WO2019085894A1 - Nitrogen-containing fused ring compound, preparation method therefor, and use thereof - Google Patents

Nitrogen-containing fused ring compound, preparation method therefor, and use thereof 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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PCT/CN2018/112660
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French (fr)
Chinese (zh)
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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
    • 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.

Abstract

The present invention discloses a nitrogen-containing fused ring compound, a preparation method therefor, and a use thereof. The structure of the nitrogen-containing fused ring compound of the present invention is represented by formula (I) below, wherein each group is as defined in the specification. The nitrogen-containing fused ring compound of the present invention is a novel, specific irreversible FGFR kinase inhibitor applicable to the treatment of related diseases such as tumors caused by FGFR kinase abnormalities.

Description

一类含氮稠环化合物及其制备方法和用途Nitrogen-containing fused ring compound, preparation method and use thereof
本申请要求申请日为2017年10月30日的中国专利申请CN201711040023.5的优先权。本申请引用上述中国专利申请的全文。The present application claims priority from Chinese patent application CN201711040023.5, filed on October 30, 2017. This application cites the entire text of the above-mentioned Chinese patent application.
技术领域Technical field
本发明属于药物化学领域，具体涉及一类含氮稠环类化合物及其制备方法和用途。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.
背景技术Background technique
受体酪氨酸激酶的异常表达激活或基因突变在肿瘤的发生、发展、侵袭转移和耐药性产生等各个环节均发挥关键作用，以成为抗肿瘤药物研发的重要靶点。其中，成纤维生长因子受体(FGFR)是酪氨酸激酶家族的重要成员，主要包括FGFR1、FGFR2、FGFR3和FGFR4四种亚型。由于基因扩增、突变、融合或配体诱导等原因，FGFR各成员持续激活，诱导肿瘤细胞增殖、侵袭，促进血管生成并促进肿瘤恶化。FGFRs在多种肿瘤中高表达并异常激活，并且与肿瘤病人的不良预后密切相关。因此，FGFRs被公认为是抗肿瘤重要靶点，FGFR小分子抑制剂的研发逐步受到越来越多的关注。Abnormal expression activation or gene mutation of receptor tyrosine kinase plays a key role in tumor occurrence, development, invasion and metastasis, and drug resistance, and has become an important target for anti-tumor drug development. Among them, fibroblast growth factor receptor (FGFR) is an important member of the tyrosine kinase family, including four subtypes of FGFR1, FGFR2, FGFR3 and FGFR4. Due to gene amplification, mutation, fusion or ligand induction, FGFR members continue to activate, induce tumor cell proliferation, invasion, promote angiogenesis and promote tumor progression. FGFRs are highly expressed and abnormally activated in a variety of tumors and are closely associated with poor prognosis in cancer patients. Therefore, FGFRs are recognized as an important target for anti-tumor, and the development of FGFR small molecule inhibitors has gradually received more and more attention.
最近，来自美国基因泰克公司的研究人员发现精准地靶向FGFR4蛋白能够抑制肝细胞癌的生长，为肝细胞治疗药物的开发提供了一种全新的思路。迄今发现的20多种成纤维生长因子(FGF)中仅有FGF19能与FGFR4特异性结合。FGF19是FGFR4的配体，负责调节肝脏正常胆汁分泌和肝细胞增殖，其过表达或过度激活能够促进肝细胞增殖，诱导肝癌形成。这已在转基因小鼠中证实，敲除FGFR4基因可阻断肝细胞癌的生成。同时，临床发现多种癌症如肝细胞癌、胃癌、胰腺癌和胆管癌等恶性肿瘤的发生中均伴随着肿瘤组织的FGFR基因的过表达和过度激活。因此，特异性靶向成纤维细胞生长因子受体FGFR很可能成为多种肿瘤治疗的新策略，近年来引起各大制药公司的广泛关注。但是，现有FGFR抑制剂类化合物如BGJ398、AZD4547、AP24534、BLU9931等普遍存在或靶点选择性差、或靶点抑制活性不高、或化合物药代性质较差、或容易产生突变耐药等问题，导致FGFR抑制剂类化合物的临床应用受阻。因此，发现和寻找FGFR高选择性、高活性、抗耐药、高成药性的新型化合物成为当前一大热点。Recently, researchers from the United States Genentech found that the precise targeting of FGFR4 protein can inhibit the growth of hepatocellular carcinoma, providing a new way of thinking for the development of hepatocellular therapeutic drugs. Of the more than 20 fibroblast growth factors (FGF) found to date, only FGF19 specifically binds to FGFR4. 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. At the same time, it has been found that the occurrence of malignant tumors such as hepatocellular carcinoma, gastric cancer, pancreatic cancer and cholangiocarcinoma is accompanied by overexpression and overactivation of FGFR gene in tumor tissues. Therefore, the specific targeting of fibroblast growth factor receptor FGFR is likely to become a new strategy for a variety of cancer treatments, which has caused widespread concern among major pharmaceutical companies in recent years. However, existing 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.
发明内容Summary of the invention
本发明所要解决的技术问题在于为了克服现有技术中已有的FGFR抑制剂类化合物普遍存在或靶点选择性差、或靶点抑制活性不高、或化合物药代性质较差、或容易产生耐药等问题，因而提供了一类含氮稠环类化合物及其制备方法和用途，本发明的含氮稠环类化合物属于新型的特异性FGFR激酶不可逆抑制剂，可以用于治疗FGFR激酶异常引起的相关疾病如肿瘤。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.
本发明是通过下述技术方案来解决上述技术问题的。The present invention solves the above technical problems by the following technical solutions.
本发明提供了一种如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，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,
Figure PCTCN2018112660-appb-000001
Figure PCTCN2018112660-appb-000001
式中：In the formula:
R 1、R 2、R 3和R 4独立地选自氢、卤素、烷基、环烷基、杂环烷基、烷氧基、氨基；优选自氢、卤素、烷基、烷氧基； 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独立地选自氢、卤素、氰基、烷基、烷氧基、氨基、羟基等；优选自氢、卤素、烷基； 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独立地选自氢、卤素、氰基、C 1-C 6烷基、烷氧基、烷基氨基、烯基、炔基、酰基、磺酰基、5-8元芳基或杂芳基、3-8元环烷基或杂环烷基等；优选自氢、卤素、C 1-C 6烷基、3-6元环烷基、4-8元杂环烷基等； 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独立地选自CRa或N；Ra独立地选自氢、卤素；M is independently selected from CRa or N; Ra is independently selected from hydrogen, halogen;
Cy分别选自3-8元环烷基或杂环烷基、4-8元芳基或杂芳基；优选自5-6元的环烷基、杂环烷基、芳基或杂芳基；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独立地选自氢、卤素、氰基、羟基、氨基、烷基、烯基、炔基、烷氧基、烷基氨基、酰基、磺酰基、芳基、杂芳基、环烷基、杂环烷基等；优选自氢、卤素、C 1-C 6烷基、3-8元环烷基、4-8元杂环烷基等； 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和R 10独立地选自氢、卤素、氰基、硝基、烷基、砜基、亚砜基、三氟甲基等；优选自氢、卤素； 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;
上述的任一基团上的一个或多个氢原子可以被选自下组的取代基取代：包括但不限于氘、卤素、羟基、氨基、氰基、砜基或亚砜基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8烷基氨基、C 2-C 6烯基、C 2-C 6炔基、C 2-C 6酰基或磺酰基、5-8元芳基或杂芳基、4-8元环烷基或杂环烷基；其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O、P或S，所述的杂环烷基包含1-3个选自下组的杂原子：N、O、P或S。 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.
进一步地，本发明的如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，Further, 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独立地选自CH或N；M is independently selected from CH or N;
R 1、R 2独立地优选自氢、卤素，优选自氟、氯；R 3、R 4独立地选自卤素、烷氧基、烷基、氨基、环烷基或杂环烷基，进一步优选自氟、甲氧基； 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独立地选自氢、卤素、烷基；进一步优选自氢、氟、甲基； R 5 is independently selected from the group consisting of hydrogen, halogen, alkyl; further preferably from hydrogen, fluorine, methyl;
R 6优选自氢、卤素、C 1-C 6烷基，并且C 1-C 6烷基上的氢原子可以被3-8元的环烷基或杂环烷基、5-8元芳基或杂芳基取代；进一步优选为氢、氟、C 1-C 6烷基、-(CH 2)n-R b-,其中n＝0-6,优选为2-3，R b优选为氨基苯环、氨基吡啶环、哌啶环、哌嗪环、高哌嗪环、四氢吡咯环等，并且上述环系中的氨基或氮原子上的氢可以被丙烯酰基所取代； 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. Or a heteroaryl group; further preferably hydrogen, fluorine, C 1 -C 6 alkyl, -(CH 2 )nR b -, wherein n=0-6, preferably 2-3, and R b is preferably an aminobenzene ring , an aminopyridine ring, a piperidine ring, a piperazine ring, a homopiperazine ring, a tetrahydropyrrole ring, etc., and the hydrogen in the amino group or the nitrogen atom in the above ring system may be substituted by an acryloyl group;
R 7独立地选自氢、卤素、烷基、氰基、羟基、氨基、杂环烷基、烷氧基、烷基氨基、酰基或磺酰基等，进一步优选自氢、氟、氰基、氨基、烷基或杂环烷基等；更为优选地为氢、氟、甲基、乙基、哌嗪环、吗啉环、哌啶环、吡咯烷等； 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和R 10独立地选自氢、卤素；进一步优选自氢、氟； R 8 , R 9 and R 10 are independently selected from hydrogen, halogen; further preferably from hydrogen, fluorine;
Cy分别优选自5-6元的环烷基、杂环烷基、芳基或杂芳基；进一步优选为四氢呋喃环、四氢吡喃环、四氢吡咯环、哌啶环、苯环、吡啶环或吡唑环等。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.
更进一步地，本发明的如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，所述如式(I)所示的化合物具有如下通式：Further, 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:
Figure PCTCN2018112660-appb-000002
Figure PCTCN2018112660-appb-000002
其中，Cy优选自四氢呋喃环、四氢吡喃环、四氢吡咯环、哌啶环、苯环、吡啶环或 吡唑环等；R 6优选自氢、氟、甲基、乙基、丙基、环丙甲基、环戊基、甲氧基乙基、二甲氨基乙基、氰基乙基、-(CH 2)n-丙烯酰苯胺、-(CH 2)n-丙烯酰氨基吡咯烷、-(CH 2)n-丙烯酰哌嗪等，其中n＝1-6；R 7优选自氢、氟、甲基、哌嗪基、吡咯烷基、哌啶基等。 Wherein, 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. , cyclopropylmethyl, cyclopentyl, methoxyethyl, dimethylaminoethyl, cyanoethyl, -(CH 2 )n-acryloylaniline, -(CH 2 )n-acrylamidopyrrolidine And -(CH 2 )n-acryloyl piperazine and the like, wherein n = 1-6; and R 7 is preferably hydrogen, fluorine, methyl, piperazinyl, pyrrolidinyl, piperidinyl or the like.
更进一步地，本发明的如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，所述如式(I)所示的化合物具有如下通式：Further, 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:
Figure PCTCN2018112660-appb-000003
Figure PCTCN2018112660-appb-000003
其中Cy、R 7的定义如上所述，m优选自1-3。 Wherein Cy and R 7 are as defined above, and m is preferably from 1-3.
更进一步地，本发明的如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，所述如式(I)所示的化合物为如下任一化合物：Further, 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:
Figure PCTCN2018112660-appb-000004
Figure PCTCN2018112660-appb-000004
Figure PCTCN2018112660-appb-000005
Figure PCTCN2018112660-appb-000005
Figure PCTCN2018112660-appb-000006
Figure PCTCN2018112660-appb-000006
Figure PCTCN2018112660-appb-000007
Figure PCTCN2018112660-appb-000007
本发明提供了一种如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，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,
Figure PCTCN2018112660-appb-000008
Figure PCTCN2018112660-appb-000008
式中，In the formula,
R 1、R 2、R 3和R 4各自独立地选自氢、卤素、C 1-C 6烷基、3-8元环烷基、3-8元杂环烷基、C 1-C 6烷氧基、3-8元杂环烷氧基、或氨基；各自独立地优选选自氢、卤素、3-8元环烷基、C 1-C 6烷基或C 1-C 6烷氧基； 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选自氢、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基、氨基或羟基； 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选自CR a或N；其中，R a选自氢、卤素、C 1-C 6烷基、或C 1-C 6烷氧基； 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选自3-8元环烷基(优选5-6元环烷基)或3-8元杂环烷基(优选5-6元杂环烷基)、6-10元芳基或5-10元杂芳基(优选5-8元杂芳基)；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);
R 6选自氢、卤素、氰基、氨基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6氘代烷基、C 1-C 6卤代烷基、N(R e)(R f)-(CH 2) y-、O(R g)-C 1-C 6亚烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷基 -C(＝O)-C 1-C 6亚烷基、C 1-C 6烷基-S(＝O) 2-C 1-C 6亚烷基、6-10元芳基-(CH 2) z-、5-10元杂芳基-(CH 2) o-、3-8元环烷基-(CH 2) m-、或3-8元杂环烷基-(CH 2) n-；其中，R e、R f和R g各自独立地选自氢、C 1-C 6烷基或四氢吡咯烷基，y选自0-5中的任一整数；所述四氢吡咯烷基被一个或多个取代基取代，所述的取代基选自氢、C 1-C 6烷基、丙烯酰基或卤代丙烯酰基；或者，R e、R f与其所连氮原子共同构成一个四氢吡咯环或哌嗪环或哌啶环，所述四氢吡咯环或哌嗪环或哌啶环被一个或多个取代基取代，所述的取代基选自氢、C 1-C 6烷基、丙烯酰基或卤代丙烯酰基(例如氟代丙烯酰基)；所述的6-10元芳基、5-10元杂芳基、3-8元环烷基、和3-8元杂环烷基或各自独立地被选自氢、C 1-C 6烷基、丙烯酰基和丙烯酰胺基中的一个或多个取代基所取代；z、o、m、n各自独立地选自0-5中的任一整数； R 6 is selected from hydrogen, halo, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, N ( R e )(R f )-(CH 2 ) y -, O(R g )-C 1 -C 6 alkylene, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6- alkyl-C(=O)-C 1 -C 6 alkylene, C 1 -C 6 alkyl-S(=O) 2 -C 1 -C 6 alkylene, 6-10 membered aryl- (CH 2 ) z -, 5-10 membered heteroaryl-(CH 2 ) o -, 3-8 membered cycloalkyl-(CH 2 ) m -, or 3-8 membered heterocycloalkyl-(CH 2 ) n -; wherein R e , R f and R g are each independently selected from hydrogen, C 1 -C 6 alkyl or tetrahydropyrrolidinyl, and y is selected from any integer from 0 to 5; The hydropyrrolidinyl group is substituted by one or more substituents selected from hydrogen, C 1 -C 6 alkyl, acryloyl or haloacryloyl; or R e , R f and the nitrogen atom to which it is attached Co-constituting a tetrahydropyrrole ring or a piperazine ring or a piperidine ring, which is substituted with one or more substituents selected from hydrogen, C 1 -C 6 alkyl group, an acryloyl group or a halogenated acryloyl group (e.g. 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选自氢、卤素、氰基、硝基、C 1-C 6烷基、C 1-C 6烷基-SO 2-、C 1-C 6烷基-SO-、或C 1-C 6卤代烷基； 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;
且，R 6和R 8不同时为氢； And R 6 and R 8 are not hydrogen at the same time;
R 7选自氢、卤素、氰基、氰基乙基、2,3-二羟基丙基、O(R h)-C 1-C 6烷基、N(R i)(R j)-(CH 2) p-、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷基-SO 2-、C 1-C 6烷基-SO-、6-10元芳基、5-10元杂芳基、3-8元环烷基、或3-8元杂环烷基；其中，R h、R i和R j各自独立地选自氢、C 1-C 6烷基、或二甲胺基乙基，p选自0-5中的任一整数；或者，R i和R j共同构成一个5-7元含氮杂环烷基；所述的C 1-C 6烷基、C 1-C 6烷氧基、6-10元芳基、5-10元杂芳基、3-8元环烷基、和3-8元杂环烷基各自独立地被氢、C 1-C 6烷基、氰基-C 1-C 6烷基、C 1-C 6烷氧基-C 1-C 6烷基、吡唑基-C 1-C 6烷基、四氢吡咯基、***啉基、哌嗪基、哌啶基、高哌嗪基、二甲胺基乙基、氧杂环丁基和二甲胺基中的一个或多个取代基所取代； 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 i and R j together constitute one 5-7 membered nitrogen-containing heterocycloalkyl; said C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, 6-10 membered aryl group, 5-10 membered heteroaryl group, 3-8 member The cycloalkyl group and the 3-8 membered heterocycloalkyl group are each independently hydrogen, C 1 -C 6 alkyl, cyano-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 - C 6 alkyl, pyrazolyl-C 1 -C 6 alkyl, tetrahydropyrrolyl, morphinolinyl, piperazinyl, piperidinyl, homopiperazinyl, dimethylaminoethyl, oxetane Substituted with one or more substituents in the dimethylamino group;
R 9和R 10各自独立地选自氢、卤素、氰基、硝基、C 1-C 6烷基、C 1-C 6烷基-SO 2-、C 1-C 6烷基-SO-、N(R c)(R d)-(CH 2)x-；或者，R 9和R 10共同构成一个5-7元的被C 1-C 6烷基取代的含氮杂环烷基；其中，R c和R d各自独立地选自氢或C 1-C 6烷基，x选自0-5中的任一整数； 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;
上述定义中所述的各个环系可为单环、并环、稠环、桥环或螺环；所述的杂芳基或可被部分氧化(氧代基)和/或还原(部分饱和)；所述的杂芳基包含1-3个选自下组的杂原子：N、O、P和S，所述的杂环烷基包含1-3个选自下组的杂原子：N、O、P和S。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.
进一步地，本发明的如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，Further, 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,
式中，In the formula,
R 1和R 2各自独立地优选选自氢或卤素(例如氟或氯)，进一步各自独立地优选选自氟或氯； 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和R 4各自独立地优选选自卤素(例如氟或氯)、3-8元环烷基(例如环丙基)或C 1-C 6烷氧基(例如甲氧基)，进一步各自独立地优选选自氟、氯、甲氧基或环丙基； 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优选选自氢、卤素或C 1-C 6烷基；进一步优选选自氢、氟或甲基； R 5 is preferably selected from hydrogen, halogen or C 1 -C 6 alkyl; further preferably selected from hydrogen, fluorine or methyl;
M优选选自CH或N；M is preferably selected from CH or N;
Cy优选选自5-6元环烷基(进一步优选4-6元的环烷基)、5-6元杂环烷基(进一步优选4-6元杂环烷基)、6元芳基或5-8元杂芳基；更进一步优选选自四氢呋喃环、四氢吡喃环、四氢吡咯环、哌啶环、苯环、吡啶环、吡唑环、2,3-二氢苯并呋喃环、2,3-二氢吲哚环或四氢噻吩环；Cy或被进一步氧化，所述的氧化发生在环上杂原子(例如
Figure PCTCN2018112660-appb-000009
)；且Cy与母核上其他结构片段(两个氮原子)的连接位点为邻位关系； 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. a ring, a 2,3-dihydroindole ring or a tetrahydrothiophene ring; Cy is further oxidized, said oxidation occurring at the ring heteroatom (eg
Figure PCTCN2018112660-appb-000009
And; the connection site of Cy with other structural fragments (two nitrogen atoms) on the mother nucleus is in an ortho relationship;
R 6优选选自氢、卤素(例如氟)、C 1-C 6烷基(例如甲基、乙基、正丙基或异丙基)、C 1-C 6氘代烷基(例如-CD 3)、C 1-C 6卤代烷基(例如-CH 2F、-CHF 2)、N(R e)(R f)-(CH 2) y-、O(R g)-C 1-C 6亚烷基、C 1-C 6烷基-S(＝O) 2-C 1-C 6亚烷基(例如CH 3SO 2-CH 2CH 2CH 2-)、6-10元芳基-(CH 2) z-、5-10元杂芳基-(CH 2) o-、3-8元环烷基-(CH 2) m-、或3-8元杂环烷基-(CH 2) n-；其中，R e、R f和R g各自独立地选自氢、C 1-C 6烷基或四氢吡咯烷基，y选自0-5中的任一整数；所述四氢吡咯烷基被一个或多个取代基取代，所述的取代基选自氢、C 1-C 6烷基、丙烯酰基或氟代丙烯酰基；或者，R e、R f与其所连氮原子共同构成一个四氢吡咯环或哌嗪环，所述四氢吡咯环或哌嗪环被一个或多个取代基取代，所述的取代基选自氢、C 1-C 6烷基、丙烯酰基或氟代丙烯酰基；所述的6-10元芳基、5-10元杂芳基、3-8元环烷基、和3-8元杂环烷基各自独立地被选自氢、C 1-C 6烷基、丙烯酰基和丙烯酰胺基中的一个或多个取代基所取代；z、o、m、n各自独立地选自0-5中的任一整数； 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). 3 ), C 1 -C 6 haloalkyl (for example -CH 2 F, -CHF 2 ), N(R e )(R f )-(CH 2 ) y -, O(R g )-C 1 -C 6 Alkylene, C 1 -C 6 alkyl-S(=O) 2 -C 1 -C 6 alkylene (eg CH 3 SO 2 -CH 2 CH 2 CH 2 -), 6-10 membered aryl- (CH 2 ) z -, 5-10 membered heteroaryl-(CH 2 ) o -, 3-8 membered cycloalkyl-(CH 2 ) m -, or 3-8 membered heterocycloalkyl-(CH 2 ) n -; wherein R e , R f and R g are each independently selected from hydrogen, C 1 -C 6 alkyl or tetrahydropyrrolidinyl, and y is selected from any integer from 0 to 5; The hydropyrrolidinyl group is substituted by one or more substituents selected from hydrogen, C 1 -C 6 alkyl, acryloyl or fluoroacryloyl; or R e , R f and the nitrogen atom to which it is attached Co-constituting a tetrahydropyrrole ring or a piperazine ring, which is substituted by one or more substituents selected from hydrogen, C 1 -C 6 alkyl, acryloyl Or a fluoroacryloyl group; the 6-10 membered aryl group, a 5-10 membered heteroaryl group, The 3-8 membered cycloalkyl group and the 3-8 membered heterocycloalkyl group are each independently substituted with one or more substituents selected from the group consisting of hydrogen, C 1 -C 6 alkyl, acryloyl, and acrylamide; z, o, m, n are each independently selected from any of 0-5;
当R 6为N(R e)(R f)-(CH 2) y-时，所述的N(R e)(R f)-(CH 2) y-中，R e和R f各自独立地优选选自氢、C 1-C 6烷基(例如甲基、乙基、正丙基或异丙基)或四氢吡咯烷基，所述的四氢吡咯烷基优选被一个选自氢、C 1-C 6烷基(例如甲基、乙基、正丙基或异丙基)、丙烯酰 基或氟代丙烯酰基的取代基所取代；y优选选自0、1、2或3；所述的N(R e)(R f)-(CH 2) y-进一步优选为N(CH 3) 2-CH 2-、N(CH 3) 2-CH 2CH 2-、N(CH 3) 2-CH 2CH 2CH 2-或
Figure PCTCN2018112660-appb-000010
When R 6 is N(R e )(R f )-(CH 2 ) y -, in the N(R e )(R f )-(CH 2 ) y -, R e and R f are each independent Preferably, 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 2 -, N(CH 3 ) 2 -CH 2 CH 2 -, N(CH 3 ) 2 -CH 2 CH 2 CH 2 - or
Figure PCTCN2018112660-appb-000010
当R 6为N(R e)(R f)-(CH 2) y-时，所述的N(R e)(R f)-(CH 2) y-中，R e和R f优选与其所连氮原子共同构成一个四氢吡咯环或哌嗪环，所述四氢吡咯环或哌嗪环被一个或两个或三个取代基取代，所述的取代基选自氢、C 1-C 6烷基(例如甲基)、丙烯酰基或氟代丙烯酰基；y优选选自0、1、2或3；所述的N(R e)(R f)-(CH 2) y-进一步优选为
Figure PCTCN2018112660-appb-000011
Figure PCTCN2018112660-appb-000012
When R 6 is N(R e )(R f )-(CH 2 ) y -, in the 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
Figure PCTCN2018112660-appb-000011
Figure PCTCN2018112660-appb-000012
当R 6为O(R g)-C 1-C 6亚烷基时，所述的O(R g)-C 1-C 6亚烷基优选为CH 3OCH 2-、CH 3OCH 2CH 2-、HOCH 2-、HO(CH 2) 3-、
Figure PCTCN2018112660-appb-000013
When 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 -,
Figure PCTCN2018112660-appb-000013
当R 6为6-10元芳基-(CH 2) z-时，所述的6-10元芳基-(CH 2) z-中，z优选选自0、1或2，6-10元芳基优选为苯基；所述的6-10元芳基优选被一个丙烯酰胺基所取代；R 6进一步优选为
Figure PCTCN2018112660-appb-000014
When 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
Figure PCTCN2018112660-appb-000014
当R 6为5-10元杂芳基-(CH 2) o-时，所述的5-10元杂芳基-(CH 2) o-中，o优选自0、1或2，5-10元杂芳基优选为吡啶基；所述的5-10元杂芳基优选被一个丙烯酰胺基所取代；R 6进一步优选为
Figure PCTCN2018112660-appb-000015
When 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
Figure PCTCN2018112660-appb-000015
当R 6为3-8元环烷基-(CH 2) m-时，所述的3-8元环烷基-(CH 2) m-中，m优选自0、1 或2，3-8元环烷基优选为环丙基或环戊基；R 6进一步优选为
Figure PCTCN2018112660-appb-000016
When 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
Figure PCTCN2018112660-appb-000016
当R 6为3-8元杂环烷基-(CH 2) n-时，所述的3-8元杂环烷基-(CH 2) n-中，n优选自0、1或2，3-8元杂环烷基优选为哌啶基或氧杂环丁基；所述的3-8元杂环烷基优选被一个C 1-C 6烷基(例如甲基)或丙烯酰基所取代；R 6进一步优选为
Figure PCTCN2018112660-appb-000017
When 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
Figure PCTCN2018112660-appb-000017
R 7优选选自氢、卤素(例如氟)、氰基、氰基乙基、2,3-二羟基丙基、C 1-C 6烷基(例如甲基、乙基、正丙基或异丙基)、C 1-C 6烷氧基(例如甲氧基、乙氧基、正丙氧基或异丙氧基)、O(R h)-C 1-C 6烷基、N(R i)(R j)-(CH 2) p-、或3-8元杂环烷基；其中，R h、R i和R j各自独立地选自氢、C 1-C 6烷基(例如甲基、乙基、正丙基或异丙基)、或二甲胺基乙基；p选自0、2、3、4或5；或者，R i和R j共同构成一个5-7元含氮杂环烷基(进一步优选5或6元含氮杂环烷基，例如四氢吡咯基、哌嗪基或哌啶基)；所述的3-8元杂环烷基被氢、C 1-C 6烷基、氰基-C 1-C 6烷基、C 1-C 6烷氧基-C 1-C 6烷基、吡唑基-C 1-C 6烷基、四氢吡咯基、二甲胺基乙基、氧杂环丁基和二甲胺基中的一个或多个取代基所取代； 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 or 5; or, R i and R j together form a 5-7 member a nitrogen-containing heterocycloalkyl group (further preferably a 5- or 6-membered nitrogen-containing heterocycloalkyl group such as tetrahydropyrrolyl, piperazinyl or piperidinyl); said 3-8 membered heterocycloalkyl group is hydrogen, C 1- C 6 alkyl, cyano-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, pyrazolyl-C 1 -C 6 alkyl, tetrahydropyrrole Substituted by one or more substituents of the dimethylaminoethyl, oxetanyl and dimethylamino groups;
当R 7为O(R h)-C 1-C 6亚烷基时，所述的O(R h)-C 1-C 6烷基中R h优选为氢、甲基、乙基、正丙基或异丙基，C 1-C 6亚烷基优选为-C(CH 2) 2-CH 2-或-CH 2-CH 2-； When 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 -;
当R 7为N(R i)(R j)-(CH 2) p-时，所述的N(R i)(R j)-(CH 2) p-中的R i和R j优选各自独立地为氢、甲基、乙基、正丙基、异丙基或二甲胺基乙基(例如-N(R i)(R j)为-N(CH 2)CH 2CH 3、-N(CH 3) 2、或-N(CH 2)CH 2CH 2N(CH 3) 2)，p选自0、1、2、3、4或5； When R 7 is N(R i )(R j )-(CH 2 ) p -, 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;
当R 7为被氢、C 1-C 6烷基(例如甲基、乙基或丙基)、氰基-C 1-C 6烷基(氰基乙基)、C 1-C 6烷氧基-C 1-C 6烷基(例如甲氧基乙基)、吡唑基-C 1-C 6烷基(例如N-甲基吡唑基亚甲基)、四氢吡咯基、二甲胺基乙基、氧杂环丁基和二甲胺基中的一个或多个取代基所取代的3-8元杂环烷基时，所述的一个或多个优选为一个、两个或三个；所述的取代基可相同或不同；所述的3-8元杂环烷基优选为：哌嗪基(例如
Figure PCTCN2018112660-appb-000018
)、四氢哌啶基(例如
Figure PCTCN2018112660-appb-000019
Figure PCTCN2018112660-appb-000020
)、四氢吡咯烷基(例如
Figure PCTCN2018112660-appb-000021
)、
Figure PCTCN2018112660-appb-000022
When 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 When 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
Figure PCTCN2018112660-appb-000018
), tetrahydropiperidinyl (for example)
Figure PCTCN2018112660-appb-000019
Figure PCTCN2018112660-appb-000020
), tetrahydropyrrolidinyl (for example)
Figure PCTCN2018112660-appb-000021
),
Figure PCTCN2018112660-appb-000022
R 8优选为氢、氰基、卤素(例如氟)或C 1-C 6烷基(例如甲基)； R 8 is preferably hydrogen, cyano, halogen (such as fluorine) or C 1 -C 6 alkyl (such as methyl);
R 9和R 10各自独立地优选选自氢、卤素(例如氟)、或N(R c)(R d)-(CH 2)x-，其中，x优选为0、1、2或3，R c和R d各自独立地优选选自氢或甲基(例如所述的N(R c)(R d)-(CH 2)x-为二甲胺基亚甲基)；或者，R 9和R 10共同构成N-甲基氮杂环戊基； 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;
且，R 6和R 8不同时为氢； And R 6 and R 8 are not hydrogen at the same time;
当Cy为饱和的4-6元杂环烷基时，Cy与母核上其他结构片段即两个氮原子形成两个手性碳氮键。本发明中所述如式(I)所示的化合物(当其含有一个或以上手性中心时)包括消旋化合物或其任一手性化合物；当其为手性化合物时，优选其中两个手性碳氮键呈顺式构型。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 (when it contains one or more chiral centers) 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.
更进一步地，本发明如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，所述如式(I)所示的化合物具有如下通式：Further, 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:
Figure PCTCN2018112660-appb-000023
Figure PCTCN2018112660-appb-000023
其中，among them,
X优选为氟或氯；X is preferably fluorine or chlorine;
M优选为CH或N；M is preferably CH or N;
Cy优选选自四氢呋喃环、四氢吡喃环、四氢吡咯环、哌啶环、苯环、吡啶环、吡唑环、2,3-二氢苯并呋喃环、2,3-二氢吲哚环或S-氧代四氢噻吩环；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. Anthracene ring or S-oxotetrahydrothiophene ring;
R 6优选选自氢、氟、甲基、乙基、正丙基、异丙基、-CD 3、-CH 2F、-CHF 2、CH 3SO 2-CH 2CH 2CH 2-、N(CH 3) 2-CH 2-、N(CH 3) 2-CH 2CH 2-、N(CH 3) 2-CH 2CH 2CH 2-、
Figure PCTCN2018112660-appb-000024
CH 3OCH 2-、CH 3OCH 2CH 2-、HOCH 2-、HO(CH 2) 3-、
Figure PCTCN2018112660-appb-000025
Figure PCTCN2018112660-appb-000026
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 -,
Figure PCTCN2018112660-appb-000024
CH 3 OCH 2 -, CH 3 OCH 2 CH 2 -, HOCH 2 -, HO(CH 2 ) 3 -,
Figure PCTCN2018112660-appb-000025
Figure PCTCN2018112660-appb-000026
R 7优选选自氢、氟、氰基、氰基乙基、2,3-二羟基丙基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、HO-C(CH 2) 2-CH 2-、CH 3O-CH 2-CH 2-、-N(CH 2)CH 2CH 3、-CH 2-N(CH 3) 2、-N(CH 2)CH 2CH 2N(CH 3) 2、
Figure PCTCN2018112660-appb-000027
Figure PCTCN2018112660-appb-000028
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
Figure PCTCN2018112660-appb-000027
Figure PCTCN2018112660-appb-000028
R 8优选选自氢、氰基、氟或甲基； R 8 is preferably selected from the group consisting of hydrogen, cyano, fluoro or methyl;
且R 6和R 8不同时为氢； And R 6 and R 8 are not hydrogen at the same time;
R 9和R 10各自独立地优选选自氢、氟、或二甲胺基亚甲基；或者，R 9和R 10共同构成N-甲基氮杂环戊基。 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.
更进一步地，本发明如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，所述如式(I)所示的化合物具有如下通式：Further, 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:
Figure PCTCN2018112660-appb-000029
Figure PCTCN2018112660-appb-000029
其中R 6、Cy、R 7和R 8的定义均如上所述，q选自1、2或3。 Wherein R 6 , Cy, R 7 and R 8 are as defined above, and q is selected from 1, 2 or 3.
更进一步地，本发明如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，所述如式(I)所示的化合物为如下任一化合物：Further, 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:
Figure PCTCN2018112660-appb-000030
Figure PCTCN2018112660-appb-000030
Figure PCTCN2018112660-appb-000031
Figure PCTCN2018112660-appb-000031
Figure PCTCN2018112660-appb-000032
Figure PCTCN2018112660-appb-000032
Figure PCTCN2018112660-appb-000033
Figure PCTCN2018112660-appb-000033
Figure PCTCN2018112660-appb-000034
Figure PCTCN2018112660-appb-000034
Figure PCTCN2018112660-appb-000035
Figure PCTCN2018112660-appb-000035
Figure PCTCN2018112660-appb-000036
Figure PCTCN2018112660-appb-000036
Figure PCTCN2018112660-appb-000037
Figure PCTCN2018112660-appb-000037
进一步地，本发明还提供了一种如式(I)所示的化合物的制备方法，其包括下述步骤：Further, the present invention provides a method for producing a compound represented by the formula (I), which comprises the steps of:
a)在酸或碱存在的条件下，将通式(A)化合物与α-卤代醛或卤代酮或其等效物进行缩合反应，制备得到通式(B)化合物；和a) a compound of the formula (B) is obtained by subjecting a compound of the formula (A) to an α-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);
b)在酸、碱或过渡金属催化剂存在的条件下，将通式(B)化合物与硝基苯胺类或者其它二胺类前体化合物进行取代反应或偶联反应，得到通式(C)化合物；和b) subjecting a compound of the formula (B) to a nitroaniline or other diamine precursor compound by a substitution reaction or a coupling reaction in the presence of an acid, a base or a transition metal catalyst to obtain a compound of the formula (C) ;with
c)在还原剂存在的条件下，将通式(C)化合物进行还原反应，得到通式化合物(D)；和c) subjecting the compound of the formula (C) to a reduction reaction in the presence of a reducing agent to obtain a compound of the formula (D);
d)在碱或缩合试剂存在的条件下，将通式化合物(D)与丙烯酸或者丙烯酰氯类化合物进行缩合反应，制备得到如式(I)所示的化合物；d) 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);
Figure PCTCN2018112660-appb-000038
Figure PCTCN2018112660-appb-000038
各式中，LG代表本领域此类反应中常规所用的离去基团，如卤素、砜基、亚砜基、磺酸酯基等，其他各基团的定义如上所述；In the formula, 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;
优选地，所述步骤a)、b)、c)、d)各自在溶剂中进行，且所述溶剂各自独立地选自水、甲醇、乙醇、异丙醇、丁醇、乙二醇、乙二醇甲醚、N-甲基吡咯烷酮、二甲基亚砜，四氢呋喃、甲苯、二氯甲烷、1，2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、和二氧六环中的一种或多种；Preferably, 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. Glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N- One or more of dimethylacetamide, and dioxane;
优选地，所述过渡金属催化剂选自三(二亚苄基丙酮)二钯(Pd 2(dba) 3)、四(三苯基膦)钯(Pd(PPh 3) 4)、醋酸钯、氯化钯、二氯二(三苯基膦)钯、三氟醋酸钯、三苯基膦醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双(三邻苯甲基膦)二氯化钯、和1,2-二(二苯基膦基)乙烷二氯化钯中的一种或多种；所述催化剂配体选自三叔丁基膦、四氟硼酸三叔丁基膦、三正丁基膦、三苯基膦、三对苯甲基膦、三环己基膦、和三邻苯甲基膦中的一种或多种； Preferably, 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-butylphosphine tetrafluoroborate, a tri-n-butylphosphine, a triphenylphosphine, a tri-p-phenylmethylphosphine, a tricyclohexylphosphine, and a tri-o-phenylmethylphosphine;
优选地，所述缩合试剂选自DCC、DIC、CDI、EDCI、HOAt、HOBt、BOP、PyBOP、 HATU、和TBTU中的一种或多种；Preferably, the condensation reagent is selected from one or more of DCC, DIC, CDI, EDCI, HOAt, HOBt, BOP, PyBOP, HATU, and TBTU;
优选地，所述的碱包括有机碱和/或无机碱；其中，所述无机碱选自氢化钠、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠中的一种或多种；所述有机碱选自吡啶、三乙胺、N,N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基锂、六甲基二硅基钠、和二甲基吡啶中的一种或多种；Preferably, 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;
优选地，所述酸选自盐酸、硫酸、磷酸、甲磺酸、甲苯磺酸、三氟乙酸、甲酸、乙酸，和三氟甲磺酸中的一种或多种；Preferably, 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;
优选地，所述还原剂选自铁粉、锌粉、氯化亚锡、硫代硫酸钠、亚硫酸钠、和氢气中的一种或多种。Preferably, 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.
本发明中，所述的通式(A)化合物以及上述制备方法中所涉及到的各个试剂均市售可得，或可由本领域技术人员参照现有技术中的合成方法制备得到。In the present invention, 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.
根据本发明公开的上述制备方法，本领域技术人员可采用与之相同的原理和方法，制得本发明的通式化合物(I)中涉及的各具体化合物。According to the above preparation method disclosed in the present invention, those skilled in the art can use the same principles and methods to obtain the specific compounds involved in the compound (I) of the general formula of the present invention.
进一步地，本发明还提供了一种药物组合物，其包括治疗有效量的如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，以及至少一种药用辅料。Further, the present invention provides 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.
进一步地，本发明还提供了一种如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，或上述药物组合物在制备FGFR激酶抑制剂中的应用。Further, 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.
进一步地，本发明还提供了一种如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，或上述药物组合物在制备预防和/或治疗与蛋白激酶特别是FGFR激酶活性或表达量相关的疾病的药物中的应用，特别是制备预防和/或治疗抗肿瘤药物中的应用。其中，所述的肿瘤包括但不限于以下一种或几种：非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、***癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、鼻咽癌、膀胱癌、胰腺癌等，特别是肝癌或胆管癌。Further, 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 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.
进一步地，本发明还提供了一种预防和/或***的方法，所述的方法包括给予需要其的个体治疗有效量的如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构 体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药。Further, 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.
术语the term
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning meaning All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety herein in their entirety herein
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。The above description and the following detailed description are to be considered as illustrative and not restrictive. In the present application, the use of the singular includes the plural unless otherwise specified. It must be noted that the singular forms used in the specification and claims are in the It should also be noted that "or" or "or" is used to mean "and/or" unless otherwise indicated. In addition, the terms "comprises" and "comprising", "include", "include", and "include" are not limiting.
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy and pharmacological methods, are employed unless otherwise indicated. Unless specifically defined, the terms used herein in the descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the 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. In the present specification, the group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
本发明中，当其中一个变量选自化学键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表化学键时表示该结构实际上是A-Z；当采用类似“R 1-R 2-R 3-”的形式对取代基的类型和范围进行定义时，其表示如“R 1-R 2-R 3-”所示的取代基整体上是以R 3与所述的化合物母体直接成键，并且其中的如R 1、R 2、R 3所示的取代基彼此之间通过化学键依次键合。 In the present invention, when one of the variables is selected from a chemical bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a chemical bond in ALZ, the structure is actually AZ; when a similar "R 1 -R 2 -R is adopted" When the form of 3 -" defines the type and range of the substituent, it means that the substituent as shown by "R 1 -R 2 -R 3 -" as a whole is directly bonded to the parent of the compound by R 3 And wherein the substituents represented by R 1 , R 2 , and R 3 are bonded to each other by a chemical bond.
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。 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. For example, -CH 2 O- is equivalent to -OCH 2 -.
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作 手册和论文，均通过引用方式整体并入本文。The section headings used herein are for the purpose of organizing articles only and are not to be construed as limiting the subject matter. All documents or parts of the literature cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals and papers, are hereby incorporated by reference in their entirety.
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, 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.
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specifically indicated.
在本申请中，术语“卤素”是指氟、氯、溴或碘；“羟基”是指-OH基团；“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基；“羰基”是指-C(＝O)-基团；“硝基”是指-NO 2；“氰基”是指-CN；“氨基”是指-NH 2；“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基；“羧基”是指-COOH。 In the present application, the term "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). "carbonyl" means a -C(=O)- group; "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.
在本申请中，作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中)，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。In the present application, as a group or a part of other groups (for example, in a group such as a halogen-substituted alkyl group), the term "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. Examples of 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.
在本申请中，作为基团或是其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。In the present application, the term "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.
在本申请中，作为基团或是其它基团的一部分，术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙炔基、丙-1-炔基、丁-1-炔基、戊-1-烯-4-炔基等。In the present application, the term "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.
在本申请中，作为基团或是其它基团的一部分，术语“环烷基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基，其可包括稠合环体系、桥环体系或螺环体系，具有3至15个碳原子，优选具有3至10个碳原子，更优选具有3至8个碳原子，且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明，环烷基中的碳原子可以任选地被氧化。环烷基的实例包括但 不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。In the present application, the term "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. Unless otherwise specifically indicated in the specification, a carbon atom in a cycloalkyl group may be optionally oxidized. Examples of 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]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2] Octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, bicyclo [3.2.1] octenyl, adamantyl, VIII Hydrogen-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl and the like.
在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。In the present application, the term "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 stable 3- to 20-membered non-aromatic cyclic group. Unless otherwise specified in the specification, 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. In the heterocyclic group containing a fused ring, 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. For the purposes of the present invention, 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. More preferably, it is a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of 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.
在本申请中，作为基团或是其它基团的一部分，术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。In the present application, the term "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. For the purposes of the present invention, 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. Examples of 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.
在本申请中，术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有1至15 个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、***基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁***基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]***并[4,3-b]哒嗪、[1,2,4]***并[4,3-a]吡嗪、[1,2,4]***并[4,3-c]嘧啶、[1,2,4]***并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。In the present application, the term "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. For the purposes of the present invention, 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 A stable 5- to 10-membered aromatic group derived from a hetero atom of nitrogen, oxygen, and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen, and sulfur. Examples of 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, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazole, porphyrin, quinazolinyl, phenylthio, guanidinium, phenanthroline, Isoxazolyl, phenoxazinyl, phenothiazine, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4 , 3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1, 2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine Wait.
在本申请中，术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above which is substituted by a heteroaryl group as defined above.
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。In the present application, "optional" 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. For example, "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.
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。The terms "part," "structural moiety," "chemical moiety," "group," and "chemical group", as used herein, refer 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.
“立体异构体”是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。"Stereoisomer" 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.
当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含E-和Z-几何异构体。When the compound of the present invention contains an olefinic double bond, the compounds of the present invention are intended to include E- and Z-geometric isomers unless otherwise stated.
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。"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.
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可 产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。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.
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。Conventional techniques for the preparation/isolation of individual isomers include chiral synthesis from a suitable optically pure precursor, or resolution of the racemate (or racemic form of a salt or derivative) using, for example, chiral high performance liquid chromatography. For example, see Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; AMStalcup, Chiral Separations, Annu. Rev. Anal. : 341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc.Chem .Res. 1990, 23, 128.
在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。"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, methanesulfonate, besylate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, and the like. These salts can be prepared by methods known in the art.
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁 卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。"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. For example, 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. These salts can be prepared by methods known in the art.
“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型，本发明旨在包括各种晶型及其混合物。"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.
通常，结晶化作用会产生本发明化合物的溶剂化物。本发明中使用的术语“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。溶剂可以是水，该情况下的溶剂化物为水合物。或者，溶剂可以是有机溶剂。因此，本发明的化合物可以以水合物存在，包括单水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等，以及相应的溶剂化形式。本发明化合物可形成真实的溶剂化物，但在某些情况下，也可以仅保留不定的水或者水加上部分不定溶剂的混合物。本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。本发明化合物的溶剂化物也包含在本发明的范围之内。Generally, crystallization will result in a solvate of the compound of the invention. The term "solvate" as used in the present invention 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. Alternatively, the solvent may be an organic solvent. Thus, 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.
本发明还包括上述化合物的前药。在本申请中，术语“前药”表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。因此，术语“前药”是指本发明的化合物的药学上可接受的代谢前体。当被给予有需要的个体时，前药可以不具有活性，但在体内被转化成本发明的活性化合物。前药通常在体内迅速转化，而产生本发明的母体化合物，例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。前药包括已知的氨基保护基和羧基保护基。具体的前药制备方法可参照Saulnier,M.G.,et al.,Bioorg.Med.Chem.Lett.1994,4,1985-1990；Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。The invention also includes prodrugs of the above compounds. In the present application, the term "prodrug" means a compound which can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis. Thus, the term "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. Specific prodrug preparation methods can be found in Saulnier, M. G., et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, R. B., et al., J. Med. Chem. 2000, 43, 475.
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。In the present application, "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.
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。The term "pharmaceutically acceptable" as used herein, 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.
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、 染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。In the present application, "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.
本发明所述“肿瘤”，“细胞增殖异常相关疾病”等包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、***、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。The "tumor", "cell proliferation-related diseases" and the like according to the present invention 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.
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。The terms "preventing", "preventing" and "preventing" as used herein include the possibility of reducing the occurrence or progression of a disease or condition by a patient.
本文所用的术语“治疗”和其它类似的同义词包括以下含义：The term "treatment" and other similar synonyms as used herein includes the following meanings:
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；(i) preventing a disease or condition from occurring in a mammal, particularly when such a mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;
(ii)抑制疾病或病症，即遏制其发展；(ii) inhibiting a disease or condition, ie, curbing its development;
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者(iii) alleviating the disease or condition, ie, causing the condition of the disease or condition to subside; or
(iv)减轻该疾病或病症所造成的症状。(iv) alleviating the symptoms caused by the disease or condition.
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物***的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。The term "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. For example, 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.
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。The terms "administering," "administering," "administering," and the like, as used herein, 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. 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. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体 的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。The terms "pharmaceutical combination", "drug combination", "combination", "administering other treatments", "administering other therapeutic agents" and the like, as used herein, mean a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, It includes both fixed and unfixed 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 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.
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。It will also be understood by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by a suitable protecting group. Such functional groups include a hydroxyl group, an amino group, a thiol group, and a carboxylic acid. Suitable hydroxy 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.
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。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.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合、从而构成新的或优选的技术方案。限于篇幅在此不再一一累述。It is to be understood that within the scope of the present invention, the various technical features of the present invention and the technical features specifically described hereinafter (as in the embodiments) may be combined with one another to form a new or preferred technical solution. Due to space limitations, we will not repeat them here.
具体实施方式Detailed ways
本发明人经过长期而深入的研究，制备了一类如式(I)所示结构新颖的化合物，并发现其具有较好的FGFR激酶抑制活性，且所述的化合物在极低浓度(可低于10nM)下，即对FGFR激酶产生特异性不可逆抑制作用，并且对FGFR相关的细胞增殖抑制活性相当优异(可低于10nM)，因而可以用于治疗与FGFR激酶突变或表达量异常引起的相关疾病如肿瘤。基于上述发现，发明人完成了本发明。After long-term and intensive research, 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.
下面结合具体实施例、进一步阐述本发明。应理解、这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法、通常按照常规条件、或按照制造厂商所建议的条件。除非另外说明、否则百分比和份数是重量百分比和重量份数。The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples, which do not specify the specific conditions, are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight and parts by weight unless otherwise stated.
本申请要求申请日为2017年10月30日的中国专利申请CN201711040023.5的优先权。本申请引用上述中国专利申请的全文。本发明中所涉及化合物的相关信息，如在本文中并未具体披露，可参考上述专利申请文本。The present application claims priority from Chinese patent application CN201711040023.5, filed on October 30, 2017. This application cites the entire text of the above-mentioned Chinese patent application. The relevant information of the compounds involved in the present invention, as not specifically disclosed herein, may be referred to the above patent application text.
通用方法一：甲硫基氧化成甲砜基General Method 1: Oxidation of methylthio groups to methylsulfonyl groups
Figure PCTCN2018112660-appb-000039
Figure PCTCN2018112660-appb-000039
将甲硫基中间体(1eq.)溶于二氯甲烷中，冰浴冷却下分批加入间氯过氧苯甲酸(2eq.)，室温搅拌过夜。反应完毕，反应液用硫代硫酸钠溶液淬灭，分出有机相，依次用饱和碳酸氢钠溶液和水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离纯化得到甲砜基化合物中间体。The methylthio intermediate (1 eq.) was dissolved in dichloromethane, and m-chloroperoxybenzoic acid (2 eq. After the reaction is completed, the reaction mixture is quenched with sodium thiosulfate solution, and the organic phase is separated, washed with saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure Base compound intermediate.
通用方法二：氨基取代甲砜基General Method 2: Amino-substituted methylsulfonyl
Figure PCTCN2018112660-appb-000040
Figure PCTCN2018112660-appb-000040
将甲砜基中间体(1eq.)和原料胺(2eq.)溶于无水N,N-二甲基甲酰胺中，加入叔丁醇钾(2eq.)后微波加热至100℃反应2小时。反应结束后，加入二氯甲烷萃取，有机相依次用饱和碳酸氢钠溶液和水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离纯化得到硝基化合物中间体。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,
通用方法三：氨基取代芳基氯General Method 3: Amino-substituted aryl chloride
Figure PCTCN2018112660-appb-000041
Figure PCTCN2018112660-appb-000041
将氯代芳基中间体(1eq.)和原料胺(2eq.)溶于无水N,N-二甲基甲酰胺中，氮气鼓泡十分钟，氮气保护下依次加入Pd 2(dba) 3(0.1eq.)，XantPhos(0.2eq.)和碳酸铯(2eq.)。微波加热至100℃反应1小时。反应结束后，加入二氯甲烷萃取，有机相依次用饱和碳酸氢钠溶液和水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离纯化得到中间体化合物。 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.
通用方法四：硝基还原General Method 4: Nitro Reduction
Figure PCTCN2018112660-appb-000042
Figure PCTCN2018112660-appb-000042
将硝基化合物(1eq.)溶于甲醇中，加入饱和硫代硫酸钠溶液(2eq.)和碳酸钠溶液(2eq.)，室温搅拌过夜。反应完毕，加入乙酸乙酯萃取，饱和碳酸氢钠溶液和水洗涤，无水硫酸钠干燥，过滤，减压浓缩，乙酸乙酯重结晶得到氨基中间体。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.
通用方法五：丙烯酰化General Method Five: Acrylation
Figure PCTCN2018112660-appb-000043
Figure PCTCN2018112660-appb-000043
将氨基化合物中间体(1eq.)和DIPEA(2eq.)溶于干燥的N,N-二甲基甲酰胺，冰浴冷却下缓慢滴加丙烯酰氯(1.2eq.)。滴加完毕，室温反应过夜。反应液用二氯甲烷和饱和碳酸氢钠溶液淬灭，分出有机相，分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，剩余物用制备HPLC或者Biotage Flash柱层析分离纯化，得到目标化合物。The amino compound intermediate (1 eq.) and DIPEA (2 eq.) were dissolved in dry N,N-dimethylformamide, and acryloyl chloride (1.2 eq.) was slowly added dropwise under ice-cooling. After the dropwise addition was completed, the reaction was allowed to proceed overnight at room temperature. The reaction mixture was quenched with EtOAc (EtOAc m.) The separation and purification were carried out to obtain the target compound.
中间体制备Intermediate preparation
中间体1：6-(2,6-二氯-3,5-二甲氧基-苯基)-2-甲硫基-吡啶[2,3-d]嘧啶-7-基胺Intermediate 1: 6-(2,6-Dichloro-3,5-dimethoxy-phenyl)-2-methylthio-pyridine [2,3-d]pyrimidin-7-ylamine
Figure PCTCN2018112660-appb-000044
Figure PCTCN2018112660-appb-000044
第一步：将1,3-二甲氧基-5-甲基苯(30g,0.20mol)和二氯甲烷(900mL)加入干燥的圆底烧瓶(1L)中，冰浴冷却下向上述溶液滴加二氯化砜(52.5g,0.40mol)，滴加完毕，室温搅拌过夜。反应结束后，滴加碳酸氢钠碳酸氢钠水溶液调节pH＝8，二氯甲烷萃取，分别用稀盐酸、蒸馏水洗涤，干燥，减压浓缩得到化合物2,4-二氯-1,5-二甲氧基-3-甲基苯(31g,白色固体)，直接用于下步反应。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. After completion of the reaction, sodium hydrogencarbonate aqueous sodium hydrogencarbonate solution was added dropwise to adjust pH=8, extracted with dichloromethane, washed with dilute hydrochloric acid and distilled water, dried and concentrated under reduced pressure to give compound 2,4-dichloro-1,5- Methoxy-3-methylbenzene (31 g, white solid) was used directly in the next step.
第二步：将2,4-二氯-1,5-二甲氧基-3-甲基苯(31g,0.14mol)溶解于四氯化碳(600mL)后置于干燥的圆底烧瓶(1000mL)中，室温下依次加入偶氮二异丁氰(3.0g,0.018mol)及N-溴代丁二酰亚胺(27.6g,0.154mol)。80度下反应3h，加入碳酸氢钠水溶液淬灭反应， 再用二氯甲烷萃取，有机相干燥，浓缩，甲基叔丁基醚结晶得到化合物3-溴甲基-2,4-二氯-1,5-二甲氧基苯(30g,白色固体)。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).
第三步：在干燥的1000mL圆底烧瓶中加入化合物3-溴甲基-2,4-二氯-1,5-二甲氧基苯(30g,0.1mol)和乙腈(500mL)，室温下加入三甲基硅氰(12g,0.34mmol)和四丁基氟化铵(100mL,1mol/L)。室温搅拌1h，TLC显示反应结束。反应液减压浓缩，乙酸乙酯稀释，有机相分别用水和饱和食盐水洗，干燥浓缩，浓缩物用乙酸乙酯打浆得到化合物(2,6-二氯-3,5-二甲氧基-苯基)-乙腈(20g,白色固体)。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. EtOAcjjjjjjjjjjjjjjjjjjjjjjj Base)-acetonitrile (20 g, white solid).
第四步：在干燥的250mL圆底烧瓶中，加入(2,6-二氯-3,5-二甲氧基-苯基)-乙腈(10.4g,0.028mol)和N,N-二甲基甲酰胺(100mL),室温下依次加入4-氨基-2-甲硫基-嘧啶-5-甲醛(5g,0.02mol)和碳酸钾(12.25g,0.06mol)，反应搅拌过夜直至反应完全。反应液用乙酸乙酯萃取，有机相用蒸馏水和饱和食盐水洗，干燥过滤，减压浓缩，浓缩物用硅胶柱色谱法以洗脱剂体系(二氯甲烷:甲醇＝30:1)纯化得到化合物6-(2,6-二氯-3,5-二甲氧基-苯基)-2-甲硫基-吡啶[2,3-d]嘧啶-7-基胺(3.7g,黄色固体)。LC-MS:ESI[M+H] +＝397.0/399.0；1H-NMR(400MHz,CDCl 3)δ8.80(s,1H),7.69(s,1H),6.67(s,1H),3.97(s,,6H),2.68(s,3H)。 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. 6-(2,6-Dichloro-3,5-dimethoxy-phenyl)-2-methylthio-pyridine [2,3-d]pyrimidin-7-ylamine (3.7 g, yellow solid) . LC-MS: ESI [M+H] + = 397.0 / 399.0; 1H-NMR (400 MHz, CDCl 3 ) δ 8.80 (s, 1H), 7.69 (s, 1H), 6.67 (s, 1H), 3.97 ( s,,6H), 2.68 (s, 3H).
中间体2：7-氯-3-(2,6-二氯-3,5-二甲氧基-苯基)-[1,6]萘啶-2-基胺Intermediate 2: 7-Chloro-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-[1,6]naphthyridin-2-ylamine
Figure PCTCN2018112660-appb-000045
Figure PCTCN2018112660-appb-000045
在干燥的250mL圆底烧瓶中，加入4-氨基-6-氯-吡啶-3-甲醛(2g,0.013mol)和N-甲基吡咯烷酮(20mL),然后依次加入化合物(2,6-二氯-3,5-二甲氧基-苯基)-乙腈(4.4g,0.018mol)，碳酸钾(5.27g,0.039mol),80度下搅拌反应。反应结束后，反应液用乙酸乙酯萃取，有机相依次用蒸馏水和饱和食盐水洗，干燥过滤，减压浓缩，浓缩物用硅胶柱色谱法以洗脱剂体系(二氯甲烷:甲醇＝30:1)纯化得到化合物7-氯-3-(2,6-二氯-3,5-二甲氧基-苯基)-[1,6]萘啶-2-基胺(0.8g,黄色固体)。LC-MS:ESI[M+H] +＝383.9/385.9；1H-NMR(400MHz,DMSO-d6)δ8.71(s,1H),7.88(s,1H),7.34(s,1H),7.00(s,1H),3.94(s,6H)。 In a dry 250 mL round bottom flask, 4-amino-6-chloro-pyridine-3-carbaldehyde (2 g, 0.013 mol) and N-methylpyrrolidone (20 mL) were added, followed by the addition of the compound (2,6-dichloro) -3,5-Dimethoxy-phenyl)-acetonitrile (4.4 g, 0.018 mol), potassium carbonate (5.27 g, 0.039 mol), stirred at 80 °. After the completion of the reaction, the reaction mixture was extracted with EtOAc. EtOAc (EtOAc)EtOAc. 1) Purification afforded the compound 7-chloro-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-[1,6]naphthyridin-2-ylamine (0.8 g, yellow solid ). LC-MS: ESI [M+H] + = 383.9 / 385.9; 1H-NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.78 (s, 1H), 7.34 (s, 1H), 7.00 (s, 1H), 3.94 (s, 6H).
中间体3：4-(4-甲基-哌嗪-1-基)-2-硝基-苯基胺Intermediate 3: 4-(4-Methyl-piperazin-1-yl)-2-nitro-phenylamine
Figure PCTCN2018112660-appb-000046
Figure PCTCN2018112660-appb-000046
第一步：将4-(4-甲基-哌嗪-1-基)-苯胺(5g)和三乙胺(5g)溶于干燥的乙酸乙酯(20mL)中，冰浴冷却下，滴加乙酸酐(5mL)。滴加完毕，室温反应3小时。反应液中析出固体，减压过滤，乙酸乙酯淋洗，干燥，得得N-[4-(4-甲基-哌嗪-1-基)-苯基]-乙酰胺固体(4g)。LC-MS:ESI[M+H] +＝234.3。 The first step: 4-(4-methyl-piperazin-1-yl)-phenylamine (5g) and triethylamine (5g) were dissolved in dry ethyl acetate (20mL). Add acetic anhydride (5 mL). After the dropwise addition was completed, the reaction was carried out for 3 hours at room temperature. A solid was precipitated from the reaction mixture, filtered under reduced pressure, ethyl acetate evaporated and evaporated LC-MS: ESI [M+H] + = 234.3.
第二步：将N-[4-(4-甲基-哌嗪-1-基)-苯基]-乙酰胺(4g)溶于浓硫酸(10mL)中，冰浴冷却下，缓慢滴加浓硝酸(3mL)，滴加完毕继续搅拌1小时。将反应液倒入冰块中，析出固体，减压过滤，干燥，乙酸乙酯重结晶得到N-[4-(4-甲基-哌嗪-1-基)-2-硝基-苯基]-乙酰胺固体(2.8g)。LC-MS:ESI[M+H] +＝279.1。 The second step: N-[4-(4-methyl-piperazin-1-yl)-phenyl]-acetamide (4g) was dissolved in concentrated sulfuric acid (10mL), cooled in an ice bath, slowly added dropwise Concentrated nitric acid (3 mL) was added and stirring was continued for 1 hour. The reaction solution was poured into ice, and the solid was separated, filtered, evaporated, evaporated, evaporated ]-Acetamine solid (2.8 g). LC-MS: ESI [M+H] + =279.1.
第三步：将N-[4-(4-甲基-哌嗪-1-基)-2-硝基-苯基]-乙酰胺(2.5g)溶于甲醇(10mL)中，加入4N盐酸溶液(10mL)，加热回流1小时。反应结束后，反应液用水稀释，冰浴冷却下用氨水调节pH值至8-9，乙酸乙酯萃取，水洗，无水硫酸钠干燥，过滤，减压浓缩得4-(4-甲基-哌嗪-1-基)-2-硝基-苯LC-MS:ESI[M+H] +＝237.2。1H-NMR(400MHz,DMSO-d6)δ7.68(d,J＝2.0Hz,1H),7.36(dd,J＝2.0Hz,1H),7.11(d,J＝7.2Hz,1H),3.75-3.77(m,2H),3.62-3.68(m,4H),3.04-3.10(m,2H),2.99(s,3H)。 The third step: N-[4-(4-methyl-piperazin-1-yl)-2-nitro-phenyl]-acetamide (2.5g) was dissolved in methanol (10mL), 4N hydrochloric acid was added The solution (10 mL) was heated to reflux for 1 hour. After completion of the reaction, the reaction mixture was diluted with water, and the mixture was adjusted to pH 8-9 with aq. Piperazine-1-yl)-2-nitro-benzene LC-MS: ESI [M+H] + = 237.2. 1H-NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 2.0 Hz, 1H) ), 7.36 (dd, J = 2.0 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H), 3.75-3.77 (m, 2H), 3.62-3.68 (m, 4H), 3.04-3.10 (m, 2H), 2.99 (s, 3H).
参照同样的合成方法和步骤，制备得到以下中间体3A-3F:The following intermediates 3A-3F were prepared by reference to the same synthetic methods and procedures:
中间体3A：4-(4-乙基-哌嗪-1-基)-2-硝基-苯胺Intermediate 3A: 4-(4-Ethyl-piperazin-1-yl)-2-nitro-aniline
Figure PCTCN2018112660-appb-000047
LC-MS:ESI[M+H] +＝251.2。1H-NMR(400MHz,DMSO-d6)δ7.51(d,J＝2.0Hz,1H),7.29(dd,J＝2.0,7.2Hz,1H),6.95(d,J＝7.2Hz,1H),3.11(t,J＝4.0Hz,4H),2.67(t,J＝4.0Hz,4H),2.51-2.55(m,2H),1.69(t,J＝6.0Hz,3H)。
Figure PCTCN2018112660-appb-000047
LC-MS: ESI [M+H] + = 251.2. 1H-NMR (400 MHz, DMSO-d6) δ 7.51 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 2.0, 7.2 Hz, 1H ), 6.95 (d, J = 7.2 Hz, 1H), 3.11 (t, J = 4.0 Hz, 4H), 2.67 (t, J = 4.0 Hz, 4H), 2.51-2.55 (m, 2H), 1.69 (t , J = 6.0 Hz, 3H).
中间体3B：4-(1-甲基-哌啶-4-基)-2-硝基-苯胺Intermediate 3B: 4-(1-Methyl-piperidin-4-yl)-2-nitro-aniline
Figure PCTCN2018112660-appb-000048
LC-MS:ESI[M+H] +＝236.3。1H-NMR(400MHz,DMSO-d6)δ7.90(d,J＝2.4Hz,1H),7.31(dd,J＝7.6Hz,1H),6.92(d,J＝7.6Hz,1H),3.00-3.03(m,2H),2.49-2.51(m,1H),2.34(s,3H),2.16-2.19(m,2H),1.84-1.87(m,2H),1.71-1.73(m,2H)。
Figure PCTCN2018112660-appb-000048
LC-MS: ESI [M+H] + = 236.3. 1H-NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 7.6 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 3.00-3.03 (m, 2H), 2.49-2.51 (m, 1H), 2.34 (s, 3H), 2.16-2.19 (m, 2H), 1.84-1.87 ( m, 2H), 1.71-1.73 (m, 2H).
中间体3C：[1-(4-氨基-3-硝基-苯基)-哌啶-4-基]-二甲基胺Intermediate 3C: [1-(4-Amino-3-nitro-phenyl)-piperidin-4-yl]-dimethylamine
Figure PCTCN2018112660-appb-000049
LC-MS:ESI[M+H] +＝265.1。1H-NMR(400MHz,DMSO-d6)δ8.28(s,1H),7.68(dd,J＝2.0,7.2Hz,1H),7.15(d,J＝7.2Hz,1H),3.58-3.63(m,3H),3.12-3.178(m,2H),2.94(s,6H),2.31-2.37(m,2H),1.99-2.03(m,2H)。
Figure PCTCN2018112660-appb-000049
LC-MS: ESI [M+H] + = 265.1. 1H-NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.68 (dd, J = 2.0, 7.2 Hz, 1H), 7.15 (d) , J=7.2 Hz, 1H), 3.58-3.63 (m, 3H), 3.12-3.178 (m, 2H), 2.94 (s, 6H), 2.31-2.37 (m, 2H), 1.99-2.03 (m, 2H) ).
中间体3D：4-(4-乙基-哌嗪-1-基甲基)-2-硝基-苯胺Intermediate 3D: 4-(4-Ethyl-piperazin-1-ylmethyl)-2-nitro-aniline
Figure PCTCN2018112660-appb-000050
LC-MS:ESI[M+H] +＝267.1。1H-NMR(400MHz,DMSO-d6)δ7.52(d,J＝2.0Hz,1H),7.30(dd,J＝2.4,7.2Hz,1H),6.95(d,J＝7.2Hz,1H),3.59(bs,4H),2.67(t,J＝4.0Hz,4H),3.00(t,J＝4.0Hz,4H),1.50(s,9H)。
Figure PCTCN2018112660-appb-000050
LC-MS: ESI [M+H] + = 267.1. 1H-NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 2.4, 7.2 Hz, 1H ), 6.95 (d, J = 7.2 Hz, 1H), 3.59 (bs, 4H), 2.67 (t, J = 4.0 Hz, 4H), 3.00 (t, J = 4.0 Hz, 4H), 1.50 (s, 9H) ).
中间体3E:4-(4-异丙基哌嗪-1-基)-2-硝基苯胺Intermediate 3E: 4-(4-Isopropylpiperazin-1-yl)-2-nitroaniline
Figure PCTCN2018112660-appb-000051
LC-MS:ESI[M+H]+＝265.2。1H-NMR(400MHz,DMSO-d6)δ7.51(d,J＝2.4Hz,1H),7.28(dd,J＝2.4,7.2Hz,1H),6.95(d,J＝7.2Hz,1H),3.11(t,J＝4.0Hz,4H),2.94(s,6H),2.75-2.98(m,5H),1.16(d,J＝5.2Hz,6H)。
Figure PCTCN2018112660-appb-000051
LC-MS: ESI [M+H]+========================================================================================== ), 6.95 (d, J = 7.2 Hz, 1H), 3.11 (t, J = 4.0 Hz, 4H), 2.94 (s, 6H), 2.75-2.98 (m, 5H), 1.16 (d, J = 5.2 Hz) , 6H).
中间体3F：2-硝基-4-(4-(吡咯啉-1-基)哌啶-1-基)苯胺Intermediate 3F: 2-Nitro-4-(4-(pyrrolin-1-yl)piperidin-1-yl)aniline
Figure PCTCN2018112660-appb-000052
LC-MS:ESI[M+H]+＝291.2。1H-NMR(400MHz,DMSO-d6)δ8.23(s,1H),7.65(d,J＝7.2Hz,1H),7.15(d,J＝7.2Hz,1H),3.81-3.84(m,2H),3.75-3.77(m,2H),3.73-3.74(m,3H),3.21-3.26(m,2H),2.48-2.50(m,2H),2.23-2.27(m,4H),2.08-2.10(m,2H)。
Figure PCTCN2018112660-appb-000052
LC-MS: ESI <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; = 7.2 Hz, 1H), 3.81-3.84 (m, 2H), 3.75-3.77 (m, 2H), 3.73-3.74 (m, 3H), 3.21-3.26 (m, 2H), 2.48-2.50 (m, 2H) ), 2.23 - 2.27 (m, 4H), 2.08 - 2.10 (m, 2H).
中间体4：4-(2,6-二氯-3,5-二甲氧基-苯基)-2-甲砜基[1’,2’:1,6]吡啶[2,3-d]嘧啶Intermediate 4: 4-(2,6-Dichloro-3,5-dimethoxy-phenyl)-2-methylsulfonyl [1',2':1,6]pyridine [2,3-d Pyrimidine
Figure PCTCN2018112660-appb-000053
Figure PCTCN2018112660-appb-000053
将6-(2,6-二氯-3,5-二甲氧基-苯基)-2-甲硫基-吡啶并[2,3-d]嘧啶-7-基胺(4g)和1,2-二氯-1-乙氧基乙烷(400mg)溶于N,N-二甲基甲酰胺(15mL)中，搅拌下加入对甲苯磺酸(0.2g)，加热搅拌过夜。反应结束后，加入二氯甲烷(50mL)和饱和碳酸氢钠溶液(15mL)。分出有机相，分别用稀盐酸和水洗，无水硫酸钠干燥，过滤，减压浓缩，乙酸乙酯重结晶得到4-(2,6-二氯-3,5-二甲氧基-苯基)-8-甲硫基-3,7,9,9b-四氮杂-环戊基[a]萘(3.1g)。LC-MS:ESI[M+H] +＝421.3/423.3。1H-NMR(400MHz,CDCl3)δ9.03(s,1H),8.43(s,1H),7.67(s,1H),7.35(s,1H),6.70(s,1H),3.97(s,6H),2.74(s,3H)。 6-(2,6-Dichloro-3,5-dimethoxy-phenyl)-2-methylthio-pyrido[2,3-d]pyrimidin-7-ylamine (4g) and 1 2-Dichloro-1-ethoxyethane (400 mg) was dissolved in N,N-dimethylformamide (15 mL), and p-toluenesulfonic acid (0.2 g) was added with stirring and stirred overnight. After the reaction was completed, dichloromethane (50 mL) and a saturated sodium hydrogen carbonate solution (15 mL) were added. The organic phase was separated, washed with dilute aqueous hydrochloric acid and water, dried over anhydrous sodium sulfate, filtered, evaporated. Benzo)-8-methylthio-3,7,9,9b-tetraaza-cyclopentyl[a]naphthalene (3.1 g). LC-MS: ESI <RTI ID=0.0></RTI></RTI></RTI><RTI ID =0.0></RTI></RTI></RTI><RTIgt;</RTI><RTIgt; , 1H), 6.70 (s, 1H), 3.97 (s, 6H), 2.74 (s, 3H).
将上述甲硫基中间体(3.1g)溶于氯仿(20mL)，冰浴冷却下分批加入间-氯过氧苯甲酸(2.8g)，室温搅拌过夜。淬灭反应，乙酸乙酯萃取，洗涤，浓缩，柱层析分离纯化得到4-(2,6-二氯-3,5-二甲氧基-苯基)-2-甲砜基[1’,2’:1,6]吡啶[2,3-d]嘧啶(黄色固体，2.0g)。LC-MS:ESI[M+H] +＝453.3/455.3,1H-NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.78(s,1H),7.88-8.03(m,1H),7.81(s,1H),7.08(s,1H),4.01(s,6H),3.58(s,3H)。 The above-mentioned methylthio intermediate (3.1 g) was dissolved in chloroform (20 mL), and m-chloroperoxybenzoic acid (2.8 g) was added portionwise, and the mixture was stirred at room temperature overnight. The reaction is quenched, extracted with ethyl acetate, washed, concentrated, and purified by column chromatography to give 4-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-methylsulfonyl [1' , 2': 1,6]pyridine [2,3-d]pyrimidine (yellow solid, 2.0 g). </ RTI><RTI ID =0.0></RTI></RTI><RTI ID =0.0></RTI></RTI><RTI ID =0.0></RTI></RTI><RTIgt; , 7.81 (s, 1H), 7.08 (s, 1H), 4.01 (s, 6H), 3.58 (s, 3H).
采用相同的合成步骤和方法，以不同的卤代醛和卤代酮或其等效物为原料，制备得到以下中间体4A-4H。The following intermediates 4A-4H were prepared using the same synthetic procedures and procedures, starting from different halo aldehydes and halo ketones or their equivalents.
Figure PCTCN2018112660-appb-000054
Figure PCTCN2018112660-appb-000054
Figure PCTCN2018112660-appb-000055
Figure PCTCN2018112660-appb-000055
中间体5：3-[6-(2,6-二氯-3,5-二甲氧基-苯基)-2-甲砜基-咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-8-基)丙醛Intermediate 5: 3-[6-(2,6-Dichloro-3,5-dimethoxy-phenyl)-2-methylsulfonyl-imidazole [1',2':1,6]pyridine [2,3-d]pyrimidin-8-yl)propanal
Figure PCTCN2018112660-appb-000056
Figure PCTCN2018112660-appb-000056
第一步：将6-(2,6-二氯-3,5-二甲氧基-苯基)-2-甲硫基-吡啶并[2,3-d]嘧啶-7-基胺(4g)和三乙胺(3g)溶于N,N-二甲基甲酰胺(15mL)中，搅拌下加入5-氯-4-氧代-戊酸甲酯(3.2g)。滴加完毕，加热至80度搅拌过夜。反应完毕，加入二氯甲烷(40mL)萃取，有机相依次用饱和碳酸氢钠和水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离纯化得到3-[4-(2,6-二氯-3,5-二甲氧基-苯基)-8-甲硫基-3,7,9,9b-四氮杂-环戊基[a]萘-2-基]- 丙酸甲酯(2.4g)。LC-MS:ESI[M+H] +＝507.3/507.3。 First step: 6-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-methylthio-pyrido[2,3-d]pyrimidin-7-ylamine ( 4 g) and triethylamine (3 g) were dissolved in N,N-dimethylformamide (15 mL), and methyl 5-chloro-4-oxo-pentanoate (3.2 g) was added with stirring. After the dropwise addition was completed, the mixture was heated to 80 ° C overnight. After completion of the reaction, the mixture was extracted with methylene chloride (40 mL). EtOAc (EtOAc m. 6-Dichloro-3,5-dimethoxy-phenyl)-8-methylthio-3,7,9,9b-tetraaza-cyclopentyl[a]naphthalen-2-yl]-prop Methyl ester (2.4 g). LC-MS: ESI [M+H] + = 507.3 / 507.3.
第二步：将3-[4-(2,6-二氯-3,5-二甲氧基-苯基)-8-甲硫基-3,7,9,9b-四氮杂-环戊基[a]萘-2-基]-丙酸甲酯(2.4g)溶于无水甲醇(20mL)，冰浴冷却下分批加入硼氢化钠(150mg)固体，加热回流2小时。反应液中加入饱和氯化铵溶液淬灭反应，减压除去溶剂，二氯甲烷萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，柱层析分离纯化得到3-[4-(2,6-二氯-3,5-二甲氧基-苯基)-8-甲硫基-3,7,9,9b-四氮杂-环戊基[a]萘-2-基]-丙-1-醇(1.8g)。LC-MS:ESI[M+H] +＝480.1/482.1。 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. [4-(2,6-Dichloro-3,5-dimethoxy-phenyl)-8-methylthio-3,7,9,9b-tetraaza-cyclopentyl[a]naphthalene- 2-yl]-propan-1-ol (1.8 g). LC-MS: ESI [M+H] + = 480.1 / 4821.
第三步：将3-[4-(2,6-二氯-3,5-二甲氧基-苯基)-8-甲硫基-3,7,9,9b-四氮杂-环戊基[a]萘-2-基]-丙-1-醇(1.8g)溶于乙酸乙酯(20mL),加入Dess-Martin氧化剂(1.3g)，加热回流3小时。反应液中加入硫代硫酸钠溶液淬灭反应，分出有机相，有机相分别用饱和碳酸氢钠溶液和水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离纯化，得到3-[4-(2,6-二氯-3,5-二甲氧基-苯基)-8-甲硫基-3,7,9,9b-四氮杂-环戊基[a]萘-2-基]-丙醛(1.1g)。LC-MS:ESI[M+H] +＝478.2/480.2。 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. 3-[4-(2,6-Dichloro-3,5-dimethoxy-phenyl)-8-methylthio-3,7,9,9b-tetraaza-cyclopentyl[a] Naphthalen-2-yl]-propanal (1.1 g). LC-MS: ESI [M+H] + = 478.2 / 480.2.
第四步：将上述3-[4-(2,6-二氯-3,5-二甲氧基-苯基)-8-甲硫基-3,7,9,9b-四氮杂-环戊基[a]萘-2-基]-丙醛(1.0g)溶于氯仿(20mL)，冰浴冷却下分批加入间-氯过氧苯甲酸(2.2g),室温搅拌过夜。反应完毕，反应液中加入硫代硫酸钠溶液淬灭反应，分出有机相，有机相分别用饱和碳酸氢钠溶液和水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离纯化，得到3-(6-(2,6-二氯-3,5-二甲氧基)-2-(甲砜基)咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-8-基)丙醛(0.6g)。LC-MS:ESI[M+H] +＝509.1/511.1。 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 organic phase is washed with saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, filtered, Purification afforded 3-(6-(2,6-dichloro-3,5-dimethoxy)-2-(methylsulfonyl)imidazole [1',2':1,6]pyridine [2, 3-d]pyrimidin-8-yl)propanal (0.6 g). LC-MS: ESI [M+H] + =509.
采用上述相同的方法和步骤制备得到以下中间体：The following intermediates were prepared using the same methods and procedures as above:
Figure PCTCN2018112660-appb-000057
Figure PCTCN2018112660-appb-000057
Figure PCTCN2018112660-appb-000058
Figure PCTCN2018112660-appb-000058
中间体6：1-甲基-4-硝基-3-氨基-吡唑Intermediate 6: 1-Methyl-4-nitro-3-amino-pyrazole
Figure PCTCN2018112660-appb-000059
Figure PCTCN2018112660-appb-000059
第一步：将三乙胺(2.5mL,17.3mmol)加入到冰浴冷却下的1-甲基-4-硝基-1H-吡唑-3-羧酸(1.6g,8.64mmol)与N,N-二甲基甲酰胺(15mL)和叔丁醇(5mL)的溶液中，随后加入叠氮磷酸二苯酯DPPA(3.6g,12.97mmol)，反应液加热到80℃搅拌4h。反应完毕，减压除去部分溶剂后用乙酸乙酯稀释。有机相用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，柱层析分离纯化得到1-甲基-4-硝基-3-叔丁氧羰基氨基-吡唑(2g,90％)。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 .
第二步：将1-甲基-4-硝基-3-叔丁氧羰基氨基-吡唑(2g,7.8mmol)溶于二氯甲烷(10mL)中，冰浴冷却下，向其中缓慢滴加三氟乙酸(6mL)。滴加完毕，反应液室温搅拌过夜。反应完毕，减压浓缩，得到1-甲基-4-硝基-3-氨基-吡唑(1g,80％).ESI-MS:m/z＝157(M+H) +。 The second step: 1-methyl-4-nitro-3-tert-butoxycarbonylamino-pyrazole (2g, 7.8mmol) was dissolved in dichloromethane (10mL), cooled in an ice bath, slowly dripped into it Trifluoroacetic acid (6 mL) was added. After the dropwise addition was completed, the reaction solution was stirred at room temperature overnight. The mixture was then concentrated under reduced pressure to give 1-methyl-4-nitro-3-amino - pyrazole (1g, 80%) ESI- MS:. M / z = 157 (M + H) +.
采用类似的方法制备得到以下中间体：The following intermediates were prepared in a similar manner:
Figure PCTCN2018112660-appb-000060
Figure PCTCN2018112660-appb-000060
Figure PCTCN2018112660-appb-000061
Figure PCTCN2018112660-appb-000061
中间体7-A：1-(2-氯-6-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)-N,N-二甲基甲胺Intermediate 7-A: 1-(2-Chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1',2':1,6]pyridine [2, 3-d]pyrimidin-8-yl)-N,N-dimethylmethylamine
Figure PCTCN2018112660-appb-000062
Figure PCTCN2018112660-appb-000062
将6-(2,6-二氯-3,5-二甲氧基-苯基)-2-甲硫基-吡啶并[2,3-d]嘧啶-7-基胺原料(3mmol)溶于无水四氢呋喃(15mL),冰浴冷却下向其中加入磺酰氯(2.54ml,30mmol)，室温反应1h。反应结束后，向反应液中缓慢加入饱和碳酸氢钠水溶液焠灭，后用二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，蒸干溶剂，硅胶柱层析纯化得到中间体2-氯-6-(2,6-二氯-3,5-二甲氧基苯基)吡啶[2,3-d]嘧啶-7-胺(640mg)。LC-MS：385.1/387.1。1H-NMR(400MHz,CDCl3)δ8.80(s,1H),7.69(s,1H),6.67(s,1H),3.97(s,,6H)。Dissolving 6-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-methylthio-pyrido[2,3-d]pyrimidin-7-ylamine starting material (3 mmol) Sulfuryl chloride (2.54 ml, 30 mmol) was added to anhydrous tetrahydrofuran (15 mL). After the reaction, the reaction mixture was quenched with saturated aqueous sodium hydrogen sulfate, and then extracted with dichloromethane. Chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyridine [2,3-d]pyrimidin-7-amine (640 mg). LC-MS: 385.1/387.1. 1H-NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.69 (s, 1H), 6.67 (s, 1H), 3.97 (s, 6H).
将上述中间体(500mg)溶于无水N,N-二甲基甲酰胺(10mL)，室温下加入1,3-二溴丙-2-酮(1.1eq)，80度加热搅拌至反应完成，二氯甲烷萃取，依次用饱和碳酸氢钠、水洗涤，无水硫酸钠干燥，过滤，减压浓缩，粗品未经纯化直接用于下一步反应。The above intermediate (500 mg) was dissolved in anhydrous N,N-dimethylformamide (10 mL), 1,3-dibromopropan-2-one (1.1 eq) was added at room temperature, and stirred at 80 °C until the reaction was completed. The organic layer was extracted with EtOAc (EtOAc m.).
将上述粗品溶于无水N,N-二甲基甲酰胺(10mL)中，冰浴下加入二甲胺的醇溶液(1.1eq)，室温搅拌2小时，反应完成。二氯甲烷萃取，依次用饱和碳酸氢钠、水洗涤，无水硫酸钠干燥，过滤，减压浓缩，剩余物柱层析纯化得到目标化合物。MS(ESI+)m/z:466.1/468.1The crude product was dissolved in anhydrous N,N-dimethylformamide (10 mL). EtOAc was evaporated. The organic layer was extracted with EtOAc (EtOAc m. MS (ESI+) m/z: 466.1/468.1
中间体7-B：2-氯-6-(2,6-di氯-3,5-二甲氧基苯基)-8-((4-甲基哌嗪-1-基)甲基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶Intermediate 7-B: 2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-((4-methylpiperazin-1-yl)methyl) Imidazole [1',2':1,6]pyridine [2,3-d]pyrimidine
Figure PCTCN2018112660-appb-000063
采用中间体7-A相同的方法制备得到中间体7-B。MS(ESI+)m/z:521.2/521.2。
Figure PCTCN2018112660-appb-000063
Intermediate 7-B was prepared in the same manner as Intermediate 7-A. MS (ESI+) m/z: 521.2 / 521.2.
实施例制备Example preparation
采用中间体1-7为主要起始原料，以及其它商品化的试剂如哌嗪，四氢吡咯、邻苯二胺，四氢呋喃二氨，四氢吡喃二胺、吡唑二胺，丙烯酰氯、丙烯酸等原料(手性四氢呋喃二胺和四氢吡喃二胺采用专利文献WO2014144737中相同的方法制备得到各手性异构体原料)，分别采用通用方法一至五的合成方法依次制备合成得到如下实施例化合物：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. Example compound:
实施例1：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)苯基)-2-氟丙烯酰胺Example 1: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)imidazo[1',2':1,6]pyridine [2,3- d]pyrimidin-2-yl)amino)phenyl)-2-fluoroacrylamide
Figure PCTCN2018112660-appb-000064
LC-MS:ESI[M+H] +＝553.2/555.2；1H-NMR(400MHz,CD3OD)δ9.83(s,1H),9.50(s,1H),9.14(s,1H),8.16(s,1H),7.87(d,J＝7.6Hz,1H),7.69(d,J＝6.8Hz,1H),7.52(s,1H),7.50(s,1H),7.21-7.31(m,2H),7.06(s,1H),6.24(dd,J＝2.0,17.2Hz，1H)，5.72(dd,J＝2.0,10.4Hz,1H),3.99(s,6H)。
Figure PCTCN2018112660-appb-000064
LC-MS: ESI [M+H] + = 553.2 / 555.2; 1H-NMR (400 MHz, CD3OD) δ 9.83 (s, 1H), 9.50 (s, 1H), 9.14 (s, 1H), 8.16 (s) , 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 6.8 Hz, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 7.21 - 7.31 (m, 2H) , 7.06 (s, 1H), 6.24 (dd, J = 2.0, 17.2 Hz, 1H), 5.72 (dd, J = 2.0, 10.4 Hz, 1H), 3.99 (s, 6H).
实施例2：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1,2-a][1,6]萘啶-8-基)氨基)苯基)-2-氟丙烯酰胺Example 2: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthyridin-8- Amino)phenyl)-2-fluoroacrylamide
Figure PCTCN2018112660-appb-000065
LC-MS:ESI[M+H] +＝552.4/554.4；1H-NMR(400MHz,CD3OD)δ9.88(s,1H),8.83(s,1H),8.74(s,1H),8.33(s,1H),7.70(d,J＝7.6Hz,1H),7.63(d,J＝7.6Hz,1H),7.50(s,1H),7.46(s,1H),7.15-7.28(m,3H),7.06(s,1H),6.24(dd,J＝2.0,16.8Hz,1H),5.72(dd, J＝2.0,10.4Hz,1H),4.00(s,6H)。
Figure PCTCN2018112660-appb-000065
LC-MS: ESI [M+H] + = 552.4 / 554.4; 1H-NMR (400 MHz, CD3OD) δ 9.88 (s, 1H), 8.83 (s, 1H), 8.74 (s, 1H), 8.33 (s) , 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.46 (s, 1H), 7.15-7.28 (m, 3H) , 7.06 (s, 1H), 6.24 (dd, J = 2.0, 16.8 Hz, 1H), 5.72 (dd, J = 2.0, 10.4 Hz, 1H), 4.00 (s, 6H).
实施例3：N-(3-((6-(2,6-二氯-3,5-二甲氧基苯)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-1-甲基-1H-吡唑-4-基)-2-氟丙烯酰胺Example 3: N-(3-((6-(2,6-Dichloro-3,5-dimethoxybenzene)imidazole [1',2':1,6]pyridine [2,3-d Pyrimidin-2-yl)amino)-1-methyl-1H-pyrazol-4-yl)-2-fluoroacrylamide
Figure PCTCN2018112660-appb-000066
LC-MS:ESI[M+H] +＝557.2559.2；1H-NMR(400MHz,CD3OD)δ10.91(s,1H),10.07(s,1H),9.14(s,1H),8.64(s,1H),8.47(s,1H),7.51-7.60(m,2H),7.07(s,1H),6.37(dd,J＝1.6,8.8Hz,1H),5.84(d,J＝10.4Hz,1H),3.99(s,6H),3.93(s,1H)。
Figure PCTCN2018112660-appb-000066
LC-MS: ESI [M+H] + = 557.2559.2; 1H-NMR (400 MHz, CD3OD) δ 10.91 (s, 1H), 10.07 (s, 1H), 9.14 (s, 1H), 8.64 (s) , 1H), 8.47 (s, 1H), 7.51-7.60 (m, 2H), 7.07 (s, 1H), 6.37 (dd, J = 1.6, 8.8 Hz, 1H), 5.84 (d, J = 10.4 Hz, 1H), 3.99 (s, 6H), 3.93 (s, 1H).
实施例4：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(4-甲基哌嗪-1-基)苯基)丙烯酰胺Example 4: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [ 2,3-d]pyrimidin-2-yl)amino)-5-(4-methylpiperazin-1-yl)phenyl)acrylamide
Figure PCTCN2018112660-appb-000067
LC-MS:ESI[M+2H] +＝647.5/649.5；1H-NMR(400MHz,CD3OD)δ9.89(s,1H),9.09(s,1H),8.11(s,1H),7.48-7.51(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)。
Figure PCTCN2018112660-appb-000067
</ 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).
实施例5：N-(4-((6-(2,6-二氯-3,5-二甲氧基苯)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢呋喃-3-基)-2-氟丙烯酰胺Example 5: N-(4-((6-(2,6-Dichloro-3,5-dimethoxybenzene)imidazole [1',2':1,6]pyridine [2,3-d Pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)-2-fluoroacrylamide
Figure PCTCN2018112660-appb-000068
LC-MS:ESI[M+H] +＝547.3/549.3；1H-NMR(400MHz,CD3OD)δ9.04(s,1H),8.42(s,1H),8.20(s,1H),8.01(s,1H),7.51(s,1H),7.46(d,J＝8.4Hz,1H),7.06(s,1H),6.10-6.17(m,1H),5.86-5.90(m,1H),4.75-4.86(m,2H),4.14-4.18(m,1H),4.03-4.07(m,1H),3.99(s,6H),3.84-3.86(m,1H),3.65-3.69(m,1H)。
Figure PCTCN2018112660-appb-000068
LC-MS: ESI [M+H] + = 547.3/549.3; 1H-NMR (400 MHz, CD3OD) δ 9.04 (s, 1H), 8.42 (s, 1H), 8.20 (s, 1H), 8. , 1H), 7.51 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.06 (s, 1H), 6.10-6.17 (m, 1H), 5.86-5.90 (m, 1H), 4.75- 4.86 (m, 2H), 4.14 - 4.18 (m, 1H), 4.03-4.07 (m, 1H), 3.99 (s, 6H), 3.84-3.86 (m, 1H), 3.65-3.69 (m, 1H).
实施例6：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-3-甲基苯基)-2-氟丙烯酰胺Example 6: N-(2-((6-(2,6-Dichloro-3,5-dimethoxybenzene)imidazole [1',2':1,6]pyridine [2,3-d Pyrimidin-2-yl)amino)-3-methylphenyl)-2-fluoroacrylamide
Figure PCTCN2018112660-appb-000069
LC-MS:ESI[M+H] +＝567.4/569.4；1H-NMR(400MHz,CD3OD)δ9.62(s,1H),9.15(s,1H),9.07(s,1H),8.22(s,1H),7.91(d,J＝8.4Hz,1H),7.54(s,1H),7.52(s,1H), 7.31(t,J＝8.0Hz,1H),7.13(d,J＝7.2Hz,1H),7.07(s,1H),6.22(d,J＝8.4Hz,1H),5.73(d,J＝10.4Hz,1H),3.99(s,6H),2.32(s,3H)。
Figure PCTCN2018112660-appb-000069
LC-MS: ESI [M+H] + = 567.4 / 569.4; 1H-NMR (400 MHz, CD3OD) δ 9.62 (s, 1H), 9.15 (s, 1H), 9.07 (s, 1H), 8.22 (s) , 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.52 (s, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 7.2 Hz) , 1H), 7.07 (s, 1H), 6.22 (d, J = 8.4 Hz, 1H), 5.73 (d, J = 10.4 Hz, 1H), 3.99 (s, 6H), 2.32 (s, 3H).
实施例7：N-(4-((6-(2,6-二氯-3,5-二甲氧基苯)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢-2H-吡喃-3-基)-2-氟丙烯酰胺Example 7: N-(4-((6-(2,6-Dichloro-3,5-dimethoxybenzene)imidazole [1',2':1,6]pyridine [2,3-d Pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl)-2-fluoroacrylamide
Figure PCTCN2018112660-appb-000070
LC-MS:ESI[M+H] +＝543.2/545.2；1H-NMR(400MHz,CD3OD)δ8.75(s,1H),8.14(s,1H),7.51(s,1H),7.16(s,1H),6.61(s,1H),6.14-6.36(m,2H),5.69(d,J＝10.0Hz,1H),4.51(m,1H),4.33(m,1H),4.02(m,1H),3.63-3.89(m,9H),2.25(m,1H),1.72(m,1H)。
Figure PCTCN2018112660-appb-000070
LC-MS: ESI [M+H] + = 543.2 / 545.2; 1H-NMR (400 MHz, CD3OD) δ 8.75 (s, 1H), 8.14 (s, 1H), 7.51 (s, 1H), 7.16 (s) , 1H), 6.61 (s, 1H), 6.14-6.36 (m, 2H), 5.69 (d, J = 10.0 Hz, 1H), 4.51 (m, 1H), 4.33 (m, 1H), 4.02 (m, 1H), 3.63 - 3.89 (m, 9H), 2.25 (m, 1H), 1.72 (m, 1H).
实施例8：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(4-乙基哌嗪-1-基)苯基)丙烯酰胺Example 8: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [ 2,3-d]pyrimidin-2-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)acrylamide
Figure PCTCN2018112660-appb-000071
LC-MS:ESI[M+H] +＝661.2/663.2；1H-NMR(400MHz,CD3OD)δ9.71(s,1H),9.26(s,1H),9.08(s,1H),8.11(s,1H),7.61(s,1H),7.49-7.61(m,3H),7.29(s,1H),7.06(s,1H),6.89(d,J＝8.0Hz,1H),6.23(d,J＝16.8Hz,1H),5.69(d,J＝8.4Hz,1H),3.99(s,6H),3.31(m,4H),3.15(m,4H),2.36-2.39(m,5H),1.05(t,J＝6.8Hz,3H)。
Figure PCTCN2018112660-appb-000071
LC-MS: ESI [M+H] + = 661.2 / 663.2; 1H-NMR (400 MHz, CD3OD) δ 9.71 (s, 1H), 9.26 (s, 1H), 9.08 (s, 1H), 8.11 (s) , 1H), 7.61 (s, 1H), 7.49-7.61 (m, 3H), 7.29 (s, 1H), 7.06 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.23 (d, J = 16.8 Hz, 1H), 5.69 (d, J = 8.4 Hz, 1H), 3.99 (s, 6H), 3.31 (m, 4H), 3.15 (m, 4H), 2.36-2.39 (m, 5H), 1.05 (t, J = 6.8 Hz, 3H).
实施例9：N-(2-((8-(3-(4-丙烯酰基哌嗪-1-基)丙基)-6-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)苯基)丙烯酰胺Example 9: N-(2-((8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxy) Phenyl)imidazo[1',2':1,6]pyridine[2,3-d]pyrimidin-2-yl)amino)phenyl)acrylamide
Figure PCTCN2018112660-appb-000072
Figure PCTCN2018112660-appb-000072
第一步：将3-[6-(2,6-二氯-3,5-二甲氧基-苯基)-2-甲砜基-咪唑[1',2':1,6]吡啶并[2,3-d]嘧啶-8-基)丙醛(500mg)溶于无水四氢呋喃(10mL),冰水浴冷却下加入N-Boc-哌嗪(200mg)，搅拌十分钟后缓慢加入氰基硼氢化钠(120mg)，继续搅拌过夜。反应完毕，加入饱和氯化钠溶液淬灭反应，乙酸乙酯萃取(20mLx3)，饱和食盐水洗涤，无水硫酸钠干 燥，过滤减压浓缩，柱层析分离纯化得到叔丁基4-(3-(6-(2,6-二氯-3,5-二甲氧基苯基)-2-(甲砜基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)丙基)哌嗪-1-甲酸酯(320mg)。LC-MS:ESI[M+H] +＝679.2/681.2。 First step: 3-[6-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-methylsulfonyl-imidazole [1',2':1,6]pyridine And [2,3-d]pyrimidin-8-yl)propanal (500 mg) was dissolved in anhydrous tetrahydrofuran (10 mL). N-Boc-piperazine (200 mg) was added under ice-cooling, and stirred for ten minutes. Sodium borohydride (120 mg) was added and stirring was continued overnight. After completion of the reaction, the reaction was quenched with saturated sodium chloride solution, ethyl acetate (20 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate. -(6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylsulfonyl)imidazole [1',2':1,6]pyridine [2,3-d Pyrimidine-8-yl)propyl)piperazine-1-carboxylate (320 mg). LC-MS: ESI [M+H] + =671.
第二步：将上述叔丁基4-(3-(6-(2,6-二氯-3,5-二甲氧基苯基)-2-(甲砜基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)丙基)哌嗪-1-甲酸酯(320mg)溶于无水N,N-二甲基甲酰胺(5mL)中，加入邻苯二胺(240mg)，加热至100度搅拌过夜。反应完毕，反应液倒入冰水中，析出固体，过滤，滤饼干燥，乙酸乙酯重结晶得到叔丁基4-(3-(2-((2-氨基苯基)氨基)-6-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)丙基)哌嗪-1-甲酸酯(215mg)。LC-MS:ESI[M+H] +＝707.2/709.2。 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. After completion of the reaction, the reaction mixture was poured into ice water, a solid was precipitated, filtered, and the filter cake was dried, and ethyl acetate was recrystallized to give tert-butyl 4-(3-(2-(2-aminophenyl)amino)-6- ( 2,6-Dichloro-3,5-dimethoxyphenyl)imidazo[1',2':1,6]pyridine[2,3-d]pyrimidin-8-yl)propyl)piperazine- 1-formate (215 mg). LC-MS: ESI [M+H] + = 707.2 / 709.2.
第三步：将上述叔丁基4-(3-(2-((2-氨基苯基)氨基)-6-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)丙基)哌嗪-1-甲酸酯(215mg)溶于二氯甲烷(10mL)，冰浴冷却下加入4N的氯化氢/二氧六环溶液(5mL)，室温搅拌2小时，减压浓缩除去过量氯化氢和溶剂，得到黄色固体N1-(6-(2,6-二氯-3,5-二甲氧基苯基)-8-(3-(哌嗪-1-基)丙基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)苯-1,2-二胺(210mg)，未经纯化，直接用于下一步反应。LC-MS:ESI[M+H] +＝607.5/609.5。 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-diamine (210 mg) was used in the next step without purification. LC-MS: ESI [M+H] + = 607.5 / 609.5.
第四步：将上述黄色固体(50mg)溶于无水N,N-二甲基甲酰胺(5mL),加入三乙胺(0.2mL)，冰浴冷却下滴加丙烯酰氯(0.08mL)，室温搅拌过夜。反应完毕，加入乙酸乙酯和水淬灭反应，分出有机相，分别用饱和食盐水，饱和氯化铵洗涤，无水硫酸钠干燥，过滤，浓缩，剩余物用反相HPLC制备纯化得到N-(2-((8-(3-(4-丙烯酰基哌嗪-1-基)丙基)-6-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)苯基)丙烯酰胺(黄色固体，12mg)。LC-MS:ESI[M+H] +＝715.0/717.0；1H-NMR(400MHz,CD3OD)δ9.92(s,1H),9.47(s,1H),9.11(s,1H),7.90(s,1H),7.86(d,J＝7.6Hz,1H),7.68(d,J＝7.6Hz,1H),7.47(s,1H),7.21-7.30(m,2H),7.06(s,1H),6.74-6.81(m,1H),6.47-6.54(m,1H),6.24(d,J＝18.4Hz,1H),6.09(d,J＝18.4Hz,1H),5.65-5.73(m,2H),3.99(s,4H),3.47(m,6H),2.64(t,J＝7.2Hz,2H),2.30-2.32(m,6H),1.77(t,J＝7.2Hz,2H)。 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. -(2-((8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)imidazole [ 1', 2': 1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)phenyl)acrylamide (yellow solid, 12 mg). LC-MS: ESI [M+H] + = 715.0 / 717.0; 1H-NMR (400 MHz, CD3OD) δ 9.92 (s, 1H), 9. 7. (s, 1H), 9.11 (s, 1H), 7.90 (s) , 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.47 (s, 1H), 7.21-7.30 (m, 2H), 7.06 (s, 1H) , 6.74-6.81 (m, 1H), 6.47-6.54 (m, 1H), 6.24 (d, J = 18.4 Hz, 1H), 6.09 (d, J = 18.4 Hz, 1H), 5.65-5.73 (m, 2H) ), 3.99 (s, 4H), 3.47 (m, 6H), 2.64 (t, J = 7.2 Hz, 2H), 2.30-2.32 (m, 6H), 1.77 (t, J = 7.2 Hz, 2H).
实施例10：N-(2-((2-(3-(4-丙烯酰哌嗪-1-基)丙基)-4-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1,2-a][1,6]萘啶-8-基)氨基)苯基)丙烯酰胺Example 10: N-(2-((2-(3-(4-acryloylpiperazin-1-yl)propyl)-4-(2,6-dichloro-3,5-dimethoxy) Phenyl)imidazo[1,2-a][1,6]naphthyridin-8-yl)amino)phenyl)acrylamide
Figure PCTCN2018112660-appb-000073
LC-MS:ESI[M+H] +＝714.5/716.5。1H-NMR(400MHz,CD3OD)δ9.93(s,1H),9.45(s,1H),9.14(s,1H),7.92(s,1H),7.85(d,J＝7.6Hz,1H),7.66(d,J＝7.6Hz,1H),7.45(s,1H),7.21-7.29(m,3H),7.04(s,1H),6.73-6.80(m,1H),6.42-6.49(m,1H),6.22(d,J＝18.4Hz,1H),6.10(d,J＝18.4Hz,1H),5.65-5.71(m,2H),3.94(s,4H),3.44(m,6H),2.63(t,J＝7.2Hz,2H),2.28-2.33(m,6H),1.79(t,J＝7.2Hz,2H)。
Figure PCTCN2018112660-appb-000073
LC-MS: ESI [M+H] + = 714.5 / 716.5. 1H-NMR (400 MHz, CD3OD) δ 9.93 (s, 1H), 9.45 (s, 1H), 9.14 (s, 1H), 7.92 (s) , 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.21-7.29 (m, 3H), 7.04 (s, 1H) , 6.73-6.80 (m, 1H), 6.42-6.49 (m, 1H), 6.22 (d, J = 18.4 Hz, 1H), 6.10 (d, J = 18.4 Hz, 1H), 5.65-5.71 (m, 2H) ), 3.94 (s, 4H), 3.44 (m, 6H), 2.63 (t, J = 7.2 Hz, 2H), 2.28-2.33 (m, 6H), 1.79 (t, J = 7.2 Hz, 2H).
实施例11：N-((3S,4R)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢呋喃-3-基)-2-氟丙烯酰胺Example 11: 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)-2-fluoroacrylamide
Figure PCTCN2018112660-appb-000074
LC-MS:ESI[M+H] +＝547.3/549.3。H-NMR(400MHz,CDCl3)8.86(s,1H),8.26(s,1H),8.01(s,1H),7.58(s,1H),7.26(s,1H),6.93(bs,1H),6.68(s,1H),6.41(bs,1H),5.51-5.63(m,1H),4.91-4.99(m,2H),4.27(bs,1H),3.84-3.96(m,7H),3.71(bs,1H)。
Figure PCTCN2018112660-appb-000074
LC-MS: ESI [M+H] + = 54.3/549.3. H-NMR (400MHz, CDCl3) 8.86 (s, 1H), 8.26 (s, 1H), 8.01 (s, 1H), 7.58 (s, 1H), 7.26 (s, 1H), 6.93 (bs, 1H), 6.68 (s, 1H), 6.41 (bs, 1H), 5.51-5.63 (m, 1H), 4.91-4.99 (m, 2H), 4.27 (bs, 1H), 3.84-3.96 (m, 7H), 3.71 ( Bs, 1H).
实施例12：N-((3R,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢呋喃-3-基)-2-氟丙烯酰胺Example 12: N-((3R,4S)-4-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)imidazole [1', 2': 1,6] Pyridine [2,3-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)-2-fluoroacrylamide
Figure PCTCN2018112660-appb-000075
LC-MS:ESI[M+H] +＝547.3/549.1。H-NMR(400MHz,CDCl3)8.86(s,1H),8.26(s,1H),8.01(s,1H),7.58(s,1H),7.26(s,1H),6.93(bs,1H),6.68(s,1H),6.41(bs,1H),5.51-5.63(m,1H),4.91-4.99(m,2H),4.27(bs,1H),3.84-3.96(m,7H),3.71(bs,1H)。
Figure PCTCN2018112660-appb-000075
LC-MS: ESI [M+H] + = 547.3/549.1. H-NMR (400MHz, CDCl3) 8.86 (s, 1H), 8.26 (s, 1H), 8.01 (s, 1H), 7.58 (s, 1H), 7.26 (s, 1H), 6.93 (bs, 1H), 6.68 (s, 1H), 6.41 (bs, 1H), 5.51-5.63 (m, 1H), 4.91-4.99 (m, 2H), 4.27 (bs, 1H), 3.84-3.96 (m, 7H), 3.71 ( Bs, 1H).
实施例13：N-((3S,4R)-4-((6-(2,6-二氯-3,5-二甲氧基苯胺)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢呋喃-3-基)甲基丙烯酰胺Example 13: N-((3S,4R)-4-((6-(2,6-Dichloro-3,5-dimethoxyaniline)imidazole [1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)methacrylamide
Figure PCTCN2018112660-appb-000076
LC-MS:ESI[M+H] +＝543.1/545.1。H-NMR(400MHz,CDCl3)8.83(s,1H),8.21(s,1H),8.00(s,1H),7.54(s,1H),7.23(s,1H),6.89(bs,1H),6.65(s,1H),6.37(bs,1H),5.51-5.60(m,1H),4.88-4.93(m,2H),4.21(bs,1H),3.81-3.93(m,7H),3.70(bs,1H),2.03(s,3H)。
Figure PCTCN2018112660-appb-000076
LC-MS: ESI [M+H] + = 54. / 545.1. H-NMR (400MHz, CDCl3) 8.83 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.54 (s, 1H), 7.23 (s, 1H), 6.89 (bs, 1H), 6.65 (s, 1H), 6.37 (bs, 1H), 5.51-5.60 (m, 1H), 4.88-4.93 (m, 2H), 4.21 (bs, 1H), 3.81-3.93 (m, 7H), 3.70 ( Bs, 1H), 2.03 (s, 3H).
实施例14：N-((3R,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢呋喃-3-基)甲基丙烯酰胺Example 14: N-((3R,4S)-4-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)imidazole [1', 2': 1,6] Pyridine [2,3-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)methacrylamide
Figure PCTCN2018112660-appb-000077
LC-MS:ESI[M+H] +＝543.3/545.3。H-NMR(400MHz,CDCl3)8.82(s,1H),8.24(s,1H),8.00(s,1H),7.55(s,1H),7.24(s,1H),6.90(bs,1H),6.65(s,1H),6.37(bs,1H),5.51-5.60(m,1H),4.88-4.93(m,2H),4.21(bs,1H),3.81-3.92(m,7H),3.68(bs,1H),2.01(s,3H)。
Figure PCTCN2018112660-appb-000077
LC-MS: ESI [M+H] + =543.3/545.3. H-NMR (400MHz, CDCl3) 8.82 (s, 1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.55 (s, 1H), 7.24 (s, 1H), 6.90 (bs, 1H), 6.65 (s, 1H), 6.37 (bs, 1H), 5.51-5.60 (m, 1H), 4.88-4.93 (m, 2H), 4.21 (bs, 1H), 3.81-3.92 (m, 7H), 3.68 ( Bs, 1H), 2.01 (s, 3H).
实施例15：2-氰基-N-((3S,4R)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰胺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
Figure PCTCN2018112660-appb-000078
LC-MS:ESI[M+H] +＝554.4/556.4。
Figure PCTCN2018112660-appb-000078
LC-MS: ESI [M+H] + = 554.4 / 556.4.
实施例16：N-((3S,4R)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰胺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
Figure PCTCN2018112660-appb-000079
LC-MS:ESI[M+H] +＝543.1/545.1。H-NMR(400MHz,CD3OD)δ8.77(s,1H),7.59(bs,1H),7.25(s,1H),7.19(s,1H),6.63(s,1H),6.19-6.21(m,2H),6.02(bs,1H),5.53-5.56(m,1H),4.90-4.96(m,1H),4.52(bs,1H),4.32(bs,1H),4.16(bs,1H),3.95(s,6H),3.78-3.80(m,1H),3.67(bs,1H),2.24(s,3H)。
Figure PCTCN2018112660-appb-000079
LC-MS: ESI [M+H] + = 54. / 545.1. H-NMR (400MHz, CD3OD) δ 8.77 (s, 1H), 7.59 (bs, 1H), 7.25 (s, 1H), 7.19 (s, 1H), 6.63 (s, 1H), 6.19-6.21 (m) , 2H), 6.02 (bs, 1H), 5.53-5.56 (m, 1H), 4.90-4.96 (m, 1H), 4.52 (bs, 1H), 4.32 (bs, 1H), 4.16 (bs, 1H), 3.95 (s, 6H), 3.78-3.80 (m, 1H), 3.67 (bs, 1H), 2.24 (s, 3H).
实施例17：N-((3R,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰胺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
Figure PCTCN2018112660-appb-000080
LC-MS:ESI[M+H] +＝543.4/545.1。H-NMR(400MHz,CD3OD)δ8.77(s,1H),7.59(bs,1H),7.25(s,1H),7.19(s,1H),6.63(s,1H),6.19-6.21(m,2H),6.02(bs,1H),5.53-5.56(m,1H),4.90-4.96(m,1H),4.52(bs,1H),4.32(bs,1H),4.16(bs,1H),3.95(s,6H),3.78-3.80(m,1H),3.67(bs,1H),2.24(s,3H)。。
Figure PCTCN2018112660-appb-000080
LC-MS: ESI [M+H] + = 543.4 / 545.1. H-NMR (400MHz, CD3OD) δ 8.77 (s, 1H), 7.59 (bs, 1H), 7.25 (s, 1H), 7.19 (s, 1H), 6.63 (s, 1H), 6.19-6.21 (m) , 2H), 6.02 (bs, 1H), 5.53-5.56 (m, 1H), 4.90-4.96 (m, 1H), 4.52 (bs, 1H), 4.32 (bs, 1H), 4.16 (bs, 1H), 3.95 (s, 6H), 3.78-3.80 (m, 1H), 3.67 (bs, 1H), 2.24 (s, 3H). .
实施例18：N-((3S,4R)-4-((6-(2,6--3,5-二甲氧基苯基)-8-(三氘代甲基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰胺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
Figure PCTCN2018112660-appb-000081
LC-MS:ESI[M+H] +＝546.2/548.2。H-NMR(400MHz,CD3OD)δ8.75(s,1H),7.59(bs,1H),7.23(s,1H),7.19(s,1H),6.61(s,1H),6.19-6.20(m,2H),6.01(bs,1H),5.53-5.56(m,1H),4.90-4.96(m,1H),4.52(bs,1H),4.33(bs,1H),4.16(bs,1H),3.94(s,6H),3.78-3.80(m,1H),3.65(bs,1H)
Figure PCTCN2018112660-appb-000081
LC-MS: ESI [M+H] + = 546.2 / 548.2. H-NMR (400MHz, CD3OD) δ 8.75 (s, 1H), 7.59 (bs, 1H), 7.23 (s, 1H), 7.19 (s, 1H), 6.61 (s, 1H), 6.19-6.20 (m) , 2H), 6.01 (bs, 1H), 5.53-5.56 (m, 1H), 4.90-4.96 (m, 1H), 4.52 (bs, 1H), 4.33 (bs, 1H), 4.16 (bs, 1H), 3.94(s,6H), 3.78-3.80(m,1H), 3.65(bs,1H)
实施例19：N-((3R,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-(三氘代甲基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰胺Example 19: N-((3R,4S)-4-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-(tridemethyl)imidazole [ 1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide
Figure PCTCN2018112660-appb-000082
LC-MS:ESI[M+H] +＝546.3/548.3。H-NMR(400MHz,CD3OD)δ8.77(s,1H),7.57(bs,1H),7.21(s,1H),7.18(s,1H),6.60(s,1H),6.18-6.20(m,2H),6.01(bs,1H),5.51-5.56(m,1H),4.91-4.93(m,1H),4.53-4.55(m,1H),4.31-4.33(m,1H),4.16(bs,1H),3.95(s,6H),3.78-3.80(m,1H),3.67(bs,1H)。
Figure PCTCN2018112660-appb-000082
LC-MS: ESI [M+H] + = 54.3/548.3. H-NMR (400MHz, CD3OD) δ 8.77 (s, 1H), 7.57 (bs, 1H), 7.21 (s, 1H), 7.18 (s, 1H), 6.60 (s, 1H), 6.18-6.20 (m) , 2H), 6.01 (bs, 1H), 5.51-5.56 (m, 1H), 4.91-4.93 (m, 1H), 4.53-4.55 (m, 1H), 4.31-4.33 (m, 1H), 4.16 (bs , 1H), 3.95 (s, 6H), 3.78-3.80 (m, 1H), 3.67 (bs, 1H).
实施例20：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)苯基)丙烯酰胺Example 20: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)phenyl)acrylamide
Figure PCTCN2018112660-appb-000083
LC-MS:ESI[M+H] +＝549.2/551.2，H-NMR(400MHz,CD3OD)δ8.87(s,1H),8.32(s,1H),7.89(s,1H),7.77-7.81(m,3H),7.25(s,1H),7.21(s,1H),6.63(s,1H),6.43-6.47(m,1H),6.31-6.35(m,1H),5.73-5.75(m,1H),4.91-5.01(m,1H),3.94(s,6H),2.37(s,3H)。
Figure PCTCN2018112660-appb-000083
</ RTI>< RTI (m, 3H), 7.25 (s, 1H), 7.21 (s, 1H), 6.63 (s, 1H), 6.43-6.47 (m, 1H), 6.31-6.35 (m, 1H), 5.73-5.75 (m , 1H), 4.91-5.01 (m, 1H), 3.94 (s, 6H), 2.37 (s, 3H).
实施例21：N-(3-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢-2H-吡喃-4-基)丙烯酰胺Example 21: N-(3-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide
Figure PCTCN2018112660-appb-000084
LC-MS:ESI[M+H] +＝557.2/559.2。
Figure PCTCN2018112660-appb-000084
LC-MS: ESI [M+H] + = 557.2 / 559.2.
实施例22：N-((3S,4S)-3-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢-2H-吡喃-4-基)丙烯酰胺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
Figure PCTCN2018112660-appb-000085
LC-MS:ESI[M+H] +＝557.2559.2。
Figure PCTCN2018112660-appb-000085
LC-MS: ESI [M+H] + = 557.2559.2.
实施例23：N-((3R,4R)-3-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢-2H-吡喃-4-基)丙烯酰胺Example 23: N-((3R,4R)-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
Figure PCTCN2018112660-appb-000086
LC-MS:ESI[M+H] +＝557.2/559.2。
Figure PCTCN2018112660-appb-000086
LC-MS: ESI [M+H] + = 557.2 / 559.2.
实施例24：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯基)-2-甲基咪唑[1,2-a][1,6]萘啶-8-基)氨基)-5-(4-甲基哌嗪-1-基)苯基)丙烯酰胺Example 24: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-methylimidazo[1,2-a][1,6] Naphthyridine-8-yl)amino)-5-(4-methylpiperazin-1-yl)phenyl)acrylamide
Figure PCTCN2018112660-appb-000087
LC-MS:ESI[M+H] +＝646.5/648.4。H-NMR(400MHz,CD3OD)δ8.70(s,1H),8.14(s,1H),7.96(s,1H),7.46(s,1H),7.22-7.24(m,2H),7.76(dd,J＝8.8,2.8Hz,1H),6.66(s,1H),6.48(s,1H),6.40(s,1H),6.36(s,1H),6.18-6.24(m,1H),5.73(d,J＝8.8Hz,1H), 3.96(s,6H),3.35(t,J＝4.8Hz,4H),2.65(t,J＝4.8Hz,4H),2.54(s,3H),2.37(s,3H)。
Figure PCTCN2018112660-appb-000087
LC-MS: ESI [M+H] + = 646.5 / 648.4. H-NMR (400MHz, CD3OD) δ 8.70 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.46 (s, 1H), 7.22-7.24 (m, 2H), 7.76 (dd , J=8.8, 2.8 Hz, 1H), 6.66 (s, 1H), 6.48 (s, 1H), 6.40 (s, 1H), 6.36 (s, 1H), 6.18-6.24 (m, 1H), 5.73 ( d, J = 8.8 Hz, 1H), 3.96 (s, 6H), 3.35 (t, J = 4.8 Hz, 4H), 2.65 (t, J = 4.8 Hz, 4H), 2.54 (s, 3H), 2.37 ( s, 3H).
实施例25：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯)-2-甲基咪唑[1,2-a][1,6]萘啶-8-基)氨基)-5-(4-乙基哌嗪-1-基)苯基)丙烯酰胺Example 25: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-methylimidazo[1,2-a][1,6]naphthalene Pyridin-8-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)acrylamide
Figure PCTCN2018112660-appb-000088
LC-MS:ESI[M+H] +＝660.2/662.2。H-NMR(400MHz,CD3OD)δ8.70(s,1H),8.14(s,1H),7.96(s,1H),7.47(s,1H),7.22-7.25(m,2H),7.76(dd,J＝8.8,2.8Hz,1H),6.66(s,1H),6.48(s,1H),6.40(s,1H),6.36(s,1H),6.15-6.22(m,1H),5.71(d,J＝8.8Hz,1H),3.96(s,6H),3.35(t,J＝4.8Hz,4H),2.65(t,J＝4.8Hz,4H),2.51(q,J＝7.2Hz,2H),2.37(s,3H),1.16(t,J＝7.2Hz,3H)。
Figure PCTCN2018112660-appb-000088
LC-MS: ESI [M+H] + = 660.2 / 662.2. H-NMR (400MHz, CD3OD) δ 8.70 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.47 (s, 1H), 7.22-7.25 (m, 2H), 7.76 (dd , J=8.8, 2.8 Hz, 1H), 6.66 (s, 1H), 6.48 (s, 1H), 6.40 (s, 1H), 6.36 (s, 1H), 6.15-6.22 (m, 1H), 5.71 ( d, J = 8.8 Hz, 1H), 3.96 (s, 6H), 3.35 (t, J = 4.8 Hz, 4H), 2.65 (t, J = 4.8 Hz, 4H), 2.51 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H).
实施例26：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯)-2-甲基咪唑[1,2-a][1,6]萘啶-8-基)氨基)-5-(4-异丙基哌嗪-1-基)苯基)丙烯酰胺Example 26: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-methylimidazo[1,2-a][1,6]naphthalene Pyridin-8-yl)amino)-5-(4-isopropylpiperazin-1-yl)phenyl)acrylamide
Figure PCTCN2018112660-appb-000089
LC-MS:ESI[M+H] +＝674.3/676.3。
Figure PCTCN2018112660-appb-000089
LC-MS: ESI [M+H] + = 674.3 / 676.3.
实施例27：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯)-2-甲基咪唑[1,2-a][1,6]萘啶-8-基)氨基)-5-(1-甲基哌啶-4-基)苯基)丙烯酰胺Example 27: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-methylimidazo[1,2-a][1,6]naphthalene Pyridin-8-yl)amino)-5-(1-methylpiperidin-4-yl)phenyl)acrylamide
Figure PCTCN2018112660-appb-000090
LC-MS:ESI[M+H] +＝645.2/647.2。
Figure PCTCN2018112660-appb-000090
LC-MS: ESI [M+H] + =645.2/647.2.
实施例28：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯)-2-甲基咪唑[1,2-a][1,6]萘啶-8-基)氨基)-5-(4-(二甲基氨基)哌啶-1-基)苯基)丙烯酰胺Example 28: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-methylimidazo[1,2-a][1,6]naphthalene Pyridin-8-yl)amino)-5-(4-(dimethylamino)piperidin-1-yl)phenyl)acrylamide
Figure PCTCN2018112660-appb-000091
LC-MS:ESI[M+H] +＝674.2/676.2。
Figure PCTCN2018112660-appb-000091
LC-MS: ESI [M+H] + = 674.2 / 676.2.
实施例29：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯)-2-甲基咪唑[1,2-a][1,6]萘啶-8-基)氨基)-5-(4-(吡咯啉-1-基)哌啶-1-基)苯基)丙烯酰胺Example 29: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-methylimidazo[1,2-a][1,6]naphthalene Pyridin-8-yl)amino)-5-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)acrylamide
Figure PCTCN2018112660-appb-000092
LC-MS:ESI[M+H] +＝700.2/702.2。
Figure PCTCN2018112660-appb-000092
LC-MS: ESI [M+H] + = 700.2 / 702.2.
实施例30：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(4-乙基哌嗪-1-基)苯基)丙烯酰胺Example 30: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [ 2,3-d]pyrimidin-2-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)acrylamide
Figure PCTCN2018112660-appb-000093
LC-MS:ESI[M+H] +＝661.2/663.2。H-NMR(400MHz,CD3OD)δ8.77(s,1H),7.76(dd,J＝8.8,2.8Hz,1H),7.35(s,1H),7.22-7.24(m,2H),6.54(s,1H),6.44(s,1H),6.37(s,1H),6.34(s,1H),6.15-6.20(m,1H),5.68(d,J＝8.8Hz,1H),3.96(s,6H),3.37(t,J＝4.8Hz,4H),2.69(t,J＝4.8Hz,4H),2.54(q,J＝7.2Hz,2H),2.35(s,3H),1.17(t,J＝7.2Hz,3H)。
Figure PCTCN2018112660-appb-000093
LC-MS: ESI [M+H] + = 661.2 / 663.2. H-NMR (400MHz, CD3OD) δ 8.77 (s, 1H), 7.76 (dd, J = 8.8, 2.8 Hz, 1H), 7.35 (s, 1H), 7.22-7.24 (m, 2H), 6.54 (s) , 1H), 6.44 (s, 1H), 6.37 (s, 1H), 6.34 (s, 1H), 6.15-6.20 (m, 1H), 5.68 (d, J = 8.8 Hz, 1H), 3.96 (s, 6H), 3.37 (t, J = 4.8 Hz, 4H), 2.69 (t, J = 4.8 Hz, 4H), 2.54 (q, J = 7.2 Hz, 2H), 2.35 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H).
实施例31：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(1-乙基哌啶-4-基)苯基)丙烯酰胺Example 31: 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-ethylpiperidin-4-yl)phenyl)acrylamide
Figure PCTCN2018112660-appb-000094
LC-MS:ESI[M+H] +＝660.1/662.1。
Figure PCTCN2018112660-appb-000094
LC-MS: ESI [M+H] + = 66. / 6621.
实施例32：N-(3-((6-(2,6-二氯-3,5-二甲氧基苯)-8-meth基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-1-(2-羟乙基)-1H-吡唑-4-基)丙烯酰胺Example 32: N-(3-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazole [1',2':1,6]pyridine [ 2,3-d]pyrimidin-2-yl)amino)-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)acrylamide
Figure PCTCN2018112660-appb-000095
LC-MS:ESI[M+H] +＝583.4/585.4。
Figure PCTCN2018112660-appb-000095
LC-MS: ESI [M+H] + = 583.4 / 585.4.
实施例33：N-(3-((4-(2,6-二氯-3,5-二甲氧基苯)咪唑[1,2-a][1,6]萘啶-8-基)氨基)-1-(1-甲基哌嗪-4-基)-1H-吡唑-4-基)-2-氟丙烯酰胺Example 33: N-(3-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthyridin-8-yl) Amino)-1-(1-methylpiperazin-4-yl)-1H-pyrazol-4-yl)-2-fluoroacrylamide
Figure PCTCN2018112660-appb-000096
LC-MS:ESI[M+H] +＝639.5/641.5。
Figure PCTCN2018112660-appb-000096
LC-MS: ESI [M+H] + = 639.5/64.
实施例34：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶 -2-基)氨基)-5-(4-甲基哌嗪-1-基)苯基)-2-氟丙烯酰胺Example 34: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [ 2,3-d]pyrimidin-2-yl)amino)-5-(4-methylpiperazin-1-yl)phenyl)-2-fluoroacrylamide
Figure PCTCN2018112660-appb-000097
LC-MS:ESI[M+H] +＝665.5/667.5。
Figure PCTCN2018112660-appb-000097
LC-MS: ESI [M+H] + = 665.5 / 667.5.
实施例35：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯)-2-甲基咪唑[1,2-a][1,6]萘啶-8-基)氨基)-5-(4-甲基哌嗪-1-基)苯基)-2-氟丙烯酰胺Example 35: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-methylimidazo[1,2-a][1,6]naphthalene Pyridin-8-yl)amino)-5-(4-methylpiperazin-1-yl)phenyl)-2-fluoroacrylamide
Figure PCTCN2018112660-appb-000098
LC-MS:ESI[M+H] +＝664.2/666.2。
Figure PCTCN2018112660-appb-000098
LC-MS: ESI [M+H] + = 664.2 / 666.2.
实施例36：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-3-氟苯基)丙烯酰胺Example 36: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [ 2,3-d]pyrimidin-2-yl)amino)-3-fluorophenyl)acrylamide
Figure PCTCN2018112660-appb-000099
LC-MS:ESI[M+H] +＝567.4。H-NMR(400MHz,CD3OD)δ8.89(s,1H),8.15(s,1H),7.67(s,1H),7.35(s,1H),7.03-7.07(m,2H),6.66(s,1H),6.31-6.37(m,2H),5.70-5.72(m,1H),4.92-5.01(m,2H),3.95(s,6H),2.33(s,3H)。
Figure PCTCN2018112660-appb-000099
LC-MS: ESI [M+H] + = 567.4. H-NMR (400MHz, CD3OD) δ 8.89 (s, 1H), 8.15 (s, 1H), 7.67 (s, 1H), 7.35 (s, 1H), 7.03-7.07 (m, 2H), 6.66 (s) , 1H), 6.31-6.37 (m, 2H), 5.70-5.72 (m, 1H), 4.92-5.01 (m, 2H), 3.95 (s, 6H), 2.33 (s, 3H).
实施例37：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯)-2-甲基咪唑[1,2-a][1,6]萘啶-8-基)氨基)-3-氟苯基)丙烯酰胺Example 37: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-methylimidazo[1,2-a][1,6]naphthalene Pyridin-8-yl)amino)-3-fluorophenyl)acrylamide
Figure PCTCN2018112660-appb-000100
LC-MS:ESI[M+H] +＝566.2/568.2。
Figure PCTCN2018112660-appb-000100
LC-MS: ESI [M+H] + = 566.2 / 568.2.
实施例38：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(4-乙基哌嗪-1-基)苯基)丙烯酰胺Example 38: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [ 2,3-d]pyrimidin-2-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)acrylamide
Figure PCTCN2018112660-appb-000101
LC-MS:ESI[M+H] +＝661.5/663.5。
Figure PCTCN2018112660-appb-000101
LC-MS: ESI [M+H] + = 661.5 / 663.5.
实施例39：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯)-2-甲基咪唑[1,2-a][1,6]萘啶-8-基)氨基)-5-甲氧基苯基)丙烯酰胺Example 39: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-methylimidazo[1,2-a][1,6]naphthalene Pyridin-8-yl)amino)-5-methoxyphenyl)acrylamide
Figure PCTCN2018112660-appb-000102
LC-MS:ESI[M+H] +＝578.4/580.4。
Figure PCTCN2018112660-appb-000102
LC-MS: ESI [M+H] + = 578.4 / 580.4.
实施例40：N-((3S,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢-2H-吡喃-3-基)丙烯酰胺Example 40: N-((3S,4S)-4-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazole [1', 2': 1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl)acrylamide
Figure PCTCN2018112660-appb-000103
LC-MS:ESI[M+H] +＝557.4。H-NMR(400MHz,CD3OD)δ9.02(s,1H),8.12(s,1H),7.96(s,1H),7.54(s,1H),7.10(d,J＝12Hz,1H),6.48(bs,1H),6.03(bs,1H),5.76-5.81(m,1H),5.57(bs,1H),5.54-5.55(m,1H),4.45-4.56(m,2H),4.02(s,6H),3.77-3.80(m,2H),3.61(bs,1H),2.26(s,3H),1.80-2.04(m,2H)。
Figure PCTCN2018112660-appb-000103
LC-MS: ESI [M+H] + = 557.4. H-NMR (400MHz, CD3OD) δ 9.02 (s, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.54 (s, 1H), 7.10 (d, J = 12 Hz, 1H), 6.48 (bs, 1H), 6.03 (bs, 1H), 5.76-5.81 (m, 1H), 5.57 (bs, 1H), 5.54-5.55 (m, 1H), 4.45-4.56 (m, 2H), 4.02 (s) , 6H), 3.77-3.80 (m, 2H), 3.61 (bs, 1H), 2.26 (s, 3H), 1.80-2.04 (m, 2H).
实施例41：N-((3S,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯)-8-((二甲基氨基)甲基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢-2H-吡喃-3-基)丙烯酰胺Example 41: N-((3S,4S)-4-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-((dimethylamino)methyl)) Imidazole [1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl)acrylamide
Figure PCTCN2018112660-appb-000104
LC-MS:ESI[M+H] +＝600.5/602.5。
Figure PCTCN2018112660-appb-000104
LC-MS: ESI [M+H] + = 600.5 / 602.5.
实施例42：N-(2-((8-(3-(4-丙烯酰哌嗪-1-基)丙基)-6-(2,6-二氯-3,5-二甲氧基苯)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(1-乙基哌啶-4-基)苯基)丙烯酰胺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
Figure PCTCN2018112660-appb-000105
LC-MS:ESI[M+H] +＝826.2/828.2。
Figure PCTCN2018112660-appb-000105
LC-MS: ESI [M+H] + = 826.2 / 828.2.
实施例43：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯)-2-(甲氧甲基)咪唑[1,2-a][1,6]萘啶-8-基)氨基)-5-(1-乙基哌啶-4-基)苯基)丙烯酰胺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
Figure PCTCN2018112660-appb-000106
LC-MS:ESI[M+H] +＝689.4/891.4。
Figure PCTCN2018112660-appb-000106
LC-MS: ESI [M+H] + = 689.4 / 891.4.
实施例44：N-((3R,4R)-3-((6-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-yl)氨基)四氢-2H-吡喃-4-基)-2-氟丙烯酰胺Example 44: N-((3R,4R)-3-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)imidazole [1', 2': 1,6] Pyridine [2,3-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)-2-fluoroacrylamide
Figure PCTCN2018112660-appb-000107
LC-MS:ESI[M+H] +＝561.2/563.2。H-NMR(400MHz,CDCl3)δ8.81(s,1H),8.21(s,1H),7.57(s,1H),7.22(s,1H),6.98(bs,1H),6.67(s,1H),6.24(bs,1H),5.74(d,J＝44Hz,1H),5.20(d,J＝16Hz,1H),4.60(bs,1H),4.45(bs,1H),4.11(bs,1H),3.95(s,6H),3.80-3.83(m,1H),3.70-3.73(m,1H),3.67-3.68(m,1H),1.97-2.03(m,1H),1.80-1.84(m,1H)。
Figure PCTCN2018112660-appb-000107
LC-MS: ESI [M+H] + = 561.2 / 563.2. H-NMR (400MHz, CDCl3) δ8.81 (s, 1H), 8.21 (s, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 6.98 (bs, 1H), 6.67 (s, 1H) ), 6.24 (bs, 1H), 5.74 (d, J = 44 Hz, 1H), 5.20 (d, J = 16 Hz, 1H), 4.60 (bs, 1H), 4.45 (bs, 1H), 4.11 (bs, 1H) ), 3.95 (s, 6H), 3.80-3.83 (m, 1H), 3.70-3.73 (m, 1H), 3.67-3.68 (m, 1H), 1.97-2.03 (m, 1H), 1.80-1.84 (m) , 1H).
实施例45：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯)-2-二甲基咪唑[1,2-a][1,6]萘啶-8-基)氨基)-5-氟苯基)丙烯酰胺Example 45: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-dimethylimidazo[1,2-a][1,6] Naphthyridine-8-yl)amino)-5-fluorophenyl)acrylamide
Figure PCTCN2018112660-appb-000108
LC-MS:ESI[M+H] +＝566.2/568.2。
Figure PCTCN2018112660-appb-000108
LC-MS: ESI [M+H] + = 566.2 / 568.2.
实施例46：N-(2-((8-(3-(4-丙烯酰哌嗪-1-基)丙基)-6-(2,6-二氯-3,5-二甲氧基苯)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(4-(二甲基氨基)哌啶-1-基)苯基)丙烯酰胺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
Figure PCTCN2018112660-appb-000109
LC-MS:ESI[M+H] +＝841.5/543.5。
Figure PCTCN2018112660-appb-000109
LC-MS: ESI [M+H] + = 84.
实施例47：2-氰基-N-(2-((4-(2,6-二氯-3,5-二甲氧基苯)-2-甲基咪唑[1,2-a][1,6]萘啶-8-基)氨基)-5-(4-(二甲基氨基)哌啶-1-基)苯基)丙烯酰胺Example 47: 2-cyano-N-(2-((4-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methylimidazo[1,2-a][ 1,6]naphthyridin-8-yl)amino)-5-(4-(dimethylamino)piperidin-1-yl)phenyl)acrylamide
Figure PCTCN2018112660-appb-000110
LC-MS:ESI[M+H] +＝699.6/701.6。
Figure PCTCN2018112660-appb-000110
LC-MS: ESI [M+H] + = 699.6 / 701.6.
实施例48：N-(3-((8-(3-(4-丙烯酰哌嗪-1-基)丙基)-6-(2,6-二氯-3,5-二甲氧基苯)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-1-甲基-1H-吡唑-4-基)丙烯酰胺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
Figure PCTCN2018112660-appb-000111
LC-MS:ESI[M+H] +＝719.3/721.3。
Figure PCTCN2018112660-appb-000111
LC-MS: ESI [M+H] + = 719.3 / 721.3.
实施例49：N-(3-((4-(2,6-二氯-3,5-二甲氧基苯)-2-甲基咪唑[1,2-a][1,6]萘啶-8-基)氨基)-1-甲基-1H-吡唑-4-基)丙烯酰胺Example 49: N-(3-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-methylimidazo[1,2-a][1,6]naphthalene Pyridin-8-yl)amino)-1-methyl-1H-pyrazol-4-yl)acrylamide
Figure PCTCN2018112660-appb-000112
LC-MS:ESI[M+H] +＝552.4/554.4。
Figure PCTCN2018112660-appb-000112
LC-MS: ESI [M+H] + = 552.4 / 554.4.
实施例50：N-(2-((8-(3-(4-丙烯酰哌嗪-1-基)丙基)-6-(2,6-二氯-3,5-二甲氧基苯)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-氟苯基)丙烯酰胺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
Figure PCTCN2018112660-appb-000113
LC-MS:ESI[M+H] +＝733.6/735.6。
Figure PCTCN2018112660-appb-000113
LC-MS: ESI [M+H] + = 733.6 / 735.6.
实施例51：N-((3S,4S)-4-((8-(3-(4-丙烯酰哌嗪-1-基)丙基)-6-(2,6-二氯-3,5-二甲氧基苯)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢-2H-吡喃-3-基)丙烯酰胺Example 51: N-((3S,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)tetrahydro-2H-pyran-3-yl)acrylamide
Figure PCTCN2018112660-appb-000114
LC-MS:ESI[M+H] +＝723.5/725.5。
Figure PCTCN2018112660-appb-000114
LC-MS: ESI [M+H] + = 723.5 / 725.5.
实施例52：N-(4-((8-(3-(4-丙烯酰哌嗪-1-基)丙基)-6-(2,6-二氯-3,5-二甲氧基苯)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰胺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
Figure PCTCN2018112660-appb-000115
LC-MS:ESI[M+H] +＝709.6/711.6。
Figure PCTCN2018112660-appb-000115
LC-MS: ESI [M+H] + = 709.6 / 711.6.
实施例53：N-((3S,4R)-4-((8-(3-(4-丙烯酰哌嗪-1-基)丙基)-6-(2,6-二氯-3,5-二甲氧基苯)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰胺Example 53: N-((3S,4R)-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
Figure PCTCN2018112660-appb-000116
LC-MS:ESI[M+H] +＝709.2/711.2。
Figure PCTCN2018112660-appb-000116
LC-MS: ESI [M+H] + = 709.2 / 711.2.
实施例54：N-((3R,4S)-4-((8-(3-(4-丙烯酰哌嗪-1-基)丙基)-6-(2,6-二氯-3,5-二甲氧基苯)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰胺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
Figure PCTCN2018112660-appb-000117
LC-MS:ESI[M+H] +＝709.5/711.5。
Figure PCTCN2018112660-appb-000117
LC-MS: ESI [M+H] + = 709.5 / 711.5.
实施例55：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯)-2-(甲氧甲基)咪唑[1,2-a][1,6]萘啶-8-基)氨基)-5-氟苯基)丙烯酰胺Example 55: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methoxymethyl)imidazole [1,2-a][1 ,6]naphthyridine-8-yl)amino)-5-fluorophenyl)acrylamide
Figure PCTCN2018112660-appb-000118
LC-MS:ESI[M+H] +＝596.4/598.4。
Figure PCTCN2018112660-appb-000118
LC-MS: ESI [M+H] + = 596.4 / 598.4.
实施例56：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯)-2-(3-(二甲基氨基)丙基)咪唑[1,2-a][1,6]萘啶-8-基)氨基)-5-氟苯基)丙烯酰胺Example 56: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(3-(dimethylamino)propyl)imidazole [1, 2-a][1,6]naphthyridin-8-yl)amino)-5-fluorophenyl)acrylamide
Figure PCTCN2018112660-appb-000119
Figure PCTCN2018112660-appb-000119
以中间体5为原料，用二甲胺替换Boc-哌嗪，采用实施例9相同的方法合成制备得到实施例56化合物。LC-MS:ESI[M+H] +＝637.5/639.5。 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.
实施例57：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯)咪唑[1,2-a][1,6]萘啶-8-基)氨基)苯基)甲基丙烯酰胺Example 57: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthyridin-8-yl) Amino)phenyl)methacrylamide
Figure PCTCN2018112660-appb-000120
LC-MS:ESI[M+H] +＝548.4/550.4。
Figure PCTCN2018112660-appb-000120
LC-MS: ESI [M+H] + = 548.4 / 550.4.
实施例58：2-氰基-N-(2-((4-(2,6-二氯-3,5-二甲氧基苯)咪唑[1,2-a][1,6]萘啶-8-基)氨基)苯基)丙烯酰胺Example 58: 2-cyano-N-(2-((4-(2,6-dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthalene Pyridin-8-yl)amino)phenyl)acrylamide
Figure PCTCN2018112660-appb-000121
LC-MS:ESI[M+H] +＝559.2/561.2。
Figure PCTCN2018112660-appb-000121
LC-MS: ESI [M+H] + = 559.2 / 561.2.
实施例59：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-4,5-二氟苯基)丙烯酰胺Example 59: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-4,5-difluorophenyl)acrylamide
Figure PCTCN2018112660-appb-000122
LC-MS:ESI[M+H] +＝585.2；H-NMR(400MHz,CDCl3)δ9.83(s,1H),9.58(s,1H),9.14(s,1H),7.85-7.95(m,3H),7.49(s,1H),7.06(s,1H),6.47-6.54(m,1H),6.26(d,J＝16Hz,1H),5.74(d,J＝12Hz,1H),3.99(s,6H),2.28(s,3H)。
Figure PCTCN2018112660-appb-000122
LC-MS: ESI [M+H] + = 585.2; H-NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 9.58 (s, 1H), 9.14 (s, 1H), 7.85-7.95 (m) , 3H), 7.49 (s, 1H), 7.06 (s, 1H), 6.47-6.54 (m, 1H), 6.26 (d, J = 16 Hz, 1H), 5.74 (d, J = 12 Hz, 1H), 3.99 (s, 6H), 2.28 (s, 3H).
实施例60：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-3,5-二氟苯基)丙烯酰胺Example 60: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-3,5-difluorophenyl)acrylamide
Figure PCTCN2018112660-appb-000123
LC-MS:ESI[M+H] +＝585.2；H-NMR(400MHz,CDCl3)δ10.08(s,1H), 9.93(s,1H),9.17(s,1H),8.82(bs,1H),8.33(s,1H),7.47-7.52(m,2H),7.06(s,1H),6.63-6.67(m,1H),6.34(d,J＝16Hz,1H),5.82(d,J＝12Hz,1H),3.99(s,6H),2.30(s,3H)。
Figure PCTCN2018112660-appb-000123
LC-MS: ESI [M+H] + = 585.2; H-NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 9.93 (s, 1H), 9.17 (s, 1H), 8.82 (bs, 1H) ), 8.33 (s, 1H), 7.47-7.52 (m, 2H), 7.06 (s, 1H), 6.63-6.67 (m, 1H), 6.34 (d, J = 16 Hz, 1H), 5.82 (d, J) = 12 Hz, 1H), 3.99 (s, 6H), 2.30 (s, 3H).
实施例61：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-甲基苯基甲基苯基)丙烯酰胺Example 61: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-methylphenylmethylphenyl)acrylamide
Figure PCTCN2018112660-appb-000124
LC-MS:ESI[M+H] +＝563.4；H-NMR(400MHz,CDCl3)δ9.80(s,1H),9.33(s,1H),9.09(s,1H),7.89(s,1H),7.73(s,1H),7.50(s,1H),7.46(s,1H),7.10(d,J＝8Hz,1H),7.05(s,1H),6.46-6.53(m,1H),6.22-6.26(d,J＝16Hz,1H),5.72(d,J＝12Hz，1H),3.99(s,6H),2.34(s,3H),2.27(s,3H)。
Figure PCTCN2018112660-appb-000124
LC-MS: ESI [M+H] + = 563.4; H-NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 9.33 (s, 1H), 9.09 (s, 1H), 7.89 (s, 1H) ), 7.73 (s, 1H), 7.50 (s, 1H), 7.46 (s, 1H), 7.10 (d, J = 8 Hz, 1H), 7.05 (s, 1H), 6.46-6.53 (m, 1H), 6.22-6.26 (d, J = 16 Hz, 1H), 5.72 (d, J = 12 Hz, 1H), 3.99 (s, 6H), 2.34 (s, 3H), 2.27 (s, 3H).
实施例62：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(三幅甲氧基)苯基苯基)丙烯酰胺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
Figure PCTCN2018112660-appb-000125
LC-MS:ESI[M+H] +＝633.2；H-NMR(400MHz,CDCl3)δ9.88(s,1H),9.61(s,1H),9.13(s,1H),7.93-7.95(m,3H),7.49(s,1H),7.27(d,J＝8Hz,1H),7.06(s,1H),6.50-6.57(m,1H),6.27(d,J＝16Hz,1H),5.75(d,J＝12Hz,1H),3.99(s,6H),2.28(s,3H)。
Figure PCTCN2018112660-appb-000125
LC-MS: ESI [M+H] + = 633.2; H-NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 9.61 (s, 1H), 9.13 (s, 1H), 7.93-7.95 (m) , 3H), 7.49 (s, 1H), 7.27 (d, J = 8 Hz, 1H), 7.06 (s, 1H), 6.50-6.57 (m, 1H), 6.27 (d, J = 16 Hz, 1H), 5.75 (d, J = 12 Hz, 1H), 3.99 (s, 6H), 2.28 (s, 3H).
实施例63：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-3-氟苯基苯基氟苯基)丙烯酰胺Example 63: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-3-fluorophenylphenylfluorophenyl)acrylamide
Figure PCTCN2018112660-appb-000126
LC-MS:ESI[M+H] +＝567.4；H-NMR(400MHz,CDCl3)δ8.89(s,1H),8.15(s,1H),7.67(s,1H),7.35(s,1H),7.03-7.07(m,2H),6.66(s,1H),6.31-6.37(m,2H),5.70-5.72(m，1H),4.92-5.01(m，2H),3.95(s,6H),2.33(s,3H)。
Figure PCTCN2018112660-appb-000126
</RTI>< RTI ), 7.03-7.07 (m, 2H), 6.66 (s, 1H), 6.31-6.37 (m, 2H), 5.70-5.72 (m, 1H), 4.92-5.01 (m, 2H), 3.95 (s, 6H) ), 2.33 (s, 3H).
实施例64：N-(3-((6-(2,6-二氯-3,5-二甲氧基苯基)咪唑咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢-2H-吡喃-4-基)-2-氟丙烯酰胺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
Figure PCTCN2018112660-appb-000127
LC-MS:ESI[M+H] +＝561.2；H-NMR(400MHz,CDCl3)δ8.81(s,1H), 8.21(s,1H),7.57(s,1H),7.22(s,1H),6.98(bs,1H),6.67(s,1H),6.24(bs,1H),5.74(d,J＝44Hz,1H),5.20(d,J＝16Hz,1H),4.60(bs,1H),4.45(bs,1H),4.11(bs,1H),3.95(s,6H),3.80-3.83(m,1H),3.70-3.73(m,1H),3.67-3.68(m,1H),1.97-2.03(m,1H),1.80-1.84(m,1H)。
Figure PCTCN2018112660-appb-000127
</ RTI>< RTI ), 6.98 (bs, 1H), 6.67 (s, 1H), 6.24 (bs, 1H), 5.74 (d, J = 44 Hz, 1H), 5.20 (d, J = 16 Hz, 1H), 4.60 (bs, 1H) ), 4.45 (bs, 1H), 4.11 (bs, 1H), 3.95 (s, 6H), 3.80-3.83 (m, 1H), 3.70-3.73 (m, 1H), 3.67-3.68 (m, 1H), 1.97-2.03 (m, 1H), 1.80-1.84 (m, 1H).
实施例65：N-(4-((6-(2,6-二氯-3,5-二甲氧基苯基)咪唑咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)四氢呋喃-3-基)甲基丙烯酰胺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
Figure PCTCN2018112660-appb-000128
LC-MS:ESI[M+H] +＝543.1；H-NMR(400MHz,CDCl3)δ8.87(s,1H),8.27(s,1H),8.01(s,1H),7.59(s,1H),7.27(s,1H),6.94(bs,1H),6.69(s,1H),6.43(bs,1H),5.52-5.64(m,1H),4.92-5.00(m,2H),4.26-4.28(m,2H),3.97(s,6H),3.85(bs,1H),3.71(bs,1H),1.90(s,3H)。
Figure PCTCN2018112660-appb-000128
</RTI>< RTI ), 7.27 (s, 1H), 6.94 (bs, 1H), 6.69 (s, 1H), 6.43 (bs, 1H), 5.52-5.64 (m, 1H), 4.92-5.00 (m, 2H), 4.26- 4.28 (m, 2H), 3.97 (s, 6H), 3.85 (bs, 1H), 3.71 (bs, 1H), 1.90 (s, 3H).
实施例66：N-(2-((8-(环丙基)-6-(2,6-二氯-3,5-二甲氧基苯基)咪唑咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-氟苯基苯基氟苯基)丙烯酰胺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
Figure PCTCN2018112660-appb-000129
LC-MS:ESI[M+H] +＝593.2/595.2。
Figure PCTCN2018112660-appb-000129
LC-MS: ESI [M+H] + = 59.
实施例67：N-(2-((8-环戊基-6-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-苯基氟苯基)丙烯酰胺Example 67: N-(2-((8-Cyclopentyl-6-(2,6-dichloro-3,5-dimethoxyphenyl)imidazole [1', 2': 1,6] Pyridine [2,3-d]pyrimidin-2-yl)amino)-5-phenylfluorophenyl)acrylamide
Figure PCTCN2018112660-appb-000130
LC-MS:ESI[M+H] +＝621.2623.2。
Figure PCTCN2018112660-appb-000130
LC-MS: ESI [M+H] + = 621.262.
实施例68：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-((二甲基氨基)甲基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-苯基氟苯基)丙烯酰胺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
Figure PCTCN2018112660-appb-000131
LC-MS:ESI[M+H] +＝610.5/612.5。H-NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.25(s,1H),7.17(s,1H),6.89-6.92(m,1H),6.68(s,1H),6.28-6.35(m,3H), 5.96-6.02(m,1H),5.40-5.49(m,2H),4.52(s,2H),4.41(d,J＝14.4Hz,1H),3.98(s,6H),3.37(s,6H)。
Figure PCTCN2018112660-appb-000131
LC-MS: ESI [M+H] + = 61. </ RTI><RTIgt; -6.35(m,3H), 5.96-6.02(m,1H),5.40-5.49(m,2H),4.52(s,2H),4.41(d,J=14.4Hz,1H),3.98(s,6H ), 3.37 (s, 6H).
实施例69：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-((4-甲基甲基哌嗪-1-基)甲基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-苯基氟苯基)丙烯酰胺Example 69: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-((4-methylmethylpiperazin-1-yl)) Methyl)imidazole [1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-phenylfluorophenyl)acrylamide
Figure PCTCN2018112660-appb-000132
LC-MS:ESI[M+H] +＝665.2/667.2。
Figure PCTCN2018112660-appb-000132
LC-MS: ESI [M+H] + = 665.2 / 667.2.
实施例70：N-(2-((6-(2,6-二氟-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(4-甲基甲基哌嗪-1-基)苯基)丙烯酰胺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
Figure PCTCN2018112660-appb-000133
LC-MS:ESI[M+H] +＝615.4；H-NMR(400MHz,DMSO-d6)δ9.72(s,1H),9.16(s,1H),9.05(s,1H),7.87(s,1H),7.65(bs,1H),7.43(s,1H),7.28(s,1H),6.90(d,J＝7.2Hz,1H),6.46-6.50(m,1H),6.24(dd,J＝1.6,16.8Hz,1H),5.72(dd,J＝2.0,10.0Hz,1H),3.99(s,6H),3.29(t,J＝4.8Hz,4H),3.16(t,J＝4.8Hz,4H),2.27(s,3H),2.24(s,3H)。
Figure PCTCN2018112660-appb-000133
LC-MS: ESI [M+H] + = 615.4; H-NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.16 (s, 1H), 9.05 (s, 1H), 7.78 (s) , 1H), 7.65 (bs, 1H), 7.43 (s, 1H), 7.28 (s, 1H), 6.90 (d, J = 7.2 Hz, 1H), 6.46-6.50 (m, 1H), 6.24 (dd, J = 1.6, 16.8 Hz, 1H), 5.72 (dd, J = 2.0, 10.0 Hz, 1H), 3.99 (s, 6H), 3.29 (t, J = 4.8 Hz, 4H), 3.16 (t, J = 4.8) Hz, 4H), 2.27 (s, 3H), 2.24 (s, 3H).
实施例71：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(2-氧杂-7-氮杂螺[3.5]辛-7-基)苯基)丙烯酰胺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
Figure PCTCN2018112660-appb-000134
LC-MS:ESI[M+H] +＝674.3/676.3。
Figure PCTCN2018112660-appb-000134
LC-MS: ESI [M+H] + = 674.3 / 676.3.
实施例72：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(3-甲基-3,6-二氮杂双环[3.1.1]庚-6-基)苯基)甲基丙烯酰胺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
Figure PCTCN2018112660-appb-000135
LC-MS:ESI[M+H] +＝673.2/675.2。
Figure PCTCN2018112660-appb-000135
LC-MS: ESI [M+H] + = 673.2 / 675.2.
实施例73：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(六氢吡罗[1,2-a]吡嗪-2(1H)-基)苯基)丙烯酰胺Example 73: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-(hexahydropyrrolidin[1,2-a]pyrazine-2(1H)-yl)phenyl)acrylamide
Figure PCTCN2018112660-appb-000136
LC-MS:ESI[M+H] +＝673.4/675.4。
Figure PCTCN2018112660-appb-000136
LC-MS: ESI [M+H] + = 673.4 / 675.4.
实施例74：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(4-甲基甲基哌嗪-1-基)苯基)甲基丙烯酰胺Example 74: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-(4-methylmethylpiperazin-1-yl)phenyl)methacrylamide
Figure PCTCN2018112660-appb-000137
LC-MS:ESI[M+H] +＝660.2/662.2。H-NMR(400MHz,CDCl3)δ9.40(s,1H),9.12(d,J＝4.8Hz,1H),9.06(s,1H),7.88(s,1H),7.63-7.65(m,1H),7.44(s,1H),7.15(d,J＝2.8Hz,1H),7.05(s,1H),6.90-6.93(m,1H),5.78(s,1H),5.46(s,1H),3.98(s,6H),3.26-3.29(m,4H),3.13-3.17(m,4H),2.27(s,3H),2.21(s,3H),1.82(s,3H)
Figure PCTCN2018112660-appb-000137
LC-MS: ESI [M+H] + = 660.2 / 662.2. H-NMR (400MHz, CDCl3) δ 9.40 (s, 1H), 9.12 (d, J = 4.8 Hz, 1H), 9.06 (s, 1H), 7.88 (s, 1H), 7.63-7.65 (m, 1H) ), 7.44 (s, 1H), 7.15 (d, J = 2.8 Hz, 1H), 7.05 (s, 1H), 6.90-6.93 (m, 1H), 5.78 (s, 1H), 5.46 (s, 1H) , 3.98 (s, 6H), 3.26-3.29 (m, 4H), 3.13-3.17 (m, 4H), 2.27 (s, 3H), 2.21 (s, 3H), 1.82 (s, 3H)
实施例75：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(4-乙基哌嗪-1-基)苯基)丙烯酰胺Example 75: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)acrylamide
Figure PCTCN2018112660-appb-000138
LC-MS:ESI[M+H] +＝660.2/662.2；H-NMR(400MHz,CDCl3)δ8.70(s,1H),8.14(s,1H),7.96(s,1H),7.47(s,1H),7.22-7.25(m,2H),7.76(dd,J＝8.8,2.8Hz,1H),6.66(s,1H),6.48(s,1H),6.40(s,1H),6.36(s,1H),6.15-6.22(m,1H),5.71(d,J＝8.8Hz,1H),3.96(s,6H),3.35(t,J＝4.8Hz,4H),2.65(t,J＝4.8Hz,4H),2.51(q,J＝7.2Hz,2H),2.37(s,3H),1.16(t,J＝7.2Hz,3H)。
Figure PCTCN2018112660-appb-000138
LC-MS: ESI [M+H] + = 660.2 / 662.2; H-NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7. , 1H), 7.22-7.25 (m, 2H), 7.76 (dd, J = 8.8, 2.8 Hz, 1H), 6.66 (s, 1H), 6.48 (s, 1H), 6.40 (s, 1H), 6.36 ( s, 1H), 6.15-6.22 (m, 1H), 5.71 (d, J = 8.8 Hz, 1H), 3.96 (s, 6H), 3.35 (t, J = 4.8 Hz, 4H), 2.65 (t, J = 4.8 Hz, 4H), 2.51 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H).
实施例76：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-异丙基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-氟苯基)丙烯酰胺Example 76: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-isopropylimidazole [1', 2': 1,6] Pyridine [2,3-d]pyrimidin-2-yl)amino)-5-fluorophenyl)acrylamide
Figure PCTCN2018112660-appb-000139
LC-MS:ESI[M+H] +＝595.1/597.0；H-NMR(400MHz,DMSO-d6)δ9.75(d,J＝6.4Hz,1H),9.53(s,1H),9.09(s,1H),7.75-7.81(m,2H),7.66-7.69(m,1H),7.46(s,1H),7.06-7.12(m,2H),6.50(dd,J＝10.4,16.8Hz,1H),6.23(dd,J＝1.6,16.8Hz,1H),5.69(dd,J＝1.6,10.4Hz,1H),3.96(s,6H),2.89-2.93(m,1H),1.22(d,J＝4.8Hz,6H)。
Figure PCTCN2018112660-appb-000139
LC-MS: ESI [M+H] + = 495. </RTI>< / RTI>< / RTI>< / RTI>< / RTI>< / RTI>< / RTI>< / RTI>< / RTI>< / RTI>< / RTI><RTIgt; , 1H), 7.75-7.81 (m, 2H), 7.66-7.69 (m, 1H), 7.46 (s, 1H), 7.06-7.12 (m, 2H), 6.50 (dd, J = 10.4, 16.8 Hz, 1H ), 6.23 (dd, J = 1.6, 16.8 Hz, 1H), 5.69 (dd, J = 1.6, 10.4 Hz, 1H), 3.96 (s, 6H), 2.89-2.93 (m, 1H), 1.22 (d, J = 4.8 Hz, 6H).
实施例77：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-异丙基咪唑[1',2':1,6]吡啶[2,3-d] 嘧啶-2-基)氨基)-5-(4-甲基哌嗪-1-基)苯基)丙烯酰胺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
Figure PCTCN2018112660-appb-000140
LC-MS:ESI[M+H] +＝675.2/677.2。H-NMR(400MHz,DMSO-d6)δ9.68(s,1H),9.19(s,1H),9.04(s,1H),7.82(s,1H),7.56(s,1H),7.42(s,1H),7.29(s,1H),7.05(s,1H),6.88(dd,J＝2.4,8.8Hz,1H),6.44-6.51(m,1H),6.23(dd,J＝2.4,16.8Hz,1H),6.69(dd,J＝1.6,10.4Hz,1H),3.99(s,6H),3.26-3.29(m,4H),3.14-3.17(m,4H),2.89-2.93(m,1H),2.24(s,3H),1.21(t,J＝6.8Hz,6H)。
Figure PCTCN2018112660-appb-000140
LC-MS: ESI [M+H] + = 675.2 / 677.2. H-NMR (400MHz, DMSO-d6) δ 9.68 (s, 1H), 9.19 (s, 1H), 9.04 (s, 1H), 7.82 (s, 1H), 7.56 (s, 1H), 7.42 (s) , 1H), 7.29 (s, 1H), 7.05 (s, 1H), 6.88 (dd, J = 2.4, 8.8 Hz, 1H), 6.44 - 6.51 (m, 1H), 6.23 (dd, J = 2.4, 16.8 Hz, 1H), 6.69 (dd, J = 1.6, 10.4 Hz, 1H), 3.99 (s, 6H), 3.26-3.29 (m, 4H), 3.14 - 3.17 (m, 4H), 2.89 - 2.93 (m, 1H), 2.24 (s, 3H), 1.21 (t, J = 6.8 Hz, 6H).
实施例78：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-异丙基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(4-甲基哌嗪-1-基)苯基)甲基丙烯酰胺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
Figure PCTCN2018112660-appb-000141
LC-MS:ESI[M+H] +＝689.2/691.2。
Figure PCTCN2018112660-appb-000141
LC-MS: ESI [M+H] + = 68.
实施例79：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1,2-a][1,6]萘啶-8-基)氨基)-5-(4-甲基哌嗪-1-基)苯基)甲基丙烯酰胺Example 79: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)imidazo[1,2-a][1,6]naphthyridin-8- Amino)-5-(4-methylpiperazin-1-yl)phenyl)methacrylamide
Figure PCTCN2018112660-appb-000142
LC-MS:ESI[M+H] +＝646.1/648.1。
Figure PCTCN2018112660-appb-000142
LC-MS: ESI [M+H] + =646.
实施例80：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1,2-a][1,6]萘啶-8-基)氨基氨基)-5-(4-甲基哌嗪-1-基)苯基)-2-丙烯酰胺氟丙烯酰胺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
Figure PCTCN2018112660-appb-000143
LC-MS:ESI[M+H] +＝650.1/652.1。
Figure PCTCN2018112660-appb-000143
LC-MS: ESI [M+H] + = 65. / 6521.
实施例81：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-异丙基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(哌嗪-1-基)苯基)丙烯酰胺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
Figure PCTCN2018112660-appb-000144
LC-MS:ESI[M+H] +＝661.4/663.4。
Figure PCTCN2018112660-appb-000144
LC-MS: ESI [M+H] + = 661.4 / 663.4.
实施例82：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(哌嗪-1-基)苯基)丙烯酰胺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
Figure PCTCN2018112660-appb-000145
LC-MS:ESI[M+H] +＝633.2/635.2。
Figure PCTCN2018112660-appb-000145
LC-MS: ESI [M+H] + = 633.2 / 635.2.
实施例83：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-异丙基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(1-甲基哌嗪-4-基)苯基)丙烯酰胺Example 83: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-isopropylimidazole [1', 2': 1,6] Pyridine [2,3-d]pyrimidin-2-yl)amino)-5-(1-methylpiperazin-4-yl)phenyl)acrylamide
Figure PCTCN2018112660-appb-000146
LC-MS:ESI[M+H] +＝674.5/676.4。
Figure PCTCN2018112660-appb-000146
LC-MS: ESI [M+H] + = 674.5 / 676.4.
实施例84：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(1-甲基哌嗪-4-基)苯基)丙烯酰胺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
Figure PCTCN2018112660-appb-000147
LC-MS:ESI[M+H] +＝646.2/648.1。
Figure PCTCN2018112660-appb-000147
LC-MS: ESI [M+H] + = 646.2 / 648.1.
实施例85：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-((二甲基氨基)甲基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(1-甲基哌嗪-4-基)苯基)丙烯酰胺Example 85: 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-(1-methylpiperazin-4-yl)phenyl)acrylamide
Figure PCTCN2018112660-appb-000148
采用实施例68相同的方法制备，得到实施例85，LC-MS:ESI[M+H] +＝689.1/691.1。
Figure PCTCN2018112660-appb-000148
Prepared in the same manner as Example 68 to give Example 85, LC-MS: ESI [M+H] + = 689.1/691.1.
实施例86：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-((二甲基氨基)甲基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-3-氟苯基)丙烯酰胺Example 86: 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)-3-fluorophenyl)acrylamide
Figure PCTCN2018112660-appb-000149
LC-MS:ESI[M+H] +＝610.1/612.1。
Figure PCTCN2018112660-appb-000149
LC-MS: ESI [M+H] + = 61. / 6121.
实施例87：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-(甲氧甲基)咪唑[1',2':1,6]吡啶 [2,3-d]嘧啶-2-基)氨基)-5-氟苯基)丙烯酰胺Example 87: 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-fluorophenyl)acrylamide
Figure PCTCN2018112660-appb-000150
LC-MS:ESI[M+H] +＝597.4/599.4。
Figure PCTCN2018112660-appb-000150
LC-MS: ESI [M+H] + = 597.4 / 599.4.
实施例88：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-(甲氧甲基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-(4-异丙基哌嗪-1-基)苯基)丙烯酰胺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
Figure PCTCN2018112660-appb-000151
LC-MS:ESI[M+H] +＝705.2/707.2。
Figure PCTCN2018112660-appb-000151
LC-MS: ESI [M+H] + = 705.2 / 707.2.
实施例89：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-((二甲基氨基)甲基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-甲氧基苯基)丙烯酰胺Example 89: 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-methoxyphenyl)acrylamide
Figure PCTCN2018112660-appb-000152
LC-MS:ESI[M+H] +＝622.3/624.3。
Figure PCTCN2018112660-appb-000152
LC-MS: ESI [M+H] + = 622.3 / 624.3.
实施例90：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯基)-2-甲基咪唑[1,2-a][1,6]萘啶-8-基)氨基)-5-(4-乙基哌嗪-1-基)苯基)甲基丙烯酰胺Example 90: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-methylimidazo[1,2-a][1,6] Naphthyridine-8-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)methacrylamide
Figure PCTCN2018112660-appb-000153
LC-MS:ESI[M+H] +＝674.1/676.1。
Figure PCTCN2018112660-appb-000153
LC-MS: ESI [M+H] + =674.
实施例91：N-(2-((4-(2,6-二氯-3,5-二甲氧基苯基)-2-甲基咪唑[1,2-a][1,6]萘啶-8-基)氨基)-5-(4-乙基哌嗪-1-基)苯基)-2-氟丙烯酰胺Example 91: N-(2-((4-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-methylimidazo[1,2-a][1,6] Naphthyridine-8-yl)amino)-5-(4-ethylpiperazin-1-yl)phenyl)-2-fluoroacrylamide
Figure PCTCN2018112660-appb-000154
LC-MS:ESI[M+H] +＝678.2/680.2。
Figure PCTCN2018112660-appb-000154
LC-MS: ESI [M+H] + = 678.2 / 680.2.
实施例92：(E)-N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-氟苯基)-4-(二甲基氨基)丁-2-烯酰胺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
Figure PCTCN2018112660-appb-000155
LC-MS:ESI[M+H] +＝624.2/626.2。
Figure PCTCN2018112660-appb-000155
LC-MS: ESI [M+H] + = 624.2 / 626.2.
实施例93：N-(2-((6-(2,6-二氯-3,5-二甲氧基苯基)-8-((1-甲基哌啶-4-基)甲基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)-5-氟苯基)丙烯酰胺Example 93: N-(2-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-((1-methylpiperidin-4-yl)methyl) Imidazole [1',2':1,6]pyridine [2,3-d]pyrimidin-2-yl)amino)-5-fluorophenyl)acrylamide
Figure PCTCN2018112660-appb-000156
LC-MS:ESI[M+H] +＝664.3/666.2。
Figure PCTCN2018112660-appb-000156
LC-MS: ESI [M+H] + = 664.3 / 666.2.
测试例1本发明化合物对FGFR1和FGFR4激酶抑制活性的测定Test Example 1 Determination of Inhibitory Activity of FGFR1 and FGFR4 Kinases by the Compounds of the Invention
(1)配制1×Kinase buffer；(2)化合物浓度梯度的配制：受试化合物测试浓度为10μM起始,3倍稀释10个浓度，复孔测试，在96孔板中梯度稀释成100倍终浓度的10个不同浓度的溶液。然后用1×Kinase buffer将各浓度的化合物进一步稀释成5倍终浓度的中间稀释溶液；(3)将配制好的化合物溶液各取5μL分别加入384孔板的化合物孔，每个浓度单孔测试；阴性对照孔和阳性对照孔中分别加5μL的5％DMSO；(4)用1×Kinase buffer配制2.5倍终浓度的激酶溶液；(5)在化合物孔和阳性对照孔分别加10μL的2.5倍终浓度的激酶溶液；在阴性对照孔中加10μL的1×Kinase buffer；(6)1000rpm离心30秒，振荡混匀后室温孵育10分钟；(7)用1×Kinase buffer配制2.5倍终浓度的ATP和Kinase substrate22的混合溶液；(8)加入10μL的2.5倍终浓度的ATP和底物的混合溶液，起始反应；(9)将384孔板1000rpm离心30秒，振荡混匀后28℃分别孵育相应的时间；(10)加入30μL终止检测液停止激酶反应，1000rpm离心30秒，振荡混匀；(11)用Caliper EZ ReaderⅡ读取转化率，以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC 50值。 (1) Preparation of 1×Kinase buffer; (2) Preparation of compound concentration gradient: test compound concentration starting at 10 μM, dilution of 3 times at 10 concentrations, double-well test, gradient dilution into 100-fold in 96-well plate Concentration of 10 different concentrations of solution. Then, each concentration of the compound was further diluted to a 5-fold final concentration of the intermediate dilution solution by using 1×Kinase buffer; (3) 5 μL of each of the prepared compound solutions was separately added to the compound holes of the 384-well plate, and each concentration was tested for single hole. 5 μL of 5% DMSO was added to the negative control well and the positive control well; (4) 2.5 times the final concentration of the kinase solution was prepared with 1×Kinase buffer; (5) 2.5 times of 10 μL of the compound well and the positive control well were added respectively. Final concentration of kinase solution; add 10 μL of 1×Kinase buffer to the negative control well; (6) centrifuge at 1000 rpm for 30 seconds, mix by shaking and incubate for 10 minutes at room temperature; (7) Prepare 2.5 times final concentration with 1×Kinase buffer a mixed solution of ATP and Kinase substrate 22; (8) adding 10 μL of a 2.5-fold final concentration of ATP and a mixed solution of the substrate to initiate the reaction; (9) centrifuging the 384-well plate at 1000 rpm for 30 seconds, shaking and mixing, respectively, at 28 ° C Incubate for the corresponding time; (10) Add 30 μL of the stop solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and shake to mix; (11) Read the conversion rate with Caliper EZ Reader II, using the log value of the concentration as the X-axis, percent inhibition For the Y axis, use the analysis software G raphPad Prism 5 of the log (inhibitor) vs.response-Variable slope fitting dose-response curve to arrive at individual compounds activity IC 50 value pairs.
2.结果：本发明提供的实施例1-实施例93，显示了较高的FGFR1或FGFR4的抑制活性，大部分实施例化合物对FGFR1的IC 50值小于10nM，有的甚至小于1nM，如实 施例4、实施例8、实施例27、实施例30、实施例38、实施例70、实施例75等；大部分实施例对FGFR4的抑制活性IC 50小于10nM，显示了较强的酶抑制活性。具体活性结果如下表所示： 2. Results: 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. Example 4, Example 8, Example 27, Example 30, Example 38, Example 70, Example 75, etc.; most of the examples have an inhibitory activity on FGFR4 with an IC 50 of less than 10 nM, showing strong enzyme inhibitory activity. . The specific activity results are shown in the following table:
表1实施例化合物对FGFR1/FGFR 4的激酶抑制活性Table 1. Kinase inhibitory activity of the compound of the example on FGFR1/FGFR 4
Figure PCTCN2018112660-appb-000157
Figure PCTCN2018112660-appb-000157
Figure PCTCN2018112660-appb-000158
Figure PCTCN2018112660-appb-000158
Figure PCTCN2018112660-appb-000159
Figure PCTCN2018112660-appb-000159
表1中，IC 50<10nM用“++++”表示；10nM<IC 50<100nM用“+++”表示；100<IC 50<500nM用“++”表示；IC50>500nM用“+”表示。 In Table 1, 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.
进一步测试结果表明，本发明实施例较对比化合物显示了更佳的FGFR激酶抑制活性或者FGFR激酶的亚型选择性，具体结果如下表2、表3所示：Further test results showed that the examples of the present invention showed better FGFR kinase inhibitory activity or subtype selectivity of FGFR kinase than the comparative compounds, and the specific results are shown in Table 2 and Table 3 below:
表2部分实施例化合物的激酶抑制活性比较Table 2 Comparison of Kinase Inhibitory Activity of Some Example Compounds
Figure PCTCN2018112660-appb-000160
Figure PCTCN2018112660-appb-000160
Figure PCTCN2018112660-appb-000161
Figure PCTCN2018112660-appb-000161
由表2可以看出，与对比化合物相比，本发明实施例化合物对FGFR1或FGFR4的激酶活性具有显著的提高(约4-100倍)，如实施例4的FGFR1活性提高了将近100倍。As can be seen from Table 2, 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.
表3部分实施例化合物对FGFR1/FGFR4激酶选择性比较Table 3 Comparison of the selectivity of some example compounds to FGFR1/FGFR4 kinase
Figure PCTCN2018112660-appb-000162
Figure PCTCN2018112660-appb-000162
由表3可以看出，通过实施例44化合物与表中对比化合物5比较，以及实施例13化合物与表中对比化合物6比较，发现本发明化合物对于FGFR1具有较高的抑制活性(FGFR1抑制活性IC 50小于30nM)，同时显示了FGFR1/FGFR4之间更高的亚型选择性(FGFR4/FGFR1的激酶选择性至少提高了一个数量级)。 As can be seen from Table 3, 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).
测试例2：本发明化合物对FGFR介导的肿瘤细胞增殖能力的影响试验Test Example 2: Effect of the compound of the present invention on FGFR-mediated tumor cell proliferation ability
1、试验方法：取处于对数生长期的Hep3B细胞(ATCC)按合适密度接种至96孔培养板中，每孔90μL，培养过夜后，加入不同浓度的化合物作用72hr，并设定溶剂对照组(阴性对照)。待化合物作用细胞72h后，化合物对细胞增殖的影响采用CCK-8细胞计数试剂盒(Dojindo)检测，每孔加入10μL CCK-8试剂，置于37℃培养箱中放置2-4小时 后，用全波长式微孔板酶标仪SpectraMax 190读数，测定波长为450nm。采用以下公式计算化合物对肿瘤细胞生长的抑制率(％):抑制率(％)＝(OD阴性对照孔-OD给药孔)/OD阴性对照孔×100％。IC 50值采用酶标仪随机附带软件以四参数法回归求得。 1. Test method: Hep3B cells (ATCC) in logarithmic growth phase were inoculated into 96-well culture plates at a suitable density, 90 μL 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 μL 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. The inhibition rate (%) of the compound on tumor cell growth was calculated by the following formula: 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.
2、结果:本发明提供的部分实施例1-实施例93，对Hep3B细胞的增值抑制活性显示了较强的活性，绝大部分化合物的IC 50值小于500nM，部分实施例化合物如实施例4、实施例8、实施例9、实施例20、实施例24、实施例27、实施例30、实施例32、实施例38、实施例39、实施例45、实施例49、实施例61、实施例63、实施例70、实施例75、实施例84等抑制活性IC 50值甚至小于20nM。 2. Results: 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.
测试例3：实施例化合物不不同激酶抑制活性的测试Test Example 3: Test of Example Compounds Not Different in Kinase Inhibitory Activity
本发明化合物对不同激酶如EGFR、VEGFR、PDGFR、FGFR、RET，MET，Src，Lyn、Syk、MEK、CDK、RAF、ROS等的抑制活性也进行了测试，部分实施例化合物如实施例4、实施例8、实施例9、实施例20、实施例24、实施例27、实施例30、实施例32、实施例38、实施例39、实施例45、实施例49、实施例61、实施例63、实施例70、实施例75、实施例84等显示了较好的激酶选择性，选择性大于100倍。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 8, Example 9, Example 20, Example 24, Example 27, Example 30, Example 32, Example 38, Example 39, Example 45, Example 49, Example 61, Example 63. Example 70, Example 75, Example 84, etc., showed better kinase selectivity with a selectivity greater than 100-fold.
测试例4：实施例化合物对不同肿瘤细胞的增殖抑制活性测试Test Example 4: Proliferation inhibitory activity test of the compound of the example on different tumor cells
采用SRB染色法或CCK8法，测试多种肿瘤细胞，如HuH-7、JHH-7、DMS114、SNU-16、KG1、UM-UC-14、HCT116、NCI-H716、MCF-7、Colo-205、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、KYSE140、HUCC-T1、PANC-1等的增殖抑制活性，部分实施例化合物如实施例4、实施例8、实施例9、实施例24、实施例27、实施例30、实施例32、实施例38、实施例39、实施例45、实施例49、实施例61、实施例63、实施例70、实施例75、实施例84等对不同细胞的增值抑制显示了较强的抑制活性，显示了较好的抗肿瘤活性，对多种肿瘤细胞特别是肝癌、胆管癌、胃癌、膀胱癌等的增殖抑制活性均小于500nM。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.
测试例5：实施例化合物在大鼠、小鼠的体内药代动力学参数测试Test Example 5: In vivo pharmacokinetic parameter test of the compound of the example in rats and mice
1、6只雄性SPF级SD大鼠(上海西普尔-必凯实验动物)分成两组，受试化合物配置成合适溶液或混悬液；一组静脉注射给药，一组口服给药。经颈静脉穿刺采血，每个样品 采集约0.2mL/时间点，肝素钠抗凝，采血时间点如下：给药前及给药后5、15和30min，1、2、4、6、8和24h；血液样本采集后置于冰上，离心分离血浆(离心条件：8000转/分钟，6分钟，2-8℃)，收集的血浆分析前存放于-80℃。血浆样品采用LC-MS/MS进行分析。1, 6 male SPF grade SD rats (Shanghai Shipu-Beikai experimental animals) were divided into two groups, and the test compound was configured into a suitable solution or suspension; one group was administered intravenously, and one group was administered orally. Blood was collected by jugular vein puncture, and each sample was collected at about 0.2 mL/time. Heparin sodium was anticoagulated. The time of blood collection was as follows: before, and after 5, 15 and 30 min, 1, 2, 4, 6, and 8 after administration. 24 h; blood samples were collected and placed on ice, and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ° C), and the collected plasma was stored at -80 ° C before analysis. Plasma samples were analyzed by LC-MS/MS.
根据药物的血药浓度数据，使用药代动力学计算软件WinNonlin5.2非房室模型分别计算供试品的药代动力学参数AUC 0-t、AUC 0-∞、MRT 0-∞、C max、T max、T 1/2和Vd等参数及其平均值和标准差。此外，生物利用度(F)将通过下面的公式进行计算。 According to the blood concentration data of the drug, 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. In addition, the bioavailability (F) will be calculated by the following formula.
Figure PCTCN2018112660-appb-000163
Figure PCTCN2018112660-appb-000163
对于浓度低于定量下限的样品，在进行药代动力学参数计算时，在达到Cmax以前取样的样品应以零值计算，在达到Cmax以后取样点样品应以无法定量(BLQ)计算。For samples with concentrations below the lower limit of quantitation, 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.
2、本专利部分实施例化合物如实施例2，实施例4，实施例8，实施例24，实施例31，实施例36，实施例45，实施例57，实施例63，实施例75，实施例83等显示了较好的大鼠、小鼠的体内吸收和代谢性质，并且AUC/Cmax等指标均显示了化合物优良的药代性质。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.
测试例6：实施例化合物的ADME测试Test Example 6: ADME test of example compounds
(1)代谢稳定性试验：用体系为150μL的肝微粒体(终浓度0.5mg/mL)进行代谢稳定性温孵，体系含NADPH(终浓度1mM)、1μM受试化合物和阳性对照咪达***或阴性对照阿替洛尔，分别在0min、5min、10min和30min用含替硝唑的乙腈终止反应，涡旋10min，15000rmp离心10min，取50μL上清于96孔板中进样。通过测定原药的相对减少量计算化合物代谢稳定性。(1) Metabolic stability test: 150 μL of liver microsomes (final concentration 0.5 mg/mL) were used for metabolic stability incubation. The system contained NADPH (final concentration 1 mM), 1 μM 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 μL 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.
(2)直接抑制试验(DI试验)：用体系为100μL的人肝微粒体(终浓度0.2mg/mL)进行直接抑制温孵，体系含NADPH(终浓度1mM)、10μM化合物、阳性抑制剂cocktail(酮康唑10μM，奎尼丁10μM，磺胺苯吡唑100μM，α-萘黄酮10μM，反苯环丙胺1000μM)、阴性对照(0.1％DMSO的BPS)和混合探针底物(咪达***10μM、睾酮100μM、右美沙芬10μM、双氯芬酸20μM、非那西丁100μM，美芬妥英100μM)，温孵20min后终止反应。通过测定代谢物的相对生成量计算酶相对活性。(2) Direct inhibition test (DI test): direct inhibition of incubation with 100 μL of human liver microsomes (final concentration 0.2 mg/mL) containing NADPH (final concentration 1 mM), 10 μM compound, positive inhibitor cocktail (ketoconazole 10 μM, quinidine 10 μM, sulfaphenazole 100 μM, α-naphthoflavone 10 μM, tranylcypromine 1000 μM), negative control (0.1% DMSO in BPS) and mixed probe substrate (midazolam) 10 μM, testosterone 100 μM, dextromethorphan 10 μM, diclofenac 20 μM, phenacetin 100 μM, mefenexine 100 μM), 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.
本发明部分实施例化合物如实施例4、实施例8、实施例9、实施例24、实施例27、实施例30、实施例32、实施例38实施例45、实施例49、实施例61、实施例63、实施例70、实施例75、实施例84等显示了较好的ADME性质，具有较好的微粒体稳定性和代谢酶抑制活性，对主要代谢酶如CYP1A2，CYP2C8，CYP3A4，CYP2D6，CYP2C9 等抑制的IC 50均大于15uM。 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.
测试例7：实施例化合物对裸小鼠移植瘤生长抑制的测试Test Example 7: Test of inhibition of growth inhibition of nude mice by the compound of the example
1、取生长旺盛期的瘤组织剪切成1.5mm 3左右，在无菌条件下，接种于裸小鼠右侧腋窝皮下。裸小鼠皮下移植瘤用游标卡尺测量移植瘤直径，待肿瘤平均体积至130mm 3左右将动物随机分组。实施例化合物(用含1％Tween80的注射用水配置到所需浓度后待用)以给定剂量每天口服给药，连续给药三周，溶剂对照组给等量溶剂。整个实验过程中，每周2次测量移植瘤直径，同时称量小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为：TV＝1/2×a×b 2，其中a、b分别表示长、宽。根据测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为：RTV＝Vt/V0。其中V0为分笼给药时(即d0)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标为1)相对肿瘤增殖率T/C(％)，计算公式如下：T/C(％)＝(TRTV/CRTV)×100％，TRTV：治疗组RTV；CRTV：阴性对照组RTV；2)肿瘤体积增长抑制率GI％，计算公式如下：GI％＝[1-(TVt-TV0)/(CVt-CT0)]×100％，TVt为治疗组每次测量的瘤体积；TV0为治疗组分笼给药时所得瘤体积；CVt为对照组每次测量的瘤体积；CV0为对照组分笼给药时所得瘤体积；3)瘤重抑制率，计算公式如下：瘤重抑制率％＝(Wc-WT)/Wc×100％，Wc：对照组瘤重，WT：治疗组瘤重。 1. 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) was orally administered at a given dose per day for three weeks, and the solvent control group was given an equal amount of solvent. The diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed. The formula for calculating tumor volume (TV) is: TV = 1/2 × a × b 2 , where a and b represent length and width, respectively. The relative tumor volume (RTV) was calculated based on the measured results, and the calculation formula was: RTV=Vt/V0. Where V0 is the measured tumor volume at the time of sub-cage administration (ie, d0), and Vt is the tumor volume at each measurement. The evaluation index of antitumor activity is 1) relative tumor proliferation rate T/C (%), and the formula is as follows: T/C (%) = (TRTV/CRTV) × 100%, TRTV: treatment group RTV; CRTV: negative control Group RTV; 2) tumor volume growth inhibition rate GI%, calculated as follows: GI% = [1-(TVt-TV0) / (CVt-CT0)] × 100%, TVt is the tumor volume measured by the treatment group each time; TV0 is the tumor volume obtained when the therapeutic component is administered; CVt is the tumor volume measured in the control group; CV0 is the tumor volume obtained when the cage is administered in the control group; 3) the tumor weight inhibition rate is calculated as follows: Inhibition rate%=(Wc-WT)/Wc×100%, Wc: control tumor weight, WT: tumor weight of treatment group.
2、部分实施例化合物如实施例4，实施例8，实施例37，实施例38，实施例45，实施例76，实施例77，实施例84等对于裸鼠移植瘤显示了较好的抑制作用，在较低的给药剂量下即显示了较高的抑瘤率，甚至在小于20mg/kg给药剂量下抑瘤率高达80％以上。2. 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.
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。While the invention has been described with respect to the preferred embodiments of the embodiments of the embodiments of the invention modify. Accordingly, the scope of the invention is defined by the appended claims.

Claims (9)

  1. 一种如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph thereof or Prodrug,
    Figure PCTCN2018112660-appb-100001
    Figure PCTCN2018112660-appb-100001
    式中，In the formula,
    R 1、R 2、R 3和R 4各自独立地选自氢、卤素、C 1-C 6烷基、3-8元环烷基、3-8元杂环烷基、C 1-C 6烷氧基、3-8元杂环烷氧基或氨基； 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;
    R 5选自氢、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基、氨基或羟基； 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选自CR a或N；其中，R a选自氢、卤素、C 1-C 6烷基、或C 1-C 6烷氧基； 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选自3-8元环烷基或3-8元杂环烷基、6-10元芳基或5-10元杂芳基；Cy is selected from a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group;
    R 6选自氢、卤素、氰基、氨基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6氘代烷基、C 1-C 6卤代烷基、N(R e)(R f)-(CH 2) y-、O(R g)-C 1-C 6亚烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷基-C(＝O)-C 1-C 6亚烷基、C 1-C 6烷基-S(＝O) 2-C 1-C 6亚烷基、6-10元芳基-(CH 2) z-、5-10元杂芳基-(CH 2) o-、3-8元环烷基-(CH 2) m-、或3-8元杂环烷基-(CH 2) n-；其中，R e、R f和R g各自独立地选自氢、C 1-C 6烷基或四氢吡咯烷基，y选自0-5中的任一整数；所述四氢吡咯烷基被一个或多个取代基取代，所述的取代基选自氢、C 1-C 6烷基、丙烯酰基或氟代丙烯酰基；或者，R e、R f与其所连氮原子共同构成一个四氢吡咯环或哌嗪环或哌啶环，所述四氢吡咯环或哌嗪环或哌啶环被一个或多个取代基取代，所述的取代基选自氢、C 1-C 6烷基、丙烯酰基或卤代丙烯酰基；所述的6-10元芳基、5-10元杂芳基、3-8元环烷基、和3-8元杂环烷基或各自独立地被选自氢、C 1-C 6烷基、丙烯酰基和丙烯酰胺基中的一个或多个取代基所取代；z、o、m、n各自独立地选自0-5中的任一整数； R 6 is selected from hydrogen, halo, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, N ( R e )(R f )-(CH 2 ) y -, O(R g )-C 1 -C 6 alkylene, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6- alkyl-C(=O)-C 1 -C 6 alkylene, C 1 -C 6 alkyl-S(=O) 2 -C 1 -C 6 alkylene, 6-10 membered aryl- (CH 2 ) z -, 5-10 membered heteroaryl-(CH 2 ) o -, 3-8 membered cycloalkyl-(CH 2 ) m -, or 3-8 membered heterocycloalkyl-(CH 2 ) n -; wherein R e , R f and R g are each independently selected from hydrogen, C 1 -C 6 alkyl or tetrahydropyrrolidinyl, and y is selected from any integer from 0 to 5; The hydropyrrolidinyl group is substituted by one or more substituents selected from hydrogen, C 1 -C 6 alkyl, acryloyl or fluoroacryloyl; or R e , R f and the nitrogen atom to which it is attached Co-constituting a tetrahydropyrrole ring or a piperazine ring or a piperidine ring, which is substituted with one or more substituents selected from hydrogen, C 1 -C 6 alkyl group, an acryloyl group or a halogenated acryloyl group; a 6-10 membered aryl, 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, an acryloyl group, and acrylamide group one or more substituents ; z, o, m, n are each independently selected from any of 0-5;
    R 8选自氢、卤素、氰基、硝基、C 1-C 6烷基、C 1-C 6烷基-SO 2-、C 1-C 6烷基-SO-、或C 1-C 6卤代烷基； 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;
    且，R 6和R 8不同时为氢； And R 6 and R 8 are not hydrogen at the same time;
    R 7选自氢、卤素、氰基、氰基乙基、2,3-二羟基丙基、O(R h)-C 1-C 6烷基、 N(R i)(R j)-(CH 2) p-、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷基-SO 2-、C 1-C 6烷基-SO-、6-10元芳基、5-10元杂芳基、3-8元环烷基、或3-8元杂环烷基；其中，R h、R i和R j各自独立地选自氢、C 1-C 6烷基、或二甲胺基乙基，p选自0-5中的任一整数；或者，R i和R j共同构成一个5-7元含氮杂环烷基；所述的C 1-C 6烷基、C 1-C 6烷氧基、6-10元芳基、5-10元杂芳基、3-8元环烷基、和3-8元杂环烷基各自独立地被氢、C 1-C 6烷基、氰基-C 1-C 6烷基、C 1-C 6烷氧基-C 1-C 6烷基、吡唑基-C 1-C 6烷基、四氢吡咯基、***啉基、哌嗪基、哌啶基、高哌嗪基、二甲胺基乙基、氧杂环丁基和二甲胺基中的一个或多个取代基所取代； 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 i and R j together constitute one 5-7 membered nitrogen-containing heterocycloalkyl; said C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, 6-10 membered aryl group, 5-10 membered heteroaryl group, 3-8 member The cycloalkyl group and the 3-8 membered heterocycloalkyl group are each independently hydrogen, C 1 -C 6 alkyl, cyano-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 - C 6 alkyl, pyrazolyl-C 1 -C 6 alkyl, tetrahydropyrrolyl, morphinolinyl, piperazinyl, piperidinyl, homopiperazinyl, dimethylaminoethyl, oxetane Substituted with one or more substituents in the dimethylamino group;
    R 9和R 10各自独立地选自氢、卤素、氰基、硝基、C 1-C 6烷基、C 1-C 6烷基-SO 2-、C 1-C 6烷基-SO-、N(R c)(R d)-(CH 2)x-；或者，R 9和R 10共同构成一个5-7元的被C 1-C 6烷基取代的含氮杂环烷基；其中，R c和R d各自独立地选自氢或C 1-C 6烷基，x选自0-5中的任一整数； 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;
    上述定义中所述的各个环系各自独立地为单环、并环、稠环、桥环或螺环；所述的杂芳基或被部分氧化和/或还原；所述的杂芳基包含1-3个选自下组的杂原子：N、O、P和S，所述的杂环烷基包含1-3个选自下组的杂原子：N、O、P和S。Each of the ring systems described in the above definitions are each independently a monocyclic ring, a fused ring, a bridged ring or a spiro ring; the heteroaryl group is either partially oxidized and/or reduced; the heteroaryl group comprises 1-3 heteroatoms selected from the group consisting of N, O, P and S, said heterocycloalkyl comprising 1-3 heteroatoms selected from the group consisting of N, O, P and S.
  2. 如权利要求1所述的如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于，A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, according to claim 1 a polymorph or prodrug characterized by
    式中，In the formula,
    R 1、R 2、R 3和R 4各自独立地选自氢、卤素、3-8元环烷基、C 1-C 6烷基或C 1-C 6烷氧基；其中，R 1和R 2各自独立地优选选自氢或卤素，进一步各自独立地优选选自氟或氯；R 3和R 4各自独立地优选选自卤素、3-8元环烷基或C 1-C 6烷氧基，进一步各自独立地优选选自氟、氯、甲氧基或环丙基； R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, 3-8 membered cycloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; wherein R 1 and R 2 are each independently preferably selected from hydrogen or halogen, further each independently preferably selected from fluorine or chlorine; R 3 and R 4 are each independently preferably selected from halogen, 3-8 membered cycloalkyl or C 1 -C 6 alkane. The oxy group, further independently independently selected from the group consisting of fluorine, chlorine, methoxy or cyclopropyl;
    和/或，R 5选自氢、卤素或C 1-C 6烷基；优选选自氢、氟或甲基； And/or R 5 is selected from hydrogen, halogen or C 1 -C 6 alkyl; preferably selected from hydrogen, fluoro or methyl;
    和/或，M选自CH或N；And/or, M is selected from CH or N;
    和/或，Cy选自5-6元环烷基、5-6元杂环烷基、6元芳基或5-8元杂芳基，优选选自4-6元的环烷基或4-6元杂环烷基、6元芳基或5-8元杂芳基；进一步优选选自四氢呋喃环、四氢吡喃环、四氢吡咯环、哌啶环、苯环、吡啶环、吡唑环、2,3-二氢苯并呋喃环、2,3-二氢吲哚环或四氢噻吩环；Cy或被进一步氧化，所述的氧化发生在环上杂原子；且Cy与母核上其他结构片段的连接位点为邻位关系；And/or Cy is selected from a 5-6 membered cycloalkyl group, a 5-6 membered heterocycloalkyl group, a 6 membered aryl group or a 5-8 membered heteroaryl group, preferably selected from a 4-6 membered cycloalkyl group or 4 a 6-membered heterocycloalkyl group, a 6-membered aryl group or a 5-8 membered heteroaryl group; further 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, and a pyridyl group. An azole ring, a 2,3-dihydrobenzofuran ring, a 2,3-dihydroanthracene ring or a tetrahydrothiophene ring; Cy is further oxidized, said oxidation occurring on a ring heteroatom; and Cy and a mother The attachment sites of other structural fragments on the nucleus are in an orthotopic relationship;
    和/或，R 6选自氢、卤素、C 1-C 6烷基、C 1-C 6氘代烷基、C 1-C 6卤代烷基、 N(R e)(R f)-(CH 2) y-、O(R g)-C 1-C 6亚烷基、C 1-C 6烷基-S(＝O) 2-C 1-C 6亚烷基、6-10元芳基-(CH 2) z-、5-10元杂芳基-(CH 2) o-、3-8元环烷基-(CH 2) m-、或3-8元杂环烷基-(CH 2) n-；其中，R e、R f和R g各自独立地选自氢、C 1-C 6烷基或四氢吡咯烷基，y选自0-5中的任一整数；所述四氢吡咯烷基被一个或多个取代基取代，所述的取代基选自氢、C 1-C 6烷基、丙烯酰基或氟代丙烯酰基；或者，R e、R f与其所连氮原子共同构成一个四氢吡咯环或哌嗪环，所述四氢吡咯环或哌嗪环被一个或多个取代基取代，所述的取代基选自氢、C 1-C 6烷基、丙烯酰基或氟代丙烯酰基；所述的6-10元芳基、5-10元杂芳基、3-8元环烷基、和3-8元杂环烷基各自独立地被选自氢、C 1-C 6烷基、丙烯酰基和丙烯酰胺基中的一个或多个取代基所取代；z、o、m、n各自独立地选自0-5中的任一整数； And/or R 6 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkyl, N(R e )(R f )-(CH 2 ) y -, O(R g )-C 1 -C 6 alkylene, C 1 -C 6 alkyl-S(=O) 2 -C 1 -C 6 alkylene, 6-10 membered aryl -(CH 2 ) z -, 5-10 membered heteroaryl-(CH 2 ) o -, 3-8 membered cycloalkyl-(CH 2 ) m -, or 3-8 membered heterocycloalkyl-(CH 2 ) n - wherein R e , R f and R g are each independently selected from hydrogen, C 1 -C 6 alkyl or tetrahydropyrrolidinyl, and y is selected from any integer from 0 to 5; Tetrahydropyrrolidinyl is substituted by one or more substituents selected from hydrogen, C 1 -C 6 alkyl, acryloyl or fluoroacryloyl; or, R e , R f and its attached nitrogen The atoms together form a tetrahydropyrrole or piperazine ring which is substituted by one or more substituents selected from the group consisting of hydrogen, C 1 -C 6 alkyl, propylene An acyl or fluoroacryloyl group; said 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl, and 3-8 membered heterocycloalkyl are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl group, an acryloyl group, and acrylamide group in a Or more substituents; z, o, m, n are each independently an integer of 0-5 is selected from any one of;
    当R 6为N(R e)(R f)-(CH 2) y-时，所述的N(R e)(R f)-(CH 2) y-中，R e和R f各自独立地优选选自氢、C 1-C 6烷基或四氢吡咯烷基，所述的四氢吡咯烷基优选被一个选自氢、C 1-C 6烷基、丙烯酰基或氟代丙烯酰基的取代基所取代；y优选选自0、1、2或3；所述的N(R e)(R f)-(CH 2) y-进一步优选为N(CH 3) 2-CH 2-、N(CH 3) 2-CH 2CH 2-、N(CH 3) 2-CH 2CH 2CH 2-或
    Figure PCTCN2018112660-appb-100002
    When R 6 is N(R e )(R f )-(CH 2 ) y -, in the N(R e )(R f )-(CH 2 ) y -, R e and R f are each independent Preferably, it is selected from hydrogen, C 1 -C 6 alkyl or tetrahydropyrrolidinyl, and the tetrahydropyrrolidinyl group is preferably one selected from hydrogen, C 1 -C 6 alkyl, acryloyl or fluoroacryloyl Substituted by a substituent; y is preferably selected from 0, 1, 2 or 3; said N(R e )(R f )-(CH 2 ) y - further preferably N(CH 3 ) 2 -CH 2 - , N(CH 3 ) 2 -CH 2 CH 2 -, N(CH 3 ) 2 -CH 2 CH 2 CH 2 - or
    Figure PCTCN2018112660-appb-100002
    当R 6为N(R e)(R f)-(CH 2) y-时，所述的N(R e)(R f)-(CH 2) y-中，R e和R f优选与其所连氮原子共同构成一个四氢吡咯环或哌嗪环，所述四氢吡咯环或哌嗪环被一个或两个或三个取代基取代，所述的取代基选自氢、C 1-C 6烷基、丙烯酰基或氟代丙烯酰基；y优选选自0、1、2或3；所述的N(R e)(R f)-(CH 2) y-进一步优选为
    Figure PCTCN2018112660-appb-100003
    Figure PCTCN2018112660-appb-100004
    When R 6 is N(R e )(R f )-(CH 2 ) y -, in the 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, acryloyl or fluoroacryloyl; y is preferably selected from 0, 1, 2 or 3; said N(R e )(R f )-(CH 2 ) y - further preferably
    Figure PCTCN2018112660-appb-100003
    Figure PCTCN2018112660-appb-100004
    当R 6为O(R g)-C 1-C 6亚烷基时，所述的O(R g)-C 1-C 6亚烷基优选为CH 3OCH 2-、 CH 3OCH 2CH 2-、HOCH 2-、HO(CH 2) 3-、
    Figure PCTCN2018112660-appb-100005
    When 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 -,
    Figure PCTCN2018112660-appb-100005
    当R 6为6-10元芳基-(CH 2) z-时，所述的6-10元芳基-(CH 2) z-中，z优选选自0、1或2，6-10元芳基优选为苯基；所述的6-10元芳基优选被一个丙烯酰胺基所取代；R 6进一步优选为
    Figure PCTCN2018112660-appb-100006
    When 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
    Figure PCTCN2018112660-appb-100006
    当R 6为5-10元杂芳基-(CH 2) o-时，所述的5-10元杂芳基-(CH 2) o-中，o优选自0、1或2，5-10元杂芳基优选为吡啶基；所述的5-10元杂芳基优选被一个丙烯酰胺基所取代；R 6进一步优选为
    Figure PCTCN2018112660-appb-100007
    When 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
    Figure PCTCN2018112660-appb-100007
    当R 6为3-8元环烷基-(CH 2) m-时，所述的3-8元环烷基-(CH 2) m-中，m优选自0、1或2，3-8元环烷基优选为环丙基或环戊基；R 6进一步优选为
    Figure PCTCN2018112660-appb-100008
    When 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
    Figure PCTCN2018112660-appb-100008
    当R 6为3-8元杂环烷基-(CH 2) n-时，所述的3-8元杂环烷基-(CH 2) n-中，n优选自0、1或2，3-8元杂环烷基优选为哌啶基或氧杂环丁基；所述的3-8元杂环烷基优选被一个C 1-C 6烷基或丙烯酰基所取代；R 6进一步优选为
    Figure PCTCN2018112660-appb-100009
    When 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, 3-8 membered heterocyclic group is preferably piperidinyl or oxetanyl; a 3-8 membered heterocycloalkyl preferably substituted with a C 1 -C 6 alkyl group or a propylene group; R 6 is further Preferred
    Figure PCTCN2018112660-appb-100009
    和/或，R 7选自氢、卤素、氰基、氰基乙基、2,3-二羟基丙基、C 1-C 6烷基、C 1-C 6烷氧基、O(R h)-C 1-C 6烷基、N(R i)(R j)-(CH 2) p-、或3-8元杂环烷基；其中，R h、R i和R j各自独立地选自氢、C 1-C 6烷基、或二甲胺基乙基；p选自0、2、3、4或5；或者，R i和R j共同构成一个5或6元含氮杂环烷基；所述的3-8元杂环烷基被氢、C 1-C 6烷基、氰基-C 1-C 6烷基、C 1-C 6烷氧基-C 1-C 6烷基、吡唑基-C 1-C 6烷基、四氢吡咯基、二甲胺基乙基、氧杂环丁基和二甲胺基中的一个或多个取代基所取代； And/or R 7 is selected from the group consisting of hydrogen, halogen, cyano, cyanoethyl, 2,3-dihydroxypropyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, O (R h -C 1 -C 6 alkyl, N(R i )(R j )-(CH 2 ) p -, 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; p is selected from 0, 2, 3, 4 or 5; or, R i and R j together form a 5 or 6 membered aza a cycloalkyl group; the 3-8 membered heterocycloalkyl group is hydrogen, C 1 -C 6 alkyl, cyano-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C Substituted with one or more substituents of 6 alkyl, pyrazolyl-C 1 -C 6 alkyl, tetrahydropyrrolyl, dimethylaminoethyl, oxetanyl and dimethylamino;
    当R 7为O(R h)-C 1-C 6亚烷基时，所述的O(R h)-C 1-C 6烷基中R h优选为氢、甲基、乙基、正丙基或异丙基，C 1-C 6亚烷基优选为-C(CH 2) 2-CH 2-或-CH 2-CH 2-； When 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 -;
    当R 7为N(R i)(R j)-(CH 2) p-时，所述的N(R i)(R j)-(CH 2) p-中的R i和R j优选各自独立地为 氢、甲基、乙基、正丙基、异丙基或二甲胺基乙基，p选自0、1、2、3、4或5； When R 7 is N(R i )(R j )-(CH 2 ) p -, 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, p is selected from 0, 1, 2, 3, 4 or 5;
    当R 7为被氢、C 1-C 6烷基、氰基-C 1-C 6烷基、C 1-C 6烷氧基-C 1-C 6烷基、吡唑基-C 1-C 6烷基、四氢吡咯基、二甲胺基乙基、氧杂环丁基和二甲胺基中的一个或多个取代基所取代的3-8元杂环烷基时，所述的一个或多个优选为一个、两个或三个；所述的取代基相同或不同；所述的3-8元杂环烷基优选为：哌嗪基、四氢哌啶基、四氢吡咯烷基、
    Figure PCTCN2018112660-appb-100010
    Figure PCTCN2018112660-appb-100011
    When R 7 is hydrogen, C 1 -C 6 alkyl, cyano-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, pyrazolyl-C 1 - When a 3-8 membered heterocycloalkyl group is substituted with one or more substituents of a C 6 alkyl group, a tetrahydropyrrolyl group, a dimethylaminoethyl group, an oxetanyl group, and a dimethylamino group, One or more of them are preferably one, two or three; the substituents are the same or different; the 3-8 membered heterocycloalkyl group is preferably: piperazinyl, tetrahydropiperidinyl, tetrahydrogen Pyrrolidinyl,
    Figure PCTCN2018112660-appb-100010
    Figure PCTCN2018112660-appb-100011
    和/或，R 8优选为氢、氰基、卤素或C 1-C 6烷基； And/or R 8 is preferably hydrogen, cyano, halogen or C 1 -C 6 alkyl;
    和/或，R 9和R 10各自独立地选自氢、卤素、或N(R c)(R d)-(CH 2)x-，其中，x优选为0、1、2或3，R c和R d各自独立地优选选自氢或甲基；或者，R 9和R 10共同构成N-甲基氮杂环戊基； And/or R 9 and R 10 are each independently selected from hydrogen, halogen, 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; or R 9 and R 10 together form an N-methylazetidyl;
    且，R 6和R 8不同时为氢。 Further, R 6 and R 8 are not hydrogen at the same time.
  3. 如权利要求1所述的如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于，A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, according to claim 1 a polymorph or prodrug characterized by
    其中，所述如式(I)所示的化合物具有如下通式：Wherein the compound represented by the formula (I) has the following formula:
    Figure PCTCN2018112660-appb-100012
    Figure PCTCN2018112660-appb-100012
    其中，among them,
    X为氟或氯；X is fluorine or chlorine;
    和/或，M为CH或N；And / or, M is CH or N;
    和/或，Cy选自四氢呋喃环、四氢吡喃环、四氢吡咯环、哌啶环、苯环、吡啶环、吡唑环、2,3-二氢苯并呋喃环、2,3-二氢吲哚环或S-氧代四氢噻吩环；And/or, Cy is 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, 2,3- Indoline or S-oxotetrahydrothiophene ring;
    和/或，R 6选自氢、氟、甲基、乙基、正丙基、异丙基、-CD 3、-CH 2F、-CHF 2、CH 3SO 2-CH 2CH 2CH 2-、N(CH 3) 2-CH 2-、N(CH 3) 2-CH 2CH 2-、N(CH 3) 2-CH 2CH 2CH 2-、
    Figure PCTCN2018112660-appb-100013
    CH 3OCH 2-、CH 3OCH 2CH 2-、HOCH 2-、HO(CH 2) 3-、
    Figure PCTCN2018112660-appb-100014
    Figure PCTCN2018112660-appb-100015
    And/or R 6 is 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 -,
    Figure PCTCN2018112660-appb-100013
    CH 3 OCH 2 -, CH 3 OCH 2 CH 2 -, HOCH 2 -, HO(CH 2 ) 3 -,
    Figure PCTCN2018112660-appb-100014
    Figure PCTCN2018112660-appb-100015
    和/或，R 7选自氢、氟、氰基、氰基乙基、2,3-二羟基丙基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、HO-C(CH 2) 2-CH 2-、CH 3O-CH 2-CH 2-、-N(CH 2)CH 2CH 3、-CH 2-N(CH 3) 2、-N(CH 2)CH 2CH 2N(CH 3) 2、
    Figure PCTCN2018112660-appb-100016
    Figure PCTCN2018112660-appb-100017
    And/or, R 7 is selected from the group consisting of hydrogen, fluorine, cyano, cyanoethyl, 2,3-dihydroxypropyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy , n-propoxy, 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
    Figure PCTCN2018112660-appb-100016
    Figure PCTCN2018112660-appb-100017
    和/或，R 8选自氢、氰基、氟或甲基； And/or R 8 is selected from the group consisting of hydrogen, cyano, fluoro or methyl;
    和/或，R 9和R 10各自独立地选自氢、氟、或二甲胺基亚甲基；或者，R 9和R 10共同构成N-甲基氮杂环戊基； And/or, R 9 and R 10 are each independently selected from hydrogen, fluorine, or dimethylaminomethylene; or, R 9 and R 10 together form an N-methylazetidyl;
    且R 6和R 8不同时为氢。 And R 6 and R 8 are not hydrogen at the same time.
  4. 如权利要求1-3任一项所述的如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于，A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer thereof, according to any one of claims 1-3 Body, solvate, polymorph or prodrug, characterized in that
    其中，所述如式(I)所示的化合物具有如下通式：Wherein the compound represented by the formula (I) has the following formula:
    Figure PCTCN2018112660-appb-100018
    Figure PCTCN2018112660-appb-100018
    其中R 6、Cy、R 7和R 8的定义均如权利要求1-3任一项所述，q选自1、2或3。 Wherein R 6 , Cy, R 7 and R 8 are as defined in any one of claims 1 to 3, and q is selected from 1, 2 or 3.
  5. 如权利要求1所述的如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于，A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, according to claim 1 a polymorph or prodrug characterized by
    其中，所述如式(I)所示的化合物为如下任一化合物：Wherein the compound represented by the formula (I) is any one of the following compounds:
    Figure PCTCN2018112660-appb-100019
    Figure PCTCN2018112660-appb-100019
    Figure PCTCN2018112660-appb-100020
    Figure PCTCN2018112660-appb-100020
    Figure PCTCN2018112660-appb-100021
    Figure PCTCN2018112660-appb-100021
    Figure PCTCN2018112660-appb-100022
    Figure PCTCN2018112660-appb-100022
    Figure PCTCN2018112660-appb-100023
    Figure PCTCN2018112660-appb-100023
    Figure PCTCN2018112660-appb-100024
    Figure PCTCN2018112660-appb-100024
    Figure PCTCN2018112660-appb-100025
    Figure PCTCN2018112660-appb-100025
    Figure PCTCN2018112660-appb-100026
    Figure PCTCN2018112660-appb-100026
  6. 一种如权利要求1-5任一项所述的如式(I)所示化合物的制备方法，其特征在于，其包括下述步骤：A process for the preparation of a compound of formula (I) according to any one of claims 1 to 5, which comprises the steps of:
    a)在酸或碱存在的条件下，将通式(A)化合物与α-卤代醛或卤代酮或其等效物进行缩合反应，制备得到通式(B)化合物；和a) a compound of the formula (B) is obtained by subjecting a compound of the formula (A) to an α-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);
    b)在酸、碱或过渡金属催化剂存在的条件下，将通式(B)化合物与硝基苯胺类或者其它二胺类前体化合物进行取代反应或偶联反应，得到通式(C)化合物；和b) subjecting a compound of the formula (B) to a nitroaniline or other diamine precursor compound by a substitution reaction or a coupling reaction in the presence of an acid, a base or a transition metal catalyst to obtain a compound of the formula (C) ;with
    c)在还原剂存在的条件下，将通式(C)化合物进行还原反应，得到通式化合物(D)；和c) subjecting the compound of the formula (C) to a reduction reaction in the presence of a reducing agent to obtain a compound of the formula (D);
    d)在碱或缩合试剂存在的条件下，将通式化合物(D)与丙烯酸或者丙烯酰氯类化合物进行缩合反应，制备得到如式(I)所示的化合物；d) 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);
    Figure PCTCN2018112660-appb-100027
    Figure PCTCN2018112660-appb-100027
    各式中，LG为卤素、砜基、亚砜基、或磺酸酯基，其他各基团的定义如权利要求1-5任一项所述。In the formula, LG is a halogen, a sulfone group, a sulfoxide group, or a sulfonate group, and the other groups are as defined in any one of claims 1 to 5.
  7. 一种药物组合物，其包括治疗有效量的如权利要求1-5任一项所述的式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，以及至少一种药用辅料。A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, Diastereomers, tautomers, solvates, polymorphs or prodrugs, and at least one pharmaceutical excipient.
  8. 一种如权利要求1-5任一项所述的如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，或如 权利要求7所述的药物组合物在制备FGFR激酶抑制剂中的应用。A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof, according to any one of claims 1 to 5 Use of an isomer, solvate, polymorph or prodrug, or a pharmaceutical composition according to claim 7 for the preparation of a FGFR kinase inhibitor.
  9. 一种如权利要求1-5任一项所述的如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，或如权利要求7所述的药物组合物在制备预防和/或治疗与蛋白激酶特别是FGFR激酶活性或表达量相关的疾病的药物中的应用，特别是制备预防和/或治疗抗肿瘤药物中的应用；其中，所述的肿瘤选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、***癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、鼻咽癌、脑癌、白血病、淋巴癌、鼻咽癌、或胰腺癌；特别是肝癌或胆管癌。A compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof, according to any one of claims 1 to 5 An isomer, solvate, polymorph or prodrug, or a pharmaceutical composition according to claim 7 in the manufacture of a medicament for preventing and/or treating a disease associated with a protein kinase, particularly a FGFR kinase activity or expression level Use, in particular for the preparation of a medicament for the prevention and/or treatment of antitumor drugs; wherein the tumor is selected from the group consisting of 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, nasopharyngeal cancer, brain cancer, leukemia, lymphoma, nasopharyngeal cancer, or pancreatic cancer; especially liver cancer or cholangiocarcinoma.
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