WO2022053046A1 - Composé de pyrazolopyridine ou sel de celui-ci, procédé de préparation correspondant et utilisation associée - Google Patents

Composé de pyrazolopyridine ou sel de celui-ci, procédé de préparation correspondant et utilisation associée Download PDF

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WO2022053046A1
WO2022053046A1 PCT/CN2021/118001 CN2021118001W WO2022053046A1 WO 2022053046 A1 WO2022053046 A1 WO 2022053046A1 CN 2021118001 W CN2021118001 W CN 2021118001W WO 2022053046 A1 WO2022053046 A1 WO 2022053046A1
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mmol
compound
methyl
pyrazol
pyridin
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PCT/CN2021/118001
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English (en)
Chinese (zh)
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程耀邦
王永辉
董志强
周娟
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上海辉启生物医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed 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
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention belongs to the technical field of chemical medicine, and in particular relates to a pyrazolopyridine compound with RET inhibitory activity, a preparation method thereof, and a pharmaceutical composition containing the compound, and also relates to the preparation of the pyrazolopyridine compound for prevention or treatment and Use in medicine for RET-related diseases.
  • RET REarranged during Transfection protein is a receptor tyrosine kinase (RTK) and a transmembrane glycoprotein, expressed by the proto-oncogene RET located on chromosome 10, in the kidney and intestine of embryonic stage. It plays an important role in the development of the nervous system and is also critical in a variety of tissues, such as neurons, neuroendocrine, hematopoietic tissues, and male germ cells. Unlike other receptor tyrosine kinases, RET does not bind directly to ligand molecules: such as artemin, glial cell-derived neurotrophic factor (GDNF), and nerve growth factor (NGF), all of which are It belongs to the GNDF family of ligands (GFLs).
  • GDNF glial cell-derived neurotrophic factor
  • NGF nerve growth factor
  • GFR ⁇ GDNF family receptor alpha
  • RET protein GDNF family receptor alpha
  • PI3K PI3K
  • JAK-STAT PKA
  • PKC PKC
  • RET oncogenic activation of RET
  • one is a new fusion protein generated by chromosomal rearrangement, usually a fusion of the kinase domain of RET and a protein containing a self-dimerization domain; the other is RET mutation directly or indirectly.
  • RET kinase activity is activated.
  • RET chromosomal rearrangements are found in 10%-20% of papillary thyroid cancer (PTC) patients; RET point mutations are found in 60% of medullary medullary thyroid carcinomas (MTC); in all non-small cell lung cancers ( About 1-2% of patients with NSCLC have RET fusion proteins, of which KIF5B is the most common.
  • Drugs currently on the market or under clinical development that are selectively designed to target RET have shown good efficacy and safety in clinical trials of non-small cell lung cancer and thyroid cancer.
  • the present invention relates to compounds useful in the prevention or treatment of RET-related diseases.
  • the compounds of the present invention exhibit satisfactory RET inhibitory activity, and also exhibit good performance in in vivo and/or in vitro pharmacokinetic assays, indicative of improved druggability and improved bioavailability. Therefore, the compounds of the present invention can not only achieve the purpose of preventing or treating RET-related diseases, but also the prepared medicaments are expected to have improved absorption, increased efficacy at the same dose, or provide the same efficacy and/or lower doses. or reduce possible side effects.
  • the present invention also provides the use of a compound of the present invention in the manufacture of a medicament for the prevention or treatment of a disease associated with RET, a pharmaceutical composition comprising the compound, and the prevention and/or treatment of RET associated with RET by administering the compound methods related to the disease.
  • R 1 is selected from hydrogen, halogen, cyano, nitro and C 1 -C 6 alkyl optionally substituted with halogen or cyano;
  • R 2 is selected from hydrogen, C 6 -C 10 aryl, 5-9 membered heteroaryl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3 -8-membered heterocycloalkenyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 alkylthio, wherein said aryl, heteroaryl, cycloalkyl, cycloalkene group, heterocycloalkyl, heterocycloalkenyl, alkyl, alkoxy and alkylthio optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen, cyano, nitro, hydroxy , C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 alkylthio;
  • R 3 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 alkylthio;
  • R 4 is selected from hydrogen, C 6 -C 10 aryl, 5-9 membered heteroaryl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3 -8-membered heterocycloalkenyl, 3-8 membered heterocycloalkyloxy, 3-8 membered heterocycloalkenyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 - C alkylthio , wherein the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkyl, alkoxy and alkylthio groups are optionally independently selected Substituted from 1, 2 or 3 of the following: halogen, cyano, nitro, C1 - C6 alkyl, C1 - C6 alkoxy and C1 - C6 alkylthi
  • R 5 is selected from halogen, cyano, nitro, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 alkylthio;
  • Ring A is selected from C 6 -C 10 arylene, 5-9 membered heteroarylene, C 3 -C 8 cycloalkylene, C 3 -C 8 cycloalkenylene, 3-8 membered heterocycloalkane base and 3- to 8-membered heterocycloalkenyl rings;
  • Ring B is selected from C 6 -C 10 aryl, 5-9 membered heteroaryl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, 3-8 membered heterocycloalkyl and 3-8 A membered heterocycloalkenyl ring;
  • n 0, 1, 2, or 3;
  • n 0, 1, 2 or 3.
  • a compound of formula (I) in another aspect of the present invention there is provided a compound of formula (I), its stereoisomers, tautomers, stable isotopic variants for use in the treatment or prevention, especially for the treatment of RET-related diseases , a pharmaceutically acceptable salt or solvate.
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the present invention is provided for preventing or treating RET-related diseases.
  • the pharmaceutical composition may additionally contain additional therapeutically active ingredients suitable for use in combination with the compounds of the present invention.
  • a pharmaceutical combination comprising a compound of the present invention and an additional active agent.
  • a method for preventing or treating a disease associated with RET in an individual comprising administering an effective amount of a compound of the invention described herein or comprising its pharmaceutical composition.
  • the RET-related disease described in the present invention is selected from tumors or irritable bowel syndrome (IBS), and tumors include but are not limited to non-small cell lung cancer, small cell lung cancer, papillary thyroid cancer, medullary thyroid cancer, Differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, polyendocrine tumor 2A or 2B, pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosa Gangliomas, pancreatic duct adenocarcinoma, multiple endocrine tumors, testicular cancer, chronic monocytic leukemia, salivary gland cancer, ovarian cancer, cervical cancer, etc.
  • IBS irritable bowel syndrome
  • halo or halogen as used herein means fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). Preferred halo are fluoro or chloro.
  • halogen-substituted groups as used herein is intended to include mono- or polyhalogenated groups wherein one or more (eg, 2, 3, 4, 5 or 6) of the same or different halogen substituents One or more (eg 2, 3, 4, 5 or 6) hydrogens in the group.
  • cyano as used herein means the group -CN.
  • nitro as used herein means the group -NO2 .
  • hydroxyl refers to -OH.
  • alkyl refers to a straight or branched chain saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms. Specifically, the alkyl group has 1 to 10, eg, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.
  • Ci - C6 alkyl refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, examples of which are methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, etc.
  • Particular alkyl groups have 1 to 3 carbon atoms.
  • alkoxy means the group -O-alkyl, wherein alkyl has the meaning set forth herein. Specifically, the term includes the groups -OC 1-6 alkyl, more specifically -OC 1-3 alkyl. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy, isopropoxy), butoxy (including n-butoxy, isobutoxy, tert-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy, neopentyloxy), hexyloxy (including n-hexyloxy, isohexyloxy) and the like. Particular alkoxy groups have 1 to 3 carbon atoms.
  • alkylthio refers to an -S-alkyl group, wherein the alkyl group is as defined above for "alkyl”. Specifically, the term includes the groups -SC 1-6 alkyl, more specifically -SC 1-3 alkyl.
  • alkylthio include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio, isopropylthio), butylthio (including n-butylthio, isobutylthio, tert-butylthio), pentylthio (including n-pentylthio, isopentylthio, neopentylthio), hexylthio (including n-hexylthio, isohexylthio) and the like.
  • Particular alkylthio groups have 1 to 3 carbon atoms.
  • halogen-substituted C1 - C6 alkyl refers to the C1 - C6 alkyl groups described above, wherein one or more (eg 1, 2, 3, 4 or 5) ) hydrogen atoms are replaced by halogens. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different, and may be located on the same or different C atoms.
  • halogen substituted C1 - C6 alkyl are eg -CH2F , -CHF2 , -CF3 , -CCl3 , -C2F5 , -C2Cl5 , -CH2CF3 , -CH 2 Cl, -CH 2 CH 2 CF 3 or -CF(CF 3 ) 2 , etc.
  • halogen-substituted C1 - C6alkoxy refers to the above-described C1 - C6alkoxy groups, wherein one or more (eg 1, 2, 3, 4 or 5) hydrogen atoms are replaced by halogens. It will be understood by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different, and may be located on the same or different C atoms.
  • halogen substituted C 1 -C 6 alkoxy are eg -OCH 2 F, -OCHF 2 , -OCF 3 , -OCCl 3 , -OC 2 F 5 , -OC 2 Cl 5 , -OCH 2 CF 3 , -OCH 2 Cl or -OCH 2 CH 2 CF 3 , etc.
  • cycloalkyl refers to a monocyclic, fused polycyclic, bridged polycyclic or spirocyclic non-aromatic saturated monovalent hydrocarbon ring structure having the specified number of ring atoms. Cycloalkyl groups may have 3 to 12 carbon atoms (ie C3 - C12 cycloalkyl), eg 3 to 10, 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms .
  • Suitable cycloalkyl groups include, but are not limited to, monocyclic structures, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; or polycyclic (eg, bicyclic) structures, including spiro Ring, fused or bridged systems such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, spiro[3.4]octyl, bicyclo[3.1.1]hexyl, bicyclo[3.1. 1] heptyl or bicyclo[3.2.1] octyl, etc.).
  • monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl
  • polycyclic (eg, bicyclic) structures including spiro Ring
  • cycloalkylene refers to a cycloalkyl group as defined above, but which is a divalent group and the two bonds are not on the same ring atom.
  • Cycloalkylene may have 3 to 12 carbon atoms (ie C3- C12cycloalkylene ), eg 3 to 10, 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atom.
  • suitable cycloalkylene groups include, but are not limited to, monocyclic structures such as cyclopropylene, cyclobutylene, cyclopentylene (eg, cyclopent-1,2-diyl, cyclopent-1,3- diyl), cyclohexylene (e.g.
  • cycloalkenyl means a monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic non-aromatic unsaturated hydrocarbon ring structure having the specified number of ring atoms, comprising at least one (eg, 1, 2, or 3) carbon-carbon double bonds.
  • Cycloalkenyl groups may have 3 to 12 carbon atoms (ie, C3 - C12 cycloalkenyl groups), such as 3 to 10, 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms .
  • Suitable cycloalkenyl groups include, but are not limited to, monocyclic structures such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptene cycloheptadienyl, cycloheptatrienyl, or cyclooctenyl.
  • cycloalkenylene refers to a cycloalkenyl group as defined above, but which is a divalent group in which the two bonds are not on the same ring atom.
  • Cycloalkenylene may have 3 to 12 carbon atoms (ie, C3 - C12 cycloalkenylene), for example 3 to 10, 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atom.
  • Suitable cycloalkenylene groups include, but are not limited to, monocyclic structures such as cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclopentadienylene, cyclohexenylene, cyclohexylene Dienyl, cycloheptenylene, cycloheptadienylene, cycloheptatrienylene or cyclooctenylene.
  • heterocycloalkyl as used herein means a monocyclic, fused, monocyclic, fused ring comprising one or more (eg 1, 2, 3 or 4) heteroatoms independently selected from O, N and S and the specified number of ring atoms
  • Heterocycloalkyl may have 3 to 12 ring members (may be referred to as 3-12 membered heterocycloalkyl), for example 3 to 10 ring members, 3 to 8 ring members, 3 to 7 ring members, 4 to 7 ring members, 5 to 6 ring members.
  • Heterocycloalkyl groups typically contain up to 4 (eg, 1, 2, 3, or 4) heteroatoms.
  • suitable heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl).
  • -pyrrolidinyl tetrahydrofuranyl (eg 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothienyl (eg 1-tetrahydrothienyl, 2-tetrahydrothienyl and 3-tetrahydrothienyl) thienyl), piperidinyl (such as 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (such as 4-tetrahydropyranyl), Tetrahydrothiopyranyl (eg 4-tetrahydrothiopyranyl), morpholinyl (eg morpholino), thiomorpholinyl, dioxanyl, piperazinyl or azepanyl, diazepine Cycloheptyl groups such as 1,4-diazacycloheptyl, 3,6-
  • heterocycloalkylene as used herein means a heterocycloalkyl group as defined above, but which is a divalent group in which the two bonds are not on the same ring atom.
  • Heterocycloalkylene may have 3 to 12 ring members (may be referred to as 3-12 membered heterocycloalkylene), such as 3 to 10 ring members, 3 to 8 ring members, 3 to 7 ring members, 4 to 7 ring members, 5 to 6 ring members.
  • Heterocycloalkylenes typically contain up to 4 (eg, 1, 2, 3, or 4) heteroatoms.
  • heterocycloalkylenes examples include, but are not limited to, azetidine, oxetylene, thietanylene, pyrrolidylene (eg, pyrrolidine-1,2-di pyrrolidine-1,3-diyl, pyrrolidine-2,3-diyl), tetrahydrofuranylidene (such as tetrahydrofuran-2,4-diyl, tetrahydrofuran-2,3-diyl and tetrahydrofuran-2, 5-diyl), piperidinylene (e.g.
  • heterocycloalkenyl as used herein means “heterocycloalkyl” as defined herein containing at least one (eg, 1, 2 or 3) double bond.
  • suitable heterocycloalkenyl groups include, but are not limited to:
  • tetrahydropyranyl eg 4-tetrahydropyranyl
  • tetrahydrothiopyranyl eg 4-tetrahydrothiopyranyl
  • heterocycloalkenylene means a heterocycloalkenyl group as defined above, but which is a divalent group in which the two bonds are not on the same ring atom.
  • suitable heterocycloalkenylene groups include, but are not limited to:
  • aryl as used herein means a monovalent aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom in an aromatic ring system. Specifically, aryl refers to a monocyclic or fused polycyclic aromatic ring structure having the specified number of ring atoms. In particular, the term includes groups comprising 6 to 14, such as 6 to 10, preferably 6, ring members. Particular aryl groups include phenyl and naphthyl, the most particular aryl group being phenyl.
  • arylene as used herein means an aryl group as defined above, but which is a divalent group in which the two bonds are not on the same ring atom.
  • Particular arylene groups include phenylene groups such as benzene-1,2-diyl, benzene-1,3-diyl or benzene-1,4-diyl.
  • heteroaryl as used herein means a monocyclic or fused ring comprising one or more (eg 1, 2, 3 or 4) heteroatoms independently selected from O, N and S and the specified number of ring atoms
  • a heteroaryl group can be, for example, a 5-6 membered monocyclic ring, or a fused bicyclic structure formed from two 5-membered rings fused, or a fused 5-membered ring and a 4-membered ring.
  • the heteroaryl ring contains at least one ring nitrogen atom, at least one ring sulfur atom, or at least one epoxy atom.
  • a heteroaryl group can be a 5-6 membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N, O, or S.
  • suitable 5-membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl;
  • suitable 6-membered monocyclic heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazine base.
  • heteroarylene as used herein means a heteroaryl group as defined above, but which is a divalent group in which the two bonds are not on the same ring atom.
  • a heteroarylene group can be a 5-6 membered heteroarylene group containing 1 or 2 heteroatoms independently selected from N, O, or S.
  • suitable 5-membered monocyclic heteroarylenes include, but are not limited to, pyrrolidine, furanylene, thienylene, imidazolylylene, furazanylidene, oxazolylylene, oxadiazolylylene, oxane Triazolyl, isoxazolylylene, thiazolylidene, isothiazolylidene, pyrazolylidene, triazolylylene, and tetrazolylylene;
  • suitable 6-membered monocyclic heteroaryl groups include, but are not limited to Pyridinyl, pyrazinylene, pyridazinylene, pyrimidinylene and triazinylene; preferred
  • Substituents described as "optionally substituted” mean that the group may be unsubstituted or substituted by one or more (eg, 0, 1, 2, 3, 4, or 5 or more, or any derivatized therein). range) is substituted with the listed substituents for that group, wherein the substituents may be the same or different.
  • an optionally substituted group is substituted with 1 substituent.
  • an optionally substituted group is substituted with 2 substituents.
  • an optionally substituted group is substituted with 3 substituents.
  • an optionally substituted group is substituted with 4 substituents.
  • heterocycles whether aromatic or non-aromatic, in which the maximum number of heteroatoms or the type of heteroatoms contained is determined by ring size, degree of unsaturation, and valence of the heteroatoms. Decide.
  • a heterocycle can have 1 to 4 heteroatoms, provided that the heterocycle or heteroaromatic ring is chemically feasible and stable.
  • pharmaceutically acceptable means approved by or by the appropriate agency in each country, or listed in a generally recognized pharmacopoeia for use in animals and more particularly in humans, or when administered in an appropriate amount to animals such as humans Molecular entities and compositions that do not produce adverse, allergic or other adverse reactions.
  • pharmaceutically acceptable salt means a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound.
  • such salts are nontoxic and can be inorganic acid addition salts or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids, which Organic acids such as acetic acid, propionic acid, caproic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandel acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butyl Acetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
  • prodrug means a compound having a cleavable group that becomes a compound of the present invention pharmaceutically active in vivo by solvolysis or under physiological conditions, including derivatives of the compound of the present invention.
  • Prodrugs include acid derivatives well known in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, or anhydrides or mixed anhydrides.
  • Simple aliphatic or aromatic esters, amides, and anhydrides derived from the pendant acid groups of the compounds of the present invention are particularly suitable prodrugs.
  • Particular such prodrugs are C1-8 alkyl, C2-8 alkenyl, optionally substituted C6-10 aryl, and ( C6-10 aryl)-( C1- 4 alkyl) esters.
  • the present invention also includes all pharmaceutically acceptable isotopic compounds that are identical to the compounds of the present invention, except that one or more atoms have the same atomic number but an atomic mass or mass number different from the atomic mass or mass that predominates in nature number of atomic substitutions.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (eg, 2H, 3H); isotopes of carbon (eg, 11C, 13C, and 14C); isotopes of chlorine (eg, 36Cl); isotopes of fluorine isotopes of iodine (such as 123I and 125I); isotopes of nitrogen (such as 13N and 15N); isotopes of oxygen (such as 15O, 17O, and 18O); isotopes of phosphorus (such as 32P); and isotopes of sulfur ( such as 35S).
  • isotopes of hydrogen eg, 2H, 3H
  • isotopes of carbon eg, 11C, 13C, and 14C
  • isotopes of chlorine eg, 36Cl
  • isotopes of fluorine isotopes of iodine such as 123
  • stereoisomer refers to isomers formed due to at least one asymmetric center. In compounds having one or more (eg, 1, 2, 3, or 4) asymmetric centers, it may give rise to racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist as mixtures of two or more different structural forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. For example, a nitroso-oxime can exist in solution in equilibrium in the following tautomeric forms:
  • the compounds of the present invention are intended to be available as stereoisomers (which include cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotational isomers, conformational isomers, atropisomers and mixtures thereof).
  • stereoisomers which include cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotational isomers, conformational isomers, atropisomers and mixtures thereof).
  • the compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (eg, racemic mixtures and pairs of diastereomers).
  • solvate refers to solvent addition forms containing stoichiometric or non-stoichiometric amounts of solvent, including, for example, solvates with water, such as hydrates, or solvates with organic solvents, such as Methanol, ethanol or acetonitrile, ie as methanolate, ethanolate or acetonitrile, respectively; or in the form of any polymorph. It should be understood that such solvates of the compounds of the present invention also include solvates of pharmaceutically acceptable salts of the compounds of the present invention.
  • prophylaxis means administering to an individual, such as a mammal, such as a human, the administration of an or Various compounds of the present invention result in a reduced risk of developing a defined disease.
  • prevention encompasses the use of the compounds of the present invention prior to the diagnosis or determination of any clinical and/or pathological symptoms.
  • treating refers to administering one or more compounds of the invention described herein to a subject, eg, a mammal, eg, a human, having the disease, or a symptom of the disease, for the purpose of To cure, alleviate, alleviate or affect the disease or symptoms of the disease.
  • the disease is a RET-related disease as defined herein, especially an inflammatory or autoimmune disease.
  • RET-related diseases are selected from tumors or irritable bowel syndrome (IBS), tumors including but not limited to non-small cell lung cancer, small cell lung cancer, papillary thyroid cancer, medullary thyroid cancer, Differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, polyendocrine tumor 2A or 2B, pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosa Gangliomas, pancreatic duct adenocarcinoma, multiple endocrine tumors, testicular cancer, chronic monocytic leukemia, salivary gland cancer, ovarian cancer, cervical cancer, etc.
  • IBS irritable bowel syndrome
  • cancer refers to the growth and proliferation of neoplastic cells, whether malignant or benign, and all precancerous cells and cancer cells and tissues.
  • the cancer or tumor includes but is not limited to colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma Carcinoma, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterine cancer, pemphigus cancer, liver cancer, auditory nerve tumor, oligodendroglioma, brain (meningioma), neuroblastoma, eye cancer.
  • the term "therapeutically effective amount” means an amount sufficient to reduce or completely alleviate the symptoms or other deleterious effects of the disorder; reverse, completely stop or slow the progression of the disorder; or reduce the risk of exacerbation of the disorder when administered to an individual to treat a disease.
  • the amount, "effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc. of the individual to be treated.
  • the term "individual” as used herein includes human or non-human animals.
  • exemplary human subjects include human subjects (referred to as patients) or normal subjects with a disease (eg, a disease described herein).
  • Non-human animals in the present invention include all vertebrates such as non-mammals (eg birds, amphibians, reptiles) and mammals such as non-human primates, livestock and/or domesticated animals (eg sheep, dogs) , cats, cows, pigs, etc.).
  • compositions refers to comprising one or more compounds of formula (I) or its stereoisomers, tautomers, stable isotope derivatives, pharmaceutically acceptable salts or solvents compositions and carriers generally accepted in the art for the delivery of biologically active compounds to organisms such as humans.
  • the term "pharmaceutical combination" as used herein means that a compound of the present invention may be used in combination with other active agents for the purposes of the present invention.
  • the other active agent may be one or more additional compounds of the present invention, or may be a second or additional (eg, third) compound that is compatible with, that is, does not adversely affect each other, or has complementary activities. ) compound.
  • Such active agents are suitably combined in amounts effective to achieve the intended purpose.
  • the other active agents may be co-administered with the compound of the present invention in a single pharmaceutical composition, or administered separately from the compound of the present invention in separate discrete units, either simultaneously or sequentially when administered separately. The sequential administrations may be close or distant in time.
  • pharmaceutically acceptable excipient or carrier refers to one or more compatible solid or liquid filler or gelling substances, which are pharmacologically inactive, incompatible with the other ingredients in the composition and should be acceptable for administration to warm-blooded animals, such as humans, for use as a carrier or vehicle for the compounds of the present invention in administration forms, examples of which include, but are not limited to, cellulose and its derivatives such as carboxymethyl cellulose sodium, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as magnesium stearate), calcium sulfate, vegetable oils, polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) class), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, etc.
  • cellulose and its derivatives such as carboxymethyl cellulose sodium, cellulose acetate,
  • the stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates and prodrugs are as described in the definitions section above.
  • the compounds of the present invention are in free form of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof; most preferably a compound of formula (I) in free form or a pharmaceutically acceptable salt thereof.
  • Certain compounds of the present invention may exist in polymorphic or amorphous forms, which also fall within the scope of the present invention.
  • the compound of formula (I) may be in the form of a co-crystal with another chemical entity, and this specification includes all such co-crystals.
  • the compounds of the present invention may exist as individual enantiomers or as mixtures of enantiomers.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof which is a single enantiomer with an enantiomeric excess (%ee) of >95, >98%, or >99%.
  • a single enantiomer is present in >99% enantiomeric excess (%ee).
  • the present invention provides compounds of formula (I), stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof:
  • R 1 is selected from hydrogen, halogen, cyano, nitro and C 1 -C 6 alkyl optionally substituted with halogen or cyano;
  • R 2 is selected from hydrogen, C 6 -C 10 aryl, 5-9 membered heteroaryl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3 -8-membered heterocycloalkenyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 alkylthio, wherein said aryl, heteroaryl, cycloalkyl, cycloalkene group, heterocycloalkyl, heterocycloalkenyl, alkyl, alkoxy and alkylthio optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen, cyano, nitro, hydroxy , C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 alkylthio;
  • R 3 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 alkylthio;
  • R 4 is selected from hydrogen, C 6 -C 10 aryl, 5-9 membered heteroaryl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3 -8-membered heterocycloalkenyl, 3-8 membered heterocycloalkyloxy, 3-8 membered heterocycloalkenyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 - C alkylthio , wherein the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkyl, alkoxy and alkylthio groups are optionally independently selected Substituted from 1, 2 or 3 of the following: halogen, cyano, nitro, C1 - C6 alkyl, C1 - C6 alkoxy and C1 - C6 alkylthi
  • R 5 is selected from halogen, cyano, nitro, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 alkylthio;
  • Ring A is selected from C 6 -C 10 arylene, 5-9 membered heteroarylene, C 3 -C 8 cycloalkylene, C 3 -C 8 cycloalkenylene, 3-8 membered heterocycloalkane base and 3- to 8-membered heterocycloalkenyl rings;
  • Ring B is selected from C 6 -C 10 aryl, 5-9 membered heteroaryl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, 3-8 membered heterocycloalkyl and 3-8 A membered heterocycloalkenyl ring;
  • n 0, 1, 2, or 3;
  • n 0, 1, 2 or 3.
  • R1 is halo, cyano or nitro.
  • R1 is cyano
  • R is selected from 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms independently selected from N, O or S (specific examples include pyrrolyl , furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl), C 1 -C 6 Alkyl, C1 -C6alkoxy, and C1 - C6alkylthio, optionally substituted with 1, 2 , or 3 groups independently selected from halogen, hydroxy, and C1 - C6 alkyl;
  • R2 is selected from 5-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S (specific examples include pyrrolyl, furan base, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or pyrazolyl), C 1 -C 6 alkoxy and C 1 -C 6 alkylthio, which are optional is substituted with 1 group independently selected from hydroxy and C 1 -C 6 alkyl;
  • R2 is selected from 5 containing 1, 2 or 3 heteroatoms independently selected from N, O or S, optionally substituted with C1 - C6 alkyl Member heteroaryl (specific examples include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or pyrazolyl) and C 1 - optionally substituted by hydroxy C 6 alkoxy;
  • R 2 is methyl substituted pyrazolyl or hydroxy substituted C 1 -C 6 alkoxy
  • R 2 is
  • R3 is selected from hydrogen and C1 - C6 alkyl.
  • R3 is selected from hydrogen and C1 - C3 alkyl.
  • R3 is hydrogen or methyl.
  • R3 is hydrogen
  • the carbon to which R3 is attached is in the S or R configuration.
  • R4 is selected from phenyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, 5- 6-membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, 5-6 membered heterocycloalkyloxy, 5-6 membered heterocycloalkenyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 alkylthio, optionally substituted with 1, 2 or 3 groups independently selected from halogen, hydroxy and C 1 -C 6 alkyl;
  • the 5-6 membered heteroaryl group is selected from pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyridyl oxazinyl, pyridazinyl and pyrimidinyl;
  • the 5-6 heterocycloalkyl group is selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, di oxanyl or piperazinyl;
  • the 5-6 membered heterocycloalkenyl is selected from the group consisting of pyrrolinyl, dihydrofuranyl, dihydrothienyl, tetrahydropyridyl, tetrahydropyranyl and tetrahydrothiopyranyl.
  • R4 is selected from 5 -membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S (specific examples include pyrrolyl, furan base, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or pyrazolyl), 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyloxy, C 1 - C6 alkyl and C1 - C6 alkoxy optionally substituted with 1, 2 or 3 groups independently selected from halogen and C1 - C6 alkyl.
  • R4 is selected from the group consisting of pyrazolyl, pyrrolidinyl, tetrahydropyranyloxy, morpholinyl, tetrahydrofuranyloxy, C1 - C6 alkyl and C1 - C6alkoxy optionally substituted with halogen.
  • R4 is Pyrrolidin-1-yl, methoxy, ethoxy, isopropoxy, trifluoromethoxy or CF3 .
  • R 5 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 alkylthio;
  • R 5 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 alkylthio.
  • R 5 is selected from C 1 -C 3 alkyl
  • R 5 is selected from methyl, ethyl and propyl, preferably methyl;
  • m is 0 or 1 .
  • n is 0 or 1 .
  • m is 1 .
  • n is zero.
  • Ring A is selected from phenylene, 5-9 membered heteroarylene containing 1, 2 or 3 heteroatoms independently selected from N, O or S, C3- C8cycloalkylene , C3 - C8cycloalkenylene , 3-8 membered heterocycloalkylene containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 3-8 membered heterocycloalkenyl rings containing 1, 2 or 3 heteroatoms independently selected from N, O or S;
  • Ring A is selected from phenylene, 5-6 membered heteroarylene containing 1, 2 or 3 heteroatoms independently selected from N, O or S, C3- C8cycloalkylene , C3 - C8cycloalkenylene , 3-8 membered heterocycloalkylene containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and 3-8 membered heterocycloalkenylene containing 1, 2 or 3 heteroatoms independently selected from N, O or S;
  • Ring A is selected from phenylene, 5-membered heteroarylene containing 1, 2 or 3 heteroatoms independently selected from N, O or S, C3 -C6cycloalkylene, C3 - C6cycloalkenylene , 3-6 membered heterocycloalkylene containing 1, 2 or 3 heteroatoms independently selected from N, O or S, and containing 1 , 2 or 3 heteroatoms independently selected from N, O or S 3-6 membered heterocycloalkenylene;
  • Ring A is selected from the group consisting of phenylene, pyrrolylene, furanylene, thienylene, imidazolylide, furazanylidene, oxazolylide, oxadiene azolyl, oxtriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridylene, sub Pyrazinyl, pyridazinylene, pyrimidinyl, triazinylene, azetidine, pyrrolidylene, pyrrolidylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclohexylene Cycloheptyl, piperazinylene, piperidinylene, tetrahydropyridylene, 3,6-diaza-
  • Ring A is selected from the group consisting of pyrazolylidene, thiadiazolylidene, pyrrolidylene, pyrrolidylene, cyclohexylene, piperazinylene, piperidine , tetrahydropyridylene, 3,6-diaza-bicyclo[3.1.1]heptylene, 3-aza-bicyclo[3.2.1]octylene, and 1,4-diazacyclo Heptyl.
  • Ring A is selected from
  • Ring B is selected from phenyl, 5-9 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, C3 -C8cycloalkyl , C3- C8cycloalkenyl , 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S and containing 1, 2 or 3 3-8 membered heterocycloalkenyl rings of heteroatoms independently selected from N, O or S;
  • Ring B is selected from phenyl and 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S;
  • Ring B is selected from phenyl, 6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S;
  • Ring B is selected from the group consisting of phenyl, pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxtriazolyl, Isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl rings.
  • Ring B is a pyridyl ring.
  • the compound of formula (I) of the present invention covers each of the above independent embodiments or each specific embodiment, and also covers the embodiment formed by any combination or sub-combination of each of the above-mentioned embodiments or specific embodiments, and also covers the above Any preferred or exemplified combination constitutes an embodiment.
  • the compound of formula (I) of the present invention has the structure of formula (Ia),
  • R 1 , R 2 , R 3 , R 4 , R 5 , m, n and A each have the meanings defined above for the compounds of formula (I) in general or in the specific embodiment.
  • the compound of formula (I) of the present invention has the structure of formula (Ib),
  • R 1 , R 2 , R 3 , R 4 , R 5 , n and A each have the meanings defined above for the compounds of formula (I) in general or in the specific embodiment.
  • the compound of formula (I) of the present invention has the structure of formula (Ic),
  • R 2 , R 3 , R 4 , R 5 , n and A each have the meanings defined above for the general or specific embodiments of compounds of formula (I).
  • the present invention provides a class of pyrazolopyridine compounds with the structural features of the general formula (I). It has been found through research that such compounds can effectively inhibit RET kinase, RET fusion and mutation activities, and serve as a susceptor for related diseases with abnormal RET expression. medicine.
  • High RET kinase inhibitory activity an IC50 in the range of 0.1 nM to 1 ⁇ M, preferably in the range of 0.1 nM to 0.1 ⁇ M, in a kinase RET inhibition assay; and/or
  • the present invention also provides technical solutions in the following aspects.
  • the present invention provides compounds of the present invention for use as medicaments, particularly as RET inhibitors.
  • the present invention provides compounds of the present invention for use in the treatment, especially in the treatment and/or prevention of RET-related diseases.
  • the present invention provides the invention for the treatment and/or prevention of diseases in which RET contributes to the development and progression of the disease or in which inhibition of RET will reduce the incidence of the disease, reduce or eliminate the symptoms of the disease
  • Compounds such as tumors or irritable bowel syndrome (IBS), tumors including but not limited to non-small cell lung cancer, small cell lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer , refractory differentiated thyroid cancer, multiple endocrine tumors 2A or 2B, pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal ganglionoma, pancreatic duct adenocarcinoma, Multiple endocrine tumors, testicular cancer, chronic monocytic leukemia, salivary gland cancer, ovarian cancer, cervical cancer, etc.
  • IBS irritable bowel syndrome
  • the compounds of the present invention can be formulated into pharmaceutical compositions according to standard pharmaceutical practice. Meanwhile, based on the good pharmacokinetic properties, improved AUCO-last and good druggability of the compounds of the present invention, medicines with better pharmacokinetic properties and higher bioavailability can be prepared from the compounds of the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-described compound of the present invention and a pharmaceutically acceptable excipient.
  • compositions of the present invention are provided for use in the prevention or treatment of RET-related diseases, eg, in mammals such as human subjects.
  • compositions of the present invention may additionally comprise additional therapeutically active ingredients suitable for use in combination with the compounds of the present invention.
  • compositions of the present invention can be formulated by techniques known to those skilled in the art, such as those disclosed in Remington's Pharmaceutical Sciences 20th Edition.
  • the pharmaceutical compositions of the present invention described above can be prepared by admixing a compound of the present invention with one or more pharmaceutically acceptable excipients.
  • the preparation may further include the step of admixing one or more other active ingredients with a compound of the present invention and one or more pharmaceutically acceptable excipients.
  • excipients for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.
  • diluents such as glucose, lactose or mannitol
  • carriers pH adjusters, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives agents, antioxidants, opacifiers, glidants, processing aids, colorants, perfuming agents, flavoring agents, other known additives.
  • compositions of the present invention can be administered in a standard manner.
  • suitable modes of administration include oral, intravenous, rectal, parenteral, topical, transdermal, ocular, nasal, buccal or pulmonary (inhalation) administration, wherein parenteral infusion includes intramuscular, intravenous, intraarterial, peritoneal Intra or subcutaneous administration.
  • the compounds of the present invention may be formulated by methods known in the art, for example, as tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, Ointments, creams, drops, aerosols, dry powder formulations and sterile injectable aqueous or oily solutions or suspensions.
  • a prophylactic or therapeutic dose of a compound of the invention will vary depending on a range of factors, including the individual being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician.
  • effective doses range from about 0.0001 to about 5000 mg per kg body weight per day, eg, about 0.01 to about 1000 mg/kg/day (single or divided administration). For a 70 kg person, this would add up to about 0.007 mg/day to about 7000 mg/day, eg, about 0.7 mg/day to about 1500 mg/day.
  • the content or amount of the compound of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, For example 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.; accordingly, the pharmaceutical composition of the present invention will comprise 0.05 to 99% w/w (weight percent), such as 0.05 to 80% w/w, such as 0.10 to 70% w/w, eg, 0.10 to 50% w/w of a compound of the invention, all weight percentages are based on the total composition. It will be understood that it may be necessary in certain circumstances to use doses above these limits.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, the composition being formulated for oral administration.
  • the composition may be presented in unit dosage form, eg, in the form of a tablet, capsule, or oral liquid.
  • Such unit dosage forms may contain 0.1 mg to 1 g, eg, 5 mg to 250 mg, of a compound of the present invention as the active ingredient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, the composition being formulated for topical administration.
  • Topical administration can be in the form of, for example, creams, lotions, ointments or transdermal patches.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, the composition being formulated for administration by inhalation.
  • Administration by inhalation can be by oral inhalation or intranasal administration.
  • the compounds of the present invention can be effectively used in the present invention in daily doses, eg up to 500 ⁇ g, such as 0.1-50 ⁇ g, 0.1-40 ⁇ g, 0.1-30 ⁇ g, 0.1-20 ⁇ g or 0.1-10 ⁇ g of the present invention compound.
  • compositions of the present invention for oral inhalation may be formulated as dry powders, suspensions (in liquid or gas) or solutions (in liquid), and may be in any suitable form and using any suitable inhaler device known in the art Administration includes, for example, metered dose inhalers (MDIs), dry powder inhalers (DPIs), nebulizers, and soft mist inhalers. Multi-chamber devices can be used to deliver the compounds of the present specification and one or more other active ingredients, when present.
  • MDIs metered dose inhalers
  • DPIs dry powder inhalers
  • nebulizers nebulizers
  • soft mist inhalers soft mist inhalers
  • the compounds of the present invention can be used in methods of treating various disorders in animals, especially mammals such as humans.
  • the present invention provides a method of modulating, especially inhibiting, RET activity, the method comprising contacting a cell with a compound of the invention as previously described to modulate, especially inhibit, RET activity in the cell.
  • the present invention provides a method of preventing or treating a disease associated with RET (eg, a disease treatable or preventable by RET inhibition), the method comprising administering to an individual in need thereof an effective amount of the present invention as previously described A compound of the invention or a pharmaceutical composition of the invention comprising the same.
  • a disease associated with RET eg, a disease treatable or preventable by RET inhibition
  • the present invention provides the use of a compound of the present invention as previously described, or a pharmaceutical composition comprising the same, for inhibiting RET activity, or for treating and/or preventing RET-related diseases, such as by RET inhibition Treatable or preventable disease.
  • the present invention also provides the use of the aforementioned compound of the present invention or the pharmaceutical composition comprising the same in the preparation of medicines, especially the use of medicines with RET receptor inhibitor activity.
  • the present invention provides the use of a compound of the present invention as described above, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment or prevention of a disease associated with RET, such as a disease treatable or preventable by RET inhibition , wherein the compound or pharmaceutical composition is optionally combined with one or more chemotherapy or immunotherapy.
  • the present invention also provides a process for the preparation of compounds of formula (I), and general synthetic schemes for synthesizing the compounds of the present invention are exemplified below.
  • appropriate reaction conditions are known to those skilled in the art or can be routinely determined.
  • the starting materials and reagents used in the preparation of these compounds are generally commercially available unless otherwise specified, or can be prepared by the methods below, methods analogous to those given below, or methods known in the art.
  • the raw materials and intermediates in the synthetic reaction scheme can be separated and purified by conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like.
  • the materials can be characterized using conventional methods including physical constants and spectral data.
  • the reaction can be carried out in the presence of a condensing agent, which is a condensing agent well known in the art for the coupling of carboxylic acids and amines, including but not limited to 1-propylphosphoric anhydride (T3P), EDC, DCC , HATU, EDCI, etc.; the reaction is preferably carried out in a suitable organic solvent, and the organic solvent can be selected from dichloromethane, tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methyl Pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, dimethylsulfoxide and any combination thereof; the reaction is preferably in the presence of a suitable base Carry out under, described base includes but not limited to sodium carbonate, potassium carbonate, cesium carbonate, N,N-diisopropylethylamine, trie
  • the reaction is preferably carried out in a suitable organic solvent, which can be selected from dichloromethane, tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, N,N - dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, dimethyl sulfoxide and any combination thereof, optionally with water; the reaction is preferably carried out in a suitable base Carry out in the presence of, the alkali includes but not limited to sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, N,N-diisopropylethylamine, triethylamine, HOBt or pyridine, preferably, the described
  • the base is N,N-diisopropylethylamine; the reaction is preferably carried out at a suitable temperature, eg 0-200°C, 10-100°C, 20-50°C or room temperature
  • the above synthetic scheme only exemplifies the preparation methods of some compounds in the present invention.
  • the compounds of the present invention, or stereoisomers, tautomers, stable isotopic derivatives, pharmaceutically acceptable salts or solvates thereof, can be prepared by a variety of methods, including the methods given above, in the Examples
  • the given method or a similar method can be prepared by those of ordinary skill in the art on the basis of the above-mentioned synthetic scheme and in combination with conventional techniques in the art.
  • experimental materials and reagents used in the following examples can be obtained from commercial sources, prepared according to methods in the prior art, or prepared according to methods similar to those disclosed in this application.
  • HATU 2-(7-Azobenzotriazole)-N,N,N',N',-tetramethylurea hexafluorophosphate
  • PE petroleum ether
  • silica gel 300-400 mesh
  • GF254 (0.25 mm) is used for thin-layer chromatography
  • Varian- 400 nuclear magnetic resonance instrument liquid chromatography mass spectrometry (LC/MS) using Agilent TechnologiESI 6120 liquid mass spectrometer.
  • the raw materials used in the present invention are all commercially available raw materials, which can be used directly without further purification, and the temperatures used in the present invention are all in degrees Celsius.
  • Step 1 Synthesis of 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate
  • Step 2 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1-methyl- Synthesis of 1H-pyrazole-5-carboxylic acid methyl ester
  • Step 4 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1-methyl-1H-pyrazol-5-carboxamide
  • Step 1 Synthesis of methyl 3-hydroxy-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylate
  • Step 2 Synthesis of 1-(4-methoxybenzyl)-3-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-5-carboxylic acid methyl ester
  • Step 3 1-(4-Methoxybenzyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H -Synthesis of methyl pyrazole-5-carboxylate
  • Step 4 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1-(4- Synthesis of methyl methoxybenzyl)-1H-pyrazole-5-carboxylate
  • Step 5 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1-(4- Synthesis of methoxybenzyl)-1H-pyrazole-5-carboxylic acid
  • Step 6 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxamide
  • Step 7 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1H-pyrazole-5-carboxamide
  • Step 1 Synthesis of tert-butyl 4-(5-bromopyridin-3-yl)piperazine-1-carboxylate
  • Step 2 Synthesis of 1-amino-3-bromo-5-(4-tert-butoxycarbonyl)piperazin-1-yl)pyridine-1-onium-2,4,6-trimethylbenzenesulfonate
  • Step 3 Synthesis of tert-butyl 4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)piperazine-1-carboxylate
  • Step 4 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazine-1-carboxylic acid Synthesis of tert-butyl ester
  • Step 6 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)piperazine-1-carboxamide and its hydrochloride
  • Step 1 Synthesis of 1-amino-3-bromo-5-fluoropyridine-1-onium 2,4,6-trimethylbenzenesulfonate
  • Step 3 Synthesis of 1-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-4-methylpiperidine-4-carboxylic acid ethyl ester
  • Step 4 1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-4-methylpiperin Synthesis of ethyl pyridine-4-carboxylate
  • Step 6 1-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-4-methylpiperidine-4-carboxamide and its hydrochloride
  • Step 2 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3,6-di Synthesis of Azabicyclo[3.1.1]heptane-6-carboxylate tert-butyl ester
  • Step 3 4-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1, Synthesis of 5-a]pyridine-3-carbonitrile trifluoroacetate
  • Step 4 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide
  • Example 7 1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-(4-Fluoro-1H-pyrazol-1 -yl)pyridin-3-yl)methyl)piperidine-4-carboxamide (compound 7) and its hydrochloride (compound 7-1)
  • Step 1 Synthesis of 1-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester
  • Step 4 1-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)piperidine-4-carboxamide and its hydrochloride
  • Step 2 Synthesis of 3-benzyl-3-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester
  • Step 3 Synthesis of ethyl 3-azabicyclo[3.2.1]octane-8-carboxylate
  • Step 4 3-(6-Bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester synthesis
  • Step 7 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3-azabicyclo[3.2.1]octane-8-carboxamide
  • Step 1 Synthesis of (S)-4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester
  • Step 2 (S)-4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-2 -Synthesis of tert-butyl methylpiperazine-1-carboxylate
  • Step 4 (S)-4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N Synthesis of -((6-(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2-methylpiperazine-1-carboxamide
  • Step 1 Synthesis of (R)-4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester
  • Step 2 (R)-4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-2 -Synthesis of tert-butyl methylpiperazine-1-carboxylate
  • Step 4 (R)-4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N Synthesis of -((6-(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2-methylpiperazine-1-carboxamide
  • Example 11 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-(4-Fluoro-1H-pyrazol-1 -yl)pyridin-3-yl)methyl)-1,4-diazepan-1-carboxamide (Compound 11)
  • Step 1 Synthesis of 4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-1,4-diazepan-1-carboxylic acid tert-butyl ester
  • Step 2 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1,4-di Synthesis of tert-butyl azepan-1-carboxylate
  • Step 3 4-(1,4-Diazepan-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine Synthesis of -3-carbonitrile hydrochloride
  • Step 4 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1,4-diazepan-1-carboxamide
  • Step 1 Synthesis of methyl 1-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)azetidine-3-carboxylate
  • Step 2 1-(3-cyano-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazolo[1, Synthesis of methyl 5-a]pyridin-4-yl)azetidine-3-carboxylate
  • Step 3 Synthesis of methyl 1-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)azetidine-3-carboxylate
  • Example 13 1-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-(4-Fluoro-1H-pyrazol-1 -yl)pyridin-3-yl)methyl)azetidine-3-carboxamide (Compound 13)
  • Step 2 1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)azetidine-3-carboxamide
  • Step 1 1-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -methoxypyridin-3-yl)methyl)azetidine-3-carboxamide
  • Step 1 Synthesis of tert-butyl 3-(5-bromopyridin-3-yl)azetidine-1-carboxylate
  • Step 3 Synthesis of tert-butyl 3-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)azetidine-1-carboxylate
  • Step 4 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)azetidine- Synthesis of tert-butyl 1-formate
  • Step 6 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)azetidine-1-carboxamide
  • Step 1 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-2,5-di Synthesis of Hydrogen-1H-pyrrole-1-carboxylate tert-butyl ester
  • Step 2 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyrrolidine-1-carboxylic acid Synthesis of tert-butyl ester
  • Step 4 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)pyrrolidine-1-carboxamide
  • Step 1 4-(2,5-Dihydro-1H-pyrrol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine Synthesis of -3-carbonitrile hydrochloride
  • Step 2 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -methoxypyridin-3-yl)methyl)-2,5-dihydro-1H-pyrrole-1-carboxamide
  • Step 1 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(1- Synthesis of (6-methoxypyridin-3-yl)ethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide
  • Step 1 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(1- Synthesis of (6-(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide and its hydrochloride
  • Step 1 3-(3-Cyano-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazolo[1, Synthesis of 5-a]pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester
  • reaction solution was cooled to room temperature and poured into EA (30.0 mL). After the solution was filtered through celite, the filter cake was washed with EA (20.0 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (12.2 g, crude product, black solid).
  • Step 2 Synthesis of 3-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester
  • Step 3 3-(3-Cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-2,5-dihydro- Synthesis of tert-butyl 1H-pyrrole-1-carboxylate
  • Step 4 4-(2,5-Dihydro-1H-pyrrol-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3 - Synthesis of formonitrile hydrochloride
  • Step 5 3-(3-Cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N-((6-methylpropoxy) Synthesis of Oxypyridin-3-yl)methyl)-2,5-dihydro-1H-pyrrole-1-carboxamide
  • Example 21 3-(3-Cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N-((6- (4-Fluoro-1H-pyrazol-1 -yl)pyridin-3-yl)methyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (Compound 21) and its hydrochloride (Compound 21-1) Synthesis
  • Step 1 3-(3-Cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N-((6-( Synthesis of 4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2,5-dihydro-1H-pyrrole-1-carboxamide and its hydrochloride
  • Step 1 Synthesis of 3-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester
  • Step 2 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-2,5-di Synthesis of Hydrogen-1H-pyrrole-1-carboxylate tert-butyl ester
  • Step 3 4-(2,5-Dihydro-1H-pyrrol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine Synthesis of -3-carbonitrile hydrochloride
  • Step 4 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2,5-dihydro-1H-pyrrole-1-carboxamide
  • Example 23 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-(4-Fluoro-1H-pyrazol-1 -yl)pyridin-3-yl)methyl)piperidine-1-carboxamide (compound 23) and its hydrochloride (compound 23-1)
  • Step 5 Synthesis of 4-(6-Bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
  • Step 6 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3,6-di Synthesis of Hydropyridine-1(2H)-carboxylate tert-butyl ester
  • Step 7 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidine-1-carboxylic acid Synthesis of tert-butyl ester
  • Step 9 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)piperidine-1-carboxamide hydrochloride
  • Example 24 4-(3-Cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N-((6- Synthesis of (4-fluoro-1H-pyrazol-1 -yl)pyridin-3-yl)methyl)-3,6-dihydropyridine-1(2H)-carboxamide (compound 24)
  • Step 1 4-(3-Cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydropyridine Synthesis of -1(2H)-tert-butyl formate
  • Step 3 4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N-((6-( Synthesis of 4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-dihydropyridine-1(2H)-carboxamide
  • Example 25 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-(4-Fluoro-1H-pyrazol-1 -yl)pyridin-3-yl)methyl)-3,6-dihydropyridine-1(2H)-carboxamide (Compound 25)
  • Step 1 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3,6-di Synthesis of Hydropyridine-1(2H)-carboxylate tert-butyl ester
  • Step 2 6-(1-Methyl-1H-pyrazol-4-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a] Synthesis of pyridine-3-carbonitrile hydrochloride
  • Step 3 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-dihydropyridine-1(2H)-carboxamide
  • Step 1 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)cyclohex-3-ene Synthesis of -1-formic acid methyl ester
  • Step 2 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)cyclohexane-1- Synthesis of methyl formate
  • Step 4 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)cyclohexanamide
  • Example 27 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-(4-Fluoro-1H-pyrazol-1 -yl)pyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide (Compound 27)
  • Step 2 6-(1-Methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine Synthesis of azolo[1,5-a]pyridine-3-carbonitrile
  • Step 4 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide
  • Example 28 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-methoxypyridin-3-yl) methyl)-1H-pyrazole-1-carboxamide (compound 28) and its hydrochloride (compound 28-1)
  • Step 1 6-(1-Methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine Synthesis of azolo[1,5-a]pyridine-3-carbonitrile
  • Step 3 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -methoxypyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide and its hydrochloride
  • Step 1 Synthesis of 1-(6-methoxypyridin-3-yl)ethan-1-one oxime
  • Step 3 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(1- Synthesis of (6-methoxypyridin-3-yl)ethyl)-1H-pyrazole-1-carboxamide
  • Step 1 Synthesis of (R,E)-N-(1-(6-methoxypyridin-3-yl)ethylene)-2-methylpropyl-2-sulfinamide
  • Step 2 Synthesis of (R)-N-((S)-1-(6-methoxypyridin-3-yl)ethyl)-2-methylpropyl-2-sulfinamide
  • Lithium tri-sec-butylborohydride (1.0 M in THF, 8.65 mL, 8.65 mmol) was added dropwise to (R,E)-N-(1-(6-methyl) at -70°C under argon oxypyridin-3-yl)ethylene)-2-methylpropyl-2-sulfinamide (2.00 g, 7.86 mmol) in dry tetrahydrofuran (60.0 mL). The reaction mixture was stirred at -70°C for 90 minutes. To the reaction solution was added saturated aqueous ammonium chloride solution (80.0 mL). The organic phase was separated, and the aqueous phase was extracted with EA (80.0 mL ⁇ 2).
  • Step 4 (S)-4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N Synthesis of -(1-(6-Methoxypyridin-3-yl)ethyl)-1H-pyrazole-1-carboxamide
  • Chiral analysis method Chiral column: Reprosil Chiral-OM 100*3mm 3 ⁇ m; Mobile phase: A: Supercritical CO 2 , B: MeOH (0.1% DEA); Gradient: A 60%, B 40% for 5min; Flow rate: 1.5mL/min; column temperature: 35°C.
  • Example 32 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-(trifluoromethyl)pyridin -3-yl)methyl)-1H-pyrazole-1-carboxamide (compound 32) and its hydrochloride (compound 32-1)
  • Step 1 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide and its hydrochloride
  • Example 33 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-ethoxypyridin-3-yl) methyl)-1H-pyrazole-1-carboxamide (compound 33) and its hydrochloride (compound 33-1)
  • Step 3 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -ethoxypyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide and its hydrochloride
  • Step 1 4-(1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-6-(4,4,5,5-tetramethyl-1,3 Synthesis of ,2-dioxaborolane-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
  • Step 5 4-(3-Cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N-((6-( Synthesis of 4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide
  • Example 35 4-(3-Cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N-(1-( 6-(4-Fluoro-1H-pyrazol- 1-yl)pyridin-3-yl)ethyl)-1H-pyrazole-1-carboxamide (Compound 35) and its hydrochloride (Compound 35-1) Synthesis
  • Step 1 4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N-(1-(6 Synthesis of -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1H-pyrazole-1-carboxamide hydrochloride
  • Example 36 4-(3-Cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N-((6- Synthesis of Methoxypyridin-3-yl) methyl)-1H-pyrazole-1-carboxamide (Compound 36) and Its Hydrochloride (Compound 36-1)
  • Step 1 4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N-((6-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N-((6-methylpropoxy) Synthesis of oxypyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide hydrochloride
  • Step 1 4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N-(1-(6 Synthesis of -methoxypyridin-3-yl)ethyl)-1H-pyrazole-1-carboxamide
  • Example 38 1-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-(4-Fluoro-1H-pyrazol-1 -yl)pyridin-3-yl)methyl)-1H-pyrazole-4-carboxamide (Compound 38)
  • Step 1 Synthesis of 1-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester
  • Step 4 1-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-carboxamide
  • Step 1 6-(1-Methyl-1H-pyrazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)pyrazolo[1,5-a] Synthesis of pyridine-3-carbonitrile
  • Step 2 5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1,3,4 -Synthesis of ethyl thiadiazole-2-carboxylate
  • Step 3 5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1,3,4 -Synthesis of potassium thiadiazole-2-carboxylate
  • Step 4 5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(1- Synthesis of (6-methoxypyridin-3-yl)ethyl)-1,3,4-thiadiazole-2-carboxamide
  • Step 1 (S)-3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N Synthesis of -(1-(6-Methoxypyridin-3-yl)ethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide
  • Step 2 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -isopropoxypyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide
  • Step 2 N-((6-(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3-(4,4,5,5-tetramethyl-1, Synthesis of 3,2-Dioxaborolane-2-yl)-1H-pyrrole-1-carboxamide
  • Step 3 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1H-pyrrole-1-carboxamide
  • Step 3 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(pyrrolidin-1-yl)pyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide
  • Step 3 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -(trifluoromethoxy)pyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide
  • Example 46 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-((tetrahydro-2H-pyran-4 -yl)oxy)pyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide (Compound 46)
  • Step 3 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide
  • Step 3 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 -Synthesis of morpholinopyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide
  • Example 48 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-((tetrahydrofuran-3-yl) oxy)pyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide (Compound 48)
  • Step 3 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6 Synthesis of -((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)methyl)-1H-pyrazole-1-carboxamide
  • Step 3 Synthesis of (R,E)-N-(1-(6-isopropoxypyridin-3-yl)ethylene)-2-methylpropyl-2-sulfinamide
  • Step 4 Synthesis of (R)-N-((S)-1-(6-isopropoxypyridin-3-yl)ethyl)-2-methylpropyl-2-sulfinamide
  • lithium tri-sec-butylborohydride (1.0 M in THF, 36.8 mL, 36.8 mmol) was added dropwise to (R,E)-N-(1-(6-isopropoxypyridine- 3-yl)ethylene)-2-methylpropyl-2-sulfinamide (5.20 g, 18.4 mmol) in tetrahydrofuran (70.0 mL).
  • the reaction mixture was stirred at -70°C under argon for 2 hours.
  • the reaction mixture was quenched with saturated ammonium chloride (150 mL) and extracted with EA (120 mL x 3).
  • Step 6 Synthesis of (S)-(1-(6-isopropoxypyridin-3-yl)ethyl)phenylcarbamate
  • Step 7 (S)-4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N Synthesis of -(1-(6-isopropoxypyridin-3-yl)ethyl)-1H-pyrazole-1-carboxamide
  • Step 2 Synthesis of 1-(6-isopropoxypyridin-3-yl)ethan-1-one oxime
  • Step 4 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(1- Synthesis of (6-isopropoxypyridin-3-yl)ethyl)-1H-pyrazole-1-carboxamide
  • the reaction mixture was cooled to room temperature, diluted with EA (200 mL), washed with saturated brine (15.0 mL ⁇ 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product.
  • LC-MS (ESI) m/z 496.1 [M+H] + .
  • Step 5 (R)-4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N Synthesis of -(1-(6-isopropoxypyridin-3-yl)ethyl)-1H-pyrazole-1-carboxamide
  • Kinase RET inhibition assays were performed using methods similar to those described in the literature (Vivek Subbiah, J.F.G., Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Cancer Discov, 2018.8(7):836-849).
  • the inhibitory effect of the compounds on the kinase RET was detected by the Caliper Mobility Shift Assay method.
  • the final concentration of the compounds tested was 1000nM, 3-fold serial dilution, a total of 10 concentrations, and repeated well detection.
  • the compounds to be tested were dissolved in 100% DMSO (Sigma, D8418-1L, SHBG3288V) to prepare a 10 mM stock solution, which was stored in a nitrogen cabinet away from light.
  • DMSO 100% DMSO
  • 1 ⁇ Kinase buffer 1 ⁇ Kinase buffer
  • a compound concentration gradient as follows: the initial test concentration of the compound to be tested is 1000nM, serially diluted 3 times with DMSO in a 384-well plate (Corning, 3573, 12619003), a total of 10 concentrations, repeated well test , the final concentrations were 1000, 333, 111, 37, 12.3, 4.12, 1.37, 0.457, 0.152, 0.0508nM, respectively, and then transferred 250nl to the 384 reaction plate with Echo550 (Labcyte, model: Echo 550), and the negative control wells and 250nl of 100% DMSO were added to the positive control wells.
  • Echo550 Labelcyte, model: Echo 550
  • a kinase solution of RET (Carna, Cat. No. 08-159, Lot No. 13CBS-0134E) was prepared at 2.5 times the final concentration (1 nM final concentration) in 1 ⁇ Kinase buffer. Add 10 ⁇ L of 2.5 times final concentration of kinase solution to compound wells and positive control wells respectively; add 10 ⁇ L of 1 ⁇ Kinase buffer to negative control wells.
  • the reaction plate was centrifuged at 1000 rpm (Eppendorf, model: 5430) for 30 seconds, the reaction plate was shaken and mixed, and incubated at room temperature for 10 minutes.
  • the 384-well plate was centrifuged at 1000 rpm for 30 seconds, shaken and mixed, and incubated at room temperature for 60 minutes.
  • Conversion %_sample is the conversion rate reading of the sample
  • Conversion %_min is the mean value of the negative control wells, representing the conversion rate reading of the wells without enzymatic activity
  • Conversion %_max is the average value of the positive control wells, representing no Conversion readings for wells inhibited by compounds.
  • RET wild type
  • IC50 nM 1 9.4 2 1.3 3-1 3.5 4-1 3.9 5-1 4.9 6 56.7 7-1 3.4 8 10.8 9 9.5 10 1.7 11 3.6 12 74.9 13 0.5 14 9.1 15 14.6 16 2.6 17 1.8 18 1.5 19-1 0.7 20 22.8 21-1 1.6 twenty two 0.5 23-1 5.9 twenty four 16.8 25 3.5 26 11.2 27 0.6 28-1 1.8 29 0.7 30 1.0
  • the kit uses luciferase as the detection substance. Luciferase needs the participation of ATP in the process of luminescence.
  • CellTiter-Glo TM reagent is added to the cell culture medium to measure the luminescence value. The light signal is proportional to the amount of ATP in the system. ATP is positively correlated with the number of viable cells, thereby determining the proliferative activity of cells.
  • DMSO dilute it 100 times with PBS to prepare a solution with a final concentration of 10 times, the highest concentration is 100 ⁇ M, and add 10 ⁇ L of the test compound to each well of a 96-well plate seeded with cells.
  • the solution ie, diluted 10-fold, reached a final concentration of 10 ⁇ M.
  • the final concentration of the compound to be tested starts from 10 ⁇ M, and the serial dilution is 3-fold, with a total of 9 concentrations, each with 3 replicate wells.
  • the 96-well plate to which the test compound and cells had been added was incubated at 37° C., 5% CO 2 , and 95% humidity for an additional 72 hours, after which CellTiter-Glo analysis was performed.
  • Luminescent Cell Viability Assay Promega, G7572
  • equilibrate the cell plate to room temperature for 30 minutes.
  • An equal volume of CellTiter-Glo solution was added to each well and the cells were lysed by shaking on an orbital shaker for 5 minutes.
  • the cell plate was placed at room temperature for 20 minutes to stabilize the luminescence signal, and the luminescence value was read with a SpectraMax multi-label microplate reader (MD, M3).
  • Liver microsomes (protein concentration of 0.56 mg/mL) were added to 1 ⁇ M compound working solution (diluted to 100 ⁇ M from 10 mM DMSO stock solution with 100% acetonitrile, organic phase content: 99% ACN, 1% DMSO), and pre-incubated at 37°C for 10 min Afterwards, a cofactor (NADPH) (prepared from magnesium chloride solution) was added to initiate the reaction. After incubating for an appropriate time (eg 5, 10, 20, 30 and 60 minutes), take a sample and add an appropriate stop solution (ice acetonitrile containing 200ng/mL tolbutamide and 200ng/mL labetalol (ie acetonitrile at 4°C) ) to stop the reaction.
  • NADPH cofactor
  • the PK determination method of each compound is as follows: 6 CD-1 mice (sourced from Shanghai Lingchang Biotechnology Co., Ltd.) were divided into two groups, 3 mice in each group. One group was administered intravenously (IV) at a dose of 1 mg/kg in a vehicle of 5% DMSO/95% (20% Captisol); one group was administered by oral (Po) gavage at a dose of 5 mg/kg in a vehicle 1% HPMC. Blood was collected from saphenous vein of lower leg in each group at 0, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration. About 40 ⁇ L of blood was collected into anticoagulant tubes containing EDTA-K2.
  • the compound concentration in plasma was determined by UPLC-MS/MS method, and the pharmacokinetic parameters of the obtained data were calculated by Phoenix WinNolin 6.4 pharmacokinetic software.

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Abstract

L'invention concerne un composé de pyrazolopyridine ou un sel de celui-ci, un procédé de préparation correspondant et une utilisation associée, en particulier, un composé de formule (I), dans laquelle R 1, R 2, R 3, R 4, R 5, le cycle A et le cycle B, m et n sont tels que définis dans la description, ou un stéréoisomère, un tautomère, un dérivé isotopique stable, un sel pharmaceutiquement acceptable, ou un solvate de celui-ci, et son procédé de préparation, une composition pharmaceutique le contenant, et l'utilisation du composé dans la préparation d'un médicament pour le traitement ou la prévention de maladies associées à RET.
PCT/CN2021/118001 2020-09-14 2021-09-13 Composé de pyrazolopyridine ou sel de celui-ci, procédé de préparation correspondant et utilisation associée WO2022053046A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108349969A (zh) * 2015-07-16 2018-07-31 阵列生物制药公司 作为RET激酶抑制剂的取代的吡唑并[1,5-a]吡啶化合物
WO2020048596A1 (fr) * 2018-09-06 2020-03-12 F. Hoffmann-La Roche Ag Nouveaux composés de pyrazolopyridine pour le traitement d'une maladie auto-immune
WO2020094084A1 (fr) * 2018-11-07 2020-05-14 南京明德新药研发有限公司 Dérivé tricyclique utilisé comme inhibiteur de ret
CN111285882A (zh) * 2018-12-07 2020-06-16 四川科伦博泰生物医药股份有限公司 稠环化合物、包含其的药物组合物及其制备方法和用途
CN111635400A (zh) * 2019-03-02 2020-09-08 察略盛医药科技(上海)有限公司 吡唑并[1,5-a]吡啶类衍生物、及其制备方法和用途
WO2020233641A1 (fr) * 2019-05-20 2020-11-26 浙江同源康医药股份有限公司 Composé utilisé comme inhibiteur de kinase ret et son utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108349969A (zh) * 2015-07-16 2018-07-31 阵列生物制药公司 作为RET激酶抑制剂的取代的吡唑并[1,5-a]吡啶化合物
WO2020048596A1 (fr) * 2018-09-06 2020-03-12 F. Hoffmann-La Roche Ag Nouveaux composés de pyrazolopyridine pour le traitement d'une maladie auto-immune
WO2020094084A1 (fr) * 2018-11-07 2020-05-14 南京明德新药研发有限公司 Dérivé tricyclique utilisé comme inhibiteur de ret
CN111285882A (zh) * 2018-12-07 2020-06-16 四川科伦博泰生物医药股份有限公司 稠环化合物、包含其的药物组合物及其制备方法和用途
CN111635400A (zh) * 2019-03-02 2020-09-08 察略盛医药科技(上海)有限公司 吡唑并[1,5-a]吡啶类衍生物、及其制备方法和用途
WO2020233641A1 (fr) * 2019-05-20 2020-11-26 浙江同源康医药股份有限公司 Composé utilisé comme inhibiteur de kinase ret et son utilisation

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