WO2022053046A1 - Pyrazolopyridine compound or salt thereof, and preparation method therefor and use thereof - Google Patents

Pyrazolopyridine compound or salt thereof, and preparation method therefor and use thereof 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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French (fr)
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
    • 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.

Abstract

A pyrazolopyridine compound or a salt thereof, a preparation method therefor and the use thereof, in particular, a compound of formula (I), wherein R 1, R 2, R 3, R 4, R 5, ring A and B, m and n are as defined in the description, or a stereoisomer, a tautomer, a stable isotopic derivative, a pharmaceutically acceptable salt, or a solvate thereof, and a preparation method therefor, a pharmaceutical composition containing same, and the use of the compound in the preparation of a drug for treating or preventing RET-related diseases.

Description

吡唑并吡啶类化合物或其盐及其制备方法和用途Pyrazolopyridine compound or its salt and its preparation method and use 技术领域technical field
本发明属于化学医药技术领域，具体涉及具有RET抑制活性的吡唑并吡啶类化合物及其制备方法和含有所述化合物的药物组合物，还涉及该吡唑并吡啶类化合物在制备预防或治疗与RET有关的疾病的药物中的用途。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.
背景技术Background technique
RET(REarranged during Transfection)蛋白是一种受体酪氨酸激酶(RTK)，同时也是一种跨膜的糖蛋白，由位于10号染色体上的原癌基因RET表达，在胚胎阶段的肾脏和肠神经系统的发育中起着重要作用，另外在多种组织内也很关键，如神经元、神经内分泌、造血组织和男性生殖细胞等。和其他的受体酪氨酸激酶不同，RET并不是直接结合到配体分子：如神经导向素(artemin)、胶质细胞源性神经营养因子(GDNF)、神经生长因子(NGF)，这些都是属于GNDF家族配体(GFLs)。这些配体通常结合到GDNF家族受体α(GFRα)，形成的GFLs-GFRα复合物介导了RET蛋白的自二聚化，引起胞内结构域上酪氨酸的反式自磷酸化反应，招募相关接头蛋白，激活细胞增殖等信号传导的级联反应，从而导致细胞的过度增殖和癌症的产生，相关的信号通路包括MAPK、PI3K、JAK-STAT、PKA、PKC等等。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). These ligands usually bind to the GDNF family receptor alpha (GFRα), and the GFLs-GFRα complex formed mediates the autodimerization of the RET protein, resulting in trans-autophosphorylation of tyrosine on the intracellular domain, Recruit related adaptor proteins and activate the cascade of signaling such as cell proliferation, resulting in excessive cell proliferation and cancer. The related signaling pathways include MAPK, PI3K, JAK-STAT, PKA, PKC and so on.
RET的致癌激活机制主要有两个：一是染色体的重排产生的新的融合蛋白，通常是RET的激酶结构域和包含自二聚化结构域的蛋白融合；二是RET突变直接或间接地激活了RET激酶活性。这些体细胞或生殖细胞水平地改变涉及多种癌症的发病机制。10％-20％的乳头状甲状腺癌(PTC)患者存在RET染色体重排；而在髓样性甲状腺髓样癌(MTC)中发现有60％存在RET点突变；在所有的非小细胞肺癌(NSCLC)患者中，大概有1-2％的具有RET融合蛋白，其中KIF5B最为常见。There are two main mechanisms of 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. These alterations at the somatic or germ cell level are involved in the pathogenesis of various cancers. 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.
目前主要采取的具有RET抑制活性的多重激酶抑制剂来治疗RET融合的癌症病人。但是在此条件下，由于脱靶效应及药物毒性，药物的剂量不足以达到足够抑制RET的表达水平。此外，在治疗癌症的过程中，癌细胞会通过变异产生耐药性。而一旦耐药性产生，病人的治疗选择将会变得非常有限。因此选择性地抑制异常的RET表达，RET融合及突变的药物非常急需。Currently, multiple kinase inhibitors with RET inhibitory activity are mainly used to treat RET fusion cancer patients. However, under this condition, due to off-target effects and drug toxicity, the dose of the drug was insufficient to achieve a sufficient level of inhibiting RET expression. In addition, during the treatment of cancer, cancer cells develop drug resistance through mutation. Once drug resistance develops, the patient's treatment options become very limited. Therefore, drugs that selectively inhibit abnormal RET expression, RET fusions and mutations are urgently needed.
目前上市或临床在研的选择性地针对RET靶点设计的药物，在非小细胞肺癌和甲状腺癌的临床实验上表现出了好的疗效及安全性。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.
目前，仍然非常需要发现和开发新的RET抑制剂化合物以用于预防和/或治疗与RET有关的疾病。这样的化合物除了应具有令人满意的RET抑制活性外，还期望基于结构的优化而具备良好的、甚至改进的成药性，以便为相关疾病患者提供更多用药选择的同时还能提供更好的治疗效果。Currently, there is still a great need to discover and develop new RET inhibitor compounds for the prevention and/or treatment of RET-related diseases. In addition to satisfactory RET inhibitory activity, such compounds are also expected to have good or even improved druggability based on structure optimization, so as to provide more drug options for patients with related diseases and better drug resistance. treatment effect.
发明简述Brief description of the invention
本发明涉及可用于预防或治疗与RET有关的疾病的化合物。特别地，已经鉴定，本发明的化合物显示令人满意的RET抑制活性，而且在体内和/或体外药代动力学实验中显示良好的性能，预示着改进的成药性和改进的生物利用度。因此，本发明化合物不仅可实现用于预防或治疗与RET有关的疾病的目的，而且所制备的药物有望具有改善的吸收、在同等剂量下疗效提高、或以更低的剂量提供相同疗效和/或降低可能的副作用。由此，本发明还提供了本发明化合物在制备用于预防或治疗与RET有关的疾病的药物中的用途、包含所述化合物的药物组合物和通过施用所述化合物预防和/或治疗与RET有关的疾病的方法。The present invention relates to compounds useful in the prevention or treatment of RET-related diseases. In particular, it has been identified that 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. Thus, 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.
因此，在本发明的一方面，提供式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物：Accordingly, in one aspect of the present invention there is provided a compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof:
Figure PCTCN2021118001-appb-000001
Figure PCTCN2021118001-appb-000001
其中：in:
R 1选自氢、卤素、氰基、硝基和任选被卤素或氰基取代的C 1-C 6烷基； R 1 is selected from hydrogen, halogen, cyano, nitro and C 1 -C 6 alkyl optionally substituted with halogen or cyano;
R 2选自氢、C 6-C 10芳基、5-9元杂芳基、C 3-C 8环烷基、C 3-C 8环烯基、3-8元杂环烷基、3-8元杂环烯基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基，其中所述芳基、杂芳基、环烷基、环烯基、杂环烷基、杂环烯基、烷基、烷氧基和烷硫基任选被独立地选自以下的1、2或3个基团取代：卤素、氰基、硝基、羟基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基； 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选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基； 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选自氢、C 6-C 10芳基、5-9元杂芳基、C 3-C 8环烷基、C 3-C 8环烯基、3-8元杂环烷基、3-8元杂环烯基、3-8元杂环烷基氧基、3-8元杂环烯基氧基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基，其中所述芳基、杂芳基、环烷基、环烯基、杂环烷基、杂环烯基、烷基、烷氧基和烷硫基任选被独立地选自以下的1、2或3个基团取代：卤素、氰基、硝基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基； 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 alkylthio;
R 5选自卤素、氰基、硝基、羟基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基； 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;
环A选自C 6-C 10亚芳基、5-9元亚杂芳基、C 3-C 8亚环烷基、C 3-C 8亚环烯基、3-8元亚杂环烷基和3-8元亚杂环烯基环； 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;
环B选自C 6-C 10芳基、5-9元杂芳基、C 3-C 8环烷基、C 3-C 8环烯基、3-8元杂环烷基和3-8元杂环烯基环； 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;
m是0、1、2或3；且m is 0, 1, 2, or 3; and
n是0、1、2或3。n is 0, 1, 2 or 3.
在本发明的另一方面，提供了具有RET抑制活性、用作药物、尤其是用作RET抑制剂的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物。In another aspect of the present invention there are provided compounds of formula (I), stereoisomers, tautomers, stable isotopic variants thereof having RET inhibitory activity for use as medicaments, especially as RET inhibitors , a pharmaceutically acceptable salt or solvate.
在本发明的另一方面，提供了用于治疗或预防、尤其是用于治疗与RET有关的疾病的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物。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.
在本发明的另一方面，提供了包含本发明化合物和药学上可接受的赋形剂的药物组合物。在一个具体的方面，提供了所述本发明的药物组合物，用于预防或治疗与RET有关的疾病。在一个具体的方面，药物组合物可以另外包含适合与本发明化合物组合使用的另外的治疗活性成分。In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient. In a specific aspect, the pharmaceutical composition of the present invention is provided for preventing or treating RET-related diseases. In a specific aspect, the pharmaceutical composition may additionally contain additional therapeutically active ingredients suitable for use in combination with the compounds of the present invention.
在本发明的另一方面，提供了包含本发明化合物和另外的活性剂的药物组合(或药物组合产品)。In another aspect of the present invention, there is provided a pharmaceutical combination (or pharmaceutical combination) comprising a compound of the present invention and an additional active agent.
在本发明的另一方面，提供了用于在个体，例如哺乳动物、特别是人中预防或治疗与RET有关的疾病的方法，该方法包括施用有效量的本文所述的本发明化合物或包含其的药物组合物。In another aspect of the invention there is provided a method for preventing or treating a disease associated with RET in an individual, such as a mammal, particularly a human, the method comprising administering an effective amount of a compound of the invention described herein or comprising its pharmaceutical composition.
在本发明的另一方面，提供了上述本发明的化合物或药物组合物用于预防或治疗与RET有关的疾病的用途。In another aspect of the present invention, there is provided the use of the above-mentioned compounds or pharmaceutical compositions of the present invention for preventing or treating RET-related diseases.
在本发明的另一方面，提供了上述本发明的化合物或药物组合物在制备用于预防或治疗与RET有关的疾病的药物中的用途。In another aspect of the present invention, there is provided the use of the above-mentioned compound or pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating RET-related diseases.
优选地，本发明所述的与RET有关的疾病选自肿瘤或肠易激综合症(IBS)，肿瘤包括但不限于非小细胞肺癌、小细胞肺癌、乳头状甲状腺癌、甲状腺髓质癌、分化型甲状腺癌、复发性甲状腺癌、顽固性分化型甲状腺癌、多内分泌肿瘤2A或2B、嗜铬细胞瘤、甲状旁腺增生、乳腺癌、结肠直肠癌、乳头状肾细胞癌、胃肠黏膜神经节瘤、胰管腺癌、多发性内分泌瘤、睾丸癌、慢性单核细胞性白血病、唾腺癌、卵巢癌、子宫颈癌等。Preferably, 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.
在另外的方面，提供了用于合成本发明化合物的方法，其中代表性的合成方案和途径在下文描述。In additional aspects, methods for synthesizing the compounds of the present invention are provided, of which representative synthetic schemes and routes are described below.
通过阅读随后的详细描述，本发明的其它目的和优点对于本领域技术人员将变得显而易见。Other objects and advantages of the present invention will become apparent to those skilled in the art upon reading the ensuing detailed description.
对于上述用作药物的本发明化合物、本发明的预防或治疗方法、药物组合物、药物组合或用途而言，优选本文所定义的式(I)化合物的各个优选实施方式，更优选文中所列的具体化合物。For the above-mentioned compounds of the present invention for use as medicaments, prophylactic or therapeutic methods of the present invention, pharmaceutical compositions, pharmaceutical combinations or uses, the respective preferred embodiments of the compounds of formula (I) as defined herein are preferred, more preferably those listed herein specific compounds.
定义definition
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including those variations or substitutions of equivalent techniques that would be apparent to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
本文所用的术语“卤代”或“卤素”意指氟(F)、氯(Cl)、溴(Br)及碘(I)。优选的卤代为氟或氯。本文所用的术语“被卤素取代的”基团旨在包括单卤代或多卤代基团，其中一个或多个(例如2、3、4、5或6个)相同或不同的卤素取代基团中的一个或多个(例如2、3、4、5或6个)氢。The term "halo" or "halogen" as used herein means fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). Preferred halo are fluoro or chloro. The term "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.
本文所用的术语“氰基”意指基团-CN。The term "cyano" as used herein means the group -CN.
本文所用的术语“硝基”意指基团-NO 2。 The term "nitro" as used herein means the group -NO2 .
如本文中所使用的术语“羟基”指-OH。The term "hydroxyl" as used herein refers to -OH.
如本文中所使用的术语“烷基”指由碳原子和氢原子组成的直链或支链的饱和烃基团。具体地，烷基具有1-10个，例如1至6个、1至5个、1至4个、1至3个或1至2个碳原子。例如，如本文中所使用，术语“C 1-C 6烷基”指具有1至6个碳原子的直链或支链的饱和烃基团，其实例例如甲基、乙基、丙基(包括正丙基和异丙基)、丁基(包括正丁基、异丁基、仲丁基或叔丁基)、戊基(包括正戊基、异戊基、新戊基)、正己基、2-甲基戊基等。特定的烷基具有1至3个碳原子。 The term "alkyl" as used herein 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. For example, as used herein, the term "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.
本文所用的术语“烷氧基”意指基团-O-烷基，其中烷基具有本文所述的含义。具体地，该术语包括基团-O-C 1-6烷基，更具体的-O-C 1-3烷基。烷氧基的代表性实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基、异丙氧基)、丁氧基(包括正丁氧基、异丁氧基、叔丁氧基)、戊氧基(包括正戊氧基、异戊氧基、新戊氧基)、己氧基(包括正己氧基、异己氧基)等。特定的烷氧基具有1至3个碳原子。 The term "alkoxy," as used herein, 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.
如本文中所使用的术语“烷硫基”指-S-烷基，其中所述烷基如以上对于“烷基”所定义。具体地，该术语包括基团-S-C 1-6烷基，更具体的-S-C 1-3烷基。烷硫基的代表性实例包括但不限于甲硫基、乙硫基、丙硫基(包括正丙硫基、异丙硫基)、丁硫基(包括正丁硫基、异丁硫基、叔丁硫基)、戊硫基(包括正戊硫基、异戊硫基、新戊硫基)、己硫基(包括正己硫基、异己硫基)等。特定的烷硫基具有1至3个碳原子。如本文中所使用的术语“卤素取代的C 1-C 6烷基”指上文所述的C 1-C 6烷基，其中一个或多个(例如1、2、3、4或5个)氢原子被卤素代替。本领域 技术人员应当理解，当卤素取代基多于一个时，卤素可以相同也可以不同，并且可以位于相同或不同的C原子上。“卤素取代的C 1-C 6烷基”的实例有例如-CH 2F、-CHF 2、-CF 3、-CCl 3、-C 2F 5、-C 2Cl 5、-CH 2CF 3、-CH 2Cl、-CH 2CH 2CF 3或-CF(CF 3) 2等。 The term "alkylthio" as used herein 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. Representative examples of 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. The term "halogen-substituted C1 - C6 alkyl" as used herein 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. Examples of "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.
如本文中所使用的术语“卤素取代的C 1-C 6烷氧基”指上文所述的C 1-C 6烷氧基，其中一个或多个(例如1、2、3、4或5个)氢原子被卤素代替。本领域技术人员应当理解，当卤素取代基多于一个时，卤素可以相同也可以不同，并且可以位于相同或不同的C原子上。“卤素取代的C 1-C 6烷氧基”的实例有例如-OCH 2F、-OCHF 2、-OCF 3、-OCCl 3、-OC 2F 5、-OC 2Cl 5、-OCH 2CF 3、-OCH 2Cl或-OCH 2CH 2CF 3等。 The term "halogen-substituted C1 - C6alkoxy" as used herein 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. Examples of "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.
如本文中所使用的术语“环烷基”指具有指定环原子数的单环、稠合多环、桥接多环或螺环非芳族饱和单价烃环结构。环烷基可具有3至12个碳原子(即C 3-C 12环烷基)，例如3至10个，3至8个，3至7个，3至6个，5至6个碳原子。适合的环烷基的实例包括但不限于单环结构，如环丙基、环丁基、环戊基、环己基、环庚基或环辛基；或多环(例如双环)结构，包括螺环、稠合或桥连系统，诸如双环[1.1.1]戊基、双环[2.2.1]庚基、螺[3.4]辛烷基、双环[3.1.1]己烷基、双环[3.1.1]庚基或双环[3.2.1]辛基等)。 The term "cycloalkyl" as used herein 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 . Examples of 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.).
如本文中所使用的术语“亚环烷基”指如上所定义的环烷基，但其为二价基团，该两个价键不在同一环原子上。亚环烷基可具有3至12个碳原子(即C 3-C 12亚环烷基)，例如3至10个，3至8个，3至7个，3至6个，5至6个碳原子。适合的亚环烷基的实例包括但不限于单环结构，如亚环丙基、亚环丁基、亚环戊基(例如环戊-1,2-二基、环戊-1,3-二基)、亚环己基(例如环己-1,2-二基、环己-1,3-二基、环己-1,4-二基)、亚环庚基或亚环辛基；或多环(例如双环)结构，包括螺环、稠合或桥连系统，诸如双环[1.1.1]亚戊基、双环[2.2.1]亚庚基、螺[3.4]亚辛烷基、双环[3.1.1]亚己烷基、双环[3.1.1]亚庚基或双环[3.2.1]亚辛基等)。 The term "cycloalkylene" as used herein 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. Examples of 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. cyclohexyl-1,2-diyl, cyclohex-1,3-diyl, cyclohex-1,4-diyl), cycloheptylene or cyclooctylene; or polycyclic (eg bicyclic) structures including spiro, fused or bridged systems such as bicyclo[1.1.1]pentylene, bicyclo[2.2.1]heptylene, spiro[3.4]octylene, Bicyclo[3.1.1]hexylene, bicyclo[3.1.1]heptylene, or bicyclo[3.2.1]octylene, etc.).
本文所用的术语“环烯基”意指具有指定环原子数的单环、稠合多环、桥接多环或螺环非芳族不饱和烃环结构，包含至少一个(例如1、2、或3个)碳碳双键。环烯基可具有3至12个碳原子(即C 3-C 12环烯基)，例如3至10个，3至8个，3至7个，3至6个，5至6个碳原子。适合的环烯基的实例包括但不限于单环结构，如环丙烯基、环丁烯基、环戊烯基、环戊二烯基、环己烯基、环己二烯基、环庚烯基、环庚二烯基、环庚三烯基或环辛烯基。 The term "cycloalkenyl," as used herein, 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 . Examples of suitable cycloalkenyl groups include, but are not limited to, monocyclic structures such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptene cycloheptadienyl, cycloheptatrienyl, or cyclooctenyl.
如本文中所使用的术语“亚环烯基”指如上所定义的环烯基，但其为二价基团，该两个价键不在同一环原子上。亚环烯基可具有3至12个碳原子(即C 3-C 12亚环烯基)，例如3至10个，3至8个，3至7个，3至6个，5至6个碳原子。适合的亚环烯基的实例包括但不限于单环结构，如亚环丙烯基、亚环丁烯基、亚环戊烯基、亚环戊二烯基、亚环己烯基、亚环己二烯基、亚环庚烯基、亚环庚二烯基、亚环庚三烯基或亚环辛烯基。 The term "cycloalkenylene" as used herein 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. Examples of 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.
本文所用的术语“杂环烷基”意指包括一或多个(例如1、2、3或4个)独立地选自O、N及S的杂原子及指定环原子数的单环、稠合多环、螺环或桥接多环非芳族饱和环结构，或其N-氧化物，或其S-氧化物或S-二氧化物。杂环烷基可具有3至12个环成员(可称为3-12元杂环烷 基)，例如3至10个环成员，3至8个环成员，3至7个环成员，4至7个环成员，5至6个环成员。杂环烷基通常含有至多4个(例如1个、2个、3个或4个)杂原子。适合的杂环烷基的实例包括但不限于氮杂环丁烷基、氧杂环丁烷基、硫杂环丁基、吡咯烷基(例如1-吡咯烷基、2-吡咯烷基及3-吡咯烷基)、四氢呋喃基(例如1-四氢呋喃基、2-四氢呋喃基及3-四氢呋喃基)、四氢噻吩基(例如1-四氢噻吩基、2-四氢噻吩基及3-四氢噻吩基)、哌啶基(例如1-哌啶基、2-哌啶基、3-哌啶基及4-哌啶基)、四氢吡喃基(例如4-四氢吡喃基)、四氢噻喃基(例如4-四氢噻喃基)、吗啉基(例如吗啉代)、硫吗啉基、二噁烷基、哌嗪基或氮杂环庚烷基、二氮杂环庚烷基例如1,4-二氮杂环庚基、3,6-二氮杂-双环[3.1.1]庚基或3-氮杂-双环[3.2.1]辛基。The term "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 A polycyclic, spirocyclic or bridged polycyclic non-aromatic saturated ring structure, or its N-oxide, or its S-oxide or S-dioxide. 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. Examples of 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-diaza-bicyclo[3.1.1]heptyl or 3-aza-bicyclo[3.2.1]octyl.
本文所用的术语“亚杂环烷基”意指如上所定义的杂环烷基，但其为二价基团，该两个价键不在同一环原子上。亚杂环烷基可具有3至12个环成员(可称为3-12元亚杂环烷基)，例如3至10个环成员，3至8个环成员，3至7个环成员，4至7个环成员，5至6个环成员。亚杂环烷基通常含有至多4个(例如1个、2个、3个或4个)杂原子。适合的亚杂环烷基的实例包括但不限于氮杂亚环丁烷基、氧杂亚环丁烷基、硫杂亚环丁基、亚吡咯烷基(例如吡咯烷-1,2-二基、吡咯烷-1,3-二基、吡咯烷-2,3-二基)、亚四氢呋喃基(例如四氢呋喃-2,4-二基、四氢呋喃-2,3-二基及四氢呋喃-2,5-二基)、亚哌啶基(例如哌啶-1,2-二基、哌啶-1,3-二基、哌啶-1,4-二基、哌啶-2,4-二基)、亚四氢噻吩基、四氢吡喃基、四氢噻喃基、亚吗啉基、亚硫吗啉基、亚二噁烷基、亚哌嗪基或氮杂亚环庚烷基、二氮杂亚环庚烷基例如1,4-二氮杂亚环庚基、3,6-二氮杂-双环[3.1.1]亚庚基或3-氮杂-双环[3.2.1]亚辛基，优选The term "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. Examples of suitable heterocycloalkylenes 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. piperidine-1,2-diyl, piperidine-1,3-diyl, piperidine-1,4-diyl, piperidine-2,4-diyl group), tetrahydrothienylene, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinylene, thiomorpholinyl, dioxylene, piperazinylene, or azacycloheptylene , diazacycloheptylene such as 1,4-diazacycloheptylene, 3,6-diaza-bicyclo[3.1.1]heptylene or 3-aza-bicyclo[3.2.1 ] octylidene, preferably
Figure PCTCN2021118001-appb-000002
Figure PCTCN2021118001-appb-000002
本文所用的术语“杂环烯基”意指包含至少一个(例如1、2或3个)双键的本文所定义的“杂环烷基”。适合的杂环烯基的实例包括但不限于：The term "heterocycloalkenyl" as used herein means "heterocycloalkyl" as defined herein containing at least one (eg, 1, 2 or 3) double bond. Examples of suitable heterocycloalkenyl groups include, but are not limited to:
Figure PCTCN2021118001-appb-000003
Figure PCTCN2021118001-appb-000003
其中各W选自CH 2、NH、O及S；各Y选自NH、O、C(＝O)、SO 2及S；且各Z选自N及CH，条件是各个环中至少包含一个选自N、O或S的原子；例如吡咯啉基(例如1-吡咯啉基、2-吡咯烷基、3-吡咯啉基、4-吡咯啉基或5-吡咯啉基)、二氢呋喃基(例如1-二氢呋喃基、2-二氢呋喃基、 3-二氢呋喃基、4-二氢呋喃基或5-二氢呋喃基)、二氢噻吩基(例如1-二氢噻吩基、2-二氢噻吩基、3-二氢噻吩基或4-二氢噻吩基)、四氢吡啶基(例如1-、2-、3-、4-、5-或6-四氢吡啶基)、四氢吡喃基(例如4-四氢吡喃基)或四氢噻喃基(例如4-四氢噻喃基)。 wherein each W is selected from CH2 , NH, O, and S; each Y is selected from NH, O, C(=O), SO2, and S; and each Z is selected from N and CH , provided that each ring contains at least one Atom selected from N, O or S; for example pyrrolinyl (eg 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolinyl, 4-pyrrolinyl or 5-pyrrolinyl), dihydrofuran radicals (such as 1-dihydrofuranyl, 2-dihydrofuranyl, 3-dihydrofuranyl, 4-dihydrofuranyl or 5-dihydrofuranyl), dihydrothienyl (such as 1-dihydrothiophene) base, 2-dihydrothienyl, 3-dihydrothienyl or 4-dihydrothienyl), tetrahydropyridyl (e.g. 1-, 2-, 3-, 4-, 5- or 6-tetrahydropyridine group), tetrahydropyranyl (eg 4-tetrahydropyranyl) or tetrahydrothiopyranyl (eg 4-tetrahydrothiopyranyl).
本文所用的术语“亚杂环烯基”意指如上所定义的杂环烯基，但其为二价基团，该两个价键不在同一环原子上。适合的亚杂环烯基的实例包括但不限于：As used herein, the term "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. Examples of suitable heterocycloalkenylene groups include, but are not limited to:
Figure PCTCN2021118001-appb-000004
Figure PCTCN2021118001-appb-000004
其中各W选自CH 2、NH、O及S；各Y选自NH、O、C(＝O)、SO 2及S；且各Z选自N及CH，条件是各个环中至少包含一个选自N、O或S的原子；例如亚吡咯啉基、亚二氢呋喃基、亚二氢噻吩基、亚四氢吡啶基、亚四氢吡喃基或亚四氢噻喃基，优选 wherein each W is selected from CH2 , NH, O, and S; each Y is selected from NH, O, C(=O), SO2, and S; and each Z is selected from N and CH , provided that each ring contains at least one Atoms selected from N, O or S; for example pyrrolinylene, dihydrofuranylene, dihydrothienylene, tetrahydropyridylene, tetrahydropyranylene or tetrahydrothiopyranylene, preferably
Figure PCTCN2021118001-appb-000005
更优选
Figure PCTCN2021118001-appb-000006
Figure PCTCN2021118001-appb-000005
more preferred
Figure PCTCN2021118001-appb-000006
本文所用的术语“芳基”意指通过自芳族环系统中的单个碳原子移除一个氢原子而衍生的单价芳族烃基。具体地，芳基系指具有指定环原子数的单环或稠合多环芳族环结构。具体地，该术语包括包含6至14个、例如6至10个、优选6个环成员的基团。特定的芳基包括苯基及萘基，最具体的芳基为苯基。The term "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.
本文所用的术语“亚芳基”意指如上所定义的芳基，但其为二价基团，该两个价键不在同一环原子上。特定的亚芳基包括亚苯基，例如苯-1,2-二基、苯-1,3-二基或苯-1,4-二基。The term "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.
本文所用的术语“杂芳基”意指包括一或多个(例如1、2、3或4个)独立地选自O、N及S的杂原子及指定环原子数的单环或稠合多环芳族环结构，或其N-氧化物，或其S-氧化物或S-二氧化物。具体地，该芳族环结构可具有5至9个环成员。杂芳基可为例如5-6元单环、或由稠合的两个5元环或稠合的5元环和4元环形成的稠合双环结构。杂芳基环通常将含有至多4个杂原子、更通常至多3个杂原子、更通常至多2个、例如单个独立地选自O、N及S的杂原子，其中N和S可以是氧化状态如N氧化物、S＝O或S(O) 2。在一个实施方案中，杂芳基环含有至少一个环氮原子、至少一个环硫原子或至少一个环氧原子。例如，杂芳基可以是包含1或2个独立地选自N、O或S的杂原子的5-6元杂芳基。适合的5元单环杂芳基的实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、呋咱基、噁唑基、噁二唑基、噁三唑基、异噁唑基、噻唑基、异噻唑基、吡唑基、三唑基及四唑基；适合的6元单环杂芳基的实例包括但不限于吡啶基、吡嗪基、哒嗪基、嘧啶基及三嗪基。 The term "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 polycyclic aromatic ring structure, or its N-oxide, or its S-oxide or S-dioxide. Specifically, the aromatic ring structure may have 5 to 9 ring members. 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. Heteroaryl rings will typically contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2, such as a single heteroatom independently selected from O, N and S, where N and S may be in an oxidized state Such as N oxide, S=O or S(O) 2 . In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom, at least one ring sulfur atom, or at least one epoxy atom. For example, a heteroaryl group can be a 5-6 membered heteroaryl group containing 1 or 2 heteroatoms independently selected from N, O, or S. Examples of 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; examples of suitable 6-membered monocyclic heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazine base.
本文所用的术语“亚杂芳基”意指如上所定义的杂芳基，但其为二价基团，该两个价键不在同一环原子上。亚杂芳基可以是包含1或2个独立地选自N、O或S的杂原子的5-6元亚杂芳基。适合的5元单环亚杂芳基的实例包括但不限于亚吡咯基、亚呋喃基、亚噻吩基、亚咪唑基、亚呋咱基、亚噁唑基、亚噁二唑基、亚噁三唑基、亚异噁唑基、亚噻唑基、亚异噻唑基、亚吡唑基、亚三唑基及亚四唑基；适合的6元单环杂芳基的实例包括但不限于亚吡啶基、亚吡嗪基、亚哒嗪基、亚嘧啶基及亚三嗪基；优选The term "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. Examples of 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; examples of suitable 6-membered monocyclic heteroaryl groups include, but are not limited to Pyridinyl, pyrazinylene, pyridazinylene, pyrimidinylene and triazinylene; preferred
Figure PCTCN2021118001-appb-000007
Figure PCTCN2021118001-appb-000007
取代基被描述为“任选取代的”意指基团可以是未取代的或被一个或多个(例如0、1、2、3、4或5或更多个，或其中可衍生的任何范围)对该基团所列的取代基取代，其中所述取代基可以相同或不同。在一个实施方案中，任选取代的基团被1个取代基取代。在另一个实施方案中，任选取代的基团被2个取代基取代。在另一个实施方案中，任选取代的基团被3个取代基取代。在另一个实施方案中，任选取代的基团被4个取代基取代。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. In one embodiment, an optionally substituted group is substituted with 1 substituent. In another embodiment, an optionally substituted group is substituted with 2 substituents. In another embodiment, an optionally substituted group is substituted with 3 substituents. In another embodiment, an optionally substituted group is substituted with 4 substituents.
有机合成领域普通技术人员均理解，稳定的化学可行的杂环，无论芳族还是非芳族，其中最大杂原子数或所含杂原子的类型由环大小、不饱和度及杂原子的价数决定。一般而言，杂环可具有1至4个杂原子，前提是杂环或杂芳环在化学可行及稳定。It will be understood by those of ordinary skill in the art of organic synthesis that stable chemically feasible 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. In general, a heterocycle can have 1 to 4 heteroatoms, provided that the heterocycle or heteroaromatic ring is chemically feasible and stable.
本文所用的术语“本发明的化合物”意欲涵盖如本文所定义的通式(I)的化合物或其任一优选或具体的实施方案(包括式(Ia)和式(Ib)的化合物)、它们的立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，以及前药。类似地，本文中对“中间体”的称谓，无论其本身是否被请求保护，若上下文允许，则均意欲涵盖其游离形式以及上述各衍生形式。The term "compounds of the invention" as used herein is intended to encompass compounds of general formula (I) as defined herein or any preferred or specific embodiments thereof (including compounds of formula (Ia) and (Ib)), their Stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, and prodrugs. Similarly, reference herein to an "intermediate", whether claimed or not in itself, is intended to encompass its free form as well as each of the aforementioned derivative forms, as the context permits.
本文所用的术语“药学可接受的”意指由各个国家的相应机构批准的或可由其批准，或列于用于动物且更具体地人类的一般公认药典中，或当向动物例如人类适量施用时不会产生不利、过敏或其它不良反应的分子实体和组合物。The term "pharmaceutically acceptable" as used herein 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.
本文所用的术语“药学可接受的盐”意指药学上可接受且具有母体化合物所需药理学活性的本发明化合物的盐。具体地，此类盐无毒，可为无机酸加成盐或有机酸加成盐及碱加成盐。具体地，此类盐包括：(1)与无机酸形成的酸加成盐，该无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等；或与有机酸形成的酸加成盐，该有机酸如乙酸、丙酸、己酸、乙醇酸、丙酮酸、乳酸、丙二酸、丁二酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、葡糖庚酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡萄糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸、黏康酸等；或(2)当存在于母体化合物中的酸性质子经金属离子如碱金属离子、碱土金属离子或铝离子置换时、或与有机碱如乙醇胺、二乙醇胺、三乙醇胺、N-甲基葡糖胺等配位 时形成的盐。本领域技术人员将知道制备药用盐的一般原理和技术，例如Berge等，Pharm ScL，66，1-19.(1977)中所述的那些。The term "pharmaceutically acceptable salt" as used herein means a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Specifically, such salts are nontoxic and can be inorganic acid addition salts or organic acid addition salts and base addition salts. Specifically, 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, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) when the acidic proton present in the parent compound is converted to a metal ion such as an alkali metal ion , salts formed when substituted by alkaline earth metal ions or aluminum ions, or when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Those skilled in the art will know general principles and techniques for preparing pharmaceutically acceptable salts, such as those described in Berge et al., Pharm ScL, 66, 1-19. (1977).
本文所用的术语“前药”意指具有可裂解基团且通过溶剂分解或在生理条件下变成在体内具有药学活性的本发明化合物的化合物，包括本发明化合物的衍生物。前药包括本领域熟知的酸衍生物，如通过母体酸与适合醇反应制备的酯，或通过母体酸化合物与取代或未取代的胺反应制备的酰胺，或酸酐或混合酸酐。衍生自本发明化合物侧接的酸基的简单脂族或芳族酯、酰胺及酸酐为尤其适用的前药。特定的此类前药为本发明化合物的C 1-8烷基、C 2-8烯基、任选被取代的C 6-10芳基及(C 6-10芳基)-(C 1-4烷基)酯。 The term "prodrug" as used herein 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.
本发明还包括所有药学上可接受的同位素化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明化合物中的同位素的实例包括(但不限于)氢的同位素(例如2H、3H)；碳的同位素(例如11C、13C及14C)；氯的同位素(例如36Cl)；氟的同位素(例如18F)；碘的同位素(例如123I及125I)；氮的同位素(例如13N及15N)；氧的同位素(例如15O、17O及18O)；磷的同位素(例如32P)；及硫的同位素(例如35S)。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. Examples of 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).
如本文中所使用的术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如1个、2个、3个或4个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以以两种或更多种处于快速平衡的不同结构形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。例如，亚硝基-肟在溶液中可以下列互变异构形式平衡存在：The term "stereoisomer" as used herein 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:
Figure PCTCN2021118001-appb-000008
Figure PCTCN2021118001-appb-000008
需要理解的是，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。It is to be understood that the scope of this application covers all such in any ratio (eg 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% , 99%) isomers or mixtures thereof.
除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。Unless otherwise indicated, the compounds of the present invention are intended to be available as stereoisomers (which include cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotational isomers, conformational isomers, atropisomers and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (eg, racemic mixtures and pairs of diastereomers).
本文所用的术语“溶剂合物”是指包含化学计量的或非化学计量的溶剂的溶剂加成形式，包括例如与水的溶剂合物，例如水合物，或与有机溶剂的溶剂合物，例如甲醇、乙醇或乙腈，即分别作为甲醇化物、乙醇化物或乙腈化物；或为任何多晶型物的形式。应当理解的是，本发明化合物的这类溶剂合物还包括本发明化合物的药学可接受盐的溶剂合物。The term "solvate" as used herein 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.
本文所使用的术语“预防“意指给怀疑患上或易感于如本文所定义的与RET有关的疾病、尤其是炎症或自身免疫疾病的个体个体、例如哺乳动物、例如人施用一种或多种本发明的化合物，使得罹患所定义疾病的风险降低。术语“预防”包含在诊断或确定任何临床和/或病理症状以前使用本发明的化合物。The term "prophylaxis" as used herein 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. The term "prevention" encompasses the use of the compounds of the present invention prior to the diagnosis or determination of any clinical and/or pathological symptoms.
本文所用的术语“治疗”是指给患有所述疾病、或者具有所述疾病的症状的受试者、例如哺乳动物、例如人施用一种或多种本文所述的本发明化合物，用以治愈、缓解、减轻或影响所述疾病或所述疾病的症状。在本发明具体的实施方案中，所述疾病是本文所定义的与RET有关的疾病、尤其是炎症或自身免疫疾病。The term "treating" as used herein 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. In a specific embodiment of the invention, the disease is a RET-related disease as defined herein, especially an inflammatory or autoimmune disease.
本文所用的术语“与RET有关的疾病”意指RET对所述疾病的发生和发展起到促进作用，或抑制RET将降低疾病的发生率、减少或消除疾病病状的疾病。对于本发明而言，“与RET有关的疾病”选自肿瘤或肠易激综合症(IBS)，肿瘤包括但不限于非小细胞肺癌、小细胞肺癌、乳头状甲状腺癌、甲状腺髓质癌、分化型甲状腺癌、复发性甲状腺癌、顽固性分化型甲状腺癌、多内分泌肿瘤2A或2B、嗜铬细胞瘤、甲状旁腺增生、乳腺癌、结肠直肠癌、乳头状肾细胞癌、胃肠黏膜神经节瘤、胰管腺癌、多发性内分泌瘤、睾丸癌、慢性单核细胞性白血病、唾腺癌、卵巢癌、子宫颈癌等。As used herein, the term "disease associated with RET" means a disease in which RET contributes to the occurrence and progression of the disease, or in which inhibition of RET will reduce the incidence, reduce or eliminate disease symptoms. For the purposes of the present invention, "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.
如本文中所使用的术语“癌症”或“肿瘤”是指赘生性细胞生长和增殖，无论是恶性的还是良性的，和所有的癌前期细胞和癌细胞和组织。对本发明的化合物、方法、药物组合物、药物组合及用途而言，所述癌症或肿瘤包括但不限于结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底层细胞癌、腺癌、汗腺癌、皮脂腺癌、肺癌、白血病、膀胱癌、胃癌、子宫颈癌、睾丸癌、皮肤癌、直肠癌、甲状腺癌、肾癌、子宫癌、天疱疮癌、肝癌、听神经瘤、少突神经胶质瘤、脑(脊)膜瘤、成神经细胞瘤、眼癌。The term "cancer" or "tumor" as used herein refers to the growth and proliferation of neoplastic cells, whether malignant or benign, and all precancerous cells and cancer cells and tissues. For the compounds, methods, pharmaceutical compositions, pharmaceutical combinations and uses of the present invention, 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.
本文所使用的术语“治疗有效量“意指当向个体施用以治疗疾病时足以减轻或完全缓解病症的症状或其它有害作用；逆转、完全停止或减缓病症的进展；或降低病症恶化的风险的量，“有效量”可视化合物、疾病及其严重程度及待治疗的个体的年龄、体重等而变化。As used herein, 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.
如本文所使用的术语“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。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.).
本发明所述的“药物组合物”，指包含一种或多种式(I)化合物或者其立体异构体、互变异构体、稳定的同位素衍生物、药学上可接受的盐或溶剂合物和在本领域中通常接受的用于将生物活性化合物输送至有机体(例如人)的载体的组合物。The "pharmaceutical composition" described in the present invention 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.
本文所用的术语“药物组合”是指本发明化合物可与其它活性剂组合用于实现本发明的目的。所述其他活性剂可以是一种或多种另外的本发明化合物，或可以是与本发明化合物相容即不会相互不利影响、或具有互补活性的第二种或另外的(例如第三种)化合物。这类活性 剂以达到预期目的的有效量适宜地组合存在。所述其他活性剂可以与本发明化合物在单一药物组合物中共同施用，或与本发明化合物处于不同的离散单元中分别施用，当分别施用时可以同时或相继进行。所述相继施用在时间上可以是接近或隔远的。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.
本文所用的术语“药学上可接受的赋形剂或载体”是指一种或多种相容性固体或液体填料或凝胶物质，其药理学上无活性，与组合物中的其它成分相容，并且应是对温血动物如人给药可接受的，用作本发明化合物在施用形式中的载体或介质，其实例包括但不限于纤维素及其衍生物(如羧甲基纤维素钠、醋酸纤维素等)、明胶、滑石、固体润滑剂(如硬脂酸镁)、硫酸钙、植物油、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温类)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂等。The term "pharmaceutically acceptable excipient or carrier" as used herein 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.
应理解，当本文描述本发明化合物、包含其的药物组合物、药物组合以及相关的用途和方法时所涉及的剂量，是基于游离形式的重量，而非基于其任何盐、水合物或溶剂化物等，除非说明书中另外定义。It is to be understood that when the compounds of the invention, pharmaceutical compositions comprising them, pharmaceutical combinations, and related uses and methods are described herein, the dosages referred to are by weight in free form and not on any salt, hydrate or solvate thereof etc., unless otherwise defined in the specification.
本发明化合物Compounds of the present invention
本申请通篇使用的术语“发明的化合物”和“本发明的化合物”等，除非另外指出，涵盖本文各个实施方案及其具体或优选实施方式中定义的式(I)化合物、它们的立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，以及前药。所述立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物以及前药如上文定义部分所描述。优选地，本发明化合物为式(I)化合物的游离形式或其药学上可接受的盐或溶剂合物；最优选为式(I)化合物的游离形式或其药学上可接受的盐。As used throughout this application, the terms "compounds of the invention" and "compounds of the invention" and the like, unless otherwise indicated, encompass compounds of formula (I), their stereoisomers as defined in the various embodiments herein and specific or preferred embodiments thereof Conformers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, and prodrugs. The stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates and prodrugs are as described in the definitions section above. Preferably, 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.
本发明的某些化合物可以以多晶型或无定形形式存在，它们也落入本发明的范围内。当为固体结晶形式时，式(I)化合物可以是与另一种化学实体的共晶体形式，并且本说明书包括所有这些共晶体。Certain compounds of the present invention may exist in polymorphic or amorphous forms, which also fall within the scope of the present invention. When in solid crystalline form, 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.
在存在手性中心时，本发明的化合物可以以单独的对映异构体或对映体混合物形式存在。根据一个实施方案，提供了式(I)化合物或其药学上可接受的盐，其是对映体过量(％ee)＞95、＞98％或＞99％的单一对映体。优选地，单一对映异构体以＞99％的对映异构体过量(％ee)存在。When chiral centers are present, the compounds of the present invention may exist as individual enantiomers or as mixtures of enantiomers. According to one embodiment, there is provided 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%. Preferably, a single enantiomer is present in >99% enantiomeric excess (%ee).
具体地，一方面，本发明提供式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物：Specifically, in one aspect, the present invention provides compounds of formula (I), stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof:
Figure PCTCN2021118001-appb-000009
Figure PCTCN2021118001-appb-000009
其中：in:
R 1选自氢、卤素、氰基、硝基和任选被卤素或氰基取代的C 1-C 6烷基； R 1 is selected from hydrogen, halogen, cyano, nitro and C 1 -C 6 alkyl optionally substituted with halogen or cyano;
R 2选自氢、C 6-C 10芳基、5-9元杂芳基、C 3-C 8环烷基、C 3-C 8环烯基、3-8元杂环烷基、3-8元杂环烯基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基，其中所述芳基、杂芳基、环烷基、环烯基、杂环烷基、杂环烯基、烷基、烷氧基和烷硫基任选被独立地选自以下的1、2或3个基团取代：卤素、氰基、硝基、羟基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基； 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选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基； 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选自氢、C 6-C 10芳基、5-9元杂芳基、C 3-C 8环烷基、C 3-C 8环烯基、3-8元杂环烷基、3-8元杂环烯基、3-8元杂环烷基氧基、3-8元杂环烯基氧基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基，其中所述芳基、杂芳基、环烷基、环烯基、杂环烷基、杂环烯基、烷基、烷氧基和烷硫基任选被独立地选自以下的1、2或3个基团取代：卤素、氰基、硝基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基； 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 alkylthio;
R 5选自卤素、氰基、硝基、羟基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基； 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;
环A选自C 6-C 10亚芳基、5-9元亚杂芳基、C 3-C 8亚环烷基、C 3-C 8亚环烯基、3-8元亚杂环烷基和3-8元亚杂环烯基环； 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;
环B选自C 6-C 10芳基、5-9元杂芳基、C 3-C 8环烷基、C 3-C 8环烯基、3-8元杂环烷基和3-8元杂环烯基环； 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;
m是0、1、2或3；且m is 0, 1, 2, or 3; and
n是0、1、2或3。n is 0, 1, 2 or 3.
在一种式(I)化合物的实施方式中，R 1是卤素、氰基或硝基。 In one embodiment of the compound of formula ( I ), R1 is halo, cyano or nitro.
在一种式(I)化合物的实施方式中，R 1是氰基。 In one embodiment of the compound of formula ( I ), R1 is cyano.
在一种式(I)化合物的实施方式中，R 2选自包含1、2或3个独立地选自N、O或S的杂原子的5-6元杂芳基(具体实例包括吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡唑基、吡啶基、吡嗪基、哒嗪基或嘧啶基)、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基，其任选被独立地选自以下的1、2或3个基团取代：卤素、羟基和C 1-C 6烷基； In one embodiment of the compound of formula (I), 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;
在一种式(I)化合物的实施方式中，R 2选自包含1、2或3个独立地选自N、O或S的杂原子的5元杂芳基(具体实例包括吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基或吡唑基)、C 1-C 6烷氧基和C 1-C 6烷硫基，其任选被独立地选自以下的1个基团取代：羟基和C 1-C 6烷基； In one embodiment of the compound of formula (I), 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;
在一种式(I)化合物的实施方式中，R 2选自任选被C 1-C 6烷基取代的包含1、2或3个独立地选自N、O或S的杂原子的5元杂芳基(具体实例包括吡咯基、呋喃基、噻吩基、咪唑基、 噁唑基、异噁唑基、噻唑基、异噻唑基或吡唑基)和任选被羟基取代的C 1-C 6烷氧基； In one embodiment of a compound of formula (I), 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;
在一种式(I)化合物的实施方式中，R 2是甲基取代的吡唑基或羟基取代的C 1-C 6烷氧基； In one embodiment of the compound of formula (I), R 2 is methyl substituted pyrazolyl or hydroxy substituted C 1 -C 6 alkoxy;
在一种式(I)化合物的实施方式中，R 2是
Figure PCTCN2021118001-appb-000010
In one embodiment of the compound of formula (I), R 2 is
Figure PCTCN2021118001-appb-000010
在一种式(I)化合物的实施方式中，R 3选自氢和C 1-C 6烷基。 In one embodiment of the compound of formula (I), R3 is selected from hydrogen and C1 - C6 alkyl.
在一种式(I)化合物的实施方式中，R 3选自氢和C 1-C 3烷基。 In one embodiment of the compound of formula (I), R3 is selected from hydrogen and C1 - C3 alkyl.
在一种式(I)化合物的实施方式中，R 3是氢或甲基。 In one embodiment of a compound of formula (I), R3 is hydrogen or methyl.
在一种式(I)化合物的实施方式中，R 3是氢。 In one embodiment of the compound of formula (I), R3 is hydrogen.
在一种式(I)化合物的实施方式中，与R 3连接的碳是S或R构型的。 In one embodiment of the compound of formula (I), the carbon to which R3 is attached is in the S or R configuration.
在一种式(I)化合物的实施方式中，R 4选自苯基、包含1、2或3个独立地选自N、O或S的杂原子的5-6元杂芳基、5-6元杂环烷基、5-6元杂环烯基、5-6元杂环烷基氧基、5-6元杂环烯基氧基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基，其任选被独立地选自以下的1、2或3个基团取代：卤素、羟基和C 1-C 6烷基； In one embodiment of the compound of formula (I), 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;
优选地，所述5-6元杂芳基选自吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡唑基、吡啶基、吡嗪基、哒嗪基和嘧啶基；Preferably, the 5-6 membered heteroaryl group is selected from pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyridyl oxazinyl, pyridazinyl and pyrimidinyl;
所述5-6杂环烷基选自吡咯烷基、四氢呋喃基、四氢噻吩基、哌啶基、四氢吡喃基、四氢噻喃基)、吗啉基、硫吗啉基、二噁烷基或哌嗪基；The 5-6 heterocycloalkyl group is selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, di oxanyl or piperazinyl;
所述5-6元杂环烯基选自吡咯啉基、二氢呋喃基、二氢噻吩基、四氢吡啶基、四氢吡喃基和四氢噻喃基。The 5-6 membered heterocycloalkenyl is selected from the group consisting of pyrrolinyl, dihydrofuranyl, dihydrothienyl, tetrahydropyridyl, tetrahydropyranyl and tetrahydrothiopyranyl.
在一种式(I)化合物的实施方式中，R 4选自包含1、2或3个独立地选自N、O或S的杂原子的5元杂芳基(具体实例包括吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基或吡唑基)、5-6元杂环烷基、5-6元杂环烷基氧基、C 1-C 6烷基和C 1-C 6烷氧基，其任选被独立地选自以下的1、2或3个基团取代：卤素和C 1-C 6烷基。 In one embodiment of the compound of formula (I), 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.
在一种式(I)化合物的实施方式中，R 4选自吡唑基、吡咯烷基、四氢吡喃基氧基、吗啉基、四氢呋喃基氧基、C 1-C 6烷基和C 1-C 6烷氧基，其任选被卤素取代。 In one embodiment of the compound of formula (I), R4 is selected from the group consisting of pyrazolyl, pyrrolidinyl, tetrahydropyranyloxy, morpholinyl, tetrahydrofuranyloxy, C1 - C6 alkyl and C1 - C6alkoxy optionally substituted with halogen.
在一种式(I)化合物的实施方式中，R 4是
Figure PCTCN2021118001-appb-000011
吡咯烷-1-基、甲氧基、乙氧基、异丙氧基、三氟甲氧基或CF 3。 In one embodiment of the compound of formula (I), R4 is
Figure PCTCN2021118001-appb-000011
Pyrrolidin-1-yl, methoxy, ethoxy, isopropoxy, trifluoromethoxy or CF3 .
在一种式(I)化合物的实施方式中，R 5选自卤素、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基； In one embodiment of the compound of formula (I), R 5 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 alkylthio;
在一种式(I)化合物的实施方式中，R 5选自C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基。 In one embodiment of a compound of formula (I), R 5 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 alkylthio.
在一种式(I)化合物的实施方式中，R 5选自C 1-C 3烷基； In one embodiment of the compound of formula (I), R 5 is selected from C 1 -C 3 alkyl;
在一种式(I)化合物的实施方式中，R 5选自甲基、乙基和丙基，优选为甲基； In one embodiment of the compound of formula (I), R 5 is selected from methyl, ethyl and propyl, preferably methyl;
在一种式(I)化合物的实施方式中，m是0或1。In one embodiment of the compound of formula (I), m is 0 or 1 .
在一种式(I)化合物的实施方式中，n是0或1。In one embodiment of the compound of formula (I), n is 0 or 1 .
在一种式(I)化合物的实施方式中，m是1。In one embodiment of the compound of formula (I), m is 1 .
在一种式(I)化合物的实施方式中，n是0。In one embodiment of the compound of formula (I), n is zero.
在一种式(I)化合物的实施方式中，环A选自亚苯基、包含1、2或3个独立地选自N、O或S的杂原子的5-9元亚杂芳基、C 3-C 8亚环烷基、C 3-C 8亚环烯基、包含1、2或3个独立地选自N、O或S的杂原子的3-8元亚杂环烷基和包含1、2或3个独立地选自N、O或S的杂原子的3-8元亚杂环烯基环； In one embodiment of the compound of formula (I), 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;
在一种式(I)化合物的实施方式中，环A选自亚苯基、包含1、2或3个独立地选自N、O或S的杂原子的5-6元亚杂芳基、C 3-C 8亚环烷基、C 3-C 8亚环烯基、包含1、2或3个独立地选自N、O或S的杂原子的3-8元亚杂环烷基和包含1、2或3个独立地选自N、O或S的杂原子的3-8元亚杂环烯基； In one embodiment of the compound of formula (I), 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;
在一种式(I)化合物的实施方式中，环A选自亚苯基、包含1、2或3个独立地选自N、O或S的杂原子的5元亚杂芳基、C 3-C 6亚环烷基、C 3-C 6亚环烯基、包含1、2或3个独立地选自N、O或S的杂原子的3-6元亚杂环烷基和包含1、2或3个独立地选自N、O或S的杂原子的3-6元亚杂环烯基； In one embodiment of the compound of formula (I), 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;
在一种式(I)化合物的实施方式中，环A选自亚苯基、亚吡咯基、亚呋喃基、亚噻吩基、亚咪唑基、亚呋咱基、亚噁唑基、亚噁二唑基、亚噁三唑基、亚异噁唑基、亚噻唑基、亚异噻唑基、亚吡唑基、亚噻二唑基、亚三唑基、亚四唑基、亚吡啶基、亚吡嗪基、亚哒嗪基、嘧啶基、亚三嗪基、亚氮杂环丁烷基、亚吡咯烷基、亚吡咯啉基、亚环丁基、亚环戊基、亚环己基、亚环庚基、亚哌嗪基、亚哌啶基、亚四氢吡啶基、3,6-二氮杂-双环[3.1.1]亚庚基、3-氮杂-双环[3.2.1]亚辛基和1,4-二氮杂亚环庚基。In one embodiment of the compound of formula (I), 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-bicyclo[3.1.1]heptylene, 3-aza-bicyclo[3.2.1]idene Octyl and 1,4-diazacycloheptylene.
在一种式(I)化合物的实施方式中，环A选自亚吡唑基、亚噻二唑基、亚吡咯烷基、亚吡咯啉基、亚环己基、亚哌嗪基、亚哌啶基、亚四氢吡啶基、3,6-二氮杂-双环[3.1.1]亚庚基、3-氮杂-双环[3.2.1]亚辛基和1,4-二氮杂亚环庚基。In one embodiment of the compound of formula (I), 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.
在一种式(I)化合物的实施方式中，环A选自In one embodiment of the compound of formula (I), Ring A is selected from
Figure PCTCN2021118001-appb-000012
Figure PCTCN2021118001-appb-000012
在一种式(I)化合物的实施方式中，环B选自苯基、包含1、2或3个独立地选自N、O或S的杂原子的5-9元杂芳基、C 3-C 8环烷基、C 3-C 8环烯基、包含1、2或3个独立地选自N、O或S的杂原子的3-8元杂环烷基和包含1、2或3个独立地选自N、O或S的杂原子的3-8元杂环烯基环； In one embodiment of the compound of formula (I), 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;
在一种式(I)化合物的实施方式中，环B选自苯基和包含1、2或3个独立地选自N、O或S的杂原子的5-6元杂芳基；In one embodiment of the compound of formula (I), Ring B is selected from phenyl and 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S;
在一种式(I)化合物的实施方式中，环B选自苯基、包含1、2或3个独立地选自N、O或S的杂原子的6元杂芳基；In one embodiment of the compound of formula (I), Ring B is selected from phenyl, 6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S;
在一种式(I)化合物的实施方式中，环B选自苯基、吡咯基、呋喃基、噻吩基、咪唑基、呋咱基、噁唑基、噁二唑基、噁三唑基、异噁唑基、噻唑基、异噻唑基、吡唑基、噻二唑基、三唑基、四唑基、吡啶基、吡嗪基、哒嗪基、嘧啶基和三嗪基环。In one embodiment of the compound of formula (I), 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.
在一种式(I)化合物的实施方式中，环B是吡啶基环。In one embodiment of a compound of formula (I), Ring B is a pyridyl ring.
在一种式(I)化合物的实施方式中，基团
Figure PCTCN2021118001-appb-000013
选自 In one embodiment of the compound of formula (I), the group
Figure PCTCN2021118001-appb-000013
selected from
Figure PCTCN2021118001-appb-000014
Figure PCTCN2021118001-appb-000014
需要说明的是，本发明的式(I)化合物涵盖以上各个独立的实施方式或各个具体实施方式，还涵盖上述各个实施方式或具体实施方式的任何组合或亚组合构成的实施方式，也涵盖以上任何优选或例举的任何组合所构成的实施方式。It should be noted that 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.
应当理解的是，通式化合物中基团的组合和/或取代应当以符合价键规则为前提。It should be understood that the combination and/or substitution of groups in the compound of the general formula should be premised on compliance with the valence bond rules.
优选地，本发明的式(I)化合物具有式(Ia)结构，Preferably, the compound of formula (I) of the present invention has the structure of formula (Ia),
Figure PCTCN2021118001-appb-000015
Figure PCTCN2021118001-appb-000015
其中R 1、R 2、R 3、R 4、R 5、m、n和A各自具有上文对式(I)化合物的一般或具体实施方式中所定义的含义。 wherein 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.
更优选地，本发明的式(I)化合物具有式(Ib)结构，More preferably, the compound of formula (I) of the present invention has the structure of formula (Ib),
Figure PCTCN2021118001-appb-000016
Figure PCTCN2021118001-appb-000016
其中R 1、R 2、R 3、R 4、R 5、n和A各自具有上文对式(I)化合物的一般或具体实施方式中所定义的含义。 wherein 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.
更优选地，本发明的式(I)化合物具有式(Ic)结构，More preferably, the compound of formula (I) of the present invention has the structure of formula (Ic),
Figure PCTCN2021118001-appb-000017
Figure PCTCN2021118001-appb-000017
其中R 2、R 3、R 4、R 5、n和A各自具有上文对式(I)化合物的一般或具体实施方式中所定义的含义。 wherein 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).
最优选地，本发明式(I)化合物选自以下具体化合物实例：Most preferably, the compounds of formula (I) of the present invention are selected from the following specific compound examples:
Figure PCTCN2021118001-appb-000018
Figure PCTCN2021118001-appb-000018
Figure PCTCN2021118001-appb-000019
Figure PCTCN2021118001-appb-000019
Figure PCTCN2021118001-appb-000020
Figure PCTCN2021118001-appb-000020
发明的有益效果Beneficial Effects of Invention
本发明提供了一类具有通式(I)结构特征的吡唑并吡啶类化合物，经研究发现，该类化合物可有效抑制RET激酶、RET融合及突变活性，作为RET表达异常的相关类疾病的治疗药物。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.
本发明的化合物具有下列有益效果：The compounds of the present invention have the following beneficial effects:
高的RET激酶抑制活性；激酶RET抑制测定实验中显示IC50在0.1nM～1μM范围，优选在0.1nM～0.1μM范围；和/或High RET kinase inhibitory activity; an IC50 in the range of 0.1 nM to 1 μM, preferably in the range of 0.1 nM to 0.1 μM, in a kinase RET inhibition assay; and/or
高的RET融合及突变活性；和/或High RET fusion and mutagenesis activity; and/or
具有良好的药物代谢动力学性质，例如具有更长的t 1/2，从而例如可以加大给药间隔，更长的半衰期，使患者具有更好的依从性；和/或 have good pharmacokinetic properties, such as having a longer t 1/2 , allowing for example greater dosing intervals, longer half-life, and better patient compliance; and/or
具有改善的AUC0-t数据，具有更好的成药性，更高的生物利用度，如下文活性实施例6所验证；和/或Have improved AUCo-t data, better druggability, higher bioavailability, as demonstrated in Active Example 6 below; and/or
良好的安全性，如透膜性、P450(减少的药物相互作用风险)、溶解性等优异的性质。Good safety profile, excellent properties such as membrane permeability, P450 (reduced risk of drug interactions), solubility, etc.
基于以上本发明化合物的有益效果，本发明还提供以下各个方面的技术方案。Based on the above beneficial effects of the compounds of the present invention, the present invention also provides technical solutions in the following aspects.
用于治疗或用作药物的本发明化合物Compounds of the invention for use in therapy or as a medicament
一方面，本发明提供用作药物、尤其是用作RET抑制剂的本发明化合物。In one aspect, the present invention provides compounds of the present invention for use as medicaments, particularly as RET inhibitors.
另一方面，本发明提供用于治疗、尤其是用于治疗和/或预防与RET有关疾病的本发明化合物。In another aspect, 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.
在具体的实施方式中，本发明提供用于治疗和/或预防RET对所述疾病的发生和发展起到促进作用或抑制RET将降低疾病的发生率、减少或消除疾病病状的疾病的本发明化合物，所述疾病例如肿瘤或肠易激综合症(IBS)，肿瘤包括但不限于非小细胞肺癌、小细胞肺癌、乳头状甲状腺癌、甲状腺髓质癌、分化型甲状腺癌、复发性甲状腺癌、顽固性分化型甲状腺癌、多内分泌肿瘤2A或2B、嗜铬细胞瘤、甲状旁腺增生、乳腺癌、结肠直肠癌、乳头状肾细胞 癌、胃肠黏膜神经节瘤、胰管腺癌、多发性内分泌瘤、睾丸癌、慢性单核细胞性白血病、唾腺癌、卵巢癌、子宫颈癌等。In specific embodiments, 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.
药物组合物及其施用Pharmaceutical compositions and their administration
另一方面，为了使用本说明书的化合物用于治疗或预防目的，可以将本发明化合物根据标准药学实践配制为药物组合物。同时，基于本发明化合物良好的药物代谢动力学性质、改善的AUC0-last、良好的成药性，由本发明化合物可制备具有更好的药动学性质、更高生物利用度的药物。On the other hand, in order to use the compounds of the present specification for therapeutic or prophylactic purposes, 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.
因此，本发明提供一种药物组合物，其包含上述本发明化合物和药学可接受的赋形剂。Accordingly, the present invention provides a pharmaceutical composition comprising the above-described compound of the present invention and a pharmaceutically acceptable excipient.
在一个具体的实施方式中，提供了所述本发明的药物组合物，用于在例如哺乳动物如人个体中预防或治疗与RET有关的疾病。In a specific embodiment, the pharmaceutical 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.
在一个具体的实施方式中，本发明的药物组合物可以另外包含适合与本发明化合物组合使用的另外的治疗活性成分。In a specific embodiment, the pharmaceutical compositions of the present invention may additionally comprise additional therapeutically active ingredients suitable for use in combination with the compounds of the present invention.
本发明的药物组合物可以通过本领域技术人员已知的技术来配制，如在Remington’s Pharmaceutical Sciences第20版中公开的技术。例如，上述本发明的药物组合物，可以通过将本发明化合物与一种或多种药学可接受的赋形剂混合来制备。制备可进一步包括将一种或多种其它活性成分与本发明化合物和一种或多种药学可接受的赋形剂混合的步骤。The pharmaceutical 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. For example, 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.
选择包含在特定组合物中的赋形剂将取决于多种因素、例如给药方式和所提供的组合物的形式。合适的药学可接受的赋形剂是本领域技术人员熟知的且描述于例如Ansel,Howard C.,等,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia:Lippincott,Williams&Wilkins,2004中，包括例如佐剂、稀释剂(例如葡萄糖、乳糖或甘露醇)、载体、pH调节剂、缓冲剂、甜味剂、填充剂、稳定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、加香剂、调味剂、其它已知添加剂。The choice of 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. Philadelphia: Lippincott, Williams & Wilkins, 2004, including, for example, adjuvants , 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.
本发明的药物组合物可以以标准方式施用。例如，合适的施用方式包括口服、静脉内、直肠、肠胃外、局部、经皮、眼、鼻、颊或肺(吸入)给药，其中肠胃外输注包括肌肉、静脉内、动脉内、腹膜内或皮下施用。为了这些目的，本发明的化合物可以通过本领域已知的方法配制成例如片剂、胶囊、糖浆、粉末、颗粒、水性或油性溶液或悬浮液、(脂质)乳剂、可分散粉末、栓剂、软膏、乳膏、滴剂、气溶胶、干粉制剂和无菌可注射水性或油性溶液或悬浮液的形式。The pharmaceutical compositions of the present invention can be administered in a standard manner. For example, 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. For these purposes, 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.
本发明化合物的预防或治疗剂量的大小将根据一系列因素而变化，包括所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约5000mg，例如约0.01至约1000mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计为约0.007mg/日至约7000mg/日，例如约0.7mg/日至约1500mg/ 日。根据给药模式，本发明化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg，适合地是0.1-500mg，优选0.5-300mg，更优选1-150mg，特别优选1-50mg，例如1.5mg、2mg、4mg、10mg、25mg等；相应地，本发明的药物组合物将包含0.05至99％w/w(重量百分比)，例如0.05至80％w/w，例如0.10至70％w/w，例如0.10至50％w/w的本发明化合物，所有重量百分比均基于总组合物。应当理解，可能有必要在某些情况下使用超出这些限制的剂量。The size of 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. In general, 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. Depending on the mode of administration, 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.
在一种具体实施方式中，本发明提供了一种药物组合物，其包含本发明化合物和一种或多种药学可接受的赋形剂，该组合物被配制用于口服施用。该组合物可以以单位剂型提供，例如以片剂、胶囊或口服液体制剂的形式。这样的单位剂型可以含有0.1mg至1g，例如5mg至250mg的本发明化合物作为活性成分。In one embodiment, the present invention provides 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.
在一种具体实施方式中，本发明提供了一种药物组合物，其包含本发明化合物和一种或多种药学可接受的赋形剂，该组合物被配制用于局部施用。局部施用可以是以例如乳膏剂、洗剂、软膏剂或透皮贴剂的形式。In one embodiment, the present invention provides 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.
在一种具体实施方式中，本发明提供了一种药物组合物，其包含本发明化合物和一种或多种药学可接受的赋形剂，该组合物被配制用于吸入施用。吸入施用可以通过口服吸入，也可以通过鼻内施用。当通过口服吸入施用时，本发明的化合物可以以每日剂量有效地用于本发明，例如至多500μg，如0.1-50μg、0.1-40μg、0.1-30μg、0.1-20μg或0.1-10μg的本发明化合物。口服吸入的本发明药物组合物可以配制成干粉、悬浮液(在液体或气体中)或溶液(在液体中)，且可以以任何合适的形式和使用任何本领域已知的合适的吸入器装置施用，包括例如定量吸入器(MDI)、干粉吸入器(DPI)、喷雾器和软雾吸入器。多室装置可用于递送本说明书的化合物和一种或多种其它活性成分(当存在时)。In one embodiment, the present invention provides 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. When administered by oral inhalation, the compounds of the present invention can be effectively used in the present invention in daily doses, eg up to 500 μg, such as 0.1-50 μg, 0.1-40 μg, 0.1-30 μg, 0.1-20 μg or 0.1-10 μg of the present invention compound. Pharmaceutical 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.
治疗方法和用途Treatment methods and uses
基于上述本发明化合物具有的有益效果，本发明化合物可用于治疗动物，特别是哺乳动物例如人的各种病症的方法中。Based on the beneficial effects possessed by the compounds of the present invention as described above, the compounds of the present invention can be used in methods of treating various disorders in animals, especially mammals such as humans.
因此，另一方面，本发明提供了调节、尤其是抑制RET活性的方法，所述方法包括使细胞与如前所述的本发明化合物相接触以调节、尤其是抑制细胞中RET的活性。Thus, in another aspect, 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.
另一方面，本发明提供了预防或治疗与RET相关的疾病(例如通过RET抑制可治疗或预防的疾病)的方法，所述方法包括向需要其的个体施用有效量的如前所述的本发明化合物或包含其的本发明药物组合物。In another aspect, 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.
另一方面，本发明提供了如前所述的本发明化合物或包含其的药物组合物的用途，用于抑制RET活性，或者用于治疗和/或预防与RET相关的疾病、例如通过RET抑制可治疗或预防的疾病。In another aspect, 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.
另一方面，本发明还提供了如前所述的本发明化合物或包含其的药物组合物在制备药物中的用途，尤其是具有RET受体抑制剂活性的药物中的应用。On the other hand, 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.
另一方面，本发明提供如前所述的本发明化合物或包含其的药物组合物在制备用于治疗或预防与RET相关的疾病、例如通过RET抑制可治疗或预防的疾病的药物中的用途，其中所述化合物或药物组合物任选地与一种或多种化学治疗或免疫治疗联合。In another aspect, 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.
本发明化合物的合成Synthesis of Compounds of the Invention
本发明还提供了一种制备式(I)化合物的方法，下文举例说明了合成本发明化合物的通用合成方案。对于各反应步骤而言，适当的反应条件是本领域技术人员已知的或可以常规确定的。如果没有特别说明，在制备这些化合物中使用的原料和试剂通常可商购获得，或者可以通过下文的方法、与下文给出的方法类似的方法或本领域已知的方法制得。如果需要，合成反应流程中的原料和中间体可以采用常规技术进行分离和纯化，所述技术包括但不限于过滤、蒸馏、结晶、色谱法等。所述材料可以采用包括物理常数和波谱数据在内的常规方法表征。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. For each reaction step, 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. If necessary, 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.
合成方案1：Synthesis Scheme 1:
Figure PCTCN2021118001-appb-000021
Figure PCTCN2021118001-appb-000021
可通过包含下面步骤的方法合成本发明化合物：Compounds of the present invention can be synthesized by a method comprising the following steps:
使式I-1化合物与式I-3化合物反应得到式(I)化合物；The compound of formula I-1 is reacted with the compound of formula I-3 to obtain the compound of formula (I);
其中所述反应可在缩合剂存在下进行，所述缩合剂是本领域众所周知的用于羧酸与胺偶联的缩合剂，包括但不限于1-丙基磷酸酐(T3P)、EDC、DCC、HATU、EDCI等；所述反应优选在适合的有机溶剂中进行，所述有机溶剂可选自二氯甲烷、四氢呋喃、醚类(例如乙醚、乙二醇单甲醚等)、N-甲基吡咯烷酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,4-二氧六环、二甲基亚砜及其任意组合；所述反应优选在适合的碱存在下进行，所述的碱包括但不限于碳酸钠、碳酸钾、碳酸铯、N,N-二异丙基乙胺、三乙胺、HOBt或吡啶，优选地，所述的碱是N,N-二异丙基乙胺；所述反应优选在适合的温度下进行，例如0-200℃、10-100℃、20-50℃或室温(20-25℃)。Wherein 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, triethylamine, HOBt or pyridine, preferably, described 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 (20-25°C).
合成方案2：Synthesis Scheme 2:
Figure PCTCN2021118001-appb-000022
当可通过包含下面步骤的方法合成本发明化合物：
Figure PCTCN2021118001-appb-000022
When the compounds of the present invention can be synthesized by a method comprising the following steps:
式I-2化合物与式I-3化合物在三光气或CDI作用下得到式(I-i)化合物；Compound of formula I-2 and compound of formula I-3 are obtained under the action of triphosgene or CDI to obtain compound of formula (I-i);
其中所述反应优选在适合的有机溶剂中进行，所述有机溶剂可选自二氯甲烷、四氢呋喃、醚类(例如乙醚、乙二醇单甲醚等)、N-甲基吡咯烷酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,4-二氧六环、二甲基亚砜及其任意组合，并任选含有水；所述反应优选在适合的碱存在下进行，所述的碱包括但不限于碳酸钠、碳酸氢钠、碳酸钾、碳酸铯、N,N-二异丙基乙胺、三乙胺、HOBt或吡啶，优选地，所述的碱是N,N-二异丙基乙胺；所述反应优选在适合的温度下进行，例如0-200℃、10-100℃、20-50℃或室温(20-25℃)。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 (20-25°C).
上述合成方案只是列举了本发明中部分化合物的制备方法。本发明的化合物或者其立体异构体、互变异构体、稳定的同位素衍生物、药学上可接受的盐或溶剂合物可以通过多种方法、包括上文给出的方法、实施例中给出的方法或与之类似的方法、由本领域普通技术人员在上述合成方案的基础上、结合本领域的常规技术而制备得到。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.
具体实施方式detailed description
以下结合具体实施例，对本发明的技术方案做进一步的描述，但是本发明的保护范围并不限于这些实施例。凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。The technical solutions of the present invention will be further described below with reference to specific embodiments, but the protection scope of the present invention is not limited to these embodiments. All changes or equivalent substitutions that do not depart from the concept of the present invention are included in the protection scope of the present invention.
下列实施例中未注明具体条件的实验方法，通常按照这类反应的常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数分别是重量百分比和重量份数。除非另外说明，否则液体的比为体积比。The experimental methods without specific conditions in the following examples are generally in accordance with the conventional conditions of this type of reaction, or in accordance with the conditions suggested by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and parts by weight, respectively. Unless otherwise stated, ratios of liquids are by volume.
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得、依据现有技术的方法制得或根据与本申请公开的类似的方法制得。Unless otherwise specified, the 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.
本申请使用的缩写具有本领域通常理解的含义，除非说明书中另外清楚定义。在下面列出说明书中使用的缩写的含义：Abbreviations used herein have the meanings commonly understood in the art unless clearly defined otherwise in the specification. The meanings of the abbreviations used in the specification are listed below:
Pd(dppf)Cl 2:[1,1'-双(二苯基膦基)二茂铁]二氯化钯 Pd(dppf)Cl 2 : [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
Pd(dppf)Cl 2.DCM:[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物 Pd(dppf)Cl 2 .DCM: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex
HATU:2-(7-偶氮苯并三氮唑)-N,N,N’,N’,-四甲基脲六氟磷酸盐HATU: 2-(7-Azobenzotriazole)-N,N,N',N',-tetramethylurea hexafluorophosphate
DIEA:N,N-二异丙基乙胺DIEA:N,N-Diisopropylethylamine
DCM:二氯甲烷DCM:dichloromethane
EA:乙酸乙酯EA: Ethyl acetate
PE:石油醚PE: petroleum ether
DMF:N,N-二甲基甲酰胺DMF:N,N-Dimethylformamide
TEA:三乙胺TEA: Triethylamine
LC-MS:液相色谱质谱联用LC-MS: Liquid Chromatography Mass Spectrometry
ESI:电喷雾离子化ESI: Electrospray Ionization
m/z:质荷比m/z: mass-to-charge ratio
EDCI:1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride
HOBt:1-羟基苯并三唑HOBt: 1-Hydroxybenzotriazole
CDI:N',N-羰基二咪唑CDI:N',N-Carbonyldiimidazole
Ret.time：保留时间Ret.time: retention time
HPLC:高效液相色谱HPLC: High Performance Liquid Chromatography
合成实施例Synthesis Example
本发明提供的目标化合物制备方法中，柱层析色谱采用乳山太阳干燥剂有限公司生产的硅胶(300-400目)；薄层色谱采用GF254(0.25毫米)；核磁共振色谱(NMR)使用Varian-400核磁共振仪测定；液质联用(LC/MS)使用Agilent TechnologiESI 6120液质联用仪。In the preparation method of the target compound provided by the present invention, silica gel (300-400 mesh) produced by Rushan Sun Desiccant Co., Ltd. is used for column chromatography; 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.
此外，凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。除非另有说明，本发明使用的原料都是市售原料、无需进一步纯化可以直接使用，本发明使用的温度均为摄氏度℃。In addition, all operations involving easily oxidizable or easily hydrolyzed raw materials are carried out under nitrogen protection. Unless otherwise specified, 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.
当本发明化合物结构与化合物名称不一致时，通常以结构式所示为准，除非通过上下文可以确定化合物名称正确。When the structure of the compound of the present invention is inconsistent with the name of the compound, the structural formula is generally used, unless it can be determined from the context that the name of the compound is correct.
实施例1: 3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基) 吡啶-3-基)甲基)-1-甲基-1H-吡唑-5-甲酰胺(化合物1)的合成 Example 1: 3-(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-methyl-1H-pyrazole-5-carboxamide (Compound 1)
Figure PCTCN2021118001-appb-000023
Figure PCTCN2021118001-appb-000023
步骤1：3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯的合成Step 1: Synthesis of 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate
将4-羟基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈(500mg,2.09mmol)与TEA(0.581mL,4.18mmol)加入到DCM(10.0mL)中。在氮气保护下，并在冰浴下将三氟甲磺酸酐(0.520mL，3.14mmol)滴加到反应液中。滴加完毕后，反应混合物在冰浴下继续搅拌反应1.5小时。减压浓缩除去有机溶剂得到目标化合物(600mg,粗品,黑色油状物)。LC-MS(ESI)m/z 370.0[M-H] -。 Combine 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (500 mg, 2.09 mmol) with TEA (0.581 mL, 4.18 mmol) was added to DCM (10.0 mL). Trifluoromethanesulfonic anhydride (0.520 mL, 3.14 mmol) was added dropwise to the reaction solution under nitrogen protection and ice bath. After the dropwise addition was completed, the reaction mixture was further stirred under an ice bath for 1.5 hours. Concentrate under reduced pressure to remove the organic solvent to obtain the title compound (600 mg, crude product, black oil). LC-MS (ESI) m/z 370.0 [MH] − .
步骤2：3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1-甲基-1H-吡唑-5-甲酸甲酯的合成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
将3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯(300mg,0.808mmol)、(5-(甲氧羰基)-1-甲基-1H-吡唑-3-基)硼酸(163mg,0.889mmol)、碳酸钾(223mg,1.62mmol)和Pd(dppf)Cl 2(59.1mg,0.081mmol)加入到1,4-二氧六环(8mL)和水(1mL)的混合溶剂中。在氮气保护下，反应混合物在100℃搅拌反应3小时。将反应混合物冷却至室温，过滤。向滤液中加入水(15mL)，用EA(10mL x 2)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。经制备板分离纯化(DCM:甲醇＝20:1)得到目标化合物(95.0mg,两步收率25.2％,棕黄色固体)。LC-MS(ESI)m/z 362.1[M+H] +。 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (300 mg, 0.808 mmol) , (5-(methoxycarbonyl)-1-methyl-1H-pyrazol-3-yl)boronic acid (163 mg, 0.889 mmol), potassium carbonate (223 mg, 1.62 mmol) and Pd(dppf)Cl 2 (59.1 mg) , 0.081 mmol) was added to a mixed solvent of 1,4-dioxane (8 mL) and water (1 mL). Under nitrogen protection, the reaction mixture was stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature and filtered. To the filtrate was added water (15 mL) and extracted with EA (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification by preparative plate (DCM:methanol=20:1) gave the target compound (95.0 mg, two-step yield 25.2%, tan solid). LC-MS (ESI) m/z 362.1 [M+H] + .
步骤3：3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1-甲基-1H-吡唑-5-甲酸的合成Step 3: 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
将3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1-甲基-1H-吡唑-5-甲酸甲酯(120mg,0.332mmol)溶于四氢呋喃(2mL)和甲醇(2mL)的混合溶剂中。在室温下，滴加氢氧化钠水溶液(1mol/L,1mL)。反应混合物在室温下搅拌反应过夜。用稀盐酸(1mol/L)将反应液调至pH～4。减压浓缩得到粗品。向粗品中加入DCM和甲醇混合液(20mL,v:v＝10:1)，在室温下搅拌10分钟。过滤，滤液减压浓缩得到目标化合物(110mg,收率95.4％,棕色固体)。LC-MS(ESI)m/z[M+H] +348.1。 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1-methyl-1H- Methyl pyrazole-5-carboxylate (120 mg, 0.332 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and methanol (2 mL). At room temperature, aqueous sodium hydroxide solution (1 mol/L, 1 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction solution was adjusted to pH~4 with dilute hydrochloric acid (1 mol/L). Concentration under reduced pressure gave crude product. A mixture of DCM and methanol (20 mL, v:v=10:1) was added to the crude product, and the mixture was stirred at room temperature for 10 minutes. After filtration, the filtrate was concentrated under reduced pressure to obtain the target compound (110 mg, yield 95.4%, brown solid). LC-MS (ESI) m/z [M+H] + 348.1.
步骤4：3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-1-甲基-1H-吡唑-5-甲酰胺的合成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
将3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1-甲基-1H-吡唑-5-甲酸(70.0mg,0.202mmol)、6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(46.5mg,0.242mmol)，DIEA(0.100mL,0.604mmol)和HATU(115mg,0.302mmol)加入到DMF(3mL)中。反应混合物在室温下搅拌反应过夜。将反应液倒入水(15mL)中，EA(10mL x 2)萃取。合并有机相，用无水硫酸钠干燥，过滤。滤液减压浓缩得到粗产品。用甲醇洗，过滤得到目标化合 物(10.0mg,收率9.52％,棕黄色固体)。LC-MS(ESI)m/z 522.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.29–9.20(m,2H),8.69–8.64(m,2H),8.45(s,1H),8.38(s,1H),8.10(s,1H),8.00–7.93(m,2H),7.93–7.85(m,2H),7.41(s,1H),4.53(d,J＝5.7Hz,2H),4.16(s,3H),3.87(s,3H)。 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1-methyl-1H- Pyrazole-5-carboxylic acid (70.0 mg, 0.202 mmol), 6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (46.5 mg, 0.242 mmol), DIEA (0.100 mL) , 0.604 mmol) and HATU (115 mg, 0.302 mmol) were added to DMF (3 mL). The reaction mixture was stirred at room temperature overnight. The reaction solution was poured into water (15 mL) and extracted with EA (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Washed with methanol, filtered to obtain the title compound (10.0 mg, yield 9.52%, brown solid). LC-MS (ESI) m/z 522.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.29-9.20(m, 2H), 8.69-8.64(m, 2H), 8.45(s, 1H), 8.38(s, 1H), 8.10(s, 1H) ), 8.00–7.93(m, 2H), 7.93–7.85(m, 2H), 7.41(s, 1H), 4.53(d, J=5.7Hz, 2H), 4.16(s, 3H), 3.87(s, 3H).
实施例2： 3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)-1H-吡唑-5-甲酰胺(化合物2)的合成 Example 2: 3-(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-5-carboxamide (Compound 2)
Figure PCTCN2021118001-appb-000024
Figure PCTCN2021118001-appb-000024
步骤1:3-羟基-1-(4-甲氧基苄基)-1H-吡唑-5-甲酸甲酯的合成Step 1: Synthesis of methyl 3-hydroxy-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylate
将(4-甲氧基苄基)肼盐酸盐(2.46g,14.1mmol)和TEA(4.40mL,31.7mmol)加入到水(10.0mL)和甲醇(20.0mL)的混合溶剂中。反应混合物在0℃下搅拌15分钟后，加入丁二酸二甲酯(2.00g,14.1mmol)。反应混合物在80℃下搅拌反应4小时。反应液减压浓缩得到粗产品。将粗产品加入到水(30.0mL)中，过滤，滤饼用水(10.0mL)洗。滤饼经真空干燥后得到目标产物(2.70g，收率73.2％，黄色固体)。LC-MS(ESI)m/z 263.0[M+H] +。 (4-Methoxybenzyl)hydrazine hydrochloride (2.46 g, 14.1 mmol) and TEA (4.40 mL, 31.7 mmol) were added to a mixed solvent of water (10.0 mL) and methanol (20.0 mL). After the reaction mixture was stirred at 0°C for 15 minutes, dimethyl succinate (2.00 g, 14.1 mmol) was added. The reaction mixture was stirred at 80°C for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was added to water (30.0 mL), filtered, and the filter cake was washed with water (10.0 mL). The filter cake was dried under vacuum to obtain the target product (2.70 g, yield 73.2%, yellow solid). LC-MS (ESI) m/z 263.0 [M+H] + .
步骤2:1-(4-甲氧基苄基)-3-(((三氟甲基)磺酰基)氧基)-1H-吡唑-5-甲酸甲酯的合成Step 2: Synthesis of 1-(4-methoxybenzyl)-3-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-5-carboxylic acid methyl ester
在0℃下，向3-羟基-1-(4-甲氧基苄基)-1H-吡唑-5-甲酸甲酯(2.70g,10.3mmol)和TEA(2.86mL,20.6mmol)的DCM(25.0mL)溶液中加入三氟甲磺酸酐(5.81g,20.6mmol)。反应混合物在室温下搅拌反应1小时。向反应液中加入饱和碳酸氢钠水溶液(20.0mL)。分出有机相，水相用DCM(50.0mL×2)萃取。合并有机相，用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝100：1-15：1)得到目标化合物(2.45g，收率60.3％，黄色固体)。 1H NMR(400MHz,DMSO-d 6)δ7.17(d,J＝8.7Hz,2H),7.09(s,1H),6.90(d,J＝8.7Hz,2H),5.61(s,2H),3.86(s,3H),3.72(s,3H)。 To a solution of methyl 3-hydroxy-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylate (2.70 g, 10.3 mmol) and TEA (2.86 mL, 20.6 mmol) in DCM at 0 °C (25.0 mL) To the solution was added trifluoromethanesulfonic anhydride (5.81 g, 20.6 mmol). The reaction mixture was stirred at room temperature for 1 hour. To the reaction solution was added saturated aqueous sodium bicarbonate solution (20.0 mL). The organic phase was separated and the aqueous phase was extracted with DCM (50.0 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification by column chromatography (PE:EA=100:1-15:1) gave the target compound (2.45 g, yield 60.3%, yellow solid). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.17 (d, J=8.7 Hz, 2H), 7.09 (s, 1H), 6.90 (d, J=8.7 Hz, 2H), 5.61 (s, 2H) , 3.86(s, 3H), 3.72(s, 3H).
步骤3:1-(4-甲氧基苄基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-5-甲酸甲酯的合成Step 3: 1-(4-Methoxybenzyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H -Synthesis of methyl pyrazole-5-carboxylate
向1-(4-甲氧基苄基)-3-(((三氟甲基)磺酰基)氧基)-1H-吡唑-5-甲酸甲酯(750mg,1.90mmol)和联硼酸频哪醇酯(531mg,2.09mmol)的1,4-二氧六环(10.0mL)溶液中加入乙酸钾(560mg,5.71mmol)、1,1'-双(二苯基膦)二茂铁(52.7mg,0.095mmol)和Pd(dppf)Cl 2DCM 络合物(81.9mg,0.095mmol)。氩气保护下，反应混合物在100℃下搅拌16小时。将反应液冷却至室温后倒入EA(80.0mL)中，得到黑色溶液。溶液用硅藻土过滤，滤饼用EA(20.0mL)洗。滤液减压浓缩得到目标化合物(600mg，收率84.7％，黑色固体)。LC-MS(ESI)m/z 291.0[M-82+H] +。 To 1-(4-methoxybenzyl)-3-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-5-carboxylic acid methyl ester (750 mg, 1.90 mmol) and biboronic acid Potassium acetate (560 mg, 5.71 mmol), 1,1'-bis(diphenylphosphino)ferrocene ( 52.7 mg, 0.095 mmol) and Pd(dppf)Cl 2 DCM complex (81.9 mg, 0.095 mmol). Under argon, the reaction mixture was stirred at 100°C for 16 hours. The reaction solution was cooled to room temperature and poured into EA (80.0 mL) to obtain a black solution. The solution was filtered through celite, and the filter cake was washed with EA (20.0 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (600 mg, yield 84.7%, black solid). LC-MS (ESI) m/z 291.0 [M-82+H] + .
步骤4:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1-(4-甲氧基苄基)-1H-吡唑-5-甲酸甲酯的合成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
向3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯(500mg,1.35mmol)和1-(4-甲氧基苄基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-5-甲酸甲酯(551mg,1.48mmol)的DMF(6.00mL)混合溶液中加入碳酸钾(372mg,2.69mmol)和Pd(dppf)Cl 2DCM络合物(58.0mg,0.067mmol)。氩气保护下，反应混合液在100℃下搅拌反应5小时。将反应混合物冷却至室温后倒入水(20.0mL)中，用EA(60.0mL×2)萃取。合并有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝5：1-1：1)得到目标化合物(210mg，收率33.4％，黄色固体)。LC-MS(ESI)m/z 468.2[M+H] +。 To 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (500 mg, 1.35 mmol) and 1-(4-methoxybenzyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyridine To a mixed solution of methyl oxazole-5-carboxylate (551 mg, 1.48 mmol) in DMF (6.00 mL) was added potassium carbonate (372 mg, 2.69 mmol) and Pd(dppf)Cl 2 DCM complex (58.0 mg, 0.067 mmol). Under the protection of argon, the reaction mixture was stirred at 100 °C for 5 hours. The reaction mixture was cooled to room temperature, poured into water (20.0 mL), and extracted with EA (60.0 mL×2). The combined organic phases were 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. After separation and purification by column chromatography (PE:EA=5:1-1:1), the target compound (210 mg, yield 33.4%, yellow solid) was obtained. LC-MS (ESI) m/z 468.2 [M+H] + .
步骤5:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1-(4-甲氧基苄基)-1H-吡唑-5-甲酸的合成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
向3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1-(4-甲氧基苄基)-1H-吡唑-5-甲酸甲酯(210mg,0.449mmol)的水(1.00mL)、四氢呋喃(2.00mL)、甲醇(4.00mL)的混合溶液中加入氢氧化锂(21.5mg,0.898mmol)。反应混合液在室温下搅拌反应16小时。将反应混合物减压浓缩除去有机溶剂后，溶入到水(10.0mL)中，用1.0M盐酸溶液调节pH＝5后得到悬浊液。悬浊液过滤，滤饼用水(5.00mL)洗。经真空干燥后得到目标化合物(185mg，收率90.8％，黄色固体)。LC-MS(ESI)m/z 454.1[M+H] +。 To 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1-(4-methoxy Lithium hydroxide (21.5 mg) was added to a mixed solution of methyl benzyl)-1H-pyrazole-5-carboxylate (210 mg, 0.449 mmol) in water (1.00 mL), tetrahydrofuran (2.00 mL) and methanol (4.00 mL). , 0.898 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, dissolved in water (10.0 mL), and adjusted to pH=5 with a 1.0 M hydrochloric acid solution to obtain a suspension. The suspension was filtered, and the filter cake was washed with water (5.00 mL). The title compound (185 mg, 90.8% yield, yellow solid) was obtained after drying in vacuo. LC-MS (ESI) m/z 454.1 [M+H] + .
步骤6:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-1-(4-甲氧基苄基)-1H-吡唑-5-甲酰胺的合成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
向3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1-(4-甲氧基苄基)-1H-吡唑-5-甲酸(90.0mg,0.198mmol)和(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(45.7mg,0.238mmol)的DMF(2.00mL)溶液中加入EDCI(56.9mg,0.298mmol)、HOBt(38.5mg,0.298mmol)和DIEA(51.3mg,0.397mmol)。反应混合物室温下搅拌反应16小时。将反应混合物倒入水(15.0mL)中，用EA(60.0mL×2)萃取。合并有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩，经真空干燥后得到目标化合物(150mg,粗品,黄色固体)。 LC-MS(ESI)m/z 628.0[M+H] +。 To 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1-(4-methoxy ylbenzyl)-1H-pyrazole-5-carboxylic acid (90.0 mg, 0.198 mmol) and (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (45.7 mg, To a solution of 0.238 mmol) in DMF (2.00 mL) was added EDCI (56.9 mg, 0.298 mmol), HOBt (38.5 mg, 0.298 mmol) and DIEA (51.3 mg, 0.397 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (15.0 mL) and extracted with EA (60.0 mL x 2). The combined organic phases were washed with saturated brine (15.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and dried in vacuo to give the title compound (150 mg, crude product, yellow solid). LC-MS (ESI) m/z 628.0 [M+H] + .
步骤7:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-1H-吡唑-5-甲酰胺的合成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
3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-1-(4-甲氧基苄基)-1H-吡唑-5-甲酰胺(150mg,0.239mmol)的三氟乙酸(5.00mL)溶液在70℃下搅拌反应1小时。将反应液旋干后溶于甲醇(5.00mL)中，逐滴加入到饱和碳酸氢钠(20.0mL)溶液中，得到黄色悬浊液。过滤，滤饼用清水(10.0mL)洗，经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(9.30mg,两步收率8.47％,黄色固体)。LC-MS(ESI)m/z 508.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ14.00(s,1H),9.32(s,1H),9.13(s,1H),8.72–8.65(m,2H),8.47–8.44(m,1H),8.40(s,1H),8.13(s,1H),8.01–7.95(m,2H),7.93–7.89(m,2H),7.26(s,1H),4.55(d,J＝5.5Hz,2H),3.89(s,3H)。 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-((6-(4 -Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1-(4-methoxybenzyl)-1H-pyrazol-5-carboxamide (150 mg, 0.239 mmol) A solution of trifluoroacetic acid (5.00 mL) was stirred at 70°C for 1 hour. The reaction solution was spin-dried, dissolved in methanol (5.00 mL), and added dropwise to saturated sodium bicarbonate (20.0 mL) solution to obtain a yellow suspension. After filtration, the filter cake was washed with water (10.0 mL), and purified by preparative HPLC (acetonitrile/water containing 0.05% formic acid) to obtain the title compound (9.30 mg, 8.47% yield in two steps, yellow solid). LC-MS (ESI) m/z 508.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ14.00(s,1H), 9.32(s,1H), 9.13(s,1H), 8.72-8.65(m,2H), 8.47-8.44(m,1H) ), 8.40(s, 1H), 8.13(s, 1H), 8.01–7.95(m, 2H), 7.93–7.89(m, 2H), 7.26(s, 1H), 4.55(d, J=5.5Hz, 2H), 3.89 (s, 3H).
实施例3: 4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基) 吡啶-3-基)甲基)哌嗪-1-甲酰胺(化合物3)及其盐酸盐(化合物3-1)的合成 Example 3: 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)piperazine-1-carboxamide (compound 3) and its hydrochloride (compound 3-1)
Figure PCTCN2021118001-appb-000025
Figure PCTCN2021118001-appb-000025
步骤1：4-(5-溴吡啶-3-基)哌嗪-1-甲酸叔丁酯的合成Step 1: Synthesis of tert-butyl 4-(5-bromopyridin-3-yl)piperazine-1-carboxylate
向3-溴-5-氟吡啶(5.00g,28.4mmol)和哌嗪-1-甲酸叔丁酯(7.94g,42.6mmol)的N-甲基吡咯烷酮(50.0mL)溶液中加入碳酸钾(7.85g,56.8mmol)。反应混合物在100℃下搅拌反应16小时后，在120℃下继续搅拌反应5小时。将反应混合物冷却至室温后倒入水(100mL)中，用EA(250mL)萃取。有机相用饱和食盐水(50.0mL×3)洗涤、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝20：1-10：1)得到目标化合物(1.30g,收率13.3％,黄色固体)。LC-MS(ESI)m/z 342.1,344.1[M+H] +。 To a solution of 3-bromo-5-fluoropyridine (5.00 g, 28.4 mmol) and tert-butyl piperazine-1-carboxylate (7.94 g, 42.6 mmol) in N-methylpyrrolidone (50.0 mL) was added potassium carbonate (7.85 g g, 56.8 mmol). After the reaction mixture was stirred at 100°C for 16 hours, the stirring was continued at 120°C for 5 hours. The reaction mixture was cooled to room temperature, poured into water (100 mL), and extracted with EA (250 mL). The organic phase was washed with saturated brine (50.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=20:1-10:1), the target compound (1.30 g, yield 13.3%, yellow solid) was obtained. LC-MS (ESI) m/z 342.1, 344.1 [M+H] + .
步骤2：1-氨基-3-溴-5-(4-叔丁氧基羰基)哌嗪-1-基)吡啶-1-鎓-2,4,6-三甲基苯磺酸盐的合成Step 2: Synthesis of 1-amino-3-bromo-5-(4-tert-butoxycarbonyl)piperazin-1-yl)pyridine-1-onium-2,4,6-trimethylbenzenesulfonate
将4-(5-溴吡啶-3-基)哌嗪-1-甲酸叔丁酯(2.30g,6.72mmol)和2,4,6-三甲基苯磺酰羟胺(1.74g,8.06mmol)加入到DCM(20.0mL)中。反应混合物在0℃下搅拌反应1小时。反应液减压浓缩得目标化合物(3.75g,粗品,黄色固体)。LC-MS(ESI)m/z 357.1,359.2[M] +。 4-(5-Bromopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (2.30 g, 6.72 mmol) and 2,4,6-trimethylbenzenesulfonylhydroxylamine (1.74 g, 8.06 mmol) Added to DCM (20.0 mL). The reaction mixture was stirred at 0°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the target compound (3.75 g, crude product, yellow solid). LC-MS (ESI) m/z 357.1, 359.2 [M] + .
步骤3：4-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)哌嗪-1-甲酸叔丁酯的合成Step 3: Synthesis of tert-butyl 4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)piperazine-1-carboxylate
在0℃下，向1-氨基-3-溴-5-(4-叔丁氧基羰基)哌嗪-1-基)吡啶-1-鎓-2,4,6-三甲基苯磺酸盐(3.75g,6.73mmol)的1,4-二氧六环(35.0mL)溶液中加入丙烯腈(1.01mL,15.5mmol)及DIEA(1.45mL,8.75mmol)。反应液在0℃下搅拌反应2小时后，加入2,3-二氯-5,6-二氰基-1,4-苯醌(3.21g,14.1mmol)。反应液继续在0℃下搅拌反应1小时后，升至室温继续搅拌反应16小时。将反应混合物减压浓缩，向残留物中加入水(60.0mL)，用EA(250mL)萃取。有机相用饱和食盐水(30.0mL×5)洗、无水硫酸钠干燥、过滤，滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝100：1-9：1)得到目标化合物(1.20g,两步收率43.9％,黄色固体)。LC-MS(ESI)m/z 306.1,308.1[M-100+H] +。 To 1-amino-3-bromo-5-(4-tert-butoxycarbonyl)piperazin-1-yl)pyridine-1- onium-2,4,6-trimethylbenzenesulfonic acid at 0 °C To a solution of the salt (3.75 g, 6.73 mmol) in 1,4-dioxane (35.0 mL) was added acrylonitrile (1.01 mL, 15.5 mmol) and DIEA (1.45 mL, 8.75 mmol). After the reaction solution was stirred at 0°C for 2 hours, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.21 g, 14.1 mmol) was added. After the reaction solution was stirred at 0° C. for 1 hour, it was raised to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and water (60.0 mL) was added to the residue, followed by extraction with EA (250 mL). The organic phase was washed with saturated brine (30.0 mL×5), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. After separation and purification by column chromatography (PE:EA=100:1-9:1), the target compound (1.20 g, two-step yield 43.9%, yellow solid) was obtained. LC-MS (ESI) m/z 306.1, 308.1 [M-100+H] + .
步骤4：4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)哌嗪-1-甲酸叔丁酯的合成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
向4-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)哌嗪-1-甲酸叔丁酯(200mg,0.492mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(123mg,0.591mmol)的水(1.00mL)和1,4-二氧六环(5.00mL)混合溶液中加入碳酸钠(104mg,0.984mmol)和Pd(dppf)Cl 2(16.0mg,0.025mmol)。置换氩气三次，反应混合物在100℃下搅拌反应16小时。将反应混合物冷却至室温后倒入水(50.0mL)中，用EA(100mL×2)萃取。合并有机相用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝3：1-1：1)得到目标化合物(155mg,收率77.5％,黄色油状物)。LC-MS(ESI)m/z 408.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.92(d,J＝1.1Hz,1H),8.58(s,1H),8.34(s,1H),8.06(d,J＝0.6Hz,1H),7.30(d,J＝1.1Hz,1H),3.87(s,3H),3.65–3.54(m,4H),3.12–3.05(m,4H),1.43(s,9H)。 To tert-butyl 4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)piperazine-1-carboxylate (200 mg, 0.492 mmol) and 1-methyl-4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (123 mg, 0.591 mmol) in water (1.00 mL) and To the mixed solution of 1,4-dioxane (5.00 mL) was added sodium carbonate (104 mg, 0.984 mmol) and Pd(dppf)Cl 2 (16.0 mg, 0.025 mmol). The argon was replaced three times and the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (50.0 mL), and extracted with EA (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification by column chromatography (PE:EA=3:1-1:1) gave the target compound (155 mg, yield 77.5%, yellow oil). LC-MS (ESI) m/z 408.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.92(d,J=1.1Hz,1H),8.58(s,1H),8.34(s,1H),8.06(d,J=0.6Hz,1H) , 7.30 (d, J=1.1 Hz, 1H), 3.87 (s, 3H), 3.65–3.54 (m, 4H), 3.12–3.05 (m, 4H), 1.43 (s, 9H).
步骤5：6-(1-甲基-1H-吡唑-4-基)-4-(哌嗪-1-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐的合成Step 5: 6-(1-Methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride Synthesis
将4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)哌嗪-1-甲酸叔丁酯(150mg,0.368mmol)加入到氯化氢甲醇溶液(3.0M,8.00mL)中。反应混合物在室温下搅拌反应2小时。将反应混合物减压浓缩得到目标化合物(130mg,收率99.2％,类白色固体)。LC-MS(ESI)m/z 308.2[M+H] +。 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazine-1-carboxylic acid tert-butyl The ester (150 mg, 0.368 mmol) was added to a solution of hydrogen chloride in methanol (3.0 M, 8.00 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (130 mg, yield 99.2%, off-white solid). LC-MS (ESI) m/z 308.2 [M+H] + .
步骤6：4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)哌嗪-1-甲酰胺及其盐酸盐的合成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
向饱和碳酸氢钠水溶液(3.00mL)和DCM(5.00mL)的混合液中依次加入(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(30.3mg,0.158mmol)和三光气(28.1mg,0.095mmol)。反应混合物在室温下搅拌反应1小时。分出有机相，水相用DCM(4.00mL)萃取。合并有机相用饱和食 盐水(5.00mL×2)洗、无水硫酸钠干燥、过滤。向滤液中依次加入TEA(0.065mL,0.573mmol)和6-(1-甲基-1H-吡唑-4-基)-4-(哌嗪-1-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(65.0mg,0.189mmol)。应混合物在室温下搅拌反应15分钟。将反应液减压浓缩得到粗产品 (化合物3)。经制备HPLC(乙腈/含0.05％盐酸的水)纯化，得到盐酸盐形式的目标化合物 (化合物3-1)(18.2mg,收率17.2％,黄色固体)。LC-MS(ESI)m/z 526.3[M+H] +。 1H NMR(400MHz,MeOH-d 4)δ8.68(s,1H),8.62–8.23(m,4H),8.24–7.87(m,3H),7.77(s,1H),7.25(s,1H),4.46(s,2H),4.09-3.96(m,3H),3.85–3.63(m,4H),3.27–3.11(m,4H)。 To a mixture of saturated aqueous sodium bicarbonate (3.00 mL) and DCM (5.00 mL) was sequentially added (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (30.3 mg) , 0.158 mmol) and triphosgene (28.1 mg, 0.095 mmol). The reaction mixture was stirred at room temperature for 1 hour. The organic phase was separated and the aqueous phase was extracted with DCM (4.00 mL). The combined organic phases were washed with saturated brine (5.00 mL×2), dried over anhydrous sodium sulfate, and filtered. To the filtrate was added TEA (0.065 mL, 0.573 mmol) followed by 6-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)pyrazolo[1,5- a] Pyridine-3-carbonitrile hydrochloride (65.0 mg, 0.189 mmol). The reaction mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure to obtain a crude product (compound 3) . Purification by preparative HPLC (acetonitrile/water containing 0.05% hydrochloric acid) afforded the title compound (compound 3-1) (18.2 mg, yield 17.2%, yellow solid) as the hydrochloride salt. LC-MS (ESI) m/z 526.3 [M+H] + . 1 H NMR (400MHz, MeOH-d 4 ) δ 8.68(s, 1H), 8.62-8.23(m, 4H), 8.24-7.87(m, 3H), 7.77(s, 1H), 7.25(s, 1H) ), 4.46(s, 2H), 4.09-3.96(m, 3H), 3.85-3.63(m, 4H), 3.27-3.11(m, 4H).
实施例4： 1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)-4-甲基哌啶-4-甲酰胺(化合物4)及其盐酸盐(化合物4-1)的合成 Example 4: 1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( 6-(4-Fluoro-1H-pyrazol-1 -yl)pyridin-3-yl)methyl)-4-methylpiperidine-4-carboxamide (compound 4) and its hydrochloride (compound 4- 1) Synthesis
Figure PCTCN2021118001-appb-000026
Figure PCTCN2021118001-appb-000026
步骤1:1-氨基-3-溴-5-氟吡啶-1-鎓2,4,6-三甲基苯磺酸盐的合成Step 1: Synthesis of 1-amino-3-bromo-5-fluoropyridine-1-onium 2,4,6-trimethylbenzenesulfonate
将3-溴-5-氟吡啶(10.0g,56.8mmol)和O-2,4,6-三甲基苯磺酰羟胺(14.7g,68.2mmol)加入到DCM(150mL)中。反应混合物在0℃下搅拌反应1小时。在0℃下向反应液中缓慢加入PE(150mL)，搅拌15分钟得到白色悬浊液。过滤后得到产物(15.5g,白色固体)和粗产物(5.50g,白色固体)。LC-MS(ESI)m/z 191.1,193.1[M] +。 3-Bromo-5-fluoropyridine (10.0 g, 56.8 mmol) and O-2,4,6-trimethylbenzenesulfonylhydroxylamine (14.7 g, 68.2 mmol) were added to DCM (150 mL). The reaction mixture was stirred at 0°C for 1 hour. PE (150 mL) was slowly added to the reaction solution at 0°C, followed by stirring for 15 minutes to obtain a white suspension. The product (15.5 g, white solid) and crude product (5.50 g, white solid) were obtained after filtration. LC-MS (ESI) m/z 191.1, 193.1 [M] + .
步骤2:6-溴-4-氟吡唑并[1,5-a]吡啶-3-甲腈的合成Step 2: Synthesis of 6-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile
在0℃下，向1-氨基-3-溴-5-氟吡啶-1-鎓2,4,6-三甲基苯磺酸盐(20.0g,51.1mmol)的1,4-二氧六环(200mL)溶液中加入丙烯腈(7.74mL,118mmol)和DIEA(11.0mL,66.4mmol)。反应液在0℃下搅拌反应2小时后，加入2,3-二氯-5,6-二氰基-1,4-苯醌(23.2g,102mmol)。反应液在0℃下继续搅拌反应1小时后，升至室温继续反应16小时。将反应混合物倒入冰水(300mL)中得到棕色悬浊液。悬浊液室温搅拌20分钟后过滤，滤饼用冰水(100mL)洗涤得到固体粗品。经柱层析分离纯化(PE：EA＝100：1-10：1)得到目标化合物(5.70g,两步收率41.9％,黄色固体)。To 1-amino-3-bromo-5-fluoropyridine-1-onium 2,4,6-trimethylbenzenesulfonate (20.0 g, 51.1 mmol) in 1,4-dioxane at 0 °C To the solution of the ring (200 mL) was added acrylonitrile (7.74 mL, 118 mmol) and DIEA (11.0 mL, 66.4 mmol). After the reaction solution was stirred at 0°C for 2 hours, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (23.2 g, 102 mmol) was added. The reaction solution was stirred at 0° C. for 1 hour and then warmed to room temperature for 16 hours. The reaction mixture was poured into ice water (300 mL) to give a brown suspension. The suspension was stirred at room temperature for 20 minutes, filtered, and the filter cake was washed with ice water (100 mL) to obtain a crude solid product. Separation and purification by column chromatography (PE:EA=100:1-10:1) gave the target compound (5.70 g, two-step yield 41.9%, yellow solid).
步骤3:1-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-4-甲基哌啶-4-甲酸乙酯的合成Step 3: Synthesis of 1-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-4-methylpiperidine-4-carboxylic acid ethyl ester
向6-溴-4-氟吡唑并[1,5-a]吡啶-3-甲腈(400mg,1.67mmol)和4-甲基哌啶-4-甲酸乙酯盐酸盐(380mg,1.83mmol)的N-甲基吡咯烷酮(2.00mL)溶液加入碳酸钾(576mg,4.17mmol)。反应混合物在100℃下搅拌反应16小时。将反应混合物冷却至室温后倒入水中(25.0mL)中， 用EA(100.0mL)萃取。有机相用饱和食盐水(20.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得粗产物，经柱层析分离纯化(PE：EA＝12:1-10:1)得到目标化合物(600mg,收率81.9％,类白色固体)。LC-MS(ESI)m/z 390.9,393.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.96(d,J＝1.3Hz,1H),8.62(s,1H),7.15(d,J＝1.3Hz,1H),4.14(q,J＝7.1Hz,2H),3.30–3.21(m,2H),2.92–2.81(m,2H),2.22–2.11(m,2H),1.79–1.69(m,2H),1.26–1.20(m,6H)。 To 6-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile (400 mg, 1.67 mmol) and 4-methylpiperidine-4-carboxylic acid ethyl ester hydrochloride (380 mg, 1.83 mmol) in N-methylpyrrolidone (2.00 mL) was added potassium carbonate (576 mg, 4.17 mmol). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (25.0 mL), and extracted with EA (100.0 mL). The organic phase was washed with saturated brine (20.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (PE:EA=12:1-10:1) to obtain the target compound (600 mg, yield 81.9%, off-white solid). LC-MS (ESI) m/z 390.9, 393.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.96 (d, J=1.3 Hz, 1H), 8.62 (s, 1H), 7.15 (d, J=1.3 Hz, 1H), 4.14 (q, J= 7.1Hz, 2H), 3.30–3.21 (m, 2H), 2.92–2.81 (m, 2H), 2.22–2.11 (m, 2H), 1.79–1.69 (m, 2H), 1.26–1.20 (m, 6H) .
步骤4:1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-4-甲基哌啶-4-甲酸乙酯的合成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
向1-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-4-甲基哌啶-4-甲酸乙酯(600mg,1.53mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(383mg,1.84mmol)的水(1.50mL)和1,4-二氧六环(7.50mL)混合溶液中加入碳酸钠(325mg,3.07mmol)和Pd(dppf)Cl 2DCM络合物(66.0mg,0.077mmol)。置换氩气三次，反应混合物在80℃下搅拌反应16小时。将反应混合物冷却至室温后倒入水(25.0mL)中，用EA(60.0mL×2)萃取。合并有机相用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝3：1-2：1)得到目标化合物(490mg,收率81.3％,黄色固体)。LC-MS(ESI)m/z 393.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.89(d,J＝1.0Hz,1H),8.56(s,1H),8.38(s,1H),8.07(s,1H),7.25(d,J＝0.9Hz,1H),4.15(q,J＝7.1Hz,2H),3.87(s,3H),3.31–3.24(m,2H),2.94–2.82(m,2H),2.26–2.16(m,2H),1.82–1.71(m,2H),1.26–1.20(m,6H)。 To 1-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-4-methylpiperidine-4-carboxylic acid ethyl ester (600 mg, 1.53 mmol) and 1- Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (383 mg, 1.84 mmol) in water ( 1.50 mL) and 1,4-dioxane (7.50 mL) were added sodium carbonate (325 mg, 3.07 mmol) and Pd(dppf)Cl 2 DCM complex (66.0 mg, 0.077 mmol). The argon was replaced three times and the reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (25.0 mL), and extracted with EA (60.0 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=3:1-2:1), the target compound (490 mg, yield 81.3%, yellow solid) was obtained. LC-MS (ESI) m/z 393.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.89(d, J=1.0Hz, 1H), 8.56(s, 1H), 8.38(s, 1H), 8.07(s, 1H), 7.25(d, J=0.9Hz, 1H), 4.15 (q, J=7.1Hz, 2H), 3.87 (s, 3H), 3.31–3.24 (m, 2H), 2.94–2.82 (m, 2H), 2.26–2.16 (m , 2H), 1.82–1.71 (m, 2H), 1.26–1.20 (m, 6H).
步骤5:1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-4-甲基哌啶-4-甲酸的合成Step 5: 1-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-4-methylpiperin Synthesis of pyridine-4-carboxylic acid
向1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-4-甲基哌啶-4-甲酸乙酯(200mg,0.509mmol)的乙醇溶液(10.0mL)中加入氢氧化钠(61.2mg,1.53mmol)。反应混合物在80℃下搅拌反应20小时。将反应混合物减压浓缩除去有机溶剂后，加入到水(10.0mL)中。用3.0M稀盐酸溶液调节pH＝3后得到棕色悬浊液。过滤，滤饼用水(15.0mL)洗，干燥后得到目标化合物(140mg,收率75.3％,棕色固体)。LC-MS(ESI)m/z 365.0[M+H] +。 To 1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-4-methylpiperidine- To a solution of ethyl 4-carboxylate (200 mg, 0.509 mmol) in ethanol (10.0 mL) was added sodium hydroxide (61.2 mg, 1.53 mmol). The reaction mixture was stirred at 80°C for 20 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, and then added to water (10.0 mL). A brown suspension was obtained after adjusting pH=3 with 3.0M dilute hydrochloric acid solution. After filtration, the filter cake was washed with water (15.0 mL) and dried to obtain the title compound (140 mg, yield 75.3%, brown solid). LC-MS (ESI) m/z 365.0 [M+H] + .
步骤6:1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-4-甲基哌啶-4-甲酰胺及其盐酸盐的合成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
在室温下，向1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-4-甲基哌啶-4-甲酸(140mg,0.384mmol)的DMF(2.00mL)溶液中加入EDCI(110mg,0.576mmol)、HOBt(77.8mg,0.576mmol)、DIEA(99.3mg,0.768mmol)和(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(73.8mg,0.384mmol)。反应混合物室温下搅拌反应2小时。将反应混合物倒入水中(20.0mL)中，用EA(60.0mL)萃取。有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品 (化合物4)。经制备HPLC(乙腈/含0.05％盐酸的水)纯化得到盐酸 盐形式的目标化合物 (化合物4-1)(68.1mg,收率30.9％,黄色固体)。LC-MS(ESI)m/z 539.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.87(s,1H),8.65-8.63(m,1H),8.55(s,1H),8.42–8.38(m,1H),8.37(s,1H),8.35-8.34(m,1H),8.06(s,1H),7.90-7.88(m,1H),7.88-7.86(m,2H),7.21(s,1H),4.37(d,J＝5.8Hz,2H),3.86(s,3H),3.26–3.20(m,2H),2.95–2.88(m,2H),2.28–2.23(m,2H),1.77–1.71(m,2H),1.21(s,3H)。 To 1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-4-methyl at room temperature EDCI (110 mg, 0.576 mmol), HOBt (77.8 mg, 0.576 mmol), DIEA (99.3 mg, 0.768 mmol) and (6 -(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (73.8 mg, 0.384 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (20.0 mL) and extracted with EA (60.0 mL). The organic phase was 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 (compound 4) . Purification by preparative HPLC (acetonitrile/water containing 0.05% hydrochloric acid) gave the title compound (compound 4-1) (68.1 mg, yield 30.9%, yellow solid) as the hydrochloride salt. LC-MS (ESI) m/z 539.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.87(s,1H), 8.65-8.63(m,1H), 8.55(s,1H), 8.42-8.38(m,1H), 8.37(s,1H) ), 8.35-8.34(m, 1H), 8.06(s, 1H), 7.90-7.88(m, 1H), 7.88-7.86(m, 2H), 7.21(s, 1H), 4.37(d, J=5.8 Hz, 2H), 3.86 (s, 3H), 3.26–3.20 (m, 2H), 2.95–2.88 (m, 2H), 2.28–2.23 (m, 2H), 1.77–1.71 (m, 2H), 1.21 ( s, 3H).
实施例5： 1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)乙基)-4-甲基哌啶-4-甲酰胺(化合物5)及其盐酸盐(化合物5-1)的合成 Example 5: 1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(1 -(6-(4-Fluoro-1H-pyrazol-1 -yl)pyridin-3-yl)ethyl)-4-methylpiperidine-4-carboxamide (Compound 5) and its hydrochloride (Compound 5) 5-1) Synthesis
Figure PCTCN2021118001-appb-000027
Figure PCTCN2021118001-appb-000027
在室温下，向1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-4-甲基哌啶-4-甲酸(100mg,0.274mmol)的DMF(2.00mL)溶液中加入EDCI(80.0mg,0.412mmol)、HOBt(55.7mg,0.412mmol)、DIEA(70.9mg,0.549mmol)和1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙-1-胺(56.6mg,0.274mmol)。反应混合物室温下搅拌反应1小时。将反应混合物倒入水(15.0mL)中，用EA(60.0mL)萃取。有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品 (化合物5)。经制备HPLC(乙腈/含0.05％盐酸的水)纯化得到盐酸盐形式的目标化合物 (化合物5-1)(65.2mg,收率40.4％,灰色固体)。LC-MS(ESI)m/z 553.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.86(d,J＝0.7Hz,1H),8.65(d,J＝4.0Hz,1H),8.56(s,1H),8.41(d,J＝2.0Hz,1H),8.37(s,1H),8.12(d,J＝7.7Hz,1H),8.06(s,1H),7.97–7.93(m,1H),7.91–7.86(m,2H),7.19(s,1H),5.14–5.05(m,1H),3.87(s,3H),3.29–3.18(m,2H),2.97–2.82(m,2H),2.36–2.19(m,2H),1.80–1.67(m,2H),1.46(d,J＝7.1Hz,3H),1.21(s,3H)。 To 1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-4-methyl at room temperature EDCI (80.0 mg, 0.412 mmol), HOBt (55.7 mg, 0.412 mmol), DIEA (70.9 mg, 0.549 mmol) and 1 -(6-(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine (56.6 mg, 0.274 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (15.0 mL) and extracted with EA (60.0 mL). The organic phase was 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 (compound 5) . Purification by preparative HPLC (acetonitrile/water with 0.05% hydrochloric acid) afforded the title compound (compound 5-1) (65.2 mg, 40.4% yield, grey solid) as the hydrochloride salt. LC-MS (ESI) m/z 553.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.86(d,J=0.7Hz,1H),8.65(d,J=4.0Hz,1H),8.56(s,1H),8.41(d,J= 2.0Hz, 1H), 8.37(s, 1H), 8.12(d, J=7.7Hz, 1H), 8.06(s, 1H), 7.97-7.93(m, 1H), 7.91-7.86(m, 2H), 7.19(s,1H), 5.14–5.05(m,1H), 3.87(s,3H), 3.29–3.18(m,2H), 2.97–2.82(m,2H), 2.36–2.19(m,2H), 1.80–1.67 (m, 2H), 1.46 (d, J=7.1 Hz, 3H), 1.21 (s, 3H).
实施例6： 3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-甲酰胺(化合物6)的合成 Example 6: 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( 6-(4-Fluoro-1H-pyrazol-1 -yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide (Compound 6) Synthesis
Figure PCTCN2021118001-appb-000028
Figure PCTCN2021118001-appb-000028
步骤1：3-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-3,6-二氮杂双环[3.1.1]庚烷-6-甲酸叔丁酯的合成Step 1: 3-(6-Bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid Synthesis of tert-butyl ester
向6-溴-4-氟吡唑并[1,5-a]吡啶-3-甲腈(400mg,1.67mmol)和3,6-二氮杂双环[3.1.1]庚烷-6-甲酸叔丁酯(398mg,2.01mmol)的N-甲基吡咯烷酮(5.00mL)溶液加入碳酸钾(577mg,4.18mmol)。封管，反应混合物在100℃下搅拌反应16小时。将反应混合物冷却至室温后，倒入水(20.0mL)中，用EA(20.0mL×3)萃取。合并有机相，用饱和食盐水(20.0mL×3)洗、无水硫酸钠干燥、过滤，滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝85：15)得到目标化合物(75.0mg,收率11.0％,白色固体)。LC-MS(ESI)m/z 418.1,420.1[M+H] +。 To 6-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile (400 mg, 1.67 mmol) and 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid To a solution of tert-butyl ester (398 mg, 2.01 mmol) in N-methylpyrrolidone (5.00 mL) was added potassium carbonate (577 mg, 4.18 mmol). The tube was sealed and the reaction mixture was stirred at 100°C for 16 hours. After cooling the reaction mixture to room temperature, it was poured into water (20.0 mL) and extracted with EA (20.0 mL×3). The organic phases were combined, washed with saturated brine (20.0 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Separation and purification by column chromatography (PE:EA=85:15) gave the title compound (75.0 mg, yield 11.0%, white solid). LC-MS (ESI) m/z 418.1, 420.1 [M+H] + .
步骤2：3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-3,6-二氮杂双环[3.1.1]庚烷-6-甲酸叔丁酯的合成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
向3-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-3,6-二氮杂双环[3.1.1]庚烷-6-甲酸叔丁酯(75.0mg,0.179mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(44.9mg,0.218mmol)的水(1.00mL)和1,4-二氧六环(5.00mL)溶液中加入碳酸钠(38.1mg,0.359mmol)和Pd(dppf)Cl 2DCM络合物(7.80mg,0.009mmol)。氩气保护下，反应混合物在80℃下搅拌反应16小时。将反应混合物冷却至室温后倒入水(10.0mL)中，用EA(10.0mL×3)萃取。合并有机相用饱和食盐水(10.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝2：3)得到目标化合物(60.0mg,收率79.4％,白色固体)。LC-MS(ESI)m/z 420.2[M+H] +。 1H NMR(400MHz,CDCl 3)δ8.38(d,J＝1.2Hz,1H),8.20(s,1H),7.74(d,J＝0.6Hz,1H),7.64(s,1H),7.12(d,J＝1.2Hz,1H),4.34-4.30(m,2H),3.99(s,3H),2.64–2.59(m,1H),2.41-2.38(m,1H),1.46(s,9H),1.34–1.23(m,4H)。 To 3-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl Esters (75.0 mg, 0.179 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H- To a solution of pyrazole (44.9 mg, 0.218 mmol) in water (1.00 mL) and 1,4-dioxane (5.00 mL) was added sodium carbonate (38.1 mg, 0.359 mmol) and Pd(dppf)Cl 2 DCM to complex Compound (7.80 mg, 0.009 mmol). Under argon, the reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (10.0 mL), and extracted with EA (10.0 mL×3). The combined organic phases were washed with saturated brine (10.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=2:3), the target compound (60.0 mg, yield 79.4%, white solid) was obtained. LC-MS (ESI) m/z 420.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.38 (d, J=1.2 Hz, 1H), 8.20 (s, 1H), 7.74 (d, J=0.6 Hz, 1H), 7.64 (s, 1H), 7.12 (d, J＝1.2Hz, 1H), 4.34-4.30(m, 2H), 3.99(s, 3H), 2.64-2.59(m, 1H), 2.41-2.38(m, 1H), 1.46(s, 9H) ), 1.34–1.23 (m, 4H).
步骤3:4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈三氟乙酸盐的合成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
在0℃下，向3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-3,6-二氮杂双环[3.1.1]庚烷-6-甲酸叔丁酯(50.0mg,0.119mmol)的DCM溶液(2.00mL)中加入三氟乙酸(0.500mL)。反应混合物在室温下搅拌反应1小时。将反应混合物减压浓缩，得到目标化合物(50.0mg,粗品,灰色固体)。LC-MS(ESI)m/z 320.2[M+H] +。 At 0 °C, to 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3, To a solution of tert-butyl 6-diazabicyclo[3.1.1]heptane-6-carboxylate (50.0 mg, 0.119 mmol) in DCM (2.00 mL) was added trifluoroacetic acid (0.500 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (50.0 mg, crude, gray solid). LC-MS (ESI) m/z 320.2 [M+H] + .
步骤4:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-甲酰胺的合成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
向(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(66.3mg,0.345mmol)的碳酸氢钠水溶液(2.50mL)与DCM(5.00mL)混合液中加入三光气(61.4mg,0.207mmol)。反应混合物在室温下搅 拌反应1小时。反应混合物用DCM(10.0mL)萃取。有机相用饱和食盐水(4.00mL×3)洗、无水硫酸钠干燥、过滤。向滤液中加入TEA(69.8mg,0.690mmol)和4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈三氟乙酸盐(50.0mg,0.157mmol)。反应混合物在室温下搅拌反应20分钟。反应液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％氨的水)纯化得到目标化合物 (化合物6)(16.1mg,两步收率25.1％,白色固体)。LC-MS(ESI)m/z 538.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.87(s,1H),8.57(s,1H),8.46(d,J＝4.3Hz,1H),8.34–8.30(m,2H),8.03(s,1H),7.88–7.82(m,2H),7.75–7.71(m,1H),7.35(t,J＝5.7Hz,1H),7.27(s,1H),4.34–4.27(m,4H),3.86(s,3H),3.79–3.74(m,2H),3.57–3.52(m,2H),3.23–3.15(m,1H),2.18(d,J＝7.9Hz,1H)。 To a mixture of (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (66.3 mg, 0.345 mmol) in aqueous sodium bicarbonate (2.50 mL) and DCM (5.00 mL) To this was added triphosgene (61.4 mg, 0.207 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with DCM (10.0 mL). The organic phase was washed with saturated brine (4.00 mL×3), dried over anhydrous sodium sulfate, and filtered. To the filtrate was added TEA (69.8 mg, 0.690 mmol) and 4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-(1-methyl-1H-pyrazole- 4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile trifluoroacetate (50.0 mg, 0.157 mmol). The reaction mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure to obtain a crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% ammonia) afforded the title compound (compound 6) (16.1 mg, 25.1% yield over two steps, white solid). LC-MS (ESI) m/z 538.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.87(s, 1H), 8.57(s, 1H), 8.46(d, J=4.3Hz, 1H), 8.34-8.30(m, 2H), 8.03( s, 1H), 7.88–7.82 (m, 2H), 7.75–7.71 (m, 1H), 7.35 (t, J=5.7Hz, 1H), 7.27 (s, 1H), 4.34–4.27 (m, 4H) , 3.86 (s, 3H), 3.79–3.74 (m, 2H), 3.57–3.52 (m, 2H), 3.23–3.15 (m, 1H), 2.18 (d, J=7.9Hz, 1H).
实施例7： 1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)哌啶-4-甲酰胺(化合物7)及其盐酸盐(化合物7-1)的合成 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)
Figure PCTCN2021118001-appb-000029
Figure PCTCN2021118001-appb-000029
步骤1：1-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)哌啶-4-甲酸乙酯的合成Step 1: Synthesis of 1-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester
向6-溴-4-氟吡唑并[1,5-a]吡啶-3-甲腈(600mg,2.50mmol)和哌啶-4-甲酸乙酯盐酸盐(581mg,3.00mmol)的N-甲基吡咯烷酮(6.00mL)溶液中加入无水碳酸钾(863mg,6.30mmol)。封管，反应混合物在100℃下搅拌反应16小时。将反应混合物冷却至室温后加入水(20.0mL)中，用EA(60.0mL)萃取。有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤，滤液减压浓缩得粗产物。柱层析分离纯化(EA:PE＝0:100--15:100)得到目标化合物(280mg,收率29.7％,白色固体)。LC-MS(ESI)m/z 377.2,379.2[M+H] +。 To 6-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile (600 mg, 2.50 mmol) and piperidine-4-carboxylic acid ethyl ester hydrochloride (581 mg, 3.00 mmol) in N - To the methylpyrrolidone (6.00 mL) solution was added anhydrous potassium carbonate (863 mg, 6.30 mmol). The tube was sealed and the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, added to water (20.0 mL), and extracted with EA (60.0 mL). The organic phase was washed with saturated brine (15.0 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Separation and purification by column chromatography (EA:PE=0:100--15:100) gave the target compound (280 mg, yield 29.7%, white solid). LC-MS (ESI) m/z 377.2, 379.2 [M+H] + .
步骤2：1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)哌啶-4-甲酸乙酯的合成Step 2: 1-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidine-4-carboxylic acid Synthesis of Ethyl Ester
向1-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)哌啶-4-甲酸乙酯(120mg,0.318mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(79.7mg,0.383mmol)的水(1.00mL)和1,4-二氧六环(5.00mL)混合溶液中加入无水碳酸钠(67.7mg,0.640mmol)和Pd(dppf)Cl 2DCM络合物(13.0mg,0.016mmol)。置换氩气三次，反应混合物在80℃下搅拌反应过夜。将反应液冷却至室温，倒入水(10.0mL)中，用EA(15.0mL×3)萃取。合并有机相用饱和食盐水(20.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经 柱层析分离纯化(EA:PE＝0:100—60:100)得到目标化合物(115mg,收率95.5％,白色固体)。LC-MS(ESI)m/z 379.3[M+H] +。 To ethyl 1-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)piperidine-4-carboxylate (120 mg, 0.318 mmol) and 1-methyl-4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (79.7 mg, 0.383 mmol) in water (1.00 mL) and To the mixed solution of 1,4-dioxane (5.00 mL) was added anhydrous sodium carbonate (67.7 mg, 0.640 mmol) and Pd(dppf)Cl 2 DCM complex (13.0 mg, 0.016 mmol). The argon was replaced three times and the reaction mixture was stirred at 80°C overnight. The reaction solution was cooled to room temperature, poured into water (10.0 mL), and extracted with EA (15.0 mL×3). The combined organic phases were washed with saturated brine (20.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (EA:PE=0:100-60:100), the target compound (115 mg, yield 95.5%, white solid) was obtained. LC-MS (ESI) m/z 379.3 [M+H] + .
步骤3:1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)哌啶-4-甲酸的合成Step 3: 1-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidine-4-carboxylic acid Synthesis
向1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)哌啶-4-甲酸乙酯(115mg,0.304mmol)的乙醇(8.00mL)和水(2.00mL)混合溶液中加入氢氧化钠(36.5mg,0.913mmol)。反应混合物在室温下搅拌反应4小时。减压浓缩除去有机溶剂，加入水(10.0mL)，用1.0M的盐酸水溶液调pH到4，得到悬浊液。过滤，滤饼用水(20.0mL)洗，干燥后得到目标化合物(100mg,收率93.9％,白色固体)。LC-MS(ESI)m/z 351.2[M+H] +。 To 1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (115 mg, 0.304 mmol) in a mixed solution of ethanol (8.00 mL) and water (2.00 mL) was added sodium hydroxide (36.5 mg, 0.913 mmol). The reaction mixture was stirred at room temperature for 4 hours. The organic solvent was removed by concentration under reduced pressure, water (10.0 mL) was added, and the pH was adjusted to 4 with 1.0 M aqueous hydrochloric acid to obtain a suspension. After filtration, the filter cake was washed with water (20.0 mL), and dried to obtain the title compound (100 mg, yield 93.9%, white solid). LC-MS (ESI) m/z 351.2 [M+H] + .
步骤4:1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)哌啶-4-甲酰胺及其盐酸盐的合成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
将1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)哌啶-4-甲酸(100mg,0.285mmol)和(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(54.9mg,0.285mmol)溶于DMF(8.00mL)中。加入DIEA(73.8mg,0.571mmol)、EDCI(82.1mg,0.428mmol)和HOBt(57.8mg,0.428mmol)。反应混合物在室温下搅拌反应16小时。将反应液缓缓加入水(10.0mL)中，用EA(10.0mL×2)萃取。有机相用饱和食盐水(10.0mL×2)洗、无水硫酸钠干燥，过滤。滤液减压浓缩得到粗产品 (化合物7)。经制备HPLC(乙腈/含0.05％盐酸的水)纯化得到 盐酸盐形式 的目标化合物 (化合物7-1)(6.92mg,盐酸盐,收率4.32％,白色固体)。LC-MS(ESI)m/z 525.4[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.88(s,1H),8.68(d,J＝4.4Hz,1H),8.58–8.50(m,2H),8.36(s,2H),8.06(s,1H),7.91(d,J＝4.1Hz,1H),7.88(s,2H),7.24(s,1H),4.35(d,J＝5.5Hz,2H),3.87(s,3H),3.52–3.47(m,2H),2.80(t,J＝10.9Hz,2H),2.46–2.37(m,1H),2.06–1.93(m,2H),1.93–1.84(m,2H)。 1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidine-4-carboxylic acid (100 mg , 0.285 mmol) and (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (54.9 mg, 0.285 mmol) were dissolved in DMF (8.00 mL). DIEA (73.8 mg, 0.571 mmol), EDCI (82.1 mg, 0.428 mmol) and HOBt (57.8 mg, 0.428 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was slowly added to water (10.0 mL) and extracted with EA (10.0 mL×2). The organic phase was washed with saturated brine (10.0 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product (compound 7) . Purification by preparative HPLC (acetonitrile/water containing 0.05% hydrochloric acid) afforded the title compound (compound 7-1) as hydrochloride salt (6.92 mg, hydrochloride salt, yield 4.32%, white solid). LC-MS (ESI) m/z 525.4 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.88(s, 1H), 8.68(d, J=4.4Hz, 1H), 8.58-8.50(m, 2H), 8.36(s, 2H), 8.06( s, 1H), 7.91(d, J=4.1Hz, 1H), 7.88(s, 2H), 7.24(s, 1H), 4.35(d, J=5.5Hz, 2H), 3.87(s, 3H), 3.52–3.47 (m, 2H), 2.80 (t, J=10.9Hz, 2H), 2.46–2.37 (m, 1H), 2.06–1.93 (m, 2H), 1.93–1.84 (m, 2H).
实施例8： 3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)-3-氮杂双环[3.2.1]辛烷-8-甲酰胺(化合物8)的合成 Example 8: 3-(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-azabicyclo[3.2.1]octane-8-carboxamide (Compound 8)
Figure PCTCN2021118001-appb-000030
Figure PCTCN2021118001-appb-000030
步骤1:3-苄基-3-氮杂双环[3.2.1]辛烷-8-甲腈的合成Step 1: Synthesis of 3-benzyl-3-azabicyclo[3.2.1]octane-8-carbonitrile
将3-苄基-3-氮杂双环[3.2.1]辛烷-8-酮(5.95g,27.6mmol)和对甲苯磺酰甲基异氰(9.70g,49.7mmol)加入到1,2-二氯乙烷(185mL)中。在氮气保护下，冰浴下加入无水乙醇(2.90 mL,63.5mmol)后，分四次加入叔丁醇钾(10.8g,96.6mmol)。反应混合物在50℃下搅拌反应18小时。将反应混合物冷却至室温，倾入饱和氯化钠水溶液(80mL)中，用EA(100mL×3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩得粗产物。经柱层析分离纯化(PE:EA＝100:1-5:1)得到目标化合物(3.85g,收率61.6％,白色固体)。LC-MS(ESI)m/z 227.2[M+H] +。 3-Benzyl-3-azabicyclo[3.2.1]octan-8-one (5.95 g, 27.6 mmol) and p-toluenesulfonylmethyl isocyanide (9.70 g, 49.7 mmol) were added to 1,2 - in dichloroethane (185 mL). Under nitrogen protection, anhydrous ethanol (2.90 mL, 63.5 mmol) was added under an ice bath, and then potassium tert-butoxide (10.8 g, 96.6 mmol) was added in four portions. The reaction mixture was stirred at 50°C for 18 hours. The reaction mixture was cooled to room temperature, poured into saturated aqueous sodium chloride solution (80 mL), and extracted with EA (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=100:1-5:1), the target compound (3.85 g, yield 61.6%, white solid) was obtained. LC-MS (ESI) m/z 227.2 [M+H] + .
步骤2:3-苄基-3-氮杂双环[3.2.1]辛烷-8-甲酸乙酯的合成Step 2: Synthesis of 3-benzyl-3-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester
将3-苄基-3-氮杂双环[3.2.1]辛烷-8-甲腈(1.60g,7.07mmol)加入到氯化氢乙醇溶液(12.0mL)中。封管密闭，反应混合物在80℃下搅拌反应16小时。补加氯化氢乙醇溶液(6.00mL)，反应混合物继续在80℃下搅拌反应16小时。反应液冷却至室温后，缓缓倾入水(60.0mL)中，用饱和碳酸氢钠溶液调节pH到8，用EA(120mL×2)萃取。合并有机相用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE:EA＝100:1)得到目标化合物(1.05g,收率54.3％,无色油状物)。LC-MS(ESI)m/z 274.3[M+H] +。 3-Benzyl-3-azabicyclo[3.2.1]octane-8-carbonitrile (1.60 g, 7.07 mmol) was added to a solution of hydrogen chloride in ethanol (12.0 mL). The tube was sealed and the reaction mixture was stirred at 80°C for 16 hours. An additional solution of hydrogen chloride in ethanol (6.00 mL) was added, and the reaction mixture was further stirred at 80° C. for 16 hours. After the reaction solution was cooled to room temperature, it was slowly poured into water (60.0 mL), adjusted to pH 8 with saturated sodium bicarbonate solution, and extracted with EA (120 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification by column chromatography (PE:EA=100:1) gave the target compound (1.05 g, yield 54.3%, colorless oil). LC-MS (ESI) m/z 274.3 [M+H] + .
步骤3:3-氮杂双环[3.2.1]辛烷-8-甲酸乙酯的合成Step 3: Synthesis of ethyl 3-azabicyclo[3.2.1]octane-8-carboxylate
将3-苄基-3-氮杂双环[3.2.1]辛烷-8-甲酸乙酯(1.05g,3.84mmol)溶于甲醇(20.0mL)中。加入钯碳(100mg)，置换氢气三次。反应混合物在室温下搅拌反应16小时。过滤，滤饼用甲醇(10.0mL)洗，滤液减压浓缩后得到目标化合物(690mg,收率97.8％,类白色固体)。LC-MS(ESI)m/z 184.1[M+H] +。 3-Benzyl-3-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (1.05 g, 3.84 mmol) was dissolved in methanol (20.0 mL). Palladium on carbon (100 mg) was added, and hydrogen was replaced three times. The reaction mixture was stirred at room temperature for 16 hours. After filtration, the filter cake was washed with methanol (10.0 mL), and the filtrate was concentrated under reduced pressure to obtain the target compound (690 mg, yield 97.8%, off-white solid). LC-MS (ESI) m/z 184.1 [M+H] + .
步骤4:3-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-3-氮杂双环[3.2.1]辛烷-8-甲酸乙酯的合成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
向6-溴-4-氟吡唑并[1,5-a]吡啶-3-甲腈(600mg,2.50mmol)和3-氮杂双环[3.2.1]辛烷-8-甲酸乙酯(550mg,3.00mmol)的N-甲基吡咯烷酮(5.00mL)溶液中加入DIEA(646mg,5.00mmol)。反应混合物在100℃下搅拌反应16小时。将反应液冷却至室温后倒入水(20.0mL)中，用EA(80.0mL)萃取。有机相用饱和食盐水洗，无水硫酸钠干燥、过滤、滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝20：1-10：1)得到目标化合物(800mg,收率79.4％,类白色固体)。LC-MS(ESI)m/z 403.1,405.1[M+H] +。 To 6-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile (600 mg, 2.50 mmol) and ethyl 3-azabicyclo[3.2.1]octane-8-carboxylate ( To a solution of 550 mg, 3.00 mmol) in N-methylpyrrolidone (5.00 mL) was added DIEA (646 mg, 5.00 mmol). The reaction mixture was stirred at 100°C for 16 hours. The reaction solution was cooled to room temperature, poured into water (20.0 mL), and extracted with EA (80.0 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. After separation and purification by column chromatography (PE:EA=20:1-10:1), the target compound (800 mg, yield 79.4%, off-white solid) was obtained. LC-MS (ESI) m/z 403.1, 405.1 [M+H] + .
步骤5:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-3-氮杂双环[3.2.1]辛烷-8-甲酸乙酯的合成Step 5: 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3-azabicyclo [3.2.1] Synthesis of ethyl octane-8-carboxylate
向3-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-3-氮杂双环[3.2.1]辛烷-8-甲酸乙酯(300mg,0.744mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑(186mg,0.893mmol)的水(0.600mL)和1,4-二氧六环(3.00mL)混合溶液中加入碳酸钠(158mg,1.49mmol)和Pd(dppf)Cl 2(48.1mg,0.056mmol)。氩气保护下，反应混合物在80℃下搅拌反应 16小时。将反应液冷却至室温后倒入水(15.0mL)中，用EA(25.0mL×2)萃取。合并有机相用无水硫酸钠干燥、过滤、滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝4：1-2：1)得到目标化合物(120mg,粗品,黄色油状物)。LC-MS(ESI)m/z 405.1[M+H] +。 To 3-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (300 mg, 0.744 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazole (186 mg, 0.893 mmol) To a mixed solution of water (0.600 mL) and 1,4-dioxane (3.00 mL) was added sodium carbonate (158 mg, 1.49 mmol) and Pd(dppf)Cl 2 (48.1 mg, 0.056 mmol). Under argon, the reaction mixture was stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, poured into water (15.0 mL), and extracted with EA (25.0 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Separation and purification by column chromatography (PE:EA=4:1-2:1) gave the title compound (120 mg, crude product, yellow oil). LC-MS (ESI) m/z 405.1 [M+H] + .
步骤6:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-3-氮杂双环[3.2.1]辛烷-8-甲酸的合成Step 6: 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3-azabicyclo [3.2.1] Synthesis of octane-8-carboxylic acid
将3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-3-氮杂双环[3.2.1]辛烷-8-甲酸乙酯(120mg,0.297mmol)溶于乙醇(5.00mL)中，加入氢氧化钠(23.7mg,0.593mmol)。反应混合物在室温下搅拌反应3小时。将反应混合物减压浓缩，残留物溶于水(6.00mL)中，加入1.0M盐酸调节pH＝4得到悬浊液，过滤。滤饼用水(5.00mL)洗。真空干燥得到目标化合物(80.0mg,两步收率71.4％,黄色固体)。LC-MS(ESI)m/z 377.3[M+H] +。 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3-azabicyclo[3.2 .1] Ethyl octane-8-carboxylate (120 mg, 0.297 mmol) was dissolved in ethanol (5.00 mL) and sodium hydroxide (23.7 mg, 0.593 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (6.00 mL), and 1.0 M hydrochloric acid was added to adjust pH=4 to obtain a suspension, which was filtered. The filter cake was washed with water (5.00 mL). Vacuum drying gave the title compound (80.0 mg, 71.4% over two steps, yellow solid). LC-MS (ESI) m/z 377.3 [M+H] + .
步骤7:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-3-氮杂双环[3.2.1]辛烷-8-甲酰胺的合成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
向3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-3-氮杂双环[3.2.1]辛烷-8-甲酸(80.0mg,0.213mmol)和(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(40.9mg,0.213mmol)的DMF(2.00mL)溶液中加入EDCI(61.2mg,0.319mmol)、HOBt(41.3mg,0.319mmol)和DIEA(54.9mg,0.425mmol)。反应混合物室温下搅拌反应1小时。将反应混合物倒入水中(10.0mL)中，用EA(30.0mL)萃取。有机相用饱和食盐水(10.0mL×3)洗，无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(10.1mg,收率7.97％,黄色固体)。LC-MS(ESI)m/z 551.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.90(s,1H),8.69(d,J＝4.5Hz,1H),8.59(s,1H),8.50-8.46(m,1H),8.37–8.33(m,2H),8.06(s,1H),7.94–7.88(m,2H),7.88–7.84(m,1H),7.30(s,1H),4.35(d,J＝5.7Hz,2H),3.88(s,3H),3.48–3.43(m,2H),3.01–2.95(m,2H),2.72–2.67(m,2H),2.15–2.08(m,2H),1.70–1.63(m,2H),1.27–1.21(m,1H)。 To 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3-azabicyclo[3.2 .1] Octane-8-carboxylic acid (80.0 mg, 0.213 mmol) and (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (40.9 mg, 0.213 mmol) To a solution of DMF (2.00 mL) was added EDCI (61.2 mg, 0.319 mmol), HOBt (41.3 mg, 0.319 mmol) and DIEA (54.9 mg, 0.425 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (10.0 mL) and extracted with EA (30.0 mL). The organic phase was washed with saturated brine (10.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (10.1 mg, 7.97% yield, yellow solid). LC-MS (ESI) m/z 551.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.90(s, 1H), 8.69(d, J=4.5Hz, 1H), 8.59(s, 1H), 8.50-8.46(m, 1H), 8.37– 8.33(m, 2H), 8.06(s, 1H), 7.94-7.88(m, 2H), 7.88-7.84(m, 1H), 7.30(s, 1H), 4.35(d, J=5.7Hz, 2H) ,3.88(s,3H),3.48–3.43(m,2H),3.01–2.95(m,2H),2.72–2.67(m,2H),2.15–2.08(m,2H),1.70–1.63(m, 2H), 1.27–1.21 (m, 1H).
实施例9： (S)-4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑 -1-基)吡啶-3-基)甲基)-2-甲基哌嗪-1-甲酰胺(化合物9)的合成 Example 9: (S)-4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)- Synthesis of N-((6-(4-Fluoro-1H-pyrazol- 1-yl)pyridin-3-yl)methyl)-2-methylpiperazine-1-carboxamide (Compound 9)
Figure PCTCN2021118001-appb-000031
Figure PCTCN2021118001-appb-000031
步骤1:(S)-4-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-2-甲基哌嗪-1-甲酸叔丁酯的合成Step 1: Synthesis of (S)-4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester
向6-溴-4-氟吡唑并[1,5-a]吡啶-3-甲腈(350mg,1.46mmol)和(S)-2-甲基哌嗪-1-甲酸叔丁酯(292mg,1.46mmol)的N-甲基吡咯烷酮(3.00mL)溶液加入碳酸钾(403mg,2.91mmol)。反应混合物在100℃下搅拌反应16小时。将反应混合物冷却至室温后倒入水(15.0mL)中，用EA(60.0mL)萃取。有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝12:1-10:1)得到目标化合物(100mg,收率16.3％,类白色固体)。LC-MS(ESI)m/z 364.0,366.0[M-100+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.04(d,J＝1.3Hz,1H),8.65(s,1H),7.19(d,J＝1.2Hz,1H),4.37–4.25(m,1H),3.78–3.72(m,1H),3.62–3.50(m,2H),3.30–3.28(m,1H),3.19–3.13(m,1H),3.10–3.03(m,1H),1.43(s,9H),1.24(d,J＝6.7Hz,3H)。 To 6-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile (350 mg, 1.46 mmol) and (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (292 mg , 1.46 mmol) in N-methylpyrrolidone (3.00 mL) was added potassium carbonate (403 mg, 2.91 mmol). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (15.0 mL), and extracted with EA (60.0 mL). The organic phase was 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. After separation and purification by column chromatography (PE:EA=12:1-10:1), the target compound (100 mg, yield 16.3%, off-white solid) was obtained. LC-MS (ESI) m/z 364.0, 366.0 [M-100+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.04(d,J=1.3Hz,1H),8.65(s,1H),7.19(d,J=1.2Hz,1H), 4.37-4.25(m, 1H), 3.78–3.72 (m, 1H), 3.62–3.50 (m, 2H), 3.30–3.28 (m, 1H), 3.19–3.13 (m, 1H), 3.10–3.03 (m, 1H), 1.43 ( s, 9H), 1.24 (d, J=6.7Hz, 3H).
步骤2:(S)-4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-2-甲基哌嗪-1-甲酸叔丁酯的合成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
向(S)-4-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-2-甲基哌嗪-1-甲酸叔丁酯(100mg,0.238mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑(59.4mg,0.286mmol)的水(0.200mL)和1,4-二氧六环(1.00mL)溶液中加入碳酸钠(50.5mg,0.476mmol)和Pd(dppf)Cl 2DCM络合物(10.3mg,0.012mmol)。氩气保护下，反应混合物在80℃下搅拌反应16小时。将反应混合物冷却至室温后倒入EA(60mL×2)中得到黑色溶液。经无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝3：1-1：1)得到目标化合物(90.0mg,收率89.7％,黄色油状物)。LC-MS(ESI)m/z 444.2[M+Na] +。 To (S)-tert-butyl 4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (100 mg, 0.238 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazole (59.4 mg, 0.286 mmol) To a solution of water (0.200 mL) and 1,4-dioxane (1.00 mL) was added sodium carbonate (50.5 mg, 0.476 mmol) and Pd(dppf)Cl 2 DCM complex (10.3 mg, 0.012 mmol). Under argon, the reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature and poured into EA (60 mL×2) to obtain a black solution. Dry over anhydrous sodium sulfate and filter. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification by column chromatography (PE:EA=3:1-1:1) gave the target compound (90.0 mg, yield 89.7%, yellow oil). LC-MS (ESI) m/z 444.2 [M+Na] + .
步骤3:(S)-6-(1-甲基-1H-吡唑-4-基)-4-(3-甲基哌嗪-1-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐的合成Step 3: (S)-6-(1-Methyl-1H-pyrazol-4-yl)-4-(3-methylpiperazin-1-yl)pyrazolo[1,5-a]pyridine Synthesis of -3-carbonitrile hydrochloride
将(S)-4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-2-甲基哌嗪-1-甲酸叔丁酯(90.0mg,0.214mmol)加入到氯化氢甲醇溶液(3.0M,6.00mL)中。反应混合物在室温下搅拌反应4小时。反应混合物减压浓缩后得到目标化合物(80.0mg,收率100％,黄色固体)。LC-MS(ESI)m/z 322.1[M+H] +。 (S)-4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-2-methyl tert-butyl piperazine-1-carboxylate (90.0 mg, 0.214 mmol) was added to a solution of hydrogen chloride in methanol (3.0 M, 6.00 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (80.0 mg, yield 100%, yellow solid). LC-MS (ESI) m/z 322.1 [M+H] + .
步骤4:(S)-4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-2-甲基哌嗪-1-甲酰胺的合成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
向(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(35.8mg,0.186mmol)的饱和碳酸氢钠水溶液(3.00mL)与DCM(5.00mL)混合液中加入三光气(33.2mg,0.112mmol)。反应混合物在室温下搅拌反应1小时。反应液用DCM(10.0mL×1)萃取。有机相用饱和食盐水(4.00mL×3)洗、 无水硫酸钠干燥、过滤。向滤液中加入TEA(56.5mg,0.558mmol)和(S)-6-(1-甲基-1H-吡唑-4-基)-4-(3-甲基哌嗪-1-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(80.0mg,0.224mmol)。反应混合物在室温下搅拌反应20分钟。将反应液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(15.1mg,收率12.5％,白色固体)。LC-MS(ESI)m/z 540.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.95(s,1H),8.69(d,J＝4.3Hz,1H),8.60(s,1H),8.39–8.34(m,2H),8.08(s,1H),7.93–7.88(m,3H),7.30(s,2H),4.49–4.39(m,1H),4.37–4.27(m,2H),3.88(s,3H),3.83–3.74(m,1H),3.65–3.50(m,3H),3.29–3.20(m,1H),3.17–3.07(m,1H),1.27(d,J＝6.3Hz,3H)。 To (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (35.8 mg, 0.186 mmol) in saturated aqueous sodium bicarbonate (3.00 mL) was mixed with DCM (5.00 mL) To the solution was added triphosgene (33.2 mg, 0.112 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with DCM (10.0 mL×1). The organic phase was washed with saturated brine (4.00 mL×3), dried over anhydrous sodium sulfate, and filtered. To the filtrate was added TEA (56.5 mg, 0.558 mmol) and (S)-6-(1-methyl-1H-pyrazol-4-yl)-4-(3-methylpiperazin-1-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile hydrochloride (80.0 mg, 0.224 mmol). The reaction mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure to obtain a crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (15.1 mg, 12.5% yield, white solid). LC-MS (ESI) m/z 540.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.95(s, 1H), 8.69(d, J=4.3Hz, 1H), 8.60(s, 1H), 8.39-8.34(m, 2H), 8.08( s, 1H), 7.93–7.88 (m, 3H), 7.30 (s, 2H), 4.49–4.39 (m, 1H), 4.37–4.27 (m, 2H), 3.88 (s, 3H), 3.83–3.74 ( m, 1H), 3.65–3.50 (m, 3H), 3.29–3.20 (m, 1H), 3.17–3.07 (m, 1H), 1.27 (d, J=6.3 Hz, 3H).
实施例10： (R)-4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡 唑-1-基)吡啶-3-基)甲基)-2-甲基哌嗪-1-甲酰胺(化合物10)的合成 Example 10: (R)-4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)- Synthesis of N-((6-(4-Fluoro-1H-pyrazol -1-yl)pyridin-3-yl)methyl)-2-methylpiperazine-1-carboxamide (Compound 10)
Figure PCTCN2021118001-appb-000032
Figure PCTCN2021118001-appb-000032
步骤1:(R)-4-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-2-甲基哌嗪-1-甲酸叔丁酯的合成Step 1: Synthesis of (R)-4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester
向6-溴-4-氟吡唑并[1,5-a]吡啶-3-甲腈(300mg,1.25mmol)和(R)-2-甲基哌嗪-1-甲酸叔丁酯(375mg,1.87mmol)的N-甲基吡咯烷酮(2.00mL)溶液加入碳酸钾(346mg,2.50mmol)。反应混合物在100℃下搅拌反应16小时。将反应混合物冷却至室温后倒入水(20.0mL)中，用EA(20.0mL×3)萃取。合并有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤，滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝9:1)得到目标化合物(80.0mg，收率15.2％，灰色固体)。LC-MS(ESI)m/z 364.0,366.0[M-56+H] +。 1H NMR(400MHz,CDCl 3)δ8.42(d,J＝1.4Hz,1H),8.20(s,1H),6.87(d,J＝1.4Hz,1H),4.54–4.46(m,1H),3.95–3.88(m,1H),3.84–3.76(m,1H),3.67–3.61(m,1H),3.17–3.12(m,1H),3.05–3.00(m,1H),2.60–2.52(m,1H),1.48(s,9H),1.37(d,J＝6.8Hz,3H)。 To 6-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile (300 mg, 1.25 mmol) and (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (375 mg , 1.87 mmol) in N-methylpyrrolidone (2.00 mL) was added potassium carbonate (346 mg, 2.50 mmol). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (20.0 mL), and extracted with EA (20.0 mL×3). The combined organic phases were washed with saturated brine (15.0 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. After separation and purification by column chromatography (PE:EA=9:1), the target compound (80.0 mg, yield 15.2%, gray solid) was obtained. LC-MS (ESI) m/z 364.0, 366.0 [M-56+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.42 (d, J=1.4 Hz, 1H), 8.20 (s, 1H), 6.87 (d, J=1.4 Hz, 1H), 4.54-4.46 (m, 1H) ,3.95–3.88(m,1H),3.84–3.76(m,1H),3.67–3.61(m,1H),3.17–3.12(m,1H),3.05–3.00(m,1H),2.60–2.52( m, 1H), 1.48 (s, 9H), 1.37 (d, J=6.8Hz, 3H).
步骤2:(R)-4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-2-甲基哌嗪-1-甲酸叔丁酯的合成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
向(R)-4-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-2-甲基哌嗪-1-甲酸叔丁酯(80.0mg,0.190mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑(50.0mg,0.240mmol)的水(1.00mL)和1,4-二氧六环(5.00mL)溶液中加入碳酸钠(42.0mg,0.396mmol)和Pd(dppf)Cl 2DCM络合物(8.00mg,0.009mmol)。氮气保护下，反应混合物在80℃下搅拌反 应16小时。将反应混合物冷却至室温后倒入EA(20.0mL)中得到黑色溶液。溶液用无水硫酸钠干燥、过滤，滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝9:1-5:1)得到目标化合物(70.0mg，收率89.1％，白色固体)。LC-MS(ESI)m/z 422.2[M+H] +。 To (R)-tert-butyl 4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-2-methylpiperazine-1-carboxylate (80.0 mg, 0.190 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazole (50.0 mg, 0.240 mmol ) in water (1.00 mL) and 1,4-dioxane (5.00 mL) was added sodium carbonate (42.0 mg, 0.396 mmol) and Pd(dppf)Cl 2 DCM complex (8.00 mg, 0.009 mmol) . Under nitrogen protection, the reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature and poured into EA (20.0 mL) to give a black solution. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=9:1-5:1), the target compound (70.0 mg, yield 89.1%, white solid) was obtained. LC-MS (ESI) m/z 422.2 [M+H] + .
步骤3:(R)-6-(1-甲基-1H-吡唑-4-基)-4-(3-甲基哌嗪-1-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐的合成Step 3: (R)-6-(1-Methyl-1H-pyrazol-4-yl)-4-(3-methylpiperazin-1-yl)pyrazolo[1,5-a]pyridine Synthesis of -3-carbonitrile hydrochloride
向(R)-4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-2-甲基哌嗪-1-甲酸叔丁酯(76.0mg,0.166mmol)的甲醇(3.00mL)溶液中加入氯化氢甲醇溶液(3.0M,3.00mL)。反应混合物在室温下搅拌反应12小时。将反应混合物减压浓缩后得到目标化合物(50.0mg,收率84.2％,灰色固体)。LC-MS(ESI)m/z 322.1[M+H] +。 To (R)-4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-2-methyl To a solution of tert-butyl piperazine-1-carboxylate (76.0 mg, 0.166 mmol) in methanol (3.00 mL) was added a solution of hydrogen chloride in methanol (3.0 M, 3.00 mL). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (50.0 mg, 84.2% yield, gray solid). LC-MS (ESI) m/z 322.1 [M+H] + .
步骤4:(R)-4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-2-甲基哌嗪-1-甲酰胺的合成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
向(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(22.4mg,0.116mmol)的饱和碳酸氢钠水溶液(3.00mL)与DCM(5.00mL)混合液中加入三光气(20.8mg,0.070mmol)。反应混合物在室温下搅拌反应1小时。用DCM(10.0mL)萃取。有机相用饱和食盐水(4.00mL×3)洗、无水硫酸钠干燥、过滤。向滤液中加入TEA(35.3mg,0.349mmol)和(R)-6-(1-甲基-1H-吡唑-4-基)-4-(3-甲基哌嗪-1-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(50.0mg,0.140mmol)。反应混合物在室温下搅拌反应20分钟。将反应液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(16.0mg,收率21.3％,白色固体)。LC-MS(ESI)m/z 540.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.15(d,J＝1.2Hz,1H),8.98(dd,J＝4.5,0.7Hz,1H),8.86(s,1H),8.84(s,1H),8.64(s,1H),8.43-8.41(m,1H),8.40-8.34(m,2H),8.18(d,J＝4.4Hz,1H),7.75(d,J＝1.0Hz,1H),7.13-7.08(m,1H),5.04-5.00(m,1H),4.92(d,J＝5.9Hz,2H),4.39(s,3H),4.31–4.26(m,3H),4.17-4.11(m,1H),3.80-3.73(m,1H),3.70-3.64(m,1H),1.82(d,J＝6.7Hz,3H)。 To (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (22.4 mg, 0.116 mmol) in saturated aqueous sodium bicarbonate (3.00 mL) was mixed with DCM (5.00 mL) To the solution was added triphosgene (20.8 mg, 0.070 mmol). The reaction mixture was stirred at room temperature for 1 hour. Extracted with DCM (10.0 mL). The organic phase was washed with saturated brine (4.00 mL×3), dried over anhydrous sodium sulfate, and filtered. To the filtrate was added TEA (35.3 mg, 0.349 mmol) and (R)-6-(1-methyl-1H-pyrazol-4-yl)-4-(3-methylpiperazin-1-yl)pyridine Azolo[1,5-a]pyridine-3-carbonitrile hydrochloride (50.0 mg, 0.140 mmol). The reaction mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure to obtain a crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (16.0 mg, 21.3% yield, white solid). LC-MS (ESI) m/z 540.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.15(d, J=1.2Hz, 1H), 8.98(dd, J=4.5, 0.7Hz, 1H), 8.86(s, 1H), 8.84(s, 1H), 8.64(s, 1H), 8.43-8.41(m, 1H), 8.40-8.34(m, 2H), 8.18(d, J=4.4Hz, 1H), 7.75(d, J=1.0Hz, 1H) ),7.13-7.08(m,1H),5.04-5.00(m,1H),4.92(d,J=5.9Hz,2H),4.39(s,3H),4.31-4.26(m,3H),4.17- 4.11 (m, 1H), 3.80-3.73 (m, 1H), 3.70-3.64 (m, 1H), 1.82 (d, J=6.7Hz, 3H).
实施例11： 4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)-1,4-二氮杂环庚烷-1-甲酰胺(化合物11)的合成 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)
Figure PCTCN2021118001-appb-000033
Figure PCTCN2021118001-appb-000033
步骤1:4-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯的合成Step 1: Synthesis of 4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-1,4-diazepan-1-carboxylic acid tert-butyl ester
将4-氟-6-溴吡唑并[1,5-a]吡啶-3-甲腈(1.00g,4.16mmol)和1,4-二氮杂环庚烷-1-甲酸叔丁酯(1.00g,4.99mmol)溶于N-甲基吡咯烷酮(5.00mL)中。向反应混合液中加入DIEA(1.08g,8.32mmol)。反应混合液在90℃下搅拌反应16小时。将反应混合物冷却至室温后倒入水(10.0mL)中，用EA(15.0mL×3)萃取。合并有机相用饱和食盐水(10.0mL×4)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝12:1-10:1)得到目标化合物(580mg，收率33.1％，淡黄色固体)。LC-MS(ESI)m/z 442.1,444.1[M+Na] +。 4-Fluoro-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile (1.00 g, 4.16 mmol) and tert-butyl 1,4-diazepan-1-carboxylate ( 1.00 g, 4.99 mmol) was dissolved in N-methylpyrrolidone (5.00 mL). To the reaction mixture was added DIEA (1.08 g, 8.32 mmol). The reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (10.0 mL), and extracted with EA (15.0 mL×3). The combined organic phases were washed with saturated brine (10.0 mL×4), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=12:1-10:1), the target compound (580 mg, yield 33.1%, pale yellow solid) was obtained. LC-MS (ESI) m/z 442.1, 444.1 [M+Na] + .
步骤2:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯的合成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
向4-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(250mg,0.595mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑(186mg,0.894mmol)的水(0.500mL)和1,4-二氧六环(3.00mL)溶液中加入碳酸钾(164mg,1.19mmol)和Pd(dppf)Cl 2DCM络合物(26.0mg,0.030mmol)。氩气保护下，反应混合液在100℃下搅拌反应6小时。将反应混合物冷却至室温后倒入水(5.00mL)中，用EA(10.0mL×2)萃取。合并有机相用饱和食盐水(10.0mL×2)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经反相柱分离纯化(C18，乙腈/含0.05％甲酸的水)得到目标化合物(145mg，收率57.8％,淡黄色固体)。LC-MS(ESI)m/z 444.3[M+Na] +。 To 4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-1,4-diazepan-1-carboxylic acid tert-butyl ester (250 mg, 0.595 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazole (186 mg, 0.894 mmol) To a solution of water (0.500 mL) and 1,4-dioxane (3.00 mL) was added potassium carbonate (164 mg, 1.19 mmol) and Pd(dppf) Cl2DCM complex (26.0 mg, 0.030 mmol). Under argon protection, the reaction mixture was stirred at 100 °C for 6 hours. The reaction mixture was cooled to room temperature, poured into water (5.00 mL), and extracted with EA (10.0 mL×2). The combined organic phases were washed with saturated brine (10.0 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Reverse-phase column separation and purification (C18, acetonitrile/water containing 0.05% formic acid) gave the title compound (145 mg, yield 57.8%, pale yellow solid). LC-MS (ESI) m/z 444.3 [M+Na] + .
步骤3:4-(1,4-二氮杂环庚烷-1-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐的合成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
4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(145mg,0.344mmol)的氯化氢甲醇溶液(3.0M,10.0mL)在室温下搅拌反应16小时。将反应混合物减压浓缩得到目标化合物(120mg，收率97.5％，白色固体)。LC-MS(ESI)m/z 322.3[M+H] +。 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1,4-diazacycle A solution of tert-butyl heptane-1-carboxylate (145 mg, 0.344 mmol) in methanol with hydrogen chloride (3.0 M, 10.0 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (120 mg, yield 97.5%, white solid). LC-MS (ESI) m/z 322.3 [M+H] + .
步骤4:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-1,4-二氮杂环庚烷-1-甲酰胺的合成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
向碳酸氢钠水溶液(3.00mL)与DCM(5.00mL)的混合液中依次加入(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(60.0mg,0.312mmol)和三光气(55.8mg,0.188mmol)。反应混合物在室温下搅拌反应1小时。反应混合物用DCM(10.0mL)萃取。有机相用饱和食盐水(5.00mL×2)洗、无水硫酸钠干燥、过滤。向滤液中依次加入TEA(94.8mg,0.936mmol)和4-(1,4-二氮杂环庚烷-1-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(120mg,0.335 mmol)。反应混合物在室温下搅拌反应30分钟。将反应混合液减压浓缩得到粗品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(23.81mg,收率13.2％,白色固体)。LC-MS(ESI)m/z 540.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.90(s,1H),8.66(d,J＝4.1Hz,1H),8.57(s,1H),8.36-8.33(m,2H),8.05(s,1H),7.96–7.79(m,3H),7.35(s,1H),7.14–7.01(m,1H),4.32(d,J＝4.9Hz,2H),3.86(s,3H),3.79–3.70(m,2H),3.60–3.51(m,2H),3.39–3.32(m,4H),2.18–2.00(m,2H)。 To a mixture of aqueous sodium bicarbonate (3.00 mL) and DCM (5.00 mL) was sequentially added (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (60.0 mg, 0.312 mmol) and triphosgene (55.8 mg, 0.188 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with DCM (10.0 mL). The organic phase was washed with saturated brine (5.00 mL×2), dried over anhydrous sodium sulfate, and filtered. To the filtrate was added TEA (94.8 mg, 0.936 mmol) followed by 4-(1,4-diazepan-1-yl)-6-(1-methyl-1H-pyrazol-4-yl) Pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride (120 mg, 0.335 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (23.81 mg, 13.2% yield, white solid). LC-MS (ESI) m/z 540.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.90(s, 1H), 8.66(d, J=4.1Hz, 1H), 8.57(s, 1H), 8.36-8.33(m, 2H), 8.05( s, 1H), 7.96–7.79 (m, 3H), 7.35 (s, 1H), 7.14–7.01 (m, 1H), 4.32 (d, J=4.9Hz, 2H), 3.86 (s, 3H), 3.79 – 3.70 (m, 2H), 3.60 – 3.51 (m, 2H), 3.39 – 3.32 (m, 4H), 2.18 – 2.00 (m, 2H).
实施例12： 1-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-((6-甲氧基吡啶-3-基) 甲基)氮杂环丁烷-3-甲酰胺(化合物12)的合成 Example 12: 1-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N-((6- Synthesis of Methoxypyridin-3-yl) methyl)azetidine-3-carboxamide (Compound 12)
Figure PCTCN2021118001-appb-000034
Figure PCTCN2021118001-appb-000034
步骤1:1-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)氮杂环丁烷-3-甲酸甲酯的合成Step 1: Synthesis of methyl 1-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)azetidine-3-carboxylate
向6-溴-4-氟吡唑并[1,5-a]吡啶-3-甲腈(720mg,3.00mmol)和氮杂环丁烷-3-甲酸甲酯盐酸盐(500mg,3.30mmol)的N-甲基吡咯烷酮(10.0mL)溶液加入DIEA(1.16g,9.00mmol)。反应混合液在100℃下搅拌反应8小时。将反应混合物冷却至室温后倒入水(30.0mL)中，搅拌1小时，过滤。滤饼用水(10.0mL)洗，干燥后得到目标化合物(625mg，收率62.2％，淡黄色固体)。LC-MS(ESI)m/z 335.1,337.1[M+H] +。 To 6-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile (720 mg, 3.00 mmol) and methyl azetidine-3-carboxylate hydrochloride (500 mg, 3.30 mmol) ) in N-methylpyrrolidone (10.0 mL) was added DIEA (1.16 g, 9.00 mmol). The reaction mixture was stirred at 100°C for 8 hours. The reaction mixture was cooled to room temperature, poured into water (30.0 mL), stirred for 1 hour, and filtered. The filter cake was washed with water (10.0 mL), and dried to obtain the title compound (625 mg, yield 62.2%, pale yellow solid). LC-MS (ESI) m/z 335.1, 337.1 [M+H] + .
步骤2:1-(3-氰基-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑并[1,5-a]吡啶-4-基)氮杂环丁烷-3-甲酸甲酯的合成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
向1-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)氮杂环丁烷-3-甲酸甲酯(1.10g,3.28mmol)和联硼酸频哪醇酯(4.17g,16.4mmol)的干燥1,4-二氧六环(20.0mL)溶液中加入乙酸钾(644mg,6.56mmol)和Pd(dppf)Cl 2DCM络合物(141mg,0.164mmol)。氩气保护下，反应混合物在90℃下搅拌反应16小时。将反应混合物冷却至室温后倒入EA(100mL)中。过滤，滤饼用EA(20.0mL)洗。滤液减压浓缩得到目标化合物(6.00g，粗品,黑色固体)。LC-MS(ESI)m/z 383.2[M+H] +。 To methyl 1-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)azetidine-3-carboxylate (1.10 g, 3.28 mmol) and biboronic acid To a solution of aldolester (4.17 g, 16.4 mmol) in dry 1,4-dioxane (20.0 mL) was added potassium acetate (644 mg, 6.56 mmol) and Pd(dppf)Cl 2 DCM complex (141 mg, 0.164 mmol). Under argon, the reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and poured into EA (100 mL). Filter and wash the filter cake with EA (20.0 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (6.00 g, crude product, black solid). LC-MS (ESI) m/z 383.2 [M+H] + .
步骤3:1-(3-氰基-6-羟基吡唑并[1,5-a]吡啶-4-基)氮杂环丁烷-3-甲酸甲酯的合成Step 3: Synthesis of methyl 1-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)azetidine-3-carboxylate
在0℃下，向1-(3-氰基-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑并[1,5-a]吡啶-4-基)氮杂环丁烷-3-甲酸甲酯(6.00g,15.7mmol)的四氢呋喃(200mL)溶液中加入氢氧化钠(2.51g,62.8mmol)。随后滴加30％过氧化氢(12.8mL,126mmol)。反应混合液在室温下搅 拌反应1小时。向反应混合液中加入饱和氯化铵水溶液(100mL)，在室温下搅拌15分钟。分出有机相，水相用EA(80.0mL×2)萃取。合并有机相用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产物。经柱层析分离纯化(PE：EA＝4:1-1:1)得到目标化合物(320mg，两步收率35.8％，黄色固体)。LC-MS(ESI)m/z 273.3[M+H] +。 To 1-(3-cyano-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazolo at 0°C To a solution of methyl [1,5-a]pyridin-4-yl)azetidine-3-carboxylate (6.00 g, 15.7 mmol) in tetrahydrofuran (200 mL) was added sodium hydroxide (2.51 g, 62.8 mmol). 30% hydrogen peroxide (12.8 mL, 126 mmol) was then added dropwise. The reaction mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution (100 mL) was added to the reaction mixture, followed by stirring at room temperature for 15 minutes. The organic phase was separated, and the aqueous phase was extracted with EA (80.0 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=4:1-1:1), the target compound (320 mg, 35.8% yield in two steps, yellow solid) was obtained. LC-MS (ESI) m/z 273.3 [M+H] + .
步骤4:1-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)氮杂环丁烷-3-甲酸的合成Step 4: 1-(3-Cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)azetidine-3- Synthesis of Formic Acid
向1-(3-氰基-6-羟基吡唑并[1,5-a]吡啶-4-基)氮杂环丁烷-3-甲酸甲酯(300mg,1.10mmol)的四氢呋喃(6.00mL)溶液中加入氢氧化钠水溶液(2.0N,1.10mL,2.20mmol)。反应混合液在室温下搅拌反应15分钟，然后加入2,2-二甲基环氧乙烷(0.983mL,11.0mmol)。封管密闭条件下，反应混合液在85℃下搅拌反应8小时。将反应混合物减压浓缩得到粗品。经制备HPLC(含0.05％甲酸的水/乙腈)纯化得到目标化合物(80.0mg,收率22.0％,类白色固体)。LC-MS(ESI)m/z 331.0[M+H] +。 To methyl 1-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)azetidine-3-carboxylate (300 mg, 1.10 mmol) in tetrahydrofuran (6.00 mL) ) solution was added aqueous sodium hydroxide solution (2.0N, 1.10 mL, 2.20 mmol). The reaction mixture was stirred at room temperature for 15 minutes, then 2,2-dimethyloxirane (0.983 mL, 11.0 mmol) was added. The reaction mixture was stirred and reacted at 85° C. for 8 hours under the condition of sealing the tube. The reaction mixture was concentrated under reduced pressure to give crude product. Purification by preparative HPLC (0.05% formic acid in water/acetonitrile) afforded the title compound (80.0 mg, 22.0% yield, off-white solid). LC-MS (ESI) m/z 331.0 [M+H] + .
步骤5:1-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-((6-甲氧基吡啶-3-基)甲基)氮杂环丁烷-3-甲酰胺的合成Step 5: 1-(3-Cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N-((6-methylpropoxy) Synthesis of Oxypyridin-3-yl)methyl)azetidine-3-carboxamide
向1-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)氮杂环丁烷-3-甲酸(80.0mg,0.242mmol)和(6-甲氧基吡啶-3-基)甲胺(40.2mg,0.291mmol)的DMF(2.00mL)溶液中加入EDCI(69.5mg,0.363mmol)、HOBt(49.1mg,0.363mmol)和DIEA(62.6mg,0.484mmol)。反应混合物在室温下搅拌反应16小时。将反应混合物倒入水(15.0mL)中，用EA(100mL)萃取。有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(含0.05％甲酸的水/乙腈)纯化得到目标化合物(21.9mg,收率20.0％,黄色固体)。LC-MS(ESI)m/z 451.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.56–8.51(m,1H),8.48(s,1H),8.16(d,J＝1.8Hz,1H),8.06(d,J＝2.2Hz,1H),7.62–7.58(m,1H),6.78(d,J＝8.5Hz,1H),6.35(d,J＝1.7Hz,1H),4.67(s,1H),4.34–4.29(m,2H),4.24(d,J＝5.7Hz,2H),4.16–4.11(m,2H),3.82(s,3H),3.78(s,2H),3.59–3.50(m,1H),1.21(s,6H)。 to 1-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)azetidine-3-carboxylic acid ( 80.0 mg, 0.242 mmol) and (6-methoxypyridin-3-yl)methanamine (40.2 mg, 0.291 mmol) in DMF (2.00 mL) were added EDCI (69.5 mg, 0.363 mmol), HOBt (49.1 mg) , 0.363 mmol) and DIEA (62.6 mg, 0.484 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (15.0 mL) and extracted with EA (100 mL). The organic phase was 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. Purification by preparative HPLC (0.05% formic acid in water/acetonitrile) afforded the title compound (21.9 mg, 20.0% yield, yellow solid). LC-MS (ESI) m/z 451.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.56-8.51(m,1H),8.48(s,1H),8.16(d,J=1.8Hz,1H),8.06(d,J=2.2Hz, 1H), 7.62–7.58 (m, 1H), 6.78 (d, J=8.5Hz, 1H), 6.35 (d, J=1.7Hz, 1H), 4.67 (s, 1H), 4.34–4.29 (m, 2H) ), 4.24(d, J=5.7Hz, 2H), 4.16–4.11(m, 2H), 3.82(s, 3H), 3.78(s, 2H), 3.59–3.50(m, 1H), 1.21(s, 6H).
实施例13： 1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)氮杂环丁烷-3-甲酰胺(化合物13)的合成 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)
Figure PCTCN2021118001-appb-000035
Figure PCTCN2021118001-appb-000035
步骤1:1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)氮杂环丁烷-3-甲酸的合成Step 1: 1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)azetidine- Synthesis of 3-carboxylic acid
向1-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)氮杂环丁烷-3-甲酸甲酯(175mg,0.522mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(130mg,0.627mmol)的水(1.00mL)和1,4-二氧六环(5.00mL)溶液中加入碳酸钠(111mg,1.04mmol)和Pd(dppf)Cl 2DCM络合物(22.5mg,0.026mmol)。氮气保护下，反应混合物在100℃下搅拌反应4小时。将反应混合物冷却至室温，浓缩后加水(10.0mL)。用稀盐酸(2.0M)调pH约到4，过滤。滤饼干燥后得到目标化合物(52.0mg，收率30.9％,灰白色固体)。LC-MS(ESI)m/z 323.2[M+H] +。 To methyl 1-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)azetidine-3-carboxylate (175 mg, 0.522 mmol) and 1-methyl -4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (130 mg, 0.627 mmol) in water (1.00 mL) ) and 1,4-dioxane (5.00 mL) were added sodium carbonate (111 mg, 1.04 mmol) and Pd(dppf)Cl 2 DCM complex (22.5 mg, 0.026 mmol). Under nitrogen protection, the reaction mixture was stirred at 100°C for 4 hours. The reaction mixture was cooled to room temperature, concentrated and water (10.0 mL) was added. Adjust pH to about 4 with dilute hydrochloric acid (2.0M) and filter. The filter cake was dried to give the title compound (52.0 mg, 30.9% yield, off-white solid). LC-MS (ESI) m/z 323.2 [M+H] + .
步骤2:1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)氮杂环丁烷-3-甲酰胺的合成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
在室温下，向1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)氮杂环丁烷-3-甲酸(50.0mg,0.155mmol)、(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(35.7mg,0.186mmol),EDCI(44.6mg,0.232mmol)和HOBt(31.4mg,0.232mmol)的DMF(1.50mL)溶液中加DIEA(40.1mg,0.310mmol)。反应混合物室温下搅拌反应16小时。将反应混合物倒入水(10.0mL)中，过滤。滤饼经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(18.5mg,收率24.0％,白色固体)。LC-MS(ESI)m/z 497.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.75(s,1H),8.72–8.65(m,2H),8.56(s,1H),8.40–8.34(m,2H),8.07(s,1H),7.94–7.86(m,3H),6.80(s,1H),4.41–4.34(m,4H),4.26–4.19(m,2H),3.88(s,3H),3.66–3.59(m,1H)。 To 1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)azetidine at room temperature Alkane-3-carboxylic acid (50.0 mg, 0.155 mmol), (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (35.7 mg, 0.186 mmol), EDCI (44.6 mg , 0.232 mmol) and HOBt (31.4 mg, 0.232 mmol) in DMF (1.50 mL) was added DIEA (40.1 mg, 0.310 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (10.0 mL) and filtered. The filter cake was purified by preparative HPLC (acetonitrile/water with 0.05% formic acid) to give the title compound (18.5 mg, 24.0% yield, white solid). LC-MS (ESI) m/z 497.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.75(s,1H), 8.72-8.65(m,2H), 8.56(s,1H), 8.40-8.34(m,2H), 8.07(s,1H) ), 7.94–7.86(m, 3H), 6.80(s, 1H), 4.41–4.34(m, 4H), 4.26–4.19(m, 2H), 3.88(s, 3H), 3.66–3.59(m, 1H ).
实施例14： 1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-甲氧基吡啶-3-基) 甲基)氮杂环丁烷-3-甲酰胺(化合物14)的合成 Example 14: 1-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-Methoxypyridin-3-yl) methyl)azetidine-3-carboxamide (Compound 14)
Figure PCTCN2021118001-appb-000036
Figure PCTCN2021118001-appb-000036
步骤1:1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-甲氧基吡啶-3-基)甲基)氮杂环丁烷-3-甲酰胺的合成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
1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)氮杂环丁烷-3-甲酸(60.0mg,0.186mmol)和(6-甲氧基吡啶-3-基)甲胺(30.9mg,0.223mmol)的DMF(1.50mL)溶液中加入EDCI(53.4mg,0.279mmol)、HOBt(37.7mg,0.279mmol)和DIEA(48.1mg,0.372mmol)。 反应混合物室温下搅拌反应16小时。将反应混合物倒入水(15.0mL)中，用EA(100mL)萃取。有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(10.5mg,收率12.7％,类白色固体)。LC-MS(ESI)m/z 443.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.75–8.74(m,1H),8.58–8.53(m,2H),8.37(s,1H),8.07(s,2H),7.62–7.59(m,1H),6.80–6.76(m,2H),4.38–4.33(m,2H),4.24(d,J＝5.7Hz,2H),4.23–4.18(m,2H),3.88(s,3H),3.82(s,3H),3.64–3.55(m,1H)。 1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)azetidine-3-carboxylic acid (60.0 mg, 0.186 mmol) and (6-methoxypyridin-3-yl)methanamine (30.9 mg, 0.223 mmol) in DMF (1.50 mL) were added EDCI (53.4 mg, 0.279 mmol), HOBt (37.7 mg, 0.279 mmol) and DIEA (48.1 mg, 0.372 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (15.0 mL) and extracted with EA (100 mL). The organic phase was 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. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (10.5 mg, 12.7% yield, off-white solid). LC-MS (ESI) m/z 443.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.75-8.74(m,1H), 8.58-8.53(m,2H), 8.37(s,1H), 8.07(s,2H), 7.62-7.59(m) ,1H),6.80–6.76(m,2H),4.38–4.33(m,2H),4.24(d,J=5.7Hz,2H),4.23–4.18(m,2H),3.88(s,3H), 3.82 (s, 3H), 3.64–3.55 (m, 1H).
实施例15： 3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)氮杂环丁烷-1-甲酰胺(化合物15)的合成 Example 15: 3-(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-1-carboxamide (Compound 15)
Figure PCTCN2021118001-appb-000037
Figure PCTCN2021118001-appb-000037
步骤1：3-(5-溴吡啶-3-基)氮杂环丁烷-1-甲酸叔丁酯的合成Step 1: Synthesis of tert-butyl 3-(5-bromopyridin-3-yl)azetidine-1-carboxylate
向3,5-二溴吡啶(5.50g,23.2mmol)的无水四氢呋喃(50.0mL)溶液中加入(1-(叔丁氧羰基)氮杂环丁烷-3-基)碘化锌(II)(8.65g,34.8mmol)(溶于100mL无水四氢呋喃溶液中)和四(三苯基膦)钯(2.68g,2.32mmol)。氮气保护下，反应混合物在60℃下搅拌反应过夜。将反应液冷却至室温后，加入饱和氯化铵溶液(50.0mL)。用EA(75.0mL×2)萃取。合并有机相用无水硫酸钠干燥，过滤，减压浓缩得到粗产品。经柱层析分离纯化(C18,乙腈/水含0.05％甲酸)得到粗品。将粗品加入到PE和EA(5:1)的混合溶剂中，在室温下搅拌反应2小时，过滤。滤饼经真空干燥得到目标化合物(1.40g，收率19.3％，白色固体)。LC-MS(ESI)m/z 313.2,315.2[M+H] +。 To a solution of 3,5-dibromopyridine (5.50 g, 23.2 mmol) in dry tetrahydrofuran (50.0 mL) was added (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide ) (8.65 g, 34.8 mmol) (dissolved in 100 mL of anhydrous tetrahydrofuran solution) and tetrakis(triphenylphosphine)palladium (2.68 g, 2.32 mmol). Under nitrogen protection, the reaction mixture was stirred at 60°C overnight. After cooling the reaction solution to room temperature, saturated ammonium chloride solution (50.0 mL) was added. Extracted with EA (75.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Separation and purification by column chromatography (C18, acetonitrile/water with 0.05% formic acid) gave the crude product. The crude product was added to a mixed solvent of PE and EA (5:1), the reaction was stirred at room temperature for 2 hours, and filtered. The filter cake was dried in vacuo to give the title compound (1.40 g, 19.3% yield, white solid). LC-MS (ESI) m/z 313.2, 315.2 [M+H] + .
步骤2：1-氨基-3-溴-5-(1-(叔丁氧羰基)氮杂环丁烷-3-基)吡啶-1-鎓2,4,6-三甲基苯磺酸盐的合成Step 2: 1-Amino-3-bromo-5-(1-(tert-butoxycarbonyl)azetidin-3-yl)pyridine-1-onium 2,4,6-trimethylbenzenesulfonate Synthesis
冰浴下，向3-(5-溴吡啶-3-基)氮杂环丁烷-1-甲酸叔丁酯(1.36g,4.34mmol)的DCM(20.0mL)溶液中缓慢加入2,4,6-三甲基磺酰羟胺(1.03g,4.78mmol)。反应混合物在0℃下搅拌反应4小时。混合物减压浓缩得到目标化合物(2.50g，粗品，白色固体)。LC-MS(ESI)m/z 369.1,371.1[M+CH 3CN] +。 To a solution of tert-butyl 3-(5-bromopyridin-3-yl)azetidine-1-carboxylate (1.36 g, 4.34 mmol) in DCM (20.0 mL) was slowly added 2,4, 6-Trimethylsulfonylhydroxylamine (1.03 g, 4.78 mmol). The reaction mixture was stirred at 0°C for 4 hours. The mixture was concentrated under reduced pressure to give the title compound (2.50 g, crude, white solid). LC-MS (ESI) m/z 369.1, 371.1 [M+ CH3CN ] + .
步骤3：3-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)氮杂环丁烷-1-甲酸叔丁酯的合成Step 3: Synthesis of tert-butyl 3-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)azetidine-1-carboxylate
在0℃下，向1-氨基-3-溴-5-(1-(叔丁氧羰基)氮杂环丁烷-3-基)吡啶-1-鎓2,4,6-三甲基苯 磺酸盐(2.50g,4.73mmol)的1,4-二氧六环(30.0mL)溶液中加入丙烯腈(577mg,10.9mmol)和DIEA(795mg,6.15mmol)。反应液在0℃下搅拌反应2小时后，加入2,3-二氯-5,6-二氰基-1,4-苯醌(2.25g,9.91mmol)。将反应混合物升至室温继续搅拌反应16小时。将反应混合物倒入EA(20.0mL)中，然后过滤除去滤渣。滤液用饱和碳酸钠(60.0mL×5)溶液洗，无水硫酸钠干燥，过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(570mg,两步收率34.8％,粉红色固体)。LC-MS(ESI)m/z 418.1,420.1[M+CH 3CN+H] +。 To 1-amino-3-bromo-5-(1-(tert-butoxycarbonyl)azetidin-3-yl)pyridine-1-onium 2,4,6-trimethylbenzene at 0 °C To a solution of the sulfonate (2.50 g, 4.73 mmol) in 1,4-dioxane (30.0 mL) was added acrylonitrile (577 mg, 10.9 mmol) and DIEA (795 mg, 6.15 mmol). After the reaction solution was stirred at 0°C for 2 hours, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.25 g, 9.91 mmol) was added. The reaction mixture was warmed to room temperature and stirring was continued for 16 hours. The reaction mixture was poured into EA (20.0 mL), and the filter residue was removed by filtration. The filtrate was washed with saturated sodium carbonate (60.0 mL×5) solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (570 mg, 34.8% over two steps, pink solid). LC-MS (ESI) m/z 418.1, 420.1 [M+ CH3CN +H] + .
步骤4：3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)氮杂环丁烷-1-甲酸叔丁酯的合成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
向3-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)氮杂环丁烷-1-甲酸叔丁酯(420mg,1.11mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(255mg,1.23mmol)的水(0.500mL)和1,4-二氧六环(5.00mL)混合溶液中加入碳酸钾(308mg,2.23mmol)和Pd(dppf)Cl 2DCM络合物(48.0mg,0.0557mmol)。氩气保护下，反应混合物在90℃下搅拌反应8小时。将反应液冷却至室温后，向反应液中加入EA(15.0mL)，然后用无水硫酸钠干燥，过滤。减压浓缩得到粗产品。经柱层析分离(PE：EA＝1:1-1:3)纯化得到目标化合物(400mg，收率94.7％，淡黄色固体)。LC-MS(ESI)m/z 279.1[M-100+H] +。 To tert-butyl 3-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)azetidine-1-carboxylate (420 mg, 1.11 mmol) and 1-methyl yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (255 mg, 1.23 mmol) in water (0.500 mL) and 1,4-dioxane (5.00 mL) were added potassium carbonate (308 mg, 2.23 mmol) and Pd(dppf)Cl 2 DCM complex (48.0 mg, 0.0557 mmol). Under argon, the reaction mixture was stirred at 90°C for 8 hours. After cooling the reaction solution to room temperature, EA (15.0 mL) was added to the reaction solution, dried over anhydrous sodium sulfate, and filtered. Concentration under reduced pressure gave crude product. Purified by column chromatography (PE:EA=1:1-1:3) to obtain the title compound (400 mg, yield 94.7%, pale yellow solid). LC-MS (ESI) m/z 279.1 [M-100+H] + .
步骤5：4-(氮杂环丁烷-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐的合成Step 5: 4-(azetidin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile Synthesis of hydrochloride
3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)氮杂环丁烷-1-甲酸叔丁酯(220mg,0.581mmol)的氯化氢甲醇溶液(3.0M,8.00mL)在室温下搅拌反应过夜。将反应混合物减压浓缩后得到目标化合物(180mg，收率98.4％，白色固体)。LC-MS(ESI)m/z 279.1[M+H] +。 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)azetidine-1-carboxylic acid A solution of tert-butyl ester (220 mg, 0.581 mmol) in methanol (3.0 M, 8.00 mL) of hydrogen chloride was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain the title compound (180 mg, yield 98.4%, white solid). LC-MS (ESI) m/z 279.1 [M+H] + .
步骤6：3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)氮杂环丁烷-1-甲酰胺的合成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
向CDI(60.3mg,0.372mmol)的DMF(2.00mL)溶液中加入(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(65.9mg,0.343mmol)和DIEA(73.9mg,0.572mmol)。反应混合物在室温下搅拌反应过夜。向混合液中加入4-(氮杂环丁烷-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(90.0mg,0.286mmol)。反应混合物在50℃下搅拌反应2小时。将反应混合物冷却至室温后加入水(10.0mL)中，用EA(15.0mL×2)萃取。合并有机相用饱和食盐水(10.0mL×2)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(60.96mg,收率42.9％,白色固体)。LC-MS(ESI)m/z 497.1 [M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.19-9.16(m,1H),8.67-8.65(m,1H),8.63(s,1H),8.47(s,1H),8.37–8.35(m,1H),8.16(s,1H),7.92–7.88(m,2H),7.87–7.84(m,2H),7.15(t,J＝5.9Hz,1H),4.38–4.31(m,3H),4.27(d,J＝5.9Hz,2H),4.22–4.17(m,2H),3.89(s,3H)。 To a solution of CDI (60.3 mg, 0.372 mmol) in DMF (2.00 mL) was added (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (65.9 mg, 0.343 mmol) and DIEA (73.9 mg, 0.572 mmol). The reaction mixture was stirred at room temperature overnight. To the mixture was added 4-(azetidin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3- Formonitrile hydrochloride (90.0 mg, 0.286 mmol). The reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was cooled to room temperature, added to water (10.0 mL), and extracted with EA (15.0 mL×2). The combined organic phases were washed with saturated brine (10.0 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (60.96 mg, 42.9% yield, white solid). LC-MS (ESI) m/z 497.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.19-9.16(m,1H), 8.67-8.65(m,1H), 8.63(s,1H), 8.47(s,1H), 8.37-8.35(m) ,1H),8.16(s,1H),7.92-7.88(m,2H),7.87-7.84(m,2H),7.15(t,J＝5.9Hz,1H),4.38-4.31(m,3H), 4.27 (d, J=5.9 Hz, 2H), 4.22–4.17 (m, 2H), 3.89 (s, 3H).
实施例16： 3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)吡咯烷-1-甲酰胺(化合物16)的合成 Example 16: 3-(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)pyrrolidine-1-carboxamide (Compound 16)
Figure PCTCN2021118001-appb-000038
Figure PCTCN2021118001-appb-000038
步骤1:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯的合成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
向3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯(400mg,1.07mmol)和3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(349mg,1.18mmol)的水(1.00mL)和1,4-二氧六环(4.00mL)混合溶液中加入碳酸钾(297mg,2.15mmol)和Pd(dppf)Cl 2DCM络合物(46.3mg,0.054mmol)。氩气保护下，反应混合液在90℃下搅拌反应4小时。将反应混合物冷却至室温后倒入水(10.0mL)中，用EA(15.0mL×3)萃取。合并有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤、减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝1:1-1:3)得到目标化合物(300mg，收率71.3％，淡黄色固体)。LC-MS(ESI)m/z 413.1[M+Na] +。 To 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (400 mg, 1.07 mmol) and tert-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid To a mixed solution of butyl ester (349 mg, 1.18 mmol) in water (1.00 mL) and 1,4-dioxane (4.00 mL) was added potassium carbonate (297 mg, 2.15 mmol) and Pd(dppf)Cl 2 DCM complex (46.3 mg, 0.054 mmol). Under the protection of argon, the reaction mixture was stirred at 90°C for 4 hours. The reaction mixture was cooled to room temperature, poured into water (10.0 mL), and extracted with EA (15.0 mL×3). The combined organic phases were washed with saturated brine (15.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=1:1-1:3), the target compound (300 mg, yield 71.3%, pale yellow solid) was obtained. LC-MS (ESI) m/z 413.1 [M+Na] + .
步骤2:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)吡咯烷-1-甲酸叔丁酯的合成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
向3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(300mg,0.768mmol)的EA溶液(8.00mL)中加入钯碳(100mg)。在氢气氛围下，反应混合物在40℃下搅拌反应24小时。将反应混合物过滤，滤液减压浓缩得到目标化合物(250mg，收率82.9％,淡黄色固体)。LC-MS(ESI)m/z 293.1[M-100+H] +。 To 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-2,5-dihydro- To a solution of 1H-pyrrole-1-carboxylate tert-butyl ester (300 mg, 0.768 mmol) in EA (8.00 mL) was added palladium on carbon (100 mg). Under a hydrogen atmosphere, the reaction mixture was stirred at 40°C for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (250 mg, yield 82.9%, pale yellow solid). LC-MS (ESI) m/z 293.1 [M-100+H] + .
步骤3:6-(1-甲基-1H-吡唑-4-基)-4-(吡咯烷-3-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐的合成Step 3: 6-(1-Methyl-1H-pyrazol-4-yl)-4-(pyrrolidin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride Synthesis
3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)吡咯烷-1-甲酸叔丁酯(250mg,0.637mmol)的氯化氢甲醇溶液(3.0M,6.00mL)在室温下搅拌反应过夜。将反应混合物减压浓缩得到目标化合物(200mg，收率95.5％，白色固体)。LC-MS(ESI)m/z 293.3[M+H] +。 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 0.637 mmol) of hydrogen chloride in methanol (3.0 M, 6.00 mL) The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain the title compound (200 mg, yield 95.5%, white solid). LC-MS (ESI) m/z 293.3 [M+H] + .
步骤4:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)吡咯烷-1-甲酰胺的合成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
在室温下，向CDI(91.3mg,0.563mmol)的DMF(2.00mL)溶液中加入2-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(100mg,0.520mmol)和DIEA(112mg,0.867mmol)。反应混合物在室温下搅拌反应16小时。向混合液中加入6-(1-甲基-1H-吡唑-4-基)-4-(吡咯烷-3-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(142mg,0.443mmol)。反应混合物在50℃下搅拌反应3小时。将反应混合物倒入水(10.0mL)中，用EA(15.0mL×2)萃取。合并有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤、减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)和手性柱纯化得到目标化合物(23.3mg,收率10.6％,白色固体)。LC-MS(ESI)m/z 511.2[M+H] +。 1H NMR(400MHz,MeOH-d 4)δ8.87(d,J＝1.3Hz,1H),8.48(dd,J＝4.5,0.8Hz,1H),8.40(s,1H),8.37–8.35(m,1H),8.06(s,1H),7.90(d,J＝0.7Hz,1H),7.88–7.81(m,2H),7.69–7.66(m,1H),7.57(s,1H),7.06–6.99(m,1H),4.49–4.37(m,2H),4.17–4.10(m,1H),3.96–3.88(m,4H),3.84–3.76(m,1H),3.62–3.53(m,2H),2.58–2.50(m,1H),2.38–2.30(m,1H)。 To a solution of CDI (91.3 mg, 0.563 mmol) in DMF (2.00 mL) was added 2-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine ( 100 mg, 0.520 mmol) and DIEA (112 mg, 0.867 mmol). The reaction mixture was stirred at room temperature for 16 hours. To the mixture was added 6-(1-methyl-1H-pyrazol-4-yl)-4-(pyrrolidin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile salt acid salt (142 mg, 0.443 mmol). The reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was poured into water (10.0 mL) and extracted with EA (15.0 mL x 2). The combined organic phases were washed with saturated brine (15.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) and chiral column gave the title compound (23.3 mg, 10.6% yield, white solid). LC-MS (ESI) m/z 511.2 [M+H] + . 1 H NMR (400 MHz, MeOH-d 4 ) δ 8.87 (d, J=1.3 Hz, 1H), 8.48 (dd, J=4.5, 0.8 Hz, 1H), 8.40 (s, 1H), 8.37–8.35 ( m, 1H), 8.06 (s, 1H), 7.90 (d, J=0.7Hz, 1H), 7.88–7.81 (m, 2H), 7.69–7.66 (m, 1H), 7.57 (s, 1H), 7.06 –6.99(m,1H),4.49–4.37(m,2H),4.17–4.10(m,1H),3.96–3.88(m,4H),3.84–3.76(m,1H),3.62–3.53(m, 2H), 2.58–2.50 (m, 1H), 2.38–2.30 (m, 1H).
实施例17： 3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-甲氧基吡啶-3-基) 甲基)-2,5-二氢-1H-吡咯-1-甲酰胺(化合物17)的合成 Example 17: 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-Methoxypyridin-3-yl) methyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (Compound 17)
Figure PCTCN2021118001-appb-000039
Figure PCTCN2021118001-appb-000039
步骤1:4-(2,5-二氢-1H-吡咯-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐的合成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
3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(220mg,0.512mmol)的氯化氢甲醇溶液(3.0M,8.00mL)在室温下搅拌反应过夜。将反应混合物减压浓缩得到目标化合物(180mg，粗产物，灰色固体)。LC-MS(ESI)m/z 291.2[M+H] +。 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-2,5-dihydro-1H - tert-butyl pyrrole-1-carboxylate (220 mg, 0.512 mmol) in methanol with hydrogen chloride (3.0 M, 8.00 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the title compound (180 mg, crude product, gray solid). LC-MS (ESI) m/z 291.2 [M+H] + .
步骤2:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-甲氧基吡啶-3-基)甲基)-2,5-二氢-1H-吡咯-1-甲酰胺的合成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
在室温下，向CDI(58.1mg,0.358mmol)的DMF(2.00mL)溶液中加入(6-甲氧基吡啶-3-基)甲胺(45.7mg,0.330mmol)和DIEA(71.2mg,0.550mmol)。反应混合物在室温下搅拌反 应16小时。向反应混合液中加入4-(2,5-二氢-1H-吡咯-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(90.0mg,0.275mmol)。反应混合物在50℃下搅拌反应3小时。将反应混合物冷却至室温后倒入水(10.0mL)中，用EA(15.0mL×2)萃取。合并有机相用饱和食盐水(10.0mL×2)洗、无水硫酸钠干燥、过滤、减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(7.52mg,两步收率6.01％,白色固体)。LC-MS(ESI)m/z 455.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.24(d,J＝1.3Hz,1H),8.68(s,1H),8.38(s,1H),8.11(s,1H),8.10(d,J＝2.0Hz,1H),7.88(d,J＝1.2Hz,1H),7.69–7.65(m,1H),6.92–6.88(m,1H),6.78(d,J＝8.4Hz,1H),6.37–6.35(m,1H),4.62–4.58(m,2H),4.36–4.32(m,2H),4.23(d,J＝5.7Hz,2H),3.88(s,3H),3.83(s,3H)。 To a solution of CDI (58.1 mg, 0.358 mmol) in DMF (2.00 mL) at room temperature was added (6-methoxypyridin-3-yl)methanamine (45.7 mg, 0.330 mmol) and DIEA (71.2 mg, 0.550 mmol). The reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 4-(2,5-dihydro-1H-pyrrol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a] Pyridine-3-carbonitrile hydrochloride (90.0 mg, 0.275 mmol). The reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature, poured into water (10.0 mL), and extracted with EA (15.0 mL×2). The combined organic phases were washed with saturated brine (10.0 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (7.52 mg, 6.01% over two steps, white solid). LC-MS (ESI) m/z 455.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.24(d, J=1.3Hz, 1H), 8.68(s, 1H), 8.38(s, 1H), 8.11(s, 1H), 8.10(d, J=2.0Hz, 1H), 7.88 (d, J=1.2Hz, 1H), 7.69–7.65 (m, 1H), 6.92–6.88 (m, 1H), 6.78 (d, J=8.4Hz, 1H), 6.37–6.35 (m, 1H), 4.62–4.58 (m, 2H), 4.36–4.32 (m, 2H), 4.23 (d, J=5.7Hz, 2H), 3.88 (s, 3H), 3.83 (s, 3H).
实施例18： 3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-甲氧基吡啶-3- 基)乙基)-2,5-二氢-1H-吡咯-1-甲酰胺(化合物18)的合成 Example 18: 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 (Compound 18)
Figure PCTCN2021118001-appb-000040
Figure PCTCN2021118001-appb-000040
步骤1:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-甲氧基吡啶-3-基)乙基)-2,5-二氢-1H-吡咯-1-甲酰胺的合成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
在室温下，向CDI(58.1mg,0.358mmol)的DMF(2.00mL)溶液中加入1-(6-甲氧基吡啶-3-基)乙-1-胺(50.3mg,0.330mmol)和DIEA(71.2mg,0.550mmol)。反应混合物在室温下搅拌反应16小时。向反应混合液中加入4-(2,5-二氢-1H-吡咯-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(90.0mg,0.275mmol)。反应混合物在50℃下搅拌反应3小时。将反应混合物冷却至室温后倒入水(10.0mL)中，用EA(15.0mL×2)萃取。合并有机相用饱和食盐水(10.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(50.88mg,收率39.4％,白色固体)。LC-MS(ESI)m/z 469.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.24(d,J＝1.3Hz,1H),8.68(s,1H),8.38(s,1H),8.14(d,J＝2.4Hz,1H),8.12(s,1H),7.88(d,J＝1.2Hz,1H),7.75–7.71(m,1H),6.78(d,J＝8.6Hz,1H),6.61(d,J＝8.0Hz,1H),6.37–6.34(m,1H),4.91–4.86(m,1H),4.62–4.57(m,2H),4.38–4.33(m,2H),3.88(s,3H),3.82(s,3H),1.42(d,J＝7.1Hz,3H)。 To a solution of CDI (58.1 mg, 0.358 mmol) in DMF (2.00 mL) was added 1-(6-methoxypyridin-3-yl)ethan-1-amine (50.3 mg, 0.330 mmol) and DIEA at room temperature (71.2 mg, 0.550 mmol). The reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 4-(2,5-dihydro-1H-pyrrol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a] Pyridine-3-carbonitrile hydrochloride (90.0 mg, 0.275 mmol). The reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature, poured into water (10.0 mL), and extracted with EA (15.0 mL×2). The combined organic phases were washed with saturated brine (10.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (50.88 mg, 39.4% yield, white solid). LC-MS (ESI) m/z 469.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.24(d, J=1.3Hz, 1H), 8.68(s, 1H), 8.38(s, 1H), 8.14(d, J=2.4Hz, 1H) ,8.12(s,1H),7.88(d,J＝1.2Hz,1H),7.75–7.71(m,1H),6.78(d,J＝8.6Hz,1H),6.61(d,J＝8.0Hz, 1H), 6.37–6.34 (m, 1H), 4.91–4.86 (m, 1H), 4.62–4.57 (m, 2H), 4.38–4.33 (m, 2H), 3.88 (s, 3H), 3.82 (s, 3H), 1.42 (d, J=7.1 Hz, 3H).
实施例19： 3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-(4-氟-1H-吡唑 -1-基)吡啶-3-基)乙基)-2,5-二氢-1H-吡咯-1-甲酰胺(化合物19)及其盐酸盐(化合物19-1)的合成 Example 19: 3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(1 -(6-(4-Fluoro-1H-pyrazol- 1-yl)pyridin-3-yl)ethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (compound 19) and salts thereof Synthesis of Acid Acid (Compound 19-1)
Figure PCTCN2021118001-appb-000041
Figure PCTCN2021118001-appb-000041
步骤1:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-2,5-二氢-1H-吡咯-1-甲酰胺及其盐酸盐的合成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
在0℃下，向CDI(71.0mg,0.438mmol)的DMF(4.00mL)溶液中加入1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙-1-胺(83.3mg,0.404mmol)和DIEA(87.0mg,0.674mmol)。反应混合物在室温下搅拌反应过夜。向混合液中加入4-(2,5-二氢-1H-吡咯-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(110mg,0.337mmol)。反应混合物在50℃下搅拌反应2小时。将反应混合物冷却至室温后加入水(10.0mL)，用EA(10.0mL×2)萃取。合并有机相用饱和食盐水(10.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品 (化合物 19)。经制备HPLC(乙腈/含0.05％盐酸的水)纯化得到盐酸盐形式的目标化合物 (化合物19-1)(54.1mg,两步收率38.7％,白色固体)。LC-MS(ESI)m/z 523.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.25(s,1H),8.71–8.64(m,2H),8.47(d,J＝1.9Hz,1H),8.39(s,1H),8.13(s,1H),8.04–7.99(m,1H),7.93–7.86(m,3H),6.77(d,J＝7.7Hz,1H),6.38(s,1H),5.03–4.96(m,1H),4.63(s,2H),4.44–4.34(m,2H),3.89(s,3H),1.49(d,J＝7.1Hz,3H)。 To a solution of CDI (71.0 mg, 0.438 mmol) in DMF (4.00 mL) at 0 °C was added 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethane- 1-amine (83.3 mg, 0.404 mmol) and DIEA (87.0 mg, 0.674 mmol). The reaction mixture was stirred at room temperature overnight. To the mixture was added 4-(2,5-dihydro-1H-pyrrol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a ]pyridine-3-carbonitrile hydrochloride (110 mg, 0.337 mmol). The reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was cooled to room temperature, water (10.0 mL) was added, and extracted with EA (10.0 mL×2). The combined organic phases were washed with saturated brine (10.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product (compound 19) . Purification by preparative HPLC (acetonitrile/water with 0.05% hydrochloric acid) afforded the title compound (compound 19-1) as the hydrochloride salt (54.1 mg, 38.7% yield over two steps, white solid). LC-MS (ESI) m/z 523.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.25(s,1H),8.71-8.64(m,2H),8.47(d,J=1.9Hz,1H),8.39(s,1H),8.13( s, 1H), 8.04–7.99 (m, 1H), 7.93–7.86 (m, 3H), 6.77 (d, J=7.7Hz, 1H), 6.38 (s, 1H), 5.03–4.96 (m, 1H) , 4.63 (s, 2H), 4.44–4.34 (m, 2H), 3.89 (s, 3H), 1.49 (d, J=7.1 Hz, 3H).
实施例20： 3-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-((6-甲氧基吡啶-3-基) 甲基)-2,5-二氢-1H-吡咯-1-甲酰胺(化合物20)的合成 Example 20: 3-(3-Cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N-((6- Synthesis of Methoxypyridin-3-yl) methyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (Compound 20)
Figure PCTCN2021118001-appb-000042
Figure PCTCN2021118001-appb-000042
步骤1:3-(3-氰基-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑并[1,5-a]吡啶-4-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯的合成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
向3-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(2.20g,5.65mmol)和联硼酸频哪醇酯(7.17g,28.2mmol)的无水1,4-二氧六环(30.0mL)溶液中加入乙酸钾(1.11g,11.3mmol)和Pd(dppf)Cl 2DCM络合物(244mg,0.283mmol)。氮气保护下，反 应混合物在90℃下搅拌反应过夜。将反应液冷却至室温后倒入EA(30.0mL)中，溶液通过硅藻土过滤后，滤饼再用EA(20.0mL)洗。滤液减压浓缩得到目标化合物(12.2g，粗品，黑色固体)。 To 3-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (2.20 g, To a solution of 5.65 mmol) and pinacol diboronate (7.17 g, 28.2 mmol) in anhydrous 1,4-dioxane (30.0 mL) was added potassium acetate (1.11 g, 11.3 mmol) and Pd(dppf)Cl 2 DCM complex (244 mg, 0.283 mmol). Under nitrogen, the reaction mixture was stirred at 90°C overnight. The 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).
步骤2:3-(3-氰基-6-羟基吡唑并[1,5-a]吡啶-4-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯的合成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
在0℃下，向3-(3-氰基-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑并[1,5-a]吡啶-4-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(12.2g,28.0mmol)的四氢呋喃(300mL)溶液中加入氢氧化钠(4.47g,112mmol)，并慢慢滴加30％的过氧化氢水溶液(22.8mL,224mmol)。反应混合液在室温下搅拌反应2小时。向反应混合液中加入饱和氯化铵水溶液(150mL)，然后室温下搅拌15分钟。分离有机相，水相用EA(100mL×2)萃取。合并有机相用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝5:1-1:1)得到目标化合物(1.20g，两步收率65.1％，黄色固体)。LC-MS(ESI)m/z 227.0[M-100+H] +。 To 3-(3-cyano-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyrazolo at 0°C Sodium hydroxide ( 4.47 g, 112 mmol), and 30% aqueous hydrogen peroxide (22.8 mL, 224 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution (150 mL) was added to the reaction mixture, followed by stirring at room temperature for 15 minutes. The organic phase was separated and the aqueous phase was extracted with EA (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=5:1-1:1), the target compound (1.20 g, two-step yield 65.1%, yellow solid) was obtained. LC-MS (ESI) m/z 227.0 [M-100+H] + .
步骤3:3-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯的合成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
向3-(3-氰基-6-羟基吡唑并[1,5-a]吡啶-4-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(400mg,1.23mmol)的四氢呋喃(5.00mL)溶液中加入氢氧化钠水溶液(2.0N,1.23mL,2.46mmol)。反应混合液在室温下搅拌反应15分钟后加入2,2-二甲基环氧乙烷(1.10mL,12.3mmol)。封管密闭后，反应混合液在80℃下搅拌反应16小时。将反应液冷却至室温，减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝3：1-1：1)得到目标化合物(350mg，收率71.7％，黄色固体)。LC-MS(ESI)m/z 399.1[M+H] +。 To 3-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (400 mg, 1.23 mmol) in tetrahydrofuran (5.00 mL) was added aqueous sodium hydroxide solution (2.0 N, 1.23 mL, 2.46 mmol). The reaction mixture was stirred at room temperature for 15 minutes and then 2,2-dimethyloxirane (1.10 mL, 12.3 mmol) was added. After sealing the tube, the reaction mixture was stirred at 80° C. for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. After separation and purification by column chromatography (PE:EA=3:1-1:1), the target compound (350 mg, yield 71.7%, yellow solid) was obtained. LC-MS (ESI) m/z 399.1 [M+H] + .
步骤4:4-(2,5-二氢-1H-吡咯-3-基)-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐的合成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
将3-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(250mg,0.627mmol)加入到氯化氢甲醇溶液(3.0M,10.0mL)中。反应混合物在室温下搅拌反应过夜。减压浓缩得到目标化合物(200mg，收率95.2％，白色固体)。LC-MS(ESI)m/z 299.1[M+H] +。 3-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-2,5-dihydro-1H- To a solution of hydrogen chloride in methanol (3.0 M, 10.0 mL) was added tert-butyl pyrrole-1-carboxylate (250 mg, 0.627 mmol). The reaction mixture was stirred at room temperature overnight. Concentration under reduced pressure gave the title compound (200 mg, yield 95.2%, white solid). LC-MS (ESI) m/z 299.1 [M+H] + .
步骤5:3-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-((6-甲氧基吡啶-3-基)甲基)-2,5-二氢-1H-吡咯-1-甲酰胺的合成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
向CDI(63.0mg,0.389mmol)的DMF(3.00mL)溶液中加入(6-甲氧基吡啶-3-基)甲胺(49.5mg,0.358mmol)和DIEA(77.2mg,0.597mmol)。反应混合物在室温下搅拌反应16小时。向混合液中加入4-(2,5-二氢-1H-吡咯-3-基)-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-甲腈 盐酸盐(100mg,0.299mmol)。反应混合物在50℃下搅拌反应3小时。将反应混合物冷却至室温后加入水(10.0mL)中。用EA(15.0mL×2)萃取。合并有机相用饱和食盐水(10.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(67.0mg,收率48.5％,白色固体)。LC-MS(ESI)m/z 463.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.67(d,J＝2.0Hz,1H),8.61(s,1H),8.09(d,J＝2.0Hz,1H),7.66(dd,J＝8.5,2.4Hz,1H),7.41(d,J＝1.8Hz,1H),6.88(t,J＝5.8Hz,1H),6.77(d,J＝8.5Hz,1H),6.37(s,1H),4.70(s,1H),4.55–4.49(m,2H),4.35–4.29(m,2H),4.22(d,J＝5.7Hz,2H),3.85(s,2H),3.82(s,3H),1.21(s,6H)。 To a solution of CDI (63.0 mg, 0.389 mmol) in DMF (3.00 mL) was added (6-methoxypyridin-3-yl)methanamine (49.5 mg, 0.358 mmol) and DIEA (77.2 mg, 0.597 mmol). The reaction mixture was stirred at room temperature for 16 hours. To the mixture was added 4-(2,5-dihydro-1H-pyrrol-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine -3-carbonitrile hydrochloride (100 mg, 0.299 mmol). The reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature and added to water (10.0 mL). Extracted with EA (15.0 mL x 2). The combined organic phases were washed with saturated brine (10.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (67.0 mg, 48.5% yield, white solid). LC-MS (ESI) m/z 463.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.67 (d, J=2.0 Hz, 1H), 8.61 (s, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.66 (dd, J= 8.5, 2.4Hz, 1H), 7.41 (d, J=1.8Hz, 1H), 6.88 (t, J=5.8Hz, 1H), 6.77 (d, J=8.5Hz, 1H), 6.37 (s, 1H) ,4.70(s,1H),4.55-4.49(m,2H),4.35-4.29(m,2H),4.22(d,J＝5.7Hz,2H),3.85(s,2H),3.82(s,3H ), 1.21(s, 6H).
实施例21： 3-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)-2,5-二氢-1H-吡咯-1-甲酰胺(化合物21)及其盐酸盐(化合物21-1)的合成 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
Figure PCTCN2021118001-appb-000043
Figure PCTCN2021118001-appb-000043
步骤1:3-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-2,5-二氢-1H-吡咯-1-甲酰胺及其盐酸盐的合成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
向CDI(63.0mg,0.389mmol)的DMF(3.00mL)溶液中加入(6-(4-氟-1H-吡唑-1-基)吡啶3-基)甲胺(68.9mg,0.358mmol)和DIEA(77.2mg,0.597mmol)。反应混合物在室温下搅拌反应16小时后,向混合液中加入4-(2,5-二氢-1H-吡咯-3-基)-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(100mg,0.299mmol)。反应混合物在50℃下搅拌反应3小时。将反应混合物冷却至室温后加入水(10.0mL)，用EA(15.0mL×2)萃取。合并有机相用饱和食盐水(10.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品 (化合物21)。经制备HPLC(乙腈/水含0.05％盐酸)纯化得到 盐酸盐形式的目标化合物 (化合物21-1)(50.3mg,收率30.4％,白色固体)。LC-MS(ESI)m/z 517.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.69–8.66(m,2H),8.61(s,1H),8.41(d,J＝1.6Hz,1H),7.96–7.90(m,2H),7.90–7.86(m,1H),7.42(d,J＝1.9Hz,1H),7.02(t,J＝5.9Hz,1H),6.40–6.37(m,1H),4.69(s,1H),4.58–4.53(m,2H),4.38–4.32(m,4H),3.85(s,2H),1.21(s,6H)。 To a solution of CDI (63.0 mg, 0.389 mmol) in DMF (3.00 mL) was added (6-(4-fluoro-1H-pyrazol-1-yl)pyridin3-yl)methanamine (68.9 mg, 0.358 mmol) and DIEA (77.2 mg, 0.597 mmol). After the reaction mixture was stirred at room temperature for 16 hours, 4-(2,5-dihydro-1H-pyrrol-3-yl)-6-(2-hydroxy-2-methylpropoxy) was added to the mixture. Pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride (100 mg, 0.299 mmol). The reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature, water (10.0 mL) was added, and extracted with EA (15.0 mL×2). The combined organic phases were washed with saturated brine (10.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product (compound 21) . Purification by preparative HPLC (acetonitrile/water containing 0.05% hydrochloric acid) afforded the title compound (compound 21-1) (50.3 mg, yield 30.4%, white solid) as the hydrochloride salt . LC-MS (ESI) m/z 517.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.69-8.66(m, 2H), 8.61(s, 1H), 8.41(d, J=1.6Hz, 1H), 7.96-7.90(m, 2H), 7.90–7.86 (m, 1H), 7.42 (d, J=1.9Hz, 1H), 7.02 (t, J=5.9Hz, 1H), 6.40–6.37 (m, 1H), 4.69 (s, 1H), 4.58 – 4.53(m, 2H), 4.38 – 4.32(m, 4H), 3.85(s, 2H), 1.21(s, 6H).
实施例22： 3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)-2,5-二氢-1H-吡咯-1-甲酰胺(化合物22)的合成 Example 22: 3-(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)-2,5-dihydro-1H-pyrrole-1-carboxamide (Compound 22)
Figure PCTCN2021118001-appb-000044
Figure PCTCN2021118001-appb-000044
步骤1:3-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯的合成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
向6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯(300mg,0.811mmol)和3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(227mg,0.770mmol)的水(1.00mL)和四氢呋喃(5.00mL)混合溶液中加入乙酸钾(159mg,1.62mmol)和Pd(dppf)Cl 2DCM络合物(34.9mg,0.041mmol)。氩气保护下，反应混合物在30℃下搅拌反应8小时。将反应液倒入EA(80.0mL)中得到黑色溶液。溶液用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝100：1-9：1)得到目标化合物(250mg，收率79.2％，白色固体)。LC-MS(ESI)m/z 411.0,413.0[M+Na] +。 1H NMR(400MHz,CDCl 3)δ8.67(s,1H),8.27(s,1H),7.36(s,1H),6.37(s,1H),4.57–4.43(m,4H),1.51(s,9H)。 To 6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (300 mg, 0.811 mmol) and 3-(4,4,5,5-tetramethyl) yl-1,3,2-dioxaborol-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (227 mg, 0.770 mmol) in water (1.00 mL) Potassium acetate (159 mg, 1.62 mmol) and Pd(dppf)Cl 2 DCM complex (34.9 mg, 0.041 mmol) were added to the mixed solution with tetrahydrofuran (5.00 mL). Under argon, the reaction mixture was stirred at 30°C for 8 hours. The reaction solution was poured into EA (80.0 mL) to obtain a black solution. The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=100:1-9:1), the target compound (250 mg, yield 79.2%, white solid) was obtained. LC-MS (ESI) m/z 411.0, 413.0 [M+Na] + . 1 H NMR (400MHz, CDCl 3 ) δ 8.67(s, 1H), 8.27(s, 1H), 7.36(s, 1H), 6.37(s, 1H), 4.57-4.43(m, 4H), 1.51( s, 9H).
步骤2:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯的合成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
向3-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(250mg,0.642mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(147mg,0.706mmol)的水(1.00mL)和1，4-二氧六环(5.00mL)溶液中加入碳酸钠(136mg,1.28mmol)和Pd(dppf)Cl 2DCM络合物(27.7mg,0.032mmol)。氩气保护下，反应混合物在100℃下搅拌反应6小时。将反应混合物冷却至室温后倒入EA(80.0mL)中得到黑色溶液。溶液用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝3：1-1：2)得到目标化合物(160mg，收率63.8％,黄色固体)。LC-MS(ESI)m/z 413.1[M+Na] +。 1H NMR(400MHz,DMSO-d 6)δ9.23(s,1H),8.67(s,1H),8.39(d,J＝4.1Hz,1H),8.12(s,1H),7.89(s,1H),6.31(s,1H),4.62–4.54(m,2H),4.35–4.27(m,2H),3.88(s,3H),1.46(s,9H)。 To 3-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (250 mg, 0.642 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (147 mg, 0.706 mmol) in water (1.00 mL) and 1,4-dioxane (5.00 mL) was added sodium carbonate (136 mg, 1.28 mmol) and Pd(dppf)Cl 2 DCM complex (27.7 mg, 0.032 mmol) . Under argon, the reaction mixture was stirred at 100°C for 6 hours. The reaction mixture was cooled to room temperature and poured into EA (80.0 mL) to give a black solution. The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=3:1-1:2), the target compound (160 mg, yield 63.8%, yellow solid) was obtained. LC-MS (ESI) m/z 413.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d 6 )δ 9.23(s, 1H), 8.67(s, 1H), 8.39(d, J=4.1Hz, 1H), 8.12(s, 1H), 7.89(s, 1H), 6.31 (s, 1H), 4.62–4.54 (m, 2H), 4.35–4.27 (m, 2H), 3.88 (s, 3H), 1.46 (s, 9H).
步骤3:4-(2,5-二氢-1H-吡咯-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐的合成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
3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(160mg,0.410mmol)的氯化氢甲醇溶液(3.0M,6.00mL)在室温下搅拌反应16小时。将反应混合物减压得到目标化合物(130mg，收率97.1％，类白色固体)。LC-MS(ESI)m/z 291.2 [M+H] +。 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-2,5-dihydro-1H - tert-butyl pyrrole-1-carboxylate (160 mg, 0.410 mmol) in methanol with hydrogen chloride (3.0 M, 6.00 mL) The reaction was stirred at room temperature for 16 hours. The reaction mixture was decompressed to obtain the title compound (130 mg, yield 97.1%, off-white solid). LC-MS (ESI) m/z 291.2 [M+H] + .
步骤4:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-2,5-二氢-1H-吡咯-1-甲酰胺的合成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
在室温下，向CDI(83.8mg,0.517mmol)的DMF(3.00mL)溶液中加入(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(91.7mg,0.477mmol)和DIEA(103mg,0.796mmol)。反应混合物在室温下搅拌反应16小时。向反应混合液中加入4-(2,5-二氢-1H-吡咯-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(130mg,0.398mmol)。反应混合物在50℃下搅拌反应3小时。将反应混合物倒入水(20.0mL)中，用EA(40.0mL×2)萃取。合并有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(66.4mg,收率30.1％,黄色固体)。LC-MS(ESI)m/z 509.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.25–9.23(m,1H),8.70–8.66(m,2H),8.42–8.40(m,1H),8.38(s,1H),8.12(s,1H),7.96–7.93(m,1H),7.92–7.87(m,3H),7.07–7.03(m,1H),6.39–6.36(m,1H),4.65–4.60(m,2H),4.39–4.34(m,4H),3.88(s,3H)。 To a solution of CDI (83.8 mg, 0.517 mmol) in DMF (3.00 mL) was added (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (91.7 mg) at room temperature , 0.477 mmol) and DIEA (103 mg, 0.796 mmol). The reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 4-(2,5-dihydro-1H-pyrrol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5- a] Pyridine-3-carbonitrile hydrochloride (130 mg, 0.398 mmol). The reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was poured into water (20.0 mL) and extracted with EA (40.0 mL x 2). The combined organic phases were 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. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (66.4 mg, 30.1% yield, yellow solid). LC-MS (ESI) m/z 509.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.25-9.23(m,1H), 8.70-8.66(m,2H), 8.42-8.40(m,1H), 8.38(s,1H), 8.12(s ,1H),7.96–7.93(m,1H),7.92–7.87(m,3H),7.07–7.03(m,1H),6.39–6.36(m,1H),4.65–4.60(m,2H),4.39 -4.34(m, 4H), 3.88(s, 3H).
实施例23： 4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)哌啶-1-甲酰胺(化合物23)及其盐酸盐(化合物23-1)的合成 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)
Figure PCTCN2021118001-appb-000045
Figure PCTCN2021118001-appb-000045
步骤1：1-氨基-3-溴-5-甲氧基吡啶-2,4,6-三甲基苯磺酸盐的合成Step 1: Synthesis of 1-amino-3-bromo-5-methoxypyridine-2,4,6-trimethylbenzenesulfonate
3-溴-5-甲氧基吡啶(5.00g,26.6mmol)和O-2,4,6-三甲基苯磺酰羟胺(8.59g,39.9mmol)的DCM(75.0mL)溶液在0℃下搅拌反应1小时。在0℃下向反应液中缓慢加入PE(75.0mL)，继续搅拌15分钟得到一个白色悬浊液。悬浊液过滤后得到白色固体。固体干燥后得到目标化合物(10.2g,收率95.1％,类白色固体)。LC-MS(ESI)m/z 202.9,204.9[M] +。 1H NMR(400MHz,DMSO-d 6)δ8.62–8.59(m,1H),8.58–8.35(m,3H),8.16–8.13(m,1H),6.64(s,2H),3.86(s,3H),2.39(s,6H),2.06(s,3H)。 A solution of 3-bromo-5-methoxypyridine (5.00 g, 26.6 mmol) and O-2,4,6-trimethylbenzenesulfonylhydroxylamine (8.59 g, 39.9 mmol) in DCM (75.0 mL) at 0 °C The reaction was stirred for 1 hour. PE (75.0 mL) was slowly added to the reaction solution at 0°C, and stirring was continued for 15 minutes to obtain a white suspension. The suspension was filtered to obtain a white solid. The target compound (10.2 g, yield 95.1%, off-white solid) was obtained after the solid was dried. LC-MS (ESI) m/z 202.9, 204.9 [M] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.62-8.59(m,1H),8.58-8.35(m,3H),8.16-8.13(m,1H),6.64(s,2H),3.86(s , 3H), 2.39(s, 6H), 2.06(s, 3H).
步骤2：6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-甲腈的合成Step 2: Synthesis of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile
在0℃下，向1-氨基-3-溴-5-甲氧基吡啶-2,4,6-三甲基苯磺酸盐(10.2g,25.3mmol)的1,4-二氧六环(100mL)溶液中在加入丙烯腈(3.09g,58.2mmol)和DIEA(5.44mL,32.9 mmol)。反应液在0℃下搅拌反应2小时后，加入2,3-二氯-5,6-二氰基-1,4-苯醌(12.1g,53.1mmol)。反应液在室温下搅拌反应1小时后升温至室温继续搅拌16小时。将反应混合物倒入冰水(100mL)中得到棕色悬浊液。悬浊液过滤，滤饼用水(50.0mL)洗，得到类白色固体。经柱层析分离纯化(PE：EA＝100：1-9：1)得到目标化合物(2.60g,收率40.8％,黄色固体)。LC-MS(ESI)m/z 252.0,254.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.95–8.91(m,1H),8.60–8.56(m,1H),7.24–7.22(m,1H),4.03(s,3H)。 To 1-amino-3-bromo-5-methoxypyridine-2,4,6-trimethylbenzenesulfonate (10.2 g, 25.3 mmol) in 1,4-dioxane at 0 °C (100 mL) solution was added acrylonitrile (3.09 g, 58.2 mmol) and DIEA (5.44 mL, 32.9 mmol). After the reaction solution was stirred at 0°C for 2 hours, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (12.1 g, 53.1 mmol) was added. The reaction solution was stirred at room temperature for 1 hour, then warmed to room temperature and stirred for 16 hours. The reaction mixture was poured into ice water (100 mL) to give a brown suspension. The suspension was filtered, and the filter cake was washed with water (50.0 mL) to obtain an off-white solid. After separation and purification by column chromatography (PE:EA=100:1-9:1), the target compound (2.60 g, yield 40.8%, yellow solid) was obtained. LC-MS (ESI) m/z 252.0, 254.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.95-8.91 (m, 1H), 8.60-8.56 (m, 1H), 7.24-7.22 (m, 1H), 4.03 (s, 3H).
步骤3：6-溴-4-羟基吡唑并[1,5-a]吡啶-3-甲腈的合成Step 3: Synthesis of 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile
氩气保护下，向6-溴-4-甲氧基吡唑并[1,5-a]吡啶-3-甲腈(1.50g,5.95mmol)的1,2-二氯乙烷(25.0mL)溶液中加入无水三氯化铝(2.38g,17.9mmol)。反应混合物在80℃下搅拌反应16小时。将反应混合物冷却至室温，加入稀盐酸(1.0M，15.0mL)和水(30.0mL)。用EA(120mL×3)萃取。合并有机相用无水硫酸钠干燥、过滤，滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝5：1-3：1)得到目标化合物(900mg，收率63.5％,黄色固体)。LC-MS(ESI)m/z 239.1[M+H] +。 Under argon, a solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (1.50 g, 5.95 mmol) in 1,2-dichloroethane (25.0 mL) was added. ) solution was added anhydrous aluminum trichloride (2.38 g, 17.9 mmol). The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature and diluted hydrochloric acid (1.0 M, 15.0 mL) and water (30.0 mL) were added. Extracted with EA (120 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. After separation and purification by column chromatography (PE:EA=5:1-3:1), the target compound (900 mg, yield 63.5%, yellow solid) was obtained. LC-MS (ESI) m/z 239.1 [M+H] + .
步骤4：6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯的合成Step 4: Synthesis of 6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate
向6-溴-4-羟基吡唑并[1,5-a]吡啶-3-甲腈(900mg,3.78mmol)和1,1,1-三氟-N-苯基-N-((三氟甲基)磺酰基)甲磺酰胺(1.62g,4.54mmol)的N,N-二甲基乙酰胺(8.00mL)溶液中加入DIEA(1.25mL,7.56mmol)。反应混合物在室温下搅拌反应16小时。补加1,1,1-三氟-N-苯基-N-((三氟甲基)磺酰基)甲磺酰胺(1.35g,3.78mmol)和DIEA(0.625mL,3.78mmol)。反应混合物在室温下继续搅拌反应3小时。将反应混合物倒入水(25.0mL)中，用EA(80.0mL)萃取。有机相用饱和食盐水(20.0mL×3)洗、无水硫酸钠干燥、过滤，滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝12：1)得到目标化合物(1.30g,收率92.9％,黄色固体)。LC-MS(ESI)m/z 367.9,369.9[M-H] -。 To 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (900 mg, 3.78 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoro-N-phenyl-N-((trifluoro) To a solution of fluoromethyl)sulfonyl)methanesulfonamide (1.62 g, 4.54 mmol) in N,N-dimethylacetamide (8.00 mL) was added DIEA (1.25 mL, 7.56 mmol). The reaction mixture was stirred at room temperature for 16 hours. Additional 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.35 g, 3.78 mmol) and DIEA (0.625 mL, 3.78 mmol) were added. The reaction mixture was continued to stir at room temperature for 3 hours. The reaction mixture was poured into water (25.0 mL) and extracted with EA (80.0 mL). The organic phase was washed with saturated brine (20.0 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. After separation and purification by column chromatography (PE:EA=12:1), the target compound (1.30 g, yield 92.9%, yellow solid) was obtained. LC-MS (ESI) m/z 367.9, 369.9 [MH] − .
步骤5：4-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯的合成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
向6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯(800mg,2.16mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(668mg,2.16mmol)的水(1.50mL)和四氢呋喃(7.50mL)混合溶液中加入乙酸钾(424mg,4.32mmol)和Pd(dppf)Cl 2DCM络合物(140mg,0.162mmol)。置换氩气三次，反应混合物在40℃下搅拌反应16小时。将反应混合物冷却至室温后倒入水(25.0mL)中，用EA(60.0mL×2)萃取。合并有机相用无水硫酸钠干燥、过滤，滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝12：1-10：1)得到目标化合物(590mg,收率67.5％,白色固体)。LC-MS(ESI)m/z 302.9,304.9 [M-100+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.31(d,J＝1.6Hz,1H),8.68(s,1H),7.65(d,J＝1.5Hz,1H),6.05(s,1H),4.08–4.02(m,2H),3.64–3.57(m,2H),2.49–2.43(m,2H),1.44(s,9H)。 To 6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (800 mg, 2.16 mmol) and 4-(4,4,5,5-tetramethyl) (668 mg, 2.16 mmol) in water (1.50 mL) To the mixed solution with tetrahydrofuran (7.50 mL) was added potassium acetate (424 mg, 4.32 mmol) and Pd(dppf)Cl 2 DCM complex (140 mg, 0.162 mmol). The argon was replaced three times and the reaction mixture was stirred at 40°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (25.0 mL), and extracted with EA (60.0 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. After separation and purification by column chromatography (PE:EA=12:1-10:1), the target compound (590 mg, yield 67.5%, white solid) was obtained. LC-MS (ESI) m/z 302.9, 304.9 [M-100+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.31(d, J=1.6Hz, 1H), 8.68(s, 1H), 7.65(d, J=1.5Hz, 1H), 6.05(s, 1H) , 4.08–4.02 (m, 2H), 3.64–3.57 (m, 2H), 2.49–2.43 (m, 2H), 1.44 (s, 9H).
步骤6：4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯的合成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
向4-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(200mg,0.496mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)吡唑(124mg,0.595mmol)的水(0.60mL)和1,4-二氧六环(3.00mL)混合溶液中加入碳酸钠(105mg,0.992mmol)和Pd(dppf)Cl 2DCM络合物(21.4mg,0.025mmol)。置换氩气三次，反应混合物在80℃下搅拌反应16小时。将反应混合物冷却至室温后倒入水(20.0mL)中，用EA(50.0mL×2)萃取。合并有机相用无水硫酸钠干燥、过滤，滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝3：1-1：1)得到目标化合物(165mg,收率82.3％,黄色固体)。LC-MS(ESI)m/z 405.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.19(d,J＝1.4Hz,1H),8.63(s,1H),8.38(s,1H),8.11(d,J＝0.6Hz,1H),7.75(d,J＝1.0Hz,1H),6.08–6.04(m,1H),4.10–4.05(m,2H),3.89(s,3H),3.67–3.62(m,2H),2.55–2.52(m,2H),1.46(s,9H)。 To 4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (200 mg, 0.496 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (124 mg, 0.595 mmol) in water ( 0.60 mL) and 1,4-dioxane (3.00 mL) were added sodium carbonate (105 mg, 0.992 mmol) and Pd(dppf)Cl 2 DCM complex (21.4 mg, 0.025 mmol). The argon was replaced three times and the reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (20.0 mL), and extracted with EA (50.0 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. After separation and purification by column chromatography (PE:EA=3:1-1:1), the target compound (165 mg, yield 82.3%, yellow solid) was obtained. LC-MS (ESI) m/z 405.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.19(d,J=1.4Hz,1H),8.63(s,1H),8.38(s,1H),8.11(d,J=0.6Hz,1H) ,7.75(d,J＝1.0Hz,1H),6.08-6.04(m,1H),4.10-4.05(m,2H),3.89(s,3H),3.67-3.62(m,2H),2.55-2.52 (m, 2H), 1.46 (s, 9H).
步骤7：4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)哌啶-1-甲酸叔丁酯的合成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
向4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(165mg,0.408mmol)的EA(10.0mL)溶液中加入二氧化铂(185mg,0.816mmol)。氢气置换3次。反应混合物在室温下搅拌反应24小时。将反应混合物通过硅藻土过滤，滤饼用EA(10.0mL)洗。滤液减压浓缩得到粗产品。经反相制备(乙腈/水含0.05％甲酸)纯化得到目标化合物(50.0mg,收率30.1％,白色固体)。LC-MS(ESI)m/z 307.4[M-100+H] +。 To 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydropyridine To a solution of -1(2H)-tert-butylcarboxylate (165 mg, 0.408 mmol) in EA (10.0 mL) was added platinum dioxide (185 mg, 0.816 mmol). The hydrogen was replaced 3 times. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through celite and the filter cake was washed with EA (10.0 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. Purification by reverse phase preparation (acetonitrile/water with 0.05% formic acid) afforded the title compound (50.0 mg, 30.1% yield, white solid). LC-MS (ESI) m/z 307.4 [M-100+H] + .
步骤8：6-(1-甲基-1H-吡唑-4-基)-4-(哌啶-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐的合成Step 8: 6-(1-Methyl-1H-pyrazol-4-yl)-4-(piperidin-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride Synthesis
4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)哌啶-1-甲酸叔丁酯(50.0mg,0.123mmol)的氯化氢甲醇溶液(3.0M,5.00mL)在室温下搅拌反应16小时。将反应混合物减压浓缩得到目标化合物(42.0mg,收率99.5％,淡黄色固体)。LC-MS(ESI)m/z 307.1[M+H] +。 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidine-1-carboxylic acid tert-butyl ester (50.0 mg, 0.123 mmol) of hydrogen chloride in methanol (3.0 M, 5.00 mL) The reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (42.0 mg, yield 99.5%, pale yellow solid). LC-MS (ESI) m/z 307.1 [M+H] + .
步骤9：4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)哌啶-1-甲酰胺盐酸盐的合成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
向碳酸氢钠水溶液(2.50mL)与DCM(5.00mL)的混合液中依次加入(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(19.6mg,0.102mmol)和三光气(18.2mg,0.061mmol)。反应混合物在室温下搅拌反应1小时。用DCM(8.00mL)萃取。有机相用饱和食盐水(3.00mL×3)洗、无 水硫酸钠干燥、过滤。向滤液中依次加入TEA(31.0mg,0.306mmol)和6-(1-甲基-1H-吡唑-4-基)-4-(哌啶-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(42.0mg,0.123mmol)。反应混合物在室温下搅拌反应20分钟。将反应液倒入水(20.0mL)中，用DCM(30.0mL×3)萃取。合并有机相用无水硫酸钠干燥、过滤，滤液减压浓缩得到粗产品 (化合物23)。经制备HPLC(乙腈/水含0.05％盐酸)纯化得到盐酸盐形式的目标化合物 (化合物23-1)(16.0mg,收率23.2％,淡黄色固体)。LC-MS(ESI)m/z 525.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.14–9.11(m,1H),8.67(d,J＝4.4Hz,1H),8.63(s,1H),8.42(s,1H),8.39–8.36(m,1H),8.11(s,1H),7.93–7.86(m,3H),7.67(s,1H),7.34–7.26(m,1H),4.34–4.30(s,2H),4.25(d,J＝13.0Hz,2H),3.88(s,3H),3.43–3.33(m,1H),2.91–2.82(m,2H),2.00–1.92(m,2H),1.80–1.68(m,2H)。 To a mixture of aqueous sodium bicarbonate (2.50 mL) and DCM (5.00 mL) was sequentially added (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (19.6 mg, 0.102 mmol) and triphosgene (18.2 mg, 0.061 mmol). The reaction mixture was stirred at room temperature for 1 hour. Extracted with DCM (8.00 mL). The organic phase was washed with saturated brine (3.00 mL×3), dried over anhydrous sodium sulfate, and filtered. To the filtrate was added TEA (31.0 mg, 0.306 mmol) followed by 6-(1-methyl-1H-pyrazol-4-yl)-4-(piperidin-4-yl)pyrazolo[1,5- a] Pyridine-3-carbonitrile hydrochloride (42.0 mg, 0.123 mmol). The reaction mixture was stirred at room temperature for 20 minutes. The reaction solution was poured into water (20.0 mL) and extracted with DCM (30.0 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (compound 23) . Purification by preparative HPLC (acetonitrile/water with 0.05% hydrochloric acid) afforded the title compound (compound 23-1) (16.0 mg, yield 23.2%, pale yellow solid) as the hydrochloride salt. LC-MS (ESI) m/z 525.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.14-9.11(m,1H),8.67(d,J=4.4Hz,1H),8.63(s,1H),8.42(s,1H),8.39- 8.36(m, 1H), 8.11(s, 1H), 7.93–7.86(m, 3H), 7.67(s, 1H), 7.34–7.26(m, 1H), 4.34–4.30(s, 2H), 4.25( d, J＝13.0Hz, 2H), 3.88(s, 3H), 3.43-3.33(m, 1H), 2.91-2.82(m, 2H), 2.00-1.92(m, 2H), 1.80-1.68(m, 2H).
实施例24： 4-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)-3,6-二氢吡啶-1(2H)-甲酰胺(化合物24)的的合成 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)
Figure PCTCN2021118001-appb-000046
Figure PCTCN2021118001-appb-000046
步骤1:4-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯的合成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
将4-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(400mg,0.992mmol)、2,2-二甲基环氧乙烷(715mg,9.92mmol)、碳酸铯(970mg,2.98mmol)、2-二叔丁基磷-3,4,5,6-四甲基-2',4',6'-三异丙基联苯(76.3mg,0.159mmol)和三(二亚苄基丙酮)二钯(36.3mg,0.0397mmol)分别加入到水(2.00mL)和1,4-二氧六环(6.00mL)的混合溶剂中。氩气保护下，反应混合物在100℃下搅拌反应16小时。将反应混合物冷却至室温，分出有机相，减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝55:45)得到目标化合物(65.0mg,收率30.0％,米白色固体)。LC-MS(ESI)m/z 313.2[M-100+H] +。 1H NMR(400MHz,CDCl 3)δ8.17(s,1H),8.09(d,J＝2.1Hz,1H),7.05(d,J＝1.8Hz,1H),6.01–5.97(m,1H),4.19–4.14(m,2H),3.83(s,2H),3.77(t,J＝5.6Hz,2H),2.54-2.45(m,2H),1.50(s,9H),1.38(s,6H)。 4-(6-Bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (400 mg, 0.992 mmol), 2,2-dimethyloxirane (715mg, 9.92mmol), cesium carbonate (970mg, 2.98mmol), 2-di-tert-butylphosphorus-3,4,5,6-tetramethyl- 2',4',6'-Triisopropylbiphenyl (76.3mg, 0.159mmol) and tris(dibenzylideneacetone)dipalladium (36.3mg, 0.0397mmol) were added to water (2.00mL) and 1 , 4-dioxane (6.00 mL) in a mixed solvent. Under argon, the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, and the organic phase was separated and concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=55:45), the target compound (65.0 mg, yield 30.0%, off-white solid) was obtained. LC-MS (ESI) m/z 313.2 [M-100+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (s, 1H), 8.09 (d, J=2.1 Hz, 1H), 7.05 (d, J=1.8 Hz, 1H), 6.01-5.97 (m, 1H) ,4.19-4.14(m,2H),3.83(s,2H),3.77(t,J=5.6Hz,2H),2.54-2.45(m,2H),1.50(s,9H),1.38(s,6H ).
步骤2:6-(2-羟基-2-甲基丙氧基)-4-(1,2,3,6-四氢吡啶-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐的合成Step 2: 6-(2-Hydroxy-2-methylpropoxy)-4-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridine- Synthesis of 3-carbonitrile hydrochloride
室温下，将4-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(65.0mg,0.158mmol)和3.0M的氯化氢甲醇溶液(1.00mL)加入到甲醇(1.00mL)中。反应混合物在室温下搅拌反应2小时。将反应混合物减压浓缩得到目标化合物 (50.0mg,收率90.9％,类白色固体)。LC-MS(ESI)m/z 313.2[M+H] +。 At room temperature, 4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydro Pyridine-1(2H)-carboxylate tert-butyl ester (65.0 mg, 0.158 mmol) and a 3.0 M solution of hydrogen chloride in methanol (1.00 mL) were added to methanol (1.00 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (50.0 mg, yield 90.9%, off-white solid). LC-MS (ESI) m/z 313.2 [M+H] + .
步骤3:4-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-3,6-二氢吡啶-1(2H)-甲酰胺的合成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
向碳酸氢钠水溶液(2.50mL)与DCM(5.00mL)的混合液中加入(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(60.6mg,0.315mmol)。搅拌15分钟后，加入三光气(56.1mg,0.189mmol)。反应混合物在室温下搅拌反应2小时。加入DCM(5.00mL)和水(2.50mL)。分出有机相依次用水(5.00mL)和饱和食盐水(5.00mL)洗、无水硫酸钠干燥、过滤。To a mixture of aqueous sodium bicarbonate (2.50 mL) and DCM (5.00 mL) was added (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (60.6 mg, 0.315 mmol). After stirring for 15 minutes, triphosgene (56.1 mg, 0.189 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. DCM (5.00 mL) and water (2.50 mL) were added. The organic phase was separated, washed successively with water (5.00 mL) and saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and filtered.
向上述滤液中依次加入TEA(63.7mg,0.630mmol)和6-(2-羟基-2-甲基丙氧基)-4-(1,2,3,6-四氢吡啶-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(50.0mg,0.143mmol)。反应混合物在室温下搅拌反应半小时。加入水(15.0mL)，用DCM(20.0mL×2)萃取。合并有机相依次用水(15.0mL)及饱和食盐水(15.0mL)洗、无水硫酸钠干燥、过滤，滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(11.8mg,收率14.0％,米白色固体)。LC-MS(ESI)m/z 531.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.67(d,J＝3.2Hz,1H),8.61(s,1H),8.55(s,1H),8.38(s,1H),7.95–7.85(m,3H),7.34–7.21(m,2H),6.09–6.03(m,1H),4.74–4.65(m,1H),4.33(d,J＝4.4Hz,2H),4.06(s,2H),3.83(s,2H),3.69–3.59(m,2H),2.55–2.50(m,2H),1.21(s,6H)。 To the above filtrate was added TEA (63.7 mg, 0.630 mmol) followed by 6-(2-hydroxy-2-methylpropoxy)-4-(1,2,3,6-tetrahydropyridin-4-yl) Pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride (50.0 mg, 0.143 mmol). The reaction mixture was stirred at room temperature for half an hour. Water (15.0 mL) was added and extracted with DCM (20.0 mL x 2). The combined organic phases were washed successively with water (15.0 mL) and saturated brine (15.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (11.8 mg, 14.0% yield, off-white solid). LC-MS (ESI) m/z 531.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.67(d, J=3.2Hz, 1H), 8.61(s, 1H), 8.55(s, 1H), 8.38(s, 1H), 7.95-7.85( m, 3H), 7.34–7.21 (m, 2H), 6.09–6.03 (m, 1H), 4.74–4.65 (m, 1H), 4.33 (d, J=4.4Hz, 2H), 4.06 (s, 2H) , 3.83 (s, 2H), 3.69–3.59 (m, 2H), 2.55–2.50 (m, 2H), 1.21 (s, 6H).
实施例25： 4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)-3,6-二氢吡啶-1(2H)-甲酰胺(化合物25)的的合成 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)
Figure PCTCN2021118001-appb-000047
Figure PCTCN2021118001-appb-000047
步骤1:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯的合成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
向3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯(80.0mg,0.215mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(66.6mg,0.215mmol)的水(0.300mL)和四氢呋喃(1.50mL)混合溶液中加入乙酸钾(42.3mg,0.431mmol)和Pd(dppf)Cl 2DCM络合物(13.9mg,0.016mmol)。置换氩气三次，反应混合物在50℃下搅拌反应4小时。将反应混合物冷却至室温，静置分层。有机相减压浓缩得到 粗产品。经柱层析分离纯化(PE：EA＝3：1-1：1)得到目标化合物(60mg,收率68.8％,淡黄色固体)。LC-MS(ESI)m/z 405.1[M+H] +。 To 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (80.0 mg, 0.215 mmol ) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid To a mixed solution of tert-butyl ester (66.6 mg, 0.215 mmol) in water (0.300 mL) and tetrahydrofuran (1.50 mL) was added potassium acetate (42.3 mg, 0.431 mmol) and Pd(dppf)Cl 2 DCM complex (13.9 mg, 0.016 mmol). The argon was replaced three times and the reaction mixture was stirred at 50°C for 4 hours. The reaction mixture was cooled to room temperature, and the layers were allowed to stand. The organic phase was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=3:1-1:1), the target compound (60 mg, yield 68.8%, pale yellow solid) was obtained. LC-MS (ESI) m/z 405.1 [M+H] + .
步骤2:6-(1-甲基-1H-吡唑-4-基)-4-(1,2,3,6-四氢吡啶-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐的合成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
将4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(60.0mg,0.148mmol)加入到氯化氢甲醇溶液(3.0M,5.00mL)中。反应混合物在室温下搅拌反应16小时。反应混合物减压浓缩后得到目标化合物(48.0mg,收率94.9％,淡黄色固体)。LC-MS(ESI)m/z 305.2[M+H] +。 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydropyridine tert-Butyl -1(2H)-carboxylate (60.0 mg, 0.148 mmol) was added to a solution of hydrogen chloride in methanol (3.0 M, 5.00 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (48.0 mg, yield 94.9%, pale yellow solid). LC-MS (ESI) m/z 305.2 [M+H] + .
步骤3:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-3,6-二氢吡啶-1(2H)-甲酰胺的合成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
向(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(22.6mg,0.117mmol)的碳酸氢钠水溶液(2.50mL)与DCM(5.00mL)混合液中加入三光气(20.9mg,0.070mmol)。反应混合物在室温下搅拌反应1小时。用DCM(10.0mL)萃取。有机相用饱和食盐水(4.00mL×3)洗、无水硫酸钠干燥、过滤。向滤液中加入TEA(35.6mg,0.352mmol)和6-(1-甲基-1H-吡唑-4-基)-4-(1,2,3,6-四氢吡啶-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(48.0mg,0.141mmol)。反应混合物在室温下搅拌反应20分钟。将反应液倒入水(10.0mL)中，用DCM(30.0mL×3)萃取。合并有机相用无水硫酸钠干燥、过滤，滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(28.2mg,收率46.1％,白色固体)。LC-MS(ESI)m/z 523.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.20–9.17(m,1H),8.68(d,J＝4.4Hz,1H),8.63(s,1H),8.40–8.38(m,1H),8.37(s,1H),8.10(s,1H),7.94–7.86(m,3H),7.75–7.72(m,1H),7.28(t,J＝5.4Hz,1H),6.10–6.06(m,1H),4.34(d,J＝5.4Hz,2H),4.12–4.06(m,2H),3.88(s,3H),3.70–3.64(m,2H),2.56–2.53(m,2H)。 To a mixture of (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (22.6 mg, 0.117 mmol) in aqueous sodium bicarbonate (2.50 mL) and DCM (5.00 mL) To this was added triphosgene (20.9 mg, 0.070 mmol). The reaction mixture was stirred at room temperature for 1 hour. Extracted with DCM (10.0 mL). The organic phase was washed with saturated brine (4.00 mL×3), dried over anhydrous sodium sulfate, and filtered. To the filtrate was added TEA (35.6 mg, 0.352 mmol) and 6-(1-methyl-1H-pyrazol-4-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl) Pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride (48.0 mg, 0.141 mmol). The reaction mixture was stirred at room temperature for 20 minutes. The reaction solution was poured into water (10.0 mL) and extracted with DCM (30.0 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (28.2 mg, 46.1% yield, white solid). LC-MS (ESI) m/z 523.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.20-9.17(m,1H),8.68(d,J=4.4Hz,1H),8.63(s,1H),8.40-8.38(m,1H), 8.37(s, 1H), 8.10(s, 1H), 7.94-7.86(m, 3H), 7.75-7.72(m, 1H), 7.28(t, J=5.4Hz, 1H), 6.10-6.06(m, 1H), 4.34 (d, J=5.4Hz, 2H), 4.12–4.06 (m, 2H), 3.88 (s, 3H), 3.70–3.64 (m, 2H), 2.56–2.53 (m, 2H).
实施例26： 4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)环己酰胺(化合物26)的的合成 Example 26: 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)cyclohexanamide (Compound 26)
Figure PCTCN2021118001-appb-000048
Figure PCTCN2021118001-appb-000048
步骤1:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)环己-3-烯-1-甲酸甲酯的合 成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
向3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯(100mg,0.269mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)环己-3-烯-1-甲酸甲酯(72.2mg,0.269mmol)的水(0.500mL)和四氢呋喃(2.50mL)混合溶液中加入乙酸钾(52.9mg,0.538mmol)和Pd(dppf)Cl 2DCM络合物(17.4mg,0.020mmol)。置换氩气3次。反应混合物在50℃搅拌反应5小时。将反应液冷却至室温后分离有机相。减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝3：1-1：1)得到目标化合物(90.0mg,收率92.5％,淡黄色固体)。LC-MS(ESI)m/z 362.0[M+H] +。 To 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (100 mg, 0.269 mmol) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)cyclohex-3-ene-1-carboxylate (72.2 mg, To a mixed solution of 0.269 mmol) in water (0.500 mL) and tetrahydrofuran (2.50 mL) was added potassium acetate (52.9 mg, 0.538 mmol) and Pd(dppf)Cl 2 DCM complex (17.4 mg, 0.020 mmol). Argon was replaced 3 times. The reaction mixture was stirred at 50°C for 5 hours. After cooling the reaction solution to room temperature, the organic phase was separated. Concentration under reduced pressure gave crude product. After separation and purification by column chromatography (PE:EA=3:1-1:1), the target compound (90.0 mg, yield 92.5%, pale yellow solid) was obtained. LC-MS (ESI) m/z 362.0 [M+H] + .
步骤2:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)环己烷-1-甲酸甲酯的合成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
在室温下，将4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)环己-3-烯-1-甲酸甲酯(90.0mg,0.249mmol)加入到甲醇(15.0mL)和EA(15.0mL)混合溶剂中。加入钯碳(30.0mg)。在氢气氛围下，反应混合物在室温下搅拌反应32小时。反应混合物通过硅藻土过滤，滤饼用EA(20.0mL)洗。滤液减压浓缩得到目标化合物(50.0mg,收率55.2％,白色固体)。LC-MS(ESI)m/z 364.3[M+H] +。 At room temperature, 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)cyclohex-3 -Methyl ene-1-carboxylate (90.0 mg, 0.249 mmol) was added to a mixed solvent of methanol (15.0 mL) and EA (15.0 mL). Palladium on carbon (30.0 mg) was added. Under a hydrogen atmosphere, the reaction mixture was stirred at room temperature for 32 hours. The reaction mixture was filtered through celite and the filter cake was washed with EA (20.0 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (50.0 mg, yield 55.2%, white solid). LC-MS (ESI) m/z 364.3 [M+H] + .
步骤3:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)环己烷-1-甲酸的合成Step 3: 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)cyclohexane-1- Synthesis of Formic Acid
向4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)环己烷-1-甲酸甲酯(50.0mg,0.138mmol)的水(0.500mL)、四氢呋喃(1.00mL)和甲醇(2.00mL)的混合溶液中加入一水合氢氧化锂(8.66mg,0.206mmol)。反应混合物在室温下搅拌反应16小时。将反应混合物减压浓缩除去有机溶剂后，加入到水(10.0mL)中。用1.0M盐酸溶液调节pH＝4。混合液用EA(20.0mL×3)萃取。合并有机相，用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％盐酸的水)纯化得到目标化合物(12.0mg,收率25.0％,白色固体)。LC-MS(ESI)m/z 350.4[M+H] +。 to 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)cyclohexane-1-carboxylic acid methyl To a mixed solution of the ester (50.0 mg, 0.138 mmol) in water (0.500 mL), tetrahydrofuran (1.00 mL) and methanol (2.00 mL) was added lithium hydroxide monohydrate (8.66 mg, 0.206 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, and then added to water (10.0 mL). Adjust pH=4 with 1.0M hydrochloric acid solution. The mixture was extracted with EA (20.0 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% hydrochloric acid) afforded the title compound (12.0 mg, 25.0% yield, white solid). LC-MS (ESI) m/z 350.4 [M+H] + .
步骤4:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)环己酰胺的合成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
在室温下，向4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)环己烷-1-甲酸(12.0mg,0.034mmol)的DMF(0.500mL)溶液中加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(9.97mg,0.052mmol)、HOBt(7.03mg,0.052mmol)、DIEA(8.88mg,0.069mmol)和(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(6.59mg,0.034mmol)。反应混合物室温下搅拌反应16小时。将反应混合物倒入水(10.0mL)中，用EA(30.0mL)萃取。有机相用饱和食盐水(5.00mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％ 甲酸的水)纯化得到目标化合物(4.46mg,收率25.1％,白色固体)。LC-MS(ESI)m/z 524.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.10(d,J＝0.8Hz,1H),8.65–8.62(m,1H),8.61(s,1H),8.46-8.41(m,1H),8.40(s,1H),8.38–8.35(m,1H),8.07(s,1H),7.92–7.86(m,3H),7.49(s,1H),4.39–4.34(m,2H),3.87(s,3H),2.69–2.63(m,2H),2.19–2.13(m,2H),1.92–1.85(m,4H),1.79–1.71(m,2H)。 To 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)cyclohexane- To a solution of 1-carboxylic acid (12.0 mg, 0.034 mmol) in DMF (0.500 mL) was added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.97 mg, 0.052 mmol), HOBt (7.03 mg, 0.052 mmol), DIEA (8.88 mg, 0.069 mmol) and (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (6.59 mg, 0.034 mmol) . The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (10.0 mL) and extracted with EA (30.0 mL). The organic phase was washed with saturated brine (5.00 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (4.46 mg, 25.1% yield, white solid). LC-MS (ESI) m/z 524.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.10(d,J=0.8Hz,1H),8.65-8.62(m,1H),8.61(s,1H),8.46-8.41(m,1H), 8.40(s, 1H), 8.38–8.35(m, 1H), 8.07(s, 1H), 7.92–7.86(m, 3H), 7.49(s, 1H), 4.39–4.34(m, 2H), 3.87( s, 3H), 2.69–2.63 (m, 2H), 2.19–2.13 (m, 2H), 1.92–1.85 (m, 4H), 1.79–1.71 (m, 2H).
实施例27： 4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)-1H-吡唑-1-甲酰胺(化合物27)的的合成 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)
Figure PCTCN2021118001-appb-000049
Figure PCTCN2021118001-appb-000049
步骤1:6-溴-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈的合成Step 1: 6-Bromo-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-methyl Synthesis of Nitriles
向6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯(850mg,2.30mmol)和1-(四氢-2H-吡喃-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(607mg,2.18mmol)的水(2.00mL)和四氢呋喃(10.0mL)混合溶液中加入乙酸钾(451mg,4.60mmol)和Pd(dppf)Cl 2DCM络合物(149mg,0.173mmol)。氩气保护下，反应混合物在40℃下搅拌反应16小时。将反应混合物冷却至室温后倒入EA(40.0mL)中得到黑色溶液。溶液用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝10：1-5：1)得到目标化合物(550mg,收率64.3％,黄色固体)。LC-MS(ESI)m/z 371.9,373.9[M+H] +。 1H NMR(400MHz,CDCl 3)δ8.67–8.65(m,1H),8.27(s,1H),8.11(s,1H),7.84(s,1H),7.48–7.46(m,1H),5.53–5.48(m,1H),3.81–3.70(m,2H),2.21–2.16(m,2H),1.75–1.70(m,2H),1.68–1.62(m,2H)。 To 6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (850 mg, 2.30 mmol) and 1-(tetrahydro-2H-pyran-2- ( 2.00 mL) and tetrahydrofuran (10.0 mL) were added potassium acetate (451 mg, 4.60 mmol) and Pd(dppf)Cl 2 DCM complex (149 mg, 0.173 mmol). Under argon, the reaction mixture was stirred at 40°C for 16 hours. The reaction mixture was cooled to room temperature and poured into EA (40.0 mL) to give a black solution. The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=10:1-5:1), the target compound (550 mg, yield 64.3%, yellow solid) was obtained. LC-MS (ESI) m/z 371.9, 373.9 [M+H] + . 1 H NMR (400MHz, CDCl 3 )δ8.67-8.65(m,1H), 8.27(s,1H), 8.11(s,1H), 7.84(s,1H), 7.48-7.46(m,1H), 5.53–5.48 (m, 1H), 3.81–3.70 (m, 2H), 2.21–2.16 (m, 2H), 1.75–1.70 (m, 2H), 1.68–1.62 (m, 2H).
步骤2:6-(1-甲基-1H-吡唑-4-基)-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈的合成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
向6-溴-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈(550mg,1.48mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(369mg,1.77mmol)的水(2.00mL)和1,4-二氧六环(10.0mL)混合溶液中加入碳酸钠(314mg,2.96mmol)和Pd(dppf)Cl 2DCM络合物(63.8mg,0.074mmol)。氩气保护下，反应混合物在80℃下搅拌反应16小时。将反应混合物冷却至室温后倒入EA(30.0mL)中得到黑色溶液。溶液用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝3：1-1：2)得到 目标化合物(320mg,收率58.0％,黄色固体)。LC-MS(ESI)m/z 374.0[M+H] +。 To 6-bromo-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( 550mg, 1.48mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole ( To a mixed solution of 369 mg, 1.77 mmol) in water (2.00 mL) and 1,4-dioxane (10.0 mL) was added sodium carbonate (314 mg, 2.96 mmol) and Pd(dppf)Cl 2 DCM complex (63.8 mg) , 0.074 mmol). Under argon, the reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature and poured into EA (30.0 mL) to give a black solution. The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=3:1-1:2), the target compound (320 mg, yield 58.0%, yellow solid) was obtained. LC-MS (ESI) m/z 374.0 [M+H] + .
步骤3:6-(1-甲基-1H-吡唑-4-基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈三氟乙酸盐的合成Step 3: 6-(1-Methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitriletris Synthesis of Fluoroacetate
将6-(1-甲基-1H-吡唑-4-基)-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈(320mg,0.857mmol)和三氟乙酸(0.500mL)加入到DCM(15.0mL)中。反应混合物在室温下搅拌反应16小时。反应混合物减压浓缩得到目标化合物(330mg,收率95.4％,黄色固体)。LC-MS(ESI)m/z 290.1[M+H] +。 6-(1-Methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile (320 mg, 0.857 mmol) and trifluoroacetic acid (0.500 mL) were added to DCM (15.0 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (330 mg, yield 95.4%, yellow solid). LC-MS (ESI) m/z 290.1 [M+H] + .
步骤4:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-1H-吡唑-1-甲酰胺的合成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
向(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(31.7mg,0.165mmol)的饱和碳酸氢钠水溶液(3.00mL)和DCM(5.00mL)的混合液中加入三光气(29.4mg,0.099mmol)。反应混合物在室温下搅拌反应1小时。用DCM(10.0mL)萃取。有机相用饱和食盐水(4.00mL×3)洗、无水硫酸钠干燥、过滤。向滤液中加入TEA(50.2mg,0.496mmol)和6-(1-甲基-1H-吡唑-4-基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈三氟乙酸盐(80.0mg,0.198mmol)。反应混合物在室温下搅拌反应20分钟。将反应液用水(15.0mL)稀释，DCM(3.00mL×2)萃取。合并有机相用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(4.10mg,收率4.08％,白色固体)。LC-MS(ESI)m/z 508.4[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.45–9.41(m,1H),9.27(s,1H),8.81(s,1H),8.71–8.67(m,2H),8.49–8.46(m,1H),8.39(s,1H),8.26(s,1H),8.13(s,1H),8.03–7.96(m,2H),7.95–7.90(m,2H),4.55(d,J＝5.7Hz,2H),3.89(s,3H)。 To a solution of (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (31.7 mg, 0.165 mmol) in saturated aqueous sodium bicarbonate (3.00 mL) and DCM (5.00 mL) To the mixture was added triphosgene (29.4 mg, 0.099 mmol). The reaction mixture was stirred at room temperature for 1 hour. Extracted with DCM (10.0 mL). The organic phase was washed with saturated brine (4.00 mL×3), dried over anhydrous sodium sulfate, and filtered. To the filtrate was added TEA (50.2 mg, 0.496 mmol) and 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5 -a]pyridine-3-carbonitrile trifluoroacetate (80.0 mg, 0.198 mmol). The reaction mixture was stirred at room temperature for 20 minutes. The reaction solution was diluted with water (15.0 mL) and extracted with DCM (3.00 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (4.10 mg, 4.08% yield, white solid). LC-MS (ESI) m/z 508.4 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.45-9.41(m,1H), 9.27(s,1H), 8.81(s,1H), 8.71-8.67(m,2H), 8.49-8.46(m ,1H),8.39(s,1H),8.26(s,1H),8.13(s,1H),8.03–7.96(m,2H),7.95–7.90(m,2H),4.55(d,J=5.7 Hz, 2H), 3.89 (s, 3H).
实施例28： 4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-甲氧基吡啶-3-基) 甲基)-1H-吡唑-1-甲酰胺(化合物28)及其盐酸盐(化合物28-1)的合成 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)
Figure PCTCN2021118001-appb-000050
Figure PCTCN2021118001-appb-000050
步骤1:6-(1-甲基-1H-吡唑-4-基)-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈的合成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
向3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基三氟甲磺酸酯(800mg,2.15mmol)和1-(四氢-2H-吡喃-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑 (659mg,2.37mmol)的水(1.20mL)和四氢呋喃(6.00mL)混合溶液中加入碳酸钠(457mg,4.31mmol)和Pd(dppf)Cl 2DCM络合物(92.8mg,0.108mmol)。氩气保护下，反应混合物在60℃下搅拌反应5小时。将反应混合物冷却至室温后倒入EA(60.0mL)中得到黑色溶液。溶液用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝3：1-1：5)得到目标化合物(700mg，收率87.0％，黄色固体)。LC-MS(ESI)m/z 396.1[M+Na] +。 To 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (800 mg, 2.15 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) To a mixed solution of -1H-pyrazole (659 mg, 2.37 mmol) in water (1.20 mL) and tetrahydrofuran (6.00 mL) was added sodium carbonate (457 mg, 4.31 mmol) and Pd(dppf)Cl 2 DCM complex (92.8 mg, 0.108 mmol). Under argon, the reaction mixture was stirred at 60°C for 5 hours. The reaction mixture was cooled to room temperature and poured into EA (60.0 mL) to give a black solution. The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=3:1-1:5), the target compound (700 mg, yield 87.0%, yellow solid) was obtained. LC-MS (ESI) m/z 396.1 [M+Na] + .
步骤2:6-(1-甲基-1H-吡唑-4-基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐的合成Step 2: 6-(1-Methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile salt Synthesis of acid salts
6-(1-甲基-1H-吡唑-4-基)-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈(700mg,1.87mmol)的氯化氢甲醇溶液(3.0M,10.0mL)在室温下搅拌反应16小时。将反应混合物减压浓缩得到目标化合物(600mg，收率98.2％，黄色固体)。LC-MS(ESI)m/z 290.3[M+H] +。 6-(1-Methyl-1H-pyrazol-4-yl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[ A solution of 1,5-a]pyridine-3-carbonitrile (700 mg, 1.87 mmol) in methanol of hydrogen chloride (3.0 M, 10.0 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (600 mg, yield 98.2%, yellow solid). LC-MS (ESI) m/z 290.3 [M+H] + .
步骤3:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-甲氧基吡啶-3-基)甲基)-1H-吡唑-1-甲酰胺及其盐酸盐的合成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
在室温下，向CDI(64.7mg,0.399mmol)的DMF(2.00mL)溶液中加入(6-甲氧基吡啶-3-基)甲胺(46.7mg,0.338mmol)和DIEA(79.4mg,0.614mmol)。反应混合物在室温下搅拌反应16小时。向反应混合液中加入6-(1-甲基-1H-吡唑-4-基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(100mg,0.307mmol)。反应混合物在70℃下搅拌反应8小时。将反应混合物冷却至室温后倒入水(15.0mL)中，用EA(100mL)萃取。有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品 (化合物28)。经制备(乙腈/含0.05％盐酸的水)纯化得到盐酸盐形式的目标化合物 (化合物28-1)(19.6mg,收率13.0％,黄色固体)。LC-MS(ESI)m/z 454.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.33–9.28(m,1H),9.27–9.25(m,1H),8.80–8.78(m,1H),8.68(s,1H),8.39(s,1H),8.25–8.23(m,1H),8.19–8.16(m,1H),8.13(s,1H),7.98–7.95(m,1H),7.77–7.73(m,1H),6.83(d,J＝8.5Hz,1H),4.42(d,J＝6.2Hz,2H),3.89(s,3H),3.84(s,3H)。 To a solution of CDI (64.7 mg, 0.399 mmol) in DMF (2.00 mL) at room temperature was added (6-methoxypyridin-3-yl)methanamine (46.7 mg, 0.338 mmol) and DIEA (79.4 mg, 0.614 mmol). The reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3- Formonitrile hydrochloride (100 mg, 0.307 mmol). The reaction mixture was stirred at 70°C for 8 hours. The reaction mixture was cooled to room temperature, poured into water (15.0 mL), and extracted with EA (100 mL). The organic phase was washed with saturated brine (15.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product (compound 28) . Purification by preparative (acetonitrile/water with 0.05% hydrochloric acid) afforded the title compound (compound 28-1) (19.6 mg, 13.0% yield, yellow solid) as the hydrochloride salt. LC-MS (ESI) m/z 454.0 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.33-9.28(m,1H), 9.27-9.25(m,1H), 8.80-8.78(m,1H), 8.68(s,1H), 8.39(s ,1H),8.25–8.23(m,1H),8.19–8.16(m,1H),8.13(s,1H),7.98–7.95(m,1H),7.77–7.73(m,1H),6.83(d , J=8.5Hz, 1H), 4.42 (d, J=6.2Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H).
实施例29： 4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-甲氧基吡啶-3- 基)乙基)-1H-吡唑-1-甲酰胺(化合物29)的合成 Example 29: 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 (Compound 29)
Figure PCTCN2021118001-appb-000051
Figure PCTCN2021118001-appb-000051
步骤1:1-(6-甲氧基吡啶-3-基)乙-1-酮肟的合成Step 1: Synthesis of 1-(6-methoxypyridin-3-yl)ethan-1-one oxime
向1-(6-甲氧基吡啶-3-基)乙烷-1-酮(1.00g,6.62mmol)的乙醇(10.0mL)溶液中加入盐酸羟胺(919mg,13.2mmol)和乙酸钠(1.09g,13.2mmol)的水(5.00mL)溶液。反应混合物在90℃下搅拌反应2小时。将反应液减压浓缩后得到的固体残渣加入到水(30.0mL)中。过滤，滤饼用水(30.0mL)洗。滤饼经真空干燥后得到目标产物(1.05g，收率95.5％，白色固体)。LC-MS(ESI)m/z 167.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ11.20(s,1H),8.42–8.39(m,1H),8.00–7.95(m,1H),6.85–6.82(m,1H),3.87(s,3H),2.14(s,3H)。 To a solution of 1-(6-methoxypyridin-3-yl)ethan-1-one (1.00 g, 6.62 mmol) in ethanol (10.0 mL) was added hydroxylamine hydrochloride (919 mg, 13.2 mmol) and sodium acetate (1.09 g, 13.2 mmol) in water (5.00 mL). The reaction mixture was stirred at 90°C for 2 hours. The solid residue obtained by concentrating the reaction solution under reduced pressure was added to water (30.0 mL). After filtration, the filter cake was washed with water (30.0 mL). The filter cake was dried under vacuum to obtain the desired product (1.05 g, yield 95.5%, white solid). LC-MS (ESI) m/z 167.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.20(s,1H), 8.42-8.39(m,1H), 8.00-7.95(m,1H), 6.85-6.82(m,1H), 3.87(s) , 3H), 2.14(s, 3H).
步骤2:1-(6-甲氧基吡啶-3-基)乙-1-胺的合成Step 2: Synthesis of 1-(6-methoxypyridin-3-yl)ethan-1-amine
在-10℃下，向1-(6-甲氧基吡啶-3-基)乙-1-酮肟(1.05g,6.32mmol)的甲醇溶液中(20.0mL)加入六水合氯化镍(3.00g,12.6mmol)，然后缓慢加入硼氢化钠(1.91g,50.5mmol)。反应混合物在室温下搅拌反应3小时。向反应混合物中加入丙酮(10.0mL)淬灭反应。经硅藻土过滤，EA(100mL)洗涤后得到黑色滤液。滤液减压浓缩得到粗产品。经柱层析分离纯化(DCM：甲醇＝100：1-10:1)得到目标化合物(350mg，收率36.4％，黄色油状物)。 1H NMR(400MHz,DMSO-d 6)δ8.15–8.10(m,1H),7.77–7.72(m,1H),6.78(d,J＝8.5Hz,1H),4.11–4.00(m,1H),3.82(s,3H),3.51(br s,2H),1.29(d,J＝6.5Hz,3H)。 To a methanol solution (20.0 mL) of 1-(6-methoxypyridin-3-yl)ethan-1-one oxime (1.05 g, 6.32 mmol) at -10 °C was added nickel chloride hexahydrate (3.00 g, 12.6 mmol), then sodium borohydride (1.91 g, 50.5 mmol) was added slowly. The reaction mixture was stirred at room temperature for 3 hours. Acetone (10.0 mL) was added to the reaction mixture to quench the reaction. Filtered through celite and washed with EA (100 mL) to obtain a black filtrate. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification by column chromatography (DCM:methanol=100:1-10:1) gave the title compound (350 mg, yield 36.4%, yellow oil). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.15-8.10 (m, 1H), 7.77-7.72 (m, 1H), 6.78 (d, J=8.5Hz, 1H), 4.11-4.00 (m, 1H) ), 3.82(s, 3H), 3.51(br s, 2H), 1.29(d, J=6.5Hz, 3H).
步骤3:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-甲氧基吡啶-3-基)乙基)-1H-吡唑-1-甲酰胺的合成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
在室温下，向CDI(74.7mg,0.460mmol)的DMF(2.00mL)溶液中加入1-(6-甲氧基吡啶-3-基)乙-1-胺(51.4mg,0.338mmol)和DIEA(79.3mg,0.614mmol)，反应混合物在室温下搅拌反应16小时加入6-(1-甲基-1H-吡唑-4-基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(100mg,0.307mmol)。反应混合物在70℃下搅拌反应5小时。将反应混合物冷却至室温后倒入水(20.0mL)中，用EA(100mL)萃取。有机相分离后用饱和食盐水(15.0mL×3)洗涤、无水硫酸钠干燥、过滤、滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(37.5mg,收率26.1％,黄色固体)。LC-MS(ESI)m/z 468.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.27–9.25(m,1H),9.14(d,J＝8.4Hz,1H),8.77(s,1H),8.68(s,1H),8.38(s,1H),8.25(s,1H),8.23–8.21(m,1H),8.12(s,1H),7.97–7.95(m,1H),7.87–7.83(m,1H),6.82(d,J＝8.6Hz,1H),5.10-5.03(m,1H),3.89(s,3H),3.83(s,3H),1.58(d,J＝7.1Hz,3H)。 To a solution of CDI (74.7 mg, 0.460 mmol) in DMF (2.00 mL) was added 1-(6-methoxypyridin-3-yl)ethan-1-amine (51.4 mg, 0.338 mmol) and DIEA at room temperature (79.3 mg, 0.614 mmol), the reaction mixture was stirred at room temperature for 16 hours and 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazole was added and [1,5-a]pyridine-3-carbonitrile hydrochloride (100 mg, 0.307 mmol). The reaction mixture was stirred at 70°C for 5 hours. The reaction mixture was cooled to room temperature, poured into water (20.0 mL), and extracted with EA (100 mL). The organic phase was separated, washed with saturated brine (15.0 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (37.5 mg, 26.1% yield, yellow solid). LC-MS (ESI) m/z 468.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.27-9.25(m, 1H), 9.14(d, J=8.4Hz, 1H), 8.77(s, 1H), 8.68(s, 1H), 8.38( s, 1H), 8.25(s, 1H), 8.23–8.21(m, 1H), 8.12(s, 1H), 7.97–7.95(m, 1H), 7.87–7.83(m, 1H), 6.82(d, J=8.6 Hz, 1H), 5.10-5.03 (m, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 1.58 (d, J=7.1 Hz, 3H).
实施例30： (S)-4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-甲氧基吡啶 -3-基)乙基)-1H-吡唑-1-甲酰胺(化合物30)的合成 Example 30: (S)-4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)- Synthesis of N-(1-(6-Methoxypyridin- 3-yl)ethyl)-1H-pyrazole-1-carboxamide (Compound 30)
Figure PCTCN2021118001-appb-000052
Figure PCTCN2021118001-appb-000052
步骤1:(R,E)-N-(1-(6-甲氧基吡啶-3-基)亚乙基)-2-甲基丙基-2-亚磺酰胺的合成Step 1: Synthesis of (R,E)-N-(1-(6-methoxypyridin-3-yl)ethylene)-2-methylpropyl-2-sulfinamide
向1-(6-甲氧基吡啶-3-基)乙-1-酮(1.25g,8.27mmol)的1,2-二氯乙烷(12.0mL)溶液中加入(R)-2-甲基丙基-2-亚磺胺(1.25g,10.3mmol)和钛酸四乙酯(6.93mL,33.1mmol)。反应混合物在110℃下微波管密闭搅拌反应2小时。将反应混合物冷却至室温。减压浓缩除去有机溶剂后溶于EA(100mL)和水(20.0mL)中得到悬浊液。过滤，滤饼用EA(30.0mL)洗。滤液用无水硫酸钠干燥，过滤。减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝10：1-4:1)得到目标化合物(2.00g，收率95.2％，黄色油状物)。LC-MS(ESI)m/z 255.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.74(d,J＝2.3Hz,1H),8.21(dd,J＝8.8,2.5Hz,1H),6.93(d,J＝8.8Hz,1H),3.93(s,3H),2.71(s,3H),1.21(s,9H)。 To a solution of 1-(6-methoxypyridin-3-yl)ethan-1-one (1.25 g, 8.27 mmol) in 1,2-dichloroethane (12.0 mL) was added (R)-2-methyl propyl-2-sulfinamide (1.25 g, 10.3 mmol) and tetraethyl titanate (6.93 mL, 33.1 mmol). The reaction mixture was stirred at 110°C in a microwave tube for 2 hours. The reaction mixture was cooled to room temperature. It was concentrated under reduced pressure to remove the organic solvent and dissolved in EA (100 mL) and water (20.0 mL) to obtain a suspension. After filtration, the filter cake was washed with EA (30.0 mL). The filtrate was dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave crude product. Separation and purification by column chromatography (PE:EA=10:1-4:1) gave the title compound (2.00 g, yield 95.2%, yellow oil). LC-MS (ESI) m/z 255.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.74 (d, J=2.3Hz, 1H), 8.21 (dd, J=8.8, 2.5Hz, 1H), 6.93 (d, J=8.8Hz, 1H) , 3.93(s, 3H), 2.71(s, 3H), 1.21(s, 9H).
步骤2:(R)-N-((S)-1-(6-甲氧基吡啶-3-基)乙基)-2-甲基丙基-2-亚磺酰胺的合成Step 2: Synthesis of (R)-N-((S)-1-(6-methoxypyridin-3-yl)ethyl)-2-methylpropyl-2-sulfinamide
在-70℃并在氩气保护下，将三仲丁基硼氢化锂(1.0M的THF溶液，8.65mL,8.65mmol)滴加到(R,E)-N-(1-(6-甲氧基吡啶-3-基)亚乙基)-2-甲基丙基-2-亚磺酰胺(2.00g,7.86mmol)的干燥四氢呋喃(60.0mL)溶液中。反应混合液在-70℃下搅拌反应90分钟。向反应液中加入饱和氯化铵水溶液(80.0mL)。分出有机相，水相用EA(80.0mL×2)萃取。合并有机相用无水硫酸钠干燥，过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(DCM：MeOH＝100：1-20:1)得到目标化合物(1.50g，收率74.4％，无色油状物)。LC-MS(ESI)m/z 257.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.10(d,J＝2.4Hz,1H),7.67(dd,J＝8.6,2.5Hz,1H),6.79(d,J＝8.6Hz,1H),5.38(d,J＝5.1Hz,1H),4.43–4.36(m,1H),3.83(s,3H),1.45(d,J＝6.7Hz,3H),1.09(s,9H)。 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). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification by column chromatography (DCM:MeOH=100:1-20:1) gave the title compound (1.50 g, yield 74.4%, colorless oil). LC-MS (ESI) m/z 257.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.10 (d, J=2.4Hz, 1H), 7.67 (dd, J=8.6, 2.5Hz, 1H), 6.79 (d, J=8.6Hz, 1H) , 5.38 (d, J=5.1 Hz, 1H), 4.43–4.36 (m, 1H), 3.83 (s, 3H), 1.45 (d, J=6.7 Hz, 3H), 1.09 (s, 9H).
步骤3:(S)-1-(6-甲氧基吡啶-3-基)乙-1-胺的合成Step 3: Synthesis of (S)-1-(6-methoxypyridin-3-yl)ethan-1-amine
在0℃下，将盐酸1,4-二氧六环溶液(4.0M,15.0mL,60.0mmol)滴加到(R)-N-((S)-1-(6-甲氧基吡啶-3-基)乙基)-2-甲基丙基-2-亚磺酰胺(1.50g,5.85mmol)的甲醇(15.0mL)溶液中。反应混合液在室温下搅拌反应1小时。将反应混合物倒入饱和碳酸氢钠水溶液(100mL)中，用混合溶剂(DCM：MeOH＝10:1，100mL×5)萃取。合并有机相用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(DCM：MeOH＝20：1-10:1)得到目标化合物(650mg，收率73.0％，淡黄色油状物)。 1H NMR(400MHz,DMSO-d 6)δ8.09(d,J＝2.4 Hz,1H),7.71(dd,J＝8.5,2.5Hz,1H),6.75(d,J＝8.5Hz,1H),4.00–3.94(m,1H),3.81(s,3H),1.23(d,J＝6.6Hz,3H)。 A solution of hydrochloric acid in 1,4-dioxane (4.0 M, 15.0 mL, 60.0 mmol) was added dropwise to (R)-N-((S)-1-(6-methoxypyridine- 3-yl)ethyl)-2-methylpropyl-2-sulfinamide (1.50 g, 5.85 mmol) in methanol (15.0 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (100 mL), and extracted with a mixed solvent (DCM:MeOH=10:1, 100 mL×5). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification by column chromatography (DCM:MeOH=20:1-10:1) gave the title compound (650 mg, yield 73.0%, pale yellow oil). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.09 (d, J=2.4 Hz, 1H), 7.71 (dd, J=8.5, 2.5 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H) , 4.00–3.94 (m, 1H), 3.81 (s, 3H), 1.23 (d, J=6.6Hz, 3H).
步骤4:(S)-4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-甲氧基吡啶-3-基)乙基)-1H-吡唑-1-甲酰胺的合成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
在室温下，向CDI(69.7mg,0.430mmol)的DMF(3.00mL)溶液中加入(S)-1-(6-甲氧基吡啶-3-基)乙-1-胺(49.0mg,0.322mmol)和DIEA(55.6mg,0.430mmol)。反应混合物在室温下搅拌反应2小时后加入6-(1-甲基-1H-吡唑-4-基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(70.0mg,0.215mmol)。反应混合物在70℃下搅拌反应16小时。将反应混合物冷却至室温后用EA(100mL)稀释。饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(32.0mg,收率31.9％,Ret.time＝1.861min,e.e.95.2％,白色固体)。手性分析方法:手性柱:Reprosil Chiral-OM 100*3mm 3μm；流动相:A:Supercritical CO 2，B:MeOH(0.1％DEA)；梯度:A 60％,B 40％for 5min；流速:1.5mL/min；柱温:35℃。LC-MS(ESI)m/z 468.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.26(d,J＝1.4Hz,1H),9.14(d,J＝8.4Hz,1H),8.77(d,J＝0.7Hz,1H),8.68(s,1H),8.38(s,1H),8.25(d,J＝0.7Hz,1H),8.22(d,J＝2.4Hz,1H),8.12(d,J＝0.6Hz,1H),7.96(d,J＝1.4Hz,1H),7.85(dd,J＝8.6,2.5Hz,1H),6.82(d,J＝8.6Hz,1H),5.12–5.02(m,1H),3.89(s,3H),3.83(s,3H),1.58(d,J＝7.1Hz,3H)。 To a solution of CDI (69.7 mg, 0.430 mmol) in DMF (3.00 mL) at room temperature was added (S)-1-(6-methoxypyridin-3-yl)ethan-1-amine (49.0 mg, 0.322 mmol) and DIEA (55.6 mg, 0.430 mmol). The reaction mixture was stirred at room temperature for 2 hours after which 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a was added. ]pyridine-3-carbonitrile hydrochloride (70.0 mg, 0.215 mmol). The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature and diluted with EA (100 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. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (32.0 mg, 31.9% yield, Ret.time=1.861 min, ee95.2%, white solid). Chiral analysis method: Chiral column: Reprosil Chiral-OM 100*3mm 3μm; 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. LC-MS (ESI) m/z 468.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (d, J=1.4 Hz, 1H), 9.14 (d, J=8.4 Hz, 1H), 8.77 (d, J=0.7 Hz, 1H), 8.68 (s,1H),8.38(s,1H),8.25(d,J=0.7Hz,1H),8.22(d,J=2.4Hz,1H),8.12(d,J=0.6Hz,1H),7.96 (d, J=1.4Hz, 1H), 7.85 (dd, J=8.6, 2.5Hz, 1H), 6.82 (d, J=8.6Hz, 1H), 5.12–5.02 (m, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 1.58 (d, J=7.1 Hz, 3H).
实施例31：(R)-4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-甲氧基吡啶-3-基)乙基)-1H-吡唑-1-甲酰胺(化合物31)的合成Example 31: (R)-4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)- Synthesis of N-(1-(6-Methoxypyridin-3-yl)ethyl)-1H-pyrazole-1-carboxamide (Compound 31)
Figure PCTCN2021118001-appb-000053
Figure PCTCN2021118001-appb-000053
4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-甲氧基吡啶-3-基)乙基)-1H-吡唑-1-甲酰胺(50mg溶于约20mL甲醇，进样体积1.0mL)经Waters SFC 150(室温,100bar,214nm)和250*25mm 10μm Dr.maish Reprosil Chiral-OM(超临界二氧化碳：甲醇，50:50,3.0min,70mL/min)分离得到化合物30(21.4mg，白色固体，Ret.time＝1.883min,e.e.100％)和化合物31(24.8mg，白色固体，Ret.time＝2.256min,e.e.98.7％)。通过上面实施例30的合成中所用的手性分析方法确证了化合物的构型和纯度。4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(1-(6- Methoxypyridin-3-yl)ethyl)-1H-pyrazole-1-carboxamide (50 mg in ca. 20 mL methanol, injection volume 1.0 mL) was purified by Waters SFC 150 (room temperature, 100 bar, 214 nm) and 250* 25mm 10μm Dr.maish Reprosil Chiral-OM (supercritical carbon dioxide: methanol, 50:50, 3.0min, 70mL/min) isolated compound 30 (21.4mg, white solid, Ret.time=1.883min, ee100%) and Compound 31 (24.8 mg, white solid, Ret. time=2.256 min, ee 98.7%). The configuration and purity of the compound were confirmed by the chiral analysis method used in the synthesis of Example 30 above.
化合物31：LC-MS(ESI)m/z 468.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.26(d,J＝1.2 Hz,1H),9.14(d,J＝8.4Hz,1H),8.77(s,1H),8.68(s,1H),8.38(s,1H),8.25(s,1H),8.22(d,J＝2.3Hz,1H),8.12(s,1H),7.96(d,J＝1.2Hz,1H),7.85(dd,J＝8.6,2.4Hz,1H),6.82(d,J＝8.5Hz,1H),5.12–5.02(m,1H),3.89(s,3H),3.83(s,3H),1.58(d,J＝7.1Hz,3H)。 Compound 31: LC-MS (ESI) m/z 468.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.26(d, J=1.2 Hz, 1H), 9.14(d, J=8.4 Hz, 1H), 8.77(s, 1H), 8.68(s, 1H) ,8.38(s,1H),8.25(s,1H),8.22(d,J=2.3Hz,1H),8.12(s,1H),7.96(d,J=1.2Hz,1H),7.85(dd, J=8.6, 2.4Hz, 1H), 6.82(d, J=8.5Hz, 1H), 5.12–5.02(m, 1H), 3.89(s, 3H), 3.83(s, 3H), 1.58(d, J =7.1Hz, 3H).
实施例32： 4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(三氟甲基)吡啶 -3-基)甲基)-1H-吡唑-1-甲酰胺(化合物32)及其盐酸盐(化合物32-1)的合成 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)
Figure PCTCN2021118001-appb-000054
Figure PCTCN2021118001-appb-000054
步骤1:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吡唑-1-甲酰胺及其盐酸盐的合成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
在室温下，向三光气(25.5mg,0.086mmol)的DCM(8.00mL)溶液中加入6-(1-甲基-1H-吡唑-4-基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(70.0mg,0.215mmol)和DIEA(55.5mg,0.430mmol)的DCM(4.00mL)溶液。反应混合物在室温下搅拌反应2小时。加入(6-(三氟甲基)吡啶-3-基)甲胺(37.9mg,0.215mmol)。反应混合物在室温下搅拌反应16小时。将反应混合物减压浓缩得到粗品 (化合物32)。经制备HPLC(乙腈/水含0.05％盐酸)纯化得到盐酸盐形式的目标化合物 (化合物32-1)(20.0mg,收率17.6％,白色固体)。LC-MS(ESI)m/z 492.0[M+H] +。 1H NMR(400MHz,DMSO-d 6) 1H NMR(400MHz,DMSO-d 6)δ9.48(t,J＝6.2Hz,1H),9.27(d,J＝1.4Hz,1H),8.81(d,J＝0.7Hz,1H),8.80–8.77(m,1H),8.69(s,1H),8.39(s,1H),8.28(d,J＝0.7Hz,1H),8.14–8.12(m,1H),8.08–8.04(m,1H),7.97(d,J＝1.5Hz,1H),7.94–7.90(m,1H),4.63(d,J＝6.0Hz,2H),3.89(s,3H)。 To a solution of triphosgene (25.5 mg, 0.086 mmol) in DCM (8.00 mL) was added 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4 at room temperature -yl)pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride (70.0 mg, 0.215 mmol) and DIEA (55.5 mg, 0.430 mmol) in DCM (4.00 mL). The reaction mixture was stirred at room temperature for 2 hours. (6-(Trifluoromethyl)pyridin-3-yl)methanamine (37.9 mg, 0.215 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product (compound 32) . Purification by preparative HPLC (acetonitrile/water with 0.05% hydrochloric acid) afforded the title compound (compound 32-1) (20.0 mg, 17.6% yield, white solid) as its hydrochloride salt. LC-MS (ESI) m/z 492.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.48 (t, J=6.2 Hz, 1H), 9.27 (d, J=1.4 Hz, 1H), 8.81 ( d, J=0.7Hz, 1H), 8.80–8.77(m, 1H), 8.69(s, 1H), 8.39(s, 1H), 8.28(d, J=0.7Hz, 1H), 8.14–8.12(m ,1H),8.08–8.04(m,1H),7.97(d,J=1.5Hz,1H),7.94–7.90(m,1H),4.63(d,J=6.0Hz,2H),3.89(s, 3H).
实施例33： 4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-乙氧基吡啶-3-基) 甲基)-1H-吡唑-1-甲酰胺(化合物33)及其盐酸盐(化合物33-1)的合成 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)
Figure PCTCN2021118001-appb-000055
Figure PCTCN2021118001-appb-000055
步骤1：2-乙氧基-5-氰基吡啶的合成Step 1: Synthesis of 2-ethoxy-5-cyanopyridine
2-氯-5-氰基吡啶(1.00g,7.22mmol)和乙醇钠(982mg,14.4mmol)的无水DMF(10.0 mL)溶液在室温下搅拌反应16小时。将反应混合物倒入水(40.0mL)中得到悬浊液。过滤，滤饼用水(20.0mL)洗。滤饼经真空干燥得到目标化合物(850mg,收率79.5％,黄色固体)。LC-MS(ESI)m/z 149.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.68(d,J＝2.2Hz,1H),8.14(dd,J＝8.7,2.4Hz,1H),6.98(d,J＝8.7Hz,1H),4.39(q,J＝7.1Hz,2H),1.33(t,J＝7.1Hz,3H)。 A solution of 2-chloro-5-cyanopyridine (1.00 g, 7.22 mmol) and sodium ethoxide (982 mg, 14.4 mmol) in dry DMF (10.0 mL) was stirred at room temperature for 16 hours. The reaction mixture was poured into water (40.0 mL) to obtain a suspension. After filtration, the filter cake was washed with water (20.0 mL). The filter cake was dried under vacuum to obtain the title compound (850 mg, 79.5% yield, yellow solid). LC-MS (ESI) m/z 149.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.68 (d, J=2.2Hz, 1H), 8.14 (dd, J=8.7, 2.4Hz, 1H), 6.98 (d, J=8.7Hz, 1H) , 4.39 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
步骤2：(6-乙氧基吡啶-3-基)甲胺的合成Step 2: Synthesis of (6-ethoxypyridin-3-yl)methanamine
室温下，2-乙氧基-5-氰基吡啶(300mg,2.02mmol)和雷尼镍(300mg)的氨水(4.00mL)和乙醇(12.0mL)混合溶液在氢气环境下搅拌反应16小时。将反应液过滤后，滤饼用乙醇(10.0mL)洗。滤液减压浓缩得到目标化合物(260mg,收率84.3％,绿色油状物)。At room temperature, a mixed solution of 2-ethoxy-5-cyanopyridine (300 mg, 2.02 mmol) and Raney nickel (300 mg) in ammonia (4.00 mL) and ethanol (12.0 mL) was stirred for 16 hours under hydrogen atmosphere. After filtering the reaction solution, the filter cake was washed with ethanol (10.0 mL). The filtrate was concentrated under reduced pressure to obtain the target compound (260 mg, yield 84.3%, green oil).
步骤3:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-乙氧基吡啶-3-基)甲基)-1H-吡唑-1-甲酰胺及其盐酸盐的合成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
在室温下，向CDI(45.3mg,0.279mmol)的DMF(4.00mL)溶液中加入(6-乙氧基吡啶-3-基)甲胺(39.3mg,0.258mmol)和DIEA(55.5mg,0.430mmol)。反应混合物在室温下搅拌反应3小时后，向反应混合物中加入6-(1-甲基-1H-吡唑-4-基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(70.0mg,0.215mmol)。反应混合物在60℃下搅拌反应16小时。将反应混合物冷却至室温后倒入水(15.0mL)中，用EA(100mL)萃取。有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品 (化合物33)。经制备HPLC(乙腈/含0.05％盐酸的水)纯化得到盐酸盐形式的目标化合物 (化合物33-1)(14.3mg,收率13.2％,类白色固体)。LC-MS(ESI)m/z 468.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.30(t,J＝6.1Hz,1H),9.27–9.25(m,1H),8.79(s,1H),8.68(s,1H),8.39(s,1H),8.24(s,1H),8.16–8.14(m,1H),8.13(s,1H),7.98–7.95(m,1H),7.73(dd,J＝8.5,2.4Hz,1H),6.79(d,J＝8.6Hz,1H),4.41(d,J＝6.2Hz,2H),4.28(q,J＝7.0Hz,2H),3.89(s,3H),1.30(t,J＝7.0Hz,3H)。 To a solution of CDI (45.3 mg, 0.279 mmol) in DMF (4.00 mL) at room temperature was added (6-ethoxypyridin-3-yl)methanamine (39.3 mg, 0.258 mmol) and DIEA (55.5 mg, 0.430 mmol). After the reaction mixture was stirred at room temperature for 3 hours, 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[ 1,5-a]pyridine-3-carbonitrile hydrochloride (70.0 mg, 0.215 mmol). The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (15.0 mL), and extracted with EA (100 mL). The organic phase was washed with saturated brine (15.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product (compound 33) . Purification by preparative HPLC (acetonitrile/water containing 0.05% hydrochloric acid) afforded the title compound (compound 33-1) as the hydrochloride salt (14.3 mg, 13.2% yield, off-white solid). LC-MS (ESI) m/z 468.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.30(t, J=6.1Hz, 1H), 9.27-9.25(m, 1H), 8.79(s, 1H), 8.68(s, 1H), 8.39( s, 1H), 8.24 (s, 1H), 8.16–8.14 (m, 1H), 8.13 (s, 1H), 7.98–7.95 (m, 1H), 7.73 (dd, J=8.5, 2.4Hz, 1H) ,6.79(d,J＝8.6Hz,1H),4.41(d,J＝6.2Hz,2H),4.28(q,J＝7.0Hz,2H),3.89(s,3H),1.30(t,J＝ 7.0Hz, 3H).
实施例34： 4-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)-1H-吡唑-1-甲酰胺(化合物34)的合成 Example 34: 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-pyrazol-1-carboxamide (compound 34)
Figure PCTCN2021118001-appb-000056
Figure PCTCN2021118001-appb-000056
步骤1:4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑并[1,5-a]吡啶-3-甲腈的合成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
向6-溴-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈(1.00g,2.69 mmol)和联硼酸频哪醇酯(2.73g,10.7mmol)的干燥1,4-二氧六环(25.0mL)溶液中加入乙酸钾(527mg,5.37mmol)和Pd(dppf)Cl 2DCM络合物(116mg,0.134mmol)。氩气保护下，反应混合物在90℃下搅拌反应5小时。将反应混合物冷却至室温后倒入EA(80.0mL)中得到黑色溶液。溶液用无水硫酸钠干燥、过滤。滤液减压浓缩得到目标化合物(5.20g，粗品，黑色固体)。LC-MS(ESI)m/z 420.2[M+H] +。 To 6-bromo-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile ( To a solution of 1.00 g, 2.69 mmol) and pinacol diboronate (2.73 g, 10.7 mmol) in dry 1,4-dioxane (25.0 mL) was added potassium acetate (527 mg, 5.37 mmol) and Pd (dppf) Cl2DCM complex (116 mg, 0.134 mmol). Under argon, the reaction mixture was stirred at 90°C for 5 hours. The reaction mixture was cooled to room temperature and poured into EA (80.0 mL) to give a black solution. The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (5.20 g, crude product, black solid). LC-MS (ESI) m/z 420.2 [M+H] + .
步骤2:6-羟基-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈的合成Step 2: 6-Hydroxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-methan Synthesis of Nitriles
在0℃下，向4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑并[1,5-a]吡啶-3-甲腈(5.20g,12.4mmol)的四氢呋喃(200mL)溶液中加入氢氧化钠(1.98g,49.6mmol)。随后滴加30％过氧化氢水溶液(10.1mL,99.2mmol)。反应混合液在室温下搅拌反应1小时。向反应混合液中加入饱和氯化铵水溶液(80.0mL)后在室温下搅拌30分钟。分离有机相，水相用EA(80.0mL×2)萃取。合并有机相用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝3:1-1:1)得到目标化合物(290mg，两步收率34.9％，黄色固体)。LC-MS(ESI)m/z 332.2[M+Na] +。 To 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-6-(4,4,5,5-tetramethyl- To a solution of 1,3,2-dioxaborol-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (5.20 g, 12.4 mmol) in tetrahydrofuran (200 mL) was added hydrogen Sodium oxide (1.98 g, 49.6 mmol). Aqueous 30% hydrogen peroxide (10.1 mL, 99.2 mmol) was then added dropwise. The reaction mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution (80.0 mL) was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The organic phase was separated and the aqueous phase was extracted with EA (80.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=3:1-1:1), the target compound (290 mg, 34.9% yield in two steps, yellow solid) was obtained. LC-MS (ESI) m/z 332.2 [M+Na] + .
步骤3:6-(2-羟基-2-甲基丙氧基)-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈的合成Step 3: 6-(2-Hydroxy-2-methylpropoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo Synthesis of [1,5-a]pyridine-3-carbonitrile
向6-羟基-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈的四氢呋喃(6.00mL)溶液中加入氢氧化钠水溶液(2.0N,0.940mL,1.88mmol)。反应混合液在室温下搅拌反应15分钟后加入2,2-二甲基环氧乙烷(0.837mL,9.38mmol)。封管密闭后，反应混合液在90℃下搅拌反应8小时。将反应液冷却至室温后倒入EA(50.0mL)中得到黄色溶液。溶液用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝3：1-1：2)得到目标化合物(255mg，收率71.3％，黄色固体)。LC-MS(ESI)m/z 404.2[M+Na] +。 to 6-hydroxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile To the solution in tetrahydrofuran (6.00 mL) was added aqueous sodium hydroxide solution (2.0 N, 0.940 mL, 1.88 mmol). The reaction mixture was stirred at room temperature for 15 minutes and then 2,2-dimethyloxirane (0.837 mL, 9.38 mmol) was added. After sealing the tube, the reaction mixture was stirred and reacted at 90° C. for 8 hours. The reaction solution was cooled to room temperature and poured into EA (50.0 mL) to obtain a yellow solution. The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=3:1-1:2), the target compound (255 mg, yield 71.3%, yellow solid) was obtained. LC-MS (ESI) m/z 404.2 [M+Na] + .
步骤4:6-(2-羟基-2-甲基丙氧基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐的合成Step 4: 6-(2-Hydroxy-2-methylpropoxy)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride Synthesis
将6-(2-羟基-2-甲基丙氧基)-4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈(255mg,0.669mmol)加入到氯化氢甲醇溶液(3.0M,5.00mL)中。反应混合物在室温下搅拌反应1小时。减压浓缩后得到目标化合物(215mg，收率96.3％，淡黄色固体)。LC-MS(ESI)m/z 298.1[M+H] +。 6-(2-Hydroxy-2-methylpropoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyridine-3-carbonitrile (255 mg, 0.669 mmol) was added to a methanolic solution of hydrogen chloride (3.0 M, 5.00 mL). The reaction mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the title compound (215 mg, yield 96.3%, pale yellow solid) was obtained. LC-MS (ESI) m/z 298.1 [M+H] + .
步骤5:4-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-1H-吡唑-1-甲酰胺的合成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
向(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(124mg,0.644mmol)的碳酸氢钠水溶液(10.0mL)与DCM(15.0mL)混合液中加入三光气(191mg,0.644mmol)。反应混合物在室温下搅 拌反应1小时。用DCM(15.0mL×2)萃取。合并有机相用饱和食盐水(15.0mL×2)洗、无水硫酸钠干燥、过滤后得黄色滤液。向上述滤液中加入TEA(0.179mL,1.29mmol)和6-(2-羟基-2-甲基丙氧基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(215mg,0.644mmol)。反应混合物在室温下搅拌反应15小时。将反应液减压浓缩得到粗品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(20.0mg,收率6.21％,白色固体)。LC-MS(ESI)m/z 516.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.44–9.36(m,1H),8.77(s,1H),8.73–8.66(m,2H),8.60(s,1H),8.47(s,1H),8.23(s,1H),8.02–7.97(m,1H),7.96–7.88(m,2H),7.51(s,1H),4.72(s,1H),4.58–4.49(m,2H),3.88(s,2H),1.23(s,6H)。 To a mixture of (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (124 mg, 0.644 mmol) in aqueous sodium bicarbonate (10.0 mL) and DCM (15.0 mL) Triphosgene (191 mg, 0.644 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Extracted with DCM (15.0 mL x 2). The combined organic phases were washed with saturated brine (15.0 mL×2), dried over anhydrous sodium sulfate, and filtered to obtain a yellow filtrate. To the above filtrate was added TEA (0.179 mL, 1.29 mmol) and 6-(2-hydroxy-2-methylpropoxy)-4-(1H-pyrazol-4-yl)pyrazolo[1,5- a] Pyridine-3-carbonitrile hydrochloride (215 mg, 0.644 mmol). The reaction mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (20.0 mg, 6.21% yield, white solid). LC-MS (ESI) m/z 516.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.44-9.36(m,1H), 8.77(s,1H), 8.73-8.66(m,2H), 8.60(s,1H), 8.47(s,1H) ), 8.23(s, 1H), 8.02–7.97(m, 1H), 7.96–7.88(m, 2H), 7.51(s, 1H), 4.72(s, 1H), 4.58–4.49(m, 2H), 3.88(s, 2H), 1.23(s, 6H).
实施例35： 4-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-(4-氟-1H-吡唑 -1-基)吡啶-3-基)乙基)-1H-吡唑-1-甲酰胺(化合物35)及其盐酸盐(化合物35-1)的合成 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
Figure PCTCN2021118001-appb-000057
Figure PCTCN2021118001-appb-000057
步骤1:4-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙基)-1H-吡唑-1-甲酰胺盐酸盐的合成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
向CDI(28.4mg,0.175mmol)的DMF(1.50mL)溶液中加入1-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)乙-1-胺(30.5mg,0.148mmol)和DIEA(34.8mg,0.269mmol)。反应混合物在室温下搅拌反应16小时后，向混合液中加入6-(2-羟基-2-甲基丙氧基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(45.0mg,0.135mmol)。反应混合物在50℃下搅拌反应8小时。将反应混合物倒入水(15.0mL)中，用EA(80.0mL)萃取。有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤、滤液减压浓缩得到粗产品 (化合物35)。经制备HPLC(乙腈/含0.05％盐酸的水)纯化得到盐酸盐形式的目标化合物 (化合物35-1)(19.2mg,收率24.8％,白色固体)。LC-MS(ESI)m/z 530.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.28(d,J＝8.4Hz,1H),8.75(s,1H),8.71–8.69(m,1H),8.68(d,J＝4.4Hz,1H),8.60(s,1H),8.55–8.53(m,1H),8.24(s,1H),8.13–8.09(m,1H),7.92(s,1H),7.91(d,J＝4.0Hz,1H),7.52–7.50(m,1H),5.22–5.13(m,1H),4.70(s,1H),3.87(s,2H),1.63(d,J＝7.0Hz,3H),1.22(s,6H)。 To a solution of CDI (28.4 mg, 0.175 mmol) in DMF (1.50 mL) was added 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine (30.5 mg, 0.148 mmol) and DIEA (34.8 mg, 0.269 mmol). After the reaction mixture was stirred at room temperature for 16 hours, 6-(2-hydroxy-2-methylpropoxy)-4-(1H-pyrazol-4-yl)pyrazolo[1, 5-a]pyridine-3-carbonitrile hydrochloride (45.0 mg, 0.135 mmol). The reaction mixture was stirred at 50°C for 8 hours. The reaction mixture was poured into water (15.0 mL) and extracted with EA (80.0 mL). The organic phase was washed with saturated brine (15.0 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (compound 35) . Purification by preparative HPLC (acetonitrile/water with 0.05% hydrochloric acid) afforded the title compound (compound 35-1) as the hydrochloride salt (19.2 mg, yield 24.8%, white solid). LC-MS (ESI) m/z 530.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.28(d,J=8.4Hz,1H),8.75(s,1H),8.71-8.69(m,1H),8.68(d,J=4.4Hz, 1H), 8.60(s, 1H), 8.55-8.53(m, 1H), 8.24(s, 1H), 8.13-8.09(m, 1H), 7.92(s, 1H), 7.91(d, J=4.0Hz ,1H),7.52–7.50(m,1H),5.22–5.13(m,1H),4.70(s,1H),3.87(s,2H),1.63(d,J=7.0Hz,3H),1.22( s, 6H).
实施例36： 4-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-((6-甲氧基吡啶-3-基) 甲基)-1H-吡唑-1-甲酰胺(化合物36)及其盐酸盐(化合物36-1)的合成 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)
Figure PCTCN2021118001-appb-000058
Figure PCTCN2021118001-appb-000058
步骤1:4-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-((6-甲氧基吡啶-3-基)甲基)-1H-吡唑-1-甲酰胺盐酸盐的合成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
在室温下，向CDI(88.3mg,0.545mmol)的DMF(2.00mL)溶液中加入(6-甲氧基吡啶-3-基)甲胺(63.7mg,0.461mmol)和DIEA(108mg,0.838mmol)。反应混合物在室温下搅拌反应16小时。向混合液中加入6-(2-羟基-2-甲基丙氧基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(140mg,0.419mmol)。反应混合物在60℃下搅拌反应6小时。将反应混合物冷却至室温后倒入水中(15.0mL)中，用EA(80.0mL)萃取。有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤、滤液减压浓缩得到粗产品 (化合物36)。经制备HPLC(乙腈/含0.05％盐酸的水)纯化得到盐酸盐形式的目标化合物 (化合物36-1)(12.8mg,收率6.13％,黄色固体)。LC-MS(ESI)m/z 462.1[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.66–8.65(m,1H),8.48(d,J＝2.1Hz,1H),8.35(s,1H),8.32–8.30(m,1H),8.28–8.24(m,1H),8.06–8.04(m,1H),7.43(d,J＝2.1Hz,1H),7.33–7.28(m,1H),4.60(s,2H),4.11(s,3H),3.91(s,2H),1.34(s,6H)。 To a solution of CDI (88.3 mg, 0.545 mmol) in DMF (2.00 mL) was added (6-methoxypyridin-3-yl)methanamine (63.7 mg, 0.461 mmol) and DIEA (108 mg, 0.838 mmol) at room temperature ). The reaction mixture was stirred at room temperature for 16 hours. To the mixture was added 6-(2-hydroxy-2-methylpropoxy)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile salt acid salt (140 mg, 0.419 mmol). The reaction mixture was stirred at 60°C for 6 hours. The reaction mixture was cooled to room temperature, poured into water (15.0 mL), and extracted with EA (80.0 mL). The organic phase was washed with saturated brine (15.0 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (compound 36) . Purification by preparative HPLC (acetonitrile/water with 0.05% hydrochloric acid) afforded the title compound (compound 36-1) (12.8 mg, yield 6.13%, yellow solid) as the hydrochloride salt. LC-MS (ESI) m/z 462.1 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ 8.66–8.65 (m, 1H), 8.48 (d, J=2.1 Hz, 1H), 8.35 (s, 1H), 8.32–8.30 (m, 1H), 8.28 –8.24(m, 1H), 8.06 – 8.04(m, 1H), 7.43(d, J=2.1Hz, 1H), 7.33 – 7.28(m, 1H), 4.60(s, 2H), 4.11(s, 3H ), 3.91(s, 2H), 1.34(s, 6H).
实施例37： 4-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-甲氧基吡啶-3- 基)乙基)-1H-吡唑-1-甲酰胺(化合物37)的合成 Example 37: 4-(3-Cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N-(1-( Synthesis of 6-Methoxypyridin-3 -yl)ethyl)-1H-pyrazole-1-carboxamide (Compound 37)
Figure PCTCN2021118001-appb-000059
Figure PCTCN2021118001-appb-000059
步骤1:4-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-甲氧基吡啶-3-基)乙基)-1H-吡唑-1-甲酰胺的合成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
在室温下，向CDI(61.9mg,0.382mmol)的DMF(2.00mL)溶液中加入1-(6-甲氧基吡啶-3-基)乙-1-胺(46.5mg,0.306mmol)和DIEA(65.8mg,0.509mmol)。反应混合物在室温下搅拌反应2小时后，向反应混合物中加入6-(2-羟基-2-甲基丙氧基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(85.0mg,0.255mmol)。反应混合物在55℃下搅拌反应16小时。将反应混合物冷却至室温后倒入水(20.0mL)中，用EA(100mL)萃取。有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％ 甲酸的水)纯化得到目标化合物(45.0mg,收率37.1％,类白色固体)。LC-MS(ESI)m/z 476.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.12(d,J＝8.4Hz,1H),8.73(d,J＝0.6Hz,1H),8.70(d,J＝2.1Hz,1H),8.60(s,1H),8.23–8.20(m,2H),7.85(dd,J＝8.6,2.5Hz,1H),7.50(d,J＝2.1Hz,1H),6.81(d,J＝8.6Hz,1H),5.10–5.01(m,1H),4.70(s,1H),3.87(s,2H),3.83(s,3H),1.57(d,J＝7.1Hz,3H),1.22(s,6H)。 To a solution of CDI (61.9 mg, 0.382 mmol) in DMF (2.00 mL) was added 1-(6-methoxypyridin-3-yl)ethan-1-amine (46.5 mg, 0.306 mmol) and DIEA at room temperature (65.8 mg, 0.509 mmol). After the reaction mixture was stirred at room temperature for 2 hours, 6-(2-hydroxy-2-methylpropoxy)-4-(1H-pyrazol-4-yl)pyrazolo[1, 5-a]pyridine-3-carbonitrile hydrochloride (85.0 mg, 0.255 mmol). The reaction mixture was stirred at 55°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (20.0 mL), and extracted with EA (100 mL). The organic phase was 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. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (45.0 mg, 37.1% yield, off-white solid). LC-MS (ESI) m/z 476.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.12 (d, J=8.4 Hz, 1H), 8.73 (d, J=0.6 Hz, 1H), 8.70 (d, J=2.1 Hz, 1H), 8.60 (s,1H),8.23–8.20(m,2H),7.85(dd,J=8.6,2.5Hz,1H),7.50(d,J=2.1Hz,1H),6.81(d,J=8.6Hz, 1H), 5.10–5.01(m, 1H), 4.70(s, 1H), 3.87(s, 2H), 3.83(s, 3H), 1.57(d, J=7.1Hz, 3H), 1.22(s, 6H) ).
实施例38： 1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)-1H-吡唑-4-甲酰胺(化合物38)的合成 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)
Figure PCTCN2021118001-appb-000060
Figure PCTCN2021118001-appb-000060
步骤1:1-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-1H-吡唑-4-甲酸乙酯的合成Step 1: Synthesis of 1-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester
向6-溴-4-氟吡唑并[1,5-a]吡啶-3-甲腈(1.00g,4.17mmol)和1H-吡唑-4-甲酸乙酯(701mg,5.00mmol)的N-甲基吡咯烷酮(6.00mL)溶液中加入DIEA(1.38mL,8.33mmol)。反应混合液在90℃下搅拌反应16小时。将反应混合物冷却至室温后倒入水(20.0mL)中，用EA(200mL)萃取。有机相用饱和食盐水(20.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产物。经柱层析分离纯化(PE：EA＝10:1-4:1)得到目标化合物(920mg，收率61.3％，黄色固体)。LC-MS(ESI)m/z 360.1,362.1[M+H] +。 To 6-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carbonitrile (1.00 g, 4.17 mmol) and 1H-pyrazole-4-carboxylic acid ethyl ester (701 mg, 5.00 mmol) in N - DIEA (1.38 mL, 8.33 mmol) was added to a solution of methylpyrrolidone (6.00 mL). The reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (20.0 mL), and extracted with EA (200 mL). The organic phase was washed with saturated brine (20.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=10:1-4:1), the target compound (920 mg, yield 61.3%, yellow solid) was obtained. LC-MS (ESI) m/z 360.1, 362.1 [M+H] + .
步骤2:1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1H-吡唑-4-甲酸乙酯的合成Step 2: 1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1H-pyrazol- Synthesis of 4-ethyl formate
向1-(6-溴-3-氰基吡唑并[1,5-a]吡啶-4-基)-1H-吡唑-4-甲酸乙酯(500mg,1.39mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(318mg,1.53mmol)的水(1.20mL)和1，4-二氧六环(6.00mL)混合溶液中加入碳酸钾(384mg,2.78mmol)和Pd(dppf)Cl 2DCM络合物(59.8mg,0.069mmol)。氩气保护下，反应混合物在100℃下搅拌反应16小时。将反应混合物冷却至室温后倒入水(20.0mL)中，用EA(60.0mL×2)萃取。合并有机相用无水硫酸钠干燥、过滤。滤液减压浓缩除去有机溶剂得到粗产品。经柱层析分离纯化(PE：EA＝3：1-1：2)得到目标化合物(390mg，收率77.7％,白色固体)。 To 1-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (500 mg, 1.39 mmol) and 1-methyl -4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (318 mg, 1.53 mmol) in water (1.20 mL) ) and 1,4-dioxane (6.00 mL) were added potassium carbonate (384 mg, 2.78 mmol) and Pd(dppf)Cl 2 DCM complex (59.8 mg, 0.069 mmol). Under argon, the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (20.0 mL), and extracted with EA (60.0 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product. After separation and purification by column chromatography (PE:EA=3:1-1:2), the target compound (390 mg, yield 77.7%, white solid) was obtained.
步骤3:1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1H-吡唑-4-甲酸的合成Step 3: 1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1H-pyrazol- Synthesis of 4-carboxylic acid
向1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1H-吡唑-4-甲酸乙酯(120mg,0.332mmol)的水(1.00mL)和乙醇(6.00mL)的混合溶液中加入氢氧化钠(26.6mg,0.664mmol)。反应混合液在室温下搅拌反应16小时。将反应混合物减压浓缩除去有机溶剂 后，加入到水(3.00mL)中，用1.0M盐酸溶液调节pH＝5后得到悬浊液。悬浊液过滤，滤饼用水(10.0mL)洗，干燥后得到目标化合物(100mg，收率90.3％，白色固体)。LC-MS(ESI)m/z 334.1[M+H] +。 To 1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1H-pyrazol-4- To a mixed solution of ethyl formate (120 mg, 0.332 mmol) in water (1.00 mL) and ethanol (6.00 mL) was added sodium hydroxide (26.6 mg, 0.664 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, then added to water (3.00 mL), and adjusted to pH=5 with a 1.0 M hydrochloric acid solution to obtain a suspension. The suspension was filtered, the filter cake was washed with water (10.0 mL), and dried to obtain the title compound (100 mg, yield 90.3%, white solid). LC-MS (ESI) m/z 334.1 [M+H] + .
步骤4:1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-1H-吡唑-4-甲酰胺的合成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
在室温下，1-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1H-吡唑-4-甲酸(100mg,0.300mmol)和(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(63.4mg,0.330mmol)的DMF(2.00mL)溶液中加入EDCI(86.3mg,0.450mmol)、HOBt(60.8mg,0.450mmol)和DIEA(77.5mg,0.600mmol)。反应混合物在室温下搅拌反应2小时。将反应混合物倒入水(15.0mL)中，用EA(80.0mL)萃取。有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(15.3mg,收率10.0％,白色固体)。LC-MS(ESI)m/z 508.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.39(s,1H),8.98(t,J＝6.0Hz,1H),8.85(s,1H),8.72(s,1H),8.69(d,J＝4.2Hz,1H),8.45(s,1H),8.42(s,1H),8.30(s,1H),8.21(s,1H),8.16(s,1H),7.98–7.89(m,3H),4.55(d,J＝5.4Hz,2H),3.89(s,3H)。 1-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1H-pyrazole at room temperature -4-carboxylic acid (100 mg, 0.300 mmol) and (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (63.4 mg, 0.330 mmol) in DMF (2.00 mL) To this was added EDCI (86.3 mg, 0.450 mmol), HOBt (60.8 mg, 0.450 mmol) and DIEA (77.5 mg, 0.600 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (15.0 mL) and extracted with EA (80.0 mL). The organic phase was 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. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (15.3 mg, 10.0% yield, white solid). LC-MS (ESI) m/z 508.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.39(s, 1H), 8.98(t, J=6.0Hz, 1H), 8.85(s, 1H), 8.72(s, 1H), 8.69(d, J=4.2Hz, 1H), 8.45(s, 1H), 8.42(s, 1H), 8.30(s, 1H), 8.21(s, 1H), 8.16(s, 1H), 7.98–7.89(m, 3H) ), 4.55(d, J=5.4Hz, 2H), 3.89(s, 3H).
实施例39： 5-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-甲氧基吡啶-3- 基)乙基)-1,3,4-噻二唑-2-甲酰胺(化合物39)的合成 Example 39: 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 (Compound 39)
Figure PCTCN2021118001-appb-000061
Figure PCTCN2021118001-appb-000061
步骤1：6-(1-甲基-1H-吡唑-4-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑并[1,5-a]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] 吡啶-3-甲腈的合成Synthesis of pyridine-3-carbonitrile
向3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基三氟甲基磺酸酯(200mg,0.539mmol)和联硼酸频哪醇酯(684mg,2.69mmol)的干燥1,4-二氧六环(5.00mL)溶液中加入乙酸钾(106mg,1.08mmol)和Pd(dppf)Cl 2DCM络合物(23.2mg,0.027mmol)。氩气保护下，反应混合物在90℃下搅拌16小时。将反应混合物冷却至室温后倒入水(20.0mL)中，用EA(50.0mL x 3)萃取。合并有机相用无水硫酸钠干燥、过滤。滤液减压浓缩得到目标化合物(200mg，粗品，黑色固体)。LC-MS(ESI)m/z 350.1[M+H] +。 To 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (200 mg, 0.539 mmol ) and pinacol biboronate (684 mg, 2.69 mmol) in dry 1,4-dioxane (5.00 mL) was added potassium acetate (106 mg, 1.08 mmol) and Pd(dppf)Cl 2 DCM complex (23.2 mg, 0.027 mmol). Under argon, the reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and poured into water (20.0 mL) and extracted with EA (50.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (200 mg, crude product, black solid). LC-MS (ESI) m/z 350.1 [M+H] + .
步骤2：5-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1,3,4-噻二唑-2-甲酸乙酯的 合成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
向6-(1-甲基-1H-吡唑-4-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑并[1,5-a]吡啶-3-甲腈(200mg,0.573mmol)和5-溴-1,3,4-噻二唑-2-甲酸乙酯(163mg,0.687mmol)的甲苯(6.00mL)和水(3.00mL)混合溶液中加入4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(9.95mg,0.017mmol)、乙酸钯(3.86mg,0.017mmol)和N-甲基吗啉(174mg,1.72mmol)。氩气保护下，反应混合物在80℃下搅拌反应5小时。将反应液减压浓缩后加入到水(30.0mL)和EA(50.0mL)中。分出有机相，水相用混合溶剂(DCM：甲醇＝10:1,80.0mL x 3)萃取。合并有机相用无水硫酸钠干燥、过滤。滤液减压浓缩得到目标化合物(70.0mg，两步收率34.3％，黄色固体)。LC-MS(ESI)m/z 380.0[M+H] +。 To 6-(1-methyl-1H-pyrazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (200 mg, 0.573 mmol) and ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (163 mg, 0.687 mmol) To the mixed solution of toluene (6.00 mL) and water (3.00 mL) was added 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (9.95 mg, 0.017 mmol), palladium acetate (3.86 mg, 0.017 mmol) and N-methylmorpholine (174 mg, 1.72 mmol). Under argon, the reaction mixture was stirred at 80°C for 5 hours. The reaction solution was concentrated under reduced pressure and added to water (30.0 mL) and EA (50.0 mL). The organic phase was separated, and the aqueous phase was extracted with a mixed solvent (DCM:methanol=10:1, 80.0 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (70.0 mg, 34.3% in two-step yield, yellow solid). LC-MS (ESI) m/z 380.0 [M+H] + .
步骤3:5-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1,3,4-噻二唑-2-甲酸钾的合成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
在0℃下，向5-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1,3,4-噻二唑-2-甲酸乙酯(70.0mg,0.185mmol)的水(1.00mL)和乙醇(3.00mL)混合溶液中加入氢氧化钾(12.8mg,0.194mmol)。反应混合液在室温下搅拌反应5小时。将反应液减压浓缩得到目标化合物(80.0mg，粗品，黄色固体)。LC-MS(ESI)m/z 393.2[M+H+41] +。 At 0 °C, to 5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1, To a mixed solution of ethyl 3,4-thiadiazole-2-carboxylate (70.0 mg, 0.185 mmol) in water (1.00 mL) and ethanol (3.00 mL) was added potassium hydroxide (12.8 mg, 0.194 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (80.0 mg, crude product, yellow solid). LC-MS (ESI) m/z 393.2 [M+H+41] + .
步骤4:5-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-甲氧基吡啶-3-基)乙基)-1,3,4-噻二唑-2-甲酰胺的合成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
在室温下，向5-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-1,3,4-噻二唑-2-甲酸钾(80.0mg,0.205mmol)和1-(6-甲氧基吡啶-3-基)乙-1-胺(37.5mg,0.247mmol)的DMF(3.00mL)溶液中加入EDCI(59.1mg,0.308mmol)、HOBt(41.6mg,0.308mmol)和DIEA(53.1mg,0.411mmol)。反应混合物室温下搅拌反应16小时后，将反应混合物在50℃下继续搅拌反应4小时。将反应混合物倒入EA(100mL)中，用饱和食盐水(15.0mL×3)洗。有机相用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(4.05mg,两步收率4.52％,黄色固体)。LC-MS(ESI)m/z 486.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ10.00(d,J＝8.4Hz,1H),9.49(d,J＝1.4Hz,1H),8.76(s,1H),8.45(s,1H),8.34(d,J＝1.4Hz,1H),8.23(d,J＝2.4Hz,1H),8.18(s,1H),7.85(dd,J＝8.6,2.5Hz,1H),6.83(d,J＝8.5Hz,1H),5.23–5.18(m,1H),3.90(s,3H),3.83(s,3H),1.57(d,J＝7.1Hz,3H)。 To 5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1,3 at room temperature , Potassium 4-thiadiazole-2-carboxylate (80.0 mg, 0.205 mmol) and 1-(6-methoxypyridin-3-yl)ethan-1-amine (37.5 mg, 0.247 mmol) in DMF (3.00 mL) ) solution was added EDCI (59.1 mg, 0.308 mmol), HOBt (41.6 mg, 0.308 mmol) and DIEA (53.1 mg, 0.411 mmol). After the reaction mixture was stirred at room temperature for 16 hours, the reaction mixture was further stirred at 50°C for 4 hours. The reaction mixture was poured into EA (100 mL), and washed with saturated brine (15.0 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (4.05 mg, 4.52% over two steps, yellow solid). LC-MS (ESI) m/z 486.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.00 (d, J=8.4 Hz, 1H), 9.49 (d, J=1.4 Hz, 1H), 8.76 (s, 1H), 8.45 (s, 1H) ,8.34(d,J＝1.4Hz,1H),8.23(d,J＝2.4Hz,1H),8.18(s,1H),7.85(dd,J＝8.6,2.5Hz,1H),6.83(d, J=8.5Hz, 1H), 5.23–5.18 (m, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 1.57 (d, J=7.1Hz, 3H).
实施例40： (R)-3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-甲氧基吡啶 -3-基)乙基)-2,5-二氢-1H-吡咯-1-甲酰胺(化合物40) Example 40: (R)-3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)- N-(1-(6-Methoxypyridin- 3-yl)ethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (Compound 40)
Figure PCTCN2021118001-appb-000062
Figure PCTCN2021118001-appb-000062
3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-甲氧基吡啶-3-基)乙基)-2,5-二氢-1H-吡咯-1-甲酰胺(50mg溶于约20mL乙醇，进样体积1.5mL)经Waters SFC 150(室温,100bar,214nm)和250*25mm 10μm Dr.maish Reprosil Chiral-OM(超临界二氧化碳：乙醇，65:35,5.0min,70mL/min)分离得到 化合物40(15.2mg，白色固体，Ret.time＝3.609min,e.e.99.1％)和 化合物41(20.7mg，白色固体，Ret.time＝4.225min,e.e.98.2％)。手性分析方法:手性柱:
Figure PCTCN2021118001-appb-000063
250*4.6mm 5μm；流动相:A:Supercritical CO 2,B:EtOH(0.1％DEA)；梯度:A 60％,B 40％for 12min；流速:2.8mL/min；柱温:35℃。 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(1-(6- Methoxypyridin-3-yl)ethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (50 mg dissolved in about 20 mL of ethanol, injection volume 1.5 mL) via Waters SFC 150 (room temperature, 100 bar) , 214nm) and 250*25mm 10μm Dr.maish Reprosil Chiral-OM (supercritical carbon dioxide: ethanol, 65:35, 5.0min, 70mL/min) to separate compound 40 (15.2mg, white solid, Ret.time=3.609min) , ee99.1%) and compound 41 (20.7 mg, white solid, Ret.time=4.225 min, ee98.2%). Chiral Analysis Method: Chiral Column:
Figure PCTCN2021118001-appb-000063
250*4.6mm 5μm; mobile phase: A: Supercritical CO 2 , B: EtOH (0.1% DEA); gradient: A 60%, B 40% for 12min; flow rate: 2.8mL/min; column temperature: 35°C.
化合物40:LC-MS(ESI)m/z 469.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.24(d,J＝1.2Hz,1H),8.68(s,1H),8.38(s,1H),8.14(d,J＝2.3Hz,1H),8.12(s,1H),7.88(d,J＝1.2Hz,1H),7.74(dd,J＝8.6,2.5Hz,1H),6.78(d,J＝8.5Hz,1H),6.61(d,J＝8.0Hz,1H),6.37–6.33(m,1H),4.93–4.84(m,1H),4.63–4.56(m,2H),4.39–4.30(m,2H),3.88(s,3H),3.82(s,3H),1.42(d,J＝7.1Hz,3H)。 Compound 40: LC-MS (ESI) m/z 469.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.24(d, J=1.2Hz, 1H), 8.68(s, 1H), 8.38(s, 1H), 8.14(d, J=2.3Hz, 1H) ,8.12(s,1H),7.88(d,J＝1.2Hz,1H),7.74(dd,J＝8.6,2.5Hz,1H),6.78(d,J＝8.5Hz,1H),6.61(d, J=8.0Hz, 1H), 6.37–6.33 (m, 1H), 4.93–4.84 (m, 1H), 4.63–4.56 (m, 2H), 4.39–4.30 (m, 2H), 3.88 (s, 3H) , 3.82 (s, 3H), 1.42 (d, J=7.1 Hz, 3H).
实施例41： (S)-3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-甲氧基吡啶 -3-基)乙基)-2,5-二氢-1H-吡咯-1-甲酰胺(化合物41)的合成 Example 41: (S)-3-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)- Synthesis of N-(1-(6-Methoxypyridin- 3-yl)ethyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (Compound 41)
Figure PCTCN2021118001-appb-000064
Figure PCTCN2021118001-appb-000064
步骤1:(S)-3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-甲氧基吡啶-3-基)乙基)-2,5-二氢-1H-吡咯-1-甲酰胺的合成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
在室温下，向CDI(49.6mg,0.306mmol)的DMF(2.00mL)溶液中加入(S)-1-(6-甲氧基吡啶-3-基)乙-1-胺(34.9mg,0.230mmol)和DIEA(39.5mg,0.306mmol)。反应混合物在室温下搅拌反应2小时。向混合液中加入4-(2,5-二氢-1H-吡咯-3-基)-6-(1-甲基-1H-吡唑-4-基)吡唑 并[1,5-a]吡啶-3-甲腈盐酸盐(50.0mg,0.153mmol)。反应混合物在55℃下搅拌反应16小时。将反应混合物冷却至室温后倒入EA(100mL)中。用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％碳酸氢铵的水)纯化得到目标化合物(27.0mg,收率37.7％,Ret.time＝4.220min,e.e.96.2％,白色固体)。手性分析方法(与实施例40的合成中的方法一致:手性柱:
Figure PCTCN2021118001-appb-000065
250*4.6mm 5μm；流动相:A:Supercritical CO 2,B:EtOH(0.1％DEA)；梯度:A 60％,B 40％for 12min；流速:2.8mL/min；柱温:35℃)。LC-MS(ESI)m/z 469.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.24(d,J＝1.3Hz,1H),8.68(s,1H),8.38(s,1H),8.14(d,J＝2.4Hz,1H),8.12(s,1H),7.88(d,J＝1.2Hz,1H),7.73(dd,J＝8.6,2.5Hz,1H),6.78(d,J＝8.5Hz,1H),6.61(d,J＝8.0Hz,1H),6.37–6.34(m,1H),4.93–4.84(m,1H),4.62–4.58(m,2H),4.37–4.33(m,2H),3.88(s,3H),3.82(s,3H),1.42(d,J＝7.1Hz,3H)。 To a solution of CDI (49.6 mg, 0.306 mmol) in DMF (2.00 mL) at room temperature was added (S)-1-(6-methoxypyridin-3-yl)ethan-1-amine (34.9 mg, 0.230 mmol) and DIEA (39.5 mg, 0.306 mmol). The reaction mixture was stirred at room temperature for 2 hours. To the mixture was added 4-(2,5-dihydro-1H-pyrrol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a ]pyridine-3-carbonitrile hydrochloride (50.0 mg, 0.153 mmol). The reaction mixture was stirred at 55°C for 16 hours. The reaction mixture was cooled to room temperature and poured into EA (100 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. Purification by preparative HPLC (acetonitrile/water with 0.05% ammonium bicarbonate) afforded the title compound (27.0 mg, 37.7% yield, Ret.time=4.220 min, ee 96.2%, white solid). Chiral analysis method (consistent with the method in the synthesis of Example 40: Chiral column:
Figure PCTCN2021118001-appb-000065
250*4.6mm 5μm; Mobile Phase: A: Supercritical CO 2 , B: EtOH (0.1% DEA); Gradient: A 60%, B 40% for 12min; Flow Rate: 2.8mL/min; Column Temperature: 35°C). LC-MS (ESI) m/z 469.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.24(d, J=1.3Hz, 1H), 8.68(s, 1H), 8.38(s, 1H), 8.14(d, J=2.4Hz, 1H) ,8.12(s,1H),7.88(d,J＝1.2Hz,1H),7.73(dd,J＝8.6,2.5Hz,1H),6.78(d,J＝8.5Hz,1H),6.61(d, J=8.0Hz, 1H), 6.37–6.34 (m, 1H), 4.93–4.84 (m, 1H), 4.62–4.58 (m, 2H), 4.37–4.33 (m, 2H), 3.88 (s, 3H) , 3.82 (s, 3H), 1.42 (d, J=7.1 Hz, 3H).
实施例42： 4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-异丙氧基吡啶-3- 基)甲基)-1H-吡唑-1-甲酰胺(化合物42)的合成 Example 42: 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-isopropoxypyridin-3 -yl)methyl)-1H-pyrazole-1-carboxamide (Compound 42)
Figure PCTCN2021118001-appb-000066
Figure PCTCN2021118001-appb-000066
步骤1:(6-异丙氧基吡啶-3-基)甲胺的合成Step 1: Synthesis of (6-isopropoxypyridin-3-yl)methanamine
在室温下，6-异丙氧基-3-氰基吡啶(300mg,1.85mmol)和雷尼镍(300mg)的氨水(28％，4.00mL)和乙醇(14.0mL)溶液在氢气环境下搅拌反应16小时。过滤，滤饼用乙醇(10.0mL)洗。滤液减压浓缩得到目标化合物(270mg,收率87.8％,绿色油状物)。 1H NMR(400MHz,DMSO-d 6)δ8.00(s,1H),7.63(s,1H),6.69(s,1H),5.27–5.14(m,1H),3.92–3.42(m,2H),2.34–1.43(m,2H),1.26(d,J＝6.1Hz,6H)。 A solution of 6-isopropoxy-3-cyanopyridine (300 mg, 1.85 mmol) and Raney nickel (300 mg) in ammonia (28%, 4.00 mL) and ethanol (14.0 mL) was stirred under hydrogen atmosphere at room temperature The reaction was carried out for 16 hours. After filtration, the filter cake was washed with ethanol (10.0 mL). The filtrate was concentrated under reduced pressure to obtain the target compound (270 mg, yield 87.8%, green oil). 1 H NMR (400MHz, DMSO-d 6 )δ8.00(s,1H), 7.63(s,1H), 6.69(s,1H), 5.27-5.14(m,1H), 3.92-3.42(m,2H) ), 2.34–1.43 (m, 2H), 1.26 (d, J=6.1 Hz, 6H).
步骤2:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-异丙氧基吡啶-3-基)甲基)-1H-吡唑-1-甲酰胺的合成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
在室温下，向CDI(79.6mg,0.491mmol)的DMF(4.00mL)溶液中加入(6-异丙氧基吡啶-3-基)甲胺(61.2mg,0.368mmol)和DIEA(63.5mg,0.491mmol)。反应混合物在室温下搅拌反应2小时后，加入6-(1-甲基-1H-吡唑-4-基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(80.0mg,0.246mmol)。反应混合物在70℃下搅拌反应16小时。将反应混合物冷却至室温后倒入EA(100mL)中。用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液 减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％盐酸的水)纯化得到目标化合物粗品。再经超临界流体色谱(二氧化碳/甲醇)纯化得到目标化合物(9.18mg,收率7.76％,白色固体)。LC-MS(ESI)m/z 482.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.29(t,J＝6.3Hz,1H),9.26(d,J＝1.4Hz,1H),8.79(s,1H),8.68(s,1H),8.39(s,1H),8.24(s,1H),8.14(d,J＝2.3Hz,1H),8.13(s,1H),7.96(d,J＝1.4Hz,1H),7.70(dd,J＝8.5,2.4Hz,1H),6.73(d,J＝8.5Hz,1H),5.26–5.19(m,1H),4.40(d,J＝6.1Hz,2H),3.89(s,3H),1.27(d,J＝6.2Hz,6H)。 To a solution of CDI (79.6 mg, 0.491 mmol) in DMF (4.00 mL) at room temperature was added (6-isopropoxypyridin-3-yl)methanamine (61.2 mg, 0.368 mmol) and DIEA (63.5 mg, 0.491 mmol). After the reaction mixture was stirred at room temperature for 2 hours, 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5- a] Pyridine-3-carbonitrile hydrochloride (80.0 mg, 0.246 mmol). The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature and poured into EA (100 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. Purification by preparative HPLC (acetonitrile/water with 0.05% hydrochloric acid) afforded the crude title compound. Then, it was purified by supercritical fluid chromatography (carbon dioxide/methanol) to obtain the target compound (9.18 mg, yield 7.76%, white solid). LC-MS (ESI) m/z 482.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.29(t, J=6.3Hz, 1H), 9.26(d, J=1.4Hz, 1H), 8.79(s, 1H), 8.68(s, 1H) ,8.39(s,1H),8.24(s,1H),8.14(d,J=2.3Hz,1H),8.13(s,1H),7.96(d,J=1.4Hz,1H),7.70(dd, J=8.5, 2.4Hz, 1H), 6.73 (d, J=8.5Hz, 1H), 5.26–5.19 (m, 1H), 4.40 (d, J=6.1Hz, 2H), 3.89 (s, 3H), 1.27 (d, J=6.2 Hz, 6H).
实施例43： 3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1- 基)吡啶-3-基)甲基)-1H-吡咯-1-甲酰胺(化合物43)的合成 Example 43: 3-(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-pyrrole-1-carboxamide (Compound 43)
Figure PCTCN2021118001-appb-000067
Figure PCTCN2021118001-appb-000067
步骤1:3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡咯的合成Step 1: Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrrole
在0℃下，向3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1-(三异丙基硅烷基)-1H-吡咯(350mg,1.00mmol)的四氢呋喃(6.00mL)溶液中加入四丁基氟化铵(1.0M的THF溶液,2.00mL,2.00mmol)。反应混合液在室温下搅拌反应2小时。加入饱和氯化铵溶液(15.0mL)，用EA(50.0mL x 3)萃取。合并有机相用饱和食盐水(15.0mL x 3)洗，无水硫酸钠干燥、过滤。滤液减压浓缩得到目标化合物(190mg，收率98.3％，黄色固体)。LC-MS(ESI)m/z 194.1[M+H] +。 To 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1-(triisopropylsilyl) at 0 °C To a solution of -1H-pyrrole (350 mg, 1.00 mmol) in tetrahydrofuran (6.00 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 2.00 mL, 2.00 mmol). The reaction mixture was stirred at room temperature for 2 hours. Saturated ammonium chloride solution (15.0 mL) was added and extracted with EA (50.0 mL x 3). The combined organic phases were washed with saturated brine (15.0 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (190 mg, yield 98.3%, yellow solid). LC-MS (ESI) m/z 194.1 [M+H] + .
步骤2:N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡咯-1-甲酰胺的合成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
在室温下，向CDI(239mg,1.48mmol)的DMF(5.00mL)溶液中加入2-(6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲胺(227mg,1.18mmol)。反应混合物在室温下搅拌反应16小时得反应液。向3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊环-2-基)-1H-吡咯(190mg,0.984mmol)的DMF(5.00mL)溶液中加入氢化钠(51.2mg,1.28mmol)，反应混合物在0℃下搅拌反应2小时后加入上述反应液。反应混合物继续在室温下搅拌反应2小时。将反应混合物倒入饱和氯化铵(20.0mL)中，用EA(60.0mL×3)萃取。合并有机相用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到目标化合物(220mg,粗品，黄色固体)。LC-MS(ESI)m/z 412.2[M+H] +。 To a solution of CDI (239 mg, 1.48 mmol) in DMF (5.00 mL) was added 2-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methanamine (227 mg) at room temperature , 1.18 mmol). The reaction mixture was stirred at room temperature for 16 hours to obtain a reaction solution. To 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (190 mg, 0.984 mmol) in DMF (5.00 mL) Sodium hydride (51.2 mg, 1.28 mmol) was added to the solution, and the reaction mixture was stirred and reacted at 0° C. for 2 hours, and then the above reaction solution was added. The reaction mixture was continued to stir at room temperature for 2 hours. The reaction mixture was poured into saturated ammonium chloride (20.0 mL) and extracted with EA (60.0 mL x 3). The combined organic phases were 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 title compound (220 mg, crude product, yellow solid). LC-MS (ESI) m/z 412.2 [M+H] + .
步骤3:3-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-1H-吡咯-1-甲酰胺的合成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
向三氟甲基磺酸3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基酯(160mg,0.431mmol)和N-((6-(4-氟-1H-吡唑-1-基)吡啶-3-基)甲基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡咯-1-甲酰胺(213mg,0.517mmol)的水(1.00mL)和1,4-二氧六环(10.0mL)溶液中加入碳酸钠(91.3mg,0.862mmol)和Pd(dppf)Cl 2.DCM(18.6mg,0.022mmol)。氩气保护下，反应混合物在100℃下搅拌反应5小时。将反应混合物减压浓缩得到粗品。经柱层析分离纯化(PE：EA＝3：1-1：2)得到目标化合物粗品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(9.02mg,收率3.79％,类白色固体)。LC-MS(ESI)m/z 507.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.20(d,J＝1.4Hz,1H),9.06(t,J＝5.5Hz,1H),8.70(dd,J＝4.6,0.6Hz,1H),8.66(s,1H),8.48(d,J＝1.6Hz,1H),8.40(s,1H),8.12(s,1H),8.02–7.98(m,1H),7.94–7.90(m,3H),7.83(d,J＝1.4Hz,1H),7.60–7.57(m,1H),6.72–6.69(m,1H),4.56(d,J＝5.4Hz,2H),3.88(s,3H)。 To trifluoromethanesulfonate 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl ester (160 mg, 0.431 mmol ) and N-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3-(4,4,5,5-tetramethyl-1,3 , 2-dioxaborol-2-yl)-1H-pyrrole-1-carboxamide (213 mg, 0.517 mmol) in water (1.00 mL) and 1,4-dioxane (10.0 mL) To this was added sodium carbonate (91.3 mg, 0.862 mmol) and Pd(dppf) Cl2.DCM (18.6 mg, 0.022 mmol). Under argon, the reaction mixture was stirred at 100°C for 5 hours. The reaction mixture was concentrated under reduced pressure to give crude product. After separation and purification by column chromatography (PE:EA=3:1-1:2), the crude product of the target compound was obtained. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (9.02 mg, 3.79% yield, off-white solid). LC-MS (ESI) m/z 507.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.20 (d, J=1.4Hz, 1H), 9.06 (t, J=5.5Hz, 1H), 8.70 (dd, J=4.6, 0.6Hz, 1H) ,8.66(s,1H),8.48(d,J=1.6Hz,1H),8.40(s,1H),8.12(s,1H),8.02–7.98(m,1H),7.94–7.90(m,3H ), 7.83(d, J=1.4Hz, 1H), 7.60–7.57 (m, 1H), 6.72–6.69 (m, 1H), 4.56 (d, J=5.4Hz, 2H), 3.88 (s, 3H) .
实施例44： 4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(吡咯烷-1-基)吡 啶-3-基)甲基)-1H-吡唑-1-甲酰胺(化合物44)的合成 Example 44: 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-(pyrrolidin-1-yl)pyridin- 3-yl)methyl)-1H-pyrazole-1-carboxamide (compound 44)
Figure PCTCN2021118001-appb-000068
Figure PCTCN2021118001-appb-000068
步骤1:6-(吡咯烷-1-基)-3-氰基吡啶的合成Step 1: Synthesis of 6-(pyrrolidin-1-yl)-3-cyanopyridine
向6-氯-3-氰基吡啶(1.00g,7.22mmol)和四氢吡咯(616mg,8.66mmol)的DMF(10.0mL)溶液中加入碳酸钾(1.99g,14.4mmol)。氩气保护下，反应混合物在70℃下搅拌反应16小时。将反应混合物冷却至室温后倒入EA(200mL)中。用饱和食盐水(20.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝10：1)得到目标化合物(1.15g，收率92.0％，淡黄色固体)。LC-MS(ESI)m/z 174.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.45(d,J＝1.8Hz,1H),7.79(dd,J＝9.0,2.3Hz,1H),6.53(d,J＝8.9Hz,1H),3.54–3.34(m,4H),2.01–1.88(m,4H)。 To a solution of 6-chloro-3-cyanopyridine (1.00 g, 7.22 mmol) and tetrahydropyrrole (616 mg, 8.66 mmol) in DMF (10.0 mL) was added potassium carbonate (1.99 g, 14.4 mmol). Under argon, the reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature and poured into EA (200 mL). Washed with saturated brine (20.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification by column chromatography (PE:EA=10:1) gave the title compound (1.15 g, yield 92.0%, pale yellow solid). LC-MS (ESI) m/z 174.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.45 (d, J=1.8Hz, 1H), 7.79 (dd, J=9.0, 2.3Hz, 1H), 6.53 (d, J=8.9Hz, 1H) , 3.54–3.34 (m, 4H), 2.01–1.88 (m, 4H).
步骤2:(6-(吡咯烷-1-基)吡啶-3-基)甲胺的合成Step 2: Synthesis of (6-(pyrrolidin-1-yl)pyridin-3-yl)methanamine
向6-(吡咯烷-1-基)-3-氰基吡啶(100mg,0.577mmol)的氨水(28％，1.50mL)和乙醇(10.0mL)溶液中加入雷尼镍(30.0mg)。室温下，反应混合物在氢气环境下搅拌反应16小时。 过滤，滤饼用乙醇(10.0mL)洗。滤液减压浓缩得到目标化合物(90.0mg,收率88.0％,白色固体)。LC-MS(ESI)m/z 178.2[M+H] +。 1H NMR(400MHz,MeOH-d 4)δ7.94(d,J＝2.1Hz,1H),7.53(dd,J＝8.7,2.4Hz,1H),6.48(d,J＝8.7Hz,1H),3.64(s,2H),3.43–3.39(m,4H),2.04–2.00(m,4H)。 To a solution of 6-(pyrrolidin-1-yl)-3-cyanopyridine (100 mg, 0.577 mmol) in ammonia (28%, 1.50 mL) and ethanol (10.0 mL) was added Raney nickel (30.0 mg). The reaction mixture was stirred under hydrogen atmosphere for 16 hours at room temperature. After filtration, the filter cake was washed with ethanol (10.0 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (90.0 mg, yield 88.0%, white solid). LC-MS (ESI) m/z 178.2 [M+H] + . 1 H NMR (400MHz, MeOH-d 4 ) δ 7.94 (d, J=2.1Hz, 1H), 7.53 (dd, J=8.7, 2.4Hz, 1H), 6.48 (d, J=8.7Hz, 1H) , 3.64 (s, 2H), 3.43–3.39 (m, 4H), 2.04–2.00 (m, 4H).
步骤3:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(吡咯烷-1-基)吡啶-3-基)甲基)-1H-吡唑-1-甲酰胺的合成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
在0℃下，向CDI(69.7mg,0.430mmol)的干燥DMF(3.00mL)溶液中加入(6-(吡咯烷-1-基)吡啶-3-基)甲胺(57.1mg,0.322mmol)和DIEA(55.6mg,0.430mmol)。反应混合物在室温下搅拌反应2小时后加入6-(1-甲基-1H-吡唑-4-基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(70.0mg,0.215mmol)。反应混合物在70℃下搅拌反应16小时。将反应混合物冷却至室温后倒入EA(100mL)中，用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(20.4mg,收率17.7％,黄色固体)。LC-MS(ESI)m/z 493.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.26(d,J＝1.0Hz,1H),9.16(t,J＝6.1Hz,1H),8.78(s,1H),8.68(s,1H),8.24–8.19(m,2H),8.13(s,1H),8.07(d,J＝1.9Hz,1H),7.96(d,J＝1.0Hz,1H),7.53(dd,J＝8.6,2.2Hz,1H),6.42(d,J＝8.7Hz,1H),4.31(d,J＝6.1Hz,2H),3.89(s,3H),3.37–3.33(m,4H),1.95–1.89(m,4H)。 To a solution of CDI (69.7 mg, 0.430 mmol) in dry DMF (3.00 mL) at 0 °C was added (6-(pyrrolidin-1-yl)pyridin-3-yl)methanamine (57.1 mg, 0.322 mmol) and DIEA (55.6 mg, 0.430 mmol). The reaction mixture was stirred at room temperature for 2 hours after which 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a was added. ]pyridine-3-carbonitrile hydrochloride (70.0 mg, 0.215 mmol). The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature, poured into EA (100 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. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (20.4 mg, 17.7% yield, yellow solid). LC-MS (ESI) m/z 493.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.26(d, J=1.0Hz, 1H), 9.16(t, J=6.1Hz, 1H), 8.78(s, 1H), 8.68(s, 1H) ,8.24–8.19(m,2H),8.13(s,1H),8.07(d,J=1.9Hz,1H),7.96(d,J=1.0Hz,1H),7.53(dd,J=8.6,2.2 Hz, 1H), 6.42 (d, J=8.7Hz, 1H), 4.31 (d, J=6.1Hz, 2H), 3.89 (s, 3H), 3.37–3.33 (m, 4H), 1.95–1.89 (m , 4H).
实施例45： 4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(三氟甲氧基)吡 啶-3-基)甲基)-1H-吡唑-1-甲酰胺(化合物45)的合成 Example 45: 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-(trifluoromethoxy)pyridin- 3-yl)methyl)-1H-pyrazole-1-carboxamide (Compound 45)
Figure PCTCN2021118001-appb-000069
Figure PCTCN2021118001-appb-000069
步骤1:3-氰基-6-(三氟甲氧基)吡啶的合成Step 1: Synthesis of 3-cyano-6-(trifluoromethoxy)pyridine
在氩气环境下，2-羟基-5-氰基吡啶(500mg,4.16mmol)和 1-三氟甲基-1,2-苯碘酰-3(H)- 酮(658mg，2.08mmol)的硝基甲烷(6.00mL)溶液在100℃下搅拌反应16小时。将反应混合物冷却至室温后倒入DCM(25.0mL)中。过滤，滤饼用DCM(10.0mL)洗。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝20：1)得到目标化合物(60.0mg，收率7.66％，类白色固体)。 1H NMR(400MHz,DMSO-d 6)δ8.95–8.89(m,1H),8.55(dd,J＝8.6,2.3Hz,1H),7.57–7.50(m,1H)。 19F NMR(376MHz,DMSO-d 6)δ-55.37(s)。 Under Ar A solution of nitromethane (6.00 mL) was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature and poured into DCM (25.0 mL). After filtration, the filter cake was washed with DCM (10.0 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification by column chromatography (PE:EA=20:1) gave the target compound (60.0 mg, yield 7.66%, off-white solid). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.95-8.89 (m, 1H), 8.55 (dd, J=8.6, 2.3 Hz, 1H), 7.57-7.50 (m, 1H). 19 F NMR (376 MHz, DMSO-d 6 ) δ-55.37(s).
步骤2:(6-(三氟甲氧基)吡啶-3-基)甲胺的合成Step 2: Synthesis of (6-(trifluoromethoxy)pyridin-3-yl)methanamine
在室温下，3-氰基-6-(三氟甲氧基)吡啶(60.0mg,0.319mmol)和雷尼镍(30.0mg)的氨水(28％,1.00mL)和乙醇(5.00mL)的混合溶液在氢气环境下搅拌反应16小时。将反应液过滤，滤饼用乙醇(5.00mL)洗。滤液减压浓缩得到目标化合物(45.0mg,收率73.4％,绿色油状物)。LC-MS(ESI)m/z 193.3[M+H] +。 19F NMR(376MHz,DMSO-d 6)δ-55.07(s)。 A solution of 3-cyano-6-(trifluoromethoxy)pyridine (60.0 mg, 0.319 mmol) and Raney nickel (30.0 mg) in ammonia (28%, 1.00 mL) and ethanol (5.00 mL) at room temperature The mixed solution was stirred for 16 hours under hydrogen atmosphere. The reaction solution was filtered, and the filter cake was washed with ethanol (5.00 mL). The filtrate was concentrated under reduced pressure to obtain the target compound (45.0 mg, yield 73.4%, green oil). LC-MS (ESI) m/z 193.3 [M+H] + . 19 F NMR (376 MHz, DMSO-d 6 ) δ-55.07(s).
步骤3:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-(三氟甲氧基)吡啶-3-基)甲基)-1H-吡唑-1-甲酰胺的合成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
在室温下，向CDI(44.8mg,0.276mmol)的干燥DMF(2.00mL)溶液中加入(6-(三氟甲氧基)吡啶-3-基)甲胺(42.5mg,0.221mmol)和DIEA(47.6mg,0.368mmol)。反应混合物在室温下搅拌反应2小时后，加入6-(1-甲基-1H-吡唑-4-基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(60.0mg,0.184mmol)。反应混合物在70℃下搅拌反应16小时。将反应混合物冷却至室温后倒入EA(120mL)中。用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。减压浓缩。所得残留经制备(乙腈/含0.05％甲酸的水)纯化得到目标化合物(5.08mg,收率5.44％,白色固体)。LC-MS(ESI)m/z 508.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.42(t,J＝6.2Hz,1H),9.27(d,J＝1.3Hz,1H),8.80(s,1H),8.68(s,1H),8.39–8.37(m,2H),8.26(s,1H),8.13(s,1H),8.03(dd,J＝8.4,2.4Hz,1H),7.97(d,J＝1.3Hz,1H),7.31(d,J＝8.4Hz,1H),4.54(d,J＝6.2Hz,2H),3.89(s,3H)。 To a solution of CDI (44.8 mg, 0.276 mmol) in dry DMF (2.00 mL) was added (6-(trifluoromethoxy)pyridin-3-yl)methanamine (42.5 mg, 0.221 mmol) and DIEA at room temperature (47.6 mg, 0.368 mmol). After the reaction mixture was stirred at room temperature for 2 hours, 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5- a] Pyridine-3-carbonitrile hydrochloride (60.0 mg, 0.184 mmol). The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature and poured into EA (120 mL). Washed with saturated brine (15.0 mL×3), dried over anhydrous sodium sulfate, and filtered. Concentrate under reduced pressure. The resulting residue was purified by preparative (acetonitrile/water with 0.05% formic acid) to give the title compound (5.08 mg, 5.44% yield, white solid). LC-MS (ESI) m/z 508.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.42(t, J=6.2Hz, 1H), 9.27(d, J=1.3Hz, 1H), 8.80(s, 1H), 8.68(s, 1H) , 8.39–8.37(m, 2H), 8.26(s, 1H), 8.13(s, 1H), 8.03(dd, J=8.4, 2.4Hz, 1H), 7.97(d, J=1.3Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 4.54 (d, J=6.2 Hz, 2H), 3.89 (s, 3H).
实施例46： 4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-((四氢-2H-吡喃-4- 基)氧基)吡啶-3-基)甲基)-1H-吡唑-1-甲酰胺(化合物46)的合成 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)
Figure PCTCN2021118001-appb-000070
Figure PCTCN2021118001-appb-000070
步骤1:6-((四氢-2H-吡喃-4-基)氧基)-3-氰基吡啶的合成Step 1: Synthesis of 6-((tetrahydro-2H-pyran-4-yl)oxy)-3-cyanopyridine
氩气保护，在冰水浴下，向氢化钠(426mg,10.6mmol)的干燥DMF(10.0mL)溶液中加入四氢-2H-吡喃-4-醇(1.00g,9.83mmol)，并在冰浴下搅拌反应10分钟后加入6-氟-3-氰基吡啶(1.00g,8.19mmol)的干燥DMF(5.00mL)溶液。反应混合物在室温下搅拌反应16小时。向反应液中加入饱和氯化铵水溶液(30.0mL)。用EA(100mL×2)萃取。合并有机相用饱和食盐水(25.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析 分离纯化(PE：EA＝10：1)得到目标化合物(1.32g，收率78.9％，白色固体)。 1H NMR(400MHz,DMSO-d 6)δ8.71–8.65(m,1H),8.15(dd,J＝8.7,2.4Hz,1H),7.03–6.96(m,1H),5.34–5.19(m,1H),3.93–3.79(m,2H),3.57–3.42(m,2H),2.11–1.90(m,2H),1.74–1.57(m,2H)。 Under an argon atmosphere, to a solution of sodium hydride (426 mg, 10.6 mmol) in dry DMF (10.0 mL) was added tetrahydro-2H-pyran-4-ol (1.00 g, 9.83 mmol) under an ice-water bath, and the solution was cooled on ice. The reaction was stirred under a bath for 10 minutes before a solution of 6-fluoro-3-cyanopyridine (1.00 g, 8.19 mmol) in dry DMF (5.00 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. To the reaction solution was added saturated aqueous ammonium chloride solution (30.0 mL). Extracted with EA (100 mL x 2). The combined organic phases were washed with saturated brine (25.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=10:1), the target compound (1.32 g, yield 78.9%, white solid) was obtained. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.71-8.65 (m, 1H), 8.15 (dd, J=8.7, 2.4Hz, 1H), 7.03-6.96 (m, 1H), 5.34-5.19 (m , 1H), 3.93–3.79 (m, 2H), 3.57–3.42 (m, 2H), 2.11–1.90 (m, 2H), 1.74–1.57 (m, 2H).
步骤2:(6-((四氢-2H-吡喃-4-基)氧基)吡啶-3-基)甲胺的合成Step 2: Synthesis of (6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)methanamine
向6-((四氢-2H-吡喃-4-基)氧基)-3-氰基吡啶(100mg,0.490mmol)的氨水(28％，1.50mL)和乙醇(10.0mL)混合溶液中加入雷尼镍(30.0mg)。室温下，反应混合物在氢气环境下搅拌反应16小时。过滤，滤饼用乙醇(10.0mL)洗。滤液减压浓缩得到目标化合物(90.0mg,收率88.3％,无色油状物)。 1H NMR(400MHz,MeOH-d 4)δ8.05(d,J＝2.1Hz,1H),7.67(dd,J＝8.5,2.4Hz,1H),6.75(d,J＝8.5Hz,1H),5.19–5.11(m,1H),3.98–3.92(m,2H),3.72(s,2H),3.63–3.56(m,2H),2.08–2.00(m,2H),1.78–1.67(m,2H)。 To a mixed solution of 6-((tetrahydro-2H-pyran-4-yl)oxy)-3-cyanopyridine (100 mg, 0.490 mmol) in ammonia (28%, 1.50 mL) and ethanol (10.0 mL) Raney nickel (30.0 mg) was added. The reaction mixture was stirred under hydrogen atmosphere for 16 hours at room temperature. After filtration, the filter cake was washed with ethanol (10.0 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (90.0 mg, yield 88.3%, colorless oil). 1 H NMR (400 MHz, MeOH-d 4 ) δ 8.05 (d, J=2.1 Hz, 1H), 7.67 (dd, J=8.5, 2.4 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H) ,5.19–5.11(m,1H),3.98–3.92(m,2H),3.72(s,2H),3.63–3.56(m,2H),2.08–2.00(m,2H),1.78–1.67(m, 2H).
步骤3:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-((四氢-2H-吡喃-4-基)氧基)吡啶-3-基)甲基)-1H-吡唑-1-甲酰胺的合成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
在0℃下，向CDI(69.7mg,0.430mmol)的干燥DMF(3.00mL)溶液中加入(6-((四氢-2H-吡喃-4-基)氧基)吡啶-3-基)甲胺(67.1mg,0.322mmol)和DIEA(55.6mg,0.430mmol)。反应混合物在室温下搅拌反应2小时后，加入6-(1-甲基-1H-吡唑-4-基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(70.0mg,0.215mmol)。反应混合物在70℃下搅拌反应16小时。将反应混合物冷却至室温后倒入EA(100mL)中。用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(24.5mg,收率21.8％,白色固体)。LC-MS(ESI)m/z 524.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.30(t,J＝6.2Hz,1H),9.26(d,J＝1.1Hz,1H),8.79(s,1H),8.68(s,1H),8.39(s,1H),8.24(s,1H),8.14(d,J＝2.1Hz,1H),8.13(s,1H),7.96(d,J＝1.1Hz,1H),7.73(dd,J＝8.5,2.3Hz,1H),6.79(d,J＝8.5Hz,1H),5.20–5.13(m,1H),4.41(d,J＝6.1Hz,2H),3.89(s,3H),3.88–3.82(m,2H),3.52–3.45(m,2H),2.02–1.95(m,2H),1.66–1.56(m,2H)。 To a solution of CDI (69.7 mg, 0.430 mmol) in dry DMF (3.00 mL) at 0 °C was added (6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl) Methylamine (67.1 mg, 0.322 mmol) and DIEA (55.6 mg, 0.430 mmol). After the reaction mixture was stirred at room temperature for 2 hours, 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5- a] Pyridine-3-carbonitrile hydrochloride (70.0 mg, 0.215 mmol). The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature and poured into EA (100 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. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (24.5 mg, 21.8% yield, white solid). LC-MS (ESI) m/z 524.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.30(t, J=6.2Hz, 1H), 9.26(d, J=1.1Hz, 1H), 8.79(s, 1H), 8.68(s, 1H) ,8.39(s,1H),8.24(s,1H),8.14(d,J=2.1Hz,1H),8.13(s,1H),7.96(d,J=1.1Hz,1H),7.73(dd, J=8.5, 2.3Hz, 1H), 6.79 (d, J=8.5Hz, 1H), 5.20–5.13 (m, 1H), 4.41 (d, J=6.1Hz, 2H), 3.89 (s, 3H), 3.88–3.82 (m, 2H), 3.52–3.45 (m, 2H), 2.02–1.95 (m, 2H), 1.66–1.56 (m, 2H).
实施例47： 4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-吗啉代吡啶-3-基) 甲基)-1H-吡唑-1-甲酰胺(化合物47)的合成 Example 47: 4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(( Synthesis of 6-morpholinopyridin-3-yl) methyl)-1H-pyrazole-1-carboxamide (compound 47)
Figure PCTCN2021118001-appb-000071
Figure PCTCN2021118001-appb-000071
步骤1:6-吗啉代-3-氰基吡啶的合成Step 1: Synthesis of 6-morpholino-3-cyanopyridine
室温下，将DIEA(1.19mL,7.22mmol)和吗啉(0.692mL,7.94mmol)分别滴加到6-氯-3-氰基吡啶(1.00g,7.22mmol)的水(2.50mL)和DMF(8.00mL)溶液中。氩气保护下，反应混合物在90℃下搅拌反应16小时。将反应混合物冷却至室温后倒入EA(200mL)中。用饱和食盐水(25.0mL×5)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到目标化合物(1.30g，收率95.2％，黄色固体)。LC-MS(ESI)m/z 190.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.52–8.49(m,1H),7.88(dd,J＝9.1,2.4Hz,1H),6.95–6.90(m,1H),3.70–3.66(m,4H),3.64–3.60(m,4H)。 DIEA (1.19 mL, 7.22 mmol) and morpholine (0.692 mL, 7.94 mmol) were added dropwise to 6-chloro-3-cyanopyridine (1.00 g, 7.22 mmol) in water (2.50 mL) and DMF, respectively, at room temperature (8.00 mL) solution. Under argon, the reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and poured into EA (200 mL). Washed with saturated brine (25.0 mL×5), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.30 g, yield 95.2%, yellow solid). LC-MS (ESI) m/z 190.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.52-8.49(m,1H),7.88(dd,J=9.1,2.4Hz,1H),6.95-6.90(m,1H),3.70-3.66(m , 4H), 3.64–3.60 (m, 4H).
步骤2:(6-吗啉代吡啶-3-基)甲胺的合成Step 2: Synthesis of (6-morpholinopyridin-3-yl)methanamine
向6-吗啉代-3-氰基吡啶(100mg,0.528mmol)的氨水(28％，1.50mL)和乙醇(10.0mL)溶液中加入雷尼镍(30.0mg)。室温下，反应混合物在氢气环境下搅拌反应16小时。过滤，滤饼用乙醇(10.0mL)洗。滤液减压浓缩得到目标化合物(90.0mg,收率88.1％,类白色固体)。LC-MS(ESI)m/z 177.1[M-16] +。 1H NMR(400MHz,MeOH-d 4)δ8.07(d,J＝2.2Hz,1H),7.60(dd,J＝8.7,2.5Hz,1H),6.81(d,J＝8.7Hz,1H),3.80–3.76(m,4H),3.68(s,2H),3.45–3.41(m,4H)。 To a solution of 6-morpholino-3-cyanopyridine (100 mg, 0.528 mmol) in ammonia (28%, 1.50 mL) and ethanol (10.0 mL) was added Raney nickel (30.0 mg). The reaction mixture was stirred under hydrogen atmosphere for 16 hours at room temperature. After filtration, the filter cake was washed with ethanol (10.0 mL). The filtrate was concentrated under reduced pressure to obtain the target compound (90.0 mg, yield 88.1%, off-white solid). LC-MS (ESI) m/z 177.1 [M-16] + . 1 H NMR (400MHz, MeOH-d 4 ) δ 8.07 (d, J=2.2Hz, 1H), 7.60 (dd, J=8.7, 2.5Hz, 1H), 6.81 (d, J=8.7Hz, 1H) , 3.80–3.76 (m, 4H), 3.68 (s, 2H), 3.45–3.41 (m, 4H).
步骤3:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-吗啉代吡啶-3-基)甲基)-1H-吡唑-1-甲酰胺的合成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
在0℃下，向CDI(69.7mg,0.430mmol)的干燥DMF(3.00mL)溶液中加入(6-吗啉代吡啶-3-基)甲胺(62.3mg,0.322mmol)和DIEA(55.6mg,0.430mmol)。反应混合物在室温下搅拌反应2小时后加入6-(1-甲基-1H-吡唑-4-基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(70.0mg,0.215mmol)。反应混合物在70℃下搅拌反应16小时。将反应混合物冷却至室温后倒入EA(100mL)中。用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(14.7mg,收率13.5％,白色固体)。LC-MS(ESI)m/z 509.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.26(d,J＝1.4Hz,1H),9.22(t,J＝6.2Hz,1H),8.78(s,1H),8.68(s,1H),8.39(s,1H),8.23(s,1H),8.15(d,J＝2.2Hz,1H),8.13(s,1H),7.96(d,J＝1.4Hz,1H),7.60(dd,J＝8.7,2.4Hz,1H),6.83(d,J＝8.8Hz,1H),4.35(d,J＝6.1Hz,2H),3.89(s,3H),3.70–3.67(m,4H),3.43–3.39(m,4H)。 To a solution of CDI (69.7 mg, 0.430 mmol) in dry DMF (3.00 mL) at 0°C was added (6-morpholinopyridin-3-yl)methanamine (62.3 mg, 0.322 mmol) and DIEA (55.6 mg) , 0.430 mmol). The reaction mixture was stirred at room temperature for 2 hours after which 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a was added. ]pyridine-3-carbonitrile hydrochloride (70.0 mg, 0.215 mmol). The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature and poured into EA (100 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. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (14.7 mg, 13.5% yield, white solid). LC-MS (ESI) m/z 509.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.26(d, J=1.4Hz, 1H), 9.22(t, J=6.2Hz, 1H), 8.78(s, 1H), 8.68(s, 1H) ,8.39(s,1H),8.23(s,1H),8.15(d,J=2.2Hz,1H),8.13(s,1H),7.96(d,J=1.4Hz,1H),7.60(dd, J=8.7, 2.4Hz, 1H), 6.83(d, J=8.8Hz, 1H), 4.35(d, J=6.1Hz, 2H), 3.89(s, 3H), 3.70–3.67(m, 4H), 3.43–3.39 (m, 4H).
实施例48： 4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-((四氢呋喃-3-基) 氧基)吡啶-3-基)甲基)-1H-吡唑-1-甲酰胺(化合物48)的合成 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)
Figure PCTCN2021118001-appb-000072
Figure PCTCN2021118001-appb-000072
步骤1:6-((四氢呋喃-3-基)氧基)-3-氰基吡啶的合成Step 1: Synthesis of 6-((tetrahydrofuran-3-yl)oxy)-3-cyanopyridine
氩气保护，在冰水浴下，向氢化钠(426mg,10.6mmol)的干燥DMF(10.0mL)溶液中加入四氢呋喃-3-醇(866mg,9.83mmol)，并在冰浴下搅拌反应10分钟后加入6-氟-3-氰基吡啶(1.00g,8.19mmol)的干燥DMF(5.00mL)溶液。反应混合物在室温下搅拌反应16小时。向反应液中加入饱和氯化铵水溶液(30.0mL)，用EA(100mL x 2)萃取。合并有机相用饱和食盐水(25.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝5：1)得到目标化合物(1.30g，收率83.5％，白色固体)。 1H NMR(400MHz,DMSO-d 6)δ8.71–8.68(m,1H),8.16(dd,J＝8.7,2.2Hz,1H),7.01(d,J＝8.7Hz,1H),5.59–5.55(m,1H),3.93–3.82(m,2H),3.81–3.73(m,2H),2.32–2.20(m,1H),2.06–1.98(m,1H)。 Under argon protection, to a solution of sodium hydride (426 mg, 10.6 mmol) in dry DMF (10.0 mL) was added tetrahydrofuran-3-ol (866 mg, 9.83 mmol) under an ice-water bath, and the reaction was stirred under an ice-bath for 10 minutes A solution of 6-fluoro-3-cyanopyridine (1.00 g, 8.19 mmol) in dry DMF (5.00 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. Saturated aqueous ammonium chloride solution (30.0 mL) was added to the reaction solution, followed by extraction with EA (100 mL x 2). The combined organic phases were washed with saturated brine (25.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification by column chromatography (PE:EA=5:1) gave the target compound (1.30 g, yield 83.5%, white solid). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71–8.68 (m, 1H), 8.16 (dd, J=8.7, 2.2 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 5.59– 5.55 (m, 1H), 3.93–3.82 (m, 2H), 3.81–3.73 (m, 2H), 2.32–2.20 (m, 1H), 2.06–1.98 (m, 1H).
步骤2:(6-((四氢呋喃-3-基)氧基)吡啶-3-基)甲胺的合成Step 2: Synthesis of (6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)methanamine
向6-((四氢呋喃-3-基)氧基)-3-氰基吡啶(100mg,0.526mmol)的氨水(28％，1.50mL)和乙醇(10.0mL)溶液中加入雷尼镍(30.0mg)。室温下，反应混合物在氢气环境下搅拌反应16小时。过滤，滤饼用乙醇(10.0mL)洗。滤液减压浓缩得到目标化合物(95.0mg,收率93.0％,无色油状物)。 1H NMR(400MHz,MeOH-d 4)δ8.06(d,J＝2.4Hz,1H),7.68(dd,J＝8.5,2.5Hz,1H),6.75(d,J＝8.5Hz,1H),5.52–5.46(m,1H),4.02–3.91(m,2H),3.90–3.84(m,2H),3.72(s,2H),2.31–2.21(m,1H),2.14–2.06(m,1H)。 To a solution of 6-((tetrahydrofuran-3-yl)oxy)-3-cyanopyridine (100 mg, 0.526 mmol) in ammonia (28%, 1.50 mL) and ethanol (10.0 mL) was added Raney nickel (30.0 mg) ). The reaction mixture was stirred under hydrogen atmosphere for 16 hours at room temperature. After filtration, the filter cake was washed with ethanol (10.0 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (95.0 mg, yield 93.0%, colorless oil). 1 H NMR (400MHz, MeOH-d 4 ) δ 8.06 (d, J=2.4Hz, 1H), 7.68 (dd, J=8.5, 2.5Hz, 1H), 6.75 (d, J=8.5Hz, 1H) ,5.52–5.46(m,1H),4.02–3.91(m,2H),3.90–3.84(m,2H),3.72(s,2H),2.31–2.21(m,1H),2.14–2.06(m, 1H).
步骤3:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-((6-((四氢呋喃-3-基)氧基)吡啶-3-基)甲基)-1H-吡唑-1-甲酰胺的合成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
在0℃下，向CDI(69.7mg,0.430mmol)的干燥DMF(3.00mL)溶液中加入(6-((四氢呋喃-3-基)氧基)吡啶-3-基)甲胺(62.6mg,0.322mmol)和DIEA(55.6mg,0.430mmol)。反应混合物在室温下搅拌反应2小时后，加入6-(1-甲基-1H-吡唑-4-基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(70.0mg,0.215mmol)。反应混合物在70℃下搅拌反应16小时。将反应混合物冷却至室温后倒入EA(100mL)中。用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经制备HPLC(乙腈/含0.05％甲酸的水)纯化得到目标化合物(19.8mg,收率18.0％,白色固体)。LC-MS(ESI)m/z 510.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.31(t,J＝6.1Hz,1H),9.26(d,J＝1.2Hz,1H),8.79(s,1H),8.68(s,1H),8.39(s, 1H),8.24(s,1H),8.15(d,J＝2.0Hz,1H),8.13(s,1H),7.96(d,J＝1.3Hz,1H),7.74(dd,J＝8.5,2.4Hz,1H),6.81(d,J＝8.5Hz,1H),5.51–5.46(m,1H),4.42(d,J＝6.1Hz,2H),3.93–3.90(m,1H),3.89(s,3H),3.86–3.80(m,1H),3.78–3.72(m,2H),2.28–2.17(m,1H),2.02–1.93(m,1H)。 To a solution of CDI (69.7 mg, 0.430 mmol) in dry DMF (3.00 mL) at 0 °C was added (6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)methanamine (62.6 mg, 0.322 mmol) and DIEA (55.6 mg, 0.430 mmol). After the reaction mixture was stirred at room temperature for 2 hours, 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5- a] Pyridine-3-carbonitrile hydrochloride (70.0 mg, 0.215 mmol). The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature and poured into EA (100 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. Purification by preparative HPLC (acetonitrile/water with 0.05% formic acid) afforded the title compound (19.8 mg, 18.0% yield, white solid). LC-MS (ESI) m/z 510.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.31(t, J=6.1Hz, 1H), 9.26(d, J=1.2Hz, 1H), 8.79(s, 1H), 8.68(s, 1H) , 8.39(s, 1H), 8.24(s, 1H), 8.15(d, J=2.0Hz, 1H), 8.13(s, 1H), 7.96(d, J=1.3Hz, 1H), 7.74(dd, J=8.5, 2.4Hz, 1H), 6.81 (d, J=8.5Hz, 1H), 5.51–5.46 (m, 1H), 4.42 (d, J=6.1Hz, 2H), 3.93–3.90 (m, 1H) ), 3.89 (s, 3H), 3.86–3.80 (m, 1H), 3.78–3.72 (m, 2H), 2.28–2.17 (m, 1H), 2.02–1.93 (m, 1H).
实施例49： (S)-4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-异丙氧基吡 啶-3-基)乙基)-1H-吡唑-1-甲酰胺(化合物49)的合成 Example 49: (S)-4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)- Synthesis of N-(1-(6-isopropoxypyridin- 3-yl)ethyl)-1H-pyrazole-1-carboxamide (compound 49)
Figure PCTCN2021118001-appb-000073
Figure PCTCN2021118001-appb-000073
步骤1:2-异丙氧基-5-氰基吡啶的合成Step 1: Synthesis of 2-isopropoxy-5-cyanopyridine
在0℃下，向叔丁醇钾(12.1g,108mmol)的无水四氢呋喃(300mL)溶液中加入异丙醇(8.28mL,108mmol)。反应混合物在0℃下搅拌反应5分钟。向反应混合物中加入6-氯烟酸腈(10.0g,72.2mmol)后继续在室温下搅拌反应2小时。反应混合物用饱和氯化铵(120mL)淬灭后用EA(200mL×3)萃取。合并有机相用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝100：1-20:1)得到目标化合物(10.0g，收率85.4％，白色固体)。 1H NMR(400MHz,DMSO-d 6)δ8.67(d,J＝2.0Hz,1H),8.12(dd,J＝8.7,2.4Hz,1H),6.93(d,J＝8.7Hz,1H),5.36–5.27(m,1H),1.31(d,J＝6.2Hz,6H)。 To a solution of potassium tert-butoxide (12.1 g, 108 mmol) in dry tetrahydrofuran (300 mL) at 0 °C was added isopropanol (8.28 mL, 108 mmol). The reaction mixture was stirred at 0°C for 5 minutes. 6-Chloronicotinonitrile (10.0 g, 72.2 mmol) was added to the reaction mixture and the reaction was continued to stir at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride (120 mL) and extracted with EA (200 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. After separation and purification by column chromatography (PE:EA=100:1-20:1), the target compound (10.0 g, yield 85.4%, white solid) was obtained. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.67 (d, J=2.0Hz, 1H), 8.12 (dd, J=8.7, 2.4Hz, 1H), 6.93 (d, J=8.7Hz, 1H) , 5.36–5.27 (m, 1H), 1.31 (d, J=6.2Hz, 6H).
步骤2:1-(6-异丙氧基吡啶-3-基)乙-1-酮的合成Step 2: Synthesis of 1-(6-isopropoxypyridin-3-yl)ethan-1-one
在0℃和氩气保护下，向2-异丙氧基-5-氰基吡啶(10.0g,61.7mmol)的无水四氢呋喃(180mL)溶液中滴加甲基溴化镁溶液(3.0M in THF，61.7mL，185mmol)。反应混合物在室温下搅拌反应16小时。在0℃下反应液用稀盐酸(1.0M，100mL)淬灭后用EA(200mL×3)萃取。合并有机相用无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝100：1-20：1)得到目标化合物(5.00g，收率49.8％，黄色油状物)。LC-MS(ESI)m/z 180.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.81(d,J＝2.4Hz,1H),8.14(dd,J＝8.7,2.4Hz,1H),6.84(d,J＝8.7Hz,1H),5.40–5.29(m,1H),2.54(s,3H),1.32(d,J＝6.2Hz,6H)。 To a solution of 2-isopropoxy-5-cyanopyridine (10.0 g, 61.7 mmol) in dry tetrahydrofuran (180 mL) was added dropwise methylmagnesium bromide solution (3.0 M in THF, 61.7 mL, 185 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was quenched with dilute hydrochloric acid (1.0 M, 100 mL) at 0° C. and extracted with EA (200 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification by column chromatography (PE:EA=100:1-20:1) gave the title compound (5.00 g, yield 49.8%, yellow oil). LC-MS (ESI) m/z 180.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.81 (d, J=2.4Hz, 1H), 8.14 (dd, J=8.7, 2.4Hz, 1H), 6.84 (d, J=8.7Hz, 1H) , 5.40–5.29 (m, 1H), 2.54 (s, 3H), 1.32 (d, J=6.2Hz, 6H).
步骤3:(R,E)-N-(1-(6-异丙氧基吡啶-3-基)亚乙基)-2-甲基丙基-2-亚磺酰胺的合成Step 3: Synthesis of (R,E)-N-(1-(6-isopropoxypyridin-3-yl)ethylene)-2-methylpropyl-2-sulfinamide
向1-(6-异丙氧基吡啶-3-基)乙-1-酮(5.00g,27.9mmol)和(R)-2-甲基丙基-2-亚磺酰胺(3.72g,30.7mmol)的无水四氢呋喃(80.0mL)溶液中加入钛酸四乙酯(11.7mL,55.8mmol)。 反应混合物在75℃下搅拌反应16小时。将反应混合物减压浓缩后用EA(100mL)稀释，再滴加水(10.0mL)得到悬浊液。悬浊液通过硅藻土过滤，滤饼用EA(15.0mL)洗。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝20：1-4：1)得到目标化合物(5.20g，收率66.0％，黄色油状物)。 1H NMR(400MHz,DMSO-d 6)δ8.72(d,J＝2.4Hz,1H),8.18(dd,J＝8.8,2.5Hz,1H),6.84(d,J＝8.8Hz,1H),5.36–5.29(m,1H),2.70(s,3H),1.31(d,J＝6.2Hz,6H),1.21(s,9H)。 To 1-(6-isopropoxypyridin-3-yl)ethan-1-one (5.00 g, 27.9 mmol) and (R)-2-methylpropyl-2-sulfinamide (3.72 g, 30.7 mmol) in dry tetrahydrofuran (80.0 mL) was added tetraethyl titanate (11.7 mL, 55.8 mmol). The reaction mixture was stirred at 75°C for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with EA (100 mL), and water (10.0 mL) was added dropwise to obtain a suspension. The suspension was filtered through celite and the filter cake was washed with EA (15.0 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification by column chromatography (PE:EA=20:1-4:1) gave the title compound (5.20 g, yield 66.0%, yellow oil). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.72 (d, J=2.4Hz, 1H), 8.18 (dd, J=8.8, 2.5Hz, 1H), 6.84 (d, J=8.8Hz, 1H) , 5.36–5.29 (m, 1H), 2.70 (s, 3H), 1.31 (d, J=6.2Hz, 6H), 1.21 (s, 9H).
步骤4:(R)-N-((S)-1-(6-异丙氧基吡啶-3-基)乙基)-2-甲基丙基-2-亚磺酰胺的合成Step 4: Synthesis of (R)-N-((S)-1-(6-isopropoxypyridin-3-yl)ethyl)-2-methylpropyl-2-sulfinamide
-70℃氩气保护下，三仲丁基硼氢化锂(1.0M in THF,36.8mL,36.8mmol)滴加到(R,E)-N-(1-(6-异丙氧基吡啶-3-基)亚乙基)-2-甲基丙基-2-亚磺酰胺(5.20g,18.4mmol)的四氢呋喃(70.0mL)溶液中。反应混合物在-70℃氩气保护下搅拌反应2小时。反应混合物用饱和氯化铵(150mL)淬灭后用EA(120mL×3)萃取。合并有机相用饱和氯化铵(30.0mL×2)和饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥，过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝4：1-二氯甲烷：甲醇＝15:1)得到目标化合物(4.80g，收率91.7％，黄色固体)。LC-MS(ESI)m/z 285.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.07(d,J＝2.4Hz,1H),7.64(dd,J＝8.6,2.5Hz,1H),6.70(d,J＝8.6Hz,1H),5.36(d,J＝5.1Hz,1H),5.24–5.18(m,1H),4.41–4.33(m,1H),1.44(d,J＝6.7Hz,3H),1.29–1.25(m,6H),1.09(s,9H)。 Under argon at -70°C, 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). The combined organic phases were washed with saturated ammonium chloride (30.0 mL×2) and 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. After separation and purification by column chromatography (PE:EA=4:1-dichloromethane:methanol=15:1), the title compound (4.80 g, yield 91.7%, yellow solid) was obtained. LC-MS (ESI) m/z 285.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.07 (d, J=2.4Hz, 1H), 7.64 (dd, J=8.6, 2.5Hz, 1H), 6.70 (d, J=8.6Hz, 1H) ,5.36(d,J＝5.1Hz,1H),5.24-5.18(m,1H),4.41-4.33(m,1H),1.44(d,J＝6.7Hz,3H),1.29-1.25(m,6H) ), 1.09(s, 9H).
步骤5:(S)-1-(6-异丙氧基吡啶-3-基)乙-1-胺的合成Step 5: Synthesis of (S)-1-(6-isopropoxypyridin-3-yl)ethan-1-amine
在0℃下，向(R)-N-((S)-1-(6-异丙氧基吡啶-3-基)乙基)-2-甲基丙基-2-亚磺酰胺(4.80g,16.9mmol)的甲醇(40.0mL)溶液中滴加盐酸的1,4-二氧六环溶液(4.0M,40.0mL,160mmol)。反应混合液在室温下搅拌反应2小时。将反应混合物减压浓缩得到粗产品。经柱层析分离纯化(EA：MeOH：TEA＝100：1：1-20:1:1)得到目标化合物(2.50g，收率82.2％，淡黄色油状物)。 1H NMR(400MHz,MeOH-d 4)δ8.05(d,J＝2.5Hz,1H),7.69(dd,J＝8.6,2.5Hz,1H),6.70(d,J＝8.6Hz,1H),5.22–5.12(m,1H),4.03(q,J＝6.7Hz,1H),1.38(d,J＝6.7Hz,3H),1.30(d,J＝6.2Hz,6H)。 To (R)-N-((S)-1-(6-isopropoxypyridin-3-yl)ethyl)-2-methylpropyl-2-sulfinamide (4.80 g, 16.9 mmol) in methanol (40.0 mL) was added dropwise a solution of hydrochloric acid in 1,4-dioxane (4.0 M, 40.0 mL, 160 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. Separation and purification by column chromatography (EA:MeOH:TEA=100:1:1-20:1:1) gave the title compound (2.50 g, yield 82.2%, pale yellow oil). 1 H NMR (400MHz, MeOH-d 4 ) δ 8.05 (d, J=2.5Hz, 1H), 7.69 (dd, J=8.6, 2.5Hz, 1H), 6.70 (d, J=8.6Hz, 1H) , 5.22–5.12 (m, 1H), 4.03 (q, J=6.7Hz, 1H), 1.38 (d, J=6.7Hz, 3H), 1.30 (d, J=6.2Hz, 6H).
步骤6:(S)-(1-(6-异丙氧基吡啶-3-基)乙基)氨基甲酸苯酯的合成Step 6: Synthesis of (S)-(1-(6-isopropoxypyridin-3-yl)ethyl)phenylcarbamate
向(S)-1-(6-异丙氧基吡啶-3-基)乙-1-胺(500mg,2.77mmol)和TEA(0.770mL,5.54mmol)的DCM(25.0mL)溶液中滴加氯甲酸苯酯(521mg,3.33mmol)的DCM(5.00mL)溶液，滴加时间超过1分钟。反应混合物在室温下搅拌反应30分钟。反应液减压浓缩得到粗产品。经柱层析分离纯化(PE：EA＝100:1-10:1)得到目标化合物(800mg,收率96.0％,白色固体)。LC-MS(ESI)m/z 301.2[M+H] +。 To a solution of (S)-1-(6-isopropoxypyridin-3-yl)ethan-1-amine (500 mg, 2.77 mmol) and TEA (0.770 mL, 5.54 mmol) in DCM (25.0 mL) was added dropwise Phenyl chloroformate (521 mg, 3.33 mmol) in DCM (5.00 mL) was added dropwise over 1 min. The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain a crude product. After separation and purification by column chromatography (PE:EA=100:1-10:1), the target compound (800 mg, yield 96.0%, white solid) was obtained. LC-MS (ESI) m/z 301.2 [M+H] + .
步骤7:(S)-4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-异丙氧基吡啶 -3-基)乙基)-1H-吡唑-1-甲酰胺的合成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
在室温下，向6-(1-甲基-1H-吡唑-4-基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(900mg,2.76mmol)和DIEA(0.912mL,5.52mmol)的DMF(10.0mL)溶液中加入(S)-(1-(6-异丙氧基吡啶-3-基)乙基)氨基甲酸苯酯(996mg,3.32mmol)。反应混合物在70℃下搅拌反应16小时。将反应混合物冷却至室温后用EA(200mL)稀释。用饱和食盐水(30.0mL×3)洗涤、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(DCM：MeOH＝100:1-50:1)得到黄色固体。固体经反相制备(乙腈/水含0.1％甲酸＝0％-55％)纯化得到目标化合物(410mg,收率29.9％,Ret.time＝5.94min,e.e.96.7％,白色固体)。手性分析方法:手性柱:DAICEL
Figure PCTCN2021118001-appb-000074
流动相:A:Supercritical CO 2，B:MeOH(0.1％DEA)；梯度:A 60％,B 40％for 8min；流速:2.0mL/min；柱温:35℃。LC-MS(ESI)m/z 496.4[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.26(s,1H),9.12(d,J＝8.4Hz,1H),8.77(s,1H),8.68(s,1H),8.38(s,1H),8.25(s,1H),8.19(d,J＝2.4Hz,1H),8.12(s,1H),7.95(s,1H),7.82(dd,J＝8.6,2.5Hz,1H),6.73(d,J＝8.6Hz,1H),5.26–5.18(m,1H),5.09–5.02(m,1H),3.89(s,3H),1.58(d,J＝7.1Hz,3H),1.27(d,J＝6.2Hz,6H)。 To 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-methyl at room temperature To a solution of nitrile hydrochloride (900 mg, 2.76 mmol) and DIEA (0.912 mL, 5.52 mmol) in DMF (10.0 mL) was added (S)-(1-(6-isopropoxypyridin-3-yl)ethyl ) phenyl carbamate (996 mg, 3.32 mmol). The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature and diluted with EA (200 mL). Washed with saturated brine (30.0 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Separation and purification by column chromatography (DCM:MeOH=100:1-50:1) gave a yellow solid. The solid was purified by reverse phase preparation (acetonitrile/water with 0.1% formic acid = 0%-55%) to give the title compound (410 mg, yield 29.9%, Ret.time = 5.94 min, ee 96.7%, white solid). Chiral Analysis Method: Chiral Column: DAICEL
Figure PCTCN2021118001-appb-000074
Mobile phase: A: Supercritical CO 2 , B: MeOH (0.1% DEA); gradient: A 60%, B 40% for 8 min; flow rate: 2.0 mL/min; column temperature: 35°C. LC-MS (ESI) m/z 496.4 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.26(s, 1H), 9.12(d, J=8.4Hz, 1H), 8.77(s, 1H), 8.68(s, 1H), 8.38(s, 1H), 8.25(s, 1H), 8.19(d, J=2.4Hz, 1H), 8.12(s, 1H), 7.95(s, 1H), 7.82(dd, J=8.6, 2.5Hz, 1H), 6.73(d,J＝8.6Hz,1H),5.26-5.18(m,1H),5.09-5.02(m,1H),3.89(s,3H),1.58(d,J＝7.1Hz,3H),1.27 (d, J=6.2 Hz, 6H).
实施例50： (R)-4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-异丙氧基吡 啶-3-基)乙基)-1H-吡唑-1-甲酰胺(化合物50)的合成 Example 50: (R)-4-(3-Cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)- Synthesis of N-(1-(6-isopropoxypyridin- 3-yl)ethyl)-1H-pyrazole-1-carboxamide (Compound 50)
Figure PCTCN2021118001-appb-000075
Figure PCTCN2021118001-appb-000075
步骤1:1-(6-异丙氧基吡啶-3-基)乙-1-酮的合成Step 1: Synthesis of 1-(6-isopropoxypyridin-3-yl)ethan-1-one
在0℃和氩气保护下，向2-异丙氧基-5-氰基吡啶(730mg,4.50mmol)的无水四氢呋喃(20.0mL)溶液中滴加甲基溴化镁溶液(3.0M in THF,4.50mL,13.5mmol)。反应混合物在0℃下搅拌反应2小时后在室温下继续搅拌反应16小时。反应液用1.0M盐酸溶液淬灭，用饱和碳酸氢钠溶液调节pH～9。用EA(80.0mL×2)萃取。合并有机相用无水硫酸钠干燥、过滤、滤液减压浓缩得到粗产品。经柱层析分离纯化(硅胶，PE：EA＝100：1-10:1)得到目标化合物(550mg，收率68.2％，黄色油状物)。LC-MS(ESI)m/z 180.3[M+H] +。 To a solution of 2-isopropoxy-5-cyanopyridine (730 mg, 4.50 mmol) in dry tetrahydrofuran (20.0 mL) was added dropwise methylmagnesium bromide solution (3.0 M in THF, 4.50 mL, 13.5 mmol). The reaction mixture was stirred at 0°C for 2 hours and then at room temperature for 16 hours. The reaction solution was quenched with 1.0M hydrochloric acid solution, and adjusted to pH~9 with saturated sodium bicarbonate solution. Extracted with EA (80.0 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Separation and purification by column chromatography (silica gel, PE:EA=100:1-10:1) gave the title compound (550 mg, yield 68.2%, yellow oil). LC-MS (ESI) m/z 180.3 [M+H] + .
步骤2:1-(6-异丙氧基吡啶-3-基)乙-1-酮肟的合成Step 2: Synthesis of 1-(6-isopropoxypyridin-3-yl)ethan-1-one oxime
向1-(6-异丙氧基吡啶-3-基)乙-1-酮(550mg,3.07mmol)的乙醇(6.00mL)溶液中加入 盐酸羟胺(427mg,6.14mmol)和乙酸钠(503mg,6.14mmol)的水(3.00mL)溶液。反应混合物在90℃下搅拌反应2小时。将反应混合物冷却后减压浓缩。加入EA(100mL)。分出有机相用饱和食盐水(15.0mL×2)洗涤、无水硫酸钠干燥、过滤。滤液减压浓缩得到目标化合物(580mg，收率97.3％，淡黄色固体)。LC-MS(ESI)m/z 195.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ11.17(s,3H),8.40–8.35(m,1H),7.94(dd,J＝8.7,2.5Hz,1H),6.78–6.71(m,1H),5.32–5.20(m,1H),2.13(s,3H),1.29(d,J＝6.2Hz,6H)。 To a solution of 1-(6-isopropoxypyridin-3-yl)ethan-1-one (550 mg, 3.07 mmol) in ethanol (6.00 mL) was added hydroxylamine hydrochloride (427 mg, 6.14 mmol) and sodium acetate (503 mg, 6.14 mmol) in water (3.00 mL). The reaction mixture was stirred at 90°C for 2 hours. The reaction mixture was cooled and concentrated under reduced pressure. EA (100 mL) was added. The organic phase was separated, washed with saturated brine (15.0 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (580 mg, yield 97.3%, pale yellow solid). LC-MS (ESI) m/z 195.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 11.17 (s, 3H), 8.40-8.35 (m, 1H), 7.94 (dd, J=8.7, 2.5Hz, 1H), 6.78-6.71 (m, 1H) ), 5.32–5.20 (m, 1H), 2.13 (s, 3H), 1.29 (d, J=6.2Hz, 6H).
步骤3:1-(6-异丙氧基吡啶-3-基)乙-1-胺的合成Step 3: Synthesis of 1-(6-isopropoxypyridin-3-yl)ethan-1-amine
在-10℃下，向1-(6-异丙氧基吡啶-3-基)乙-1-酮肟(580mg,2.99mmol)的甲醇(15.0mL)溶液中加入六水合氯化镍(1.42g,5.97mmol)，然后缓慢加入硼氢化钠(904mg,23.9mmol)。反应混合物在室温下搅拌反应2小时。向反应液中加入丙酮(10.0mL)淬灭反应。减压浓缩得到粗产品。经柱层析分离纯化(DCM：MeOH＝20:1-7:1)得到目标化合物(265mg，收率49.2％，黑色油状物)。 1H NMR(400MHz,MeOH-d 4)δ8.06(d,J＝2.5Hz,1H),7.70(dd,J＝8.6,2.5Hz,1H),6.71(d,J＝8.6Hz,1H),5.21–5.14(m,1H),4.11–4.02(m,1H),1.40(d,J＝6.7Hz,3H),1.31(d,J＝6.2Hz,6H)。 To a solution of 1-(6-isopropoxypyridin-3-yl)ethan-1-one oxime (580 mg, 2.99 mmol) in methanol (15.0 mL) at -10 °C was added nickel chloride hexahydrate (1.42 g, 5.97 mmol), then sodium borohydride (904 mg, 23.9 mmol) was added slowly. The reaction mixture was stirred at room temperature for 2 hours. Acetone (10.0 mL) was added to the reaction solution to quench the reaction. Concentration under reduced pressure gave crude product. Separation and purification by column chromatography (DCM:MeOH=20:1-7:1) gave the title compound (265 mg, yield 49.2%, black oil). 1 H NMR (400MHz, MeOH-d 4 ) δ 8.06 (d, J=2.5Hz, 1H), 7.70 (dd, J=8.6, 2.5Hz, 1H), 6.71 (d, J=8.6Hz, 1H) , 5.21–5.14 (m, 1H), 4.11–4.02 (m, 1H), 1.40 (d, J=6.7Hz, 3H), 1.31 (d, J=6.2Hz, 6H).
步骤4:4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-异丙氧基吡啶-3-基)乙基)-1H-吡唑-1-甲酰胺的合成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
在室温下，向CDI(318mg,1.96mmol)的DMF(12.0mL)溶液中加入1-(6-异丙氧基吡啶-3-基)乙-1-胺(266mg,1.47mmol)和DIEA(254mg,1.96mmol)。反应混合物在室温下搅拌反应2小时后，加入6-(1-甲基-1H-吡唑-4-基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(320mg,0.984mmol)。反应混合物在70℃下搅拌反应16小时。将反应混合物冷却至室温后用EA(200mL)稀释，用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经柱层析分离纯化(DCM：MeOH＝100:1-30:1)得粗品。粗品经液相制备(乙腈/水含0.05％甲酸)纯化得到目标化合物(45.0mg,收率9.24％,类白色固体)。LC-MS(ESI)m/z 496.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.26(d,J＝1.3Hz,1H),9.12(d,J＝8.4Hz,1H),8.78–8.76(m,1H),8.68(s,1H),8.38(s,1H),8.26–8.24(m,1H),8.19(d,J＝2.3Hz,1H),8.12(s,1H),7.96(d,J＝1.3Hz,1H),7.82(dd,J＝8.6,2.5Hz,1H),6.73(d,J＝8.5Hz,1H),5.26–5.18(m,1H),5.10–5.01(m,1H),3.89(s,3H),1.58(d,J＝7.0Hz,3H),1.27(d,J＝6.2Hz,6H)。 To a solution of CDI (318 mg, 1.96 mmol) in DMF (12.0 mL) at room temperature was added 1-(6-isopropoxypyridin-3-yl)ethan-1-amine (266 mg, 1.47 mmol) and DIEA ( 254 mg, 1.96 mmol). After the reaction mixture was stirred at room temperature for 2 hours, 6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5- a] Pyridine-3-carbonitrile hydrochloride (320 mg, 0.984 mmol). The reaction mixture was stirred at 70°C for 16 hours. 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. The crude product was obtained by separation and purification by column chromatography (DCM:MeOH=100:1-30:1). The crude product was purified by liquid phase preparation (acetonitrile/water containing 0.05% formic acid) to give the title compound (45.0 mg, yield 9.24%, off-white solid). LC-MS (ESI) m/z 496.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (d, J=1.3 Hz, 1H), 9.12 (d, J=8.4 Hz, 1H), 8.78-8.76 (m, 1H), 8.68 (s, 1H), 8.38(s, 1H), 8.26–8.24(m, 1H), 8.19(d, J=2.3Hz, 1H), 8.12(s, 1H), 7.96(d, J=1.3Hz, 1H), 7.82(dd,J=8.6,2.5Hz,1H),6.73(d,J=8.5Hz,1H),5.26-5.18(m,1H),5.10-5.01(m,1H),3.89(s,3H) , 1.58 (d, J=7.0Hz, 3H), 1.27 (d, J=6.2Hz, 6H).
步骤5:(R)-4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-异丙氧基吡啶-3-基)乙基)-1H-吡唑-1-甲酰胺的合成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
消旋体4-(3-氰基-6-(1-甲基-1H-吡唑-4-基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-异丙氧基吡啶 -3-基)乙基)-1H-吡唑-1-甲酰胺(45mg溶于约16mL甲醇，进样体积8.0mL)经Waters SFC 150(室温,100bar,214nm)和a 250*25mm 10μm Dr.maish Reprosil Chiral-OM(超临界二氧化碳：甲醇，45:55,5.6min,100mL/min)分离得到化合物50(23.68mg，白色固体，Ret.time＝2.95min,e.e.100％)和化合物49(18.47mg，白色固体，Ret.time＝5.94min,e.e.100％)。通过上面实施例49的合成中所用的手性分析方法确证了化合物的构型和纯度。LC-MS(ESI)m/z 496.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.26(d,J＝1.2Hz,1H),9.12(d,J＝8.5Hz,1H),8.80–8.75(m,1H),8.68(s,1H),8.38(s,1H),8.27–8.22(m,1H),8.19(d,J＝2.3Hz,1H),8.12(s,1H),7.96(d,J＝1.3Hz,1H),7.82(dd,J＝8.6,2.5Hz,1H),6.73(d,J＝8.6Hz,1H),5.29–5.16(m,1H),5.15–4.96(m,1H),3.89(s,3H),1.58(d,J＝7.1Hz,3H),1.27(d,J＝6.2Hz,6H)。 Racemate 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-N-(1- (6-Isopropoxypyridin-3-yl)ethyl)-1H-pyrazole-1-carboxamide (45 mg in ca. 16 mL methanol, injection volume 8.0 mL) was purified by Waters SFC 150 (room temperature, 100 bar, 214 nm) ) and a 250*25mm 10μm Dr.maish Reprosil Chiral-OM (supercritical carbon dioxide: methanol, 45:55, 5.6min, 100mL/min) to separate compound 50 (23.68mg, white solid, Ret.time=2.95min, ee 100%) and compound 49 (18.47 mg, white solid, Ret. time=5.94 min, ee 100%). The configuration and purity of the compound were confirmed by the chiral analysis method used in the synthesis of Example 49 above. LC-MS (ESI) m/z 496.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (d, J=1.2 Hz, 1H), 9.12 (d, J=8.5 Hz, 1H), 8.80-8.75 (m, 1H), 8.68 (s, 1H), 8.38(s, 1H), 8.27–8.22(m, 1H), 8.19(d, J=2.3Hz, 1H), 8.12(s, 1H), 7.96(d, J=1.3Hz, 1H), 7.82(dd,J=8.6,2.5Hz,1H),6.73(d,J=8.6Hz,1H),5.29-5.16(m,1H),5.15-4.96(m,1H),3.89(s,3H) , 1.58 (d, J=7.1 Hz, 3H), 1.27 (d, J=6.2 Hz, 6H).
实施例51： (S)-4-(3-氰基-6-(2-羟基-2-甲基丙氧基)吡唑并[1,5-a]吡啶-4-基)-N-(1-(6-异丙氧基吡 啶-3-基)乙基)-1H-吡唑-1-甲酰胺(化合物51)的合成 Example 51: (S)-4-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)-N- Synthesis of (1-(6-isopropoxypyridin- 3-yl)ethyl)-1H-pyrazole-1-carboxamide (Compound 51)
Figure PCTCN2021118001-appb-000076
Figure PCTCN2021118001-appb-000076
在室温下，向6-(2-羟基-2-甲基丙氧基)-4-(1H-吡唑-4-基)吡唑并[1,5-a]吡啶-3-甲腈盐酸盐(120mg,0.360mmol)和DIEA(0.119mL,0.719mmol)的DMF(4.00mL)溶液中加入(S)-(1-(6-异丙氧基吡啶-3-基)乙基)氨基甲酸苯酯(130mg,0.431mmol)。反应混合物在70℃下搅拌反应16小时。将反应混合物冷却至室温后用EA(80.0mL)稀释。再用饱和食盐水(15.0mL×3)洗、无水硫酸钠干燥、过滤。滤液减压浓缩得到粗产品。经硅胶柱层析分离纯化(二氯甲烷：甲醇＝100：1-30：1)得到粗品。粗品经反相制备(乙腈/水含0.01％甲酸)纯化得到目标化合物(85.1mg,收率47.0％,白色固体)。LC-MS(ESI)m/z 504.3[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.10(d,J＝8.4Hz,1H),8.73(s,1H),8.70(d,J＝2.0Hz,1H),8.60(s,1H),8.23–8.21(m,1H),8.18(d,J＝2.4Hz,1H),7.81(dd,J＝8.6,2.5Hz,1H),7.50(d,J＝2.0Hz,1H),6.73(d,J＝8.6Hz,1H),5.25–5.18(m,1H),5.08–4.99(m,1H),4.70(s,1H),3.87(s,2H),1.57(d,J＝7.1Hz,3H),1.27(d,J＝6.2Hz,6H),1.22(s,6H)。 To 6-(2-hydroxy-2-methylpropoxy)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile salt at room temperature (S)-(1-(6-isopropoxypyridin-3-yl)ethyl)amino Phenyl formate (130 mg, 0.431 mmol). The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature and diluted with EA (80.0 mL). It was 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. The crude product was obtained by separation and purification by silica gel column chromatography (dichloromethane:methanol=100:1-30:1). The crude product was purified by reverse phase preparation (acetonitrile/water with 0.01% formic acid) to give the title compound (85.1 mg, 47.0% yield, white solid). LC-MS (ESI) m/z 504.3 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.10(d, J=8.4Hz, 1H), 8.73(s, 1H), 8.70(d, J=2.0Hz, 1H), 8.60(s, 1H) ,8.23–8.21(m,1H),8.18(d,J＝2.4Hz,1H),7.81(dd,J＝8.6,2.5Hz,1H),7.50(d,J＝2.0Hz,1H),6.73( d, J=8.6Hz, 1H), 5.25–5.18 (m, 1H), 5.08–4.99 (m, 1H), 4.70 (s, 1H), 3.87 (s, 2H), 1.57 (d, J=7.1Hz) , 3H), 1.27(d, J=6.2Hz, 6H), 1.22(s, 6H).
活性实施例Active Example
如无特别说明，以下活性实施例中所用的实验材料、试剂、操作和方法均可从市售渠道 获得或基于现有技术容易地获知或制备。Unless otherwise specified, the experimental materials, reagents, operations and methods used in the following active examples can be obtained from commercial sources or easily known or prepared based on the prior art.
活性实施例1：激酶RET抑制测定Activity Example 1: Kinase RET Inhibition Assay
采用类似于文献(Vivek Subbiah,J.F.G.,Precision Targeted Therapy with BLU-667 for RET-Driven Cancers.Cancer Discov,2018.8(7):836-849)所述的方法进行激酶RET抑制测定。利用Caliper Mobility Shift Assay方法检测化合物对激酶RET的抑制效果，化合物测试终浓度为从1000nM起始，3倍系列稀释，共计10个浓度，复孔检测。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.
将待测化合物溶解在100％DMSO(Sigma,D8418-1L,SHBG3288V)中，配制成10mM储存液，于氮气柜中避光保存。配制1×Kinase buffer，同时如下配制化合物浓度梯度：待测化合物起始测试浓度为1000nM，在384孔板(Corning,3573,12619003)中用DMSO 3倍系列稀释，共10个浓度，复孔测试，终浓度分别为1000、333、111、37、12.3、4.12、1.37、0.457、0.152、0.0508nM，然后用Echo550(Labcyte，型号：Echo 550)转移250nl到384反应板中备用，阴性对照孔和阳性对照孔中分别加250nl 100％DMSO。用1×Kinase buffer配制2.5倍终浓度(终浓度为1nM)的RET(Carna,货号08-159,批号13CBS-0134E)的激酶溶液。在化合物孔和阳性对照孔分别加10μL 2.5倍终浓度的激酶溶液；在阴性对照孔中加10μL 1×Kinase buffer。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. Prepare 1×Kinase buffer, and at the same time prepare 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. 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 μL of 2.5 times final concentration of kinase solution to compound wells and positive control wells respectively; add 10 μL of 1×Kinase buffer to negative control wells.
将反应板1000rpm离心(Eppendorf，型号：5430)30秒，将反应板振荡混匀后室温孵育10分钟。用1×Kinase buffer配制25倍终浓度(终浓度为16μM)的ATP和15倍终浓度(终浓度为3μM)的Kinase substrate 2(GL,货号112394，批号P171207-MJ112394)的混合溶液，并加入15μL该混合溶液至各孔中，开始反应。将384孔板1000rpm离心30秒，振荡混匀后室温孵育60分钟。加入30μL含EDTA的终止检测液停止激酶反应，1000rpm离心30秒，振荡混匀。用酶标仪(Perkin Elmer，型号：Caliper EZ ReaderⅡ)读取转化率。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. Prepare a mixed solution of 25-fold final concentration (final concentration of 16 μM) of ATP and 15-fold final concentration (final concentration of 3 μM) of Kinase substrate 2 (GL, Cat. No. 112394, Lot No. P171207-MJ112394) with 1×Kinase buffer, and add 15 μL of this mixed solution was added to each well to start the reaction. The 384-well plate was centrifuged at 1000 rpm for 30 seconds, shaken and mixed, and incubated at room temperature for 60 minutes. Add 30 μL of stop detection solution containing EDTA to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and mix by shaking. The conversion rate was read with a microplate reader (Perkin Elmer, model: Caliper EZ Reader II).
采用以下公式进行计算：Calculated using the following formula:
％抑制＝(转化％_max-转化％_样品)/(转化％_样品-转化％_min)*100% Inhibition=(Conversion%_max-Conversion%_Sample)/(Conversion%_Sample-Conversion%_min)*100
其中：“转化％_样品”是样品的转化率读数；“转化％_min”是阴性对照孔均值，代表没有酶活的孔的转化率读数；“转化％_max”是阳性对照孔均值，代表没有化合物抑制的孔的转化率读数。Where: "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.
以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，Taking the log value of the concentration as the X-axis and the percentage inhibition rate as the Y-axis, the log(inhibitor) vs.response-Variable slope of the analysis software GraphPad Prism 5 was used to fit the dose-response curve,
计算公式：Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))Calculation formula: Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
从而得出各个化合物对酶活性的IC 50值。 The IC50 values for the enzymatic activity of each compound were thus derived.
表1 RET激酶实验结果Table 1 RET kinase assay results
化合物编号.Compound number. RET(野生型)IC 50(nM) RET (wild type) IC50 (nM)
11 9.49.4
22 1.31.3
3-13-1 3.53.5
4-14-1 3.93.9
5-15-1 4.94.9
66 56.756.7
7-17-1 3.43.4
88 10.810.8
99 9.59.5
1010 1.71.7
1111 3.63.6
1212 74.974.9
1313 0.50.5
1414 9.19.1
1515 14.614.6
1616 2.62.6
1717 1.81.8
1818 1.51.5
19-119-1 0.70.7
2020 22.822.8
21-121-1 1.61.6
22twenty two 0.50.5
23-123-1 5.95.9
24twenty four 16.816.8
2525 3.53.5
2626 11.211.2
2727 0.60.6
28-128-1 1.81.8
2929 0.70.7
3030 1.01.0
3131 3.53.5
32-132-1 3.73.7
33-133-1 0.80.8
3434 1.21.2
35-135-1 1.61.6
36-136-1 15.615.6
3737 14.514.5
3838 3.03.0
3939 3.83.8
4040 9.09.0
4141 1.31.3
4242 0.70.7
4343 0.70.7
4444 0.70.7
4545 2.02.0
4646 1.51.5
4747 3.73.7
4848 1.41.4
4949 0.70.7
5050 2.72.7
5151 3.03.0
活性实施例2：细胞增殖试验Active Example 2: Cell Proliferation Assay
采用CellTiter-Glo TM活细胞检测试剂盒，测试了本发明化合物对细胞增殖的抑制作用。该试剂盒采用萤光素酶作检测物，发光过程中萤光素酶需要ATP的参与，向细胞培养基中加入CellTiter-Glo TM试剂，测量发光值，光信号和体系中ATP量成正比，而ATP又和活细胞数正相关，由此确定细胞的增殖活性。 Using CellTiter-Glo TM live cell detection kit, the inhibitory effect of the compounds of the present invention on cell proliferation was tested. 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.
细胞培养和接种：收获处于对数生长期的细胞(Ba/F3 KIF5B-RET,得自康源博创，RPMI1640(Hyclone,SH30027.01)+10％FBS(GBICO,10099-141)中稳定转染)，并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。分别添加90μL细胞悬液至96孔透明平底黑壁板(Thermo,165305)中，调整细胞浓度到3000/孔/90ul。将96孔板中的细胞置于37℃、5％CO 2、95％湿度条件下培养过夜(Thermo，Model 3100 Series)。 Cell culture and seeding: Harvest cells in the logarithmic growth phase (Ba/F3 KIF5B-RET, obtained from Kangyuan Bochuang, stably transduced in RPMI1640 (Hyclone, SH30027.01) + 10% FBS (GBICO, 10099-141) staining), and cell counts were performed using a platelet counter. Cell viability was detected by trypan blue exclusion method to ensure cell viability was above 90%. 90 μL of cell suspension was added to a 96-well transparent flat-bottom black-walled plate (Thermo, 165305) respectively, and the cell concentration was adjusted to 3000/well/90ul. Cells in 96-well plates were incubated overnight at 37°C, 5% CO2 , 95% humidity (Thermo, Model 3100 Series).
先用DMSO作为溶剂配制10000μM的待测化合物母液，然后用PBS稀释100倍，配制成10倍终浓度的溶液，最高浓度为100μM，在接种有细胞的96孔板中每孔加入10μL待测化合物溶液，即又稀释10倍，浓度达到最终终浓度10μM。将待测化合物终浓度从10μM开始，3倍系列稀释，共9个浓度，每个3个复孔。将已加入待测化合物和细胞的96孔板置于37℃、5％CO 2、95％湿度条件下继续培养72小时，之后进行CellTiter-Glo分析。 First, use DMSO as a solvent to prepare 10,000 μM stock solution of the test compound, then dilute it 100 times with PBS to prepare a solution with a final concentration of 10 times, the highest concentration is 100 μM, and add 10 μL 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 μM. The final concentration of the compound to be tested starts from 10 μM, 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.
融化CellTiter-Glo试剂(
Figure PCTCN2021118001-appb-000077
Luminescent Cell Viability Assay,Promega,G7572)并平衡细胞板至室温30分钟。每孔加入等体积的CellTiter-Glo溶液，在定轨摇床上振动5分钟使细胞裂解。将细胞板放置于室温20分钟以稳定冷光信号，用SpectraMax多标记微孔板检测仪(MD,M3)读取冷光值。 Thaw CellTiter-Glo reagent (
Figure PCTCN2021118001-appb-000077
Luminescent Cell Viability Assay, Promega, G7572) and 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).
使用GraphPad Prism 7.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 50值。 Data were analyzed using GraphPad Prism 7.0 software, and a dose-response curve was fitted to the data using nonlinear S-curve regression, from which IC50 values were calculated.
细胞存活率(％)＝(Lum 待测药-Lum 培养液对照)/(Lum 细胞对照-Lum 培养液对照)×100％ Cell viability (%)=(Lum test drug- Lum culture medium control )/(Lum cell control -Lum culture medium control )×100%
表2细胞增殖实验结果Table 2 Results of cell proliferation experiments
Figure PCTCN2021118001-appb-000078
Figure PCTCN2021118001-appb-000078
Figure PCTCN2021118001-appb-000079
Figure PCTCN2021118001-appb-000079
活性实施例3：人和小鼠肝微粒体代谢稳定性实验Active Example 3: Metabolic Stability Experiment of Human and Mouse Liver Microsomes
根据本领域常规的体外代谢稳定性研究的标准方法，例如(Kerns,Edward H.and Di Li(2008).Drug-like Properties:Concepts,Structure Design and Methods:from ADME to Toxicity Optimization.San Diego:Academic Press；Di,Li等人，Optimization of a Higher Throughput Microsomal Stability Screening Assay for Profiling Drug Discovery Candidates,J.Biomol.Screen.2003,8(4),453.)中所述的方法，类似地如下进行本发明化合物的肝微粒体代谢稳定性试验。According to standard methods of in vitro metabolic stability studies routine in the field, for example (Kerns, Edward H. and Di Li (2008). Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization. San Diego: Academic Press; Di, Li et al., Optimization of a Higher Throughput Microsomal Stability Screening Assay for Profiling Drug Discovery Candidates, J. Biomol. Screen. 2003, 8(4), 453.) The method described in this paper was similarly performed as follows Liver microsomal metabolic stability test of inventive compounds.
Figure PCTCN2021118001-appb-000080
Figure PCTCN2021118001-appb-000080
将肝微粒体(蛋白浓度为0.56mg/mL)加入1μM化合物工作液(由10mM DMSO储备液用100％乙腈稀释到100μM，有机相含量：99％ACN，1％DMSO)，37℃预孵育10min后，加入 辅助因子(NADPH)(由氯化镁溶液配制)启动反应。孵育适当时间(如5、10、20、30和60分钟)后取样，加入适当终止液(含有200ng/mL甲苯磺丁脲和200ng/mL拉贝洛尔的冰乙腈(即4℃的乙腈))，终止反应。Liver microsomes (protein concentration of 0.56 mg/mL) were added to 1 μM compound working solution (diluted to 100 μM 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.
样品处理(n＝1)：各加合适样品，涡旋后高速离心，取上清液，采用HPLC-MS/MS对底物进行检测。把0min时间点峰面积作为100％。其他时间点的峰面积转换为百分剩余量，各时间点的百分剩余量的自然对数对孵育时间作图，求算出斜率(-k)，然后按固有清除率(Clint)＝(k*孵育液体积)/肝微粒体质量，计算出Clint(uL/min/mg)及化合物半衰期(T1/2，min)。结果见表3。Sample treatment (n=1): each appropriate sample was added, vortexed and centrifuged at high speed, the supernatant was taken, and the substrate was detected by HPLC-MS/MS. The peak area at the 0 min time point was taken as 100%. The peak area at other time points was converted into the percentage residual amount, the natural logarithm of the residual amount at each time point was plotted against the incubation time, and the slope (-k) was calculated, and then the inherent clearance rate (Clint) = (k *volume of incubation solution)/mass of liver microsomes to calculate Clint (uL/min/mg) and compound half-life (T1/2, min). The results are shown in Table 3.
表3.人和小鼠肝微粒体代谢稳定性实验结果Table 3. Experimental results of metabolic stability of human and mouse liver microsomes
Figure PCTCN2021118001-appb-000081
Figure PCTCN2021118001-appb-000081
活性实施例4：本发明化合物在小鼠中的药代动力学(PK)测定Active Example 4: Pharmacokinetic (PK) Determination of Compounds of the Invention in Mice
每个化合物的PK测定方法如下：6只CD-1小鼠(来源上海灵畅生物科技有限公司)分为两组，每组3只。其中一组通过静脉(IV)给药，剂量为1mg/kg，溶媒为5％DMSO/95％(20％Captisol)；一组通过口服(Po)灌胃给药，剂量为5mg/kg，溶媒为1％HPMC。每一组在给药后0、0.083、0.25、0.5、1、2、4、6、8、24h分别通过小腿隐静脉采血。将约40μL血液收集到含EDTA-K2的抗凝管中。在收集完成后迅速将采血管倒置至少5次，以确保混合均匀，然后放置在冰上。采集到的各时间点血液在4℃，8000rpm离心5分钟以获得 血浆。另取1.5mL离心管标记好化合物名称，动物编号，时间点，将血浆转移至该管中。血浆保存在-80℃直至分析。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 μL of blood was collected into anticoagulant tubes containing EDTA-K2. Immediately after collection, invert the blood collection tube at least 5 times to ensure uniform mixing and place on ice. The blood collected at each time point was centrifuged at 4°C, 8000 rpm for 5 minutes to obtain plasma. Another 1.5mL centrifuge tube was marked with the compound name, animal number, and time point, and the plasma was transferred to this tube. Plasma was stored at -80°C until analysis.
采用UPLC-MS/MS方法测定血浆中化合物浓度，用Phoenix WinNolin 6.4药代动力学软件对所得数据进行药代动力学参数计算。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.
具体实验结果如下，结果表明化合物药代吸收较好，具有药代动力学优势。The specific experimental results are as follows. The results show that the compound has better pharmacokinetic absorption and has the advantages of pharmacokinetics.
表4.实施例化合物体内PK结果Table 4. In vivo PK results of example compounds
Figure PCTCN2021118001-appb-000082
Figure PCTCN2021118001-appb-000082
表5.实施例化合物体内PK结果Table 5. In vivo PK results of example compounds
Figure PCTCN2021118001-appb-000083
Figure PCTCN2021118001-appb-000083
本领域技术人员将了解，上文描述本质上为示例性及说明性的，且欲说明本发明及其优选实施方案。通过常规实验，技术人员将了解可作出明显修正及变化而不悖离本发明的精神。在随附申请专利范围内的所有此类修正欲包括于其中。因此，本发明意欲并非由上述描述而是由以下权利要求范围及其等效物定义。Those skilled in the art will appreciate that the foregoing description is exemplary and explanatory in nature and is intended to illustrate the invention and preferred embodiments thereof. Through routine experimentation, the skilled artisan will appreciate that obvious modifications and changes can be made without departing from the spirit of the invention. All such modifications as come within the scope of the appended claims are intended to be included therein. Accordingly, it is intended that the invention be defined not by the above description but by the scope of the following claims and their equivalents.
本说明书中所引用的所有公开出版物以引用方式并入本文中。All publications cited in this specification are incorporated herein by reference.

Claims (22)

  1. 式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物：Compounds of formula (I), stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof:
    Figure PCTCN2021118001-appb-100001
    Figure PCTCN2021118001-appb-100001
    其中：in:
    R 1选自氢、卤素、氰基、硝基和任选被卤素或氰基取代的C 1-C 6烷基； R 1 is selected from hydrogen, halogen, cyano, nitro and C 1 -C 6 alkyl optionally substituted with halogen or cyano;
    R 2选自氢、C 6-C 10芳基、5-9元杂芳基、C 3-C 8环烷基、C 3-C 8环烯基、3-8元杂环烷基、3-8元杂环烯基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基，其中所述芳基、杂芳基、环烷基、环烯基、杂环烷基、杂环烯基、烷基、烷氧基和烷硫基任选被独立地选自以下的1、2或3个基团取代：卤素、氰基、硝基、羟基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基； 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选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基； 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选自氢、C 6-C 10芳基、5-9元杂芳基、C 3-C 8环烷基、C 3-C 8环烯基、3-8元杂环烷基、3-8元杂环烯基、3-8元杂环烷基氧基、3-8元杂环烯基氧基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基，其中所述芳基、杂芳基、环烷基、环烯基、杂环烷基、杂环烯基、烷基、烷氧基和烷硫基任选被独立地选自以下的1、2或3个基团取代：卤素、氰基、硝基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基； 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 alkylthio;
    R 5选自卤素、氰基、硝基、羟基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基； 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;
    环A选自C 6-C 10亚芳基、5-9元亚杂芳基、C 3-C 8亚环烷基、C 3-C 8亚环烯基、3-8元亚杂环烷基和3-8元亚杂环烯基环； 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;
    环B选自C 6-C 10芳基、5-9元杂芳基、C 3-C 8环烷基、C 3-C 8环烯基、3-8元杂环烷基和3-8元杂环烯基环； 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;
    m是0、1、2或3；且m is 0, 1, 2, or 3; and
    n是0、1、2或3。n is 0, 1, 2 or 3.
  2. 根据权利要求1所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R 1是卤素、氰基或硝基；优选地，R 1是氰基。 The compound of formula (I), its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate according to claim 1, wherein R 1 is halogen, cyano or nitro; preferably, R 1 is cyano.
  3. 根据权利要求1-2中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R 2选自包含1、2或3个独立地选自N、O或S的杂原子的5-6元杂芳基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基，其任选被独立地选自以下的1、2或3个基团取代：卤素、羟基和C 1-C 6烷基；其中优选地所述5-6元杂芳基包括吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡唑基、吡啶基、吡嗪基、哒嗪基或嘧啶基； A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1-2, wherein R 2 is selected from 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, C1 - C6 alkyl, C1 - C6 alkoxy and C1 -C 6 alkylthio, which is optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen, hydroxy and C 1 -C 6 alkyl; wherein preferably the 5-6 membered heteroaryl radicals include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl;
    优选地，R 2选自任选被C 1-C 6烷基取代的包含1、2或3个独立地选自N、O或S的杂原子的5元杂芳基和任选被羟基取代的C 1-C 6烷氧基；其中优选地所述5元杂芳基包括吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基或吡唑基。 Preferably, R is selected from 5-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, optionally substituted with C1 - C6 alkyl and optionally substituted with hydroxy C 1 -C 6 alkoxy; wherein preferably the 5-membered heteroaryl group includes pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or pyridine azolyl.
  4. 根据权利要求1-3中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R 2选自甲基取代的吡唑基或羟基取代的C 1-C 6烷氧基； A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 3, wherein R 2 is selected from methyl-substituted pyrazolyl or hydroxy-substituted C 1 -C 6 alkoxy;
    优选地，R 2是
    Figure PCTCN2021118001-appb-100002
    Preferably, R 2 is
    Figure PCTCN2021118001-appb-100002
  5. 根据权利要求1-4中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R 3选自氢和C 1-C 6烷基； A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 4, wherein R 3 is selected from hydrogen and C 1 -C 6 alkyl;
    优选地，R 3选自氢和C 1-C 3烷基； Preferably, R 3 is selected from hydrogen and C 1 -C 3 alkyl;
    更优选地，R 3是氢或甲基； More preferably, R is hydrogen or methyl;
    更优选地，R 3是氢。 More preferably, R3 is hydrogen.
  6. 根据权利要求1-5中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，A compound of formula (I) according to any one of claims 1 to 5, a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof,
    其中R 4选自苯基、包含1、2或3个独立地选自N、O或S的杂原子的5-6元杂芳基、5-6元杂环烷基、5-6元杂环烯基、5-6元杂环烷基氧基、5-6元杂环烯基氧基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基，其任选被独立地选自以下的1、2或3个基团取代：卤素、羟基和C 1-C 6烷基；优选地，所述5-6元杂芳基选自吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡唑基、吡啶基、吡嗪基、哒嗪基和嘧啶基，所述5-6杂环烷基选自吡咯烷基、四氢呋喃基、四氢噻吩基、哌啶基、四氢吡喃基、四氢噻喃基)、吗啉基、硫吗啉基、二噁烷基或哌嗪基，所述5-6元杂环烯基选自吡咯啉基、二氢呋喃基、二氢噻吩基、四氢吡啶基、四氢吡喃基和四氢噻喃基； wherein R4 is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, 5-6 membered heteroatom containing 1, 2 or 3 heteroatoms independently selected from N, O or S Cycloalkenyl, 5-6 membered heterocycloalkyloxy, 5-6 membered heterocycloalkenyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 alkylthio group, which is optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen, hydroxy and C1 - C6 alkyl; preferably, the 5-6 membered heteroaryl group is selected from pyrrolyl , furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl, the 5-6 hetero Cycloalkyl is selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl or piperazine base, the 5-6 membered heterocycloalkenyl is selected from pyrrolinyl, dihydrofuranyl, dihydrothienyl, tetrahydropyridyl, tetrahydropyranyl and tetrahydrothiopyranyl;
    优选地，R 4选自包含1、2或3个独立地选自N、O或S的杂原子的5元杂芳基、5-6元杂环烷基、5-6元杂环烷基氧基、C 1-C 6烷基和C 1-C 6烷氧基，其任选被独立地选自以下的1、 2或3个基团取代：卤素和C 1-C 6烷基；优选地，所述5元杂芳基选自吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基和吡唑基。 Preferably, R4 is selected from 5 -membered heteroaryl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S oxy, C 1 -C 6 alkyl and C 1 -C 6 alkoxy, optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of halogen and C 1 -C 6 alkyl; Preferably, the 5-membered heteroaryl group is selected from pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl and pyrazolyl.
  7. 根据权利要求1-6中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R 4选自吡唑基、吡咯烷基、四氢吡喃基氧基、吗啉基、四氢呋喃基氧基、C 1-C 6烷基和C 1-C 6烷氧基，其任选被卤素取代； A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 6, wherein R 4 is selected from pyrazolyl, pyrrolidinyl, tetrahydropyranyloxy, morpholinyl, tetrahydrofuranyloxy, C1 - C6 alkyl and C1 - C6 alkoxy, optionally halogenated replace;
    优选地，R 4是
    Figure PCTCN2021118001-appb-100003
    吡咯烷-1-基、甲氧基、乙氧基、异丙氧基、三氟甲氧基或CF 3。     Preferably, R4 is
    Figure PCTCN2021118001-appb-100003
    Pyrrolidin-1-yl, methoxy, ethoxy, isopropoxy, trifluoromethoxy or CF3 .
  8. 根据权利要求1-7中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中，R 5选自卤素、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基。 A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 7, wherein, R 5 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 1 -C 6 alkylthio.
  9. 根据权利要求1-8中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中R 5选自C 1-C 3烷基；例如选自甲基、乙基和丙基，优选为甲基。 A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 8, wherein R 5 is selected from C 1 -C 3 alkyl; for example from methyl, ethyl and propyl, preferably methyl.
  10. 根据权利要求1-9中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中，A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 9, wherein,
    m是0或1；优选地m是1；和/或m is 0 or 1; preferably m is 1; and/or
    n是0或1，优选地n是0。n is 0 or 1, preferably n is 0.
  11. 根据权利要求1-10中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中环A选自亚苯基、包含1、2或3个独立地选自N、O或S的杂原子的5-9元亚杂芳基、C 3-C 8亚环烷基、C 3-C 8亚环烯基、包含1、2或3个独立地选自N、O或S的杂原子的3-8元亚杂环烷基和包含1、2或3个独立地选自N、O或S的杂原子的3-8元亚杂环烯基环； A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 10, wherein the 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 - C 8 cycloalkenylene, 3-8 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 a 3-8 membered heterocycloalkenylene ring of a heteroatom of S;
    优选地，环A选自亚苯基、包含1、2或3个独立地选自N、O或S的杂原子的5-6元亚杂芳基、C 3-C 8亚环烷基、C 3-C 8亚环烯基、包含1、2或3个独立地选自N、O或S的杂原子的3-8元亚杂环烷基和包含1、2或3个独立地选自N、O或S的杂原子的3-8元亚杂环烯基。 Preferably, 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 containing 1, 2 or 3 independently selected heteroatoms 3-8 membered heterocycloalkenylene from heteroatoms of N, O or S.
  12. 根据权利要求1-11中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中环A选自亚苯基、包含1、2或3个独立地选自N、O或S的杂原子的5元亚杂芳基、C 3-C 6亚环烷基、C 3-C 6亚环烯基、包含1、2或3个独立地选自N、O或S的杂原子的3-6元亚杂环烷基和包含1、2或3个独立地选自N、O或S的杂原子的3-6元亚杂环烯基。 A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 11, wherein the 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 - C6cycloalkylene Cycloalkenyl, 3-6 membered heterocycloalkylene containing 1, 2 or 3 heteroatoms independently selected from N, O or S and 1, 2 or 3 heteroatoms independently selected from N, O or S The heteroatom of 3-6 membered heterocycloalkenylene.
  13. 根据权利要求1-12中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中环A选自亚苯基、亚吡咯基、亚呋喃基、亚噻吩基、亚咪唑基、亚呋咱基、亚噁唑基、亚噁二唑基、亚噁三唑基、亚异噁唑基、亚噻唑基、亚异噻唑基、亚吡唑基、亚噻二唑基、亚三唑基、亚四唑基、亚吡啶基、亚吡嗪基、亚哒嗪基、嘧啶基、亚三嗪基、亚氮杂环丁烷基、亚吡咯烷基、亚吡咯啉基、亚环丁基、亚环戊基、亚环己基、亚环庚基、亚哌嗪基、亚哌啶基、亚四氢吡啶基、3,6-二氮杂-双环[3.1.1]亚庚基、3-氮杂-双环[3.2.1]亚辛基和1,4-二氮杂亚环庚基。A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 12, wherein the ring A is selected from phenylene, pyrrolylene, furanylene, thienylene, imidazolylide, furazanylidene, oxazolylide, oxadiazolylide, oxatriazolylide, isoxazolylidene , thiazolyl, isothiazolyl, pyrazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridylene, pyrazinylene, pyridazinyl, pyrimidinyl, tris Azinyl, azetidine, pyrrolidylene, pyrrolidylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, piperazinylene, piperidinylene, Tetrahydropyridylene, 3,6-diaza-bicyclo[3.1.1]heptylene, 3-aza-bicyclo[3.2.1]octylene, and 1,4-diazacycloheptylene .
  14. 根据权利要求1-13中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中环A选自亚吡唑基、亚噻二唑基、亚吡咯烷基、亚吡咯啉基、亚环己基、亚哌嗪基、亚哌啶基、亚四氢吡啶基、3,6-二氮杂-双环[3.1.1]亚庚基、3-氮杂-双环[3.2.1]亚辛基和1,4-二氮杂亚环庚基；A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 13, wherein the ring A is selected from pyrazolylidene, thiadiazolylidene, pyrrolidylene, pyrrolinylene, cyclohexylene, piperazinylene, piperidinylene, tetrahydropyridylene, 3,6-diaza Hetero-bicyclo[3.1.1]heptylene, 3-aza-bicyclo[3.2.1]octylene and 1,4-diazacycloheptylene;
    Figure PCTCN2021118001-appb-100004
    Figure PCTCN2021118001-appb-100004
  15. 根据权利要求1-14中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中环B选自苯基、包含1、2或3个独立地选自N、O或S的杂原子的5-9元杂芳基、C 3-C 8环烷基、C 3-C 8环烯基、包含1、2或3个独立地选自N、O或S的杂原子的3-8元杂环烷基和包含1、2或3个独立地选自N、O或S的杂原子的3-8元杂环烯基环； A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 14, wherein the 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 - C8cycloalkene radical, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S and 1, 2 or 3 heteroatoms independently selected from N, O or S 3-8 membered heterocycloalkenyl ring;
    优选地，环B选自苯基和包含1、2或3个独立地选自N、O或S的杂原子的5-6元杂芳基。Preferably, Ring B is selected from phenyl and 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S.
  16. 根据权利要求1-15中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中环B选自苯基、包含1、2或3个独立地选自N、O或S的杂原子的6元杂芳基；A compound of formula (I) according to any one of claims 1-15, a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, wherein the ring B is selected from phenyl, 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O or S;
    优选地，环B选自苯基、吡咯基、呋喃基、噻吩基、咪唑基、呋咱基、噁唑基、噁二唑基、噁三唑基、异噁唑基、噻唑基、异噻唑基、吡唑基、噻二唑基、三唑基、四唑基、吡啶基、吡嗪基、哒嗪基、嘧啶基和三嗪基环；Preferably, ring B is selected from phenyl, pyrrolyl, furyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxazolyl, thiazolyl, isothiazole pyrazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl rings;
    更优选地，环B是吡啶基环。More preferably, Ring B is a pyridyl ring.
  17. 根据权利要求1-16中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中基团
    Figure PCTCN2021118001-appb-100005
    选自     A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 16, wherein the radical group
    Figure PCTCN2021118001-appb-100005
    selected from
    Figure PCTCN2021118001-appb-100006
    Figure PCTCN2021118001-appb-100006
  18. 根据权利要求1-17中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物，其中式(I)化合物具有式(Ia)结构，A compound of formula (I), a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 17, wherein formula (I) compound has the structure of formula (Ia),
    Figure PCTCN2021118001-appb-100007
    Figure PCTCN2021118001-appb-100007
    其中R 1、R 2、R 3、R 4、R 5、m、n和A各自具有权利要求1-17中所定义的含义； wherein R 1 , R 2 , R 3 , R 4 , R 5 , m, n and A each have the meanings defined in claims 1-17;
    更优选地，式(I)化合物具有式(Ib)结构，More preferably, the compound of formula (I) has the structure of formula (Ib),
    Figure PCTCN2021118001-appb-100008
    Figure PCTCN2021118001-appb-100008
    其中R 1、R 2、R 3、R 4、R 5、n和A各自具有权利要求1-17中所定义的含义； wherein R 1 , R 2 , R 3 , R 4 , R 5 , n and A each have the meanings defined in claims 1-17;
    更优选地，式(I)化合物具有式(Ic)结构，More preferably, the compound of formula (I) has the structure of formula (Ic),
    Figure PCTCN2021118001-appb-100009
    Figure PCTCN2021118001-appb-100009
    其中R 2、R 3、R 4、R 5、n和A各自具有权利要求1-17中所定义的含义。 wherein R 2 , R 3 , R 4 , R 5 , n and A each have the meanings defined in claims 1-17.
  19. 选自以下的根据权利要求1所述的式(I)化合物：Compounds of formula (I) according to claim 1 selected from the group consisting of:
    Figure PCTCN2021118001-appb-100010
    Figure PCTCN2021118001-appb-100010
    Figure PCTCN2021118001-appb-100011
    Figure PCTCN2021118001-appb-100011
    Figure PCTCN2021118001-appb-100012
    Figure PCTCN2021118001-appb-100012
    或其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物。or a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof.
  20. 药物组合物，其包含根据权利要求1-19中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物和药学上可接受的赋形剂；所述药物组合物任选地另外包含适合与根据权利要求1-19中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物组合使用的另外的治疗活性成分。A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-19, a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or Solvates and pharmaceutically acceptable excipients; the pharmaceutical composition optionally additionally comprises a compound of formula (I), a stereoisomer thereof, a compound suitable for use with any one of claims 1-19, Additional therapeutically active ingredients used in combination with tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates.
  21. 药物组合产品，其包含根据权利要求1-19中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物和另外的活性剂。A pharmaceutical combination comprising a compound of formula (I) according to any one of claims 1-19, a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or Solvates and additional active agents.
  22. 根据权利要求1-19中任何一项所述的式(I)化合物、其立体异构体、互变异构体、稳定的同位素变体、药学上可接受的盐或溶剂合物或根据权利要求20所述的药物组合物在制备用于预防或治疗与RET有关的疾病的药物中的用途；A compound of formula (I) according to any one of claims 1-19, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates or Use of the pharmaceutical composition described in claim 20 in the preparation of a medicament for the prevention or treatment of RET-related diseases;
    优选地，所述的与RET有关的疾病选自肿瘤或肠易激综合症(IBS)，肿瘤包括但不限于非小细胞肺癌、小细胞肺癌、乳头状甲状腺癌、甲状腺髓质癌、分化型甲状腺癌、复发性甲状腺癌、顽固性分化型甲状腺癌、多内分泌肿瘤2A或2B、嗜铬细胞瘤、甲状旁腺增生、乳腺癌、结肠直肠癌、乳头状肾细胞癌、胃肠黏膜神经节瘤、胰管腺癌、多发性内分泌瘤、睾丸癌、慢性单核细胞性白血病、唾腺癌、卵巢癌、子宫颈癌等。Preferably, the RET-related disease 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 mucosal ganglion cancer, pancreatic duct adenocarcinoma, multiple endocrine tumors, testicular cancer, chronic monocytic leukemia, salivary gland cancer, ovarian cancer, cervical cancer, etc.
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