WO2021174581A1 - Nouvelle utilisation d'un composé d'indazole - Google Patents

Nouvelle utilisation d'un composé d'indazole Download PDF

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WO2021174581A1
WO2021174581A1 PCT/CN2020/079469 CN2020079469W WO2021174581A1 WO 2021174581 A1 WO2021174581 A1 WO 2021174581A1 CN 2020079469 W CN2020079469 W CN 2020079469W WO 2021174581 A1 WO2021174581 A1 WO 2021174581A1
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optionally substituted
groups
methyl
independent
alkyl
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Chinese (zh)
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刘青松
刘静
王蓓蕾
王傲莉
王俊杰
邹凤鸣
亓爽
刘青旺
王文超
王黎
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安徽中科拓苒药物科学研究有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • This application relates to a new use of indazole compounds. More specifically, the present invention relates to the use of indazole compounds in the prevention or treatment of diseases related to kinase activity carrying TRKA/B/C fusion genes and/or mutations.
  • Tropomyosin-related kinases are a class of nerve growth factor receptors, composed of highly homologous tropomyosin-related kinase A (TRKA) and tropomyosin related kinases.
  • TRKA tropomyosin-related kinase A
  • TRKB tropomyosin-related kinase B
  • TRKC tropomyosin-related kinase C
  • TRK kinase is believed to be related to the growth, differentiation and apoptosis of neuronal cells.
  • TRK kinase is believed to be related to the growth, differentiation and apoptosis of neuronal cells.
  • tumors such as papillary thyroid cancer, Pancreatic cancer, colorectal cancer, breast cancer, melanoma, non-small cell lung cancer, acute myeloid leukemia, neuroblastoma, etc.
  • TRK kinase is tightly combined with corresponding ligands, such as nerve growth factor NGF and TRKA, brain-derived neurotrophic factor BDNF or neurotrophic factor NT-4 and TRKB, neurotrophic factor NT-3 and TRKC.
  • NT-3 can bind and activate three TRK proteins, but it binds to TRKC more closely than TRKA and TRKB.
  • the ligand binds to TRK kinase, TRK kinase undergoes autophosphorylation through dimerization, thereby activating downstream signaling pathways, including RAS/RAF/MEK/ERK, PI3K/AKT and PLC ⁇ signaling pathways. Therefore, when TRK dysfunction leads to excessive activation of downstream channels, it may lead to the occurrence of the above-mentioned cancers.
  • TRK kinase inhibitors have been reported for the treatment of various cancers and pain. After the first-generation TRK kinase inhibitors are administered, patients will have drug-resistant mutations, and most small molecule inhibitors in clinical practice are mainly the first-generation TRK kinase inhibitors.
  • the second point kinase inhibitor LOXO-195 (NCT03215511) jointly developed by Bayer and LOXO Oncology is currently being treated on patients who have been treated with Larotrectinib to produce drug-resistant mutations, and certain treatments have been obtained. effect.
  • TRKs mutations were found, including solvent-front mutations (such as TRKA/G595R, TRKC/G623R), xDFG mutations (such as TRKA/G667C, TRKA/G667S, TRKC/G696A, TRKC/G696C) and Gatekeeper mutations (TRKA/F589L, TRKC) /F617L), etc.
  • solvent-front mutations such as TRKA/G595R, TRKC/G623R
  • xDFG mutations such as TRKA/G667C, TRKA/G667S, TRKC/G696A, TRKC/G696C
  • TRKA/F589L, TRKC TRKC/F617L
  • TRK inhibitor Larotrectinib which can be used to treat TRKA's F589L, V573M, G667C, G667S, G667A mutations, TRKB's F633L, G709C mutations, and/ Or TRKC's F617L, G696A, G696C mutation-related diseases, and these compounds are used in the treatment of cancers or other related diseases related to these mutations.
  • the present invention provides a selective kinase inhibitor, including a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, and its use in the treatment of TRKA/B/ Use or method of C mutation and/or fusion gene disease:
  • Y is selected from -NH- or -(CH 2 ) n -, where n is an integer from 0 to 3;
  • R 1 is selected is optionally substituted with 1-3 independent R 4 groups are phenyl, optionally substituted with 1-3 independent R 4 groups pyridyl, optionally substituted with 1-3 Pyrazolyl substituted with independent R 4 groups, and pyrimidinyl optionally substituted with 1 to 3 independent R 4 groups;
  • R 2 is selected from hydrogen and C 1-6 alkyl
  • R 3 is selected from C 1-6 alkyl, C 1-6 alkylamino optionally substituted with 1-2 independent R 5 groups, and optionally 1-3 independent R 4 groups substituted phenyl, optionally substituted with 1-3 independent R 4 groups naphthyl, optionally substituted with 1-3 independent R 4 groups pyridyl, optionally substituted with 1-3 A piperazinyl group substituted with two independent R 4 groups, and a piperidinyl group optionally substituted with 1 to 3 independent R 4 groups;
  • R 4 is independently selected from halogen, amino, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1 -6 alkylamino, C 2-6 alkamido, (4-methylpiperazin-1-yl) methyl, morpholinomethyl, morpholino, 4-methylpiperazin-1-yl, 4 -Piperidinyl and 4-tetrahydropyranyl;
  • R 5 is independently selected from amino, hydroxyl, and C 1-6 alkylthio.
  • Y is a direct bond or -CH 2 -.
  • R 1 is selected from phenyl, pyridyl, pyrazolyl, and pyrimidinyl optionally substituted with 1-3 independent R 4 groups, wherein R 4 is independently selected from halogen , Amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and (4-methylpiperazin-1-yl) methyl; R 1 is more preferably optionally Methyl, amino, or halogen-substituted phenyl, 2-pyridyl, 3-pyridyl, 4-pyrazolyl, and 5-pyrimidinyl; R 1 is particularly preferably 2-pyridyl.
  • R 2 is hydrogen or methyl
  • R 3 is selected from optionally substituted with 1-2 independent R 5 groups substituted with C 1-6 alkyl, C 1-6 alkylamino, and optionally substituted with 1- 3 R 4 groups independently substituted with phenyl, naphthyl, pyridyl, piperazinyl, and piperidinyl, wherein R 4 is independently selected from halogen, amino, C 1-6 alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, and (4-methylpiperazin-1-yl)methyl, R 5 is independently selected from amino, hydroxy, and methylthio; R 3 is more preferably optionally Ci-6 alkyl substituted by amino, hydroxy, or methylthio, dimethylamino, N-piperazinyl optionally substituted by methyl, optionally halogen, trifluoromethyl, or methoxy Group-substituted phenyl, naphthyl, 4-pyridinyl, 3-piperidinyl, and 4-piperinyl, where
  • R 3 when Y is a direct bond, R 3 is selected from C 1-6 alkyl optionally substituted with amino, hydroxyl, or methylthio, and 4-pyridyl; when Y is- When CH 2 -, R 3 is selected from phenyl optionally substituted with methoxy, N-piperazinyl optionally substituted with methyl, and 4-piperidinyl optionally substituted with methyl.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the kinase inhibitor of the present invention, a pharmaceutically acceptable carrier or excipient, and optionally other therapeutic agents.
  • the present invention also relates to the use of kinase inhibitors or pharmaceutical compositions comprising them to reduce or inhibit TRKA, TRKB, TRKC or their point mutations in cells or subjects, such as F589L, V573M, G667C, G667S, and G667A of TRKA Methods and uses of the F633L and G709C mutations of TRKB, and/or the F617L, G696A and G696C mutations of TRKC.
  • the present invention also relates to the use of kinase inhibitors or pharmaceutical compositions comprising them to prevent or treat TRKA, TRKB, TRKC or their point mutations such as F589L, V573M, G667C, G667S and TRKA in a subject.
  • TRKA TRKA
  • TRKB TRKB
  • TRKC TRKC
  • Figure 1a shows the effect of compound 9 and LOXO-101 in BaF3-tel-TRKA cell tumor transplantation mouse model on the body weight of mice
  • Figure 1b shows the effect of compound 9 and LOXO-101 in BaF3-tel-TRKA cells Tumor suppression effect in a mouse model of tumor transplantation.
  • Figure 2a shows the effect of compound 9 and LOXO-195 on the body weight of mice after administration in the BaF3-LMNA-TRKA-F589L cell tumor transplantation mouse model
  • Figure 2b shows the effect of compound 9 and LOXO-195 in BaF3-LMNA- Tumor suppression effect of TRKA-F589L cell tumor transplantation mouse model.
  • the present invention adopts conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the technical scope of the art.
  • mass spectrometry NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology
  • nomenclature and laboratory operations and techniques related to the analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are known to those skilled in the art.
  • the aforementioned techniques and steps can be implemented by conventional methods well known in the art and described in various general documents and more specific documents, which are cited and discussed in this specification.
  • alkyl refers to an aliphatic hydrocarbon group, which can be a branched or straight chain alkyl group. According to the structure, the alkyl group may be a monovalent group or a divalent group (ie, an alkylene group). In the present invention, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a "lower alkyl group” having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl and the like.
  • alkyl includes all possible configurations and conformations of the alkyl group.
  • the "propyl” mentioned herein includes n-propyl and isopropyl
  • butyl includes n-butyl.
  • Pentyl includes n-pentyl, isopropyl, neopentyl, tert-pentyl, and pent-3-yl.
  • alkoxy refers to -O-alkyl, where alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like.
  • alkoxyalkyl means that an alkyl group as defined herein is substituted with an alkoxy group as defined herein.
  • cycloalkyl refers to a monocyclic or polycyclic group, which contains only carbon and hydrogen. Cycloalkyl groups include groups having 3-12 ring atoms. Depending on the structure, the cycloalkyl group may be a monovalent group or a divalent group (for example, a cycloalkylene group). In the present invention, the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, more preferably a "lower cycloalkyl group” having 3 to 6 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantane base.
  • alkyl (cycloalkyl) or "cycloalkylalkyl” means that an alkyl group as defined herein is substituted with a cycloalkyl group as defined herein.
  • Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
  • aromatic group refers to a planar ring having a delocalized ⁇ electron system and containing 4n+2 ⁇ electrons, where n is an integer.
  • the aryl ring can be composed of five, six, seven, eight, nine, or more than nine atoms.
  • the aromatic group may be optionally substituted.
  • aryl includes carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or "heteroaryl” or “heteroaryl”) groups (e.g., pyridine).
  • the term includes monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.
  • aryl as used herein means that each atom of the aromatic ring is a carbon atom.
  • the aryl ring can be composed of five, six, seven, eight, nine, or more than nine atoms.
  • Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracenyl, fluorenyl, and indenyl.
  • the aryl group may be a monovalent group or a divalent group (ie, an arylene group).
  • aryloxy refers to -O-aryl, where aryl is as defined herein.
  • heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the N-containing "heteroaryl” moiety means that at least one skeleton atom in the ring of the aromatic group is a nitrogen atom.
  • the heteroaryl group may be a monovalent group or a divalent group (ie, heteroarylene).
  • heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazole Group, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indazinyl, phthalazinyl, pyridazinyl, isoindyl Dolyl, pterridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl , Naphthyridiny
  • alkyl(aryl) or “aralkyl” means that an alkyl group as defined herein is substituted with an aryl group as defined herein.
  • Non-limiting alkyl (aryl) groups include benzyl, phenethyl, and the like.
  • alkyl(heteroaryl) or “heteroarylalkyl” means that an alkyl group as defined herein is substituted by a heteroaryl group as defined herein.
  • heteroalkyl as used herein means that one or more of the backbone chain atoms in the alkyl group defined herein is a heteroatom, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or a combination thereof.
  • the heteroatom(s) can be located at any position within the heteroalkyl group or at the position where the heteroalkyl group is connected to the rest of the molecule.
  • heterocycloalkyl or “heterocyclyl” as used herein means that one or more of the atoms constituting the ring in the non-aromatic ring are heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heterocycloalkyl ring can be composed of three, four, five, six, seven, eight, nine, or more than nine atoms.
  • the heterocycloalkyl ring may be optionally substituted.
  • heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimines, cyclic carbamates, tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiolan, 1,4- Oxythiolane, 1,4-oxathiolane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, Pakistan Bituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene,
  • alkyl(heterocycloalkyl) or “heterocycloalkylalkyl” means that an alkyl group as defined herein is substituted by a heterocycloalkyl group as defined herein.
  • alkoxy(heterocycloalkyl) or “heterocycloalkylalkoxy” means that an alkoxy group as defined herein is substituted by a heterocycloalkyl group as defined herein.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • haloalkyl examples include structures of alkyl, alkoxy, or heteroalkyl in which at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are the same or different from each other.
  • hydroxyl refers to the -OH group.
  • cyano refers to the -CN group.
  • ester group refers to a chemical moiety having the formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (connected through a ring carbon) and heterocyclyl (connected through a ring carbon).
  • amino refers to the -NH 2 group.
  • aminoacyl refers to the -CO-NH 2 group.
  • amido or “amido” refers to -NR-CO-R', where R and R'are each independently hydrogen or alkyl.
  • alkylamino refers to an amino substituent further substituted with one or two alkyl groups, specifically referring to the group -NRR', wherein R and R'are each independently selected from hydrogen or lower alkyl, with the condition of- NRR' is not -NH 2 .
  • Alkyl amino includes groups wherein the nitrogen -NH 2 group is connected to at least one compound of an alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like.
  • Dialkyl amino includes groups wherein the nitrogen -NH 2 group is connected to at least two additional alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.
  • arylamino and diarylamino refer to amino substituents further substituted by one or two aryl groups, specifically referring to the group -NRR', wherein R and R'are each independently selected from hydrogen, Lower alkyl, or aryl, where N is connected to at least one or two aryl groups, respectively.
  • cycloalkylamino refers to an amino substituent further substituted with one or two cycloalkyl groups as defined herein.
  • heteroalkylamino refers to an amino substituent further substituted with one or two heteroalkyl groups as defined herein.
  • aralkylamino herein refers to a group -NRR' in which R is lower aralkyl and R'is hydrogen, lower alkyl, aryl, or lower aralkyl.
  • heteroarylamino refers to an amino substituent further substituted with one or two heteroaryl groups as defined herein.
  • heterocycloalkylamino means that an amino group as defined herein is substituted by a heterocycloalkyl group as defined herein.
  • alkylaminoalkyl means that an alkyl group as defined herein is substituted with an alkylamino group as defined herein.
  • aminoalkyl refers to an alkyl substituent further substituted with one or more amino groups.
  • aminoalkoxy refers to an alkoxy substituent further substituted with one or more amino groups.
  • hydroxyalkyl or "hydroxyalkyl” refers to an alkyl substituent further substituted with one or more hydroxy groups.
  • cyanoalkyl refers to an alkyl substituent further substituted with one or more cyano groups.
  • acyl refers to the monovalent atomic group remaining after the hydroxyl group is removed from an organic or inorganic oxyacid.
  • the general formula is R-M(O)-, where M is usually C.
  • alkanoyl or “alkylcarbonyl” refers to a carbonyl group further substituted with an alkyl group.
  • Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, hexanoyl and the like.
  • arylcarbonyl means that the carbonyl group defined herein is substituted with an aryl group defined herein.
  • alkoxycarbonyl refers to a carbonyl group further substituted with an alkoxy group.
  • heterocycloalkylcarbonyl refers to a carbonyl group further substituted with a heterocycloalkyl group.
  • alkylaminocarbonyl cycloalkylaminocarbonyl
  • arylaminocarbonyl arylaminocarbonyl
  • aralkylaminocarbonyl heteroarylaminocarbonyl
  • alkylcarbonylalkyl or “alkanoylalkyl” refers to an alkyl group further substituted with an alkylcarbonyl group.
  • alkylcarbonylalkoxy or “alkanoylalkoxy” refers to an alkoxy group further substituted with an alkylcarbonyl group.
  • heterocycloalkylcarbonylalkyl refers to an alkyl group further substituted with a heterocycloalkylcarbonyl group.
  • mercapto refers to the -SH group.
  • alkylthio means that a mercapto group as defined herein is substituted with an alkyl group as defined herein.
  • alkylaminosulfone group means that the sulfone group as defined herein is substituted with an alkylamino group as defined herein.
  • alkylsulfoneamino or "cycloalkylsulfoneamino” means that the amino group as defined herein is substituted with an alkylsulfone group or a cyclic alkylsulfone group as defined herein.
  • quaternary ammonium group refers to -N + RR'R", wherein R, R'and R" are each independently selected from alkyl groups having 1-8 carbon atoms.
  • optional means that one or more events described later may or may not occur, and include both events that occur and events that do not occur.
  • optionally substituted or “substituted” means that the mentioned group can be substituted by one or more additional groups, each and independently selected from alkyl, cycloalkyl , Aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, cyano, halogen, amido, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroaryl Alkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc.
  • the amino protecting group is preferably selected from the group consisting of pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trifluoroacetyl, and the like.
  • tyrosine protein kinase as used herein is a type of kinase that catalyzes the transfer of ⁇ -phosphate from ATP to protein tyrosine residues, and can catalyze a variety of substrate protein tyrosine residues. Base phosphorylation plays an important role in cell growth, proliferation, and differentiation.
  • the term “inhibition”, “inhibition” or “inhibitor” of a kinase means that the activity of the phosphotransferase is inhibited.
  • a “metabolite” of a compound disclosed herein is a derivative of a compound formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound formed when the compound is metabolized.
  • metabolized refers to the total number of processes in which a specific substance is changed by an organism (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Therefore, enzymes can produce specific structures and convert them into compounds.
  • cytochrome P450 catalyzes various oxidation and reduction reactions
  • diphosphate glucosyltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups.
  • Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing a tissue sample from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both of these methods are known in the art.
  • the metabolite of the compound is formed through an oxidation process and corresponds to the corresponding hydroxyl-containing compound.
  • the compound is metabolized into a pharmaceutically active metabolite.
  • modulation refers to directly or indirectly interacting with a target to change the activity of the target. For example, it includes enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or extending the activity of the target.
  • target protein refers to a protein molecule or part of a protein that can be bound by a selective binding compound.
  • the target protein is tyrosine kinase TRKA (wild-type or various mutations or combinations thereof), TRKB (wild-type or various mutations or combinations thereof), TRKC (wild-type or various mutations or combinations thereof). combination).
  • IC 50 refers to a 50% of the maximum effect is obtained in the analysis of the inhibition effect of such measurement, concentration or dosage.
  • EC 50 refers to a measured dose, concentration or amount of a compound, at a dose of 50% of maximal expression of the compound to induce, stimulate or enhance a particular reaction assays rely on specific reaction caused.
  • the GI 50 used herein refers to the concentration of the drug required to inhibit 50% of the cell growth, that is, the drug concentration at which the drug inhibits or controls the growth of 50% of the cells (such as cancer cells).
  • Novel kinase inhibitor of the present invention Novel kinase inhibitor of the present invention
  • the present invention provides a novel kinase inhibitor, including a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof,
  • Y is selected from -NH- or -(CH 2 ) n -, where n is an integer from 0 to 3, and when n is 0, Y represents a direct bond;
  • R 1 is selected from aryl and heteroaryl optionally substituted with 1-3 independent R 4 groups;
  • R 2 is selected from hydrogen and C 1-6 alkyl
  • R 3 is selected from C 1-6 alkyl, C 1-6 alkylamino optionally substituted with 1-2 independent R 5 groups, and optionally 1-3 independent R 4 groups Substituted aryl, heteroaryl and heterocyclic groups;
  • R 4 is independently selected from halogen, amino, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1 -6 alkylamino, C 2-6 alkamido, (4-methylpiperazin-1-yl) methyl, morpholinomethyl, morpholino, 4-methylpiperazin-1-yl, 4 -Piperidinyl and 4-tetrahydropyranyl;
  • R 5 is independently selected from amino, hydroxyl, and C 1-6 alkylthio.
  • Y is a direct bond or -CH 2 -.
  • R 1 is selected from phenyl, pyridyl, pyrazolyl, and pyrimidinyl optionally substituted with 1-3 independent R 4 groups, wherein R 4 is independently selected from halogen , Amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and (4-methylpiperazin-1-yl) methyl; R 1 is more preferably optionally Methyl, amino, or halogen-substituted phenyl, 2-pyridyl, 3-pyridyl, 4-pyrazolyl, and 5-pyrimidinyl; R 1 is particularly preferably 2-pyridyl.
  • R 2 is hydrogen or methyl
  • R 3 is selected from optionally substituted with 1-2 independent R 5 groups substituted with C 1-6 alkyl, C 1-6 alkylamino, and optionally substituted with 1- 3 R 4 groups independently substituted with phenyl, naphthyl, pyridyl, piperazinyl, and piperidinyl, wherein R 4 is independently selected from halogen, amino, C 1-6 alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, and (4-methylpiperazin-1-yl)methyl, R 5 is independently selected from amino, hydroxy, and methylthio; R 3 is more preferably optionally Ci-6 alkyl substituted by amino, hydroxy, or methylthio, dimethylamino, N-piperazinyl optionally substituted by methyl, optionally halogen, trifluoromethyl, or methoxy Group-substituted phenyl, naphthyl, 4-pyridinyl, 3-piperidinyl, and 4-piperinyl, where
  • R 3 when Y is a direct bond, R 3 is selected from C 1-6 alkyl optionally substituted with amino, hydroxyl, or methylthio, and 4-pyridyl; when Y is- When CH 2 -, R 3 is selected from phenyl optionally substituted with methoxy, N-piperazinyl optionally substituted with methyl, and 4-piperidinyl optionally substituted with methyl.
  • the inhibitor of the present invention includes the compound of Table 1 below or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof.
  • novel kinase inhibitors Described herein are novel kinase inhibitors.
  • the pharmaceutically acceptable salts, solvates, esters, acids, pharmaceutically active metabolites and prodrugs of this compound are also described herein.
  • the compounds described herein are administered to an organism in need and metabolized in its body to produce metabolites, and the produced metabolites are then used to produce the desired effect, including the desired therapeutic effect.
  • the compounds described herein can be formulated and/or used as pharmaceutically acceptable salts.
  • the types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of a compound with a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reaction with organic acids such as acetic acid, propionic acid, caproic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, lemon Acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid Acid, 1,2-ethanedisulfonic acid, 2-
  • Acceptable organic bases include ethanolamine, diethanolamine, Triethanolamine, trimethylamine, N-methylglucamine, etc.; acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like.
  • the corresponding counterions of pharmaceutically acceptable salts can be analyzed and identified using various methods, including but not limited to ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any of them. combination.
  • the salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, solvent evaporation, or lyophilization in the case of an aqueous solution.
  • the screening and characterization of pharmaceutically acceptable salts, polymorphs, and/or solvates can be accomplished using a variety of techniques, including but not limited to thermal analysis, X-ray diffraction, spectroscopy, microscopy methods, and elemental analysis.
  • the various spectroscopic techniques used include but are not limited to Raman, FTIR, UVIS and NMR (liquid and solid state).
  • Various microscopy techniques include, but are not limited to, IR microscopy and Raman microscopy.
  • the application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, pharmaceutically active metabolite or prodrug of the compound, and a pharmaceutically acceptable Carriers or excipients, and optionally other therapeutic agents.
  • the drug containing the compound of the present invention can be administered to a patient by at least one of injection, oral administration, inhalation, rectal and transdermal administration.
  • Other therapeutic agents can be selected from the following drugs: immunosuppressive agents (e.g. tacrolimus, cyclosporine, rapamycin, methotrine, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate) FTY720), glucocorticoid drugs (e.g.
  • prednisone cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, hydrohydroxyprednisolone, beclomethasone , Fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), non-steroidal anti-inflammatory drugs (such as salicylate, arylalkanoic acid, 2-arylpropionic acid, N-arylanthranilic acid, Oxicams, coxibs, or sulfanilides), allergy vaccines, antihistamines, antileukotrienes, ⁇ -agonists, theophylline, anticholinergics, or other selective kinase inhibitors (e.g.
  • the other therapeutic agents mentioned can also be rapamycin, crizotinib, tamoxifen, raloxifene, anastrozole, exemestane, letrozole , Herceptin TM (trastuzumab), Gleevec TM (imatinib), taxol TM (paclitaxel), cyclophosphamide, lovastatin, Miele tetracycline (Minosine), cytarabine, 5-fluorouracil (5-FU), methotrexate (MTX), taxotere TM (docetaxel), Zoladex TM (goserelin), vincristine, vinblastine, nocodazole oxazole, teniposide, etoposide, GEMZAR (TM) (gemcitabine), epothilone (epothilone), the promise of this
  • other therapeutic agents may also be cytokines such as G-CSF (granulocyte colony stimulating factor).
  • other therapeutic agents may also be, for example, but not limited to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, doxorubicin and 5-fluorouracil), AC (sub- Driamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide and paclitaxel) or CMFP (cyclophosphamide, A Methotrexate, 5-fluorouracil and prednisone).
  • CMF cyclophosphamide, methotrexate and 5-fluorouracil
  • CAF cyclophosphamide, doxorubicin and 5-fluorouracil
  • AC sub- Driamycin
  • the amount of a given drug depends on many factors, such as the specific dosing regimen, the type of disease or condition and its severity, and the subject in need of treatment Or the uniqueness of the host (such as body weight), but, according to specific surrounding conditions, including, for example, the specific drug that has been used, the route of administration, the condition to be treated, and the subject or host to be treated, the dose to be administered may be known in the art
  • the method is routinely decided.
  • the administered dose is typically in the range of 0.02-5000 mg/day, for example about 1-1500 mg/day.
  • the required dose can conveniently be expressed as one dose, or simultaneous (or within a short period of time) or divided doses at appropriate intervals, such as two, three, four or more divided doses per day.
  • the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.
  • the kinase inhibitor of the present invention includes a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug, or pharmaceutical composition, used to reduce or inhibit cell or subject TRKA, TRKB, TRKC or their point mutations such as TRKA's F589L, V573M, G667C, G667S and G667A, TRKB's F633L and G709C mutations, and/or TRKC's F617L, G696A and G696C mutant kinase activity, and/or in the test Prevention or treatment of TRKA, TRKB, TRKC or their point mutations such as TRKA's F589L, V573M, G667C, G667S and G667A, TRKB's F633L and G709C mutations, and/or TRKC's F617L, G696A and G696C mutations and other kinase activities Related illnesses.
  • the compound of formula (I) or its pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug, or its pharmaceutical composition can be used to treat, prevent or ameliorate one or more diseases selected from the following group : Solid tumors (including benign or especially malignant types), especially sarcomas, gastrointestinal stromal tumors (Gastrointestinal Stromal Tumors, GIST), colorectal cancer (colon cancer), acute myeloblastic leukemia (Acute Myeloblastic Leukemia, AML), chronic Myelogenous Leukemia (Chronic Myelogenous Leukemia, CML), neoplasia, thyroid cancer, systemic mastocytosis, eosinophilia syndrome, fibrosis, lupus erythematosus, graft-versus-host disease, neurofibroma, pulmonary hypertension, Alzheimer's disease, seminoma, dysgerminoma, mast cell tumor, lung cancer, bronchial cancer, testi
  • the inhibitor of the present invention or its pharmaceutical composition can be used to treat or prevent the F589L, V573M, G667C, G667S, and G667A mutations of TRKA, the F633L and G709C mutations of TRKB, and/or the F617L, G696A, and G696C mutations of TRKC.
  • Related diseases include:
  • the compound of formula (I) or its pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug, or its pharmaceutical composition can be used to treat, prevent or ameliorate autoimmune diseases selected from the following group: Arthritis, rheumatoid arthritis, osteoarthritis, lupus, rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes , Myasthenia gravis, Hashimoto's thyroiditis, Ord's hyroiditis, Graves' disease, rheumatoid arthritis syndrome ( syndrome), multiple sclerosis, infectious neuronitis (Guillain-Barré syndrome), acute disseminated encephalomyelitis, Addison's disease, visual ocular twin-myosyndromic twin syndrome, rigidity Spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpas
  • the compound of formula (I) of the present invention or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, or a pharmaceutical composition thereof can be used for the treatment of TRKA, TRKB, TRKC or their pharmaceutical composition.
  • Point mutations such as TRKA’s F589L, V573M, G667C, G667S and G667A, TRKB’s F633L and G709C mutations, and/or TRKC’s F617L, G696A and G696C mutations and other kinase activity-related disorders: papillary thyroid cancer, pancreatic cancer, colorectal cancer Cancer, breast cancer, melanoma, non-small cell lung cancer, acute myeloid leukemia, neuroblastoma, pain, dermatitis or asthma.
  • the compound of formula (I) can be synthesized using standard synthesis techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein.
  • the solvent, temperature and other reaction conditions given herein can be changed according to the skill in the art.
  • the following synthesis methods can also be used.
  • the reactions can be used sequentially to provide the compounds described herein; or they can be used to synthesize fragments that are subsequently added by the methods described herein and/or methods known in the art.
  • provided herein are methods of preparing the kinase inhibitor compounds described herein and methods of using them.
  • the compounds described herein can be synthesized using the following synthetic scheme. A method similar to that described below can be used to synthesize the compound by using appropriate optional starting materials.
  • the starting materials used to synthesize the compounds described herein can be synthesized or can be obtained from commercial sources.
  • the compounds described herein and other related compounds with different substituents can be synthesized using techniques and raw materials known to those skilled in the art.
  • the general methods for preparing the compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various moieties in the molecules provided herein.
  • reaction product can be separated and purified using conventional techniques, including but not limited to methods such as filtration, distillation, crystallization, and chromatography. These products can be characterized using conventional methods, including physical constants and spectral data.
  • N-(4-Methylthiazol-2-yl)acetamide Add 4-methylthiazol-2-amine (2g) in a 100mL round-bottomed flask, then add anhydrous dichloromethane (50mL), triethylamine ( 3.9mL), slowly add acetyl chloride (1.5mL) dropwise. The reaction system was reacted for 4 hours under argon protection at room temperature. After the reaction, the solvent was evaporated to dryness under reduced pressure, and the resultant was neutralized with saturated sodium bicarbonate to pH>10, and then extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried with anhydrous sodium sulfate.
  • the reaction system was heated to 130°C for 14 hours under the protection of argon. After the reaction, the solvent was evaporated to dryness under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried with anhydrous sodium sulfate. The organic phase is filtered and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by pressurized silica gel column chromatography to obtain the pure product, MS (ESI) m/z (M+1)+: 460.18.
  • the reaction system was stirred at room temperature for 14 hours under the protection of argon. After the reaction, the solvent was evaporated to dryness under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried with anhydrous sodium sulfate. The organic phase is filtered and evaporated to dryness under reduced pressure to obtain a crude product.
  • the crude product was dissolved in anhydrous dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added.
  • the reaction system was stirred at room temperature for 14 hours under the protection of argon. After the reaction, the solvent was evaporated to dryness under reduced pressure, and the resultant was diluted with water and neutralized with saturated sodium bicarbonate solution to pH>10.
  • the aqueous phase was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase is filtered and evaporated to dryness under reduced pressure to obtain a crude product.
  • the crude product was purified by pressurized silica gel column chromatography to obtain compound 1, MS (ESI) m/z (M+1)+: 550.24.
  • Example 2 The synthesis of Example 2 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 540.09.
  • Example 3 The synthesis of Example 3 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 520.14.
  • Example 4 The synthesis of Example 4 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 439.14.
  • Example 5 The synthesis of Example 5 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 361.11.
  • Example 6 The synthesis of Example 6 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 506.13.
  • Example 7 The synthesis of Example 7 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 502.17.
  • Example 8 The synthesis of Example 8 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 512.18.
  • Example 9 The synthesis of Example 9 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 474.21.
  • Example 10 The synthesis of Example 10 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 486.12.
  • Example 11 The synthesis of Example 11 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 459.20.
  • Example 12 The synthesis of Example 12 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 419.17.
  • Example 13 The synthesis of Example 13 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 459.20.
  • Example 14 The synthesis of Example 14 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 445.18.
  • Example 15 The synthesis of Example 15 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 465.16.
  • Example 16 The synthesis of Example 16 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 458.20.
  • Example 17 The synthesis of Example 17 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 405.15.
  • Example 18 The synthesis of Example 18 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 447.20.
  • Example 19 The synthesis of Example 19 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 404.16.
  • Example 20 The synthesis of Example 20 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 481.18.
  • the reaction system was heated to 130°C for 14 hours under the protection of argon. After the reaction, the solvent was evaporated to dryness under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried with anhydrous sodium sulfate. The organic phase is filtered and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by pressurized silica gel column chromatography to obtain the pure product, MS (ESI) m/z (M+1)+: 455.23.
  • N-(5-(3-Iodo-1H-indazole-6-yl)-4-methylthiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (21d) Add N-(5-(1H-indazol-6-yl)-4-methylthiazol-2-yl)-2-(4-methylpiperazin-1-yl)ethyl into a 50mL round bottom flask After the amide (0.6g) was added N,N-dimethylformamide (10mL), iodine (0.8g) and potassium hydroxide (0.4g). The reaction system was stirred at room temperature for 8 hours under the protection of argon.
  • the reaction system was heated to 80°C for 14 hours under the protection of argon. After the reaction, the solvent was evaporated to dryness under reduced pressure, and the resultant was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried with anhydrous sodium sulfate. The organic phase is filtered and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by pressurized silica gel column chromatography to obtain compound 21, MS (ESI) m/z (M+1)+: 451.21.
  • Example 22 The synthesis of Example 22 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 448.18.
  • Example 23 The synthesis of Example 23 was accomplished by using procedures similar to those described in Example 21. MS(ESI) m/z(M+1)+: 464.20.
  • Example 24 The synthesis of Example 24 was accomplished by using procedures similar to those described in Example 21. MS(ESI) m/z(M+1)+: 448.19.
  • Example 25 The synthesis of Example 25 was accomplished by using procedures similar to those described in Example 21. MS(ESI) m/z(M+1)+: 466.18.
  • Example 26 The synthesis of Example 26 was accomplished by using procedures similar to those described in Example 21. MS(ESI) m/z(M+1)+: 465.19.
  • Example 27 The synthesis of Example 27 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 473.21.
  • Example 28 The synthesis of Example 28 was accomplished by using procedures similar to those described in Example 21. MS(ESI) m/z(M+1)+: 494.13.
  • Example 29 The synthesis of Example 29 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 521.14.
  • Example 30 The synthesis of Example 30 was accomplished by using procedures similar to those described in Example 1. MS(ESI) m/z(M+1)+: 376.13.
  • fluorescein-carrying human colorectal cancer cell KM-12-LUC (expressing TPM3-NTRK1 gene) (purchased from the Japanese Collection of Research Bioresources Cell Bank, Japan), and mouse original B cell BaF3 ( Purchased from ATCC).
  • this example also selected mouse BaF3-tel-TRKA (stable expression of TRKA wild-type kinase), BaF3-LMNA-TRKA (stable expression of LMNA-TRKA fusion kinase), BaF3-LMNA-TRKA/V573M (stable expression of TRKA) /V573M mutant kinase), BaF3-LMNA-TRKA/F589L (stable expression of TRKA/F589L mutant kinase), BaF3-LMNA-TRKA/G667C (stable expression of TRKA/G667C mutant kinase), BaF3-LMNA-TRKA/G667S (stable expression) TRKA/G667S mutant kinase), BaF3-tel-TRKB (stable expression of TRKB wild-type kinase), BaF3-tel-TRKB/F633L (stable expression of TRKB/F633L mutant kinase), BaF3-tel-TR
  • TRKA, TRKB, TRKC, TRKA/V573M, TRKA/F589L, TRKA/G667C, TRKA/G667S, TRKB/F633L, TRKB/G709C, TRKC were amplified by PCR /F617L, TRKC/G696A, TRKC/G696C kinase region sequence, and inserted into the MSCV-Puro vector (purchased from Clontech) with N-terminal TEL fragment and/or LMNA fragment and/or TPR fragment, respectively, by retroviral method , Stably transferred into mouse BaF3 cells, and withdrawn IL-3 growth factor, and finally got dependent on TRKA, TRKB, TRKC, TRKA/V573M, TRKA/F589L, TRKA/G667C, TRKA/G667S, TRKB/F633L, TRKB/G709C, TRKC/F617L,
  • the results in Table 2 indicate that the compounds of the present invention have strong inhibitory activity against TRK. Further, as shown in Table 3, after testing the mutant TRKA kinase, it was found that the compound of the present invention has a strong inhibitory effect on TRKA/V573M, TRKA/F589L, TRKA/G667C, and TRKA/G667S.
  • the resistance point mutation of the first-generation TRK inhibitor LOXO-101 the compound of the present invention can overcome the above-mentioned mutations to the first-generation TRK inhibitor LOXO-101, and the effect on the cell is also better than the second-generation TRK inhibitor.
  • Generation TRK inhibitor LOXO-195 the compounds of the present invention also have a strong inhibitory effect on wild-type and mutant TRKB and TRKC.
  • mice (1) Purchasing 4-6 weeks old Bal b/c female nude mice from Beijing Weitong Lihua Laboratory Animal Co., Ltd., and raising them in SPF-level laboratories. The drinking water and litter are all sterilized by autoclaving. All operations related to mice were performed under sterile conditions.
  • mice were orally administered methyl cellulose (HKI) vehicle (5 mice) every day; the dose of compound 9 at a dose of 40 mg/kg and 80 mg/kg mouse weight was once a day (each 5 mice); LOXO-101 (purchased from MedChemExpress, China) at a dose of 80 mg/kg mouse weight twice a day (5 mice).
  • HKI methyl cellulose
  • mice For the mouse model of BaF3-LMNA-TrKA-F589L, starting from the 6th day, the corresponding mice will be orally administered with methylcellulose (HKI) vehicle (5 mice) every day; the dose is 40mg/kg, 80mg /kg of compound 9 once a day (5 mice each); LOXO-195 at a dose of 80 mg/kg mouse weight twice a day (5 mice).
  • HKI methylcellulose
  • the present invention provides a new use of indazole inhibitor compounds, which can be used to reduce or inhibit the TRKA/B/C mutation and/or fusion gene carried by cells or subjects, such as TRKA's V573M, F589L, G667C/ S mutation, the F633L and G709C mutations of TRKB, and/or the kinase activity of the F617L, G696A and G696C mutations of TRKC, and/or the prevention or treatment of TRKA/B/C mutations and/or fusion genes in the subject, for example TRKA's V573M, F589L, G667C/S mutations, TRKB's F633L, G709C mutations and/or TRKC's F617L, G696A/C mutations are activity-related disorders. Therefore, the present invention is suitable for industrial applications.

Abstract

L'invention concerne une nouvelle utilisation d'un composé de formule (I) ou un sel pharmaceutiquement acceptable, un solvate, un ester, un acide, un métabolite ou un promédicament de celui-ci, qui sont utilisés pour traiter des maladies portant des mutations de TRKA/B/C et/ou des gènes de fusion, en particulier des maladies portant une ou plusieurs mutations de V573M, F589L et G667C/S de TRKA, des mutations F633L et G709C de TRKB, et/ou des mutations F617L et G696A/C de TRKC.
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