 g, 0.14 mol) was dissolved in carbon tetrachloride (600 mL) and placed in a dry round bottom flask ( In 1000 mL), azobisisobutyronitrile (3.0 g, 0.018 mol) and N-bromosuccinimide (27.6 g, 0.154 mol) were successively added at room temperature. The reaction was carried out at 80 °C for 3 h, the reaction was quenched with aqueous sodium bicarbonate, and then extracted with dichloromethane. The organic phase was dried, concentrated, and crystallized from methyl tert-butyl ether to give 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 (30 g, 0.1 mol) and acetonitrile (500 mL) to a dry 1000 mL 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 completed. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjj Base)-acetonitrile (20 g, white solid).
  • Step 4 In a dry 250 mL round bottom flask, add (2,6-dichloro-3,5-dimethoxy-phenyl)-acetonitrile (10.4 g, 0.028 mol) and N,N-dimethyl Base carboxamide (100 mL) was added 4-amino-2-methylthio-pyrimidine-5-carbaldehyde (5 g, 0.02 mol) and potassium carbonate (12.25 g, 0.06 mol), and then stirred overnight until the reaction was completed. The reaction mixture was extracted with EtOAc. EtOAc (EtOAc m.
  • Step 2 3-[4-(2,6-Dichloro-3,5-dimethoxy-phenyl)-8-methylthio-3,7,9,9b-tetraaza-cyclo Methyl amyl [a]naphthalen-2-yl]-propanoate (2.4 g) was dissolved in anhydrous methanol (20 mL). The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, and the solvent was evaporated.
  • the third step 3-[4-(2,6-dichloro-3,5-dimethoxy-phenyl)-8-methylthio-3,7,9,9b-tetraaza-cyclo Amyl [a]naphthalen-2-yl]-propan-1-ol (1.8 g) was dissolved in ethyl acetate (20 mL), and then evaporated and evaporated. The reaction mixture was quenched by the addition of sodium thiosulfate solution, and the organic phase was separated. The organic phase was washed with saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, filtered, and evaporated.
  • the fourth step the above 3-[4-(2,6-dichloro-3,5-dimethoxy-phenyl)-8-methylthio-3,7,9,9b-tetraaza-
  • the cyclopentyl [a]naphthalen-2-yl]-propanal 1.0 g was dissolved in chloroform (20 mL), and m-chloroperoxybenzoic acid (2.2 g) was added portionwise, and the mixture was stirred at room temperature overnight. After the reaction is completed, the reaction solution is quenched by the addition of sodium thiosulfate solution, and the organic phase is separated.
  • the first step triethylamine (2.5 mL, 17.3 mmol) was added to 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (1.6 g, 8.64 mmol) and N under ice cooling. A solution of N-dimethylformamide (15 mL) and tert-butanol (5 mL) was then added to diphenylphosphonium diphenyl ester DPPA (3.6 g, 12.97 mmol). The reaction mixture was heated to 80 ° C and stirred for 4 h. After completion of the reaction, a part of the solvent was removed under reduced pressure and then diluted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate .
  • Intermediates 1-7 are used as the main starting materials, as well as other commercial reagents such as piperazine, tetrahydropyrrole, o-phenylenediamine, tetrahydrofuran diamine, tetrahydropyrandiamine, pyrazolediamine, acryloyl chloride, Raw materials such as acrylic acid (chiral tetrahydrofuran diamine and tetrahydropyrandiamine are prepared by the same method as in patent document WO2014144737), and the synthetic methods of general methods one to five are sequentially prepared and synthesized as follows.
  • ⁇ / RTI > ⁇ RTI (m, 2H), 7.06 (s, 1H), 6.09-6.18 (m, 4H), 5.57-5.67 (m, 2H), 3.96 (s, 6H), 3.76-3.78 (m, 4H), 2.48-2.54 (m, 4H), 2.27 (s, 3H), 2.24 (s, 3H).
  • the second step the above tert-butyl 4-(3-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)imidazole [1',2 ':1,6]pyridine [2,3-d]pyrimidin-8-yl)propyl)piperazine-1-carboxylate (320 mg) dissolved in anhydrous N,N-dimethylformamide (5 mL) To the o-phenylenediamine (240 mg), it was heated to 100 ° C overnight.
  • the third step the above tert-butyl 4-(3-(2-((2-aminophenyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)imidazole [1',2':1,6]pyridine [2,3-d]pyrimidin-8-yl)propyl)piperazine-1-carboxylate (215 mg) dissolved in dichloromethane (10 mL), ice bath 4N hydrogen chloride / dioxane solution (5 mL) was added under cooling, and the mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure to remove excess hydrogen chloride and solvent to give a yellow solid N1-(6-(2,6-dichloro-3,5- Dimethoxyphenyl)-8-(3-(piperazin-1-yl)propyl)imidazo[1',2':1,6]pyridine[2,3-d]pyrimidin-2-yl) Benzene-1,2-di
  • the fourth step the above yellow solid (50 mg) was dissolved in anhydrous N,N-dimethylformamide (5 mL), triethylamine (0.2 mL) was added, and acryloyl chloride (0.08 mL) was added dropwise under ice-cooling. Stir at room temperature overnight. After the reaction was completed, the reaction was quenched with ethyl acetate and water, and then evaporated, evaporated, evaporated, evaporated, evaporated.
  • Example 15 2-cyano-N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)imidazole [1', 2' :1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide
  • Example 16 N-((3S,4R)-4-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazole [1', 2' :1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide
  • Example 17 N-((3R,4S)-4-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazole [1', 2' :1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide
  • Example 18 N-((3S,4R)-4-((6-(2,6--3,5-dimethoxyphenyl)-8-(tridemethyl)imidazole [1' , 2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide
  • Example 22 N-((3S,4S)-3-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazole [1', 2' :1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide
  • Example 42 N-(2-((8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxy) Benzene imidazole [1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-(1-ethylpiperidin-4-yl)phenyl)acrylamide
  • Example 43 N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methoxymethyl)imidazole [1,2-a][1 ,6]naphthyridine-8-yl)amino)-5-(1-ethylpiperidin-4-yl)phenyl)acrylamide
  • Example 46 N-(2-((8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxy) Benzene imidazole [1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-(4-(dimethylamino)piperidin-1-yl)benzene Acrylamide
  • Example 48 N-(3-((8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxy) Benzene iodide [1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-1-methyl-1H-pyrazol-4-yl)acrylamide
  • Example 50 N-(2-((8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxy) Benzene imidazole [1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-fluorophenyl)acrylamide
  • Example 52 N-(4-((8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxy) Benzene iodide [1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide
  • Example 54 N-((3R,4S)-4-((8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3, 5-dimethoxybenzene)imidazo[1',2':1,6]pyridine[2,3-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide
  • Example 56 The compound of Example 56 was prepared by the same procedure as in Example 9 using Intermediate 5 as a starting material and substituting Boc-piperazine with dimethylamine.
  • LC-MS: ESI [M+H] + 637.5 / 639.5.
  • Example 62 N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-(trimethoxy)phenylphenyl)acrylamide
  • Example 64 N-(3-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)imidazolium [1',2':1,6]pyridine [2,3 -d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)-2-fluoroacrylamide
  • Example 65 N-(4-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)imidazolidinium [1',2':1,6]pyridine [2,3 -d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)methacrylamide
  • Example 66 N-(2-((8-(cyclopropyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)imidazole imidazole [1', 2': 1 ,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-fluorophenylphenylfluorophenyl)acrylamide
  • Example 68 N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-((dimethylamino)methyl)imidazole [1', 2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-phenylfluorophenyl)acrylamide
  • Example 70 N-(2-((6-(2,6-Difluoro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-(4-methylmethylpiperazin-1-yl)phenyl)acrylamide
  • Example 71 N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-(2-oxa-7-azaspiro[3.5]oct-7-yl)phenyl)acrylamide
  • Example 72 N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-(3-methyl-3,6-diazabicyclo[3.1.1]hept-6-yl)phenyl)methacrylamide
  • Example 77 N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-isopropylimidazole [1', 2': 1,6] Pyridine [2,3-d]pyrimidin-2-yl)amino)-5-(4-methylpiperazin-1-yl)phenyl)acrylamide
  • Example 78 N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-isopropylimidazole [1', 2': 1,6] Pyridine [2,3-d]pyrimidin-2-yl)amino)-5-(4-methylpiperazin-1-yl)phenyl)methacrylamide
  • Example 80 N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthyridin-8- Aminoamino)-5-(4-methylpiperazin-1-yl)phenyl)-2-acrylamide fluoroacrylamide
  • Example 81 N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-isopropylimidazole [1', 2': 1,6] Pyridine [2,3-d]pyrimidin-2-yl)amino)-5-(piperazin-1-yl)phenyl)acrylamide
  • Example 82 N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-(piperazin-1-yl)phenyl)acrylamide
  • Example 84 N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-(1-methylpiperazin-4-yl)phenyl)acrylamide
  • Example 88 N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-(methoxymethyl)imidazole [1', 2': 1 ,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-(4-isopropylpiperazin-1-yl)phenyl)acrylamide
  • Example 92 (E)-N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazole [1', 2': 1 ,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-fluorophenyl)-4-(dimethylamino)but-2-enamide
  • Test Example 1 Determination of Inhibitory Activity of FGFR1 and FGFR4 Kinases by the Compounds of the Invention
  • Example 1 - Example 93 provided by the present invention shows higher inhibitory activity of FGFR1 or FGFR4, and most of the example compounds have an IC 50 value of less than 10 nM for FGFR1, and some even less than 1 nM, as implemented.
  • the specific activity results are shown in the following table:
  • IC 50 ⁇ 10 nM is represented by "++++”; 10 nM ⁇ IC 50 ⁇ 100 nM is represented by “+++”; 100 ⁇ IC 50 ⁇ 500 nM is represented by “++”;IC50>500 nM is "+” Said.
  • the compounds of the present invention showed a significant increase in the kinase activity of FGFR1 or FGFR4 (about 4-100 fold) compared to the comparative compound, and the FGFR1 activity of Example 4 was increased nearly 100-fold.
  • the compound of the present invention was found to have a higher inhibitory activity against FGFR1 by comparison of the compound of Example 44 with the comparative compound 5 in the table, and the compound of Example 13 compared with the comparative compound 6 in the table (FGFR1 inhibitory activity IC) 50 less than 30 nM) also showed a higher subtype selectivity between FGFR1/FGFR4 (the kinase selectivity of FGFR4/FGFR1 was increased by at least an order of magnitude).
  • Test Example 2 Effect of the compound of the present invention on FGFR-mediated tumor cell proliferation ability
  • Test method Hep3B cells (ATCC) in logarithmic growth phase were inoculated into 96-well culture plates at a suitable density, 90 ⁇ L per well. After culture overnight, different concentrations of compounds were added for 72 hr, and the solvent control group was set. (negative control). After the compound was treated for 72h, the effect of the compound on cell proliferation was detected by CCK-8 cell counting kit (Dojindo). Add 10 ⁇ L of CCK-8 reagent to each well and place in a 37 ° C incubator for 2-4 hours. The full-wavelength microplate reader SpectraMax 190 reads at a wavelength of 450 nm.
  • inhibition rate (%) (OD negative control well-OD administration well) / OD negative control well ⁇ 100%.
  • IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
  • Example 1 to 93 Some of the Examples 1 to 93 provided by the present invention showed strong activity against the proliferation-inhibiting activity of Hep3B cells, and most of the compounds had an IC 50 value of less than 500 nM, and some of the example compounds were as in Example 4. , Example 8, Example 9, Example 20, Example 24, Example 27, Example 30, Example 32, Example 38, Example 39, Example 45, Example 49, Example 61, Implementation The inhibitory activity IC 50 values of Example 63, Example 70, Example 75, and Example 84 were even less than 20 nM.
  • Test Example 3 Test of Example Compounds Not Different in Kinase Inhibitory Activity
  • the compounds of the present invention are also tested for inhibitory activities against different kinases such as EGFR, VEGFR, PDGFR, FGFR, RET, MET, Src, Lyn, Syk, MEK, CDK, RAF, ROS, etc.
  • Some of the example compounds are as in Example 4.
  • Example 70, Example 75, Example 84, etc. showed better kinase selectivity with a selectivity greater than 100-fold.
  • Test Example 4 Proliferation inhibitory activity test of the compound of the example on different tumor cells
  • a variety of tumor cells such as HuH-7, JHH-7, DMS114, SNU-16, KG1, UM-UC-14, HCT116, NCI-H716, MCF-7, Colo-205, were tested by SRB staining or CCK8 assay.
  • KMS11, RT-112, OPM-2, NCI-H460, SNU-869, CNE, NCI-H2122, NCI-H1299, A549, MG63, Kappars-299, SK-OV-3, U87MG, BT474, LNCAP, A498 Proliferation inhibitory activity of KYSE140, HUCC-T1, PANC-1, etc., and some example compounds are as in Example 4, Example 8, Example 9, Example 24, Example 27, Example 30, Example 32, and implementation.
  • Example 38, Example 39, Example 45, Example 49, Example 61, Example 63, Example 70, Example 75, Example 84, etc. showed increased inhibitory activity against different cell proliferation inhibition, showing It has good anti-tumor activity, and its proliferation inhibitory activity against various tumor cells, especially liver cancer, cholangiocarcinoma, gastric cancer and bladder cancer, is less than 500 nM.
  • Test Example 5 In vivo pharmacokinetic parameter test of the compound of the example in rats and mice
  • the pharmacokinetic parameters ANU 0-t , AUC 0- ⁇ , MRT 0- ⁇ , C max of the test sample were calculated using the non-compartment model of the pharmacokinetic calculation software WinNonlin5.2. , T max , T 1/2 and Vd parameters and their mean and standard deviation.
  • the bioavailability (F) will be calculated by the following formula.
  • samples taken prior to reaching Cmax should be calculated as zero values when calculating the pharmacokinetic parameters. Samples at the sampling point should be incapable of quantification (BLQ) after reaching Cmax.
  • Example 2 Some of the compounds of the present patent example are as in Example 2, Example 4, Example 8, Example 24, Example 31, Example 36, Example 45, Example 57, Example 63, Example 75, Example 83 and the like showed better in vivo absorption and metabolism properties of rats and mice, and indicators such as AUC/Cmax showed excellent pharmacokinetic properties of the compounds.
  • Metabolic stability test 150 ⁇ L of liver microsomes (final concentration 0.5 mg/mL) were used for metabolic stability incubation.
  • the system contained NADPH (final concentration 1 mM), 1 ⁇ M test compound and positive control midazolam.
  • the lenil or negative control atenolol was stopped at 0 min, 5 min, 10 min and 30 min with tinidazole-containing acetonitrile, vortexed for 10 min, centrifuged at 15000 rpm for 10 min, and 50 ⁇ L of supernatant was injected into a 96-well plate.
  • the metabolic stability of the compound was calculated by measuring the relative reduction in the original drug.
  • Direct inhibition test direct inhibition of incubation with 100 ⁇ L of human liver microsomes (final concentration 0.2 mg/mL) containing NADPH (final concentration 1 mM), 10 ⁇ M compound, positive inhibitor cocktail (ketoconazole 10 ⁇ M, quinidine 10 ⁇ M, sulfaphenazole 100 ⁇ M, ⁇ -naphthoflavone 10 ⁇ M, tranylcypromine 1000 ⁇ M), negative control (0.1% DMSO in BPS) and mixed probe substrate (midazolam) 10 ⁇ M, testosterone 100 ⁇ M, dextromethorphan 10 ⁇ M, diclofenac 20 ⁇ M, phenacetin 100 ⁇ M, mefenexine 100 ⁇ M), and the reaction was terminated after incubation for 20 min. The relative activity of the enzyme was calculated by measuring the relative amount of production of the metabolite.
  • Example 4 Some embodiments of the present invention are as in Example 4, Example 8, Example 9, Example 24, Example 27, Example 30, Example 32, Example 38 Example 45, Example 49, Example 61, Example 63, Example 70, Example 75, Example 84 and the like showed better ADME properties, and had better microsome stability and metabolic enzyme inhibitory activity against major metabolic enzymes such as CYP1A2, CYP2C8, CYP3A4, CYP2D6.
  • the IC 50 of inhibition by CYP2C9 and the like is greater than 15 uM.
  • Test Example 7 Test of inhibition of growth inhibition of nude mice by the compound of the example
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of the nude mice under aseptic conditions.
  • the nude mice were transplanted subcutaneously with a vernier caliper to measure the diameter of the transplanted tumor.
  • the animals were randomly divided into tumors with an average volume of about 130 mm 3 .
  • the compound of the example administered to the desired concentration with water for injection containing 1% Tween 80
  • the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
  • Example 4 Some of the example compounds, such as Example 4, Example 8, Example 37, Example 38, Example 45, Example 76, Example 77, Example 84, etc. showed better inhibition on xenografted tumors in nude mice. The effect is that at a lower dose, a higher tumor inhibition rate is exhibited, and even at a dose of less than 20 mg/kg, the tumor inhibition rate is as high as 80% or more.

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Abstract

La présente invention concerne un composé cyclique fusionné contenant de l'azote, son procédé de préparation et son utilisation. La structure du composé cyclique fusionné contenant de l'azote selon la présente invention est représentée par la formule (I), chaque groupe étant tel que défini dans la spécification. Le composé cyclique fusionné contenant de l'azote selon la présente invention est un nouvel inhibiteur de kinase FGFR irréversible spécifique utile dans le traitement de maladies associées telles que des tumeurs provoquées par des anomalies de kinase FGFR.
PCT/CN2018/112660 2017-10-30 2018-10-30 Composé cyclique fusionné contenant de l'azote, son procédé de préparation et son utilisation WO2019085894A1 (fr)

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CN110950867A (zh) * 2018-09-27 2020-04-03 首药控股(北京)有限公司 一种fgfr4激酶抑制剂及其制备方法和用途
CN112094269B (zh) * 2020-01-01 2021-12-07 上海凌达生物医药有限公司 一类饱和六元环并杂环类化合物、制备方法和用途
CN114516849A (zh) * 2020-11-18 2022-05-20 江苏恒盛药业有限公司 一种1-(4-氨基苯基)-4-(4-羟基苯基)哌嗪的合成方法
WO2023078413A1 (fr) * 2021-11-04 2023-05-11 微境生物医药科技(上海)有限公司 Inhibiteur du fgfr2, son procédé de préparation et son utilisation pharmaceutique

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CN1646529A (zh) * 2002-04-03 2005-07-27 霍夫曼-拉罗奇有限公司 咪唑并稠合化合物
CN104540809A (zh) * 2012-07-11 2015-04-22 蓝印药品公司 成纤维细胞生长因子受体的抑制剂
WO2018004258A1 (fr) * 2016-06-28 2018-01-04 한미약품 주식회사 Nouveau dérivé hétérocyclique et son utilisation

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WO2018004258A1 (fr) * 2016-06-28 2018-01-04 한미약품 주식회사 Nouveau dérivé hétérocyclique et son utilisation

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