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WO2022188792A1 - Composé hétérocyclique ayant une activité inhibitrice de protéine kinase, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation - Google Patents

Composé hétérocyclique ayant une activité inhibitrice de protéine kinase, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation 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
alkyl
reaction
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Chinese (zh)
Inventor
陈忠辉
韩晓军
田强
宋宏梅
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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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 or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—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)

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Abstract

La présente invention concerne un composé de formule (I), une composition pharmaceutique le comprenant, son procédé de préparation et son utilisation pour la prévention ou le traitement de maladies ou d'états associés à une tumeur.
PCT/CN2022/079826 2021-03-12 2022-03-09 Composé hétérocyclique ayant une activité inhibitrice de protéine kinase, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation Ceased WO2022188792A1 (fr)

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