WO2021174581A1 - New use of indazole compound - Google Patents

New use of indazole compound 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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PCT/CN2020/079469
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French (fr)
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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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
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    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • 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

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

Disclosed is new use of a compound of formula (I) or a pharmaceutically acceptable salt, a solvate, an ester, an acid, a metabolite or a prodrug thereof, which are used for treating diseases carrying TRKA/B/C mutations and/or fusion genes, particularly diseases carrying one or more mutations of V573M, F589L and G667C/S mutations of TRKA, F633L and G709C mutations of TRKB and/or F617L and G696A/C mutations of TRKC.

Description

吲唑类化合物的新用途New uses of indazole compounds 技术领域Technical field
本申请涉及一种吲唑类化合物的新用途。更具体地，本发明涉及吲唑类化合物在预防或治疗携带TRKA/B/C融合基因和/或突变的激酶活性相关的疾病中的用途。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.
背景技术Background technique
原肌球蛋白相关激酶(Tropomyosin-related kinase)，统称为TrK家族蛋白，是一类神经生长因子受体，由高度同源性的原肌球蛋白相关激酶A(TRKA)、原肌球蛋白相关激酶B(TRKB)、原肌球蛋白相关激酶C(TRKC)三种蛋白组成，分别由相应的NTRK1、NTRK2和NTRK3基因编码。1982年，科学家Mariano Barbacid和他的同事在结直肠癌中发现了NTRK1基因，随后确定其为致癌基因。TRK激酶被认为与神经元细胞的生长、分化以及凋亡有关，然而，近几十年的研究结果表明，TRK激酶的部分缺失、发生融合以及过表达以后与多种肿瘤如***状甲状腺癌、胰腺癌、结直肠癌、乳癌、黑色素瘤、非小细胞肺癌、急性髓性白血病、成神经细胞瘤等的发生发展、侵袭转移和恶化等有着密切关系(Emiliano Cocco1,Maurizio Scaltriti1,Alexander Drilon，NTRK fusion-positive cancers and TRK inhibitor therapy.Nat.Rev.Clin.Oncol.2018,15,731-747.)。Tropomyosin-related kinases (Tropomyosin-related kinases), collectively referred to as TrK family proteins, are a class of nerve growth factor receptors, composed of highly homologous tropomyosin-related kinase A (TRKA) and tropomyosin related kinases. Kinase B (TRKB) and tropomyosin-related kinase C (TRKC) are composed of three proteins, which are respectively encoded by the corresponding NTRK1, NTRK2 and NTRK3 genes. In 1982, scientist Mariano Barbacid and his colleagues discovered the NTRK1 gene in colorectal cancer and subsequently determined that it was an oncogene. TRK kinase is believed to be related to the growth, differentiation and apoptosis of neuronal cells. However, research results in recent decades have shown that partial deletion, fusion, and overexpression of TRK kinase are associated with a variety of tumors such as papillary thyroid cancer, Pancreatic cancer, colorectal cancer, breast cancer, melanoma, non-small cell lung cancer, acute myeloid leukemia, neuroblastoma, etc. are closely related to the development, invasion, metastasis, and deterioration (Emiliano Cocco1, Maurizio Scaltriti1, Alexander Drilon, NTRK) fusion-positive cancers and TRK inhibitor therapy.Nat.Rev.Clin.Oncol.2018,15,731-747.).
通常TRK激酶与相应的配体紧密结合，如神经生长因子NGF与TRKA，脑源性神经营养因子BDNF或者神经营养因子NT-4与TRKB，神经营养因子NT-3与TRKC。NT-3可以结合并激活三种TRK蛋白，但是它与TRKC的结合紧密程度高于TRKA和TRKB。当配体与TRK激酶结合以后，TRK激酶通过二聚而发生自磷酸化，从而激活下游的信号通路，主要包括RAS/RAF/MEK/ERK、PI3K/AKT以及PLCγ信号通路。因此，当TRK功能失调导致下游通道被过度激活时，可能会导致上述癌症的发生。Usually 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. When 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 PLCγ signaling pathways. Therefore, when TRK dysfunction leads to excessive activation of downstream channels, it may lead to the occurrence of the above-mentioned cancers.
已报道的TRK激酶抑制剂用于治疗多种癌症以及疼痛。第一代TRK激酶抑制剂用药以后患者会出现耐药突变，而临床上大部分小分子抑制剂主要是第一代TRK激酶抑制剂。为了解决获得性耐药的问题， 拜耳和LOXO Oncology公司合作研发的第二点激酶抑制剂LOXO-195(NCT03215511)，目前在接受Larotrectinib治疗产生耐药突变的患者上进行治疗，并取得一定的治疗作用。例如在临床I期和II期的NTRK阳性的患者，包括非小细胞肺癌、结直肠癌、胆管癌、胰腺癌、甲状腺癌、肉瘤、胃肠间质瘤等多名患者在接受Larotrectinib治疗后，发现了TRKs突变，主要包括溶剂前沿突变(如TRKA/G595R、TRKC/G623R)、xDFG突变(如TRKA/G667C、TRKA/G667S、TRKC/G696A、TRKC/G696C)以及Gatekeeper突变(TRKA/F589L、TRKC/F617L)等，这些新出现的突变能让Entrectinib和Larotrectinib无法与激酶结合，从而产生耐药。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. In order to solve the problem of acquired drug resistance, 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. For example, in clinical stage I and II patients with NTRK positive, including non-small cell lung cancer, colorectal cancer, cholangiocarcinoma, pancreatic cancer, thyroid cancer, sarcoma, gastrointestinal stromal tumors and many other patients after receiving Larotrectinib treatment, 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., these newly emerged mutations can prevent Entrectinib and Larotrectinib from binding to kinases, resulting in drug resistance.
目前急需开发出能够克服第一代TRK抑制剂Larotrectinib临床上的耐药突变的新型药物，用于治疗与例如TRKA的F589L、V573M、G667C、G667S、G667A突变，TRKB的F633L、G709C突变，和/或TRKC的F617L、G696A、G696C突变相关的疾病，并将这些化合物应用于与这些突变相关的癌症或者其它相关疾病的治疗中。There is an urgent need to develop new drugs that can overcome the clinical resistance mutations of the first-generation 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.
发明内容Summary of the invention
本发明提供一种选择性的激酶抑制剂，包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，以及其用于治疗携带TRKA/B/C突变和/或融合基因的疾病的用途或方法：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:
Figure PCTCN2020079469-appb-000001
Figure PCTCN2020079469-appb-000001
其中，in,
X为-(CH＝CH) m-，其中m为0或1； X is -(CH=CH) m -, where m is 0 or 1;
Y选自-NH-或-(CH 2) n-，其中n为0-3的整数； Y is selected from -NH- or -(CH 2 ) n -, where n is an integer from 0 to 3;
R 1选自任选地被1-3个独立的R 4基团取代的苯基、任选地被1-3个独立的R 4基团取代的吡啶基、任选地被1-3个独立的R 4基团取代的吡唑基、和任选地被1-3个独立的R 4基团取代的嘧啶基； 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选自氢和C 1-6烷基； R 2 is selected from hydrogen and C 1-6 alkyl;
R 3选自任选地被1-2个独立的R 5基团取代的C 1-6烷基、C 1-6烷基氨基、以及任选地被1-3个独立的R 4基团取代的苯基、任选地被1-3个独立的R 4基团取代的萘基、任选地被1-3个独立的R 4基团取代的吡啶基、任选地被1-3个独立的R 4基团取代的哌嗪基、和任选地被1-3个独立的R 4基团取代的哌啶基； 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独立地选自卤素、氨基、C 1-6烷基、C 3-6环烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟基烷基、C 1-6烷基氨基、C 2-6烷酰胺基、(4-甲基哌嗪-1-基)甲基、吗啉甲基、吗啉基、4-甲基哌嗪-1-基、4-哌啶基、和4-四氢吡喃基； 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独立地选自氨基、羟基、和C 1-6烷硫基。 R 5 is independently selected from amino, hydroxyl, and C 1-6 alkylthio.
在优选的实施方式中，X为-(CH＝CH)-。In a preferred embodiment, X is -(CH=CH)-.
在另一优选的实施方式中，Y为直接键或-CH 2-。 In another preferred embodiment, Y is a direct bond or -CH 2 -.
在另外优选的实施方式中，R 1选自任选地被1-3个独立的R 4基团取代的苯基、吡啶基、吡唑基、和嘧啶基，其中R 4独立地选自卤素、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、和(4-甲基哌嗪-1-基)甲基；R 1更优选为任选地被甲基、氨基或卤素取代的苯基、2-吡啶基、3-吡啶基、4-吡唑基、和5-嘧啶基；R 1特别优选为2-吡啶基。 In another preferred embodiment, 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.
在另外优选的实施方式中，R 2为氢或甲基。 In another preferred embodiment, R 2 is hydrogen or methyl.
在另外优选的实施方式中，R 3选自任选地被1-2个独立的R 5基团取代的C 1-6烷基、C 1-6烷基氨基、以及任选地被1-3个独立的R 4基团取代的苯基、萘基、吡啶基、哌嗪基、和哌啶基，其中R 4独立地选自卤素、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、和(4-甲基哌嗪-1-基)甲基，R 5独立地选自氨基、羟基、和甲硫基；R 3更优选为任选地被氨基、羟基、或甲硫基取代的C 1-6烷基、二甲氨基、任选地被甲基取代的N-哌嗪基、任选地被卤素、三氟甲基、或甲氧基取代的苯基、萘基、4-吡啶基、3-哌啶基、和任选地被甲基取代的4-哌啶基；R 3特别优选为甲基、2-丙基、1-氨基-3-甲硫基-丙基、1-氨基-3-甲基-丁基、甲基取代的N-哌嗪基、甲氧基取代的苯基、4-吡啶基、或4-哌啶基。 In a further preferred embodiment, 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-piperidinyl optionally substituted by methyl; R 3 is particularly preferably methyl, 2-propyl, 1- Amino-3-methylthio-propyl, 1-amino-3-methyl-butyl, methyl-substituted N-piperazinyl, methoxy-substituted phenyl, 4-pyridyl, or 4-piperyl Pyridyl.
在特别优选的实施方式中，当Y为直接键时，R 3选自任选地被氨基、羟基、或甲硫基取代的C 1-6烷基、和4-吡啶基；当Y为-CH 2-时， R 3选自任选地被甲氧基取代的苯基、任选地被甲基取代的N-哌嗪基、和任选地被甲基取代的4-哌啶基。 In a particularly preferred embodiment, 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.
在另一方面，本发明还涉及一种药物组合物，其包括本发明的激酶抑制剂，以及药学上可接受的载体或赋形剂，以及任选的其它治疗剂。In another aspect, the present invention also relates to a pharmaceutical composition comprising the kinase inhibitor of the present invention, a pharmaceutically acceptable carrier or excipient, and optionally other therapeutic agents.
在其他方面，本发明还涉及采用激酶抑制剂或包括其的药物组合物降低或抑制细胞或受试者的TRKA、TRKB、TRKC或者它们的点突变如TRKA的F589L、V573M、G667C、G667S和G667A，TRKB的F633L和G709C突变，和/或TRKC的F617L、G696A和G696C突变激酶活性的方法和用途。In other aspects, 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.
在又一方面，本发明还涉及采用激酶抑制剂或包括其的药物组合物在受试者中预防或治疗与TRKA、TRKB、TRKC或者它们的点突变如TRKA的F589L、V573M、G667C、G667S和G667A，TRKB的F633L和G709C突变，和/或TRKC的F617L、G696A和G696C突变活性相关病症的方法和用途。In yet another aspect, 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. Methods and uses of disorders related to G667A, TRKB's F633L and G709C mutations, and/or TRKC's F617L, G696A and G696C mutation activities.
附图说明Description of the drawings
图1a示出化合物9和LOXO-101在BaF3-tel-TRKA细胞肿瘤移植小鼠模型中给药后对小鼠体重的影响；图1b示出化合物9和LOXO-101在BaF3-tel-TRKA细胞肿瘤移植小鼠模型中的肿瘤抑制效果。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.
图2a示出化合物9和LOXO-195在BaF3-LMNA-TRKA-F589L细胞肿瘤移植小鼠模型中给药后对小鼠体重的影响；图2b示出化合物9和LOXO-195在BaF3-LMNA-TRKA-F589L细胞肿瘤移植小鼠模型中的肿瘤抑制效果。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.
具体实施方式Detailed ways
术语the term
除非另外定义，所有本文使用的科技术语都具有与要求保护的主题所属领域的技术人员一般理解相同的含义。Unless otherwise defined, all scientific and technological terms used herein have the same meaning as generally understood by those skilled in the art to which the claimed subject matter belongs.
除非另有说明，本发明采用本领域技术范围内的质谱、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学等常规方法。除非 提供具体的定义，否则与本文描述的分析化学、合成有机化学、以及医学和药物化学等化学上相关的命名和实验室操作和技术，是本领域技术人员已知的。一般而言，前述技术和步骤可以通过本领域众所周知的和在各种一般文献和更具体文献中描述的常规方法来实施，这些文献在本说明书中被引用和讨论。Unless otherwise specified, 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. Unless specific definitions are provided, 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. Generally speaking, 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.
术语“烷基”是指脂肪族烃基团，可以是支链或直链的烷基。根据结构，烷基可以是单价基团或双价基团(即亚烷基)。在本发明中，烷基优选是具有1-8个碳原子的烷基，更优选具有1-6个碳原子的“低级烷基”，甚至更优选具有1-4个碳原子的烷基。典型的烷基包括但不限于甲基、乙基、丙基、丁基、戊基、己基等。应理解，本文提到的“烷基”包括可能存在的所有构型和构象的该烷基，例如本文提到的“丙基”包括正丙基和异丙基，“丁基”包括正丁基、异丁基和叔丁基，“戊基”包括正戊基、异丙基、新戊基、叔戊基、和戊-3-基等。The term "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. It should be understood that the "alkyl" mentioned herein includes all possible configurations and conformations of the alkyl group. For example, the "propyl" mentioned herein includes n-propyl and isopropyl, and "butyl" includes n-butyl. "Pentyl" includes n-pentyl, isopropyl, neopentyl, tert-pentyl, and pent-3-yl.
术语“烷氧基”是指-O-烷基，其中烷基如本文中定义。典型的烷氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等。The term "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.
术语“烷氧基烷基”是指本文定义的烷基被本文定义的烷氧基取代。The term "alkoxyalkyl" means that an alkyl group as defined herein is substituted with an alkoxy group as defined herein.
术语“环烷基”是指单环或多环基，其仅含有碳和氢。环烷基包括具有3-12个环原子的基团。根据结构，环烷基可以是单价基团或双价基团(例如亚环烷基)。在本发明中，环烷基优选是具有3-8个碳原子的环烷基，更优选具有3-6个碳原子的“低级环烷基”。环烷基的例子包括但不限于，环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环戊烯基、环己烯基、环庚烯基和金刚烷基。The term "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. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantane base.
术语“烷基(环烷基)”或“环烷基烷基”是指本文定义的烷基被本文定义的环烷基取代。非限制性的环烷基烷基包括环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基等。The term "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.
术语“芳香基”是指平面环具有离域的π电子***并且含有4n+2个π电子，其中n是整数。芳香基环可以由五、六、七、八、九或多于九个原子构成。芳香基可以是任选取代的。术语“芳香基”包括碳环芳基(例如苯基)和杂环芳基(或“杂芳基”或“杂芳香基”)基团(例如吡啶)。 该术语包括单环或稠环多环(即共用相邻的碳原子对的环)基团。The term "aromatic group" refers to a planar ring having a delocalized π electron system and containing 4n+2 π 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. The term "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.
本文使用的术语“芳基”是指芳香基环中每一个构成环的原子都是碳原子。芳基环可以由五、六、七、八、九或多于九个原子构成。芳基可以是任选取代的。芳基的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。根据结构，芳基可以是单价基团或双价基团(即亚芳基)。The term "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. According to the structure, the aryl group may be a monovalent group or a divalent group (ie, an arylene group).
术语“芳氧基”是指-O-芳基，其中芳基如本文中定义。The term "aryloxy" refers to -O-aryl, where aryl is as defined herein.
术语“杂芳基”是指芳基中包括一个或多个选自氮、氧和硫的环杂原子。含N“杂芳基”部分是指芳香基中环上至少有一个骨架原子是氮原子。根据结构，杂芳基可以是单价基团或双价基团(即亚杂芳基)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、***基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、吲唑基、吲嗪基、酞嗪基、哒嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、萘啶基和呋喃并吡啶基等。The term "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. According to the structure, the heteroaryl group may be a monovalent group or a divalent group (ie, heteroarylene). Examples of 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 , Naphthyridinyl and furopyridinyl and so on.
术语“烷基(芳基)”或“芳烷基”是指本文定义的烷基被本文定义的芳基取代。非限制性的烷基(芳基)包括苄基、苯乙基等。The term "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.
术语“烷基(杂芳基)”或“杂芳基烷基”是指本文定义的烷基被本文定义的杂芳基取代。The term "alkyl(heteroaryl)" or "heteroarylalkyl" means that an alkyl group as defined herein is substituted by a heteroaryl group as defined herein.
本文使用的术语“杂烷基”是指本文定义的烷基中的一个或多个骨架链原子是杂原子，例如氧、氮、硫、硅、磷或它们的组合。所述杂原子(一个或多个)可以位于杂烷基内部的任意位置或在杂烷基与分子的其余部分相连的位置。The term "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.
本文使用的术语“杂环烷基”或“杂环基”是指非芳香基环中一个或多个构成环的原子是选自氮、氧和硫的杂原子。杂环烷基环可以由三、四、五、六、七、八、九或多于九个原子构成。杂环烷基环可以是任选取代的。杂环烷基的实例包括但不限于内酰胺、内酯、环亚胺、环硫代亚胺、环氨基甲酸酯、四氢噻喃、4H-吡喃、四氢吡喃、哌啶、1,3-二噁英、1,3-二噁烷、1,4-二噁英、1,4-二噁烷、哌嗪、1,3-氧硫杂环己烷、1,4-氧硫杂环己二烯、1,4-氧硫杂环己烷、四氢-1,4-噻嗪、2H-1,2- 噁嗪、马来酰亚胺、琥珀酰亚胺、巴比妥酸、硫代巴比妥酸、二氧代哌嗪、乙内酰脲、二氢尿嘧啶、吗啉、三噁烷、六氢-1,3,5-三嗪、四氢噻吩、四氢呋喃、吡咯啉、吡咯烷、咪唑烷，吡咯烷酮、吡唑啉、吡唑烷、咪唑啉、咪唑烷、1,3-二氧杂环戊烯、1,3-二氧杂环戊烷、1,3-二硫杂环戊烯、1,3-二硫杂环戊烷、异噁唑啉、异噁唑烷、噁唑啉、噁唑烷、噁唑烷酮、噻唑啉、噻唑烷和1,3-氧硫杂环戊烷。根据结构，杂环烷基可以是单价基团或双价基团(即亚杂环烷基)。The term "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. Examples of 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, Tetrahydrofuran, pyrrolidine, pyrrolidine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1 ,3-Dithiolan, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine and 1,3-oxathiolane. Depending on the structure, the heterocycloalkyl group may be a monovalent group or a divalent group (ie, heterocycloalkylene).
术语“烷基(杂环烷基)”或“杂环烷基烷基”是指本文定义的烷基被本文定义的杂环烷基取代。The term "alkyl(heterocycloalkyl)" or "heterocycloalkylalkyl" means that an alkyl group as defined herein is substituted by a heterocycloalkyl group as defined herein.
术语“烷氧基(杂环烷基)”或“杂环烷基烷氧基”是指本文定义的烷氧基被本文定义的杂环烷基取代。The term "alkoxy(heterocycloalkyl)" or "heterocycloalkylalkoxy" means that an alkoxy group as defined herein is substituted by a heterocycloalkyl group as defined herein.
术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
术语“卤代烷基”、“卤代烷氧基”和“卤代杂烷基”包括烷基、烷氧基或杂烷基的结构，其中至少一个氢被卤原子置换。在某些实施方式中，如果两个或更多氢原子被卤原子置换，所述卤原子彼此相同或不同。The terms "haloalkyl", "haloalkoxy" and "haloheteroalkyl" 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.
术语“羟基”是指-OH基团。The term "hydroxyl" refers to the -OH group.
术语“氰基”是指-CN基团。The term "cyano" refers to the -CN group.
术语“酯基”是指具有式-COOR的化学部分，其中R选自烷基、环烷基、芳基、杂芳基(通过环碳连接)和杂环基(通过环碳连接)。The term "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).
术语“氨基”是指-NH 2基团。 The term "amino" refers to the -NH 2 group.
术语“氨酰基”是指-CO-NH 2基团。 The term "aminoacyl" refers to the -CO-NH 2 group.
术语“酰胺基”或“酰氨基”是指-NR-CO-R’，其中R和R’各自独立地为氢或烷基。The term "amido" or "amido" refers to -NR-CO-R', where R and R'are each independently hydrogen or alkyl.
术语“烷基氨基”是指进一步被一个或两个烷基取代的氨基取代基，具体是指基团-NRR’，其中R和R’各自独立地选自氢或低级烷基，条件是-NRR’不是-NH 2。“烷基氨基”包括其中-NH 2的氮连接至少一个烷基基团的化合物的基团。烷基氨基基团的例子包括但不限于，甲基氨基、乙基氨基等。“二烷基氨基”包括其中-NH 2的氮连接至少两个其它烷基基团的基团。二烷基氨基基团的例子包括但不限于，二甲基氨基、二乙基氨基等。 The term "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.
术语“芳基氨基”和“二芳基氨基”是指进一步被一个或两个芳基取 代的氨基取代基，具体是指基团-NRR’，其中R和R’各自独立地选自氢、低级烷基、或芳基，其中N分别连接至少一个或两个芳基基团。The terms "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.
术语“环烷基氨基”是指进一步被一个或两个本文所定义的环烷基取代的氨基取代基。The term "cycloalkylamino" refers to an amino substituent further substituted with one or two cycloalkyl groups as defined herein.
术语“杂烷基氨基”是指进一步被一个或两个本文所定义的杂烷基取代的氨基取代基。The term "heteroalkylamino" refers to an amino substituent further substituted with one or two heteroalkyl groups as defined herein.
本文的术语“芳烷基氨基”是指其中R是低级芳烷基且R’是氢、低级烷基、芳基或低级芳烷基的基团-NRR’。The term "aralkylamino" herein refers to a group -NRR' in which R is lower aralkyl and R'is hydrogen, lower alkyl, aryl, or lower aralkyl.
术语“杂芳基氨基”是指进一步被一个或两个本文所定义的杂芳基取代的氨基取代基。The term "heteroarylamino" refers to an amino substituent further substituted with one or two heteroaryl groups as defined herein.
术语“杂环烷基氨基”是指本文定义的氨基被本文定义的杂环烷基取代。The term "heterocycloalkylamino" means that an amino group as defined herein is substituted by a heterocycloalkyl group as defined herein.
术语“烷基氨基烷基”是指本文定义的烷基被本文定义的烷基氨基取代。The term "alkylaminoalkyl" means that an alkyl group as defined herein is substituted with an alkylamino group as defined herein.
术语“氨基烷基”是指进一步被一个或多个氨基取代的烷基取代基。The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups.
术语“氨基烷氧基”是指进一步被一个或多个氨基取代的烷氧基取代基。The term "aminoalkoxy" refers to an alkoxy substituent further substituted with one or more amino groups.
术语“羟烷基”或“羟基烷基”是指进一步被一个或多个羟基取代的烷基取代基。The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent further substituted with one or more hydroxy groups.
术语“氰基烷基”是指进一步被一个或多个氰基取代的烷基取代基。The term "cyanoalkyl" refers to an alkyl substituent further substituted with one or more cyano groups.
术语“酰基”是指有机或无机含氧酸去掉羟基后剩下的一价原子团，通式为R-M(O)-，其中M通常为C。The term "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.
术语“羰基”是由碳和氧两种原子通过双键连接而成的有机官能团(C＝O)。The term "carbonyl" is an organic functional group (C=O) formed by two atoms of carbon and oxygen connected by a double bond.
术语“烷酰基”或“烷基羰基”是指进一步被一个烷基取代的羰基。典型的烷酰基包括但不限于乙酰基、丙酰基、丁酰基、戊酰基、己酰基等。The term "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.
术语“芳基羰基”是指本文定义的羰基被本文定义的芳基取代。The term "arylcarbonyl" means that the carbonyl group defined herein is substituted with an aryl group defined herein.
术语“烷氧基羰基”是指进一步被一个烷氧基取代的羰基。The term "alkoxycarbonyl" refers to a carbonyl group further substituted with an alkoxy group.
术语“杂环烷基羰基”是指进一步被一个杂环烷基取代的羰基。The term "heterocycloalkylcarbonyl" refers to a carbonyl group further substituted with a heterocycloalkyl group.
术语“烷基氨基羰基”、“环烷基氨基羰基”、“芳基氨基羰基”、“芳烷基氨基羰基”、“杂芳基氨基羰基”分别是指本文定义的羰基分别被本文定义的烷基氨基、环烷基氨基、芳基氨基、芳烷基氨基、或杂芳基氨基取代。The terms "alkylaminocarbonyl", "cycloalkylaminocarbonyl", "arylaminocarbonyl", "aralkylaminocarbonyl" and "heteroarylaminocarbonyl" respectively refer to the carbonyl groups defined herein as defined herein. Alkylamino, cycloalkylamino, arylamino, aralkylamino, or heteroarylamino substitution.
术语“烷基羰基烷基”或“烷酰基烷基”是指进一步被一个烷基羰基取代的烷基。The term "alkylcarbonylalkyl" or "alkanoylalkyl" refers to an alkyl group further substituted with an alkylcarbonyl group.
术语“烷基羰基烷氧基”或“烷酰基烷氧基”是指进一步被一个烷基羰基取代的烷氧基。The term "alkylcarbonylalkoxy" or "alkanoylalkoxy" refers to an alkoxy group further substituted with an alkylcarbonyl group.
术语“杂环烷基羰基烷基”是指进一步被一个杂环烷基羰基取代的烷基。The term "heterocycloalkylcarbonylalkyl" refers to an alkyl group further substituted with a heterocycloalkylcarbonyl group.
术语“巯基”是指-SH基团。术语“烷硫基”是指本文所定义的巯基被本文所定义的烷基取代。The term "mercapto" refers to the -SH group. The term "alkylthio" means that a mercapto group as defined herein is substituted with an alkyl group as defined herein.
术语“砜基”或“磺酰基”是指磺酸失去羟基后的官能团，具体是指-S(＝O) 2-基团。 The term "sulfone group" or "sulfonyl group" refers to a functional group after sulfonic acid loses a hydroxyl group, and specifically refers to a -S(=O) 2 -group.
术语“亚砜基”或“亚磺酰基”是指-S(＝O)-。The term "sulfoxide" or "sulfinyl" refers to -S(=O)-.
术语“氨基砜基”或“氨基磺酰基”是指-S(＝O) 2-NH 2基团。 The term "amino sulfone group" or "aminosulfonyl" refers to -S (= O) 2 -NH 2 group.
术语“烷基亚砜基”或“烷基亚磺酰基”是指-S(＝O)-R，其中R为烷基。The term "alkylsulfoxide" or "alkylsulfinyl" refers to -S(=O)-R, where R is an alkyl group.
术语“烷基砜基”或“烷基磺酰基”是指-S(＝O) 2-R，其中R为烷基。 The term "alkylsulfone" or "alkylsulfonyl" refers to -S(=O) 2- R, where R is an alkyl group.
术语“烷基氨基砜基”是指本文定义的砜基被本文定义的烷基氨基取代。The term "alkylaminosulfone group" means that the sulfone group as defined herein is substituted with an alkylamino group as defined herein.
术语“烷基砜基氨基”或“环烷基砜基氨基”是指本文定义的氨基被本文定义的烷基砜基或环烷基砜基取代。The term "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.
术语“环烷基砜基”和“环烷基磺酰基”是指-S(＝O) 2-R，其中R为环烷基。 The terms "cycloalkylsulfone" and "cycloalkylsulfonyl" refer to -S(=O) 2 -R, where R is cycloalkyl.
术语“烷基磺酰胺基”和“环烷基磺酰胺基”是指-NH-S(＝O) 2-R，其中R分别为烷基和环烷基。 The terms "alkylsulfonamido" and "cycloalkylsulfonamido" refer to -NH-S(=O) 2 -R, where R is an alkyl group and a cycloalkyl group, respectively.
术语“季铵基”是指-N +RR’R”，其中R、R’和R”各自独立地选自具有1-8个碳原子的烷基。 The term "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.
术语“任选”指后面描述的一个或多个事件可以发生或可以不发生，并且包括发生的事件和不发生的事件两者。术语“任选取代的”或“取代 的”是指所提及的基团可以被一个或多个额外的基团取代，所述额外的基团各自并且独立地选自烷基、环烷基、芳基、杂芳基、杂环基、羟基、烷氧基、氰基、卤素、酰胺基、硝基、卤代烷基、氨基、甲磺酰基、烷基羰基、烷氧基羰基、杂芳基烷基、杂环烷基烷基、氨酰基、氨基保护基等。其中，氨基保护基优选选自新戊酰基、叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、苄基、对甲氧苄基、烯丙氧羰基、和三氟乙酰基等。The term "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. The term "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. Among them, 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.
本文使用的术语“酪氨酸蛋白激酶(tyrosine protein kinase，TPK)”是一类催化ATP上γ-磷酸转移到蛋白酪氨酸残基上的激酶，能催化多种底物蛋白质酪氨酸残基磷酸化，在细胞生长、增殖、分化中具有重要作用。The term "tyrosine protein kinase (TPK)" as used herein is a type of kinase that catalyzes the transfer of γ-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.
本文使用的术语激酶的“抑制”、“抑制的”或“抑制剂”，是指磷酸转移酶活性被抑制。As used herein, the term "inhibition", "inhibition" or "inhibitor" of a kinase means that the activity of the phosphotransferase is inhibited.
本文公开的化合物的“代谢物”是当该化合物被代谢时形成的化合物的衍生物。术语“活性代谢物”是指当该化合物被代谢时形成的化合物的生物活性衍生物。本文使用的术语“被代谢”，是指特定物质被生物体改变的过程总和(包括但不限于水解反应和由酶催化的反应，例如氧化反应)。因此，酶可以产生特定的结构转变为化合物。例如，细胞色素P450催化各种氧化和还原反应，同时二磷酸葡萄糖甘酸基转移酶催化活化的葡萄糖醛酸分子至芳香醇、脂肪族醇、羧酸、胺和游离的巯基的转化。新陈代谢的进一步的信息可以从《The Pharmacological Basis of Therapeutics》，第九版，McGraw-Hill(1996)获得。本文公开的化合物的代谢物可以通过将化合物给予宿主并分析来自该宿主的组织样品、或通过将化合物与肝细胞在体外孵育并且分析所得化合物来鉴别。这两种方法都是本领域已知的。在一些实施方式中，化合物的代谢物是通过氧化过程形成并与相应的含羟基化合物对应。在一些实施方式中，化合物被代谢为药物活性代谢物。本文使用的术语“调节”，是指直接或间接与靶标相互作用，以改变靶标的活性，仅仅举例来说，包括增强靶标的活性、抑制靶标的活性、限制靶标的活性或者延长靶标的活性。A "metabolite" of a compound disclosed herein is a derivative of a compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. The term "metabolized" as used herein 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. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while diphosphate glucosyltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be obtained from "The Pharmacological Basis of Therapeutics", Ninth Edition, McGraw-Hill (1996). 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. In some embodiments, the metabolite of the compound is formed through an oxidation process and corresponds to the corresponding hydroxyl-containing compound. In some embodiments, the compound is metabolized into a pharmaceutically active metabolite. The term "modulation" as used herein 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.
本文使用的术语“靶蛋白”是指能被选择性结合化合物所结合的蛋 白质分子或部分蛋白质。在某些实施方式中，靶蛋白是酪氨酸激酶TRKA(野生型或各种突变或其组合)、TRKB(野生型或各种突变或其组合)、TRKC(野生型或各种突变或其组合)。The term "target protein" as used herein refers to a protein molecule or part of a protein that can be bound by a selective binding compound. In some embodiments, 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).
本文使用的IC 50是指在测量这样的效应的分析中获得最大效应的50％抑制的特定测试化合物的量、浓度或剂量。 An amount of a particular test compound used herein, 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.
本文使用的EC 50是指测定化合物的剂量、浓度或量，其引起特定测定化合物诱导、刺激或加强的特定反应的50％的最大表达的剂量依赖反应。 As used herein, 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.
本文使用的GI 50是指使50％细胞生长被抑制所需的药物浓度，即药物使50％细胞(如癌细胞)的生长得到抑制或控制时的药物浓度。 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).
本发明新型的激酶抑制剂Novel kinase inhibitor of the present invention
本发明提供一种新型的激酶抑制剂，包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物，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,
Figure PCTCN2020079469-appb-000002
Figure PCTCN2020079469-appb-000002
其中，in,
X为-(CH＝CH) m-，其中m为0或1，当m为0时X表示直接键； X is -(CH=CH) m -, where m is 0 or 1, when m is 0, X represents a direct bond;
Y选自-NH-或-(CH 2) n-，其中n为0-3的整数，当n为0时Y表示直接键； 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选自任选地被1-3个独立的R 4基团取代的芳基和杂芳基； R 1 is selected from aryl and heteroaryl optionally substituted with 1-3 independent R 4 groups;
R 2选自氢和C 1-6烷基； R 2 is selected from hydrogen and C 1-6 alkyl;
R 3选自任选地被1-2个独立的R 5基团取代的C 1-6烷基、C 1-6烷基氨基、以及任选地被1-3个独立的R 4基团取代的芳基、杂芳基和杂环基； 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独立地选自卤素、氨基、C 1-6烷基、C 3-6环烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟基烷基、C 1-6烷基氨基、C 2-6烷酰胺基、(4-甲基哌嗪-1-基)甲基、吗啉甲基、吗啉基、4-甲基哌嗪-1-基、4-哌啶基、和4- 四氢吡喃基； 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独立地选自氨基、羟基、和C 1-6烷硫基。 R 5 is independently selected from amino, hydroxyl, and C 1-6 alkylthio.
在优选的实施方式中，X为-(CH＝CH)-。In a preferred embodiment, X is -(CH=CH)-.
在另一优选的实施方式中，Y为直接键或-CH 2-。 In another preferred embodiment, Y is a direct bond or -CH 2 -.
在另外优选的实施方式中，R 1选自任选地被1-3个独立的R 4基团取代的苯基、吡啶基、吡唑基、和嘧啶基，其中R 4独立地选自卤素、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、和(4-甲基哌嗪-1-基)甲基；R 1更优选为任选地被甲基、氨基或卤素取代的苯基、2-吡啶基、3-吡啶基、4-吡唑基、和5-嘧啶基；R 1特别优选为2-吡啶基。 In another preferred embodiment, 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.
在另外优选的实施方式中，R 2为氢或甲基。 In another preferred embodiment, R 2 is hydrogen or methyl.
在另外优选的实施方式中，R 3选自任选地被1-2个独立的R 5基团取代的C 1-6烷基、C 1-6烷基氨基、以及任选地被1-3个独立的R 4基团取代的苯基、萘基、吡啶基、哌嗪基、和哌啶基，其中R 4独立地选自卤素、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、和(4-甲基哌嗪-1-基)甲基，R 5独立地选自氨基、羟基、和甲硫基；R 3更优选为任选地被氨基、羟基、或甲硫基取代的C 1-6烷基、二甲氨基、任选地被甲基取代的N-哌嗪基、任选地被卤素、三氟甲基、或甲氧基取代的苯基、萘基、4-吡啶基、3-哌啶基、和任选地被甲基取代的4-哌啶基；R 3特别优选为甲基、2-丙基、1-氨基-3-甲硫基-丙基、1-氨基-3-甲基-丁基、甲基取代的N-哌嗪基、甲氧基取代的苯基、4-吡啶基、或4-哌啶基。 In a further preferred embodiment, 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-piperidinyl optionally substituted by methyl; R 3 is particularly preferably methyl, 2-propyl, 1- Amino-3-methylthio-propyl, 1-amino-3-methyl-butyl, methyl-substituted N-piperazinyl, methoxy-substituted phenyl, 4-pyridyl, or 4-piperyl Pyridyl.
在特别优选的实施方式中，当Y为直接键时，R 3选自任选地被氨基、羟基、或甲硫基取代的C 1-6烷基、和4-吡啶基；当Y为-CH 2-时，R 3选自任选地被甲氧基取代的苯基、任选地被甲基取代的N-哌嗪基、和任选地被甲基取代的4-哌啶基。 In a particularly preferred embodiment, 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.
对于各个变量，上述基团的任意组合也在本文考虑之中。可以理解的是：本文所提供的化合物上的取代基和取代模式可以由本领域技术人员进行选择，以便提供化学上稳定的且可以使用本领域已知的技术以及本文阐述的技术合成的化合物。For each variable, any combination of the above groups is also considered herein. It is understood that the substituents and substitution patterns on the compounds provided herein can be selected by those skilled in the art in order to provide chemically stable compounds that can be synthesized using techniques known in the art and the techniques described herein.
在优选的实施方式中，本发明的抑制剂包括下表1的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药。In a preferred embodiment, 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.
表1Table 1
Figure PCTCN2020079469-appb-000003
Figure PCTCN2020079469-appb-000003
Figure PCTCN2020079469-appb-000004
Figure PCTCN2020079469-appb-000004
本文描述的是新型的激酶抑制剂。本文也描述了此化合物的药学可接受的盐、溶剂化物、酯、酸、药物活性代谢物和前药。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.
在另外的或进一步的实施方式中，将本文描述的化合物给予有需要的生物体后在其体内代谢产生代谢物，所产生的代谢物然后用于产生期望的效果，包括期望的治疗效果。In additional or further embodiments, 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.
本文描述的化合物可以被制成和/或被用作药学可接受的盐。药学可接受的盐的类型包括但不限于：(1)酸加成盐、通过将化合物的游 离碱形式与药学可接受的无机酸反应形成，所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸、偏磷酸等；或与有机酸反应形成，所述有机酸如乙酸、丙酸、己酸、环戊烷丙酸、羟基乙酸、丙酮酸、乳酸、丙二酸、苹果酸、柠檬酸、琥珀酸、马来酸、酒石酸、反丁烯二酸、三氟乙酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、甲苯磺酸、4-甲基双环-[2.2.2]辛-2-烯-1-甲酸、2-萘磺酸、叔丁基乙酸、葡庚糖酸、4,4'-亚甲基双-(3-羟基-2-烯-1-甲酸)、3-苯基丙酸、三甲基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、水杨酸、羟基萘酸、硬脂酸、粘康酸等；(2)碱加成盐，其在母体化合物中的酸性质子被金属离子置换时形成，例如碱金属离子(例如锂、钠、钾)、碱土金属离子(例如镁或钙)或铝离子；或与有机碱或无机碱配位，可接受的有机碱包括乙醇胺、二乙醇胺、三乙醇胺、三甲胺、N-甲基葡萄糖胺等；可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠、氢氧化钠等。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-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, 2-naphthalene Sulfonic acid, tert-butyl acetic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, ten Dialkyl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, hydroxynaphthoic acid, stearic acid, muconic acid, etc.; (2) Alkali addition salts, the acidic protons of which in the parent compound are replaced by metal ions It is formed at the same time, such as alkali metal ions (such as lithium, sodium, potassium), alkaline earth metal ions (such as magnesium or calcium) or aluminum ion; or coordinated with organic or inorganic bases. 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.
药学可接受的盐的相应的平衡离子可以使用各种方法分析和鉴定，所述方法包括但不限于离子交换色谱、离子色谱、毛细管电泳、电感耦合等离子体、原子吸收光谱、质谱或它们的任何组合。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.
使用以下技术的至少一种回收所述盐：过滤、用非溶剂沉淀接着过滤、溶剂蒸发，或水溶液的情况下使用冻干法。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.
筛选和表征药学可接受的盐、多晶型和/或溶剂化物可以使用多种技术完成，所述技术包括但不限于热分析、X射线衍射、光谱、显微镜方法、元素分析。使用的各种光谱技术包括但不限于Raman、FTIR、UVIS和NMR(液体和固体状态)。各种显微镜技术包括但不限于IR显微镜检术和拉曼(Raman)显微镜检术。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.
本发明的药物组合物The pharmaceutical composition of the present invention
本申请还提供药物组合物，其包含至少一种式(I)的化合物或所述化合物的药学可接受的盐、溶剂化物、酯、酸、药物活性代谢物或前药、以及药学可接受的载体或赋形剂、以及任选的其它治疗剂。The application also provides 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.
在治疗过程中，可以根据情况单独或与一种或多种其它的治疗剂组合使用。可以通过注射、口服、吸入、直肠和经皮施用中的至少一 种将包含本发明化合物的药物施用给患者。其它的治疗剂可以选自以下药物：免疫抑制剂(例如他克莫司、环抱菌素、雷帕霉素、甲氨蝶岭、环磷酰胺、硫唑嘌呤、巯嘌呤、麦考酚酯或FTY720)、糖皮质激素类药(例如***、醋酸可的松、***龙、甲泼尼龙、***、倍他米松、曲安西龙、氢羟强的松龙、倍氯米松、醋酸氟氢可的松、醋酸脱氧皮质酮、醛固酮)、非甾体抗炎药(例如水杨酸盐、芳基烷酸、2-芳基丙酸、N-芳基邻氨基苯甲酸、昔康类、考昔类或硫酰替苯胺)、***反应疫苗、抗组胺药、抗白三烯药、β-激动剂、茶碱、抗胆碱药或其它选择性激酶抑制剂(例如mTOR抑制剂、c-Met抑制剂)或her2抗体-药物。另外，所提及的其它治疗剂还可以是雷帕霉素(Rapamycin)、克唑替尼(Crizotinib)、他莫昔芬、雷洛昔芬、阿那曲唑、依西美坦、来曲唑、赫赛汀 TM(曲妥珠单抗)、格列卫 TM(伊马替尼)、紫杉醇 TM(紫杉醇)、环磷酰胺、洛伐他汀、美诺四环素(Minosine)、阿糖胞苷、5-氟尿嘧啶(5-FU)、甲氨蝶呤(MTX)、紫杉特尔 TM(多西他赛)、诺雷德 TM(戈舍瑞林)、长春新碱、长春碱、诺考达唑、替尼泊苷、依托泊苷、健择 TM(吉西他滨)、埃博霉素(Epothilone)、诺唯本、喜树碱、柔红霉素(Daunonibicin)、更生霉素、米托蒽醌、安吖啶、多柔比星(亚德里亚霉素)、表柔比星或伊达比星。或者，其它治疗剂也可以是细胞因子例如G-CSF(粒细胞集落刺激因子)。或者，其它治疗剂也可以是，例如但不限于，CMF(环磷酰胺、甲氨蝶呤和5-氟尿嘧啶)、CAF(环磷酰胺、亚德里亚霉素和5-氟尿嘧啶)、AC(亚德里亚霉素和环磷酰胺)、FEC(5-氟尿嘧啶、表柔比星和环磷酰胺)、ACT或ATC(亚德里亚霉素、环磷酰胺和紫杉醇)或CMFP(环磷酰胺、甲氨蝶呤、5-氟尿嘧啶和***)。 In the course of treatment, it can be used alone or in combination with one or more other therapeutic agents according to the situation. 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, β-agonists, theophylline, anticholinergics, or other selective kinase inhibitors (e.g. mTOR inhibitors) , C-Met inhibitor) or her2 antibody-drug. In addition, 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 CD, camptothecin, daunorubicin (Daunonibicin), dactinomycin, mitoxantrone , Amsacrine, doxorubicin (adriamycin), epirubicin or idarubicin. Alternatively, other therapeutic agents may also be cytokines such as G-CSF (granulocyte colony stimulating factor). Alternatively, 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).
在本发明的实施方式中，在根据本发明对患者进行治疗时，给定药物的量取决于诸多因素，如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重)，但是，根据特定的周围情况，包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主，施用剂量可由本领域已知的方法常规决定。通常，就成人治疗使用的剂量而言，施用剂量典型地在0.02-5000mg/天，例如约1-1500mg/天的范围。该所需剂量可以方便地 被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量，例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是，尽管给出了上述剂量范围，但具体的有效量可根据患者的情况并结合医师诊断而适当调节。In the embodiments of the present invention, when a patient is treated according to the present invention, 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. Generally, in terms of doses used in adult therapy, 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. Those skilled in the art can understand that, although the above-mentioned dosage range is given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.
本发明的药物的用途Use of the medicine of the present invention
本发明的激酶抑制剂包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药、或药物组合物，用于降低或抑制细胞或受试者的TRKA、TRKB、TRKC或者它们的点突变如TRKA的F589L、V573M、G667C、G667S和G667A，TRKB的F633L和G709C突变，和/或TRKC的F617L、G696A和G696C突变激酶活性，并且/或者在受试者中预防或治疗与TRKA、TRKB、TRKC或者它们的点突变如TRKA的F589L、V573M、G667C、G667S和G667A，TRKB的F633L和G709C突变，和/或TRKC的F617L、G696A和G696C突变等激酶活性相关病症。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.
式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，或其药物组合物可用于治疗、预防或改善一种或多种选自下组的疾病：实体瘤(包括良性或者尤其恶性类型)、尤其肉瘤、胃肠道间质肿瘤(Gastrointestinal Stromal Tumors，GIST)、结直肠癌(colon cancer)、急性粒细胞白血病(Acute Myeloblastic Leukemia，AML)、慢性髓性白血病(Chronic Myelogenous Leukemia，CML)、瘤形成、甲状腺癌、***性肥大细胞病、嗜酸性粒细胞增多综合征、纤维变性、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、***瘤、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、睾丸上皮内瘤形成、黑色素瘤、乳癌、神经母细胞瘤、***状/滤泡型甲状腺癌、恶性淋巴瘤、非霍奇金淋巴瘤、2型多发性内分泌瘤形成、嗜铬细胞瘤、甲状腺癌、甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、***癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、***癌、***、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、以及其他增生性或增殖性疾病或类似疾病、或其 组合。特别优选治疗胃肠道间质瘤、结直肠癌、急性粒细胞白血病、慢性髓性白血病、甲状腺癌或类似疾病、或其组合。最优选地，本发明的抑制剂或其药物组合物可用于治疗或预防TRKA的F589L、V573M、G667C、G667S和G667A突变，TRKB的F633L和G709C突变，和/或TRKC的F617L、G696A和G696C突变相关的疾病。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, testicular intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, papillary/follicular thyroid cancer, malignant Lymphoma, non-Hodgkin's lymphoma, type 2 multiple endocrine tumor formation, pheochromocytoma, thyroid cancer, parathyroid hyperplasia/adenoma, colon cancer, colorectal adenoma, ovarian cancer, prostate cancer, gelatinization Plasma cell tumor, brain tumor, malignant glioma, pancreatic cancer, malignant pleural mesothelioma, hemangioblastoma, hemangioma, kidney cancer, liver cancer, adrenal cancer, bladder cancer, stomach cancer, rectal cancer, vagina cancer, cervical cancer Cancer, endometrial cancer, multiple myeloma, neck and head tumors, and other proliferative or proliferative diseases or similar diseases, or combinations thereof. It is particularly preferred to treat gastrointestinal stromal tumors, colorectal cancer, acute myeloid leukemia, chronic myelogenous leukemia, thyroid cancer or similar diseases, or a combination thereof. Most preferably, 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.
式(I)所述化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，或其药物组合物可用于治疗、预防或改善选自下组的自身免疫性疾病：关节炎、风湿性关节炎、骨关节炎、狼疮、类风湿性关节炎、炎性肠病、银屑病性关节炎、骨关节炎、斯蒂尔病(Still's disease)、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎(Hashimoto's thyroiditis)、奥德甲状腺炎(Ord's hyroiditis)、格雷夫斯病(Graves'disease)、类风湿性关节炎综合征(
Figure PCTCN2020079469-appb-000005
syndrome)、多发性硬化症、传染性神经元炎(Guillain-Barré syndrome)、急性播散性脑脊髓炎、阿狄森病(Addison's disease)、视性眼阵孪-肌阵孪综合征、强直性脊椎炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、乳糜泻(coeliac disease)、古德帕斯彻综合征(Goodpasture's syndrome)、特发性血小板减少性紫癜、视神经炎、硬皮病、原发性胆汁性肝硬化、莱特尔综合征(Reiter's syndrome)、高安动脉炎(Takayasu's arteritis)、颞动脉炎、温型自身免疫性溶血性贫血、韦格纳肉芽肿病(Wegener's granulomatosis)、银屑病、全身脱毛、贝赫切特病(Behcet's disease)、慢性疲劳、家族性自主神经功能异常、子宫内膜异位、间质性膀胱炎、神经肌强直、硬皮病或外阴痛。 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 (
Figure PCTCN2020079469-appb-000005
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, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, Scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis granulomatosis), psoriasis, whole body hair loss, Behcet's disease, chronic fatigue, familial autonomic dysfunction, endometriosis, interstitial cystitis, neuromuscular rigidity, scleroderma or Vulvar pain.
特别地，本发明的式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药，或其药物组合物可用于治疗以下与TRKA、TRKB、TRKC或者它们的点突变如TRKA的F589L、V573M、G667C、G667S和G667A，TRKB的F633L和G709C突变，和/或TRKC的F617L、G696A和G696C突变等激酶活性相关病症：***状甲状腺癌、胰腺癌、结直肠癌、乳癌、黑色素瘤、非小细胞肺癌、急性髓性白血病、成神经细胞瘤、疼痛、皮炎或哮喘。In particular, 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.
化合物的制备Compound preparation
使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本文描述的方法组合，可以合成式(I)的化合物。另外，本文给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。作为进一步的指导，也可以利用以下的合成方法。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. In addition, the solvent, temperature and other reaction conditions given herein can be changed according to the skill in the art. As further guidance, the following synthesis methods can also be used.
所述反应可以按顺序使用，以提供本文描述的化合物；或它们可以用于合成片段，所述片段通过本文描述的方法和/或本领域已知的方法随后加入。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.
在某些实施方式中，本文提供的是本文描述的激酶抑制剂化合物的制备方法及其使用方法。在某些实施方式中，本文描述的化合物可以使用以下合成的方案合成。可以使用与下述类似的方法，通过使用适当的可选择的起始原料，合成化合物。In certain embodiments, provided herein are methods of preparing the kinase inhibitor compounds described herein and methods of using them. In certain embodiments, 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.
用于合成本文描述的化合物的起始原料可以被合成或可以从商业来源获得。本文描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本文公开的化合物的一般方法可以来自本领域已知的反应，并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改，以引入本文提供的分子中的各种部分。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.
如果需要，反应产物可以使用常规技术分离和纯化，包括但不限于过滤、蒸馏、结晶、色谱等方法。这些产物可以使用常规方法表征，包括物理常数和图谱数据。If necessary, the 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.
制备式(I)的化合物的合成方案的非限制性实施例参见以下合成路线。For non-limiting examples of synthetic schemes for preparing compounds of formula (I), see the following synthetic routes.
实施例1：(E)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻唑Example 1: (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazole -2-基)-4-((4-甲基哌嗪-1-基)甲基)苯甲酰胺-2-yl)-4-((4-methylpiperazin-1-yl)methyl)benzamide
Figure PCTCN2020079469-appb-000006
Figure PCTCN2020079469-appb-000006
N-(4-甲基噻唑-2-基)乙酰胺：在100mL圆底烧瓶中加入4-甲基噻唑-2-胺(2g)后加入无水二氯甲烷(50mL)、三乙胺(3.9mL)，慢慢滴加乙酰氯(1.5mL)。反应体系在室温下、氩气保护反应4小时。反应结束后，体系在减压下蒸干溶剂，所得物用饱和碳酸氢钠中和至pH>10后，用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品，MS(ESI)m/z(M+1)+：157.05。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 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)+: 157.05.
(E)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)噻唑-2-基)乙酰胺：在圆底烧瓶中加入N-(4-甲基噻唑-2-基)乙酰胺(1.0g)后加入二甲亚砜(20mL)、(E)-6-碘-3-(2-(吡啶-2-基)乙烯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑(3.1g)、四三苯基膦钯(0.37g)和碳酸铯(6.2g)。反应体系在氩气保护下加热至130℃反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品，MS(ESI)m/z(M+1)+：460.18。(E)-N-(4-Methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indyl (Azol-6-yl)thiazol-2-yl)acetamide: Add N-(4-methylthiazol-2-yl)acetamide (1.0g) in a round bottom flask and then add dimethyl sulfoxide (20mL), (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.1g), four Palladium triphenylphosphine (0.37g) and cesium carbonate (6.2g). 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.
(E)-4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻唑-2-胺：在100mL圆底烧瓶中加入(E)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)噻唑-2-基)乙酰胺(2.0g)、乙醇(20mL)和6摩尔/升盐酸(15mL)。反应体系在氩气保护下加热至90℃反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用饱和碳酸氢钠中和至pH>10后，有固体析出，过滤，得粗品。粗品经乙酸乙酯洗涤， 得纯品，MS(ESI)m/z(M+1)+：334.11。(E)-4-Methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazol-2-amine: add to a 100mL round bottom flask (E)-N-(4-Methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indyl Azol-6-yl)thiazol-2-yl)acetamide (2.0 g), ethanol (20 mL), and 6 mol/liter hydrochloric acid (15 mL). The reaction system was heated to 90°C for 14 hours under the protection of argon. After the reaction, the system was evaporated to dry the solvent under reduced pressure. After the resultant was neutralized with saturated sodium bicarbonate to pH>10, a solid precipitated out and filtered to obtain a crude product. The crude product was washed with ethyl acetate to obtain a pure product, MS (ESI) m/z (M+1)+: 334.11.
(E)-6-(2-氨基-4-甲基噻唑-5-基)-3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-1-甲酸叔丁酯：在50mL圆底烧瓶中加入(E)-4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻唑-2-胺(1g)后加入无水N,N-二甲基甲酰胺(10mL)、三乙胺(0.9mL)、二碳酸二叔丁酯(1.0g)。反应体系在室温下、氩气保护反应4小时。反应结束后，体系在减压下蒸干溶剂，所得物用饱和碳酸氢钠中和至pH>10后用乙酸乙酯萃取水相。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品，MS(ESI)m/z(M+1)+：434.17。(E)-6-(2-Amino-4-methylthiazol-5-yl)-3-(2-(pyridin-2-yl)vinyl)-1H-indazole-1-carboxylic acid tert-butyl ester: Add (E)-4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazol-2-amine ( 1g) and then anhydrous N,N-dimethylformamide (10mL), triethylamine (0.9mL), and di-tert-butyl dicarbonate (1.0g) were added. 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 the aqueous phase was 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)+: 434.17.
(E)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻唑-2-基)-4-((4-甲基哌嗪-1-基)甲基)苯甲酰胺(1)：在圆底烧瓶中加入(E)-6-(2-氨基-4-甲基噻唑-5-基)-3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-1-甲酸叔丁酯(0.05g)后加入N,N-二甲基甲酰胺(5mL)、4-((4-甲基哌嗪-1-基)甲基)苯甲酸(0.03g)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.07g)和三乙胺(0.03mL)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。(E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazol-2-yl)-4-( (4-Methylpiperazin-1-yl)methyl)benzamide (1): Add (E)-6-(2-amino-4-methylthiazol-5-yl)- in a round bottom flask 3-(2-(pyridin-2-yl)vinyl)-1H-indazole-1-carboxylic acid tert-butyl ester (0.05g) and then add N,N-dimethylformamide (5mL), 4-(( 4-Methylpiperazin-1-yl)methyl)benzoic acid (0.03g), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluoro Phosphate (0.07g) and triethylamine (0.03mL). 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.
粗品溶于无水二氯甲烷(2毫升)，加入三氟乙酸(1毫升)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用饱和碳酸氢钠溶液中和至pH>10。水相用乙酸乙酯萃取，有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物1，MS(ESI)m/z(M+1)+：550.24。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.
实施例2：(E)-4-氯-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)Example 2: (E)-4-chloro-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl) 噻唑-2-基)-3-(三氟甲基)苯甲酰胺Thiazol-2-yl)-3-(trifluoromethyl)benzamide
Figure PCTCN2020079469-appb-000007
Figure PCTCN2020079469-appb-000007
实施例2的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：540.09。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.
实施例3：(E)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻唑Example 3: (E)-N-(4-Methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazole -2-基)-2-(3-(三氟甲基)苯基)乙酰胺-2-yl)-2-(3-(trifluoromethyl)phenyl)acetamide
Figure PCTCN2020079469-appb-000008
Figure PCTCN2020079469-appb-000008
实施例3的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：520.14。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.
实施例4：(E)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻唑Example 4: (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazole -2-基)异烟酰胺-2-yl)isonicotinamide
Figure PCTCN2020079469-appb-000009
Figure PCTCN2020079469-appb-000009
实施例4的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：439.14。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.
实施例5：(E)-N-(5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻唑-2-基)Example 5: (E)-N-(5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazol-2-yl) 乙酰胺Acetamide
Figure PCTCN2020079469-appb-000010
Figure PCTCN2020079469-appb-000010
实施例5的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：361.11。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.
实施例6：(E)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻唑Example 6: (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazole -2-基)-3-(三氟甲基)苯甲酰胺-2-yl)-3-(trifluoromethyl)benzamide
Figure PCTCN2020079469-appb-000011
Figure PCTCN2020079469-appb-000011
实施例6的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：506.13。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.
实施例7：(E)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻唑Example 7: (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazole -2-基)-2-(萘-1-基)乙酰胺-2-yl)-2-(naphthalene-1-yl)acetamide
Figure PCTCN2020079469-appb-000012
Figure PCTCN2020079469-appb-000012
实施例7的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：502.17。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.
实施例8：(E)-2-(3,4-甲氧基苯基)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯Example 8: (E)-2-(3,4-methoxyphenyl)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)ethylene) 基)-1H-吲唑-6-基)噻唑-2-基)乙酰胺(Yl)-1H-indazol-6-yl)thiazol-2-yl)acetamide
Figure PCTCN2020079469-appb-000013
Figure PCTCN2020079469-appb-000013
实施例8的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：512.18。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.
实施例9：(E)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻唑Example 9: (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazole -2-基)-2-(4-甲基哌嗪-1-基)乙酰胺-2-yl)-2-(4-methylpiperazin-1-yl)acetamide
Figure PCTCN2020079469-appb-000014
Figure PCTCN2020079469-appb-000014
实施例9的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：474.21。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.
实施例10：(E)-2-(3-氯苯基)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-Example 10: (E)-2-(3-chlorophenyl)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H- 吲唑-6-基)噻唑-2-基)乙酰胺Indazol-6-yl)thiazol-2-yl)acetamide
Figure PCTCN2020079469-appb-000015
Figure PCTCN2020079469-appb-000015
实施例10的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：486.12。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.
实施例11：(E)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻Example 11: (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiol 唑-2-基)-2-(哌啶-4-基)乙酰胺(Azol-2-yl)-2-(piperidin-4-yl)acetamide
Figure PCTCN2020079469-appb-000016
Figure PCTCN2020079469-appb-000016
实施例11的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：459.20。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.
实施例12：(E)-2-(二甲氨基)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-Example 12: (E)-2-(dimethylamino)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H- 吲唑-6-基)噻唑-2-基)乙酰胺Indazol-6-yl)thiazol-2-yl)acetamide
Figure PCTCN2020079469-appb-000017
Figure PCTCN2020079469-appb-000017
实施例12的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：419.17。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.
实施例13：(E)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻Example 13: (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiol 唑-2-基)-2-(哌啶-3-基)乙酰胺(Azol-2-yl)-2-(piperidin-3-yl)acetamide
Figure PCTCN2020079469-appb-000018
Figure PCTCN2020079469-appb-000018
实施例13的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：459.20。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.
实施例14:(E)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻Example 14: (E)-N-(4-Methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiol 唑-2-基)哌啶-4-甲酰胺(Azol-2-yl)piperidine-4-carboxamide
Figure PCTCN2020079469-appb-000019
Figure PCTCN2020079469-appb-000019
实施例14的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：445.18。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.
实施例15：(E)-2-氨基-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-Example 15: (E)-2-amino-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6- 基)噻唑-2-基)-4-(甲硫基)丁酰胺(Yl)thiazol-2-yl)-4-(methylthio)butanamide
Figure PCTCN2020079469-appb-000020
Figure PCTCN2020079469-appb-000020
实施例15的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：465.16。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.
实施例16：(E)-1-甲基-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-Example 16: (E)-1-Methyl-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6- 基)噻唑-2-基)哌啶-4甲酰胺(Yl)thiazol-2-yl)piperidine-4 carboxamide
Figure PCTCN2020079469-appb-000021
Figure PCTCN2020079469-appb-000021
实施例16的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：458.20。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.
实施例17：(E)-2-氨基-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-Example 17: (E)-2-amino-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6- 基)噻唑-2-基)丙酰胺(Yl)thiazol-2-yl)propionamide
Figure PCTCN2020079469-appb-000022
Figure PCTCN2020079469-appb-000022
实施例17的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：405.15。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.
实施例18：(E)-2-氨基-4-甲基-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-Example 18: (E)-2-amino-4-methyl-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H- 吲唑-6-基)噻唑-2-基)戊酰胺Indazol-6-yl)thiazol-2-yl)valeramide
Figure PCTCN2020079469-appb-000023
Figure PCTCN2020079469-appb-000023
实施例18的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：447.20。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.
实施例19：(E)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻Example 19: (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiol 唑-2-基)异丁酰胺(Azol-2-yl) isobutyramide
Figure PCTCN2020079469-appb-000024
Figure PCTCN2020079469-appb-000024
实施例19的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：404.16。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.
实施例20：(E)-2-氨基-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-Example 20: (E)-2-amino-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazole-6- 基)噻唑-2-基)-3-苯基丙酰胺(Yl)thiazol-2-yl)-3-phenylpropionamide
Figure PCTCN2020079469-appb-000025
Figure PCTCN2020079469-appb-000025
实施例20的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：481.18。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.
实施例21：N-(4-甲基-5-(3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基)噻唑-2-Example 21: N-(4-methyl-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)thiazole-2- 基)-2-(4-甲基哌嗪-1-基)乙酰胺Yl)-2-(4-methylpiperazin-1-yl)acetamide
Figure PCTCN2020079469-appb-000026
Figure PCTCN2020079469-appb-000026
2-(4-甲基哌嗪-1-基)-N-(4-甲基噻唑-2-基)乙酰胺(21a)：在圆底烧瓶中加入4-甲基噻唑-2-胺(1.0g)后加入N,N-二甲基甲酰胺(20mL)、2-(4-甲基哌嗪-1-基)乙酸(1.5g)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(5.0g)和三乙胺(2.5mL)。反应体系在氩气保护下室温搅拌14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品，MS(ESI)m/z(M+1)+：255.13。2-(4-Methylpiperazin-1-yl)-N-(4-methylthiazol-2-yl)acetamide (21a): Add 4-methylthiazol-2-amine ( 1.0g) and then add N,N-dimethylformamide (20mL), 2-(4-methylpiperazin-1-yl)acetic acid (1.5g), 2-(7-benzotriazole oxide) -N,N,N',N'-tetramethylurea hexafluorophosphate (5.0g) and triethylamine (2.5mL). 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 purified by pressurized silica gel column chromatography to obtain the pure product, MS (ESI) m/z (M+1)+: 255.13.
N-(4-甲基-5-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)噻唑-2-基)-2-(4-甲基哌嗪-1-基)乙酰胺(21b)：在圆底烧瓶中加入2-(4-甲基哌嗪-1-基)-N-(4-甲基噻唑-2-基)乙酰胺(1.0g)后加入二甲亚砜(10mL)、6-碘-1-(四氢-2H-吡喃-2-基)-1H-吲唑(1.3g)、四三苯基膦钯(0.45g)和碳酸铯(3.8g)。反应体系在氩气保护下加热至130℃反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品，MS(ESI)m/z(M+1)+：455.23。N-(4-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thiazol-2-yl)-2-(4-methyl Piperazin-1-yl)acetamide (21b): Add 2-(4-methylpiperazin-1-yl)-N-(4-methylthiazol-2-yl)acetamide ( 1.0g) and then add dimethyl sulfoxide (10mL), 6-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.3g), tetrakistriphenylphosphine palladium (0.45 g) and cesium carbonate (3.8g). 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-(1H-吲唑-6-基)-4-甲基噻唑-2-基)-2-(4-甲基哌嗪-1-基)乙酰胺(21c)：在50mL圆底烧瓶中加入N-(4-甲基-5-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-6-基)噻唑-2-基)-2-(4-甲基哌嗪-1-基)乙酰胺(1.0g)、乙醇(10mL)和6摩尔/升盐酸(5mL)。反应体系在氩气保护下加热至90℃反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用饱和碳酸氢钠中和至pH>10后，有固体析出，过滤，得粗品。粗品经乙酸乙 酯洗涤，得纯品，MS(ESI)m/z(M+1)+：371.17。N-(5-(1H-indazol-6-yl)-4-methylthiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (21c): in a 50mL circle Add N-(4-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)thiazol-2-yl)-2-( 4-methylpiperazin-1-yl)acetamide (1.0 g), ethanol (10 mL), and 6 mol/liter hydrochloric acid (5 mL). The reaction system was heated to 90°C for 14 hours under the protection of argon. After the reaction, the system was evaporated to dry the solvent under reduced pressure. After the resultant was neutralized with saturated sodium bicarbonate to pH>10, a solid precipitated out and filtered to obtain a crude product. The crude product was washed with ethyl acetate to obtain a pure product, MS (ESI) m/z (M+1)+: 371.17.
N-(5-(3-碘-1H-吲唑-6-yl)-4-甲基噻唑-2-基)-2-(4-甲基哌嗪-1-基)乙酰胺(21d)：在50mL圆底烧瓶中加入N-(5-(1H-吲唑-6-基)-4-甲基噻唑-2-基)-2-(4-甲基哌嗪-1-基)乙酰胺(0.6g)后加入N,N-二甲基甲酰胺(10mL)、碘(0.8g)和氢氧化钾(0.4g)。反应体系在氩气保护下室温搅拌8小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后，水相用乙酸乙酯萃取，有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品，MS(ESI)m/z(M+1)+：497.06。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. After the reaction, the system was evaporated to dry the solvent under reduced pressure. After the resultant was diluted with water, the aqueous phase was 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)+: 497.06.
N-(5-(1-乙酰基-3-碘-1H-吲唑-6-基)-4-甲基噻唑-2-基)-2-(4-甲基哌嗪-1-基)乙酰胺(21e)：在50mL圆底烧瓶中加入N-(5-(3-碘-1H-吲唑-6-yl)-4-甲基噻唑-2-基)-2-(4-甲基哌嗪-1-基)乙酰胺(0.5g)后加入无水二氯甲烷(10mL)、三乙胺(0.3mL)、乙酰氯(0.1g)。反应体系在室温下、氩气保护反应4小时。反应结束后，体系在减压下蒸干溶剂，所得物用饱和碳酸氢钠中和至pH>10后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得纯品，MS(ESI)m/z(M+1)+：538.07。N-(5-(1-Acetyl-3-iodo-1H-indazol-6-yl)-4-methylthiazol-2-yl)-2-(4-methylpiperazin-1-yl) Acetamide (21e): Add N-(5-(3-iodo-1H-indazole-6-yl)-4-methylthiazol-2-yl)-2-(4-methyl) in a 50mL round bottom flask Piperazine-1-yl)acetamide (0.5g), anhydrous dichloromethane (10mL), triethylamine (0.3mL), and acetyl chloride (0.1g) were added. 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 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)+: 538.07.
N-(4-甲基-5-(3-(1-甲基-1H-吡唑-4-基)-1H-吲唑-6-基)噻唑-2-基)-2-(4-甲基哌嗪-1-基)乙酰胺(21)：在圆底烧瓶中加入N-(5-(1-乙酰基-3-碘-1H-吲唑-6-基)-4-甲基噻唑-2-基)-2-(4-甲基哌嗪-1-基)乙酰胺(0.1g)后加入1,4-二氧六环(10mL)、水(2mL)、(1-甲基-1H-吡唑-4-基)硼酸(0.03g)、四三苯基膦钯(0.02g)和碳酸钾(0.07g)。反应体系在氩气保护下加热至80℃反应14小时。反应结束后，体系在减压下蒸干溶剂，所得物用水稀释后用乙酸乙酯萃取。有机相分别用水、饱和食盐水洗涤后用无水硫酸钠干燥。有机相经过滤，减压蒸干后得粗品。粗品经加压硅胶柱层析提纯后得化合物21，MS(ESI)m/z(M+1)+：451.21。N-(4-methyl-5-(3-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl)thiazol-2-yl)-2-(4- Methylpiperazin-1-yl)acetamide (21): Add N-(5-(1-acetyl-3-iodo-1H-indazol-6-yl)-4-methyl to a round bottom flask Thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (0.1g), then add 1,4-dioxane (10mL), water (2mL), (1-methyl Yl-1H-pyrazol-4-yl)boronic acid (0.03g), palladium tetrakistriphenylphosphine (0.02g) and potassium carbonate (0.07g). 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.
实施例22：(E)-2-羟基-4-甲基-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-Example 22: (E)-2-hydroxy-4-methyl-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H- 吲唑-6-基)噻唑-2-基)戊酰胺Indazol-6-yl)thiazol-2-yl)valeramide
Figure PCTCN2020079469-appb-000027
Figure PCTCN2020079469-appb-000027
实施例22的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：448.18。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.
实施例23：N-(5-(3-(2-氨基嘧啶-5-基)-1H-吲唑-6-基)-4-甲基噻唑-2-Example 23: N-(5-(3-(2-Aminopyrimidin-5-yl)-1H-indazol-6-yl)-4-methylthiazole-2- 基)-2-(4-甲基哌嗪-1-基)乙酰胺Yl)-2-(4-methylpiperazin-1-yl)acetamide
Figure PCTCN2020079469-appb-000028
Figure PCTCN2020079469-appb-000028
实施例23的合成通过使用类似于实施例21中所述的步骤完成。MS(ESI)m/z(M+1)+：464.20。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.
实施例24：N-(4-甲基-5-(3-(吡啶-3-基)-1H-吲唑-6-基)噻唑-2-基)-2-(4-Example 24: N-(4-Methyl-5-(3-(pyridin-3-yl)-1H-indazol-6-yl)thiazol-2-yl)-2-(4- 甲基哌嗪-1-基)乙酰胺Methylpiperazin-1-yl)acetamide
Figure PCTCN2020079469-appb-000029
Figure PCTCN2020079469-appb-000029
实施例24的合成通过使用类似于实施例21中所述的步骤完成。MS(ESI)m/z(M+1)+：448.19。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.
实施例25：N-(5-(3-(5-氟吡啶-3-基)-1H-吲唑-6-基)-4-甲基噻唑Example 25: N-(5-(3-(5-fluoropyridin-3-yl)-1H-indazol-6-yl)-4-methylthiazole -2-yl)-2-(4-甲基哌嗪-1-基)乙酰胺-2-yl)-2-(4-methylpiperazin-1-yl)acetamide
Figure PCTCN2020079469-appb-000030
Figure PCTCN2020079469-appb-000030
实施例25的合成通过使用类似于实施例21中所述的步骤完成。MS(ESI)m/z(M+1)+：466.18。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.
实施例26：N-(5-(3-(3-氟苯基)-1H-吲唑-6-基)-4-甲基噻唑-2-基)-2-(4-甲Example 26: N-(5-(3-(3-fluorophenyl)-1H-indazol-6-yl)-4-methylthiazol-2-yl)-2-(4-methyl 基哌嗪-1-基)乙酰胺Piperazin-1-yl)acetamide
Figure PCTCN2020079469-appb-000031
Figure PCTCN2020079469-appb-000031
实施例26的合成通过使用类似于实施例21中所述的步骤完成。MS(ESI)m/z(M+1)+：465.19。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.
实施例27：(E)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻Example 27: (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiol 唑-2-基)-2-(1-甲基哌啶-4-基)乙酰胺(Azol-2-yl)-2-(1-methylpiperidin-4-yl)acetamide
Figure PCTCN2020079469-appb-000032
Figure PCTCN2020079469-appb-000032
实施例27的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：473.21。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.
实施例28：N-(4-甲基-5-(3-(吡啶-3-基)-1H-吲唑-6-基)噻唑-2-Example 28: N-(4-Methyl-5-(3-(pyridin-3-yl)-1H-indazol-6-yl)thiazole-2- 基)-2-(3-(三氟甲基)苯基)乙酰胺Yl)-2-(3-(trifluoromethyl)phenyl)acetamide
Figure PCTCN2020079469-appb-000033
Figure PCTCN2020079469-appb-000033
实施例28的合成通过使用类似于实施例21中所述的步骤完成。MS(ESI)m/z(M+1)+：494.13。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.
实施例29：(E)-1-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻Example 29: (E)-1-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiol 唑-2-基)-3-(3-(三氟甲基)苯基)脲Azol-2-yl)-3-(3-(trifluoromethyl)phenyl)urea
Figure PCTCN2020079469-appb-000034
Figure PCTCN2020079469-appb-000034
实施例29的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：521.14。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.
实施例30：(E)-N-(4-甲基-5-(3-(2-(吡啶-2-基)乙烯基)-1H-吲唑-6-基)噻Example 30: (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiol 唑-2-基)乙酰胺(Azol-2-yl)acetamide
Figure PCTCN2020079469-appb-000035
Figure PCTCN2020079469-appb-000035
实施例30的合成通过使用类似于实施例1中所述的步骤完成。MS(ESI)m/z(M+1)+：376.13。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.
实施例31：对癌细胞增殖的影响Example 31: Effect on the proliferation of cancer cells
通过测试本发明的化合物对癌细胞生长的影响，进一步评估文中化合物对癌细胞增殖的抑制作用、及其对抑制癌细胞增殖的选择性。By testing the effects of the compounds of the present invention on the growth of cancer cells, the inhibitory effect of the compounds in the text on the proliferation of cancer cells and their selectivity in inhibiting the proliferation of cancer cells were further evaluated.
本实施例中选用了带有荧光素的人结直肠癌细胞KM-12-LUC(表 达TPM3-NTRK1基因)(购自Japanese Collection of Research Bioresources Cell Bank，日本)、和小鼠原B细胞BaF3(购自ATCC)。此外，本实施例还选用了小鼠BaF3-tel-TRKA(稳定表达TRKA野生型激酶)、BaF3-LMNA-TRKA(稳定表达LMNA-TRKA融合激酶)、BaF3-LMNA-TRKA/V573M(稳定表达TRKA/V573M突变激酶)、BaF3-LMNA-TRKA/F589L(稳定表达TRKA/F589L突变激酶)、BaF3-LMNA-TRKA/G667C(稳定表达TRKA/G667C突变激酶)、BaF3-LMNA-TRKA/G667S(稳定表达TRKA/G667S突变激酶)、BaF3-tel-TRKB(稳定表达TRKB野生型激酶)、BaF3-tel-TRKB/F633L(稳定表达TRKB/F633L突变型激酶)、BaF3-tel-TRKB/G709C(稳定表达TRKB/G709C突变型激酶)、BaF3-tel-TRKC(稳定表达TRKC野生型激酶)、BaF3-tel-TRKC/F617L(稳定表达TRKC/F617L突变型激酶)、BaF3-tel-TRKC/G696A(稳定表达TRKC/G696A突变型激酶)、BaF3-tel-TRKC/G696C(稳定表达TRKC/G696C突变型激酶)。上述细胞系均由本实验室构建，构建方法为：经PCR分别扩增人类TRKA、TRKB、TRKC、TRKA/V573M、TRKA/F589L、TRKA/G667C、TRKA/G667S、TRKB/F633L、TRKB/G709C、TRKC/F617L、TRKC/G696A、TRKC/G696C激酶区序列，并分别***到带有N端TEL片段和/或LMNA片段和/或TPR片段的MSCV-Puro载体(购自Clontech)，通过逆转录病毒方法，稳定转入小鼠BaF3细胞，并且撤除IL-3生长因子，最终得到依赖TRKA、TRKB、TRKC、TRKA/V573M、TRKA/F589L、TRKA/G667C、TRKA/G667S、TRKB/F633L、TRKB/G709C、TRKC/F617L、TRKC/G696A、TRKC/G696C转入蛋白的细胞系。In this example, 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). In addition, 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-TRKB/G709C (stable expression of TRKB) /G709C mutant kinase), BaF3-tel-TRKC (stable expression of TRKC wild-type kinase), BaF3-tel-TRKC/F617L (stable expression of TRKC/F617L mutant kinase), BaF3-tel-TRKC/G696A (stable expression of TRKC) /G696A mutant kinase), BaF3-tel-TRKC/G696C (stable expression of TRKC/G696C mutant kinase). The above cell lines were all constructed by our laboratory. The construction method was as follows: human 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, TRKC/G696A, and TRKC/G696C are transformed into protein cell lines.
在实施例中将不同浓度(0.000508μM、0.00152μM、0.00457μM、0.0137μM、0.0411μM、0.123μM、0.370μM、1.11μM、3.33μM、10μM于DMSO中)的本发明化合物及对照化合物LOXO-101、LOXO-195(购自中国，MedChem Express)分别加入到上述细胞中，并孵育72小时，通过CCK-8(购自中国，MedChem Express)细胞活力检测试剂盒(CCK-8可被活细胞中的脱氢酶还原为具有高度水溶性的黄色甲瓒产物，生成的甲瓒物数量与活细胞的数量成正比)对孵育后的细胞进 行检测，通过酶标仪对活细胞的数目进行定量，并计算各个化合物和对照化合物的GI 50(结果示于表2至表4中)。 In the examples, different concentrations (0.000508 μM, 0.00152 μM, 0.00457 μM, 0.0137 μM, 0.0411 μM, 0.123 μM, 0.370 μM, 1.11 μM, 3.33 μM, 10 μM in DMSO) of the compound of the present invention and the reference compound LOXO-101 , LOXO-195 (purchased from China, MedChem Express) were added to the above cells, and incubated for 72 hours, through the CCK-8 (purchased from China, MedChem Express) cell viability detection kit (CCK-8 can be used in living cells The dehydrogenase is reduced to a highly water-soluble yellow formazan product, and the amount of formazan produced is proportional to the number of living cells) The cells after incubation are detected, and the number of living cells is quantified by a microplate reader. The GI 50 of each compound and the control compound was calculated (the results are shown in Table 2 to Table 4).
表2的结果表明，本发明的化合物对于TRK具有很强的抑制活性。进一步地，如表3所示，在对突变型TRKA激酶进行检测后，发现本发明的化合物对于TRKA/V573M、TRKA/F589L、TRKA/G667C、TRKA/G667S都有很强的抑制作用，对于第一代TRK抑制剂LOXO-101的耐药点突变，本发明的化合物能够克服上述突变后对于第一代TRK抑制剂LOXO-101的耐药性问题，在细胞上的作用结果也优于第二代TRK抑制剂LOXO-195。另外，如表4所示，本发明的化合物对于野生型和突变型的TRKB和TRKC也有很强的抑制作用。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. In addition, as shown in Table 4, the compounds of the present invention also have a strong inhibitory effect on wild-type and mutant TRKB and TRKC.
表2.本发明的化合物对于TRKA的抑制活性Table 2. The inhibitory activity of the compounds of the present invention on TRKA
Figure PCTCN2020079469-appb-000036
Figure PCTCN2020079469-appb-000036
表3.本发明的化合物对于TRKA野生型以及相关突变型的抑制活性Table 3. The inhibitory activity of the compounds of the present invention on TRKA wild-type and related mutants
Figure PCTCN2020079469-appb-000037
Figure PCTCN2020079469-appb-000037
Figure PCTCN2020079469-appb-000038
Figure PCTCN2020079469-appb-000038
表4.本发明的化合物对于TRKB/C野生型以及相关突变型的抑制活性Table 4. The inhibitory activity of the compounds of the present invention on TRKB/C wild-type and related mutants
Figure PCTCN2020079469-appb-000039
Figure PCTCN2020079469-appb-000039
进一步检测了本发明的化合物9对于带有荧光素标签的结直肠癌细胞系人结直肠癌细胞KM-12-LUC(表达TPM3-NTRK1基因)的抗增殖作用。表5所示的结果表明，本发明的化合物9能够抑制该细胞的增殖，同时选用了第一代和第二代的TRK抑制剂LOXO-101和LOXO-195作为对照化合物，并且化合物9的抑制作用优于两个对照化合物。The anti-proliferation effect of compound 9 of the present invention on colorectal cancer cell line human colorectal cancer cell line KM-12-LUC (expressing TPM3-NTRK1 gene) with fluorescein label was further tested. The results shown in Table 5 show that the compound 9 of the present invention can inhibit the proliferation of the cell. At the same time, the first and second generation TRK inhibitors LOXO-101 and LOXO-195 are selected as the control compounds, and the compound 9 inhibits The effect is better than the two control compounds.
表5.本发明的化合物对于人结直肠癌细胞KM-12-LUC的抗增殖作用Table 5. Anti-proliferative effects of the compounds of the present invention on human colorectal cancer cell KM-12-LUC
GI 50/μM GI 50 /μM KM-12-LUCKM-12-LUC
化合物9Compound 9 0.0020.002
LOXO-101LOXO-101 0.0110.011
LOXO-195LOXO-195 0.0050.005
实施例32：动物实验Example 32: Animal experiment
在本实施例中，分别测试化合物9及对照化合物LOXO-101和LOXO-195在BaF3-tel-TRKA、BaF3-LMNA-TRKA-F589L的小鼠模型中的实验结果。In this example, the experimental results of compound 9 and the control compounds LOXO-101 and LOXO-195 in the mouse models of BaF3-tel-TRKA and BaF3-LMNA-TRKA-F589L were tested respectively.
实验步骤如下：The experimental steps are as follows:
(1)从北京维通利华实验动物有限责任公司购买饲养4-6周龄的Bal b/c雌性裸鼠，饲养于SPF级实验室中，饮水及垫料均经高压消毒无菌处理，有关小鼠的所有操作均在无菌条件下进行。(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.
(2)第0天分别在所有小鼠左侧背部皮下分别注入约5×10 6个BaF3-tel-TRKA和5×10 6个BaF3-LMNA-TRKA-F589L细胞(由本实验室构建)。 (2) On day 0, about 5×10 6 BaF3-tel-TRKA and 5×10 6 BaF3-LMNA-TRKA-F589L cells (built by our laboratory) were injected subcutaneously on the left back of all mice.
(3)从第6天开始，每天使对应小鼠口服给药甲基纤维素(HKI)溶媒(5只小鼠)；剂量为40mg/kg、80mg/kg鼠重的化合物9每天一次(各5只小鼠)；剂量为80mg/kg鼠重的LOXO-101每天两次(购自MedChemExpress，中国)(5只小鼠)。对于BaF3-LMNA-TrKA-F589L的小鼠模型从第6天开始，每天使对应小鼠口服给药甲基纤维素(HKI)溶媒(5只小鼠)；剂量为剂量为40mg/kg、80mg/kg的化合物9每天一次(各5只小鼠)；剂量为80mg/kg鼠重的LOXO-195每天两次(5只小鼠)。(3) Starting from day 6, the corresponding 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). 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).
(4)从第6天(开始，每天用游标卡尺测量皮下肿瘤的长/宽，并每天记录小鼠体重，分别确定化合物9、LOXO-101、LOXO-195对小鼠体重的影响。(4) Starting from day 6, measure the length/width of the subcutaneous tumor with a vernier caliper every day, and record the weight of the mouse every day to determine the effects of compound 9, LOXO-101, and LOXO-195 on the weight of the mice, respectively.
(5)统计内皮下肿瘤生长趋势，肿瘤体积计算方法：长×宽×宽/2mm 3。 (5) Calculate the growth trend of subendothelial tumors, the calculation method of tumor volume: length×width×width/2mm 3 .
实验结果如图1a-b和2a-b所示。化合物9在BaF3-tel-TrKA的小鼠肿瘤模型中，每天用药剂量为40mg/kg时已经表现出很好的抑制小鼠肿瘤的效果，且随着用药天数的增加，化合物9对小鼠肿瘤的抑制作用愈发显著，并且优于对照化合物LOXO-101的80mg/kg每天两次给药的效果。化合物9在BaF3-LMNA-TrKA-F589L的小鼠肿瘤模型中，化合物9在每天给药剂量为40mg/kg时已经表现出很好的抑制小鼠肿瘤的效果，优于对照化合物LOXO-195的80mg/kg每天两次给药的效果。The experimental results are shown in Figures 1a-b and 2a-b. In the mouse tumor model of BaF3-tel-TrKA, compound 9 has shown a good effect of inhibiting tumors in mice when the daily dose is 40 mg/kg, and with the increase of the number of days of administration, compound 9 has an effect on mouse tumors. The inhibitory effect of LXO is more and more significant, and is better than the 80 mg/kg twice daily administration of the control compound LOXO-101. Compound 9 in the BaF3-LMNA-TrKA-F589L mouse tumor model, compound 9 has shown a good tumor inhibition effect in mice at a daily dose of 40 mg/kg, which is better than the control compound LOXO-195 The effect of 80mg/kg twice a day.
工业应用性Industrial applicability
本发明提供一种吲唑类抑制剂化合物的新用途，其可以用于降低或抑制细胞或受试者的携带TRKA/B/C突变和/或融合基因，例如TRKA的V573M、F589L、G667C/S突变，TRKB的F633L和G709C突变，和/或TRKC的F617L、G696A和G696C突变的激酶活性，并且/或者在受试者中预防或治疗与TRKA/B/C突变和/或融合基因，例如TRKA的V573M、F589L、G667C/S突变，TRKB的F633L、G709C突变和/或TRKC的F617L、G696A/C突变的活性相关病症。因而，本发明适于工业应用。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.
尽管本文对本发明作了详细说明，但本发明不限于此，本技术领域的技术人员可以根据本发明的原理进行修改，因此，凡按照本发明的原理进行的各种修改都应当理解为落入本发明的保护范围。Although the present invention has been described in detail herein, the present invention is not limited to this. Those skilled in the art can make modifications based on the principles of the present invention. Therefore, all modifications made in accordance with the principles of the present invention should be understood as falling into The scope of protection of the present invention.

Claims (11)

  1. 一种式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前体药物用于治疗携带TRKA/B/C突变和/或融合基因的疾病的用途，所述疾病选自***状甲状腺癌、胰腺癌、结直肠癌、乳癌、黑色素瘤、非小细胞肺癌、急性髓性白血病、成神经细胞瘤、疼痛、皮炎和哮喘，Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug for the treatment of diseases carrying TRKA/B/C mutations and/or fusion genes, so The disease is selected from the group consisting of papillary thyroid cancer, pancreatic cancer, colorectal cancer, breast cancer, melanoma, non-small cell lung cancer, acute myeloid leukemia, neuroblastoma, pain, dermatitis and asthma,
    Figure PCTCN2020079469-appb-100001
    Figure PCTCN2020079469-appb-100001
    其中，in,
    X为-(CH＝CH) m-，其中m为0或1； X is -(CH=CH) m -, where m is 0 or 1;
    Y选自-NH-或-(CH 2) n-，其中n为0-3的整数； Y is selected from -NH- or -(CH 2 ) n -, where n is an integer from 0 to 3;
    R 1选自任选地被1-3个独立的R 4基团取代的苯基、任选地被1-3个独立的R 4基团取代的吡啶基、任选地被1-3个独立的R 4基团取代的吡唑基、和任选地被1-3个独立的R 4基团取代的嘧啶基； 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选自氢和C 1-6烷基； R 2 is selected from hydrogen and C 1-6 alkyl;
    R 3选自任选地被1-2个独立的R 5基团取代的C 1-6烷基、C 1-6烷基氨基、以及任选地被1-3个独立的R 4基团取代的苯基、任选地被1-3个独立的R 4基团取代的萘基、任选地被1-3个独立的R 4基团取代的吡啶基、任选地被1-3个独立的R 4基团取代的哌嗪基、和任选地被1-3个独立的R 4基团取代的哌啶基； 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独立地选自卤素、氨基、C 1-6烷基、C 3-6环烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟基烷基、C 1-6烷基氨基、C 2-6烷酰胺基、(4-甲基哌嗪-1-基)甲基、吗啉甲基、吗啉基、4-甲基哌嗪-1-基、4-哌啶基、和4-四氢吡喃基； 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独立地选自氨基、羟基、和C 1-6烷硫基。 R 5 is independently selected from amino, hydroxyl, and C 1-6 alkylthio.
  2. 根据权利要求1所述的用途，其中X为-(CH＝CH)-。The use according to claim 1, wherein X is -(CH=CH)-.
  3. 根据权利要求1所述的用途，其中Y为直接键或-CH 2-。 The use according to claim 1, wherein Y is a direct bond or -CH 2 -.
  4. 根据权利要求1所述的用途，其中R 1选自任选地被1-3个独立的R 4基团取代的苯基、吡啶基、吡唑基、和嘧啶基，其中R 4独立地选自卤素、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、和(4-甲基哌嗪-1-基)甲基。 The use according to claim 1, wherein 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.
  5. 根据权利要求4所述的用途，其中R 1选自任选地被甲基、氨基或卤素取代的苯基、2-吡啶基、3-吡啶基、4-吡唑基、和5-嘧啶基。 The use according to claim 4, wherein R 1 is selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyrazolyl, and 5-pyrimidinyl optionally substituted by methyl, amino or halogen .
  6. 根据权利要求1所述的用途，其中R 2为氢或甲基。 The use according to claim 1, wherein R 2 is hydrogen or methyl.
  7. 根据权利要求1所述的用途，其中R 3选自任选地被1-2个独立的R 5基团取代的C 1-6烷基、C 1-6烷基氨基、以及任选地被1-3个独立的R 4基团取代的苯基、萘基、吡啶基、哌嗪基、和哌啶基，其中R 4独立地选自卤素、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、和(4-甲基哌嗪-1-基)甲基，R 5独立地选自氨基、羟基、和甲硫基。 The use according to claim 1, wherein R 3 is selected from C 1-6 alkyl, C 1-6 alkylamino optionally substituted with 1-2 independent R 5 groups, and optionally Phenyl, naphthyl, pyridyl, piperazinyl, and piperidinyl 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 5 is independently selected from amino, hydroxy, and methylthio.
  8. 根据权利要求7所述的用途，其中R 3选自任选地被氨基、羟基、或甲硫基取代的C 1-6烷基、二甲氨基、任选地被甲基取代的N-哌嗪基、任选地被卤素、三氟甲基、或甲氧基取代的苯基、萘基、4-吡啶基、3-哌啶基、和任选地被甲基取代的4-哌啶基。 The use according to claim 7, wherein R 3 is selected from C 1-6 alkyl optionally substituted with amino, hydroxy, or methylthio, dimethylamino, N-piperidine optionally substituted with methyl Azinyl, phenyl optionally substituted by halogen, trifluoromethyl, or methoxy, naphthyl, 4-pyridyl, 3-piperidinyl, and 4-piperidine optionally substituted by methyl base.
  9. 根据权利要求1所述的用途，其中当Y为直接键时，R 3选自任选地被氨基、羟基、或甲硫基取代的C 1-6烷基、和4-吡啶基；当Y为-CH 2-时，R 3选自任选地被甲氧基取代的苯基、任选地被甲基取代的N-哌嗪基、和任选地被甲基取代的4-哌啶基。 The use according to claim 1, wherein when Y is a direct bond, R 3 is selected from C 1-6 alkyl optionally substituted by amino, hydroxy, or methylthio, and 4-pyridyl; when Y When -CH 2 -, R 3 is selected from phenyl optionally substituted with methoxy, N-piperazinyl optionally substituted with methyl, and 4-piperidine optionally substituted with methyl base.
  10. 根据权利要求1所述的用途，其中式(I)的化合物选自，The use according to claim 1, wherein the compound of formula (I) is selected from,
    Figure PCTCN2020079469-appb-100002
    Figure PCTCN2020079469-appb-100002
    Figure PCTCN2020079469-appb-100003
    Figure PCTCN2020079469-appb-100003
    Figure PCTCN2020079469-appb-100004
    Figure PCTCN2020079469-appb-100004
  11. 根据权利要求1-10中任一项所述的用途，其中所述疾病是携带选自TRKA的V573M、F589L、G667C、和/或G667S突变，TRKB的F633L、和/或G709C突变，以及TRKC的F617L、G696A、和/或G696C突变中的一种或两种以上突变的疾病。The use according to any one of claims 1-10, wherein the disease is a disease that carries V573M, F589L, G667C, and/or G667S mutations selected from TRKA, F633L, and/or G709C mutations of TRKB, and TRKC A disease in which one or more of the F617L, G696A, and/or G696C mutations are mutated.
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CN101790526A (en) * 2007-06-08 2010-07-28 雅培制药有限公司 5-heteroaryl substituted indazoles as kinase inhibitors
CN102134234A (en) * 2011-01-18 2011-07-27 南京工业大学 Indazolyl urea compounds and preparation method and medicinal use thereof
CN102958927A (en) * 2010-05-12 2013-03-06 Abbvie公司 Indazole inhibitors of kinase

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CN101790526A (en) * 2007-06-08 2010-07-28 雅培制药有限公司 5-heteroaryl substituted indazoles as kinase inhibitors
CN102958927A (en) * 2010-05-12 2013-03-06 Abbvie公司 Indazole inhibitors of kinase
CN102134234A (en) * 2011-01-18 2011-07-27 南京工业大学 Indazolyl urea compounds and preparation method and medicinal use thereof

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