WO2022188792A1 - Heterocyclic compound having protein kinase inhibitory activity, pharmaceutical composition comprising same, preparation method therefor, and use thereof - Google Patents

Heterocyclic compound having protein kinase inhibitory activity, pharmaceutical composition comprising same, preparation method therefor, and use thereof Download PDF

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WO2022188792A1
WO2022188792A1 PCT/CN2022/079826 CN2022079826W WO2022188792A1 WO 2022188792 A1 WO2022188792 A1 WO 2022188792A1 CN 2022079826 W CN2022079826 W CN 2022079826W WO 2022188792 A1 WO2022188792 A1 WO 2022188792A1
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compound
ring
reaction
alkyl
μmol
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Chinese (zh)
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陈忠辉
韩晓军
田强
宋宏梅
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN202280009776.2A priority Critical patent/CN116761801A/en
Publication of WO2022188792A1 publication Critical patent/WO2022188792A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—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 present invention relates to heterocyclic compounds having protein kinase inhibitory activity, pharmaceutical compositions containing them, methods for their preparation, and their use in the prevention or treatment of diseases or conditions associated with RAF and/or RAS kinase activity.
  • Protein kinases are a class of enzymes that catalyze protein phosphorylation reactions. By mediating cell signaling processes, protein phosphorylation regulates cellular physiological activities, such as cell survival, proliferation, differentiation, apoptosis, and metabolism. The dysfunction of protein kinases is closely related to many diseases (including tumors, autoimmune diseases, inflammatory reactions, central nervous system diseases, cardiovascular diseases and diabetes, etc.).
  • RAF is an ATP kinase and an important part of the RAS-RAF-MEK signaling pathway. It is divided into three subtypes, A, B, and C, with high homology and similar domains. RAF exists in the cytoplasm as an inactive monomer. After RAS is stimulated by upstream growth factors, it changes from an inactive conformation (GDP binding) to an active conformation (GTP binding), thereby recruiting intracellular RAF to the cell membrane and promoting its dimerization and phosphorylation, and the activated RAF is phosphorylated in turn Activation of MEK and ERK ultimately regulates cell proliferation, differentiation, apoptosis and metastasis (Karoulia Z et al., Nat Rev Cancer.
  • the mutated B-RAF can continuously activate the MAPK signaling pathway in the form of monomer (V600 mutation) or dimer (non-V600 mutation) independent of RAS.
  • RAF inhibitors inhibit the RAS-RAF-MEK signaling pathway by inhibiting the activity of RAF monomers and dimers, and can be used for the treatment of RAS or RAF mutant tumors, and the applicable population accounts for about 1/3 of tumor patients.
  • Applicable tumor types mainly include melanoma, NSCLC, CRC, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, etc.
  • ⁇ C-OUT RAF inhibitors represented by Vemurafenib can effectively inhibit the kinase activity of V600 point mutant BRAF.
  • ⁇ C-OUT inhibitors cannot effectively inhibit RAF activation, and drug resistance has emerged after clinical use.
  • the present invention provides novel compounds as RAF inhibitors, which have a good inhibitory effect on RAF and/or RAS kinase, and have good properties such as pharmacokinetics.
  • the compound of the present invention can inhibit the activity of RAF dimer, can overcome the dimer resistance mechanism caused by the existing RAF inhibitor, reduce the abnormal activation toxicity of ERK, and can be applied to the treatment of RAS or RAF mutant tumors.
  • One aspect of the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically labeled Compound, N-oxide or Prodrug:
  • Ring A is selected from benzene ring, 5-6 membered heteroaromatic ring and 4-10 membered heterocyclic ring;
  • Ring B is selected from C 3-8 hydrocarbon rings, C 6-10 aromatic rings, 5-10 membered heteroaromatic rings and 4-10 membered heterocyclic rings;
  • W 1 , W 2 and W 3 are each independently selected from N and CR 2 ;
  • R 1 is selected from C 6-10 aryl and 5-10 membered heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with one or more substituents independently selected from: -NHR 6 , hydroxy, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 1-6 heteroalkyl (eg C 1-6 alkoxy), oxo, C 3-6 cycloalkyl and 4-10 membered heterocyclyl;
  • R 2 at each occurrence is independently selected from H, CN, hydroxy, halogen, C 1-6 alkyl and C 1-6 alkoxy, wherein each of said alkyl and alkoxy is optionally replaced by a or multiple halogen substitutions;
  • R 3 is L 2 -R 3 '
  • L 2 is independently at each occurrence a direct bond or -(CH 2 ) n -;
  • R 4 at each occurrence is independently selected from H, hydroxy, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl, C 3-6 cycloalkoxy and 4-10 membered heterocyclyl;
  • R and R at each occurrence are each independently selected from H, C 1-6 alkyl , C 3-8 cycloalkyl and 4-10 membered heterocyclyl, wherein said alkyl, cycloalkyl and each of the heterocyclyl groups is optionally substituted with one or more halogens;
  • R 20a , R 20b , R 23a , R 23b , R 24a , R 25a and R 25b are each independently selected from H, OH, -NHCH 3 , -N(CH 3 ) 2 , C 1-6 alkyl, C 1 -6 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclyl; wherein each of said alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally independently replaced by one or more Substituted with a substituent selected from the group consisting of halogen, C 1-6 alkyl and 4-10 membered heterocyclyl;
  • R 21 and R 22 are each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the alkyl, alkoxy , cycloalkyl and heterocyclyl are each optionally substituted with one or more halogens;
  • n 1, 2, 3, 4 or 5;
  • n 1, 2 or 3;
  • g is 1, 2, 3 or 4;
  • Ring A is a pyrazole ring or an imidazole ring
  • Ring B is a benzene ring, an isoxazole ring or a quinoline ring, R 1 is not and
  • R 1 is And when ring B is a benzene ring or an isoxazole ring, R 1 is substituted by at least one -NH 2 group.
  • compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, Co-crystals, solvates, metabolites, isotopically-labeled compounds, N-oxides or prodrugs and one or more pharmaceutically acceptable carriers.
  • Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopic label thereof, thereof
  • Use of a compound, N-oxide or prodrug of the present invention, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with RAF and/or RAS kinase activity Use of a compound, N-oxide or prodrug of the present invention, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with RAF and/or RAS kinase activity.
  • Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopic label thereof, thereof
  • a compound, N-oxide or prodrug, or a pharmaceutical composition of the present invention for use in the prevention or treatment of a disease or condition associated with RAF and/or RAS kinase activity.
  • Another aspect of the present invention provides a method of preventing or treating a disease or condition associated with RAF and/or RAS kinase activity, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable compound thereof salts, esters, stereoisomers, tautomers, polymorphs, co-crystals, solvates, metabolites, isotopically-labeled compounds, N-oxides or prodrugs, or pharmaceutical combinations of the present invention thing.
  • Another aspect of the present invention provides methods of preparing the compounds of the present invention.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, eg, 1 to 6, carbon atoms.
  • C 1-6 alkyl and C 1-4 alkyl refer to linear or branched groups having 1-6 carbon atoms and 1-4 carbon atoms, respectively (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), any of which is optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen (in which case this group is referred to as "haloalkyl”) (eg CH2F , CHF2 , CF3 , CC
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (ie methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl).
  • heteroalkyl refers to an optionally substituted alkyl group having one or more backbone chain atoms independently selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus or its combination. Numerical ranges may be given (eg C1-6 heteroalkyl) to refer to the number of carbons in the chain, which in this example includes 1-6 carbon atoms. For example, a -CH2OCH2CH3 group is referred to as a C3heteroalkyl . The attachment to the rest of the molecule can be through a heteroatom or a carbon atom in the heteroalkyl chain.
  • haloalkyl refers to an alkyl group substituted with one or more (such as 1 to 3) of the same or different halogen atoms
  • C 1-8 haloalkyl refers to haloalkyl groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1 to 4 carbon atoms, respectively, such as -CF 3 , -C 2 F 5 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 Cl or -CH 2 CH 2 CF 3 and the like.
  • hydroxyalkyl refers to a group formed by replacing a hydrogen atom in an alkyl group with one or more hydroxy groups, such as C1-4 hydroxyalkyl or C1-3 hydroxyalkyl, Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH) CH3 , and the like.
  • alkoxy means a group in which an oxygen atom is inserted at any reasonable position in an alkyl group (as defined above), being C 1-8 alkoxy, C 1-6 alkoxy , C 1-4 alkoxy or C 1-3 alkoxy.
  • C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy alkoxy, tert-butoxy, pentyloxy, hexyloxy, -CH2 - OCH3 , etc.
  • the alkoxy group is optionally substituted with one or more (such as 1 to 3) the same or different substituents .
  • haloalkoxy means, the hydrogen atom of the alkoxy group is replaced by one or more, such as 1 to 3, the same or different halogen atoms.
  • alkenyl means a linear or branched monovalent hydrocarbon group containing one or more double bonds and, for example, having 2-6 carbon atoms (“C 2-6 alkenyl”) .
  • the compound of the present invention contains an alkenyl group, the compound may exist in pure E (ent ought) form, pure Z (zusammen) form, or any mixture thereof.
  • alkynyl refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, eg ethynyl, 2-propynyl, 2 -butynyl, 1,3-butadiynyl, etc.
  • the alkynyl group is optionally substituted with one or more, such as 1 to 3, the same or different substituents.
  • the term "conjunctive ring” or “fused ring” refers to a ring system formed by two or more ring structures sharing two adjacent atoms with each other.
  • spirocycle refers to a ring system formed by two or more cyclic structures that share one ring atom with each other.
  • bridged ring refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.
  • hydrocarbon ring or “cyclohydrocarbyl” refers to a saturated or partially unsaturated cyclic aliphatic group
  • C 3-8 hydrocarbon ring refers to a hydrocarbon ring having 3 to 8 ring-forming carbon atoms Saturated or partially unsaturated monocyclic or polycyclic (such as bicyclic) alkyl groups, eg, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • cycloalkyl refers to a saturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring group, including but not limited to monocycloalkyl (such as cyclopropyl, cyclobutyl, cyclo) pentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and bicycloalkyl groups, including spiro, para (fused) or bridged ring systems (ie, spirocycloalkyl, para (fused) cyclo)alkyl and bridged cycloalkyl, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, etc.).
  • the cycloalkyl group is optionally substituted with one or more (such as 1 to 3) the same or different substituents.
  • C 3-8 cycloalkyl refers to a cycloalkyl group having 3 to 8 ring carbon atoms, such as C 3-6 cycloalkyl, which may be a monocyclic alkyl group, such as cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or bicycloalkyl, such as C5-8 spirocycloalkyl, C5-8 bridged cycloalkyl, C5-8 fused cycloalkyl , C 5-6 spirocycloalkyl, C 5-6 bridged cycloalkyl or C 5-6 fused cycloalkyl.
  • cycloalkoxy means -O-cycloalkyl, wherein cycloalkyl is as defined above.
  • Representative examples of cycloalkoxy include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • heterocyclyl or “heterocycle” refers to groups having 2 or more (eg, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ) carbon atoms, and aliphatic monocyclic or polycyclic (e.g. paracyclic, spirocyclic or bridged) groups of one or more (e.g. 1, 2, 3 or 4) heteroatoms, so
  • 4-11 membered heterocyclyl means an aliphatic heterocyclyl containing 4-11 ring atoms, including but not limited to 4-10 membered heterocyclyl, 4-9 membered heterocyclyl, 4- 8-membered heterocyclyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl, 3-8 membered heterocyclyl, 3-7 membered heterocyclyl, 4-7 membered nitrogen-containing heterocyclyl, 4- 7-membered oxygen-containing heterocyclic group, 4-7-membered sulfur-containing heterocyclic group, 5-6-membered nitrogen-containing heterocyclic group, 5-6-membered oxygen-containing heterocyclic group, 5-6-membered sulfur-containing heterocyclic group, etc.
  • nitrogen-containing heterocyclyl each optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur.
  • 4-11 membered heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidone (such as ), imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl.
  • a heterocyclyl group can form a junction ring structure with a heterocyclyl group or a cycloalkyl group, and the point of attachment of the junction ring structure and other groups can be on any heterocyclyl group or cycloalkyl group.
  • the heterocyclyl group also includes, but is not limited to, heterocyclylnoheterocyclyl, heterocyclylnocycloalkyl, monoheterocyclylnomonoheterocyclyl, monoheterocyclylnomonocycloalkyl, such as 3- 7-membered (mono)heterocyclyl and 3-7-membered (mono)heterocyclyl, 3-7-membered (mono)heterocyclyl and (mono)cycloalkyl, 3-7-membered (mono)heterocyclyl and C 4-6 (Mono)cycloalkyl, examples of which include, but are not limited to, pyrrolidinocyclopropyl, cyclopentylaziridinopropyl, pyrrolidinocyclobutyl, pyrrolidinopyrrolidinyl, pyrrolidinopiperidyl, pyrrolidinopiperazinyl
  • the heterocyclic group also includes a bridged heterocyclic group and a spiro heterocyclic group.
  • bridged heterocycle refers to two saturated rings formed by sharing two non-directly connected ring atoms containing one or more (eg 1, 2, 3 or 4) heteroatoms (eg oxygen, nitrogen and/or sulfur) cyclic structures including, but not limited to, 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7- 10-membered oxygen-containing bridged heterocycle, 7-10-membered sulfur-containing bridged heterocycle, etc., for example Wait.
  • the "nitrogen-bridged heterocycle”, “oxygen-bridged heterocycle”, and “sulfur-bridged heterocycle” optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur.
  • spiroheterocycle refers to a ring formed by two or more saturated rings sharing a ring atom containing one or more (eg, 1, 2, 3, or 4) heteroatoms (eg oxygen atom, nitrogen atom, sulfur atom) cyclic structure, including but not limited to 5-10 membered spiroheterocycle, 6-10 membered spiroheterocycle, 6-10 membered nitrogen-containing spiroheterocycle, 6-10 membered spiroheterocycle Oxygen-containing spiroheterocycle, 6-10 membered sulfur-containing spiroheterocycle, etc., for example
  • the "nitrogen-containing spiroheterocycle", “oxygen-containing spiroheterocycle” and “sulfur-containing spiroheterocycle” optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur.
  • 6-10 membered nitrogen-containing spiroheterocyclyl refers to a spiroheterocyclyl group containing a total of 6-10 ring atoms and wherein at least one of the ring atoms is a nitrogen atom.
  • Examples of groups obtained by condensing a heterocyclic group with an aryl group include, but are not limited to:
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated pi electron system.
  • C 6-12 aryl (aromatic ring) means an aryl group (aromatic ring) containing 6 to 12 carbon atoms, such as a C 6-10 aryl (aromatic ring), such as For phenyl (benzene ring) or naphthyl (naphthalene ring).
  • Aryl is optionally substituted with one or more (such as 1 to 3) substituents (eg, halogen, OH, CN, NO2, C1 - C6 alkyl, etc.), the same or different.
  • fused polycyclic aromatic group includes bicyclic or polycyclic ring systems containing at least one aromatic ring (eg, a benzene ring), such as
  • heteroaryl or “heteroaromatic ring” refers to a monocyclic or polycyclic aromatic group containing one or more identical or different heteroatoms, including monocyclic heteroaryl groups and containing at least a bicyclic or polycyclic ring system of a heteroaromatic ring (aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, For example 5, 6, 7, 8, 9 or 10 ring atoms.
  • the heteroatom can be oxygen, nitrogen or sulfur.
  • 5-10 membered heteroaryl or "5-10 membered heteroaromatic ring” means a heteroaryl (heteroaryl ring) containing 5 to 10 (eg, 5 to 6) ring atoms ), including 5-10-membered nitrogen-containing heteroaryl, 5-10-membered oxygen-containing heteroaryl, 5-10-membered sulfur-containing heteroaryl, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered oxygen-containing heteroaryl Aryl, 5-6 membered sulfur-containing heteroaryl, etc.
  • nitrogen-containing heteroaryl each optionally contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur.
  • examples include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl , thiadiazolyl, etc., or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and 5-10 membered cyclic groups containing these groups.
  • heteroaryl eg monoheteroaryl
  • aryl eg monocyclic aryl, eg phenyl
  • heterocyclyl eg monoheterocyclyl
  • cycloalkyl eg monocycloalkyl
  • another heteroaryl group such as another monoheteroaryl group
  • share two adjacent atoms with each other to form a junctional ring structure, the point of attachment of which can be on any heteroaromatic ring or on other rings including but not limited to (monoaryl) ) heteroaryl(mono)heteroaryl, (mono)heteroaryl(mono)aryl, (mono)heteroaryl(mono)heterocyclyl, and (mono)heteroaryl(mono) Cycloalkyl such as 5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroaryl, 5
  • halo or halogen group is defined to include F, Cl, Br or I.
  • substituted means that one or more (eg, one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the designated group, provided that no more than the designated atom is present in the normal valences in the case and the substitutions form stable compounds. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be independently and/or together independently Selected optional substituents are substituted. If a nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected optional substitution of substituents.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
  • the point of attachment of a substituent can be from any suitable position on the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically-labeled compounds that are identical to the compounds of the present invention, except that one or more atoms have the same atomic number but an atomic mass or mass number different from the atomic mass that predominates in nature or atomic substitution of mass numbers.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (eg, deuterium (2H), tritium ( 3H )); isotopes of carbon (eg, 11C , 13C , and14C ) ; isotopes of chlorine (eg 36 Cl); isotopes of fluorine (eg 18 F); isotopes of iodine (eg 123 I and 125 I); isotopes of nitrogen (eg 13 N and 15 N); isotopes of oxygen (eg 15 O) , 17 O and 18 O); isotopes of phosphorus (eg 32 P); and isotopes of sulfur (eg 35 S).
  • isotopes of hydrogen eg, deuterium (2H), tritium ( 3H )
  • isotopes of carbon eg, 11C , 13C , and14C
  • isotopes of chlorine eg
  • Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (eg, assays).
  • the radioisotopes tritium (ie 3 H) and carbon-14 (ie 14 C) are particularly useful for this purpose due to their ease of incorporation and ease of detection.
  • Substitution with positron emitting isotopes such as11C , 18F , 15O , and13N can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies.
  • Isotopically-labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically-labeled reagent in place of the previously employed non-labeled reagent.
  • Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, eg, D2O , acetone-d6, or DMSO - d6.
  • stereoisomer refers to isomers formed due to at least one asymmetric center. In compounds having one or more (eg, one, two, three or four) asymmetric centers, it may give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and individual of diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. For example, a nitroso-oxime can exist in solution in equilibrium in the following tautomeric forms:
  • Solid lines may be used in this article solid wedge or virtual wedge
  • the chemical bonds of the compounds of the present invention are depicted.
  • the use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, a specific enantiomer, racemic mixture, etc.).
  • the use of real or dashed wedges to delineate bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomer exists.
  • real and imaginary wedges are used to define relative, rather than absolute, stereochemistry.
  • the compounds of the present invention are intended to be available as stereoisomers (which include cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotational isomers, conformational isomers, atropisomers and mixtures thereof).
  • stereoisomers which include cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotational isomers, conformational isomers, atropisomers and mixtures thereof).
  • the compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (eg, racemic mixtures and pairs of diastereomers).
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • Co-crystal refers to the combination of drug active molecules and other physiologically acceptable molecules of acids, bases, salts, and non-ionic compounds in the same crystal lattice by hydrogen bonds, ⁇ - ⁇ stacking, van der Waals forces and other non-covalent bonds. .
  • compositions of the present invention may exist in free form for use in therapy, or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs which are administered to patients in need thereof After administration, the compounds of the invention or their metabolites or residues can be provided directly or indirectly. Accordingly, references herein to "compounds of the present invention" are also intended to encompass the various derivative forms of the compounds described above.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • acid addition salts for example, hexafluorophosphate, meglumine salt and the like.
  • suitable salts see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002).
  • esters means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release free acid or alcohol forms of the present invention) compound).
  • the compounds of the present invention may themselves also be esters.
  • the compounds of the present invention may exist in the form of solvates (eg, hydrates), wherein the compounds of the present invention comprise a polar solvent, such as water, methanol or ethanol, as a structural element of the crystal lattice of the compound.
  • a polar solvent such as water, methanol or ethanol
  • the amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
  • nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to oxidize to oxides.
  • nitrogen-containing heterocycles capable of forming N-oxides.
  • tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include, but are not limited to, use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide , alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane to oxidize heterocycles and tertiary amines.
  • MCPBA m-chloroperoxybenzoic acid
  • hydrogen peroxide alkyl hydroperoxides
  • alkyl hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxiranes such as dimethyldioxirane
  • metabolites of the compounds of the present invention ie substances formed in the body upon administration of the compounds of the present invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like, of the administered compound.
  • the present invention includes metabolites of the compounds of the present invention, including compounds prepared by methods of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity when administered into or onto the body can be converted into compounds of the invention having the desired activity, for example, by hydrolytic cleavage.
  • prodrugs will be functional derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as “pro-moiety (eg as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" Prepared by substituting appropriate functional groups present in the compounds of the present invention.
  • the present invention also encompasses compounds of the present invention that contain protecting groups.
  • protecting groups In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecule, thereby forming chemically protected forms of the compounds of the present invention. This can be accomplished by conventional protecting groups, such as those described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, Isotopically labeled compounds, N-oxides or prodrugs:
  • Ring A is selected from benzene ring, 5-6 membered heteroaromatic ring and 4-10 membered heterocyclic ring;
  • Ring B is selected from C 3-8 hydrocarbon rings, C 6-10 aromatic rings, 5-10 membered heteroaromatic rings and 4-10 membered heterocyclic rings;
  • W 1 , W 2 and W 3 are each independently selected from N and CR 2 ;
  • R 1 is selected from C 6-10 aryl and 5-10 membered heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with one or more substituents independently selected from: -NHR 6 , hydroxy, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 1-6 heteroalkyl (eg C 1-6 alkoxy), oxo, C 3-6 cycloalkyl and 4-10 membered heterocyclyl;
  • R 2 at each occurrence is independently selected from H, CN, hydroxy, halogen, C 1-6 alkyl and C 1-6 alkoxy, wherein each of said alkyl and alkoxy is optionally replaced by a or multiple halogen substitutions;
  • R 3 is L 2 -R 3 '
  • L 2 is independently at each occurrence a direct bond or -(CH 2 ) n -;
  • R 4 at each occurrence is independently selected from H, hydroxy, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl, C 3-6 cycloalkoxy and 4-10 membered heterocyclyl;
  • R and R at each occurrence are each independently selected from H, C 1-6 alkyl , C 3-8 cycloalkyl and 4-10 membered heterocyclyl, wherein said alkyl, cycloalkyl and each of the heterocyclyl groups is optionally substituted with one or more halogens;
  • R 20a , R 20b , R 23a , R 23b , R 24a , R 25a and R 25b are each independently selected from H, OH, -NHCH 3 , -N(CH 3 ) 2 , C 1-6 alkyl, C 1 -6 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclyl; wherein each of said alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally independently replaced by one or more Substituted with a substituent selected from the group consisting of halogen, C 1-6 alkyl and 4-10 membered heterocyclyl;
  • R 21 and R 22 are each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the alkyl, alkoxy , cycloalkyl and heterocyclyl are each optionally substituted with one or more halogens;
  • n 1, 2, 3, 4 or 5;
  • n 1, 2 or 3;
  • g is 1, 2, 3 or 4;
  • Ring A is a pyrazole ring or an imidazole ring
  • Ring B is a benzene ring, an isoxazole ring or a quinoline ring, R 1 is not and
  • R 1 is And when ring B is a benzene ring or an isoxazole ring, R 1 is substituted by at least one -NH 2 group.
  • R 1 when R 1 is And when ring B is a benzene ring, an isoxazole ring or a quinoline ring, R 1 is substituted by at least one -NH 2 group.
  • R 1 is selected from C 6-10 aryl and 5-10 membered heteroaryl, wherein each of said aryl and heteroaryl is optionally selected by one or more independently selected from the following Substituent substitution: -NHR 6 , hydroxyl, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 1- 6 -heteroalkyl (eg C 1-6 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl.
  • Substituent substitution -NHR 6 , hydroxyl, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 1- 6 -heteroalkyl (eg C 1-6 alkoxy), C 3-6 cycloalkyl and 4-10 membered
  • R 1 when R 1 is unsubstituted, R 1 is not
  • Ring A is selected from a benzene ring, a 5-6 membered heteroaromatic ring, and a 4-6 membered heterocyclic ring.
  • Ring A is a 5-6 membered heteroaromatic ring.
  • Ring A is a 4-6 membered heterocycle.
  • Ring A is a pyridine ring, an oxazole ring, an oxadiazole ring, a triazole ring, or a pyrazole ring.
  • Ring A is a pyridine ring, a triazole ring, or a pyrazole ring.
  • Ring A is This group is attached to the R 1 group through one of the two positions marked with * or ** and is attached to the R 1 group through the other position group connection;
  • X and V are each independently selected from C, CR and N ;
  • U, Y and Z are each independently selected from O, S, CHR4 , CR4 , NR4 and N;
  • X, Y, Z, U, and V is a heteroatom-containing group.
  • Ring A is This group is attached to the R 1 group through one of the two positions marked with * or ** and is attached to the R 1 group through the other position group connection;
  • X is selected from CR 4 and N;
  • U, Y and Z are each independently selected from CR and N ;
  • X, U, Y and Z are not simultaneously CR4 .
  • X is N, U is CH, and Y and Z are both N; or X is N, U and Z are both CH, and Y is N.
  • Ring A is The above groups are linked to the R 1 group through the positions marked with *, and are linked to the R 1 group through the positions marked with ** group connection.
  • Ring A is The above groups are linked to the R 1 group through the positions marked with *, and are linked to the R 1 group through the positions marked with ** group connection.
  • the compounds of the present invention have the structure shown in Formula I-A:
  • Ring B, R 1 , R 2 , R 3 , W 1 , W 2 and W 3 are as defined above for formula I;
  • Z and Y are each independently selected from CH and N;
  • n 1, 2 or 3.
  • the compounds of the present invention have the structure shown in Formula I-B:
  • Ring B, R 1 , R 2 , R 3 , W 1 , W 2 and W 3 are as defined above for formula I;
  • Z and Y are each independently selected from CH and N;
  • n 1, 2 or 3.
  • the compounds of the present invention have the structures shown in Formula I-C:
  • R 1 , R 2 , R 3 , W 1 , W 2 and W 3 are as defined above for formula I;
  • Z and Y are each independently selected from CH and N;
  • h 0, 1, 2, or 3;
  • n 1, 2 or 3.
  • Ring B is selected from C 6-10 aromatic rings, 5-10 membered heteroaromatic rings, and 4-10 membered heterocyclic rings.
  • ring B is a C 5-6 hydrocarbon ring, a benzene ring, a 5-10 membered heteroaromatic ring, or a 4-6 membered heterocyclic ring.
  • ring B is a C 5-6 saturated hydrocarbon ring, a benzene ring, a 5-6 membered heteroaromatic ring or a 4-6 membered heterocyclic ring.
  • Ring B is a cyclopentane ring, a benzene ring, a pyridine ring, a pyridazine ring, an isoquinoline ring, a dihydropyrrolidine ring, or Pyrrolidine ring.
  • ring B is a benzene ring, a 5-6 membered heteroaromatic ring or a 4-6 membered heterocyclic ring; preferably, ring B is a benzene ring , pyridine ring or pyrrolidine ring.
  • ring B is a benzene ring or a 5-6 membered heteroaromatic ring; preferably, ring B is a benzene ring or a pyridine ring.
  • Ring B is a 4-6 membered heterocycle; preferably, Ring B is a pyrrolidine ring.
  • W1, W2, and W3 are each independently selected from N, CH , and CF.
  • the present invention provides formula I, formula IA, formula IB and formula IC, It is a benzene ring or a pyridine ring.
  • W1, W2, and W3 are each independently selected from N and CH .
  • R 1 is substituted with at least one -NHR 6 group; preferably, R 1 is substituted with at least one -NH 2 group.
  • R 1 is selected from phenyl, naphthyl and 5-10 membered heteroaryl, wherein said phenyl, naphthyl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: -NHR 6 , hydroxy, halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), oxo, C 3-6 cycloalkyl and 4-10 membered Heterocyclyl.
  • substituents independently selected from the group consisting of: -NHR 6 , hydroxy, halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy),
  • R 1 is selected from phenyl, naphthyl, pyridyl, pyrazolyl, thiazolyl, pyrimidinyl and 9-10 A membered paracyclic heteroaryl, wherein the phenyl, naphthyl, pyridyl, pyrazolyl, thiazolyl, pyrimidinyl and 9-10 membered paracyclic heteroaryl groups are each optionally independently selected by one or more Substituted from the following substituents: -NHR 6 , hydroxy, halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), oxo, C 3-6 cycloalkyl and 4-10 membered heterocyclyl.
  • R 1 is selected from wherein the Each is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1- 4 -haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl.
  • R 1 is selected from wherein the Each is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1- 4 -haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl.
  • R 1 is selected from
  • R 1 is selected from wherein the Each is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1- 4 -haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl.
  • R 1 is selected from wherein the Each is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1- 4 -haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl.
  • R 1 is selected from
  • each occurrence of R 2 is independently selected from H, CN, halogen, C 1-4 alkyl, and C 1-4 alkoxy, wherein said alkyl and alkoxy are each optionally substituted with one or more halogens ; preferably, each occurrence of R is independently H, halogen, or C1-4 alkyl ; more preferably, each occurrence of R2 is independently H, F or methyl.
  • each occurrence of R 2 is independently H or C 1-4 alkyl; more preferably, R 2 Each occurrence is independently H or methyl.
  • each occurrence of R 3 ' is independently selected from H, halogen, CN, C 1-4 alkyl, C 1-4 alkoxy and 4-6 membered heterocyclyl, wherein the alkyl, alkoxy and heterocyclyl are optionally selected by one or more independently selected from halogen, CN and C 1-4 alkane Substituent substitution of the base;
  • each occurrence of R 3 ' is independently selected from H, halogen, C 1-4 alkyl, and C 1 at each occurrence. -4 alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogens.
  • each occurrence of R3 ' is independently selected from H, F, Cl, CN, -CHF 2 , -CF 3 , -OCH 3 , -OCF 3 , morpholinyl, N-methylpiperazinyl.
  • each occurrence of R3 ' is independently selected from the group consisting of H, F, Cl, -CF3 , and -OCF3 . .
  • R 4 is selected from H, halogen, C 1-4 alkyl, and C 1-4 heteroalkyl; preferably, R 4 is H or methyl; more preferably, R 4 is H.
  • R at each occurrence is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, and 4-6 membered heterocyclyl, wherein said alkyl, cyclo Alkyl and heterocyclyl are each optionally substituted with one or more halogens ; preferably, R6 is independently H at each occurrence.
  • R 20a , R 20b , R 23a , R 23b , R 24a , R 25a and R 25b are each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl and 4 -10-membered heterocyclyl; the alkyl, cycloalkyl and heterocyclyl groups are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6 alkyl, and 4-10 membered heterocyclic group.
  • R 20a , R 20b , R 23a , R 23b , R 24a , R 25a and R 25b are each independently selected from H, C 1-4 alkyl and C 3-6 cycloalkyl, wherein The alkyl and cycloalkyl groups are each optionally substituted with one or more halogens.
  • R 21 and R 22 are each independently selected from C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, and 4-6 membered heterocyclyl, wherein The alkyl, alkoxy, cycloalkyl and heterocyclyl groups are each optionally substituted with one or more halogens.
  • m is 1, 2, or 3.
  • n 1 or 2.
  • g is 1 or 2.
  • Ring A is This group is attached to the R 1 group through one of the two positions marked with * or ** and is attached to the R 1 group through the other position group connection;
  • X is selected from CR 4 and N;
  • U, Y and Z are each independently selected from CR and N ;
  • Ring B is a benzene ring or a 5-6 membered heteroaromatic ring
  • W 1 , W 2 and W 3 are each independently selected from N and CH;
  • R 1 is selected from phenyl, naphthyl and 5-10 membered heteroaryl, wherein each of said phenyl, naphthyl and heteroaryl is optionally substituted with one or more substituents independently selected from:- NHR 6 , hydroxy, halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl ( For example C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl;
  • R 2 at each occurrence is independently selected from H, CN, halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein each of said alkyl and alkoxy is optionally replaced by one or more halogen substitution;
  • R 3 is L 2 -R 3 '
  • L 2 is independently at each occurrence a direct bond or -(CH 2 ) n -;
  • R 3 ' at each occurrence is independently selected from H, halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein said alkyl and alkoxy are optionally replaced by one or more halogens replace;
  • R 4 is selected from H, halogen, C 1-4 alkyl and C 1-4 heteroalkyl
  • R 6 at each occurrence is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl optionally substituted with one or more halogens;
  • n 1, 2 or 3;
  • n 1, 2 or 3;
  • g 1 or 2.
  • Ring A is This group is attached to the R 1 group through one of the two positions marked with * or ** and is attached to the R 1 group through the other position group connection;
  • X is selected from CR 4 and N;
  • U, Y and Z are each independently selected from CR and N ;
  • Ring B is a 4-6 membered heterocycle
  • W 1 , W 2 and W 3 are each independently selected from N and CH;
  • R 1 is selected from phenyl, naphthyl and 5-10 membered heteroaryl, wherein each of said phenyl, naphthyl and heteroaryl is optionally substituted with one or more substituents independently selected from:- NHR 6 , hydroxy, halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl ( For example C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl;
  • R 2 at each occurrence is independently selected from H, CN, halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein each of said alkyl and alkoxy is optionally replaced by one or more halogen substitution;
  • R 3 is L 2 -R 3 '
  • L 2 is independently at each occurrence a direct bond or -(CH 2 ) n -;
  • R 3 ' at each occurrence is independently selected from H, halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein said alkyl and alkoxy are optionally replaced by one or more halogens replace;
  • R 4 is selected from H, halogen, C 1-4 alkyl and C 1-4 heteroalkyl
  • R 6 at each occurrence is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl optionally substituted with one or more halogens;
  • n 1, 2 or 3;
  • n 1, 2 or 3;
  • g 1 or 2.
  • Ring A is The above groups are linked to the R 1 group through the positions marked with *, and are linked to the R 1 group through the positions marked with ** group connection;
  • Ring B is a cyclopentane ring, a benzene ring, a pyridine ring, a pyridazine ring, an isoquinoline ring, a dihydropyrrolidine ring or a pyrrolidine ring;
  • W 1 , W 2 and W 3 are each independently selected from N, CH and CF;
  • R 1 is selected from
  • R 2 is independently at each occurrence H, halogen or C 1-4 alkyl
  • R 3 ' at each occurrence is independently selected from H, halogen, CN, C 1-4 alkyl, C 1-4 alkoxy and 4-6 membered heterocyclyl, wherein said alkyl, alkoxy radical and heterocyclyl are optionally substituted with one or more substituents independently selected from halogen, CN and C 1-4 alkyl;
  • R 4 is H or methyl
  • n 1, 2 or 3;
  • n 1, 2 or 3;
  • g 1 or 2.
  • ring B is a benzene ring or a 5-6 membered heteroaromatic ring
  • W 1 , W 2 and W 3 are each independently selected from N and CH;
  • R 1 is selected from
  • R 2 is independently at each occurrence H or C 1-4 alkyl
  • R 3 ' at each occurrence is independently selected from H, halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein said alkyl and alkoxy are optionally replaced by one or more halogens replace;
  • R 4 is selected from H, halogen, C 1-4 alkyl and C 1-4 heteroalkyl
  • n 1, 2 or 3;
  • g 1 or 2.
  • ring B is a 4-6 membered heterocycle
  • W 1 , W 2 and W 3 are each independently selected from N and CH;
  • R 1 is selected from phenyl, naphthyl and 5-10 membered heteroaryl, wherein each of said phenyl, naphthyl and heteroaryl is optionally substituted with one or more substituents independently selected from:- NHR 6 , hydroxy, halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl ( For example C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl;
  • R 2 is independently at each occurrence H or C 1-4 alkyl
  • R 3 ' at each occurrence is independently selected from H, halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein said alkyl and alkoxy are optionally replaced by one or more halogens replace;
  • R 4 is selected from H, halogen, C 1-4 alkyl and C 1-4 heteroalkyl
  • n 1, 2 or 3;
  • g 1 or 2.
  • ring B is a 4-6 membered heterocycle
  • W 1 , W 2 and W 3 are each independently selected from N and CH;
  • R 1 is selected from
  • R 2 is independently at each occurrence H or C 1-4 alkyl
  • R 3 ' at each occurrence is independently selected from H, halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein said alkyl and alkoxy are optionally replaced by one or more halogens replace;
  • R 4 is selected from H, halogen, C 1-4 alkyl and C 1-4 heteroalkyl
  • n 1, 2 or 3;
  • g 1 or 2.
  • the present invention encompasses any combination of the above embodiments.
  • compounds of the present invention include, but are not limited to:
  • the present invention provides a method of preparing a compound of Formula I-A, comprising the steps of:
  • Rings B, R 1 , R 2 , R 3 , Z, Y, W 1 , W 2 , W 3 and m are as defined above for formula IA;
  • Hal is Br or I.
  • the first step compound I-A-1 reacts with boron-containing reagent to generate compound I-A-2;
  • a boron-containing reagent that can be used is, for example, B 2 (pin) 2 .
  • Catalysts that can be used are, for example, Pd(OAc) 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , etc.
  • ligands that can be used are PPh 3 , DPPF, BINOL, BINAP or Pcy 3 , etc.
  • the base is, for example, Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , KOAc, NaHCO 3 or K 2 CO 3 or the like.
  • Solvents that can be used are, for example, 1,4-dioxane, DMF, DMSO or CH 3 CN.
  • the reaction temperature is, for example, 50°C to 120°C.
  • the condensation reaction is preferably carried out in the presence of a condensing agent and a base.
  • a condensing agent are T3P , HATU, CDI, HOBt, DMAP, DCC, DIC, EDC, HBTU, HCTU or PyBOP and the like.
  • Useful bases are pyridine, TEA, DIPEA , tBuOK , tBuONa , tBuOLi , NaH , NaOH , Cs2CO3 , K3PO4 or Na2CO3 and the like.
  • Useful solvents are pyridine, THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, acetone, CH3CN , 1,4-dioxane or toluene and the like.
  • the reaction temperature is 0°C to 120°C, eg, room temperature.
  • the compound IA-3 can be prepared as an acid halide first, and the available acid halide reagents are thionyl chloride, oxalyl chloride and the like.
  • the reaction can be carried out under the catalysis of a small amount of DMF or in a system without DMF; the reaction temperature is 0°C to 120°C; the resulting acid halide compound is then reacted with compound IA-2 in the presence of a base to form compound IA -4.
  • the usable base is TEA or DIPEA, etc.
  • the usable solvent is THF, DCM, DCE, CH3CN , 1,4-dioxane or toluene, etc.
  • the reaction can be carried out at 0°C to 120°C.
  • compound I-A-4 is hydrolyzed to generate compound I-A-5;
  • the hydrolysis reaction is preferably carried out in the presence of a base.
  • a base are NH4OAc , NaIO4 , NaOH or KOH and the like.
  • Useful solvents are THF, MeOH, EtOH, CH3CN , 1,4-dioxane or water and the like.
  • the reaction temperature is 0°C to 80°C, eg, room temperature or 50°C.
  • step compound I-A-6 and I-A-7 are subjected to coupling reaction (such as Suzuki reaction) to generate compound I-A-8;
  • the catalyst that can be used in the coupling reaction is, for example, Pd(OAc) 2 , Pd(PPh 3 ) 4 or Pd(dppf)Cl 2 , etc.;
  • the base that can be used is, for example, Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , AcOK, NaHCO 3 or K 2 CO 3 , etc.
  • the available ligands are PPh 3 , DPPF, BINOL, BINAP or PCy 3 , etc.
  • the available solvents are toluene/H 2 O, 1,4- Dioxane/H 2 O, DMF/H 2 O, DMSO/H 2 O or CH 3 CN/H 2 O, etc.
  • the reaction temperature may be 60°C to 120°C.
  • Step 5 Compound I-A-5 and I-A-8 are coupled to generate Compound I-A;
  • the catalyst that can be used in the coupling reaction is, for example, Cu(OAc) 2 or CuBr, etc.; the ligand that can be used is, for example, DMAP or 2,2'-bipyridine, and the base that can be used is pyridine, TEA, Cs 2 CO 3 , Na 2 CO 3 or K 2 CO 3 etc., the solvent that can be used is 1,4-dioxane, DCM, DMF or CH 3 CN etc., and the reaction temperature can be 0°C to 120°C, for example 90°C.
  • the present invention provides a method of preparing a compound of Formula I-B, comprising the steps of:
  • Rings B, R 1 , R 2 , R 3 , Z, Y, W 1 , W 2 , W 3 and m are as defined above for formula IB;
  • Hal is Br or I.
  • the first step Compound I-B-1 and I-B-2 undergo condensation reaction to generate compound I-B-3;
  • reaction conditions are as described in the second step of the method for the preparation of compounds of formula I-A (Scheme A).
  • reaction conditions are as described in the first step of the method for the preparation of compounds of formula I-A (Scheme A).
  • compound I-B-4 is hydrolyzed to generate compound I-B-5;
  • reaction conditions are as described in the third step of the method for the preparation of compounds of formula I-A (Scheme A).
  • reaction conditions are as described in step 5 of the method for the preparation of compounds of formula I-A (Scheme A).
  • the present invention provides methods of preparing compounds of formula I-C comprising the steps of:
  • R 1 , R 2 , R 3 , Z, Y, W 1 , W 2 , W 3 , m and h are as defined above for formula IC.
  • compound I-A-2 reacts with triphosgene to generate compound I-C-1;
  • Solvents that can be used in the reaction are, for example, THF, DCM or toluene.
  • the reaction temperature is 0°C to 100°C, for example 30°C.
  • the reaction is preferably carried out in the presence of a base.
  • bases are, for example, DIPEA, TEA or pyridine and the like.
  • Useful solvents are, for example, toluene, THF, DCM or 1,4-dioxane and the like.
  • the reaction temperature is 0°C to 120°C, for example 100°C.
  • compound I-C-3 is hydrolyzed to generate compound I-C-4;
  • reaction conditions are as described in the third step of the method for the preparation of compounds of formula I-A (Scheme A).
  • reaction conditions are as described in step 5 of the method for the preparation of compounds of formula I-A (Scheme A).
  • compositions, formulations and methods of treatment are provided.
  • the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, of the present invention compounds, co-crystals, solvates, metabolites, isotopically-labeled compounds, N-oxides or prodrugs and one or more pharmaceutically acceptable carriers.
  • the present invention provides pharmaceutical formulations, which are preferably solid formulations, semisolid formulations, liquid formulations, or gaseous formulations.
  • the pharmaceutical composition or formulation may further comprise one or more other therapeutic agents.
  • the pharmaceutical composition or formulation can be administered by oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or transdermal routes.
  • the present invention provides compounds of the present invention, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, co-crystals, solvates, metabolites, Isotopically labeled compounds, N-oxides or prodrugs, or pharmaceutical compositions of the present invention, or pharmaceutical formulations of the present invention in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with RAF and/or RAS kinase activity the use of.
  • the present invention provides compounds of the present invention, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, co-crystals, solvates, metabolites, Isotopically labeled compounds, N-oxides or prodrugs, or pharmaceutical compositions of the present invention, or pharmaceutical formulations of the present invention, in the manufacture of a medicament for modulating (eg, reducing or inhibiting) the activity of RAF and/or RAS kinases use.
  • the present invention provides compounds of the present invention, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, co-crystals, solvates, metabolites, Isotopically labeled compounds, N-oxides or prodrugs, or pharmaceutical compositions of the present invention, or pharmaceutical formulations of the present invention, for use in the prevention or treatment of diseases or conditions associated with RAF and/or RAS kinase activity.
  • the present invention provides a method of preventing or treating a disease or condition associated with RAF and/or RAS kinase activity, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable agent thereof acceptable salts, esters, stereoisomers, tautomers, polymorphs, co-crystals, solvates, metabolites, isotopically labeled compounds, N-oxides or prodrugs, or The pharmaceutical composition, or the pharmaceutical formulation of the present invention.
  • the disease or condition associated with RAF and/or RAS kinase activity is preferably cancer or tumor.
  • the cancer or tumor is preferably lung cancer (eg, non-small cell lung cancer), breast cancer, ovarian cancer, stomach cancer, liver cancer, kidney cancer, bone cancer, colorectal cancer, bowel cancer, pancreatic cancer, head and neck cancer , uterine cancer, esophageal cancer, thyroid cancer, bladder cancer, blood cancer, lymphoma, multiple myeloma, melanoma, glioma, brain tumor or sarcoma.
  • lung cancer eg, non-small cell lung cancer
  • breast cancer ovarian cancer
  • stomach cancer liver cancer, kidney cancer, bone cancer, colorectal cancer, bowel cancer, pancreatic cancer, head and neck cancer
  • uterine cancer esophageal cancer
  • thyroid cancer bladder cancer
  • blood cancer lymphoma
  • multiple myeloma multiple myeloma
  • melanoma glioma
  • brain tumor or sarcoma e.g, sarcoma
  • “Pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered and which, within the scope of sound medical judgment, is suitable for contact with humans and/or tissue from other animals without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the present invention may act systemically and/or locally. For this purpose, they can be administered by a suitable route.
  • compositions of the present invention may be administered in suitable dosage forms.
  • an effective amount refers to the amount of a compound which, when administered, will alleviate to some extent one or more symptoms of the condition being treated.
  • Dosage regimens can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition.
  • the amount of the compound of the invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. In general, effective doses range from about 0.0001 to about 50 mg per kg body weight per day. In some cases, dose levels not higher than the lower end of the foregoing ranges may be sufficient, while in other cases larger doses may be employed without causing any deleterious side effects, provided that the larger dose is first The dose is divided into several smaller doses to be administered throughout the day.
  • the compound of the present invention may be present in a pharmaceutical composition or pharmaceutical preparation in an amount or amount of about 0.01 mg to about 1000 mg.
  • treating means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term is applied or one or more symptoms of such disorder or condition.
  • preventing refers to administration to a subject not suffering from a disease to prevent the onset of the disease or delay the onset or reduce the severity of one or more symptoms of a disorder or condition.
  • an “individual” as used herein includes a human or non-human animal.
  • exemplary human subjects include human subjects (referred to as patients) or normal subjects with a disease (eg, a disease described herein).
  • Non-human animals in the present invention include all vertebrates such as non-mammals (eg birds, amphibians, reptiles) and mammals such as non-human primates, livestock and/or domesticated animals (eg sheep, dogs) , cats, cows, pigs, etc.).
  • the pharmaceutical compositions or formulations of the present invention may further comprise one or more additional therapeutic or prophylactic agents (eg, other drugs used in the treatment of cancer or neoplastic diseases).
  • the methods of treatment of the present invention may also include administration of one or more additional therapeutic or prophylactic agents (eg, other drugs used to treat cancer or neoplastic diseases).
  • the compounds of the present invention are isolated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and/or flash column chromatography (Flash column chromatography), and their structures are confirmed by 1 H NMR and/or MS. Reaction monitoring was performed by TLC or LC-MS.
  • Prep-HPLC purification of the compounds in the examples was carried out by Aglient 1260 or Waters 2489 HPLC, and the separation column model was Waters SunFire Prep C 18 OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m), Waters Xbridge Prep C 18 OBD ( 19mm ⁇ 150mm ⁇ 5.0 ⁇ m) or YMC Actus Triart C 18 (20mm ⁇ 150mm ⁇ 5.0 ⁇ m), column temperature is 25°C, detection wavelength is 214nm, 254nm or 280nm, mobile phase A is acetonitrile, mobile phase B is 0.05% Formic acid aqueous solution or 0.05% ammonium bicarbonate aqueous solution or 0.05% TFA aqueous solution, the volume ratio of the mobile phase is adjusted according to the polarity of the compound; the flow rate of the mobile phase is 28 mL/min.
  • TLC used silica gel GF 254 as the stationary phase.
  • Flash column chromatography uses a Biotage flash column chromatograph.
  • Microwave reactions were performed using a BiotageInitiator microwave reactor.
  • reaction temperature is room temperature (15-30°C).
  • the reagents used in this application were purchased from companies such as Acros Organics, Aldrich Chemical Company, or Tuber Chemicals.
  • Step 7 N-(3-Chloro-2-fluorophenyl)-3-(4-(4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d] Preparation of pyrimidin-7-yl)-1H-1,2,3-triazol-1-yl)-4-methylbenzamide (compound 1k)
  • Step 8 3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-1,2,3-triazol-1-yl)-N-(3- Preparation of chloro-2-fluorophenyl)-4-methylbenzamide (compound 1)
  • Step 7 3-(4-(4-((2,4-dimethoxybenzyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)-4-methyl Preparation of methyl benzoate (compound 2i)
  • Step 8 3-(4-(4-((2,4-dimethoxybenzyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)-4-methyl Preparation of Benzoic Acid (Compound 2j)
  • Step 9 N-(3-Chloro-2-fluorophenyl)-3-(4-(4-((2,4-dimethoxybenzyl)amino)quinazolin-8-yl)- Preparation of 1H-pyrazol-1-yl)-4-methylbenzamide (compound 2k)
  • Step 10 3-(4-(4-Aminoquinazolin-8-yl)-1H-pyrazol-1-yl)-N-(3-chloro-2-fluorophenyl)-4-methyl Preparation of benzamide (compound 2)
  • Step 1 Preparation of 3-bromo-N-(2,4-dimethoxybenzyl)imidazo[1,2-a]pyrazin-8-amine (compound 5b)
  • the first step preparation of tert-butyl (5-((3-chloro-2-fluorophenyl)carbamoyl)-2-methylphenyl)carbamate (compound 10b)
  • the fourth step preparation of (5-((3-chloro-2-fluorophenyl)carbamoyl)-2-methylphenyl)boronic acid (compound 10e)
  • Step 6 3-(4-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-1H-pyrazol-1-yl)-N-(3-chloro-2-fluoro Preparation of phenyl)-4-methylbenzamide (compound 10)
  • the first step preparation of 3-bromo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (compound 11c)
  • the third step preparation of (2-methyl-5-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)boronic acid (compound 11e)
  • Step 2 N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (Compound 17)
  • the first step preparation of 2-(5-isocyanato-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (compound 19a)
  • Step 5 N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- Preparation of 3-(trifluoromethoxy)pyrrolidine-1-carboxamide (Compound 19)
  • Step 2 N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (Compound 26)
  • Step 2 N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-3-(trifluoromethyl)pyrrolidine-1-carboxamide (compound 27)
  • the first step N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-3-( Preparation of 2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (compound 29b)
  • Step 6 N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-4-(morpholinomethyl)benzamide (compound 32)
  • Step 6 N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-fluoro-4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (compound 33)
  • the fifth step N-(5-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-fluoro-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (compound 36)
  • Step 1 Preparation of 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (compound 37b)
  • Step 6 7-(1-(5-Amino-4-fluoro-2-methylphenyl)-1H-pyrazol-4-yl)-N-(4-methoxybenzyl)imidazo[ Preparation of 2,1-f][1,2,4]triazin-4-amine (compound 38g)
  • Step 8 N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-fluoro-4-methylphenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carboxamide (compound 38)
  • the third step N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-2-fluoro-4-methylphenyl)-3,3-difluorocyclopentane-1-carboxamide (compound 40d) preparation
  • Step 2 N-(4-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-5-methylpyridin-2-yl)-3-(trifluoromethyl)benzamide (compound 42c) preparation
  • the first step preparation of N-(5-bromo-6-methylpyridin-3-yl)-2-(trifluoromethyl)isonicotinamide (compound 44a)
  • Step 2 N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-6-methylpyridin-3-yl)-2-(trifluoromethyl)isonicotinamide (compound 44b) preparation
  • Step 2 N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-fluoro-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 45)
  • Step 6 N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-fluoro-4-methylphenyl)-3-(difluoromethyl)benzamide (compound 47)
  • the first step preparation of (5-bromo-6-methylpyridin-3-yl) tert-butyl carbamate (compound 50a)
  • Step 2 7-(1-(5-Amino-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-N,N-bis(4-methoxybenzyl)imidazole Preparation of [2,1-f][1,2,4]triazin-4-amine (Compound 50b)
  • the first step preparation of N-(5-bromo-2,4-difluorophenyl)-3-(trifluoromethyl)benzamide (compound 51b)
  • Step 2 N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-2,4-difluorophenyl)-3-(trifluoromethyl)benzamide (compound 51c) preparation
  • Step 2 N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 6-methylpyridin-3-yl)-3-(2-cyanopropan-2-yl)benzamide (Compound 52)
  • Step 2 N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 6-methylpyridin-3-yl)-4-(trifluoromethyl)pyridineamide (Compound 53)
  • the fourth step the preparation of 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzoic acid (compound 54e)
  • Step 6 N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 6-methylpyridin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 54)
  • Step 2 N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-2-fluoro-4-methylphenyl)-3-cyanobenzamide (compound 56c) preparation
  • Step 2 N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-2-fluoro-4-methylphenyl)-3-methoxybenzamide (compound 57c) preparation
  • Example 58 N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 2-Fluoro-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 58)
  • Step 2 N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-fluoro-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 58)
  • Step 2 N-(3-(4-(4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidin-7-yl)-3-methyl Preparation of -1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 59c)

Abstract

The present invention relates to a compound of formula (I), a pharmaceutical composition comprising same, a preparation method therefor, and a use thereof for preventing or treating tumor-related diseases or conditions.

Description

具有蛋白激酶抑制活性的杂环化合物、包含其的药物组合物及其制备方法和用途Heterocyclic compound with protein kinase inhibitory activity, pharmaceutical composition containing same, preparation method and use thereof 发明领域Field of Invention
本发明涉及具有蛋白激酶抑制活性的杂环化合物、包含其的药物组合物、其制备方法及其用于预防或治疗与RAF和/或RAS激酶活性相关的疾病或病况。The present invention relates to heterocyclic compounds having protein kinase inhibitory activity, pharmaceutical compositions containing them, methods for their preparation, and their use in the prevention or treatment of diseases or conditions associated with RAF and/or RAS kinase activity.
发明背景Background of the Invention
蛋白激酶是一类催化蛋白质磷酸化反应的酶。通过介导细胞信号传导过程，蛋白质磷酸化调控细胞的生理活动，例如细胞的存活、增殖、分化、凋亡与代谢等。蛋白激酶的功能失调与很多疾病(包括肿瘤、自身免疫病、炎性反应、中枢神经系统疾病、心血管疾病及糖尿病等)密切相关。Protein kinases are a class of enzymes that catalyze protein phosphorylation reactions. By mediating cell signaling processes, protein phosphorylation regulates cellular physiological activities, such as cell survival, proliferation, differentiation, apoptosis, and metabolism. The dysfunction of protein kinases is closely related to many diseases (including tumors, autoimmune diseases, inflammatory reactions, central nervous system diseases, cardiovascular diseases and diabetes, etc.).
RAF属于ATP激酶，是RAS-RAF-MEK信号通路的重要组成部分，其分为A、B、C三种亚型，具有高度的同源性和相似的结构域。RAF在胞质中以无活性的单体形式存在。RAS受到上游生长因子刺激后，从非活性构象(GDP结合)转变成活性构象(GTP结合)，从而将胞内RAF募集到细胞膜并促使其发生二聚化和磷酸化，活化的RAF依次磷酸化激活MEK和ERK，最终调节细胞的增殖、分化、凋亡和转移(Karoulia Z等人，Nat Rev Cancer.2017 Nov；17(11)：676-691)。突变的B-RAF能够不依赖RAS，以单体(V600突变)或二聚体(非V600突变)的形式持续激活MAPK信号通路。RAF抑制剂通过抑制RAF单体和二聚体活性，从而抑制RAS-RAF-MEK信号通路，以用于RAS或RAF突变肿瘤的治疗，适用人群约占肿瘤患者的1/3。适用的肿瘤类型主要包括黑色素瘤、NSCLC、CRC、卵巢癌、子宫内膜癌、甲状腺癌、胰腺癌等。RAF is an ATP kinase and an important part of the RAS-RAF-MEK signaling pathway. It is divided into three subtypes, A, B, and C, with high homology and similar domains. RAF exists in the cytoplasm as an inactive monomer. After RAS is stimulated by upstream growth factors, it changes from an inactive conformation (GDP binding) to an active conformation (GTP binding), thereby recruiting intracellular RAF to the cell membrane and promoting its dimerization and phosphorylation, and the activated RAF is phosphorylated in turn Activation of MEK and ERK ultimately regulates cell proliferation, differentiation, apoptosis and metastasis (Karoulia Z et al., Nat Rev Cancer. 2017 Nov;17(11):676-691). The mutated B-RAF can continuously activate the MAPK signaling pathway in the form of monomer (V600 mutation) or dimer (non-V600 mutation) independent of RAS. RAF inhibitors inhibit the RAS-RAF-MEK signaling pathway by inhibiting the activity of RAF monomers and dimers, and can be used for the treatment of RAS or RAF mutant tumors, and the applicable population accounts for about 1/3 of tumor patients. Applicable tumor types mainly include melanoma, NSCLC, CRC, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, etc.
以Vemurafenib为代表的αC-OUT类RAF抑制剂能够有效的抑制V600点突变BRAF的激酶活性。但是，对于RAS突变、野生型B-RAF以及非V600点突变的BRAF驱动肿瘤，αC-OUT抑制剂均无法有效抑制RAF激活，且在临床上使用后已出现耐药。αC-OUT RAF inhibitors represented by Vemurafenib can effectively inhibit the kinase activity of V600 point mutant BRAF. However, for RAS-mutated, wild-type B-RAF, and non-V600 point-mutated BRAF-driven tumors, αC-OUT inhibitors cannot effectively inhibit RAF activation, and drug resistance has emerged after clinical use.
发明概述SUMMARY OF THE INVENTION
本发明提供新的作为RAF抑制剂的化合物，其对RAF和/或RAS激酶具有良好的抑制作用，并且具有良好的药物代谢动力学等性质。本发明的化合物能够抑制RAF二聚体活性，能够克服现有RAF抑制剂引起的二聚体耐药机制，降低ERK反常激活毒性，可应用于RAS或RAF突变肿瘤治疗。The present invention provides novel compounds as RAF inhibitors, which have a good inhibitory effect on RAF and/or RAS kinase, and have good properties such as pharmacokinetics. The compound of the present invention can inhibit the activity of RAF dimer, can overcome the dimer resistance mechanism caused by the existing RAF inhibitor, reduce the abnormal activation toxicity of ERK, and can be applied to the treatment of RAS or RAF mutant tumors.
本发明的一个方面提供式I的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药：One aspect of the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically labeled Compound, N-oxide or Prodrug:
Figure PCTCN2022079826-appb-000001
Figure PCTCN2022079826-appb-000001
其中：in:
环A选自苯环、5-6元杂芳环和4-10元杂环；Ring A is selected from benzene ring, 5-6 membered heteroaromatic ring and 4-10 membered heterocyclic ring;
环B选自C 3-8烃环、C 6-10芳环、5-10元杂芳环和4-10元杂环； Ring B is selected from C 3-8 hydrocarbon rings, C 6-10 aromatic rings, 5-10 membered heteroaromatic rings and 4-10 membered heterocyclic rings;
W 1、W 2和W 3各自独立地选自N和CR 2； W 1 , W 2 and W 3 are each independently selected from N and CR 2 ;
L 1选自-NR 5-C(＝O)-、-C(＝O)-NR 5-、-NR 5-、-NR 5-S(＝O)-、-NR 5-S(＝O) 2-、-S(＝O)-NR 5-和-S(＝O) 2-NR 5-； L 1 is selected from -NR 5 -C(=O)-, -C(=O)-NR 5 -, -NR 5 -, -NR 5 -S(=O)-, -NR 5 -S(=O ) 2 -, -S(=O)-NR 5 - and -S(=O) 2 -NR 5 -;
R 1选自C 6-10芳基和5-10元杂芳基，其中所述芳基和杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：-NHR 6、羟基、卤素、CN、NO 2、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6卤代烷氧基、C 1-6杂烷基(例如C 1-6烷氧基)、氧代基、C 3-6环烷基和4-10元杂环基； R 1 is selected from C 6-10 aryl and 5-10 membered heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with one or more substituents independently selected from: -NHR 6 , hydroxy, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 1-6 heteroalkyl (eg C 1-6 alkoxy), oxo, C 3-6 cycloalkyl and 4-10 membered heterocyclyl;
R 2在每次出现时各自独立地选自H、CN、羟基、卤素、C 1-6烷基和C 1-6烷氧基，其中所述烷基和烷氧基各自任选地被一个或多个卤素取代； R 2 at each occurrence is independently selected from H, CN, hydroxy, halogen, C 1-6 alkyl and C 1-6 alkoxy, wherein each of said alkyl and alkoxy is optionally replaced by a or multiple halogen substitutions;
R 3为L 2-R 3’； R 3 is L 2 -R 3 ';
L 2在每次出现时各自独立地为直接键或-(CH 2) n-； L 2 is independently at each occurrence a direct bond or -(CH 2 ) n -;
R 3’在每次出现时各自独立地选自H、羟基、卤素、CN、NO 2、C 1-6烷基、C 1-6杂烷基(例如C 1-6烷氧基)、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8环烷氧基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、-NR 20aR 20b、-SR 21、-S(＝O)R 22、-S(＝O) 2R 22、-S(＝O)NR 20aR 20b、-S(＝O) 2NR 20aR 20b、-NR 20aS(＝O)R 20b、-NR 20aS(＝O) 2R 20b、-C(＝O)R 21、-C(＝O)NR 23aR 23b、-NR 23aC(＝O)R 23b和-NR 24aC(＝O)NR 25aR 25b，其中所述烷基、杂烷基(例如烷氧基)、烯基、炔基、环烷基、环烷氧基、杂环基、芳基和杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：羟基、卤素、CN、NO 2、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基和4-10元杂环基； R 3 ' at each occurrence is independently selected from H, hydroxy, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 heteroalkyl (eg C 1-6 alkoxy), C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heterocycle Aryl, -NR 20a R 20b , -SR 21 , -S(=O)R 22 , -S(=O) 2 R 22 , -S(=O)NR 20a R 20b , -S(=O) 2 NR 20a R 20b , -NR 20a S(=O)R 20b , -NR 20a S(=O) 2 R 20b , -C(=O)R 21 , -C(=O)NR 23a R 23b , -NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b wherein said alkyl, heteroalkyl (eg alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkane Each of oxy, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NO2, C1-4alkyl , C1 -4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclic group;
R 4在每次出现时各自独立地选自H、羟基、卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基、C 3-6环烷氧基和4-10元杂环基； R 4 at each occurrence is independently selected from H, hydroxy, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl, C 3-6 cycloalkoxy and 4-10 membered heterocyclyl;
R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-8环烷基和4-10元杂环基，其中所述烷基、环烷基和杂环基各自任选地被一个或多个卤素取代； R and R at each occurrence are each independently selected from H, C 1-6 alkyl , C 3-8 cycloalkyl and 4-10 membered heterocyclyl, wherein said alkyl, cycloalkyl and each of the heterocyclyl groups is optionally substituted with one or more halogens;
R 20a、R 20b、R 23a、R 23b、R 24a、R 25a和R 25b各自独立地选自H、OH、-NHCH 3、-N(CH 3) 2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和4-10元杂环基；其中所述烷基、烷氧基、环烷基和杂环基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、C 1-6烷基和4-10元杂环基； R 20a , R 20b , R 23a , R 23b , R 24a , R 25a and R 25b are each independently selected from H, OH, -NHCH 3 , -N(CH 3 ) 2 , C 1-6 alkyl, C 1 -6 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclyl; wherein each of said alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally independently replaced by one or more Substituted with a substituent selected from the group consisting of halogen, C 1-6 alkyl and 4-10 membered heterocyclyl;
R 21和R 22各自独立地选自C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和4-10元杂环基，其中所述烷基、烷氧基、环烷基和杂环基各自任选地被一个或多个卤素取代； R 21 and R 22 are each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the alkyl, alkoxy , cycloalkyl and heterocyclyl are each optionally substituted with one or more halogens;
m为1、2、3、4或5；m is 1, 2, 3, 4 or 5;
n为1、2或3；并且n is 1, 2 or 3; and
g为1、2、3或4；g is 1, 2, 3 or 4;
条件是：i)当R 1未被取代，环A为吡唑环或咪唑环，并且环B为苯环、异噁唑环或喹啉环时，R 1不是
Figure PCTCN2022079826-appb-000002
并且 The conditions are: i) When R 1 is unsubstituted, Ring A is a pyrazole ring or an imidazole ring, and Ring B is a benzene ring, an isoxazole ring or a quinoline ring, R 1 is not
Figure PCTCN2022079826-appb-000002
and
ii)当R 1为
Figure PCTCN2022079826-appb-000003
且环B为苯环或异噁唑环时，R 1至少被一个-NH 2基团取代。 ii) When R 1 is
Figure PCTCN2022079826-appb-000003
And when ring B is a benzene ring or an isoxazole ring, R 1 is substituted by at least one -NH 2 group.
本发明的另一方面提供药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药以及一种或多种药学上可接受的载体。Another aspect of the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, Co-crystals, solvates, metabolites, isotopically-labeled compounds, N-oxides or prodrugs and one or more pharmaceutically acceptable carriers.
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，或者本发明的药物组合物在制备用于预防或治疗与RAF和/或RAS激酶活性相关的疾病或病况的药物中的用途。Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopic label thereof, thereof Use of a compound, N-oxide or prodrug of the present invention, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with RAF and/or RAS kinase activity.
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，或者本发明的药物组合物，其用于预防或治疗与RAF和/或RAS激酶活性相关的疾病或病况。Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopic label thereof, thereof A compound, N-oxide or prodrug, or a pharmaceutical composition of the present invention, for use in the prevention or treatment of a disease or condition associated with RAF and/or RAS kinase activity.
本发明的另一方面提供预防或治疗与RAF和/或RAS激酶活性相关的疾病或病况的方法，所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，或者本发明的药物组合物。Another aspect of the present invention provides a method of preventing or treating a disease or condition associated with RAF and/or RAS kinase activity, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable compound thereof salts, esters, stereoisomers, tautomers, polymorphs, co-crystals, solvates, metabolites, isotopically-labeled compounds, N-oxides or prodrugs, or pharmaceutical combinations of the present invention thing.
本发明的另一方面提供制备本发明的化合物的方法。Another aspect of the present invention provides methods of preparing the compounds of the present invention.
发明详述Detailed description of the invention
定义definition
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including those variations or substitutions of equivalent techniques that would be apparent to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，其不排除其它未列举的元素或方法步骤，尽管其它未列举的元素或方法步骤不一定存在(即，这些术语也涵盖术语“基本上由......组成”和“由......组成”)。The terms "comprising", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open ended and do not exclude other unrecited elements or method steps, although other unrecited elements or method steps are not necessarily present (ie, these terms also encompass the terms "consisting essentially of" and "consisting of").
如本文中所使用，术语“烷基”定义为线性或支化饱和脂肪族烃。在一些实施方案中，烷基具有1至12个，例如1至6个碳原子。例如，如本文中所使用，术语“C 1-6烷基”和“C 1-4烷基”分别指具有 1-6个碳原子和1-4个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基)，其任选地被一个或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CH 2F、CHF 2、CF 3、CCl 3、C 2F 5、C 2Cl 5、CH 2CF 3、CH 2Cl或-CH 2CH 2CF 3等)。术语“C 1-4烷基”指具有1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。 As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, eg, 1 to 6, carbon atoms. For example, as used herein, the terms "C 1-6 alkyl" and "C 1-4 alkyl" refer to linear or branched groups having 1-6 carbon atoms and 1-4 carbon atoms, respectively (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), any of which is optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen (in which case this group is referred to as "haloalkyl") (eg CH2F , CHF2 , CF3 , CCl3 , C 2 F 5 , C 2 Cl 5 , CH 2 CF 3 , CH 2 Cl or -CH 2 CH 2 CF 3 etc.). The term "C 1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (ie methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl).
如本文中所使用，术语“杂烷基”指任选被取代的烷基，其具有一个或多个独立地选自除碳以外的原子的骨架链原子，例如氧、氮、硫、磷或其组合。可以给出数值范围(例如C 1-6杂烷基)是指链中的碳数目，在此实例中包括1-6个碳原子。例如，-CH 2OCH 2CH 3基团被称为C 3杂烷基。与分子其余部分的连接可以通过杂烷基链中的杂原子或碳原子进行。 As used herein, the term "heteroalkyl" refers to an optionally substituted alkyl group having one or more backbone chain atoms independently selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus or its combination. Numerical ranges may be given (eg C1-6 heteroalkyl) to refer to the number of carbons in the chain, which in this example includes 1-6 carbon atoms. For example, a -CH2OCH2CH3 group is referred to as a C3heteroalkyl . The attachment to the rest of the molecule can be through a heteroatom or a carbon atom in the heteroalkyl chain.
如本文中所使用，术语“卤代烷基”是指被一个或多个(诸如1至3个)相同或不同的卤素原子取代的烷基，术语“C 1-8卤代烷基”、“C 1-6卤代烷基”和“C 1-4卤代烷基”分别指具有1至8个碳原子、1至6个碳原子和1-4个碳原子的卤代烷基，例如-CF 3、-C 2F 5、-CHF 2、-CH 2F、-CH 2CF 3、-CH 2Cl或-CH 2CH 2CF 3等。 As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) of the same or different halogen atoms, the terms "C 1-8 haloalkyl", "C 1- " 6 haloalkyl" and "C 1-4 haloalkyl" refer to haloalkyl groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1 to 4 carbon atoms, respectively, such as -CF 3 , -C 2 F 5 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 Cl or -CH 2 CH 2 CF 3 and the like.
如本文中所使用，术语“羟烷基”是指烷基中的氢原子被一个或多个羟基取代所形成的基团，例如C 1-4羟烷基或C 1-3羟烷基，其实例包括但不限于羟甲基、羟乙基、羟丙基、羟丁基、-CH(OH)CH 3等。 As used herein, the term "hydroxyalkyl" refers to a group formed by replacing a hydrogen atom in an alkyl group with one or more hydroxy groups, such as C1-4 hydroxyalkyl or C1-3 hydroxyalkyl, Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH) CH3 , and the like.
如本文中所使用，术语“烷氧基”意指在烷基(如上文所定义)任意合理的位置插入氧原子的基团，为C 1-8烷氧基、C 1-6烷氧基、C 1-4烷氧基或C 1-3烷氧基。C 1-6烷氧基的代表性实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基、-CH 2-OCH 3等，所述烷氧基任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。如术语“卤代烷氧基”是指所述烷氧基的氢原子被一个或多个(诸如1至3个)相同或不同的卤素原子取代。 As used herein, the term "alkoxy" means a group in which an oxygen atom is inserted at any reasonable position in an alkyl group (as defined above), being C 1-8 alkoxy, C 1-6 alkoxy , C 1-4 alkoxy or C 1-3 alkoxy. Representative examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy alkoxy, tert-butoxy, pentyloxy, hexyloxy, -CH2 - OCH3 , etc., the alkoxy group is optionally substituted with one or more (such as 1 to 3) the same or different substituents . As the term "haloalkoxy" means, the hydrogen atom of the alkoxy group is replaced by one or more, such as 1 to 3, the same or different halogen atoms.
如本文中所使用，术语“烯基”意指线性的或支化的单价烃基，其包含一个或多个双键，且例如具有2-6个碳原子(“C 2-6烯基”)。所述烯基为例如-CH＝CH 2、-CH 2CH＝CH 2、-C(CH 3)＝CH 2、-CH 2-CH＝CH-CH 3、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。 As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon group containing one or more double bonds and, for example, having 2-6 carbon atoms ("C 2-6 alkenyl") . The alkenyl groups are eg -CH=CH 2 , -CH 2 CH=CH 2 , -C(CH 3 )=CH 2 , -CH 2 -CH=CH-CH 3 , 2-pentenyl, 3-pentenyl Alkenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3- Pentenyl. When a compound of the present invention contains an alkenyl group, the compound may exist in pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof.
如本文中所使用，术语“炔基”表示包含一个或多个三键的单价烃基，其优选具有2、3、4、5或6个碳原子，例如乙炔基、2-丙炔基、2-丁炔基、1，3-丁二炔基等。所述炔基任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, eg ethynyl, 2-propynyl, 2 -butynyl, 1,3-butadiynyl, etc. The alkynyl group is optionally substituted with one or more, such as 1 to 3, the same or different substituents.
如本文中所使用，术语“并环”或“稠环”指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的环系。As used herein, the term "conjunctive ring" or "fused ring" refers to a ring system formed by two or more ring structures sharing two adjacent atoms with each other.
如本文中所使用，术语“螺环”指由两个或两个以上环状结构彼此共用一个环原子所形成的环系。As used herein, the term "spirocycle" refers to a ring system formed by two or more cyclic structures that share one ring atom with each other.
如本文中所使用，术语“桥环”指由两个或两个以上环状结构彼此共用两个不直接相连的原子所形成的环系。As used herein, the term "bridged ring" refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.
如本文中所使用，术语“烃环”或“环烃基”指饱和或部分不饱和的环状脂肪族基团，术语“C 3-8烃环”指具有3至8个成环碳原子的饱和或部分不饱和的单环或多环(诸如双环)烷基，例如环丙基、环丁基、环戊基等。 As used herein, the term "hydrocarbon ring" or "cyclohydrocarbyl" refers to a saturated or partially unsaturated cyclic aliphatic group, and the term "C 3-8 hydrocarbon ring" refers to a hydrocarbon ring having 3 to 8 ring-forming carbon atoms Saturated or partially unsaturated monocyclic or polycyclic (such as bicyclic) alkyl groups, eg, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
如本文中所使用，术语“环烷基”指饱和的非芳族单环或多环(诸如双环)烃环基，包括但不限于单环烷基(诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基等)和双环烷基，包括螺环、并环(稠环)或桥环系统(即，螺环烷基、并环(稠环)烷基和桥环烷基，诸如双环[1.1.1]戊基、双环[2.2.1]庚基等)。本发明中，环烷基任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。环烷基上的碳原子任选地被氧代(oxo)基团取代(即形成C＝O)。术语“C 3-8环烷基”指具有3至8个成环碳原子的环烷基，例如C 3-6环烷基，其可以是单环烷基，例如环丙基、环丁基、环戊基、环己基、环庚基或环辛基，也可以是双环烷基，例如C 5-8螺环烷基、C 5-8桥环烷基、C 5-8稠环烷基、C 5-6螺环烷基、C 5-6桥环烷基或C 5-6稠环烷基。 As used herein, the term "cycloalkyl" refers to a saturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring group, including but not limited to monocycloalkyl (such as cyclopropyl, cyclobutyl, cyclo) pentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and bicycloalkyl groups, including spiro, para (fused) or bridged ring systems (ie, spirocycloalkyl, para (fused) cyclo)alkyl and bridged cycloalkyl, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, etc.). In the present invention, the cycloalkyl group is optionally substituted with one or more (such as 1 to 3) the same or different substituents. The carbon atoms on the cycloalkyl are optionally substituted with oxo groups (ie forming C=O). The term "C 3-8 cycloalkyl" refers to a cycloalkyl group having 3 to 8 ring carbon atoms, such as C 3-6 cycloalkyl, which may be a monocyclic alkyl group, such as cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or bicycloalkyl, such as C5-8 spirocycloalkyl, C5-8 bridged cycloalkyl, C5-8 fused cycloalkyl , C 5-6 spirocycloalkyl, C 5-6 bridged cycloalkyl or C 5-6 fused cycloalkyl.
如本文中所使用，术语“环烷氧基”意指-O-环烷基，其中环烷基如上文所定义。环烷氧基的代表性实例包括但不限于环丙氧基、环丁氧基、环戊氧基、环己氧基等。As used herein, the term "cycloalkoxy" means -O-cycloalkyl, wherein cycloalkyl is as defined above. Representative examples of cycloalkoxy include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
如本文中所使用，术语“杂环基”或“杂环”指具有2个或2个以上(例如3、4、5、6、7、8、9、10、11、12、13或14个)碳原子，以及一个或多个(例如1个、2个、3个或4个)杂原子的脂肪族的单环或多环(例如并环、螺环或桥环)基团，所述杂原子包括但不限于氧原子、氮原子和硫原子，所述杂环基上的碳原子和杂原子任选地被氧代基团取代(例如形成C＝O、S(＝O)或S(＝O) 2)。 As used herein, the term "heterocyclyl" or "heterocycle" refers to groups having 2 or more (eg, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ) carbon atoms, and aliphatic monocyclic or polycyclic (e.g. paracyclic, spirocyclic or bridged) groups of one or more (e.g. 1, 2, 3 or 4) heteroatoms, so The heteroatoms include, but are not limited to, oxygen, nitrogen, and sulfur atoms, and carbon atoms and heteroatoms on the heterocyclyl are optionally substituted with oxo groups (eg, to form C=O, S(=O) or S(=O) 2 ).
例如：“4-11元杂环基”意指含有4-11个环原子的脂肪族的杂环基，包括但不限于4-10元杂环基、4-9元杂环基、4-8元杂环基、4-7元杂环基、5-6元杂环基、3-8元杂环基、3-7元杂环基、4-7元含氮杂环基、4-7元含氧杂环基、4-7元含硫杂环基、5-6元含氮杂环基、5-6元含氧杂环基、5-6元含硫杂环基等，所述“含氮杂环基”、“含氧杂环基”和“含硫杂环基”各自任选地还含有一个或多个独立地选自氧、氮和硫的其他杂原子。4-11元杂环基的实例包括但不限于环氧乙烷基、氮丙啶基、氮杂环丁基、氧杂环丁基、四氢呋喃基、吡咯烷基、吡咯烷酮基(如
Figure PCTCN2022079826-appb-000004
)、咪唑烷基、吡唑烷基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基、三噻烷基(trithianyl)。 For example: "4-11 membered heterocyclyl" means an aliphatic heterocyclyl containing 4-11 ring atoms, including but not limited to 4-10 membered heterocyclyl, 4-9 membered heterocyclyl, 4- 8-membered heterocyclyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl, 3-8 membered heterocyclyl, 3-7 membered heterocyclyl, 4-7 membered nitrogen-containing heterocyclyl, 4- 7-membered oxygen-containing heterocyclic group, 4-7-membered sulfur-containing heterocyclic group, 5-6-membered nitrogen-containing heterocyclic group, 5-6-membered oxygen-containing heterocyclic group, 5-6-membered sulfur-containing heterocyclic group, etc. The "nitrogen-containing heterocyclyl", "oxygen-containing heterocyclyl" and "sulfur-containing heterocyclyl" each optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of 4-11 membered heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidone (such as
Figure PCTCN2022079826-appb-000004
), imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl.
本发明中，杂环基可以与杂环基或环烷基形成并环结构，所述并环结构与其他基团的连接点可以在任一杂环基上或环烷基上，因此，本发明的杂环基还包括(但不限于)杂环基并杂环基、杂环基并环烷基、单杂环基并单杂环基、单杂环基并单环烷基，例如3-7元(单)杂环基并3-7元(单)杂环基、3-7元(单)杂环基并(单)环烷基、3-7元(单)杂环基并C 4-6(单)环烷基，其实例包括但不限于吡咯烷基并环丙基、环戊基并氮杂环丙基、吡咯烷基并环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、哌啶基并吗啉基、
Figure PCTCN2022079826-appb-000005
In the present invention, a heterocyclyl group can form a junction ring structure with a heterocyclyl group or a cycloalkyl group, and the point of attachment of the junction ring structure and other groups can be on any heterocyclyl group or cycloalkyl group. Therefore, the present invention The heterocyclyl group also includes, but is not limited to, heterocyclylnoheterocyclyl, heterocyclylnocycloalkyl, monoheterocyclylnomonoheterocyclyl, monoheterocyclylnomonocycloalkyl, such as 3- 7-membered (mono)heterocyclyl and 3-7-membered (mono)heterocyclyl, 3-7-membered (mono)heterocyclyl and (mono)cycloalkyl, 3-7-membered (mono)heterocyclyl and C 4-6 (Mono)cycloalkyl, examples of which include, but are not limited to, pyrrolidinocyclopropyl, cyclopentylaziridinopropyl, pyrrolidinocyclobutyl, pyrrolidinopyrrolidinyl, pyrrolidinopiperidyl, pyrrolidinopiperazinyl, piperidinomorpholinyl,
Figure PCTCN2022079826-appb-000005
本发明中，杂环基还包括桥杂环基和螺杂环基。In the present invention, the heterocyclic group also includes a bridged heterocyclic group and a spiro heterocyclic group.
如本文中所使用，术语“桥杂环”是指两个饱和环共用两个不直接相连的环原子形成的含有一个或多个(例如1个、2个、3个或4个)杂原子(例如氧原子、氮原子和/或硫原子)的环状结构，包括但不限于7-10元桥杂环、8-10元桥杂环、7-10元含氮桥杂环、7-10元含氧桥杂环、7-10元含硫桥杂环等，例如
Figure PCTCN2022079826-appb-000006
Figure PCTCN2022079826-appb-000007
等。所述“含氮桥杂环”、“含氧桥杂环”、“含硫桥杂环”任选地还含有一个或多个独立地选自氧、氮和硫的其他杂原子。 As used herein, the term "bridged heterocycle" refers to two saturated rings formed by sharing two non-directly connected ring atoms containing one or more (eg 1, 2, 3 or 4) heteroatoms (eg oxygen, nitrogen and/or sulfur) cyclic structures including, but not limited to, 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7- 10-membered oxygen-containing bridged heterocycle, 7-10-membered sulfur-containing bridged heterocycle, etc., for example
Figure PCTCN2022079826-appb-000006
Figure PCTCN2022079826-appb-000007
Wait. The "nitrogen-bridged heterocycle", "oxygen-bridged heterocycle", and "sulfur-bridged heterocycle" optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur.
如本文中所使用，术语“螺杂环”是指由两个或两个以上饱和环共用一个环原子形成的含有一个或多个(例如1个、2个、3个或4个)杂原子(例如氧原子、氮原子、硫原子)的环状结构，包括但不限于5-10元螺杂环、6-10元螺杂环、6-10元含氮螺杂环、6-10元含氧螺杂环、6-10元含硫螺杂环等，例如
Figure PCTCN2022079826-appb-000008
Figure PCTCN2022079826-appb-000009
Figure PCTCN2022079826-appb-000010
所述“含氮螺杂环”、“含氧螺杂环”、“含硫螺杂环”任选地还含有一个或多个独立地选自氧、氮、硫的其他杂原子。术语“6-10元含氮螺杂环基”是指含有共计6-10个环原子并且其中至少一个环原子为氮原子的螺杂环基。 As used herein, the term "spiroheterocycle" refers to a ring formed by two or more saturated rings sharing a ring atom containing one or more (eg, 1, 2, 3, or 4) heteroatoms (eg oxygen atom, nitrogen atom, sulfur atom) cyclic structure, including but not limited to 5-10 membered spiroheterocycle, 6-10 membered spiroheterocycle, 6-10 membered nitrogen-containing spiroheterocycle, 6-10 membered spiroheterocycle Oxygen-containing spiroheterocycle, 6-10 membered sulfur-containing spiroheterocycle, etc., for example
Figure PCTCN2022079826-appb-000008
Figure PCTCN2022079826-appb-000009
Figure PCTCN2022079826-appb-000010
The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle" and "sulfur-containing spiroheterocycle" optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. The term "6-10 membered nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl group containing a total of 6-10 ring atoms and wherein at least one of the ring atoms is a nitrogen atom.
杂环基与芳基稠合所得基团的实例包括但不限于：
Figure PCTCN2022079826-appb-000011
Figure PCTCN2022079826-appb-000012
Examples of groups obtained by condensing a heterocyclic group with an aryl group include, but are not limited to:
Figure PCTCN2022079826-appb-000011
Figure PCTCN2022079826-appb-000012
如本文中所使用，术语“芳基”或“芳环”指具有共轭π电子系统的全碳单环或稠合多环芳族基团。如本文中所使用，术语“C 6-12芳基(芳环)”意指含有6至12个碳原子的芳基(芳环)，例如为C 6-10芳基(芳环)，例如为苯基(苯环)或萘基(萘环)。芳基任选地被一个或多个(诸如1至3个)相同或不同的取代基(例如卤素、OH、CN、NO 2、C 1-C 6烷基等)取代。术语“稠合多环芳族基团”包括含有至少一个芳环(例如苯环)的双环或多环环系，例如
Figure PCTCN2022079826-appb-000013
As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated pi electron system. As used herein, the term "C 6-12 aryl (aromatic ring)" means an aryl group (aromatic ring) containing 6 to 12 carbon atoms, such as a C 6-10 aryl (aromatic ring), such as For phenyl (benzene ring) or naphthyl (naphthalene ring). Aryl is optionally substituted with one or more (such as 1 to 3) substituents (eg, halogen, OH, CN, NO2, C1 - C6 alkyl, etc.), the same or different. The term "fused polycyclic aromatic group" includes bicyclic or polycyclic ring systems containing at least one aromatic ring (eg, a benzene ring), such as
Figure PCTCN2022079826-appb-000013
如本文中所使用，术语“杂芳基”或“杂芳环”指含有一个或多个相同或不同杂原子的单环或多环芳族基团，包括单环的杂芳基和含有至少一个杂芳环(至少含有一个杂原子的芳族环系)的双环或多环环系，其可以具有5、6、7、8、9、10、11、12、13或14个环原子，例如5、6、7、8、9或10个环原子。所述杂原子可以是氧、氮或硫。所述杂芳基上的碳原子和杂原子任选地被氧代基团取代(例如形成C＝O、S(＝O)或S(＝O) 2)。 As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic group containing one or more identical or different heteroatoms, including monocyclic heteroaryl groups and containing at least a bicyclic or polycyclic ring system of a heteroaromatic ring (aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, For example 5, 6, 7, 8, 9 or 10 ring atoms. The heteroatom can be oxygen, nitrogen or sulfur. The carbon atoms and heteroatoms on the heteroaryl group are optionally substituted with oxo groups (eg to form C=O, S(=O) or S(=O) 2 ).
如本文中所使用，术语“5-10元杂芳基”或“5-10元杂芳环”意指含有5至10个(例如5至6个)环原子的杂芳基(杂芳环)，包括5-10元含氮杂芳基、5-10元含氧杂芳基、5-10元含硫杂芳基、5-6元含氮杂芳基、5-6元含氧杂芳基、5-6元含硫杂芳基等。所述“含氮杂芳基”、“含氧杂芳基”和“含硫杂芳基”各自任选地含有一个或多个独立地选自氧、氮和硫的其他杂原子。其实例包括但不限于噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、三唑基、四唑基、噁二唑基、噻二唑基等，或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及包含这些基团的5-10元并环基团。As used herein, the term "5-10 membered heteroaryl" or "5-10 membered heteroaromatic ring" means a heteroaryl (heteroaryl ring) containing 5 to 10 (eg, 5 to 6) ring atoms ), including 5-10-membered nitrogen-containing heteroaryl, 5-10-membered oxygen-containing heteroaryl, 5-10-membered sulfur-containing heteroaryl, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered oxygen-containing heteroaryl Aryl, 5-6 membered sulfur-containing heteroaryl, etc. The "nitrogen-containing heteroaryl", "oxygen-containing heteroaryl" and "sulfur-containing heteroaryl" each optionally contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl , thiadiazolyl, etc., or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and 5-10 membered cyclic groups containing these groups.
本发明中，杂芳基(例如单杂芳基)可以与芳基(例如单环芳基，例如苯基)、杂环基(例如单杂环基)、环烷基(例如单环烷基)或另一杂芳基(例如另一单杂芳基)彼此共用两个相邻的原子形成并环结构，其连接点可以在任一杂芳环上或其它环上，包括但不限于(单)杂芳基并(单)杂芳基、(单)杂芳基并(单环)芳基、(单)杂芳基并(单)杂环基和(单)杂芳基并(单)环烷基，例如5-6元(单)杂芳基并5-6元(单)杂芳基、5-6元(单)杂芳基并苯基、5-6元(单)杂芳基并5-6元(单)杂环基或5-6元(单)杂芳基并C4-6(单)环烷基(例如5-6元杂芳基并环丁基、5-6元杂芳基并环戊基或5-6元杂芳基并环己基)，其实例包括但不限于吲哚基、异吲哚基、吲唑基、苯并咪唑、喹啉基、异喹啉基、
Figure PCTCN2022079826-appb-000014
Figure PCTCN2022079826-appb-000015
Figure PCTCN2022079826-appb-000016
等。 In the present invention, heteroaryl (eg monoheteroaryl) can be combined with aryl (eg monocyclic aryl, eg phenyl), heterocyclyl (eg monoheterocyclyl), cycloalkyl (eg monocycloalkyl) ) or another heteroaryl group (such as another monoheteroaryl group) share two adjacent atoms with each other to form a junctional ring structure, the point of attachment of which can be on any heteroaromatic ring or on other rings, including but not limited to (monoaryl) ) heteroaryl(mono)heteroaryl, (mono)heteroaryl(mono)aryl, (mono)heteroaryl(mono)heterocyclyl, and (mono)heteroaryl(mono) Cycloalkyl such as 5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroarylacyl, 5-6 membered (mono)heteroaryl 5-6 membered (mono)heterocyclyl or 5-6 membered (mono)heteroaryl and C4-6 (mono)cycloalkyl (for example, 5-6 membered heteroaryl and cyclobutyl, 5-6 membered heteroarylcyclopentyl or 5-6 membered heteroarylcyclohexyl), examples of which include but are not limited to indolyl, isoindolyl, indazolyl, benzimidazole, quinolinyl, isoquinoline Linyl,
Figure PCTCN2022079826-appb-000014
Figure PCTCN2022079826-appb-000015
Figure PCTCN2022079826-appb-000016
Wait.
如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br or I.
术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。The term "substituted" means that one or more (eg, one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the designated group, provided that no more than the designated atom is present in the normal valences in the case and the substitutions form stable compounds. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
如果取代基被描述为“任选地被一个或多个......取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。If a substituent is described as "optionally substituted with one or more", the substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be independently and/or together independently Selected optional substituents are substituted. If a nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected optional substitution of substituents.
如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。If substituents are described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4 个、5个或10个。As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。Unless indicated, as used herein, the point of attachment of a substituent can be from any suitable position on the substituent.
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。When the bond of a substituent is shown as a bond connecting two atoms in a ring, such substituent may be bonded to any ring-forming atom in the substitutable ring.
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含于本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘( 2H)、氚( 3H))；碳的同位素(例如 11C、 13C及 14C)；氯的同位素(例如 36Cl)；氟的同位素(例如 18F)；碘的同位素(例如 123I及 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 15O、 17O及 18O)；磷的同位素(例如 32P)；及硫的同位素(例如 35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即 3H)及碳-14(即 14C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如 11C、 18F、 15O及 13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D 2O、丙酮-d 6或DMSO-d 6。 The present invention also includes all pharmaceutically acceptable isotopically-labeled compounds that are identical to the compounds of the present invention, except that one or more atoms have the same atomic number but an atomic mass or mass number different from the atomic mass that predominates in nature or atomic substitution of mass numbers. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (eg, deuterium (2H), tritium ( 3H )); isotopes of carbon (eg, 11C , 13C , and14C ) ; isotopes of chlorine (eg 36 Cl); isotopes of fluorine (eg 18 F); isotopes of iodine (eg 123 I and 125 I); isotopes of nitrogen (eg 13 N and 15 N); isotopes of oxygen (eg 15 O) , 17 O and 18 O); isotopes of phosphorus (eg 32 P); and isotopes of sulfur (eg 35 S). Certain isotopically-labeled compounds of the invention (eg, those incorporating radioisotopes) are useful in drug and/or substrate tissue distribution studies (eg, assays). The radioisotopes tritium (ie 3 H) and carbon-14 (ie 14 C) are particularly useful for this purpose due to their ease of incorporation and ease of detection. Substitution with positron emitting isotopes such as11C , 18F , 15O , and13N can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically-labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically-labeled reagent in place of the previously employed non-labeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, eg, D2O , acetone-d6, or DMSO - d6.
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。例如，亚硝基-肟在溶液中可以下列互变异构形式平衡存在：The term "stereoisomer" refers to isomers formed due to at least one asymmetric center. In compounds having one or more (eg, one, two, three or four) asymmetric centers, it may give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and individual of diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. For example, a nitroso-oxime can exist in solution in equilibrium in the following tautomeric forms:
Figure PCTCN2022079826-appb-000017
Figure PCTCN2022079826-appb-000017
要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。It is to be understood that the scope of this application covers all such in any ratio (eg 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% %) of isomers or mixtures thereof.
本文中可使用实线
Figure PCTCN2022079826-appb-000018
实楔形
Figure PCTCN2022079826-appb-000019
或虚楔形
Figure PCTCN2022079826-appb-000020
描绘本发明的化合物的化学键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。 Solid lines may be used in this article
Figure PCTCN2022079826-appb-000018
solid wedge
Figure PCTCN2022079826-appb-000019
or virtual wedge
Figure PCTCN2022079826-appb-000020
The chemical bonds of the compounds of the present invention are depicted. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, a specific enantiomer, racemic mixture, etc.). The use of real or dashed wedges to delineate bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomer exists. When present in a racemic mixture, real and imaginary wedges are used to define relative, rather than absolute, stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to be available as stereoisomers (which include cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotational isomers, conformational isomers, atropisomers and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (eg, racemic mixtures and pairs of diastereomers).
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
共晶是指药物活性分子与其它生理上可接受的酸、碱、盐、非离子化合物分子以氢键、π-π堆积作用、范德华力和其它非共价键相连而结合在同一晶格中。Co-crystal refers to the combination of drug active molecules and other physiologically acceptable molecules of acids, bases, salts, and non-ionic compounds in the same crystal lattice by hydrogen bonds, π-π stacking, van der Waals forces and other non-covalent bonds. .
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、N-氧化物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。It will also be appreciated that certain compounds of the present invention may exist in free form for use in therapy, or, where appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs which are administered to patients in need thereof After administration, the compounds of the invention or their metabolites or residues can be provided directly or indirectly. Accordingly, references herein to "compounds of the present invention" are also intended to encompass the various derivative forms of the compounds described above.
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。例如六氟磷酸盐、葡甲胺盐等。适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts：Properties，Selection，and Use”(Wiley-VCH，2002)。Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. For example, hexafluorophosphate, meglumine salt and the like. For a review of suitable salts see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002).
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。As used herein, the term "ester" means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release free acid or alcohol forms of the present invention) compound). The compounds of the present invention may themselves also be esters.
本发明的化合物可以溶剂合物(例如水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非 化学计量比存在。The compounds of the present invention may exist in the form of solvates (eg, hydrates), wherein the compounds of the present invention comprise a polar solvent, such as water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物。本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括但不限于用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist，Comprehensive Organic Synthesis，vol.7，pp 748-750；A.R.Katritzky和A.J.Boulton，Eds.，Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry，vol.22，pp 390-392，A.R.Katritzky和A.J.Boulton，Eds.，Academic Press。Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to oxidize to oxides. One skilled in the art will recognize nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include, but are not limited to, use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide , alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane to oxidize heterocycles and tertiary amines. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see e.g.: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; A.R. Katritzky and A.J. Boulton, Eds., Academic Press and G.W.H.Cheeseman and E.S.G.Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。Also included within the scope of the present invention are metabolites of the compounds of the present invention, ie substances formed in the body upon administration of the compounds of the present invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like, of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by methods of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier，1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity when administered into or onto the body can be converted into compounds of the invention having the desired activity, for example, by hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as "pro-moiety (eg as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" Prepared by substituting appropriate functional groups present in the compounds of the present invention.
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在T.W.Greene&P.G.M.Wuts，Protective Groups in Organic Synthesis，JohnWiley&Sons，1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。The present invention also encompasses compounds of the present invention that contain protecting groups. In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecule, thereby forming chemically protected forms of the compounds of the present invention. This can be accomplished by conventional protecting groups, such as those described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。The term "about" means within ±10% of the stated value, preferably within ±5%, more preferably within ±2%.
化合物compound
在一些实施方案中，本发明提供式I的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药：In some embodiments, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, Isotopically labeled compounds, N-oxides or prodrugs:
Figure PCTCN2022079826-appb-000021
Figure PCTCN2022079826-appb-000021
其中：in:
环A选自苯环、5-6元杂芳环和4-10元杂环；Ring A is selected from benzene ring, 5-6 membered heteroaromatic ring and 4-10 membered heterocyclic ring;
环B选自C 3-8烃环、C 6-10芳环、5-10元杂芳环和4-10元杂环； Ring B is selected from C 3-8 hydrocarbon rings, C 6-10 aromatic rings, 5-10 membered heteroaromatic rings and 4-10 membered heterocyclic rings;
W 1、W 2和W 3各自独立地选自N和CR 2； W 1 , W 2 and W 3 are each independently selected from N and CR 2 ;
L 1选自-NR 5-C(＝O)-、-C(＝O)-NR 5-、-NR 5-、-NR 5-S(＝O)-、-NR 5-S(＝O) 2-、-S(＝O)-NR 5-和-S(＝O) 2-NR 5-； L 1 is selected from -NR 5 -C(=O)-, -C(=O)-NR 5 -, -NR 5 -, -NR 5 -S(=O)-, -NR 5 -S(=O ) 2 -, -S(=O)-NR 5 - and -S(=O) 2 -NR 5 -;
R 1选自C 6-10芳基和5-10元杂芳基，其中所述芳基和杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：-NHR 6、羟基、卤素、CN、NO 2、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6卤代烷氧基、C 1-6杂烷基(例如C 1-6烷氧基)、氧代基、C 3-6环烷基和4-10元杂环基； R 1 is selected from C 6-10 aryl and 5-10 membered heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with one or more substituents independently selected from: -NHR 6 , hydroxy, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 1-6 heteroalkyl (eg C 1-6 alkoxy), oxo, C 3-6 cycloalkyl and 4-10 membered heterocyclyl;
R 2在每次出现时各自独立地选自H、CN、羟基、卤素、C 1-6烷基和C 1-6烷氧基，其中所述烷基和烷氧基各自任选地被一个或多个卤素取代； R 2 at each occurrence is independently selected from H, CN, hydroxy, halogen, C 1-6 alkyl and C 1-6 alkoxy, wherein each of said alkyl and alkoxy is optionally replaced by a or multiple halogen substitutions;
R 3为L 2-R 3’； R 3 is L 2 -R 3 ';
L 2在每次出现时各自独立地为直接键或-(CH 2) n-； L 2 is independently at each occurrence a direct bond or -(CH 2 ) n -;
R 3’在每次出现时各自独立地选自H、羟基、卤素、CN、NO 2、C 1-6烷基、C 1-6杂烷基(例如C 1-6烷氧基)、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8环烷氧基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、-NR 20aR 20b、-SR 21、-S(＝O)R 22、-S(＝O) 2R 22、-S(＝O)NR 20aR 20b、-S(＝O) 2NR 20aR 20b、-NR 20aS(＝O)R 20b、-NR 20aS(＝O) 2R 20b、-C(＝O)R 21、-C(＝O)NR 23aR 23b、-NR 23aC(＝O)R 23b和-NR 24aC(＝O)NR 25aR 25b，其中所述烷基、杂烷基(例如烷氧基)、烯基、炔基、环烷基、环烷氧基、杂环基、芳基和杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：羟基、卤素、CN、NO 2、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基和4-10元杂环基； R 3 ' at each occurrence is independently selected from H, hydroxy, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 heteroalkyl (eg C 1-6 alkoxy), C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heterocycle Aryl, -NR 20a R 20b , -SR 21 , -S(=O)R 22 , -S(=O) 2 R 22 , -S(=O)NR 20a R 20b , -S(=O) 2 NR 20a R 20b , -NR 20a S(=O)R 20b , -NR 20a S(=O) 2 R 20b , -C(=O)R 21 , -C(=O)NR 23a R 23b , -NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b wherein said alkyl, heteroalkyl (eg alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkane Each of oxy, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NO2, C1-4alkyl , C1 -4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclic group;
R 4在每次出现时各自独立地选自H、羟基、卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基、C 3-6环烷氧基和4-10元杂环基； R 4 at each occurrence is independently selected from H, hydroxy, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl, C 3-6 cycloalkoxy and 4-10 membered heterocyclyl;
R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-8环烷基和4-10元杂环基，其中所述烷基、环烷基和杂环基各自任选地被一个或多个卤素取代； R and R at each occurrence are each independently selected from H, C 1-6 alkyl , C 3-8 cycloalkyl and 4-10 membered heterocyclyl, wherein said alkyl, cycloalkyl and each of the heterocyclyl groups is optionally substituted with one or more halogens;
R 20a、R 20b、R 23a、R 23b、R 24a、R 25a和R 25b各自独立地选自H、OH、-NHCH 3、-N(CH 3) 2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和4-10元杂环基；其中所述烷基、烷氧基、环烷基和杂环基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、C 1-6烷基和4-10元杂环基； R 20a , R 20b , R 23a , R 23b , R 24a , R 25a and R 25b are each independently selected from H, OH, -NHCH 3 , -N(CH 3 ) 2 , C 1-6 alkyl, C 1 -6 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclyl; wherein each of said alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally independently replaced by one or more Substituted with a substituent selected from the group consisting of halogen, C 1-6 alkyl and 4-10 membered heterocyclyl;
R 21和R 22各自独立地选自C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和4-10元杂环基，其中所述烷基、烷氧基、环烷基和杂环基各自任选地被一个或多个卤素取代； R 21 and R 22 are each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the alkyl, alkoxy , cycloalkyl and heterocyclyl are each optionally substituted with one or more halogens;
m为1、2、3、4或5；m is 1, 2, 3, 4 or 5;
n为1、2或3；并且n is 1, 2 or 3; and
g为1、2、3或4；g is 1, 2, 3 or 4;
条件是：i)当R 1未被取代，环A为吡唑环或咪唑环，并且环B为苯环、异噁唑环或喹啉环时，R 1不是
Figure PCTCN2022079826-appb-000022
并且 The conditions are: i) When R 1 is unsubstituted, Ring A is a pyrazole ring or an imidazole ring, and Ring B is a benzene ring, an isoxazole ring or a quinoline ring, R 1 is not
Figure PCTCN2022079826-appb-000022
and
ii)当R 1为
Figure PCTCN2022079826-appb-000023
且环B为苯环或异噁唑环时，R 1至少被一个-NH 2基团取代。 ii) When R 1 is
Figure PCTCN2022079826-appb-000023
And when ring B is a benzene ring or an isoxazole ring, R 1 is substituted by at least one -NH 2 group.
在某些实施方案中，当R 1为
Figure PCTCN2022079826-appb-000024
且环B为苯环、异噁唑环或喹啉环时，R 1至少被一个-NH 2基团取代。 In certain embodiments, when R 1 is
Figure PCTCN2022079826-appb-000024
And when ring B is a benzene ring, an isoxazole ring or a quinoline ring, R 1 is substituted by at least one -NH 2 group.
在某些实施方案中，R 1选自C 6-10芳基和5-10元杂芳基，其中所述芳基和杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：-NHR 6、羟基、卤素、CN、NO 2、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6卤代烷氧基、C 1-6杂烷基(例如C 1-6烷氧基)、C 3-6环烷基和4-10元杂环基。 In certain embodiments, R 1 is selected from C 6-10 aryl and 5-10 membered heteroaryl, wherein each of said aryl and heteroaryl is optionally selected by one or more independently selected from the following Substituent substitution: -NHR 6 , hydroxyl, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 1- 6 -heteroalkyl (eg C 1-6 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl.
在某些实施方案中，当R 1未被取代时，R 1不是
Figure PCTCN2022079826-appb-000025
In certain embodiments, when R 1 is unsubstituted, R 1 is not
Figure PCTCN2022079826-appb-000025
在某些实施方案中，环A选自苯环、5-6元杂芳环和4-6元杂环。In certain embodiments, Ring A is selected from a benzene ring, a 5-6 membered heteroaromatic ring, and a 4-6 membered heterocyclic ring.
在某些实施方案中，环A为5-6元杂芳环。In certain embodiments, Ring A is a 5-6 membered heteroaromatic ring.
在某些实施方案中，环A为4-6元杂环。In certain embodiments, Ring A is a 4-6 membered heterocycle.
在某些实施方案中，环A为吡啶环、噁唑环、噁二唑环、三唑环或吡唑环。In certain embodiments, Ring A is a pyridine ring, an oxazole ring, an oxadiazole ring, a triazole ring, or a pyrazole ring.
在某些实施方案中，环A为吡啶环、三唑环或吡唑环。In certain embodiments, Ring A is a pyridine ring, a triazole ring, or a pyrazole ring.
在某些实施方案中，环A为
Figure PCTCN2022079826-appb-000026
该基团通过*或**标记的两个位置之一与R 1基团连接，并且通过另一位置与
Figure PCTCN2022079826-appb-000027
基团连接； In certain embodiments, Ring A is
Figure PCTCN2022079826-appb-000026
This group is attached to the R 1 group through one of the two positions marked with * or ** and is attached to the R 1 group through the other position
Figure PCTCN2022079826-appb-000027
group connection;
其中：in:
X和V各自独立地选自C、CR 4和N； X and V are each independently selected from C, CR and N ;
U、Y和Z各自独立地选自O、S、CHR 4、CR 4、NR 4和N； U, Y and Z are each independently selected from O, S, CHR4 , CR4 , NR4 and N;
条件是X、Y、Z、U和V中的至少一个为含杂原子的基团。Provided that at least one of X, Y, Z, U, and V is a heteroatom-containing group.
在某些实施方案中，环A为
Figure PCTCN2022079826-appb-000028
该基团通过*或**标记的两个位置之一与R 1基团连接，并且通过另一位置与
Figure PCTCN2022079826-appb-000029
基团连接； In certain embodiments, Ring A is
Figure PCTCN2022079826-appb-000028
This group is attached to the R 1 group through one of the two positions marked with * or ** and is attached to the R 1 group through the other position
Figure PCTCN2022079826-appb-000029
group connection;
其中：in:
X选自CR 4和N； X is selected from CR 4 and N;
U、Y和Z各自独立地选自CR 4和N； U, Y and Z are each independently selected from CR and N ;
条件是X、U、Y和Z不同时为CR 4。 Provided that X, U, Y and Z are not simultaneously CR4 .
优选地，X为N，U为CH，并且Y和Z均为N；或者X为N，U和Z均为CH，并且Y为N。Preferably, X is N, U is CH, and Y and Z are both N; or X is N, U and Z are both CH, and Y is N.
在某些实施方案中，环A为
Figure PCTCN2022079826-appb-000030
Figure PCTCN2022079826-appb-000031
以上基团通过*标记的位置与R 1基团连接，并且通过**标记的位置与
Figure PCTCN2022079826-appb-000032
基团连接。 In certain embodiments, Ring A is
Figure PCTCN2022079826-appb-000030
Figure PCTCN2022079826-appb-000031
The above groups are linked to the R 1 group through the positions marked with *, and are linked to the R 1 group through the positions marked with **
Figure PCTCN2022079826-appb-000032
group connection.
在某些实施方案中，环A为
Figure PCTCN2022079826-appb-000033
以上基团通过*标记的位置与R 1基团连接，并且通过**标记的位置与
Figure PCTCN2022079826-appb-000034
基团连接。 In certain embodiments, Ring A is
Figure PCTCN2022079826-appb-000033
The above groups are linked to the R 1 group through the positions marked with *, and are linked to the R 1 group through the positions marked with **
Figure PCTCN2022079826-appb-000034
group connection.
在一些实施方案中，本发明的化合物具有式I-A所示的结构：In some embodiments, the compounds of the present invention have the structure shown in Formula I-A:
Figure PCTCN2022079826-appb-000035
Figure PCTCN2022079826-appb-000035
其中：in:
环B、R 1、R 2、R 3、W 1、W 2和W 3如上文对于式I所定义； Ring B, R 1 , R 2 , R 3 , W 1 , W 2 and W 3 are as defined above for formula I;
Z和Y各自独立地选自CH和N；并且Z and Y are each independently selected from CH and N; and
m为1、2或3。m is 1, 2 or 3.
在一些实施方案中，本发明的化合物具有式I-B所示的结构：In some embodiments, the compounds of the present invention have the structure shown in Formula I-B:
Figure PCTCN2022079826-appb-000036
Figure PCTCN2022079826-appb-000036
其中：in:
环B、R 1、R 2、R 3、W 1、W 2和W 3如上文对于式I所定义； Ring B, R 1 , R 2 , R 3 , W 1 , W 2 and W 3 are as defined above for formula I;
Z和Y各自独立地选自CH和N；并且Z and Y are each independently selected from CH and N; and
m为1、2或3。m is 1, 2 or 3.
在一些实施方案中，本发明的化合物具有式I-C所示的结构：In some embodiments, the compounds of the present invention have the structures shown in Formula I-C:
Figure PCTCN2022079826-appb-000037
Figure PCTCN2022079826-appb-000037
其中：in:
R 1、R 2、R 3、W 1、W 2和W 3如上文对于式I所定义； R 1 , R 2 , R 3 , W 1 , W 2 and W 3 are as defined above for formula I;
Z和Y各自独立地选自CH和N；Z and Y are each independently selected from CH and N;
h为0、1、2或3；并且h is 0, 1, 2, or 3; and
m为1、2或3。m is 1, 2 or 3.
在某些实施方案中，本发明提供的式I、式I-A和式I-B中，环B选自C 6-10芳环、5-10元杂芳环和4-10元杂环。 In certain embodiments, in Formula I, Formula IA, and Formula IB provided herein, Ring B is selected from C 6-10 aromatic rings, 5-10 membered heteroaromatic rings, and 4-10 membered heterocyclic rings.
在某些实施方案中，本发明提供的式I、式I-A和式I-B中，环B为C 5-6烃环、苯环、5-10元杂芳环或4-6元杂环。 In certain embodiments, in formula I, formula IA and formula IB provided by the present invention, ring B is a C 5-6 hydrocarbon ring, a benzene ring, a 5-10 membered heteroaromatic ring, or a 4-6 membered heterocyclic ring.
在某些实施方案中，本发明提供的式I、式I-A和式I-B中，环B为C 5-6饱和烃环、苯环、5-6元杂芳环或4-6元杂环。 In certain embodiments, in formula I, formula IA and formula IB provided by the present invention, ring B is a C 5-6 saturated hydrocarbon ring, a benzene ring, a 5-6 membered heteroaromatic ring or a 4-6 membered heterocyclic ring.
在某些实施方案中，本发明提供的式I、式I-A和式I-B中，环B为环戊烷环、苯环、吡啶环、哒嗪环、异喹啉环、二氢吡咯烷环或吡咯烷环。In certain embodiments, in Formula I, Formula I-A and Formula I-B provided by the present invention, Ring B is a cyclopentane ring, a benzene ring, a pyridine ring, a pyridazine ring, an isoquinoline ring, a dihydropyrrolidine ring, or Pyrrolidine ring.
在某些实施方案中，本发明提供的式I、式I-A和式I-B中，环B为苯环、5-6元杂芳环或4-6元杂环；优选地，环B为苯环、吡啶环或吡咯烷环。In certain embodiments, in formula I, formula I-A and formula I-B provided by the present invention, ring B is a benzene ring, a 5-6 membered heteroaromatic ring or a 4-6 membered heterocyclic ring; preferably, ring B is a benzene ring , pyridine ring or pyrrolidine ring.
在某些实施方案中，本发明提供的式I、式I-A和式I-B中，环B为苯环或5-6元杂芳环；优选地，环B为苯环或吡啶环。In certain embodiments, in formula I, formula I-A and formula I-B provided by the present invention, ring B is a benzene ring or a 5-6 membered heteroaromatic ring; preferably, ring B is a benzene ring or a pyridine ring.
在某些实施方案中，本发明提供的式I、式I-A和式I-B中，环B为4-6元杂环；优选地，环B为吡咯烷环。In certain embodiments, in Formula I, Formula I-A and Formula I-B provided by the present invention, Ring B is a 4-6 membered heterocycle; preferably, Ring B is a pyrrolidine ring.
在某些实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，W 1、W 2和W 3各自独立地选自N、CH和CF。 In certain embodiments, in Formula I , Formula IA, Formula IB, and Formula IC provided herein, W1, W2, and W3 are each independently selected from N, CH , and CF.
在某些实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，
Figure PCTCN2022079826-appb-000038
为苯环或吡啶环。 In certain embodiments, the present invention provides formula I, formula IA, formula IB and formula IC,
Figure PCTCN2022079826-appb-000038
It is a benzene ring or a pyridine ring.
在某些实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，W 1、W 2和W 3各自独立地选自N和CH。 In certain embodiments, in Formula I , Formula IA, Formula IB, and Formula IC provided herein, W1, W2, and W3 are each independently selected from N and CH .
在某些实施方案中，L 1选自-NR 5-C(＝O)-、-C(＝O)-NR 5-、-NR 5-、-NR 5-S(＝O) 2-和-S(＝O) 2-NR 5-；其中，R 5在每次出现时独立地选自H、C 1-4烷基、C 3-6环烷基和4-6元杂环基，其中所述烷基、环烷基和杂环基各自任选地被一个或多个卤素取代。 In certain embodiments, L 1 is selected from the group consisting of -NR 5 -C(=O)-, -C(=O)-NR 5 -, -NR 5 -, -NR 5 -S(=O) 2 - and -S(=O) 2 -NR 5 -; wherein R 5 at each occurrence is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl groups are each optionally substituted with one or more halogens.
在某些实施方案中，L 1选自-NR 5-C(＝O)-、-C(＝O)-NR 5-和-NR 5-；其中，R 5在每次出现时独立地选自H、C 1-4烷基、C 3-6环烷基和4-6元杂环基，其中所述烷基、环烷基和杂环基各自任选地被一个或多个卤素取代；优选地，R 5在每次出现时独立地为H。 In certain embodiments, L 1 is selected from -NR 5 -C(=O)-, -C(=O)-NR 5 - and -NR 5 -; wherein R 5 is independently selected at each occurrence from H, C 1-4 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl is optionally substituted with one or more halogens ; preferably, R5 is independently H at each occurrence.
在某些实施方案中，L 1为-NH-、-NH-C(＝O)-或-C(＝O)-NH-。 In certain embodiments, L1 is -NH-, -NH - C(=O)-, or -C(=O)-NH-.
在某些实施方案中，L 1为-NH-C(＝O)-或-C(＝O)-NH-。 In certain embodiments, L1 is -NH - C(=O)- or -C(=O)-NH-.
在某些实施方案中，本发明提供的式I、式I-A和式I-B中，R 1至少被一个-NHR 6基团取代；优选地，R 1至少被一个-NH 2基团取代。 In certain embodiments, in formula I, formula IA and formula IB provided by the present invention, R 1 is substituted with at least one -NHR 6 group; preferably, R 1 is substituted with at least one -NH 2 group.
在某些实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，R 1选自苯基、萘基和5-10元杂芳基，其中所述苯基、萘基和杂芳基各自任选地被一个或多个独立地选自下列的取代基取代： -NHR 6、羟基、卤素、CN、NO 2、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、氧代基、C 3-6环烷基和4-10元杂环基。 In certain embodiments, in formula I, formula IA, formula IB and formula IC provided by the present invention, R 1 is selected from phenyl, naphthyl and 5-10 membered heteroaryl, wherein said phenyl, naphthyl and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: -NHR 6 , hydroxy, halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), oxo, C 3-6 cycloalkyl and 4-10 membered Heterocyclyl.
在某些实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，R 1选自苯基、萘基、吡啶基、吡唑基、噻唑基、嘧啶基和9-10元并环杂芳基，其中所述苯基、萘基、吡啶基、吡唑基、噻唑基、嘧啶基和9-10元并环杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：-NHR 6、羟基、卤素、CN、NO 2、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、氧代基、C 3-6环烷基和4-10元杂环基。 In certain embodiments, in formula I, formula IA, formula IB and formula IC provided by the present invention, R 1 is selected from phenyl, naphthyl, pyridyl, pyrazolyl, thiazolyl, pyrimidinyl and 9-10 A membered paracyclic heteroaryl, wherein the phenyl, naphthyl, pyridyl, pyrazolyl, thiazolyl, pyrimidinyl and 9-10 membered paracyclic heteroaryl groups are each optionally independently selected by one or more Substituted from the following substituents: -NHR 6 , hydroxy, halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), oxo, C 3-6 cycloalkyl and 4-10 membered heterocyclyl.
在某些实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，R 1选自
Figure PCTCN2022079826-appb-000039
Figure PCTCN2022079826-appb-000040
Figure PCTCN2022079826-appb-000041
其中所述
Figure PCTCN2022079826-appb-000042
Figure PCTCN2022079826-appb-000043
各自任选地被一个或多个独立地选自下列的取代基取代：羟基、卤素、CN、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基和4-10元杂环基。 In certain embodiments, in formula I, formula IA, formula IB and formula IC provided by the present invention, R 1 is selected from
Figure PCTCN2022079826-appb-000039
Figure PCTCN2022079826-appb-000040
Figure PCTCN2022079826-appb-000041
wherein the
Figure PCTCN2022079826-appb-000042
Figure PCTCN2022079826-appb-000043
Each is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1- 4 -haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl.
在优选的实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，R 1选自
Figure PCTCN2022079826-appb-000044
Figure PCTCN2022079826-appb-000045
其中所述
Figure PCTCN2022079826-appb-000046
Figure PCTCN2022079826-appb-000047
各自任选地被一个或多个独立地选自下列的取代基取代：羟基、卤素、CN、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基和4-10元杂环基。 In a preferred embodiment, in formula I, formula IA, formula IB and formula IC provided by the present invention, R 1 is selected from
Figure PCTCN2022079826-appb-000044
Figure PCTCN2022079826-appb-000045
wherein the
Figure PCTCN2022079826-appb-000046
Figure PCTCN2022079826-appb-000047
Each is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1- 4 -haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl.
在优选的实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，R 1选自
Figure PCTCN2022079826-appb-000048
Figure PCTCN2022079826-appb-000049
Figure PCTCN2022079826-appb-000050
In a preferred embodiment, in formula I, formula IA, formula IB and formula IC provided by the present invention, R 1 is selected from
Figure PCTCN2022079826-appb-000048
Figure PCTCN2022079826-appb-000049
Figure PCTCN2022079826-appb-000050
在某些实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，R 1选自
Figure PCTCN2022079826-appb-000051
Figure PCTCN2022079826-appb-000052
其中所述
Figure PCTCN2022079826-appb-000053
Figure PCTCN2022079826-appb-000054
各自任选地被一个或多个独立地选自下列的取代基取代：羟基、卤素、CN、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基和4-10元杂环基。 In certain embodiments, in formula I, formula IA, formula IB and formula IC provided by the present invention, R 1 is selected from
Figure PCTCN2022079826-appb-000051
Figure PCTCN2022079826-appb-000052
wherein the
Figure PCTCN2022079826-appb-000053
Figure PCTCN2022079826-appb-000054
Each is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1- 4 -haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl.
在优选的实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，R 1选自
Figure PCTCN2022079826-appb-000055
Figure PCTCN2022079826-appb-000056
其中所述
Figure PCTCN2022079826-appb-000057
Figure PCTCN2022079826-appb-000058
各自任选地被一个或多个独立地选自下列的取代基取代：羟基、卤素、CN、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基和4-10元杂环基。 In a preferred embodiment, in formula I, formula IA, formula IB and formula IC provided by the present invention, R 1 is selected from
Figure PCTCN2022079826-appb-000055
Figure PCTCN2022079826-appb-000056
wherein the
Figure PCTCN2022079826-appb-000057
Figure PCTCN2022079826-appb-000058
Each is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1- 4 -haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl.
在优选的实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，R 1选自
Figure PCTCN2022079826-appb-000059
Figure PCTCN2022079826-appb-000060
In a preferred embodiment, in formula I, formula IA, formula IB and formula IC provided by the present invention, R 1 is selected from
Figure PCTCN2022079826-appb-000059
Figure PCTCN2022079826-appb-000060
在某些实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，R 2在每次出现时各自独立地选自H、CN、卤素、C 1-4烷基和C 1-4烷氧基，其中所述烷基和烷氧基各自任选地被一个或多个卤素取代；优选地，R 2在每次出现时各自独立地为H、卤素或C 1-4烷基；更优选地，R 2在每次出现时各自独立地为H、F或甲基。 In certain embodiments, in Formula I, Formula IA, Formula IB, and Formula IC provided herein, each occurrence of R 2 is independently selected from H, CN, halogen, C 1-4 alkyl, and C 1-4 alkoxy, wherein said alkyl and alkoxy are each optionally substituted with one or more halogens ; preferably, each occurrence of R is independently H, halogen, or C1-4 alkyl ; more preferably, each occurrence of R2 is independently H, F or methyl.
在某些实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，R 2在每次出现时各自独立地为H或C 1-4烷基；更优选地，R 2在每次出现时各自独立地为H或甲基。 In certain embodiments, in Formula I, Formula IA, Formula IB, and Formula IC provided herein, each occurrence of R 2 is independently H or C 1-4 alkyl; more preferably, R 2 Each occurrence is independently H or methyl.
在某些实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，R 3’在每次出现时各自独立地选自H、羟基、卤素、CN、C 1-4烷基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基、C 3-6环烷氧基、4-6元杂环基、苯基、5-6元杂芳基、-NR 20aR 20b、-SR 21、-S(＝O)R 22、-S(＝O) 2R 22、-S(＝O)NR 20aR 20b、 -S(＝O) 2NR 20aR 20b、-NR 20aS(＝O)R 20b、-NR 20aS(＝O) 2R 20b、-C(＝O)R 21、-C(＝O)NR 23aR 23b、-NR 23aC(＝O)R 23b和-NR 24aC(＝O)NR 25aR 25b，其中所述烷基、杂烷基(例如烷氧基)、环烷基、环烷氧基、杂环基、苯基和杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：羟基、卤素、CN、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基和4-10元杂环基。 In certain embodiments, in Formula I, Formula IA, Formula IB, and Formula IC provided herein, each occurrence of R 3 ' is independently selected from H, hydroxy, halogen, CN, C 1-4 alkanes base, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 4-6 membered heterocyclyl, phenyl, 5- 6-membered heteroaryl, -NR 20a R 20b , -SR 21 , -S(=O)R 22 , -S(=O) 2 R 22 , -S(=O)NR 20a R 20b , -S(= O) 2 NR 20a R 20b , -NR 20a S(=O)R 20b , -NR 20a S(=O) 2 R 20b , -C(=O)R 21 , -C(=O)NR 23a R 23b , -NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b , wherein the alkyl, heteroalkyl (eg alkoxy), cycloalkyl, cycloalkoxy, Heterocyclyl, phenyl, and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl.
在某些实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，R 3’在每次出现时各自独立地选自H、卤素、CN、C 1-4烷基、C 1-4烷氧基和4-6元杂环基，其中所述烷基、烷氧基和杂环基任选地被一个或多个独立地选自卤素、CN和C 1-4烷基的取代基取代； In certain embodiments, in Formula I, Formula IA, Formula IB, and Formula IC provided herein, each occurrence of R 3 ' is independently selected from H, halogen, CN, C 1-4 alkyl, C 1-4 alkoxy and 4-6 membered heterocyclyl, wherein the alkyl, alkoxy and heterocyclyl are optionally selected by one or more independently selected from halogen, CN and C 1-4 alkane Substituent substitution of the base;
在某些实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，R 3’在每次出现时各自独立地选自H、卤素、C 1-4烷基和C 1-4烷氧基，其中所述烷基和烷氧基任选地被一个或多个卤素取代。 In certain embodiments, in Formula I, Formula IA, Formula IB, and Formula IC provided herein, each occurrence of R 3 ' is independently selected from H, halogen, C 1-4 alkyl, and C 1 at each occurrence. -4 alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogens.
在某些实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，R 3’在每次出现时各自独立地选自H、F、Cl、CN、
Figure PCTCN2022079826-appb-000061
-CHF 2、-CF 3、-OCH 3、-OCF 3、吗啉基、N-甲基哌嗪基。 In certain embodiments, in Formula I, Formula IA, Formula IB, and Formula IC provided herein, each occurrence of R3 ' is independently selected from H, F, Cl, CN,
Figure PCTCN2022079826-appb-000061
-CHF 2 , -CF 3 , -OCH 3 , -OCF 3 , morpholinyl, N-methylpiperazinyl.
在某些实施方案中，本发明提供的式I、式I-A、式I-B和式I-C中，R 3’在每次出现时各自独立地选自H、F、Cl、-CF 3和-OCF 3。 In certain embodiments, in Formula I, Formula IA, Formula IB, and Formula IC provided herein, each occurrence of R3 ' is independently selected from the group consisting of H, F, Cl, -CF3 , and -OCF3 . .
在某些实施方案中，R 4选自H、卤素、C 1-4烷基和C 1-4杂烷基；优选地，R 4为H或甲基；更优选地，R 4为H。 In certain embodiments, R 4 is selected from H, halogen, C 1-4 alkyl, and C 1-4 heteroalkyl; preferably, R 4 is H or methyl; more preferably, R 4 is H.
在某些实施方案中，R 6在每次出现时独立地选自H、C 1-4烷基、C 3-6环烷基和4-6元杂环基，其中所述烷基、环烷基和杂环基各自任选地被一个或多个卤素取代；优选地，R 6在每次出现时独立地为H。 In certain embodiments, R at each occurrence is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, and 4-6 membered heterocyclyl, wherein said alkyl, cyclo Alkyl and heterocyclyl are each optionally substituted with one or more halogens ; preferably, R6 is independently H at each occurrence.
在某些实施方案中，R 20a、R 20b、R 23a、R 23b、R 24a、R 25a和R 25b各自独立地选自H、C 1-6烷基、C 3-8环烷基和4-10元杂环基；所述烷基、环烷基和杂环基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、C 1-6烷基和4-10元杂环基。 In certain embodiments, R 20a , R 20b , R 23a , R 23b , R 24a , R 25a and R 25b are each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl and 4 -10-membered heterocyclyl; the alkyl, cycloalkyl and heterocyclyl groups are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6 alkyl, and 4-10 membered heterocyclic group.
在某些实施方案中，R 20a、R 20b、R 23a、R 23b、R 24a、R 25a和R 25b各自独立地选自H、C 1-4烷基和C 3-6环烷基，其中所述烷基和环烷基各自任选地被一个或多个卤素取代。 In certain embodiments, R 20a , R 20b , R 23a , R 23b , R 24a , R 25a and R 25b are each independently selected from H, C 1-4 alkyl and C 3-6 cycloalkyl, wherein The alkyl and cycloalkyl groups are each optionally substituted with one or more halogens.
在某些实施方案中，R 21和R 22各自独立地选自C 1-4烷基、C 1-4烷氧基、C 3-6环烷基和4-6元杂环基，其中所述烷基、烷氧基、环烷基和杂环基各自任选地被一个或多个卤素取代。 In certain embodiments, R 21 and R 22 are each independently selected from C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, and 4-6 membered heterocyclyl, wherein The alkyl, alkoxy, cycloalkyl and heterocyclyl groups are each optionally substituted with one or more halogens.
在某些实施方案中，m为1、2或3。In certain embodiments, m is 1, 2, or 3.
在某些实施方案中，n为1或2。In certain embodiments, n is 1 or 2.
在某些实施方案中，g为1或2。In certain embodiments, g is 1 or 2.
在某些实施方案中，本发明提供的式I化合物中，环A为
Figure PCTCN2022079826-appb-000062
该基团通过*或**标记的两个位置之一与R 1基团连接，并且通过另一位置与
Figure PCTCN2022079826-appb-000063
基团连接； In certain embodiments, in the compounds of formula I provided by the present invention, Ring A is
Figure PCTCN2022079826-appb-000062
This group is attached to the R 1 group through one of the two positions marked with * or ** and is attached to the R 1 group through the other position
Figure PCTCN2022079826-appb-000063
group connection;
其中：in:
X选自CR 4和N； X is selected from CR 4 and N;
U、Y和Z各自独立地选自CR 4和N； U, Y and Z are each independently selected from CR and N ;
条件是X、U、Y和Z不同时为CR 4； provided that X, U, Y and Z are not simultaneously CR 4 ;
环B为苯环或5-6元杂芳环；Ring B is a benzene ring or a 5-6 membered heteroaromatic ring;
W 1、W 2和W 3各自独立地选自N和CH； W 1 , W 2 and W 3 are each independently selected from N and CH;
L 1为-NH-C(＝O)-或-C(＝O)-NH-； L 1 is -NH-C(=O)- or -C(=O)-NH-;
R 1选自苯基、萘基和5-10元杂芳基，其中所述苯基、萘基和杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：-NHR 6、羟基、卤素、CN、NO 2、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基和4-10元杂环基； R 1 is selected from phenyl, naphthyl and 5-10 membered heteroaryl, wherein each of said phenyl, naphthyl and heteroaryl is optionally substituted with one or more substituents independently selected from:- NHR 6 , hydroxy, halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl ( For example C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl;
R 2在每次出现时各自独立地选自H、CN、卤素、C 1-4烷基和C 1-4烷氧基，其中所述烷基和烷氧基各自任选地被一个或多个卤素取代； R 2 at each occurrence is independently selected from H, CN, halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein each of said alkyl and alkoxy is optionally replaced by one or more halogen substitution;
R 3为L 2-R 3’； R 3 is L 2 -R 3 ';
L 2在每次出现时各自独立地为直接键或-(CH 2) n-； L 2 is independently at each occurrence a direct bond or -(CH 2 ) n -;
R 3’在每次出现时各自独立地选自H、卤素、C 1-4烷基和C 1-4烷氧基，其中所述烷基和烷氧基任 选地被一个或多个卤素取代； R 3 ' at each occurrence is independently selected from H, halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein said alkyl and alkoxy are optionally replaced by one or more halogens replace;
R 4选自H、卤素、C 1-4烷基和C 1-4杂烷基； R 4 is selected from H, halogen, C 1-4 alkyl and C 1-4 heteroalkyl;
R 6在每次出现时独立地选自H、C 1-4烷基、C 3-6环烷基和4-6元杂环基，其中所述烷基、环烷基和杂环基各自任选地被一个或多个卤素取代； R 6 at each occurrence is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl optionally substituted with one or more halogens;
m为1、2或3；m is 1, 2 or 3;
n为1、2或3；n is 1, 2 or 3;
g为1或2。g is 1 or 2.
在某些实施方案中，本发明提供的式I化合物中，环A为
Figure PCTCN2022079826-appb-000064
该基团通过*或**标记的两个位置之一与R 1基团连接，并且通过另一位置与
Figure PCTCN2022079826-appb-000065
基团连接； In certain embodiments, in the compounds of formula I provided by the present invention, Ring A is
Figure PCTCN2022079826-appb-000064
This group is attached to the R 1 group through one of the two positions marked with * or ** and is attached to the R 1 group through the other position
Figure PCTCN2022079826-appb-000065
group connection;
其中：in:
X选自CR 4和N； X is selected from CR 4 and N;
U、Y和Z各自独立地选自CR 4和N； U, Y and Z are each independently selected from CR and N ;
条件是X、U、Y和Z不同时为CR 4； provided that X, U, Y and Z are not simultaneously CR 4 ;
环B为4-6元杂环；Ring B is a 4-6 membered heterocycle;
W 1、W 2和W 3各自独立地选自N和CH； W 1 , W 2 and W 3 are each independently selected from N and CH;
L 1为-NH-C(＝O)-或-C(＝O)-NH-； L 1 is -NH-C(=O)- or -C(=O)-NH-;
R 1选自苯基、萘基和5-10元杂芳基，其中所述苯基、萘基和杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：-NHR 6、羟基、卤素、CN、NO 2、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基和4-10元杂环基； R 1 is selected from phenyl, naphthyl and 5-10 membered heteroaryl, wherein each of said phenyl, naphthyl and heteroaryl is optionally substituted with one or more substituents independently selected from:- NHR 6 , hydroxy, halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl ( For example C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl;
R 2在每次出现时各自独立地选自H、CN、卤素、C 1-4烷基和C 1-4烷氧基，其中所述烷基和烷氧基各自任选地被一个或多个卤素取代； R 2 at each occurrence is independently selected from H, CN, halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein each of said alkyl and alkoxy is optionally replaced by one or more halogen substitution;
R 3为L 2-R 3’； R 3 is L 2 -R 3 ';
L 2在每次出现时各自独立地为直接键或-(CH 2) n-； L 2 is independently at each occurrence a direct bond or -(CH 2 ) n -;
R 3’在每次出现时各自独立地选自H、卤素、C 1-4烷基和C 1-4烷氧基，其中所述烷基和烷氧基任选地被一个或多个卤素取代； R 3 ' at each occurrence is independently selected from H, halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein said alkyl and alkoxy are optionally replaced by one or more halogens replace;
R 4选自H、卤素、C 1-4烷基和C 1-4杂烷基； R 4 is selected from H, halogen, C 1-4 alkyl and C 1-4 heteroalkyl;
R 6在每次出现时独立地选自H、C 1-4烷基、C 3-6环烷基和4-6元杂环基，其中所述烷基、环烷基和杂环基各自任选地被一个或多个卤素取代； R 6 at each occurrence is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl optionally substituted with one or more halogens;
m为1、2或3；m is 1, 2 or 3;
n为1、2或3；n is 1, 2 or 3;
g为1或2。g is 1 or 2.
在某些实施方案中，本发明提供的式I化合物中，环A为
Figure PCTCN2022079826-appb-000066
Figure PCTCN2022079826-appb-000067
以上基团通过*标记的位置与R 1基团连接，并且通过**标记的位置与
Figure PCTCN2022079826-appb-000068
基团连接； In certain embodiments, in the compounds of formula I provided by the present invention, Ring A is
Figure PCTCN2022079826-appb-000066
Figure PCTCN2022079826-appb-000067
The above groups are linked to the R 1 group through the positions marked with *, and are linked to the R 1 group through the positions marked with **
Figure PCTCN2022079826-appb-000068
group connection;
环B为环戊烷环、苯环、吡啶环、哒嗪环、异喹啉环、二氢吡咯烷环或吡咯烷环；Ring B is a cyclopentane ring, a benzene ring, a pyridine ring, a pyridazine ring, an isoquinoline ring, a dihydropyrrolidine ring or a pyrrolidine ring;
W 1、W 2和W 3各自独立地选自N、CH和CF； W 1 , W 2 and W 3 are each independently selected from N, CH and CF;
L 1为-NH-、-NH-C(＝O)-或-C(＝O)-NH-； L 1 is -NH-, -NH-C(=O)- or -C(=O)-NH-;
R 1选自
Figure PCTCN2022079826-appb-000069
Figure PCTCN2022079826-appb-000070
R 1 is selected from
Figure PCTCN2022079826-appb-000069
Figure PCTCN2022079826-appb-000070
R 2在每次出现时各自独立地为H、卤素或C 1-4烷基； R 2 is independently at each occurrence H, halogen or C 1-4 alkyl;
R 3’在每次出现时各自独立地选自H、卤素、CN、C 1-4烷基、C 1-4烷氧基和4-6元杂环基，其中所述烷基、烷氧基和杂环基任选地被一个或多个独立地选自卤素、CN和C 1-4烷基的取代基取代； R 3 ' at each occurrence is independently selected from H, halogen, CN, C 1-4 alkyl, C 1-4 alkoxy and 4-6 membered heterocyclyl, wherein said alkyl, alkoxy radical and heterocyclyl are optionally substituted with one or more substituents independently selected from halogen, CN and C 1-4 alkyl;
R 4为H或甲基； R 4 is H or methyl;
m为1、2或3；m is 1, 2 or 3;
n为1、2或3；n is 1, 2 or 3;
g为1或2。g is 1 or 2.
在某些实施方案中，本发明提供的式I、式I-A和式I-B化合物中，环B为苯环或5-6元杂芳环；In certain embodiments, in the compounds of formula I, formula I-A and formula I-B provided by the present invention, ring B is a benzene ring or a 5-6 membered heteroaromatic ring;
W 1、W 2和W 3各自独立地选自N和CH； W 1 , W 2 and W 3 are each independently selected from N and CH;
L 1为-NH-C(＝O)-或-C(＝O)-NH-； L 1 is -NH-C(=O)- or -C(=O)-NH-;
R 1选自
Figure PCTCN2022079826-appb-000071
Figure PCTCN2022079826-appb-000072
R 1 is selected from
Figure PCTCN2022079826-appb-000071
Figure PCTCN2022079826-appb-000072
R 2在每次出现时各自独立地为H或C 1-4烷基； R 2 is independently at each occurrence H or C 1-4 alkyl;
R 3’在每次出现时各自独立地选自H、卤素、C 1-4烷基和C 1-4烷氧基，其中所述烷基和烷氧基任选地被一个或多个卤素取代； R 3 ' at each occurrence is independently selected from H, halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein said alkyl and alkoxy are optionally replaced by one or more halogens replace;
R 4选自H、卤素、C 1-4烷基和C 1-4杂烷基； R 4 is selected from H, halogen, C 1-4 alkyl and C 1-4 heteroalkyl;
m为1、2或3；m is 1, 2 or 3;
g为1或2。g is 1 or 2.
在某些实施方案中，本发明提供的式I、式I-A和式I-B化合物中，环B为4-6元杂环；In certain embodiments, in the compounds of formula I, formula I-A and formula I-B provided by the present invention, ring B is a 4-6 membered heterocycle;
W 1、W 2和W 3各自独立地选自N和CH； W 1 , W 2 and W 3 are each independently selected from N and CH;
L 1为-NH-C(＝O)-或-C(＝O)-NH-； L 1 is -NH-C(=O)- or -C(=O)-NH-;
R 1选自苯基、萘基和5-10元杂芳基，其中所述苯基、萘基和杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：-NHR 6、羟基、卤素、CN、NO 2、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基和4-10元杂环基； R 1 is selected from phenyl, naphthyl and 5-10 membered heteroaryl, wherein each of said phenyl, naphthyl and heteroaryl is optionally substituted with one or more substituents independently selected from:- NHR 6 , hydroxy, halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl ( For example C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl;
R 2在每次出现时各自独立地为H或C 1-4烷基； R 2 is independently at each occurrence H or C 1-4 alkyl;
R 3’在每次出现时各自独立地选自H、卤素、C 1-4烷基和C 1-4烷氧基，其中所述烷基和烷氧基任选地被一个或多个卤素取代； R 3 ' at each occurrence is independently selected from H, halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein said alkyl and alkoxy are optionally replaced by one or more halogens replace;
R 4选自H、卤素、C 1-4烷基和C 1-4杂烷基； R 4 is selected from H, halogen, C 1-4 alkyl and C 1-4 heteroalkyl;
m为1、2或3；m is 1, 2 or 3;
g为1或2。g is 1 or 2.
在某些实施方案中，本发明提供的式I、式I-A和式I-B化合物中，环B为4-6元杂环；In certain embodiments, in the compounds of formula I, formula I-A and formula I-B provided by the present invention, ring B is a 4-6 membered heterocycle;
W 1、W 2和W 3各自独立地选自N和CH； W 1 , W 2 and W 3 are each independently selected from N and CH;
L 1为-NH-C(＝O)-或-C(＝O)-NH-； L 1 is -NH-C(=O)- or -C(=O)-NH-;
R 1选自
Figure PCTCN2022079826-appb-000073
Figure PCTCN2022079826-appb-000074
R 1 is selected from
Figure PCTCN2022079826-appb-000073
Figure PCTCN2022079826-appb-000074
R 2在每次出现时各自独立地为H或C 1-4烷基； R 2 is independently at each occurrence H or C 1-4 alkyl;
R 3’在每次出现时各自独立地选自H、卤素、C 1-4烷基和C 1-4烷氧基，其中所述烷基和烷氧基任选地被一个或多个卤素取代； R 3 ' at each occurrence is independently selected from H, halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein said alkyl and alkoxy are optionally replaced by one or more halogens replace;
R 4选自H、卤素、C 1-4烷基和C 1-4杂烷基； R 4 is selected from H, halogen, C 1-4 alkyl and C 1-4 heteroalkyl;
m为1、2或3；m is 1, 2 or 3;
g为1或2。g is 1 or 2.
本发明涵盖以上各实施方案的任意组合。The present invention encompasses any combination of the above embodiments.
在一些实施方案中，本发明的化合物包括，但不限于：In some embodiments, compounds of the present invention include, but are not limited to:
Figure PCTCN2022079826-appb-000075
Figure PCTCN2022079826-appb-000075
Figure PCTCN2022079826-appb-000076
Figure PCTCN2022079826-appb-000076
Figure PCTCN2022079826-appb-000077
Figure PCTCN2022079826-appb-000077
制备方法Preparation
在某些实施方案中，本发明提供制备式I-A的化合物的方法，其包括以下步骤：In certain embodiments, the present invention provides a method of preparing a compound of Formula I-A, comprising the steps of:
路线Aroute A
Figure PCTCN2022079826-appb-000078
Figure PCTCN2022079826-appb-000078
其中：in:
环B、R 1、R 2、R 3、Z、Y、W 1、W 2、W 3和m如上文对于式I-A所定义；且 Rings B, R 1 , R 2 , R 3 , Z, Y, W 1 , W 2 , W 3 and m are as defined above for formula IA; and
Hal为Br或I。Hal is Br or I.
第一步：化合物I-A-1和含硼试剂反应生成化合物I-A-2；The first step: compound I-A-1 reacts with boron-containing reagent to generate compound I-A-2;
可使用的含硼试剂例如为B 2(pin) 2。可使用的催化剂例如为Pd(OAc) 2、Pd(PPh 3) 4、Pd(dppf)Cl 2等，可使用的配体例如为PPh 3、DPPF、BINOL、BINAP或Pcy 3等，可使用的碱例如为Cs 2CO 3、K 3PO 4、Na 2CO 3、KOAc、NaHCO 3或K 2CO 3等。可使用的溶剂例如为1，4-二氧六环、DMF、DMSO或CH 3CN。反应温度例如为50℃至120℃。 A boron-containing reagent that can be used is, for example, B 2 (pin) 2 . Catalysts that can be used are, for example, Pd(OAc) 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , etc., and ligands that can be used are PPh 3 , DPPF, BINOL, BINAP or Pcy 3 , etc. The base is, for example, Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , KOAc, NaHCO 3 or K 2 CO 3 or the like. Solvents that can be used are, for example, 1,4-dioxane, DMF, DMSO or CH 3 CN. The reaction temperature is, for example, 50°C to 120°C.
第二步：化合物I-A-2和I-A-3经缩合反应生成化合物I-A-4；The second step: Compound I-A-2 and I-A-3 undergo condensation reaction to generate compound I-A-4;
所述缩合反应优选在缩合剂和碱的存在下进行。可用的缩合剂为T 3P、HATU、CDI、HOBt、DMAP、DCC、DIC、EDC、HBTU、HCTU或PyBOP等。可用的碱为吡啶、TEA、DIPEA、 tBuOK、 tBuONa、 tBuOLi、NaH、NaOH、Cs 2CO 3、K 3PO 4或Na 2CO 3等。可用的溶剂为吡啶、THF、DCM、DCE、MeOH、EtOH、DMF、DMSO、丙酮、CH 3CN、1，4-二氧六环或甲苯等。反应温度为0℃至120℃，例如室温。 The condensation reaction is preferably carried out in the presence of a condensing agent and a base. Useful condensing agents are T3P , HATU, CDI, HOBt, DMAP, DCC, DIC, EDC, HBTU, HCTU or PyBOP and the like. Useful bases are pyridine, TEA, DIPEA , tBuOK , tBuONa , tBuOLi , NaH , NaOH , Cs2CO3 , K3PO4 or Na2CO3 and the like. Useful solvents are pyridine, THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, acetone, CH3CN , 1,4-dioxane or toluene and the like. The reaction temperature is 0°C to 120°C, eg, room temperature.
或者先将化合物I-A-3制备成酰卤，可用的酰卤化试剂如氯化亚砜、草酰氯等。该反应可在少量DMF催化下进行，也可在不含DMF的体系中进行；反应温度为0℃至120℃；所生成的酰卤化合物再与化合物I-A-2在碱存在下反应生成化合物I-A-4。可用的碱为TEA或DIPEA等；可用的溶剂为THF、DCM、DCE、CH 3CN、1，4-二氧六环或甲苯等；该反应可在0℃至120℃下进行。 Alternatively, the compound IA-3 can be prepared as an acid halide first, and the available acid halide reagents are thionyl chloride, oxalyl chloride and the like. The reaction can be carried out under the catalysis of a small amount of DMF or in a system without DMF; the reaction temperature is 0°C to 120°C; the resulting acid halide compound is then reacted with compound IA-2 in the presence of a base to form compound IA -4. The usable base is TEA or DIPEA, etc.; the usable solvent is THF, DCM, DCE, CH3CN , 1,4-dioxane or toluene, etc.; the reaction can be carried out at 0°C to 120°C.
第三步：化合物I-A-4经水解反应生成化合物I-A-5；The third step: compound I-A-4 is hydrolyzed to generate compound I-A-5;
所述水解反应优选在碱的存在下进行。可用的碱为NH 4OAc、NaIO 4、NaOH或KOH等。可用的溶剂为THF、MeOH、EtOH、CH 3CN、1，4-二氧六环或水等。反应温度为0℃至80℃，例如室温或50℃。 The hydrolysis reaction is preferably carried out in the presence of a base. Useful bases are NH4OAc , NaIO4 , NaOH or KOH and the like. Useful solvents are THF, MeOH, EtOH, CH3CN , 1,4-dioxane or water and the like. The reaction temperature is 0°C to 80°C, eg, room temperature or 50°C.
第四步：化合物I-A-6和I-A-7经偶联反应(如Suzuki反应)生成化合物I-A-8；The fourth step: compound I-A-6 and I-A-7 are subjected to coupling reaction (such as Suzuki reaction) to generate compound I-A-8;
所述偶联反应可使用的催化剂例如为Pd(OAc) 2、Pd(PPh 3) 4或Pd(dppf)Cl 2等；可使用的碱例如为Cs 2CO 3、K 3PO 4、Na 2CO 3、AcOK、NaHCO 3或K 2CO 3等，可使用的配体例如为PPh 3、DPPF、BINOL、BINAP或PCy 3等，可使用的溶剂例如为甲苯/H 2O、1，4-二氧六环/H 2O、DMF/H 2O、DMSO/H 2O或CH 3CN/H 2O等，且反应温度可为60℃至120℃。 The catalyst that can be used in the coupling reaction is, for example, Pd(OAc) 2 , Pd(PPh 3 ) 4 or Pd(dppf)Cl 2 , etc.; the base that can be used is, for example, Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , AcOK, NaHCO 3 or K 2 CO 3 , etc., the available ligands are PPh 3 , DPPF, BINOL, BINAP or PCy 3 , etc., the available solvents are toluene/H 2 O, 1,4- Dioxane/H 2 O, DMF/H 2 O, DMSO/H 2 O or CH 3 CN/H 2 O, etc., and the reaction temperature may be 60°C to 120°C.
第五步：化合物I-A-5和I-A-8经偶联反应生成化合物I-A；Step 5: Compound I-A-5 and I-A-8 are coupled to generate Compound I-A;
所述偶联反应可使用的催化剂例如为Cu(OAc) 2或CuBr等；可使用的配体例如为DMAP或2，2’-联吡啶等，可使用的碱例如为吡啶、TEA、Cs 2CO 3、Na 2CO 3或K 2CO 3等，可使用的溶剂例如为1，4-二氧六环、DCM、DMF或CH 3CN等，且反应温度可为0℃至120℃，例如90℃。 The catalyst that can be used in the coupling reaction is, for example, Cu(OAc) 2 or CuBr, etc.; the ligand that can be used is, for example, DMAP or 2,2'-bipyridine, and the base that can be used is pyridine, TEA, Cs 2 CO 3 , Na 2 CO 3 or K 2 CO 3 etc., the solvent that can be used is 1,4-dioxane, DCM, DMF or CH 3 CN etc., and the reaction temperature can be 0°C to 120°C, for example 90°C.
在某些实施方案中，本发明提供制备式I-B的化合物的方法，其包括以下步骤：In certain embodiments, the present invention provides a method of preparing a compound of Formula I-B, comprising the steps of:
路线Broute B
Figure PCTCN2022079826-appb-000079
Figure PCTCN2022079826-appb-000079
其中：in:
环B、R 1、R 2、R 3、Z、Y、W 1、W 2、W 3和m如上文对于式I-B所定义；且 Rings B, R 1 , R 2 , R 3 , Z, Y, W 1 , W 2 , W 3 and m are as defined above for formula IB; and
Hal为Br或I。Hal is Br or I.
第一步：化合物I-B-1和I-B-2经缩合反应生成化合物I-B-3；The first step: Compound I-B-1 and I-B-2 undergo condensation reaction to generate compound I-B-3;
该反应条件如式I-A的化合物的制备方法(路线A)中第二步所述。The reaction conditions are as described in the second step of the method for the preparation of compounds of formula I-A (Scheme A).
第二步：化合物I-B-3和含硼试剂反应生成化合物I-B-4；The second step: compound I-B-3 reacts with boron-containing reagent to generate compound I-B-4;
该反应条件如式I-A的化合物的制备方法(路线A)中第一步所述。The reaction conditions are as described in the first step of the method for the preparation of compounds of formula I-A (Scheme A).
第三步：化合物I-B-4经水解反应生成化合物I-B-5；The third step: compound I-B-4 is hydrolyzed to generate compound I-B-5;
该反应条件如式I-A的化合物的制备方法(路线A)中第三步所述。The reaction conditions are as described in the third step of the method for the preparation of compounds of formula I-A (Scheme A).
第四步：化合物I-B-5和I-A-8经偶联反应生成化合物I-B；The fourth step: compound I-B-5 and I-A-8 are coupled to generate compound I-B;
该反应条件如式I-A的化合物的制备方法(路线A)中第五步所述。The reaction conditions are as described in step 5 of the method for the preparation of compounds of formula I-A (Scheme A).
在某些实施方案中，本发明提供制备式I-C的化合物的方法，其包括以下步骤：In certain embodiments, the present invention provides methods of preparing compounds of formula I-C comprising the steps of:
路线Croute C
Figure PCTCN2022079826-appb-000080
Figure PCTCN2022079826-appb-000080
其中：in:
R 1、R 2、R 3、Z、Y、W 1、W 2、W 3、m和h如上文对于式I-C所定义。 R 1 , R 2 , R 3 , Z, Y, W 1 , W 2 , W 3 , m and h are as defined above for formula IC.
第一步：化合物I-A-2和三光气反应生成化合物I-C-1；The first step: compound I-A-2 reacts with triphosgene to generate compound I-C-1;
所述反应可使用的溶剂例如为THF、DCM或甲苯。反应温度为0℃至100℃，例如30℃。Solvents that can be used in the reaction are, for example, THF, DCM or toluene. The reaction temperature is 0°C to 100°C, for example 30°C.
第二步：化合物I-C-1和和1-C-2反应生成化合物I-C-3；The second step: compound I-C-1 reacts with 1-C-2 to generate compound I-C-3;
所述反应优选在碱的存在下进行。可用的碱例如为DIPEA、TEA或吡啶等。可用的溶剂例如为甲苯、THF、DCM或1，4-二氧六环等。反应温度为0℃至120℃，例如100℃。The reaction is preferably carried out in the presence of a base. Useful bases are, for example, DIPEA, TEA or pyridine and the like. Useful solvents are, for example, toluene, THF, DCM or 1,4-dioxane and the like. The reaction temperature is 0°C to 120°C, for example 100°C.
第三步：化合物I-C-3经水解反应生成化合物I-C-4；The third step: compound I-C-3 is hydrolyzed to generate compound I-C-4;
该反应条件如式I-A的化合物的制备方法(路线A)中第三步所述。The reaction conditions are as described in the third step of the method for the preparation of compounds of formula I-A (Scheme A).
第四步：化合物I-C-4和I-A-8经偶联反应生成化合物I-C；The fourth step: compound I-C-4 and I-A-8 are coupled to generate compound I-C;
该反应条件如式I-A的化合物的制备方法(路线A)中第五步所述。The reaction conditions are as described in step 5 of the method for the preparation of compounds of formula I-A (Scheme A).
药物组合物、制剂和治疗方法Pharmaceutical compositions, formulations and methods of treatment
在一些实施方案中，本发明提供药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药以及一种或多种药学上可接受的载体。In some embodiments, the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, of the present invention compounds, co-crystals, solvates, metabolites, isotopically-labeled compounds, N-oxides or prodrugs and one or more pharmaceutically acceptable carriers.
在一些实施方案中，本发明提供药物制剂，所述药物制剂优选为固体制剂、半固体制剂、液体制剂或气态制剂。In some embodiments, the present invention provides pharmaceutical formulations, which are preferably solid formulations, semisolid formulations, liquid formulations, or gaseous formulations.
在一些实施方案中，所述药物组合物或药物制剂还可包含一种或多种其它治疗剂。In some embodiments, the pharmaceutical composition or formulation may further comprise one or more other therapeutic agents.
在一些实施方案中，所述药物组合物或药物制剂可通过口服、静脉内、动脉内、皮下、腹膜内、肌内或经皮途径给药。In some embodiments, the pharmaceutical composition or formulation can be administered by oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or transdermal routes.
在一些实施方案中，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，或者本发明的药物组合物、或者本发明的药物制剂在制备用于预防或治疗与RAF和/或RAS激酶活性相关的疾病或病况的药物中的用途。In some embodiments, the present invention provides compounds of the present invention, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, co-crystals, solvates, metabolites, Isotopically labeled compounds, N-oxides or prodrugs, or pharmaceutical compositions of the present invention, or pharmaceutical formulations of the present invention in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with RAF and/or RAS kinase activity the use of.
在一些实施方案中，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，或者本发明的药物组合物、或者本发明的药物制剂在制备用于调节(例如降低或抑制)RAF和/或RAS激酶的活性的药物中的用途。In some embodiments, the present invention provides compounds of the present invention, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, co-crystals, solvates, metabolites, Isotopically labeled compounds, N-oxides or prodrugs, or pharmaceutical compositions of the present invention, or pharmaceutical formulations of the present invention, in the manufacture of a medicament for modulating (eg, reducing or inhibiting) the activity of RAF and/or RAS kinases use.
在一些实施方案中，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，或者本发明的药物组合物、或者本发明的药物制剂，其用于预防或治疗与RAF和/或RAS激酶活性相关的疾病或病况。In some embodiments, the present invention provides compounds of the present invention, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, co-crystals, solvates, metabolites, Isotopically labeled compounds, N-oxides or prodrugs, or pharmaceutical compositions of the present invention, or pharmaceutical formulations of the present invention, for use in the prevention or treatment of diseases or conditions associated with RAF and/or RAS kinase activity.
在一些实施方案中，本发明提供预防或治疗与RAF和/或RAS激酶活性相关的疾病或病况的方法，所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，或者本发明的药物组合物、或者本发明的药物制剂。In some embodiments, the present invention provides a method of preventing or treating a disease or condition associated with RAF and/or RAS kinase activity, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable agent thereof acceptable salts, esters, stereoisomers, tautomers, polymorphs, co-crystals, solvates, metabolites, isotopically labeled compounds, N-oxides or prodrugs, or The pharmaceutical composition, or the pharmaceutical formulation of the present invention.
在一些实施方案中，所述与RAF和/或RAS激酶活性相关的疾病或病况优选为癌症或肿瘤。In some embodiments, the disease or condition associated with RAF and/or RAS kinase activity is preferably cancer or tumor.
在一些实施方案中，所述癌症或肿瘤优选为肺癌(例如非小细胞肺癌)、乳腺癌、卵巢癌、胃癌、肝癌、肾癌、骨癌、结直肠癌、肠癌、胰腺癌、头颈癌、子宫癌、食管癌、甲状腺癌、膀胱癌、血癌、淋巴瘤、多发性骨髓瘤、黑色素瘤、胶质瘤、脑瘤或肉瘤。In some embodiments, the cancer or tumor is preferably lung cancer (eg, non-small cell lung cancer), breast cancer, ovarian cancer, stomach cancer, liver cancer, kidney cancer, bone cancer, colorectal cancer, bowel cancer, pancreatic cancer, head and neck cancer , uterine cancer, esophageal cancer, thyroid cancer, bladder cancer, blood cancer, lymphoma, multiple myeloma, melanoma, glioma, brain tumor or sarcoma.
本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。"Pharmaceutically acceptable carrier" as used herein refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered and which, within the scope of sound medical judgment, is suitable for contact with humans and/or tissue from other animals without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
本发明的药物组合物可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药。The pharmaceutical compositions of the present invention may act systemically and/or locally. For this purpose, they can be administered by a suitable route.
对于这些给药途径，可以适合的剂型给药本发明的药物组合物。For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.
如本文中所使用的术语“有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。The term "effective amount" as used herein refers to the amount of a compound which, when administered, will alleviate to some extent one or more symptoms of the condition being treated.
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应 根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。Dosage regimens can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition.
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而在其它情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。The amount of the compound of the invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. In general, effective doses range from about 0.0001 to about 50 mg per kg body weight per day. In some cases, dose levels not higher than the lower end of the foregoing ranges may be sufficient, while in other cases larger doses may be employed without causing any deleterious side effects, provided that the larger dose is first The dose is divided into several smaller doses to be administered throughout the day.
本发明的化合物在药物组合物或药物制剂中的含量或用量可以是约0.01mg至约1000mg。The compound of the present invention may be present in a pharmaceutical composition or pharmaceutical preparation in an amount or amount of about 0.01 mg to about 1000 mg.
除非另外说明，否则如本文中所使用，术语“治疗(treating)”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展。Unless otherwise specified, the term "treating" as used herein means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term is applied or one or more symptoms of such disorder or condition.
术语“预防(preventing)”指对未患疾病的受试者施用，以防止疾病发生或延迟病症或病况的一种或多种症状的发生或降低其严重性。The term "preventing" refers to administration to a subject not suffering from a disease to prevent the onset of the disease or delay the onset or reduce the severity of one or more symptoms of a disorder or condition.
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。An "individual" as used herein includes a human or non-human animal. Exemplary human subjects include human subjects (referred to as patients) or normal subjects with a disease (eg, a disease described herein). "Non-human animals" in the present invention include all vertebrates such as non-mammals (eg birds, amphibians, reptiles) and mammals such as non-human primates, livestock and/or domesticated animals (eg sheep, dogs) , cats, cows, pigs, etc.).
在一些实施方案中，本发明的药物组合物或药物制剂还可以包含一种或多种另外的治疗剂或预防剂(例如其它用于治疗癌症或肿瘤疾病的药物)。在一些实施方案中，本发明的治疗方法还可以包括给药一种或多种另外的治疗剂或预防剂(例如其它用于治疗癌症或肿瘤疾病的药物)。In some embodiments, the pharmaceutical compositions or formulations of the present invention may further comprise one or more additional therapeutic or prophylactic agents (eg, other drugs used in the treatment of cancer or neoplastic diseases). In some embodiments, the methods of treatment of the present invention may also include administration of one or more additional therapeutic or prophylactic agents (eg, other drugs used to treat cancer or neoplastic diseases).
实施例Example
以下结合实施例进一步描述本发明，但提供这些实施例并非意图限制本发明的范围。The present invention is further described below in conjunction with the examples, but these examples are not intended to limit the scope of the present invention.
本文中所用的缩写具有以下含义：Abbreviations used herein have the following meanings:
Figure PCTCN2022079826-appb-000081
Figure PCTCN2022079826-appb-000081
Figure PCTCN2022079826-appb-000082
Figure PCTCN2022079826-appb-000082
本发明的化合物通过制备TLC、硅胶柱色谱法、Prep-HPLC和/或快速柱色谱法(Flash柱色谱法)来分离纯化，其结构通过 1H NMR和/或MS来确证。反应监测采用TLC或LC-MS进行。 The compounds of the present invention are isolated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and/or flash column chromatography (Flash column chromatography), and their structures are confirmed by 1 H NMR and/or MS. Reaction monitoring was performed by TLC or LC-MS.
分离方法：实施例中化合物的Prep-HPLC纯化均采用Aglient 1260型或Waters 2489型HPLC进行，分离柱型号为Waters SunFire Prep C 18 OBD(19mm×150mm×5.0μm)、Waters Xbridge Prep C 18 OBD(19mm×150mm×5.0μm)或YMC Actus Triart C 18(20mm×150mm×5.0μm)，柱温均为25℃，检测波长为214nm、254nm或280nm，流动相A为乙腈，流动相B为0.05％甲酸水溶液或者0.05％碳酸氢铵水溶液或者0.05％TFA水溶液，流动相的体积比根据化合物的极性不同而进行调节；流动相流速为28mL/min。 Separation method: Prep-HPLC purification of the compounds in the examples was carried out by Aglient 1260 or Waters 2489 HPLC, and the separation column model was Waters SunFire Prep C 18 OBD (19mm × 150mm × 5.0 μm), Waters Xbridge Prep C 18 OBD ( 19mm×150mm×5.0μm) or YMC Actus Triart C 18 (20mm×150mm×5.0μm), column temperature is 25℃, detection wavelength is 214nm, 254nm or 280nm, mobile phase A is acetonitrile, mobile phase B is 0.05% Formic acid aqueous solution or 0.05% ammonium bicarbonate aqueous solution or 0.05% TFA aqueous solution, the volume ratio of the mobile phase is adjusted according to the polarity of the compound; the flow rate of the mobile phase is 28 mL/min.
1H NMR波谱法采用Bruker超导核磁共振波谱仪(型号AVACE III HD 400MHz)。 1 H NMR spectroscopy was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400 MHz).
LC/MS采用Aglient 1260 Infinity/Aglient 6120 Quadrupole。LC/MS used Aglient 1260 Infinity/Aglient 6120 Quadrupole.
TLC采用硅胶GF 254作为固定相。TLC used silica gel GF 254 as the stationary phase.
柱色谱法一般使用200～300目硅胶(青岛海洋)作为固定相。Column chromatography generally uses 200-300 mesh silica gel (Qingdao Marine) as the stationary phase.
快速柱色谱法使用Biotage快速柱色谱仪。Flash column chromatography uses a Biotage flash column chromatograph.
Prep-HPLC采用Agilent 1260型和Waters 2489型。Agilent Model 1260 and Waters Model 2489 were used for Prep-HPLC.
微波反应使用BiotageInitiator微波反应器进行。Microwave reactions were performed using a BiotageInitiator microwave reactor.
在以下实施例中，如无特殊说明，反应的温度为室温(15-30℃)。In the following examples, unless otherwise specified, the reaction temperature is room temperature (15-30°C).
本申请中所使用的试剂购自Acros Organics、Aldrich Chemical Company或特伯化学等公司。The reagents used in this application were purchased from companies such as Acros Organics, Aldrich Chemical Company, or Tuber Chemicals.
实施例1：3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-1，2，3-三唑-1-基)-N-(3-氯-2-氟苯基)-4-甲基苯甲酰胺(化合物1)Example 1: 3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-1,2,3-triazol-1-yl)-N-(3- Chloro-2-fluorophenyl)-4-methylbenzamide (Compound 1)
Figure PCTCN2022079826-appb-000083
Figure PCTCN2022079826-appb-000083
第一步：7-溴-N-(2，4-二甲氧基苄基)噻吩并[3，2-d]嘧啶-4-胺(化合物1c)的制备Step 1: Preparation of 7-bromo-N-(2,4-dimethoxybenzyl)thieno[3,2-d]pyrimidin-4-amine (Compound 1c)
将化合物1a(3g，12.02mmol)溶于DMF(15mL)中，再依次加入化合物1b(2.11g，12.62mmol)和DIPEA(2.33g，18.03mmol)，加完后20℃搅拌反应16小时。反应结束后，加入乙酸乙酯稀释反应液，水洗3次，有机相经无水硫酸钠干燥，过滤后减压浓缩得到化合物1c(4.46g)。MS m/z(ESI)：379.9[M+H] +。 Compound 1a (3 g, 12.02 mmol) was dissolved in DMF (15 mL), then compound 1b (2.11 g, 12.62 mmol) and DIPEA (2.33 g, 18.03 mmol) were added in sequence, and the reaction was stirred at 20° C. for 16 hours after the addition. After the reaction, ethyl acetate was added to dilute the reaction solution, washed three times with water, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1c (4.46 g). MS m/z (ESI): 379.9 [M+H] + .
第二步：N-(2，4-二甲氧基苄基)-7-((三甲基硅基)乙炔基)噻吩并[3，2-d]嘧啶-4-胺(化合物1d)的制备Step 2: N-(2,4-Dimethoxybenzyl)-7-((trimethylsilyl)ethynyl)thieno[3,2-d]pyrimidin-4-amine (Compound 1d) preparation
将化合物1c(1.00g，2.63mmol)、双三苯基膦二氯化钯(184.58mg，262.98μmol)和碘化亚铜(25.04mg，131.49μmol)加入到加压反应器中，再加入三乙胺(15mL)和1，4-二氧六环(15mL)，氮气保护下加入三甲基乙炔基硅(2.58g，26.30mmol)，加完后密封加热到50℃反应18小时。反应结束后将反应液减压浓缩干，粗产物经硅胶快速柱色谱法(石油醚/乙酸乙酯＝2/1)分离纯化，得到化合物1d(735.00mg)。MS m/z(ESI)：398.2[M+H] +。 Compound 1c (1.00 g, 2.63 mmol), bistriphenylphosphine palladium dichloride (184.58 mg, 262.98 μmol) and cuprous iodide (25.04 mg, 131.49 μmol) were added to a pressurized reactor followed by three Ethylamine (15 mL) and 1,4-dioxane (15 mL) were added under nitrogen protection, trimethylethynyl silicon (2.58 g, 26.30 mmol) was added, and after the addition, it was sealed and heated to 50° C. to react for 18 hours. After the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the crude product was separated and purified by silica gel flash column chromatography (petroleum ether/ethyl acetate=2/1) to obtain compound 1d (735.00 mg). MS m/z (ESI): 398.2 [M+H] + .
第三步：N-(2，4-二甲氧基苄基)-7-乙炔基噻吩并[3，2-d]嘧啶-4-胺(化合物1e)的制备The third step: preparation of N-(2,4-dimethoxybenzyl)-7-ethynylthieno[3,2-d]pyrimidin-4-amine (compound 1e)
将化合物1d(300.00mg，754.59μmol)和碳酸钾(208.58mg，1.51mmol)加入到甲醇(15mL)中，在25℃反应3小时。反应结束后用100mL乙酸乙酯稀释反应液，水洗3次，饱和食盐水洗涤1次，有 机相经无水硫酸钠干燥，过滤后减压浓缩。粗产物经硅胶快速柱色谱法(石油醚/乙酸乙酯＝3/2)分离纯化，得到化合物1e(200.00mg)。MS m/z(ESI)：326.1[M+H] +。 Compound 1d (300.00 mg, 754.59 μmol) and potassium carbonate (208.58 mg, 1.51 mmol) were added to methanol (15 mL) and reacted at 25° C. for 3 hours. After the reaction, the reaction solution was diluted with 100 mL of ethyl acetate, washed three times with water and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel flash column chromatography (petroleum ether/ethyl acetate=3/2) to obtain compound 1e (200.00 mg). MS m/z (ESI): 326.1 [M+H] + .
第四步：3-叠氮基-4-甲基苯甲酸甲酯(化合物1g)的制备The fourth step: the preparation of methyl 3-azido-4-methylbenzoate (compound 1g)
将化合物1f(4.2g，25.43mmol)加入到稀盐酸(3M，6mL)中，然后在0℃下缓慢加入亚硝酸钠(1.75g，25.43mmol)的水(2mL)溶液，0℃下搅拌30min后，再缓慢加入叠氮化钠(1.98g，30.51mmol)的水(2mL)溶液，加完后室温反应3.5hr。反应结束后向反应液中加入100mL水，用乙酸乙酯萃取3次，有机相用饱和氯化钠洗涤，无水硫酸钠干燥，过滤后减压浓缩除去溶剂，经C18柱反相柱色谱法(乙腈/0.05％甲酸水溶液＝60/40)分离纯化，得到化合物1g(3.57g)。MS m/z(ESI)：192.1[M+H] +。 Compound 1f (4.2 g, 25.43 mmol) was added to dilute hydrochloric acid (3 M, 6 mL), then sodium nitrite (1.75 g, 25.43 mmol) in water (2 mL) solution was slowly added at 0 °C, and stirred at 0 °C for 30 min After that, a solution of sodium azide (1.98 g, 30.51 mmol) in water (2 mL) was slowly added, and the reaction was carried out at room temperature for 3.5 hr after the addition. After the reaction, 100 mL of water was added to the reaction solution, extracted three times with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and subjected to C18 column reversed-phase column chromatography. (Acetonitrile/0.05% aqueous formic acid=60/40) was separated and purified to obtain 1 g of compound (3.57 g). MS m/z (ESI): 192.1 [M+H] + .
第五步：3-(4-(4-(((2，4-二甲氧基苄基)氨基)噻吩并[3，2-d]嘧啶-7-基)-1H-1，2，3-三唑-1-基)-4-甲基苯甲酸甲酯(化合物1h)的制备The fifth step: 3-(4-(4-(((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidin-7-yl)-1H-1,2, Preparation of methyl 3-triazol-1-yl)-4-methylbenzoate (compound 1h)
将化合物1g(96.95mg，507.09μmol)和1e(110mg，338.06μmol)加入到水(2mL)和乙腈(2mL)中，然后依次加入五水硫酸铜(5.40mg，33.81μmol)和水合肼(16.92mg，338.06μmol)，加完后50℃反应4hr。反应结束后向反应液中加入50mL水稀释，再用乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤后减压浓缩除去溶剂，经C18柱的反相柱色谱法(乙腈/0.05％甲酸水溶液＝65/35)分离纯化，得到化合物1h(105mg)。MS m/z(ESI)：517.2[M+H] +。 Compounds 1 g (96.95 mg, 507.09 μmol) and 1e (110 mg, 338.06 μmol) were added to water (2 mL) and acetonitrile (2 mL), followed by copper sulfate pentahydrate (5.40 mg, 33.81 μmol) and hydrazine hydrate (16.92 mg, 338.06 μmol), and reacted at 50° C. for 4 hr after the addition. After the reaction, 50 mL of water was added to the reaction solution to dilute, and then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent. Chromatography (acetonitrile/0.05% aqueous formic acid=65/35) gave compound 1h (105 mg). MS m/z (ESI): 517.2 [M+H] + .
第六步：3-(4-(4-(((2，4-二甲氧基苄基)氨基)噻吩并[3，2-d]嘧啶-7-基)-1H-1，2，3-三唑-1-基)-4-甲基苯甲酸(化合物1i)的制备The sixth step: 3-(4-(4-(((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidin-7-yl)-1H-1,2, Preparation of 3-triazol-1-yl)-4-methylbenzoic acid (compound 1i)
将化合物1h(130.00mg，251.66μmol)加入到四氢呋哺(3mL)和水(1mL)，再加入氢氧化钠(30.20mg，754.98μmol)，25℃反应12小时。反应结束后减压除去有机溶剂，冰浴下滴加稀盐酸调节溶液pH至弱酸性，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤后减压浓缩得到化合物1i(95.00mg)。MS m/z(ESI)：503.1[M+H] +。 Compound 1h (130.00 mg, 251.66 μmol) was added to tetrahydrofuran (3 mL) and water (1 mL), and then sodium hydroxide (30.20 mg, 754.98 μmol) was added to react at 25° C. for 12 hours. After the reaction was completed, the organic solvent was removed under reduced pressure, diluted hydrochloric acid was added dropwise under an ice bath to adjust the pH of the solution to weak acidity, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 1i (95.00 mg). MS m/z (ESI): 503.1 [M+H] + .
第七步：N-(3-氯-2-氟苯基)-3-(4-(4-((2，4-二甲氧基苄基)氨基)噻吩并[3，2-d]嘧啶-7-基)-1H-1，2，3-三唑-1-基)-4-甲基苯甲酰胺(化合物1k)的制备Step 7: N-(3-Chloro-2-fluorophenyl)-3-(4-(4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d] Preparation of pyrimidin-7-yl)-1H-1,2,3-triazol-1-yl)-4-methylbenzamide (compound 1k)
将化合物1i(80mg，159.19μmol)与1j(23.17mg，159.19μmol)溶于吡啶(3mL)，再滴加1-丙基磷酸酐(0.3mL，50％于DMF中)，于25℃反应1小时。反应结束后减压除去吡啶，加入饱和碳酸氢钠水溶液5mL，用乙酸乙酯萃取，有机相经无水硫酸钠干燥，过滤后减压浓缩，经硅胶快速柱色谱法(DCM/MeOH＝10/1)分离纯化，得到化合物1k(92.00mg)。MS m/z(ESI)：630.2[M+H] +。 Compound 1i (80 mg, 159.19 μmol) and 1j (23.17 mg, 159.19 μmol) were dissolved in pyridine (3 mL), 1-propylphosphoric anhydride (0.3 mL, 50% in DMF) was added dropwise, and the reaction was carried out at 25°C for 1 Hour. After the reaction, pyridine was removed under reduced pressure, 5 mL of saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel flash column chromatography (DCM/MeOH=10/ 1) Separation and purification to obtain compound 1k (92.00 mg). MS m/z (ESI): 630.2 [M+H] + .
第八步：3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-1，2，3-三唑-1-基)-N-(3-氯-2-氟苯基)-4-甲基苯甲酰胺(化合物1)的制备Step 8: 3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-1,2,3-triazol-1-yl)-N-(3- Preparation of chloro-2-fluorophenyl)-4-methylbenzamide (compound 1)
将化合物1k(20.00mg，31.74μmol)溶于三氟乙酸(3mL)，升温至80℃反应16小时。反应结束后减压除去溶剂，然后经Prep-HPLC分离纯化，得到化合物1(2.50mg)。MS m/z(ESI)：480.1[M+H] +。 Compound 1k (20.00 mg, 31.74 μmol) was dissolved in trifluoroacetic acid (3 mL), and the temperature was raised to 80° C. to react for 16 hours. After the reaction, the solvent was removed under reduced pressure, and then separated and purified by Prep-HPLC to obtain compound 1 (2.50 mg). MS m/z (ESI): 480.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.48(s，1H)，9.09(s，1H)，8.66(s，1H)，8.50(s，1H)，8.17(d，J＝2.0Hz，1H)，8.11(dd，J＝8.0，1.6Hz，1H)，7.70(d，J＝8.0Hz，1H)，7.64(s，2H)，7.62-7.56(m，1H)，7.54-7.41(m，1H)，7.27(td，J＝8.1，1.3Hz，1H)，2.33(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.48 (s, 1H), 9.09 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.17 (d, J=2.0 Hz, 1H), 8.11(dd, J=8.0, 1.6Hz, 1H), 7.70(d, J=8.0Hz, 1H), 7.64(s, 2H), 7.62-7.56(m, 1H), 7.54-7.41(m , 1H), 7.27 (td, J=8.1, 1.3Hz, 1H), 2.33 (s, 3H).
实施例2：3-(4-(4-氨基喹唑啉-8-基)-1H-吡唑-1-基)-N-(3-氯-2-氟苯基)-4-甲基苯甲酰胺(化合物2)Example 2: 3-(4-(4-Aminoquinazolin-8-yl)-1H-pyrazol-1-yl)-N-(3-chloro-2-fluorophenyl)-4-methyl benzamide (compound 2)
Figure PCTCN2022079826-appb-000084
Figure PCTCN2022079826-appb-000084
第一步：8-溴喹唑啉-4(3H)-酮(化合物2b)的制备The first step: preparation of 8-bromoquinazolin-4(3H)-one (compound 2b)
反应瓶中加入化合物2a(2g，9.26mmol)和甲酰胺(20mL)，氮气保护下135℃反应5小时。待反应结束后将反应液冷却至室温，反应液即析出大量固体，加入100ml水稀释，过滤，滤饼用清水洗涤，经50℃减压干燥得到化合物2b(1.89g)。MS m/z(ESI)：224.9[M+H] +。 Compound 2a (2 g, 9.26 mmol) and formamide (20 mL) were added to the reaction flask, and the reaction was carried out at 135° C. for 5 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, and a large amount of solid was precipitated from the reaction solution, which was diluted with 100 ml of water, filtered, and the filter cake was washed with water and dried under reduced pressure at 50° C. to obtain compound 2b (1.89 g). MS m/z (ESI): 224.9 [M+H] + .
第二步：8-溴-N-(2，4-二甲氧基苄基)喹唑啉-4-胺(化合物2c)的制备The second step: preparation of 8-bromo-N-(2,4-dimethoxybenzyl)quinazolin-4-amine (compound 2c)
将化合物2b(1.89g，8.40mmol)、DBU(3.84g，25.20mmol)和1b(2.11g，12.60mmol)依次加入到DMF(50mL)中，再向反应液中加入PyBrOP(5.87g，12.60mmol)，加完后室温反应14hr。反应结束后加水淬灭，乙酸乙酯萃取，有机相用水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗品用DCM打浆，固体过滤干燥后，得到化合物2c(1.5g)。MS m/z(ESI)：374.0[M+H] +。 Compound 2b (1.89 g, 8.40 mmol), DBU (3.84 g, 25.20 mmol) and 1b (2.11 g, 12.60 mmol) were successively added to DMF (50 mL), and PyBrOP (5.87 g, 12.60 mmol) was added to the reaction solution. ), and reacted at room temperature for 14hr after the addition. After the reaction was completed, water was added to quench, extracted with ethyl acetate, the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was slurried with DCM and the solid was filtered and dried to give compound 2c (1.5 g). MS m/z (ESI): 374.0 [M+H] + .
第三步：N-(2，4-二甲氧基苄基)-8-(1H-吡唑-4-基)喹唑啉-4-胺(化合物2e)的制备The third step: preparation of N-(2,4-dimethoxybenzyl)-8-(1H-pyrazol-4-yl)quinazolin-4-amine (compound 2e)
反应瓶中加入化合物2c(250mg，0.67mmol)、2d(197mg，1.00mmol)、K 2CO 3(277mg，2.00mmol)、Pd(dppf)Cl 2·DCM(55mg，67μmol)、1，4-二氧六环(8mL)和水(1.5mL)，氮气保护，升温至100℃反应20hr。反应结束后冷却至室温，加入60ml水稀释，用乙酸乙酯萃取，有机相用盐水洗涤，经无水硫酸钠干燥，过滤后浓缩。粗产物经硅胶柱色谱法(MeOH∶DCM＝5∶95)分离纯化，得到化合物2e(140mg)。MS m/z(ESI)：362.2[M+H] +。 Compound 2c (250 mg, 0.67 mmol), 2d (197 mg, 1.00 mmol), K 2 CO 3 (277 mg, 2.00 mmol), Pd(dppf)Cl 2 ·DCM (55 mg, 67 μmol), 1,4- Dioxane (8 mL) and water (1.5 mL), under nitrogen protection, were heated to 100° C. and reacted for 20 hr. After the reaction, it was cooled to room temperature, diluted with 60 ml of water, extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel column chromatography (MeOH:DCM=5:95) to give compound 2e (140 mg). MS m/z (ESI): 362.2 [M+H] + .
第四步：3-碘-4-甲基苯甲酸甲酯(化合物2f)的制备The fourth step: the preparation of methyl 3-iodo-4-methylbenzoate (compound 2f)
将化合物1f(1g，6.05mmol)加入水(24mL)中，氮气保护下在0℃缓慢滴加浓盐酸(12M，2.52mL)，滴完后将NaNO 2(469mg，6.66mmol)的水溶液缓慢滴加到混合溶液中，0℃反应1hr。然后再将KI(3.05g，18.16mmol)的水溶液缓慢滴加到反应中，滴加完成后反应保持在0℃反应2hr。反应结束后用氨水调节反应液pH至弱碱性，用乙酸乙酯萃取，有机相经无水硫酸钠干燥后过滤，浓缩。粗产物经硅胶柱色谱法(PE∶EA＝95∶5)分离纯化，得到化合物2f(1.28g)。 Compound 1f (1 g, 6.05 mmol) was added to water (24 mL), concentrated hydrochloric acid (12 M, 2.52 mL) was slowly added dropwise at 0 °C under nitrogen protection, and an aqueous solution of NaNO 2 (469 mg, 6.66 mmol) was slowly dropped after the dropping It was added to the mixed solution and reacted at 0°C for 1 hr. Then, an aqueous solution of KI (3.05 g, 18.16 mmol) was slowly added dropwise to the reaction, and the reaction was kept at 0° C. for 2 hr after the dropwise addition was completed. After the reaction, the pH of the reaction solution was adjusted to weakly alkaline with ammonia water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (PE:EA=95:5) to obtain compound 2f (1.28 g).
第五步：4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯甲酸甲酯(化合物2g)的制备The fifth step: preparation of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoate (compound 2g)
反应瓶中加入化合物2f(200mg，0.72mmol)、联硼酸频那醇酯(239mg，0.94mmol)、Pd(dppf)Cl 2(59mg，72.45μmol)、醋酸钾(161mg，1.45mmol)和1，4-二氧六环(10mL)，氮气保护下90℃反应16hr。反应结束后加入60mL水稀释，用EA(30mL x3)萃取，合并有机相，用盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶柱色谱法(EA∶PE＝1∶20)分离纯化，得到化合物2g(140mg)。 Compound 2f (200 mg, 0.72 mmol), pinacol biborate (239 mg, 0.94 mmol), Pd(dppf)Cl 2 (59 mg, 72.45 μmol), potassium acetate (161 mg, 1.45 mmol) and 1 were added to the reaction flask. 4-Dioxane (10 mL) was reacted at 90° C. for 16 hr under nitrogen protection. After the reaction, 60 mL of water was added to dilute, extracted with EA (30 mL x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated and purified by silica gel column chromatography (EA:PE=1:20) to obtain compound 2g (140 mg).
第六步：(5-(甲氧羰基)-2-甲基苯基)硼酸(化合物2h)的制备The sixth step: preparation of (5-(methoxycarbonyl)-2-methylphenyl)boronic acid (compound 2h)
反应瓶中加入化合物2g(130mg，0.47mmol)、NaIO 4(302mg，1.41mmol)和MeCN(5mL)，再加入醋酸铵(73mg，0.94mmol)的水(2mL)溶液，氮气保护，40℃反应16hr。反应结束后加入60mL水稀释，用EA(30mL x3)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤后浓缩，得到化合物2h(90mg)。MS m/z(ESI)：195.2[M+H] +。 Compound 2g (130mg, 0.47mmol), NaIO 4 (302mg, 1.41mmol) and MeCN (5mL) were added to the reaction flask, and then a solution of ammonium acetate (73mg, 0.94mmol) in water (2mL) was added, and the reaction was carried out at 40°C under nitrogen protection. 16hr. After the reaction, 60 mL of water was added to dilute, extracted with EA (30 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 2h (90 mg). MS m/z (ESI): 195.2 [M+H] + .
第七步：3-(4-(4-((2，4-二甲氧基苄基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)-4-甲基苯甲酸甲酯(化合物2i)的制备Step 7: 3-(4-(4-((2,4-dimethoxybenzyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)-4-methyl Preparation of methyl benzoate (compound 2i)
反应瓶中加入化合物2e(255mg，0.50mmol)、2h(80mg，0.41mmol)、Cu(OAc) 2(74.90mg，0.41mmol)、吡啶(98mg，1.24mmol)、DMAP(101mg，0.82mmol)和1，4-二氧六环(6mL)，然后外温100℃敞口反应12hr。反应结束后加入60mL水稀释，用EA(30mL x3)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶柱色谱法(DCM∶MeOH＝95∶5)分离纯化，得到化合物2i(130mg)。MS m/z(ESI)：510.2[M+H] +。 Compound 2e (255mg, 0.50mmol), 2h (80mg, 0.41mmol), Cu(OAc) 2 (74.90mg, 0.41mmol), pyridine (98mg, 1.24mmol), DMAP (101mg, 0.82mmol) and 1,4-dioxane (6 mL), and then reacted at an external temperature of 100 °C for 12 hr. After the reaction, 60 mL of water was added to dilute, extracted with EA (30 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel column chromatography (DCM:MeOH=95:5) to give compound 2i (130 mg). MS m/z (ESI): 510.2 [M+H] + .
第八步：3-(4-(4-((2，4-二甲氧基苄基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)-4-甲基苯甲酸(化合物2j)的制备Step 8: 3-(4-(4-((2,4-dimethoxybenzyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)-4-methyl Preparation of Benzoic Acid (Compound 2j)
反应瓶中加入化合物2i(130mg，0.26mmol)和MeOH(4mL)，再加入NaOH(31mg，0.77mmol)的H2O(1.5mL)溶液，氮气保护下室温反应2hr。反应结束后用2N盐酸调节溶液pH至5-6，减压蒸除有机溶剂，有固体析出。固体经过滤干燥，得到化合物2j(180mg)。MS m/z(ESI)：496.2[M+H] +。 Compound 2i (130 mg, 0.26 mmol) and MeOH (4 mL) were added to the reaction flask, then NaOH (31 mg, 0.77 mmol) in H2O (1.5 mL) solution was added, and the reaction was carried out at room temperature for 2 hr under nitrogen protection. After the reaction was completed, the pH of the solution was adjusted to 5-6 with 2N hydrochloric acid, the organic solvent was evaporated under reduced pressure, and a solid was precipitated. The solid was filtered and dried to give compound 2j (180 mg). MS m/z (ESI): 496.2 [M+H] + .
第九步：N-(3-氯-2-氟苯基)-3-(4-(4-((2，4-二甲氧基苄基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)-4-甲基苯甲酰胺(化合物2k)的制备Step 9: N-(3-Chloro-2-fluorophenyl)-3-(4-(4-((2,4-dimethoxybenzyl)amino)quinazolin-8-yl)- Preparation of 1H-pyrazol-1-yl)-4-methylbenzamide (compound 2k)
反应瓶中加入化合物2j(65mg，131.17μmol)、1j(19mg，131.17μmol)和吡啶(3mL)，搅拌溶解后加入T 3P(2mL，50％于DMF中)，氮气保护下室温反应过夜。反应结束后直接将反应液旋干，加入60mL水稀释，用饱和碳酸氢钠溶液调节溶液pH至7-8，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶柱色谱法(DCM∶MeOH＝97∶3)分离纯化，得到化合物2k(75mg)。MS m/z(ESI)：623.3[M+H] +。 Compound 2j (65 mg, 131.17 μmol), 1j (19 mg, 131.17 μmol) and pyridine (3 mL) were added to the reaction flask, and T 3 P (2 mL, 50% in DMF) was added after stirring to dissolve, and the reaction was carried out at room temperature overnight under nitrogen protection. After the reaction, the reaction solution was directly rotated to dryness, diluted with 60 mL of water, adjusted to pH 7-8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. ,concentrate. The crude product was isolated and purified by silica gel column chromatography (DCM:MeOH=97:3) to give compound 2k (75 mg). MS m/z (ESI): 623.3 [M+H] + .
第十步：3-(4-(4-氨基喹唑啉-8-基)-1H-吡唑-1-基)-N-(3-氯-2-氟苯基)-4-甲基苯甲酰胺(化合物2)的制备Step 10: 3-(4-(4-Aminoquinazolin-8-yl)-1H-pyrazol-1-yl)-N-(3-chloro-2-fluorophenyl)-4-methyl Preparation of benzamide (compound 2)
反应瓶中加入化合物2k(75mg，0.12mmol)和TFA(5mL)，氮气保护下70℃反应2hr。反应结束后加入60mL水稀释，饱和NaHCO 3溶液调节溶液pH至7-8，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经Prep-HPLC分离纯化，得到化合物2(13mg)。MS m/z(ESI)：473.2[M+H] +。 Compound 2k (75 mg, 0.12 mmol) and TFA (5 mL) were added to the reaction flask, and the reaction was carried out at 70° C. for 2 hr under nitrogen protection. After the reaction, 60 mL of water was added to dilute, and saturated NaHCO 3 solution was used to adjust the pH of the solution to 7-8, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to Prep-HPLC Isolation and purification gave compound 2 (13 mg). MS m/z (ESI): 473.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.45(s，1H)，9.00(s，1H)，8.57(s，1H)，8.50(s，1H)，8.19(dd，J＝7.6，1.6Hz，1H)，8.15-8.09(m，2H)，8.00(dd，J＝8.0，2.0Hz，1H)，7.81(br，2H)，7.64-7.45(m，4H)，7.30-7.23(m，1H)，2.41(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 9.00 (s, 1H), 8.57 (s, 1H), 8.50 (s, 1H), 8.19 (dd, J=7.6, 1.6 Hz, 1H), 8.15-8.09(m, 2H), 8.00(dd, J=8.0, 2.0Hz, 1H), 7.81(br, 2H), 7.64-7.45(m, 4H), 7.30-7.23(m, 1H), 2.41(s, 3H).
实施例3：N-(3-(4-(6-氨基吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物3)Example 3: N-(3-(4-(6-Aminopyridin-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzene Formamide (compound 3)
Figure PCTCN2022079826-appb-000085
Figure PCTCN2022079826-appb-000085
第一步：N-(4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)-3-(三氟甲基)苯甲酰胺(化合物3c)的制备The first step: N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-3-( Preparation of trifluoromethyl)benzamide (compound 3c)
将化合物3a(500mg，2.14mmol)和3b(407.78mg，2.14mmol)溶于吡啶(3mL)中，然后滴加1-丙基磷酸酐(4.0mL，50％于DMF中)，加完后25℃反应1小时。反应结束后减压除去吡啶，加入饱和碳酸氢钠水溶液5mL，乙酸乙酯萃取，有机相经无水硫酸钠干燥，过滤后减压浓缩，粗产物经硅胶柱色谱法(DCM∶MeOH＝10∶1)分离纯化，得到化合物3c(530.00mg)。MS m/z(ESI)：406.1[M+H] +。 Compounds 3a (500 mg, 2.14 mmol) and 3b (407.78 mg, 2.14 mmol) were dissolved in pyridine (3 mL), then 1-propylphosphoric anhydride (4.0 mL, 50% in DMF) was added dropwise for 25 °C to react for 1 hour. After the reaction, pyridine was removed under reduced pressure, 5 mL of saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (DCM:MeOH=10: 1) Separation and purification to obtain compound 3c (530.00 mg). MS m/z (ESI): 406.1 [M+H] + .
第二步：(2-甲基-5-(3-(三氟甲基)苯甲酰胺基)苯基)硼酸(化合物3d)的制备The second step: preparation of (2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)boronic acid (compound 3d)
将化合物3c(531mg，1.31mmol)、醋酸铵(202.02mg，2.62mmol)和高碘酸钠(840.85mg，3.93mmol)加入到乙腈(10mL)和水(5mL)中，升温至50℃反应16小时。反应结束后滴加稀盐酸调节反应液pH至弱酸性，反应液直接用C18柱反相柱色谱法(乙腈/0.05％甲酸水溶液＝28/72)纯化，得到化合物3d(130.00mg)。MS m/z(ESI)：323.9[M+H] +。 Compound 3c (531 mg, 1.31 mmol), ammonium acetate (202.02 mg, 2.62 mmol) and sodium periodate (840.85 mg, 3.93 mmol) were added to acetonitrile (10 mL) and water (5 mL), and the temperature was raised to 50 °C for reaction 16 Hour. After the reaction, dilute hydrochloric acid was added dropwise to adjust the pH of the reaction solution to weak acidity, and the reaction solution was directly purified by C18 column reversed-phase column chromatography (acetonitrile/0.05% aqueous formic acid=28/72) to obtain compound 3d (130.00 mg). MS m/z (ESI): 323.9 [M+H] + .
第三步：2-硝基-5-(1H-吡唑-4-基)吡啶(化合物3f)的制备The third step: preparation of 2-nitro-5-(1H-pyrazol-4-yl)pyridine (compound 3f)
依次向瓶中加入化合物2d(5.26g，27.09mmol)、3e(5g，24.63mmol)、Pd(PPh 3) 4(569.26mg，492.63μmol)、Na 2CO 3(2.61g，24.63mmol)、H2O(10mL)和DMF(50mL)，氮气保护下110℃搅拌16hr。反应结束后将反应液冷至室温，然后倒入500ml水中，有黄色固体析出，抽滤，滤饼再经硅胶快速柱色谱法(DCM∶MeOH＝10∶1)分离纯化，得到化合物3f(2.5g)。MS m/z(ESI)：191.1[M+H] +。 Compound 2d (5.26 g, 27.09 mmol), 3e (5 g, 24.63 mmol), Pd(PPh 3 ) 4 (569.26 mg, 492.63 μmol), Na 2 CO 3 (2.61 g, 24.63 mmol), H 2 O were added to the bottle in turn (10 mL) and DMF (50 mL), stirred at 110 °C for 16 hr under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature, then poured into 500 ml of water, a yellow solid was precipitated, suction filtered, and the filter cake was separated and purified by silica gel flash column chromatography (DCM:MeOH=10:1) to obtain compound 3f (2.5 g). MS m/z (ESI): 191.1 [M+H] + .
第四步：N-(4-甲基-3-(4-(6-硝基吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺(化合物3g)的制备The fourth step: N-(4-methyl-3-(4-(6-nitropyridin-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl) Preparation of benzamide (compound 3g)
将化合物3f(147.15mg，773.82μmol)、3d(100mg，309.53μmol)、吡啶(48.97mg，619.05μmol，49.81μL)、DMAP(113.44mg，928.58μmol)、Cu(OAc) 2(56.22mg，309.53μmol)和1，4-二氧六环(10mL)加入反应瓶中，空气氛围下90℃搅拌16hr。反应结束后加水稀释，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，浓缩，粗产物经硅胶快速柱色谱法(DCM/MeOH＝96/4)纯化，得到化合物3g(17mg).MS m/z(ESI)：468.1[M+H] +。 Compound 3f (147.15 mg, 773.82 μmol), 3d (100 mg, 309.53 μmol), pyridine (48.97 mg, 619.05 μmol, 49.81 μL), DMAP (113.44 mg, 928.58 μmol), Cu(OAc) 2 (56.22 mg, 309.53 μmol) and 1,4-dioxane (10 mL) were added to the reaction flask, and stirred at 90° C. for 16 hr in an air atmosphere. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel flash column chromatography (DCM/MeOH=96/4) to obtain compound 3g (17mg) .MS m/z (ESI): 468.1 [M+H] + .
第五步：N-(3-(4-(6-氨基吡啶-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物3)的制备The fifth step: N-(3-(4-(6-aminopyridin-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzene Preparation of formamide (compound 3)
将化合物3g(17mg，36.37μmol)加入到甲醇(4mL)和水(1mL)中，再加入铁粉(10.16mg，181.86μmol)和氯化铵(5.84mg，109.11μmol)，加完后80℃搅拌4hr。反应结束后用硅藻土层过滤，滤液浓缩至干，粗产物经Prep-HPLC分离纯化，得到化合物3(9.11mg)。MS m/z(ESI)：438.0[M+H] +。 Compound 3g (17mg, 36.37μmol) was added to methanol (4mL) and water (1mL), then iron powder (10.16mg, 181.86μmol) and ammonium chloride (5.84mg, 109.11μmol) were added, and the addition was completed at 80°C Stir for 4hrs. After the reaction, it was filtered through a celite layer, the filtrate was concentrated to dryness, and the crude product was separated and purified by Prep-HPLC to obtain compound 3 (9.11 mg). MS m/z (ESI): 438.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.61(s，1H)，8.38(s，1H)，8.34-8.25(m，3H)，8.08(s，1H)，7.99(d，J＝7.8Hz，1H)，7.91(d，J＝2.0Hz，1H)，7.83-7.75(m，2H)，7.70(dd，J＝8.4，2.4Hz，1H)，7.41(d，J＝8.4Hz，1H)，6.49(d，J＝8.4Hz，1H)，5.94(s，2H)，2.27(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.61 (s, 1H), 8.38 (s, 1H), 8.34-8.25 (m, 3H), 8.08 (s, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.91 (d, J=2.0Hz, 1H), 7.83-7.75 (m, 2H), 7.70 (dd, J=8.4, 2.4Hz, 1H), 7.41 (d, J=8.4Hz, 1H) ), 6.49(d, J=8.4Hz, 1H), 5.94(s, 2H), 2.27(s, 3H).
实施例4：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物4)Example 4: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-3-(trifluoromethyl)benzamide (Compound 4)
Figure PCTCN2022079826-appb-000086
Figure PCTCN2022079826-appb-000086
第一步：7-溴-N，N-双(4-甲氧基苄基)咪唑并[2，1-f][1，2，4]三嗪-4-胺(化合物4c)的制备First step: Preparation of 7-bromo-N,N-bis(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (compound 4c)
将化合物4a(500mg，2.34mmol)溶于DMF(10mL)中，冰水浴中加入NaH(373.79mg，9.34mmol，60％纯度)，搅拌30min后再加入化合物4b(914.68mg，5.84mmol)，加完后自然升至室温搅拌16hr。反应结束后加水淬灭，乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法 (PE/EA＝23/77)纯化，得到化合物4c(770mg)。MS m/z(ESI)：454.1[M+H] +。 Compound 4a (500 mg, 2.34 mmol) was dissolved in DMF (10 mL), NaH (373.79 mg, 9.34 mmol, 60% purity) was added to an ice-water bath, and compound 4b (914.68 mg, 5.84 mmol) was added after stirring for 30 min. After completion, it was naturally raised to room temperature and stirred for 16hrs. After the reaction was completed, water was added to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography (PE/EA=23/77) to give compound 4c (770 mg). MS m/z (ESI): 454.1 [M+H] + .
第二步：N，N-双(4-甲氧基苄基)-7-(1H-吡唑-4-基)咪唑并[2，1-f][1，2，4]三嗪-4-胺(化合物4d)的制备Step 2: N,N-Bis(4-methoxybenzyl)-7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazine- Preparation of 4-amine (compound 4d)
依次将化合物4c(233mg，512.86μmol)、2d(199.03mg，1.03mmol)、碳酸钾(212.64mg，1.54mmol)、Pd(dppf)Cl 2·DCM(41.88mg，51.29μmol)、1，4-二氧六环(10mL)和水(2.5mL)加入到反应瓶中，氮气保护下95℃搅拌16hr。反应结束后减压除去有机溶剂，加水稀释，EA萃取，有机相用无水硫酸钠干燥，过滤，浓缩，粗产物经硅胶快速柱色谱法(DCM/MeOH＝96/4)分离纯化，得到化合物4d(200mg)。MS m/z(ESI)：442.0[M+H] +。 Compound 4c (233 mg, 512.86 μmol), 2d (199.03 mg, 1.03 mmol), potassium carbonate (212.64 mg, 1.54 mmol), Pd(dppf)Cl 2 ·DCM (41.88 mg, 51.29 μmol), 1,4- Dioxane (10 mL) and water (2.5 mL) were added to the reaction flask, and stirred at 95° C. for 16 hr under nitrogen protection. After the reaction, the organic solvent was removed under reduced pressure, diluted with water, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by silica gel flash column chromatography (DCM/MeOH=96/4) to obtain the compound 4d (200 mg). MS m/z (ESI): 442.0 [M+H] + .
第三步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物4e)的制备The third step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 4e) preparation
将化合物4d(200mg，453.02μmol)、3d(175.63mg，543.62μmol)、吡啶(71.67mg，906.03μmol，72.91μL)、DMAP(138.36mg，1.13mmol)、Cu(OAc) 2(82.28mg，453.02μmol)和1，4-二氧六环(10mL)加入反应瓶中，空气氛围下90℃搅拌16hr。反应结束后加水稀释，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，浓缩，粗产物经硅胶快速柱色谱法(DCM/MeOH＝96/4)分离纯化，得到化合物4e(160mg)。MS m/z(ESI)：719.0[M+H] +。 Compound 4d (200 mg, 453.02 μmol), 3d (175.63 mg, 543.62 μmol), pyridine (71.67 mg, 906.03 μmol, 72.91 μL), DMAP (138.36 mg, 1.13 mmol), Cu(OAc) 2 (82.28 mg, 453.02 μmol) and 1,4-dioxane (10 mL) were added to the reaction flask, and stirred at 90° C. for 16 hr in an air atmosphere. After the reaction, it was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated and purified by silica gel flash column chromatography (DCM/MeOH=96/4) to obtain compound 4e (160 mg) . MS m/z (ESI): 719.0 [M+H] + .
第四步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物4)的制备Fourth step: N-(3-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 4)
将化合物4e(240mg，333.92μmol)溶于TFA(6mL)中，100℃搅拌16hr。反应结束后将溶剂浓缩干，加入饱和碳酸氢钠溶液调节溶液pH约8，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经硅胶快速柱色谱法(DCM/MeOH＝90/10)粗纯化，再经C18柱反相柱色谱法(乙腈/0.05％碳酸氢铵水溶液＝62/38)纯化，得到化合物4(80mg)。MS m/z(ESI)：479.0[M+H] +。 Compound 4e (240 mg, 333.92 μmol) was dissolved in TFA (6 mL) and stirred at 100° C. for 16 hr. After the reaction, the solvent was concentrated to dryness, saturated sodium bicarbonate solution was added to adjust the pH of the solution to about 8, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was subjected to silica gel flash column chromatography (DCM/MeOH=90/10) was crudely purified, and then purified by C18 column reversed-phase column chromatography (acetonitrile/0.05% aqueous ammonium bicarbonate solution=62/38) to obtain compound 4 (80 mg). MS m/z (ESI): 479.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.65(s，1H)，8.71(s，1H)，8.45(s，1H)，8.37-8.23(m，3H)，8.22-8.14(m，2H)，8.03-7.94(m，3H)，7.87-7.77(m，2H)，7.45(d，J＝8.4Hz，1H)，2.28(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.65 (s, 1H), 8.71 (s, 1H), 8.45 (s, 1H), 8.37-8.23 (m, 3H), 8.22-8.14 (m, 2H) ), 8.03-7.94(m, 3H), 7.87-7.77(m, 2H), 7.45(d, J=8.4Hz, 1H), 2.28(s, 3H).
实施例5：N-(3-(4-(8-氨基咪唑并[1，2-a]吡嗪-3-基]-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物5)Example 5: N-(3-(4-(8-Aminoimidazo[1,2-a]pyrazin-3-yl]-1H-pyrazol-1-yl)-4-methylphenyl) -3-(Trifluoromethyl)benzamide (Compound 5)
Figure PCTCN2022079826-appb-000087
Figure PCTCN2022079826-appb-000087
第一步：3-溴-N-(2，4-二甲氧基苄基)咪唑并[1，2-a]吡嗪-8-胺(化合物5b)的制备Step 1: Preparation of 3-bromo-N-(2,4-dimethoxybenzyl)imidazo[1,2-a]pyrazin-8-amine (compound 5b)
将化合物5a(500mg，2.15mmol)和K 2CO 3(890.46mg，6.45mmol)加入到DMF(5mL)中，然后再加入化合物1b(539.45mg，3.23mmol)。加完后在90℃搅拌12小时。反应结束后反应液在冰水浴下降温，搅拌下滴入100mL水，有固体析出，固体经过滤和干燥，得到化合物5b(605mg)。MS m/z(ESI)：362.9[M+H] +。 Compound 5a (500 mg, 2.15 mmol) and K2CO3 ( 890.46 mg, 6.45 mmol) were added to DMF ( 5 mL) followed by compound 1b (539.45 mg, 3.23 mmol). After the addition was complete, it was stirred at 90°C for 12 hours. After the reaction, the temperature of the reaction solution was lowered in an ice-water bath, and 100 mL of water was added dropwise with stirring, and a solid was precipitated. The solid was filtered and dried to obtain compound 5b (605 mg). MS m/z (ESI): 362.9 [M+H] + .
第二步：N-(2，4-二甲氧基苄基)-3-(1H-吡唑-4-基)咪唑并[1，2-a]吡嗪-8-胺(化合物5c)的制备The second step: N-(2,4-dimethoxybenzyl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (compound 5c) preparation
将化合物5b(540mg，1.49mmol)与2d(317.33mg，1.64mmol)溶于1，4-二氧六环(4mL)和水(1mL)中，再加入[1，1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(121.32mg，148.67μmol)和碳酸钾(615.51mg，4.46mmol)，氮气保护下，升温至99℃反应3小时。反应结束后将反应液降至室温，向反应液中加入100mL水，再用乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤后减压浓缩除去溶剂，粗产物经C18住反相柱色谱法纯化(乙腈/0.05％甲酸水溶液＝31/69)分离纯化，得到化合物5c(321mg)。MS m/z(ESI)：351.1[M+H] +。 Compound 5b (540 mg, 1.49 mmol) and 2d (317.33 mg, 1.64 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), followed by the addition of [1,1′-bis(diphenylene)] phosphine)ferrocene]dichloropalladium dichloromethane complex (121.32mg, 148.67μmol) and potassium carbonate (615.51mg, 4.46mmol) were heated to 99°C for 3 hours under nitrogen protection. After the reaction, the reaction solution was lowered to room temperature, 100 mL of water was added to the reaction solution, and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent. The product was isolated and purified by C18 reverse phase column chromatography (acetonitrile/0.05% aqueous formic acid = 31/69) to give compound 5c (321 mg). MS m/z (ESI): 351.1 [M+H] + .
第三步：N-(3-(4-(8-(((2，4-二甲氧基苄基)氨基)咪唑并[1，2-a]吡嗪-3-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物5d)的制备The third step: N-(3-(4-(8-(((2,4-dimethoxybenzyl)amino)imidazo[1,2-a]pyrazin-3-yl)-1H- Preparation of Pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 5d)
将化合物5c(130.14mg，371.43μmol)和3d(80mg，247.62μmol)加入到25mL单口瓶中，再加入吡啶(39.17mg，495.24μmol)、醋酸铜(44.98mg，247.62μmol)和4-二甲氨基吡啶(90.76mg，742.86μmol)，以1，4-二氧六环(3mL)做溶剂，升温至100℃敞口反应16小时。反应液经过滤除去固体，滤液浓缩后经C18柱反相柱色谱法(乙腈/0.05％甲酸水溶液＝65/35)纯化，得到化合物5d(105.00mg)。MS m/z(ESI)：628.0[M+H] +。 Compound 5c (130.14mg, 371.43μmol) and 3d (80mg, 247.62μmol) were added to a 25mL single-neck flask, followed by pyridine (39.17mg, 495.24μmol), copper acetate (44.98mg, 247.62μmol) and 4-dimethylformaldehyde Aminopyridine (90.76 mg, 742.86 μmol), using 1,4-dioxane (3 mL) as a solvent, was heated to 100° C. for an open reaction for 16 hours. The reaction solution was filtered to remove solids, and the filtrate was concentrated and purified by C18 column reversed-phase column chromatography (acetonitrile/0.05% aqueous formic acid=65/35) to obtain compound 5d (105.00 mg). MS m/z (ESI): 628.0 [M+H] + .
第四步：N-(3-(4-(8-氨基咪唑并[1，2-a]吡嗪-3-基]-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物5)的制备The fourth step: N-(3-(4-(8-aminoimidazo[1,2-a]pyrazin-3-yl]-1H-pyrazol-1-yl)-4-methylphenyl) - Preparation of 3-(trifluoromethyl)benzamide (compound 5)
将化合物5d(80mg，127.47μmol)溶于三氟乙酸(3mL)中，升温至80℃反应16小时。反应结束后减压除去溶剂，粗产物经C18柱反向柱色谱法(乙腈/0.05％甲酸水溶液＝45/55)纯化，得到化合物5(7.56mg)。MS m/z(ESI)：477.9[M+H] +。 Compound 5d (80 mg, 127.47 μmol) was dissolved in trifluoroacetic acid (3 mL), and the temperature was raised to 80° C. to react for 16 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the crude product was purified by reversed column chromatography on a C18 column (acetonitrile/0.05% aqueous formic acid=45/55) to obtain compound 5 (7.56 mg). MS m/z (ESI): 477.9 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.65(s，1H)，8.69(s，1H)，8.32(s，1H)，8.30-8.25(m，2H)，8.01-7.96(m，2H)，7.87(d，J＝4.8Hz，1H)，7.84-7.77(m，3H)，7.45(d，J＝8.4Hz，1H)，7.29(d，J＝4.8Hz，1H)，6.95(s，2H)，2.29(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.65 (s, 1H), 8.69 (s, 1H), 8.32 (s, 1H), 8.30-8.25 (m, 2H), 8.01-7.96 (m, 2H) ), 7.87(d, J=4.8Hz, 1H), 7.84-7.77(m, 3H), 7.45(d, J=8.4Hz, 1H), 7.29(d, J=4.8Hz, 1H), 6.95(s , 2H), 2.29(s, 3H).
实施例6：N-(3-(4-(4-氨基喹唑啉-8-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物6)Example 6: N-(3-(4-(4-Aminoquinazolin-8-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl) ) benzamide (compound 6)
Figure PCTCN2022079826-appb-000088
Figure PCTCN2022079826-appb-000088
第一步：N-(3-(4-(4-((2，4-二甲氧基苄基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物6a)的制备The first step: N-(3-(4-(4-((2,4-dimethoxybenzyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)-4 Preparation of -methylphenyl)-3-(trifluoromethyl)benzamide (compound 6a)
反应瓶中加入化合物2e(50mg，0.14mmol)、3d(45mg，0.14mmol)、Cu(OAc) 2(28mg，0.14mmol)、吡啶(33mg，0.42mmol)、DMAP(34mg，0.28mmol)和1，4-二氧六环(3mL)，然后100℃敞口反应16小时。反应结束后加入60mL水稀释，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶柱色谱法(DCM∶MeOH＝10∶1)分离纯化，得到化合物6a(35mg)。MS m/z(ESI)：639.0[M+H] +。 Compound 2e (50 mg, 0.14 mmol), 3d (45 mg, 0.14 mmol), Cu(OAc) 2 (28 mg, 0.14 mmol), pyridine (33 mg, 0.42 mmol), DMAP (34 mg, 0.28 mmol) and 1 were added to the reaction flask , 4-dioxane (3 mL), and then reacted at 100°C for 16 hours. After the reaction was completed, 60 mL of water was added to dilute, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain compound 6a (35 mg). MS m/z (ESI): 639.0 [M+H] + .
第二步：N-(3-(4-(4-氨基喹唑啉-8-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物6)的制备The second step: N-(3-(4-(4-aminoquinazolin-8-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl) ) preparation of benzamide (compound 6)
反应瓶中加入化合物6a(35mg，55μmol)和TFA(5mL)，氮气保护下70℃反应2hr。反应结束后加水稀释，饱和NaHCO 3溶液调节溶液pH至7-8，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经Prep-HPLC分离纯化，得到化合物6(7mg)。MS m/z(ESI)：488.9[M+H] +。 Compound 6a (35 mg, 55 μmol) and TFA (5 mL) were added to the reaction flask, and the reaction was carried out at 70° C. for 2 hr under nitrogen protection. After the reaction was completed, it was diluted with water, the pH of the solution was adjusted to 7-8 with saturated NaHCO 3 solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated and purified by Prep-HPLC , to obtain compound 6 (7 mg). MS m/z (ESI): 488.9 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.64(s，1H)，8.95(s，1H)，8.54(s，1H)，8.50(s，1H)，8.34-8.27(m，2H)，8.20(dd，J＝7.6，1.2Hz，1H)，8.12(dd，J＝8.4，1.6Hz，1H)，8.01-7.95(m，2H)，7.91-7.66(m，4H)，7.52(t，J＝8.0Hz，1H)，7.44(d，J＝8.4Hz，1H)，2.30(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.64(s, 1H), 8.95(s, 1H), 8.54(s, 1H), 8.50(s, 1H), 8.34-8.27(m, 2H), 8.20 (dd, J=7.6, 1.2Hz, 1H), 8.12 (dd, J=8.4, 1.6Hz, 1H), 8.01-7.95 (m, 2H), 7.91-7.66 (m, 4H), 7.52 (t, J=8.0Hz, 1H), 7.44 (d, J=8.4Hz, 1H), 2.30 (s, 3H).
实施例7：3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-N-(3-氯-2-氟苯基)-4-甲基苯甲酰胺(化合物7)Example 7: 3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)-N-( 3-Chloro-2-fluorophenyl)-4-methylbenzamide (Compound 7)
Figure PCTCN2022079826-appb-000089
Figure PCTCN2022079826-appb-000089
第一步：N-(7-溴咪唑并[2，1-f][1，2，4]三嗪-4-基)-N-叔丁氧羰基氨基甲酸叔丁酯(化合物7a)的制备The first step: tert-butyl N-(7-bromoimidazo[2,1-f][1,2,4]triazin-4-yl)-N-tert-butoxycarbonylcarbamate (compound 7a) preparation
反应瓶中依次加入化合物4a(150mg，0.7mmol)、TEA(355mg，3.5mmol)、DMAP(9mg，70μmmol)、THF(5mL)和(Boc) 2O(459mg，2.10mmol)，氮气保护下25℃反应14hr。反应结束后加入60mL水稀释，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶柱色谱法(EA∶PE＝1∶10)分离纯化，得到化合物7a(230mg，0.56mmol)。MS m/z(ESI)：413.8[M+H] +。 Compound 4a (150 mg, 0.7 mmol), TEA (355 mg, 3.5 mmol), DMAP (9 mg, 70 μmmol), THF (5 mL) and (Boc) 2 O (459 mg, 2.10 mmol) were added to the reaction flask in sequence, and under nitrogen protection, 25 °C reaction for 14hr. After the reaction was completed, 60 mL of water was added to dilute, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated and purified by silica gel column chromatography (EA:PE=1:10) to obtain compound 7a (230 mg, 0.56 mmol). MS m/z (ESI): 413.8 [M+H] + .
第二步：7-(1H-吡唑-4-基)咪唑并[2，1-f][1，2，4]三嗪-4-胺(化合物7b)的制备Step 2: Preparation of 7-(1H-pyrazol-4-yl)imidazo[2,1-f][1,2,4]triazin-4-amine (compound 7b)
反应瓶中加入化合物7a(230mg，0.56mmol)、2d(215mg，1.11mmol)、K 2CO 3(230mg，1.67mmol)、Pd(dppf)Cl 2·DCM(45mg，55μmol)、1，4-二氧六环(8mL)和H2O(1.5mL)，氮气保护下100℃反应过夜。反应结束后将反应液冷却至室温，加入60mL水稀释，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶柱色谱法(MeOH∶DCM＝5∶95)分离纯化，得到化合物7b(60mg)。MS m/z(ESI)：202.2[M+H] +。 Compound 7a (230 mg, 0.56 mmol), 2d (215 mg, 1.11 mmol), K 2 CO 3 (230 mg, 1.67 mmol), Pd(dppf)Cl 2 ·DCM (45 mg, 55 μmol), 1,4- Dioxane (8 mL) and H2O (1.5 mL) were reacted at 100°C overnight under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature, diluted with 60 mL of water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel column chromatography (MeOH:DCM=5:95) to obtain compound 7b (60 mg). MS m/z (ESI): 202.2 [M+H] + .
第三步：3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯甲酸甲酯(化合物7c)的制备The third step: 3-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)-4-methyl Preparation of methyl benzoate (compound 7c)
反应瓶中加入化合物7b(30mg，0.15mmol)、2h(29mg，0.15mmol)、Cu(OAc) 2(30mg，0.15mmol)、吡啶(35mg，0.45mmol)、DMAP(35mg，0.30mmol)和1，4-二氧六环(3mL)，加完后100℃敞口反应20小时。反应结束后加入60mL水稀释，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶柱色谱法(DCM∶MeOH＝10∶1)分离纯化，得到化合物7c(10mg)。MS m/z(ESI)：350.0[M+H] +。 Compound 7b (30 mg, 0.15 mmol), 2h (29 mg, 0.15 mmol), Cu(OAc) 2 (30 mg, 0.15 mmol), pyridine (35 mg, 0.45 mmol), DMAP (35 mg, 0.30 mmol) and 1 were added to the reaction flask , 4-dioxane (3 mL), and reacted at 100 °C for 20 hours after the addition. After the reaction was completed, 60 mL of water was added to dilute, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain compound 7c (10 mg). MS m/z (ESI): 350.0 [M+H] + .
第四步：3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯甲酸(化合物7d)的制备The fourth step: 3-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)-4-methyl Preparation of benzoic acid (compound 7d)
反应瓶中加入化合物7c(10mg，29μmol)和MeOH(3mL)，再加入NaOH(6mg，0.14mmol)的H 2O(1mL)溶液，氮气保护下室温反应2hr。反应结束后用2N盐酸调节溶液pH至5-6，直接减压蒸除溶剂，得到化合物7d(9mg)。MS m/z(ESI)：336.0[M+H] +。 Compound 7c (10 mg, 29 μmol) and MeOH (3 mL) were added to the reaction flask, and then NaOH (6 mg, 0.14 mmol) in H 2 O (1 mL) solution was added, and the reaction was carried out at room temperature for 2 hr under nitrogen protection. After the reaction, the pH of the solution was adjusted to 5-6 with 2N hydrochloric acid, and the solvent was directly evaporated under reduced pressure to obtain compound 7d (9 mg). MS m/z (ESI): 336.0 [M+H] + .
第五步：3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-N-(3-氯-2-氟苯基)-4-甲基苯甲酰胺(化合物7)的制备The fifth step: 3-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)-N-( Preparation of 3-chloro-2-fluorophenyl)-4-methylbenzamide (compound 7)
反应瓶中加入化合物7d(9mg，28μmol)、1j(5mg，28μmol)和吡啶(2mL)，搅拌溶解后加入T 3P(1mL，DMF中50％)，氮气保护下室温反应过夜。反应结束后直接将反应液浓缩干，加入60mL水稀释，用饱和碳酸氢钠溶液调节pH至7-8，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经Prep-HPLC分离纯化，得到化合物7(3mg)。MS m/z(ESI)：462.9[M+H] +。 Compound 7d (9 mg, 28 μmol), 1j (5 mg, 28 μmol) and pyridine (2 mL) were added to the reaction flask, stirred and dissolved, T 3 P (1 mL, 50% in DMF) was added, and the reaction was carried out at room temperature overnight under nitrogen protection. After the reaction, the reaction solution was directly concentrated to dryness, diluted with 60 mL of water, adjusted to pH 7-8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrate. The crude product was isolated and purified by Prep-HPLC to give compound 7 (3 mg). MS m/z (ESI): 462.9 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.45(s，1H)，8.79(s，1H)，8.47(s，1H)，8.26(s，1H)，8.22-8.16 (m，2H)，8.12-8.08(m，1H)，8.05-7.98(m，2H)，7.63(d，J＝8.0Hz，1H)，7.60-7.55(m，1H)，7.51-7.45(m，1H)，7.30-7.24(m，1H)，2.38(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 8.79 (s, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 8.22-8.16 (m, 2H), 8.12-8.08(m, 1H), 8.05-7.98(m, 2H), 7.63(d, J=8.0Hz, 1H), 7.60-7.55(m, 1H), 7.51-7.45(m, 1H), 7.30- 7.24(m, 1H), 2.38(s, 3H).
实施例8：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物8)Example 8: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- 3-(Trifluoromethyl)benzamide (Compound 8)
Figure PCTCN2022079826-appb-000090
Figure PCTCN2022079826-appb-000090
第一步：N-(2，4-二甲氧基苄基)-7-(1H-吡唑-4-基)噻吩并[3，2-d]嘧啶-4-胺(化合物8a)的制备The first step: N-(2,4-dimethoxybenzyl)-7-(1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4-amine (compound 8a) preparation
依次将化合物1c(300mg，788.94μmol)、2d(229.63mg，1.18mmol)、碳酸钾(327.11mg，2.37mmol)、Pd(dppf)Cl 2·DCM(64.42mg，78.89μmol)、1，4-二氧六环(12mL)和H 2O(3mL)加入反应瓶中，氮气保护下95℃搅拌16hr。反应结束后将溶剂浓缩干，粗产物经硅胶快速柱色谱法(DCM/MeOH＝96/4)分离纯化，得到化合物8a(250mg)。MS m/z(ESI)：368.0[M+H] +。 Compound 1c (300 mg, 788.94 μmol), 2d (229.63 mg, 1.18 mmol), potassium carbonate (327.11 mg, 2.37 mmol), Pd(dppf)Cl 2 ·DCM (64.42 mg, 78.89 μmol), 1,4- Dioxane (12 mL) and H 2 O (3 mL) were added to the reaction flask, and stirred at 95° C. for 16 hr under nitrogen protection. After the reaction, the solvent was concentrated to dryness, and the crude product was separated and purified by silica gel flash column chromatography (DCM/MeOH=96/4) to obtain compound 8a (250 mg). MS m/z (ESI): 368.0 [M+H] + .
第二步：N-(3-(4-(4-((2，4-二甲氧基苄基)氨基)噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物8b)的制备Step 2: N-(3-(4-(4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazole Preparation of -1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 8b)
将化合物8a(90.98mg，247.62μmol)、3d(80mg，247.62μmol)、吡啶(39.17mg，495.24μmol，39.85μL)、DMAP(90.76mg，742.86μmol)、Cu(OAc) 2(44.98mg，247.62μmol)和1，4-二氧六环(8mL)加入反应瓶中，90℃敞口反应16hr。反应结束后加水稀释，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(DCM/MeOH＝92/8)分离纯化，得到化合物8b(87mg)。MS m/z(ESI)：645.0[M+H] +。 Compound 8a (90.98 mg, 247.62 μmol), 3d (80 mg, 247.62 μmol), pyridine (39.17 mg, 495.24 μmol, 39.85 μL), DMAP (90.76 mg, 742.86 μmol), Cu(OAc) 2 (44.98 mg, 247.62 μmol) and 1,4-dioxane (8 mL) were added to the reaction flask, and the reaction was carried out at 90° C. for 16 hr. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel flash column chromatography (DCM/MeOH=92/8) to give compound 8b (87 mg). MS m/z (ESI): 645.0 [M+H] + .
第三步：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物8)的制备Step 3: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- Preparation of 3-(trifluoromethyl)benzamide (Compound 8)
将化合物8b(87.31mg，135.43μmol)溶于TFA(4mL)，85℃搅拌3hr。反应结束后浓缩除去溶剂，饱和碳酸氢钠溶液调溶液pH至约8。乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经Prep-HPLC分离纯化，得到化合物8(23.21mg)。MS m/z(ESI)：494.9[M+H] +。 Compound 8b (87.31 mg, 135.43 μmol) was dissolved in TFA (4 mL) and stirred at 85°C for 3 hr. After the reaction was completed, the solvent was removed by concentration, and the pH of the solution was adjusted to about 8 with saturated sodium bicarbonate solution. It was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated and purified by Prep-HPLC to give compound 8 (23.21 mg). MS m/z (ESI): 494.9 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.64(s，1H)，8.80(s，1H)，8.49(s，1H)，8.48(s，1H)，8.34-8.31(m，2H)，8.29(d，J＝7.6Hz，1H)，7.99(d，J＝7.6Hz，1H)，7.95(d，J＝2.4Hz，1H)，7.85-7.78(m，2H)，7.53(s，2H)，7.44(d，J＝8.8Hz，1H)，2.28(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.64(s, 1H), 8.80(s, 1H), 8.49(s, 1H), 8.48(s, 1H), 8.34-8.31(m, 2H), 8.29 (d, J=7.6Hz, 1H), 7.99 (d, J=7.6Hz, 1H), 7.95 (d, J=2.4Hz, 1H), 7.85-7.78 (m, 2H), 7.53 (s, 2H) ), 7.44(d, J=8.8Hz, 1H), 2.28(s, 3H).
实施例9：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-氯-2-氟苯甲酰胺(化合物9)Example 9: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-3-chloro-2-fluorobenzamide (Compound 9)
Figure PCTCN2022079826-appb-000091
Figure PCTCN2022079826-appb-000091
第一步：3-氯-2-氟-N-(4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)苯甲酰胺(化合物9b)的制备The first step: 3-chloro-2-fluoro-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) ) Phenyl) Benzamide (Compound 9b) Preparation
将化合物3a(200.00mg，857.95μmol)和9a(149.76mg，857.95μmol)溶于吡啶(5mL)，然后滴加1-丙基磷酸酐(3mL，DMF中50％)，加完后于25℃反应12小时。反应结束后减压除去吡啶，向反应液中加入饱和碳酸氢钠水溶液，用乙酸乙酯萃取，有机相经无水硫酸钠干燥，过滤后减压浓缩，粗产物经硅胶快速柱色谱法(石油醚/乙酸乙酯＝4/1)分离纯化，得到化合物9b(192.00mg)。MS m/z(ESI)：390.0[M+H] +。 Compounds 3a (200.00 mg, 857.95 μmol) and 9a (149.76 mg, 857.95 μmol) were dissolved in pyridine (5 mL), and then 1-propylphosphoric anhydride (3 mL, 50% in DMF) was added dropwise. The reaction was carried out for 12 hours. After the reaction, pyridine was removed under reduced pressure, saturated aqueous sodium bicarbonate solution was added to the reaction solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was subjected to silica gel flash column chromatography (petroleum ether/ethyl acetate=4/1) was separated and purified to obtain compound 9b (192.00 mg). MS m/z (ESI): 390.0 [M+H] + .
第二步：(5-(3-氯-2-氟苯甲酰胺基)-2-甲基苯基)硼酸(化合物9c)的制备The second step: preparation of (5-(3-chloro-2-fluorobenzamido)-2-methylphenyl)boronic acid (compound 9c)
将化合物9b(190.00mg，487.61μmol)、醋酸铵(75.17mg，975.22μmol)、高碘酸钠(312.89mg，1.46mmol)加入到乙腈(5mL)和水(2mL)中，升温至50℃反应16小时。反应结束后滴加稀盐酸调节反应液pH至弱酸性，然后直接将反应液浓缩干。粗产物经硅胶快速柱色谱法(二氯甲烷/甲醇＝10/1)分离纯化，得到化合物9c(130.00mg)。MS m/z(ESI)：307.9[M+H] +。 Compound 9b (190.00 mg, 487.61 μmol), ammonium acetate (75.17 mg, 975.22 μmol), and sodium periodate (312.89 mg, 1.46 mmol) were added to acetonitrile (5 mL) and water (2 mL), and the temperature was raised to 50 °C for reaction 16 hours. After the reaction, dilute hydrochloric acid was added dropwise to adjust the pH of the reaction solution to weak acidity, and then the reaction solution was directly concentrated to dryness. The crude product was separated and purified by silica gel flash column chromatography (dichloromethane/methanol=10/1) to obtain compound 9c (130.00 mg). MS m/z (ESI): 307.9 [M+H] + .
第三步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-氯-2-氟苯甲酰胺(化合物9)的制备The third step: N-(3-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-3-chloro-2-fluorobenzamide (compound 9)
将化合物7b(14.00mg，69.59μmol)、9c(21.40mg，69.59μmol)、吡啶(11.01mg，139.17μmol)、醋酸铜(12.64mg，69.59μmol)和4-二甲氨基吡啶(25.50mg，208.76μmol)加入到1，4-二氧六环(4mL)中，升温至90℃敞口反应16小时。反应结束后滤除固体，滤液浓缩后经制备硅胶板(二氯甲烷/甲醇＝15/1)纯化得粗产物，粗产物再经C18柱反相柱色谱法(乙腈/0.05％碳酸氢铵水溶液＝60/40)分离纯化，得到化合物9(3.00mg)。MS m/z(ESI)：462.9[M+H] +。 Compound 7b (14.00 mg, 69.59 μmol), 9c (21.40 mg, 69.59 μmol), pyridine (11.01 mg, 139.17 μmol), copper acetate (12.64 mg, 69.59 μmol) and 4-dimethylaminopyridine (25.50 mg, 208.76 μmol) was added to 1,4-dioxane (4 mL), and the temperature was raised to 90° C. for an open reaction for 16 hours. After the reaction, the solid was filtered off, and the filtrate was concentrated and purified by preparative silica gel plate (dichloromethane/methanol=15/1) to obtain the crude product, which was then subjected to C18 column reversed-phase column chromatography (acetonitrile/0.05% aqueous ammonium bicarbonate solution). =60/40) was isolated and purified to obtain compound 9 (3.00 mg). MS m/z (ESI): 462.9 [M+H] + .
1HNMR(400MHz，DMSO-d 6)δ10.75(s，1H)，8.69(s，1H)，8.43(s，1H)，8.25(s，1H)，8.18(s，1H)，8.17(s，1H)，7.98(s，1H)，7.92(d，J＝2.0Hz，1H)，7.81-7.76(m，1H)，7.69-7.64(m，2H)，7.43(d，J＝8.8Hz，1H)，7.38(t，J＝8.0Hz，1H)，2.26(s，3H). 1 HNMR (400MHz, DMSO-d 6 ) δ 10.75(s, 1H), 8.69(s, 1H), 8.43(s, 1H), 8.25(s, 1H), 8.18(s, 1H), 8.17(s , 1H), 7.98(s, 1H), 7.92(d, J=2.0Hz, 1H), 7.81-7.76(m, 1H), 7.69-7.64(m, 2H), 7.43(d, J=8.8Hz, 1H), 7.38(t, J=8.0Hz, 1H), 2.26(s, 3H).
实施例10：3-(4-(8-氨基咪唑并[1，2-a]吡嗪-3-基)-1H-吡唑-1-基)-N-(3-氯-2-氟苯基)-4-甲基苯甲酰胺(化合物10)Example 10: 3-(4-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-1H-pyrazol-1-yl)-N-(3-chloro-2-fluoro Phenyl)-4-methylbenzamide (Compound 10)
Figure PCTCN2022079826-appb-000092
Figure PCTCN2022079826-appb-000092
第一步：(5-((3-氯-2-氟苯基)氨基甲酰基)-2-甲基苯基)氨基甲酸叔丁酯(化合物10b)的制备The first step: preparation of tert-butyl (5-((3-chloro-2-fluorophenyl)carbamoyl)-2-methylphenyl)carbamate (compound 10b)
将化合物10a(1g，3.98mmol)和1j(868.9mg，5.97mmol)加入到吡啶(6mL)中，然后加入T 3P(5mL，50％于DMF中)，加完后室温搅拌16hr。反应结束后减压除去吡啶，加水稀释，再用饱和碳酸氢钠溶液调节溶液pH至约8，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，浓缩，得到化合物10b(1.45g)。 Compounds 10a (1 g, 3.98 mmol) and 1j ( 868.9 mg, 5.97 mmol) were added to pyridine (6 mL), followed by T3P (5 mL, 50% in DMF) and stirred at room temperature for 16 hrs. After the reaction, the pyridine was removed under reduced pressure, diluted with water, the pH of the solution was adjusted to about 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 10b (1.45g) .
第二步：3-氨基-N-(3-氯-2-氟苯基)-4-甲基苯甲酰胺(化合物10c)的制备The second step: preparation of 3-amino-N-(3-chloro-2-fluorophenyl)-4-methylbenzamide (compound 10c)
将化合物10b(1.45g，3.83mmol)溶于MeOH(5mL)和DCM(5mL)中，再滴入HCl的1，4-二氧六环溶液(15mL，4M)，加完后室温反应2小时。反应结束后减压除去溶剂，加水稀释，再用饱和碳酸氢钠溶液调节溶液pH至约8，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(DCM/MeOH＝96/4)分离纯化，得到化合物10c(1.45g)。MS m/z(ESI)：279.0[M+H] +。 Compound 10b (1.45 g, 3.83 mmol) was dissolved in MeOH (5 mL) and DCM (5 mL), and then a solution of HCl in 1,4-dioxane (15 mL, 4 M) was added dropwise. After the addition, the reaction was performed at room temperature for 2 hours. . After the reaction, the solvent was removed under reduced pressure, diluted with water, the pH of the solution was adjusted to about 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel flash column chromatography (DCM/MeOH=96/4) to give compound 10c (1.45 g). MS m/z (ESI): 279.0 [M+H] + .
第三步：N-(3-氯-2-氟苯基)-4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯甲酰胺(化合物10d)的制备The third step: N-(3-chloro-2-fluorophenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- Preparation of 2-yl)benzamide (compound 10d)
将化合物10c(900mg，3.23mmol)和氢溴酸(2mL，48％)加入到MeOH(4mL)中，然后依次缓慢加入亚硝酸钠(267.38mg，3.88mmol)的水(1mL)溶液、联硼酸频那醇酯(1.48g，5.81mmol)和醋酸钾(633.84mg，6.46mmol)的水(1mL)溶液，加完后室温下搅拌3小时。反应结束后向反应液中加入100mL水，再用乙酸乙酯萃取。有机相用饱和氯化钠洗涤，无水硫酸钠干燥，过滤后减压浓缩除去溶剂，粗产物经C18柱反相柱色谱法(乙腈/0.05％甲酸水溶液＝55/45)纯化，得到化合物10d(51mg)。MS m/z(ESI)：390.2[M+H] +。 Compound 10c (900 mg, 3.23 mmol) and hydrobromic acid (2 mL, 48%) were added to MeOH (4 mL), followed by slowly adding sodium nitrite (267.38 mg, 3.88 mmol) in water (1 mL), bisboronic acid A solution of pinacol ester (1.48 g, 5.81 mmol) and potassium acetate (633.84 mg, 6.46 mmol) in water (1 mL) was added and stirred at room temperature for 3 hours. After the reaction, 100 mL of water was added to the reaction solution, followed by extraction with ethyl acetate. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent. The crude product was purified by C18 column reversed-phase column chromatography (acetonitrile/0.05% aqueous formic acid=55/45) to obtain compound 10d (51 mg). MS m/z (ESI): 390.2 [M+H] + .
第四步：(5-((3-氯-2-氟苯基)氨基甲酰基)-2-甲基苯基)硼酸(化合物10e)的制备The fourth step: preparation of (5-((3-chloro-2-fluorophenyl)carbamoyl)-2-methylphenyl)boronic acid (compound 10e)
将化合物10d(51mg，130.88μmol)、醋酸铵(20.18mg，261.77μmol)、高碘酸钠(83.99mg，392.65μmol)加入到25mL单口瓶中，再加入乙腈(4mL)和水(1mL)，加完后升温至50℃反应16小时。反应结束后滴加稀盐酸调节溶液pH至弱酸性，反应液直接用C18柱反相柱色谱法(乙腈/0.05％甲酸水溶液＝32/68)纯化，得到化合物10e(130.00mg)。MS m/z(ESI)：308.1[M+H] +。 Compound 10d (51mg, 130.88μmol), ammonium acetate (20.18mg, 261.77μmol), sodium periodate (83.99mg, 392.65μmol) were added to a 25mL single-neck bottle, and then acetonitrile (4mL) and water (1mL) were added, After the addition, the temperature was raised to 50°C for 16 hours. After the reaction, dilute hydrochloric acid was added dropwise to adjust the pH of the solution to weak acidity, and the reaction solution was directly purified by C18 column reversed-phase column chromatography (acetonitrile/0.05% aqueous formic acid=32/68) to obtain compound 10e (130.00 mg). MS m/z (ESI): 308.1 [M+H] + .
第五步：N-(3-氯-2-氟苯基)-3-(4-(8-((2，4-二甲氧基苄基)氨基)咪唑并[1，2-a]吡嗪-3-基)-1H-吡唑-1-基)-4-甲基苯甲酰胺(化合物10f)的制备The fifth step: N-(3-chloro-2-fluorophenyl)-3-(4-(8-((2,4-dimethoxybenzyl)amino)imidazo[1,2-a] Preparation of Pyrazin-3-yl)-1H-pyrazol-1-yl)-4-methylbenzamide (Compound 10f)
将化合物5c(34.18mg，97.56μmol)和10e(20mg，65.04μmol)加入到25mL单口瓶中，再加入吡啶(10.29mg，130.08μmol)、醋酸铜(11.81mg，65.04μmol)、4-二甲氨基吡啶(23.84mg，195.11μmol)和1，4-二氧六环(3mL)，加完后升温至100℃敞口反应16小时。反应结束后将反应液降至室温，滤除固体，滤液浓缩后经C18柱反相柱色谱法(乙腈/0.05％甲酸水溶液＝60/40)纯化，得到化合物10f(15mg)。MS m/z(ESI)：612.0[M+H] +。 Compound 5c (34.18mg, 97.56μmol) and 10e (20mg, 65.04μmol) were added to a 25mL single-neck flask, followed by pyridine (10.29mg, 130.08μmol), copper acetate (11.81mg, 65.04μmol), 4-dimethylacetate After adding aminopyridine (23.84 mg, 195.11 μmol) and 1,4-dioxane (3 mL), the temperature was raised to 100° C. for open reaction for 16 hours. After the reaction, the reaction solution was cooled to room temperature, and the solid was filtered off. The filtrate was concentrated and purified by C18 column reversed-phase column chromatography (acetonitrile/0.05% aqueous formic acid=60/40) to obtain compound 10f (15 mg). MS m/z (ESI): 612.0 [M+H] + .
第六步：3-(4-(8-氨基咪唑并[1，2-a]吡嗪-3-基)-1H-吡唑-1-基)-N-(3-氯-2-氟苯基)-4-甲基苯甲酰胺(化合 物10)的制备Step 6: 3-(4-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-1H-pyrazol-1-yl)-N-(3-chloro-2-fluoro Preparation of phenyl)-4-methylbenzamide (compound 10)
将化合物10f(13mg，21.24μmol)溶于三氟乙酸(3mL)，升温至80℃反应16小时。反应结束后减压除去溶剂，然后经C18柱反相柱色谱法(乙腈/0.05％甲酸水溶液＝50/50)纯化，得到化合物10(2.55mg)。MS m/z(ESI)：462.1[M+H] +。 Compound 10f (13 mg, 21.24 μmol) was dissolved in trifluoroacetic acid (3 mL), and the temperature was raised to 80° C. to react for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, and then purified by C18 column reversed-phase column chromatography (acetonitrile/0.05% aqueous formic acid=50/50) to obtain compound 10 (2.55 mg). MS m/z (ESI): 462.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.50(s，1H)，8.77(s，1H)，8.30(s，1H)，8.13(s，1H)，8.02(d，J＝8.0Hz，1H)，7.90(d，J＝4.4Hz，1H)，7.82(s，1H)，7.63(d，J＝8.0Hz，1H)，7.56(t，J＝7.5Hz，1H)，7.47(t，J＝7.6Hz，1H)，7.33-7.22(m，2H)，6.96(s，2H)，2.40(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.50 (s, 1H), 8.77 (s, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.90(d, J=4.4Hz, 1H), 7.82(s, 1H), 7.63(d, J=8.0Hz, 1H), 7.56(t, J=7.5Hz, 1H), 7.47(t, J=7.6Hz, 1H), 7.33-7.22(m, 2H), 6.96(s, 2H), 2.40(s, 3H).
实施例11：3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基-N-(3-(三氟甲基)苯基)苯甲酰胺(化合物11)Example 11: 3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)-4-methan yl-N-(3-(trifluoromethyl)phenyl)benzamide (Compound 11)
Figure PCTCN2022079826-appb-000093
Figure PCTCN2022079826-appb-000093
第一步：3-溴-4-甲基-N-(3-(三氟甲基)苯基)苯甲酰胺(化合物11c)的制备The first step: preparation of 3-bromo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (compound 11c)
将化合物11a(280.00mg，1.30mmol)和11b(209.79mg，1.30mmol)溶于N，N-二甲基甲酰胺(15mL)，然后加入HATU(594.10mg，1.56mmol)和N，N-二异丙基乙胺(336.56mg，2.60mmol)，25℃反应12小时。反应结束后用乙酸乙酯稀释反应液，水洗3次，饱和氯化钠溶液洗涤，有机相经无水硫酸钠干燥，过滤后减压浓缩，经硅胶柱色谱法(石油醚/乙酸乙酯＝4/1)分离纯化，得到化合物11c(370mg)。MS m/z(ESI)：357.8[M+H] +。 Compounds 11a (280.00 mg, 1.30 mmol) and 11b (209.79 mg, 1.30 mmol) were dissolved in N,N-dimethylformamide (15 mL), followed by the addition of HATU (594.10 mg, 1.56 mmol) and N,N-bismuth Isopropylethylamine (336.56 mg, 2.60 mmol) was reacted at 25°C for 12 hours. After the reaction, the reaction solution was diluted with ethyl acetate, washed three times with water, and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 4/1) was isolated and purified to obtain compound 11c (370 mg). MS m/z (ESI): 357.8 [M+H] + .
第二步：4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-N-(3-(三氟甲基)苯基)苯甲酰胺(化合物11d)的制备The second step: 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-N-(3-(trifluoromethyl) Preparation of phenyl)phenyl)benzamide (compound 11d)
将化合物11c(150mg，0.42mmol)与联硼酸频那醇酯(253.94mg，1.26mmol)溶于1，4-二氧六环(10mL)中，加入[1，1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(34.20mg，0.04mmol)和醋酸钾(246.62mg，2.51mmol)，氮气保护下加热到80℃反应12小时。反应结束后，将反应液降至室温，向反应液中加入水稀释，用乙酸乙酯萃取，无水硫酸钠干燥，过滤后减压浓缩，将粗产物经硅胶柱色谱法(石油醚/乙酸乙酯＝4/1)分离纯化，得到化合物11d(190mg)。MS m/z(ESI)：406.0[M+H] +。 Compound 11c (150 mg, 0.42 mmol) and pinacol biboronate (253.94 mg, 1.26 mmol) were dissolved in 1,4-dioxane (10 mL), and [1,1′-bis(diphenyl) was added. Phosphine)ferrocene]dichloropalladium dichloromethane complex (34.20 mg, 0.04 mmol) and potassium acetate (246.62 mg, 2.51 mmol) were heated to 80°C under nitrogen to react for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (petroleum ether/acetic acid). ethyl ester=4/1) was isolated and purified to obtain compound 11d (190 mg). MS m/z (ESI): 406.0 [M+H] + .
第三步：(2-甲基-5-((3-(三氟甲基)苯基)氨基甲酰基)苯基)硼酸(化合物11e)的制备The third step: preparation of (2-methyl-5-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)boronic acid (compound 11e)
除将化合物9b替换为化合物11d外，以与实施例9第二步相同的方法进行制备，将粗产物经硅胶柱色谱法(二氯甲烷/甲醇＝10/1)分离纯化，得到化合物11e(60mg)。MS m/z(ESI)：324.0[M+H] +。 The preparation was carried out in the same manner as in the second step of Example 9 except that compound 9b was replaced by compound 11d, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain compound 11e ( 60mg). MS m/z (ESI): 324.0 [M+H] + .
第四步：3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基-N-(3-(三氟甲基)苯基)苯甲酰胺(化合物11f)的制备The fourth step: 3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)-1H - Preparation of pyrazol-1-yl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (compound 11f)
除将化合物3d替换为化合物11e外，以与实施例4第三步相同的方法进行制备，将粗产物经制备硅胶板(二氯甲烷/甲醇＝15/1)纯化，得到化合物11f(10mg)。MS m/z(ESI)：719.1[M+H] +。 The preparation was carried out in the same manner as the third step of Example 4 except that compound 3d was replaced by compound 11e, and the crude product was purified by preparative silica gel plate (dichloromethane/methanol=15/1) to obtain compound 11f (10 mg) . MS m/z (ESI): 719.1 [M+H] + .
第五步：3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基-N-(3-(三氟甲基)苯基)苯甲酰胺(化合物11)的制备The fifth step: 3-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)-4-methyl Preparation of yl-N-(3-(trifluoromethyl)phenyl)benzamide (compound 11)
将化合物11f(10.00mg，13.22μmol)溶于三氟乙酸(3mL)，升温至99℃反应16小时。反应结束后减压除去溶剂，后经Prep-HPLC分离纯化，得到化合物11的三氟乙酸盐(2mg)。MS m/z(ESI)：479.0[M+H] +。 Compound 11f (10.00 mg, 13.22 μmol) was dissolved in trifluoroacetic acid (3 mL), and the temperature was raised to 99° C. to react for 16 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the compound was separated and purified by Prep-HPLC to obtain the trifluoroacetic acid salt of compound 11 (2 mg). MS m/z (ESI): 479.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.63(s，1H)，8.78(s，1H)，8.48(s，1H)，8.28(s，1H)，8.24(s，1H)，8.19(s，2H)，8.12(d，J＝1.6Hz，1H)，8.08(d，J＝8.8Hz，1H)，8.04(dd，J＝8.0，2.0Hz，1H)，8.00(s，1H)，7.65-7.59(m，2H)，7.47(d，J＝8.0Hz，1H)，2.37(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.63 (s, 1H), 8.78 (s, 1H), 8.48 (s, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 8.19 ( s, 2H), 8.12 (d, J=1.6Hz, 1H), 8.08 (d, J=8.8Hz, 1H), 8.04 (dd, J=8.0, 2.0Hz, 1H), 8.00 (s, 1H), 7.65-7.59(m, 2H), 7.47(d, J=8.0Hz, 1H), 2.37(s, 3H).
实施例12：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-氯-4-氟苯甲酰胺(化合物12)Example 12: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-3-chloro-4-fluorobenzamide (Compound 12)
Figure PCTCN2022079826-appb-000094
Figure PCTCN2022079826-appb-000094
第一步：3-氯-4-氟-N-(4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)苯甲酰胺(化合物12b)的制备The first step: 3-chloro-4-fluoro-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) ) Phenyl) Benzamide (Compound 12b) Preparation
将化合物12a(200mg，1.15mmol)和3a(267.09mg，1.15mmol)溶于吡啶(4mL)中，再加入T 3P(3mL，50％于DMF中)，加完后25℃搅拌16hr。反应结束后减压除去吡啶，滴入饱和碳酸氢钠溶液淬灭，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(DCM/MeOH＝99/1)分离纯化，得化合物12b(250mg)。MS m/z(ESI)：389.9[M+H] +。 Compounds 12a (200 mg, 1.15 mmol) and 3a (267.09 mg, 1.15 mmol) were dissolved in pyridine (4 mL), T3P ( 3 mL, 50% in DMF) was added, and the mixture was stirred at 25°C for 16 hr. After the reaction was completed, pyridine was removed under reduced pressure, quenched by dropwise addition of saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel flash column chromatography (DCM/MeOH=99/1) to obtain compound 12b (250 mg). MS m/z (ESI): 389.9 [M+H] + .
第二步：(5-(3-氯-4-氟苯甲酰胺基)-2-甲基苯基)硼酸(化合物12c)的制备The second step: preparation of (5-(3-chloro-4-fluorobenzamido)-2-methylphenyl)boronic acid (compound 12c)
将化合物12b(320mg，821.24μmol)溶于MeCN(16mL)中，再加入NaIO 4(526.97mg，2.46mmol)、醋酸铵(126.61mg，1.64mmol)和水(5mL)，加完后50℃反应16hr。反应结束后滤除固体，滤液浓缩后经硅胶快速柱色谱法(DCM/MeOH＝85/15)分离纯化，得到化合物12c(150mg)。MS m/z(ESI)：308.1[M+H] +。 Compound 12b (320 mg, 821.24 μmol) was dissolved in MeCN (16 mL), and then NaIO 4 (526.97 mg, 2.46 mmol), ammonium acetate (126.61 mg, 1.64 mmol) and water (5 mL) were added, and the reaction was performed at 50° C. 16hr. After the reaction was completed, the solid was filtered off, and the filtrate was concentrated and separated and purified by silica gel flash column chromatography (DCM/MeOH=85/15) to obtain compound 12c (150 mg). MS m/z (ESI): 308.1 [M+H] + .
第三步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-氯-4-氟苯甲酰胺(化合物12d)的制备The third step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-4-methylphenyl)-3-chloro-4-fluorobenzamide (compound 12d) preparation
将化合物12c(41.79mg，135.91μmol)、4d(50mg，113.25μmol)、吡啶(17.92mg，226.51μmol，18.23μL)、DMAP(34.59mg，283.14μmol)、Cu(OAc) 2(20.57mg，113.25μmol)和1，4-二氧六环(10mL)加入反应瓶中，90℃敞口反应16hr。反应结束后加水稀释，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(DCM/MeOH＝96/4)分离纯化，得到化合物12d(25mg)。MS m/z(ESI)：703.1[M+H] +。 Compound 12c (41.79 mg, 135.91 μmol), 4d (50 mg, 113.25 μmol), pyridine (17.92 mg, 226.51 μmol, 18.23 μL), DMAP (34.59 mg, 283.14 μmol), Cu(OAc) 2 (20.57 mg, 113.25 μmol) μmol) and 1,4-dioxane (10 mL) were added to the reaction flask, and the reaction was carried out at 90° C. for 16 hr. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel flash column chromatography (DCM/MeOH=96/4) to give compound 12d (25 mg). MS m/z (ESI): 703.1 [M+H] + .
第四步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-氯-4-氟苯甲酰胺(化合物12)的制备Fourth step: N-(3-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-3-chloro-4-fluorobenzamide (compound 12)
将化合物12d(25mg，35.55μmol)溶于TFA(3mL)，100℃搅拌16hr。反应结束后将溶剂浓缩干，加入饱和碳酸氢钠溶液调节溶液pH至约8，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经Prep-HPLC分离纯化，得到化合物12(5.16mg)。MS m/z(ESI)：463.0[M+H] +。 Compound 12d (25 mg, 35.55 μmol) was dissolved in TFA (3 mL) and stirred at 100° C. for 16 hr. After the reaction, the solvent was concentrated to dryness, saturated sodium bicarbonate solution was added to adjust the pH of the solution to about 8, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by Prep-HPLC to give compound 12 (5.16 mg). MS m/z (ESI): 463.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.52(s，1H)，8.69(s，1H)，8.44(s，1H)，8.28-8.21(m，2H)，8.20-8.13(m，2H)，8.05-7.97(m，2H)，7.94(d，J＝2.0Hz，1H)，7.80(dd，J＝8.4，2.0Hz，1H)，7.62(t，J＝8.8Hz，1H)，7.43(d，J＝8.4Hz，1H)，2.27(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.52 (s, 1H), 8.69 (s, 1H), 8.44 (s, 1H), 8.28-8.21 (m, 2H), 8.20-8.13 (m, 2H) ), 8.05-7.97 (m, 2H), 7.94 (d, J=2.0Hz, 1H), 7.80 (dd, J=8.4, 2.0Hz, 1H), 7.62 (t, J=8.8Hz, 1H), 7.43 (d, J=8.4Hz, 1H), 2.27 (s, 3H).
实施例13：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-氯苯甲酰胺(化合物13)Example 13: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-3-chlorobenzamide (Compound 13)
Figure PCTCN2022079826-appb-000095
Figure PCTCN2022079826-appb-000095
第一步：3-氯-N-(4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)苯甲酰胺(化合物13b)的制备The first step: 3-chloro-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl) Preparation of benzamide (compound 13b)
除将化合物9a替换成化合物13a外，以与实施例9第一步相同的方法进行制备，将粗产物经硅胶快速柱色谱法(石油醚/乙酸乙酯＝4/1)分离纯化，得到化合物13b(200.00mg)。MS m/z(ESI)：372.0[M+H] +。 The preparation was carried out in the same manner as in the first step of Example 9, except that compound 9a was replaced by compound 13a, and the crude product was separated and purified by silica gel flash column chromatography (petroleum ether/ethyl acetate=4/1) to obtain compound 13b (200.00 mg). MS m/z (ESI): 372.0 [M+H] + .
第二步：(5-(3-氯苯甲酰胺基)-2-甲基苯基)硼酸(化合物13c)的制备The second step: preparation of (5-(3-chlorobenzamido)-2-methylphenyl)boronic acid (compound 13c)
除将化合物9b替换成化合物13b外，以与实施例9第二步相同的方法进行制备，将粗产物经硅胶快速柱色谱法(二氯甲烷/甲醇＝10/1)分离纯化，得到化合物13c(105.00mg)。MS m/z(ESI)：289.9[M+H] +。 The preparation was carried out in the same manner as in the second step of Example 9 except that compound 9b was replaced by compound 13b, and the crude product was separated and purified by silica gel flash column chromatography (dichloromethane/methanol=10/1) to obtain compound 13c (105.00 mg). MS m/z (ESI): 289.9 [M+H] + .
第三步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-氯苯甲酰胺(化合物13d)的制备The third step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-4-methylphenyl)-3-chlorobenzamide (compound 13d) preparation
除将化合物11e替换成化合物13c外，以与实施例11第四步相同的方法进行制备，将粗产物经硅胶快速柱色谱法(二氯甲烷/甲醇＝15/1)分离纯化，得到化合物13d(45.00mg)。MS m/z(ESI)：685.9[M+H] +。 The preparation was carried out in the same manner as in the fourth step of Example 11 except that compound 11e was replaced with compound 13c, and the crude product was separated and purified by silica gel flash column chromatography (dichloromethane/methanol=15/1) to obtain compound 13d (45.00 mg). MS m/z (ESI): 685.9 [M+H] + .
第四步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-氯苯甲酰胺(化合物13)的制备Fourth step: N-(3-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-3-chlorobenzamide (compound 13)
除将化合物11f替换成化合物13d外，以与实施例11第五步相同的方法进行制备，得到化合物13的三氟乙酸盐(25.00mg)。MS m/z(ESI)：445.0[M+H] +。 The preparation was carried out in the same manner as in the fifth step of Example 11, except that compound 11f was replaced by compound 13d, to obtain the trifluoroacetic acid salt of compound 13 (25.00 mg). MS m/z (ESI): 445.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.52(s，1H)，8.69(s，1H)，8.44(s，1H)，8.29(brs，1H)，8.20(brs，1H)，8.19(s，1H)，8.04(t，J＝1.6Hz，1H)，7.99(s，1H)，7.96(d，J＝2.0Hz，1H)，7.95-7.93(m，1H)，7.81(dd，J＝8.4，2.4Hz，1H)，7.70-7.67(m，1H)，7.59(t，J＝8.0Hz，1H)，7.43(d，J＝8.4Hz，1H)，2.27(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.52 (s, 1H), 8.69 (s, 1H), 8.44 (s, 1H), 8.29 (brs, 1H), 8.20 (brs, 1H), 8.19 ( s, 1H), 8.04 (t, J=1.6Hz, 1H), 7.99 (s, 1H), 7.96 (d, J=2.0Hz, 1H), 7.95-7.93 (m, 1H), 7.81 (dd, J =8.4, 2.4Hz, 1H), 7.70-7.67(m, 1H), 7.59(t, J=8.0Hz, 1H), 7.43(d, J=8.4Hz, 1H), 2.27(s, 3H).
实施例14：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-2-氯-4-氟苯甲酰胺(化合物14)Example 14: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- 2-Chloro-4-fluorobenzamide (Compound 14)
Figure PCTCN2022079826-appb-000096
Figure PCTCN2022079826-appb-000096
第一步：2-氯-4-氟-N-(4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)苯甲酰胺(化合物14b)的制备The first step: 2-chloro-4-fluoro-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) ) Phenyl) Benzamide (Compound 14b) Preparation
将化合物3a(550.0mg，2.4mmol)和14a(486.2mg，2.8mmol)溶于吡啶(10.0mL)中，然后滴加T 3P(4mL，50％EA溶液)，加完后25℃反应12小时。反应结束后减压浓缩除去溶剂，乙酸乙酯稀释反应液，饱和碳酸氢钠水溶液洗涤3次，有机相经无水硫酸钠干燥，过滤后浓缩，粗产物经硅胶快 速柱色谱法(PE/EA＝4/1)分离纯化，得到化合物14b(510.0mg)。MS m/z(ESI)：390.0[M+H] +。 Compounds 3a (550.0 mg, 2.4 mmol) and 14a (486.2 mg, 2.8 mmol) were dissolved in pyridine (10.0 mL), and then T 3 P (4 mL, 50% EA solution) was added dropwise. After the addition, the reaction was performed at 25°C for 12 Hour. After the reaction was completed, the solvent was concentrated under reduced pressure to remove the solvent, the reaction solution was diluted with ethyl acetate, washed three times with saturated aqueous sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was subjected to silica gel flash column chromatography (PE/EA). =4/1) separation and purification to obtain compound 14b (510.0 mg). MS m/z (ESI): 390.0 [M+H] + .
第二步：(5-(2-氯-4-氟苯甲酰胺基)-2-甲基苯基)硼酸(化合物14c)的制备The second step: preparation of (5-(2-chloro-4-fluorobenzamido)-2-methylphenyl)boronic acid (compound 14c)
将化合物14b(510.0mg，1.3mmol)溶于乙腈(6.0mL)和水(2.0mL)中，再依次加入NaIO 4(839.96mg，3.9mmol)和乙酸铵(201.8mg，2.6mmol)，升温至50℃反应16小时。反应结束后用稀盐酸调节pH至弱酸性，减压浓缩，粗产物经硅胶柱快速柱色谱法(DCM/MeOH＝10/1)分离纯化，得到化合物14c(185.0mg)。MS m/z(ESI)：307.9[M+H] +。 Compound 14b (510.0 mg, 1.3 mmol) was dissolved in acetonitrile (6.0 mL) and water (2.0 mL), then NaIO 4 (839.96 mg, 3.9 mmol) and ammonium acetate (201.8 mg, 2.6 mmol) were added successively, and the temperature was raised to The reaction was carried out at 50°C for 16 hours. After the reaction, the pH was adjusted to weakly acidic with dilute hydrochloric acid, concentrated under reduced pressure, and the crude product was separated and purified by silica gel flash column chromatography (DCM/MeOH=10/1) to obtain compound 14c (185.0 mg). MS m/z (ESI): 307.9 [M+H] + .
第三步：2-氯-N-(3-(4-(4-((2，4-二甲氧基苄基)氨基)噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-4-氟苯甲酰胺(化合物14d)的制备Step 3: 2-Chloro-N-(3-(4-(4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidin-7-yl)- Preparation of 1H-pyrazol-1-yl)-4-methylphenyl)-4-fluorobenzamide (compound 14d)
将化合物14c(55.0mg，178.9μmol)和8a(65.7mg，178.9μmol)溶于1，4-二氧六环(3.0mL)中，再依次加入乙酸铜(32.5mg，178.9μmol)、吡啶(28.3mg，357.7μmol)和DMAP(65.6mg，536.6μmol)，加完后99℃反应16小时。反应结束后减压浓缩除去溶剂，乙酸乙酯稀释反应液，饱和碳酸氢钠水溶液洗涤3次，有机相经无水硫酸钠干燥，过滤后浓缩，粗产物经硅胶柱色谱法(DCM/MeOH＝10/1)分离纯化，得到化合物14d(35.0mg)。MS m/z(ESI)：629.8[M+H] +。 Compounds 14c (55.0 mg, 178.9 μmol) and 8a (65.7 mg, 178.9 μmol) were dissolved in 1,4-dioxane (3.0 mL), and then copper acetate (32.5 mg, 178.9 μmol), pyridine ( 28.3 mg, 357.7 μmol) and DMAP (65.6 mg, 536.6 μmol), react at 99° C. for 16 hours after the addition. After the reaction was completed, the solvent was concentrated under reduced pressure to remove the solvent, the reaction solution was diluted with ethyl acetate, washed three times with saturated aqueous sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was subjected to silica gel column chromatography (DCM/MeOH= 10/1) was isolated and purified to obtain compound 14d (35.0 mg). MS m/z (ESI): 629.8 [M+H] + .
第四步：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-2-氯-4-氟苯甲酰胺(化合物14)的制备Step 4: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- Preparation of 2-chloro-4-fluorobenzamide (compound 14)
将化合物14d(35.0mg，55.6μmol)加入到三氟乙酸(2.0mL)中，80℃反应2小时。反应结束后将反应液浓缩干，加入饱和碳酸氢钠水溶液碱化，二氯甲烷萃取，有机相经无水硫酸钠干燥，过滤后浓缩，粗产物经Prep-HPLC分离纯化，得到化合物14(8.4mg)。MS m/z(ESI)：479.0[M+H] +。 Compound 14d (35.0 mg, 55.6 μmol) was added to trifluoroacetic acid (2.0 mL) and reacted at 80° C. for 2 hours. After the reaction, the reaction solution was concentrated to dryness, saturated aqueous sodium bicarbonate solution was added for alkalization, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated and purified by Prep-HPLC to obtain compound 14 (8.4 mg). MS m/z (ESI): 479.0 [M+H] + .
1HNMR(400MHz，DMSO-d 6)δ10.71(s，1H)，8.74(s，1H)，8.55(s，1H)，8.41(d，J＝9.6Hz，2H)，8.03(s，2H)，7.94(d，J＝2.4Hz，1H)，7.71(dd，J＝8.8，6.4Hz，1H)，7.63(td，J＝9.2，2.4Hz，2H)，7.49-7.30(m，2H)，2.25(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.71 (s, 1H), 8.74 (s, 1H), 8.55 (s, 1H), 8.41 (d, J=9.6 Hz, 2H), 8.03 (s, 2H) ), 7.94 (d, J=2.4Hz, 1H), 7.71 (dd, J=8.8, 6.4Hz, 1H), 7.63 (td, J=9.2, 2.4Hz, 2H), 7.49-7.30 (m, 2H) , 2.25(s, 3H).
实施例15：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-2-(三氟甲基)异烟酰胺(化合物15)Example 15: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- 2-(Trifluoromethyl)isonicotinamide (Compound 15)
Figure PCTCN2022079826-appb-000097
Figure PCTCN2022079826-appb-000097
第一步：N-(4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)-2-(三氟甲基)异烟酰胺(化合物15b)的制备The first step: N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-2-( Preparation of trifluoromethyl)isonicotinamide (compound 15b)
反应瓶中加入化合物15a(350mg，1.50mmol)、3a(301mg，1.58mmol)和吡啶(3mL)，搅拌溶解后加入T3P(2mL，50％(w/w)EA溶液)，氮气保护，室温反应过夜。反应结束后直接将反应液旋干，加入40mL水，用饱和NaHCO 3溶液调节pH至7-8，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物15b(520mg)。MS m/z(ESI)：407.0[M+H] +。 Compound 15a (350 mg, 1.50 mmol), 3a (301 mg, 1.58 mmol) and pyridine (3 mL) were added to the reaction flask. After stirring and dissolving, T3P (2 mL, 50% (w/w) EA solution) was added, and the reaction was carried out at room temperature under nitrogen protection. overnight. After the reaction, the reaction solution was directly rotated to dryness, 40 mL of water was added, the pH was adjusted to 7-8 with saturated NaHCO 3 solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the compound 15b (520 mg). MS m/z (ESI): 407.0 [M+H] + .
第二步：(2-甲基-5-(2-(三氟甲基)异烟酰胺基)苯基)硼酸(化合物15c)的制备The second step: preparation of (2-methyl-5-(2-(trifluoromethyl)isonicotinamido)phenyl)boronic acid (compound 15c)
反应瓶中加入化合物15b(520mg，1.28mmol)、NaIO 4(821mg，3.84mmol)和MeCN(20mL)，然后再加入醋酸铵(246.69mg，3.20mmol)的H 2O(5mL)溶液，加完后氮气保护，50℃反应16hr。反应结束后，向反应液加入60mL水稀释，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物15c(310mg)。MS m/z(ESI)：325.0[M+H] +。 Compound 15b (520 mg, 1.28 mmol), NaIO 4 (821 mg, 3.84 mmol) and MeCN (20 mL) were added to the reaction flask, and then a solution of ammonium acetate (246.69 mg, 3.20 mmol) in H 2 O (5 mL) was added. After nitrogen protection, the reaction was carried out at 50 °C for 16 hr. After the reaction, 60 mL of water was added to the reaction solution to dilute, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 15c (310 mg). MS m/z (ESI): 325.0 [M+H] + .
第三步：N-(3-(4-(4-((2，4-二甲氧基苄基)氨基)噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-2-(三氟甲基)异烟酰胺(化合物15d)的制备The third step: N-(3-(4-(4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazole Preparation of -1-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (compound 15d)
反应瓶中依次加入化合物8a(50mg，136μmol)、15c(53mg，163μmol)、Cu(OAc) 2(27mg，136μmol)、吡啶(32mg，408μmol)、DMAP(33mg，272μmol)和1，4-二氧六环(3mL)，加完后100℃敞口反应过夜。反应结束后向反应液加入60mL水稀释，用乙酸乙酯萃取，有机相用饱和食盐水洗涤， 无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶柱色谱法(MeOH∶DCM＝6∶94)分离纯化，得到化合物15d(40mg)。MS m/z(ESI)：646.1[M+H] +。 Compound 8a (50 mg, 136 μmol), 15c (53 mg, 163 μmol), Cu(OAc) 2 (27 mg, 136 μmol), pyridine (32 mg, 408 μmol), DMAP (33 mg, 272 μmol) and 1,4-diol were added to the reaction flask in sequence. Oxane (3 mL) was added and reacted overnight at 100°C. After the reaction, 60 mL of water was added to the reaction solution to dilute, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel column chromatography (MeOH:DCM=6:94) to give compound 15d (40 mg). MS m/z (ESI): 646.1 [M+H] + .
第四步：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-2-(三氟甲基)异烟酰胺(化合物15)的制备Step 4: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- Preparation of 2-(trifluoromethyl)isonicotinamide (Compound 15)
反应瓶中加入化合物15d(40mg，61.95μmol)和TFA(3mL)，氮气保护下80℃反应3hr。反应结束后将反应液减压浓缩至干，加入乙酸乙酯，用饱和NaHCO 3溶液调节pH至7-8，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经Pre-HPLC纯化，得到化合物15(9mg)。MS m/z(ESI)：496.0[M+H] +。 Compound 15d (40 mg, 61.95 μmol) and TFA (3 mL) were added to the reaction flask, and the reaction was carried out at 80° C. for 3 hr under nitrogen protection. After the reaction, the reaction solution was concentrated to dryness under reduced pressure, ethyl acetate was added, the pH was adjusted to 7-8 with saturated NaHCO 3 solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. ,concentrate. The crude product was purified by Pre-HPLC to give compound 15 (9 mg). MS m/z (ESI): 496.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.86(s，1H)，9.01(d，J＝5.2Hz，1H)，8.81(s，1H)，8.51-8.46(m，2H)，8.40(s，1H)，8.32(s，1H)，8.24-8.19(m，1H)，7.94(d，J＝2.4Hz，1H)，7.82(dd，J＝8.4，2.4Hz，1H)，7.52(s，2H)，7.46(d，J＝8.4Hz，1H)，2.29(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.86 (s, 1H), 9.01 (d, J=5.2 Hz, 1H), 8.81 (s, 1H), 8.51-8.46 (m, 2H), 8.40 ( s, 1H), 8.32 (s, 1H), 8.24-8.19 (m, 1H), 7.94 (d, J=2.4Hz, 1H), 7.82 (dd, J=8.4, 2.4Hz, 1H), 7.52 (s , 2H), 7.46 (d, J=8.4Hz, 1H), 2.29 (s, 3H).
实施例16：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-氯-4-氟苯甲酰胺(化合物16)Example 16: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- 3-Chloro-4-fluorobenzamide (Compound 16)
Figure PCTCN2022079826-appb-000098
Figure PCTCN2022079826-appb-000098
第一步：3-氯-N-(3-(4-(4-((2，4-二甲氧基苄基)氨基)噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-4-氟苯甲酰胺(化合物16a)的制备First step: 3-chloro-N-(3-(4-(4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidin-7-yl)- Preparation of 1H-pyrazol-1-yl)-4-methylphenyl)-4-fluorobenzamide (compound 16a)
将化合物8a(80mg，217.73μmol)、12c(87.04mg，283.05μmol)、吡啶(34.45mg，435.46μmol，35.04μL)、DMAP(66.50mg，544.33μmol)、Cu(OAc) 2(39.55mg，217.73μmol)和1，4-二氧六环(4mL)加入反应瓶中，敞口反应，90℃搅拌16hr。反应结束后加水稀释，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，浓缩，经硅胶快速柱色谱法(DCM/MeOH＝96/4)分离纯化，得到化合物16a(80mg)。MS m/z(ESI)：629.0[M+H] +。 Compound 8a (80 mg, 217.73 μmol), 12c (87.04 mg, 283.05 μmol), pyridine (34.45 mg, 435.46 μmol, 35.04 μL), DMAP (66.50 mg, 544.33 μmol), Cu(OAc) 2 (39.55 mg, 217.73 μmol) and 1,4-dioxane (4 mL) were added to the reaction flask, and the reaction was carried out with an open mouth, and stirred at 90° C. for 16 hr. After the reaction was completed, it was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel flash column chromatography (DCM/MeOH=96/4) to obtain compound 16a (80 mg). MS m/z (ESI): 629.0 [M+H] + .
第二步：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-氯-4-氟苯甲酰胺(化合物16)的制备Step 2: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- Preparation of 3-chloro-4-fluorobenzamide (compound 16)
将化合物16a(80mg，127.17μmol)溶于TFA(4mL)中，85℃搅拌3hr。反应结束后浓缩干溶剂，用饱和碳酸氢钠溶液调节pH约8。乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经Prep-HPLC分离纯化，得到化合物16(10.81mg)。MS m/z(ESI)：479.1[M+H] +。 Compound 16a (80 mg, 127.17 μmol) was dissolved in TFA (4 mL) and stirred at 85°C for 3 hr. After the reaction, the dry solvent was concentrated, and the pH was adjusted to about 8 with saturated sodium bicarbonate solution. It was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by Prep-HPLC to give compound 16 (10.81 mg). MS m/z (ESI): 479.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.52(s，1H)，8.79(s，1H)，8.48(d，J＝8.0Hz，2H)，8.32(s，1H)，8.23(dd，J＝7.2，2.4Hz，1H)，8.05-7.98(m，1H)，7.93(d，J＝2.0Hz，1H)，7.80(dd，J＝8.4，2.0Hz，1H)，7.62(t，J＝8.8Hz，1H)，7.53(s，2H)，7.42(d，J＝8.8Hz，1H)，2.27(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.52 (s, 1H), 8.79 (s, 1H), 8.48 (d, J=8.0 Hz, 2H), 8.32 (s, 1H), 8.23 (dd, J=7.2, 2.4Hz, 1H), 8.05-7.98 (m, 1H), 7.93 (d, J=2.0Hz, 1H), 7.80 (dd, J=8.4, 2.0Hz, 1H), 7.62 (t, J =8.8Hz, 1H), 7.53(s, 2H), 7.42(d, J=8.8Hz, 1H), 2.27(s, 3H).
实施例17：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-2-(三氟甲基)异烟酰胺(化合物17)Example 17: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-2-(trifluoromethyl)isonicotinamide (Compound 17)
Figure PCTCN2022079826-appb-000099
Figure PCTCN2022079826-appb-000099
第一步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-2-(三氟甲基)异烟酰胺(化合物17a)的制备The first step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (compound 17a) preparation
反应瓶中依次加入化合物4d(50mg，113.25μmol)、15c(44mg，135.91μmol)、Cu(OAc) 2(23mg，113.25μmol)、吡啶(27mg，339.76μmol)、DMAP(28mg，226.51μmol)和1，4-二氧六环(3mL)，加热100℃敞口反应过夜。反应结束后向反应液中加入60mL水，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶柱色谱法(MeOH∶DCM＝6∶94)分离纯化，得到化合物17a(50mg)。MS m/z(ESI)：720.2[M+H] +。 Compound 4d (50 mg, 113.25 μmol), 15c (44 mg, 135.91 μmol), Cu(OAc) 2 (23 mg, 113.25 μmol), pyridine (27 mg, 339.76 μmol), DMAP (28 mg, 226.51 μmol) and 1,4-dioxane (3 mL) was heated at 100°C for an open reaction overnight. After the reaction, 60 mL of water was added to the reaction solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel column chromatography (MeOH:DCM=6:94) to give compound 17a (50 mg). MS m/z (ESI): 720.2 [M+H] + .
第二步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-2-(三氟甲基)异烟酰胺(化合物17)的制备Step 2: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (Compound 17)
反应瓶中加入化合物17a(50mg，69.47μmol)和TFA(3mL)，氮气保护下80℃反应16hr。反应结束后将反应液减压浓缩至干，加入乙酸乙酯，用饱和NaHCO 3溶液调节pH至7-8，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经Pre-HPLC纯化，得到化合物17(4mg)。MS m/z(ESI)：480.0[M+H] +。 Compound 17a (50 mg, 69.47 μmol) and TFA (3 mL) were added to the reaction flask, and the reaction was carried out at 80° C. for 16 hr under nitrogen protection. After the reaction, the reaction solution was concentrated to dryness under reduced pressure, ethyl acetate was added, the pH was adjusted to 7-8 with saturated NaHCO 3 solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. ,concentrate. The crude product was purified by Pre-HPLC to give compound 17 (4 mg). MS m/z (ESI): 480.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.86(s，1H)，9.01(d，J＝4.8Hz，1H)，8.70(s，1H)，8.44(s，1H)，8.39(s，1H)，8.26(br，1H)，8.23-8.13(m，3H)，7.99(s，1H)，7.95(d，J＝2.0Hz，1H)，7.82(dd，J＝8.4，2.0Hz，1H)，7.47(d，J＝8.4Hz，1H)，2.29(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.86 (s, 1H), 9.01 (d, J=4.8 Hz, 1H), 8.70 (s, 1H), 8.44 (s, 1H), 8.39 (s, 1H), 8.26 (br, 1H), 8.23-8.13 (m, 3H), 7.99 (s, 1H), 7.95 (d, J=2.0Hz, 1H), 7.82 (dd, J=8.4, 2.0Hz, 1H) ), 7.47(d, J=8.4Hz, 1H), 2.29(s, 3H).
实施例18：N-(3-(1-(4-氨基喹唑啉-8-基)-1H-吡唑-4-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物18)Example 18: N-(3-(1-(4-Aminoquinazolin-8-yl)-1H-pyrazol-4-yl)-4-methylphenyl)-3-(trifluoromethyl) ) benzamide (compound 18)
Figure PCTCN2022079826-appb-000100
Figure PCTCN2022079826-appb-000100
第一步：N-(3-碘-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物18b)的制备The first step: preparation of N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 18b)
除将化合物9a替换为化合物3b，化合物3a替换为化合物18a外，以与实施例9第一步相同的方法进行制备，得到化合物18b(267.00mg)。MS m/z(ESI)：405.9[M+H] +。 The preparation was carried out in the same manner as in the first step of Example 9, except that compound 9a was replaced by compound 3b, and compound 3a was replaced by compound 18a to obtain compound 18b (267.00 mg). MS m/z (ESI): 405.9 [M+H] + .
第二步：N-(4-甲基-3-(1H-吡唑-4-基)苯基)-3-(三氟甲基)苯甲酰胺(化合物18c)的制备Step 2: Preparation of N-(4-methyl-3-(1H-pyrazol-4-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 18c)
将化合物18b(200.00mg，493.64μmol)和2d(191.57mg，987.28μmol)溶于1，4-二氧六环(6mL)与水(2mL)的混合溶剂中，然后加入[1，1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(40.31mg，49.36μmol)和碳酸钾(204.67mg，1.48mmol)，氮气保护，加热到99℃反应16小时。反应液降温至室温，向反应液中加入20mL水，再用乙酸乙酯萃取3次，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩，硅胶快速柱色谱法(二氯甲烷/甲醇＝20/1)得到化合物18c(113mg)。MS m/z(ESI)：346.0[M+H] +。 Compounds 18b (200.00 mg, 493.64 μmol) and 2d (191.57 mg, 987.28 μmol) were dissolved in a mixed solvent of 1,4-dioxane (6 mL) and water (2 mL), and then [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (40.31 mg, 49.36 μmol) and potassium carbonate (204.67 mg, 1.48 mmol) were heated to 99° C. for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel flash column chromatography. (dichloromethane/methanol=20/1) to obtain compound 18c (113 mg). MS m/z (ESI): 346.0 [M+H] + .
第三步：(4-((2，4-2甲氧基苄基)氨基)喹唑啉-8-基)硼酸(化合物18d)的制备The third step: preparation of (4-((2,4-2methoxybenzyl)amino)quinazolin-8-yl)boronic acid (compound 18d)
将化合物2c(200.00mg，0.54mmol)、联硼酸频那醇酯(253.94mg，2.67mmol)、[1，1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(87.29mg，0.11mmol)和乙酸钾(262.24mg，2.67mmol)加入到1，4-二氧六环(10mL)中，氮气保护下，微波加热到130℃反应3hr。反应结束后将反应液降至室温，过滤除去固体，滤液经C18柱反相柱色谱法(乙腈/0.05％甲酸水溶液＝45/55)分离纯化，得到化合物18d(154mg)。MS m/z(ESI)：340.1[M+H] +。 Compound 2c (200.00 mg, 0.54 mmol), pinacol diboronate (253.94 mg, 2.67 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane Compound (87.29 mg, 0.11 mmol) and potassium acetate (262.24 mg, 2.67 mmol) were added to 1,4-dioxane (10 mL), and heated to 130° C. for 3 hr by microwave heating under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature, and the solid was removed by filtration. The filtrate was separated and purified by C18 column reversed-phase column chromatography (acetonitrile/0.05% aqueous formic acid=45/55) to obtain compound 18d (154 mg). MS m/z (ESI): 340.1 [M+H] + .
第四步：N-(3-(1-(4-((2，4-二甲氧基苄基)氨基)喹唑啉-8-基)-1H-吡唑-4-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物18e)的制备The fourth step: N-(3-(1-(4-((2,4-dimethoxybenzyl)amino)quinazolin-8-yl)-1H-pyrazol-4-yl)-4 Preparation of -methylphenyl)-3-(trifluoromethyl)benzamide (compound 18e)
除将化合物9c替换成化合物18d，化合物7b替换成化合物18c外，以与实施例9第三步相同的方法进行制备，粗产物经制备柱色谱法(二氯甲烷/甲醇＝15/1)分离纯化，得到化合物18e(9.00mg)。MS m/z(ESI)：639.2[M+H] +。 The preparation was carried out in the same manner as in the third step of Example 9, except that compound 9c was replaced by compound 18d, and compound 7b was replaced by compound 18c, and the crude product was separated by preparative column chromatography (dichloromethane/methanol=15/1). Purification gave compound 18e (9.00 mg). MS m/z (ESI): 639.2 [M+H] + .
第五步：N-(3-(1-(4-氨基喹唑啉-8-基)-1H-吡唑-4-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物18)的制备The fifth step: N-(3-(1-(4-aminoquinazolin-8-yl)-1H-pyrazol-4-yl)-4-methylphenyl)-3-(trifluoromethyl) ) preparation of benzamide (compound 18)
将化合物18e(9mg，13.39μmol)加入到TFA(5mL)中，加热至70℃反应4hr。反应结束后减压除 去溶剂，粗产物经Prep-HPLC分离纯化，得到化合物18的三氟乙酸盐(2.50mg)。MS m/z(ESI)：489.0[M+H] +。 Compound 18e (9 mg, 13.39 μmol) was added to TFA (5 mL), heated to 70° C. and reacted for 4 hr. After the reaction, the solvent was removed under reduced pressure, and the crude product was separated and purified by Prep-HPLC to obtain the trifluoroacetic acid salt of compound 18 (2.50 mg). MS m/z (ESI): 489.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.50(s，1H)，9.30-8.70(m，3H)，8.63(s，1H)，8.35(d，J＝8.0Hz，2H)，8.32(s，1H)，8.29(d，J＝7.6Hz，1H)，8.14(s，1H)，7.98(d，J＝8.0Hz，1H)，7.91(s，1H)，7.82-7.76(m，2H)，7.66(dd，J＝8.4，2.0Hz，1H)，7.33(d，J＝8.4Hz，1H)，2.45(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.50 (s, 1H), 9.30-8.70 (m, 3H), 8.63 (s, 1H), 8.35 (d, J=8.0 Hz, 2H), 8.32 ( s, 1H), 8.29 (d, J=7.6Hz, 1H), 8.14 (s, 1H), 7.98 (d, J=8.0Hz, 1H), 7.91 (s, 1H), 7.82-7.76 (m, 2H) ), 7.66 (dd, J=8.4, 2.0Hz, 1H), 7.33 (d, J=8.4Hz, 1H), 2.45 (s, 3H).
实施例19：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲氧基)吡咯烷-1-甲酰胺(化合物19)Example 19: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- 3-(Trifluoromethoxy)pyrrolidine-1-carboxamide (Compound 19)
Figure PCTCN2022079826-appb-000101
Figure PCTCN2022079826-appb-000101
第一步：2-(5-异氰酸酯基-2-甲基苯基)-4，4，5，5-四甲基-1，3，2-二氧杂硼烷(化合物19a)的制备The first step: preparation of 2-(5-isocyanato-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (compound 19a)
将化合物3a(275mg，1.18mmol)溶于无水THF(8mL)中，加入三光气(700mg，2.36mmol)，加毕氮气保护下30℃反应3hr。反应结束后用乙酸乙酯稀释，饱和碳酸氢钠水溶液洗涤3次，有机相经无水硫酸钠干燥后过滤浓缩，得到化合物19a(300mg)，直接用于下一步反应。Compound 3a (275 mg, 1.18 mmol) was dissolved in anhydrous THF (8 mL), triphosgene (700 mg, 2.36 mmol) was added, and the reaction was carried out at 30° C. for 3 hr under nitrogen protection. After the reaction, it was diluted with ethyl acetate, washed three times with saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 19a (300 mg), which was directly used in the next reaction.
第二步：N-(4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)-3-(三氟甲氧基)吡咯烷-1-甲酰胺(化合物19c)的制备The second step: N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-3-( Preparation of trifluoromethoxy)pyrrolidine-1-carboxamide (compound 19c)
反应瓶中加入化合物19a(300mg，1.16mmol)、19b(333mg，1.74mmol)、DIPEA(225mg，1.74mmol)和甲苯(10mL)，加完后氮气保护，100℃反应15hr。反应结束后，向反应液中加水淬灭反应，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经硅胶柱色谱法(EA∶PE＝3∶1)分离纯化，得到化合物19c(320mg)。MS m/z(ESI)：415.2[M+H] +。 Compound 19a (300 mg, 1.16 mmol), 19b (333 mg, 1.74 mmol), DIPEA (225 mg, 1.74 mmol) and toluene (10 mL) were added to the reaction flask. After the addition, nitrogen protection was performed, and the reaction was carried out at 100° C. for 15 hr. After the reaction, water was added to the reaction solution to quench the reaction, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was subjected to silica gel column chromatography (EA:PE=3 : 1) separation and purification to obtain compound 19c (320 mg). MS m/z (ESI): 415.2 [M+H] + .
第三步：(2-甲基-5-(3-(三氟甲氧基)吡咯烷-1-甲酰胺基)苯基)硼酸(化合物19d)的制备The third step: preparation of (2-methyl-5-(3-(trifluoromethoxy)pyrrolidine-1-carboxamido)phenyl)boronic acid (compound 19d)
反应瓶中加入化合物19c(320mg，772.53μmol)、NaIO 4(496mg，2.32mmol)和MeCN(10mL)，再加入醋酸铵(149mg，1.93mmol)的H 2O(2mL)溶液，加完后氮气保护，50℃反应16hr。反应结束后，加入60mL水稀释，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到化合物19d(230mg)。MS m/z(ESI)：333.1[M+H] +。 Compound 19c (320 mg, 772.53 μmol), NaIO 4 (496 mg, 2.32 mmol) and MeCN (10 mL) were added to the reaction flask, and a solution of ammonium acetate (149 mg, 1.93 mmol) in H 2 O (2 mL) was added. After the addition, nitrogen Protection, 50 ℃ reaction 16hr. After the reaction, 60 mL of water was added to dilute, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 19d (230 mg). MS m/z (ESI): 333.1 [M+H] + .
第四步：N-(3-(4-(4-((2，4-二甲氧基苄基)氨基)噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲氧基)吡咯烷-1-甲酰胺(化合物19e)的制备The fourth step: N-(3-(4-(4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazole Preparation of -1-yl)-4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (compound 19e)
反应瓶中依次加入化合物8a(75mg，204.12μmol)、19d(81mg，244.95μmol)、Cu(OAc) 2(41mg，204.12μmol)、吡啶(49mg，612.37μmol)、DMAP(50mg，408.25μmol)和1，4-二氧六环(3mL)，加完后外温100℃敞口反应过夜。反应结束后加入30mL水，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经硅胶柱色谱法(MeOH∶DCM＝6∶94)分离纯化，得到化合物19e(55mg)。MS m/z(ESI)：654.2[M+H] +。 Compound 8a (75 mg, 204.12 μmol), 19d (81 mg, 244.95 μmol), Cu(OAc) 2 (41 mg, 204.12 μmol), pyridine (49 mg, 612.37 μmol), DMAP (50 mg, 408.25 μmol) and 1,4-dioxane (3 mL), after the addition, the external temperature was 100°C and the reaction was carried out overnight. After the reaction, 30 mL of water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (MeOH:DCM=6:94). Compound 19e (55 mg) was obtained. MS m/z (ESI): 654.2 [M+H] + .
第五步：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲氧基)吡咯烷-1-甲酰胺(化合物19)的制备Step 5: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- Preparation of 3-(trifluoromethoxy)pyrrolidine-1-carboxamide (Compound 19)
反应瓶中加入化合物19e(55mg，84.14μmol)和TFA(3mL)，氮气保护下70℃反应3hr。反应结束后直接将反应液浓缩干，加入EA溶解后，用饱和NaHCO 3溶液调节pH至7-8，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经Pre-HPLC纯化，得到化合物19(5mg)。MS m/z(ESI)：504.0[M+H] +。 Compound 19e (55 mg, 84.14 μmol) and TFA (3 mL) were added to the reaction flask, and the reaction was carried out at 70° C. for 3 hr under nitrogen protection. After the reaction, the reaction solution was directly concentrated to dryness. After adding EA to dissolve, the pH was adjusted to 7-8 with saturated NaHCO 3 solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. , the crude product was purified by Pre-HPLC to give compound 19 (5 mg). MS m/z (ESI): 504.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ8.73(s，1H)，8.50-8.46(m，2H)，8.43(s，1H)，8.30(s，1H)，7.67(d，J＝2.0Hz，1H)，7.57-7.49(m，3H)，7.28(d，J＝8.4Hz，1H)，5.18-5.13(m，1H)，3.68-3.64(m，2H)，3.63-3.57(m，1H)，3.49-3.44(m，1H)，2.27-2.15(m，5H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.73 (s, 1H), 8.50-8.46 (m, 2H), 8.43 (s, 1H), 8.30 (s, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.57-7.49(m, 3H), 7.28(d, J=8.4Hz, 1H), 5.18-5.13(m, 1H), 3.68-3.64(m, 2H), 3.63-3.57(m, 1H), 3.49-3.44 (m, 1H), 2.27-2.15 (m, 5H).
实施例20：N-(3-(4-(4-氨基喹唑啉-8-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲氧基)吡咯烷-1-甲酰胺(化合物20)Example 20: N-(3-(4-(4-Aminoquinazolin-8-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethoxy yl)pyrrolidine-1-carboxamide (Compound 20)
Figure PCTCN2022079826-appb-000102
Figure PCTCN2022079826-appb-000102
第一步：N-(3-(4-(4-((2，4-二甲氧基苄基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲氧基)吡咯烷-1-甲酰胺(化合物20a)的制备The first step: N-(3-(4-(4-((2,4-dimethoxybenzyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)-4 Preparation of -methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (compound 20a)
反应瓶中依次加入化合物2e(50mg，138.35μmol)、19d(55mg，166.02μmol)、Cu(OAc) 2(28mg，138.35μmol)、吡啶(33mg，415.06μmol)、DMAP(34mg，276.70μmol)和1，4-二氧六环(3mL)，加完后100℃敞口反应过夜。反应结束后加入60mL水稀释，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶柱色谱法(MeOH∶DCM＝1∶10)分离纯化，得到化合物20a(30mg)。MS m/z(ESI)：648.3[M+H] +。 Compound 2e (50 mg, 138.35 μmol), 19d (55 mg, 166.02 μmol), Cu(OAc) 2 (28 mg, 138.35 μmol), pyridine (33 mg, 415.06 μmol), DMAP (34 mg, 276.70 μmol) and 1,4-dioxane (3 mL) was added and reacted at 100°C overnight. After the reaction was completed, 60 mL of water was added to dilute, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel column chromatography (MeOH:DCM=1:10) to obtain compound 20a (30 mg). MS m/z (ESI): 648.3 [M+H] + .
第二步：N-(3-(4-(4-氨基喹唑啉-8-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲氧基)吡咯烷-1-甲酰胺(化合物20)的制备The second step: N-(3-(4-(4-aminoquinazolin-8-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethoxy Preparation of yl)pyrrolidine-1-carboxamide (compound 20)
反应瓶中加入化合物20a(30mg，46.32μmol)和TFA(3mL)，氮气保护，80℃反应2hr。反应结束后，将反应液浓缩干，加入乙酸乙酯，用饱和NaHCO 3溶液调节pH至7-8，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经Pre-HPLC纯化，得到化合物20(6mg)。MS m/z(ESI)：498.2[M+H] +。 Compound 20a (30 mg, 46.32 μmol) and TFA (3 mL) were added to the reaction flask, under nitrogen protection, and reacted at 80° C. for 2 hr. After the reaction, the reaction solution was concentrated to dryness, ethyl acetate was added, the pH was adjusted to 7-8 with saturated NaHCO 3 solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. . The crude product was purified by Pre-HPLC to give compound 20 (6 mg). MS m/z (ESI): 498.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ8.89(s，1H)，8.54-8.44(m，3H)，8.18(dd，J＝7.2，1.2Hz，1H)，8.11(dd，J＝8.4，1.2Hz，1H)，7.92-7.66(m，3H)，7.57-7.48(m，2H)，7.28(d，J＝8.4Hz，1H)，5.20-5.11(m，1H)，3.71-3.65(m，2H)，3.64-3.57(m，1H)，3.49-3.43(m，1H)，2.26-2.14(m，5H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.89 (s, 1H), 8.54-8.44 (m, 3H), 8.18 (dd, J=7.2, 1.2 Hz, 1H), 8.11 (dd, J=8.4 , 1.2Hz, 1H), 7.92-7.66(m, 3H), 7.57-7.48(m, 2H), 7.28(d, J=8.4Hz, 1H), 5.20-5.11(m, 1H), 3.71-3.65( m, 2H), 3.64-3.57 (m, 1H), 3.49-3.43 (m, 1H), 2.26-2.14 (m, 5H).
实施例21：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-氟-5-(三氟甲基)苯甲酰胺(化合物21)Example 21: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-3-fluoro-5-(trifluoromethyl)benzamide (Compound 21)
Figure PCTCN2022079826-appb-000103
Figure PCTCN2022079826-appb-000103
第一步：3-氟-N-(4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)-5-(三氟甲基)苯甲酰胺(化合物21b)的制备The first step: 3-fluoro-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl) - Preparation of 5-(trifluoromethyl)benzamide (compound 21b)
将化合物21a(535.64mg，2.57mmol)、3a(600mg，2.57mmol)溶于吡啶(4mL)中，再加入T3P(3mL，50％DMF溶液)，25℃搅拌16hr。反应结束后减压除去吡啶，滴入饱和碳酸氢钠溶液淬灭，EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经硅胶快速柱色谱法(DCM/MeOH＝98/2)分离纯化，得到化合物21b(1g)。MS m/z(ESI)：424.1[M+H] +。 Compound 21a (535.64 mg, 2.57 mmol) and 3a (600 mg, 2.57 mmol) were dissolved in pyridine (4 mL), T3P (3 mL, 50% DMF solution) was added, and the mixture was stirred at 25°C for 16 hr. After the reaction, pyridine was removed under reduced pressure, quenched by dropwise addition of saturated sodium bicarbonate solution, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel flash column chromatography (DCM/MeOH= 98/2) was isolated and purified to obtain compound 21b (1 g). MS m/z (ESI): 424.1 [M+H] + .
第二步：(5-(3-氟-5-(三氟甲基)苯甲酰胺基)-2-甲基苯基)硼酸(化合物21c)的制备The second step: preparation of (5-(3-fluoro-5-(trifluoromethyl)benzamido)-2-methylphenyl)boronic acid (compound 21c)
将化合物21b(1g，2.36mmol)溶于MeCN(15mL)中，再加入NaIO 4(1.52g，7.09mmol)、醋酸铵(364.28mg，4.73mmol)和水(10mL)，加完后50℃反应16hr。反应结束后抽滤，浓缩除去乙腈，加 水稀释，EA萃取，有机相经无水硫酸钠干燥，过滤，浓缩，得到化合物21c(600mg)。MS m/z(ESI)：342.1[M+H] +。 Compound 21b (1 g, 2.36 mmol) was dissolved in MeCN (15 mL), and then NaIO 4 (1.52 g, 7.09 mmol), ammonium acetate (364.28 mg, 4.73 mmol) and water (10 mL) were added, and the reaction was performed at 50° C. 16hr. After the reaction was completed, suction filtered, concentrated to remove acetonitrile, diluted with water, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 21c (600 mg). MS m/z (ESI): 342.1 [M+H] + .
第三步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-氟-5-(三氟甲基)苯甲酰胺(化合物21d)的制备The third step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-4-methylphenyl)-3-fluoro-5-(trifluoromethyl)benzamide (compound 21d) preparation
将化合物21c(92.71mg，271.81μmol)、4d(100mg，226.51μmol)、吡啶(35.83mg，453.02μmol，36.45μL)、DMAP(69.18mg，566.27μmol)、Cu(OAc) 2(41.14mg，226.51μmol)和1，4-二氧六环(6mL)加入反应瓶中，敞口反应，90℃搅拌16hr。反应结束后，直接硅胶快速柱色谱法(DCM/MeOH＝95/5)分离纯化，得到化合物21d(40mg)。MS m/z(ESI)：737.2[M+H] +。 Compound 21c (92.71 mg, 271.81 μmol), 4d (100 mg, 226.51 μmol), pyridine (35.83 mg, 453.02 μmol, 36.45 μL), DMAP (69.18 mg, 566.27 μmol), Cu(OAc) 2 (41.14 mg, 226.51 μmol) μmol) and 1,4-dioxane (6 mL) were added to the reaction flask, and the reaction was carried out with an open mouth, and stirred at 90° C. for 16 hr. After completion of the reaction, direct silica gel flash column chromatography (DCM/MeOH=95/5) was used for separation and purification to obtain compound 21d (40 mg). MS m/z (ESI): 737.2 [M+H] + .
第四步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-氟-5-(三氟甲基)苯甲酰胺(化合物21)的制备Fourth step: N-(3-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-3-fluoro-5-(trifluoromethyl)benzamide (compound 21)
将化合物21d(40mg，54.30μmol)溶于TFA(3mL)中，100℃搅拌16hr。反应结束后将反应液浓缩干，用饱和碳酸氢钠溶液调节pH约8，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经Prep-HPLC分离纯化，得到化合物21(5.45mg)。MS m/z(ESI)：497.1[M+H] +。 Compound 21d (40 mg, 54.30 μmol) was dissolved in TFA (3 mL) and stirred at 100° C. for 16 hr. After the reaction, the reaction solution was concentrated to dryness, adjusted to pH about 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by Prep-HPLC to give compound 21 (5.45 mg). MS m/z (ESI): 497.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.68(s，1H)，8.70(s，1H)，8.44(s，1H)，8.25(s，1H)，8.22-8.10(m，4H)，8.02-7.97(m，2H)，7.94(d，J＝2.0Hz，1H)，7.82(dd，J＝8.4，2.0Hz，1H)，7.45(d，J＝8.4Hz，1H)，2.28(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.68(s, 1H), 8.70(s, 1H), 8.44(s, 1H), 8.25(s, 1H), 8.22-8.10(m, 4H), 8.02-7.97(m, 2H), 7.94(d, J=2.0Hz, 1H), 7.82(dd, J=8.4, 2.0Hz, 1H), 7.45(d, J=8.4Hz, 1H), 2.28(s , 3H).
实施例22：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-5-氯-2-氟苯甲酰胺(化合物22)Example 22: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-5-chloro-2-fluorobenzamide (Compound 22)
Figure PCTCN2022079826-appb-000104
Figure PCTCN2022079826-appb-000104
第一步：5-氯-2-氟-N-(4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)苯甲酰胺(化合物22b)的制备The first step: 5-chloro-2-fluoro-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) ) phenyl) benzamide (compound 22b) preparation
将化合物3a(300mg，1.29mmol)与22a(247.11mg，1.42mmol)溶于吡啶(10mL)，然后滴加1-丙基磷酸酐(2.5mL，50％DMF溶液)，于25℃反应3小时。反应结束后减压除去溶剂，加入饱和碳酸氢钠水溶液5mL，乙酸乙酯萃取，有机相经无水硫酸钠干燥，过滤后减压浓缩，粗产物经C18柱反相柱色谱法(乙腈/0.05％甲酸水溶液＝80/20)分离纯化，得到化合物22b(415.00mg)。MS m/z(ESI)：390.1[M+H] +。 Compound 3a (300 mg, 1.29 mmol) and 22a (247.11 mg, 1.42 mmol) were dissolved in pyridine (10 mL), then 1-propylphosphoric anhydride (2.5 mL, 50% DMF solution) was added dropwise, and the reaction was carried out at 25°C for 3 hours . After the reaction, the solvent was removed under reduced pressure, 5 mL of saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was subjected to C18 column reversed-phase column chromatography (acetonitrile/0.05 % formic acid aqueous solution=80/20) was isolated and purified to obtain compound 22b (415.00 mg). MS m/z (ESI): 390.1 [M+H] + .
第二步：(5-(5-氯-2-氟苯甲酰胺基)-2-甲基苯基)硼酸(化合物22c)的制备The second step: preparation of (5-(5-chloro-2-fluorobenzamido)-2-methylphenyl)boronic acid (compound 22c)
将化合物22b(411mg，1.05mmol)、醋酸铵(162.61mg，2.11mmol)、高碘酸钠(676.82mg，3.16mmol)加入到乙腈(15mL)和水(5mL)中，升温至50℃反应16小时。反应结束后将反应液浓缩，后经C18柱反相柱色谱法(乙腈/0.05％甲酸水溶液＝32/68)分离纯化，得到化合物22c(235.00mg)。MS m/z(ESI)：308.1[M+H] +。 Compound 22b (411 mg, 1.05 mmol), ammonium acetate (162.61 mg, 2.11 mmol), sodium periodate (676.82 mg, 3.16 mmol) were added to acetonitrile (15 mL) and water (5 mL), and the temperature was raised to 50 °C for reaction 16 Hour. After the completion of the reaction, the reaction solution was concentrated, and then separated and purified by C18 column reversed-phase column chromatography (acetonitrile/0.05% aqueous formic acid=32/68) to obtain compound 22c (235.00 mg). MS m/z (ESI): 308.1 [M+H] + .
第三步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-5-氯-2-氟苯甲酰胺(化合物22d)的制备The third step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-4-methylphenyl)-5-chloro-2-fluorobenzamide (compound 22d) preparation
将化合物4d(50.25mg，113.82μmol)、22c(35mg，113.82μmol)、吡啶(41.71mg，341.45μmol)、醋酸铜(20.67mg，113.82μmol)和4-二甲氨基吡啶(25.50mg，208.76μmol)加入到1，4-二氧六环(5mL)中，升温至100℃敞口反应3小时。反应结束后将反应液降至室温，过滤除去固体，滤液浓缩后经C18柱反相柱色谱法(乙腈/0.05％甲酸水溶液＝65/35)分离纯化，得化合物22d(35.00mg)。Compound 4d (50.25 mg, 113.82 μmol), 22c (35 mg, 113.82 μmol), pyridine (41.71 mg, 341.45 μmol), copper acetate (20.67 mg, 113.82 μmol) and 4-dimethylaminopyridine (25.50 mg, 208.76 μmol) ) was added to 1,4-dioxane (5 mL), and the temperature was raised to 100° C. for open reaction for 3 hours. After the reaction, the reaction solution was cooled to room temperature, and the solid was removed by filtration. The filtrate was concentrated and separated and purified by C18 column reversed-phase column chromatography (acetonitrile/0.05% aqueous formic acid=65/35) to obtain compound 22d (35.00 mg).
第四步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-5-氯-2-氟苯甲酰胺(化合物22)的制备Fourth step: N-(3-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-5-chloro-2-fluorobenzamide (compound 22)
将化合物22d(30.00mg，42.66μmol)溶于三氟乙酸(3mL)，升温至99℃反应16小时。反应结束 后减压除去溶剂，然后经C18柱反相柱色谱法(乙腈/0.05％碳酸氢铵水溶液＝51/49)分离纯化，得到化合物22(3.91mg)。MS m/z(ESI)：463.0[M+H] +。 Compound 22d (30.00 mg, 42.66 μmol) was dissolved in trifluoroacetic acid (3 mL), and the temperature was raised to 99° C. to react for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, followed by separation and purification by C18 column reversed-phase column chromatography (acetonitrile/0.05% aqueous ammonium bicarbonate solution=51/49) to obtain compound 22 (3.91 mg). MS m/z (ESI): 463.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.71(s，1H)，8.68(s，1H)，8.43(s，1H)，8.25(s，1H)，8.18(s，1H)，8.17-8.13(m，1H)，7.98(s，1H)，7.91(d，J＝2.0Hz，1H)，7.80-7.75(m，1H)，7.72-7.63(m，2H)，7.49-7.39(m，2H)，2.26(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.71(s, 1H), 8.68(s, 1H), 8.43(s, 1H), 8.25(s, 1H), 8.18(s, 1H), 8.17- 8.13(m, 1H), 7.98(s, 1H), 7.91(d, J=2.0Hz, 1H), 7.80-7.75(m, 1H), 7.72-7.63(m, 2H), 7.49-7.39(m, 2H), 2.26(s, 3H).
实施例23：N-(3-(4-(4-氨基喹唑啉-8-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)吡咯烷-1-甲酰胺(化合物23)Example 23: N-(3-(4-(4-Aminoquinazolin-8-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl) ) pyrrolidine-1-carboxamide (compound 23)
Figure PCTCN2022079826-appb-000105
Figure PCTCN2022079826-appb-000105
第一步：N-(4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)-3-(三氟甲基)吡咯烷-1-甲酰胺(23b)的制备The first step: N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-3-( Preparation of trifluoromethyl)pyrrolidine-1-carboxamide (23b)
反应瓶中依次加入化合物19a(165mg，636.80μmol)、23a(168mg，955.20μmol)、DIPEA(124mg，955.20μmol)和甲苯(5mL)，氮气保护下100℃反应15hr。反应结束后加入60mL水，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶柱色谱法(EA∶PE＝1∶3)分离纯化，得到化合物23b(200mg)。MS m/z(ESI)：399.1[M+H] +。 Compound 19a (165 mg, 636.80 μmol), 23a (168 mg, 955.20 μmol), DIPEA (124 mg, 955.20 μmol) and toluene (5 mL) were sequentially added to the reaction flask, and reacted at 100° C. for 15 hr under nitrogen protection. After the reaction, 60 mL of water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated and purified by silica gel column chromatography (EA:PE=1:3) to obtain compound 23b (200 mg). MS m/z (ESI): 399.1 [M+H] + .
第二步：(2-甲基-5-(3-(三氟甲基)吡咯烷-1-甲酰胺基)苯基)硼酸(化合物23c)的制备Step 2: Preparation of (2-methyl-5-(3-(trifluoromethyl)pyrrolidine-1-carboxamido)phenyl)boronic acid (compound 23c)
反应瓶中加入化合物23b(200mg，502.23μmol)、NaIO 4(322mg，1.51mmol)和MeCN(8mL)，再加入醋酸铵(97mg，1.26mmol)的H 2O(2mL)溶液，氮气保护，50℃反应16hr。反应结束后加入60mL水，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物23c(155mg)。MS m/z(ESI)：317.0[M+H] +。 Compound 23b (200 mg, 502.23 μmol), NaIO 4 (322 mg, 1.51 mmol) and MeCN (8 mL) were added to the reaction flask, followed by a solution of ammonium acetate (97 mg, 1.26 mmol) in H 2 O (2 mL), under nitrogen protection, 50 °C reaction for 16hr. After the reaction, 60 mL of water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 23c (155 mg). MS m/z (ESI): 317.0 [M+H] + .
第三步：N-(3-(4-(4-((2，4-二甲氧基苄基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)吡咯烷-1-甲酰胺(化合物23d)的制备The third step: N-(3-(4-(4-((2,4-dimethoxybenzyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)-4 Preparation of -methylphenyl)-3-(trifluoromethyl)pyrrolidine-1-carboxamide (compound 23d)
反应瓶中依次加入化合物2e(50mg，138.35μmol)、23c(53mg，166.02μmol)、Cu(OAc) 2(28mg，138.35μmol)、吡啶(33mg，415.06μmol)、DMAP(34mg，276.70μmol)和1，4-二氧六环(3mL)，加热至100℃反应过夜。反应结束后加入60mL水，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(MeOH∶DCM＝1∶10)分离纯化，得到化合物23d(45mg)。MS m/z(ESI)：632.2[M+H] +。 Compound 2e (50 mg, 138.35 μmol), 23c (53 mg, 166.02 μmol), Cu(OAc) 2 (28 mg, 138.35 μmol), pyridine (33 mg, 415.06 μmol), DMAP (34 mg, 276.70 μmol) and 1,4-dioxane (3 mL), heated to 100°C and reacted overnight. After the reaction, 60 mL of water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel flash column chromatography (MeOH:DCM=1:10) to give compound 23d (45 mg). MS m/z (ESI): 632.2 [M+H] + .
第四步：N-(3-(4-(4-氨基喹唑啉-8-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)吡咯烷-1-甲酰胺(化合物23)的制备The fourth step: N-(3-(4-(4-aminoquinazolin-8-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl) ) Preparation of pyrrolidine-1-carboxamide (compound 23)
反应瓶中加入化合物23d(45mg，71.24μmol)和TFA(3mL)，氮气保护下75℃反应5hr。反应结束后减压蒸除溶剂，加入乙酸乙酯，用饱和NaHCO 3溶液调节pH至7-8，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经Pre-HPLC纯化，得到化合物23(12mg)。MS m/z(ESI)：482.1[M+H] +。 Compound 23d (45 mg, 71.24 μmol) and TFA (3 mL) were added to the reaction flask, and the reaction was carried out at 75° C. for 5 hr under nitrogen protection. After the reaction, the solvent was evaporated under reduced pressure, ethyl acetate was added, the pH was adjusted to 7-8 with saturated NaHCO 3 solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by Pre-HPLC to give compound 23 (12 mg). MS m/z (ESI): 482.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ8.90(s，1H)，8.53-8.50(m，2H)，8.48(s，1H)，8.19(dd，J＝7.6，1.2Hz，1H)，8.12(dd，J＝8.4，1.2Hz，1H)，7.97-7.68(m，3H)，7.58-7.50(m，2H)，7.29(d，J＝8.4Hz，1H)，3.74-3.68(m，1H)，3.61-3.54(m，1H)，3.53-3.45(m，2H)，3.33-3.27(m，1H)，2.25-2.18(m，4H)，2.08-1.99(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.90 (s, 1H), 8.53-8.50 (m, 2H), 8.48 (s, 1H), 8.19 (dd, J=7.6, 1.2Hz, 1H), 8.12 (dd, J=8.4, 1.2Hz, 1H), 7.97-7.68 (m, 3H), 7.58-7.50 (m, 2H), 7.29 (d, J=8.4Hz, 1H), 3.74-3.68 (m, 1H), 3.61-3.54(m, 1H), 3.53-3.45(m, 2H), 3.33-3.27(m, 1H), 2.25-2.18(m, 4H), 2.08-1.99(m, 1H).
实施例24：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)吡咯烷-1-甲酰胺(化合物24)Example 24: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- 3-(Trifluoromethyl)pyrrolidine-1-carboxamide (Compound 24)
Figure PCTCN2022079826-appb-000106
Figure PCTCN2022079826-appb-000106
第一步：N-(3-(4-(4-((2，4-二甲氧基苄基)氨基)噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)吡咯烷-1-甲酰胺(化合物24a)的制备The first step: N-(3-(4-(4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazole Preparation of -1-yl)-4-methylphenyl)-3-(trifluoromethyl)pyrrolidine-1-carboxamide (compound 24a)
反应瓶中依次加入化合物8a(50mg，136.08μmol)、23c(52mg，163.30μmol)、Cu(OAc) 2(27mg，136.08μmol)、吡啶(32mg，408.25μmol)、DMAP(33mg，272.16μmol)和1，4-二氧六环(3mL)，100℃敞口反应过夜。反应结束后加入60mL水，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(MeOH∶DCM＝6∶94)分离纯化，得到化合物24a(55mg)。MS m/z(ESI)：638.2[M+H] +。 Compound 8a (50 mg, 136.08 μmol), 23c (52 mg, 163.30 μmol), Cu(OAc) 2 (27 mg, 136.08 μmol), pyridine (32 mg, 408.25 μmol), DMAP (33 mg, 272.16 μmol) and 1,4-Dioxane (3 mL) was reacted at 100° C. overnight. After the reaction, 60 mL of water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel flash column chromatography (MeOH:DCM=6:94) to give compound 24a (55 mg). MS m/z (ESI): 638.2 [M+H] + .
第二步：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)吡咯烷-1-甲酰胺(化合物24)的制备Step 2: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- Preparation of 3-(trifluoromethyl)pyrrolidine-1-carboxamide (Compound 24)
反应瓶中加入化合物24a(55mg，86.25μmol)和TFA(3mL)，氮气保护下80℃反应5hr。反应结束后减压蒸除溶剂，加入乙酸乙酯，用饱和NaHCO 3溶液调节pH至7-8，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经Pre-HPLC纯化，得到化合物24(12mg)。MS m/z(ESI)：488.0[M+H] +。 Compound 24a (55 mg, 86.25 μmol) and TFA (3 mL) were added to the reaction flask, and the reaction was carried out at 80° C. for 5 hr under nitrogen protection. After the reaction, the solvent was evaporated under reduced pressure, ethyl acetate was added, the pH was adjusted to 7-8 with saturated NaHCO 3 solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by Pre-HPLC to give compound 24 (12 mg). MS m/z (ESI): 488.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ8.75(s，1H)，8.50(s，1H)，8.48(s，1H)，8.46-8.44(m，1H)，8.32(s，1H)，7.69(d，J＝2.4Hz，1H)，7.57(dd，J＝8.4，2.4Hz，1H)，7.53(s，2H)，7.29(d，J＝8.4Hz，1H)，3.74-3.68(m，1H)，3.60-3.54(m，1H)，3.53-3.45(m，2H)，3.33-3.27(m，1H)，2.25-2.18(m，4H)，2.07-2.00(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.75(s, 1H), 8.50(s, 1H), 8.48(s, 1H), 8.46-8.44(m, 1H), 8.32(s, 1H), 7.69(d, J=2.4Hz, 1H), 7.57(dd, J=8.4, 2.4Hz, 1H), 7.53(s, 2H), 7.29(d, J=8.4Hz, 1H), 3.74-3.68(m , 1H), 3.60-3.54(m, 1H), 3.53-3.45(m, 2H), 3.33-3.27(m, 1H), 2.25-2.18(m, 4H), 2.07-2.00(m, 1H).
实施例25：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-氯苯甲酰胺(化合物25)Example 25: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- 3-Chlorobenzamide (Compound 25)
Figure PCTCN2022079826-appb-000107
Figure PCTCN2022079826-appb-000107
第一步：3-氯-N-(3-(4-(4-((2，4-二甲氧基苄基)氨基)噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)苯甲酰胺(化合物25a)的制备First step: 3-chloro-N-(3-(4-(4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidin-7-yl)- Preparation of 1H-pyrazol-1-yl)-4-methylphenyl)benzamide (compound 25a)
除将化合物3d更换为化合物13c外，以与实施例8第二步相同的方法进行制备，粗产物经硅胶快速柱色谱法(二氯甲烷/甲醇＝15/1)分离纯化，得到化合物25a(12.00mg)。MS m/z(ESI)：611.2[M+H] +。 The preparation was carried out in the same manner as in the second step of Example 8 except that compound 3d was replaced with compound 13c, and the crude product was separated and purified by silica gel flash column chromatography (dichloromethane/methanol=15/1) to obtain compound 25a ( 12.00 mg). MS m/z (ESI): 611.2 [M+H] + .
第二步：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-氯苯甲酰胺(化合物25)的制备Step 2: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- Preparation of 3-chlorobenzamide (compound 25)
将化合物25a(9mg，13.39μmol)加入到TFA(3mL)中，加热至70℃反应4hr。反应结束后减压除去溶剂，粗产物经C18柱反相柱色谱法(乙腈/0.05％碳酸氢铵水溶液＝40/60)分离纯化，得到化合物25(7.00mg)。MS m/z(ESI)：461.0[M+H] +。 Compound 25a (9 mg, 13.39 μmol) was added to TFA (3 mL), heated to 70° C. and reacted for 4 hr. After the reaction, the solvent was removed under reduced pressure, and the crude product was separated and purified by C18 column reversed-phase column chromatography (acetonitrile/0.05% aqueous ammonium bicarbonate solution=40/60) to obtain compound 25 (7.00 mg). MS m/z (ESI): 461.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.53(s，1H)，8.81(s，1H)，8.50(s，1H)，8.48(s，1H)，8.34(s，1H)，8.05(t，J＝1.6Hz，1H)，7.96-7.94(m，2H)，7.82(dd，J＝8.4，2.0Hz，1H)，7.71-7.68(m，1H)，7.60(t，J＝8.0Hz，1H)，7.54(s，2H)，7.43(d，J＝8.8Hz，1H)，2.29(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 8.81 (s, 1H), 8.50 (s, 1H), 8.48 (s, 1H), 8.34 (s, 1H), 8.05 ( t, J=1.6Hz, 1H), 7.96-7.94 (m, 2H), 7.82 (dd, J=8.4, 2.0Hz, 1H), 7.71-7.68 (m, 1H), 7.60 (t, J=8.0Hz) , 1H), 7.54(s, 2H), 7.43(d, J=8.8Hz, 1H), 2.29(s, 3H).
实施例26：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲氧基)吡咯烷-1-甲酰胺(化合物26)Example 26: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (Compound 26)
Figure PCTCN2022079826-appb-000108
Figure PCTCN2022079826-appb-000108
第一步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯 基)-3-(三氟甲氧基)吡咯烷-1-甲酰胺(化合物26a)的制备The first step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (compound 26a) preparation
反应瓶中依次加入化合物4d(60mg，135.91μmol)、19d(52mg，156.59μmol)、Cu(OAc) 2(27mg，135.91μmol)、吡啶(32mg，407.72μmol)、DMAP(33mg，271.81μmol)和1，4-二氧六环(3mL)，加热至100℃敞口反应过夜。反应结束后加入60mL水，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(MeOH∶DCM＝6∶94)分离纯化，得到化合物26a(50mg)。 Compound 4d (60 mg, 135.91 μmol), 19d (52 mg, 156.59 μmol), Cu(OAc) 2 (27 mg, 135.91 μmol), pyridine (32 mg, 407.72 μmol), DMAP (33 mg, 271.81 μmol) and 1,4-dioxane (3 mL), heated to 100°C for overnight reaction. After the reaction, 60 mL of water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel flash column chromatography (MeOH:DCM=6:94) to give compound 26a (50 mg).
第二步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲氧基)吡咯烷-1-甲酰胺(化合物26)的制备Step 2: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (Compound 26)
反应瓶中加入化合物26a(50mg，68.71μmol)和TFA(3mL)，氮气保护下80℃反应过夜。反应结束后，减压蒸除溶剂，加入乙酸乙酯，用饱和NaHCO 3溶液调节pH至7-8，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经Pre-HPLC纯化，得到化合物26(5mg)。MS m/z(ESI)：488.2[M+H] +。 Compound 26a (50 mg, 68.71 μmol) and TFA (3 mL) were added to the reaction flask, and the reaction was carried out at 80° C. overnight under nitrogen protection. After the reaction, the solvent was evaporated under reduced pressure, ethyl acetate was added, the pH was adjusted to 7-8 with saturated NaHCO 3 solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. . The crude product was purified by Pre-HPLC to give compound 26 (5 mg). MS m/z (ESI): 488.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ8.64(d，J＝0.4Hz，1H)，8.50(s，1H)，8.42(d，J＝0.8Hz，1H)，8.29-8.14(m，3H)，7.99(s，1H)，7.70(d，J＝2.4Hz，1H)，7.57(dd，J＝8.4，2.0Hz，1H)，7.30(d，J＝8.8Hz，1H)，5.21-5.14(m，1H)，3.68(d，J＝3.2Hz，2H)，3.65-3.58(m，1H)，3.51-3.43(m，1H)，2.27-2.14(m，5H). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.64 (d, J=0.4Hz, 1H), 8.50 (s, 1H), 8.42 (d, J=0.8Hz, 1H), 8.29-8.14 (m, 3H), 7.99(s, 1H), 7.70(d, J=2.4Hz, 1H), 7.57(dd, J=8.4, 2.0Hz, 1H), 7.30(d, J=8.8Hz, 1H), 5.21- 5.14 (m, 1H), 3.68 (d, J=3.2Hz, 2H), 3.65-3.58 (m, 1H), 3.51-3.43 (m, 1H), 2.27-2.14 (m, 5H).
实施例27：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)吡咯烷-1-甲酰胺(化合物27)Example 27: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-3-(trifluoromethyl)pyrrolidine-1-carboxamide (Compound 27)
Figure PCTCN2022079826-appb-000109
Figure PCTCN2022079826-appb-000109
第一步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)吡咯烷-1-甲酰胺(化合物27a)的制备The first step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)pyrrolidine-1-carboxamide (compound 27a) preparation
反应瓶中依次加入化合物4d(60mg，135.91μmol)、23c(54mg，171.35μmol)、Cu(OAc) 2(27mg，135.91μmol)、吡啶(32mg，407.72μmol)、DMAP(33mg，271.81μmol)、1，4-二氧六环(3mL)，加热至100℃敞口反应过夜。反应结束后加入60mL水，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩。粗产物经硅胶快速柱色谱法(MeOH∶DCM＝10∶90)分离纯化，得到化合物27a(45mg)。 Compound 4d (60 mg, 135.91 μmol), 23c (54 mg, 171.35 μmol), Cu(OAc) 2 (27 mg, 135.91 μmol), pyridine (32 mg, 407.72 μmol), DMAP (33 mg, 271.81 μmol), 1,4-dioxane (3 mL), heated to 100°C for overnight reaction. After the reaction was completed, 60 mL of water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel flash column chromatography (MeOH:DCM=10:90) to give compound 27a (45 mg).
第二步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)吡咯烷-1-甲酰胺(化合物27)的制备Step 2: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-3-(trifluoromethyl)pyrrolidine-1-carboxamide (compound 27)
反应瓶中加入化合物27a(45mg，63.23μmol)和TFA(3mL)，氮气保护下80℃反应过夜。反应结束后，减压蒸除溶剂，加入乙酸乙酯，用饱和NaHCO 3溶液调节pH至7-8，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经Pre-HPLC纯化，得到化合物27(4.5mg)。MS m/z(ESI)：472.1[M+H] +。 Compound 27a (45 mg, 63.23 μmol) and TFA (3 mL) were added to the reaction flask, and the reaction was carried out at 80° C. overnight under nitrogen protection. After the reaction, the solvent was evaporated under reduced pressure, ethyl acetate was added, the pH was adjusted to 7-8 with saturated NaHCO 3 solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. . The crude product was purified by Pre-HPLC to give compound 27 (4.5 mg). MS m/z (ESI): 472.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ8.64(d，J＝0.4Hz，1H)，8.49(s，1H)，8.41(d，J＝0.8Hz，1H)，8.29-8.14(m，3H)，7.99(s，1H)，7.70(d，J＝2.4Hz，1H)，7.57(dd，J＝8.4，2.4Hz，1H)，7.30(d，J＝8.4Hz，1H)，3.74-3.67(m，1H)，3.60-3.53(m，1H)，3.53-3.43(m，2H)，3.33-3.25(m，1H)，2.25-2.17(m，4H)，2.08-1.99(m，1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (d, J=0.4 Hz, 1H), 8.49 (s, 1H), 8.41 (d, J=0.8 Hz, 1H), 8.29-8.14 (m, 3H), 7.99(s, 1H), 7.70(d, J=2.4Hz, 1H), 7.57(dd, J=8.4, 2.4Hz, 1H), 7.30(d, J=8.4Hz, 1H), 3.74- 3.67(m, 1H), 3.60-3.53(m, 1H), 3.53-3.43(m, 2H), 3.33-3.25(m, 1H), 2.25-2.17(m, 4H), 2.08-1.99(m, 1H) ).
实施例28：N-(4-甲基-3-(4-(5-(吗啉代吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲氧基)吡咯烷-1-甲酰胺(化合物28)Example 28: N-(4-Methyl-3-(4-(5-(morpholinopyridin-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethane Oxy)pyrrolidine-1-carboxamide (Compound 28)
Figure PCTCN2022079826-appb-000110
Figure PCTCN2022079826-appb-000110
第一步：4-(5-溴吡啶-3-基)吗啉(化合物28b)的制备Step 1: Preparation of 4-(5-bromopyridin-3-yl)morpholine (compound 28b)
向反应瓶中依次加入化合物28a(1.68g，7.09mmol)、Pd 2(dba) 3(195mg，212.95μmol)、Cs 2CO 3(3.24g，9.94mmol)、XantPhos(123mg，212.58μmol)、吗啉(682mg，7.83mmol)和1，4-二氧六环(15mL)，氮气保护下，微波加热至90℃反应4hr。反应结束后加水稀释，二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩，经硅胶快速柱色谱法(EA/PE＝1/3)分离纯化，得到化合物28b(220mg)。MS m/z(ESI)：243.0[M+H] +。 Compound 28a (1.68 g, 7.09 mmol), Pd 2 (dba) 3 (195 mg, 212.95 μmol), Cs 2 CO 3 (3.24 g, 9.94 mmol), XantPhos (123 mg, 212.58 μmol), Cs 2 CO 3 (3.24 g, 9.94 mmol), XantPhos (123 mg, 212.58 μmol), and Phosphine (682 mg, 7.83 mmol) and 1,4-dioxane (15 mL) were heated to 90° C. by microwave for 4 hr under nitrogen protection. After the reaction, it was diluted with water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel flash column chromatography (EA/PE=1/3) to obtain compound 28b (220 mg). MS m/z (ESI): 243.0 [M+H] + .
第二步：4-(5-(1H-吡唑-4-基)吡啶-3-基)吗啉(化合物28c)的制备Step 2: Preparation of 4-(5-(1H-pyrazol-4-yl)pyridin-3-yl)morpholine (compound 28c)
向反应瓶中依次加入化合物28b(311.29mg，1.60mmol)、2d(130mg，534.76μmol)、Pd(PPh 3) 2Cl 2(75.07mg，106.95μmol)、NaHCO 3(179.70mg，2.14mmol)、DMF(4mL)和H 2O(1mL)，氮气保护下，120℃搅拌16hr。反应结束后加水稀释，EA萃取，有机相用无水硫酸钠干燥，过滤，浓缩，经硅胶快速柱色谱法(DCM/MeOH＝92/8)分离纯化，得到化合物28c(40mg)。MS m/z(ESI)：231.1[M+H] +。 Compound 28b (311.29 mg, 1.60 mmol), 2d (130 mg, 534.76 μmol), Pd(PPh 3 ) 2 Cl 2 (75.07 mg, 106.95 μmol), NaHCO 3 (179.70 mg, 2.14 mmol), DMF (4 mL) and H 2 O (1 mL) were stirred at 120° C. for 16 hr under nitrogen protection. After the reaction was completed, it was diluted with water, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel flash column chromatography (DCM/MeOH=92/8) to obtain compound 28c (40 mg). MS m/z (ESI): 231.1 [M+H] + .
第三步：N-(4-甲基-3-(4-(5-(吗啉代吡啶-3-基)-1H-吡唑-1-基)苯基)-3-(三氟甲氧基)吡咯烷-1-甲酰胺(化合物28)的制备The third step: N-(4-methyl-3-(4-(5-(morpholinopyridin-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl) Preparation of oxy)pyrrolidine-1-carboxamide (compound 28)
将化合物28c(20mg，86.86μmol)、19d(34.61mg，104.23μmol)、吡啶(13.74mg，173.71μmol)、DMAP(31.83mg，260.57μmol)、Cu(OAc) 2(15.78mg，86.86μmol)和1，4-二氧六环(4mL)加入反应瓶中，95℃敞口反应16hr。反应结束后，用硅胶快速柱色谱法(DCM/MeOH＝93/7)粗纯化，再经Prep-HPLC分离纯化，得到化合物28(4.59mg)。MS m/z(ESI)：517.2[M+H] +。 Compounds 28c (20 mg, 86.86 μmol), 19d (34.61 mg, 104.23 μmol), pyridine (13.74 mg, 173.71 μmol), DMAP (31.83 mg, 260.57 μmol), Cu(OAc) 2 (15.78 mg, 86.86 μmol) and 1,4-Dioxane (4 mL) was added to the reaction flask, and the reaction was carried out at 95° C. for 16 hr. After the reaction was completed, it was crudely purified by silica gel flash column chromatography (DCM/MeOH=93/7), and then separated and purified by Prep-HPLC to obtain compound 28 (4.59 mg). MS m/z (ESI): 517.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ8.64(s，1H)，8.48(s，1H)，8.43(d，J＝1.2Hz，1H)，8.30(s，1H)，8.18(d，J＝2.4Hz，1H)，7.69(d，J＝2.0Hz，1H)，7.63(t，J＝2.0Hz，1H)，7.54(dd，J＝8.4，2.0Hz，1H)，7.28(d，J＝8.4Hz，1H)，5.20-5.14(m，1H)，3.79(t，J＝4.4Hz，4H)，3.67(d，J＝2.4Hz，2H)，3.65-3.58(m，1H)，3.50-3.42(m，1H)，3.26(t，J＝4.4Hz，4H)，2.30-2.15(m，5H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (s, 1H), 8.48 (s, 1H), 8.43 (d, J=1.2 Hz, 1H), 8.30 (s, 1H), 8.18 (d, J=2.4Hz, 1H), 7.69 (d, J=2.0Hz, 1H), 7.63 (t, J=2.0Hz, 1H), 7.54 (dd, J=8.4, 2.0Hz, 1H), 7.28 (d, J=8.4Hz, 1H), 5.20-5.14 (m, 1H), 3.79 (t, J=4.4Hz, 4H), 3.67 (d, J=2.4Hz, 2H), 3.65-3.58 (m, 1H), 3.50-3.42(m, 1H), 3.26(t, J=4.4Hz, 4H), 2.30-2.15(m, 5H).
实施例29：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(2，2，2-三氟乙基)-2，5-二氢-1H-吡咯-1-甲酰胺(化合物29)Example 29: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (Compound 29)
Figure PCTCN2022079826-appb-000111
Figure PCTCN2022079826-appb-000111
第一步：N-(4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)-3-(2，2，2-三氟乙基)-2，5-二氢-1H-吡咯-1-甲酰胺(化合物29b)的制备The first step: N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-3-( Preparation of 2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (compound 29b)
除将化合物23a更换为化合物29a外，以与实施例23第一步相同的方法进行制备，得到化合物 29b(158mg)。MS m/z(ESI)：411.0[M+H] +。 The preparation was carried out in the same manner as in the first step of Example 23, except that compound 23a was replaced by compound 29a, to obtain compound 29b (158 mg). MS m/z (ESI): 411.0 [M+H] + .
第二步：(2-甲基-5-(3-(2，2，2-三氟乙基)-2，5-二氢-1H-吡咯-1-甲酰胺基)苯基)硼酸(化合物29c)的制备The second step: (2-methyl-5-(3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamido)phenyl)boronic acid ( Preparation of compound 29c)
除将化合物23b更换为化合物29b外，以与实施例23第二步相同的方法进行制备，得到化合物29c(90mg)。MS m/z(ESI)：329.0[M+H] +。 The preparation was carried out in the same manner as in the second step of Example 23 except that compound 23b was replaced with compound 29b to obtain compound 29c (90 mg). MS m/z (ESI): 329.0 [M+H] + .
第三步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(2，2，2-三氟乙基)-2，5-二氢-1H-吡咯-1-甲酰胺(化合物29d)的制备The third step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide Preparation of (Compound 29d)
除将化合物23c更换为化合物29c外，以与实施例23第三步相同的方法进行制备，得到化合物29d(69mg)。MS m/z(ESI)：724.0[M+H] +。 The preparation was carried out in the same manner as in the third step of Example 23 except that compound 23c was replaced with compound 29c to obtain compound 29d (69 mg). MS m/z (ESI): 724.0 [M+H] + .
第四步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(2，2，2-三氟乙基)-2，5-二氢-1H-吡咯-1-甲酰胺(化合物29)的制备Fourth step: N-(3-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (Compound 29)
除将化合物4e更换为化合物29d外，以与实施例4第四步相同的方法进行制备，得到化合物29(35mg)。MS m/z(ESI)：484.0[M+H] +。 The preparation was carried out in the same manner as in the fourth step of Example 4 except that compound 4e was replaced with compound 29d to obtain compound 29 (35 mg). MS m/z (ESI): 484.0 [M+H] + .
1HNMR(400MHz，DMSO-d 6)δ8.65(s，1H)，8.46(s，1H)，8.42(s，1H)，8.26(brs，1H)，8.19(s，1H)，8.18(brs，1H)，7.99(s，1H)，7.72(d，J＝2.4Hz，1H)，7.59(dd，J＝8.4，2.4Hz，1H)，7.30(d，J＝8.4Hz，1H)，5.96(s，1H)，4.27-4.18(m，4H)，3.35-3.29(m，2H)，2.22(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.65(s, 1H), 8.46(s, 1H), 8.42(s, 1H), 8.26(brs, 1H), 8.19(s, 1H), 8.18(brs , 1H), 7.99 (s, 1H), 7.72 (d, J=2.4Hz, 1H), 7.59 (dd, J=8.4, 2.4Hz, 1H), 7.30 (d, J=8.4Hz, 1H), 5.96 (s, 1H), 4.27-4.18 (m, 4H), 3.35-3.29 (m, 2H), 2.22 (s, 3H).
实施例30：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(2，2，2-三氟乙基)吡咯烷-1-甲酰胺(化合物30)Example 30: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 30)
Figure PCTCN2022079826-appb-000112
Figure PCTCN2022079826-appb-000112
将化合物29(28mg，57.92μmol)溶于甲醇(5mL)中，加入Pd/C(7.03mg，10％)，氢气置换3次，于40℃下反应12hr。反应结束后用硅藻土过滤，滤液浓缩，粗产物经硅胶快速柱层析(DCM/MeOH＝10/1)纯化，得到化合物30(12mg)。MS m/z(ESI)：486.0[M+H] +。 Compound 29 (28 mg, 57.92 μmol) was dissolved in methanol (5 mL), Pd/C (7.03 mg, 10%) was added, hydrogen was replaced three times, and the reaction was carried out at 40° C. for 12 hr. After the reaction was completed, it was filtered through celite, the filtrate was concentrated, and the crude product was purified by silica gel flash column chromatography (DCM/MeOH=10/1) to obtain compound 30 (12 mg). MS m/z (ESI): 486.0 [M+H] + .
1HNMR(400MHz，DMSO-d 6)δ8.63(s，1H)，8.41(s，1H)，8.39(s，1H)，8.27(brs，1H)，8.19(s，1H)，8.18(brs，1H)，7.99(s，1H)，7.71(d，J＝2.4Hz，1H)，7.58(dd，J＝8.4，2.0Hz，1H)，7.28(d，J＝8.4Hz，1H)，3.74-3.66(m，1H)，3.58-3.52(m，1H)，3.35-3.30(m，2H)，3.05(t，J＝9.2Hz，1H)，2.52-2.45(m，2H)，2.21(s，3H)，2.15-2.07(m，1H)，1.73-1.63(m，1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.63 (s, 1H), 8.41 (s, 1H), 8.39 (s, 1H), 8.27 (brs, 1H), 8.19 (s, 1H), 8.18 (brs , 1H), 7.99 (s, 1H), 7.71 (d, J=2.4Hz, 1H), 7.58 (dd, J=8.4, 2.0Hz, 1H), 7.28 (d, J=8.4Hz, 1H), 3.74 -3.66(m, 1H), 3.58-3.52(m, 1H), 3.35-3.30(m, 2H), 3.05(t, J=9.2Hz, 1H), 2.52-2.45(m, 2H), 2.21(s) , 3H), 2.15-2.07 (m, 1H), 1.73-1.63 (m, 1H).
实施例31：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(氰基甲基)吡咯烷-1-甲酰胺(化合物31)Example 31: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-3-(cyanomethyl)pyrrolidine-1-carboxamide (Compound 31)
Figure PCTCN2022079826-appb-000113
Figure PCTCN2022079826-appb-000113
第一步：2-(吡咯烷-3-基)乙腈(化合物31b)的制备Step 1: Preparation of 2-(pyrrolidin-3-yl)acetonitrile (Compound 31b)
将化合物31a(500.0mg，2.4mmol)溶于TFA(2.0mL)中，25℃反应1小时。反应结束减压浓缩除去溶剂，得到化合物31b(250.0mg)。Compound 31a (500.0 mg, 2.4 mmol) was dissolved in TFA (2.0 mL) and reacted at 25°C for 1 hour. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain compound 31b (250.0 mg).
第二步：3-(氰基甲基)-N-(4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)吡咯烷-1-甲酰胺(化合物31c)的制备The second step: 3-(cyanomethyl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2- Preparation of yl)phenyl)pyrrolidine-1-carboxamide (compound 31c)
将化合物19a(350.0mg，1.4mmol)和31b(223.2mg，2.0mmol)溶于甲苯(5.0mL)中，再加入DIPEA(523.7mg，4.1mmol)，加完后100℃反应15小时。反应结束后减压浓缩除去溶剂，乙酸乙酯稀释反应液，饱和碳酸氢钠水溶液洗涤3次，有机相经无水硫酸钠干燥，过滤后浓缩，粗产物经硅胶柱层析(PE/EA＝3/1)分离纯化，得到化合物31c(336.0mg)。MS m/z(ESI)：370.1[M+H] +。 Compounds 19a (350.0 mg, 1.4 mmol) and 31b (223.2 mg, 2.0 mmol) were dissolved in toluene (5.0 mL), DIPEA (523.7 mg, 4.1 mmol) was added, and the reaction was performed at 100° C. for 15 hours. After the reaction was completed, the solvent was concentrated under reduced pressure to remove the solvent, the reaction solution was diluted with ethyl acetate, washed three times with saturated aqueous sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was subjected to silica gel column chromatography (PE/EA= 3/1) separation and purification to obtain compound 31c (336.0 mg). MS m/z (ESI): 370.1 [M+H] + .
第三步：(5-(3-(氰基甲基)吡咯烷-1-甲酰胺基)-2-甲基苯基)硼酸(化合物31d)的制备The third step: preparation of (5-(3-(cyanomethyl)pyrrolidine-1-carboxamido)-2-methylphenyl)boronic acid (compound 31d)
将化合物31c(336.0mg，909.9μmol)溶于乙腈(8.0mL)和水(3.0mL)中，再依次加入NaIO 4(583.9mg，2.7mmol)和乙酸铵(140.3mg，1.8mmol)，升温至50℃反应16小时。反应结束后乙酸乙酯稀释反应液，饱和碳酸氢钠水溶液洗涤3次，有机相经无水硫酸钠干燥，过滤后浓缩，得到化合物31d(270.0mg)。MS m/z(ESI)：288.0[M+H] +。 Compound 31c (336.0 mg, 909.9 μmol) was dissolved in acetonitrile (8.0 mL) and water (3.0 mL), followed by NaIO 4 (583.9 mg, 2.7 mmol) and ammonium acetate (140.3 mg, 1.8 mmol), and the temperature was increased to The reaction was carried out at 50°C for 16 hours. After the reaction, the reaction solution was diluted with ethyl acetate, washed three times with saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 31d (270.0 mg). MS m/z (ESI): 288.0 [M+H] + .
第四步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(氰基甲基)吡咯烷-1-甲酰胺(化合物31e)的制备The fourth step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-4-methylphenyl)-3-(cyanomethyl)pyrrolidine-1-carboxamide (compound 31e) preparation
将化合物31d(97.6mg，339.8μmol)和4d(100.0mg，226.5μmol)溶于1，4-二氧六环(5.0mL)中，再依次加入乙酸铜(45.2mg，226.5μmol)、吡啶(17.9mg，226.5μmol)和DMAP(27.7mg，226.5μmol)，加完后99℃反应16小时。反应结束后减压浓缩除去溶剂，乙酸乙酯稀释反应液，饱和碳酸氢钠水溶液洗涤3次，有机相经无水硫酸钠干燥，过滤后浓缩，粗产物经硅胶柱层析(DCM/MeOH＝20/1)分离纯化，得到化合物31e(105.0mg)。MS m/z(ESI)：683.1[M+H] +。 Compounds 31d (97.6 mg, 339.8 μmol) and 4d (100.0 mg, 226.5 μmol) were dissolved in 1,4-dioxane (5.0 mL), and then copper acetate (45.2 mg, 226.5 μmol), pyridine ( 17.9 mg, 226.5 μmol) and DMAP (27.7 mg, 226.5 μmol), react at 99° C. for 16 hours after the addition. After the reaction was completed, the solvent was concentrated under reduced pressure to remove the solvent, the reaction solution was diluted with ethyl acetate, washed three times with saturated aqueous sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was subjected to silica gel column chromatography (DCM/MeOH= 20/1) was isolated and purified to obtain compound 31e (105.0 mg). MS m/z (ESI): 683.1 [M+H] + .
第五步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-3-(氰基甲基)吡咯烷-1-甲酰胺(化合物31)的制备The fifth step: N-(3-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-3-(cyanomethyl)pyrrolidine-1-carboxamide (compound 31)
将化合物31e(105.0mg，153.8μmol)加入到三氟乙酸(3.0mL)中，80℃反应16小时。反应结束后将反应液浓缩干，加入饱和碳酸氢钠水溶液碱化，二氯甲烷萃取，浓缩得粗产物，粗产物经Prep-HPLC分离纯化，得到化合物31(3.3mg)。MS m/z(ESI)：443.2[M+H] +。 Compound 31e (105.0 mg, 153.8 μmol) was added to trifluoroacetic acid (3.0 mL) and reacted at 80° C. for 16 hours. After the reaction, the reaction solution was concentrated to dryness, and saturated aqueous sodium bicarbonate solution was added for alkalization, extracted with dichloromethane, and concentrated to obtain a crude product. The crude product was separated and purified by Prep-HPLC to obtain compound 31 (3.3 mg). MS m/z (ESI): 443.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ8.64(s，1H)，8.46-8.36(m，2H)，8.32-8.15(m，3H)，7.99(s，1H)，7.71(d，J＝2.4Hz，1H)，7.58(dd，J＝8.4，2.0Hz，1H)，7.28(d，J＝8.8Hz，1H)，3.70-3.60(m，1H)，3.60-3.49(m，1H)，3.43-3.37(m，1H)，3.18-3.03(m，1H)，2.79-2.64(m，2H)，2.61-2.55(m，1H)，2.21(s，3H)，2.15-2.02(m，1H)，1.76-1.61(m，1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (s, 1H), 8.46-8.36 (m, 2H), 8.32-8.15 (m, 3H), 7.99 (s, 1H), 7.71 (d, J = 2.4Hz, 1H), 7.58 (dd, J=8.4, 2.0Hz, 1H), 7.28 (d, J=8.8Hz, 1H), 3.70-3.60 (m, 1H), 3.60-3.49 (m, 1H) , 3.43-3.37(m, 1H), 3.18-3.03(m, 1H), 2.79-2.64(m, 2H), 2.61-2.55(m, 1H), 2.21(s, 3H), 2.15-2.02(m, 1H), 1.76-1.61(m, 1H).
实施例32：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-4-(吗啉代甲基)苯甲酰胺(化合物32)Example 32: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-4-(morpholinomethyl)benzamide (Compound 32)
Figure PCTCN2022079826-appb-000114
Figure PCTCN2022079826-appb-000114
第一步：(4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)氨基甲酸叔丁酯(化合物32a)的制备The first step: (4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl) tert-butyl carbamate ( Preparation of compound 32a)
将化合物3a(300.00mg，1.29mmol)溶于二碳酸二叔丁酯(2mL)，升温至80℃反应2小时。反应液直接减压浓缩，再经硅胶快速柱层析(石油醚/乙酸乙酯＝4/1)纯化，得到化合物32a(418mg)。Compound 3a (300.00 mg, 1.29 mmol) was dissolved in di-tert-butyl dicarbonate (2 mL), and the temperature was raised to 80° C. to react for 2 hours. The reaction solution was directly concentrated under reduced pressure, and then purified by silica gel flash column chromatography (petroleum ether/ethyl acetate=4/1) to obtain compound 32a (418 mg).
第二步：(5-((叔丁氧羰基)氨基)-2-甲基苯基)硼酸(化合物32b)的制备The second step: preparation of (5-((tert-butoxycarbonyl)amino)-2-methylphenyl)boronic acid (compound 32b)
除将化合物31c更换为化合物32a外，以与实施例31第三步相同的方法进行制备，得到化合物32b(110mg)。The preparation was carried out in the same manner as the third step of Example 31 except that compound 31c was replaced with compound 32a to obtain compound 32b (110 mg).
第三步：(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)氨基甲酸叔丁酯(化合物32c)的制备The third step: (3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)- Preparation of tert-butyl 1H-pyrazol-1-yl)-4-methylphenyl)carbamate (compound 32c)
除将化合物31d更换为化合物32b外，以与实施例31第四步相同的方法进行制备，得到化合物32c(82mg)。MS m/z(ESI)：647.0[M+H] +。 The preparation was carried out in the same manner as in the fourth step of Example 31 except that compound 31d was replaced with compound 32b to obtain compound 32c (82 mg). MS m/z (ESI): 647.0 [M+H] + .
第四步：7-(1-(5-氨基-2-甲基苯基)-1H-吡唑-4-基)-N，N-双(4-甲氧基苄基)咪唑并[2，1-f][1，2，4]三嗪-4-胺(化合物32d)的制备The fourth step: 7-(1-(5-amino-2-methylphenyl)-1H-pyrazol-4-yl)-N,N-bis(4-methoxybenzyl)imidazo[2 , Preparation of 1-f][1,2,4]triazin-4-amine (Compound 32d)
将化合物32c(42mg，0.13mmol)加入到盐酸的1，4-二氧六环溶液(4M，2.0mL)中，20℃反应2小时。反应结束后直接将反应液浓缩干，得到化合物32d的盐酸盐(37.8mg)。MS m/z(ESI)：547.0[M+H] +。 Compound 32c (42 mg, 0.13 mmol) was added to a 1,4-dioxane solution of hydrochloric acid (4 M, 2.0 mL), and the reaction was carried out at 20°C for 2 hours. After the completion of the reaction, the reaction solution was directly concentrated to dryness to obtain the hydrochloride salt of compound 32d (37.8 mg). MS m/z (ESI): 547.0 [M+H] + .
第五步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-4-(吗啉代甲基)苯甲酰胺(化合物32f)的制备The fifth step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl )-1H-pyrazol-1-yl)-4-methylphenyl)-4-(morpholinomethyl)benzamide (compound 32f) preparation
将化合物32d的盐酸盐(37.8mg，64.83μmol)和32e(21.51mg，97.24μmol)溶于吡啶(2mL)中，再加入T 3P(1mL，50％于EA中)，加完后20℃反应12hr。反应结束后减压除去溶剂，乙酸乙酯稀释反应液，加入饱和碳酸氢钠水溶液洗涤3次，有机相经无水硫酸钠干燥，过滤，浓缩，粗产物经Prep-TLC纯化(DCM/MeOH＝15/1)，得到化合物32f(33mg)。MS m/z(ESI)：750.0[M+H] +。 The hydrochloride salt of compound 32d (37.8 mg, 64.83 μmol) and 32e (21.51 mg, 97.24 μmol) were dissolved in pyridine (2 mL), and T 3 P (1 mL, 50% in EA) was added for 20 °C reaction for 12hr. After the reaction, the solvent was removed under reduced pressure, the reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution for 3 times, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by Prep-TLC (DCM/MeOH= 15/1) to give compound 32f (33 mg). MS m/z (ESI): 750.0 [M+H] + .
第六步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-4-(吗啉代甲基)苯甲酰胺(化合物32)的制备Step 6: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-4-(morpholinomethyl)benzamide (compound 32)
除将化合物4e更换为化合物32f外，以与实施例4第四步相同的方法进行制备，得到化合物32(16mg)。MS m/z(ESI)：510.1[M+H] +。 The preparation was carried out in the same manner as in the fourth step of Example 4 except that compound 4e was replaced with compound 32f to obtain compound 32 (16 mg). MS m/z (ESI): 510.1 [M+H] + .
1HNMR(400MHz，DMSO-d 6)δ10.41(s，1H)，8.70(s，1H)，8.45(s，1H)，8.27(brs，1H)，8.20(s，1H)，8.19(brs，1H)，8.00(s，1H)，7.99(d，J＝2.0Hz，1H)，7.96(s，1H)，7.94(s，1H)，7.82(dd，J＝8.4，2.4Hz，1H)，7.50(s，1H)，7.48(s，1H)，7.42(d，J＝8.4Hz，1H)，3.60(t，J＝4.4Hz，4H)，3.56(s，2H)，2.42-2.35(m，4H)，2.27(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.41 (s, 1H), 8.70 (s, 1H), 8.45 (s, 1H), 8.27 (brs, 1H), 8.20 (s, 1H), 8.19 (brs , 1H), 8.00(s, 1H), 7.99(d, J=2.0Hz, 1H), 7.96(s, 1H), 7.94(s, 1H), 7.82(dd, J=8.4, 2.4Hz, 1H) , 7.50(s, 1H), 7.48(s, 1H), 7.42(d, J=8.4Hz, 1H), 3.60(t, J=4.4Hz, 4H), 3.56(s, 2H), 2.42-2.35( m, 4H), 2.27(s, 3H).
实施例33：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(三氟甲氧基)吡咯烷-1-甲酰胺(化合物33)Example 33: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 2-Fluoro-4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (Compound 33)
Figure PCTCN2022079826-appb-000115
Figure PCTCN2022079826-appb-000115
第一步：2-氟-4-甲基-5-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯胺(化合物33b)的制备The first step: 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (compound 33b) preparation
将化合物33a(1g，4.90mmol)、联硼酸频那醇酯(1.37g，5.39mmol)、[1，1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(200.12mg，245.05μmol)和乙酸钾(1.44g，14.70mmol)加入到1，4-二氧六环(10mL)中，氮气保护下，加热到100℃反应12hr。反应结束后将反应液降至室温，过滤除去固体，滤液浓缩后经硅胶快速柱层析(PE/EA＝3/1)分离纯化，得到化合物33b(704mg)。MS m/z(ESI)：252.1[M+H] +。 Compound 33a (1 g, 4.90 mmol), pinacol biboronate (1.37 g, 5.39 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane was complexed Compound (200.12 mg, 245.05 μmol) and potassium acetate (1.44 g, 14.70 mmol) were added to 1,4-dioxane (10 mL), heated to 100° C. for 12 hr under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature, and the solid was removed by filtration. The filtrate was concentrated and separated and purified by silica gel flash column chromatography (PE/EA=3/1) to obtain compound 33b (704 mg). MS m/z (ESI): 252.1 [M+H] + .
第二步：2-(4-氟-5-异氰酸酯基-2-甲基苯基)-4，4，5，5-四甲基-1，3，2-二氧杂硼烷(化合物33c)的制备The second step: 2-(4-fluoro-5-isocyanato-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (compound 33c ) preparation
除将化合物3a更换为化合物33b外，以与实施例19第一步相同的方法进行制备，得到化合物33c(200mg)。The preparation was carried out in the same manner as in the first step of Example 19, except that compound 3a was replaced by compound 33b, to obtain compound 33c (200 mg).
第三步：N-(2-氟-4-甲基-5-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)-3-(三氟甲氧基)吡咯烷-1-甲酰胺(化合物33d)的制备The third step: N-(2-Fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl) Preparation of -3-(trifluoromethoxy)pyrrolidine-1-carboxamide (compound 33d)
除将化合物19a更换为化合物33c外，以与实施例19第二步相同的方法进行制备，得到化合物33d(147mg)。MS m/z(ESI)：433.0[M+H] +。 The preparation was carried out in the same manner as in the second step of Example 19, except that compound 19a was replaced with compound 33c to obtain compound 33d (147 mg). MS m/z (ESI): 433.0 [M+H] + .
第四步：(4-氟-2-甲基-5-(3-(三氟甲氧基)吡咯烷-1-甲酰胺基)苯基)硼酸(化合物33e)的制备The fourth step: preparation of (4-fluoro-2-methyl-5-(3-(trifluoromethoxy)pyrrolidine-1-carboxamido)phenyl)boronic acid (compound 33e)
除将化合物19c更换为化合物33d外，以与实施例19第三步相同的方法进行制备，得到化合物33e(75mg)。MS m/z(ESI)：351.0[M+H] +。 The preparation was carried out in the same manner as the third step of Example 19 except that compound 19c was replaced with compound 33d to obtain compound 33e (75 mg). MS m/z (ESI): 351.0 [M+H] + .
第五步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(三氟甲氧基)吡咯烷-1-甲酰胺(化合物33f)的制备The fifth step: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl )-1H-pyrazol-1-yl)-2-fluoro-4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (compound 33f) preparation
除将化合物19d更换为化合物33e外，以与实施例26第一步相同的方法进行制备，得到化合物33f(32mg)。MS m/z(ESI)：746.0[M+H] +。 The preparation was carried out in the same manner as in the first step of Example 26, except that compound 19d was replaced with compound 33e, to obtain compound 33f (32 mg). MS m/z (ESI): 746.0 [M+H] + .
第六步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(三氟甲氧基)吡咯烷-1-甲酰胺(化合物33)的制备Step 6: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-fluoro-4-methylphenyl)-3-(trifluoromethoxy)pyrrolidine-1-carboxamide (compound 33)
除将化合物4e更换为化合物33f外，以与实施例4第四步相同的方法进行制备，得到化合物33(13mg)。MS m/z(ESI)：506.0[M+H] +。 The preparation was carried out in the same manner as the fourth step of Example 4 except that compound 4e was replaced with compound 33f to obtain compound 33 (13 mg). MS m/z (ESI): 506.0 [M+H] + .
1HNMR(400MHz，DMSO-d 6)δ8.64(s，1H)，8.42(s，1H)，8.27(brs，1H)，8.24(s，1H)，8.19(s，1H)，8.18(brs，1H)，7.98(s，1H)，7.66(d，J＝7.6Hz，1H)，7.34(d，J＝11.6Hz，1H)，5.17(s，1H)，3.72-3.66(m，2H)，3.65-3.59(m，1H)，3.52-3.44(m，1H)，2.28-2.16(m，2H)，2.23(s，3H). 1 HNMR (400MHz, DMSO-d 6 ) δ 8.64(s, 1H), 8.42(s, 1H), 8.27(brs, 1H), 8.24(s, 1H), 8.19(s, 1H), 8.18(brs , 1H), 7.98(s, 1H), 7.66(d, J=7.6Hz, 1H), 7.34(d, J=11.6Hz, 1H), 5.17(s, 1H), 3.72-3.66(m, 2H) , 3.65-3.59(m, 1H), 3.52-3.44(m, 1H), 2.28-2.16(m, 2H), 2.23(s, 3H).
实施例34：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-3-(三氟甲基)苯甲酰胺(化合物34)Example 34: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 6-Methylpyridin-3-yl)-3-(trifluoromethyl)benzamide (Compound 34)
Figure PCTCN2022079826-appb-000116
Figure PCTCN2022079826-appb-000116
第一步：N-(5-溴-6-甲基吡啶-3-基)-3-(三氟甲基)苯甲酰胺(化合物34b)的制备The first step: preparation of N-(5-bromo-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide (compound 34b)
将化合物34a(500mg，2.63mmol)与3b(491.89mg，2.63mmol)溶于吡啶(5mL)，然后滴加1-丙基磷酸酐(2mL，50％于EA中)，在25℃反应16小时。反应结束后减压除去吡啶，加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，有机相经无水硫酸钠干燥，过滤后减压浓缩，经硅胶快速柱层析(DCM/MeOH＝20/1)纯化，得到化合物34b(876.00mg)。MS m/z(ESI)：360.9[M+H] +。 Compound 34a (500 mg, 2.63 mmol) and 3b (491.89 mg, 2.63 mmol) were dissolved in pyridine (5 mL), then 1-propylphosphoric anhydride (2 mL, 50% in EA) was added dropwise, and the reaction was carried out at 25°C for 16 hours . After the reaction, pyridine was removed under reduced pressure, saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to flash column chromatography on silica gel (DCM/MeOH=20/1) Purification gave compound 34b (876.00 mg). MS m/z (ESI): 360.9 [M+H] + .
第二步：N-(6-甲基-5-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)吡啶-3-基)-3-(三氟甲基)苯甲酰胺(化合物34c)的制备Second step: N-(6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridin-3-yl)- Preparation of 3-(trifluoromethyl)benzamide (compound 34c)
将化合物34b(215mg，790.31μmol)、联硼酸频那醇酯(202mg，790.31μmol)、KOAc(239.91mg，2.37mmol)和Pd(dppf)Cl 2·DCM(64.49mg，79.03μmol)加入1，4-二氧六环(15mL)中，氮气保护下85℃反应16小时。反应结束后将反应液降至室温，过滤除去固体，滤液浓缩后经硅胶快速柱层析(DCM/MeOH＝10/1)分离纯化，得到化合物34c(320mg)。MS m/z(ESI)：407.0[M+H] +。 Compound 34b (215 mg, 790.31 μmol), pinacol diboronate (202 mg, 790.31 μmol), KOAc (239.91 mg, 2.37 mmol) and Pd(dppf)Cl2 · DCM (64.49 mg, 79.03 μmol) were added to 1, In 4-dioxane (15 mL), the reaction was carried out at 85°C for 16 hours under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature, and the solid was removed by filtration. The filtrate was concentrated and separated and purified by silica gel flash column chromatography (DCM/MeOH=10/1) to obtain compound 34c (320 mg). MS m/z (ESI): 407.0 [M+H] + .
第三步：(2-甲基-5-(3-(三氟甲基)苯甲酰胺基)吡啶-3-基)硼酸(化合物34d)的制备The third step: preparation of (2-methyl-5-(3-(trifluoromethyl)benzamido)pyridin-3-yl)boronic acid (compound 34d)
将化合物34c(320.00mg，787.78μmol)、醋酸铵(151.80mg，1.97mmol)和高碘酸钠(505.5mg，2.36mmol)加入到乙腈(10mL)和水(2.5mL)中，升温至50℃反应16小时。反应结束后加水稀释，EA萃取，有机相用无水硫酸钠干燥，过滤后浓缩，得到化合物34d(255.00mg)。MS m/z(ESI)：325.0[M+H] +。 Compound 34c (320.00 mg, 787.78 μmol), ammonium acetate (151.80 mg, 1.97 mmol) and sodium periodate (505.5 mg, 2.36 mmol) were added to acetonitrile (10 mL) and water (2.5 mL), and the temperature was raised to 50°C The reaction was carried out for 16 hours. After the reaction, it was diluted with water, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 34d (255.00 mg). MS m/z (ESI): 325.0 [M+H] + .
第四步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶 -3-基)-3-(三氟甲基)苯甲酰胺(化合物34e)的制备Fourth step: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl )-1H-pyrazol-1-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide (compound 34e) preparation
将化合物4d(50.00mg，113.25μmol)、34d(47.71mg，147.23μmol)、吡啶(17.92mg，226.51μmol)、醋酸铜(20.57mg，113.25μmol)和4-二甲氨基吡啶(34.59mg，283.14μmol)加入到1，4-二氧六环(4mL)中，空气氛围下90℃搅拌16hr。反应结束后加水稀释，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，浓缩，粗产物经Prep-TLC(二氯甲烷/甲醇＝15/1)纯化，得到化合物34e(35mg)。MS m/z(ESI)：720.1[M+H] +。 Compound 4d (50.00 mg, 113.25 μmol), 34d (47.71 mg, 147.23 μmol), pyridine (17.92 mg, 226.51 μmol), copper acetate (20.57 mg, 113.25 μmol) and 4-dimethylaminopyridine (34.59 mg, 283.14 μmol) was added to 1,4-dioxane (4 mL), and stirred at 90° C. for 16 hr in an air atmosphere. After the reaction was completed, it was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by Prep-TLC (dichloromethane/methanol=15/1) to obtain compound 34e (35 mg). MS m/z (ESI): 720.1 [M+H] + .
第五步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-3-(三氟甲基)苯甲酰胺(化合物34)的制备The fifth step: N-(5-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide (compound 34)
将化合物34e(31.00mg，43.07μmol)加入到三氟乙酸(2mL)中，升温至99℃反应3小时。反应结束后将溶剂浓缩干，粗产物经Prep-HPLC纯化，得到化合物34(18.00mg)。MS m/z(ESI)：480.1[M+H] +。 Compound 34e (31.00 mg, 43.07 μmol) was added to trifluoroacetic acid (2 mL), and the temperature was raised to 99° C. to react for 3 hours. After the reaction, the solvent was concentrated to dryness, and the crude product was purified by Prep-HPLC to obtain compound 34 (18.00 mg). MS m/z (ESI): 480.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.88(s，1H)，8.98(d，J＝2.4Hz，1H)，8.83(s，1H)，8.52(s，1H)，8.40(d，J＝2.4Hz，1H)，8.37(s，1H)，8.35-8.27(m，2H)，8.25-8.17(m，2H)，8.06-.800(m，2H)，7.84(t，J＝8.0Hz，1H)，2.52(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.88 (s, 1H), 8.98 (d, J=2.4 Hz, 1H), 8.83 (s, 1H), 8.52 (s, 1H), 8.40 (d, J=2.4Hz, 1H), 8.37(s, 1H), 8.35-8.27(m, 2H), 8.25-8.17(m, 2H), 8.06-.800(m, 2H), 7.84(t, J=8.0 Hz, 1H), 2.52(s, 3H).
实施例35：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物35)Example 35: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 2-Fluoro-4-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 35)
Figure PCTCN2022079826-appb-000117
Figure PCTCN2022079826-appb-000117
第一步：N-(2-氟-4-甲基-5-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)-3-(三氟甲基)苯甲酰胺(化合物35a)的制备The first step: N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl) - Preparation of 3-(trifluoromethyl)benzamide (compound 35a)
将化合物3b(113.57mg，597.36μmol)和33b(150mg，597.36μmol)溶于吡啶(3mL)中，再加入1-丙基磷酸酐(1mL，50％于EA中)，25℃搅拌16hr。反应结束后减压除去吡啶，加入饱和碳酸氢钠水溶液淬灭，乙酸乙酯萃取，有机相经无水硫酸钠干燥，过滤后减压浓缩，粗产物经硅胶柱色谱法(DCM/MeOH＝97/3)分离纯化，得到化合物35a(100mg)。MS m/z(ESI)：424.1[M+H] +。 Compounds 3b (113.57 mg, 597.36 μmol) and 33b (150 mg, 597.36 μmol) were dissolved in pyridine (3 mL), 1-propylphosphoric anhydride (1 mL, 50% in EA) was added, and the mixture was stirred at 25° C. for 16 hr. After the reaction, pyridine was removed under reduced pressure, quenched by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (DCM/MeOH=97 /3) Separation and purification to obtain compound 35a (100 mg). MS m/z (ESI): 424.1 [M+H] + .
第二步：(4-氟-2-甲基-5-(3-(三氟甲基)苯甲酰胺基)苯基)硼酸(化合物35b)的制备Step 2: Preparation of (4-fluoro-2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)boronic acid (compound 35b)
将化合物35a(160mg，378.06μmol)、高碘酸钠(242.59mg，1.13mmol)和醋酸铵(72.85mg，945.16μmol)加入到乙腈(16mL)和水(4mL)中，氮气保护下50℃反应16hr。反应结束后加水稀释，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后浓缩，经硅胶快速柱层析(DCM/MeOH＝92/8)分离纯化，得到化合物35b(80mg)。MS m/z(ESI)：342.0[M+H] +。 Compound 35a (160 mg, 378.06 μmol), sodium periodate (242.59 mg, 1.13 mmol) and ammonium acetate (72.85 mg, 945.16 μmol) were added to acetonitrile (16 mL) and water (4 mL), and reacted at 50°C under nitrogen protection 16hr. After the reaction was completed, it was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel flash column chromatography (DCM/MeOH=92/8) to obtain compound 35b ( 80 mg). MS m/z (ESI): 342.0 [M+H] + .
第三步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物35c)的制备The third step: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-2-fluoro-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 35c) preparation
将化合物35b(100mg，226.51μmol)、吡啶(35.83mg，453.02μmol，36.45μL)、DMAP(69.18mg，566.27μmol)和Cu(OAc) 2(41.14mg，226.51μmol)加入到1，4-二氧六环(4mL)中，空气氛围下90℃搅拌16hr。反应结束后，直接硅胶快速柱层析(PE/EA＝3/2)分离纯化，得到化合物35c(20mg)。MS m/z(ESI)：737.0[M+H] +。 Compound 35b (100 mg, 226.51 μmol), pyridine (35.83 mg, 453.02 μmol, 36.45 μL), DMAP (69.18 mg, 566.27 μmol) and Cu(OAc) 2 (41.14 mg, 226.51 μmol) were added to 1,4-di In oxane (4 mL), the mixture was stirred at 90° C. for 16 hr under air atmosphere. After the completion of the reaction, direct silica gel flash column chromatography (PE/EA=3/2) was used for separation and purification to obtain compound 35c (20 mg). MS m/z (ESI): 737.0 [M+H] + .
第四步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物35)的制备Fourth step: N-(5-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-fluoro-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 35)
将化合物35c(20mg，27.15μmol)溶于三氟乙酸(3mL)中，100℃搅拌16hr。反应结束后将溶剂浓缩干，经Prep-HPLC分离纯化，得到化合物35的三氟乙酸盐(8.39mg)。MS m/z(ESI)：497.2[M+H] +。 Compound 35c (20 mg, 27.15 μmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at 100° C. for 16 hr. After the reaction, the solvent was concentrated to dryness and separated and purified by Prep-HPLC to obtain the trifluoroacetic acid salt of compound 35 (8.39 mg). MS m/z (ESI): 497.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.57(s，1H)，8.70(s，1H)，8.45(s，1H)，8.34(s，2H)，8.29(d，J＝8.0Hz，1H)，8.25(br，1H)，8.20(s，1H)，8.05-7.98(m，2H)，7.85-7.76(m，2H)，7.48(d，J＝11.2Hz，1H)，2.29(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.57 (s, 1H), 8.70 (s, 1H), 8.45 (s, 1H), 8.34 (s, 2H), 8.29 (d, J=8.0 Hz, 1H), 8.25(br, 1H), 8.20(s, 1H), 8.05-7.98(m, 2H), 7.85-7.76(m, 2H), 7.48(d, J=11.2Hz, 1H), 2.29(s , 3H).
实施例36：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(2，2，2-三氟乙基)吡咯烷-1-甲酰胺(化合物36)Example 36: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 2-Fluoro-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 36)
Figure PCTCN2022079826-appb-000118
Figure PCTCN2022079826-appb-000118
第一步：N-(2-氟-4-甲基-5-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)-3-(2，2，2-三氟乙基)-2，5-二氢-1H-吡咯-1-甲酰胺(化合物36a)的制备The first step: N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl) - Preparation of 3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (compound 36a)
将化合物33c(130mg，469.15μmol)、29a(88mg，469.15μmol)和DIPEA(182mg，1.41mmol)加入到甲苯(5mL)中，氮气保护下100℃反应12hr。反应结束后向反应液中加水稀释，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩，粗品经硅胶柱层析(PE/EA＝3/1)纯化，得到化合物36a(70mg)。MS m/z(ESI)：429.2[M+H] +。 Compound 33c (130 mg, 469.15 μmol), 29a (88 mg, 469.15 μmol) and DIPEA (182 mg, 1.41 mmol) were added to toluene (5 mL) and reacted at 100° C. for 12 hr under nitrogen protection. After the reaction, the reaction solution was diluted with water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE/EA=3/1). , to obtain compound 36a (70 mg). MS m/z (ESI): 429.2 [M+H] + .
第二步：(4-氟-2-甲基-5-(3-(2，2，2-三氟乙基)-2，5-二氢-1H-吡咯-1-甲酰胺基)苯基)硼酸(化合物36b)的制备The second step: (4-fluoro-2-methyl-5-(3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamido)benzene Preparation of boronic acid (compound 36b)
反应瓶中加入化合物36a(70mg，163.46μmol)、NaIO 4(105mg，490.39μmol)和MeCN(4mL)，再加入醋酸铵(31mg，408.66μmol)的H 2O(1mL)溶液，氮气保护下50℃反应过夜。反应结束后向反应液中加水稀释，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩，得到化合物36b(50mg)。MS m/z(ESI)：347.1[M+H] +。 Compound 36a (70 mg, 163.46 μmol), NaIO 4 (105 mg, 490.39 μmol) and MeCN (4 mL) were added to the reaction flask, and a solution of ammonium acetate (31 mg, 408.66 μmol) in H 2 O (1 mL) was added under nitrogen protection for 50 °C reaction overnight. After the reaction was completed, the reaction solution was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 36b (50 mg). MS m/z (ESI): 347.1 [M+H] + .
第三步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(2，2，2-三氟乙基)-2，5-二氢-1H-吡咯-1-甲酰胺(化合物36c)的制备The third step: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-2-fluoro-4-methylphenyl)-3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole- Preparation of 1-carboxamide (compound 36c)
反应瓶中加入化合物4d(60mg，135.91μmol)、36b(56mg，163.09μmol)、Cu(OAc) 2(27mg，135.91μmol)、吡啶(32mg，407.72μmol)、DMAP(33mg，271.81μmol)和1，4-二氧六环(10mL)，空气氛围下99℃反应过夜。反应结束后向反应液中加水稀释，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩，粗品经硅胶柱层析(DCM/MeOH＝9/1)纯化，得到化合物36c(60mg)。MS m/z(ESI)：742.2[M+H] +。 Compound 4d (60 mg, 135.91 μmol), 36b (56 mg, 163.09 μmol), Cu(OAc) 2 (27 mg, 135.91 μmol), pyridine (32 mg, 407.72 μmol), DMAP (33 mg, 271.81 μmol) and 1 were added to the reaction flask , 4-dioxane (10 mL), and reacted at 99 °C overnight in an air atmosphere. After the reaction, the reaction solution was diluted with water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM/MeOH=9/1). , to obtain compound 36c (60 mg). MS m/z (ESI): 742.2 [M+H] + .
第四步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(2，2，2-三氟乙基)-2，5-二氢-1H-吡咯-1-甲酰胺(化合物36d)的制备Fourth step: N-(5-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-fluoro-4-methylphenyl)-3-(2,2,2-trifluoroethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (compound 36d)
将化合物36c(60mg，80.89μmol)加入到TFA(5mL)中，80℃反应过夜。反应结束后，直接将溶剂减压浓缩至干，再加入水稀释，用饱和碳酸氢钠溶液调节pH至7-8，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩，粗品用Prep-TLC纯化(DCM/MeOH＝10/1)，得到化合物36d(15mg)。MS m/z(ESI)：502.1[M+H] +。 Compound 36c (60 mg, 80.89 μmol) was added to TFA (5 mL) and reacted at 80°C overnight. After the reaction, the solvent was directly concentrated to dryness under reduced pressure, then diluted with water, adjusted to pH 7-8 with saturated sodium bicarbonate solution, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After concentrated under reduced pressure, the crude product was purified by Prep-TLC (DCM/MeOH=10/1) to obtain compound 36d (15 mg). MS m/z (ESI): 502.1 [M+H] + .
第五步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(2，2，2-三氟乙基)吡咯烷-1-甲酰胺(化合物36)的制备The fifth step: N-(5-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-fluoro-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (compound 36)
将化合物36d(15mg，29.91μmol)和钯碳(4mg，10％含量)加入到MeOH(5mL)，氢气置换三次，40℃反应过夜。反应结束后经硅藻土过滤，浓缩，粗产物经Pre-HPLC纯化，得到化合物36(2mg)。MS m/z(ESI)：504.0[M+H] +。 Compound 36d (15 mg, 29.91 μmol) and palladium on carbon (4 mg, 10% content) were added to MeOH (5 mL), replaced by hydrogen three times, and reacted at 40° C. overnight. After the reaction was completed, it was filtered through celite, concentrated, and the crude product was purified by Pre-HPLC to obtain compound 36 (2 mg). MS m/z (ESI): 504.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ8.62(s，1H)，8.40(s，1H)，8.28-8.14(m，3H)，8.05(s，1H)，7.97(s，1H)，7.65(d，J＝7.2Hz，1H)，7.31(d，J＝11.2Hz，1H)，3.71-3.64(m，1H)，3.58-3.51(m，1H)，3.05(t，J＝9.2Hz，1H)，2.49-2.37(m，4H)，2.21(s，3H)，2.14-2.05(m，1H)，1.73-1.61(m，1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.62(s, 1H), 8.40(s, 1H), 8.28-8.14(m, 3H), 8.05(s, 1H), 7.97(s, 1H), 7.65(d, J=7.2Hz, 1H), 7.31(d, J=11.2Hz, 1H), 3.71-3.64(m, 1H), 3.58-3.51(m, 1H), 3.05(t, J=9.2Hz) , 1H), 2.49-2.37(m, 4H), 2.21(s, 3H), 2.14-2.05(m, 1H), 1.73-1.61(m, 1H).
实施例37：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-氟苯基)-3-(三氟甲基)苯甲酰胺(化合物37)Example 37: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Fluorophenyl)-3-(trifluoromethyl)benzamide (Compound 37)
Figure PCTCN2022079826-appb-000119
Figure PCTCN2022079826-appb-000119
第一步：4-氟-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯胺(化合物37b)的制备Step 1: Preparation of 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (compound 37b)
向反应瓶中依次加入化合物37a(2g，10.53mmol)、联硼酸频那醇酯(2.94g，11.58mmol)、KOAc(3.10g，31.58mmol)、Pd(dppf)Cl 2·DCM(429.78mg，526.28μmol)和1，4-二氧六环(15mL)，氮气保护下100℃搅拌16hr。反应结束后加水稀释，EA萃取，有机相用无水硫酸钠干燥，过滤，浓缩，快速柱层析(PE/EA＝7/3)分离纯化，得到化合物37b(2.0g)。MS m/z(ESI)：238.1[M+H] +。 Compound 37a (2 g, 10.53 mmol), pinacol biboronate (2.94 g, 11.58 mmol), KOAc (3.10 g, 31.58 mmol), Pd(dppf)Cl 2 ·DCM (429.78 mg, 526.28 μmol) and 1,4-dioxane (15 mL), stirred at 100 °C for 16 hr under nitrogen protection. After the reaction was completed, it was diluted with water, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by flash column chromatography (PE/EA=7/3) to obtain compound 37b (2.0 g). MS m/z (ESI): 238.1 [M+H] + .
第二步：N-(4-氟-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)-3-(三氟甲基)苯甲酰胺(化合物37c)的制备The second step: N-(4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-3-(tri Preparation of fluoromethyl)benzamide (compound 37c)
将化合物37b(300mg，1.27mmol)和3b(240.58mg，1.27mmol)溶于吡啶(3mL)中，再加入1-丙基磷酸酐(3mL，50％于EA中)，25℃搅拌16hr。反应结束后减压除去吡啶，加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，有机相经无水硫酸钠干燥，过滤后减压浓缩，粗产物经硅胶柱色谱法(DCM/MeOH＝97/3)分离纯化，得到化合物37c(350mg)。MS m/z(ESI)：410.1[M+H] +。 Compounds 37b (300 mg, 1.27 mmol) and 3b (240.58 mg, 1.27 mmol) were dissolved in pyridine (3 mL), 1-propylphosphoric anhydride (3 mL, 50% in EA) was added, and the mixture was stirred at 25°C for 16 hr. After the reaction, pyridine was removed under reduced pressure, saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (DCM/MeOH=97/3 ) was isolated and purified to obtain compound 37c (350 mg). MS m/z (ESI): 410.1 [M+H] + .
第三步：(2-氟-5-(3-(三氟甲基)苯甲酰胺基)苯基)硼酸(化合物37d)的制备The third step: preparation of (2-fluoro-5-(3-(trifluoromethyl)benzamido)phenyl)boronic acid (compound 37d)
将化合物37c(100mg，244.39μmol)和高碘酸钠(156.82mg，733.17μmol)加入到乙腈(16mL)中，再加入醋酸铵(47.09mg，610.98μmol)的水(4mL)溶液，氮气保护下50℃反应16hr。反应结束后加水稀释，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后浓缩，得到化合物37d(50mg)。MS m/z(ESI)：328.0[M+H] +。 Compound 37c (100 mg, 244.39 μmol) and sodium periodate (156.82 mg, 733.17 μmol) were added to acetonitrile (16 mL), followed by a solution of ammonium acetate (47.09 mg, 610.98 μmol) in water (4 mL), under nitrogen protection 50°C for 16hrs. After the reaction, it was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 37d (50 mg). MS m/z (ESI): 328.0 [M+H] + .
第四步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-氟苯基)-3-(三氟甲基)苯甲酰胺(化合物37e)的制备The fourth step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-4-fluorophenyl)-3-(trifluoromethyl)benzamide (compound 37e) preparation
将化合物37d(50mg，152.89μmol)、4d(67.50mg，152.89μmol)、吡啶(36.28mg，458.66μmol)、Cu(OAc) 2(27.77mg，152.89μmol)和4A分子筛(0.1g)加入到干燥二氯甲烷(4mL)，25℃搅拌16hr。反应结束后加水淬灭，DCM萃取，有机相用无水硫酸钠干燥，过滤，浓缩，粗产物经Prep-TLC纯化(DCM/MeOH＝10/1)，得到化合物37e(10mg)。MS m/z(ESI)：723.2[M+H] +。 Compounds 37d (50 mg, 152.89 μmol), 4d (67.50 mg, 152.89 μmol), pyridine (36.28 mg, 458.66 μmol), Cu(OAc) 2 (27.77 mg, 152.89 μmol) and 4A molecular sieves (0.1 g) were added to dryness Dichloromethane (4 mL) was stirred at 25°C for 16 hr. After the reaction was completed, water was added to quench, extracted with DCM, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by Prep-TLC (DCM/MeOH=10/1) to obtain compound 37e (10 mg). MS m/z (ESI): 723.2 [M+H] + .
第五步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-氟苯基)-3-(三氟甲基)苯甲酰胺(化合物37)的制备The fifth step: N-(3-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-fluorophenyl)-3-(trifluoromethyl)benzamide (compound 37)
将化合物37e(10mg，13.84μmol)溶于三氟乙酸(2mL)中，100℃搅拌16hr。反应结束后浓缩干溶剂，加入饱和碳酸氢钠溶液淬灭，EA萃取，有机相用无水硫酸钠干燥，过滤，浓缩，经Prep-HPLC分离纯化，得到化合物37(0.72mg)。MS m/z(ESI)：483.1[M+H] +。 Compound 37e (10 mg, 13.84 μmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at 100° C. for 16 hr. After the reaction, the solvent was concentrated to dryness, quenched by adding saturated sodium bicarbonate solution, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by Prep-HPLC to obtain compound 37 (0.72 mg). MS m/z (ESI): 483.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.74(s，1H)，8.94(d，J＝2.4Hz，1H)，8.54(s，1H)，8.44(dd，J＝7.2，2.8Hz，1H)，8.34(s，1H)，8.33-8.25(m，2H)，8.22(s，1H)，8.20(br，1H)，8.05(s，1H)，8.00(d，J＝7.8Hz，1H)，7.91-7.85(m，1H)，7.82(t，J＝7.8Hz，1H)，7.55(dd，J＝11.4，9.0Hz，1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 8.94 (d, J=2.4 Hz, 1H), 8.54 (s, 1H), 8.44 (dd, J=7.2, 2.8 Hz, 1H), 8.34(s, 1H), 8.33-8.25(m, 2H), 8.22(s, 1H), 8.20(br, 1H), 8.05(s, 1H), 8.00(d, J=7.8Hz, 1H ), 7.91-7.85 (m, 1H), 7.82 (t, J=7.8Hz, 1H), 7.55 (dd, J=11.4, 9.0Hz, 1H).
实施例38：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-1-(2，2，2-三氟乙基)吡咯烷-3-甲酰胺(化合物38)Example 38: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 2-Fluoro-4-methylphenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carboxamide (Compound 38)
Figure PCTCN2022079826-appb-000120
Figure PCTCN2022079826-appb-000120
第一步：1-(2，2，2-三氟乙基)吡咯烷-3-甲酸乙酯(化合物38b)的制备Step 1: Preparation of ethyl 1-(2,2,2-trifluoroethyl)pyrrolidine-3-carboxylate (compound 38b)
将化合物38a(369mg，2.05mmol，盐酸盐)、K 2CO 3(567.77mg，4.11mmol)和2，2，2-三氟乙基三氟甲烷磺酸酯(715.13mg，3.08mmol)依次加入到DMF(10mL)中，室温搅拌12hr。反应结束后加水稀释，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后浓缩，经硅胶快速柱层析(PE/EA＝3/1)分离纯化，得到化合物38b(220mg)。MS m/z(ESI)：226.1[M+H] +。 Compound 38a (369 mg, 2.05 mmol, hydrochloride), K 2 CO 3 (567.77 mg, 4.11 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (715.13 mg, 3.08 mmol) were sequentially Added to DMF (10 mL) and stirred at room temperature for 12 hr. After the reaction was completed, it was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and separated and purified by silica gel flash column chromatography (PE/EA=3/1) to obtain compound 38b ( 220mg). MS m/z (ESI): 226.1 [M+H] + .
第二步：1-(2，2，2-三氟乙基)吡咯烷-3-羧酸(化合物38c)的制备The second step: preparation of 1-(2,2,2-trifluoroethyl)pyrrolidine-3-carboxylic acid (compound 38c)
将化合物38b(100mg，444.03μmol)加入THF(2mL)和H 2O(2mL)中，再加入LiOH(106.35mg，4.44mmol)，室温搅拌12hr。反应结束后将反应液浓缩干，经硅胶快速柱层析(DCM/MeOH＝10/1)分离纯化，得到化合物38c(56mg)。MS m/z(ESI)：198.1[M+H] +。 Compound 38b (100 mg, 444.03 μmol) was added to THF (2 mL) and H 2 O (2 mL), then LiOH (106.35 mg, 4.44 mmol) was added, and the mixture was stirred at room temperature for 12 hr. After the reaction, the reaction solution was concentrated to dryness, and separated and purified by silica gel flash column chromatography (DCM/MeOH=10/1) to obtain compound 38c (56 mg). MS m/z (ESI): 198.1 [M+H] + .
第三步：(2-氟-4-甲基-5-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)氨基甲酸叔丁酯(化合物38d)的制备The third step: (2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)carbamic acid Preparation of tert-butyl ester (compound 38d)
将化合物33b(820mg，3.27mmol)加入到(Boc) 2O(10mL)中，升温至80℃反应2hr。反应结束后将反应液浓缩干，经硅胶快速柱层析(PE/EA＝85/15)分离纯化，得到化合物38d(1.15g)。 Compound 33b (820 mg, 3.27 mmol) was added to (Boc) 2 O (10 mL), and the temperature was raised to 80° C. to react for 2 hr. After the reaction, the reaction solution was concentrated to dryness, and separated and purified by silica gel flash column chromatography (PE/EA=85/15) to obtain compound 38d (1.15 g).
第四步：(5-((叔丁氧羰基)氨基)-4-氟-2-甲基苯基)硼酸(化合物38e)的制备The fourth step: preparation of (5-((tert-butoxycarbonyl)amino)-4-fluoro-2-methylphenyl)boronic acid (compound 38e)
将化合物38d(1.15g，3.11mmol)和高碘酸钠(2.00g，9.33mmol)加入到MeCN(40mL)中，再滴加醋酸铵(479.53mg，6.22mmol)的H 2O(10mL)溶液，然后升温至50℃反应16hr。反应结束后将反应液浓缩干，经硅胶快速柱层析(DCM/MeOH＝10/1)分离纯化，得到化合物38e(760mg)。 Compound 38d (1.15 g, 3.11 mmol) and sodium periodate (2.00 g, 9.33 mmol) were added to MeCN (40 mL), followed by dropwise addition of ammonium acetate (479.53 mg, 6.22 mmol) in H 2 O (10 mL) , and then the temperature was raised to 50 °C for 16 hr. After the reaction, the reaction solution was concentrated to dryness, and separated and purified by silica gel flash column chromatography (DCM/MeOH=10/1) to obtain compound 38e (760 mg).
第五步：(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)氨基甲酸叔丁酯(化合物38f)的制备Fifth step: (5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl)- Preparation of tert-butyl 1H-pyrazol-1-yl)-2-fluoro-4-methylphenyl)carbamate (compound 38f)
将化合物4d(300mg，679.53μmol)、38e(219.41mg，815.43μmol)、Cu(OAc)2(135.67mg，679.53μmol)、吡啶(161.25mg，2.04mmol，164.04μL)和DMAP(166.04mg，1.36mmol)加入到1，4-二氧六环(10mL)中，空气氛围下99℃反应16hr。反应结束后加水稀释，乙酸乙酯萃取，有机相经无水硫酸钠干燥，过滤后减压浓缩，经硅胶快速柱层析(DCM/MeOH＝10/1)纯化，得到化合物38f(126mg)。MS m/z(ESI)：665.0[M+H] +。 Compound 4d (300 mg, 679.53 μmol), 38e (219.41 mg, 815.43 μmol), Cu(OAc)2 (135.67 mg, 679.53 μmol), pyridine (161.25 mg, 2.04 mmol, 164.04 μL) and DMAP (166.04 mg, 1.36 mmol) was added to 1,4-dioxane (10 mL) and reacted at 99 °C for 16 hr in an air atmosphere. After the reaction, it was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel flash column chromatography (DCM/MeOH=10/1) to obtain compound 38f (126 mg). MS m/z (ESI): 665.0 [M+H] + .
第六步：7-(1-(5-氨基-4-氟-2-甲基苯基)-1H-吡唑-4-基)-N-(4-甲氧基苄基)咪唑并[2，1-f][1，2，4]三嗪-4-胺(化合物38g)的制备Step 6: 7-(1-(5-Amino-4-fluoro-2-methylphenyl)-1H-pyrazol-4-yl)-N-(4-methoxybenzyl)imidazo[ Preparation of 2,1-f][1,2,4]triazin-4-amine (compound 38g)
将化合物38f(126mg，189.55μmol)加入到TFA(3mL)和DCM(5mL)中，反应25℃搅拌3hr。反应结束后将反应液浓缩干，得到化合物38g(105mg)。MS m/z(ESI)：445.0[M+H] +。 Compound 38f (126 mg, 189.55 μmol) was added to TFA (3 mL) and DCM (5 mL), and the reaction was stirred at 25° C. for 3 hr. After the completion of the reaction, the reaction solution was concentrated to dryness to obtain 38 g (105 mg) of compound. MS m/z (ESI): 445.0 [M+H] + .
第七步：N-(2-氟-5-(4-(4-((4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-1-(2，2，2-三氟乙基)吡咯烷-3-甲酰胺(化合物38h)的制备Step Seven: N-(2-Fluoro-5-(4-(4-((4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine- Preparation of 7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carboxamide (compound 38h)
将化合物38g(20mg，45.00μmol)和38c(8.87mg，45.00μmol)加入吡啶(1mL)中，再加入T 3P(0.3mL，50％于EA中)，反应25℃搅拌16hr。反应结束后将反应液浓缩干，经prep-TLC(PE/EA＝1/1)纯化，得到化合物38h(25mg)。MS m/z(ESI)：624.3[M+H] +。 Compounds 38g (20 mg, 45.00 μmol) and 38c (8.87 mg, 45.00 μmol) were added to pyridine (1 mL), followed by T 3 P (0.3 mL, 50% in EA), and the reaction was stirred at 25° C. for 16 hr. After the reaction, the reaction solution was concentrated to dryness, and purified by prep-TLC (PE/EA=1/1) to obtain compound 38h (25 mg). MS m/z (ESI): 624.3 [M+H] + .
第八步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-1-(2，2，2-三氟乙基)吡咯烷-3-甲酰胺(化合物38)的制备Step 8: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-fluoro-4-methylphenyl)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carboxamide (compound 38)
将化合物38h(25mg，40.09μmol)加入TFA(6mL)中，反应升温至100℃搅拌16hr。反应结束后将反应液浓缩干，经Prep-HPLC纯化，得到化合物38(7.6mg)。MS m/z(ESI)：504.8[M+H] +。 Compound 38h (25 mg, 40.09 μmol) was added to TFA (6 mL), and the reaction was warmed to 100° C. and stirred for 16 hr. After the reaction, the reaction solution was concentrated to dryness, and purified by Prep-HPLC to obtain compound 38 (7.6 mg). MS m/z (ESI): 504.8 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ9.94(s，1H)，8.64(s，1H)，8.42(s，1H)，8.30-8.14(m，3H)，8.06(d，J＝7.4Hz，1H)，7.99(s，1H)，7.40(d，J＝11.6Hz，1H)，3.33-3.19(m，3H)，3.07(t，J＝8.7Hz，1H)，2.89-2.76(m，2H)，2.70(dd，J＝15.3，8.0Hz，1H)，2.23(s，3H)，2.10-1.96(m，2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.64 (s, 1H), 8.42 (s, 1H), 8.30-8.14 (m, 3H), 8.06 (d, J=7.4 Hz, 1H), 7.99(s, 1H), 7.40(d, J=11.6Hz, 1H), 3.33-3.19(m, 3H), 3.07(t, J=8.7Hz, 1H), 2.89-2.76(m , 2H), 2.70 (dd, J=15.3, 8.0Hz, 1H), 2.23 (s, 3H), 2.10-1.96 (m, 2H).
实施例39：N-(5-(4-(8-氨基咪唑并[1，2-a]吡嗪-3-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-3-(三氟甲基)苯甲酰胺(化合物39)Example 39: N-(5-(4-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-1H-pyrazol-1-yl)-6-methylpyridine-3 -yl)-3-(trifluoromethyl)benzamide (Compound 39)
Figure PCTCN2022079826-appb-000121
Figure PCTCN2022079826-appb-000121
第一步：N-(5-溴-6-甲基吡啶-3-基)-3-(三氟甲基)苯甲酰胺(化合物39a)的制备The first step: preparation of N-(5-bromo-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide (compound 39a)
将化合物3b(200mg，1.05mmol)和34a(196.76mg，1.05mmol)溶于吡啶(5mL)中，再加入T 3P(2mL，50％于EA中)，25℃反应过夜。反应结束后减压除去吡啶，滴入饱和碳酸氢钠溶液淬灭，EA萃取，水洗，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到化合物39a(370mg)。MS m/z(ESI)：359.0[M+H] +。 Compounds 3b (200 mg, 1.05 mmol) and 34a (196.76 mg, 1.05 mmol) were dissolved in pyridine (5 mL), T3P ( 2 mL, 50% in EA) was added, and the reaction was carried out at 25°C overnight. After the reaction, pyridine was removed under reduced pressure, quenched by dropwise addition of saturated sodium bicarbonate solution, extracted with EA, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 39a (370 mg). MS m/z (ESI): 359.0 [M+H] + .
第二步：N-(5-(4-(8-((2，4-二甲氧基苄基)氨基)咪唑并[1，2-a]吡嗪-3-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-3-(三氟甲基)苯甲酰胺(化合物39b)的制备The second step: N-(5-(4-(8-((2,4-dimethoxybenzyl)amino)imidazo[1,2-a]pyrazin-3-yl)-1H-pyridine Preparation of azol-1-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide (compound 39b)
将化合物5c(30mg，85.62μmol)、39a(34mg，94.19μmol)、DMEDA(15mg，171.25μmol)、CuI(16mg，85.62μmol)、Cs 2CO 3(69.74mg，214.06μmol)和DMF(2mL)加入微波管中，氮气保护下，微波120℃反应2hr。反应结束后向反应液中加水稀释，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到粗产物。粗品经硅胶柱层析(DCM/MeOH＝20/1)纯化，得到化合物39b(30mg)。MS m/z(ESI)：629.3[M+H] +。 Compound 5c (30 mg, 85.62 μmol), 39a (34 mg, 94.19 μmol), DMEDA (15 mg, 171.25 μmol), CuI (16 mg, 85.62 μmol), Cs 2 CO 3 (69.74 mg, 214.06 μmol) and DMF (2 mL) were combined It was put into a microwave tube, and under nitrogen protection, the reaction was carried out at 120° C. for 2 hr in the microwave. After the reaction, the reaction solution was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain compound 39b (30 mg). MS m/z (ESI): 629.3 [M+H] + .
第三步：N-(5-(4-(8-氨基咪唑并[1，2-a]吡嗪-3-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-3-(三氟甲基)苯甲酰胺(化合物39)的制备The third step: N-(5-(4-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-1H-pyrazol-1-yl)-6-methylpyridine-3 Preparation of -yl)-3-(trifluoromethyl)benzamide (Compound 39)
反应瓶中加入化合物39b(50mg，79.54μmol)和TFA(3mL)，氮气保护下80℃反应3hr。反应结束后减压除去溶剂，加水稀释后用饱和NaHCO 3溶液调节pH至7-8，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到粗产物。粗品经Pre-HPLC纯化，得到化合物39(10mg)。MS m/z(ESI)：479.1[M+H] +。 Compound 39b (50 mg, 79.54 μmol) and TFA (3 mL) were added to the reaction flask, and the reaction was carried out at 80° C. for 3 hr under nitrogen protection. After the reaction was completed, the solvent was removed under reduced pressure, diluted with water and adjusted to pH 7-8 with saturated NaHCO solution, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude solution. product. The crude product was purified by Pre-HPLC to give compound 39 (10 mg). MS m/z (ESI): 479.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.89(s，1H)，8.96(d，J＝2.4Hz，1H)，8.81(s，1H)，8.42(d，J＝2.4Hz，1H)，8.39-8.29(m，3H)，8.03(d，J＝7.6Hz，1H)，7.92-7.81(m，3H)，7.33(d，J＝4.8Hz，1H)，6.97(s，2H)，2.54(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.89 (s, 1H), 8.96 (d, J=2.4 Hz, 1H), 8.81 (s, 1H), 8.42 (d, J=2.4 Hz, 1H) , 8.39-8.29(m, 3H), 8.03(d, J=7.6Hz, 1H), 7.92-7.81(m, 3H), 7.33(d, J=4.8Hz, 1H), 6.97(s, 2H), 2.54(s, 3H).
实施例40：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3，3-二氟环戊烷-1-甲酰胺(化合物40)Example 40: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 2-Fluoro-4-methylphenyl)-3,3-difluorocyclopentane-1-carboxamide (Compound 40)
Figure PCTCN2022079826-appb-000122
Figure PCTCN2022079826-appb-000122
第一步：3，3-二氟-N-(2-氟-4-甲基-5-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)环戊烷-1-甲酰胺(化合物40b)的制备The first step: 3,3-difluoro-N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- Preparation of 2-yl)phenyl)cyclopentane-1-carboxamide (compound 40b)
将化合物33b(80mg，318.59μmol)和40a(50.22mg，334.52μmol)溶于吡啶(3mL)中，再加入T 3P(2mL，50％于EA中)，25℃搅拌反应过夜。反应结束后旋转蒸发移除吡啶，滴入饱和碳酸氢钠溶液淬灭，EA萃取，水洗，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物40b(120mg)。MS m/z(ESI)：384.3[M+H] +。 Compounds 33b (80 mg, 318.59 μmol) and 40a (50.22 mg, 334.52 μmol) were dissolved in pyridine ( 3 mL), T3P (2 mL, 50% in EA) was added, and the reaction was stirred at 25°C overnight. After the reaction, pyridine was removed by rotary evaporation, quenched by dropwise addition of saturated sodium bicarbonate solution, extracted with EA, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 40b (120 mg). MS m/z (ESI): 384.3 [M+H] + .
第二步：(5-(3，3-二氟环戊烷-1-甲酰胺基)-4-氟-2-甲基苯基)硼酸(化合物40c)的制备The second step: preparation of (5-(3,3-difluorocyclopentane-1-carboxamido)-4-fluoro-2-methylphenyl)boronic acid (compound 40c)
反应瓶中加入化合物40b(120mg，313.14μmol)、NaIO 4(201mg，939.43μmol)和MeCN(4mL)，再加入醋酸铵(60mg，782.86μmol)的H 2O(1mL)溶液，氮气保护下50℃反应过夜。反应结束后向反应液中加水稀释，用EA萃取，有机相用饱和食盐盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到化合物40c(90mg)。MS m/z(ESI)：302.2[M+H] +。 Compound 40b (120 mg, 313.14 μmol), NaIO 4 (201 mg, 939.43 μmol) and MeCN (4 mL) were added to the reaction flask, and a solution of ammonium acetate (60 mg, 782.86 μmol) in H 2 O (1 mL) was added under nitrogen protection for 50 °C reaction overnight. After the reaction, the reaction solution was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 40c (90 mg). MS m/z (ESI): 302.2 [M+H] + .
第三步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3，3-二氟环戊烷-1-甲酰胺(化合物40d)的制备The third step: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-2-fluoro-4-methylphenyl)-3,3-difluorocyclopentane-1-carboxamide (compound 40d) preparation
将化合物4d(55mg，124.58μmol)、40c(45mg，149.50μmol)、Cu(OAc) 2(23mg，124.58μmol)、DMAP(30mg，249.16μmol)、吡啶(25mg，311.45μmol)和1，4-二氧六环(5mL)加入反应瓶中，空气氛围下90℃反应过夜。反应结束后向反应液中加水稀释，用EA萃取，有机相用饱和食盐盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到粗产物。粗品经硅胶柱层析(DCM/MeOH＝94/6)纯化，得到化合物40d(50mg)。MS m/z(ESI)：697.3[M+H] +。 Compound 4d (55 mg, 124.58 μmol), 40c (45 mg, 149.50 μmol), Cu(OAc) 2 (23 mg, 124.58 μmol), DMAP (30 mg, 249.16 μmol), pyridine (25 mg, 311.45 μmol) and 1,4- Dioxane (5 mL) was added to the reaction flask, and the reaction was carried out at 90° C. overnight under an air atmosphere. After the reaction, the reaction solution was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM/MeOH=94/6) to obtain compound 40d (50 mg). MS m/z (ESI): 697.3 [M+H] + .
第四步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3，3-二氟环戊烷-1-甲酰胺(化合物40)的制备Fourth step: N-(5-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-Fluoro-4-methylphenyl)-3,3-difluorocyclopentane-1-carboxamide (Compound 40)
反应瓶中化合物40d(50mg，71.76μmol)和TFA(5mL)，氮气保护下90℃反应过夜。反应结束后减压除去溶剂，加水稀释后用饱和NaHCO 3溶液调节pH至7-8，用EA萃取，有机相用饱和食盐盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到粗产物。粗品经Pre-HPLC纯化，得到化合物40(2mg，)。MS m/z(ESI)：457.1[M+H] +。 Compound 40d (50 mg, 71.76 μmol) and TFA (5 mL) in the reaction flask were reacted at 90° C. overnight under nitrogen protection. After the reaction was completed, the solvent was removed under reduced pressure, diluted with water and adjusted to pH 7-8 with saturated NaHCO solution, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude solution. product. The crude product was purified by Pre-HPLC to give compound 40 (2 mg,). MS m/z (ESI): 457.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.03(s，1H)，8.64(s，1H)，8.42(s，1H)，8.26(br，1H)，8.21-8.15(m，2H)，8.05(d，J＝7.2Hz，1H)，7.98(s，1H)，7.40(d，J＝11.6Hz，1H)，2.41-2.33(m，2H)，2.27-2.21(m，4H)，2.20-2.05(m，3H)，1.96-1.88(m，1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.03 (s, 1H), 8.64 (s, 1H), 8.42 (s, 1H), 8.26 (br, 1H), 8.21-8.15 (m, 2H), 8.05(d, J=7.2Hz, 1H), 7.98(s, 1H), 7.40(d, J=11.6Hz, 1H), 2.41-2.33(m, 2H), 2.27-2.21(m, 4H), 2.20 -2.05(m, 3H), 1.96-1.88(m, 1H).
实施例41：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-4-(三氟甲基)吡啶酰胺(化合物41)Example 41: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 2-Fluoro-4-methylphenyl)-4-(trifluoromethyl)pyridineamide (Compound 41)
Figure PCTCN2022079826-appb-000123
Figure PCTCN2022079826-appb-000123
第一步：N-(2-氟-4-甲基-5-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)-4-(三氟甲基)吡啶酰胺(化合物41b)的制备The first step: N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl) - Preparation of 4-(trifluoromethyl)picolinamide (compound 41b)
除将化合物3b更换为化合物41a外，以与实施例35第一步相同的方法进行制备，得到化合物41b(130mg)。MS m/z(ESI)：425.4[M+H] +。 The preparation was carried out in the same manner as in the first step of Example 35, except that compound 3b was replaced with compound 41a, to obtain compound 41b (130 mg). MS m/z (ESI): 425.4 [M+H] + .
第二步：(4-氟-2-甲基-5-(4-(三氟甲基)吡啶酰胺基)苯基)硼酸(化合物41c)的制备Step 2: Preparation of (4-fluoro-2-methyl-5-(4-(trifluoromethyl)picolinamido)phenyl)boronic acid (compound 41c)
除将化合物35a更换为化合物41b外，以与实施例35第二步相同的方法进行制备，得到化合物41c(80mg)。The preparation was carried out in the same manner as in the second step of Example 35, except that compound 35a was replaced with compound 41b, to obtain compound 41c (80 mg).
第三步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-4-(三氟甲基)吡啶酰胺(化合物41d)的制备The third step: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-2-fluoro-4-methylphenyl)-4-(trifluoromethyl)pyridineamide (compound 41d) preparation
除将化合物35b更换为化合物41c外，以与实施例35第三步相同的方法进行制备，得到化合物41d(50mg)。MS m/z(ESI)：738.3[M+H] +。 The preparation was carried out in the same manner as the third step of Example 35 except that compound 35b was replaced with compound 41c to obtain compound 41d (50 mg). MS m/z (ESI): 738.3 [M+H] + .
第四步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-4-(三氟甲基)吡啶酰胺(化合物41)的制备Fourth step: N-(5-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-Fluoro-4-methylphenyl)-4-(trifluoromethyl)pyridineamide (Compound 41)
除将化合物35c更换为化合物41d外，以与实施例35第四步相同的方法进行制备，得到化合物41(9.58mg)。MS m/z(ESI)：498.1[M+H] +。 The preparation was carried out in the same manner as in the fourth step of Example 35 except that compound 35c was replaced with compound 41d to obtain compound 41 (9.58 mg). MS m/z (ESI): 498.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.63(s，1H)，9.08(d，J＝5.0Hz，1H)，8.70(s，1H)，8.45(s，1H)，8.37(s，1H)，8.27(s，1H)，8.23-8.14(m，3H)，8.09(d，J＝7.2Hz，1H)，8.00(s，1H)，7.51(d，J＝11.4Hz，1H)，2.29(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.63 (s, 1H), 9.08 (d, J=5.0 Hz, 1H), 8.70 (s, 1H), 8.45 (s, 1H), 8.37 (s, 1H), 8.27(s, 1H), 8.23-8.14(m, 3H), 8.09(d, J=7.2Hz, 1H), 8.00(s, 1H), 7.51(d, J=11.4Hz, 1H), 2.29(s, 3H).
实施例42：N-(4-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-5-甲基吡啶-2-基)-3-(三氟甲基)苯甲酰胺(化合物42)Example 42: N-(4-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 5-Methylpyridin-2-yl)-3-(trifluoromethyl)benzamide (Compound 42)
Figure PCTCN2022079826-appb-000124
Figure PCTCN2022079826-appb-000124
第一步：N-(4-溴-5-甲基吡啶-2-基)-3-(三氟甲基)苯甲酰胺(化合物42b)的制备The first step: preparation of N-(4-bromo-5-methylpyridin-2-yl)-3-(trifluoromethyl)benzamide (compound 42b)
除将化合物34a更换为化合物42a外，以与实施例39第一步相同的方法进行制备，得到化合物42b(160mg)。The preparation was carried out in the same manner as in the first step of Example 39, except that compound 34a was replaced by compound 42a, to obtain compound 42b (160 mg).
第二步：N-(4-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-5-甲基吡啶-2-基)-3-(三氟甲基)苯甲酰胺(化合物42c)的制备Step 2: N-(4-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-5-methylpyridin-2-yl)-3-(trifluoromethyl)benzamide (compound 42c) preparation
除将化合物39a更换为化合物42b，化合物5c更换为化合物4d外，以与实施例39第二步相同的方法进行制备，得到化合物42c(18mg)。MS m/z(ESI)：720.3[M+H] +。 The preparation was carried out in the same manner as in the second step of Example 39, except that compound 39a was replaced by compound 42b, and compound 5c was replaced by compound 4d to obtain compound 42c (18 mg). MS m/z (ESI): 720.3 [M+H] + .
第三步：N-(4-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-5-甲基吡啶-2-基)-3-(三氟甲基)苯甲酰胺(化合物42)的制备The third step: N-(4-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 5-methylpyridin-2-yl)-3-(trifluoromethyl)benzamide (Compound 42)
除将化合物39b更换为化合物42c外，以与实施例39第三步相同的方法进行制备，得到化合物42(12.3mg)。MS m/z(ESI)：480.1[M+H] +。 The preparation was carried out in the same manner as in the third step of Example 39, except that compound 39b was replaced with compound 42c to obtain compound 42 (12.3 mg). MS m/z (ESI): 480.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ11.40(s，1H)，8.92(s，1H)，8.56(s，1H)，8.49(s，1H)，8.44(s，1H)，8.42(s，1H)，8.37-8.27(m，2H)，8.22(s，2H)，8.05(s，1H)，7.99(d，J＝7.8Hz，1H)，7.78(t，J＝7.8Hz，1H)，2.45(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.40(s, 1H), 8.92(s, 1H), 8.56(s, 1H), 8.49(s, 1H), 8.44(s, 1H), 8.42( s, 1H), 8.37-8.27 (m, 2H), 8.22 (s, 2H), 8.05 (s, 1H), 7.99 (d, J=7.8Hz, 1H), 7.78 (t, J=7.8Hz, 1H) ), 2.45(s, 3H).
实施例43：N-(5-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(2-氰基丙烷-2-基)苯甲酰胺(化合物43)Example 43: N-(5-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-2-fluoro-4-methyl Phenyl)-3-(2-cyanopropan-2-yl)benzamide (Compound 43)
Figure PCTCN2022079826-appb-000125
Figure PCTCN2022079826-appb-000125
第一步：3-(2-氰基丙烷-2-基)-N-(2-氟-4-甲基-5-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)苯甲酰胺(化合物43b)的制备The first step: 3-(2-cyanopropan-2-yl)-N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2 - Preparation of dioxaborol-2-yl)phenyl)benzamide (compound 43b)
将化合物33b(160mg，637.19μmol)和43a(120mg，637.19μmol)溶于吡啶(3mL)中，再加入T 3P(2mL，50％于EA中)，25℃下反应过夜。反应结束后旋转蒸发移除吡啶，滴入饱和碳酸氢钠溶液淬灭，EA萃取，有机相经水洗，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到产物43b(216mg)。MS m/z(ESI)：423.2[M+H] +。 Compounds 33b (160 mg, 637.19 μmol) and 43a (120 mg, 637.19 μmol) were dissolved in pyridine ( 3 mL), T3P (2 mL, 50% in EA) was added, and the reaction was carried out at 25°C overnight. After the reaction, pyridine was removed by rotary evaporation, quenched by dropwise addition of saturated sodium bicarbonate solution, extracted with EA, the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the product 43b (216 mg). MS m/z (ESI): 423.2 [M+H] + .
第二步：(5-(3-(2-氰基丙烷-2-基)苯甲酰胺基)-4-氟-2-甲基苯基)硼酸(化合物43c)的制备The second step: preparation of (5-(3-(2-cyanopropan-2-yl)benzamido)-4-fluoro-2-methylphenyl)boronic acid (compound 43c)
反应瓶中加入43b(216mg，511.49μmol)、NaIO 4(328mg，1.53mmol)和MeCN(10mL)，再加入醋酸铵(99mg，1.28mmol)的H 2O(2mL)溶液，氮气保护下50℃反应过夜。反应结束后向反应液中加水稀释，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到化合物43c(140mg)。MS m/z(ESI)：341.2[M+H] +。 43b (216 mg, 511.49 μmol), NaIO 4 (328 mg, 1.53 mmol) and MeCN (10 mL) were added to the reaction flask, followed by a solution of ammonium acetate (99 mg, 1.28 mmol) in H 2 O (2 mL), under nitrogen protection at 50° C. React overnight. After the reaction was completed, the reaction solution was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 43c (140 mg). MS m/z (ESI): 341.2 [M+H] + .
第三步：3-(2-氰基丙烷-2-基)-N-(5-(4-(4-((2，4-二甲氧基苄基)氨基)噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)苯甲酰胺(化合物43d)的制备The third step: 3-(2-cyanopropan-2-yl)-N-(5-(4-(4-((2,4-dimethoxybenzyl)amino)thieno[3,2 Preparation of -d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-2-fluoro-4-methylphenyl)benzamide (compound 43d)
将化合物8a(50mg，136.08μmol)、43c(51mg，149.69μmol)、Cu(OAc) 2(27mg，136.08μmol)、DMAP(33mg，272.16μmol)、吡啶(27mg，340.21μmol)和1，4-二氧六环(3mL)加入反应瓶中，空气氛围下90℃反应过夜。反应结束后向反应液中加水稀释，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产物。粗品经硅胶柱层析(DCM/MeOH＝96/4)纯化，得到化合物43d(30mg)。MS m/z(ESI)：662.3[M+H] +。 Compound 8a (50 mg, 136.08 μmol), 43c (51 mg, 149.69 μmol), Cu(OAc) 2 (27 mg, 136.08 μmol), DMAP (33 mg, 272.16 μmol), pyridine (27 mg, 340.21 μmol) and 1,4- Dioxane (3 mL) was added to the reaction flask, and the reaction was carried out at 90° C. overnight in an air atmosphere. After the reaction, the reaction solution was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM/MeOH=96/4) to obtain compound 43d (30 mg). MS m/z (ESI): 662.3 [M+H] + .
第四步：N-(5-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(2-氰基丙烷-2-基)苯甲酰胺(化合物43)的制备The fourth step: N-(5-(4-(4-aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-2-fluoro-4-methyl Preparation of phenyl)-3-(2-cyanopropan-2-yl)benzamide (compound 43)
反应瓶中加入化合物43d(30mg，45.33μmol)和TFA(3mL)，氮气保护下80℃反应过夜。反应结束后减压除去溶剂，加水稀释后用饱和NaHCO 3溶液调节pH至7-8，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗品经Pre-HPLC纯化，得到化合物43(6mg)。MS m/z(ESI)：512.3[M+H] +。 Compound 43d (30 mg, 45.33 μmol) and TFA (3 mL) were added to the reaction flask, and the reaction was carried out at 80° C. overnight under nitrogen protection. After the reaction, the solvent was removed under reduced pressure, diluted with water and adjusted to pH 7-8 with saturated NaHCO 3 solution, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to Pre-HPLC Purification gave compound 43 (6 mg). MS m/z (ESI): 512.3 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.37(s，1H)，8.77(s，1H)，8.47(d，J＝7.3Hz，2H)，8.31(s，1H)，8.10(t，J＝2.0Hz，1H)，7.99-7.95(m，1H)，7.81-7.76(m，1H)，7.73(d，J＝7.2Hz，1H)，7.62(t，J＝7.6Hz，1H)，7.52(s，2H)，7.45(d，J＝11.2Hz，1H)，2.28(s，3H)，1.75(s，6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.37 (s, 1H), 8.77 (s, 1H), 8.47 (d, J=7.3 Hz, 2H), 8.31 (s, 1H), 8.10 (t, J=2.0Hz, 1H), 7.99-7.95 (m, 1H), 7.81-7.76 (m, 1H), 7.73 (d, J=7.2Hz, 1H), 7.62 (t, J=7.6Hz, 1H), 7.52(s, 2H), 7.45(d, J=11.2Hz, 1H), 2.28(s, 3H), 1.75(s, 6H).
实施例44：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-2-(三氟甲基)异烟酰胺(化合物44)Example 44: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 6-Methylpyridin-3-yl)-2-(trifluoromethyl)isonicotinamide (Compound 44)
Figure PCTCN2022079826-appb-000126
Figure PCTCN2022079826-appb-000126
第一步：N-(5-溴-6-甲基吡啶-3-基)-2-(三氟甲基)异烟酰胺(化合物44a)的制备The first step: preparation of N-(5-bromo-6-methylpyridin-3-yl)-2-(trifluoromethyl)isonicotinamide (compound 44a)
将化合物15a(81.74mg，427.72μmol)和34a(80.00mg，427.72μmol)溶于吡啶(3mL)，然后滴加1-丙基磷酸酐(1mL，50％于DMF中)，加完后于25℃反应16小时。反应结束后减压除去吡啶，向反应液中加入饱和碳酸氢钠水溶液，用乙酸乙酯萃取，有机相经无水硫酸钠干燥，过滤后减压浓缩，得到化合物44a(146.00mg)。MS m/z(ESI)：360.1[M+H] +。 Compounds 15a (81.74 mg, 427.72 μmol) and 34a (80.00 mg, 427.72 μmol) were dissolved in pyridine (3 mL), and then 1-propylphosphoric anhydride (1 mL, 50% in DMF) was added dropwise. The reaction was carried out at °C for 16 hours. After the reaction, pyridine was removed under reduced pressure, saturated aqueous sodium bicarbonate solution was added to the reaction solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 44a (146.00 mg). MS m/z (ESI): 360.1 [M+H] + .
第二步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-2-(三氟甲基)异烟酰胺(化合物44b)的制备Step 2: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-6-methylpyridin-3-yl)-2-(trifluoromethyl)isonicotinamide (compound 44b) preparation
将化合物44a(146.00mg，405.41μmol)、4d(178.98mg，405.41μmol)、碘化亚铜(77.21mg，405.41μmol)、碳酸铯(330.23mg，1.01mmol)、N，N-二甲基甲酰胺(3mL)和N，N′-二甲基乙二胺(71.47mg，810.82μmol)依次加入微波管中，氮气保护，微波120℃反应6小时。反应结束后加水稀释，用乙酸乙酯萃取，有机相经无水硫酸钠干燥，过滤后减压浓缩，经硅胶快速柱色谱法(二氯甲烷/甲醇＝20/1)分离纯化，得到化合物44b(125.00mg)。MS m/z(ESI)：721.3[M+H] +。 Compound 44a (146.00 mg, 405.41 μmol), 4d (178.98 mg, 405.41 μmol), cuprous iodide (77.21 mg, 405.41 μmol), cesium carbonate (330.23 mg, 1.01 mmol), N,N-dimethylformaldehyde Amide (3 mL) and N,N'-dimethylethylenediamine (71.47 mg, 810.82 μmol) were successively added to a microwave tube, under nitrogen protection, and reacted at 120° C. for 6 hours by microwave. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel flash column chromatography (dichloromethane/methanol=20/1) to obtain compound 44b (125.00 mg). MS m/z (ESI): 721.3 [M+H] + .
第三步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-2-(三氟甲基)异烟酰胺(化合物44)的制备The third step: N-(5-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 6-methylpyridin-3-yl)-2-(trifluoromethyl)isonicotinamide (Compound 44)
将化合物44b(125.00mg，13.22μmol)溶于三氟乙酸(3mL)，升温至90℃反应16小时。反应结束后减压除去溶剂，后经Prep-HPLC分离纯化，得到化合物44(60mg)。MS m/z(ESI)：481.1[M+H] +。 Compound 44b (125.00 mg, 13.22 μmol) was dissolved in trifluoroacetic acid (3 mL), and the temperature was raised to 90° C. to react for 16 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the compound was separated and purified by Prep-HPLC to obtain compound 44 (60 mg). MS m/z (ESI): 481.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ11.10(s，1H)，9.05(d，J＝5.2Hz，1H)，8.08(d，J＝2.4Hz，1H)，8.84(s，1H)，8.52(s，1H)，8.45-8.33(m，3H)，8.31-8.21(m，3H)，8.05-8.02(m，1H)，2.54(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.10 (s, 1H), 9.05 (d, J=5.2 Hz, 1H), 8.08 (d, J=2.4 Hz, 1H), 8.84 (s, 1H) , 8.52(s, 1H), 8.45-8.33(m, 3H), 8.31-8.21(m, 3H), 8.05-8.02(m, 1H), 2.54(s, 3H).
实施例45：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-5-(三氟甲基)烟酰胺(化合物45)Example 45: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 2-Fluoro-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (Compound 45)
Figure PCTCN2022079826-appb-000127
Figure PCTCN2022079826-appb-000127
第一步：N-(2-氟-5-(4-((4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(三氟甲基)烟酰胺(化合物45b)的制备The first step: N-(2-Fluoro-5-(4-((4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl )-1H-pyrazol-1-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 45b) preparation
将化合物38g(17mg，38.25μmol)和45a(7.31mg，38.25μmol)加入吡啶(1mL)中，再加入T 3P(0.3mL，50％于EA中)，反应25℃搅拌16hr。反应结束后将反应液浓缩干，经prep-TLC(PE/EA＝1/1)纯化，得到化合物45b(10mg)。 Compounds 38g (17 mg, 38.25 μmol) and 45a (7.31 mg, 38.25 μmol) were added to pyridine (1 mL), followed by T 3 P (0.3 mL, 50% in EA), and the reaction was stirred at 25° C. for 16 hr. After the reaction, the reaction solution was concentrated to dryness, and purified by prep-TLC (PE/EA=1/1) to obtain compound 45b (10 mg).
第二步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-5-(三氟甲基)烟酰胺(化合物45)的制备Step 2: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-fluoro-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 45)
将化合物45b(10mg，16.19μmol)加入TFA(5mL)中，80℃搅拌16hr。反应结束后减压除去溶剂，后经Prep-HPLC分离纯化，得到化合物45(6.01mg)。MS m/z(ESI)：498.1[M+H] +。 Compound 45b (10 mg, 16.19 μmol) was added to TFA (5 mL) and stirred at 80° C. for 16 hr. After the reaction was completed, the solvent was removed under reduced pressure, and the compound was separated and purified by Prep-HPLC to obtain compound 45 (6.01 mg). MS m/z (ESI): 498.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.72(s，1H)，9.37(d，J＝1.7Hz，1H)，9.21(d，J＝1.2Hz，1H)，8.71(s，1H)，8.68(s，1H)，8.43(s，1H)，8.31-8.13(m，3H)，7.98(s，1H)，7.85(d，J＝7.2Hz，1H)，7.48(d，J＝11.3Hz，1H)，2.28(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.72 (s, 1H), 9.37 (d, J=1.7 Hz, 1H), 9.21 (d, J=1.2 Hz, 1H), 8.71 (s, 1H) , 8.68(s, 1H), 8.43(s, 1H), 8.31-8.13(m, 3H), 7.98(s, 1H), 7.85(d, J=7.2Hz, 1H), 7.48(d, J=11.3 Hz, 1H), 2.28(s, 3H).
实施例46：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(三氟甲基)烟酰胺(化合物46)Example 46: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-5-(trifluoromethyl)nicotinamide (Compound 46)
Figure PCTCN2022079826-appb-000128
Figure PCTCN2022079826-appb-000128
第一步：N-(4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)-5-(三氟甲基)烟酰胺(化合物46a)的制备The first step: N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-5-( Preparation of trifluoromethyl)nicotinamide (compound 46a)
除将化合物12a更换为化合物45a外，以与实施例12第一步相同的方法进行制备，得到化合物46a(150mg)。MS m/z(ESI)：407.1[M+H] +。 The preparation was carried out in the same manner as in the first step of Example 12 except that compound 12a was replaced with compound 45a to obtain compound 46a (150 mg). MS m/z (ESI): 407.1 [M+H] + .
第二步：(2-甲基-5-(5-(三氟甲基)烟酰胺基)苯基)硼酸(化合物46b)的制备The second step: preparation of (2-methyl-5-(5-(trifluoromethyl)nicotinamido)phenyl)boronic acid (compound 46b)
除将化合物12b更换为化合物46a外，以与实施例12第二步相同的方法进行制备，得到化合物46b(100mg)。MS m/z(ESI)：325.0[M+H] +。 The preparation was carried out in the same manner as in the second step of Example 12 except that compound 12b was replaced with compound 46a to obtain compound 46b (100 mg). MS m/z (ESI): 325.0 [M+H] + .
第三步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(三氟甲基)烟酰胺(化合物46c)的制备The third step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 46c) preparation
除将化合物12c更换为化合物46b外，以与实施例12第三步相同的方法进行制备，得到化合物46c(20mg)。The preparation was carried out in the same manner as the third step of Example 12, except that compound 12c was replaced with compound 46b, to obtain compound 46c (20 mg).
第四步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(三氟甲基)烟酰胺(化合物46)的制备Fourth step: N-(3-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 46)
除将化合物12d更换为化合物46c外，以与实施例12第四步相同的方法进行制备，得到化合物46(8.1mg)。MS m/z(ESI)：480.1[M+H] +。 The preparation was carried out in the same manner as in the fourth step of Example 12 except that compound 12d was replaced with compound 46c to obtain compound 46 (8.1 mg). MS m/z (ESI): 480.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.79(s，1H)，9.39(d，J＝1.6Hz，1H)，9.20(s，1H)，8.71(d，J＝4.1Hz，2H)，8.44(s，1H)，8.29(s，1H)，8.24-8.17(m，2H)，8.00(s，1H)，7.95(d，J＝2.1Hz，1H)，7.81(dd，J＝8.3，2.2Hz，1H)，7.46(d，J＝8.5Hz，1H)，2.29(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.79 (s, 1H), 9.39 (d, J=1.6 Hz, 1H), 9.20 (s, 1H), 8.71 (d, J=4.1 Hz, 2H) , 8.44(s, 1H), 8.29(s, 1H), 8.24-8.17(m, 2H), 8.00(s, 1H), 7.95(d, J=2.1Hz, 1H), 7.81(dd, J=8.3 , 2.2Hz, 1H), 7.46 (d, J=8.5Hz, 1H), 2.29 (s, 3H).
实施例47：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(二氟甲基)苯甲酰胺(化合物47)Example 47: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 2-Fluoro-4-methylphenyl)-3-(difluoromethyl)benzamide (Compound 47)
Figure PCTCN2022079826-appb-000129
Figure PCTCN2022079826-appb-000129
第一步：3-(二氟甲基)苯甲酸甲酯(化合物47b)的制备Step 1: Preparation of methyl 3-(difluoromethyl)benzoate (compound 47b)
将化合物47a(500mg，3.05mmol)、DCM(10mL)、EtOH(0.5mL)和BAST(2.02g，9.14mmol)依次加入反应瓶中，氮气保护下60℃反应过夜。反应结束后加水稀释，用EA萃取，有机相用饱和 食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到粗产物。粗品经硅胶柱层析(EA/PE＝1/9)纯化，得到化合物47b(490mg)。Compound 47a (500 mg, 3.05 mmol), DCM (10 mL), EtOH (0.5 mL) and BAST (2.02 g, 9.14 mmol) were successively added to the reaction flask and reacted at 60°C overnight under nitrogen protection. After the reaction was completed, it was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (EA/PE=1/9) to obtain compound 47b (490 mg).
第二步：3-(二氟甲基)苯甲酸(化合物47c)的制备Step 2: Preparation of 3-(difluoromethyl)benzoic acid (compound 47c)
反应瓶中加入化合物47b(490mg，2.63mmol)、THF(6mL)、H 2O(2mL)和LiOH·H 2O(276mg，6.58mmol)，氮气保护下25℃反应过夜。反应结束后加水稀释，用稀盐酸调节pH至4-5，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到化合物47c(450mg)。 Compound 47b (490 mg, 2.63 mmol), THF (6 mL), H 2 O (2 mL) and LiOH·H 2 O (276 mg, 6.58 mmol) were added to the reaction flask, and the reaction was carried out at 25° C. overnight under nitrogen protection. After the reaction, it was diluted with water, adjusted to pH 4-5 with dilute hydrochloric acid, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 47c (450 mg).
第三步：3-(二氟甲基)-N-(2-氟-4-甲基-5-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)苯甲酰胺(化合物47d)的制备The third step: 3-(difluoromethyl)-N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro) Preparation of alk-2-yl)phenyl)benzamide (compound 47d)
反应瓶中加入化合物33b(100mg，398.24μmol)、47c(69mg，398.24μmol)、吡啶(3mL)及T 3P(2mL，50％于EA中)，氮气保护下25℃反应3hr。反应结束后旋转蒸发移除吡啶，滴入饱和碳酸氢钠溶液淬灭，EA萃取，水洗，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到粗品，粗产物经硅胶柱层析(EA/PE＝1/9)纯化，得到化合物47d(110mg)。MS m/z(ESI)：406.1[M+H] +。 Compound 33b (100 mg, 398.24 μmol), 47c (69 mg, 398.24 μmol), pyridine (3 mL) and T 3 P (2 mL, 50% in EA) were added to the reaction flask, and the reaction was carried out at 25° C. for 3 hr under nitrogen protection. After the reaction, the pyridine was removed by rotary evaporation, quenched by dropwise addition of saturated sodium bicarbonate solution, extracted with EA, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was subjected to silica gel column chromatography (EA /PE=1/9) to obtain compound 47d (110 mg). MS m/z (ESI): 406.1 [M+H] + .
第四步：(5-(3-(二氟甲基)苯甲酰胺基)-4-氟-2-甲基苯基)硼酸(化合物47e)的制备The fourth step: preparation of (5-(3-(difluoromethyl)benzamido)-4-fluoro-2-methylphenyl)boronic acid (compound 47e)
反应瓶中加入化合物47d(110mg，271.46μmol)、NaIO 4(174mg，814.38μmol)及MeCN(6mL)，再加入醋酸铵(52mg，678.65μmol)的H 2O(1.5mL)溶液，氮气保护下55℃反应6hr。反应结束后加水稀释，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到化合物47e(80mg)。MS m/z(ESI)：324.0[M+H] +。 Compound 47d (110 mg, 271.46 μmol), NaIO 4 (174 mg, 814.38 μmol) and MeCN (6 mL) were added to the reaction flask, and a solution of ammonium acetate (52 mg, 678.65 μmol) in H 2 O (1.5 mL) was added under nitrogen protection. 55°C for 6hrs. After the reaction, it was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 47e (80 mg). MS m/z (ESI): 324.0 [M+H] + .
第五步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(二氟甲基)苯甲酰胺(化合物47f)的制备The fifth step: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl )-1H-pyrazol-1-yl)-2-fluoro-4-methylphenyl)-3-(difluoromethyl)benzamide (compound 47f) preparation
将化合物4d(40mg，90.60μmol)、47e(38mg，117.78μmol)、Cu(OAc) 2(18mg，90.60μmol)、DMAP(22mg，181.21μmol)和吡啶(18mg，226.51μmol)加入到1，4-二氧六环(5mL)中，空气氛围下100℃搅拌过夜。反应结束后，经硅胶柱层析(MeOH/DCM＝4/96)纯化，得到化合物47f(25mg)。 Compound 4d (40 mg, 90.60 μmol), 47e (38 mg, 117.78 μmol), Cu(OAc) 2 (18 mg, 90.60 μmol), DMAP (22 mg, 181.21 μmol) and pyridine (18 mg, 226.51 μmol) were added to 1,4 - in dioxane (5 mL), stirred overnight at 100°C under air. After the reaction, it was purified by silica gel column chromatography (MeOH/DCM=4/96) to obtain compound 47f (25 mg).
第六步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(二氟甲基)苯甲酰胺(化合物47)的制备Step 6: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-fluoro-4-methylphenyl)-3-(difluoromethyl)benzamide (compound 47)
反应瓶中加入化合物47f(25mg，34.78μmol)及TFA(3mL)，氮气保护下99℃反应过夜。反应结束后减压除去溶剂，加水稀释后用饱和NaHCO 3溶液调节pH至7-8，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到粗产物。粗品经Pre-HPLC纯化，得到化合物47(1.5mg)。MS m/z(ESI)：479.2[M+H] +。 Compound 47f (25 mg, 34.78 μmol) and TFA (3 mL) were added to the reaction flask, and the reaction was carried out at 99° C. overnight under nitrogen protection. After the reaction was completed, the solvent was removed under reduced pressure, diluted with water and adjusted to pH 7-8 with saturated NaHCO solution, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude solution. product. The crude product was purified by Pre-HPLC to give compound 47 (1.5 mg). MS m/z (ESI): 479.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.47(s，1H)，8.68(s，1H)，8.43(s，1H)，8.27-8.13(m，5H)，7.98(s，1H)，7.84-7.80(m，1H)，7.76(d，J＝7.2Hz，1H)，7.71(t，J＝7.6Hz，1H)，7.45(d，J＝11.2Hz，1H)，7.16(t，J＝55.6Hz，1H)，2.28(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.47(s, 1H), 8.68(s, 1H), 8.43(s, 1H), 8.27-8.13(m, 5H), 7.98(s, 1H), 7.84-7.80(m, 1H), 7.76(d, J=7.2Hz, 1H), 7.71(t, J=7.6Hz, 1H), 7.45(d, J=11.2Hz, 1H), 7.16(t, J =55.6Hz, 1H), 2.28(s, 3H).
实施例48：N-(5-(4-(8-氨基咪唑并[1，2-a]吡嗪-3-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物48)Example 48: N-(5-(4-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-1H-pyrazol-1-yl)-2-fluoro-4-methyl phenyl)-3-(trifluoromethyl)benzamide (Compound 48)
Figure PCTCN2022079826-appb-000130
Figure PCTCN2022079826-appb-000130
第一步：N-(5-(4-(8-((2，4-二甲氧基苄基)氨基)咪唑并[1，2-a]吡嗪-3-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物48a)的制备The first step: N-(5-(4-(8-((2,4-dimethoxybenzyl)amino)imidazo[1,2-a]pyrazin-3-yl)-1H-pyridine Preparation of azol-1-yl)-2-fluoro-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 48a)
将化合物5c(30mg，85.62μmol)、35b(32mg，94.19μmol)、Cu(OAc) 2(17mg，85.62μmol)、DMAP(21mg，171.25μmol)、吡啶(17mg，214.06μmol)和1，4-二氧六环(5mL)加入反应瓶中，空气氛围下100℃搅拌过夜。反应结束后，直接硅胶柱层析(MeOH/DCM＝3/97)纯化，得到产物48a(6mg)。MS m/z(ESI)：646.1[M+H] +。 Compound 5c (30 mg, 85.62 μmol), 35b (32 mg, 94.19 μmol), Cu(OAc) 2 (17 mg, 85.62 μmol), DMAP (21 mg, 171.25 μmol), pyridine (17 mg, 214.06 μmol) and 1,4- Dioxane (5 mL) was added to the reaction flask, and the mixture was stirred at 100° C. overnight under an air atmosphere. After completion of the reaction, the product was purified by direct silica gel column chromatography (MeOH/DCM=3/97) to obtain the product 48a (6 mg). MS m/z (ESI): 646.1 [M+H] + .
第二步：N-(5-(4-(8-氨基咪唑并[1，2-a]吡嗪-3-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物48)的制备The second step: N-(5-(4-(8-aminoimidazo[1,2-a]pyrazin-3-yl)-1H-pyrazol-1-yl)-2-fluoro-4-methyl Preparation of phenyl)-3-(trifluoromethyl)benzamide (compound 48)
反应瓶中加入48a(53mg，82.09μmol)和TFA(3mL)，氮气保护下90℃反应3hr。反应结束后减压除去溶剂，加水稀释后用饱和NaHCO 3溶液调节pH至7-8，用EA萃取，合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到粗产物。粗品经Pre-HPLC纯化，得到化合物48(12mg)。MS m/z(ESI)：496.1[M+H] +。 48a (53 mg, 82.09 μmol) and TFA (3 mL) were added to the reaction flask, and the reaction was carried out at 90° C. for 3 hr under nitrogen protection. After the reaction, the solvent was removed under reduced pressure, diluted with water and adjusted to pH 7-8 with saturated NaHCO solution, extracted with EA, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was purified by Pre-HPLC to give compound 48 (12 mg). MS m/z (ESI): 496.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.57(s，1H)，8.67(d，J＝0.8Hz，1H)，8.33(s，1H)，8.29(d，J＝8.0Hz，1H)，8.25(d，J＝0.8Hz，1H)，8.03-7.98(m，1H)，7.88(d，J＝4.8Hz，1H)，7.83-7.77(m，3H)，7.47(d，J＝11.2Hz，1H)，7.28(d，J＝4.8Hz，1H)，6.93(s，2H)，2.30(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.57 (s, 1H), 8.67 (d, J=0.8 Hz, 1H), 8.33 (s, 1H), 8.29 (d, J=8.0 Hz, 1H) , 8.25(d, J=0.8Hz, 1H), 8.03-7.98(m, 1H), 7.88(d, J=4.8Hz, 1H), 7.83-7.77(m, 3H), 7.47(d, J=11.2 Hz, 1H), 7.28 (d, J=4.8Hz, 1H), 6.93 (s, 2H), 2.30 (s, 3H).
实施例49：N-(5-(4-(4-氨基吡咯并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物49)Example 49: N-(5-(4-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 2-Fluoro-4-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 49)
Figure PCTCN2022079826-appb-000131
Figure PCTCN2022079826-appb-000131
第一步：7-溴-N，N-双(4-甲氧基苄基)吡咯并[2，1-f][1，2，4]三嗪-4-胺(化合物49b)的制备First step: Preparation of 7-bromo-N,N-bis(4-methoxybenzyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (compound 49b)
除将化合物4a更换为化合物49a外，以与实施例4第一步相同的方法进行制备，得到化合物49b(1.48g)。MS m/z(ESI)：455.1[M+H] +。 The preparation was carried out in the same manner as in the first step of Example 4 except that compound 4a was replaced by compound 49a to obtain compound 49b (1.48 g). MS m/z (ESI): 455.1 [M+H] + .
第二步：N，N-双(4-甲氧基苄基)-7-(1H-吡唑-4-基)吡咯并[2，1-f][1，2，4]三嗪-4-胺(化合物49c)的制备Step 2: N,N-Bis(4-methoxybenzyl)-7-(1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine- Preparation of 4-amine (compound 49c)
除将化合物4c更换为化合物49b外，以与实施例4第二步相同的方法进行制备，得到化合物49c(800mg)。MS m/z(ESI)：441.1[M+H] +。 The preparation was carried out in the same manner as in the second step of Example 4 except that compound 4c was replaced with compound 49b to obtain compound 49c (800 mg). MS m/z (ESI): 441.1 [M+H] + .
第三步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)吡咯并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物49d)的制备The third step: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-2-fluoro-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 49d) preparation
除将化合物4d更换为化合物49c，化合物3d更换为35b外，以与实施例4第三步相同的方法进行制备，得到化合物49d(65mg)。MS m/z(ESI)：736.3[M+H] +。 The preparation was carried out in the same manner as the third step of Example 4, except that compound 4d was replaced with compound 49c, and compound 3d was replaced with 35b to obtain compound 49d (65 mg). MS m/z (ESI): 736.3 [M+H] + .
第四步：N-(5-(4-(4-氨基吡咯并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物49)的制备Fourth step: N-(5-(4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-Fluoro-4-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 49)
除将化合物4e更换为化合物49d外，以与实施例4第四步相同的方法进行制备，得到化合物49(6.42mg)。MS m/z(ESI)：496.1[M+H] +。 The preparation was carried out in the same manner as in the fourth step of Example 4 except that compound 4e was replaced with compound 49d to obtain compound 49 (6.42 mg). MS m/z (ESI): 496.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.54(s，1H)，8.64(s，1H)，8.38(s，1H)，8.33(s，1H)，8.31-8.23(m，1H)，8.00(d，J＝7.8Hz，1H)，7.95(s，1H)，7.80(t，J＝7.9Hz，1H)，7.77-7.65(m，3H)，7.45(d，J＝11.2Hz，1H)，7.01(d，J＝4.5Hz，1H)，6.98(d，J＝4.5Hz，1H)，2.28(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.54(s, 1H), 8.64(s, 1H), 8.38(s, 1H), 8.33(s, 1H), 8.31-8.23(m, 1H), 8.00(d, J=7.8Hz, 1H), 7.95(s, 1H), 7.80(t, J=7.9Hz, 1H), 7.77-7.65(m, 3H), 7.45(d, J=11.2Hz, 1H) ), 7.01(d, J=4.5Hz, 1H), 6.98(d, J=4.5Hz, 1H), 2.28(s, 3H).
实施例50：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-2-氟-5-(三氟甲基)苯甲酰胺(化合物50)Example 50: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 6-Methylpyridin-3-yl)-2-fluoro-5-(trifluoromethyl)benzamide (Compound 50)
Figure PCTCN2022079826-appb-000132
Figure PCTCN2022079826-appb-000132
第一步：(5-溴-6-甲基吡啶-3-基)氨基甲酸叔丁酯(化合物50a)的制备The first step: preparation of (5-bromo-6-methylpyridin-3-yl) tert-butyl carbamate (compound 50a)
反应瓶中加入34a(200mg，1.07mmol)、(Boc) 2O(467mg，2.14mmol)、DIPEA(346mg，2.67mmol)、DMAP(13mg，0.11mmol)和DMF(5mL)，氮气保护下90℃反应过夜。反应结束后加水稀释，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到粗产物。粗品经硅胶柱层析(PE/EA＝85/15)纯化，得到化合物50a(160mg)。MS m/z(ESI)：287.0[M+H] + 34a (200 mg, 1.07 mmol), (Boc) 2 O (467 mg, 2.14 mmol), DIPEA (346 mg, 2.67 mmol), DMAP (13 mg, 0.11 mmol) and DMF (5 mL) were added to the reaction flask, under nitrogen protection at 90°C React overnight. After the reaction, it was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE/EA=85/15) to obtain compound 50a (160 mg). MS m/z(ESI): 287.0[M+H] +
第二步：7-(1-(5-氨基-2-甲基吡啶-3-基)-1H-吡唑-4-基)-N，N-双(4-甲氧基苄基)咪唑并[2，1-f][1，2，4]三嗪-4-胺(化合物50b)的制备Step 2: 7-(1-(5-Amino-2-methylpyridin-3-yl)-1H-pyrazol-4-yl)-N,N-bis(4-methoxybenzyl)imidazole Preparation of [2,1-f][1,2,4]triazin-4-amine (Compound 50b)
将化合物4d(30mg，67.95μmol)、50a(21mg，74.75μmol)、DMEDA(12mg，135.91μmol)、CuI(13mg，67.95μmol)、Cs 2CO 3(55mg，169.88μmol)和DMF(2mL)加入到微波反应器中，氮气保护下微波120℃反应3hr。反应结束后加水稀释，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到粗产物。粗品经prep-TLC(DCM/MeOH＝10/1)纯化，得到化合物50b(10mg)。MS m/z(ESI)：548.2[M+H] +。 Compound 4d (30 mg, 67.95 μmol), 50a (21 mg, 74.75 μmol), DMEDA (12 mg, 135.91 μmol), CuI (13 mg, 67.95 μmol), Cs2CO3 ( 55 mg, 169.88 μmol) and DMF (2 mL) were added In a microwave reactor, the reaction was carried out at 120 °C for 3 hr under nitrogen protection. After the reaction, it was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-TLC (DCM/MeOH=10/1) to give compound 50b (10 mg). MS m/z (ESI): 548.2 [M+H] + .
第三步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-2-氟-5-(三氟甲基)苯甲酰胺(化合物50d)的制备The third step: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-6-methylpyridin-3-yl)-2-fluoro-5-(trifluoromethyl)benzamide (compound 50d) preparation
将化合物50b(10mg，18.26μmol)和50c(3.80mg，18.26μmol)溶于吡啶(2mL)中，再加入T 3P(1mL，50％于EA中)，25℃搅拌过夜。反应结束后旋转蒸发移除吡啶，滴入饱和碳酸氢钠溶液淬灭，EA萃取，水洗，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到化合物50d(10mg)。第四步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-2-氟-5-(三氟甲基)苯甲酰胺(化合物50)的制备 Compounds 50b (10 mg, 18.26 μmol) and 50c (3.80 mg, 18.26 μmol) were dissolved in pyridine ( 2 mL), followed by T3P (1 mL, 50% in EA) and stirred at 25°C overnight. After the reaction, pyridine was removed by rotary evaporation, quenched by dropwise addition of saturated sodium bicarbonate solution, extracted with EA, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 50d (10 mg). Fourth step: N-(5-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 6-methylpyridin-3-yl)-2-fluoro-5-(trifluoromethyl)benzamide (Compound 50)
将化合物50d(10mg，13.56μmol)加入到TFA(3mL)中，氮气保护下90℃反应过夜。反应结束后减压除去溶剂，加水稀释后用饱和NaHCO 3溶液调节pH至7-8，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗品经Pre-HPLC纯化，得到化合物50(4mg)。MS m/z(ESI)：498.1[M+H] +。 Compound 50d (10 mg, 13.56 μmol) was added to TFA (3 mL) and reacted at 90° C. overnight under nitrogen protection. After the reaction, the solvent was removed under reduced pressure, diluted with water and adjusted to pH 7-8 with saturated NaHCO 3 solution, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to Pre-HPLC Purification gave compound 50 (4 mg). MS m/z (ESI): 498.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ11.02(s，1H)，8.84(d，J＝2.4Hz，1H)，8.81(s，1H)，8.50(s，1H)，8.33(d，J＝2.4Hz，1H)，8.32-8.18(m，3H)，8.17-8.14(m，1H)，8.07-7.99(m，2H)，7.67(t，J＝9.2Hz，1H)，2.51(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.02 (s, 1H), 8.84 (d, J=2.4 Hz, 1H), 8.81 (s, 1H), 8.50 (s, 1H), 8.33 (d, J=2.4Hz, 1H), 8.32-8.18(m, 3H), 8.17-8.14(m, 1H), 8.07-7.99(m, 2H), 7.67(t, J=9.2Hz, 1H), 2.51(s , 3H).
实施例51：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2，4-二氟苯基)-3-(三氟甲基)苯甲酰胺(化合物51)Example 51: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 2,4-Difluorophenyl)-3-(trifluoromethyl)benzamide (Compound 51)
Figure PCTCN2022079826-appb-000133
Figure PCTCN2022079826-appb-000133
第一步：N-(5-溴-2，4-二氟苯基)-3-(三氟甲基)苯甲酰胺(化合物51b)的制备The first step: preparation of N-(5-bromo-2,4-difluorophenyl)-3-(trifluoromethyl)benzamide (compound 51b)
除将化合物34a更换为化合物51a外，以与实施例34第一步相同的方法进行制备，得到化合物51b(680mg)。The preparation was carried out in the same manner as in the first step of Example 34, except that compound 34a was replaced by compound 51a, to obtain compound 51b (680 mg).
第二步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2，4-二氟苯基)-3-(三氟甲基)苯甲酰胺(化合物51c)的制备Step 2: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-2,4-difluorophenyl)-3-(trifluoromethyl)benzamide (compound 51c) preparation
除将化合物44a更换为化合物51b外，以与实施例44第二步相同的方法进行制备，得到化合物51c(15mg)。MS m/z(ESI)：741.3[M+H] +。 The preparation was carried out in the same manner as in the second step of Example 44, except that compound 44a was replaced with compound 51b to obtain compound 51c (15 mg). MS m/z (ESI): 741.3 [M+H] + .
第三步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2，4-二氟苯基)-3-(三氟甲基)苯甲酰胺(化合物51)的制备The third step: N-(5-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2,4-Difluorophenyl)-3-(trifluoromethyl)benzamide (Compound 51)
除将化合物44b更换为化合物51c外，以与实施例44第三步相同的方法进行制备，得到化合物51(1.0mg)。MS m/z(ESI)：501.1[M+H] +。 The preparation was carried out in the same manner as the third step of Example 44 except that compound 44b was replaced with compound 51c to obtain compound 51 (1.0 mg). MS m/z (ESI): 501.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.63(s，1H)，8.91(d，J＝2.6Hz，1H)，8.51(s，1H)，8.43(s，1H)，8.34(s，1H)，8.29(d，J＝8.3Hz，2H)，8.23-8.17(m，2H)，8.05-7.99(m，2H)，7.85-7.75(m，2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.63 (s, 1H), 8.91 (d, J=2.6 Hz, 1H), 8.51 (s, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 8.29 (d, J=8.3Hz, 2H), 8.23-8.17 (m, 2H), 8.05-7.99 (m, 2H), 7.85-7.75 (m, 2H).
实施例52：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-3-(2-氰基丙烷-2-基)苯甲酰胺(化合物52)Example 52: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 6-Methylpyridin-3-yl)-3-(2-cyanopropan-2-yl)benzamide (Compound 52)
Figure PCTCN2022079826-appb-000134
Figure PCTCN2022079826-appb-000134
第一步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-3-(2-氰基丙烷-2-基)苯甲酰胺(化合物52a)的制备The first step: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-6-methylpyridin-3-yl)-3-(2-cyanopropan-2-yl)benzamide (compound 52a) preparation
将化合物50b(32mg，58.44μmol)和43a(11mg，58.44μmol)溶于吡啶(2mL)中，再加入T 3P(1mL，50％于EA中)，25℃搅拌过夜。反应结束后旋转蒸发移除吡啶，滴入饱和碳酸氢钠溶液淬灭，EA萃取，水洗，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到化合物52a(40mg)。MS m/z(ESI)：719.1[M+H] +。 Compounds 50b (32 mg, 58.44 μmol) and 43a (11 mg, 58.44 μmol) were dissolved in pyridine ( 2 mL), followed by T3P (1 mL, 50% in EA) and stirred at 25°C overnight. After the reaction, pyridine was removed by rotary evaporation, quenched by dropwise addition of saturated sodium bicarbonate solution, extracted with EA, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 52a (40 mg). MS m/z (ESI): 719.1 [M+H] + .
第二步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-.基)-3-(2-氰基丙烷-2-基)苯甲酰胺(化合物52)的制备Step 2: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 6-methylpyridin-3-yl)-3-(2-cyanopropan-2-yl)benzamide (Compound 52)
反应瓶中加入化合物52a(40mg，55.65μmol)和TFA(3mL)，氮气保护下90℃反应过夜。反应结束后减压除去溶剂，加水稀释后用饱和NaHCO 3溶液调节pH至7-8，用EA萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到粗产物，粗品经Pre-HPLC纯化，得到化合物52(7mg)。MS m/z(ESI)：479.1[M+H] +。 Compound 52a (40 mg, 55.65 μmol) and TFA (3 mL) were added to the reaction flask, and the reaction was carried out at 90° C. overnight under nitrogen protection. After the reaction was completed, the solvent was removed under reduced pressure, diluted with water and adjusted to pH 7-8 with saturated NaHCO solution, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude solution. The product, crude was purified by Pre-HPLC to give compound 52 (7 mg). MS m/z (ESI): 479.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.70(s，1H)，8.96(d，J＝2.4Hz，1H)，8.81(s，1H)，8.50(s，1H)，8.37(d，J＝2.4Hz，1H)，8.27(br，1H)，8.21-8.16(m，2H)，8.09(t，J＝2.0Hz，1H)，8.02-7.97(m，2H)，7.82-7.77(m，1H)，7.64(t，J＝8.0Hz，1H)，2.51(s，3H)，1.76(s，6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.70 (s, 1H), 8.96 (d, J=2.4 Hz, 1H), 8.81 (s, 1H), 8.50 (s, 1H), 8.37 (d, J=2.4Hz, 1H), 8.27(br, 1H), 8.21-8.16(m, 2H), 8.09(t, J=2.0Hz, 1H), 8.02-7.97(m, 2H), 7.82-7.77(m , 1H), 7.64 (t, J=8.0Hz, 1H), 2.51 (s, 3H), 1.76 (s, 6H).
实施例53：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-4-(三氟甲基)吡啶酰胺(化合物53)Example 53: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 6-Methylpyridin-3-yl)-4-(trifluoromethyl)pyridineamide (Compound 53)
Figure PCTCN2022079826-appb-000135
Figure PCTCN2022079826-appb-000135
第一步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-4-(三氟甲基)吡啶酰胺(化合物53a)的制备The first step: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-6-methylpyridin-3-yl)-4-(trifluoromethyl)pyridineamide (compound 53a) preparation
除将化合物43a更换为化合物41a外，以与实施例52第一步相同的方法进行制备，得到化合物53a(50mg)。MS m/z(ESI)：721.3[M+H] +。 The preparation was carried out in the same manner as in the first step of Example 52 except that compound 43a was replaced with compound 41a to obtain compound 53a (50 mg). MS m/z (ESI): 721.3 [M+H] + .
第二步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-4-(三氟甲基)吡啶酰胺(化合物53)的制备Step 2: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 6-methylpyridin-3-yl)-4-(trifluoromethyl)pyridineamide (Compound 53)
除将化合物52a更换为化合物53a外，以与实施例52第二步相同的方法进行制备，得到化合物53(4.61mg)。MS m/z(ESI)：481.1[M+H] +。 The preparation was carried out in the same manner as in the second step of Example 52 except that compound 52a was replaced with compound 53a to obtain compound 53 (4.61 mg). MS m/z (ESI): 481.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ11.32(s，1H)，9.12(d，J＝2.2Hz，1H)，9.07(d，J＝5.0Hz，1H)，8.80(s，1H)，8.52(d，J＝2.2Hz，1H)，8.50(s，1H)，8.38(s，1H)，8.27(s，1H)，8.19(s，2H)，8.14(d，J＝5.0Hz，1H)，8.01(s，1H)，2.50(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.32 (s, 1H), 9.12 (d, J=2.2 Hz, 1H), 9.07 (d, J=5.0 Hz, 1H), 8.80 (s, 1H) , 8.52(d, J=2.2Hz, 1H), 8.50(s, 1H), 8.38(s, 1H), 8.27(s, 1H), 8.19(s, 2H), 8.14(d, J=5.0Hz, 1H), 8.01(s, 1H), 2.50(s, 3H).
实施例54：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯甲酰胺(化合物54)Example 54: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 6-Methylpyridin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 54)
Figure PCTCN2022079826-appb-000136
Figure PCTCN2022079826-appb-000136
第一步：4-甲基-3-(三氟甲基)苯甲酸甲酯(化合物54b)的制备Step 1: Preparation of methyl 4-methyl-3-(trifluoromethyl)benzoate (compound 54b)
将化合物54a(2g，9.80mmol)和碳酸钾(2.03g，14.70mmol)加入到DMF(10mL)中，再加入碘甲烷(2.09g，14.70mmol，914.84μL)，25℃搅拌16hr。反应结束后加水稀释，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，浓缩，得到化合物54b(2g)。Compound 54a (2 g, 9.80 mmol) and potassium carbonate (2.03 g, 14.70 mmol) were added to DMF (10 mL), then iodomethane (2.09 g, 14.70 mmol, 914.84 μL) was added, and the mixture was stirred at 25° C. for 16 hr. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 54b (2 g).
第二步：4-(溴甲基)-3-(三氟甲基)苯甲酸甲酯(化合物54c)的制备The second step: preparation of methyl 4-(bromomethyl)-3-(trifluoromethyl)benzoate (compound 54c)
将化合物54b(1g，4.58mmol)、NBS(1.63g，9.17mmol)和AIBN(75.26mg，458.35μmol)加入到CCl4(15mL)中，85℃反应16hr。反应结束后加水淬灭，DCM萃取，有机相用无水硫酸钠干燥，过滤，浓缩，粗品经硅胶快速柱层析(PE/EA＝4/1)分离纯化，得到化合物54c(800mg)。Compound 54b (1 g, 4.58 mmol), NBS (1.63 g, 9.17 mmol) and AIBN (75.26 mg, 458.35 μmol) were added to CCl4 (15 mL) and reacted at 85°C for 16 hr. After the reaction was completed, water was added to quench, extracted with DCM, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by silica gel flash column chromatography (PE/EA=4/1) to obtain compound 54c (800 mg).
第三步：4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯甲酸甲酯(化合物54d)的制备The third step: preparation of methyl 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzoate (compound 54d)
将化合物54c(200mg，673.25μmol)和N-甲基哌嗪(202.30mg，2.02mmol)溶于CHCl 3(3mL)中，25℃搅拌3hr。反应结束后加水，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩，经硅胶快速柱层析(DCM/MeOH＝10/1)分离纯化，得到化合物54d(100mg)。MS m/z(ESI)：317.1[M+H] +。 Compound 54c (200 mg, 673.25 μmol) and N-methylpiperazine (202.30 mg, 2.02 mmol) were dissolved in CHCl 3 (3 mL) and stirred at 25° C. for 3 hr. After the reaction, water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel flash column chromatography (DCM/MeOH=10/1) to obtain compound 54d (100 mg). MS m/z (ESI): 317.1 [M+H] + .
第四步：4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯甲酸(化合物54e)的制备The fourth step: the preparation of 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzoic acid (compound 54e)
将化合物54d(100mg，316.14μmol)和NaOH(37.94mg，948.41μmol)加入到H 2O(2mL)和MeOH(6mL)中，60℃搅拌3hr。反应结束后旋转蒸发移除溶剂，用稀盐酸调节pH至约6，然后经C18柱反相柱色谱法(乙腈/水＝20/80)纯化，得到化合物54e(80mg)。MS m/z(ESI)：303.1[M+H] +。 Compound 54d (100 mg, 316.14 μmol) and NaOH (37.94 mg, 948.41 μmol) were added to H 2 O (2 mL) and MeOH (6 mL) and stirred at 60° C. for 3 hr. After the reaction was completed, the solvent was removed by rotary evaporation, the pH was adjusted to about 6 with dilute hydrochloric acid, and then purified by C18 column reversed-phase column chromatography (acetonitrile/water=20/80) to obtain compound 54e (80 mg). MS m/z (ESI): 303.1 [M+H] + .
第五步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯甲酰胺(化合物54f)的制备The fifth step: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl )-1H-pyrazol-1-yl)-6-methylpyridin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl) Preparation of benzamide (compound 54f)
将化合物50b(27.17mg，49.62μmol)和54e(15mg，49.62μmol)溶于吡啶(4mL)中，再加入1-丙基磷酸酐(0.5mL，50％于EA中)，25℃搅拌16hr。反应结束后减压除去吡啶，加入饱和碳酸氢钠淬灭，EA萃取，有机相用无水硫酸钠干燥，过滤，浓缩得到化合物54f(40mg)。MS m/z(ESI)：832.4[M+H] +。 Compounds 50b (27.17 mg, 49.62 μmol) and 54e (15 mg, 49.62 μmol) were dissolved in pyridine (4 mL), 1-propylphosphoric anhydride (0.5 mL, 50% in EA) was added, and the mixture was stirred at 25° C. for 16 hr. After the reaction, pyridine was removed under reduced pressure, quenched by adding saturated sodium bicarbonate, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 54f (40 mg). MS m/z (ESI): 832.4 [M+H] + .
第六步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-6-甲基吡啶-3-基)-4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯甲酰胺(化合物54)的制备Step 6: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 6-methylpyridin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 54)
将化合物54f(40mg，48.08μmol)溶于三氟乙酸(4mL)中，100℃搅拌16hr。反应结束后将反应液浓缩干，加入饱和碳酸氢钠溶液，EA萃取，有机相用无水硫酸钠干燥，过滤，浓缩，再经Prep-HPLC分离纯化，得到化合物54(4.94mg)。MS m/z(ESI)：592.3[M+H] +。 Compound 54f (40 mg, 48.08 μmol) was dissolved in trifluoroacetic acid (4 mL) and stirred at 100° C. for 16 hr. After the reaction, the reaction solution was concentrated to dryness, saturated sodium bicarbonate solution was added, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by Prep-HPLC to obtain compound 54 (4.94 mg). MS m/z (ESI): 592.3 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.82(s，1H)，8.95(d，J＝2.0Hz，1H)，8.81(s，1H)，8.50(s，1H)，8.37(d，J＝2.0Hz，1H)，8.35-8.28(m，1H)，8.28-8.23(m，2H)，8.19(s，1H)，8.17(br，1H)，8.01(s，1H)，7.96(d，J＝8.0Hz，1H)，3.69(s，2H)，2.50-2.25(m，11H)，2.17(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.82 (s, 1H), 8.95 (d, J=2.0 Hz, 1H), 8.81 (s, 1H), 8.50 (s, 1H), 8.37 (d, J=2.0Hz, 1H), 8.35-8.28(m, 1H), 8.28-8.23(m, 2H), 8.19(s, 1H), 8.17(br, 1H), 8.01(s, 1H), 7.96(d , J=8.0Hz, 1H), 3.69(s, 2H), 2.50-2.25(m, 11H), 2.17(s, 3H).
实施例55：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-4-(吗啉代甲基)-3-(三氟甲基)苯甲酰胺(化合物55)Example 55: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-4-(morpholinomethyl)-3-(trifluoromethyl)benzamide (Compound 55)
Figure PCTCN2022079826-appb-000137
Figure PCTCN2022079826-appb-000137
第一步：4-(吗啉代甲基)-3-(三氟甲基)苯甲酸甲酯(化合物55a)的制备Step 1: Preparation of methyl 4-(morpholinomethyl)-3-(trifluoromethyl)benzoate (compound 55a)
将化合物54c(200mg，673.25μmol)和吗啉(175mg，2.02mmol)加入到CHCl 3(3mL)中，室温反应3小时。反应结束后加水稀释，二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(EA/PE＝1/3)分离纯化，得到化合物55a(131mg)。MS m/z(ESI)：304.1[M+H] +。第二步：4-(吗啉代甲基)-3-(三氟甲基)苯甲酸(化合物55b)的制备 Compound 54c (200 mg, 673.25 μmol) and morpholine (175 mg, 2.02 mmol) were added to CHCl 3 (3 mL) and reacted at room temperature for 3 hours. After the reaction was completed, it was diluted with water, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated and purified by silica gel flash column chromatography (EA/PE=1/3) to obtain compound 55a (131 mg). MS m/z (ESI): 304.1 [M+H] + . Step 2: Preparation of 4-(morpholinomethyl)-3-(trifluoromethyl)benzoic acid (compound 55b)
将化合物55a(131mg，431.95μmol)和NaOH(51mg，1.30mmol)加入到甲醇(6mL)和水(2mL)中，加热至60℃反应3小时。反应结束后，将反应液浓缩干，稀盐酸调节pH至5-6，减压浓缩除去溶剂，经C18柱反相柱色谱法(乙腈/水溶液＝60/40)分离纯化，得到化合物55b(75mg)。MS m/z(ESI)：290.1[M+H] +。 Compound 55a (131 mg, 431.95 μmol) and NaOH (51 mg, 1.30 mmol) were added to methanol (6 mL) and water (2 mL) and heated to 60° C. to react for 3 hours. After the reaction, the reaction solution was concentrated to dryness, diluted with hydrochloric acid to adjust the pH to 5-6, concentrated under reduced pressure to remove the solvent, and separated and purified by C18 column reversed-phase column chromatography (acetonitrile/water solution=60/40) to obtain compound 55b (75 mg ). MS m/z (ESI): 290.1 [M+H] + .
第三步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-4-(吗啉代甲基)-3-(三氟甲基)苯甲酰胺(化合物55c)的制备The third step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-4-methylphenyl)-4-(morpholinomethyl)-3-(trifluoromethyl)benzamide (compound 55c) preparation
将化合物32d(20mg，36.59μmol)和55b(10.58mg，36.59μmol)溶于吡啶(3mL)中，滴加T 3P(0.5mL，50％于EA中)，室温反应16小时。反应结束后减压浓缩除去溶剂，饱和碳酸氢钠水溶液调节pH至约13，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物55c(25mg)。MS m/z(ESI)：818.4[M+H] +。 Compounds 32d (20 mg, 36.59 μmol) and 55b (10.58 mg, 36.59 μmol) were dissolved in pyridine (3 mL), T 3 P (0.5 mL, 50% in EA) was added dropwise, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the solvent was concentrated under reduced pressure to remove the solvent, the pH was adjusted to about 13 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 55c (25 mg). MS m/z (ESI): 818.4 [M+H] + .
第四步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-4-(吗啉代甲基)-3-(三氟甲基)苯甲酰胺(化合物55)的制备Fourth step: N-(3-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-4-(morpholinomethyl)-3-(trifluoromethyl)benzamide (compound 55)
将化合物55c(25mg，30.57μmol)加入到三氟乙酸(3mL)中，加热至100℃反应16小时。反应结束后将反应液浓缩干，加入饱和碳酸氢钠溶液，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，浓缩，粗产物经Prep-HPLC分离纯化，得到化合物55(4.75mg)。MS m/z(ESI)：578.2[M+H] +。 Compound 55c (25 mg, 30.57 μmol) was added to trifluoroacetic acid (3 mL) and heated to 100° C. to react for 16 hours. After the reaction, the reaction solution was concentrated to dryness, saturated sodium bicarbonate solution was added, extracted three times with ethyl acetate, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC. , to obtain compound 55 (4.75 mg). MS m/z (ESI): 578.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.61(s，1H)，8.69(s，1H)，8.43(s，1H)，8.32-8.13(m，5H)，8.05-7.91(m，3H)，7.81(dd，J＝8.4，2.1Hz，1H)，7.43(d，J＝8.5Hz，1H)，3.70(s，2H)，3.67-3.57(m，4H)，2.42(d，J＝4.1Hz，4H)，2.27(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.61 (s, 1H), 8.69 (s, 1H), 8.43 (s, 1H), 8.32-8.13 (m, 5H), 8.05-7.91 (m, 3H) ), 7.81(dd, J=8.4, 2.1Hz, 1H), 7.43(d, J=8.5Hz, 1H), 3.70(s, 2H), 3.67-3.57(m, 4H), 2.42(d, J= 4.1Hz, 4H), 2.27(s, 3H).
实施例56：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-氰基苯甲酰胺(化合物56)Example 56: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 2-Fluoro-4-methylphenyl)-3-cyanobenzamide (Compound 56)
Figure PCTCN2022079826-appb-000138
Figure PCTCN2022079826-appb-000138
第一步：3-氰基-N-(2-氟-4-甲基-5-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)苯甲酰胺(化合物56b)的制备The first step: 3-cyano-N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2- Preparation of phenyl)phenyl)benzamide (compound 56b)
将化合物33b(170mg，679umol)和56a(100mg，679umol)加入到乙腈(3mL)中，再加入NMI(167 mg，2.04mmol，162uL)和TCFH(228mg，815umol)，加完后25℃反应12hr。反应结束后加EA稀释，依次用饱和碳酸氢钠溶液和柠檬酸溶液洗涤，无水硫酸钠干燥，过滤后浓缩，得到化合物56b(150mg)。MS m/z(ESI)：381.0[M+H] +。 Compounds 33b (170 mg, 679 umol) and 56a (100 mg, 679 umol) were added to acetonitrile (3 mL), then NMI (167 mg, 2.04 mmol, 162 uL) and TCFH (228 mg, 815 umol) were added, and the reaction was performed at 25°C for 12 hr after the addition was complete. . After the reaction, it was diluted with EA, washed with saturated sodium bicarbonate solution and citric acid solution in turn, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 56b (150 mg). MS m/z (ESI): 381.0 [M+H] + .
第二步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-氰基苯甲酰胺(化合物56c)的制备Step 2: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-2-fluoro-4-methylphenyl)-3-cyanobenzamide (compound 56c) preparation
将化合物4d(130mg，294umol)、56b(150mg，394umol)、吡啶(23.2mg，294umol)、DMAP(89.9mg，736umol)和Cu(OAc) 2(53.4mg，294umol)加入到1，4-二氧六环(2mL)中，然后在氧气氛围下90℃反应12hr。反应结束后加水稀释，用EA萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤后减压浓缩，粗产物经Prep-TLC(PE/EA＝2/1)纯化，得到化合物56c(40.0mg)。 Compound 4d (130 mg, 294 umol), 56b (150 mg, 394 umol), pyridine (23.2 mg, 294 umol), DMAP (89.9 mg, 736 umol) and Cu(OAc) 2 (53.4 mg, 294 umol) were added to 1,4-di in oxane (2 mL), and then reacted at 90 °C for 12 hr under an oxygen atmosphere. After the reaction was completed, it was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by Prep-TLC (PE/EA=2/1) to obtain compound 56c ( 40.0 mg).
第三步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-氰基苯甲酰胺(化合物56)的制备The third step: N-(5-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-Fluoro-4-methylphenyl)-3-cyanobenzamide (Compound 56)
将化合物56c(40.0mg，57.7umol)加入到TFA(10mL)中，100℃反应12hr。反应结束后将反应液浓缩干，加入饱和碳酸氢钠溶液，DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经Prep-HPLC分离纯化，得到化合物56(1.40mg)。MS m/z(ESI)：454.0[M+H] +。 Compound 56c (40.0 mg, 57.7 umol) was added to TFA (10 mL) and reacted at 100° C. for 12 hr. After the reaction, the reaction solution was concentrated to dryness, saturated sodium bicarbonate solution was added, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by Prep-HPLC to obtain compound 56 ( 1.40 mg). MS m/z (ESI): 454.0 [M+H] + .
1H NMR(400MHz DMSO-d 6)δ10.49(br s，1H)，8.67(s，1H)，8.42-8.41(m，2H)，8.26(d，J＝8.0Hz，1H)，8.17(s，3H)，8.09(d，J＝8.0Hz，1H)，7.97(s，1H)，7.84-7.66(m，2H)，7.45(d，J＝11.2Hz，1H)，2.27(s，3H). 1 H NMR (400 MHz DMSO-d 6 ) δ 10.49 (br s, 1H), 8.67 (s, 1H), 8.42-8.41 (m, 2H), 8.26 (d, J=8.0 Hz, 1H), 8.17 ( s, 3H), 8.09 (d, J=8.0Hz, 1H), 7.97 (s, 1H), 7.84-7.66 (m, 2H), 7.45 (d, J=11.2Hz, 1H), 2.27 (s, 3H) ).
实施例57：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-甲氧基苯甲酰胺(化合物57)Example 57: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 2-Fluoro-4-methylphenyl)-3-methoxybenzamide (Compound 57)
Figure PCTCN2022079826-appb-000139
Figure PCTCN2022079826-appb-000139
第一步：N-(2-氟-4-甲基-5-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)-3-甲氧基苯甲酰胺(化合物57b)的制备The first step: N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl) Preparation of -3-methoxybenzamide (compound 57b)
将化合物33b(412mg，1.64mmol)和57a(100mg，679umol)加入到乙腈(3mL)中，再加入NMI(161mg，1.97mmol，157uL)和TCFH(221mg，788umol)，加完后25℃反应12hr。反应结束后加EA稀释，依次用饱和碳酸氢钠溶液和柠檬酸溶液洗涤，无水硫酸钠干燥，过滤后浓缩，得到化合物57b(150mg)。MS m/z(ESI)：386.0[M+H] +。 Compound 33b (412 mg, 1.64 mmol) and 57a (100 mg, 679 umol) were added to acetonitrile (3 mL), then NMI (161 mg, 1.97 mmol, 157 uL) and TCFH (221 mg, 788 umol) were added, and the reaction was performed at 25°C for 12 hr after the addition was complete. . After the reaction, it was diluted with EA, washed with saturated sodium bicarbonate solution and citric acid solution in turn, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 57b (150 mg). MS m/z (ESI): 386.0 [M+H] + .
第二步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-甲氧基苯甲酰胺(化合物57c)的制备Step 2: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-2-fluoro-4-methylphenyl)-3-methoxybenzamide (compound 57c) preparation
将化合物4d(130mg，294umol)、57b(113mg，294umol)、吡啶(23.2mg，294umol)、DMAP(89.9mg，736umol)和Cu(OAc) 2(53.4mg，294umol)加入到1，4-二氧六环(2mL)中，然后在氧气氛围下90℃反应12hr。反应结束后加水稀释，用EA萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤后减压浓缩，粗产物经Prep-TLC(PE/EA＝2/1)纯化，得到化合物57c(40.0mg)。MS m/z(ESI)：699.1[M+H] +。 Compound 4d (130 mg, 294 umol), 57b (113 mg, 294 umol), pyridine (23.2 mg, 294 umol), DMAP (89.9 mg, 736 umol) and Cu(OAc) 2 (53.4 mg, 294 umol) were added to 1,4-di in oxane (2 mL), and then reacted at 90 °C for 12 hr under an oxygen atmosphere. After the reaction was completed, it was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by Prep-TLC (PE/EA=2/1) to obtain compound 57c ( 40.0 mg). MS m/z (ESI): 699.1 [M+H] + .
第三步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-3-甲氧基苯甲酰胺(化合物57)的制备The third step: N-(5-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-Fluoro-4-methylphenyl)-3-methoxybenzamide (Compound 57)
将化合物57c(40.0mg，57.7umol)加入到TFA(10mL)中，100℃反应12hr。反应结束后将反应液浓缩干，加入饱和碳酸氢钠溶液，DCM萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经Prep-HPLC分离纯化，得到化合物57(8.57mg)。MS m/z(ESI)：459.0[M+H] +。 Compound 57c (40.0 mg, 57.7 umol) was added to TFA (10 mL) and reacted at 100° C. for 12 hr. After the reaction, the reaction solution was concentrated to dryness, saturated sodium bicarbonate solution was added, extracted with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by Prep-HPLC to obtain compound 57 ( 8.57 mg). MS m/z (ESI): 459.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.24(s，1H)，8.67(s，1H)，8.49-8.39(m，1H)，8.27-8.09(m，3H)，7.97(s，1H)，7.72(d，J＝7.2Hz，1H)，7.59-7.50(m，2H)，7.48-7.40(m，2H)，7.18(dd，J＝2.0，8.0Hz，1H)，3.83(s，3H)，2.27(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.24 (s, 1H), 8.67 (s, 1H), 8.49-8.39 (m, 1H), 8.27-8.09 (m, 3H), 7.97 (s, 1H) ), 7.72(d, J=7.2Hz, 1H), 7.59-7.50(m, 2H), 7.48-7.40(m, 2H), 7.18(dd, J=2.0, 8.0Hz, 1H), 3.83(s, 3H), 2.27(s, 3H).
实施例58：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-4-((4-甲基 哌嗪-1-基)甲基)-3-(三氟甲基)苯甲酰胺(化合物58)Example 58: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 2-Fluoro-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 58)
Figure PCTCN2022079826-appb-000140
Figure PCTCN2022079826-appb-000140
第一步：N-(2-氟-5-(4-(4-((4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯甲酰胺(化合物58a)的制备First step: N-(2-Fluoro-5-(4-(4-((4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine- 7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl) Preparation of benzamide (compound 58a)
向化合物38g(122mg，274umol)和54e(82.9mg，274umol)的乙腈(3mL)溶液中加入NMI(90.1mg，1.10mmol)和TCFH(192mg，686umol)，25℃反应12hr。反应结束后滤除固体，滤液浓缩后得到化合物58a(300mg，粗品)。To a solution of compounds 38g (122 mg, 274 umol) and 54e (82.9 mg, 274 umol) in acetonitrile (3 mL) was added NMI (90.1 mg, 1.10 mmol) and TCFH (192 mg, 686 umol), and the reaction was carried out at 25°C for 12 hr. After the reaction, the solid was filtered off, and the filtrate was concentrated to obtain compound 58a (300 mg, crude product).
第二步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯甲酰胺(化合物58)的制备Step 2: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-fluoro-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (Compound 58)
将化合物58a(300mg，412umol)加入到TFA(5mL)中，氮气保护下100℃反应12hr。反应结束后将溶剂浓缩干，粗品经prep-HPLC纯化，得到化合物58(42.0mg)。MS m/z(ESI)：609.2[M+H] + Compound 58a (300 mg, 412 umol) was added to TFA (5 mL) and reacted at 100° C. for 12 hr under nitrogen protection. After the reaction, the solvent was concentrated to dryness, and the crude product was purified by prep-HPLC to obtain compound 58 (42.0 mg). MS m/z(ESI): 609.2[M+H] +
1H NMR(400MHz，DMSO-d 6)δ10.63(s，1H)，8.67(s，1H)，8.42(s，1H)，8.31(s，1H)，8.26-8.24(m，2H)，8.17-8.15(s，2H)，7.97-7.92(m，2H)，7.75(d，J＝6.8Hz，1H)，7.46-7.43(m，1H)，3.75(s，2H)，2.87(s，8H)，2.55(s，3H)，2.27(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.63 (s, 1H), 8.67 (s, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 8.26-8.24 (m, 2H), 8.17-8.15(s, 2H), 7.97-7.92(m, 2H), 7.75(d, J=6.8Hz, 1H), 7.46-7.43(m, 1H), 3.75(s, 2H), 2.87(s, 8H), 2.55(s, 3H), 2.27(s, 3H).
实施例59：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-3-甲基-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物59)Example 59: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-3-methyl-1H-pyrazol-1-yl)-4-methyl phenyl)-3-(trifluoromethyl)benzamide (Compound 59)
Figure PCTCN2022079826-appb-000141
Figure PCTCN2022079826-appb-000141
第一步：N-(2，4-二甲氧基苄基)-7-(3-甲基-1H-吡唑-4-基)噻吩并[3，2-d]嘧啶-4-胺(化合物59b)的制备The first step: N-(2,4-dimethoxybenzyl)-7-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4-amine Preparation of (Compound 59b)
将化合物1c(300mg，788.94μmol)、59a(656.60mg，3.16mmol)、碳酸钾(327.12mg，2.37mmol)、Pd(dppf)Cl 2.DCM(64.43mg，78.89μmol)、1，4-二氧六环(6mL)和水(1mL)加入到反应瓶中，氮气保护下90℃搅拌8小时。反应结束后减压除去有机溶剂，加水稀释，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(DCM/MeOH＝95/5)分离纯化，得到化合物59b(220mg)。MS m/z(ESI)：382.1[M+H] +。 Compound 1c (300 mg, 788.94 μmol), 59a (656.60 mg, 3.16 mmol), potassium carbonate (327.12 mg, 2.37 mmol), Pd(dppf)Cl 2 .DCM (64.43 mg, 78.89 μmol), 1,4-di Oxane (6 mL) and water (1 mL) were added to the reaction flask, and stirred at 90° C. for 8 hours under nitrogen protection. After the reaction, the organic solvent was removed under reduced pressure, diluted with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel flash column chromatography (DCM/MeOH=95/5) to give compound 59b (220 mg). MS m/z (ESI): 382.1 [M+H] + .
第二步：N-(3-(4-(4-((2，4-二甲氧基苄基)氨基)噻吩并[3，2-d]嘧啶-7-基)-3-甲基-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物59c)的制备Step 2: N-(3-(4-(4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidin-7-yl)-3-methyl Preparation of -1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 59c)
将化合物59b(75mg，196.62μmol)、3d(95.28mg，294.93μmol)、吡啶(38.88mg，491.54μmol)、DMAP(48.04mg，393.24μmol)、Cu(OAc) 2(39.25mg，196.62μmol)和1，4-二氧六环(3mL)加入反应瓶中，空气氛围下90℃搅拌16小时。反应结束后加水稀释，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，浓缩得到化合物59c(120mg)。MS m/z(ESI)：659.2[M+H] +。 Compound 59b (75 mg, 196.62 μmol), 3d (95.28 mg, 294.93 μmol), pyridine (38.88 mg, 491.54 μmol), DMAP (48.04 mg, 393.24 μmol), Cu(OAc) 2 (39.25 mg, 196.62 μmol) and 1,4-Dioxane (3 mL) was added to the reaction flask, and the mixture was stirred at 90° C. for 16 hours under an air atmosphere. After the reaction, it was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 59c (120 mg). MS m/z (ESI): 659.2 [M+H] + .
第三步：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-3-甲基-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物59)的制备The third step: N-(3-(4-(4-aminothieno[3,2-d]pyrimidin-7-yl)-3-methyl-1H-pyrazol-1-yl)-4-methyl Preparation of phenyl)-3-(trifluoromethyl)benzamide (compound 59)
将化合物59c(60mg，91.09μmol)溶于三氟乙酸(3mL)中，加热至90℃反应4小时。反应结束后 将反应液浓缩干，加入饱和碳酸氢钠溶液，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经Prep-HPLC分离纯化，得到化合物59(5.00mg)。MS m/z(ESI)：509.1[M+H] +。 Compound 59c (60 mg, 91.09 μmol) was dissolved in trifluoroacetic acid (3 mL) and heated to 90° C. to react for 4 hours. After the reaction, the reaction solution was concentrated to dryness, saturated sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by Prep-HPLC to obtain the compound 59 (5.00 mg). MS m/z (ESI): 509.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.62(s，1H)，8.76(s，1H)，8.46(s，1H)，8.34-8.26(m，2H)，8.16(s，1H)，7.99(d，J＝7.7Hz，1H)，7.92(d，J＝2.0Hz，1H)，7.80(t，J＝7.7Hz，2H)，7.51(s，2H)，7.41(d，J＝8.4Hz，1H)，2.51(s，3H)，2.31(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.62(s, 1H), 8.76(s, 1H), 8.46(s, 1H), 8.34-8.26(m, 2H), 8.16(s, 1H), 7.99 (d, J=7.7Hz, 1H), 7.92 (d, J=2.0Hz, 1H), 7.80 (t, J=7.7Hz, 2H), 7.51 (s, 2H), 7.41 (d, J=8.4 Hz, 1H), 2.51(s, 3H), 2.31(s, 3H).
实施例60：N-(5-(5-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1，2，4-噁二唑-3-基)-2-氟-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物60)Example 60: N-(5-(5-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1,2,4-oxadiazole- 3-yl)-2-fluoro-4-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 60)
Figure PCTCN2022079826-appb-000142
Figure PCTCN2022079826-appb-000142
第一步：5-氨基-4-氟-2-甲基苄腈(化合物60a)的制备Step 1: Preparation of 5-amino-4-fluoro-2-methylbenzonitrile (compound 60a)
将化合物33a(1.0g，4.9mmol)、Zn(CN) 2(774mg，6.60mmol)和四(三苯基膦)钯(40.6mg，1.1mmol)加入到DMF(5mL)中，微波150℃反应1hr。反应结束后，加入饱和碳酸氢钠溶液，再用乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩，经硅胶柱色谱法(PE/EA＝1/1)分离纯化，得到化合物60a(0.5g)。MS m/z(ESI)：151.0[M+H] +。 Compound 33a (1.0 g, 4.9 mmol), Zn(CN) 2 (774 mg, 6.60 mmol) and tetrakis(triphenylphosphine)palladium (40.6 mg, 1.1 mmol) were added to DMF (5 mL), and the reaction was carried out at 150 °C in a microwave 1hr. After the reaction, saturated sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (PE/EA=1/1) to obtain compound 60a (0.5 g). MS m/z (ESI): 151.0 [M+H] + .
第二步：N-(5-氰基-2-氟-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物60b)的制备Step 2: Preparation of N-(5-cyano-2-fluoro-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 60b)
将化合物60a(500mg，3.3mmol)和3b(627mg，6.05mmol)加入到乙腈(10mL)中，再加入NMI(1.1g，13.3mmol)和TCFH(1.87g，6.7mmol)，加完后25℃反应12hr。反应结束后减压浓缩，再加入水，用EA萃取，有机相用无水硫酸钠干燥，过滤，浓缩，得到化合物60b(2.40g，粗品)。MS m/z(ESI)：322.9[M+H] +。 Compounds 60a (500 mg, 3.3 mmol) and 3b (627 mg, 6.05 mmol) were added to acetonitrile (10 mL), then NMI (1.1 g, 13.3 mmol) and TCFH (1.87 g, 6.7 mmol) were added, and after the addition was completed, 25°C The reaction was carried out for 12 hours. After the reaction was completed, it was concentrated under reduced pressure, water was added, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 60b (2.40 g, crude product). MS m/z (ESI): 322.9 [M+H] + .
第三步：N-(2-氟-5-(N′-羟基氨基甲酰基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物60c)的制备The third step: preparation of N-(2-fluoro-5-(N'-hydroxycarbamoyl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 60c)
向化合物60b(800mg，2.48mmol)的EtOH(10mL)溶液中加入NH 2OH·HCl(517mg，7.44mmol)和Et 3N(752mg，7.44mmol)，85℃反应3hr。反应结束后浓缩除去溶剂，加水后用EA萃取，有机相用无水硫酸钠干燥，过滤后减压浓缩，得到化合物60c(700mg，粗品)。MS m/z(ESI)：355.9[M+H] +。 To a solution of compound 60b (800 mg, 2.48 mmol) in EtOH (10 mL) was added NH 2 OH·HCl (517 mg, 7.44 mmol) and Et 3 N (752 mg, 7.44 mmol), and reacted at 85° C. for 3 hr. After the reaction was completed, the solvent was concentrated to remove the solvent, water was added and extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 60c (700 mg, crude product). MS m/z (ESI): 355.9 [M+H] + .
第四步：4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-羧酸甲酯(化合物60e)的制备The fourth step: preparation of methyl 4-aminoimidazo[2,1-f][1,2,4]triazine-7-carboxylate (compound 60e)
向化合物60d(1.00g，4.67mmol)和Et 3N(1.42g，14.0mmol)的MeOH(5mL)溶液中加入Pd(dppf)Cl 2·DCM(190mg，233umol)，高压一氧化碳(1MPa)氛围下120℃反应20hr。反应结束后冷却至室温，过滤，滤饼用甲醇淋洗，滤饼干燥后得到化合物60e(700mg)。 To a solution of compound 60d (1.00 g, 4.67 mmol) and Et 3 N (1.42 g, 14.0 mmol) in MeOH (5 mL) was added Pd(dppf)Cl 2 ·DCM (190 mg, 233 umol) under high pressure carbon monoxide (1 MPa) atmosphere 120°C for 20hrs. After the reaction, it was cooled to room temperature, filtered, and the filter cake was rinsed with methanol, and the filter cake was dried to obtain compound 60e (700 mg).
第五步：4-[双(叔丁氧羰基)氨基]咪唑并[2，1-f][1，2，4]三嗪-7-羧酸甲酯(化合物60f)的制备The fifth step: preparation of methyl 4-[bis(tert-butoxycarbonyl)amino]imidazo[2,1-f][1,2,4]triazine-7-carboxylate (compound 60f)
向化合物60e(100mg，517umol)的THF(10mL)溶液中加入(Boc) 2O(338mg，1.55mmol)和DMAP(31.6mg，258umol)，25℃反应4hr。反应结束后将反应液浓缩干，加水后用EA萃取，有机相用无水硫酸钠干燥，过滤后减压浓缩，得到化合物60f(51.0mg)。MS m/z(ESI)：393.9[M+H] + To a solution of compound 60e (100 mg, 517 umol) in THF (10 mL) was added (Boc) 2 O (338 mg, 1.55 mmol) and DMAP (31.6 mg, 258 umol), and reacted at 25°C for 4 hr. After the reaction, the reaction solution was concentrated to dryness, added with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 60f (51.0 mg). MS m/z(ESI): 393.9[M+H] +
第六步：4-[双(叔丁氧羰基)氨基]咪唑并[2，1-f][1，2，4]三嗪-7-羧酸(化合物60g)的制备The sixth step: preparation of 4-[bis(tert-butoxycarbonyl)amino]imidazo[2,1-f][1,2,4]triazine-7-carboxylic acid (compound 60g)
将化合物60f(51.0mg，129umol)加入到THF(4mL)和H 2O(4mL)中，再加入LiOH·H 2O(10.8mg，259umol)，然后25℃反应1hr。反应结束后，将反应液浓缩干，得到化合物60g(70.0mg，粗品)。 Compound 60f (51.0 mg, 129 umol) was added to THF (4 mL) and H 2 O (4 mL), and then LiOH·H 2 O (10.8 mg, 259 umol) was added, and then reacted at 25° C. for 1 hr. After completion of the reaction, the reaction solution was concentrated to dryness to obtain compound 60 g (70.0 mg, crude product).
第七步：N-叔丁氧羰基-N-[7-[3-[4-氟-2-甲基-5-[[3-(三氟甲基)苯甲酰基]氨基]苯基]-1，2，4-噁二唑-5-基]咪唑并[2，1-f][1，2，4]三嗪-4-基]氨基甲酸叔丁酯(化合物60h)的制备Step 7: N-tert-butoxycarbonyl-N-[7-[3-[4-fluoro-2-methyl-5-[[3-(trifluoromethyl)benzoyl]amino]phenyl] - Preparation of tert-butyl 1,2,4-oxadiazol-5-yl]imidazo[2,1-f][1,2,4]triazin-4-yl]carbamate (compound 60h)
向化合物60g(50.0mg，140umol)和60c(53.3mg，140umol)的EA(2mL)溶液中加入Et 3N(42.7 mg，422umol)和T 3P(111mg，351umol)，25℃反应14hr，然后70℃反应12hr。反应结束后减压浓缩，粗品经C18柱反相柱色谱法(乙腈/0.05％碳酸氢铵水溶液＝42/58)纯化，得到化合物60h(30.0mg)。MS m/z(ESI)：699.2[M+H] +。 To a solution of compound 60g (50.0 mg, 140 umol) and 60c (53.3 mg, 140 umol) in EA (2 mL) was added Et 3 N (42.7 mg, 422 umol) and T 3 P (111 mg, 351 umol), reacted at 25°C for 14 hr, and then The reaction was carried out at 70°C for 12hrs. After the reaction was completed, it was concentrated under reduced pressure, and the crude product was purified by C18 column reversed-phase column chromatography (acetonitrile/0.05% aqueous ammonium bicarbonate solution=42/58) to obtain compound 60h (30.0 mg). MS m/z (ESI): 699.2 [M+H] + .
第八步：N-(5-(5-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1，2，4-噁二唑-3-基)-2-氟-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物60)的制备The eighth step: N-(5-(5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1,2,4-oxadiazole- Preparation of 3-yl)-2-fluoro-4-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 60)
将化合物60h(20.0mg，28.6umol)加入到HCl的EA溶液(5.0mL，4M)中，25℃反应48hr。反应结束后将反应液浓缩干，得到化合物60(12.5mg)。MS m/z(ESI)：499.0[M+H] +。 Compound 60h (20.0 mg, 28.6 umol) was added to HCl in EA solution (5.0 mL, 4M), and the reaction was carried out at 25°C for 48 hr. After the completion of the reaction, the reaction solution was concentrated to dryness to obtain Compound 60 (12.5 mg). MS m/z (ESI): 499.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.61(s，1H)，8.62-8.56(m，2H)，8.51(s，1H)，8.36-8.35(m，2H)，8.30-8.28(m，2H)，8.01(d，J＝8.00Hz，1H)，7.83-7.82(m，1H)，7.48(d，J＝11.2Hz，1H)，2.67(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.61 (s, 1H), 8.62-8.56 (m, 2H), 8.51 (s, 1H), 8.36-8.35 (m, 2H), 8.30-8.28 (m , 2H), 8.01(d, J=8.00Hz, 1H), 7.83-7.82(m, 1H), 7.48(d, J=11.2Hz, 1H), 2.67(s, 3H).
实施例61：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-6-氟异喹啉-3-胺(化合物61)Example 61: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-6-fluoroisoquinolin-3-amine (Compound 61)
Figure PCTCN2022079826-appb-000143
Figure PCTCN2022079826-appb-000143
第一步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-6-氟异喹啉-3-胺(化合物61b)的制备The first step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-4-methylphenyl)-6-fluoroisoquinolin-3-amine (compound 61b) preparation
将化合物32d(15mg，27.44μmol)、61a(4.98mg，27.44μmol)、BINAP(3.42mg，5.49μmol)、Pd2(dba)3(2.51mg，2.74μmol)和Cs 2CO 3(26.82mg，82.32μmol)加入甲苯(3mL)中，氮气保护下90℃反应3小时。反应结束后加入水，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得化合物61b(18mg)。MS m/z(ESI)：692.3[M+H] +。 Compound 32d (15 mg, 27.44 μmol), 61a (4.98 mg, 27.44 μmol), BINAP (3.42 mg, 5.49 μmol), Pd2(dba) 3 (2.51 mg, 2.74 μmol) and Cs2CO3 (26.82 mg, 82.32 μmol) was added to toluene (3 mL) and reacted at 90° C. for 3 hours under nitrogen protection. After the reaction, water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 61b (18 mg). MS m/z (ESI): 692.3 [M+H] + .
第二步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-6-氟异喹啉-3-胺(化合物61)的制备Step 2: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-6-fluoroisoquinolin-3-amine (compound 61)
将化合物61b(18mg，26.02μmol)溶于三氟乙酸(3mL)中，加热至90℃反应16小时。反应结束后将反应液浓缩干，加入饱和碳酸氢钠溶液，乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，粗产物经Prep-HPLC分离纯化，得到化合物61(3.10mg)。MS m/z(ESI)：452.1[M+H] +。 Compound 61b (18 mg, 26.02 μmol) was dissolved in trifluoroacetic acid (3 mL) and heated to 90° C. to react for 16 hours. After the reaction, the reaction solution was concentrated to dryness, saturated sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by Prep-HPLC to obtain compound 61 (3.10 mg). MS m/z (ESI): 452.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ9.31(s，1H)，9.05(s，1H)，8.68(s，1H)，8.41(s，1H)，8.25(s，1H)，8.17(d，J＝7.1Hz，2H)，8.05-7.96(m，2H)，7.74(d，J＝2.3Hz，1H)，7.55(ddd，J＝13.1，9.5，2.4Hz，2H)，7.33(d，J＝8.5Hz，1H)，7.23-7.14(m，2H)，2.21(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 9.31(s, 1H), 9.05(s, 1H), 8.68(s, 1H), 8.41(s, 1H), 8.25(s, 1H), 8.17( d, J=7.1Hz, 2H), 8.05-7.96 (m, 2H), 7.74 (d, J=2.3Hz, 1H), 7.55 (ddd, J=13.1, 9.5, 2.4Hz, 2H), 7.33 (d , J=8.5Hz, 1H), 7.23-7.14(m, 2H), 2.21(s, 3H).
实施例62：N-(3-(3-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1，2，4-噁二唑-5-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物62)Example 62: N-(3-(3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1,2,4-oxadiazole- 5-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 62)
Figure PCTCN2022079826-appb-000144
Figure PCTCN2022079826-appb-000144
第一步：2-甲基-5-(3-(三氟甲基)苯甲酰胺基)苯甲酸甲酯(化合物62b)的制备The first step: preparation of methyl 2-methyl-5-(3-(trifluoromethyl)benzamido)benzoate (compound 62b)
将化合物62a(1.00g，6.05mmol)和3b(1.15g，6.05mmol)加入到乙腈(10mL)中，再加入NMI(1.99g，24.2mmol，1.93mL)和TCFH(3.40g，12.1mmol)，加完后25℃反应12hr。反应结束后减压浓缩，再加入水，用EA萃取，有机相用无水硫酸钠干燥，过滤，浓缩，得到化合物62b(2.40g，粗品)。MS m/z(ESI)：337.8[M+H] +。 Compounds 62a (1.00 g, 6.05 mmol) and 3b (1.15 g, 6.05 mmol) were added to acetonitrile (10 mL), followed by NMI (1.99 g, 24.2 mmol, 1.93 mL) and TCFH (3.40 g, 12.1 mmol), After the addition, the reaction was carried out at 25°C for 12 hours. After the reaction was completed, it was concentrated under reduced pressure, water was added, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 62b (2.40 g, crude product). MS m/z (ESI): 337.8 [M+H] + .
第二步：2-甲基-5-(3-(三氟甲基)苯甲酰胺基)苯甲酸(化合物62c)的制备The second step: preparation of 2-methyl-5-(3-(trifluoromethyl)benzamido)benzoic acid (compound 62c)
将化合物62b(2.00g，5.93mmol)加入到THF(10mL)和H 2O(10mL)中，再加入LiOH·H 2O(497mg，11.8mmol)，25℃反应3hr。反应结束后减压除去乙腈，加水稀释，MTBE洗涤，然后稀盐酸调节pH至约2。水相用二氯甲烷/异丙醇(7/1)混合溶剂萃取，有机相用无水硫酸钠干燥，过滤，浓缩，粗品用C18柱反相柱层析(0.1％甲酸水溶液/MeCN＝60/40)纯化，得到化合物62c(900mg)。MS m/z(ESI)：324.0[M+H] +。 Compound 62b (2.00 g, 5.93 mmol) was added to THF (10 mL) and H 2 O (10 mL), and then LiOH·H 2 O (497 mg, 11.8 mmol) was added to react at 25° C. for 3 hr. After the reaction, acetonitrile was removed under reduced pressure, diluted with water, washed with MTBE, and then adjusted to pH 2 with dilute hydrochloric acid. The aqueous phase was extracted with a mixed solvent of dichloromethane/isopropanol (7/1), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was subjected to reverse-phase column chromatography on a C18 column (0.1% aqueous formic acid/MeCN=60 /40) was purified to give compound 62c (900 mg). MS m/z (ESI): 324.0 [M+H] + .
第三步：4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-甲腈(化合物62d)的制备The third step: preparation of 4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (compound 62d)
将化合物4c(500mg，1.10mmol)、Zn(CN) 2(258mg，2.20mmol)和四(三苯基膦)钯(20.3mg，55.0umol)加入到DMF(5mL)中，微波120℃反应5hr。反应结束后，加入饱和碳酸氢钠溶液，再用乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩，经硅胶柱色谱法(PE/EA＝1/1)分离纯化，得到化合物62d(250mg)。MS m/z(ESI)：401.0[M+H] +。 Compound 4c (500 mg, 1.10 mmol), Zn(CN) 2 (258 mg, 2.20 mmol) and tetrakis(triphenylphosphine)palladium (20.3 mg, 55.0 umol) were added to DMF (5 mL), and the reaction was carried out at 120 °C for 5 hr in microwave . After the reaction, saturated sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (PE/EA=1/1) to obtain compound 62d (250 mg). MS m/z (ESI): 401.0 [M+H] + .
第四步：4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-甲腈(化合物62e)的制备The fourth step: preparation of 4-aminoimidazo[2,1-f][1,2,4]triazine-7-carbonitrile (compound 62e)
将化合物62d(190mg，474umol)加入到TFA(3mL)中，100℃反应12hr。反应结束后将溶剂浓缩干，加入饱和碳酸氢钠溶液调节溶液pH至约8，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物62e(170mg，粗品)。MS m/z(ESI)：161.0[M+H] +。 Compound 62d (190 mg, 474 umol) was added to TFA (3 mL) and reacted at 100°C for 12 hr. After the reaction, the solvent was concentrated to dryness, saturated sodium bicarbonate solution was added to adjust the pH of the solution to about 8, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 62e (170 mg, crude product). ). MS m/z (ESI): 161.0 [M+H] + .
第五步：(7-氰基咪唑并[2，1-f][1，2，4]三嗪-4-基)氨基甲酸叔丁酯(化合物62f)的制备The fifth step: preparation of tert-butyl (7-cyanoimidazo[2,1-f][1,2,4]triazin-4-yl)carbamate (compound 62f)
将化合物62e(120mg，749umol)和(Boc) 2O(490mg，2.25mmol)加入到THF(4mL)，在0℃下加入DMAP(9.15mg，74.9umol)，加完后25℃反应3hr。反应结束后浓缩除去溶剂，加水后用EA萃取，有机相用无水硫酸钠干燥，过滤后减压浓缩，粗品经prep-TLC(PE/EA＝3/1)纯化，得到化合物62f(70.0mg)。 Compound 62e (120 mg, 749 umol) and (Boc) 2 O (490 mg, 2.25 mmol) were added to THF (4 mL), DMAP (9.15 mg, 74.9 umol) was added at 0 °C, and the reaction was performed at 25 °C for 3 hr. After the reaction was completed, the solvent was concentrated and removed. After adding water, it was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by prep-TLC (PE/EA=3/1) to obtain compound 62f (70.0 mg). ).
第六步：(7-(N′-羟基氨基甲酰基)咪唑并[2，1-f][1，2，4]三嗪-4-基)氨基甲酸叔丁酯(化合物62g)的制备The sixth step: preparation of tert-butyl (7-(N'-hydroxycarbamoyl)imidazo[2,1-f][1,2,4]triazin-4-yl)carbamate (compound 62g)
向化合物62f(70.0mg，269umol)的EtOH(2mL)溶液中加入NH 2OH·HCl(56.1mg，807umol)和Et 3N(81.6mg，807umol)，85℃反应3hr。反应结束后浓缩除去溶剂，加水后用EA萃取，有机相用无水硫酸钠干燥，过滤后减压浓缩，得到化合物62g(50.0mg，粗品)。MS m/z(ESI)：294.0[M+H] +。 To a solution of compound 62f (70.0 mg, 269 umol) in EtOH (2 mL) was added NH 2 OH·HCl (56.1 mg, 807 umol) and Et 3 N (81.6 mg, 807 umol), and reacted at 85° C. for 3 hr. After the reaction, the solvent was concentrated to remove the solvent. After adding water, the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 62g (50.0 mg, crude product). MS m/z (ESI): 294.0 [M+H] + .
第七步：(7-(N′-羟基-N-(2-甲基-5-(3-(三氟甲基)苯甲酰胺基)苯甲酰基)氨基甲酰基)咪唑并[2，1-f][1，2，4]三嗪-4-基)氨基甲酸叔丁酯(化合物62h)的制备The seventh step: (7-(N'-hydroxy-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)benzoyl)carbamoyl)imidazo[2, Preparation of tert-butyl 1-f][1,2,4]triazin-4-yl)carbamate (Compound 62h)
向化合物62g(50.0mg，170umol)和62c(55.1mg，170umol)的乙腈(2mL)溶液中加入TCFH(95.7mg，341umol)和NMI(55.9mg，682umol)，然后25℃反应12hr。反应结束后浓缩除去溶剂，加水后 用EA萃取，有机相用无水硫酸钠干燥，过滤后减压浓缩，粗品经prep-TLC(PE/EA＝0/1)纯化，得到化合物62h(25.0mg)。MS m/z(ESI)：599.1[M+H] +。 To a solution of compounds 62g (50.0 mg, 170 umol) and 62c (55.1 mg, 170 umol) in acetonitrile (2 mL) were added TCFH (95.7 mg, 341 umol) and NMI (55.9 mg, 682 umol), and then reacted at 25°C for 12 hr. After the reaction was completed, the solvent was concentrated and removed, and water was added and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep-TLC (PE/EA=0/1) to obtain compound 62h (25.0 mg). ). MS m/z (ESI): 599.1 [M+H] + .
第八步：(7-(5-(2-甲基-5-(3-(三氟甲基)苯甲酰胺基)苯基)-1，2，4-噁二唑-3-基)咪唑并[2，1-f][1，2，4]三嗪-4-基)氨基甲酸叔丁酯(化合物62i)的制备The eighth step: (7-(5-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-1,2,4-oxadiazol-3-yl) Preparation of tert-butyl imidazo[2,1-f][1,2,4]triazin-4-yl)carbamate (compound 62i)
向化合物62h(25.0mg，41.7umol)的THF(2mL)溶液中加入TBAF(13.2mg，41.7umol)，然后25℃反应2hr。反应结束后将溶剂浓缩干，粗品经C18柱反相柱色谱法(乙腈/水中性条件)纯化，得到化合物62i(15.0mg，24.5umol)。MS m/z(ESI)：581.3[M+H] +。 To a solution of compound 62h (25.0 mg, 41.7 umol) in THF (2 mL) was added TBAF (13.2 mg, 41.7 umol), and then reacted at 25°C for 2 hr. After the reaction, the solvent was concentrated to dryness, and the crude product was purified by C18 column reverse-phase column chromatography (acetonitrile/water neutral condition) to obtain compound 62i (15.0 mg, 24.5 umol). MS m/z (ESI): 581.3 [M+H] + .
第九步：N-(3-(3-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1，2，4-噁二唑-5-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物62)的制备The ninth step: N-(3-(3-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1,2,4-oxadiazole- Preparation of 5-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 62)
将化合物62i(20.0mg，34.4umol)加入到HCl的EA溶液(3.0mL，4M)中，25℃反应12hr。反应结束后浓缩除去溶剂，粗品用Prep-HPLC纯化，得到化合物62(9.20mg)。MS m/z(ESI)：481.0[M+H] +。 Compound 62i (20.0 mg, 34.4 umol) was added to HCl in EA solution (3.0 mL, 4 M) and reacted at 25°C for 12 hr. After the reaction was completed, the solvent was removed by concentration, and the crude product was purified by Prep-HPLC to obtain compound 62 (9.20 mg). MS m/z (ESI): 481.0 [M+H] + .
1H NMR(400MHz DMSO-d 6)δ10.75(s，1H)，8.61(d，J＝2.4Hz，1H)，8.56-8.46(m，2H)，8.36(s，1H)，8.32(d，J＝8.0Hz，1H)，8.30(d，J＝5.6Hz，2H)，8.07(dd，J＝8.0，2.4Hz，1H)，8.00(d，J＝7.6Hz，1H)，7.81(t，J＝8.0Hz，1H)，7.53(d，J＝8.8Hz，1H)，2.72(s，3H). 1 H NMR (400 MHz DMSO-d 6 ) δ 10.75 (s, 1H), 8.61 (d, J=2.4 Hz, 1H), 8.56-8.46 (m, 2H), 8.36 (s, 1H), 8.32 (d , J=8.0Hz, 1H), 8.30(d, J=5.6Hz, 2H), 8.07(dd, J=8.0, 2.4Hz, 1H), 8.00(d, J=7.6Hz, 1H), 7.81(t , J=8.0Hz, 1H), 7.53 (d, J=8.8Hz, 1H), 2.72 (s, 3H).
实施例63：N-(5-(5-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)噁唑-2-基)-2-氟-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物63)Example 63: N-(5-(5-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)oxazol-2-yl)-2-fluoro -4-Methylphenyl)-3-(trifluoromethyl)benzamide (Compound 63)
Figure PCTCN2022079826-appb-000145
Figure PCTCN2022079826-appb-000145
第一步：N-(5-溴-2-氟-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物63a)的制备The first step: preparation of N-(5-bromo-2-fluoro-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 63a)
将化合物33a(5.00g，24.5mmol)和3b(4.66g，24.5mmol)加入到乙腈(10mL)中，再加入TCFH(13.7g，49.0mmol)和NMI(8.05g，98.0mmol，7.81mL)，加完后25℃反应12hr。反应结束后减压除去溶剂，加入水再用EA萃取，有机相经无水硫酸钠干燥，过滤，浓缩，再经硅胶快速柱层析(PE/EA＝2/1)纯化，得到化合物63a(9.00g)。MS m/z(ESI)：375.9[M+H] +。 Compounds 33a (5.00 g, 24.5 mmol) and 3b (4.66 g, 24.5 mmol) were added to acetonitrile (10 mL) followed by TCFH (13.7 g, 49.0 mmol) and NMI (8.05 g, 98.0 mmol, 7.81 mL), After the addition, the reaction was carried out at 25°C for 12 hours. After the reaction, the solvent was removed under reduced pressure, water was added and extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (PE/EA=2/1) to obtain compound 63a ( 9.00g). MS m/z (ESI): 375.9 [M+H] + .
第二步：N，N-双(4-甲氧基苄基)-7-(噁唑-5-基)咪唑并[2，1-f][1，2，4]三嗪-4-胺(化合物63c)的制备Step 2: N,N-Bis(4-methoxybenzyl)-7-(oxazol-5-yl)imidazo[2,1-f][1,2,4]triazine-4- Preparation of amine (compound 63c)
将化合物4c(1.00g，2.20mmol)、63b(304mg，4.40mmol，281uL)、特戊酸(89.9mg，880umol，101uL)、K2CO 3(912mg，6.60mmol)、Pd(OAc) 2(24.7mg，110umol)和配体1(78.9mg，220umol)加入到DMA(5mL)中，氮气保护下110℃反应16hr。反应结束后过滤除去固体，滤液经C18柱反相柱色谱(0.05％NH4HCO 3水溶液/MeCN＝23/77)纯化，得到化合物63c(150mg)。MS m/z(ESI)：443.2[M+H] +。 Compound 4c (1.00 g, 2.20 mmol), 63b (304 mg, 4.40 mmol, 281 uL), pivalic acid (89.9 mg, 880 umol, 101 uL), K2CO3 (912 mg, 6.60 mmol), Pd(OAc) 2 (24.7 mg , 110umol) and ligand 1 (78.9mg, 220umol) were added to DMA (5mL), and reacted at 110°C for 16hr under nitrogen protection. After the reaction, the solid was removed by filtration, and the filtrate was purified by C18 column reversed-phase column chromatography (0.05% NH4HCO3 aqueous solution/MeCN=23/77) to obtain compound 63c (150 mg). MS m/z (ESI): 443.2 [M+H] + .
第三步：N-(5-(5-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)噁唑-2-基)-2-氟-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物63d)的制备The third step: N-(5-(5-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] ) oxazol-2-yl)-2-fluoro-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 63d) preparation
将化合物63c(155mg，350umol)、63a(197mg，525umol)、Pd(PPh3)4(20.2mg，17.5umol)和t-BuONa(50.5mg，525umol)加入到1，4-二氧六环(4mL)中，氮气保护下120℃反应3hr。反应结束后，将反应液浓缩干，粗产物经Prep-HPLC纯化，得到化合物63d(55.0mg)。MS m/z(ESI)：738.2[M+H] +。 Compounds 63c (155mg, 350umol), 63a (197mg, 525umol), Pd(PPh3)4 (20.2mg, 17.5umol) and t-BuONa (50.5mg, 525umol) were added to 1,4-dioxane (4mL) ), reacted at 120 °C for 3 hr under nitrogen protection. After the reaction, the reaction solution was concentrated to dryness, and the crude product was purified by Prep-HPLC to obtain compound 63d (55.0 mg). MS m/z (ESI): 738.2 [M+H] + .
第四步：N-(5-(5-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)噁唑-2-基)-2-氟-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物63)的制备The fourth step: N-(5-(5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)oxazol-2-yl)-2-fluoro Preparation of -4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 63)
将化合物63d(50.0mg，67.8umol)加入到TFA(1mL)中，100℃反应12hr。反应结束后将反应液 浓缩干，粗产物经Prep-HPLC纯化，得到化合物63(2.62mg)。MS m/z(ESI)：498.0[M+H] +。 Compound 63d (50.0 mg, 67.8 umol) was added to TFA (1 mL) and reacted at 100°C for 12 hr. After the reaction, the reaction solution was concentrated to dryness, and the crude product was purified by Prep-HPLC to obtain compound 63 (2.62 mg). MS m/z (ESI): 498.0 [M+H] + .
1H NMR(400MHz DMSO-d 6)δ10.57(s，1H)，8.46(s，1H)，8.36(s，2H)，8.32(t，J＝7.6Hz，2H)，8.28(s，1H)，8.08(s，1H)，8.00(d，J＝7.6Hz，1H)，7.92(s，1H)，7.82(t，J＝8.0Hz，1H)，7.45(d，J＝10.8Hz，1H)，2.75(s，3H). 1 H NMR (400 MHz DMSO-d 6 ) δ 10.57 (s, 1H), 8.46 (s, 1H), 8.36 (s, 2H), 8.32 (t, J=7.6 Hz, 2H), 8.28 (s, 1H) ), 8.08(s, 1H), 8.00(d, J=7.6Hz, 1H), 7.92(s, 1H), 7.82(t, J=8.0Hz, 1H), 7.45(d, J=10.8Hz, 1H) ), 2.75(s, 3H).
实施例64：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-3-甲基-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物64)Example 64: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-3-methyl-1H-pyrazole- 1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 64)
Figure PCTCN2022079826-appb-000146
Figure PCTCN2022079826-appb-000146
第一步：N，N-双(4-甲氧基苄基)-7-(3-甲基-1H-吡唑-4-基)咪唑并[2，1-f][1，2，4]三嗪-4-胺(化合物64a)的制备The first step: N,N-bis(4-methoxybenzyl)-7-(3-methyl-1H-pyrazol-4-yl)imidazo[2,1-f][1,2, 4] Preparation of triazine-4-amine (compound 64a)
将化合物4c(120mg，264.13μmol)与59a(219.83mg，1.06mmol)加入到1，4-二氧六环(6mL)和水(1mL)中，再加入Pd(dppf)Cl 2·DCM(21.57mg，26.41μmol)和碳酸钾(109.52mg，792.39μmol)，氮气保护下，升温至90℃反应6小时。反应结束后加入水稀释，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(EA/PE＝1/4)分离纯化，得到化合物64a(65mg)。MS m/z(ESI)：456.1[M+H] +。 Compound 4c (120 mg, 264.13 μmol) and 59a (219.83 mg, 1.06 mmol) were added to 1,4-dioxane (6 mL) and water (1 mL), followed by Pd(dppf)Cl 2 ·DCM (21.57 mg, 26.41 μmol) and potassium carbonate (109.52 mg, 792.39 μmol), under nitrogen protection, the temperature was raised to 90° C. to react for 6 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel flash column chromatography (EA/PE=1/4) to obtain compound 64a (65 mg). MS m/z (ESI): 456.1 [M+H] + .
第二步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-3-甲基-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物64b)的制备Step 2: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-3-methyl-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 64b) preparation
反应瓶中依次加入化合物64a(40mg，87.81μmol)、化合物3d(42.56mg，131.72μmol)、Cu(OAc) 2(17.53mg，87.81μmol)、吡啶(17.37mg，219.53μmol)、DMAP(21.46mg，175.63μmol)和1，4-二氧六环(5mL)，空气氛围下90℃反应16小时。反应结束后加入水稀释，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得化合物64b(50mg)。MS m/z(ESI)：733.2[M+H] +。 Compound 64a (40 mg, 87.81 μmol), compound 3d (42.56 mg, 131.72 μmol), Cu(OAc) 2 (17.53 mg, 87.81 μmol), pyridine (17.37 mg, 219.53 μmol), DMAP (21.46 mg) were sequentially added to the reaction flask , 175.63 μmol) and 1,4-dioxane (5 mL), reacted at 90° C. for 16 hours in an air atmosphere. After the reaction was completed, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 64b (50 mg). MS m/z (ESI): 733.2 [M+H] + .
第三步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-3-甲基-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物64)的制备The third step: N-(3-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-3-methyl-1H-pyrazole- Preparation of 1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 64)
将化合物64b(50mg，68.24μmol)溶于三氟乙酸(4mL)中，加热至90℃反应16小时。反应结束后将反应液浓缩干，加入饱和碳酸氢钠溶液，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经Prep-HPLC分离纯化，得到化合物64(3.12mg)。MS m/z(ESI)：493.1[M+H] +。 Compound 64b (50 mg, 68.24 μmol) was dissolved in trifluoroacetic acid (4 mL) and heated to 90° C. to react for 16 hours. After the reaction, the reaction solution was concentrated to dryness, saturated sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by Prep-HPLC to obtain the compound 64 (3.12 mg). MS m/z (ESI): 493.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.63(s，1H)，8.62(s，1H)，8.32(s，1H)，8.28(t，J＝6.8Hz，2H)，8.17(d，J＝7.8Hz，2H)，7.99(d，J＝7.7Hz，1H)，7.93(d，J＝2.1Hz，1H)，7.85(s，1H)，7.80(t，J＝7.5Hz，2H)，7.42(d，J＝8.5Hz，1H)，2.50(s，3H)，2.30(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.63 (s, 1H), 8.62 (s, 1H), 8.32 (s, 1H), 8.28 (t, J=6.8 Hz, 2H), 8.17 (d, J=7.8Hz, 2H), 7.99 (d, J=7.7Hz, 1H), 7.93 (d, J=2.1Hz, 1H), 7.85 (s, 1H), 7.80 (t, J=7.5Hz, 2H) , 7.42(d, J=8.5Hz, 1H), 2.50(s, 3H), 2.30(s, 3H).
实施例65：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(三氟甲基)哒嗪-3-甲酰胺(化合物65)Example 65: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (Compound 65)
Figure PCTCN2022079826-appb-000147
Figure PCTCN2022079826-appb-000147
第一步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(三氟甲基)哒嗪-3-甲酰胺(化合物65b)的制备The first step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (compound 65b) preparation
将化合物32d(26mg，47.56μmol)和65a(9.14mg，47.56μmol)溶于吡啶(4mL)中，再滴加T 3P(0.5mL，50％于EA中)，室温反应16小时。反应结束后减压浓缩除去溶剂，加入饱和碳酸氢钠水溶液，用乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物65b(25mg)。MS m/z(ESI)：721.2[M+H] +。 Compounds 32d (26 mg, 47.56 μmol) and 65a (9.14 mg, 47.56 μmol) were dissolved in pyridine (4 mL), T 3 P (0.5 mL, 50% in EA) was added dropwise, and the reaction was performed at room temperature for 16 hours. After the reaction was completed, the solvent was concentrated under reduced pressure to remove the solvent, saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 65b (25 mg). MS m/z (ESI): 721.2 [M+H] + .
第二步：N-(3-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(三氟甲基)哒嗪 -3-甲酰胺(化合物65)的制备Step 2: N-(3-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (Compound 65)
将化合物65b(25mg，34.69μmol)加入到三氟乙酸(5mL)中，加热至90℃反应16小时。反应结束后将反应液浓缩干，加入饱和碳酸氢钠溶液，用乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经Prep-HPLC分离纯化，得到化合物65(6.96mg)。MS m/z(ESI)：481.1[M+H] +。 Compound 65b (25 mg, 34.69 μmol) was added to trifluoroacetic acid (5 mL) and heated to 90° C. to react for 16 hours. After the reaction, the reaction solution was concentrated to dryness, saturated sodium bicarbonate solution was added, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to obtain Compound 65 (6.96 mg). MS m/z (ESI): 481.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ11.49(s，1H)，9.98(d，J＝1.9Hz，1H)，8.70(s，1H)，8.59(d，J＝1.4Hz，1H)，8.44(s，1H)，8.26(s，1H)，8.22-8.13(m，3H)，8.03-7.95(m，2H)，7.47(d，J＝8.6Hz，1H)，2.29(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.49 (s, 1H), 9.98 (d, J=1.9 Hz, 1H), 8.70 (s, 1H), 8.59 (d, J=1.4 Hz, 1H) , 8.44(s, 1H), 8.26(s, 1H), 8.22-8.13(m, 3H), 8.03-7.95(m, 2H), 7.47(d, J=8.6Hz, 1H), 2.29(s, 3H) ).
实施例66：N-(3-(4-(4-氨基吡咯并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(三氟甲基)哒嗪-3-甲酰胺(化合物66)Example 66: N-(3-(4-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 4-Methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (Compound 66)
Figure PCTCN2022079826-appb-000148
Figure PCTCN2022079826-appb-000148
第一步：(3-(4-(4-(双(4-甲氧基苄基)氨基)吡咯并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)氨基甲酸叔丁酯(化合物66a)的制备First step: (3-(4-(4-(bis(4-methoxybenzyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- Preparation of tert-butyl 1H-pyrazol-1-yl)-4-methylphenyl)carbamate (compound 66a)
反应瓶中依次加入化合物49c(95mg，215.67μmol)、32b(64.98mg，258.80μmol)、Cu(OAc) 2(43.06mg，215.67μmol)、吡啶(42.65mg，539.16μmol)、DMAP(52.69mg，431.33μmol)和1，4-二氧六环(6mL)，空气氛围下90℃反应16小时。反应结束后加入水稀释，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(EA/PE＝3/7)分离纯化，得到化合物66a(100mg)。MS m/z(ESI)：646.3[M+H] +。 Compound 49c (95 mg, 215.67 μmol), 32b (64.98 mg, 258.80 μmol), Cu(OAc) 2 (43.06 mg, 215.67 μmol), pyridine (42.65 mg, 539.16 μmol), DMAP (52.69 mg, 431.33 μmol) and 1,4-dioxane (6 mL), reacted at 90° C. for 16 hours under air atmosphere. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel flash column chromatography (EA/PE=3/7) to obtain compound 66a (100 mg). MS m/z (ESI): 646.3 [M+H] + .
第二步：7-(1-(5-氨基-2-甲基苯基)-1H-吡唑-4-基)-N，N-双(4-甲氧基苄基)吡咯并[2，1-f][1，2，4]三嗪-4-胺(化合物66b)的制备Step 2: 7-(1-(5-Amino-2-methylphenyl)-1H-pyrazol-4-yl)-N,N-bis(4-methoxybenzyl)pyrrolo[2 , Preparation of 1-f][1,2,4]triazin-4-amine (Compound 66b)
将化合物66a(100mg，154.86μmol)加入二氯甲烷(4mL)中，再滴入HCl的1，4-二氧六环溶液(2mL，4M)，加完后室温反应2小时。反应结束后减压除去溶剂，加水稀释，再加入用饱和碳酸氢钠溶液，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，浓缩，得到化合物66b(70mg)。MS m/z(ESI)：546.3[M+H] +。 Compound 66a (100 mg, 154.86 μmol) was added to dichloromethane (4 mL), and then HCl in 1,4-dioxane solution (2 mL, 4 M) was added dropwise, and the reaction was carried out at room temperature for 2 hours. After the reaction, the solvent was removed under reduced pressure, diluted with water, and then added with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 66b (70 mg). MS m/z (ESI): 546.3 [M+H] + .
第三步：N-(3-(4-(4-(双(4-甲氧基苄基)氨基)吡咯并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(三氟甲基)哒嗪-3-甲酰胺(化合物66c)的制备The third step: N-(3-(4-(4-(bis(4-methoxybenzyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (compound 66c) preparation
将化合物66b(70mg，128.29μmol)和65a(24.64mg，128.29μmol)溶于吡啶(5mL)中，滴加T 3P(0.5mL)，室温反应16小时。反应结束后减压浓缩除去溶剂，加入饱和碳酸氢钠水溶液，用乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到化合物66c(60mg)。MS m/z(ESI)：720.3[M+H] +。 Compounds 66b (70 mg, 128.29 μmol) and 65a (24.64 mg, 128.29 μmol) were dissolved in pyridine (5 mL), T 3 P (0.5 mL) was added dropwise, and the reaction was performed at room temperature for 16 hours. After the reaction was completed, the solvent was concentrated under reduced pressure to remove the solvent, saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 66c (60 mg). MS m/z (ESI): 720.3 [M+H] + .
第四步：N-(3-(4-(4-氨基吡咯并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(三氟甲基)哒嗪-3-甲酰胺(化合物66)的制备Fourth step: N-(3-(4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (Compound 66)
将化合物66c(60mg，83.37μmol)加入到三氟乙酸(5mL)中，加热至90℃反应16小时。反应结束后将反应液浓缩干，加入饱和碳酸氢钠溶液，用乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经Prep-HPLC分离纯化，得到化合物66(29.40mg)。MS m/z(ESI)：480.2[M+H] +。 Compound 66c (60 mg, 83.37 μmol) was added to trifluoroacetic acid (5 mL) and heated to 90° C. to react for 16 hours. After the reaction, the reaction solution was concentrated to dryness, saturated sodium bicarbonate solution was added, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to obtain Compound 66 (29.40 mg). MS m/z (ESI): 480.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ11.48(s，1H)，9.98(d，J＝1.6Hz，1H)，8.67(s，1H)，8.59(d，J＝1.1Hz，1H)，8.40(s，1H)，8.15(d，J＝1.9Hz，1H)，8.03-7.94(m，2H)，7.73(s，2H)，7.46(d，J＝8.5Hz，1H)，7.01(dd，J＝15.4，4.5Hz，2H)，2.29(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.48 (s, 1H), 9.98 (d, J=1.6 Hz, 1H), 8.67 (s, 1H), 8.59 (d, J=1.1 Hz, 1H) , 8.40(s, 1H), 8.15(d, J=1.9Hz, 1H), 8.03-7.94(m, 2H), 7.73(s, 2H), 7.46(d, J=8.5Hz, 1H), 7.01( dd, J=15.4, 4.5Hz, 2H), 2.29(s, 3H).
实施例67：N-(3-(4-(4-氨基喹唑啉-8-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(三氟甲基)哒嗪-3-甲酰胺(化合 物67)Example 67: N-(3-(4-(4-Aminoquinazolin-8-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-5-(trifluoromethyl) ) pyridazine-3-carboxamide (compound 67)
Figure PCTCN2022079826-appb-000149
Figure PCTCN2022079826-appb-000149
第一步：(3-(4-(4-((2，4-二甲氧基苄基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)-4-甲基苯基)氨基甲酸叔丁酯(化合物67a)的制备The first step: (3-(4-(4-((2,4-dimethoxybenzyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)-4-methyl Preparation of tert-butyl phenyl)carbamate (compound 67a)
反应瓶中依次加入化合物2e(155mg，428.89μmol)、32b(129.23mg，514.67μmol)、Cu(OAc) 2(85.63mg，428.89μmol)、吡啶(84.81mg，1.07mmol)、DMAP(104.79mg，857.78μmol)和1，4-二氧六环(6mL)，空气氛围下90℃反应16小时。反应结束后加入水稀释，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(EA/PE＝1/1)分离纯化，得到化合物67a(156mg)。MS m/z(ESI)：567.2[M+H] +。 Compound 2e (155 mg, 428.89 μmol), 32b (129.23 mg, 514.67 μmol), Cu(OAc) 2 (85.63 mg, 428.89 μmol), pyridine (84.81 mg, 1.07 mmol), DMAP (104.79 mg, 857.78 μmol) and 1,4-dioxane (6 mL), react at 90° C. for 16 hours under air atmosphere. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel flash column chromatography (EA/PE=1/1) to obtain compound 67a (156 mg). MS m/z (ESI): 567.2 [M+H] + .
第二步：8-(1-(5-氨基-2-甲基苯基)-1H-吡唑-4-基)-N-(2，4-二甲氧基苄基)喹唑啉-4-胺(化合物67b)的制备Step 2: 8-(1-(5-Amino-2-methylphenyl)-1H-pyrazol-4-yl)-N-(2,4-dimethoxybenzyl)quinazoline- Preparation of 4-amine (compound 67b)
将化合物67a(156mg，275.30μmol)加入二氯甲烷(4mL)中，再滴入HCl的1，4-二氧六环溶液(2mL，4M)，加完后室温反应2小时。反应结束后减压除去溶剂，加水稀释，再用饱和碳酸氢钠溶液调节溶液pH至约8，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(EA/PE＝1/1)分离纯化，得到化合物67b(75mg)。MS m/z(ESI)：467.2[M+H] +。 Compound 67a (156 mg, 275.30 μmol) was added to dichloromethane (4 mL), and then a solution of HCl in 1,4-dioxane (2 mL, 4 M) was added dropwise, and the reaction was carried out at room temperature for 2 hours. After the reaction, the solvent was removed under reduced pressure, diluted with water, the pH of the solution was adjusted to about 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel flash column chromatography (EA/PE=1/1) to obtain compound 67b (75 mg). MS m/z (ESI): 467.2 [M+H] + .
第三步：N-(3-(4-(4-((2，4-二甲氧基苄基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(三氟甲基)哒嗪-3-甲酰胺(化合物67c)的制备The third step: N-(3-(4-(4-((2,4-dimethoxybenzyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)-4 Preparation of -methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (compound 67c)
将化合物67b(75mg，160.76μmol)和65a(30.88mg，160.76μmol)溶于吡啶(3mL)中，再滴加T 3P(0.5mL，50％于EA中)，室温反应16小时。反应结束后减压浓缩除去溶剂，加入饱和碳酸氢钠水溶液，用乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物67c(60mg)。MS m/z(ESI)：641.3[M+H] +。 Compounds 67b (75 mg, 160.76 μmol) and 65a (30.88 mg, 160.76 μmol) were dissolved in pyridine (3 mL), T 3 P (0.5 mL, 50% in EA) was added dropwise, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the solvent was concentrated under reduced pressure to remove the solvent, saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 67c (60 mg). MS m/z (ESI): 641.3 [M+H] + .
第四步：N-(3-(4-(4-氨基喹唑啉-8-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(三氟甲基)哒嗪-3-甲酰胺(化合物67)的制备The fourth step: N-(3-(4-(4-aminoquinazolin-8-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-5-(trifluoromethyl) ) Preparation of pyridazine-3-carboxamide (compound 67)
将化合物67c(60mg，93.66μmol)加入到三氟乙酸(3mL)中，加热至90℃反应16小时。反应结束后将反应液浓缩干，加入饱和碳酸氢钠溶液，用乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经Prep-HPLC分离纯化，得到化合物67(2.15mg)。MS m/z(ESI)：491.2[M+H] +。 Compound 67c (60 mg, 93.66 μmol) was added to trifluoroacetic acid (3 mL) and heated to 90° C. to react for 16 hours. After the reaction, the reaction solution was concentrated to dryness, saturated sodium bicarbonate solution was added, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to obtain Compound 67 (2.15 mg). MS m/z (ESI): 491.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ11.48(s，1H)，9.97(d，J＝1.9Hz，1H)，8.95(s，1H)，8.59(d，J＝1.4Hz，1H)，8.54(s，1H)，8.50(s，1H)，8.20(d，J＝6.7Hz，1H)，8.16(d，J＝2.0Hz，1H)，8.12(d，J＝8.2Hz，1H)，7.98(dd，J＝8.4，2.1Hz，1H)，7.81(s，2H)，7.52(t，J＝7.8Hz，1H)，7.46(d，J＝8.5Hz，1H)，2.31(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.48 (s, 1H), 9.97 (d, J=1.9 Hz, 1H), 8.95 (s, 1H), 8.59 (d, J=1.4 Hz, 1H) , 8.54(s, 1H), 8.50(s, 1H), 8.20(d, J=6.7Hz, 1H), 8.16(d, J=2.0Hz, 1H), 8.12(d, J=8.2Hz, 1H) , 7.98(dd, J=8.4, 2.1Hz, 1H), 7.81(s, 2H), 7.52(t, J=7.8Hz, 1H), 7.46(d, J=8.5Hz, 1H), 2.31(s, 3H).
实施例68：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(三氟甲基)哒嗪-3-甲酰胺(化合物68)Example 68: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- 5-(Trifluoromethyl)pyridazine-3-carboxamide (Compound 68)
Figure PCTCN2022079826-appb-000150
Figure PCTCN2022079826-appb-000150
第一步：N-(4-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)-5-(三氟甲基)哒嗪-3-甲酰胺(化合物68a)的制备The first step: N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-5-( Preparation of trifluoromethyl)pyridazine-3-carboxamide (compound 68a)
将化合物3a(120mg，514.77μmol)和65a(98.88mg，514.77μmol)溶于吡啶(4mL)中，再滴加T 3P(0.5mL，50％于EA中)，室温反应16小时。反应结束后减压浓缩除去溶剂，加入饱和碳酸氢钠水溶液，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(EA/PE＝3/7)分离纯化，得到化合物68a(93mg)。MS m/z(ESI)：408.1[M+H] +。 Compounds 3a (120 mg, 514.77 μmol) and 65a (98.88 mg, 514.77 μmol) were dissolved in pyridine (4 mL), T 3 P (0.5 mL, 50% in EA) was added dropwise, and the reaction was performed at room temperature for 16 hours. After the reaction was completed, the solvent was concentrated under reduced pressure to remove the solvent, saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel flash column chromatography (EA/PE=3/7) to obtain compound 68a (93 mg). MS m/z (ESI): 408.1 [M+H] + .
第二步：(2-甲基-5-(5-(三氟甲基)哒嗪-3-甲酰胺基)苯基)硼酸(化合物68b)的制备The second step: preparation of (2-methyl-5-(5-(trifluoromethyl)pyridazine-3-carboxamido)phenyl)boronic acid (compound 68b)
反应瓶中加入化合物68a(93mg，228.39μmol)、NaIO 4(122.13mg，570.98μmol)和MeCN(5mL)，再加入醋酸铵(52.81mg，685.18μmol)的H 2O(1mL)溶液，加完后50℃反应16小时。反应结束后加水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(EA/PE＝3/7)分离纯化，得到化合物68b(50mg)。MS m/z(ESI)：326.0[M+H] +。 Compound 68a (93 mg, 228.39 μmol), NaIO 4 (122.13 mg, 570.98 μmol) and MeCN (5 mL) were added to the reaction flask, and a solution of ammonium acetate (52.81 mg, 685.18 μmol) in H 2 O (1 mL) was added. The reaction was carried out at 50°C for 16 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel flash column chromatography (EA/PE=3/7) to obtain compound 68b (50 mg). MS m/z (ESI): 326.0 [M+H] + .
第三步：N-(3-(4-(4-((2，4-二甲氧基苄基)氨基)噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(三氟甲基)哒嗪-3-甲酰胺(化合物68c)的制备The third step: N-(3-(4-(4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazole Preparation of -1-yl)-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (compound 68c)
反应瓶中依次加入化合物68b(53mg，163.30μmol)、8a(50mg，136.08μmol)、Cu(OAc) 2(27.17mg，136.08μmol)、吡啶(26.91mg，340.21μmol)、DMAP(33.25mg，272.16μmol)和1，4-二氧六环(4mL)，空气氛围下90℃反应16小时。反应结束后加入水稀释，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(EA/PE＝3/7)分离纯化，得到化合物68c(50mg)。MS m/z(ESI)：647.2[M+H] +。 Compound 68b (53 mg, 163.30 μmol), 8a (50 mg, 136.08 μmol), Cu(OAc) 2 (27.17 mg, 136.08 μmol), pyridine (26.91 mg, 340.21 μmol), DMAP (33.25 mg, 272.16 μmol) were added to the reaction flask in sequence μmol) and 1,4-dioxane (4 mL), reacted at 90° C. for 16 hours under air atmosphere. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated and purified by silica gel flash column chromatography (EA/PE=3/7) to obtain compound 68c (50 mg). MS m/z (ESI): 647.2 [M+H] + .
第四步：N-(3-(4-(4-氨基噻吩并[3，2-d]嘧啶-7-基)-1H-吡唑-1-基)-4-甲基苯基)-5-(三氟甲基)哒嗪-3-甲酰胺(化合物68)的制备Step 4: N-(3-(4-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-1-yl)-4-methylphenyl)- Preparation of 5-(trifluoromethyl)pyridazine-3-carboxamide (Compound 68)
将化合物68c(50mg，77.32μmol)加入到三氟乙酸(5mL)中，加热至90℃反应4小时。反应结束后将反应液浓缩干，加入饱和碳酸氢钠溶液，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经Prep-HPLC分离纯化，得到化合物68(4.21mg)。MS m/z(ESI)：497.1[M+H] +。 Compound 68c (50 mg, 77.32 μmol) was added to trifluoroacetic acid (5 mL) and heated to 90° C. to react for 4 hours. After the reaction, the reaction solution was concentrated to dryness, saturated sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by Prep-HPLC to obtain the compound 68 (4.21 mg). MS m/z (ESI): 497.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ11.48(s，1H)，8.81(s，1H)，8.62-8.58(m，1H)，8.49(s，1H)，8.47(s，1H)，8.33(s，1H)，8.21-8.13(m，2H)，7.98(dd，J＝8.4，2.2Hz，1H)，7.53(s，2H)，7.46(d，J＝8.6Hz，1H)，2.29(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.48(s, 1H), 8.81(s, 1H), 8.62-8.58(m, 1H), 8.49(s, 1H), 8.47(s, 1H), 8.33(s, 1H), 8.21-8.13(m, 2H), 7.98(dd, J=8.4, 2.2Hz, 1H), 7.53(s, 2H), 7.46(d, J=8.6Hz, 1H), 2.29 (s, 3H).
实施例69：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-5-(三氟甲基)哒嗪-3-甲酰胺(化合物69)Example 69: N-(5-(4-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- 2-Fluoro-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (Compound 69)
Figure PCTCN2022079826-appb-000151
Figure PCTCN2022079826-appb-000151
第一步：N-(2-氟-4-甲基-5-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)苯基)-5-(三氟甲基)哒嗪-3-甲酰胺(化合物69a)的制备The first step: N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl) - Preparation of 5-(trifluoromethyl)pyridazine-3-carboxamide (compound 69a)
将化合物33b(286mg，1.14mmol)和65a(218.79mg，1.14mmol)溶于吡啶(4mL)中，滴加T 3P(0.5mL，50％于EA中)，室温反应16小时。反应结束后减压浓缩除去溶剂，加入饱和碳酸氢钠溶液，乙酸乙酯萃取，有机相经水洗，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(PE/EA＝4/1)纯化，得到化合物69a(104mg)。MS m/z(ESI)：426.1[M+H] +。 Compounds 33b (286 mg, 1.14 mmol) and 65a (218.79 mg, 1.14 mmol) were dissolved in pyridine ( 4 mL), T3P (0.5 mL, 50% in EA) was added dropwise, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the solvent was concentrated under reduced pressure to remove the solvent, saturated sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography (PE/EA=4/1) to obtain compound 69a (104 mg). MS m/z (ESI): 426.1 [M+H] + .
第二步：(4-氟-2-甲基-5-(5-(三氟甲基)哒嗪-3-甲酰胺基)苯基)硼酸(化合物69b)的制备The second step: preparation of (4-fluoro-2-methyl-5-(5-(trifluoromethyl)pyridazine-3-carboxamido)phenyl)boronic acid (compound 69b)
反应瓶中加入化合物69a(104mg，244.6μmol)、NaIO 4(130.79mg，611.5μmol)和MeCN(5mL)，再加入醋酸铵(56.56mg，733.8μmol)的H 2O(1mL)溶液，加热至50℃反应16小时。反应结束后加水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物经硅胶快速柱色谱法(PE/EA＝1/1)纯化，得到化合物69b(56mg)。MS m/z(ESI)：344.0[M+H] +。 Compound 69a (104 mg, 244.6 μmol), NaIO 4 (130.79 mg, 611.5 μmol) and MeCN (5 mL) were added to the reaction flask, and a solution of ammonium acetate (56.56 mg, 733.8 μmol) in H 2 O (1 mL) was added and heated to The reaction was carried out at 50°C for 16 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography (PE/EA=1/1) to give compound 69b (56 mg). MS m/z (ESI): 344.0 [M+H] + .
第三步：N-(5-(4-(4-(双(4-甲氧基苄基)氨基)咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-5-(三氟甲基)哒嗪-3-甲酰胺(化合物69c)的制备The third step: N-(5-(4-(4-(bis(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-7-yl] )-1H-pyrazol-1-yl)-2-fluoro-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (compound 69c) preparation
反应瓶中依次加入化合物69b(56mg，163.09μmol)、4d(60mg，135.91μmol)、Cu(OAc) 2(27.13mg，135.91μmol)、吡啶(26.88mg，339.76μmol)、DMAP(33.21mg，271.81μmol)和1，4-二氧六环(5mL)，空气氛围下90℃反应16小时。反应结束后加入水稀释，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物69c(70mg)。MS m/z(ESI)：739.3[M+H] +。 Compound 69b (56 mg, 163.09 μmol), 4d (60 mg, 135.91 μmol), Cu(OAc) 2 (27.13 mg, 135.91 μmol), pyridine (26.88 mg, 339.76 μmol), DMAP (33.21 mg, 271.81 μmol) were added to the reaction flask in sequence μmol) and 1,4-dioxane (5 mL), reacted at 90° C. for 16 hours in an air atmosphere. After the reaction was completed, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 69c (70 mg). MS m/z (ESI): 739.3 [M+H] + .
第四步：N-(5-(4-(4-氨基咪唑并[2，1-f][1，2，4]三嗪-7-基)-1H-吡唑-1-基)-2-氟-4-甲基苯基)-5-(三氟甲基)哒嗪-3-甲酰胺(化合物69)的制备Fourth step: N-(5-(4-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)- Preparation of 2-Fluoro-4-methylphenyl)-5-(trifluoromethyl)pyridazine-3-carboxamide (Compound 69)
将化合物69c(70mg，94.76μmol)加入到三氟乙酸(4mL)中，加热至90℃反应16小时。反应结束后将反应液浓缩干，加入饱和碳酸氢钠溶液，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经Prep-HPLC分离纯化，得到化合物69(1mg)。MS m/z(ESI)：499.1[M+H] +。 Compound 69c (70 mg, 94.76 μmol) was added to trifluoroacetic acid (4 mL) and heated to 90° C. to react for 16 hours. After the reaction, the reaction solution was concentrated to dryness, saturated sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by Prep-HPLC to obtain the compound 69 (1 mg). MS m/z (ESI): 499.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ11.14(s，1H)，10.00(d，J＝1.8Hz，1H)，8.70(s，1H)，8.60(d，J＝1.5Hz，1H)，8.44(s，1H)，8.26(s，1H)，8.18(s，2H)，7.98(s，1H)，7.89(d，J＝7.2Hz，1H)，7.51(d，J＝11.2Hz，1H)，2.29(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.14 (s, 1H), 10.00 (d, J=1.8 Hz, 1H), 8.70 (s, 1H), 8.60 (d, J=1.5 Hz, 1H) , 8.44(s, 1H), 8.26(s, 1H), 8.18(s, 2H), 7.98(s, 1H), 7.89(d, J=7.2Hz, 1H), 7.51(d, J=11.2Hz, 1H), 2.29(s, 3H).
实施例70：N-(4-甲基-3-(4-(2-甲基-4-氧代-3，4-二氢喹唑啉-6-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺(化合物70)Example 70: N-(4-Methyl-3-(4-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-1H-pyrazole-1- yl)phenyl)-3-(trifluoromethyl)benzamide (Compound 70)
Figure PCTCN2022079826-appb-000152
Figure PCTCN2022079826-appb-000152
第一步：N-(3-(4-溴-1H-吡唑-1-基)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(化合物70a)的制备The first step: preparation of N-(3-(4-bromo-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 70a)
将4-溴吡唑(29mg，0.2mmol)、化合物3d(77mg，0.24mmol)、醋酸铜(36mg，0.20mmol)和DMAP(48mg，0.40mmol)置于反应瓶中，加入吡啶(40mg，0.50mmol)的1，4-二氧六环(2mL)溶液，加毕于空气球氛围下加热至90℃反应1hr。反应结束后冷却至室温，反应液经过滤，DCM淋洗，滤液减压浓缩，后经Prep-TLC(PE/EA＝5/1)分离纯化，得到化合物70a(60mg)。MS m/z(ESI)：424.0[M+H] +。 4-Bromopyrazole (29 mg, 0.2 mmol), compound 3d (77 mg, 0.24 mmol), copper acetate (36 mg, 0.20 mmol) and DMAP (48 mg, 0.40 mmol) were placed in a reaction flask, and pyridine (40 mg, 0.50 mmol) was added. mmol) in 1,4-dioxane (2 mL) solution, heated to 90° C. for 1 hr under an air balloon atmosphere. After the reaction was completed, it was cooled to room temperature, the reaction solution was filtered, rinsed with DCM, the filtrate was concentrated under reduced pressure, and then separated and purified by Prep-TLC (PE/EA=5/1) to obtain compound 70a (60 mg). MS m/z (ESI): 424.0 [M+H] + .
第二步：N-(4-甲基-3-(4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺(化合物70b)的制备The second step: N-(4-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyridine Preparation of azol-1-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 70b)
将化合物70a(60mg，0.14mmol)、B2(pin)2(54mg，0.21mmol)、Pd(dppf)Cl 2·DCM(12mg，0.014mmol)和KOAc(28mg，0.28mmol)加入到1，4-二氧六环(3mL)中，然后加热至90℃反应7hr。反应结束后冷却至室温，减压浓缩除去溶剂，加水后用DCM萃取，有机相用无水硫酸钠干燥，过滤， 浓缩，后经Prep-TLC(PE/EA＝3/1)分离纯化，得到化合物70b(30mg)。MS m/z(ESI)：472.2[M+H] +。 To the 1,4- in dioxane (3 mL), and then heated to 90 °C for 7 hr. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure to remove the solvent, added water and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by Prep-TLC (PE/EA=3/1) to obtain Compound 70b (30 mg). MS m/z (ESI): 472.2 [M+H] + .
第三步：6-溴-2-甲基喹唑啉-4(3H)-酮(化合物70d)的制备The third step: preparation of 6-bromo-2-methylquinazolin-4(3H)-one (compound 70d)
将化合物70c(108mg，0.5mmol)溶解于无水乙醇(5mL)中，加入TBHP(5.0M，0.5mL)，然后加热至110℃反应16.5hr。反应结束后减压除去溶剂，用DCM溶解可溶物，过滤并用DCM淋洗，固体干燥后得到化合物70d(70mg)。MS m/z(ESI)：239.0[M+H] +。 Compound 70c (108 mg, 0.5 mmol) was dissolved in absolute ethanol (5 mL), TBHP (5.0 M, 0.5 mL) was added, and then heated to 110° C. for 16.5 hr. After the reaction was completed, the solvent was removed under reduced pressure, the solubles were dissolved in DCM, filtered and rinsed with DCM, and the solid was dried to give compound 70d (70 mg). MS m/z (ESI): 239.0 [M+H] + .
第四步：N-(4-甲基-3-(4-(2-甲基-4-氧代-3，4-二氢喹唑啉-6-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺(化合物70)The fourth step: N-(4-methyl-3-(4-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-1H-pyrazole-1- yl)phenyl)-3-(trifluoromethyl)benzamide (Compound 70)
将化合物70d(12mg，0.05mmol)、70b(24mg，0.05mmol)、Pd(dppf)Cl 2·DCM(4mg，5μmol)和碳酸钾(20mg，0.15mmol)置于反应瓶中，加入DMF(3mL)和水(0.5mL)，氮气保护下加热至90℃反应1hr。反应结束后冷却至室温，加水稀释，用EA萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤后减压浓缩，粗产物经Prep-HPLC分离纯化，得到化合物70(4mg)。MS m/z(ESI)：504.1[M+H] +。 Compound 70d (12 mg, 0.05 mmol), 70b (24 mg, 0.05 mmol), Pd(dppf)Cl 2 ·DCM (4 mg, 5 μmol) and potassium carbonate (20 mg, 0.15 mmol) were placed in a reaction flask, and DMF (3 mL) was added ) and water (0.5 mL), heated to 90 °C under nitrogen protection for 1 hr. After the reaction, it was cooled to room temperature, diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated and purified by Prep-HPLC to obtain compound 70 (4 mg). MS m/z (ESI): 504.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ12.65(br，1H)，10.64(s，1H)，8.76(s，1H)，8.39(d，J＝2.0Hz，1H)，8.36(s，1H)，8.32(s，1H)，8.28(d，J＝8.0Hz，1H)，8.19(dd，J＝8.4Hz，2.0Hz，1H)，8.00-7.98(m，2H)，7.82-7.77(m，2H)，7.64(d，J＝8.8Hz，1H)，7.43(d，J＝8.4Hz，1H)，2.43(s，3H)，2.29(s，3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.65 (br, 1H), 10.64 (s, 1H), 8.76 (s, 1H), 8.39 (d, J=2.0 Hz, 1H), 8.36 (s, 1H), 8.32(s, 1H), 8.28(d, J=8.0Hz, 1H), 8.19(dd, J=8.4Hz, 2.0Hz, 1H), 8.00-7.98(m, 2H), 7.82-7.77( m, 2H), 7.64 (d, J=8.8Hz, 1H), 7.43 (d, J=8.4Hz, 1H), 2.43 (s, 3H), 2.29 (s, 3H).
实施例71：N-(4-甲基-3-(4-(7-氧代-5，6，7，8-四氢吡啶并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺(化合物71)Example 71: N-(4-Methyl-3-(4-(7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H -Pyrazol-1-yl)phenyl)-3-(trifluoromethyl)benzamide (Compound 71)
Figure PCTCN2022079826-appb-000153
Figure PCTCN2022079826-appb-000153
第一步：(E)-3-(4-氨基-6-氯嘧啶-5-基)丙烯酸乙酯(化合物71b)的制备Step 1: Preparation of (E)-ethyl 3-(4-amino-6-chloropyrimidin-5-yl)acrylate (compound 71b)
将化合物71b(1.23g，5.5mmol)溶解于CH 3CN(10mL)中，然后依次加入化合物71a(788mg，5.0mmol)、LiCl(424mg，10.0mmol)和Et 3N(606mg，6.0mmol)，加完后25℃反应20hr。反应结束后加入EA稀释，水洗，有机相用无水硫酸钠干燥，过滤，浓缩，后经硅胶快速柱层析(PE/EA＝1/1)分离纯化，得到化合物71c(1.0g)。MS m/z(ESI)：228.0[M+H] +。 Compound 71b (1.23 g, 5.5 mmol) was dissolved in CH 3 CN (10 mL), then compound 71 a (788 mg, 5.0 mmol), LiCl (424 mg, 10.0 mmol) and Et 3 N (606 mg, 6.0 mmol) were added sequentially, After the addition, the reaction was carried out at 25°C for 20hrs. After the reaction, EA was added for dilution, washed with water, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel flash column chromatography (PE/EA=1/1) to obtain compound 71c (1.0 g). MS m/z (ESI): 228.0 [M+H] + .
第二步：3-(4-氨基-6-氯嘧啶-5-基)丙酸乙酯(化合物71d)的制备Step 2: Preparation of ethyl 3-(4-amino-6-chloropyrimidin-5-yl)propanoate (compound 71d)
将化合物71c(228mg，1.0mmol)溶解于无水甲醇(10mL)中，加入5％Rh/C(236mg，0.1mmol)，氢气氛围下加热至40℃反应22hr。反应结束后用硅藻土过滤并用DCM和MeOH的混合溶剂淋洗，滤液浓缩得到化合物71d(220mg)。MS m/z(ESI)：230.1[M+H] +。 Compound 71c (228 mg, 1.0 mmol) was dissolved in anhydrous methanol (10 mL), 5% Rh/C (236 mg, 0.1 mmol) was added, and heated to 40° C. for 22 hr under hydrogen atmosphere. After the reaction was completed, it was filtered through celite and rinsed with a mixed solvent of DCM and MeOH, and the filtrate was concentrated to obtain compound 71d (220 mg). MS m/z (ESI): 230.1 [M+H] + .
第三步：4-氯-5，8-二氢吡啶并[2，3-d]嘧啶-7(6H)-酮(71e)的制备Step 3: Preparation of 4-chloro-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (71e)
将化合物71d(220mg，0.96mmol)溶解于无水乙醇(10mL)中，加入三乙胺(194mg，1.92mmol)，然后加热至80℃反应7hr。反应结束后冷却至室温，直接经硅胶快速柱层析(PE/EA＝3/2)分离纯化，得到化合物71e(140mg)。MS m/z(ESI)：184.0[M+H] +。 Compound 71d (220 mg, 0.96 mmol) was dissolved in absolute ethanol (10 mL), triethylamine (194 mg, 1.92 mmol) was added, and then heated to 80°C for 7 hr. After the reaction was completed, it was cooled to room temperature, and was directly separated and purified by silica gel flash column chromatography (PE/EA=3/2) to obtain compound 71e (140 mg). MS m/z (ESI): 184.0 [M+H] + .
第四步：N-(4-甲基-3-(4-(7-氧代-5，6，7，8-四氢吡啶并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基)苯基)-3-(三氟甲基)苯甲酰胺(化合物71)的制备The fourth step: N-(4-methyl-3-(4-(7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-1H Preparation of -pyrazol-1-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 71)
将化合物71e(16mg，0.09mmol)、70b(42mg，0.09mmol)、Pd(dppf)Cl 2.DCM(7mg，9μmol)和碳酸钾(37mg，0.27mmol)置于反应瓶中，加入DMF(3mL)和水(0.5mL)，然后加热至90℃反应1hr。反应结束后冷却至室温，加水稀释，用EA萃取，有机相用无水硫酸钠干燥，过滤后减压蒸出溶剂，经Prep-HPLC分离纯化得到化合物71(10mg)。MS m/z(ESI)：493.2[M+H] +。 Compound 71e (16 mg, 0.09 mmol), 70b (42 mg, 0.09 mmol), Pd(dppf)Cl 2 .DCM (7 mg, 9 μmol) and potassium carbonate (37 mg, 0.27 mmol) were placed in a reaction flask and DMF (3 mL) was added ) and water (0.5 mL), then heated to 90°C for 1 hr. After the reaction was completed, it was cooled to room temperature, diluted with water, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent, and separated and purified by Prep-HPLC to obtain compound 71 (10 mg). MS m/z (ESI): 493.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.90(s，1H)，10.65(s，1H)，8.66(s，1H)，8.61(s，1H)，8.32-8.27(m，3H)，8.00-7.96(m，2H)，7.83-7.78(m，2H)，7.44(d，J＝8.4Hz，1H)，3.15(t，J＝7.6Hz，2H)，2.62(t，J＝7.6Hz，2H)，2.25(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 10.90(s, 1H), 10.65(s, 1H), 8.66(s, 1H), 8.61(s, 1H), 8.32-8.27(m, 3H), 8.00-7.96(m, 2H), 7.83-7.78(m, 2H), 7.44(d, J=8.4Hz, 1H), 3.15(t, J=7.6Hz, 2H), 2.62(t, J=7.6Hz) , 2H), 2.25(s, 3H).
生物学评价Biological evaluation
实验例1：RAF抑制实验Experimental Example 1: RAF Inhibition Experiment
实验方法：根据TB-PMAP2K1(PSER217/221)试剂盒(ThermoFisher)的说明测定本申请实施例化合物对野生型BRAF酶、突变型CRAF酶(RAF1Y340D和Y341D)和突变型BRAF酶(BRAF V600E)活性的抑制作用。将不同的RAF酶和底物(FLUORESCEIN-MAP2K1)与不同浓度的测试化合物在室温下预孵育15min后，加入三磷酸腺苷(ATP)启动反应。在室温下孵育60min后加入EDTA和Tb标记的anti-pMAP2K1[pS217/221]抗体溶液，并于室温下孵育60min后进行检测。含RAF酶且不含化合物组为阴性对照，不含RAF酶且不含化合物组为空白对照，按照下式计算不同浓度化合物的相对抑制活性百分比(即抑制率)：Experimental method: According to the instructions of the TB-PMAP2K1 (PSER217/221) kit (ThermoFisher), the activity of the compounds of the examples in the present application on wild-type BRAF enzymes, mutant CRAF enzymes (RAF1 Y340D and Y341D) and mutant BRAF enzymes (BRAF V600E) were determined inhibitory effect. After pre-incubating different RAF enzymes and substrates (FLUORESCEIN-MAP2K1) with different concentrations of test compounds at room temperature for 15 min, adenosine triphosphate (ATP) was added to initiate the reaction. After 60min incubation at room temperature, EDTA and Tb-labeled anti-pMAP2K1[pS217/221] antibody solution were added, and the assay was performed after 60min incubation at room temperature. The group containing RAF enzyme and no compound is a negative control, and the group containing no RAF enzyme and no compound is a blank control, and the relative inhibitory activity percentage (ie, inhibition rate) of different concentrations of compounds is calculated according to the following formula:
相对抑制活性百分比＝1-(不同浓度化合物组-空白对照)/(阴性对照-空白对照)*100％Percentage of relative inhibitory activity=1-(compound groups of different concentrations-blank control)/(negative control-blank control)*100%
将不同浓度的化合物的相对抑制活性百分比相对于化合物浓度作图，按照四参数模型拟合曲线，通过下式计算IC 50值： The percent relative inhibitory activity of the compounds at different concentrations was plotted against the compound concentration, the curve was fitted according to a four-parameter model, and the IC50 value was calculated by the following formula:
y＝min+(max-min)/(1+(x/IC 50)^(-Hillslope)) y=min+(max-min)/(1+(x/IC 50 )^(-Hillslope))
其中y为相对抑制活性百分比，max和min分别为拟合曲线的最大值与最小值，x为化合物的对数浓度，Hillslope为曲线斜率。实验结果如表1-表3所示。where y is the percentage of relative inhibitory activity, max and min are the maximum and minimum values of the fitted curve, respectively, x is the logarithmic concentration of the compound, and Hillslope is the slope of the curve. The experimental results are shown in Table 1-Table 3.
表1：本申请实施例化合物对BRAF酶的抑制活性Table 1: Inhibitory activity of the compounds of the examples of this application on BRAF enzyme
化合物编号Compound number BRAF IC 50(nM) BRAF IC50 (nM)
44 4.8±1.64.8±1.6
66 28.55±11.3828.55±11.38
88 13.79±3.9513.79±3.95
99 4.8±0.34.8±0.3
2626 2.9±0.22.9±0.2
3030 3.2±0.63.2±0.6
3333 0.8±0.00.8±0.0
表2：本申请实施例化合物对BRAF V600E酶的抑制活性Table 2: Inhibitory activity of the compounds of the examples of the present application to BRAF V600E enzyme
Figure PCTCN2022079826-appb-000154
Figure PCTCN2022079826-appb-000154
Figure PCTCN2022079826-appb-000155
Figure PCTCN2022079826-appb-000155
表3：本申请实施例化合物对CRAF酶(Y340D和Y341D)的抑制活性Table 3: Inhibitory activity of the compounds of the examples of the present application on CRAF enzymes (Y340D and Y341D)
化合物编号Compound number CRAF(RAF1 Y340D和Y341D)IC 50(nM) CRAF(RAF1 Y340D and Y341D) IC 50 (nM)
44 2.8±3.22.8±3.2
66 9.00±3.389.00±3.38
88 5.05±1.165.05±1.16
99 4.0±3.74.0±3.7
2626 0.6±0.00.6±0.0
3030 0.4±0.10.4±0.1
3333 0.2±0.00.2±0.0
3434 0.3±0.20.3±0.2
实验结果表明，本申请中的化合物对BRAF、BRAF V600E和CRAF(RAF1 Y340D和Y341D)均有较强的抑制作用。The experimental results show that the compounds in the present application have strong inhibitory effects on BRAF, BRAF V600E and CRAF (RAF1 Y340D and Y341D).
实验例2：癌细胞增殖抑制实验Experimental Example 2: Cancer Cell Proliferation Inhibition Experiment
通过测试本申请实施例的化合物对癌细胞生长的影响，进一步评估本申请中的化合物对癌细胞增殖的抑制作用。By testing the effects of the compounds in the examples of the present application on the growth of cancer cells, the inhibitory effect of the compounds in the present application on the proliferation of cancer cells was further evaluated.
本实施例中选用了人黑色素瘤细胞A375(BRAF V600E突变，购自中国科学院细胞库)和人肝癌细胞HepG2(NRAS Q61K突变，购自美国ATCC)。In this example, human melanoma cell A375 (mutated BRAF V600E, purchased from the Cell Bank of the Chinese Academy of Sciences) and human hepatoma cell HepG2 (mutated NRAS Q61K, purchased from ATCC, USA) were selected.
在实施例中将不同浓度的测试化合物分别加入到上述细胞中，并孵育72小时，采用Cell Titer Glo Kit(Promega)，对活细胞中的ATP进行定量测定来检测活细胞数目。In the examples, different concentrations of the test compounds were added to the above cells, and incubated for 72 hours. Cell Titer Glo Kit (Promega) was used to quantitatively measure ATP in living cells to detect the number of living cells.
利用不含细胞的培养基的CellTiter-Glo获得背景RLU，利用含有细胞的培养基的CellTiter-Glo获得溶媒RLU。细胞抑制率＝1-(样品RLU-背景RLU)/(溶媒RLU-背景RLU)×100％，按照四参数模型拟合曲线，计算化合物的半数抑制浓度(IC 50)。本申请实施例的化合物针对各测试细胞的IC 50值如下： Background RLUs were obtained with CellTiter-Glo in cell-free medium and vehicle RLUs were obtained with CellTiter-Glo in cell-containing medium. Cell inhibition rate=1-(sample RLU-background RLU)/(vehicle RLU-background RLU)×100%, and the half-inhibitory concentration (IC 50 ) of the compound was calculated according to the four-parameter model fitting curve. The IC 50 values of the compounds of the examples of the present application against each test cell are as follows:
表4本申请实施例化合物对癌细胞增殖抑制活性Table 4 Inhibitory activity of the compounds of the examples of the present application on cancer cell proliferation
化合物编号Compound number HepG2(IC 50nM) HepG2 (IC 50 nM) A375(IC 50nM) A375 (IC 50 nM)
44 7.7±0.47.7±0.4 4.8±0.24.8±0.2
55 16.5±1.116.5±1.1 31.1±2.531.1±2.5
66 25.1±2.825.1±2.8 44.6±6.144.6±6.1
77 75.3±29.075.3±29.0 67.6±7.367.6±7.3
88 13.6±1.413.6±1.4 49.6±7.549.6±7.5
1717 7.6±0.67.6±0.6 40.1±6.840.1±6.8
21twenty one 10.6±0.110.6±0.1 11.4±0.311.4±0.3
2626 10.1±0.510.1±0.5 79.4±15.479.4±15.4
2727 25.1±1.125.1±1.1 77.4±8.877.4±8.8
2929 38.8±13.838.8±13.8 12.7±1.512.7±1.5
3030 64.9±18.564.9±18.5 13.1±1.013.1±1.0
3333 8.0±0.78.0±0.7 55.9±4.355.9±4.3
3434 6.6±0.36.6±0.3 5.5±1.15.5±1.1
3535 8.9±0.48.9±0.4 6.8±0.26.8±0.2
3636 8.5±0.58.5±0.5 18.4±2.418.4±2.4
3737 12.4±2.812.4±2.8 27.4±1.427.4±1.4
4141 34.6±4.534.6±4.5 26.7±2.126.7±2.1
4242 16.6±1.416.6±1.4 23.4±2.023.4±2.0
4343 69.6±7.669.6±7.6 34.6±4.434.6±4.4
4444 6.9±0.56.9±0.5 75.8±6.575.8±6.5
4545 4.9±0.24.9±0.2 13.4±0.613.4±0.6
4646 4.8±0.24.8±0.2 10.3±0.610.3±0.6
4747 21.8±3.321.8±3.3 32.5±3.432.5±3.4
4848 53.0±13.053.0±13.0 63.7±8.563.7±8.5
5050 11.0±2.511.0±2.5 11.3±0.311.3±0.3
5151 12.2±0.112.2±0.1 11.7±0.911.7±0.9
5252 8.0±1.18.0±1.1 6.2±0.56.2±0.5
5353 12.0±0.712.0±0.7 5.8±0.15.8±0.1
5454 11.3±0.311.3±0.3 13.2±0.813.2±0.8
5555 23.9±2.523.9±2.5 7.3±0.27.3±0.2
5656 56.4±10.656.4±10.6 36.3±4.936.3±4.9
5757 11.3±0.911.3±0.9 80.9±6.480.9±6.4
5858 20.6±1.420.6±1.4 6.2±0.86.2±0.8
5959 87.2±5.987.2±5.9 54.7±3.954.7±3.9
6464 31.1±4.431.1±4.4 54.9±5.154.9±5.1
6565 11.2±0.611.2±0.6 21.6±8.321.6±8.3
6666 37.0±2.437.0±2.4 45.6±6.545.6±6.5
6767 35.4±3.735.4±3.7 67.4±3.167.4±3.1
实验结果表明，本申请中的化合物对A375(BRAF V600E突变)细胞和HepG2(NRAS Q61K突变)细胞均有较强的抑制作用。The experimental results show that the compounds in the present application have strong inhibitory effects on A375 (BRAF V600E mutation) cells and HepG2 (NRAS Q61K mutation) cells.
实施例3：化合物在SD大鼠体内药代动力学测试Example 3: Pharmacokinetic testing of compounds in SD rats
通过灌胃(PO)雄性SD大鼠给予本申请实施例的化合物，考察药代动力学特点。The compounds of the examples of the present application were administered to male SD rats by gavage (PO), and the pharmacokinetic characteristics were investigated.
将本申请的化合物65进行PO单次给药，给药剂量是5mg/kg，给药溶媒为10％DMSO+10％solutol(15-羟基硬脂酸酯聚乙二醇酯)+80％羟丙基-β-环糊精(含量29％)生理盐水溶液。在给药前(0h)以及给药后0.25、0.5、1、2、4、6、8、24h采集血样；经尾静脉取血，置于K 2-EDTA抗凝试管中，在4000rpm下离心5min(4℃)，分离血浆，-80℃保存待测。血浆样品经沉淀蛋白处理后进行LC-MS/MS分析。应用WinNonlin 6.3软件，采用非房室模型计算药代动力学参数，结果见表5。 The compound 65 of the present application was single administered PO, the dosage was 5 mg/kg, and the administration vehicle was 10% DMSO + 10% solutol (15-hydroxystearate polyethylene glycol) + 80% hydroxyl Propyl-β-cyclodextrin (content 29%) in physiological saline solution. Blood samples were collected before administration (0h) and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration; blood was collected from the tail vein, placed in a K 2 -EDTA anticoagulation test tube, and centrifuged at 4000 rpm After 5 min (4°C), the plasma was separated and stored at -80°C for testing. Plasma samples were processed by precipitating proteins for LC-MS/MS analysis. Using WinNonlin 6.3 software, the non-compartmental model was used to calculate the pharmacokinetic parameters. The results are shown in Table 5.
表5：化合物在大鼠体内的药代动力学参数Table 5: Pharmacokinetic parameters of compounds in rats
Figure PCTCN2022079826-appb-000156
Figure PCTCN2022079826-appb-000156
结论：in conclusion:
本申请的化合物65通过PO给药后在大鼠体内吸收较好，暴露量高。The compound 65 of the present application is well absorbed in rats after PO administration, and the exposure is high.
除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications, journal articles, books, and any other publications, is incorporated by reference in its entirety.

Claims (15)

  1. 式I的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药：Compounds of Formula I or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, co-crystals, solvates, metabolites, isotopically labeled compounds, N-oxides or prodrug:
    Figure PCTCN2022079826-appb-100001
    Figure PCTCN2022079826-appb-100001
    其中：in:
    环A选自苯环、5-6元杂芳环和4-10元杂环；Ring A is selected from benzene ring, 5-6 membered heteroaromatic ring and 4-10 membered heterocyclic ring;
    环B选自C 3-8烃环、C 6-10芳环、5-10元杂芳环和4-10元杂环；优选地，环B选自C 6-10芳环、5-10元杂芳环和4-10元杂环； Ring B is selected from C 3-8 hydrocarbon ring, C 6-10 aromatic ring, 5-10 membered heteroaromatic ring and 4-10 membered heterocyclic ring; preferably, ring B is selected from C 6-10 aromatic ring, 5-10 membered heterocyclic ring Membered heteroaromatic rings and 4-10 membered heterocycles;
    W 1、W 2和W 3各自独立地选自N和CR 2； W 1 , W 2 and W 3 are each independently selected from N and CR 2 ;
    L 1选自-NR 5-C(＝O)-、-C(＝O)-NR 5-、-NR 5-、-NR 5-S(＝O)-、-NR 5-S(＝O) 2-、-S(＝O)-NR 5-和-S(＝O) 2-NR 5-； L 1 is selected from -NR 5 -C(=O)-, -C(=O)-NR 5 -, -NR 5 -, -NR 5 -S(=O)-, -NR 5 -S(=O ) 2 -, -S(=O)-NR 5 - and -S(=O) 2 -NR 5 -;
    R 1选自C 6-10芳基和5-10元杂芳基，其中所述芳基和杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：-NHR6、羟基、卤素、CN、NO 2、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6卤代烷氧基、C 1-6杂烷基(例如C 1-6烷氧基)、氧代基、C 3-6环烷基和4-10元杂环基； R 1 is selected from C 6-10 aryl and 5-10 membered heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: -NHR6, hydroxy, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, C 1-6 heteroalkyl (eg C 1 -6 alkoxy), oxo, C 3-6 cycloalkyl and 4-10 membered heterocyclyl;
    R 2在每次出现时各自独立地选自H、CN、羟基、卤素、C 1-6烷基和C 1-6烷氧基，其中所述烷基和烷氧基各自任选地被一个或多个卤素取代； R 2 at each occurrence is independently selected from H, CN, hydroxy, halogen, C 1-6 alkyl and C 1-6 alkoxy, wherein each of said alkyl and alkoxy is optionally replaced by a or multiple halogen substitutions;
    R 3为L 2-R 3’； R 3 is L 2 -R 3 ';
    L 2在每次出现时各自独立地为直接键或-(CH 2) n-； L 2 is independently at each occurrence a direct bond or -(CH 2 ) n -;
    R 3’在每次出现时各自独立地选自H、羟基、卤素、CN、NO 2、C 1-6烷基、C 1-6杂烷基(例如C 1-6烷氧基)、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8环烷氧基、4-10元杂环基、C 6-12芳基、5-10元杂芳基、-NR 20aR 20b、-SR 21、-S(＝O)R 22、-S(＝O) 2R 22、-S(＝O)NR 20aR 20b、-S(＝O) 2NR 20aR 20b、-NR 20aS(＝O)R 20b、-NR 20aS(＝O) 2R 20b、-C(＝O)R 21、-C(＝O)NR 23aR 23b、-NR 23aC(＝O)R 23b和-NR 24aC(＝O)NR 25aR 25b，其中所述烷基、杂烷基(例如烷氧基)、烯基、炔基、环烷基、环烷氧基、杂环基、芳基和杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：羟基、卤素、CN、NO 2、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基和4-10元杂环基； R 3 ' at each occurrence is independently selected from H, hydroxy, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 heteroalkyl (eg C 1-6 alkoxy), C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heterocycle Aryl, -NR 20a R 20b , -SR 21 , -S(=O)R 22 , -S(=O) 2 R 22 , -S(=O)NR 20a R 20b , -S(=O) 2 NR 20a R 20b , -NR 20a S(=O)R 20b , -NR 20a S(=O) 2 R 20b , -C(=O)R 21 , -C(=O)NR 23a R 23b , -NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b wherein said alkyl, heteroalkyl (eg alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkane Each of oxy, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NO2, C1-4alkyl , C1 -4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclic group;
    R 4在每次出现时各自独立地选自H、羟基、卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基、C 3-6环烷氧基和4-10元杂环基； R 4 at each occurrence is independently selected from H, hydroxy, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl, C 3-6 cycloalkoxy and 4-10 membered heterocyclyl;
    R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-8环烷基和4-10元杂环基，其中所述烷基、环烷基和杂环基各自任选地被一个或多个卤素取代； R and R at each occurrence are each independently selected from H, C 1-6 alkyl , C 3-8 cycloalkyl and 4-10 membered heterocyclyl, wherein said alkyl, cycloalkyl and each of the heterocyclyl groups is optionally substituted with one or more halogens;
    R 20a、R 20b、R 23a、R 23b、R 24a、R 25a和R 25b各自独立地选自H、OH、-NHCH 3、-N(CH 3) 2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和4-10元杂环基；其中所述烷基、烷氧基、环烷基和杂环基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、C 1-6烷基和4-10元杂环基； R 20a , R 20b , R 23a , R 23b , R 24a , R 25a and R 25b are each independently selected from H, OH, -NHCH 3 , -N(CH 3 ) 2 , C 1-6 alkyl, C 1 -6 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclyl; wherein each of said alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally independently replaced by one or more Substituted with a substituent selected from the group consisting of halogen, C 1-6 alkyl and 4-10 membered heterocyclyl;
    R 21和R 22各自独立地选自C 1-6烷基、C 1-6烷氧基、C 3-8环烷基和4-10元杂环基，其中所述烷基、烷氧基、环烷基和杂环基各自任选地被一个或多个卤素取代； R 21 and R 22 are each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the alkyl, alkoxy , cycloalkyl and heterocyclyl are each optionally substituted with one or more halogens;
    m为1、2、3、4或5；m is 1, 2, 3, 4 or 5;
    n为1、2或3；并且n is 1, 2 or 3; and
    g为1、2、3或4；g is 1, 2, 3 or 4;
    条件是：i)当R 1未被取代，环A为吡唑环或咪唑环，并且环B为苯环、异噁唑环或喹啉环时，R 1不是
    Figure PCTCN2022079826-appb-100002
    并且     The conditions are: i) When R 1 is unsubstituted, Ring A is a pyrazole ring or an imidazole ring, and Ring B is a benzene ring, an isoxazole ring or a quinoline ring, R 1 is not
    Figure PCTCN2022079826-appb-100002
    and
    ii)当R 1为
    Figure PCTCN2022079826-appb-100003
    且环B为苯环或异噁唑环时，R 1至少被一个-NH 2基团取代；     ii) When R 1 is
    Figure PCTCN2022079826-appb-100003
    And when ring B is a benzene ring or an isoxazole ring, R 1 is substituted by at least one -NH 2 group;
    优选地，i)当R 1未被取代，环A为吡唑环或咪唑环，并且环B为苯环、异噁唑环或喹啉环时，R 1不是
    Figure PCTCN2022079826-appb-100004
    并且     Preferably, i) when R 1 is unsubstituted, ring A is a pyrazole ring or an imidazole ring, and ring B is a benzene ring, an isoxazole ring or a quinoline ring, R 1 is not
    Figure PCTCN2022079826-appb-100004
    and
    ii)当R 1为
    Figure PCTCN2022079826-appb-100005
    且环B为苯环、异噁唑环或喹啉环时，R 1至少被一个-NH 2基团取代。     ii) When R 1 is
    Figure PCTCN2022079826-appb-100005
    And when ring B is a benzene ring, an isoxazole ring or a quinoline ring, R 1 is substituted by at least one -NH 2 group.
  2. 权利要求1的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，其中环A选自苯环、5-6元杂芳环和4-6元杂环；The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically labeled compound, N-oxidation compound or prodrug, wherein Ring A is selected from benzene ring, 5-6 membered heteroaromatic ring and 4-6 membered heterocyclic ring;
    优选地，环A为5-6元杂芳环；Preferably, Ring A is a 5-6 membered heteroaromatic ring;
    更优选地，环A为吡啶环、噁唑环、噁二唑环、三唑环或吡唑环。More preferably, Ring A is a pyridine ring, an oxazole ring, an oxadiazole ring, a triazole ring or a pyrazole ring.
  3. 权利要求1或2的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，其中环A为
    Figure PCTCN2022079826-appb-100006
    该基团通过*或**标记的两个位置之一与R 1基团连接，并且通过另一位置与
    Figure PCTCN2022079826-appb-100007
    基团连接；     The compound of claim 1 or 2 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically labeled compound, N - oxides or prodrugs wherein ring A is
    Figure PCTCN2022079826-appb-100006
    This group is attached to the R 1 group through one of the two positions marked with * or ** and is attached to the R 1 group through the other position
    Figure PCTCN2022079826-appb-100007
    group connection;
    其中：in:
    X和V各自独立地选自C、CR 4和N； X and V are each independently selected from C, CR and N ;
    U、Y和Z各自独立地选自O、S、CHR 4、CR 4、NR 4和N； U, Y and Z are each independently selected from O, S, CHR4 , CR4 , NR4 and N;
    条件是X、Y、Z、U和V中的至少一个为含杂原子的基团；provided that at least one of X, Y, Z, U, and V is a heteroatom-containing group;
    优选地，环A为
    Figure PCTCN2022079826-appb-100008
    该基团通过*或**标记的两个位置之一与R 1基团连接，并且通过另一位置与
    Figure PCTCN2022079826-appb-100009
    基团连接；     Preferably, ring A is
    Figure PCTCN2022079826-appb-100008
    This group is attached to the R 1 group through one of the two positions marked with * or ** and is attached to the R 1 group through the other position
    Figure PCTCN2022079826-appb-100009
    group connection;
    其中：in:
    X选自CR 4和N； X is selected from CR 4 and N;
    U、Y和Z各自独立地选自CR 4和N； U, Y and Z are each independently selected from CR and N ;
    条件是X、U、Y和Z不同时为CR 4； provided that X, U, Y and Z are not simultaneously CR 4 ;
    优选地，X为N，U为CH，并且Y和Z均为N；或者X为N，U和Z均为CH，并且Y为N；Preferably, X is N, U is CH, and Y and Z are both N; or X is N, U and Z are both CH, and Y is N;
    优选地，环A为
    Figure PCTCN2022079826-appb-100010
    Figure PCTCN2022079826-appb-100011
    以上基团通过*标记的位置与R 1基团连接，并且通过**标记的位置与
    Figure PCTCN2022079826-appb-100012
    基团连接。     Preferably, ring A is
    Figure PCTCN2022079826-appb-100010
    Figure PCTCN2022079826-appb-100011
    The above groups are linked to the R 1 group through the positions marked with *, and are linked to the R 1 group through the positions marked with **
    Figure PCTCN2022079826-appb-100012
    group connection.
  4. 权利要求1-3中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，其中环B为C 5-6烃环、苯环、5-10元杂芳环或4-6元杂环； The compound of any one of claims 1-3 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopic label thereof The compound, N-oxide or prodrug, wherein ring B is a C 5-6 hydrocarbon ring, a benzene ring, a 5-10-membered heteroaromatic ring or a 4-6-membered heterocyclic ring;
    优选地，环B为C 5-6饱和烃环、苯环、5-6元杂芳环或4-6元杂环； Preferably, ring B is a C 5-6 saturated hydrocarbon ring, a benzene ring, a 5-6 membered heteroaromatic ring or a 4-6 membered heterocyclic ring;
    优选地，环B为环戊烷环、苯环、吡啶环、哒嗪环、异喹啉环、二氢吡咯烷环或吡咯烷环。Preferably, Ring B is a cyclopentane ring, a benzene ring, a pyridine ring, a pyridazine ring, an isoquinoline ring, a dihydropyrrolidine ring or a pyrrolidine ring.
  5. 权利要求1-4中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，其中W 1、W 2和W 3各自独立地选自N、CH和CF。 The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopic label thereof The compound, N-oxide or prodrug of , wherein W 1 , W 2 and W 3 are each independently selected from N, CH and CF.
  6. 权利要求1-5中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，其中L 1选自-NR 5-C(＝O)-、-C(＝O)-NR 5-、-NR 5-、-NR 5-S(＝O) 2-和-S(＝O) 2-NR 5-；其中，R 5在每次出现时独立地选自H、C 1-4烷基、C 3-6环烷基和4-6元杂环基，其中所述烷基、环烷基和杂环基各自任选地被一个或多个卤素取代； The compound of any one of claims 1-5 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopic label thereof The compound, N-oxide or prodrug, wherein L 1 is selected from -NR 5 -C(=O)-, -C(=O)-NR 5 -, -NR 5 -, -NR 5 -S(= O) 2 - and -S(=O) 2 -NR 5 -; wherein R 5 at each occurrence is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more halogens;
    优选地，L 1选自-NR 5-C(＝O)-、-C(＝O)-NR 5-和-NR 5-；其中，R 5在每次出现时独立地选自H、C 1-4烷基、C 3-6环烷基和4-6元杂环基，其中所述烷基、环烷基和杂环基各自任选地被一个或多个卤素取代；优选地，R 5在每次出现时独立地为H； Preferably, L 1 is selected from -NR 5 -C(=O)-, -C(=O)-NR 5 - and -NR 5 -; wherein R 5 at each occurrence is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl is optionally substituted with one or more halogens; preferably, R5 is independently H at each occurrence ;
    更优选地，L 1为-NH-、-NH-C(＝O)-或-C(＝O)-NH-。 More preferably, L 1 is -NH-, -NH-C(=O)- or -C(=O)-NH-.
  7. 权利要求1-6中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，其中R 1选自苯基、萘基和5-10元杂芳基，其中所述苯基、萘基和杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：-NHR 6、羟基、卤素、CN、NO 2、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、氧代基、C 3-6环烷基和4-10元杂环基； The compound of any one of claims 1-6 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopic label thereof A compound, N - oxide or prodrug wherein R is selected from the group consisting of phenyl, naphthyl and 5-10 membered heteroaryl, wherein each of said phenyl, naphthyl and heteroaryl is optionally replaced by one or more substituted with substituents independently selected from the group consisting of: -NHR 6 , hydroxy, halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), oxo, C 3-6 cycloalkyl and 4-10 membered heterocyclyl;
    优选地，R 1选自苯基、萘基、吡啶基、吡唑基、噻唑基、嘧啶基和9-10元并环杂芳基，其中所述苯基、萘基、吡啶基、吡唑基、噻唑基、嘧啶基和9-10元并环杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：-NHR 6、羟基、卤素、CN、NO 2、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、氧代基、C 3-6环烷基和4-10元杂环基； Preferably, R 1 is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrazolyl, thiazolyl, pyrimidinyl and 9-10 membered cycloheteroaryl, wherein said phenyl, naphthyl, pyridyl, pyrazole , thiazolyl, pyrimidinyl, and 9-10 membered cycloheteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: -NHR6 , hydroxy, halogen, CN, NO2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), oxo , C 3-6 cycloalkyl and 4-10 membered heterocyclyl;
    优选地，R 1选自
    Figure PCTCN2022079826-appb-100013
    Figure PCTCN2022079826-appb-100014
    其中所述
    Figure PCTCN2022079826-appb-100015
    Figure PCTCN2022079826-appb-100016
    Figure PCTCN2022079826-appb-100017
    各自任选地被一个或多个独立地选自下列的取代基取代：羟基、卤素、CN、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1- 4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基和4-10元杂环基；     Preferably, R 1 is selected from
    Figure PCTCN2022079826-appb-100013
    Figure PCTCN2022079826-appb-100014
    wherein the
    Figure PCTCN2022079826-appb-100015
    Figure PCTCN2022079826-appb-100016
    Figure PCTCN2022079826-appb-100017
    Each is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1 - 4 haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl;
    优选地，R 1选自
    Figure PCTCN2022079826-appb-100018
    Figure PCTCN2022079826-appb-100019
    其中所述
    Figure PCTCN2022079826-appb-100020
    Figure PCTCN2022079826-appb-100021
    各自任选地被一个或多个独立地选自下列的取代基取代：羟基、卤素、CN、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基和4-10元杂环基；     Preferably, R 1 is selected from
    Figure PCTCN2022079826-appb-100018
    Figure PCTCN2022079826-appb-100019
    wherein the
    Figure PCTCN2022079826-appb-100020
    Figure PCTCN2022079826-appb-100021
    Each is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1- 4 haloalkoxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl;
    优选地，R 1选自
    Figure PCTCN2022079826-appb-100022
    Figure PCTCN2022079826-appb-100023
    Preferably, R 1 is selected from
    Figure PCTCN2022079826-appb-100022
    Figure PCTCN2022079826-appb-100023
  8. 权利要求1-7中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，其中R 2在每次出现时各自独立地选自H、CN、卤素、C 1-4烷基和C 1-4烷氧基，其中所述烷基和烷氧基各自任选地被一个或多个卤素取代； The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopic label thereof A compound, N- oxide or prodrug, wherein R at each occurrence is independently selected from H, CN, halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein said alkyl and alkoxy are each optionally substituted with one or more halogens;
    优选地，R 2在每次出现时各自独立地为H、卤素或C 1-4烷基； Preferably, R 2 is independently at each occurrence H, halogen or C 1-4 alkyl;
    更优选地，R 2在每次出现时各自独立地为H、F或甲基。 More preferably, each occurrence of R2 is independently H, F or methyl.
  9. 权利要求1-8中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，其中R 3’在每次出现时各自独立地选自H、羟基、卤素、CN、C 1-4烷基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基、C 3-6环烷氧基、4-6元杂环基、苯基、5-6元杂芳基、-NR 20aR 20b、-SR 21、-S(＝O)R 22、-S(＝O) 2R 22、-S(＝O)NR 20aR 20b、-S(＝O) 2NR 20aR 20b、-NR 20aS(＝O)R 20b、-NR 20aS(＝O) 2R 20b、-C(＝O)R 21、-C(＝O)NR 23aR 23b、-NR 23aC(＝O)R 23b和-NR 24aC(＝O)NR 25aR 25b，其中所述烷基、杂烷基(例如烷氧基)、环烷基、环烷氧基、杂环基、苯基和杂芳基各自任选地被一个或多个独立地选自下列的取代基取代：羟基、卤素、CN、C 1-4烷基、C 1-4卤代烷基、C 1-4羟烷基、C 1-4卤代烷氧基、C 1-4杂烷基(例如C 1-4烷氧基)、C 3-6环烷基和4-10元杂环基； The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopic label thereof A compound, N-oxide or prodrug, wherein R 3 ' at each occurrence is independently selected from H, hydroxy, halogen, CN, C 1-4 alkyl, C 1-4 heteroalkyl (e.g. C 1-4 alkoxy), C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -NR 20a R 20b , -SR 21 , -S(=O)R 22 , -S(=O) 2 R 22 , -S(=O)NR 20a R 20b , -S(=O) 2 NR 20a R 20b , -NR 20a S (=O)R 20b , -NR 20a S(=O) 2 R 20b , -C(=O)R 21 , -C(=O)NR 23a R 23b , -NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b , wherein each of said alkyl, heteroalkyl (eg, alkoxy), cycloalkyl, cycloalkoxy, heterocyclyl, phenyl, and heteroaryl is any optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, C1-4alkyl , C1-4haloalkyl , C1-4hydroxyalkyl , C1-4haloalkane oxy, C 1-4 heteroalkyl (eg C 1-4 alkoxy), C 3-6 cycloalkyl and 4-10 membered heterocyclyl;
    优选地，R 3’在每次出现时各自独立地选自H、卤素、CN、C 1-4烷基、C 1-4烷氧基和4-6元杂环基，其中所述烷基、烷氧基和杂环基任选地被一个或多个独立地选自卤素、CN和C 1-4烷基的取代基取代； Preferably, each occurrence of R3 ' is independently selected from H, halogen, CN, C1-4 alkyl, C1-4 alkoxy and 4-6 membered heterocyclyl, wherein said alkyl , alkoxy and heterocyclyl are optionally substituted with one or more substituents independently selected from halogen, CN and C 1-4 alkyl;
    优选地，R 3’在每次出现时各自独立地选自H、F、Cl、CN、
    Figure PCTCN2022079826-appb-100024
    -CHF 2、-CF 3、-OCH 3、-OCF 3、吗啉基、N-甲基哌嗪基。     Preferably, each occurrence of R3 ' is independently selected from H, F, Cl, CN,
    Figure PCTCN2022079826-appb-100024
    -CHF 2 , -CF 3 , -OCH 3 , -OCF 3 , morpholinyl, N-methylpiperazinyl.
  10. 权利要求1-9中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，其中R 4选自H、卤素、C 1-4烷基和C 1-4杂烷基； The compound of any one of claims 1-9 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopic label thereof The compound, N-oxide or prodrug, wherein R 4 is selected from H, halogen, C 1-4 alkyl and C 1-4 heteroalkyl;
    优选地，R 4为H或甲基。 Preferably, R4 is H or methyl.
  11. 权利要求1-10中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，其中R 6在每次 出现时独立地选自H、C 1-4烷基、C 3-6环烷基和4-6元杂环基，其中所述烷基、环烷基和杂环基各自任选地被一个或多个卤素取代； The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopic label thereof A compound, N-oxide or prodrug, wherein R at each occurrence is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocyclyl, wherein all The alkyl, cycloalkyl and heterocyclyl groups are each optionally substituted with one or more halogens;
    优选地，R 6在每次出现时独立地为H。 Preferably, R6 is independently H at each occurrence.
  12. 权利要求1-11中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，其中所述化合物具有式I-A所示的结构：The compound of any one of claims 1-11 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopic label thereof A compound, N-oxide or prodrug, wherein the compound has the structure shown in Formula I-A:
    Figure PCTCN2022079826-appb-100025
    Figure PCTCN2022079826-appb-100025
    其中：in:
    环B、R 1、R 2、R 3、W 1、W 2和W 3如权利要求1-11中任一项对于式I所定义； Ring B, R 1 , R 2 , R 3 , W 1 , W 2 and W 3 are as defined for formula I in any one of claims 1-11;
    Z和Y各自独立地选自CH和N；并且Z and Y are each independently selected from CH and N; and
    m为1、2或3；m is 1, 2 or 3;
    或者，所述化合物具有式I-B所示的结构：Alternatively, the compound has the structure shown in Formula I-B:
    Figure PCTCN2022079826-appb-100026
    Figure PCTCN2022079826-appb-100026
    其中：in:
    环B、R 1、R 2、R 3、W 1、W 2和W 3如权利要求1-11中任一项对于式I所定义； Ring B, R 1 , R 2 , R 3 , W 1 , W 2 and W 3 are as defined for formula I in any one of claims 1-11;
    Z和Y各自独立地选自CH和N；并且Z and Y are each independently selected from CH and N; and
    m为1、2或3；m is 1, 2 or 3;
    或者，所述化合物具有式I-C所示的结构：Alternatively, the compound has the structure shown in formula I-C:
    Figure PCTCN2022079826-appb-100027
    Figure PCTCN2022079826-appb-100027
    其中：in:
    R 1、R 2、R 3、W 1、W 2和W 3如权利要求1-11中任一项对于式I所定义； R 1 , R 2 , R 3 , W 1 , W 2 and W 3 are as defined for formula I in any one of claims 1-11;
    Z和Y各自独立地选自CH和N；Z and Y are each independently selected from CH and N;
    h为0、1、2或3；并且h is 0, 1, 2, or 3; and
    m为1、2或3。m is 1, 2 or 3.
  13. 权利要求1-12中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，其中所述化合物选自：The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopic label thereof A compound, N-oxide or prodrug, wherein said compound is selected from:
    Figure PCTCN2022079826-appb-100028
    Figure PCTCN2022079826-appb-100028
    Figure PCTCN2022079826-appb-100029
    Figure PCTCN2022079826-appb-100029
  14. 药物组合物，其包含预防或治疗有效量的权利要求1-13中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药以及一种或多种药学上可接受的载体。A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of any one of claims 1-13, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, Co-crystals, solvates, metabolites, isotopically-labeled compounds, N-oxides or prodrugs and one or more pharmaceutically acceptable carriers.
  15. 权利要求1-13中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、共晶、溶剂合物、代谢物、同位素标记的化合物、N-氧化物或前药，或者权利要求14的药物组合物在制备用于预防或治疗与RAF和/或RAS激酶活性相关的疾病或病况的药物中的用途； 所述与RAF和/或RAS激酶活性相关的疾病或病况优选为癌症或肿瘤；所述癌症或肿瘤优选为肺癌(例如非小细胞肺癌)、乳腺癌、卵巢癌、胃癌、肝癌、肾癌、骨癌、结直肠癌、肠癌、胰腺癌、头颈癌、子宫癌、食管癌、甲状腺癌、膀胱癌、血癌、淋巴瘤、多发性骨髓瘤、黑色素瘤、胶质瘤、脑瘤或肉瘤。The compound of any one of claims 1-13 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopic label thereof Use of the compound, N-oxide or prodrug of claim 14, or the pharmaceutical composition of claim 14 in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with RAF and/or RAS kinase activity; The disease or condition associated with/or RAS kinase activity is preferably cancer or tumor; the cancer or tumor is preferably lung cancer (eg non-small cell lung cancer), breast cancer, ovarian cancer, gastric cancer, liver cancer, kidney cancer, bone cancer, colorectal cancer cancer, bowel cancer, pancreatic cancer, head and neck cancer, uterine cancer, esophageal cancer, thyroid cancer, bladder cancer, blood cancer, lymphoma, multiple myeloma, melanoma, glioma, brain tumor or sarcoma.
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